Hematology/Oncology

Editors: Sarah Fittro, MD, Kian Rahbari, MD
Reviewed by Rajiv Agarwal, MD, Daniel Hausrath, MD, and Vivek Patel, MD

Anemia

Authors: Margaret Wheless, Michael Kaminski

First establish acuity: bleed or consumptive process vs slow onset anemia
- Check vitals for hypotension, tachycardia.
- Check Hgb trend from prior if available.
- Examine patient for pallor, rapid onset fatigue, AMS, feeble pulses and any signs of bleeding.
- Consider risk factors such as recent procedure, blood thinner use, falls, new medications.
- STAT repeat CBC along with haptoglobin, LDH, HFP (bilirubin) to rule out hemolysis
- If no sx/signs of acute bleeding, move onto general anemia eval below.
- Note: CBC does not accurately reflect blood loss in acute rapid bleeding scenarios so do not be falsely reassured by normal hematocrit in GI bleeds/trauma patients.

Presentation

  • Symptoms: fatigue/malaise, dyspnea on exertion, angina (if history of CAD)
  • Signs
  • Pallor, tachycardia, orthostatic hypotension, purpura, glossitis, koilonychia (in IDA)
  • Jaundice (if hemolysis)
  • Splenomegaly: suggests extramedullary hematopoiesis or sequestration
  • Neurologic symptoms: suggests B12 deficiency

Evaluation

  • CBC w/diff, retic count, peripheral blood smear, iron studies (Fe, TIBC, ferritin), nutrient studies (folate, B12, Cu)
  • RI \< 2%: hypoproliferative >> stratify based on RBC size
    • Microcytic (\<80) vs. Normocytic (80-100) vs. Macrocytic (>100)
  • Reticulocyte index (RI) > 2%: blood loss vs hemolysis
    • Hemolysis labs: Bilirubin, LDH, hapto, DAT

Reticulocyte Index \< 2%: Hypo-proliferative/Inadequate Marrow Response

Microcytic (MCV \< 80)

  • Big picture: microcytic anemias arise from inability to effectively generate hemoglobin

Thalassemia

  • Alpha thalassemia: mostly gene deletions
  • alpha thal minima (one deletion, asymptomatic carrier)
  • alpha thal minor (2 deletions, mild anemia)
  • HbH disease (3 deletions, severe anemia with gamma [infant] and beta [adult] tetrameters that cause RBC fragility and hemolysis)
  • hydrops fetalis (4 deletions, in utero hydrops fetalis and fetal demise)

  • Beta thalassemia: mostly splice site mutations, can be heterozygous (beta thal trait) or homozygous (more severe, alpha chains accumulate and precipitate, killing erythroid precursors and decreasing RBC survival)

  • Dx: + family history, onset at birth or shortly thereafter, ↓ MCV (often less than 70), ↑ RBC count, Mentzer Index (MCV/RBC) \< 13, target cells on smear, Fe studies either wnl or show evidence of Fe overload, Hb electrophoresis (gamma or beta tetramers in alpha thal; HbF or HbA2 in beta thal), genetic testing

  • Tx: per classical heme. In summary: transfusions, Fe chelators to control Fe overload; maybe luspatercept (activin receptor IIB-Fc fusion protein)

Iron Deficiency Anemia

  • Negative Fe balance>>Fe deficient erythropoiesis>>Fe deficiency anemia; Negative Fe balance >> Fe stores mobilized from RES, becoming depleted if cause not corrected. Erythroid progenitors can’t incorporate Fe into heme. Etiologies include:
  • Poor Fe intake: malnutrition, heme-poor diets—vegetarian, vegan diets
  • Impaired Fe absorption:
    • Gastric etiologies (related to decreased acidity): atrophic gastritis, H pylori, bariatric surgery, PPIs; Duodenal etiologies: Celiac disease (though may be multifactorial with malabsorption of B12/ folate, Cu and anemia of chronic inflammation) vs inherited IRIDA/Iron Refractory Iron Deficiency Anemia
  • Increased Fe demand without bleeding: pregnancy and lactation, blood donation, recent initiation of EPO therapy

  • Increased Fe demand from bleeding: Most common: GI bleeds (gastric ulcer/gastritis, parasites, GI telangiectasias, colorectal cancer), GU bleeds (heavy menstrual bleeding, heavy abnormal uterine bleeding 2/2 cervical or endometrial malignancy), iatrogenic (frequent blood draws, iHD, surgical)

  • Dx: Labs: In negative Fe balance and Fe deficiency erythropoiesis: ↓ Fe, ↑ TIBC, ↓ TSAT, ↓ Ferritin. In IDA, MCV \<80, ↓ MCHC, ↓ RBC count, Mentzer Index (MCV/RBC) >13, ↓ Ferritin (\<30 highly specific, >15 means marrow Fe stores gone), Fe/TIBC \<16%, soluble transferrin receptor (sTfR, receptor cleaved, helpful to differentiate IDA from ACD/I) increased and sTfR-ferritin index > 2-3. Consider Celiac serologies, fecal H pylori antigen, bidirectional GI scope, pelvic ultrasound

  • Tx:
  • Fe repletion indicated in all with IDA and those with Fe deficiency without anemia if no source control, goal ferritin >50 after repletion.
  • Treat underlying cause.
  • In general, start with PO Fe unless: inability to attain source control, lack of response, intolerable side effects (primarily GI, nausea, diarrhea, constipation), severe anemia (Hb \<7), need for fast response, bariatric surgery Hx, malabsorption condition, ESRD on iHD, CHF with Ferritin \<100 OR TSAT \<20 and Ferritin \<300
  • PO Fe: Most common is FeSO4, 325 mg (65 mg elemental Fe) QD vs QOD for 6W (correct anemia) to 6M (replete Fe stores). Avoid enteric coated pills, take on empty stomach, consider vitamin C (not OJ which has Ca); avoid Ca, antacids
  • IV Fe: Calculate Fe deficit with Ganzoni equation (MDCalc). Typical total dosing is \~ 1 gram. Ferric gluconate/Ferrlecit at VUMC given in 125 or 250 mg doses. Fe sucrose at VA in 100-500 mg doses. SEs include non-anaphylactic infusion reactions (less than 1%, self-limited urticaria, N/V, palpitations, dizziness; Fishbane reaction: facial flushing and myalgias of chest and back, but NO hypotension, wheezing, stridor, periorbital edema) vs true anaphylactic reactions (exceedingly rare). For non-anaphylactic reactions, allow symptoms to resolve then restart infusion at ½ the rate. Can consider 1x dose IV methylpred. Contraindications: true anaphylactic reaction in past, ongoing bacterial infection (though paucity of evidence)

Sideroblastic Anemia

  • Ringed sideroblasts are erythroblasts with Fe rich mitochondria surrounding nucleus on marrow aspirate smears stained with Prussian blue
  • Pathophysiology: impaired maturation of erythroid precursor 2/2 altered heme production within mitochondria>>more Fe taken into precursors to compensate>>Fe overloaded precursors
  • Etiologies: Congenital (often mutations in heme synthesis) vs acquired (clonal [MDS/MPN], ETOH, medication induced [isoniazid, chloramphenicol, linezolid], lead exposure, Cu deficiency
  • Dx: ↓ MCV, ↓ retic count, ↑ Ferritin, nl or ↑ Fe, ↓/nl TIBC, smear: basophilic stippling of RBCs, marrow aspirate stained with Prussian blue, Genetic studies if c/f congenital (family history, young age of presentation, etc.)
  • Tx: Address underlying cause if acquired: treat MDS/MPN, stop ETOH use, stop offending medication, eliminate lead exposure, replete Cu

Normocytic (MCV 81-100)

  • Normocytic anemia can be the beginnings of a pure microcytic or macrocytic process or the combination of microcytic and macrocytic processes that negate one another

Anemia of Chronic Disease/Inflammation

  • Etiology: infections, rheumatologic disorders (RA, SLE, Systemic Sclerosis, vasculitis, IBD), cancer, heart failure, COPD, obesity, CKD
  • Pathophysiology: inflammation >> IL-1, IL-6 from macrophages >> hepcidin from liver that 1. In macrophages: suppresses Fe2+ release and stimulates ferritin expression that sequesters Fe intracellularly. 2. In enterocytes: suppresses Fe absorption from GI. Cytokines also reduce EPO, impair erythroid progenitor differentiation/proliferation, and shorten RBC half-life.
  • Dx: ↓-low nl MCV, ↓ Fe, ↓ Transferrin and TIBC, nl to ↑ Ferritin, Fe/TIBC >18%; if uncertain if concomitant IDA can order soluble transferrin receptor (sTfR) elevated in IDA and nl or ↓ in ACD; consider CRP/ESR
  • Tx: Address underlying cause. PO vs IV Fe if contribution of IDA (ferritin \<100, TSAT\<20%). ESAs if CKD or HIV on HAART

Anemia of Chronic Kidney Disease

  • Pathophysiology: EPO essential for terminal maturation of erythroid cells; ↓ renal function associated with ↓ renal interstitial cells that produce EPO, therefore ↓ terminal maturation of erythroid progenitors. Possible contributions of uremia-related hemolysis, ESRD related Burr cells with decreased half-life, iHD blood loss
  • Dx: Normocytic, normochromic RBCs, Fe studies similar to ACD/I, EPO ↑
  • Tx: With nephro. If Fe deficiency, treat with IV Fe. If not on dialysis: ESAs when Hb \< 10 so long as TSAT >20 and Ferritin \<500 (numbers approximate and attending specific), goal Hb 10-11.5. On dialysis: ESAs preferred over HIF PHIs

Pure Red Cell Aplasia

  • Pathophysiology: absence or destruction of RBC precursors. Inherited causes like Diamond-Blackfan anemia. Destruction/acquired causes associated with thymoma; lymphoid malignancies/CLL; viruses like parvovirus B-19 (viral tropism for erythrocyte P antigen on erythroid progenitors), hepatitis, EBV; autoimmune diseases like SLE; drugs
  • Dx: Very ↓ retic index; BMBx that lacks erthroid progenitors, consider other marrow studies for heme malignancy, thoracic imaging for thymoma
  • Tx: transfusion support +/- pathology specific Tx>>thymectomy for thymoma; chemo for CLL; consider IVIG for parvo

Anemia of Hypometabolism

  • Hypothyroid: decreased TSH causes body-wide hypometabolism, decreased O2 consumption, hypo-proliferation of erythroid precursors, possible multifactorial etiology with pernicious anemia (if comorbid autoimmune diseases)
  • Addison’s disease: anemia possibly masked by plasma volume depletion
  • Protein malnutrition: from impaired EPO production/release as well as decreased metabolic rate, likely multifactorial 2/2 concomitant nutritional deficiencies (folate, B12, Cu)

Macrocytic (MCV >100)

  • Big picture: Megaloblastic anemias arise from impaired nuclear cell cycle progression of erythroid +/- other bone marrow progenitors relative to cytoplasmic maturation.
  • Retics are larger than mature RBCs so in reticulocytosis you may see macrocytosis (ie brisk reticulocytosis follow Fe repletion in Fe deficiency anemia)

Megaloblastic

  • Folate Deficiency
  • Etiology: Folate absorbed in jejunum. Poor dietary intake: inadequate green leafy vegetables (if from country where grains are not fortified with folate), anorexia, chronic excessive ETOH use. Malabsorption: Celiac disease, IBD. Increased usage: pregnancy, chronic hemolysis, other states of high cell turnover (malignancy). Iatrogneic: meds (methotrexate, trimethoprim, ethanol, antiepileptics)
  • Pathophysiology: Folate involved in DNA/RNA synthesis>>deficiency impairs nucleotide synthesis and impairs nuclear cell cycle progression
  • Dx: serum folate, consider MMA (nl) and homocysteine (↑) if folate borderline

  • Tx: Folic acid 1 mg PO QD, may increase to 5 mg PO QD, treat for 1-5 months if reversible cause, if irreversible treat indefinitely

  • B12 Deficiency

  • Etiology: B12 absorbed in terminal ileum but absorption depends on salivary R-binder, gastric H+ and IF, pancreatic enzymes. Prolonged poor intake (vegan or strict vegetarian diet as animal protein is primary source) versus prolonged poor absorption—bodily liver stores \~3Y. Gastric: autoimmune gastritis (autoAbs to IF or parietal cells), H pylori gastritis, bariatric surgery, meds: PPI and H2 blockers and metformin. Small bowel: Crohn’s (terminally ilium involvement), ileal resection, competition (SIBO, fish tapeworm). Pancreatic: pancreatic insufficiency
  • Pathophysiology: B12 is involved in DNA/RNA synthesis >> deficiency impairs nucleotide synthesis and impairs nuclear cell cycle progression
  • Dx: total B12, consider MMA (↑) and homocysteine (↑) if B12 borderline, IF Abs if c/f autoimmune gastritis. Maybe subacute combined degeneration (dorsal columns: vibration/proprio and corticospinal tract: voluntary motor function) if severe
  • Tx: Intramuscular: in patients with severe deficiency, adherence issues (lack of access, bad at taking pills): 1000 mcg IM QWeekly then monthly; Oral: 1000 mcg PO QD with nl absorption, 2000 mcg PO QD for impaired absorption

  • Note that treatment of B12 deficiency anemia with folate may transiently relieve hematologic effects of B12 deficiency but neurological symptoms persist

  • Cu Deficiency

  • Etiology: Dietary deficiency (rare), malabsorption: inherited syndromes (Menkes) versus acquired (excessive PO zinc, Celiac, CF, bariatric surgery)
  • Pathophysiology: Cu necessary for enzymatic functions including ETC, collagen crosslinking, neurotransmitter synthesis, free radical scavenging
  • Dx: serum Cu, MCV normocytic or macrocytic, may have bi-cytopenia; Bone marrow biopsy may show dysplastic changes similar to MDS
  • Tx: Address underlying cause. For repletion, per Uptodate: 8 mg elemental Cu PO QD x1W, 6 mg PO QD x1W, 4 mg PO QD x1W, 2 mg PO QD x1W then recheck

Non-megaloblastic macrocytic anemia: reticulocytosis, cirrhosis, ETOH, hypothyroid, MDS

Drugs that interfere with hematopoiesis: Chemotherapies, hydroxyurea, immunosuppressants: methotrexate, leflunomide, 6-MP, MMF, ART/NNRTIs, AEDs/phenytoin/Valproic acid and Bactrim (impaired folate metabolism), Acid suppressants (reduced B12 absorption)

Reticulocyte Index > 2%: Hyper-proliferative/Adequate Marrow Response

Intrinsic, Hereditary

Sickle Cell Disease - Etiology: autosomal recessive HBB gene mutation glu6val. Sickle cell disease is HbS/S; Heterozygosity causes sickle cell trait.
- Pathophysiology: HbS valines interact hydrophobically>>Hbs self-assemble in T conformation >> parallel bundles “stretch” RBCs; ↓ pH, ↓ pO2, ↑ pCO2, ↑ 2,3-BPG promote T state >> promote polymerization/sickling; R state, ↑ HbF and HbA2 impair polymerization
- Dx: ↑ LDH, ↓ Hapto, ↑ indirect bili; smear: sickled cells; electrophoresis
- Tx: Hydroxyurea (increases HbF), folate/multivitamin (↑ RBC turnover/metabolic need), possibly L-glutamine or crizanlizumab (anti-P selectin); RHM includes vaccines for encapsulated bacteria (Mengococcal, Hflu, Pneumococcus), Hep B, Flu, COVID; possibly alloSCT; 2 gene therapies with CRISPR-Cas9 approved in 2023; see Sickle cell crisis chapter for acute sickle complication management

Hb C: HBB mutation Glu6Lys; heterozygotes are asymptomatic carriers, homozygosity causes mild hemolytic anemia; Dxed with electrophoresis

Thalassemia: see hypo-proliferative anemia section

G6PD deficiency - Etiology: X-linked, missense mutations in G6PD gene >> decreased enzyme function
- Pathophysiology: ↓ G6PD activity >> ↓ glutathione >> ↓ protection against oxidants >> oxidized Hb and other proteins; worsened by any insult that increases oxidant stress (infection [immune effectors generate oxidants], drugs with high redox potential [dapsone, primaquine, rasburicase, nitrofurantoin, more], foods [fava beans])
- Dx: test prior to treating with oxidizing medication; functional assay of G6PD activity in RBCs-do not test during flair (cells with faulty G6PD function die first > false negative)
- Tx: remove inciting event (infection, med, food); supportive care with transfusions

Pyruvate kinase deficiency: PKLR mutations, rare, Dx: enzyme function assay

Hereditary Spherocytosis/Elliptocytosis - Pathophysiology: recessive or dominant mutations in RBC membrane proteins (Band 3 [anion transporter]), cytoskeletal proteins (a and b spectrin), and connector proteins (ankyrin, band 4.1, band 4.2) >> malformed and round membrane >> more prone to lysing
- Dx: family Hx; mild to severe hemolytic anemia depending on mutation; ↑ MCHC; smear: spherocytes or elliptocytes; DAT negative; positive osmotic fragility test, EMA binding test; genotyping
- Tx: transfusion support, prevention of Fe overload for severe disease; possibly splenectomy, RHM with vaccinations

Intrinsic Acquired

Paroxysmal Nocturnal Hemolytic Anemia - Pathophysiology: HSC PIGA mutation (anchors the complement inhibitors CD55 and CD59) >> complement on RBC membranes >> RBCs lysed. Clonal expansion of mutated HSC.
- Dx: ↑ LDH, ↓ hapto, ↑ indirect bili, flow cytometry with ↓ or absent CD55/59, possibly BMBx if concern for bone marrow failure/aplastic anemia
- Tx: heme consult, complement inhibitor and depending on severity and complications possibly allogeneic SCT vs long term immunosuppressive therapy

Spur Cell Anemia/Anemia in Liver Disease - Pathophysiology: Liver disease >> dysregulated lipid metabolism >> excess cholesterol in RBC membranes>> spur cells more fragile and have ↓ half-life; likely multifactorial with concomitant nutritional deficiencies (folate, B12, Fe, Cu, protein), Hb loss (GI bleeds from EVs), mild hemolysis (Spur cells, mild DIC), sequestration (hypersplenism)
- Dx: smear with spur cells, ↓ hapto (caution as hapto is synthesized in liver)
- Tx: cessation of alcohol, banding of varices, liver transplantation is only cure

Extrinsic Acquired

Immune-Mediated (DAT-positive) Hemolytic Anemia

  • Warm AIHA
  • Etiology: Idiopathic; lymphoproliferative disorders including CLL, MGUS, lymphomas; autoimmune disorders including SLE, RA, etc; infections including HIV, EBV, Hep C, Babesiosis; drugs; Evans Syndrome: warm AIHA with ITP
  • Pathophysiology: IgG (less common IgA, IgM) autoAbs against Rh complex or glycophorin A or B that bind best at 37C; extravascular hemolysis in RES via Fc receptors on Macrophages >> spherocytes; intravascular if severe/tons of complement fixation
  • Dx: ↑ retics; ↑ LDH, ↓ hapto, ↑ indirect bili; positive DAT IgG +/- C3d; smear: spherocytes; UA: urobilinogen, hemoglobinuria; maybe LE DVT USs as increased risk clots; may pursue lymphoproliferative, autoimmune, infectious workup

  • Tx: Transfusion support: if severe on presentation (Hb \<7) contact blood bank immediately; 1st line: glucocorticoids (ie pred 1-2 mg/kg PO daily vs methylpred IV) +/- rituximab; 2nd line immunosuppressants like MMF, cyclophosphamide, etc; 3rd line splenectomy; Folic acid 1-5 mg PO QD during hemolysis; recovery after 2-3 weeks (existing Abs need to wash out); treat underlying etiology if identified

  • Cold AIHA / Cold Agglutinin Disease

  • Etiology: Idiopathic vs Secondary to: Lymphoproliferative disorders: Waldenstrom, MGUS, CLL, lymphomas; infections: Mycoplasma and EBV; autoimmune like SLE
  • Pathophysiology: IgM autoAbs bind RBC I or i antigens at temps below 37C >> fix complement >> extra>intravascular hemolysis; different from Paroxysmal Cold Hemoglobinuria (Donath-Landsteiner Abs cause intra>extravascular hemolysis)
  • Dx: Cold induced Sxs (acrocyanosis), ↑ retic count, ↑ LDH, ↓ hapto, ↑ indirect bili; DAT + C3d, - IgG; Cold agglutinin titer > 1:64; smear: aggregating RBCs
  • Tx: Treat underlying condition, avoid cold; if symptomatic: WARMED RBC transfusion, plasmapheresis or IVIG; possibly rituximab or B cell targeting therapy if lymphoproliferative disorder; C1 inhibitor sutimlimab approved 2022

Drug-induced Hemolytic Anemia - Etiology: abx especially penicillins and cephalosporins, sulfa drugs, NSAIDs, chemotherapies and immunotherapies; may be immune or non-immune mediated
- Pathophysiology: Immune-mediated: IgG binds drug-RBC membrane protein conjugate >> macrophage phagocytosis in RES. Non-Immune-mediated: oxidative injury in G6PD deficiency; methemoglobinemia 2/2 anesthetics, antimicrobials; TMA 2/2 medications
- Dx: ↑ retic count, ↑ LDH, ↓ hapto, ↑ indirect bili; DAT IgG +/- C3d; smear with spherocytes or bite cells or schistocytes (depending on Pathophysiology)
- Tx: stop possible offending medications, transfusion support

Non-immune (DAT-negative) hemolytic anemia - Microangiopathic Hemolytic Anemia/Thrombotic Microangiopathies - Pathophysiology: TTP, Complement mediated TMA, Drug induced TMA, Shiga toxin-induced HUS, DIC, HELLP, catastrophic APS, malignant HTN
- Dx: concurrent thrombocytopenia, Smear: schistocytes, other markers of hemolysis (↓ hapto, ↑ LDH); TTP: ADAMTS13 very ↓ (\<10%); in complement-mediated TMA severely ↑ Creat from renal failure; in DIC, ↑ PT and PTT and ↓ fibrinogen
- Tx: Heme consult; treat underlying cause (see Thrombocytopenia section)

  • Macroangiopathic Hemolytic Anemia
  • Pathophysiology: sharp edges of calcium/metal/plastic lyses RBC membranes, including ECMO, prosthetic heart valve, severely sclerotic native heart valve
  • Dx: Blood smear with schistocytes, other markers of hemolysis (↓ hapto, ↑ LDH)
  • Tx: treat underlying cause if possible
  • Infections: Malaria, Babesia, C perfringens
  • Medications: Primaquine, dapsone, Rasburicase, sulfonylureas

Neutropenia and Neutropenic Fever

Authors: Jennifer Marvin-Peek, Joy Stouffer

Background

  • Neutropenia: absolute neutrophil count (ANC) \< 1500
  • Severe neutropenia: absolute neutrophil count (ANC) \<500 (use manual count if available)
Mechanism Causes Example (s)
Neutrophil production Drug associated Cytotoxic or immunosuppressive agents Methimazole, PTU, colchicine Macrolides, bactrim, dapsone, vancomycin Amphotericin, acyclovir, ganciclovir TCAs, clozapine, carbamazepine, valproate ACEI, digoxin, propranolol, procainamide
Neutrophil production Radiation exposure
Neutrophil production Malignancies Leukemias, MDS
Neutrophil production Infection Hepatitis, HIV, EBV, CMV Rickettsia, tularemia, typhoid, TB
Neutrophil production Nutritional deficiency Vitamin B12, folate, copper
Neutrophil production Other Aplastic anemia, benign ethnic neutropenia
Redistribution Splenomegaly Margination and sequestration
Congenital Genetics Benign ethnic neutropenia, familial neutropenia
Immune destruction Autoimmune RA, SLE
Immune destruction Other Autoimmune neutropenia

