Pocket Medicine (Pocket Notebook Series)

ANEMIA

↓ in RBC mass: Hct <41% or Hb <13.5 g/dL (men); Hct <36% or Hb <12 g/dL (women)

Clinical manifestations

• Symptoms: ↓ O₂ delivery → fatigue, exertional dyspnea, angina (if CAD)

• Signs: pallor (mucous membranes, palmar creases), tachycardia, orthostatic hypotension

• Other findings: jaundice (hemolysis), splenomegaly (thalassemia, neoplasm, chronic hemolysis), petechiae/purpura (bleeding disorder), glossitis (iron, folate, vitamin B₁₂ defic.), koilonychia (iron defic.), neurologic abnormalities (B₁₂ defic.)

Diagnostic evaluation

• History: bleeding, systemic illness, drugs, exposures, alcohol, diet (including pica), FHx

• CBC w/ diff.; RBC params incl. retics, MCV (nb, mixed disorder can → nl MCV), RDW

• Reticulocyte index (RI) = [reticulocyte count × (Pt’s Hct/nl Hct)]/maturation factor maturation factors for a given Hct: 45% = 1, 35% = 1.5, 25% = 2, 20% = 2.5 RI >2% → adequate marrow response; RI <2% → hypoproliferation

• Peripheral smear: select area where roughly ⅓ RBCs touch each other; ✓ RBC size, shape, inclusions (see “Appendix” & “Peripheral Smear”), WBC morphology, plt count

• Additional labs as indicated: hemolysis labs (if RI >2%, see below), iron/TIBC, ferritin, folate, B₁₂, LFTs, BUN, & Cr, TFTs, Hb electrophoresis, enzyme/gene mutation screens

• Bone marrow (BM) aspirate and biopsy (bx) with cytogenetics as indicated

MICROCYTIC ANEMIAS

Iron deficiency (Lancet 2021;397:233)

• ↓ marrow iron & depleted body iron stores → ↓ heme synthesis → microcytosis → anemia

• Special clinical manifestations: angular cheilosis, atrophic glossitis, pica (consumption of nonnutritive substances such as ice, clay), koilonychia (nail spooning)

Plummer-Vinson syndrome (iron deficiency anemia, esophageal web & atrophic glossitis)

• Etiologies: chronic bleeding (GI—incl. cancer, menstrual, parasites, NSAIDs, etc.), ↓ supply (malnutrition; ↓ absorp. due to celiac sprue, Crohn’s, ↑ gastric pH, subtotal gastrectomy), ↑ demand (preg; Blood 2017;129:940). Iron-refractory iron-defic. anemia (IRIDA; rare genetic disorder due to hepcidin dysregulation; Nat Genet 2008;40:569).

• Diagnosis (eval ideally before Rx): ↓ Fe, ↑ TIBC, ↓ ferritin (esp. <15), ↓ transferrin sat (Fe/TIBC; esp. <15%), ↑ soluble transferrin receptor; ↑ plt. Unless hx c/w other etiology, initiate workup for GIB, incl. H. pylori serology. ? Celiac labs (anti-TTG, anti-endomysial IgA Abs). Cytogenetics & molecular testing as indicated (eg, MDS, leukemia).

• Treatment: oral Fe TID (~6 wks to correct anemia; ~6 mo to replete Fe stores; nb, oral Fe does not give ⊕ Hemoccult). With severe anemia, persistent losses, prior to Epo Rx, or while inpatient, use IV iron (Fe-sucrose, -gluconate, -dextran).

Thalassemias (Lancet 2018;391:155)

• ↓ synthesis of α- or β-globin chains of Hb → ≠ subunits → destruction of RBCs and erythroid precursors; ∴ anemia from hemolysis and ineffective erythropoiesis

• α-thalassemia (NEJM 2014;371:1908): deletions in α-globin gene complex (nl 4 α genes), seen w/ Southeast Asian, Mediterranean, African, Middle East ancestry

3 α → silent carrier; 2 α → α-thal minor = mild anemia, α-thal-1 (--/αα, milder) or

α-thal-2 (-α/-α); 1 α → HbH (β₄) disease = severe anemia, hemolysis, and splenomegaly

0 α genes → Hb Barts (γ₄) = intrauterine hypoxia and hydrops fetalis

• β-thalassemia: mutations in β-globin gene → absent or ↓ gene product seen w/ Mediterranean (espec. Greek or Italian), African, or Asian ancestry

1 mutated β gene → thal minor (or trait) = mild anemia (no transfusions)

2 mutated β genes → thal intermedia (occasional transfusions) or thal major (= Cooley’s anemia; transfusion dependent) depending on severity of mutations

• Special clinical manifestations: chipmunk facies, pathologic fractures, hepatosplenomegaly (due to extramedullary hematopoiesis), high-output CHF, bilirubin gallstones, Fe overload

• Dx: MCV <70, normal Fe, ferritin, MCV/RBC count <13 [Mentzer Index, 60% Se, 98% Sp; (Ann Hem 2007;86:486)], ± ↑ retics, basophilic stippling; Hb electrophoresis: ↑ HbA₂ (α₂δ₂) in β-thal; normal pattern in α-thal trait, ∴ PCR or supravital stain for dx

• Treatment: folate; transfusions + Fe chelator [either deferoxamine (IV) or deferasirox (PO)]; ? splenectomy if ≥50% ↑ in transfusions; gene therapy in development (NEJM 2018;378:1479); luspatercept (↓ SMAD signaling) in β-thal major (NEJM 2020;382:1219)

Anemia of chronic inflammation (see below)

Sideroblastic anemia

• Defective heme biosynthesis within RBC precursors

• Etiologies: hereditary/X-linked (ALAS2 mutations), idiopathic, MDS-RARS, reversible (alcohol, lead, isoniazid, chloramphenicol, copper deficiency, hypothermia)

• Special clinical manifestations: hepatosplenomegaly, iron overload syndromes

• Dx: social, work, & TB hx; can be micro-, normo-, or macrocytic; variable populations of hypochromic RBCs; ↑ Fe, nl TIBC, ↑ ferritin, basophilic stippling, RBC Pappenheimer bodies (Fe-containing inclusions), ring sideroblasts (w/ iron-laden mitochondria) in BM

• Treatment: treat reversible causes; trial of pyridoxine, supportive transfusions for severe anemia with chelation therapy; high-dose pyridoxine for some hereditary cases

NORMOCYTIC ANEMIAS

Anemia of chronic inflammation (ACI; NEJM 2012;366:4)

• ↓ RBC production due to impaired iron utilization and functional iron deficiency from ↑ hepcidin; cytokines (IL-6, TNF-α) cause ↓ Epo responsiveness/production

• Etiologies: autoimmune disorders, chronic infection, inflammation, HIV, malignancy

• Dx: ↓ Fe, ↓ TIBC (usually normal or low transferrin sat), ± ↑ ferritin; usually normochromic, normocytic (~70% of cases) but can be microcytic if prolonged

• Coexisting iron deficiency common. Dx clues include ↓ serum ferritin levels, absence of iron staining on BM bx, ⊕ response to a trial of oral iron and/or ↑ soluble transferrin receptor/ferritin index (Am J Clin Pathol 2012;138:642).

• Treatment: treat underlying disease ± iron and/or erythropoiesis-stimulating agent (ESA; eg, Epo). Iron if ferritin <100 or Fe/TIBC <20%. Consider ESA if Epo <500. Avoid ESA in cancer if treatment goal is cure (Lancet 2009;373:1532). Transfuse PRBCs only if symptomatic & insufficient time to wait for response to Epo or underlying disease Rx.

Anemias of other chronic disorders

• Anemia of CKD: ↓ Epo; treat w/ Epo & iron (see “Chronic Kidney Disease”)

• Endocrine deficiencies: hypometabolism and ↓ O₂ demand with thyroid, pituitary, adrenal, or parathyroid disease → ↓ Epo; can be normocytic or macrocytic

Sideroblastic anemia (see above)

Pure red cell aplasia

• Destructive antibodies or lymphocytes → ineffective erythropoiesis

• Associated with thymoma, CLL, parvovirus infection, autoimmunity, drugs

• Diagnostic studies: lack of erythroid precursors on BM bx, other lines normal

• Treatment: thymectomy if thymus enlarged; IVIg if parvovirus and immunosuppressed (Clin Infect Dis 2013;56:968); immunosuppression/chemoRx if CLL or idiopathic; supportive care w/ PRBC transfusions; ? erythropoietin receptor agonist if due to antierythropoietin Ab (NEJM 2009;361:1848); consider hematopoietic cell transplantation.

MACROCYTIC ANEMIAS

includes megaloblastic and nonmegaloblastic causes

Megaloblastic anemia

• Impaired DNA synthesis → cytoplasm matures faster than nucleus → ineffective erythropoiesis and macrocytosis; due to folate or B₁₂ deficiency; also in MDS

• ✓ folate and vitamin B₁₂; ↑ LDH & indirect bilirubin (due to ineffective erythropoiesis)

• Smear: neutrophil hypersegmentation, macro-ovalocytes, anisocytosis, poikilocytosis

Folate deficiency

• Folate present in leafy green vegetables and fruit; total body stores sufficient for 2–3 mo

• Etiologies: malnutrition (alcoholics, anorectics, elderly), ↓ absorption (sprue), impaired metabolism (methotrexate, pyrimethamine, trimethoprim; NEJM 2015;373:1649), ↑ requirement (chronic hemolytic anemia, pregnancy, malignancy, dialysis)

• Diagnosis: ↓ folate; ↓ RBC folate, ↑ homocyst. but nl methylmalonic acid (unlike B₁₂ defic.)

• Treatment: folate 1–5 mg PO qd for 1–4 mo or until complete hematologic recovery; critical to r/o B₁₂ deficiency first (see below)

Vitamin B₁₂ deficiency (NEJM 2013;368:149)

• B₁₂ present only in foods of animal origin; total body stores sufficient for 2–3 y

• Binds to intrinsic factor (IF) secreted by gastric parietal cells; absorbed in terminal ileum

• Etiologies: malnutrition (alcoholics, vegans), pernicious anemia (PA, autoimmune disease against gastric parietal cells, a/w polyglandular endocrine insufficiency and ↑ risk of gastric carcinoma), other causes of ↓ absorption (gastrectomy, sprue, Crohn’s disease), ↑ competition (intestinal bacterial overgrowth, fish tapeworm)

• Clinical manifestations: neurologic changes (subacute combined degeneration) affecting peripheral nerves, posterior & lateral columns of the spinal cord and cortex → numbness, paresthesias, ↓ vibratory & positional sense, ataxia, dementia, mood

• Dx: ↓ B₁₂ (even low nl); ↑ homocysteine & methylmalonic acid; anti-IF Ab; ↑ gastrin in PA

• Treatment: 1 mg B₁₂ IM qd × 7 d → q wk × 4–8 wk → q month for life

neurologic abnormalities are reversible if treated w/in 6 mos

folate can reverse hematologic abnormalities of B₁₂ deficiency but not neurologic changes (and can “steal” B₁₂ stores → worsening of neuro complications)

oral supplementation (2 mg qd) appears feasible as well (Cochrane Rev CD004655) even w/o IF

Nonmegaloblastic macrocytic anemias

• Liver disease: often macrocytic, may see target cells, or spur cell anemia w/ hemolysis

• Alcoholism: BM suppression & macrocytosis independent of folate/B₁₂ defic. or cirrhosis

• Other causes: reticulocytosis; hypothyroid; MDS; meds impairing DNA synth (zidovudine, 5-FU, hydroxyurea, Ara-C); hereditary orotic aciduria; Lesch-Nyhan syndrome

PANCYTOPENIA

Etiologies

• Hypocellular bone marrow (nl cellularity ~100 – age): aplastic anemia, hypoplastic MDS

• Cellular bone marrow: MDS, aleukemic leukemia, PNH, severe megaloblastic anemia

• Myelophthesis (marrow replacement, PMF); systemic dis. (hypersplen, sepsis, EtOH/toxin)

Clinical manifestations

• Anemia → fatigue; neutropenia → recurrent infections; thrombocytopenia → mucosal bleeding & easy bruisability

Aplastic anemia (stem cell failure) (NEJM 2015;373:35)

• Epidemiology: 2–5 cases/10⁶/y; biphasic (major peak in adolescents, 2^nd peak in elderly)

• Diagnosis: pancytopenia w/ ↓ retics, BM bx w/ hypocellularity, usually nl cytogenetics

• Etiologies: idiopathic (½ – ⅔ of cases)

Stem cell destruction: radiation, chemotherapy, chemicals (eg, benzene)

Med rxn (eg, chloramphenicol, NSAIDs, sulfa drugs, gold, carbamazepine, antithyroid)

Viruses (HHV-6, HIV, EBV, parvovirus B19); post-viral hepatic failure (not Hep A/B/C)

Immune disorders (SLE, GVHD post-HSCT, thymoma)

PNH (see below); Fanconi’s anemia (congenital disorder w/ pancytopenia, macrocytic anemia, ↑ risk of MDS, AML, & SCC of head & neck, and multiple physical anomalies)

Shortened telomeres: seen w/ telomerase (TERT, TERC) mut. (10% of aplastic anemia), dyskeratosis congenita/DKC1 mut; a/w IPF, cirrhosis (NEJM 2009;361:2353)

Somatic mutations: PNH clones in ~50% of aplastic anemia (Haematologica 2010;95:1075)

• Treatment and prognosis

Immunosuppression (CsA/tacrolimus, ATG): 70–80% respond, with 80–90% 5-y survival in responders (96% vs. 76% w/ horse vs. rabbit ATG; NEJM 2011;365:430); 15–20% 10-y incidence of clonal disorders (mostly MDS, AML, PNH)

TPO mimetics (eg, eltrombopag): use 1^st-line w/ immunosuppression (NEJM 2022;386:11)

Supportive care: transfusions, abx, possible utility of G-CSF & Epo (if Epo <500)

Allogeneic HSCT: for young Pts → ~80% long-term survival and significantly ↓ risk of malignant evolution, but has risk of transplant-related morbidity & mortality; if possible, avoid transfusions (risk of alloimmunization) pretransplant

Myelodysplastic syndromes (MDS) (qv)

Paroxysmal nocturnal hemoglobinuria (PNH) (Blood 2009;113:6522)

• Acquired clonal stem cell disorder = inactivating somatic mutation of PIG-A gene → deficiency of GPI-anchor for CD55 & CD59 (inhib of complement) → complement-mediated RBC lysis, plt aggregation, & hypercoagulability

• Clinical: intravascular hemolytic anemia, hypercoagulability (venous >arterial; esp. intraabdominal, cerebral), smooth muscle dystonias, deficient hematopoiesis (cytopenias); a/w aplastic anemia, MDS and evolution to AML

• Dx: flow cytometry (↓ CD55 & CD59) on RBCs and granulocytes; urine hemosiderosis

• Treatment: supportive care (iron, folate, transfusions); consider anticoagulation.

Allogeneic HSCT for hypoplasia or severe thrombosis.

Pegcetacoplan (binds C3, prevents complement cascade activation) superior to eculizumab (Ab inactivates terminal complement C5s) in ↓ hemolysis & stabilizing Hb levels (NEJM 2021;384:1028). Eculizumab effective in pregnancy (NEJM 2015;373:1032); must have meningococcal vaccination.

Myelophthisic anemia (see also “Primary Myelofibrosis”)

• Infiltration of bone marrow by cancer (commonly metastatic solid tumors), leukemia, infection, fibrosis (primary myelofibrosis), granulomas, lysosomal storage disorders

HEMOLYTIC ANEMIAS

Causes of Hemolytic Anemia by Mechanism (Lancet 2000;355:1169 & 1260)
Cause	Mechanism	Examples	Mode
Intrinsic	Enzyme deficiency	G6PD deficiency	Hereditary
	Hemoglobinopathies	Sickle cell anemia, thalassemia
	Membrane abnormalities	Hereditary spherocytosis
		PNH, spur cell anemia in liver disease	Acquired
Extrinsic	Immune-mediated	Autoimmune; drug-induced, tx rxn
	Traumatic	MAHA; prostheses (valves, TIPS)
	Direct infections, toxins	Malaria, babesiosis; snake & spider venoms; Wilson’s; hypotonic infusions
	Entrapment	Hypersplenism

Diagnostic evaluation

• ↑ retic count (RI >2%), ↑ LDH, ↓ hapto (83% Se, 96% Sp), ↑ indirect bili, ✓ vit C & Cu

• Autoimmune hemolysis: Coombs’ test = direct antiglobulin test (DAT) → ⊕ if agglutination occurs when antisera against Ig or C3 are applied to patient RBCs

• Location of hemolysis (many conditions can include components of both)

Intravascular: RBC destruction in vessels (shear by mech valve, DIC, toxins); assoc. w/ hemoglobinemia, hemoglobinuria, hemosiderinuria, ↑↑ LDH, ↓ haptoglobin.