Management

  • If ANC \<500
  • Check all lines/IVs for erythema and induration daily
  • Check mouth for mucositis, mouth care after meals and before bed
  • Assess for Neutropenic Fever and Complications – see below
  • Evaluate for indications for prophylaxis – see below
  • No evidence to support use of neutropenic diet
  • No digital rectal exams or enemas/suppositories (risk of bacterial translocation)

Neutropenic Fever

  • Definition: ANC \< 500 and either a single oral temperature ≥ 38.3°C (100.9 °F) or a sustained temperature ≥ 38°C (100.4°F) for 1 hour.Neutropenic patients are unable to mount an adequate immune response and can become critically ill very quickly
  • Start antibiotics immediately (within 1 hour of fever onset)

Evaluation - Chest X-ray
- Two sets of blood cultures (one from PICC/port if present)
- Urinalysis AND urine culture (not the reflex order set)
- If diarrhea, get C. diff PCR
- If abdominal pain, consider CT A/P with IV contrast

Management - Empirically treat with cefepime (2g IV q8h) or zosyn (4.5g IV q 6h)
- Indications for vancomycin:
* Hemodynamic instability or other worrisome change in clinical status
* Skin/soft tissue infection (eg mucositis, erythema/induration around port or IV)
* Pneumonia
* Blood cultures + GPCs
- Additional Coverage:
* If concern for C-diff can start PO vancomycin 125mg q6h
* Fungal coverage: consider if risk factors (TPN) or persistent fevers (>72hrs)(eg micafungin 100 mg IV daily)
* If ESBL bacteria suspected, can page ID to start meropenem

Neutropenic Complications

Mucositis - Can range from mouth soreness to severe erosions preventing eating/drinking
- Can become secondarily infected with Candida, HSV
* Management:
* Routine oral care with a soft toothbrush to remove plaque
* Oral rinses with saline and/or sodium bicarbonate
* Magic mouthwash for symptomatic relief (or viscous lidocaine at the VA)
* Typically recovers quickly when ANC > 500

Neutropenic enterocolitis (typhlitis) - Life-threatening bacterial translocation due to breakdown of gut-mucosal barrier
- Presentation: Abdominal pain + fever
* ± abdominal distension, nausea, vomiting, watery and/or bloody diarrhea
- Diagnosis: CT A/P with oral and IV contrast
- Treatment
* Cefepime/Flagyl OR Zosyn
* If no perforation/abscess on CT scan, typically continue until 14 days after ANC recovers >500 and abdominal pain resolves
* Can change to oral regimen (eg cipro/flagyl) once ANC >500
* If perforation/abscess: will need imaging to confirm resolution, and longer duration of abx

Neutropenic Prophylaxis

  • Used if ANC is expected to be \< 500 for > 7 days
Most Common Regimens Alternatives
Bacterial levofloxacin 500mg daily (renally dosed) Cefdinir 300mg q12 hrs
ciprofloxacin 500mg BID
Viral valacyclovir 500mg BID acyclovir 400mg BID
Fungal fluconazole 400mg daily posaconazole 300mg BID x2 days then 300mg daily (preferred if AML induction)
PJP (if steroids, some ALL induction) inhaled pentamidine 300mg qmonthly
Bactrim DS 800-160mg on MWF (theoretical risk of myelosuppression, renal toxicity)		 dapsone (check G6PD)

Granulocyte-Colony Stimulating Factors (G-CSF) (eg. Filgrastim aka Neupogen)

  • Induces bone marrow production of neutrophils, goal is to reduce duration of neutropenia, often used in ALL and AML induction
  • Dose: either 300mcg or 480mcg (rounded from 5 mcg/kg/day)
  • Pegfilgrastim (Neulasta): long-acting version that is only given as an outpt

Thrombocytopenia

Author: Jamila Mammadova

Background - Classified as either mild (100K-149K), moderate (50K-99K), or severe (\<50K or \<30K)
- Can be a component of pancytopenia or bicytopenia
- Pseudothrombocytopenia: EDTA-dependent platelet clumping (lab artifact)

Mechanism Causes Example (s)
Decreased platelet production / bone marrow suppression Drug induced (most common) Antibiotics (vancomycin, linezolid, bactrim), antivirals (val/gancyclovir, zidovudine), immunosuppressants (AZA, MMF, tacrolimus), antiepileptics (valproate, carbamazepine, phenytoin), antithyroid (PTU, methimazole), NSAIDs, chemotherapies, allopurinol, colchicine
Decreased platelet production / bone marrow suppression Decreased TPO production Liver disease, medications, EtOH, nutritional deficiencies
Decreased platelet production / bone marrow suppression Infection Sepsis, HIV, tick-borne i.e. RMSF, anaplasma, erhlichia, leptospirosis, parvovirus, TB, NTM, fungal
Decreased platelet production / bone marrow suppression Primary hematologic syndromes and malignancies Myelodysplastic syndrome, heme malignancies, PNH
Decreased platelet production / bone marrow suppression Nutritional deficiency Vitamin B12, folate, copper (primary vs secondary to zinc toxicity)
Decreased platelet production / bone marrow suppression Infiltrative Malignancies (leukemia, lymphoma, myeloma, metastatic solid tumors), amyloidosis, fibrosis (myelofibrosis)
Decreased platelet production / bone marrow suppression Toxicity Radiation, EtOH, heavy metals
Redistribution Splenomegaly Conditions that cause an increase in spleen size (lymphoproliferative disorders) and conditions that cause spleen congestion (portal HTN)
Inherited Genetics Gray platelet syndrome, congenital amegakaryocytic thrombocytopenia, Wiskott-Aldrich syndrome
Increased destruction Immune mediated Immune thrombocytopenic purpura (ITP), drug-induced thrombocytopenia (quinine, rifampin, sulfonamides, beta-lactams, vancomycin, meropenem, valacyclovir, PPIs, H2 blockers, anti MTB therapy), post-transfusion purpura (PTP), heparin induced thrombocytopenia (HIT)
Increased destruction Autoimmune diseases SLE, APS, hypo- and hyperthyroid
Increased destruction Infections Sepsis (especially GN bacteremia), HIV, HBV, HCV, CMV, EBV, dengue, malaria, H. pylori
Increased consumption Primary thrombotic microangiopathies (TMA) TTP (congenital and acquired), HUS (Shiga toxin or atypical-HUS i.e. complement-mediated)
Increased consumption Secondary thrombotic microangiopathies (TMA) DIC (sepsis, trauma, APML, pancreatitis, transfusion reaction), HELLP syndrome, malignant HTN, scleroderma renal crisis, drug-induced (calcineurin inhibitors, chemo, quinines, cocaine), catastrophic APLS, GvHD, TBI, infection-associated (strep pneumo, HIV)
Increased consumption Massive hemorrhage Trauma, postpartum, coagulopathy
Others Dilutional Massive transfusion without platelet replacement
Others Mechanical destruction Prosthetic heart valves, cardiopulmonary bypass

Presentation

  • Usually asymptomatic
  • The rate of platelet count drop is more clinically significant than absolute platelet count
  • Bleeding due to low platelet counts presents as non-blanching rash (petechiae and purpura), bruising, gingival and nosebleed, menorrhagia
  • Severe bleeding may occur, typically with platelet count \<10K, and can present with hematuria, melena, hematochezia, intracranial hemorrhage (especially if prior CNS malignancy, life-threatening)
  • Some causes of thrombocytopenia have a paradoxically increased risk of thrombosis (HIT, DIC, TMA)

Evaluation

  • Repeat CBC w/ diff
  • Peripheral smear or citrated platelet count (to rule out pseudothrombocytopenia) PLUS immature platelet fraction (IPF)
  • Low IPF can point toward decreased platelet production vs. high IPF is expected in compensation for platelet destruction/consumption
  • Medication review to look for any offending drugs (see table above)
  • TMA/DIC labs: haptoglobin, LDH, LFTs, PT/PTT, fibrinogen, D-dimer, peripheral smear (for schistocytes), retics (will be high), renal function.. Can use ISTH DIC score to assess likelihood of DIC.
  • Infectious work-up (as clinically indicated):
  • Viral serologies: HIV, HBV, HCV, EBV, CMV, parvovirus
  • Sepsis: blood cultures, urine culture, sputum cultures
  • Fungal work-up: 1,3-Beta-D-Glucan, aspergillus galactomannan, urine blasto Ag, urine and serum histo Ag, crypto Ag
  • Tick-borne: RMSF, Ehrlichia, Anaplasma
  • Leptospirosis
  • TB and/or NTM: AFB, interferon-Gamma release assay
  • Autoimmune work-up (as clinically indicated): ESR, CRP, ANA w/ reflex, RF, APL antibodies
  • HIT work-up: Calculate 4T score: if ≥4, order HIT Ab ELISA. If (+) or equivocal, get serotonin-release assay (SRA) with reflex
  • Nutritional studies: B12, folate, copper, zinc
  • TSH to screen for thyroid disease
  • Abdominal U/S to look for splenomegaly (or review recent imaging)
  • Bone marrow biopsy: co-existing cytopenias (especially if not new), blasts on smear, or concerning flow cytometry findings
  • If pregnant: HELLP panel (haptoglobin, LDH, LFTs, BMP, urine PCr)

Management:

  • Hold DVT prophylaxis for platelet ≤50K
  • Hold anti-platelets (NSAIDs, ASA)
  • Three thrombocytopenia syndromes that are immediately life-threatening: DIC, HIT, and HUS – can’t miss
  • If concern for bleeding, get type and screen and blood consent
  • Platelet transfusion goals and indications
  • Generally, not indicated if not bleeding and platelet >10K
  • Avoid transfusions in HIT, TTP, HUS
  • One unit of platelet is expected to increase levels by 10-40K, but it depends on weight, ongoing rate of consumption, destruction, distribution
  • CNS or ocular bleeding, NSGY, plan for ocular surgery: goal >100K
  • Pt actively bleeding, most surgeries, therapeutic endoscopy: goal > 50K
  • Plan for central line, bronch, LP, diagnostic endoscopy, or bone marrow biopsy: goal >20K
  • Afebrile, hospitalized pts for bleeding prophylaxis: goal >10K
  • HIT management: Stop any heparin product and start argatroban. NO platelet transfusions.
  • ITP is a diagnosis of exclusion. Consult heme for management.
  • Schistocytes on smear:
  • Think TTP, HUS, or DIC when there are schistocytes on smear and thrombocytopenia
  • For TTP: calculate PLASMIC score and consider ordering ADAMTS13 levels. Consult hematology about PLEX asap. Vascath is needed for PLEX.
  • If DIC: consult hematology for management (supportive transfusions and may require heparin), identify underlying cause.

Pancytopenia and Bicytopenia

Author: Jamila Mammadova

Background 

  • Pancytopenia is a decrease in all peripheral blood lineages (RBC, WBC, PLT).
  • Many causes of pancytopenia can cause bicytopenia (decrease in any two cell lines), so the workup is similar

Framework for differential

Mechanism Causes Example (s)
Bone marrow failure and suppression Infiltrative Malignancies (leukemia, lymphoma, myeloma, metastatic solid tumors), amyloidosis, fibrosis (myelofibrosis) , hemochromatosis
Bone marrow failure and suppression Myelodysplastic and hematologic syndromes Can be primary MDS or secondary (chemo, radiation), PNH
Bone marrow failure and suppression Drug induced Antibiotics (chloramphenicol, linezolid, bactrim), antivirals (gancyclovir, zidovudine, ribavirin), immunosuppressants (AZA, MMF, MTX), antiepileptics (valproate, carbamazepine, phenytoin), antithyroid (PTU, methimazole), NSAIDs, chemotherapies
Bone marrow failure and suppression Infection Sepsis, HIV, CMV, EBV, Parvovirus, HBV, HCV, TB, histo, tick-borne
Bone marrow failure and suppression Toxicity Radiation, benzene exposure, arsenic (may be irreversible), EtOH
Bone marrow failure and suppression Autoimmune SLE, RA/Felty syndrome, sarcoidosis, autoimmune subtype of aplastic anemia, Evan’s syndrome
Bone marrow failure and suppression Nutritional deficiency Vitamin B12, folate, copper (primary vs secondary to zinc toxicity), anorexia nervosa, malabsorptive diseases (i.e. Crohn’s)
Others Hemophagocytic syndromes Hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS)
Others Consumption DIC (sepsis or acute PML)
Others Splenomegaly Congestion (portal HTN), malignancies, EBV, autoimmune disorders

Evaluation

  • HPI: B-symptoms, fatigue, dyspnea, infections, bleeding/bruising, timing of symptoms
  • Review medications (refer to the table above)
  • PMHx: autoimmune disease (SLE, RA, scleroderma), radiation, gastric surgery, malabsorption (e.g. celiac, Crohn’s), liver disease, malignancy, transplant , immunosuppression
  • Social Hx: EtOH use, malnutrition, occupational exposures, travels, hiking, exposures to fungal infections, TB, leishmaniasis, or ticks  
  • Exam: look for lymphadenopathy, hepatosplenomegaly, neuropathy, rashes, petechiae, mucosal bleed, stigmata of liver disease, cachexia, oral lesions 
  • CBC w/ diff, peripheral smear, IPF, reticulocyte count
  • TMA/DIC labs: haptoglobin, LDH, LFTs, PT/PTT, fibrinogen, D-dimer, peripheral smear (for schistocytes), retics (will be high), renal function
  • Infectious work-up (as clinically indicated):
  • Viral serologies: HIV, HBV, HCV, EBV, CMV, parvovirus
  • Sepsis: blood cultures, urine culture, sputum cultures
  • Fungal work-up: 1,3-Beta-D-Glucan, aspergillus galactomannan, urine blasto Ag, urine and serum histo Ag, crypto Ag
  • Tick-borne: RMSF, Ehrlichia, Anaplasma
  • Leptospirosis
  • TB and/or NTM: AFB, interferon-gamma release assay
  • Autoimmune work-up (as clinically indicated): ESR, CRP, ANA w/ reflex, C3/C4, RF, APL antibodies
  • Nutritional studies: B12, folate, copper, zinc, Fe
  • Abdominal U/S to look for splenomegaly (or review recent imaging)
  • HLH: ESR, CRP, ferritin, triglycerides, soluble IL-2R
  • Consider flow cyt, bone marrow biopsy, cytogenetics, and FISH (c/s heme at this stage)

Management 

  • Get type and screen and blood products transfusion consent if low counts or evidence of bleeding
  • Hold DVT prophylaxis, avoid NSAIDs and ASA for platelet\<50K
  • Identifying the cause of pancytopenia is the biggest part of management (then find respective management tips in the handbook)
  • Emergencies that may require urgent evaluation, management, or hospitalization   - can’t miss
  • Neutropenia (ANC \< 1000, or severe when ANC \< 500) with fever or other evidence of infection
  • Symptomatic anemia (cardiac symptoms like chest pain, SoB, HDUS, worsening CHF)
  • Platelets \< 10k or \< 50k with bleeding
  • Abnormal blood smear (schistocytes or blasts): suspect DIC, TMA
  • HLH (unexplained fever, hepatomegaly, lymphadenopathy, neurologic symptoms, very high ferritin, abnormal LFTs, coagulopathy)
  • When pancytopenia is slow, progressive over time, or acute without any other precipitating factors and a specific etiology is in mind (e.g. leukemia or marrow infiltrating infection), consult hematology for consideration of bone marrow syndromes and/or bone marrow biopsy 
  • Note: Bone marrow biopsy for acquired pancytopenia in the hospital setting will often not yield results that will change clinical management (most likely will show an aplastic marrow) 
  • Supportive treatments to consider:
  • Transfusions as indicated
  • Consult heme for pharmacologic support options:
  • G-CSF (Filgrastim) for neutropenia
  • Erythropoietin stimulating agents for certain anemias
  • TPO receptor agonists (Elthrombopag, Romiplostim) for certain thrombocytopenias

Leukocytosis

Author: Kenna Koehler

Background

  • Common progenitor cells (stem cells) are located in the bone marrow and give rise to erythrocytes, myeloblasts, megakaryoblasts
  • Normal WBC can vary by age and pregnancy, for the purpose of this section will assume this is for an average, non-pregnant adult
  • Chronic mild neutrophilic leukocytosis (10-20k) is common with tobacco use and obesity, both due to mechanisms related to chronic inflammation
  • Reactive (typically 11k-30k): surgery, exercise, trauma, burns, emotional stress
  • Leukemoid reaction (typically 50k-100k): severe infections (fulminant C difficile), organ rejection
  • If greater than 100k, think leukemia or myeloproliferative disorder

Evaluation

  • Neutrophilia: neutrophil count >7k
  • Bacterial infection, pregnancy, rheumatologic disease, steroids, beta agonists, lithium, colony-stimulating factors, splenectomy or functional asplenia, congenital (hereditary/chronic idiopathic neutrophilia), Down syndrome, leukocyte adhesion deficiency, malignancy, smoking, obesity
  • Lymphocytosis: >40% of WBC count or >4,500k/mm3
  • Infections (pertussis, syphilis, CMV, EBV, hepatitis A/B/C, toxo), hypersensitivity reactions, thyrotoxicosis, Addison’s disease, hematologic malignancies, “reactive”
  • Monocytosis: >8% of WBC count or >880/mm3
  • Infections (TB, fungal disease, protozoa, tick-borne), autoimmune disease, malignancy (CMML)
  • Eosinophilia: >500/mm3
  • Hypersensitivity (asthma, urticaria, atopic dermatitis, eosinophilic esophagitis), drug reactions, malignancies, connective tissue disease, idiopathic hypereosinophilic syndrome, infections (helminths, Scarlet fever, Hansen’s disease), sarcoidosis, SLE
  • Hypereosinophilia if AEC>1500, typically merits heme evaluation
  • Hypereosinophilic syndrome: AEC>1500 and organ dysfunction from eosinophils
  • Basophilia (>100/mm3)
  • CML, thyroid disease, IBC, chronic dermatitis, infections (varicella)

Venous Thromboembolism

Author: Sarah Fittro

Background

  • Includes DVTs and PE. See “Pulmonary Embolism” section in cardiology.
  • Virchow’s triad: stasis, vessel wall injury and hypercoagulability
  • Risk factors for provoked DVT/PE
  • Major risk factors: major surgery, trauma or fracture, active cancer (Pancreatic, brain, lung, ovarian, and metastatic cancers are highest risk), prior VTE, prolonged immobility such as hospitalization >3 days or SCI, inherited hypercoagulability, pregnancy and postpartum period (first 6 weeks)
  • Minor Risk Factors: older age, obesity, hormone therapy, smoking, minor surgery
  • Non-transient risk factors: malignancy (active), myeloproliferative disorders, IBD, liver disease, COPD, CHF, CKD, hereditary thrombophilia (factor V Leiden and prothrombin gene mutations most common), antiphospholipid syndrome, prior VTE.

Evaluation

  • Asymmetric calf swelling of >2cm sensitivity and specificity for DVT of 60-70%
  • Classic triad of PE: SOB, pleuritic chest pain and coughing +/- hemoptysis
  • Wells’ Criteria for DVT can help guide diagnostic testing
  • If a pt has a low pre-test probability, a negative D-dimer can rule out DVT
  • In a high pre-test probability pt a negative D-dimer is less helpful
  • Whole-leg ultrasounds with doppler is gold standard for DVT
  • CT pulmonary angiography is gold standard for PE (lesser alternative V/Q scan)

Management

  • Prophylaxis: Padua score
  • Score > 4 high risk, VTE risk \~11% over 90 days without prophylaxis. Recommend pharmacologic prophylaxis (enoxaparin 40 mg SC daily or ppx dose heparin)
  • Score \<4 is low risk; recommend ambulation and SCDs
  • Treatment (see anticoagulation section)
  • Heparins: UFH or LMWH, e.g., enoxaparin starts immediately.
  • DOACs: Rivaroxaban or apixaban can be first-line (no heparin bridge needed).
  • Warfarin: Started with UFH/LMWH overlap (5+ days) until INR is 2-3, then heparin stops.
  • Severe PE:
    • Thrombolytics (e.g., alteplase) for massive PE with hemodynamic instability
    • Embolectomy (surgical or catheter-based) if thrombolysis fails.
  • Duration of treatment
  • Provoked: 3-6 months or until provoking factor (trauma, surgery) is resolved
  • Unprovoked (e.g., cancer, genetic defects): typically requires life-long anticoagulation along with assistance from hematology

Complications*

  • Post-Thrombotic Syndrome: Chronic leg pain, swelling, ulcers from vein damage (20-50% of DVT cases). Compression stockings reduce risk of this.
  • Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Rare, from unresolved PE causing lung artery pressure buildup.

Anticoagulation in malignancy - Treatment of established VTE (ASCO 2021): LMWH or DOACs (apixaban, rivaroxaban, edoxaban). Avoid DOACs in GI/GU cancers due to bleeding risk.
- Primary Prophylaxis * Khorana Score: Predicts VTE risk in outpatients on chemo
* Apixaban 2.5 mg BID, rivaroxaban 10 mg daily, or LMWH for high-risk outpatients (e.g., pancreatic cancer, Khorana ≥2).

Additional Information

  • Should we get a follow up ultrasound?
  • When it’s typically not needed: provoked DVT with clear resolution: If DVT was triggered by transient risk and symptoms resolve, follow-up imaging isn’t routine.
  • When it’s recommended or considered: unprovoked DVT with no clear trigger suggests underlying risk (e.g., factor V Leiden, cancer). F/u ultrasound can:
    • Assess residual clot to guide whether to extend AC
    • Assess persistent residual vein occlusion which doubles recurrence risk.
  • What about IVC filters?
  • Select circumstances for these: In pts with acute DVT or PE and in whom anti-coagulation is absolutely contraindicated (thrombocytopenia, recent intra-cranial bleed, recent GI bleed) or recurrent PE despite adequate AC
  • Placement of a retrievable IVC filter should be discussed with Hematology and IR
  • Complications of IVC filters include filter thrombosis, migration/fracture, perforation and retrieval issues (PREPIC trials (1998, 2005) showed filters reduce PE risk short-term but increase DVT recurrence long-term, with no mortality benefit)

Anticoagulation

Author: Sarah Fittro

Vitamin K Antagonist

Warfarin (Coumadin) - Tx Dose: Highly individualized; typically started at 2–5 mg orally once daily, then adjusted based on INR (International Normalized Ratio).
- Target INR: * 2.0–3.0: For most indications (e.g., AF, DVT, PE).
* 2.5–3.5: For mechanical heart valves or certain other conditions.

  • Renal dose: No change needed
  • PPX: 5000u Q8H
  • Monitoring: Requires regular INR checks (initially daily or every few days, then weekly/monthly once stable).
  • Hold prior to procedure: Several days (Goal INR \<1.5)
  • Notes: Affected by diet, drug interactions, and genetics (e.g., CYP2C9, VKORC1 variants).
  • Reversal agent: Vitamin K (phytonadione). Onset within a few hours but takes 24-48 hrs for full effect.
  • No bleeding and elevated INR
    • INR \<4.5: Vitamin K not recommended
    • INR 4.5-10: 1- 2.5 mg PO Vitamin K
    • INR >10: 2.5 - 5mg PO Vitamin K
  • Minor bleeding (e.g., epistaxis, hematuria): 5–10 mg PO or IV (over 30 minutes). Consider FFP.
  • Major bleeding (e.g., intracranial hemorrhage, GI bleed): Give 10mg IV Vitamin K over 30 minutes. Combine with PCC or FFP for immediate reversal.
    • Rapid reversal INR > 5 prior to surgery: 5mg Vit K IV (24 hours prior to procedure)
    • FFP: 15 ml/kg (e.g. 4 units/70 kg person) if need reversal \<24 hrs, plus give Vitamin K
    • KCentra ($$$): Contains Factors II, VII, IX, and X with Protein C, Protein S, and heparin
    • Given instead of plasma when insufficient time for plasma/Vit K to work (i.e. for life threatening hemorrhage)
    • Avoid giving in HIT
    • Administer with Vitamin K

Heparins

Unfractionated Heparin (UFH) - Tx Dose: IV bolus of 80 U/kg (or 5,000 units), followed by continuous infusion of 18 U/kg/hour, adjusted to target aPTT (typically 1.5–2.5 times control, or 60–80 seconds).
- Renal dose: No change needed
- PPX: 5000u Q8H
- Monitoring: aPTT every 6 hours initially (automatic in order set)
- Hold prior to procedure: 6 hours
- Notes: Short half-life; used in hospital settings.
- Reversal Agent: Protamine Sulfate. 1 mg IV /100 units of heparin given in the last 2–3 hours (max 50 mg). Rapid onset.

Low molecular weight heparin (LMWH):
- Enoxaparin (Lovenox) treatment dose: DVT/PE Treatment: 1 mg/kg subQ q12h, or 1.5 mg/kg QD. Renal adjustment: 1 mg/kg once daily if CrCl \<30 mL/min.
- Dalteparin (Fragmin) treatment dose: DVT/PE Treatment: 200 units/kg subQ QD. Renal Adjustment: Monitor anti-Xa levels if CrCl \<30 mL/min.
- Monitoring: Anti-Xa levels may be checked in renal impairment, obesity, or pregnancy (target 0.5–1.0 IU/mL for twice-daily dosing).
- Hold prior to procedure: 12 hours
- Reversal Agent: Protamine Sulfate (Partial). 1 mg IV per 1 mg enoxaparin (or 100 units dalteparin) given in the last 8 hours. Incomplete reversal; additional measures (e.g., FFP) may be needed for severe bleeding.

Indirect Factor Xa Inhibitor
Fondaparinux (Arixtra)
- DVT/PE Treatment dose: * Weight \<50 kg: 5 mg subcutaneously once daily.
* Weight 50–100 kg: 7.5 mg subcutaneously once daily.
* Weight >100 kg: 10 mg subcutaneously once daily.
- Renal Adjustment: Contraindicated if CrCl \<30 mL/min.

Direct Oral Anticoagulants (DOACs)
Apixaban (Eliquis)
- Tx Dose: * DVT/PE Treatment: 10 mg twice daily for 7 days, then 5 mg twice daily.
* AF (stroke prevention): 5 mg twice daily; reduce to 2.5 mg twice daily if ≥2 of: age ≥80, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. - Renal dose: Caution in severe renal impairment (CrCl \<15 mL/min); not typically recommended.
- Hold prior to procedure: At least 48 hours
- Reversal Agent: Andexanet Alfa (Andexxa). Very $$$. Not on VUMC formulary but is on the VA formulary.

Dabigatran (Pradaxa)
- Tx Dose: * DVT/PE Treatment: 150 mg twice daily (after 5–10 days of parenteral anticoagulation, e.g., heparin).
* AF (stroke prevention): 150 mg twice daily - Renal dose: Reduce to 75 mg twice daily if CrCl 15–30 mL/min. Contraindicated if CrCl \<15 mL/min.
- Hold prior to procedure: At least 48 hours
- Reversal Agent: Idarucizumab (Praxbind). 5 g IV (given as two 2.5 g doses, 15 minutes apart). Monoclonal antibody that binds dabigatran, neutralizing its effect. Rapid onset (within minutes). Consult Hematology

Rivaroxaban (Xarelto)
- Tx Dose: * DVT/PE Treatment: 15 mg twice daily with food for 21 days, then 20 mg once daily with food.
* AF (stroke prevention): 20 mg once daily with evening meal - Renal dose: Reduce to 15 mg once daily if CrCl 15–50 mL/min. Avoid if CrCl \<15 mL/min.
- Hold prior to procedure: At least 48 hours
- Reversal Agent: Andexanet Alfa (Andexxa). Very $$$. Not on VUMC formulary but is on the VA formulary.

Edoxaban (Savaysa) - Tx Dose: * DVT/PE Treatment: 60 mg once daily (after 5–10 days of parenteral anticoagulation); reduce to 30 mg once daily if CrCl 15–50 mL/min or weight ≤60 kg.
* AF (stroke prevention): 60 mg once daily - Renal dose: 30mg QD for CrCl 15-50 mL/min. Avoid if CrCl \<15 mL/min.
- Hold prior to procedure: At least 48 hours

Additional Information - VA is starting to move towards rivaroxaban and apixaban for extended secondary thromboprophylaxis
* Write in your PADR for apixaban citing “pt uses a pillbox and cannot use dabigatran”
- Hx of GI bleed: Apixiban (Eliquis) has the best GI safety profile among DOACs. Avoid dabigatran, rivaroxaban, edoxaban (may have higher risk of GI bleed). Warfarin has higher risk of GI bleed than apixaban but lower than dabigatran or rivaroxaban in some analyses (e.g., GI bleeding rate \~1–3% per year, depending on INR control).
- Pregnancy: UFH/LMWH (other agents may cross the placenta). Warfarin is a known teratogen in 1st trimester and has fetal bleeding risk in 2nd/3rd trimester. DOACs cross placenta and there is limited human data, animal studies suggest fetal harm.
- BMI >40: Consider LMWH (dose is weight based) or warfarin (able to target INR). Fixed-dose regimens (e.g., DOACs) may underperform in extreme obesity. Apixaban or rivaroxaban can be used per ISTH guidelines (but avoid dabigatran and edoxaban)
- GI malabsorption (e.g. Crohn's): Caution with DOACs, consider LMWH or warfarin.
- Duration: Varies by condition (e.g., 3–6 months for provoked DVT, lifelong for AF or recurrent events).

Transitioning between Anticoagulants with DOACs

From To Timing
DOAC Warfarin Low-moderate risk DVT/PE: start warfarin while pt is on DOAC, stop DOAC on day 3 of warfarin therapy, and check INR on day 4
High risk DVT/PE: start LMWH or UFH, then start warfarin
DOAC LMWH Stop DOAC and start LMWH when due for next DOAC dose
DOAC UFH Start IV heparin with bolus when next DOAC dose is due
LMWH Warfarin LMWH and warfarin given simultaneously until INR is therapeutic for 24h
LMWH DOAC Stop LMWH and start DOAC when due for next dose of LMWH (within 2h)
UFH DOAC Start DOAC when IV stopped (30min prior to cessation if high risk for thrombosis)
Warfarin DOAC Start DOAC when INR \< 2.0

Peri-procedural Management of Anticoagulation

  • Temporary IVC filter indicated in pts with very recent acute VTE (within 3-4 weeks) if the procedure requires AC delay >12 hours
  • For those at high risk of thromboembolism
  • Consider continuing AC for low-bleeding-risk procedures like dental procedures, cutaneous biopsy/excision, ICD placement, and endovascular procedures.
  • Can bridge with LMWH or heparin drip
Stop before procedure Restart after procedure
Warfarin 5 days prior, check INR day of 12 to 24 hours after
Dabigatran
Rivaroxaban
Apixaban
Edoxaban		 48 hours prior (longer if CrCl 30-50 or procedure is high bleeding risk) 1 day after (2 days if high bleeding risk)
Heparin Stop infusion 4-5 hours prior 24 hours after
Enoxaparin 12 - 24 hours prior 24 hours after, (48-72 hours if high bleeding risk)

Hypercoagulable States

Author: Sarah Fittro

Background

  • Virchow’s triad: 1. Hypercoagulability 2. Stasis 3. Endothelial injury
  • Diagnostic thrombophilia testing indications
  • Recurrent unprovoked VTE
  • Severe first VTE (e.g., massive PE, no cause)
  • First VTE at \<50 years old (e.g., 32-year-old with spontaneous DVT)
  • VTE in the setting of strong family history
  • VTE in unusual vascular site (cerebral, renal, mesenteric)
  • Recurrent pregnancy loss
  • Arterial thrombosis at a young age
  • Strong family history
  • Must consider if thrombophilia testing will change clinical management
  • If the unprovoked VTE warrants indefinite anticoagulation then testing may not be helpful
  • However, if VTE provoked by minor risk factor (OCPs) with an underlying thrombophilia might change the decision, then testing may be informative
  • Separated into hereditary and acquired conditions
  • Hereditary:
    • Factor V Leiden mutation
    • Prothrombin mutation
    • Protein C or S deficiency
    • Antithrombin deficiency
    • Dysfibrinogenemia (rare)
    • Elevated factor VIII (possible genetic component)
    • Hyperhomocysteinemia (inherited component due to mutations (e.g., MTHFR))

  • Acquired

    • Antiphospholipid syndrome
    • Active cancer or occult malignancy
    • Immobilization (bedridden, hip/knee replacement)
    • Major surgery/trauma
    • Smoking
    • Obesity (BMI ≥30 kg/m², especially visceral fat)
    • Pregnancy and postpartum period (first 6 weeks)
    • Hormonal therapy (OCPs (especially estrogen-containing), hormone replacement therapy, or selective estrogen receptor modulators (e.g., tamoxifen).
    • Myeloproliferative neoplasms (e.g., polycythemia vera or essential thrombocytopenia)
    • Paroxysmal nocturnal hemoglobinuria
    • Heparin induced thrombocytopenia
    • Nephrotic syndrome (risk correlates with albumin \<2.0 g/dL)
    • Inflammatory states like inflammatory bowel disease, rheumatoid arthritis, or acute infections (e.g., sepsis).
    • Acquired hyperhomocysteinemia (elevated homocysteine from B12/folate deficiency, renal failure, or smoking)
    • Note: Travel (plane, train, automobile) is NOT on this list and this is NOT considered a provoking risk factor

  • Testing: All specific testing for hereditary disorders and APS should be performed at least 4-6 weeks after an acute thrombotic event or discontinuation of anticoagulant/thrombolytic therapies to avoid interference.

Antiphospholipid Antibody Syndrome (APLS)

Background

  • Most common acquired disorder (anti-phospholipid antibodies present in 3-5% population)
  • Thrombotic Risk: Venous (DVT, PE), arterial (stroke, MI), or microvascular thrombosis; recurrent pregnancy loss.

Evaluation

  • This is a clinicopathologic diagnosis (need both clinical and laboratory criteria)
  • Triggers: Often associated with systemic lupus erythematosus (SLE) or standalone (“primary APS”).
  • Diagnosis requires clinical event (thrombosis or pregnancy morbidity) + positive antibody test on two occasions, 12 weeks apart:
  • Lupus anticoagulant: can occur in relation to drugs or infection
  • Anticardiolipin antibodies
  • β 2GP1 (anti- β2-glycoprotein) antibodies

Management

  • Consider aspirin for primary prevention (persistent aPL without thrombosis/pregnancy loss) if high risk.
  • VTE: indefinite warfarin (INR 2-3)
  • Arterial thrombosis: warfarin +/- antiplatelet agent such as aspirin
  • Do NOT use DOACs for triple positive APLS (see TRAPS trial: rivaroxaban inferior to warfarin)
  • Hydroxychloroquine: reduces aPL levels and thrombosis risk in SLE-associated APS
  • Statins: considered in arterial APS for endothelial protection
  • Rituximab for recurrent thrombosis despite anticoagulation (controversial): call Hematology

Catastrophic APS (CAPS)

  • Presentation
  • Rapid Onset: Thrombosis in ≥3 organs, systems, or tissues within a week.
  • Common Sites:
    • Kidneys (renal failure, hypertension).
    • Lungs (acute respiratory distress syndrome [ARDS], pulmonary embolism).
    • Brain (stroke, seizures, encephalopathy).
    • Heart (myocardial infarction, valve thrombosis).
    • Skin (livedo reticularis, purpura, necrosis).
    • Adrenals (adrenal insufficiency).
  • Systemic Inflammatory Response: Fever, elevated inflammatory markers (e.g., CRP, ESR), often mimicking sepsis.

  • Triggers: Identified in \~50% of cases—e.g., infection (most common), surgery, trauma, pregnancy, or anticoagulation withdrawal.

  • Criteria for definite CAPS

  • Evidence of multi-organ involvement (3 or more) 
    • Clinical or imaging evidence of thrombosis or dysfunction (e.g., CT/MRI showing stroke, renal infarcts).
  • Confirmation by histopathology of small vessel occlusion  
  • Laboratory confirmation of aPL antibodies (detected on 2 occasions 12 weeks apart) 
  • Absence of alternative diagnoses (Exclude mimics like TTP, HUS, DIC or HIT)
  • Management
  • IV heparin and high dose steroids
  • For refractory cases: consider PLEX, IVIG, rituximab

Heparin-induced Thrombocytopenia (HIT)

Type 1: Non-immune, benign thrombocytopenia due to direct heparin effects.

  • Platelet drop within 1–4 days of heparin start.
  • Mild decrease (e.g., 10–30% from baseline).
  • No thrombosis or skin lesions.
  • No intervention needed; continue heparin if clinically indicated.
  • Platelet count normalizes with continued heparin therapy

Type 2: Immune-mediated, prothrombotic condition requiring urgent intervention.

  • Risk Factors: UFH > LMWH, surgical patients (especially orthopedic/cardiac), females, higher heparin doses.
  • Platelet count drops ≥50% from baseline.
  • Typical onset: 5–14 days after heparin exposure (first exposure).
  • Rapid onset: Within 24 hours if prior heparin exposure within 30–100 days (antibody persistence).
  • Thrombosis:
  • Venous (DVT, PE) > arterial (stroke, MI, limb ischemia).
  • Unusual sites: adrenal vein (hemorrhage), skin necrosis at injection sites.
  • Occurs in 30–50% of untreated cases; risk persists 4–6 weeks post-heparin cessation.
  • Symptoms:
  • Thrombosis-related (e.g., leg swelling, chest pain).
  • Skin lesions (erythema, necrosis) in \~10%.
  • Bleeding rare unless severe thrombocytopenia

Evaluation

  • 4T score (0-8 points):
  • Thrombocytopenia (0-2 pts): degree and nadir of platelet count drop
  • Timing (0-2 pts): timing of fall after initial or recurrent heparin exposure
  • Thrombosis (0-2 pts): thrombosis, skin necrosis, non-necrotizing lesions, acute systemic reaction to heparin

  • Other causes of thrombocytopenia (0-2 pts): more points if no alternate cause

  • Interpretation: Low (0–3), Intermediate (4–5), High (6–8)

  • Screening: Anti-PF4/heparin ELISA (IgG-specific); optical density (OD) >0.4 suggests positivity (higher OD \= higher risk).

  • Confirmation: Functional assay (e.g., serotonin release assay [SRA], heparin-induced platelet activation [HIPA]); >20% serotonin release confirms HIT.
  • The lab at VUMC will perform functional SRA reflexively for all values >0.2

Management

  • 0-3 points: Low concern for HIT; can restart heparin
  • 4-5 points: Intermediate probability (\~10%); hold heparin, start non-heparin anticoagulant
  • 6 points: High probability (\~50%); hold heparin, start non-heparin anticoagulant
  • Argatroban (direct thrombin inhibitor) for prophylaxis and treatment of thrombosis
  • Avoid platelet transfusions as can increase thrombogenic effect
  • Avoid warfarin until complete platelet recovery as may cause microthrombosis
  • Hematology consult for all confirmed HIT

Factor V Leiden Mutation

Factor V Leiden (FVL) is the most common inherited thrombophilia, caused by a point mutation (G1691A) in the F5 gene, leading to resistance of activated Factor V to inactivation by activated protein C (APC).

Evaluation

  • Screen with activated protein C resistance assay in select cases (unprovoked VTE, family history).
  • APC ratio in pt vs. normal
  • Normal >2.0, heterozygotes 1.5-2.0, homozygotes \<1.5
  • Factor V Leiden mutation can then be confirmed via PCR
  • Screen with APC assay rather than PCR initially; cost effective

Management

  • VTE treatment same as general population
  • VTE 3-8x risk in heterozygotes; 50-80x risk in homozygotes
  • Avoid combined oral contraceptives/HRT; progestin-only options safer.

Prothrombin Gene Mutation

  • Evaluation: PCR of G20210A mutation (2-4% prevalence)
  • Thrombotic Risk: Primarily affects venous system; minimal impact on arterial thrombosis (e.g., stroke, MI) unless combined with other risk factors.
  • Management: Treat VTE as usual; extend anticoagulation for unprovoked/recurrent cases; prophylaxis in high-risk settings for carriers. Avoid OCPs

Protein C and S Deficiency

Background

  • Pathophysiology: Impaired inactivation of Factors Va/VIIIa increases clotting.
  • Both are autosomal dominant; first event occurs between 10-50 years of age
  • Synthesized in liver and Vit K dependent; therefore, low levels in hepatic dysfunction and warfarin use/vitamin K deficiency
  • Protein C: low in settings of thrombosis, DIC, nephrotic syndrome, intra/post-op
  • Protein S: low in infectious (HIV) and autoimmune processes (IBD)
  • Protein S decreases during pregnancy (decreased free protein S, normal total protein S)
  • Do not misdiagnose a pregnant pt with PS deficiency

Evaluation

  • Functional Protein C and S assays

Management

  • VTE treatment same as general population
  • Avoid OCPs/HRT
  • High risk pts may require protein C concentrate prior to surgery
  • Increased risk of warfarin-induced skin necrosis

Antithrombin Deficiency

Background

  • Autosomal dominant with variable penetrance.
  • Unprovoked VTE (DVT, PE) often \<40–50 years; 50–70% lifetime risk by age 60.
  • Unusual sites: Cerebral, mesenteric, portal vein thrombosis.
  • Acquired deficiency can be caused by liver disease (decreased synthesis), nephrotic syndrome (urinary loss), DIC, or heparin therapy (consumption).
  • Transient, not genetic; managed by treating underlying condition.

Evaluation

  • Functional antithrombin activity (AT-heparin cofactor assay)
  • Then perform antigen quantity testing

Management

  • Treat VTE as usual; indefinite anticoagulation for unprovoked cases; prophylaxis in triggers; antithrombin concentrate for severe/homozygous cases.

Bleeding Coagulopathies – Sarah Fittro

Bleeding tendency or dysfunction in clot formation can occur from either a quantitative or qualitative platelet defect, deficiency or inhibitor of coagulation factors, or compromise of vascular integrity

  • Platelet disorders will present with mucocutaneous bleeding, petechiae, mild bleeding immediately following surgery, impaired wound healing
  • Coagulation defects will present with deep tissue bleeding in joints/muscles resulting in hemarthroses, hematomas, sometimes delayed but severe bleeding after surgery, and intracranial hemorrhage

Quantitative or Qualitative Platelet Defect

Thrombocytopenia: see “Thrombocytopenia” section

von Willebrand Disease (vWD): Most common inherited bleeding disorder, affecting about 1% of the population (though many cases are mild and undiagnosed) but can also be acquired or secondary to other disease states. vWF has two big jobs: - Helps platelets stick: When a blood vessel is injured, vWF binds platelets to the damaged site to form a temporary plug.
- Carries factor VIII: vWF protects factor VIII from breaking down and delivers it to where it’s needed in the coagulation cascade.

Types of vWD - Type 1 (60-80% of cases): Partial deficiency of vWF. Levels are low, but protein works.
- Type 2 (15-30% of cases): vWF is present but defective. There are subtypes: * 2A: vWF can’t form large, effective multimers (chains) needed for platelet binding.
* 2B: vWF binds too aggressively to platelets, causing them to clump and get cleared from circulation, reducing both vWF and platelets.
* 2M: vWF has trouble binding to platelets due to a structural flaw.
* 2N: vWF can’t properly carry factor VIII, mimicking mild hemophilia A. - Type 3 (1-5% of cases): Severe. Almost no vWF is produced, and factor VIII levels drop.
- Acquired vWD: Rare, caused by drugs or diseases that destroy or block vWF such as: * Lymphoproliferative disorders: CLL, NHL, plasma cell dyscrasias
* Myeloproliferative disorders: PV, ET, or myelofibrosis
* Autoimmune diseases: SLE
* Hypothyroidism
* Sheer stress: aortic stenosis – Heyde syndrome, LVAD, ECMO * Heyde syndrome is a multisystem disorder characterized by a triad of aortic stenosis (causes high shear stress in blood flow), GI bleeding (from angiodysplasia in the gut) and acquired von Willebrand disease (type 2A)

Clinical presentation: - Mild (Type 1): Easy bruising, frequent nosebleeds, menorrhagia, prolonged bleeding
- Moderate (Type 2): Similar to Type 1 but more pronounced +/- petechiae
- Severe (Type 3): Spontaneous hemarthrosis, symptoms resembling hemophilia.

Diagnosis:“vW Profile” \= vWF Ag, Factor VIII Activity, Ristocetin Cofactor Activity

Management: - Desmopressin (DDAVP): Works for most Type 1 and some Type 2 cases.
- vWF/Factor VIII Concentrates: For Type 3, severe Type 2, or when DDAVP fails.
- Antifibrinolytics (e.g., Tranexamic Acid)**:
- Platelet transfusions: Rarely, for Type 2B with severe thrombocytopenia.
- Avoid NSAIDs

Other causes of qualitative platelet defects - Uremic platelet dysfunction
- Medications: NSAIDs, anti-platelets (ASA, Plavix), SSRIs (serotonin required for platelet activation), and melatonin (suggested by pre-clinical studies)

Deficiency of Coagulation Factors

Inherited Causes

  • Hemophilia A is a deficiency of factor VIII and Hemophilia B is a deficiency of factor IX. Both are X-linked recessive and most commonly affect males.
  • Frequently presents with hemarthroses and hematomas
  • Diagnosis: isolated prolonged PTT with normalization upon mixing study
  • Management: purified/recombinant Factor VIII or IX, mild disease can be managed with desmopressin, consult Benign Hematology on admission
  • Factor XI Deficiency (Hemophilia C): Rare, autosomal recessive, caused by F11 gene mutations. Common in some populations (e.g., Ashkenazi Jews).
  • Fibrinogen Disorders: Mutations in FGA, FGB, or FGG genes can lead to afibrinogenemia (no fibrinogen) or hypofibrinogenemia (low fibrinogen).