Extravascular: more common cause. Mϕ clear damaged/opsonized RBC; splenomegaly (reticuloendothelial expansion in spleen, liver, BM, LNs); ↑ LDH ↓ hapto

• Family h/o anemia; personal or family h/o cholelithiasis

Glucose-6-phosphate dehydrogenase (G6PD) deficiency (Lancet 2008;371:64)

• X-linked defect of metabolism (G6PD mutations) w/ ↑ susceptibility to oxidative damage

• Most common in ♂ of African or Mediterranean descent (malaria-endemic areas)

• Hemolysis precipitated by drugs (sulfonamides, dapsone, nitrofurantoin, rasburicase, primaquine, doxorubicin, methylene blue), infxn, DKA, foods (favism, NEJM 2018;378:60)

• Diagnosis: smear may show RBC Heinz bodies (oxidized Hb) that result in bite cells once removed by spleen; ↓ G6PD levels (may be normal after acute hemolysis because older RBCs have already lysed and young RBCs may still have near-normal levels)

Sickle cell anemia (NEJM 2017;376:1561 & Lancet 2017;390:311)

• Recessive β-globin mutation → structurally abnl hemoglobin (HbS). ~8% African Americans heterozygotes (“sickle trait”; usually w/o sx); ~1/400 homozygotes (sickle cell disease).

• ↓ O₂ → HbS polymerizes → RBC sickles, ↓ RBC deformability → hemolysis & microvascular occlusion due to endothelial activ. & PMN adhesion (Blood 2013;122:3892)

• Anemia: chronic hemolysis ± acute aplastic (parvo. B19) or splenic sequestration crises

• Vaso-occlusion & infarction: acute chest syndrome & stroke (high mortality), pulmonary HTN, painful crises, splenic sequestration, renal papillary necrosis, avascular necrosis, dactylitis (hand–foot syndrome), priapism

• Infection: splenic infarction → overwhelming infection by encapsulated organisms; infarcted bone → osteomyelitis (Salmonella, Staph. aureus), can be life threatening

• Diagnosis: sickle-shaped RBCs and Howell-Jolly bodies on smear; Hb electrophoresis

• Treatment: hydroxyurea, folic acid; voxelotor (Hgb S polymerization inhibitor) ↓ hemolysis & ↑ Hgb (NEJM 2019;381:509)

• Vaccines: pneumo, meningo, H flu, HBV

• Pain & vaso-occlusive crises: analgesia (consider PCA; ask Pt what worked prev.), IVF, transfusion only if sx & Hgb below Pt’s baseline (often low) given alloimmunization & Fe accumulation (need chelation); Ppx w/ crizanlizumab (anti-P-selectin; NEJM 2017;376:429)

• Acute chest (fever, ↑ WBC, pulm. infilt., r/o other causes): O₂, abx, IVF, exchange txfusion

• TIA/stroke: often exchange transfusion (goal Hgb 10) ± thrombolytics

• Gene therapy in development (NEJM 2021;384:205)

Hereditary spherocytosis (HS) (Lancet 2008;372:1411)

• Defect in cytoskeleton of RBC membrane (ankyrin, α- and β-spectrin, band 3, & pallidin)

• Most common in N. European populations (1/5000 births); ⊕ FHx (75% of Pts)

• Anemia, jaundice (mostly neonates), splenomegaly, pigmented gallstones

• Diagnosis: spherocytes on smear, ⊕ osmotic fragility test (~80% Se), ↓ eosin-5-maleimide (EMA) binding (93% Se; 99% Sp; Haemat 2012;97:516), acidified glycerol lysis test (Se 95%)

• Treatment: folate, transfusions, splenectomy for moderate and severe HS (balance w/ ↑ risk of future thrombosis and infection; J Thromb Haemost 2008;6:1289)

Paroxysmal nocturnal hemoglobinuria (see above)

Autoimmune hemolytic anemia (AIHA)

• Acquired, antibody-mediated RBC destruction

• Warm AIHA: IgG Abs opsonize RBCs at body temp → removal by spleen

Etiologies: idiopathic, lymphoproliferative (CLL, NHL), autoimmune (SLE), drugs, HIV, babesiosis (NEJM 2017;376:939)

• Cold AIHA: IgM Ab binds to RBCs at temp <37°C → complement fixation → intravascular hemolysis and acrocyanosis on exposure to cold

Etiologies: idiopathic, lymphoprolif. disorders (eg, Waldenström’s; monoclonal), Mycoplasma pneumoniae infxn and infectious mononucleosis (polyclonal)

• Diagnosis: spherocytes on smear, ⊕ Coombs’; ✓ cold agglutinin titer, splenomegaly

• Treatment (Blood 2017;129:2971): treat underlying disease

Warm AIHA: corticosteroids ± splenectomy, IVIg, cytotoxic agents, rituximab

Cold AIHA: avoid cold; steroids ineffective; rituximab (Blood 2004;103:2925); complement inhibitors (sutimlimab) approved for cold agglutinin disease (NEJM 2021;384:1323)

Drug-induced hemolytic anemia

• Acquired, Ab-drug mediated destruction vs. direct drug effect. Abx: ceph., sulfa drugs, rifampin, ribavirin. CV: methyldopa, procainamide, quinidine, thiazides. TCAs, phenothiazines, NSAIDs, sulfonylureas, MTX, 5-FU, rasburicase (G6PD defic.)

• Diagnosis: Coombs’ usually negative, ↑ LDH; Treatment: discontinue offending agent

Microangiopathic hemolytic anemia (MAHA; NEJM 2014;371:654)

• Intra-arteriolar fibrin damages RBCs → acquired intravascular hemolysis

• Etiologies: hemolytic-uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), malignancy, malignant HTN, eclampsia/HELLP, mech. cardiac valves, infected vascular prostheses

• Diagnosis: schistocytes ± ↓ plts ± ↑ PT in DIC, ↑ Cr in HUS, ↑ LFTs in HELLP

• Rx: see “DIC” section in “Coagulopathies” and “TTP/HUS” sections in “Platelet Disorders”

Hypersplenism

• Stasis/trapping in spleen → Mϕ attack/remodel RBCs → spherocytosis → hemolysis

Causes of Splenomegaly
Etiology	Comments*
RES hyperplasia	Hemolytic anemia, sickle cell disease, thalassemia major
Immune hyperplasia	Infxn [HIV, EBV, CMV, TB, malaria, kala azar (“black water fever” from visceral leishmaniasis), Mycobacterium avium complex], autoimmune disorders (SLE, RA w/ Felty’s syndrome), sarcoidosis, serum sickness
Congestion	Cirrhosis, CHF, portal/splenic vein thrombosis, schistosomiasis
Infiltration (nonmalignant)	Lysosomal storage disorders (Gaucher’s, Niemann-Pick), glycogen storage diseases, histiocytosis X, splenic cysts
Neoplasm	MPN (CML, PMF, PV, ET), CMML, leukemia, lymphoma (NHL, HL, hairy cell leukemia, CLL, PLL, WM), T-LGL, myeloma, amyloid

RES = reticuloendothelial system; ^*boldface = causes of massive splenomegaly.

DISORDERS OF HEMOSTASIS

Clinical Characteristics of Bleeding Disorders
Feature	Platelet/Vascular Defect	Coagulation Defect
Site	Skin, mucous membranes	Deep in soft tissues (muscles, joints)
Lesions	Petechiae, ecchymoses	Hemarthroses, hematomas
Bleeding	After minor cuts: yes After surgery: immediate, mild	After minor cuts: unusual After surgery: delayed, severe

See “Coagulopathies” for reversal agents for anticoagulants. APC, activated protein C; AT, antithrombin; PrC, protein C; PrS, protein S; TF, tissue factor; TFPI, tissue factor pathway inhib.

Purpura (nonblanching purple/red lesions due to extravasation of RBCs into dermis)

• Nonpalpable (macular; ≤3 mm in diameter = petechiae; >3 mm = ecchymoses)

platelet disorder: thrombocytopenia, defect in platelet fxn

thromboemboli: DIC, TTP, cholesterol or fat emboli, other thrombotic microangiopathies

trauma or vascular fragility: amyloidosis, Ehlers-Danlos, scurvy

• Palpable (papular); vasculitis: leukocytoclastic, HSP, PAN, RMSF; infectious emboli: meningococcemia, bacterial endocarditis

• Purpura fulminans (aka retiform purpura): purpura + hypotension + DIC; typically due to infxn/sepsis, protein C or S deficiency or APS (see section on DIC)

PLATELET DISORDERS

THROMBOCYTOPENIA (Plt count <150,000/μL)

Thrombocytopenia and Risk of Bleeding
Platelet Count (cells/µL)	Risk
50,000–100,000	Risk with major trauma; can proceed with general surgery
<50,000	Risk with minor trauma or surgery
<20,000	Risk of spontaneous bleeding (less so with ITP)
<10,000	Risk of severe, life-threatening bleeding

Etiologies

• ↓ production

Hypocellular bone marrow: aplastic anemia (qv), rarely MDS, drugs (eg, thiazides, antibiotics, chemotherapy), alcohol, cirrhosis, viral infection

Hypercellular bone marrow: MDS, leukemia, severe megaloblastic anemia

Marrow replacement: myelofibrosis, hematologic and solid malignancies, granulomas

• ↑ destruction

Immune-mediated (distinguish primary from secondary; Blood 2009;113:2386)

1° (idiopathic): immune thrombocytopenic purpura (ITP, see below)

2°: infxn (HIV, HCV, HSV), collagen vascular dis. (SLE), APS, lymphoprolif. (CLL, lymphoma), drugs (many, including heparin, abciximab, quinidine, sulfonamides, vanco), alloimmune (posttransfusion), vaccine-induced

Non–immune-mediated: MAHA (DIC, HUS, TTP), ticlopidine/clopidogrel, vasculitis, preeclampsia/HELLP, cardiopulm bypass, CVVH, IABP, cavernous hemangioma, viral

• Abnormal distribution or pooling: splenic sequestration, dilutional, hypothermia

• Critical illness: multifactorial (Hematology Am Soc Hematol Educ Program 2017;1:660)

• Unknown: ehrlichiosis/anaplasmosis, babesiosis, RMSF

Diagnostic evaluation

• H&P: meds, infxns, underlying conditions, splenomegaly, lymph nodes, bleeding hx

• CBC with differential: isolated thrombocytopenia vs. multilineage involvement

• Peripheral smear (r/o pseudothrombocytopenia due to platelet clumping)

↑ destruction → look for large plts, ↑ MPV, schistocytes (see “Peripheral Smear” inserts)

↓ production → rarely limited to platelets → look for blasts, hypersegmented PMNs, leukoerythroblastic Δs; can see inclusion bodies (anaplasma), parasites (Babesia)

• Additional laboratory evaluations as indicated (eg, viral titers, flow cytometry, ANA, APLA)

if anemia: ✓ reticulocyte count, LDH, haptoglobin, bilirubin to detect hemolysis

if hemolytic anemia: ✓ PT, PTT, fibrinogen, D-dimer, Coombs, ANA

BM bx for unexplained thrombocytopenia, esp. if associated with splenomegaly

Primary immune thrombocytopenic purpura (ITP) (Blood 2010;115:168)

• Isolated thrombocytopenia due to immune plt destruction (auto-Ab to plts) & ↓ production (auto-Ab to megakaryocytes) without precipitant

• Clinical manifestations: insidious onset of mucocutaneous bleeding; ♀:♂ = 3:1

• Diagnosis of exclusion (r/o 2° ITP); no robust clinical or lab parameters, but typically:

CBC: isolated ↓ plt (<100,000/µL); 10% have ITP + AIHA = Evans syndrome

Peripheral smear: large platelets (not specific), r/o pseudothrombocytopenia

BM bx: ↑ megakaryocytes, nl cellularity. Consider if other CBC or smear abnl or diagnostic uncertainty (Blood 2011;117:4910).

✓ HBSAg & anti-HBc prior to rituximab (and before IVIg, which could alter results)

• Treatment: rarely indicated if plt >50,000/µL unless bleeding, trauma/surgery, anticoag.

Treatment of Primary ITP in Adults
Approach	Treatment	Notes
First-line or upfront therapy	Steroids: prednisone 0.5–2 mg/kg/d PO tapered ~4 wk, or dexamethasone 40 mg PO × 4 d	↓ Mϕ FcR & ↓ anti-plt Ab 70–90% have initial response ~20% sustained remission
	IVIg (1 g/kg/d IV × 2–3 d) Consider if need rapid ↑ in plt in 24–48 hrs; lasts 2–6 wks	Blocks Mϕ FcR, ↓ anti-plt Ab Interferes w/ Mϕ uptake Ab-coated plts; 80% have initial response
	Anti-Rh(D) Ig: alternative to IVIg if RBC Rh(D) ⊕; 50–75 mcg/kg/d	Ab-coated RBCs overwhelm Mϕ FcR Avoid if h/o hemolysis; not often used
Second-line or maint. therapy	Romiplostim, el/avatrombopag	TPO-R agonists → ↑ plt prod
	Rituximab (anti-CD20) ± dex	anti–B-cell Ab
	Splenectomy* (less common)	~65% long-term remission
	AZA, CYC, MMF	Immunosuppressants
	Danazol: 600 mg/d	Androgen (hirsutism) ↓ plt clearance
Chronic/ refractory	Romiplostim or eltrombopag	Allows splenectomy to be deferred
	Fostamatinib: 75–150 mg BID	Spleen tyrosine kinase (SYK) inhibitor
	Vinca alkaloids	Good initial response, less durable
Bleeding	Aminocaproic acid	Inhibits plasmin activation
	Methylprednisolone 1 g/d IV × 3 d	See above
	IVIg	See above
	Platelet transfusion	Given w/ IVIg or anti-Rh(D)

^*Post-splenectomy vaccinations needed. (Blood Adv 2019;3:3829; Eur J Haem 2018;100:304)

Secondary immune thrombocytopenic purpura (2° ITP)

• Diagnosis: viral serologies (HIV, HCV, HBV, EBV), H. pylori Ab, ANA, pregnancy test, APLA, TSH, parvovirus, & CMV PCR. Anti-plt Ab tests often sent but less useful.

Heparin-Induced Thrombocytopenias (Chest 2012;141:e495S; NEJM 2015;373:252)
Feature	Type I (not clin. signif)	Type II (clinically significant HIT)
Mechanism	Direct effect of heparin (non-immune)	Immune (Ab)-mediated IgG against plt factor 4—heparin complex
Incidence	10–20%	1–3% with UFH, 0–0.8% LMWH
Onset	After 1–4 d of heparin therapy	After 4–10 d, but can occur in <24 h if prior exposure w/in 100 d (persistent Ab). Postop highest risk. Can occur after heparin d/c.
Platelet nadir	>100,000/µL	~60,000/µL, ↓ >50%
Sequelae	None	Thrombotic events (HITT) in 30–50%
Management	Can continue heparin and observe	Discontinue heparin Alternative anticoagulation

• Treat underlying etiology

• Pathophysiology (type II): Ab binds heparin-PF4 → immune complex binds to plt → plt activation, further PF4 release → plt aggregates removed from circulation → thrombocytopenia; procoagulants released by plts and tissue factor released by endothelial cells damaged by HIT Abs → prothrombotic state

• Diagnosis (need clinical + pathologic)

Clinical: plt <100k or ↓ 50% from baseline; or venous (DVT/PE) or arterial (limb ischemia, CVA, MI) thrombosis (4:1 ratio); skin necrosis; ? ↑ heparin resistance

Pathologic: ⊕ HIT Ab using PF4-heparin ELISA (≥90% Se, IgG-specific ELISA Sp 94%), may confirm w/ functional plt assay (serotonin-release) (>95% Se/Sp)

Clinical context important: HIT Ab (esp. IgM ELISA) may be ⊕ in 10–20% of Pts on UFH/LMWH (Am J Hem 1996;52:90), up to 50% of cardiac bypass Pts (Circ 1997;95:1242)

Pretest prob w/ “4 T’s” criteria (Blood 2012;120:4160): ≤3 points → 99% NPV, investigate other causes; 4–5 points 22% PPV & 6–8 points 64% PPV, ✓ lab test & replace UFH

Evaluation of Suspected HIT (“4T’s”)
Factor	2 Points	1 Point	0 Points
Thrombo-cytopenia	↓ >50% and nadir ≥20k	↓ 30–50% or nadir 10–19k	↓ <30% or nadir <10k
Timing	5–10 d or ≤1 d if heparin w/in 30 d	? 5–10 d (but not clear), >10 d or ≤1 d if hep w/in 30–100 d	≤4 d w/o recent hep
Thrombosis	New thromb, skin necrosis, acute rxn after IV UFH	Prog/recurrent thromb, suspect thromb or non-nec skin lesion	None
Other cause	None apparent	Possible	Definite

• Treatment of HIT (type II) (NEJM 2015;373:252; Blood Adv 2018;2:3360)

Discontinue heparin (incl. flushes, LMWH Ppx, heparin lines). Avoid plts (anecdotal link w/ thrombosis); if given warfarin, give vit K to reverse, prevent warfarin skin necrosis.