Acquired Causes

  • Liver Disease: The liver makes most clotting factors (II, V, VII, IX, X, plus fibrinogen).
  • Vitamin K deficiency
  • Dilutional coagulopathy: Massive blood or fluid resuscitation can dilute clotting factors
  • DIC
  • Leukemia, aplastic anemia, or chemotherapy can impair factor production by affecting megakaryocytes or plasma cells.
  • Amyloidosis: can cause factor X deficiency

Inhibitors of Coagulation Factors

Acquired Inhibitors

  • Acquired Hemophilia A: Antibodies against factor VIII. Rare.
  • Onset in older age (60s)
  • Frequently presents with significant intramuscular hematomas
  • Disease associations in 50% of cases (other 50% idiopathic): autoimmune (e.g. SLE), malignancy (paraneoplastic), Pemphigus, drug-induced (e.g. interferon, penicillins), or chronic GvHD
  • Diagnosis: Elevated PTT that does not normalize with mixing study
  • Always consult hematology (rare disorder with major bleeding complications)
  • Bleeding management: Typically need a factor VIII bypassing agent (FEIBA)
  • Immunosuppression: prednisone 1mg/kg, rituximab often also used front line
  • Factor V Inhibitors: Even rarer, linked to surgery, antibiotics, or autoimmune triggers.
  • Alloantibodies in hemophilia: patients with congenital hemophilia A or B receiving factor VIII or IX infusions can develop antibodies.

Other Inhibitory Mechanisms

  • Liver disease: Beyond reducing factor production, cirrhosis can produce abnormal proteins (e.g., dysfibrinogenemia) that interfere with clotting.
  • A FVIII level can help distinguish between liver dysfunction and DIC (elevated or normal in liver dysfunction and decreased in DIC since it is not hepatically derived)
  • Drugs: Warfarin and DOACs intentionally reduce activity of vitamin K-dependent factors (II, VII, IX, X) as therapy

Compromise of Vascular Integrity

Background: Compromise of vascular integrity can contribute to a coagulopathy by disrupting the first step of hemostasis.

  • Amyloidosis: Deposits infiltrate capillaries/arterioles and impair vasoconstriction and platelet adhesion. Can present as GI bleeding, purpura or ecchymoses (Raccoon eyes)
  • Vasculitis: purpura, alveolar hemorrhage (DAH), intracranial hemorrhage, GI bleeding
  • Vitamin C deficiency (scurvy): can present with bleeding gums, GI bleeding, ecchymoses, hematomas, anemia
  • Ehlers-Danlos Syndrome: Defective collagen \= vessels tear easily, resulting in bruising or even arterial rupture.
  • Marfan Syndrome: Abnormal fibrillin in vessel walls alters subendothelial structure, potentially affecting platelet binding.
  • Hereditary hemorrhagic Telangiectasia: 2nd most common inherited bleeding disorder. Often presents with epistaxis, GI bleeding
  • DIC or thrombotic microangiopathies (e.g., HUS, TTP) can lead to endothelial injury and microclots, consuming platelets and factors, resulting in secondary bleeding.
  • Allergic reactions: Histamine increases permeability \= petechiae or ecchymosis.
  • Cushing’s Syndrome: Excess cortisol thins vessel walls \= easy bruising.
  • Infections (e.g., Ebola, Dengue): Viral damage to endothelium \= hemorrhagic fever.

Management - Labs: Normal PT, aPTT, and platelet counts rule out factor or platelet issues.
- Clinical Signs: Petechiae, purpura, or mucosal bleeding without deep hematomas suggest vascular fragility over hemophilia-like factor defects.
- Tests: Bleeding time (less used now) or skin biopsy (e.g., for collagen defects) can point to vessel problems.

Disseminated Intravascular Coagulation (DIC)

Author: Eric Singhi

Background

  • Concurrent activation of the coagulation pathway and fibrinolytic pathway
  • Consumption of platelets, fibrin, and coagulation factors 🡪 fibrinolysis 🡪 end organ damage and hemolysis
  • Etiologies:
  • Infection/sepsis, liver disease, pancreatitis, trauma
  • Malignancies: mucin-secreting pancreatic/gastric adenocarcinoma, brain tumors, prostate cancer, all acute leukemias, acute promyelocytic leukemia
  • Obstetric complications: preeclampsia/eclampsia, placental abruption
  • Acute hemolytic transfusion reaction (e.g. ABO incompatible transfusion)

Evaluation

  • Exam: petechiae, bleeding (mucosal, IV site, surgical wound site, hematuria), ecchymoses, thrombosis (i.e. cold, pulseless extremities)
  • Laboratory evaluation
  • CBC, PT/INR, aPTT, fibrinogen, d-dimer, peripheral blood smear
  • “DIC labs”: q6h fibrinogen, PT/INR, aPTT (space out when lower risk)
  • Findings suggestive of DIC: thrombocytopenia, prolonged aPTT and PT/INR, hypofibrinogenemia, elevated D-dimer, fibrin degradation products, schistocytes
  • A FVIII level can help distinguish between the DIC and liver dysfunction: elevated or normal in liver dysfunction and decreased in DIC since it is not hepatically derived

Management

  • Treat the underlying cause
  • Vitamin K for INR > 1.7 or bleeding
  • Hypofibrinogenemia treatment: Cryoprecipitate 5-10 units if fibrinogen \< 100
  • Thrombocytopenia treatment: platelet transfusion as normally indicated
  • DVT ppx if not bleeding and platelet > 50
  • VTE: anticoagulation if platelet > 50 and no massive bleeding

Transfusion Medicine

Authors: R. Dixon Dorand, Zoe Finer

For emergent transfusions, call the blood bank (615-322-2233) - RNs on 10T and 11N can follow transfusion protocols for pRBCs and plts – enter as a “Nursing Communication” or as part of the Hematology/Oncology Admission Order set.
- At VUMC, all blood products are leukoreduced to reduce the risk of febrile nonhemolytic reactions. Other special processing of blood products (such as irradiation) will be decided by blood bank based on special considerations listed in order set. Examples include: stem cell transplant, hematologic malignancy, or thalassemia
- Pts with frequent transfusions (e.g. sickle cell hemoglobinopathy) should have an “RBC Extended Phenotype” ordered (once) for minor RBC antigens to avoid immunization and antibody development to these proteins
- You may ask the VUMC hematology lab to email you pictures of the peripheral smear

VA: Orders Tab – Blood Bank Orders – follow prompts to select appropriate product. Must order both the blood product AND the transfusion order (“Transfuse blood”) - You need to specify all special processing such as irradiation
- To order “Type & Screen” as a lab, you must go to Blood Bank Orders
- Type & Screen and Transfusion results are under the Blood tab in Results

Red Blood Cell Transfusions

  • Volume 200-300 mL per unit prbc
  • In general, 1 unit of packed RBCs increases Hgb by 1g/dL and HCT by \~3%
  • Assessment of the post-transfusion Hgb can be performed 15 min following transfusion, but ideally 1 hour after completion

Indications: - Hgb \< 7 g/dL for most adults
- Hgb \< 7.5 g/dL pre cardiac surgery
- Hgb \< 8 g/dL or Hct \<25: Bone marrow failure or receiving antineoplastic therapy
* Also sometimes used in pts with pre-existing CAD, ACS, and pre-orthopedic surgery

Platelet Transfusions

  • most likely blood product to be contaminated (unable to be frozen for storage)

Indications for transfusion - \<11 k/µL: all pts, reduce risk of spontaneous hemorrhage (use on BMT, Brittingham)
- \<50 k/µL: active bleeding, scheduled to undergo select invasive procedure
- \<100 k/µL: CNS hemorrhage, intrathecal catheter * This is also the threshold used for most neurosurgical procedures

  • poor response is common
  • nonimmune mediated causes: fever, infection, splenomegaly, DIC, meds, bleeding
  • Immune mediated causes: anti-HLA antibodies and anti-human plt antigens (try cross matched or HLA matched plts for this), drug induced antibodies, plasma protein antibodies

Fresh Frozen Plasma (FFP) and Cryoprecipitate (Cryo)

Cryoprecipitate: fibrinogen, factor VIII, VWF, Factor XIII, Fibronectin (typically 1u/10kg) - low fibrinogen (\<100) with active bleeding
- fibrinogen \< 150 +massive hemorrhage, APML
- Should not be used in hemophilia or vWD (there are better options such as concentrate or recominant factors)

FFP (typically dosed 10mL/kg to correct INR)
- Once thawed, must be used in 24 hrs (due to decline in labile coagulation factors)
- Must be ABO compatible but not crossmatched or Rh typing
- Only administer FFP if INR ≥1.7 (FFP will not fix an INR \< 1.7, the average INR of a unit of plasma is 1.3-1.4)

Indications for transfusion - Bleeding:
* FFP If INR >1.6
* Cryoprecipitate if fibrinogen \<100.
- DIC:
* Fibrinogen \<100: Transfuse 5 – 10 units cryoprecipitate and repeat fibrinogen. If bleeding, consider raising transfusion threshold of cryoprecipitate to fibrinogen \<150
* Plasma exchange
* Massive transfusion
- Cirrhosis:
* General concept: PT/INR, aPTT are unreliable markers for bleeding. Fibrinogen ≤100 – 120 or thromboelastography are better surrogates for bleeding risk
* Transfuse fibrinogen ≤100 – 120 if the pt is actively bleeding or about to undergo a procedure or surgery other than paracentesis
* Transfuse FFP based on hepatology team preference (generally few indications for FFP)

Massive Transfusion Protocol

In the setting of large blood loss or ongoing bleeds - Transfuse RBCs, FFP, and Platelets (typically 1:1:1 ratio in trauma scenarios). Transfusing large amounts of RBCs can dilute coagulation factors, which is the reason for the matched ratio.
- At VUMC can order a “fastpack” which includes 2u prbc and 2u plasma
- Complications to monitor for: * Hypocalcemia, hypomagnesemia, (blood products have citrate as a preservative which binds to ca and affects mag levels) → replete with Ca gluconate and Magnesium Sulfate * Hyperkalemia – due to the breakdown of RBC in transfusion process
* Hypothermia
* Coagulopathy – due to the dilution of clotting factors discussed above.

Transfusion Premedication and Reactions

  • If you are concerned about a serious transfusion reaction, pause the transfusion and contact the blood bank ASAP
  • Order the transfusion reaction blood testing in Epic. You will send a CBC, the bag of blood products, and the completed form to the blood bank for analysis

Premedication: - Only if history of severe reaction
* Diphenhydramine 25-50mg IV
* Acetaminophen 650 mg PO
* Meperidine 25-50 mg IV (optional for chills)
* Hydrocortisone 50 mg IV (optional, for severe reactions or reactions despite acetaminophen and diphenhydramine)

Reaction Signs & Symptoms Etiology Clinical Action
Allergic (mild) Pruritus, hives limited to small area Antibodies to transfused plasma proteins Pause transfusion. Administer antihistamines. Resume transfusion if improved; NO samples necessary. If no improvement in 30 min treat as moderate to severe.
Allergic (moderate to severe) Generalized hives (>2/3 body surface), bronchospasm & dyspnea, abdominal pain, hypotension, nausea, anaphylaxis Antibodies to transfused plasma proteins usually IgE but can also be IgA. Possible allergen in blood product. Administer antihistamines, epinephrine, vasopressors and corticosteroids as needed. Send product to blood bank. Evaluate for IgA deficiency → pt may need washed blood bloods from IgA deficient donor.
Febrile Non-Hemolytic Rise of temp >1°C, chills, rigors, anxiety, headache – during or up to 4 hours after typically. Cytokines released from residual white blood cells in the blood product Mild: administer antipyretics as needed
Acute Hemolytic Hemoglobinemia/uria, fever, chills, anxiety, shock, flank pain, chest pain, unexplained bleeding, cardiac arrest Intravascular hemolysis usually due to ABO incompatibility. Clinical emergency. Ensure correct product given to correct patient. Treat shock w/vasopressors; maintain airway; administer fluids and maintain brisk diuresis; monitor for AKI.. Reach out to blood bank to assist in evaluation. Administer blood products as needed after etiology is clear.
Delayed Hemolytic Asymptomatic or anemia, fever, jaundice, mailaise, hemoglobinuria and renal failure 3 days – 2 weeks after transfusion Newly formed alloantibody or increase in previously undetectable antibody leading to hemolysis of transfused RBCs
Septic Rise of temp > 2°C, sudden hypotension or hypertension, shock Micro-organism (i.e. bacteria) in donor bag (Greater risk in apheresis vs. RBC) Send bag/tubing to transfusion medicine. Order BCx. Broad spectrum abx  Pressor support if necessary.
TRALI (Transfusion related acute lung injury) Acute respiratory distress occurring within 6 hours of transfusion. Imaging typically shows non-cardiogenic pulmonary edema unresponsive to diuretics; Dx of exclusion Usually donor HLA antibodies from transfused plasma. Recipient has corresponding antigens; causes neutrophil activation that results in extravasation of fluid into air spaces. Respiratory support! Most will resolve within 24-96 hours. Steroids, diuretics: no known benefit.
TACO - Transfusion Associated Circulatory Overload Cardiogenic pulmonary edema occurring within 6 hours from the end of transfusion. Elevated BNP is often observed. Can be seen with as little as one unit of blood. Increased oncotic and pulmonary capillary pressures (to a greater extent than crystalloid) resulting in pulmonary edema Diuretic therapy and supportive care. Typically preventable with decreasing transfusion rate

Sickle Cell Disease and Complications

Author: AJ Winer

Sickle Cell Anemia – the Basics - Pathogenesis: Recessive mutation in β-globulin of hemoglobin \=> substitution of Val for Glu \=> structurally abnormal Hgb (HbS).
- Homozygosity for HbS (Hb SS) is the classic form of sickle cell disease, but compound heterozygosity with other pathogenic beta globulin (HbSC, HbS Beta0-thal, HbS Beta+-thal)
- Epidemiology: * Often linked to Sub-Saharan Africa, but also in other regions with high malaria burden (Central/South America, Caribbean, Middle East, Mediterranean, India)
* 8% of African Americans are heterozygotes (“sickle trait”)
* \~1/400 of African Americans are homozygotes (sickle cell disease) - Pathogenesis of sickling: Decreased O2 \=> HbS polymerization \=> RBC sickling & decreased RBC deformability \=> hemolysis and microvascular occlusion
- Most common complications of SCD: acute chest syndrome, CVA, VTE (DVT, PE), pain crisis, ARF, sickle cell nephropathy, renal papillary necrosis, acute on chronic anemia, avascular necrosis, priapism, PH, hepatobiliary complications
- Diagnosis: Anemia on CBC, Hgb electrophoresis, periph blood smear

Evaluation - Labs: LDH (high), Hgb/Hct (low; check vs baseline), retic, smear, WBC
- If febrile: UA + Blood cultures
- Send Hgb S level, and compare to baseline w/ other hospital admissions
- Imaging: CXR, MRI for hip pain, Abdominal U/S or CT abdomen
- Maintain active type and cross given probability of antibodies

Management - Health Maintenance: * BP goal \<130/80
* consider hydroxyurea (reduces pain crises and ACS, improves QOL)
* proteinuria screens (for Sickle cell nephropathy), screen for s/s of respiratory symptoms (PH)
* Ensure uptodate on asplenia vaccinations: (SHiN) strep pneumo, H Flu, N meningitidis, COVID, flu - See table below for specific pathways for most common complications
- General management plans for almost all patients: * O2: * maintain high O2 goals (goal sat \~95% (higher O2 goal will help to prevent further sickling!) - Anemia: * Transfuse:
* If Hgb \<10, simple transfusion is appropriate to goal >10 (no higher than 11 due to risk of hyperviscosity) * Avoid transfusions when able, given risk of antibody formation
* Order RBC extended phenotype for minor RBC antigens to avoid immunization and Ab development to these proteins
* Match for Rh and K antigens
* Maintain low HbS% to reduce stroke - Continue folic acid 1 mg qDay
- Continue hydroxyurea if uncomplicated pain crisis * Hold if counts suppressed or concern for infection - Pain: Aggressively treat pain * Look for a care coordination yellow note in the Summary Tab; (heme clinic will have specific management preferences for individual patients)
* Will generally require opiates, likely initiation of PCA
* All SS patients should have pain plans; inpatient pain plans are in the problem list under sickle cell disease or in the care coordination section of Epic
* Outpatient plans (to which you will transition pts back prior to discharge) are not standardized in location, but can be under Media (with a pain contract) or found in notes

*Recommendations by ASH (2019)

Complication Signs/Sx Pathogenesis Workup Management
Acute Chest Syndrome (PNA, intrapulmonary sickling, pulmonary fat embolism) ACS \= new radiodensity on chest imaging AND either fever +/- respiratory symptoms (hypoxia, tachypnea, cough, chest pain) - of note, infiltrate on CXR may initially be negative, absence does not eliminate possibility Vaso-occlusion in pulmonary microvasculature. Precipitants: infection (PNA - chlamydia, bacteria, mycoplasma), pulmonary infarction, PE, fat embolism, and pain crisis \=> deoxygenation \=> sickling \=> vaso-oclusion CBC, CXR, assess pain, examine for bone pain in back or chest, assess for s/s DVT, assess for indwelling catheter Other: consider CTAPE, ECG 1. Consult heme
2. Supplemental O2 (>95%)
3. D5 ½ NS @ 150-250cc/hr (caution to avoid pulmonary edema)
4. Transfuse to Hgb 10
5. Pain control: see pt’s pain plan, consider PCA
6. Immediate Abx – CAP coverage (vs HAP if risk factors) [3rd gen cephalosporin + macrolide]
TIA Or Stroke Focal seizures, hemiparesis, speech deficit, any new neurologic insult Chronic vasooclusion \=> endothelial damage \=> Intimal hyperplasia \=> vascular stenosis + occlusion of vasculature by sickle cells. Vascular + oxidative injury \=> activation of coagulation cascade.
*O2 delivery to the brain is dependent on total Hgb concentration and % of HbS (transfusion goal of Hgb 10, HbS 15-20%)		 1. STAT non-con CTH to assess for hemorrhage vs moyamoya vasculopathy vs LVO
2. CBC
3. MRI		 For sx onset \<4-5h:
1. Prompt blood transfusion (simple, exchange, or apheresis) within 2 hours*. If Hgb \<8.5, simple transfusion to goal >10 (followed by apheresis). If Hgb >8.5, consider apheresis (decrease possibility of hyperviscosity syndrome*)
2. If hemorrhage on CTH \=> c/s heme and NSG
3. If no moyamoya vasculopathy, but LVO present \=> eval for thrombectomy + simple transfusion to achieve Hgb 10, exchange transfusion to reach Hgb S level 15-20%*
4. If moyamoya vasculopathy, simple transfusion to achieve Hgb 10, exchange transfusion to reach Hgb S level 15-20%*

For 24-72H onset: O2, transfuse for Hgb >10 and exchange transfusion for Hb S 15-20%
Aplastic crisis Sx: Dyspnea, weakness, fatigue Signs: tachycardia, pallor, acute drop in Hgb low reticulocyte count, non-palpable spleen, functional systolic murmur Parvovirus B19 infection \=> transient arrest of erythropoiesis (lasts 2-14 days) Trend CBC (often \<6) and reticulocyte count (often \<1.0%) 1.C/s benign heme
2. Blood transfusion
Splenic sequestration crisis LUQ pain, hypotension, acute-onset severe hemolytic anemia Occlusion of splenic vessels \=> pooling of RBC within spleen Reticulocyte count (high vs in aplastic crisis would be low) 1. C/s benign heme
2. IVF
3. Consider simple blood transfusion
Pain crisis/vaso-occlusive Crisis Typically acute, localized, severe pain, can be gradual Triggers: stress, exposure to cold, infectious illness VS, CBC, is pain typical or in new area, CXR Rule out can’t miss diagnoses (acute chest, multiorgan failure, CVA, PE) 1.Aggressive, prompt pain mx: opioids, NSAIDs (reference pain plan in EPIC)
2.Encourage PO intake, if cannot consider IVF
3. supplemental O2
4. consider transfusion if Hgb drop >2 and low RC
Osteonecrosis/Avascular necrosis (most often hip, sometimes shoulder) Chronic groin/hip/buttock/thigh pain with weight bearing that progresses to occurring at rest Sickling \=> disruption of bone microcirculation and increased intraosseous pressure due to bone marrow hyperplasia \=> end artery occlusion \=> necrosis PEx: pain and limited ROM with internal rotation and abduction of hip Labs: normal WBC ct, ESR, CRP Imaging: Xray (may appear normal early on), MRI 1. Pain control
2. Consider outpatient ortho referral
3. hydroxyurea if not already on
Osteomyelitis Fever, leg pain (often in pt w hx of bone infarction, avascular necrosis, or gastroenteritis) Low blood flow \=> microinfarctions \=> nidus for infection Asplenia \=> staph aureus and salmonella CBC, CT/MRI, blood/bone cultures 1. Cultures
2. Antistaph therapy + 3rd-gen cephalosporin for salmonella coverage
Splenic infarct Acute LUQ pain Stressor (high altitude, hypoxia, dehydration) \=> splenic artery occlusion CBC, Retic Ct, Tbili and DBili Abdominal U/S 1. Hydration, supplemental 2, analgesia
2. Consider future splenectomy (may recur), monitor for development of splenic abscess
Priapism Sustained unwanted painful erection lasting >4 hours Most often due to low-flow priapism (thought due to sickling of RBCs in venous sinuses \=> high pressure and prevention of outflow) History (precipitating factors: dehydration or medications), Physical exam, CBC and retic count, possible duplex U/S 1. emergent urology c/s for sympathomimetic injection vs aspiration vs shunt
2. analgesia
3. IVF if dehydrated, O2 if hypoxic
4. Hydroxyurea outpatient
Renal papillary necrosis Macroscopic hematuria +/- flank pain Often patient has sickle cell nephropathy Decreased O2 in renal medulla \=> sickling \=> RPN \=> hematuria U/A with microscopy, Creatinine, renal imaging 1. microscopic hematuria \=> hydration
2. Macroscopic hematuria – bedrest and aggressive hydration
3. consider exchange blood tx to lower %HbS
4. Outpatient start hydroxyurea for SCN (reduce proteinuria, delay/prevent CKD)

Sickle Cell Pain Crisis

Background - Present with severe pain in bone, joints, chest, abdomen
- Causes: (HIDISC) Hypoxia, Ischemia, Dehydration, Infection, Stress, Cold
- Can’t miss:
* Acute chest: new infiltrate on CXR + another clinical symptom (fever, chest pain, hypoxia). Consult Benign Hematology immediately. Do not wait until the next day.
* PE (ACS less likely in these pts), avascular necrosis of hip, priapism, stroke

Evaluation - Labs: ↑ LDH, Hgb/Hct (low; check versus baseline), retic, smear, WBC
- If febrile: UA + blood cultures
- Hgb S level only in certain circumstances (e.g. guides treatment in acute chest)
- Imaging: CXR, MRI for hip pain, abdominal U/S or CT abdomen
- Maintain active type and cross given probability of alloimmunization