Nonheparin anticoag (argatroban, bivalirudin; NEJM 2013;368:737) regardless of thrombosis; start warfarin when plt >150k, overlap ≥5 d or DOAC (Blood 2017;130:1104)

⊕ thrombosis (HITT): anticoagulate for ≥3–6 mo

⊖ thrombosis (HIT): screen for DVT; unclear duration of subsequent anticoag (until plt count recovers, often ~2–3 mo if no clot); 25–50% thrombosis rate w/in 30 d

• H/o HIT: if PF4 Ab ⊖ or SRA ⊖ (typically >100 d after dx) → may consider re-exposure to UFH (eg, for surgery); HIT recurrence low but can be seen (Blood 2014;123:2485)

Thrombotic microangiopathies (TMA; NEJM 2014;371:654; Lancet 2017;390:681)

• Endothelial injury → plt aggreg. & microvasc. thrombosis → ↓ plt & RBC hemolysis (MAHA)

• Dx: unexplained thrombocytopenia (typically <20k) + MAHA → sufficient for dx ⊕ schistocytes (>2–3/hpf), ⊖ Coombs, normal PT/PTT & fibrinogen ↑↑ LDH (tissue ischemia + hemolysis), ↑ indirect bili., ↓↓ haptoglobin, ↑ Cr (esp. in HUS)

Biopsy: arterioles filled with platelet hyaline thrombi

Ddx: DIC, vasculitis, malignant hypertension, preeclampsia/HELLP syndrome

• Thrombotic thrombocytopenic purpura (TTP)

Pathophys: ↓↓ ADAMTS13 protease activity (hereditary [Upshaw Schulman Syn.] or autoAb) → vWF multimers persist on endothelial surface → plt adhesion/aggregation → thrombosis

Clinical: pentad (all 5 in only ~5%) = ↓ plts + MAHA (100%) ± Δ MS (65%) ± renal failure (50%, late feature) ± fever (25%)

PLASMIC score to discriminate TTP from other TMAs (Lancet Haematol. 2017;4:157)

Rx: urgent plasma exchange ± glucocorticoids; FFP if delay to plasma exchange, caplacizumab (NEJM 2019;380:335), rituximab for 2° prevention (Blood Adv. 2017;1:1159),

plt transfusions contraindic. → ↑ microvascular thromb (J Thromb Haemost. 2020;18:2496)

• Hemolytic-uremic syndrome (HUS)

Pathophys: (1) Shiga toxin damages renal endothelial cells → intrarenal thrombi; or (2) complement dysregulation (hereditary or acquired), so-called “atypical HUS”

Clinical: triad = thrombocytopenia + MAHA + renal failure (bloody diarrhea if Shiga)

Rx: supportive care; eculizumab (J Nephrol 2017;30:127); plasma exchange if CNS sx

• Drug-induced TMA (clinically similar to TTP; Blood 2017;129:2857)

Immune-mediated (Ab reacts w/ plts & endothelial cells): eg, quinine, gemcitabine?

Direct toxicity mediated: eg, gemcitabine, mitomycin, tacrolimus, CsA, bevacizumab

Disseminated intravascular coagulation (DIC): see “Coagulopathies”

DISORDERS OF PLATELET FUNCTION

Mechanisms and Etiologies of Platelet Function Abnormalities
Function	Inherited	Acquired
Adhesion	Bernard-Soulier; vWD	Uremia; acquired vWD
Aggregation	Afibrinogenemia Glanzmann’s thrombasthenia	P2Y12 inhibitors, GP IIb/IIIa inhibitors Dysproteinemias (myeloma)
Granule release	Chediak-Higashi syndrome Hermansky-Pudlak syndrome	Drugs (ASA, NSAIDs); liver disease; MPN; cardiopulmonary bypass

Tests of platelet function

• Platelet aggregation tests: measure aggregation in response to agonists (eg, ADP)

von Willebrand’s disease (vWD) (NEJM 2016;375:2067)

• von Willebrand’s factor (vWF) function = platelet glue & plasma carrier of factor VIII

• vWD most common inherited bleeding disorder; ~85% (type 1) have partial quantitative vWF defic., ~15% (type 2) qualitative defic., <1% (type 3) total/near-total absence of vWF

• Acquired vWD: a/w many disorders (malig, MPN w/ ↑ plt count; autoimmune; hypo-thyroidism; drugs) and caused by different mechanisms (anti-vWF Abs, ↑ clearance, ↓ synthesis); Heyde’s syndrome = vWF destruction by severe AS, a/w GI AVMs/bleed

• Diagnosis: ↓ vWF:Ag, ↓ vWF activity (measured by ristocetin cofactor assay), ↓ factor VIII, ± ↑ PTT, ± ↓ platelets; confirm with vWF multimer analysis

• Clinical condition, factor VIII levels and ristocetin cofactor assay useful to guide Rx decision

• Rx: desmopressin (dDAVP, IV/IN; tachyphylaxis) → ↑ endothelial cell release of vWF; efficacy depends on type (avoid in type 2), ∴ ✓ response before use w/ bleeding or procedures; vWF replacement: cryo, vWF-rich factor VIII concentrates, recomb. vWF

Uremic bleeding

• Uremia → platelet dysfunction including ↓ aggregation, impaired adhesiveness

• Treatment: dDAVP, cryoprecipitate, correct anemia (improves plt aggregation and adhesion by increasing plt interactions with endothelium), consider holding anti-plt agents

COAGULOPATHIES

Further coagulation tests (JAMA 2016;316:2146)

• Mixing study: useful if ↑ PT or PTT; mix Pt’s plasma 1:1 w/ normal plasma and retest

PT/PTT normalizes → factor deficiency; PT/PTT remains elevated → factor inhibitor

• Coagulation factor levels: useful if mixing study suggests factor deficiency

DIC → all factors consumed; ∴ ↓ factors V and VIII

Liver disease → ↓ all factors except VIII; ∴↓ factor V, normal factor VIII

Vitamin K deficiency → ↓ factors II, VII, IX, X (and protein C, S); ∴ normal V and VIII

• DIC screen: ↓ fibrinogen (consumed), fibrin degradation products (FDPs, ⊕ from intense fibrinolysis), ↑ D-dimer (more specific FDP test that detects degradation of X-linked fibrin)

Hemophilias (Lancet 2016;388:187)

• X-linked recessive factor VIII (hemophilia A) or factor IX (hemophilia B) deficiency

• Classification: mild (5–25% normal factor activity), moderate (1–5%), or severe (<1%)

• Clinical manifestations: hematomas, hemarthroses, bruising, bleeding (mucosal, GI, GU)

• Diagnosis: ↑ PTT (normalizes w/mixing study), normal PT & vWF, ↓ factor VIII or IX

• Prophylaxis indicated if <1% activity of factor VIII or IX

• Rx: purified/recomb. factor VIII or IX; desmopressin (mild disease); anti-fibrinolytics (aminocaproic acid; tranexamic acid); cryo (FVIII); emicizumab (bridges factor IX and X), effective for hemophilia A w/ and w/o inhibitors (NEJM 2017;377:809 & 2018;379:811)

Coagulation factor inhibitors (anti-factor antibodies; anti-factor VIII most common)

• Etiologies: hemophilia; postpartum; lymphoproliferative & autoimmune disorders; cancers

• Diagnosis: ↑ PTT (does not normalize w/ mixing study); Bethesda assay quantitates titer

• Rx: if high titer → recomb. factor VIIa, porcine factor concentrates, activated prothrombin complex; for others → high-purity human factor, plasmapheresis, immunosuppression

Disseminated intravascular coagulation (DIC) (NEJM 2014;370:847)

• Etiologies: trauma, shock, infection, malignancy (esp. APL), obstetric complications

• Pathogenesis: massive activation of coagulation that overwhelms control mechanisms

Thrombosis in microvasculature → ischemia + microangiopathic hemolytic anemia

Acute consumption of coagulation factors and platelets → bleeding

Chronic DIC → able to compensate by ↑ factors and platelets → thrombosis

• Diagnosis: ↑ PT, ↑ PTT, ↓ fibrinogen (may be nl b/c acute phase), ⊕ FDP/D-dimer, ↓ plts, ⊕ schistos, ↑ LDH, ↓ hapto; chronic DIC: ⊕ FDP/D-dimer, variable plts, other labs nl

• Treatment: Rx underlying process; support w/ FFP, cryo (goal fbgn >100 mg/dL) & plts

Vitamin K deficiency

• Etiologies: malnutrition, ↓ absorption (antibiotic suppression of vitamin K-producing intestinal flora or malabsorption), liver disease (↓ stores), warfarin

Properties and Antidotes for Anticoagulants & Fibrinolytics (Circ 2016;134:248)
Anticoag.	t1/2	Labs	Rx for O/D w/ Serious Bleeding (+ d/c anticoag)
UFH	60–90′, RES	↑ PTT	Protamine IV 1 mg/100 U UFH (max 50 mg). For infusions, dose to reverse 2× UFH given per h.
LMWH	2–7°, K	anti-Xa*	Protamine reverses ~60%. 1 mg per 1 mg enox.
Bivalirudin	25′, K	↑ PTT	Dialysis
Argatroban	45′, L	↑ PTT	? Dialysis
Warfarin	36°, L	↑ PT	No bleeding: vit K 2.5 mg PO if INR >9, o/w no e/o clinical benefit (Blood Adv 2019;3:789) Bleeding: vit. K 10 mg IV + either 4F-PCC (KCentra, 25, 35, or 50 U/kg for INR 2–4, 4–6, or >6) or FFP 2–4 U IV q6–8h (slower, more volume)
Fibrinolytic	20′, LK	↓ fbgn	Cryo, FFP, ± tranexamic or aminocaproic acid
Rivaroxaban Apixaban Edoxaban	8–12°, K >L	↑ PT* anti-Xa*	Andexanet alfa (factor Xa decoy receptor): 800 mg bolus (30 mg/min) → 8 mg/min infusion (½ of above if taking ½ dose DOAC or ≥8 hrs since last dose; NEJM 2019;380:1326); 4F-PCC if andexanet not available
Dabigatran	~12°, K	↑ PTT*	Idarucizumab: mAb binds drug (NEJM 2017;377:431)

^*Routine monitoring not performed. Mode of excretion: K, kidney; L, liver; RES, reticuloendothelial system. 4F-PCC: prothrombin complex concentrate (FII, VII, IX, X; Protein C & S). Anti-fibrinolytics: tranexamic, aminocaproic acid.

HYPERCOAGULABLE STATES

Suspect in Pts with venous or arterial thrombosis at young age or unusual locations, recurrent thromboses or pregnancy loss, or ⊕ FHx

Inherited Hypercoagulable States
Risk Factor	Prevalence	VTE*	Comments
Factor V Leiden	3–7%	2.65	Activated protein C (APC) resistance
Prothrombin mutation	2%	1.45	G20210A → ↑ prothrombin level
Hyperhomocysteinemia	5–10%	_	Inherited or acquired (vitamin defic., hypothyroid, renal insufficiency)
Protein C deficiency	0.02–0.05%	2.8	Warfarin-induced skin necrosis risk
Protein S deficiency	0.01–1%	2.8
Antithrombin III def.	0.04%	2.8	May be heparin resistant

^*Relative risk of recurrent VTE compared to patient w/o respective thrombophilia (JAMA 2009;301:2472)

Vascular Beds Affected by Inherited and Acquired Hypercoagulable States
	Venous	Venous and Arterial
Inher.	Factor V Leiden Prothrombin mutation ↓ protein C, S or AT III	Hyperhomocysteinemia (inherited or acquired) Dysfibrinogenemia
Acquired	Stasis: immobilization, surgery, CHF Malignancy Hormonal: OCPs, HRT, tamoxifen, pregnancy Nephrotic syndrome	Platelet defects: myeloproliferative disorders, HIT, PNH (although venous >arterial) Hyperviscosity: polycythemia vera, Waldenström’s -macroglobulinemia, sickle cell, acute leukemia Vessel wall defects: vasculitis, trauma, foreign bodies Others: antiphospholipid syndrome, IBD

Diagnostic evaluation (not routinely required for initial VTE; NEJM 2017;377:1177)

• APC resistance screen; prothrombin PCR test; functional assays for proteins C and S, ATIII; homocysteine level; factor VIII levels; anticardiolipin and lupus anticoagulant Ab. Also consider nephrotic syndrome, PNH (esp. if mesenteric thrombus).

• Consider JAK2 mutation testing if suspect MPN or splanchnic thrombosis

• Proteins C & S and ATIII levels unreliable during acute thrombosis and anticoagulation ∴ levels best assessed ≥2 wk after completing anticoagulation course

• Age-appropriate malignancy screening (occult cancer in ~4% of initial unprovoked VTE; no benefit of routine abd/pelvis CT; NEJM 2015;373:697)

Treatment

• Asx w/ inherited risk factor: consider prophylactic anticoag. if develops acquired risk factor

• Thrombosis w/ inherited risk factor: see “Venous Thromboembolism”

Antiphospholipid syndrome (APS) (NEJM 2018;398:2010)

• Definition: dx requires ≥1 clinical & ≥1 laboratory criteria

Clinical: thrombosis (any) or complication of pregnancy (≥3 spont. abortions before 10 wk or ≥1 fetal loss after 10 wk or premature birth before 34 wk)

Laboratory: ⊕ lupus anticoagulant (LA), or ⊕ moderate–high titer anticardiolipin (ACL), or ⊕ β₂-glycoprotein-I (β₂-GP-I) Ab, on ≥2 occasions, at least 12 wk apart

• Features: DVT/PE/CVA, recurrent fetal loss, ↓ plts, hemolytic anemia, livedo reticularis

• “Catastrophic APS”: ≥3 organ systems in <1 wk w/ ⊕ APLA & tissue microthrombi; 44% mortality (Arth Rheum 2006;54:2568); Rx w/ plasmapheresis, rituximab

• Antiphospholipid antibodies (APLA)

✓ if: SLE, age <40 y & arterial thromb, recurrent venous thromb, spontaneous abortion

ACL: Ab against cardiolipin, a mitochondrial phospholipid; IgG more specific than IgM

LA: Ab that prolongs phospholipid-dependent coagulation reactions; ∴ ↑ PTT that does not correct with mixing study but does correct with excess phospholipids or platelets; PT not affected b/c the reaction contains much more phospholipid

β₂-GP-I: Ab against β₂-glycoprotein-I, IgG or IgM (uncertain role of Abs in pathogenesis)

False ⊕ VDRL nontreponemal test for syphilis (cardiolipin is part of Ag complex)

Risk of thromboembolic phenomena may increase with titer of APLs

• Etiologies: primary (idiopathic) or secondary due to autoimmune syndromes (eg, SLE), malignancy, infections, drug reactions

• Treatment: UFH/LMWH → warfarin (lifelong for most Pts)

Rivaroxaban inferior to warfarin in triple positive (⊕ ACL, LA, & β₂-GP) (Blood 2018;132:1365)

Initial venous thrombosis: INR 2–3 (NEJM 2003;349:1133; J Thromb Haemost 2005;3:848)

Initial arterial thrombosis: typically INR 2–3 + ASA 81 mg/d

Recurrent thrombosis on warfarin: consider INR 3–4 vs. LMWH or fondaparinux

DISORDERS OF LEUKOCYTES

Neutrophilia (>7500–10,000/µL)
Infection	Usually bacterial; ± toxic granulations, Döhle bodies
Inflammation	Burn, tissue necrosis, MI, PE, collagen vascular disease
Drugs and toxins	Corticosteroids, β-agonists, lithium, G-CSF; cigarette smoking
Stress	Release of endogenous glucocorticoids and catecholamines
Marrow stimulation	Hemolytic anemia, immune thrombocytopenia
Asplenia	Surgical, acquired (sickle cell), congenital (dextrocardia)
Neoplasm	Can be 1° (MPN) or paraneoplastic (eg, carcinomas of lung, GI)
Leukemoid reaction	>50,000/µL + left shift, not due to leukemia; unlike CML, ↑ LAP

Neutropenia (<1000/µL)
Congenital	Myelokathexis, Shwachman-Diamond-Oski, Chédiak-Higashi, retic dysgen., WHIM syndrome, cyclic neutropenia, monoMAC syndrome (↓ monos, NKs)
Infection	Viral (CMV, EBV, HIV); bacterial (Brucella, Rickettsia, TB); malaria
Nutritional	Vitamin B12 or copper deficiency
Drugs and toxins	Chemotherapeutics, clozapine, methimazole, TMP-SMX, NSAIDs, sulfasalazine, phenytoin (Am J Hem 2009;84:428), alcohol
Neoplasm	MDS, leukemia (AML, ALL, hairy cell, LGL, others)

Monocytosis (>500/µL)
Infection	Usually TB, SBE, Listeria, Brucella, Rickettsia, fungi, parasites, syphilis
Inflammation	IBD, sarcoidosis, collagen vascular diseases
Stress	MI, splenectomy, exercise (Cytokine 2013;61:364)
Neoplasm	Hodgkin lymphoma, leukemias, MPNs, carcinomas

Eosinophilia (>500/µL)
Infection	Usually parasitic (helminths)
Allergic	Drugs; asthma, hay fever, eczema; ABPA
Collagen vasc dis.	RA, EGPA (Churg-Strauss), eosinophilic fasciitis, PAN
Endocrine	Adrenal insufficiency
Neoplasm	HL, CML, mycosis fungoides, carcinomas, systemic mastocytosis
Atheroembolic dis.	Cholesterol emboli syndrome
Hypereosinophilic syndrome	Multiorgan involvement incl. heart & CNS, a/w FIP1L1-PDGFRA fusion (NEJM 2003;348:1201); often steroid resistant

Basophilia (>200/µL)
Neoplasm	MPN, CML, AML, Hodgkin lymph.
Infection	TB, smallpox, parasites
Alteration in BM or reticuloendothelial compartment	Hemolytic anemia, splenectomy
Inflammation or allergy	IBD, chronic airway inflammation

Lymphocytosis (>4000–5000/µL)
Infection	Usually viral; “atypical lymphocytes” with mononucleosis syndromes Other: pertussis, toxoplasmosis
Hypersensitivity	Drug-induced, serum sickness
Autoimmune	Rheumatoid arthritis (large granular lymphocytes), malignant thymoma
Neoplasm	Leukemia (eg, CLL, hairy cell, LGL), lymphoma (eg, mantle cell, folic.)