Management - General
* Look for a care coordination yellow note in the Summary Tab
* Heme clinic will have specific management preferences for individual pts
* Maintain hydration, IVF at 150-200 cc/hr (if no contraindication)
* Oxygen: goal sat \~95% (higher O2 goal will help to prevent further sickling)
* Continue folic acid 1 mg QD
* Continue hydroxyurea if uncomplicated pain crisis
* Hold if counts suppressed or concern for infection
* If in the MICU: consider discussion for plasma exchange (if Hgb SS or SC or S-Thal)
* Transfuse: Simple transfusion if Hgb lower than baseline and/or complications
* Avoid transfusions when able, given risk of antibody formation
- Pain
* Will generally require opiates, often initiation of PCA
* All SS pts should have pain plans. Inpt pain plans are in the problem list under sickle cell disease or in the care coordination section of Epic
* Outpt plans (to which you will transition pts back prior to discharge) are not standardized in location, but can be under Media (with a pain contract) or found in notes - Acute chest:
* Consult Hematology at time of admission
* Obtain HbS level
* Avoid dehydration. Consider LR @ 125-200 cc/hr but caution with overhydration (may worsen pulmonary edema)
* Incentive spirometry: atelectasis and hypoxia drive V/Q mismatching and further sickling
* Transfuse hgb to goal of 10 (do not exceed to avoid hyperviscosity)
* Pain control per pain plan
* Consider Abx for CAP (vs HAP if risk factors)
* Plasma exchange for moderate-severe cases (driven by hematology)

Lymphoma

Author: AJ Winer

Background - Definition: malignant disorder of lymphoid cells that reside mostly in lymphoid tissues
- Generally categorized as Hodgkin lymphoma (HL) / non-Hodgkin lymphoma (NHL)
Clinical Manifestations: Classically characterized by lymphadenopathy (usually nontender) & constitutional “B” symptoms (fevers, drenching sweats, weight loss).
- HL (10%): superficial nodal disease with orderly, anatomic spread to adjacent nodes
- NHL (90%): diffuse nodal +/- extranodal disease with non-contiguous spread
Diagnostic and staging evaluation:
- Physical Exam:
* LN (painless, firm, fixed, >1cm), head and neck, tonsils, axilla, testes, liver, spleen
- Lab tests:
* CBC, CMP, LDH, uric acid, phosphorus
* Consider HBV panel, HCV, HIV, EBV, Quant gold, treponemal Ab, ANA
- Imaging:
* CT chest, abdomen, pelvis; most will eventually need PET-CT to assess extent of disease and guide bx/therapy; MRI brain if neuro symptoms
- Pathology: diagnosis requires tissue (excisional preferred to see tissue architecture):
* Excisional lymph node biopsy: Surgical Oncology, EGS, or ENT consult
* Core biopsy: CT guided procedure consult
* Of note, steroids may impact value of biopsy results
- LP: consider for NHL with high risk of CNS involvement or presence of neurological sx
* Risk factors: Burkitt, lymphoblastic, testicular involvement, double/triple hit
* Multiple LPs may be required to diagnose CNS lymphoma
- Staging: Lugano Classification
* I. 1 LN region or single extra lymphatic organ/site without nodal involvement
* II. >2 LN regions, same side of diaphragm
* III. LN regions on both sides of diaphragm
* IV. Disseminated disease w/ 1+ extra lymphatic organ

General Management: - ECG and TTE to establish pre-chemo cardiac function—many regimens with anthracyclines
- Daily labs: CBC, TLS, LDH
- TLS prophylaxis: mIVF, allopurinol
- Treatment: see below

HL vs. NHL

Features HL (10%) NHL (90%)
Epidemiology Bimodal distribution: 15-35 years and >50 years; M>F Average 65 years, M>F, 85-90% B-cell
Histology CD15+, CD30+ (Reed Sternberg cells “owl eyes”) Varies, but majority involve B cells (can also be T cell, NK cell)
Associations EBV in immunocompromised Associated with immunodeficiency (HIV, post-transplant), autoimmune disease, infection (EBV, HTLV-1, H pylori, HCV, Borrelia, C psittacosis, Coxiella)
Lymph Node Pattern Contiguous LN spread Noncontiguous LN spread
Subtypes - Classical Hodgkin (95% - nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depleted)
- Nodular Lymphocyte-predominant (5%)		 DLBCL, Follicular, MALT, Mantle cell, Burkitt, Hairy cell, Marginal Zone, T-Cell (mycosis fungoides/Sezary), CLL/SLL, other
Prognosis - Generally better (more curable)
- IPS negative prognostic calculator: albumin \<4, hemoglobin \<10.5, male, stage IV disease, age>45, WBC count> 15K, lymphocyte \<8% of WBC count		 - Generally worse (less curable)
- Good prognosis: Follicular, marginal zone, mycosis fungoides/Sezary syndrome
- Poor prognosis: DLBCL – can arise from low grade lymphoma (Richter transformation); Double/Triple hit: bcl-2, bcl-6, or myc aberrations; mantle cell, Burkitt, lymphoblastic lymphoma, and anaplastic large cell lymphoma
Common Treatment Regimens ABVD + radiation (early stage), Nivo-AVD (advanced stage) R-CHOP, R-EPOCH, Hyper-CVAD, HD-MTX + R

Common Chemotherapy Regimens for Lymphoma:

Regimen Components Use
R-CHOP rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone NHL
R-EPOCH etoposide plus the drugs above (inpatient administration with 4 days continuous infusion followed by pushes of chemotherapy on Day 5) NHL (Double/Triple hit)
Hyper-CVAD cyclophosphamide, vincristine, doxorubicin, and dexamethasone (requires inpatient admission given BID dosing of cyclophosphamide and continuous mesna to prevent hemorrhagic cystitis) NHL
HD-MTX + R high dose methotrexate + rituximab (requires inpatient admission to follow MTX clearance and alkalize urine with continuous bicarb infusion) Primary CNS Lymphoma
ABVD doxorubicin, bleomycin, vinblastine, dacarbazine HL
Nivo-AVD Nivolumab, doxorubicin, vinblastine, dacarbazine HL

Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Definition: - CLL is a disease of monoclonal, functionally incompetent mature B lymphocytes
- CLL and SLL are different manifestations of the same disease and are distinguished by the distribution of lymphocytes. CLL is mostly in peripheral blood whereas SLL is mostly in lymph nodes and patients often present with both. Treatment plans are identical.
- CLL: >5000/uL malignant cells on peripheral smear
- SLL: \<5000/uL cells + LAN +/- splenomegaly

Epidemiology: - 15,000 new cases per year; median age at dx is 71

Manifestations: - Most often asymptomatic, identified by lymphocytosis on CBC.
- 10-20% have B symptoms, LAN in 80%, HSM in 50%, AIHA in 10%, 1-2% have ITP.
- Increased susceptibility to infections due to hypogammaglobulinemia from abnl B-cells
- 5% patients develop aggressive transformation into high-grade lymphoma (Richter’s)

Diagnostic Evaluation: - CBC with diff (B-cell count), peripheral smear (lymphocytosis, smudge cells)
- Flow cytometry: clonality with dim surface Ig CD5+, CD19+, CD20+, CD23+
- Bone marrow biopsy is not required for diagnosis but may be normo or hypercellular
- Genetics: del 11q22-23 and del(17p) are unfavorable; trisomy 12 is neutral; del 13q14 and mutation IGHV is favorable

Staging and Prognosis

Risk Status Modified Rai System Binet System
Low Risk Rai Stage 0: Lymphocytosis Binet Stage A: \<3 involved nodal areas
Intermediate Risk Rai Stage I: Lymphocytosis + LAN
Rai Stage II: Lymphocytosis + Splenomegaly and/or hepatomegaly		 Binet Stage B: >/=3 involved nodal areas
High Risk Rai Stage III: Lymphocytosis + Hgb \<11 g/dL
Rai Stage IV: Lymphocytosis + Plt \<10 x 104 g/uL		 Binet Stage C: Hgb \<10 g/dL and/or Plt \<10 x 104 g/uL

Treatment: - Observation unless “active disease” (B symptoms, symptomatic adenopathy, cytopenias, lymphocyte doubling time \< 6 months)
- First line: if no del(17p)/TP53 use BTK inhibitor until disease progression (indefinite), venetoclax+obinutuzumab (fixed duration 12 months), or BTK inhibitor + venetoclax (fixed duration 14 months); if + del(17p)/TP53, use BTK inhibitor (longest duration of response) or venetoclax + obinutuzumab (shorter duration of response
- HSCT is the only curative treatment but rarely used given excellent prognosis with current treatments

Clonal Hematopoiesis (CH)

Author: James Brogan

Background - Clonal hematopoiesis (CH) refers to the expansion of blood cells derived from a single hematopoietic stem cell (HSC) with somatic mutations
- CH can be driven by point mutations or structural variants
- CH is common in the elderly and is a premalignant state, as the somatic mutations detected in CH can lead to myeloid neoplasms such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)

  • Clonal hematopoiesis of indeterminate potential (CHIP): the presence of somatic mutations in leukemia driver genes at a VAF of ≥ 2% without meeting the criteria for hematologic malignancy
  • CHIP is associated with a 0.5% to 1% annual risk of progression to hematologic malignancy and increases the risk of cardiovascular events due to a proinflammatory state
  • Clonal cytopenia of undetermined significance (CCUS): the combination of unexplained cytopenia(s) and somatic mutations without marrow dysplasia or other diagnostic criteria for hematologic malignancies
  • CCUS carries a higher risk of progression to myeloid neoplasms compared to CHIP, particularly in cases featuring high-risk mutations
  • Idiopathic cytopenia of undetermined significance (ICUS): the presence of one or more cytopenias with no identifiable mutation or other cause

Presentation - Patients with CHIP are often asymptomatic and identified incidentally during genetic testing
- CCUS patients present with unexplained cytopenias but do not meet criteria for MDS or other hematologic malignancies
- CHIP and CCUS are associated with an increased risk of progression to myeloid neoplasms and non-hematologic complications such as cardiovascular disease (atherosclerosis, myocardial infarction and stroke) and renal disease
- Clinical pearl: consider CH-related disorders in patients with premature or unexplained cardiovascular disease, as the inflammatory effects of clonal hematopoiesis can accelerate atherosclerosis independent of traditional risk factors

Evaluation - Routine screening with next-generation sequencing (NGS) is not currently recommended for asymptomatic individuals
- Genetic testing may be considered in patients with unexplained cytopenias or during the evaluation for other hematologic conditions
- Screening for CH-related disorders typically involves NGS to detect somatic mutations in genes such as DNMT3A, TET2, and ASXL1
- Additional tests may include cytogenetic analysis and flow cytometry to rule out other hematologic malignancies
- Risk calculators, such as the Clonal Hematopoiesis Risk Score (CHRS), can stratify patients into low, intermediate or high risk

High-Risk Features for Progression from Clonal Hematopoiesis to Myeloid Neoplasm

Category Risk Factor Significance
Demographics Age ≥ 65 years Older patients have higher risk of progression
Hematologic parameters Red cell distribution width ≥ 15% Indicates altered erythropoiesis
Mean cell volume ≥ 100 femtoliters Macrocytosis suggests dyserythropoiesis
Presence of any cytopenia Suggests early bone marrow dysfunction
Mutation characteristics Variant allele frequency ≥ 20% Higher allele frequency suggests greater clonal dominance
≥ 2 mutations in leukemia driver genes Multiple mutations indicate more advanced clonal evolution
Specific mutations Splicing factor mutations (SRSF2, SF3B1, ZRSR2) Associated with higher risk of progression to MDS/AML
TP53 mutations Associated with myeloid neoplasms secondary to cancer treatment and poor outcomes
IDH1/2 mutations Higher risk of progression to AML
Clinical context Prior chemotherapy or radiation exposure Therapy-related CH has higher progression risk
Serial monitoring Increasing variant allele frequency over time Suggests active clonal expansion
Acquisition of new mutations Indicates ongoing genomic instability

Risk Stratification and Prognosis per CHRS

Risk Category Percentage of CH Patients 10-Year Risk of Myeloid Neoplasm
Low risk 90% \~0.6%
Intermediate risk 9% \~8%
High risk 1% \~30%

Management - Patients with CH-related disorders should undergo periodic CBC and clinical evaluation; however, there are no current guidelines for the frequency of evaluation
- Those with CCUS require closer surveillance due to a higher risk of progression to hematologic malignancy
- Lifestyle modifications and management of cardiovascular risk factors are crucial
- Currently, there are no FDA-approved therapies for CH-related disorders

Myelodysplastic Syndromes (MDS)

Author: Peter Hanna

Background - MDS is a malignant clonal myeloid disorder resulting in ineffective (dysplastic) hematopoiesis leading to peripheral cytopenias and a risk of transformation to acute myeloid leukemia (AML)
- Usually idiopathic, a disease of the elderly (median onset at age 70)
- The WHO has several classification schemes for MDS
* Most important for classification is the percent of blasts in the bone marrow
* Note >20% blasts in marrow \= AML. Thus MDS and AML are on a continuum

Presentation - 50% asymptomatic; symptoms can include nonspecific but gradual fatigue, weakness
- Dysplastic cells do not work properly 🡪 infections and bleeding are more likely
- Macrocytic anemia is most common finding; followed by bicytopenia or pancytopenia
- Isolated neutropenia or thrombocytopenia are unusual but possible
- Ask about secondary causes
* Exposure to chemicals (benzene, crude oil/gasoline industry, cigarette smoke), chemotherapy, radiation
* Medications, alcohol use, chronic infections (HIV)

Evaluation - Goal is to rule out reversible causes of dysplasia and cytopenias
- CBC w/differential, peripheral smear, B12, folate, HIV
* Consider copper and zinc
- Dysplastic changes on peripheral smear: hypogranulated/hyposegmented neutrophils, hypogranulated platelets and macrocytosis of RBCs
* Circulating myeloblasts can be seen
- Final diagnosis requires bone marrow biopsy

Management - Molecular characteristics define the “risk” of the disease and dictates treatments
- Prognostic scoring tools: revised international prognostic staging system (R-IPSS)
- Management general paradigm
* Asymptomatic: with low-risk disease: monitoring
* Low-risk disease + symptoms due to anemia only: transfusions, erythrocyte stimulating agents, and treatment with Luspatercept
* MDS with isolated del(5q): treated with lenalidomide
* High-risk pts: treated with hypomethylating agents
* Only curative intervention: hematopoietic stem cell transplant (HSCT)

Acute Leukemia

Author: AJ Winer

Background

  • Definition of Acute Leukemia: hematological malignancy caused by clonal proliferation of blasts (WBC precursors) in the bone marrow
  • Types:
  • Acute Myeloid Leukemia (AML): neoplastic accumulation of immature myeloid cells in the bone marrow
  • AML includes subtype Acute Promyelocytic Leukemia, defined by the translocation (15;17) PML-RARA

  • Acute Lymphoblastic Leukemia (ALL): neoplastic accumulation of immature lymphoblasts in the bone marrow

    • Includes subtypes B-ALL and T-ALL

  • Exposure: radiation, chemo (alkylating agents), smoking, benzene

  • Secondary to acquired condition: MDS, MPN, HIV, aplastic anemia, Down Syndrome

Presentation: - Symptoms - related to cytopenias: * Anemia: fatigue, pallor, dyspnea
* Functional leukopenia/neutropenia: recurrent infection
* Thrombocytopenia: gingival bleeding, epistaxis, petechiae, ecchymoses, menorrhagia
* Leukocytosis: leukemia cutis, gingival hypertrophy, leukostasis
* Extramedullary hematopoiesis: splenomegaly, hepatomegaly, lymphadenopathy

  • Oncologic Emergencies related to leukemia:
  • See oncologic emergencies for more in depth discussion, but can present with leukostasis (blast >50k, low SaO2, HA, blurry vision, neurologic sx), TLS (from rapid cell turnover), DIC (esp APL), differentiation syndrome (see section below)

Evaluation:

  • Initial studies (peripheral blood)
  • peripheral smear, search for Auer rods and schistocytes
  • Fibrinogen, PT/PTT, haptoglobin to survey for DIC
  • If high concern for AML, can send a peripheral blood FISH for 15:17 translocation (PML-RARa), cinch APL diagnosis quickly

  • immunophenotyping by flow cytometry (assess cell-surface and cytoplasmic markers: CDxx),

  • Definitive studies (done on bone marrow biopsy):

  • immunophenotyping by flow cytometry (assess cell-surface and cytoplasmic markers: CDxx),
  • genetic and mutational analysis (assess for therapeutic targets - FLT3, IDH1, etc)

  • Cytogenetic analysis (screening for gene rearrangements - PML::RARA, BCR::ABL1, etc)

  • Diagnosis of acute leukemia requires one of the following:

  • Traditionally, required 20% blasts in peripheral blood, 20% blasts in bone marrow, any pathognomonic cytogenetic abnormality of t(8;21), inv(16), t(15;17)
  • Now, for certain recurrent genetic lesions, ≥10% blasts in bone marrow or blood now indicate AML (ie AML with recurrent genetic abnormalities, AML with mutated TP53, AML with myelodysplasia-related gene mutations, etc - see ELN guidelines)
  • Exclusions to above include AML with BCR::ABL1 which requires >/=20% blasts to avoid overlap with CML in accelerated phase, among others

Management:

  • Once diagnosis is established and patient admitted to Brittingham, they will need the following:
  • Hematology admission order set
  • TLS labs q8
  • Blood product consent on admission, set RBC and Plt transfusion thresholds
  • Infectious workup if neutropenic and febrile
  • Nurse-driven electrolyte repletion
  • ECG and TTE to establish pre-chemotherapy cardiac function
  • Double lumen PICC line for chemotherapy induction if indicated
  • Daily labs: CBC, TLS, DIC
  • Bone marrow cytogenetics and flow cytometry for immunophenotype

  • LP if clinical sx suspicious of CNS involvement or if c/f ALL

  • Emergent complications of leukemia and their labs to consider:

  • DIC – check fibrinogen, PT, PTT, platelets
  • TLS – check uric acid, phosphate, K+
  • Neutropenic fever – check temp, neutrophil count, BCx

  • Leukostasis (see below)

  • Induction Therapy

  • General strategy: “induction” chemo to try to induce clinicopathologic (as opposed to molecular) “remission” \= complete remission (CR). CR is absence of symptoms, normal CBC (ANC >10k, Plt >100), and \<5% blasts in bone marrow (on day 28)
  • The choice of therapy is often affected by patient fitness, which is affected by age, presence of serious comorbidity, and functional status as measured by the ECOG scale. For instance, while a “fit” patient with AML might receive 7+3 induction therapy, patients who are older than 75, have an ECOG 4>, or patients with cardiopulmonary disease would more likely receive a regimen like azacytidine/venetoclax.
  • response is assessed with bone marrow biopsy, usually on Day 14
  • Patients stay in the hospital after induction, until their cytopenias recover (generally until neutrophil count >500)
  • From there, bone marrow transplant (for high-risk disease) or “consolidation” chemo for normal-risk or low-risk disease

Acute Myelogenous Leukemia

Background - Definition: abnormal proliferation of myeloblasts in BM or peripheral smear
- 80% of acute leukemias in adults are AML
- Classification: * Features used to confirm myeloid lineage and subclassify AML to guide treatment: morphology: blasts, granules, auer rods
* Immunophenotype: * precursor: CD34, CD45, HLA-DR
* Myeloid: CD13, CD33, CD117
* Monocyte: CD11b, CD64, CD14, CD15 * Prognosis: age, prior antecedent MPN/MDS, and genetics (cytogenetics + molecular mutation status) are independent risk factors of poor prognosis

  • European Leukemia Net (ELN) Genetic Risk classification:
Risk category Genetic Abnormality
Favorable APL: t(15;17); PML-RARa; t(8;21): RUNX1-RUNX1T1; inv(16): CBFB-MYH1; mutated NPM1 w/o FLT3-ITD or w/ FLT3-ITDlow*; biallelic mutation in CEBPA
Intermediate FLT3-ITDlow*; mutated NPM1 & FLT3-ITDhigh*; t(9;11): MLL- MLLT3; cytogenetic abnl not classified as favorable or adverse, including normal karyotype w/o mutations in FLT3-ITD & NPM1
Adverse -5 or del(5q); -7; -17/abn(17p); complex or monosomal karyotype; t(6;9): DEK-NUP214; t(9;22) BCR-ABL1; inv(3): GATA2- MECOM; wildtype NPM1 & FLT-ITD high*; mutated TP53, RUNX1, ASXL

Treatment:

  • Induction chemotherapy:
  • Based on patient fitness:
  • Typical is “7+3”: idarubicin on days 1-3 + cytarabine on days 1-7
  • Patients with poor fitness often receive hypomethylating agent (HMA) therapy with azacytidine or decitabine with Venetoclax.
  • If therapy-related AML, MDS-related AML, or AML with cytogenetics similar to MDS, use “Vyxeos” which is liposomal daunorubicin and cytarabine on days 1, 3, and 5
  • If favorable-risk dz (t(8;21) or inv(16)), use cytarabine on days 1-7, and 3 days of low-dose daunorubicin + gemtuzumab-ozogamicin

Acute Promyelocytic Leukemia (APL)

  • Definition: translocation of retinoic acid receptor: t(15;17) PML-RARA
  • Specific findings: promyelocytes on differential or Auer rods on smear

Treatment: depends on whether pt is high risk or non-high-risk, but for both, give ATRA + Arsenic Trioxide (ATO) to induce differentiation of blasts

  • Non-high-risk APL: ATRA + ATO (Induction + 4c consolidation)
  • High-risk APL: WBC >10k. Often chemo along with ATRA + ATO

Complications that can arise: DIC and differentiation syndrome

  • Differentiation syndrome:
  • Mechanism: promyelocytes will differentiate from ATRA resulting in a constellation of life-threatening complications
  • Complications include Pulmonary edema, subarachnoid hemorrhage, hypotension
  • Risk is higher with higher WBC counts before ATRA (above 20,000 especially)
  • Management: dexamethasone 10mg BID, supportive care. If critically ill, hold ATRA and ATO and consider hydroxyurea

Acute lymphogenous Leukemia

Classification:

  • Lymphoblastic neoplasms may present as:
  • ALL with >20% BM blasts
  • Lymphoblastic lymphoma with mass lesion and \<20% BM blast
  • No granules seen
  • +TdT seen in 95% of ALL
  • Lumbar puncture is performed, with co-administration of intrathecal chemo

Treatment: - Induction: * Typical induction is “HyperCVAD” (hyper-fractionated cyclophosphamide, vincristine, doxorubicin (“A” due to trade name Adriamycin), and dexamethasone
* If t(9;22) (known as Philadelphia chromosome), use tyrosine kinase inhibitor (TKI)
* If CD20+, use rituximab - Sometimes will do CNS ppx, especially if prior to BMBx
- Note that many of these regimens are adapted from Pediatric treatment protocols
- Post-remission choice of chemo depends on risk of recurrence and monitor for relapse/refractory

Overview of Common Chemotherapy Regimens:

Regimen Components Use
7+3 Cytarabine (Ara-C) x 7 d and anthracycline (e.g. idarubicin x3 d) AML Induction
Vyxeos Cytarabine + liposomal daunorubicin AML-MRC or t-AML
CLAG-M Cladribine, cytarabine (Ara-C), Filgrastim (G-CSF), mitoxantrone AML induction (relapsed/refractory)
HIDAC high-dose cytarabine AML consolidation
ATRA All-trans retinoic acid given with arsenic trioxide (ATO) APML
HyperCVAD/MA CVAD \= Cyclophosphamide, vincristine, doxorubicin, dexamethasone MA \= methotrexate/cytarabine  (Given as alternating cycles) ALL
R-CHOP rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone NHL
R-EPOCH etoposide + rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone NHL
ABVD doxorubicin, bleomycin, vinblastine, dacarbazine HL

Plasma Cell Dyscrasias

Authors: Rahul Shah, Jennifer Marvin-Peek, Michael Kaminski

Background

  • Benign, pre-malignant, and malignant conditions with clonal proliferation of plasma cells or B cells that MAY produce monoclonal Igs detected in serum and/or urine
  • Conditions include:
  • Monoclonal gammopathy of undetermined significance (MGUS)
  • Smoldering Multiple Myeloma (SMM)
  • Multiple Myeloma (MM)
  • Plasmacytoma
  • Waldenstrom’s Macroglobulinemia (WM)
  • Amyloidosis

  • POEMS Syndrome

  • NOTE MGUS, SMM, and MM represent a disease progression

  • Complications either 2/2 malignant plasma cells or their Ig product
  • Elevated protein gap (serum total protein – albumin > 4) often prompts work-up
  • Symptoms reflect underlying organ disorder 2/2 malignant cells or Ig product
  • Fatigue, weakness 2/2 anemia
  • Bone pain 2/2 lytic lesions or malignant fractures
  • Paresthesias, neuropathy 2/2 direct neuronal toxicity from Igs
  • Visual disturbances 2/2 hyper-viscosity
  • Fever, lymphadenopathy possibly 2/2 infection resulting from immunosuppression
Symptoms Signs
Fatigue, weakness, weight loss
Bone pain
Paresthesias, neuropathy, radiculopathy
Visual disturbances (if hyperviscosity present)
Lymphadenopathy (uncommon)
Fever (uncommon)		 Anemia (Hgb \<10)
Renal insufficiency (Cr > 2)
Hypercalcemia (Ca > 11.5)
Elevated protein gap (Total protein - Alb > 4)
Osteolytic bone lesions (typically central)
Unexplained heavy proteinuria
Rouleux formation on blood smear

Evaluation

  • CBC w/ diff, peripheral blood smear, CMP (esp Creat, Ca, Alb)
  • Serum Protein Electrophoresis (SPEP): detects and quantifies M-protein, ie monoclonal Ig from abnormal clonal B/plasma cell
  • Serum Immunofixation (SIF): Identifies monoclonal vs polyclonal M protein and type (IgG/A/M/D/E, kappa/lambda), whether heavy or light chain only
  • UPEP/UIF-detects Bence Jones protein/urine monoclonal kappa or lambda light chain
  • Quantitative Igs: quantifies total IgG, IgM, IgA, IgD, IgE
  • LDH and B2 microglobulin
  • Consider UA: detects albumin, not light chains so will be negative in cast nephropathy (Bence-Jones proteinuria) but may be positive in AL amyloid with nephrotic syndrome
  • Skeletal imaging to identify bone lesions: CT/PET-CT/MRI preferred over X rays
  • BM Biopsy If CRAB criteria (Calcium>11, Renal Impairment/Cr>2, Anemia/Hb\<10, Bone lesions on imaging), M-protein >1.5, non-IgG M-spike, or very abnormal FLC
  • If considering amyloidosis >> abdominal wall fat pad biopsy with Congo red staining typically sufficient vs. direct biopsy of amyloid-involved tissue

Additional Tips for Lab Interpretation | | | | | :---: | :---: | :---: | | SPEP/UPEP | Free light chains (FLC) | Urinalysis | | Initial screening test to look and quantify M-protein
Serum immunofixation determines clonality (e.g. mono or polyclonal)
  Monoclonal spike >1.5 is indicative of underlying dyscrasia
  Polyclonal spike suggests infectious, inflammatory, or reactive etiology | Ratio of kappa/lambda >3 highly suggestive of plasma cell dyscrasia or amyloidosis  
Ratio 1.65 to 3 can be due to infectious process or renal insufficiency
  Helpful in pts that only produce Bence-Jones protein (FLC w/o heavy chain) which isn’t seen on SPEP | Detects albumin, not light chains
In myeloma cast nephropathy, dipstick will be negative since proteinuria is from FLC (i.e. Bence-Jones proteinuria)
In AL amyloid, dipstick will be positive 2/2 albumin loss from nephrotic syndrome |

MGUS SMM MM
% Plasma Cells in BM \<10% 10-60% ≥ 10% (typically >30%)
Monoclonal Protein IgG, IgA, IgM: 1.5 -3 IgG or IgA >3 IgG or IgA >3
Laboratory studies Normal Hgb, Ca, Cr Normal Hgb, Ca, Cr ↓Hgb, ↑Ca, ↑Cr
Symptoms None None Lytic bone lesions, fatigue
Prognosis 1% / year progression to MM 10% / year progression to MM R-ISS staging (see below)
Monitoring and/or Treatment Monitoring only: Symptom check SPEP, FLC, CBC, BMP Usually monitoring, repeat SPEP, FLC, CBC, BMP Yearly skeletal survey Chemotherapy, plus SCT for eligible pts

Monoclonal Gammopathy of Unknown Significance (MGUS)

  • Pathophysiology: Asymptomatic, premalignant clonal neoplastic plasma cells in bone marrow with monoclonal Igs +/- abnormal free light chains

  • NOTE: sometimes paraprotein can cause symptoms in skin, nerves, kidneys, ie monoclonal gammopathy of clinical significance

  • Common, especially in elderly-prevalence >4% in 40+ year olds, >10% in 80+ year olds

  • Subdivided into non-IgM MGUS which may progress into MM, IgM MGUS which may progress into WM, and light chain MGUS which may progress into light chain MM
  • Risk of progression for non-IgM MGUS \~1%, higher if M-protein >1.5 g/dL and/or abnormal free light chain ratio
  • Dx Criteria:
  • Non-IgM MGUS: Serum monoclonal protein (IgG, IgA, IgD) \<3 g/L, clonal BM plasma cells \<10%, no CRAB SLiM
  • IgM MGUS: Serum monoclonal protein (IgM) \<3 g/L, clonal BM plasma cells \<10%, no anemia, hyperviscocity, LAD, HSM

  • Light Chain MGUS: + abnormal FLC ratio, increased level of involved free light chain, no monoclonal heavy chain, clonal BM plasma cells \<10%, no CRAB SLiM

  • Tx: No treatment. Risk stratify to determine monitoring strategy using 1. serum M protein level >1.5, 2. non-IgG MGUS, 3. abnormal FLC ratio (\<0.26 OR >1.65). Also monitor for complications including fractures, infection, blood clots

  • 0/3: repeat SPEP, FLC, CBC, CMP at 6M then Q2-3Y, +/- BMBx and imaging
  • Everyone else: BMBx and low dose whole body CT at diagnosis; repeat SPEP, FLC, CBC, CMP at 6M then Q2-3

Smoldering Multiple Myeloma (SMM)

  • Part of the continuum of MGUS > SMM > MM
  • Approximately 10% risk of progression to MM per year
  • Dx: M protein >3 g/dL and/or clonal plasma cells 10-60% on BMBx but no CRAB-SLiM

  • Risk stratify: high risk if M protein >2 g/dL, FLCr >20, plasma cells>20%

  • Tx: observe low-risk disease (repeat labs Q3-6M); high risk disease: maybe clinical trial vs monotherapy with daratumumab or lenalidomide vs lenalidomide plus dex

Multiple Myeloma (MM)

  • Neoplastic proliferation of plasma cells that produce monoclonal Ig (“M protein”)
  • S/Sxs from effects of plasma cells (bone pain, fractures, hypercalcemia, anemia) and/or Ig (renal impairment, paresthesias, protein gap, recurrent infection 2/2 hypogammaglobulinemia). Other Sxs nonspecific: generalized weakness, weight loss
  • Pathophysiology: Progression from MGUS, SMM; post-germinal plasma cell has translocation event during class switching >> oncogene (Cyclin D1/3, FGFR-3,C-MAF) next to IgH (chromosome 14) or other mutation. Additional genetic alterations (MYC, RAS/MAPK activation, TP53 deletion) >> proliferative and survival >> MM
  • Lytic Bone lesions/Hypercalcemia: MM cells activate osteoclasts 2/2 increased RANKL, cytokines, decreased OPG >> bone resorption and hypercalcemia. MM cells inhibit osteoblasts via cytokines, DKK1 >> net bone loss
  • Kidney Impairment: Severe hypercalcemia >> arteriolar vasoconstriction. Proximal tubule resorption of light chains cytotoxic 2/2 accumulation within cells, causing proximal RTA. Light chain cast nephropathy from light chains filtered by glomerulus precipitate after binding uromodulin in thick ascending loop of Henle >> obstructing intratubular casts >> inflammation, rupture of tubules
  • Anemia: bone marrow replaced by plasma cells. +/- CKD related low EPO, dilution (M protein increases plasma volume), folate/B12 deficiency, warm AIHA

- Dx: * CMP (high creatinine, high calcium, paraprotein gap)
* CBC w/ diff (normocytic normochromic anemia); Smear (Rouleaux)
* SPEP (M protein >3), SIF (IgG, IgM, OR IgA; kappa or lambda)
* For risk stratification: UPEP/UIF; B2 microglobulin; high LDH
* BMBx: IHC, flow cytometry, cytogenetics/FISH
* Imaging: cross sectional imaging preferred (low dose whole body CT wo contrast, whole body FDG-PET, whole body MRI), alternative is skeletal survey with X rays
* Criteria: BMBx: plasma cells >10% OR plasmacytoma AND 1+ CRAB-SLiM * CRAB: Hypercalcemia >11, Renal Impairment/Creatinine >2, Anemia/Hb \<10, Bone lytic lesions >5 mm on imaging (MRI, CT, X ray)
* SLiM (biomarkers): Sixty (>60% clonal plasma cells in BMBx), Light chain ratio (>100 or \<0.01), MRI (more than 1 focal lesion >5 mm)
* Less common variations: non-secretory/oligo-secretory (\~10%, Dx on imaging and biopsy), light chain only (\~20%, Dx on SFLC and UPEP/UIF)

- Tx: Risk stratify patient: age, performance status, comorbidities, R-ISS; and risk stratify disease (high risk: del17p13, t(4:14), t(14:16), t(14:20), amp1q; LDH very high; plasma cell leukemia [5% circulating plasma cells]). Determine autoSCT eligibility. Note: regimens are attending and institution specific so may vary from those listed below. * Transplant eligible: Induction with bortezomib (proteosome inhibitor), lenalidomide (immunomodulator), dexamethasone (VRd) +/- daratumumab (anti-CD38), followed by autoSCT. Maintenance therapy with lenalidomide +/- bortezomib if high risk cytogenetics. Induction with CyBorD if renal failure at diagnosis.
* Transplant ineligible: Patient specific, maybe induction with reduced intensity bortezomib, lenalidomide, and dexamethasone (VRD-lite) or lenalidomide, dexamethasone and daratumumab (DRd) with lenalidomide maintenance
* Relapsed/refractory disease: if good response to initial treatment could repeat proteasome inhibitor, lenalidomide, dara regimen +/- auto SCT; if not: clinical trials, BCMA CAR-T, BCMA/CD3 Bispecific Ab, venetoclax (only if t(11:14))
* Supportive Care: * aggressive pain management including possible RT
* bisphosphonates or denosumab to protect bones, surg fix if fracture/impending
* DVT PPX when on immunomodulatory agent like lenalidomide: ASA vs DOAC vs LMWH based on bleeding risk, comorbidities
* VZV PPX when on proteosome inhibitors, PJP PPX if on prolonged steroids

Plasmacytoma

  • Collection of monoclonal plasma cells that form a mass, may be seen in connection with MM or may be solitary
  • Solitary plasmacytomas subdivided into solitary bone plasmacytoma (SBP) and solitary extramedullary plasmacytoma (SEP)
  • Seen in \~7% of MM patients at diagnosis by PET/CT or as purple, subQ masses
    - Dx: workup as per MM (CMP, CBC, SPEP/IFE, UPEP/IFE, Igs, BMBx and aspirate, FDG PET/CT vs MRI) plus biopsy of lesion
  • Criteria for Solitary Plasmacytoma: biopsy proven tumor of clonal plasma cells, BMBx with no clonal plasma cell population (\<10%), no CRAB criteria, no lytic lesions on imaging

- Tx: Solitary: radiation, possibly surgical resection of SEP if anatomy permits; monitor for MM

Waldenstrom Macroglobulinemia (WM)/ Lymphoplasmacytic Lymphoma

  • WM \= lymphoplasmacytic lymphoma in bone marrow (pathologic finding) + IgM monoclonal gammopathy in blood
  • Pathophysiology: Post-germinal center IgM memory B cell undergoes malignant transformation, MYD88 L265P mutation common. Produces massive monoclonal IgM
  • Serum: massive IgM increases serum viscosity, slowing blood flow in capillaries >> hyper-viscosity syndrome: blurry vision, retinal hemorrhage, papilledema, headache, dizziness, AMS, TIA, bleeding diathesis, epistaxis
  • RBCs: B cell infiltration of bone marrow>>low RBC, WBC, plt production with anemia, thrombocytopenia/bleeding, and neutropenia/immunosuppression; IgM against RBC antigen>>Combs-positive autoimmune hemolytic anemia
  • Lymph Nodes/Liver/Spleen: B cell infiltration>>LAD, HSM
  • Blood Vessels: IgM precipitate in capillaries at cold temp>>cryoglobulinemia, Raynaud’s, acral cyanosis, tissue necrosis
  • Kidneys: IgM deposits into glomerular basement membrane, B cells may infiltrate, may also have glomerulonephritis from cryoglobulinemia
  • Peripheral nerves: IgM against myelin-associated glycoprotein>>distal, symmetric, sensorimotor neuropathy
  • General: B symptoms, weight loss, fatigue

- Dx: CMP (paraprotein gap), CBC (anemia), smear (rouleaux), BMBx (lymphoid, plasmacytoid cells with intranuclear vacuoles containing IgM, molecular studies for MYD88), SPEP/IFE (monoclonal IgM), Igs (IgM very high, other immunoglobulins may be low), Serum viscosity (Sxs unlikely 2/2 hyperviscosity if viscosity \<4 CP, likely symptomatic if >6), SFLC, high LDH, high B2-microglobulin; CT CAP (HSM, LAD; should not be lytic bone lesions); maybe EMG * Criteria: * IgM monoclonal gammopathy in serum
* BMBx >10% lymphocytes with plasmacytoid differentiation * Those meeting criteria for WM but lack the symptoms/signs such as hyperviscosity, anemia, LAD, HSM have SMOLDERING WM

- Tx: Asymptomatic/no end organ damage: observation q4-6M, higher risk of progression if IgM>4500, B2-micro>4, Alb\<3.5, BMBx lymphoplasmacytic population >70%. IF Sx of hyper-viscosity or end organ damage (cytopenias, neuropathy): 1st plasmapheresis to lower IgM then bendamustine+ritux (if fit pt) vs BTKi (if unfit)

Other Plasma Cell Dyscrasias

Light Chain (AL) Amyloidosis

- Pathophysiology: Monoclonal plasma cell population >> Ig with light chains that deposit as beta pleated sheets in tissues >> end organ damage * Kidneys: GBM deposition >> proteinuria up to nephrotic range
* Heart: Inter-myocyte deposition esp. in septum >> restrictive cardiomyopathy with systolic or diastolic dysfunction
* Nerves: peripheral nerve sheath deposition >> small fiber neuropathy (numbness + paresthesias), autonomic dysfunction, maybe carpal tunnel from compression
* Blood vessels: Vessel walls deposition >> fragility with easy bruisability/purpura
* Liver, spleen, tongue: HSM, macroglossia 2/2 infiltration

- Dx: All 4 necessary: 1. amyloid-related systemic syndrome 2. +Congo red tissue biopsy (usually fat pad + BMBx) 3. amyloid is light chain (mass spec or immunoelectron microscopy) 4. monoclonal plasma cell disorder (SPEP/IFIX, SFLC, UPEP/IFIX)

  • Organ involvement: CMP, coags, UPCR/UACR, trop, NT-proBNP, EKG, TTE, EMG

- Tx: Daratumumab + cyclophosphamide + bortezomib + dexamethasone (Dara-CyBorD); maybe auto SCT if candidate

POEMS Syndrome

  • “POEMS PEST”: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin changes, Papilledema, Extravascular volume overload, Sclerotic bone lesions, Thrombocytosis

  • Pathophysiology: cause unknown, likely associated with chronic overproduction of inflammatory cytokines (IL-1, IL-6, TNF-a, etc) and VEGF
    - Dx: CBC (high Hb, plts), CMP, SPEP/IFIX, UPEP/IFIX; VEGF; BMBx; glucose/A1c; hormones: AM cortisol, TSH, prolactin, T, E, other hormones; CT skeletal survey; dilated fundoscopic exam

  • Mandatory (both): peripheral neuropathy, monoclonal plasma cell disorder

  • Major (need 1/3): osteosclerotic lesions, elevated VEGF, Castleman Disease
  • Minor (need 1/6): organomegaly, volume overload, endocrinopathy, skin changes, papilledema, thrombocytosis, polycythemia

- Tx: depends on disease burden, maybe localized radiation if bony disease is limited; for disseminated disease chemotherapy (some combo of dara, lenalidomide, bortezomib, dex) +/- autoSCT; treatment of volume overload, endocrine deficiency, DVT ppx

Castleman Disease

  • Angiofollicular lymph node hyperplasia, subdivided into Unicentric (LNs in single region) and Multicentric (multiple LN regions), also subdivided by HHV-8 association
  • Pathophysiology: For HHV-8 associated: uncontrolled HHV-8 causes inflammatory cytokine release (mostly IL-6); Pathophysiology of HHV-8 negative CD poorly understood
  • Features: LAD, HSM, fever, night sweats, fatigue, fluid accumulation, cytopenias, violaceous papules, lymph node biopsy w/characteristic pathology
    - Dx: different criteria for unicentric, multicentric, but big picture you have 1. imaging evidence of LAD 2. path signs of inflammatory reaction (+/-HHV-8) 3. Clinical signs of massive inflammation (fevers, night sweats, HSM) or HHV-8 (violaceous papules) and 4. lab evidence of inflammation and organ dysfunction (high ESR/CRP, cytopenias, AKI, hypoalbuminemia) AFTER RULING OUT other Dxs (autoimmune, malignancy)
    - Tx: if associated with POEMS, treat the POEMS; if not: Unicentric: maybe resection, observation, or ritux; Multicentric: maybe ritux +/- chemo; ART if HIV

Myeloproliferative Neoplasms (MPNs)

Author: Christina Snider

Background

  • MPNs: chronic myeloid disorders caused by abnormal proliferation of mature bone marrow cell lineages (granulocytes, erythrocytes, or megakaryocytes)
  • MPNs differ from myelodysplastic syndrome (MDS); cells in MPNs are normally developed (i.e. not dysplastic)
  • Four “classic” MPNs: polycythemia vera, essential thrombocythemia, primary myelofibrosis and chronic myeloid leukemia (CML)

Polycythemia Vera (PV)

Background

  • Polycythemia is a general term: Men \= Hb/Hct > 16.5/49%; Women \= Hb/Hct > 16/48%
  • Relative polycythemia: concentrated H/H due to decreased plasma volume
  • Diuretic use, vomiting, diarrhea; H/H should normalize with fluid resuscitation
  • Absolute polycythemia: increased RBC mass
  • Primary polycythemia: inherited/acquired mutation in RBC progenitor
  • Secondary polycythemia: increase in RBC mass due to elevated serum EPO
  • Hypoxia/cardiopulmonary associated (chronic pulmonary disease, R-to-L cardiac shunts, sleep apnea, obesity hypoventilation syndrome, chronic carbon monoxide poisoning, including heavy smoking)
  • Kidney associated causes (following renal transplant, renal artery stenosis, hydronephrosis)
  • Autonomous EPO production from an EPO-producing tumors (rare)
  • Steroid Use
  • Epidemiology: Median age of diagnosis is 60 years; 25% cases present at age \<50 years.
  • >95% PV pts have JAK2 V617F mutation, but JAK2 V617F mutation is not specific to PV and can be seen in other MPNs

Presentation

  • Incidentally elevated H/H
  • Splenomegaly, generalized pruritus (post-warm bath/shower), unusual thrombosis
  • Erythromelalgia: intermittent occurrence of red, hot, painful extremities

Evaluation

  • CBC w/ diff and peripheral smear
  • EPO level
  • Rule out secondary causes: sleep study, carboxyhemoglobin, steroids
  • Peripheral blood screen for JAK2 V617F mutation

Management

  • PV treatment aims to prevent thrombosis and bleeding events.
  • Phlebotomy: maintain Hct \<45% (one unit 500 mL decreases Hct by 3%)
  • ASA 81 mg for thrombosis prevention and symptom control
  • Hydroxyurea: indicated for high-risk pts (>60 years old or with history of thrombosis)
  • Interferon-alfa, busulfan, or ruxolitinib: indicated in select high-risk pts

Essential Thrombocythemia (ET)

Background

  • Clonal stem cell disorder with increased platelet counts (>450k/uL)
  • Risks of thrombosis and hemorrhage
  • Median age of diagnosis: 60 years. Twice as common in females.