Lymphadenopathy
Viral	HIV, EBV, CMV, HSV, VZV, hepatitis, measles, rubella
Bacterial	Generalized (brucellosis, leptospirosis, TB, atypical mycobacteria, syphilis) Localized (streptococci, staphylococci, cat-scratch disease, tularemia)
Fungal/parasitic	Histo, coccidio, paracoccidioidomycosis, toxoplasmosis
Immunologic	Collagen vascular disease, drugs (eg, phenytoin), serum sickness, histiocytosis X, Castleman’s and Kawasaki disease
Neoplasm	Lymphoma, leukemia, amyloidosis, metastatic carcinoma
Other	Sarcoidosis; lipid storage diseases
Factors that favor biopsy	Pt >40 y, >2 cm, location (supraclavicular always abnl), duration >1 mo Consistency (hard vs. rubbery vs. soft) & tenderness are not reliable Exicisional biopsy preferred over fine needle aspiration (FNA)

TRANSFUSION THERAPY

Blood Products and Indications (Lancet 2013;381:1845)
Packed red blood cells (PRBCs)	For acute blood loss or to ↑ O2-carrying capacity if end organ ischemia. 1 U PRBC → ↑ Hb by ~1 g/dL. Hb goal >7 g/dL adequate for UGIB & critically ill (NEJM 2013;368:11 & 2014;371:1381), ≥8 in acute MI and peri-cardiac surgery (NEJM 2018;379;1224; JAMA 2021;325:552).
Platelets (plts) (Annals Int Med 2015;162:205)	For plts <10k (NEJM 2010;362:600) due to chemo/abx. If <20k or if <50k w/ active bleeding. Variable pre-procedure.100k for neurosurgery. 1 U → ↑ plt ~30–60k. Single donor plt apheresis ↓ alloimmunization. Contraindic: TTP/HUS, HELLP, HIT. Refractory if ↑ <5k 30–60′ post-plts. Suggests consumption such as ITP, DIC, or alloimmunization → trial ABO-matched plts & give more. If still refractory ✓ panel reactive Abs to assess utility of HLA-matched plts.
Fresh frozen plasma (FFP)	Contains all coagulation factors. For bleeding due to defic. of multiple coag factors (eg, DIC, TTP/HUS, liver disease, dilution). Nb, reverse warfarin w/ Kcentra = 4 factor PCC (JACC 2020;76:594).
Cryoprecipitate	Enriched for fibrinogen, vWF, VIII, and XIII. 1st line for fibrinogen <100 mg/dL. For bleeding in vWD factor XIII deficiency, use if other products not available.
Irradiated	Prevents donor T-cell engraftment and risk of transfusion-assoc. GVHD (HSCT, heme malignancy, congenital immunodeficiency).
CMV-negative	From CMV-negative donors. For CMV-seronegative pregnant women, transplant candidates/recipients, SCID, AIDS Pts.
Leuko- reduced	WBCs cause HLA alloimmunization & fever (cytokines) and carry CMV. For chronically transfused Pts, potential Tx recip., h/o febrile nonhemolytic transfusion rxn, cases in which CMV-neg products desired but unavailable.
IV immune globulin (IVIg)	Polyvalent IgG from >1000 donors. For postexposure prophylaxis (eg, HAV), certain autoimmune disorders (eg, ITP, Guillain-Barré, MG, CIDP), congenital or acquired hypogammaglobulinemia (CVID, CLL).
Therapeutic apheresis	Removes plasma large molec wt subst. (eg, cryoglobulinemia, Goodpasture’s, Guillain-Barré, hyperviscosity syndrome), or cells (eg, leukemia w/ hyperleukocytosis, sx thrombocytosis) from plasma. TTP: replace ADAMTS13. RBC exchange for SCD acute chest or stroke.
Massive transfusion	Large-vol. PRBC → ↓ Ca, ↑ K, ↓ plt, ↑ coags; initial ratio of 1 PRBC: 1 plt:1 FFP accepted but controversial, follow labs (JAMA Surg 2017;152:574).
Transfusion Complications (NEJM 2017;377:1261)
Noninfectious	Risk (per unit)	Infectious	Risk (per unit)
Febrile	1:100	CMV	Common
Allergic	1:100	Hepatitis B	1:220,000
Delayed hemolytic	1:50–75,000	Hepatitis C	1:1,600,000
Acute hemolytic	1:200,000	HIV	1:1,800,000
Febr. non-hemolytic	1:200	Bacteria (PRBCs)	1:500,000
TRALI	1:5000	Bacteria (platelets)	1:12,000

Transfusion reactions

• Reason why blood products (unless massive txfusion) run 1 at a time. For all rxns (except minor allergic): stop txfusion; send remaining blood product + fresh blood draw to blood bank.

• Acute hemolytic: fever, HoTN, flank pain, AKI w/in 24 h. Due to ABO incompatibility → preformed Abs vs. donor RBCs. Rx: IVF, ↑ UOP w/ diuretics, mannitol, or dopamine.

• Delayed hemolytic: generally less severe than acute hemolytic; 5–7 d after transfusion, but can be severe → hyperhemolysis. Due to undetected allo-Abs vs. minor antigens → anamnestic response. Rx usually not required; dx important for future transfusion.

• Febrile nonhemolytic: fever, rigors 0–6 h post transfusion. Due to Abs vs. donor WBCs and cytokines in blood product. Rx: acetaminophen ± meperidine; r/o infection, hemolysis.

• Allergic: urticaria; rarely, anaphylaxis due to rxn to txfused proteins, especially in IgA-deficient Pts w/ anti-IgA Abs (use washed products). Rx: urticaria → diphenhydramine; anaphylaxis → epinephrine ± steroids. Washed products ↓ rxns in chronic txfusions.

• Transfusion-associated circulatory overload (TACO): ↑ volume → pulm. edema, ↑ BP. Rx: slow transfusion rate, diuretics, O₂, ± nitrates, ± positive pressure ventilation.

• Transfusion-related acute lung injury (TRALI): non-cardiogenic pulm. edema due to donor allo-Abs (from multiparous ♀ plasma) binding recipient WBCs, which then aggregate in pulmonary vasculature and release mediators causing ↑ capillary permeability. Rx: see “ARDS.” No longer seen in US as plasma only from ♂ donors.

MYELODYSPLASTIC SYNDROMES (MDS)

Myeloid neoplasm overview (Blood 2016;127:2391)

• Categories based on clinical features, morphology, immunophenotyping, and genetics

WHO 2016 Classification of Myeloid Neoplasms & Acute Leukemia
Acute myeloid leukemia	Clonal myeloid stem cell (SC) disorder w/ ≥20% blasts
Myelodysplastic syndromes	Dysplastic clonal myeloid SC disorder → cytopenias; <20% blasts, risk of leukemic transformation
Myeloproliferative neoplasms	Nondysplastic multipotent myeloid SC clonal expansion
MDS/MPN neoplasms	Features of MDS & MPN (eg, CMML, atypical CML)
Myeloid/lymphoid malig. w/ eos & rearrangements of PDGFR or FGFR1 or w/ PCM1-JAK2	May be responsive to TKI therapy (eg, imatinib) for PDGFR rearrangement
Mastocytosis	Clonal mast cell disorder, assoc w/ KIT mutations
Myeloid neoplasms w/ germ line predisposition	MDS, MDS/MPN, acute leukemias in background of predisposing germline mutations (eg, DDX41)

Myelodysplastic syndromes (MDS) overview (Lancet 2014;383:2239)

• Acquired clonal stem cell disorder → ineffective hematopoiesis → cytopenias, dysmorphic blood cells and precursors, variable risk of leukemic transformation

• Epidemiology: 20–30,000 cases/y; median age ~70 y; male predominance (1.8×)

• Idiopathic or 2° to chemo w/ alkylating agents; ↑ risk w/ radiation, benzene

• Clinical manifestations: anemia (85%), neutropenia (50%), thrombocytopenia (40–65%)

• Diagnosis: dysplasia (usually multilineage) in peripheral smear (oval macrocytes, pseudo-Pelger-Huët anomaly) and bone marrow (≥10% dysplasia with blasts ± RS)

• Both cytogenetic [eg, del(5q), mono 7, del(7q), trisomy 8, del(20q)] and molecular abnl (TP53, EZH2, ETV6, RUNX1, ASXL1, SF3B1, DNMT3A) may carry prognostic signif

• Prior to dx MDS: exclude AML (≥20% blasts) and CMML (monos >1 × 10⁹/L); r/o 2° BM Δs (defic. of B₁₂, folate, copper); viral infxn (eg, HIV); EtOH; lead, arsenic exposures

WHO 2016 Classification Systems for MDS (Blood 2016;127:2391)
Classification	WHO 2008	Features
MDS w/ single lineage dysplasia (MDS-SLD)	RCUD (RA/RN/RT)	1 dysplastic lineage, 1–2 cytopenias, <15% RS*, <5% BM/ <1% PB blasts, no Auer rods
MDS w/ multilineage dysplasia (MDS-MLD)	RCMD	2–3 dysplastic lineages, 1–3 cytopenias, <15% RS*, <5% BM/ <1% PB blasts, no Auer rods
MDS w/ ring sideroblast (MDS-RS)	RARS	≥15% RS or ≥5% RS if SF3B1 mut. is present, <5% BM/<1% PB blasts, no Auer rods
MDS w/ isolated del(5q)	Del(5q)	Del(5q) alone or w/ 1 abnl except –7 or del(7q)
MDS w/ excess blasts (MDS-EB)	RAEB-1 RAEB-2	EB-1: 5–9% BM/2–4% PB blasts, no Auer rods EB-2: 10–19% BM/5–19% PB blasts or Auer rods
MDS, unclassifiable (MDS-U)	MDS-U	w/ 1% PB blasts, single lineage dysplasia & pancytopenia, or defining cytogenetic alteration

Certain cytogenetics [eg, t(15;17), t(8;21), inv16, t(16;16), or MLL rearrangement] classified as AML, regardless of BM blast count. BM, bone marrow; PB, peripheral blood; RS, ring sideroblast. ^* <5% RS if SF3B1 mutation.

• Rx (Am J Hematol 2012;87:692): intensity based on IPSS-R (qv), age, performance status (PS)

Poor PS, any risk → supportive care (transfusions, G-CSF, Epo, TPO-mimetic, abx prn)

Very low/low risk (IPSS-R) → ESA if Epo <500; lenalidomide (esp. for 5q synd.; Blood 2011;118:3765); luspatercept (MDS-RS). TPO-mimetic agents, transfusions.

Interm/high risk (IPSS-R) → allogeneic HSCT if medically fit, DNA methyltransferase inh azacitadine or decitabine (Lancet Oncol 2009;10:223) or oral decitabine/cedazuridine

Hypoplastic MDS (rare) → consider immunosuppression (CsA, ATG), HSCT

• Prognosis: mutations inTP53, ASXL1, EZH2, RUNX1, ETV6 (NEJM 2011; 364:2496) ↓ survival

MYELOPROLIFERATIVE NEOPLASMS (MPN)

General (NEJM 2017;376:2168)

• Results from clonal expansion of multipotent hematopoietic stem cell

• Categories of MPN: polycythemia vera (PV); essential thrombocythemia (ET); primary myelofibrosis (PMF); chronic myelogenous leukemia (CML; BCR-ABL1 ⊕); atypical CML (aCML); chronic neutrophilic leukemia (CNL); systemic mastocytosis; chronic eosinophilic leukemia; MPN-NOS/unclassifiable

• MDS/MPN neoplasms: proliferative and dysplastic features

• Mutations useful as clonal markers & dx tools:

Gain of fxn mutations in JAK2 V617F (Janus kinase) frequently present (PV ~95%, ET ~50%, PMF ~50%; NEJM 2005;352:1779)

BCR-ABL1 fusion in all cases of CML; SETBP1 in aCML

CALR exon 9 mutation, type I and II (most MPNs w/o JAK2 or MPL mutation, including ~25% of ET, ~35% of myelofibrosis Pts; NEJM 2013;369:2379 & 2391)

Type I has better prognosis.

MPL, TET2, & ASXL1 mutation w/ lower frequency

CSF3R mutation present in ~60% of CNL; KIT D816V in 90% of systemic mastocytosis

POLYCYTHEMIA VERA (PV)

Definition

• ↑ in RBC mass ± ↑ granulocytes and platelets in the absence of physiologic stimulus

Etiologies of erythrocytosis (absolute ↑ RBC)

• Acquired 1°: PV (usually JAK2+) or other MPN

• Germline 1°: Chuvash (hypoxia-sensing disorder due to VHL mutation), EGLN mutations

• Secondary: carboxyhemoglobinemia; hypoxia (OSA, COPD); inappropriate erythropoietin (renal, hepatic); Cushing’s syndrome

• Mimics: relative ↑ RBC (↓ plasma) due to dehydration; “stress” erythrocytosis (Gaisböck’s syndrome)

Clinical manifestations (common between PV and ET)

• Symptoms (often termed “vasomotor”)

Hyperviscosity (erythrocytosis): headache, dizziness, tinnitus, blurred vision

Thrombosis (hyperviscosity, thrombocytosis): ↑ risk of DVT, MI, stroke; transient visual disturbances (amaurosis, ocular migraine); Budd-Chiari syndrome; erythromelalgia = intense burning, pain and erythema of extremities due to microvascular ischemia

Bleeding (abnormal platelet function): easy bruising, epistaxis, GI bleeding

↑ histamine from basophils → pruritus, peptic ulcers; ↑ uric acid (cell turnover) → gout

• Signs: plethora, splenomegaly, hypertension, engorged retinal veins

Diagnostic evaluation

• Men: Hb >16.5 g/dL or Hct >49%, women: Hb >16 g/dL or Hct >48%

• ± ↑ WBC, platelets, basophils; ↑ uric acid, leukocyte alkaline phosphatase, vit B₁₂

• Peripheral smear → no morphologic abnormalities

• ✓ Epo to rule out secondary causes of erythrocytosis; if Epo ↓, PV more likely If Epo ↑, then ✓ SaO₂ or PaO₂, carboxyhemoglobin, BM exam

• BM bx → hypercellularity for age, trilineage growth, pleomorphic mature megakaryocytes

• JAK2 V617F mutation in ~95% of PV; other Pts typically harbor JAK2 exon 12 mutations

Treatment for JAK2 + PV

• Phlebotomy to goal Hct <45% (NEJM 2013;368:22), consider <42% in women

• Low-dose ASA in all Pts (NEJM 2004;350:114)

• Hydroxyurea if high risk of thrombosis (age ≥60, prior thrombosis) or if inadequate Hct by phlebotomy alone

• PEG IFNα preferred in younger Pts and pregnancy (Lancet Haematol 2017;4:e165)

• Ruxolitinib (JAK1/2 inhibitor) if refractory to or intolerant of hydroxyurea (NEJM 2015;372:426)

• Supportive: allopurinol (gout), H₂-blockers/antihistamines (pruritus). Avoid iron supp.