Presentation

  • Incidental thrombocytosis on CBC
  • Splenomegaly, unusual thrombosis, and erythromelalgia

Evaluation

  • Screen for conditions that cause reactive thrombocytosis: chronic inflammatory diseases, infections, bleeding/hemolysis, iron deficiency, post splenectomy
  • CBC with smear (platelet anisocytosis) ranging from very small to giant platelets
  • CMP, LDH, uric ascid, iron studies
  • BCR ABL1 testing should be sent to exclude CML
  • Bone marrow bx with staining, cytogenetics, and molecular testing for JAK2, CALR, MPL mutations

Management

  • Avoid ASA 81 in pts with platelet counts >1 million complicated by acquired von Willebrand syndrome due to increased risk of bleeding

Treatment of ET | Risk Score
(IPSET-thrombosis) | Features | Treatment | | :---: | :---: | :---: | | High | Hx of thrombosis and/or >age 60 with JAK2 V617F mutation | cytoreduction (target plt 100-400k) with hydroxyurea, systemic anticoagulation ±antiplatelet agent | | Intermediate | Age >60, no JAK2 V617F mutation, no history of thrombosis | cytoreduction (target plt 100-400k) with hydroxyurea, systemic anticoagulation ±antiplatelet agent | | Low | Age \=\<60 w/ JAK2 V617F mutation and no history of thrombosis | observation vs. daily ASA 81   | | Very Low | Age \=\<60, no JAK2 V617F mutation, no history of thrombosis | observation vs. daily ASA 81 |

Primary Myelofibrosis (PMF)

Background

  • Clonal proliferation of myeloid cells with variable morphologic maturity resulting in reactive marrow fibrosis and extramedullary hematopoiesis
  • Least favorable prognosis out of MPN

Presentation

  • Fatigue, weight loss, low grade fever, bone pain, and night sweats
  • Marked splenomegaly ±hepatomegaly (due to extramedullary hematopoiesis)

Evaluation

  • Smear: teardrop shaped RBCs (dacrocytes)
  • Bone marrow biopsy: “dry tap” due to extensive reticulin and/or collagen fibrosis mutually exclusive mutations in JAK2, MPL, or CALR

Management

  • Low risk pts: observe if asymptomatic
  • Cure by allogenic HCT transplantation in young, high-risk pts
  • Treatment of anemias include transfusion support
  • Surgical splenectomy if abdominal pain or transfusion dependent anemia (used very infrequently)

Chronic Myelogenous Leukemia (CML)

Background

  • Definition: MPN characterized by the overproduction of myeloid stem cells that can differentiate
  • Chronic phase:
  • Fatigue, weight loss, bleeding
  • Abdominal fullness and early satiety due to splenomegaly
  • WBC typically >100k. Smear shows neutrophilic cells in all stages of maturation with \<2% blasts
  • Accelerated phase: Refractory leukocytosis, 10-19% blasts in peripheral blood or bone marrow, worsening peripheral basophilia, thrombocytopenia
  • Blast phase \= acute leukemia: >20% blasts in peripheral blood or bone marrow, extramedullary proliferation of blasts

Evaluation

  • Typical findings in blood and bone marrow and confirmation of Philadelphia chromosome (BCR-ABL1 fusion gene) via conventional cytogenetics, FISH, or rt-PCR

Management

  • Hydroxyurea can be used to reduce WBC while awaiting confirmation
  • Oral tyrosine kinase inhibitors (TKI): Imatinib, dasatinib, nilotinib, and ponatinib
  • Allogenic hematopoietic cell transplantation: curative option for pts in accelerated and blast phase, as well as young pts with chronic phase CML who do not respond to TKI therapy

Bone Marrow Transplant

Authors: Chelsie Sievers, Michael Kaminski

Definitions

  • Autologous Stem Cell Transplant (AutoSCT):
  • Allogeneic Stem Cell Transplant (AlloSCT):
  • Matched Related Donor (MRD)
  • Matched Unrelated (MUD): from NMDP database
  • Mismatched Donor (MMD)

  • Haploidentical: most common parent or sibling

  • Syngeneic Stem Cell Transplant (SynSCT): identical twin, functionally \~ AutoSCT

  • Umbilical Cord Blood Transplant (UCBSCT): HSCTs from umbilical cord following delivery, frozen and banked
  • Donor specific antibodies (DSAs): testing recipient for Abs against HLAs of donors >> increased risk of graft failure from DSAs

Indications for Transplant

  • AutoSCT: multiple myeloma (most common) and other plasma cell disorders, relapsed lymphomas, solid tumors (germ cell tumors, pediatric tumors)
  • AlloSCT: malignancies including AML (most common), sometimes for MDS, CML, ALL, CLL, lymphomas; nonmalignant indications include aplastic anemia, immunodeficiency, hemoglobinopathy)
  • Important reason for AlloSCT in AML is graft vs leukemia effect whereby donated cells eliminate remnant AML tumor cells following myelo-ablative conditioning

Recipient and Donor Selection

  • Recipient: Generally younger (\<70), fit (ECOG 0-1), fewer comorbidities but variable by institution and attending; pretransplant: infectious studies (Hepatitis A/B/C, EBV, CMV, HSV, HTLV-1, toxo); T+S, DSAs, TTE, PFTs; psychosocial evaluation
  • Donor: all else being equal: better match is preferred (see below), younger is preferred, sibling preferred over non-sibling (less minor HLA mismatch), male donor (prevent Y antigen mismatch), nulliparous female (less minor HLA mismatch)
  • Graft source: most commonly peripheral HSCs harvested via apheresis after donor receives G-CSF for \~4 days, but higher chronic GvHD rates; alt is HSCs from bone marrow but more difficult, lower yield, and possibly high relapse rate, may be preferred for non-malignant SCT indications due to less GvHD; in pediatric population and very rarely adults can use umbilical cord blood HSCs

Choosing the Match

  • Molecular typing of MHC-I (HLA-A, HLA-B, HLA-C) and MHC-II (HLA-DRB1, HLA-DQB1) of donor and recipient.
  • MRD: fully matched is 10/10
  • MUD: fully matched is 10/10; NOTE may also type HLA-DPB1 so maybe 12/12;
  • MMD: 8-9/10 match, more GvHD and graft failure

  • Haploidentical: 5/10 match; cyclophosphamide on transplant days +3 and +4 decreases GvHD and graft failure, maybe more graft vs tumor via NK cells

  • MUDs chosen from banks, inequities in ability to find match based on race of recipient (white more likely to find match in bank, African American least likely

Common Conditioning Regimens

  • Myeloablative (MAC) regimens: Chemo +/- RT destroys recipient bone marrow
  • AutoSCTs: MM (high dose melphalan); Lymphoma (BEAM-BCNU, Etoposide, Ara-C, Melphalan); Solid tumors (MEC-Melphalan, Etoposide, Carboplatin)

  • AlloSCTs: Cy/TBI (Cyclophosphamide, Total Body Irradiation); Bu4/Cy (Busulfan x4 days, Cyclophosphamide, MESNA); Flu/Bu x4 (Fludarabine, Busulfan x4 days)

  • Reduced intensity (RIC)/non-myeloablative (NMA) regimens: gentler for less fit patients, lower treatment related morbidity/mortality but higher relapse rates

  • Common RIC regimens: Flu/Mel (Fludarabine + Melphalan), Flu/Bu2 (Fludarabine + Busulfan x2 days)

  • Common NMA regimens: Flu/TBI; TLI/ATG (Total Lymphoid Irradiation + Anti-Thymocyte Globulin)

  • Toxicities: Mucositis, N/V/D, Rash, Alopecia, Peripheral Neuropathy

Complications

Non-infectious

  • Oral Mucositis: peaks day +6-12; PPX with ice chips during infusion of high dose melphalan (“cryotherapy”); Tx with topical/IV pain meds

  • Diarrhea: non-oral mucositis vs Acute GvHD vs Infectious (C diff, CMV, etc)

  • Engraftment Syndrome: days-weeks after neutrophil recovery;

  • Pathophysiology: PMN recovery >> cytokine storm >> vascular leak
  • S/Sx: fever, tachycardia, rash, pulmonary edema, LE edema; AKI, transaminitis;
  • Dx of exclusion after infectious wu negative and aGvHD ruled out

  • Tx: 1 mg/kg steroids with rapid taper

  • Graft Failure: Rejection of donor stem cells, primary (never engrafted) vs secondary (engrafted then failed); Dx by measuring donor/recipient chimerism; Tx: some form of repeat transplant, growth factors, intensive immunosuppression

  • Hepatic Sinusoidal Obstruction:

  • Days-weeks following transplant in up to 15% of pts
  • Pathophysiology: hepatic sinusoidal endothelial injury >> inflammation, coagulation cascade activation >> obstructs hepatic veins >> portal HTN and organ failure; inc. risk if liver disease and MAC and previous treatment with gemtuzumab-ozo
  • Dx: EBMT diagnostic criteria: Bili>2 plus 2 of: hepatomegaly, weight gain >5%, ascites, also get RUQ US w doppler

  • PPX: UDCA; Tx: possibly defibrotide if severe

  • Idiopathic Pulmonary Syndrome: umbrella term including peri-engraftment respiratory distress syndrome (PERDS)

  • Days 30-90
  • Pathophysiology: alveolar injury 2/2 direct toxicity >> cytokine release >> alloreactive T cells >> noninfectious pneumonitis, edema resembling ARDS >> fever and hypoxia
  • Dx: CXR: diffuse infiltrates, maybe bronch and BAL

  • Tx: supportive +/- prednisone 1 mg/kg or pulse 1 g/d, etanercept 2nd line

  • Other pulmonary complications: DAH (early) versus bronchiolitis obliterans syndrome (BOS) and cryptogenic organizing PNA (COP) (late)

  • Post-transplant Lymphoproliferative Disorders (PTLD)

  • Pathophysiology: EBV reactivation iso immunosuppression>>clonal B cell proliferation; S/Sx with fever, wt loss, fatigue, LAD
  • Dx: EBV PCR, possibly Biopsy

  • Tx: reduce immunosuppression, maybe ritux

  • Graft vs Host Disease (GvHD):

  • Acute GvHD: usually day \<100; increased risk with more HLA mismatch, older donor, female donor/male recipient, peripheral blood SCT>Marrow
    • Pathophysiology: donor T cells in graft attack recipient tissues (Th1-mediated), proliferate and persist to transition to chronic inflammation and tissue damage most pronounced in skin (maculopapular rash, desquamation), luminal GI tract (diarrhea), liver (cholestatic predominant liver injury)
    • Dx: rule out infectious causes of rash/diarrhea, possibly skin biopsy; grading
    • Tx: depends on severity; Grades 1-4; Grade 1: topical steroids (skin cream/ointment vs PO nonabsorbable steroid for luminal GI); Higher grades: IV steroids (IV methylpred 1-2 mg/kg), maybe MMF, etanercept, ruxolitinib
  • Chronic GvHD: generally >100 days post alloSCT, incidence \~40%, risk factors similar to aGvHD
    • Pathophysiology: chronic inflammation 2/2 Th2/auto Ab production >> acellular fibroproliferative scleroderma-like picture; skin: rashes and skin thickening, alopecia, dystrophic nails; arthralgias/inflamed joints; mouth/eyes: xerostomia and keratoconjunctivitis sicca; luminal GI: N/V, malabsorption, dysmotility, stricture; hepatic: cholestasis; pulmonary: DOE, non-productive cough, bronchiolitis obliterans; marrow: cytopenias
    • Dx: NIH consensus criteria for Dx and grading: mild/moderate/severe; biopsy
    • Tx: Mild: topical steroids when able (skin/luminal GI); Moderate-Severe: steroids +/-immunosuppressive agents like ruxolitinib (JAK inhibitor), belumosudil (ROCK2 inhibitor), cyclophosphamide, tac
  • GvHD PPX: day \~ -3 onward, common agents include tac/MTX, tac/sirolimus, MMF; maybe add post-transplant cyclophosphamide

Infectious

  • Pre-Engraftment: Day 0 until \~ +30; risk factors: neutropenia, mucositis/lines
  • Neutropenic Fever: common, manage as per Neutropenic Fever section
  • Neutropenic enterocolitis (typhlitis): polymicrobial necrotizing infection most commonly of cecum 2/2 GPC/GNR/Anaerobes (Clost septicum)/fungi (Candida), S/Sx: fever, N/V, lower abdominal pain, diarrhea +/- blood; Dx CT w oral and IV contrast; Tx intitial ABX with zosyn or cefe/metro, maybe carbapenem, fungal coverage if febrile >72 hrs; surgery consult if concern for perf
  • Line infections: S/Sx: erythema, pain of catheter insertion site, usually pathogens are skin flora (Staph, Strep)
  • Bacteria: GPCs, GNRs, GI Strep species
  • Viruses:
    • CMV (check weekly PCR post allo-SCT, PPX with letermovir, Tx with IV ganciclovir or PO valganciclovir)
    • EBV (weekly PCR post allo-SCT, if VL >1000 on 2 occasions can Tx with preemptive ritux to reduce risk of PTLD;
    • HSV (esp with mucositis)
    • Common respiratory and enteric viruses (Flu, COVID, RSV, adeno, etc.)

  • Fungi: Candida (esp. neutropenia with mucositis), aspergillus (prolonged neutropenia)

  • Early Post-Engraftment: Engraftment until \~ +100; risk factors: impaired cellular and humoral immunity especially when immunosuppressed for GvHD

  • Bacteria: GPCs, GNRs
  • Viruses: CMV (pneumonitis, diarrhea/colitis, retinitis, hepatitis), EBV (PTLD); BK or adeno (hemorrhagic cystitis); HSV or HHV-6 related encephalitis, common respiratory and enteric viruses (Flu, COVID, RSV, adeno, etc.)

  • Fungi: Candida, Molds like aspergillus; PCP (esp with prolonged steroids for GvHD)

  • Late Post-Engraftment: after day +100; risk factors: impaired cellular and humoral immunity

  • Bacteria: Encapsulated bacteria Strep pneumonia, H flu, Neisseria (sinusitis, PNA); Nocardia (PNA +/- skin), Listeria (diarrhea, meningitis)
  • Viruses: CMV (pneumonitis, diarrhea/colitis, retinitis, hepatitis), EBV (PTLD, hepatitis); BK or adeno (hemorrhagic cystitis); JC (PML), HSV or HHV-6 (encephalitis, hepatitis), VZV (shingles, hepatitis, encephalitis), common respiratory and enteric viruses (Flu, COVID, RSV, adeno, etc.)
  • Fungi: Molds like aspergillus (PNA, invasive rhinosinusitis); Cryptococcus (PNA, skin, encephalitis); PCP (PNA, esp with prolonged steroids for GvHD)

  • Parasitic: toxoplasmosis (PNA, encephalitis)

  • Infectious PPX:

  • Bacterial: Fluoroquinolone until ANC>500 (levo or cipro)
  • Viral
    • HSV, VZV: (val)acyclovir 6-12M depending on auto vs allo SCT, immunosuppression (allo)
    • CMV: CMV seropositive recipients get letermovir PPX
  • Fungal: Usually fluconazole in pre-engraftment period, those with prolonged neutropenia or GvHD requiring immunosuppression may need coverage for molds with voriconazole or posaconazole
  • PCP: Bactim starting after engraftment then for \~6 months (autoSCT) or \~12 months (alloSCT); high variability

CAR-T cell Therapy and T cell Engagers

Authors: Chelsie Sievers, Michael Kaminski

Background

  • Chimeric antigen receptor T cells (CAR-T): collected from the pt and genetically modified to contain receptor with: targeting element (usually single chain variable fragment-scFv), a transmembrane domain, and internal signaling (CD3) and co-stimulatory (CD28 or 4-1BB) domains

  • CAR-Ts are infused into patient and recognize tumor via new receptor >> T cell killing and proliferation>>T cells persist in host

  • Bi-specific T cell Antibodies (BiAbs): engineered Abs, one domain binds CD3, the other binds a tumor antigen >> juxtaposes killer T cells with tumor >> killing. Bi-specific antibodies have 4 distinct peptides (2x heavy chains and 2x light chains)

  • Bi-specific T cell Engagers (BiTEs): CD3 binding domain and a tumor antigen binding domain >> juxtaposes T cells with tumor cells >> killing. The two domains are made from a single polypeptide, no Fc domain >> smaller and rapidly cleared by the kidneys, necessitating continuous infusions

FDA Approved CAR Ts

  • Multiple Myeloma, anti-BCMA: Abecma/idecabtagene vicleucel, Carvykti/ciltacabtagene autoleucel
  • Large B-Cell Lymphoma, anti-CD19: Breyanzi/lisocabtagene maraleucel, Kymriah/tisagenlecleucel, Tecartus/brexucabtagene autoleucel, Yescarta/axicabtagene ciloleucel
  • Follicular Lymphoma, anti-CD19: Yescarta/axicabtagene ciloleucel
  • Mantle Cell Lymphoma, anti-CD19: Tecartus/brexucabtagene autoleucel
  • Adult B-cell ALL, anti-CD19: Tecartus/brexucabtagene autoleucel

FDA Approved Bi-Specific T Cell Antibodies/Engagers

  • Multiple Myeloma: Tecvayli/teclistamab-cqyv (CD3 x BCMA BiAb); Talvey/talquetamab-tgvs (CD3 x GPRC5D [a GPCR] BiAb); Elrexfio/elranatamab-bcmm (CD3 x BCMA BiTE)
  • Adult B-cell ALL, anti-CD19: Blincyto/blinatumomab (CD3 x CD19 BiTE)
  • B-cell Lymphomas: Lunsumio/mosunetuzumab-axgb (CD3 x CD20 BiAb); Epkinly/epcoritamab-bysp (CD3 x CD20 BiAb); Columvi/glofitamab-gxbm (CD3 x CD20 BiAb)
  • NSCLC: Rybrevant/amivantamab-vmjw (CD3 x EGFR/MET BiAb)
  • SCLC: Imdelltra/tarlatamab-dlle (CD3 x DLL3 BiTE)
  • Uveal Melanoma: Kimmtrak/tebentafusp-tebn (CD3 x HLA-A*02:01/gp100 peptide BiTE)

Toxicities

  • Cytokine Release Syndrome (CRS)
  • CAR T cells (or T cells activated by BiTE/BiAb) release massive amounts of cytokines/IFNg >> macrophages produce IL-6, IL-10, TNFa, higher risk for CAR-T compared to BiTE/BiAb and with bulkier disease
  • S/Sxs: days to weeks following infusion; fever, arthralgia/myalgia, hypotension, hypoxemia, SIRS response, capillary leak syndrome; end organ damage of any organ (CV, lung, liver, kidney, CNS)
  • Dx: monitor for \~7 days following CAR-T infusion; rule out infectious causes (RVP, CXR, sputum culture, Blood Cx, Urine Cx, GIPP)

  • ASTCT Grading for CAR-T CRS:

    • Grade 1: Fever >100.4, no hypotension or hypoxia
    • Grade 2: Fever > 100.4, hypotension NOT requiring pressors and/or hypoxia requiring \< 6L NC
    • Grade 3: fever > 100.4, hypotension requiring one pressor and/or hypoxia requiring > 6L NC
    • Grade 4: fever > 100.4, hypotension requiring multiple pressors and/or hypoxia requiring positive pressure (BiPAP, intubation)

  • CTCAE v5.0 Grading for BiTE/BiAb CRS

    • Grade 1: Fever >100.4,
    • Grade 2: Fever > 100.4, hypotension responsive to fluids (no pressors) and/or hypoxia requiring \< 40% FiO2
    • Grade 3: fever > 100.4, hypotension requiring one pressor and/or hypoxia requiring > 40% FiO2
    • Grade 4: fever > 100.4, life-threatening systemic symptoms

  • Tx:

    • CAR-T CRS:
    • Grade 1: APAP
    • Grade 2: ICU transfer, APAP +/- tocilizumab 8 mg/kg IV (max 800 mg, up to 3 doses in 24 hrs, 8 hrs apart)

    • Grade 3-4: ICU transfer, APAP, tocilizumab +/- steroids (Dexamethasone 10 mg IV q6h vs methylpred 1g/d) or together

    • BiTE/BiAb CRS: refer to package inserts for agent specific CRS management

    • Grade 1: APAP +/- temporarily interrupting infusion (discuss with fellow/attending)
    • Grade 2/3: agent specific, will be some combo of interrupting infusion, APAP, resuming at lower infusion rate
    • Grade 4: Stop infusion permanently, dexamethasone 8 mg IV q8h +/- tocilizumab

  • Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

  • Pathophysiology: high systemic inflammation >> leaky BBB and cytokine diffusion into brain, maybe CAR-T trafficking into brain with local cytokine production
  • S/Sx: \~4-10 days post infusion, may be seen with CRS; altered consciousness, aphasia, impaired fine motor skills, seizures, elevated ICP Sxs like HA
  • ASTCT ICANS Grading based on AAO to year, month, city, hospital (4 pts); naming 3 objects ie naming clock, pen, button (3 pts); follow simple commands ie “show me 2 fingers” (1 pt); ability to clearly write a sentence (1 pt); ability to count backwards from 10 (1 pt):
    • Grade 1: ICE 7-9
    • Grade 2: ICE 3-6
    • Grade 3: ICE 0-2
    • Grade 4: ICE 0, seizure, unarousable, or severe cerebral edema/increased ICP
  • Workup: q4 hr neuro checks unless Grade 2 or higher then ICU transfer for q1h neuro checks; neuro consult, ophtho consult for dilated fundo exam; CT head vs MRI brain wwo contrast; EEG
  • Tx:
    • Grade 1: Supportive
    • Grade 2-3: Dexamethasone 10 mg IV q6h
    • Grade 4: methylpred 1g IV q24h
    • ASMs per neurology, maybe levetiracetam for seizure PPX

Oncologic Emergencies

Authors: Alex DeWeerd, Melanie Naranjo

Leukostasis

Definition: Hyperleukocytosis is a WBC count >100,000/microL.

Leukostasis is hyperleukocytosis + clinical symptoms of decreased tissue perfusion in end organs (CNS, lungs, heart, kidneys, etc). Typically manifests in leukemias (i.e. AML; Less common in CML/CLL unless there is a significant increase in peripheral blasts).

Pathophysiology: Leukostasis is thought to be due to increased blood viscosity caused by a large population of leukemic blasts that are less deformable than mature leukocytes. As blasts increase in the blood, plugs of these more rigid cells form in the microcirculation and impede flow. The blast-endothelial cell interactions lead to endothelial cell damage, cytokine release, and subsequent hemorrhage and local hypoxemia within tissues, most notably the CNS and lungs.

Presentation: - Common symptoms include: visual changes, headaches, dizziness, dyspnea, hypoxia, fever. Less common symptoms: abdominal pain, priapism, limb pain.

Evaluation: - CBC w/ diff, peripheral blood smear, DIC and TLS labs
- CT head to evaluate neuro deficit and to check for ICH
- Chest X-Ray vs. CT chest to evaluate dyspnea and air space abnormalities
- Note: PaO2 by ABG often falsely low from WBC consuming O2 in vitro. Trust SpO2.

Management: - Call Hematology
- Transfer/admit to ICU
- Emergent cytoreduction
* Leukapheresis: page Nephrology and place dialysis catheter
* Hydroxyurea and chemotherapy per hematology fellow
* Don’t transfuse PRBC before taking care of leukostasis as transfusion will increase viscosity

Tumor Lysis Syndrome (TLS)

Definition: A phenomenon caused by tumor cell lysis that results in the release of electrolytes into the bloodstream.

Pathophysiology: - Malignancies can be associated with high turnover rates or high sensitivity to treatment leading to quick tumor lysis. This causes release of large amounts of potassium, phosphate, and nucleic acids that can further contribute to metabolic derangements.

Presentation: - Symptoms reflect the metabolic abnormalities seen with hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia. These symptoms can include: hypotension, AKI, arrythmias, nausea, diarrhea, seizures, lethargy, and even lead to death.

Evaluation: - TLS labs (25% change from baseline in these values) * Uric acid ≥ 8, Ca2+ ≤ 7, K+ ≥ 6, or PO43- ≥ 4.5
- Risk Stratification:
* Highest risk after starting chemotherapy, but can occur spontaneously
* Highest risk if rapidly progressive, chemo-sensitive, myelo or lymphoproliferative disease; bulky disease, extensive organ/marrow infiltration
- Tumor characteristics which confer a higher risk of developing TLS
* High (>5% risk): ALL (WBC> 100K or LDH 2x ULN), AML (WBC> 100K), Burkitt’s (III/IV or LDH≥2xULN, DLBCL with bulky disease, intermediate risk + AKI/CKD
* Intermediate: ALL (WBC\<100K, LDH \<2x ULN), AML (WBC 25-100K), Burkitt’s LDH\<2x ULN), DLBCL (non-bulky, LDH>ULN), CLL (if tx with fludarabine, rituximab, lenalidomide, or venetoclax +LN 5-10 cm or ALC≥25K), plasma cell leukemia, rare chemo-sensitive solid tumors (small cell)
* Low: all others

Management: - Prevention:
* High risk: q6-8h TLS labs, IVF (±loop diuretic if volume overload), allopurinol, ± rasburicase
* Intermediate – q8h TLS labs, IVF, allopurinol
* Low – daily TLS labs, IVF
* IVF: goal to maintain UOP 80-100 mL/hr
* Allopurinol: 300 mg PO BID for CrCl > 20 mL/min, UpToDate renal dosing if lower
* Rasburicase ($$$): contraindicated in G6PD (send G6PD if not urgent and AA, Asian or Jewish descent)
* Given if uric acid > 8 mg/dL. Get fellow approval before ordering

  • Treatment: (Can use as night/cross cover handoff)
  • K+ > 5.5: STAT EKG, lokelma 10g TID, 10 U insulin+ 1 amp D50
    • If EKG changes, then calcium gluconate and D5W at 100 mL/hr with repeat BG in 1 hr
  • Uric acid > 8 with 25% change from baseline: page hematology fellow to discuss rasburicase
  • PO4 > 4.5 with 25% change from baseline: start/↑ phos binder (sevelamer)
  • IV calcium: do not administer unless symptomatic AND hyperphosphatemia is corrected
  • Hemodialysis: may be necessary if poor renal function and/or anuria. Consider Nephrology consultation early if worsening Cr, refractory symptoms, or refractory electrolyte abnormalities.