• Data for optimal mgmt of other types of PV (secondary, germline, etc.) currently lacking

Prognosis

• Median survival w/ Rx ~13.5 y (Blood 2014;124:2507); ↑ age, WBC, additional acquired somatic mutations → worse prognosis (Haematol 2013;160:251)

• Post-PV myelofibrosis (spent phase) occurs in 10–20% of cases, usually after 10 y

• Risk of transformation into acute leukemia (<2–5% lifetime)

ESSENTIAL THROMBOCYTHEMIA (ET)

Definition

• Sustained ↑ in platelets (>450,000/µL) ± ↑ RBC and granulocytes

Etiologies of thrombocytosis

• 1° = ET or other MPN; myelodysplastic syndromes (5q-syndrome); RARS-T

• 2° = reactive thrombocytosis: inflammation (RA, IBD, vasculitis), infection, trauma, acute bleed, iron deficiency, postsplenectomy, neoplasms (eg, Hodgkin lymphoma)

• Of patients with plt >1,000,000/µL, <1 in 6 will have ET

Clinical manifestations (also see “Polycythemia Vera”)

• Thrombosis with erythromelalgia (risk of thrombosis highest in Pts with leukocytosis), bleeding (acquired vWD), pruritus; mild splenomegaly; migraine, TIA; early fetal loss

Diagnostic evaluation

• Peripheral smear: large hypogranular platelets

• BM bx: megakaryocytic hyperplasia; ⊖ Phil chr; rarely minor reticulin fibrosis; nl Fe; if atypical megakaryoctyes or ↑ reticulin, consider pre-PMF (Rx same as ET, but ↑ risk MF)

• Mutations: JAK2 V617F in ~50%; CALR in ~45%; MPL in 5–10%; triple negative <5%

• Patients should not meet WHO criteria for diagnosis of CML, PV, PMF, or MDS

• Check vWF in pts w/ plt>1,000,000 and hold ASA (vide infra) if acquired vWD

Prognosis

• Low-risk Pts have overall survival ≈ control population

• Risk of transformation into acute leukemia <2–3% lifetime; risk of progression to MF ~10%

PRIMARY MYELOFIBROSIS (PMF)

Definition

• Clonal myeloproliferation with reactive marrow fibrosis & extramedullary hematopoiesis

• Prefibrotic stage (pre-PMF): megakaryocyte prolif, grade 1 reticulin fibrosis, ↑ BM cellularity. Compared w/ ET, pre-PMF has ↑ thrombosis, ↑ progression, ↓ survival (Blood 2012;120:569).

Etiologies of myelofibrosis

• 1° myelofibrosis (PMF): myeloproliferative neoplasm

• 2° myelofibrosis: post-PV/ET myelofibrosis, other hematologic (CML, AML, ALL, MDS) and solid cancers (breast, prostate), autoimmune (eg, SLE), toxin (benzene), radiation, granulomas (TB, fungal, sarcoid), deposition diseases (eg, Gaucher’s)

Clinical manifestations (BJH 2012;158:453)

• Ineffective erythropoiesis → anemia; extramedullary hematopoiesis → massive splenomegaly (abdominal pain, early satiety) ± hepatomegaly

• Tumor bulk and ↑ cell turnover → fatigue, weight loss, fever, sweats

Diagnostic evaluation (Blood 2010;115:1703 & 2016;127:2391)

• Anemia with variable WBC and platelet counts

• Peripheral smear → “leukoerythroblastic” (teardrop cells, nucleated RBCs, immature WBCs); large abnormal platelets

• BM aspirate → “dry” tap; BM bx → severe fibrosis, replacement by reticulin & collagen

• JAK2 V617F in 45–50%; CALR mut in 45–50%, MPL mut in 7–10%, triple neg in 1–2%

• No BCR-ABL translocation; Pts should not meet criteria for PV or MDS

• DIPSS score for prognosis. High-risk factors: age >65, WBC >25k, Hgb <10, peripheral blasts >1%, symptoms, complex cytogenetics, absence of CALR type 1.

Treatment (Am J Hematol 2021;96:145)

• In absence of adverse prognostic factors (eg, anemia or sx) → no treatment

• Allogeneic HSCT only potential cure → consider in young Pts w/ high-risk disease

• Supportive care: transfusions; ESA if Epo <500 (risk ↑ splenomegaly); consider androgens vs. immunomodulatory agents (eg, lenalidomide) + prednisone; hydroxyurea; ? splenectomy if refractory to transfusions, failed chemoRx, painful splenomegaly

• JAK inh: ruxolitinib (JAK1/2) ↓ sx, ↓ splenomegaly, ↑ survival; preferred (NEJM 2012;366:787 & 799); fedratinib (JAK2; JAMA Oncol 2015;1:643); pacritinib & momelotinib under study

• Median survival ~6 y (JCO 2012;30:2981); transformation into AML occurs at a rate of ~8%/y

LEUKEMIA

ACUTE LEUKEMIA

Definition

• Clonal proliferation of hematopoietic progenitor with failed differentiation into mature elements → ↑ blasts in bone marrow and periphery → ↓ RBCs, platelets, and neutrophils

Epidemiology and risk factors

• Acute myelogenous (AML): ~20k cases/y in U.S.; median age 68 y

• Acute lymphocytic (ALL): ~6k cases/y in U.S.; median age 15 y but 2^nd peak in older adults

• Risk factors: radiation, chemo (alkylating agents, topo II inhib), benzene, smoking, ? rising from acquired somatic mutations and clonal hematopoiesis (NEJM 2014;371:2477)

• Secondary to acquired hematopoietic dis.: MDS, MPN (esp. CML), aplastic anemia, PNH

• Inherited: Down’s, Klinefelter’s, Fanconi’s anemia, Bloom synd., ataxia telangiectasia, germline mut. in TP53 (Li-Fraumeni syndrome), DDX41, RUNX1, CEBPa, & GATA2

Clinical manifestations

• Cytopenias → fatigue (anemia), infection (neutropenia), bleeding (thrombocytopenia)

• Leukostasis (more in AML): blast >50k, ↓ S_aO₂, HA, blurry vision, confusion, TIA/CVA

• Tumor lysis syndrome (TLS) from rapid turnover of cells

• Disseminated intravascular coagulation (DIC; especially with APL)

• Other: leukemic infiltration of skin, gingiva (esp. with monocytic subtypes); chloroma (myeloid sarcoma): extramedullary tumor of leukemic cells, any location; anterior mediastinal mass and SVC syndrome (T-ALL/LBL); hepatosplenomegaly (ALL and monocytic leukemias); CNS (~10% of ALL; also in monocytic >myeloid leukemias): cranial neuropathies, HA

Diagnostic evaluation (Blood 2009;114:937)

• Peripheral smear: thrombocytopenia, blasts (seen in >95%; ⊕ Auer Rods in AML)

• Bone marrow: >20% blasts; mostly hypercellular; test for cytogenetics and flow cytometry for immunophenotype (AML/ALL)

• Cytogenetic anomalies: eg, in AML, t(15;17), t(8;21), inv(16) or t(16;16), complex; in ALL, Ph-chromosome [t(9;22)], hyper or hypodiploid, complex

• Molecular mutations in AML: esp FLT3 (ITD and TKD), TP53, NPM1; ALL: BCR-ABL1

• Evaluate for complications: TLS (↑ uric acid, ↑ LDH, ↑ K, ↑ PO₄, ↓ Ca), DIC (PT, PTT, fibrinogen, D-dimer, haptoglobin, bilirubin), check for G6PD (prior to giving rasburicase)

• LP (w/ co-admin of intrathecal chemotherapy to avoid seeding CSF w/ circulating blasts) for all Pts w/ ALL (CNS is sanctuary site) and for Pts w/ AML w/ CNS sx

• TTE before use of anthracyclines

• HLA typing of Pt, siblings >parents/children for potential allogeneic HSCT candidates

ACUTE MYELOGENOUS LEUKEMIA (AML)

Classification (WHO; Blood 2016;127:2391)

• Features used to confirm myeloid lineage and subclassify AML to guide treatment: morphology: blasts, ⊕ granules, ± Auer rods (eosinophilic needle-like inclusions)

• Immunophenotype: precursor: CD34, CD45, HLA-DR; myeloid: CD13, CD33, CD117; monocyte: CD11b, CD64, CD14, CD15

• Histochem.: myeloperoxidase (myeloid), non-specific esterase, and lysozyme (monocytic)

• Prognosis: age, prior antecedent MPN/MDS and genetics (cytogenetics + molecular mutation status) are key independent risk factors of poor prognosis

ENL 2017 Genetic Risk Classification (Blood 2017;129:424)
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-ITDhigh*; mutated TP53, RUNX1, ASXL1
* low/high: FLT3-ITD variant allele frequency (VAF); reflects burden of mut. leukemic cells

Upfront treatment

• Induction chemo “7+3”: 7d cont. infusion cytarabine (Ara-C) + 3d bolus anthracycline (daunorubicin or idarubicin)

• Ability to tolerate 7+3 regimen key determinant in subsequent Rx received (vide infra)

• Obtain BM bx 14–21 days after start of induction chemo to assess response

• Regimens for fit (generally age <75 y)

FLT3-ITD/TKD mutation: 7+3+midostaurin (early generation FLT3 inhib; NEJM 2017;377:454)

Core-binding factor ⊕: t(8;21) or inv(16): 7+3 ± gemtuzumab ozogamicin (mAb targ. CD33)

2° AML or w/ MDS-related changes: CPX-351 (liposomal Ara-C & daunorubicin)

Other: age <60 y: 7+3 (high-dose daunorubicin 90 mg/m²); >60 y: dauno 60 mg/m²

• Regimens for unfit (may include age ≥75 y or < 75y w/ ECOG ≥3 or severe cardiac or pulmonary comorbidity; Leukemia 2013;27:997)

Azacitadine + venetoclax (Bcl2 inhibitor) (NEJM 2020;383:617)

IDH1/2 mutation: ivosidenib or enasedinib

Consolidation therapy

• If complete remission (CR) = ANC >10³, plt >100, no RBC Rx, <5% BM blasts; CR ≠ cure

• Favorable risk: high-dose cytarabine (HiDAC); Intermediate/Poor risk: Allo-HSCT

• Consider maintenance azacitadine if cannot complete curative intent Rx (NEJM 2020;383:2526)

Refractory/relapsed disease

• Repeating mutation analysis key b/c clonal evolution common and may affect Rx

• FLT3-ITD/TKD mutation: gilteritinib (potent FLT3 inhibitor)

• IDH1 mutation: ivosidenib; IDH2 mutation: enasidenib (small-molecule inhib of IDH1 or 2)

• Chemo: MEC (mitoxantrone, etoposide, Ara-C); FLAG-Ida (fludarabine, Ara-C, G-CSF, & idarubicin); CLAM (clofarabine, Ara-C, mitoxantrone), gemtuzumab

Prognosis

• CR achieved in 70–80% of Pts <60 y and in 40–50% of Pts >60 y

• Overall survival variable, depends on prognostic factors: ranges from <10% of older Pts w/ poor-risk tumor genetics to >65% of younger Pts w/ favorable prognostic factors

Acute promyelocytic leukemia (APL) (Blood 2009;113:1875)

• Rare, ~8% of AML in U.S.; >90% cure rates

• Atypical promyelocytes (large, granular cells; bilobed nuclei) in blood and bone marrow

• Defined by translocation of retinoic acid receptor: t(15;17); PML-RARA (>95% of cases)

• Medical emergency with DIC and bleeding common

• Remarkable responses to all-trans-retinoic acid (ATRA) & arsenic trioxide (ATO) which induce differentiation of leukemic blasts. ∴ early initiation of ATRA if APL suspected

• Non-high-risk APL: ATRA + ATO (induction + 4 cycles consolidation) → CR ~100%; event-free survival 97% and overall survival 99% at 2 y (NEJM 2013;362:111)

• High-risk APL: WBC >10k at diagnosis. No clear consensus. In general, chemo (anthracycline or gemtuzumab ozogamicin) added to ATRA + ATO induction and consolidation.

• Differentiation syndrome (ATRA): ~25% of Pts; fever, pulm. infiltrates, SOB, edema, HoTN, AKI; tx w/ dexamethasone 10 mg bid, supportive care (eg, diuresis) (Blood 2008;113:775)

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL; Lancet 2020;395:1146)

Classification

• Lymphoblastic neoplasms may present as acute leukemia (ALL) w/ >20% BM blasts or as lymphoblastic lymphoma (LBL, more common in T-cell) w/ mass lesion w/ <20% BM blast

• Morphology: no granules (granules seen in myeloid lineage)

• Cytochemistry: ⊕ terminal deoxynucleotidyl transferase (TdT) in 95% of ALL, MPO ⊖

• Immunophenotype

Precursor: CD34, TdT

B: CD19; variable CD10, CD22, CD79a

T: CD1a, CD2, cytoplasmic CD3, CD5, CD7

Treatment

• Induction chemo

Ph ⊕ t(9;22) (seen in ~25% of B-ALL): tyrosine kinase inhibitor + chemo/steroids

Ph ⊖: Adolescents & young adults (<40 y): pedi-like regimen typically w/ PEG-asparaginase. Adults (40–60 y): multiagent chemo incl. anthracycline, vincristine, steroids, cyclophosphamide (CYC). Older (>60 y): reduced-intensity chemo.

• CNS prophylaxis: intrathecal MTX/cytarabine ± cranial irradiation or systemic MTX

• Post-remission therapy (choice depends on risk of recurrence)

1) Average risk: consolidation/intensification chemo (~7 mo) → maintenance (~2–3 y)

2) High risk: high-dose chemo w/ allo-HSCT considered for Pts in CR1. High-risk disease includes: Ph ⊕; Ph-like (based on gene expression); MLL translocation t(4;11); complex karyotype; hypodiploid (<44 chromosomes); early T-cell phenotype (ETP; lacks CD1a, CD8, CD5^weak, myeloid markers); minimal residual disease (MRD) = morphologic remission but flow cytometry or molec. markers of tumor still detectable.

• Relapse/refractory: salvage therapy (below), then allogeneic HSCT if able

B cell: blinatumomab (CD19 BiTE-bispecific T-cell engager; NEJM 2017;376:836), inotuzumab (CD22 Ab drug conjugate; NEJM 2016;375:740); tisagenlecleucel and brexucabtagene autoleucel (CD19 CAR-T, NEJM 2018;378:449; Lancet 2021;398:491), TKI+chemo/steroids (Ph ⊕t(9;22) only)

T cell: nelarabine ± cyclophosphamide and etoposide

Both B & T cell: chemo including high dose cytarabine regimens; clofarabine

CHRONIC MYELOGENOUS LEUKEMIA (CML; Lancet 2021;398:1914)

Definition (Blood 2009;114:937)

• Myeloproliferative neoplasm with clonal overproduction of hematopoietic myeloid stem cells that can differentiate

• Philadelphia chromosome (Ph) = t(9;22) → BCR-ABL1 fusion → ↑ Abl kinase activity

BCR-ABL1 required for diagnosis (make via karyotyping or FISH; PCR)

Epidemiology and risk factors

• ~6600 new cases/y in U.S.; median age ~64 at presentation; ~15% of adult leukemias

• ↑ risk with irradiation; no clear relation to cytotoxic drugs

Disease classification & manifestations (WHO; NCCN v 2.2022)

• Chronic phase (CP): <10% blasts (peripheral or bone marrow). Risk stratification based on Sokal (Blood 1984;63:789) or Euro scores (J Clin Pathol 2001;54:491).

• Accelerated phase (AP): 10–19% blasts, ≥20% basos, plts <100k, clonal evolution (karyotype changes) not seen at dx

• Blastic phase (BP): ≥20% blasts (peripheral or marrow) and/or extramedullary leukemia

• Most Pts asx or may have mild constitutional s/s related to splenomegaly.

• Worsening constitutional sx, bone pain, rapid ↑ in spleen size herald disease progression

Diagnostic evaluation

• Peripheral smear: leukocytosis, left-shifted with all stages of myeloid maturation; thrombocytosis, basophilia

• Bone marrow w/ karyotype: hypercellular, ↑myeloid:erythroid ratio, micromegakaryocytes

Treatment (Lancet 2015;385:1447; Hematol Oncol Clin North Am 2017;31:577)

• Tyrosine kinase inhibitors (TKI) inhibit abl kinase activity.

1^st gen: imatinib, 1^st TKI against BCR-ABL1 (NEJM 2017;376:917)

2^nd gen: nilotinib, dasatinib, bosutinib. ↑ response but ↑ toxicity. No survival difference.

3^rd gen: ponatinib; a/w ↓ risk of disease progress, preferred for int-high risk, but ↑ toxicity

Imatinib, dasatinib, nilotinib, & bosutinib approved for 1^st line Rx. Nilotinib, dasatinib, bosutinib, ponatinib, & asciminib approved for resistant disease; only ponatinib & asciminib effective on T315I mutation (NEJM 2012;367:2075, Blood 2021;138:2031).