Superior Vena Cava (SVC) Syndrome

Background - It occurs due to obstruction of blood flow in the SVC leading to upstream congestion in the upper extremities, head and neck.
- Can be secondary to a mass in the mediastinum or thrombosis (e.g. foreign body, central venous catheter)
- Commonly associated malignancies: lung cancer (NSCLC or SCLC), Non-Hodgkin or Hodgkin lymphoma, mediastinal germ cell tumors, thymic malignancies

Presentation - Facial or neck swelling without generalized edema
- Sense of head fullness, exacerbated by leaning forward or lying down
- Pulmonary: dyspnea, stridor, hoarseness, cough (due to edema narrowing the nasal passages and larynx or mechanical airway obstruction)
- Physical features include: facial/neck edema, distended neck and chest veins, upper extremity swelling, LN enlargement (supraclavicular, cervical, axillary), papilledema, and plethora.

Evaluation - CXR: may show mass, perihilar or mediastinal disease, mediastinal widening, or pleural effusion
- Contrasted CT scan ± CT Venography: phased to get a view of clot contribution to obstruction to guide decision regarding anticoagulation or stenting
- MRI/MRV may provide additional information (often not possible due to pt too sick)
- Non-malignant causes on the differential: post-radiation fibrosis, fibrosing mediastinitis (can be seen from prior infections such as histoplasma, TB, nocardiosis, aspergillus, blastomycosis), central AV fistula

Management - Assess airway and prepare for intubation if needed
- Keep head of bed elevated
- Thrombosis:
* Removal of lines/catheters associated with thrombus
* Consideration of anticoagulation
- Tumor compression: the type of tumor guides treatment (tissue biopsy is key)
* Stat/urgent consultations to consider:
* Interventional radiology: possible stenting/dilatation (Fastest modality, if available)
* Radiation oncology: radiation therapy (Takes days to weeks to work)
* Medical oncology: help with diagnosis and chemotherapy (Fast if highly chemo-responsive cancer
* Interventional pulmonology: help with tissue dx

Spinal Cord Compression

Background - Malignancies where cord compression is most common:
* Multiple myeloma, lymphoma (both Hodgkin and NHL); lung, breast, and prostate cancer
- Tumor mass, compression, and often displaced bone occupies the epidural space and impinges on the thecal sac or nerve roots of the spinal cord or any spinal nerves including the cauda equina. This can lead to edema of the spinal cord white and gray matter, which eventually leads to infarction of the cord. This vasogenic edema is where glucocorticoids can play a role.

Presentation - Back pain (most often initial symptom, typically worse at night), progressive motor, or sensory deficits (saddle anesthesia, numbness, paresthesias)
- Cauda equina syndrome: bowel or bladder incontinence, ataxia

Evaluation - Neurologic exam with sensation testing seeking level below an identified dermatome
- Back pain that exacerbated by movement -> mechanically unstable spine until proven otherwise (requires surgical evaluation and potential stabilization)
- Lab testing: If no known malignancy check CBC, CMP, SPEP, and (in males) PSA
- Bladder U/S if suspicion or retention with or without overflow incontinence
- If suspected, order whole spine MRI w and w/o contrast. If pt unable to have MRI, CT myelography may be considered.

Management - Immediate high dose steroids: give dexamethasone to minimize mineralocorticoid effects. Most common dosing is 10mg IV x1 followed by 4mg PO or IV q6h
- Consider stat/urgent consultation with:
* Spine Team (Neurosurgery or Orthopedic surgery holds pager): consult early, ask for an operative plan from them ASAP. Affects other possible interventions.
* Radiation oncology: one of the rare cases where overnight radiation would be considered. Requires that patient is able to lie flat for a CT simulation (rad onc orders this), and rad onc cannot proceed until Spine surgery makes a definitive call about whether or not to operate first
* Medical oncology: help with diagnosis and chemotherapy
- Ensure regular neuro-vascular checks and close monitoring

Brain Metastases

Background - Common malignancies: Lung (NSCLC), breast, kidney, colorectal carcinomas, and melanomas
- Significantly more common than primary brain tumors
- 80% of brain metastasis occur in the cerebrum at grey/white matter junction via hematogenous spread (smaller blood vessel diameter at the junction essentially traps tumor cells)

Presentation - Highly variable: must consider brain mets in any cancer pt with neurologic or behavioral changes
- Headache: worse in the mornings, with bending over or with Valsalva
- Nausea/vomiting
- Cognitive dysfunction: changes in memory, mood or personality
- Neuro: focal neurologic deficits, seizures, stroke (particularly melanoma, choriocarcinoma, thyroid, and renal carcinomas)
- Signs of elevated ICP: papilledema, vision changes, drowsiness, presyncope

Evaluation - STAT CT if concerned for stroke or elevated ICP
- MRI with contrast: most sensitive, can differentiate between metastases vs. other lesions
* Suggestive features: multiple lesions, location, circumscribed margins, vasogenic edema, contrast enhancement
- If pt has no known primary tumor: consider CT C/A/P ± PET to identify primary
- Biopsy with histopathology and IHC: if diagnosis in doubt or if only a single lesion is present

Management - If severe HA, N/V, focal neuro deficits: systemic glucocorticoids
* Dexamethasone 10mg IV x1 followed by 4mg IV q6h (or PO if tolerated)
- Stat/urgent consults:
* Neurosurgery: diagnostic/therapeutic intervention. Note they will need a tissue diagnosis ASAP if not known; except in cases of emergency; affects operative plan.
* Radiation oncology: will also need tissue diagnosis, and will have to coordinate with neurosurgery about timing of surgery versus radiation. Patient must be able to lie flat; they will need a CT simulation if radiation is to be offered.
* Medical oncology: help with diagnosis and chemotherapy. Evolving systemic therapies can be effective for controlling metastatic disease to the brain, particularly with melanoma and NSCLC subtypes (ALK, EGFR)

  • Ensure regular neuro-vascular checks and close monitoring
  • Do not perform LP without input from neurology

Paraneoplastic Syndromes

Author: Bailey Decoursey, Justin Lo

Hypercalcemia of Malignancy

Background - Caused by PTHrP production, osteolytic lesions, and/or rarely exogenous Vit D
* PTHrP: breast cancer, NSCLC (squamous)
* Osteolysis: multiple myeloma, Breast Cancer;
* Exogenous vit D: lymphoma

Evaluation - Correct [Ca2+] for hypoalbuminemia: [Ca2+] + 0.8 x (4.0 – albumin)
- Send basic hyperCa+2 work-up: PTH, vit D, etc (see “Hypercalcemia” section)
- PTHrP is called “Parathyroid Hormone-related Peptide-ARUP” in Epic

Management - First line: IVF without calcium such as Normosol; goal urinary output of 150-200 mL/hr
* Strict I/Os: cautious IV fluids in pts with cardiac or renal dysfunction
* Add Furosemide if hypervolemic (do not empirically start)
- Second line: zoledronic acid 4mg IV (takes 24-48 hours to see effect)
- AMS or severe hypercalcemia (>14mg/dL): calcitonin 4 IU/kg (requires attending approval)

SIADH

Background - Euvolemic hypotonic hyponatremia with urine sodium >20 and typically urine Osm >100
- Associated with: SCLC (most common), head/neck cancers, breast cancer
- See "Hyponatremia” section for additional information

Management - Free water restriction to 800mL/day
- Refractory: salt supplementation (e.g. salt tabs) ± loop diuretic

Carcinoid Syndrome

Background - Episodic flushing, diarrhea, wheezing/SOB due to secretion of histamine & serotonin
- Most common: Neuroendocrine tumors, GI (often with mets to liver and lung)

Evaluation - Urine: UR 5-HIAA (ARUP)
- Imaging to identify tumor(s): CT C/A/P

Management - Short-term treatment: subQ or IV octreotide (see UpToDate for dosing)
- Antidiarrheals (Imodium, Lomotil) to slow transit
- Long-term treatment: depot (IM) forms of octreotide and lanreotide
- Refractory: Discuss with oncologist and PharmD about Telotristat Ethyl (inhibitor of tryptophan hydroxylase, FDA approved in combination with somatostatin analog (SSA) when SSA is not sufficient to control carcinoid symptoms).

Autoimmune Encephalitis, Encephalomyelitis, and Myelitis

Background - Encephalopathy (limbic or brainstem) ± myelitis (limb ataxia, sensory deficits)
- Associated with small cell lung cancer and checkpoint inhibitor therapy

Evaluation - LP: make sure to order CSF oligoclonal bands and CSF IgG index
- “Paraneoplastic AutoAb Eval-MAYO” (add "CSF" to the front of the order name if for LP)
- NMDA-R can be ordered as a standalone test
- CT head
- EEG if concern for subclinical seizures

Management - Consult Neurology for possible immunosuppressive therapy (steroids, IVIG)

Lambert-Eaton Myasthenic Syndrome (LEMS)

Background - Muscle weakness due to autoantibody against calcium channels resulting in ↓ ACh release
- Associated with SCLC (most common) & lymphoma
- See “Myasthenia Gravis (MG) and Lambert-Eaton Myasthenic Syndrome (LEMS)” section in Neurology

Cancer of Unknown Primary

Author: Bailey Decoursey

Background - Cancer of unknown primary (CUP) accounts for 2% of all cancer diagnoses
- Often, CUP is discovered incidentally on imaging tests or due to symptomatic metastasis

Presentation - Asymptomatic and found on imaging
- Often generalized fatigue and weight loss
- May have irregular, persistent lymphadenopathy at a particular site

Initial Evaluation - Physical exam: including pelvic / breast exam for females and prostate/testicular exam for males
- CMP, CBC w/ diff, UA, PSA in males, fecal occult blood screening
- CT C/A/P with contrast (reveals the origin in up to 35% of pts)
- Once lesions are identified pt’s should undergo biopsy of the most accessible lesion
* If imaging is suggestive of GI origin, or pt has liver metastasis without other obvious dominant lesion, colonoscopy and/or upper EGD should be performed
* If physical exam with breast abnormalities, or pt has axillary lymphadenopathy, bilateral mammography should be performed
* Breast MRI may be considered even in the setting of negative mammography if clinical suspicion is high

Evaluation following biopsy - Adenocarcinoma (70% of CUP)
- Most common primary: pancreas, lung, liver, gastric, cholangiocarcinoma/HPB tree, and kidney
- Interestingly, prostate and breast cancer account for a small percentage of CUP despite being the most common malignancies
- Most common metastasis: liver, lungs, lymph nodes and bones
- Evaluation:
* Primary is most likely to be identified by biopsy
* If clinical suspicion is high for certain primary site, this should be relayed to pathology so they may perform appropriate staining
* Tissue PSA can be positive even in the setting of normal serum PSA
* Serum studies such as CEA, CA19-9, AFP, CA 125, CA15-3 are often not sensitive or specific and will often be elevated in the setting of many types of adenocarcinoma; however it is still worth obtaining these for diagnostic workup.
* Consider discussing with Oncology Fellow re: NGS molecular testing after biopsy, as occasionally finding somatic mutations from tumor specimens can help with identification of primary and guide management decisions.

  • Neuroendocrine tumors (1% of CUP)
  • High grade
  • Most common primary: lung (bronchogenic)
  • Most common metastasis: mediastinal and retroperitoneal LN
  • Evaluation: CT of chest ± bronchoscopy will likely identify site

  • If unrevealing, IHC staining and molecular cancer classifying assays will likely be helpful

  • Squamous cell carcinoma (5% of CUP)

  • Work up depends on the location of adenopathy as follows:
  • Upper and mid-cervical lymphadenopathy
  • Most common primary: head and neck cancer

  • Evaluation: CT head and neck, direct laryngoscopy, nasopharyngoscopy

  • Lower cervical/supraclavicular lymphadenopathy

  • Most common primary: lung or head and neck

  • Evaluation: CT chest, CT head and neck, direct laryngoscopy as indicated

  • Inguinal lymphadenopathy

  • Most common primary: genital or anorectal origin
  • Evaluation
  • Females: careful external and internal genital examination
  • Males: close external genital examination
  • Anoscopy and DRE in all pt

- In up to 60% of cases, a primary site may never be identified – This is important for discussing with patients and families. - Empiric chemotherapy may be initiated in consultation with medical oncology

Therapy Toxicities

Author: Rahul Shah, AJ Winer

Immune Checkpoint Inhibitor Toxicities

  • Immune checkpoint inhibitors augment the endogenous immune response against tumors, which may lead to autoimmune-like toxicities, known as immune-related adverse events (irAEs)
  • Treatment: low-dose glucocorticoids (prednisone, 0.5 mg/kg) for mild adverse events, high dose glucocorticoids (prednisone, 1-2 mg/kg) for severe adverse events. Depending on the irAE severity, future ICI therapy may be permanently discontinued.
Adverse Event Type Incidence with anti-CTLA-4
(e.g. ipilimumab)		 Incidence with anti‐PD1/PD‐L1
(e.g. nivolumab, pembrolizumab)
Skin (rash, pruritus, TEN) 30% 30%
Colitis 25% 5%
Hypothyroidism 20% 20%
Hepatitis 10% 1%
Hypophysitis 10% rare
Pneumonitis 2-5% 2-5%
Myocarditis \<1% \<1%
Neurotoxicity (GBS, myasthenia gravis, encephalitis) \<1% \<1%

Cytotoxic Agent Toxicities

Class Agent  Side Effect
Alkylating agents busulfan pulmonary fibrosis or diffuse alveolar hemorrhage
Alkylating agents cyclophosphamide myopericarditis, hemorrhagic cystitis (prevention: hydration; monitoring: daily UA, tx: mesna)
Alkylating agents ifosfamide encephalopathy (tx: methylene blue), nephrotoxicity, hemorrhagic cystitis
Antimetabolites 5- Fluorouracil (5-FU)/ Capecitabine (metabolized to FU) myelosuppression, coronary vasospasm, palmar-plantar erythrodysesthesia, mucositis
Antimetabolites cladribine, pentostatin dose reduced for CrCl
Antimetabolites cytarabine (Ara-C) irreversible cerebellar ataxia (if high dose, neuro checks required), conjunctivitis (prevent with prophylactic steroid eye drops)
Antimetabolites gemcitabine transient transaminitis, peripheral edema, rash, rarely: pulmonary toxicity, hemolytic uremic syndrome, capillary leak syndrome, PRES
Antimetabolites methotrexate stomatitis, hepatotoxicity, renal failure, high dose requires leucovorin
Antitumor antibiotics anthracyclines (doxorubicin, daunorubicin, idarubicin) HFrEF (need TTE prior). Most notable with doxorubicin.
Antitumor antibiotics bleomycin Pulmonary fibrosis. Potentiated with G-CSF
Monoclonal antibodies alemtuzumab severe and prolonged cytopenias
Monoclonal antibodies bevacizumab HTN, proteinuria, hyperglycemia, hypomag, Arterial Thromboembolism, pulm hemorrhage, GI bleeding/fistulas/perforation, wound healing complications HFrEF,
Monoclonal antibodies rituximab hypophos, hepatotoxicity, HBV reactivation (screen all pts), peripheral neuropathy; transfusion reaction during 1st time infusion
Platinum agents cisplatin, oxaliplatin, carboplatin Nephrotoxicity, worst with cisplatin. Rental tubular acidosis. Neurotoxicity (parasthesias, cold sensitivity, cramps, peripheral neuropathy), ototoxicity (high frequency hearing loss), constipation, hypomag
Taxanes docetaxel, paclitaxel hypersensitivity reaction (often require premedication with steroids and H1/H2 blockers); peripheral neuropathy
Topoisomerase inhibitors irinotecan, topotecan, etoposide irinotecan- acute diarrhea can be treated with atropine; delayed with imodium/Lomotil
Tyrosine kinase inhibitors imatinib, dasatinib, nilotinib, bosutinib QTc prolongation, pulmonary effusion, hepatotoxicity
Vinca alkaloid vincristine peripheral neuropathy and ototoxicity (vestibular system lost first)

Other treatments and toxicities:

Agent Adverse event(s) Management
Belzutifan Anemia and hypoxia Stop belzutifan, transfuse, supplement O2
BiTE/BiAb/CAR T Cells Cytokine release syndrome, ICANS See CAR T Cell Section
Radiation Therapy See Radiation Toxicity section (ie Skin, HEENT, GI) See Radiation Toxicity section

Indications for Inpt Radiation Oncology Consultation

Author: Jayden Gracie

Initial Considerations: - Is this really cancer? Must have a tissue diagnosis prior to consultation
- Is problem urgent? Clinic opens at 7:30am, so do not consult until after 7:30am unless emergent * Urgent conditions (Inpt consultation indicated, weekend treatment unlikely)
* Rule of thumb: true emergencies (label consult, 'Urgent,' may treat even on a weekend) * Spinal cord compression
* Airway collapse from mass effect
* Life-threating hemorrhage from mass
* Symptomatic brain mets (seizures, FND, ect)
* Anaplastic thyroid cancer
* Pain crisis from bone metastases
* Requiring rapid turnaround: keloids (post-surgical for keloid prevention), heterotopic ossification)

  • Everything else is generally treated outpt. Order an ambulatory referral for those pts.
  • For pts whose outpt radiation gets interrupted by admission, no need for consult. Page Rad-Onc to close the loop.

  • If in doubt, page Rad-Onc to discuss prior to placing consult.

  • Have non-radiation interventions been discussed with the team/consultants first?

  • Airway compromise: first consult IP/ENT for stent placement/trach
  • Cord compression or symptomatic brain mets: consult Neurosurgery for possible intervention
  • Spinal instability/pathologic fracture: calculate a Spinal Instability Neoplastic Score (SINS). If >6, consult Spine to assess for instability and surgical candidacy. They must have an attested note prior to radiation planning. Not that radiation helps with tumor pain but does not help with instability or pain from the fractures themselves.

  • SVC syndrome: Consult IR for emergent percutaneous stent placement if 4_ points on Kishi scoring system. Engage Med Onc since chemo has a faster effect (especially in SLCL) than radiation (days). Consider surgical consult if concerned for thymoma

  • Is the pt fit enough for radiation? Common precluding factors:

  • Pt is too unstable
  • Cannot lie flat or stay still for 10 min of treatment, 30min-45min for planning (delirium, dyspnea, uncontrolled pain, seizing)
  • Head/neck radiation requires a facemask; claustrophobia should be addressed prior (benzos)

Pre-consultation workup:

  • Brain mets
  • If symptomatic, dexamethasone 10mg IV load followed by 4mg q6 thereafter (with PPI). Rad onc can help with taper plan. Do not stop during active treatments.
  • MRI with and without, labelled 'Cmelak Sequence' in comments section. May also be a 'For Radiation Planning' box.
  • CSF sampling if suspicious of leptomeningeal spread

  • DO NOT stop keppra If already onboard for seizures.

  • Spine mets

  • Damage becomes irreversible around 48 hours from symptom onset. Do not delay treatment and consultation (spine, rad onc, ect).
  • STAT MRI with and without contrast.
  • Dexamethasone 10mg IV load followed by 4mg q6 thereafter (with PPI). Rad onc can help with taper plan. Do not stop during active treatments.

Logistical Considerations - Treatment planning takes several days to plan except in urgent/emergent circumstances.
- Rad-Onc arranges ALL TRANSPORT for their pts. No need for primary team to do anything.
- Pts must get a “CT sim” image in Rad-Onc department before starting any treatment.
- Let Rad-Onc know if pts are going for other procedures/imaging on a treatment day, or if pt is refusing treatment.
- Radiation plans cannot be transferred into or out of the Vanderbilt system. Let Rad-Onc know a few days in advance if transfers between Vanderbilt centers will be needed.
- Pts cannot get radiation at 90% SNFs. Radiation must be completed prior to dispo.
- Most CLCs do not transfer pts back and forth to radiation treatments, so if planning to discharge to CLC, radiation needs to be finished inpt or start after the CLC.
- In general, most curative RT treatments take several weeks. Most palliative regimens take 1-10d.

Radiation at the VA* - Pts need prior authorization before Rad-Onc is allowed to see VA pts at VUMC. To obtain PA, consult Med Onc and email Dr. York (medical oncologist at the VA). This may take a couple days. For Emergent cases, you do NOT have to wait on the PA. Rad-Onc can arrange for transport.
- Rad-Onc attendings do not have access to the VA system. Notes will be in VUMC system.

Radiation Toxicity

Author: Jayden Gracie

Radiation pneumonitis - 6 weeks to 6 months after RT to chest
- Presents like pneumonia with cough and SOB, so need to rule out PNA
- Imaging: chest X-ray or CT
- Treatment: steroids

Radiation dermatitis - Onset during or shortly after treatment
- Variable: redness, dry desquamation (peeling, dry skin), or wet desquamation (blistering and oozing)
- Treatment * Aquaphor or Aquaphor + lidocaine
* Lidocaine can sometimes burn over wet desquamation. For wet desquamation (especially if looks potentially infected), start on Silvadene until it dries up. Then add non-adhesive barrier dressings.
* Topical corticosteroids are helpful for itching (e.g. OTC hydrocortisone)
* Sitz baths and peri bottles useful for perineal skin reaction after RT to chest.

Mucositis - Treatment * Salt water and baking soda rinses to help clear debris out of mouth.
* Magic mouthwash, swish and spit if mouth only (as many times a day as they want) or swish and swallow up to every 4h. Can give viscous lidocaine if pt prefers.
* For weight loss >15lbs during treatments: consider G-tube but want to avoid if possible since slows swallowing function recovery
* Can try soft or liquid diet, protein drinks
* For esophagitis, can order carafate liquid formulation (to coat esophagus). May require prior auth, indication is radiation esophagitis. Consider PPI

Secretions and mouth dryness - Glycopyrrolate or Mucinex can help with thick secretions but can be drying.
- Baking soda and salt, sugarless gum
- Can try Levsin, scopolamine patches.

Nausea - Evaluate for and treat constipation, secretions, and acid reflux
- Zofran is 1st line followed by compazine

Pain flairs - Present with treatment of bony mets in up to 40% of pts. Spikes in pain usually occur either toward the end of treatment or a few days after due to inflammation.
- Treat with steroid taper per Rad-Onc

Radiation-associated dysuria - Presents with UTI-like symptoms during treatment.
- Rule out UTI
- Treatment: Hydration. Can try NSAIDs and phenazopyridine (note urine color change). Consider short steroid course next.

Bowel toxicity - Upper: nausea/vomiting, loose/watery stools.
- Lower: loose/watery stools, cramping, tenesmus, urgency
- Treatment: Try low residue diet, anti-diarrheal agents (Imodium, Lomotil), sucralfate, protozoa/5-ASA enemas
- Consider cessation or break of RT