STAMP (allosteric inhibitor): asciminib (NEJM 2019;381:2315); after ≥2 prior TKIs

Resistance: due to ↑ BCR-ABL1 expression, often 2/2 ABL kinase mutation or amplification

Side effects: N/V, diarrhea, muscle cramps, cytopenias, ↓ PO₄, ↑ QT, rarely CHF; dasatinib: pericardial & pleural effusions and pulm. HTN; nilotinib: ↑ bili & lipase, CV toxicity; ponatinib: pancreatitis and arterial vascular events (cerebral, cardiac, & PAD)

• TKI discontinuation: consider if complete molecular response (>4.5 log reduction in BCR-ABL1 transcript) for >2 y. Up to 50% of Pts remain off TKI at 2 y (ie, no molec. recurrence). Success proportional to duration of CMR and risk score at presentation.

• Consider allogeneic HSCT for AP and BP.

• CML in pregnancy: hydroxyurea & all TKIs contraind. If Rx needed, IFN (only option).

Milestones of Therapy
Definition	Optimal Time
BCR-ABL1 ratio <10% IS = 1-log reduction by QT- PCR	3 mo
BCR-ABL1 ratio <1% IS = 2-log reduction by QT-PCR (CCyR)	6 mo
BCR-ABL1 ratio <0.1% IS = 3-log reduction by QT-PCR (MMR)	12 mo
BCR-ABL1 ratio: Pt BCR-ABL1 mRNA: ABL mRNA in peripheral blood. International Scale (IS) standardizes across labs by normalizing to BCR-ABL1:ABL1 ratio in a cohort of unRx’d patients.

Prognosis (NEJM 2017;376:917)

• Chronic phase CML Rx’d w/ imatinib: 89% 5-y overall survival, 95% survival free of CML-related deaths, 7% progression to blast phase at 5 y (NEJM 2006;355:2408). Pts in CCyR (~equal to QT-PCR if 1% IS) have normal life expectancy. QT-PCR >4-log ↓ can consider TKI discontinuation trial (Lancet Onc 2018;19:747).

CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

see “Small Lymphocytic Lymphoma”

LYMPHOMA AND CLL

Definition

• Malignant disorder of lymphoid cells that reside predominantly in lymphoid tissues

• Generally characterized as Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL)

Clinical manifestations

• Lymphadenopathy (usually nontender)

HL: superficial (usually cervical/supraclavicular) ± mediastinal LAN; nodal disease with orderly, anatomic spread to adjacent nodes

NHL: diffuse; nodal and/or extranodal disease with noncontiguous spread; symptoms reflect involved sites (abdominal fullness, bone pain)

• Constitutional (“B”) symptoms: fever (>38°), drenching sweats, ↓ weight (>10% in 6 mo)

HL: periodic, recurrent “Pel-Ebstein” fever; 10–15% have pruritus; ~35% “B” symptoms

NHL: “B” symptoms vary between subtypes, ~15–50%

Diagnostic and staging evaluation

• Physical exam: lymph nodes, liver/spleen size, Waldeyer’s ring, testes (~1% of NHL), skin

• Pathology: excisional lymph node bx (not FNA b/c need surrounding architecture) with immunophenotyping and cytogenetics (Reed-Sternberg (RS) cells in HL); BM bx if cytopenias; CLL by peripheral flow in patients w/ peripheral disease; LP if CNS involvement clinically suspected

• Lab tests: CBC, BUN/Cr, LFTs, ESR, LDH, UA, Ca, alb; ✓ HBV & HCV (and must ✓ HBsAg & anti-HBc if planning rituximab Rx due to risk of HBV reactivation); HIV

• Imaging: PET-CT to assess disease burden and guide biopsy/therapy, especially in HL, DLBCL. Head CT/MRI only if neurologic symptoms.

Ann Arbor Staging System with Cotswolds Modifications
Stage	Features
I	Single lymph node (LN) region
II	≥2 LN regions on the same side of the diaphragm
III	LN regions on both sides of the diaphragm
IV	Disseminated involvement of one or more extralymphatic organs
Modifiers: A = no symptoms; B = fever, night sweats or weight loss; X = ”bulky” mediastinal disease or mass >10 cm; E = single contiguous extranodal site; H = hepatic; S = splenic

HODGKIN LYMPHOMA (HL) (Am J Hematol 2018;93:704; Lancet 2021;398:1518)

Epidemiology and risk factors

• ~9,000 cases/y; bimodal distribution (15–35 & >50 y); ↑ ♂; role of EBV in subsets of HL, esp. immunocompromised patients (eg, HIV)

Pathology

• Affected nodes show RS cells (<1%) in background of non-neoplastic inflammatory cells

• Classic RS cells: bilobed nucleus & prominent nucleoli with surrounding clear space (“owl’s eyes”). RS cells are clonal B-cells: CD15+, CD30+, CD20– (rarely +).

WHO Histologic Classification of Classical HL
Nodular sclerosis	60–80%	Collagen bands; frequent mediastinal LAN; young adults; female predominance; usually stage I or II at dx
Mixed cellularity	15–30%	Pleomorphic; older age; male predominance; ≥50% stage III or IV at presentation; intermediate prognosis
Lymphocyte rich	5%	Abundant normal-appearing lymphocytes; mediastinal LAN uncommon; male predominance; good prognosis
Lymphocyte depleted	<1%	Diffuse fibrosis and large numbers of RS cells; older, male patients; disseminated at dx; seen in HIV; worst prognosis

• Nonclassical HL (5%): nodular lymphocyte predominant (NLP); involves peripheral LN

80% present in stages I–II, Rx w/ RT vs. chemoRT w/ 4-yr PFS 88% and OS 96% (JCO 2008;26:434); consider rituximab because most NLP RS cells are CD20+

Stages III–IV treated with combination chemo (see below)

Treatment (NCCN Guidelines v5.2021)

• Stages I–II: PET adapted ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) ± RT Favorable: ABVD × 2–4 cycles ± RT (if PET ⊖ after 2 cycles reduce chemo or RT)

Unfavorable (>50 y, bulky mediastinum, “B” sx, ESR >50, >3 nodal sites): ABVD × 4–6 + RT (stop at 4 cycles if PET ⊖ after 2 cycles)

• Stages III–IV: ABVD × 6 cycles (can omit B if PET ⊖ after 2 cycles; NEJM 2016;374:2419); brentuximab (anti-CD30) may replace bleo but more toxic (NEJM 2018;378:331); add RT for select Pts as consolidation

• Refractory/relapsed disease: salvage chemo + auto HSCT ± RT

brentuximab vedotin post-ASCT yields some long-term remissions (Blood 2016;128:1562)

PD1/PDL1 blockade (pembrolizumab or nivolumab) (NEJM 2015;372:311, JCO 2017;35:19)

• Late treatment effects include ↑ risk for:

Second cancers: ~4.6× risk for up to 40 y (NEJM 2015;373:2499)

breast (if RT), ∴ annual screening at age 40 or 8–10 y post RT; leukemia/MDS; NHL

Cardiac disease (if RT or anthracycline), ? role of echo/stress at 10 y (controversial)

Pulmonary toxicity (if bleomycin); Hypothyroidism (if RT), ∴ annual TSH (if neck RT)

• International Prognostic Score (IPS; JCO 2012;30:3383) risk factors: albumin <4 g/dL, Hb <10.5 g/dL, male gender, age >45 y, stage IV, WBC ≥15 k/µL, lymphocytes <600/µL or <8% of diff. 5-yr PFS 62–88% based on # of risk factors.

NON-HODGKIN LYMPHOMA (NHL)

Epidemiology and risk factors

• 79 types of NHL, ~70,000 new cases/y; median age dx 65 y; ♂ predom; 85% B-cell origin

• Associated conditions: immunodeficiency (eg, HIV, posttransplant); autoimmune

disorders (eg, Sjögren’s, RA, SLE); infection (eg, EBV, HTLV-I, H. pylori)

• Burkitt lymphoma: (1) endemic or African (jaw mass, 80–90% EBV-related); (2) sporadic or American (20% EBV-related); (3) HIV-related

WHO Classification of Lymphoid Malignancies (Blood 2016;127:2375)
Type	Examples	Associated Abnormalities
Mature B cell aggressiveness	Burkitt’s lymphoma Diffuse large B-cell lymphoma (DLBCL) Mantle cell Marginal zone lymphoma (nodal, extranodal, splenic) Hairy cell leukemia (⊕ TRAP) Follicular lymphoma CLL/small lymphocytic lymphoma	8q24, c-MYC BCL2, MYC, MLL2, CREBBP, etc. t(11;14) BCL1-IgH → cyclin D1 AP12-MALT1 & BCL-10-Ig enh   BRAF V600E IGH-BCL2, MLL2, CREBBP IGHV, TP53, ATM, SF3B1, etc.
Mature T cell & NK cell	Peripheral T-cell lymphoma Mycosis fungoides (cutaneous lymphoma)/ Sézary syndrome (+ LAN) Anaplastic large-cell lymphoma Angioimmunoblastic T-cell lymphoma	TET2 and DNMT3A   Some ALK1 ⊕

Treatment (Lancet 2017;390:298)

• Treatment and prognosis determined by histopathologic classification rather than stage

• Rituximab (anti-CD20; NEJM 2012;366:2008) if CD20+

• Indolent: generally no cure (except allo HSCT), goal sx mgmt (bulky dis, cytopenia, “B” sx)

Follicular Lymphoma Int’l Prog. Index (FLIPI; Blood 2004;104:1258): risk factors = age >60, stage III/IV, Hb <12 g/dL, >4 nodal areas, LDH >nl. 5-yr OS 52–90% based on score.

Initial: RT if localized, rituximab + chemo (bendamustine, CVP, fludarabine), ibrutinib.

Obinutuzumab (anti-CD20) + chemo w/ obin maint ↑ PFS but ↑ tox (NEJM 2017;377:1331).

Maintenance: rituximab in indolent, aggressive, and relapsed disease (Lancet 2011;377:42)

Hairy cell: cladribine; oral BRAF inhibitor if relapsed/refractory (NEJM 2015;373:1733)

Gastric MALT: ✓ H. pylori; can cure by treating H. pylori if ⊕; RT for relapsed/refractory

• Aggressive: goal is cure (Am J Hematol 2019;94:604), treatment depends on subtype

International Prognostic Index (IPI; Blood 2007;109:1857): risk factors = age >60 y, stage III/IV, ≥2 extranodal sites, PS ≥2, LDH >nl. 4-yr OS 55–94% based on score.

R-CHOP (rituximab, cyclophosphamide, doxorubicin = hydroxydaunorubicin, vincristine = Oncovin, prednisone) (NEJM 2002;346:235 & 2008;359:613) DLBCL 10-y PFS = 45%; overall survival = 55% (Blood 2010;116:2040)

+ Radiation for localized or bulky disease

Consider CNS prophylaxis w/ intrathecal vs. systemic high-dose MTX if paranasal sinus, testicular, breast, periorbital, paravertebral, or bone marrow involved; also w/ ≥2 extranodal sites + ↑ LDH. Controversial (Blood 2021;139:413).

Refractory/relapsed disease: salvage chemo; high-dose chemo + auto-HSCT (JCO 2001;19:406); allo-HSCT if beyond 2^nd relapse (JCO 2011;29:1342)

CAR-T (qv): axicabtagene (NEJM 2017;377:2531), tisagenlecleucel (NEJM 2019;380:45), lisocabtagene (Lancet 2020;396:839), brexucabtagene (mantle cell; NEJM 2020; 382:1331)

Mantle cell: ibrutinib for relapsed/refractory disease (Lancet 2016;387:770)

• Highly aggressive

Burkitt: dose-adjusted EPOCH-R (NEJM 2013;369:1915) or CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate, ifosfamide, etoposide, high-dose cytarabine rituximab) (Blood 2008;112:2248)

All Pts receive CNS & tumor lysis syndrome prophylaxis

Rituximab ↑ event-free survival (Lancet 2016;387:2402)

High-grade B-cell lymphoma w/ rearrangements of MYC and BCL2 and/or BCL6: “double-/triple-hit”, assoc. w/ poor prognosis. Often use DA-R-EPOCH.

HIV-associated NHL (Blood 2006;107:13)

• HIV ⊕ imparts 60–100× relative risk

• NHL is an AIDS-defining malignancy along with Kaposi’s, cervical CA, anal CA

• Concurrent HAART & chemotherapy likely provide survival benefit

• DLBCL & immunoblastic lymphoma (67%): CD4 <100, EBV-associated. Burkitt lymphoma (20%): can occur with CD4 >200. Generally, treat as immunocompetent, but avoid rituximab if CD4 <50 (due to increased risk of death from infection).

• Primary CNS lymphoma (16%): CD4 <50, EBV-assoc. (also seen in Pts w/o HIV). Rx w/ high-dose MTX-based regimen + steroid ± temozolomide ± RT, consider auto HSCT.

SMALL LYMPHOCYTIC LYMPHOMA (SLL) OR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Definition (NEJM 2005;352:804; Blood 2008;111:5446)

• Monoclonal, functionally incompetent mature B lymphocytes; CLL & SLL = same disease

• CLL: >5000/µL malignant cells; SLL: <5000/µL malignant cells + LAN ± splenomegaly

• Monoclonal B lymphocytosis: resembles but does not meet CLL criteria, observe

Epidemiology and risk factors

• ~15,000 new cases/y; median age at dx is 71 y; most common adult leukemia

Clinical manifestations

• Often asx & identified by lymphocytosis on CBC; 10–20% p/w “B symptoms”

• Lymphadenopathy (80%) and hepatosplenomegaly (50%)

• Autoimmune hemolytic anemia (AIHA) (~10%) or thrombocytopenia (ITP) (~1–2%)

• Hypogammaglobulinemia ± neutropenia → ↑ susceptibility to infections

• Bone marrow failure in ~13%; monoclonal gammopathy in ~5%

• Aggressive Richter’s transformation in ~5% into high-grade lymphoma (poor prognosis)

Diagnostic evaluation

• CBC w/ diff: B-cell count

• Peripheral smear: lymphocytosis (predominantly mature-appearing small cells) “smudge” cells from damage to abnl lymphs from shear stress of making blood smear

• Flow cytometry: clonality with dim surface Ig; CD5+, CD19+, CD20+, CD23+

• Bone marrow (not req for dx): normo- or hypercellular; ≥30% small B lymphocytes

• Genetics: del 11q22-23 & del(17p) unfavorable; trisomy 12 neutral; del 13q14 and mut IGHV favorable. Nine significantly mutated genes, including TP53, NOTCH1, MYD88, and SF3B1. Key role for spliceosome mutations (NEJM 2011;365:2497; JCI 2012;122:3432).

Treatment (NEJM 2020;383:460)

• Observation unless “active disease”: Rai stage III/IV, Binet stage C, disease-related sx, progressive disease, AIHA or ITP refractory to steroids, recurrent infections

• First-line: w/o del(17p)/TP53 use acalabrutinib or ibrutinib (BTK inhibitors) or venetoclax + rituximab; with del(17p)/TP53 use acalabrutinib or venetoclax ± obinutuzumab; ibrutinib + venetoclax w 88% w/ CR but ↑ tox (NEJM 2019;380:2095)

• Second-line & beyond: in general, choose Rx w/ mechanism different from 1^st line Rx. BTK inhibitors (eg, zanubrutinib), venetoclax, chemo including fludarabine, chlorambucil, or bendamustine + rituximab. Consider allo-HSCT in relapse.

• HSCT is the only curative Rx. Rx choice balances patient/disease characteristics and goals of care. Different rates of complete remission, time to progression, and toxicities.

• Rx for complications: PCP, HSV, VZV Ppx; AIHA/ITP → steroids; recurrent infxns → IVIg

PLASMA CELL DYSCRASIAS

Monoclonal Gammopathy of Uncertain Significance (MGUS) (NEJM 2018;378:241)

• ✓ CBC, Ca, Cr, SPEP, serum free light chains, UPEP w/ immunofixation (to exclude MM)

• Close observation: repeat SPEP in 6 mo, then yearly thereafter if stable

• ~1%/y or ~25% lifetime risk → MM, WM, amyloidosis, or malign. lymphoproliferative dis.

• Abnormal serum free light chain ratio & M protein ≥1.5 g/dL: ↑ risk of progression to MM

Smoldering Multiple Myeloma

• Need whole-body MRI or PET-CT to rule out occult bone lesions

• Risk of prog. 10%/y, depends on [M protein], subtype, FLC ratio. No defined role for Rx yet though trials ongoing (NEJM 2013;369:438; Blood 2019;134:781; JCO 2020;38:1126).

MULTIPLE MYELOMA (MM)

Definition and epidemiology (Lancet 2021;397:410)

• Malignant neoplasm of plasma cells producing a monoclonal Ig = “M protein”

• ~27,000 new cases/y; median age at diagnosis 69 y; more common in African Americans

Clinical manifestations (CRAB criteria and other less common features)

• HyperCalcemia due to ↑ osteoclast activity

• Renal disease: multiple mechanisms include toxic effect of filtered light chains → renal failure (cast nephropathy) or type II RTA; amyloidosis or light chain deposition disease → nephrotic syndrome; hypercalcemia, urate nephropathy, type I cryoglobulinemia

• Anemia (normocytic) due to bone marrow involvement; rarely, may see AIHA

• Lytic Bone lesions due to ↑ osteoclast activity → pathologic fx

• Recurrent infxns due to relative hypogammaglob. (clonal plasma cells suppress nl Ig)

• Neurologic: cord compression; POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome

• Hyperviscosity: usually when IgM >4 g/dL, IgG >5 g/dL, or IgA >7 g/dL

• Coagulopathy: seen in amyloid due to binding & depletion of Factor X

• AL amyloidosis (see “Amyloidosis”)

Diagnostic and staging evaluation (Lancet Onc 2014;15:e538)

• Dx: BM plasma cells ≥10% or bx-proven plasmacytoma & ≥1 MM-defining event:

(a) myeloma-related organ or tissue impairment (ROTI) = lytic bone lesions, Ca >11 mg/dL, Cr >2 mg/dL, or Hb <10 g/dL

(b) any of the following biomarkers: BM plasma cells ≥60%, serum free light chain (FLC) ratio ≥100:1, >1 focal lesion on MRI

• Variants

Solitary bone or extramedullary plasmacytoma: no periph plasmacytosis or other ROTI

Plasma cell leukemia: plasma cell count >2000/µL in peripheral blood

Nonsecretory MM (~2% of MM Pts; MM without M protein)

• ✓ Peripheral smear for rouleaux (see insert), Ca, alb, Cr; ↓ anion gap, ↑ globulin, ↑ ESR

• Protein electrophoresis and immunofixation

Serum protein electrophoresis (SPEP): quantitates M component; ⊕ in >80% of Pts

Ddx of M component: MM, MGUS (vide supra), CLL, lymphoma, sarcoidosis, RA Polyclonal hypergam seen in inflammatory states: HIV, rheumatic diseases, cirrhosis

Urine protein electrophoresis (UPEP): detects Pts who secrete only light chains (= Bence Jones proteins), which are filtered rapidly from the blood

Immunofixation: shows component is monoclonal and identifies Ig type → IgG (50%), IgA (20%), IgD (2%), IgM (0.5%), light chain only (20%), nonsecretors (<5%)

Serum FLC assay: important for dx (esp. light chain-only Pts) and f/up response to Rx

• β₂-microglobulin (β₂M) and LDH levels reflect tumor burden

• BM bx cytogenetics: normal karyotype better than abnl. Standard risk = hyperdiploidy or t(11;14); high risk = hypodiploidy, del. 17p13 (~10% of Pts), t(4;14) & t(4;16).

• Skeletal survey (plain X-rays) to identify lytic bone lesions and areas at risk for pathologic fracture. Whole-body PET-CT (scalp to toe) or MRI often used to detect bone lesions.

Multiple Myeloma Staging Systems (OS does not account for cytogenetics)
Stage	ISS Criteria*	Durie-Salmon (DS) Criteria	ISS Median OS
I	β2M <3.5 mg/L and albumin >3.5 g/dL	All: Hb >10 g/dL; Ca ≤12 mg/dL; 0–1 lytic bone lesions; IgG <5 g/dL or IgA <3 g/dL or urine light chain <4 g/24 h	62 mo
II	Fulfilling criteria for neither I nor III		44 mo
III	β2M >5.5 mg/L	Any: Hb <8.5 g/dL; Ca >12 mg/dL; >5 lytic bone lesions; IgG >7 g/dL or IgA >5 g/dL or urine light chain >12 g/24 h	29 mo (30 mo if Cr <2 mg/dL; 15 mo if Cr ≥2 mg/dL)

^*Consider R-ISS incl chrom abnl & LDH (JCO 2005;23:3412 & 2015;61:2267).

Treatment and prognosis (NEJM 2016;375:754 & 1319; 2018;378:518 & 379:1811)

• Decisions dictated by risk stratification and transplant eligibility; generally incurable. Stratify via ISS criteria; R-ISS which includes chrom abnl & LDH (JCO 2015;61:2267).

• Rx incl. proteasome inhibitors: bortezomib (V), carfilzomib (K), ixazomib (I); immunomodulators: lenalidomide (R), thalidomide (T), pomalidomide (P); immunotherapy: daratumumab (anti-CD38, Dara), elotuzumab (anti-SLAMF7, Elo)

Other active drugs: dexamethasone (D), melphalan, panobinostat, cyclophosphamide

• Induction Rx w/ best response rate: proteasome inhib (V or K) + immunomod (eg, R). Triplet Rx ↑ OS vs. double (Lancet 2017;389:519). RVD most common regimen in US; KRD if high-risk (NEJM 2014;371:906 & 2016;374:1621). Dara-RD an option (NEJM 2019;380:2104).

Quad Rx (Dara-RVD) may improve response rates (Blood 2020;136:936).

• If not transplant eligible: induction Rx ↑ survival, not curative; consider maint chemo

• If transplant eligible: after induction chemo then high-dose melphalan + auto-HSCT. Not curative, but ↑ progression-free survival (PFS) vs. chemo alone (NEJM 2014;371:895, Lancet Onc 2015;16:1617). Offer if good perf. status & no prohibitive comorbid. Maint Rx w/ R improves PFS/OS (NEJM 2014;371:10). Timing of HSCT (upfront vs. relapse) debatable.

• Relapsed/refractory: HSCT (if good prior response, no prior HSCT), Elo-PD, Dara-PD, venetoclax (anti-Bcl-2) + dex in t(11;14); rarely use Allo-SCT. CAR-T w/ idecabtagene vicleucel (anti-B-cell maturation antigen) after >3 prior Rx: response rates >70% (NEJM 2019;380:1726 & 2021;384:705).

• Local radiation for solitary or extramedullary plasmacytoma

• Adjunctive Rx: bone: bisphosphonates (JCO 2007;25:2464), XRT for sx bony lesions

renal: avoid NSAIDs & IV contrast; consider plasmapheresis for acute renal failure

hyperviscosity syndrome: plasmapheresis; infxns: consider IVIg for recurrent infections

• Common toxicities of Rx: melphalan → myelosuppression; lenalidomide → low plts & thromboembolism; bortezomib → periph. neuropathy; steroids → hyperglycemia, infxn

WALDENSTRÖM’S MACROGLOBULINEMIA (WM)

Definition (Blood 2009;114:2375; NEJM 2012;367:826)

• B-cell neoplasm (lymphoplasmacytic lymphoma) that secretes monoclonal IgM

• 91% w/ MYD88 (NF-κB pathway) L265P mut., may distinguish from MM

• No evidence of bone lesions (IgM M component + lytic bone lesions = “IgM myeloma”)

Clinical manifestations

• Fatigue from anemia is most common sx

• Tumor infiltration: BM (cytopenias), hepatomegaly, splenomegaly, lymphadenopathy

• Circulating monoclonal IgM

Hyperviscosity syndrome (~15%): Neurologic: blurred vision (“sausage” retinal veins), HA, dizziness, Δ MS. Cardiopulmonary: congestive heart failure, pulm. infiltrates.

Type I cryoglobulinemia → Raynaud’s phenomenon

Platelet dysfxn → mucosal bleeding

• IgM deposition (skin, intestine, kidney); amyloidosis and glomerulopathy

• Autoantibody activity of IgM: Chronic AIHA (prominent rouleaux; 10% Coombs’ ⊕ = AIHA). Peripheral neuropathy: may be due to IgM against myelin-associated glycoprotein.

Diagnostic evaluation

• SPEP + immunofixation with IgM >3 g/dL; 24-h urine for UPEP (only 20% have ⊕ UPEP)

• Bone marrow biopsy: ↑ plasmacytoid lymphocytes; β₂-microglobulin for prognostic eval

• Relative serum viscosity: ratio serum viscosity to H₂O (nl 1.8); hyperviscosity when >5–6

Treatment

• Hyperviscosity: plasmapheresis; limit transfusions if possible (worsen hyperviscosity)

• Sx (eg, prog. anemia): ritux ± chemo (eg, bendamustine, Cy, etc.); ritux + ibrutinib (NEJM 2018;378:2399); zanubrutinib (Lancet Haem 2020;7:e837); everolimus or HSCT in salvage

HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)

Transplantation of donor pluripotent cells that can reconstitute all recipient blood lineages

Categories of Stem Cell Transplantation
Feature	Allogeneic (Allo)	Autologous (Auto)
Donor–recipient relationship	Immunologically distinct	Donor is also recipient
Graft-vs.-host disease	Yes	No
Graft-vs.-tumor effect	Yes	No
Risk of graft contam. w/ tumor	No	Yes
Relapse risk (leukemia)	Lower	Higher
Transplant-related mortality	Higher	Lower

• Types of Allo HSCT: based on donor/recipient matching of major HLA antigens on Chr. 6 (4 principal genes for serotyping: HLA-A, -B, -C, & -DR; each w/ 2 alleles ∴ 8 major Ag)

Matched related (MRD, sibling 8/8 major Ag match): lowest GVHD; preferred donor

Matched unrelated (MUD): ↑ risk of GVHD; ∴ matching of 10 HLA alleles (DQ also) to ↓ risk; chance of match correlates w/ ethnicity (NEJM 2014;371:339)

Mismatched related (eg, 1/8 Ag mismatch): ↑ available donor pool, but ↑ GVHD, rejection; ∴ need additional immunosuppression

Haploidentical: typically, between parents and young children or sibs (“half” match); early post-tx cyclophosphamide reduces GVH by destroying proliferating alloreactive T-cells

Umbilical cord blood: HSC processed at birth & stored. Yields lower cell number. Need 2 cords per adult. Neonatal immune cells: HLA-mismatch tolerated better, ↓ GVHD, slow immune reconstitution → ↑ late viral infections (Blood 2010;116:4693).

• Graft-vs.-host disease (GVHD): undesirable side effect of allo HSCT allogeneic T cells view host cells as foreign; ↑ incid. w/ mismatch or unrelated donors

• Graft-vs.-tumor (GVT): desired effect in allo-SCT; graft T cells attack host tumor cells

Indications (BBMT 2015;21:1863; BMT 2015;50:1037)

• Malignant disease:

Auto HSCT allows high-dose myeloablative chemo and then rescue what would be otherwise lethal cytopenias with autologous stem cells. Used in chemosensitive diseases such as relapsed/refractory DLBCL, MM, testicular germ cell tumor.

Allo HSCT produces graft-vs.-tumor (GVT) effect, in addition to hematopoietic rescue (used for AML, ALL, MDS, CML-blast crisis, CLL, lymphoma)

• Nonmalignant disease: allo HSCT replaces abnl lymphohematopoietic system w/ one from nl donor (eg, immunodeficiencies, aplastic anemia, hemoglobinopathies)

Transplantation procedure (for Allo HSCT)

• Pre-Tx conditioning regimen goal: immunosuppression to allow donor cell engraftment & anti-tumor efficacy to ↓ relapse risk. Type and dose of agents determine this balance.

Myeloablative conditioning: high-dose chemo and/or total body irradiation. Low relapse rates, high immunosuppression, higher transplant-related morbidity.

Reduced-intensity conditioning (“RIC”): lower dose of chemo → ↓ transplant-related morbidity/mortality, but ↑ relapse b/c it relies more on GVT effect (Blood 2015;126:23). Allows allo HSCT for older adults (>60) or Pts w/ comorbidities.

• Sources of hematopoietic stem cells (NEJM 2012;367:1487)

Bone marrow (BM): original source, preferred in non-malignant disease, ↓ GVHD rates

Peripheral blood stem cells (PBSC): easier to collect, more commonly used. BM vs. PBSC ≈ survival; BM ↓ chronic GVHD, PBSC ↓ graft failure, faster engraftment.

Umbilical cord blood stem cells (UCB): see above in Types of Allo HSCT

• Engraftment: absolute neutrophil count (ANC) recovers to 500/µL w/in ~2 wk w/ PBSC, ~2.5 wk w/ BM, ~4 wk w/ UCB. G-CSF accelerates recovery by 3–5 d in all scenarios.

Complications

• Either direct chemoradiotoxicities associated with preparative regimen or consequences of interaction between donor and recipient immune systems

• Engraftment syndrome: fever, rash, noncardiogenic pulm. edema, abnl LFTs, AKI, wt gain. Dx of exclusion: r/o infection, GVHD; Rx w/ 1 mg/kg steroids, rapid taper over 3–4 d.

• Sinusoidal obstruction syndrome (SOS): incidence ~10%, mortality ~30%

Previously known as veno-occlusive disease (VOD) (BBMT 2016;22:400). Mechanism: direct cytotoxic injury to hepatic venules → in situ thrombosis.

Symptoms: tender hepatomegaly, ascites, jaundice, fluid retention with severe disease → liver failure, encephalopathy, hepatorenal syndrome

Diagnosis: ↑ ALT/AST, ↑ bilirubin; ↑ PT with severe disease; Doppler U/S may show reversal of portal vein flow; ↑ hepatic wedge pressure; abnl liver bx

Treatment: supportive; prophylaxis with ursodiol; treat w/ defibrotide (Blood 2016;127:1656)

• Idiopathic pneumonia syndrome (IPS): 5–25% of Pts, >50% mortality (Blood 2003;102:2777)

Alveolar injury 2/2 direct toxicity → fever, hypoxia, diffuse infiltrates; occult infxn frequent

• Bleeding: incidence ~25%, 2/2 ↓↓ plts; sites: CNS, GI, pulm.; Ppx w plt transfusions

• Diffuse alveolar hemorrhage (DAH): Dx: bronchoscopy to exclude infection; ↑ bloody lavage fluid. Rx: 500–1000 mg Solu-Medrol × 3 d ± etanercept (BBMT 2015;1:67).

• Acute GVHD (usually within 6 mo of transplant; NEJM 2017;377:2167)

Clinical grades I–IV based on scores for skin (severity of maculopapular rash), liver (bilirubin level) and GI (volume of diarrhea); bx supports diagnosis

Prevention: immunosuppression (MTX + cyclosporine, or tacrolimus), T-cell depletion of graft, post-Tx cyclophos. for haploidentical, some high-risk allo (BBMT 2008;14:641)

Treatment: grade I → topical Rx; grades II–IV → associated with ↓ survival and ∴ treated with immunosuppressants (corticosteroids, CsA, tacrolimus, rapamycin, MMF)

• Chronic GVHD (developing or persisting >3 mo posttransplant; NEJM 2017;377:2565)

Clinical: malar rash, sicca syndrome, arthritis, obliterative bronchiolitis, bile duct degeneration, cholestasis, and many others. More common w/ PBSC than BM.

Treatment: immunosuppression; rituximab; photopheresis; ibrutinib (Blood 2017;130:21), ruxolitinib (NEJM 2021; 385:228), belumosudil (Blood 2021;138:2278)

• Graft failure

Primary = persistent neutropenia without evidence of engraftment

Secondary = delayed pancytopenia after initial engraftment; either immune mediated via immunocompetent host cells (graft rejection) or non–immune mediated (eg, CMV)

• Infectious complications

due to regimen-induced pancytopenia and immunosuppression

auto HSCT recipients: no immunosuppression ∴ at ↑ risk only pre-/postengraftment

both primary infections and reactivation events occur (eg, CMV, HSV, VZV)

Timing of Complications Following Allogeneic HSCT
	Time After Transplant and Associated Risk Factors
	Days 0–30 Mucositis; organ dysfunction; neutropenia	Days 30–90 Acute GVHD; ↓ cell immunity	>90 Days Chronic GVHD; ↓ cellular & humoral immunity
Viral infection	Respiratory and enteral viruses, BK virus
	HSV*	CMV*, HHV 6 & 7
		EBV-related lymphoma
			VZV*, JC
Bacterial infection	Gram ⊕ cocci (Staph., Strep. viridans) GNRs (Enterobacteriaceae, Pseudomonas, Legionella, S. maltophilia)		Encapsulated bacteria
Fungal infection	Candida spp.
	Aspergillus spp.
Parasitic infection		T. gondii P. carinii S. stercoralis	T. gondii P. carinii
Regimen-related	Pancytopenia		Growth failure
	Mucositis, rash, alopecia		Hypogonadism/infertility
	Nausea, vomiting, diarrhea		Hypothyroidism
	Peripheral neuropathies		Cataracts
	Hemorrhagic cystitis		Avascular necrosis of bone
	Veno-occlusive disease		2nd malignancy
	IPS/Interstitial pneumonitis
Immune-mediated	Acute GVHD		Chronic GVHD
	Primary graft failure	Secondary graft failure

^*Primarily among persons who are seropositive before transplant.

Prophylaxis/Supportive Medications During HSCT
Medication	Prophylaxis Against	Duration
Fluconazole or posaconazole	Candida	75 d
Acyclovir	HSV/VZV	365 d
Valganciclovir, ganciclovir, or letermovir if CMV ⊕	CMV	100 d or when no longer immunosuppressed
Antibiotics (eg, fluoroquinolone)	Bacterial infxn	While neutropenic
TMP-SMX or atovaquone	PCP	365 d or when off immunosupp.
Allopurinol	Hyperuricemia	Until d –1

LUNG CANCER

Epidemiology and risk factors

• Most common cause of cancer-related death for both men and women in the U.S.

• Two main types: non-small cell (NSCLC, ~85% of cases); small cell (SCLC, ~15%)

• NSCLC comprised of adeno (40%), squamous cell (SCC, 20%), & large cell (5%) carcinomas, as well as other / not classified (20%)

• Cigarette smoking: 85% of lung cancers occur in smokers; risk ∝ total pack-yrs, ↓ risk after quitting/reducing but not to baseline (Int J Cancer 2012;131:1210).

SCC & SCLC almost exclusively in smokers, adeno most common type in nonsmokers.

• Asbestos: when combined with smoking, synergistic ↑ in risk of lung cancer

• Other: RT (for other cancer); HIV; environ. toxins (radon, 2^nd-hand smoke); pulm. fibrosis

Screening (JAMA 2021;325:962)

• Annual low-dose chest CT in ≥20 pack-year current or former (quit w/in 15 y) smokers, age 50–80 y → 20% ↓ lung cancer-related mortality (NEJM 2020;382:503)

• High rates of screen-detected nodules. Multidisciplinary mgmt recommended (pulm., med onc, thoracic radiology & surgery; NCCN Guidelines: Lung Cancer Screening v.1.2022).

Clinical manifestations

• ~10% asymptomatic at dx, detected incidentally (only 16% w/ localized dis. at presentation)

• Endobronchial growth of 1° tumor: cough, hemoptysis, dyspnea, pain, wheezing, post-obstructive pneumonia; more common with squamous or small cell (central location)

• Regional spread: can cause dysphagia (esophageal compression), stridor (tracheal obstruction), hoarseness (recurrent laryngeal nerve palsy). Pleural effusions & pleural metastases specifically = metastatic disease = Stage IV.

Pancoast’s syndrome: apical tumor → brachial plexus involvement (C8, T1, T2) → Horner’s syndrome, shoulder pain, rib destruction, atrophy of hand muscles

SVC syndrome (NEJM 2007;356:1862): central tumor → SVC compression → face/arm swelling (>80%), neck/chest vein distention (~60%), SOB/cough (~50%), HA (~10%); Rx = steroids, diuretics, RT ± chemo, SVC stent if severe sx, anticoag if clot

• Extrathoracic metastases: brain (~25% of patients at dx), bone, liver, adrenal

• Paraneoplastic syndromes

Endo: SIADH (SCLC); ACTH (SCLC) → Cushing’s; PTH-rP (SCC) → hyperCa

Skeletal: digital clubbing (NSCLC), hypertrophic pulm. osteoarthropathy (adenocarcinoma) = symmetric polyarthritis and proliferative periostitis of long bones

Neuro (SCLC): Eaton-Lambert (anti-P/Q-type voltage-gated Ca²⁺ channel Abs), peripheral neuropathy (anti-Hu, anti-PCA-2, anti-CRMP5), cerebellar degeneration (anti-Hu, anti-Yo, anti-Ri, anti-Tr), encephalomyelitis (anti-Hu, anti-Ma1/2, anti-CRMP5)

Hematologic: hypercoagulable state (adenocarcinoma), DIC

Diagnostic and staging evaluation (NCCN Guidelines v.7.2021)

• Staging: based on tumor size and extent of invasion (T), regional LN involvement [N: N0 (none), N1 (ipsilat. hilar), N2 (ipsilat. mediast.), N3 (contralat., supraclav.)] and presence of metastases (M) (Chest 2017;151:193). Pleural effusions/implants = Stage IV.

5-y survival: ~70–90% for stage I, 50–60% stage II, 15–35% stage III, 0–10% stage IV (J Thorac Oncol 2016;11:39); survival improving with newer therapies (NEJM 2020;383:640).

• Imaging: CT w/ contrast of chest & abd/pelvis to assess for mets (adrenal, liver, bones).

PET-CT more Se than CT alone for detecting mediastinal and distant mets as well as

bone mets (NEJM 2009;361:32). Brain MRI for all Pts except stage IA.

• Pathology: via bronchoscopy (central lesions) or CT-guided needle bx (peripheral lesions or accessible sites of suspected metastasis); mediastinoscopy (LN bx / eval), VATS (eval. of pleural peripheral lesions), thoracentesis if pleural effusion (cytology).

• Genetics (usually just in adv/metastatic disease): ✓ EGFR (include in stage IIA-IIIB), ALK, ROS1, MET, KRAS, RET, BRAF, NTRK fusion for all non-squamous disease (incidence lower in SCC but still consider testing); PD-L1 expression

• PFTs w/ quant V/Q if Rx includes resection; need 30% nl predicted lung fxn after resection

NSCLC Treatment (NCCN Guidelines v.7.2021; Lancet 2021;398:535)

• Localized disease: surgery if possible; RT (eg, stereotactic ablative radiotherapy [SABR]) vs. chemo/RT if not (see Figure 5-7)

• Metastatic disease: >20 new Rx since 2015. Some targeted Rx substantially improves survival & are better tolerated (see Stage IV Rx table); however, 5-y survival still poor.

First-line immunotherapy (IO) ± chemo for most Pts w/o targetable mutations.

Pemetrexed + pembrolizumab often continued as maintenance when used.

Palliative care ↑ survival (NEJM 2010;363:733); palliative RT for local sx from tumor/mets.

• Avoid combining IO & targeted Rx, ↑↑ tox (eg, rash/diarrhea, lung/liver injury [can be fatal])

• Solitary brain metastasis (oligomet): surgical resection + brain radiation may ↑ survival

(NCCN Guidelines v7.2021; NEJM 2017:377:1919, 2018;378:113, & 2020;383:1711; Lancet 2021;398:1344)

Stage IV NSCLC Treatment
Type	Genetics	%	Treatment
Adeno or Other	EGFR	~15	1st line: osimertinib if L858R, ex19del (NEJM 2018;378:113)
	EGFR ex20 insertion	2–3	Subsequent Rx w/ amivantamab (JCO 2021;39:3391) or mobocertinib (JAMA Onc 2021;7:e214761) after platinum chemo
	ALK	~4	1st line: alectinib pref. b/c CNS activity (NEJM 2017;377:829)
	ROS1	2	Crizotinib pref. (JCO 2017;35:2613); entrectinib (Lancet Onc 2020;21:261)
	MET ex14 skip or amplif.	3	Capmatinib (NEJM 2020;383:944) or tepotinib (NEJM 2020;383:931)
	RET	1	Selpercatinib (NEJM 2020;383:813) or pralsetinib (Lancet Onc 2021;22: 959-969)
	BRAF V600E	1–3	Dabrafenib + trametinib (Lancet Onc 2016;17:984)
	NTRK fusions	<1	Larotrectinib (NEJM 2018;378:731)
	KRAS G12C	~13	Subsequent Rx w/ sotorasib (NEJM 2021;384:2371)
	PD-L1≥50%	30	Pembrolizumab or chemo + pembro (NEJM 2018;378:2078)
	No targets & PD-L1 <50%		Chemo (carbo/pemetrexed) + pembro (NEJM 2018;378:2078) or carbo/paclitaxel + anti-VEGF Ab (bevacizumab) + atezo (NEJM 2018;378:2288)
Squam	PD-L1 ≥50%		Pembrolizumab or chemo/pembro (NEJM 2016;375:1823)
	PD-L1 <50%		Chemo [carbo/paclitaxel] + pembro (NEJM 2018;379:2040)

Many are specific tyrosine kinase inhibitors (‘tinibs) directed against EGFR, ALK, etc. Amivantamab is an EGFR- MET bispecific mAb. Pembrolizumab is a mAb against PD-1 on lymphocytes (ie, an immune checkpoint inhibitor).

SCLC staging and treatment (NCCN Guidelines v.1.2022)

• SCLC usually disseminated at presentation; poor overall survival

• Can be very responsive to chemotherapy, but rapidly develop resistance

• Diagnosis: all have Rb & p53 mutations (Nature 2015;524:47); 90% w/ neuroendo markers

• Treatment: primarily chemo (platinum + etoposide); adding anti-PD-L1 Ab (atezolizumab)

↑ survival (NEJM 2018;379:2220), as does concurrent thoracic RT in limited-stage disease

• Prophylactic cranial irradiation (PCI) controversial. Offered to potentially ↑ survival for LS-SCLC in complete remission (NEJM 1999;341:476). Role in ES-SCLC being studied.

• Second line: low response rates, short survival. Options: lurbinectedin, single-agent chemo (eg, topotecan, docetaxel), reRx w/ platinum doublet, anti-PD-1 (eg, nivo).

BREAST CANCER

Epidemiology

• In U.S., most common cancer in women; 2^nd leading cause of cancer death in women

• Genetic risk: 15–20% ⊕ FHx → 2× ↑ risk; ~45% familial cases a/w germline mutation.

BRCA1/2: 35–85% lifetime risk of breast ca. Germline loss-of-function mutations in PALB2 a/w 35% ↑ risk breast cancer by age 70. Moderate risk mutations CHEK2 and BARD1 a/w 15–30% lifetime risk of breast cancer (NEJM 2021;384:428).

• Estrogen: ↑ risk with early menarche, late menopause, late parity or nulliparity (NEJM 2006;354:270); ↑ risk with prolonged HRT (RR = 1.24 after 5.6 y; JAMA 2003;289:3243); OCP use a/w extremely low to no ↑ risk (NEJM 2017:317:2228; JAMA Oncol 2018;4:516)

• Benign breast conditions: ↑ risk if atypia (atypical ductal or lobular hyperplasia; NEJM 2015;372:78) or proliferative (ductal hyperplasia, papilloma, radial scar, or sclerosing adenosis) features; no ↑ risk w/ cysts, simple fibroadenoma, or columnar changes

• ↑ risk with h/o ionizing radiation to chest for treatment of Hodgkin lymphoma

Prevention (if high-risk: eg, FHx, LCIS, atypical hyperplasia)

• Tamoxifen (contraindic. in preg): ↓ risk contralateral breast ca as adjuvant Rx. Approved for 1° prevent. if ↑ risk: ↓ invasive breast cancer, but ↑ DVT & uterine ca.

• Raloxifene (only if post-menopausal): ↓ risk of invas breast ca, vertebral fx, & uterine ca, ↑ risk stroke & DVT/PE (NEJM 2006;355:125); less effective than tamoxifen for prevention.

• Aromatase inhib. (post-menopausal): ↓ risk >50% (Lancet 2014;383:1041), ↑ osteoporosis

• BRCA1/2 ⊕: intensified surveillance vs. prophylactic bilat. mastectomy which ↓ risk ~90%; bilat. salpingo-oophorectomy ↓ risk of ovarian and breast cancer (NEJM 2016;374:454)

Clinical manifestations

• Breast mass (hard, irregular, fixed, nontender), nipple discharge (higher risk if unilateral, limited to 1 duct, bloody, associated with mass)

• Special types: Paget disease → unilateral nipple eczema + nipple discharge; inflammatory breast cancer → skin erythema and edema (peau d’orange)

• Metastases: lymph nodes, bone, liver, lung, brain

Screening (JAMA 2015;314:1599; Annals 2019;170:547)

• Mammography: ~20–30% ↓ in breast cancer mortality, smaller abs. benefit in women <50 y (JAMA 2018;319:1814); digital breast tomosynthesis (3-D) ↑ specificity (JAMA Oncol 2019;5:635); suspicious findings: clustered microcalcifications, spiculated, enlarging

• ACS: annual mammo starting at 45 (consider biennial after 54), cont. if life expect ≥10 y

• USPSTF: screen biennially ages 50–75 (some may want to begin at 40)

• ↑ risk: screen earlier w/ exam and mammo (age 25 in BRCA1/2 carrier, 5–10 y before earliest FHx case, 8–10 y after thoracic RT, upon dx of ↑ risk benign disease)

• MRI: superior to mammo in high-risk and young Pts; consider annually if >20% lifetime risk (eg, ⊕ FHx, BRCA1/2, prior chest RT) (Lancet 2011;378:1804)

• Germline genetic testing: if metastatic, TNBC, ♂, age ≤45y, or by FHx (NCCN v1.2022)

Diagnostic evaluation

• Palpable breast mass: age <30 y → observe for resolution over 1–2 menstrual cycles; age <30 y, unchanging mass → U/S → aspiration if mass not simple cyst;

age >30 y or solid mass on U/S or bloody aspirate or recurrence after aspiration → mammo (detect other lesions) and either fine-needle asp. or core-needle bx

clearly cancerous on exam or indeterminate read or atypia on bx → excisional bx

• Suspicious mammogram with normal exam: stereotactically guided bx

• MRI: detects contralateral cancer in 3% of Pts w/ recently dx breast cancer & contra-lateral mammo (but PPV only 21%) (NEJM 2007;356:1295); utility remains unclear

Staging

• Anatomic: tumor size, chest wall invasion, axillary LN mets (strongest prognostic factor)

• Histopathologic: type (little prognostic relevance) & grade; lymphatic/vascular invasion

In situ carcinoma: no invasion of surrounding stroma

Ductal (DCIS): ↑ risk of invasive cancer in ipsilateral breast (~30%/10 y)

Lobular (LCIS): benign entity; marker of ↑ risk of inv. cancer in either breast (~1%/y)

Invasive carcinoma: infiltrating ductal (70–80%); invasive lobular (5–10%); tubular, medullary and mucinous (10%, better prognosis); papillary (1–2%); other (1–2%)

Inflammatory breast cancer (see above): not a histologic type but a clinical reflection of tumor invasion of dermal lymphatics; very poor prognosis

Paget disease (see above): ductal cancer invading nipple epidermis ± associated mass

• Tissue biomarkers: estrogen and progesterone receptor (ER/PR), HER2

• Oncotype DX 21-gene expression recurrence score predicts which ER ⊕, HER2 ⊖ will have minimal benefit from adjuvant chemo in LN ⊖ (NEJM 2018;379:111) and LN ⊕ (1–3) disease (NEJM 2021;385:2336)

Simplified Staging & 5-y Dis. Specific Survival (CA Cancer J Clin 2017;67:290; SEER 2017)
Stage	Characteristics	Description	5-y DSS
I	Tumor ≤2 cm	Operable locoregional	99%
IIA	Tumor >2 cm or mobile axillary nodes		98%
IIB	Tumor >5 cm or 2–5 cm w/ mobile nodes		96%
IIIA	Internal mammary or fixed axillary nodes	Locally advanced	95%
IIIB/C	Chest wall, skin, infra or supraclavic. nodes	Inoperable	80–85%
IV	Distant metastases	Metastatic	27%

General Approach to Treatment (JAMA 2019;321:288 & 1716)
DCIS	Mastectomy or lumpectomy ± RT ± chemoprevention (Lancet 2016;387:849 & 866)
I	Surgery + RT
II	+ adjuv. chemo if ↑ risk: tumor >2 cm or ⊕ LN or triple ⊖ or Oncotype DX-guided + hormonal Rx for ER/PR ⊕: add ovarian suppression if ↑ risk (NEJM 2018; 379:122) + anti-HER2 Rx and chemo if HER2 ⊕ and tumor ≥1 cm or ⊕ LN
III	Neoadjuvant chemo → surgery + RT ± adjuvant chemotherapy + hormonal Rx for ER/PR ⊕: add ovarian suppression if premenopausal + anti-HER2 Rx for HER2 ⊕: usually trastuzumab + pertuzumab
IV	ER/PR ⊕: combined aromatase & CDK4/6 inhibitors (NEJM 2016; 375:1925) ER/PR ⊖/HER2 ⊕: chemo + anti-HER2 therapy Triple ⊖: chemo ± immune checkpoint inhibitor Bony mets: bisphosphonates & denosumab ↓ fractures (Cochrane 2017;CD003474)

Surgery and Radiation for Local Control
Intervention	Indication
Breast conserving	Stage I–II, lumpectomy + sentinel lymph node biopsy* + RT
Modified radical mastectomy	Large tumor relative to breast, multicentric dis., prior chest RT, diffuse microcalcifications, ⊕ margins after lumpectomy
Post mastectomy Radiation	≥4 ⊕ LN, tumor >5 cm, ⊕ surgical margins, chest wall or skin involvement (Lancet 2014;384:1848)

^*Axillary lymph node dissection indicated for palpable axillary LNs

Systemic Therapy
Indic.	Class	Examples
ER/PR ⊕ (Lancet 2017;389: 2403)	Endo (NEJM 2019;380: 1226)	Tamoxifen: adjuvant Rx for low-risk pre-meno; ↓ recurrence & ↓ mortality; 10 y superior to 5 y (Lancet 2011;378:771 & 2013;381:805) Aromatase inhib (AI; anastrozole, letrozole, exemestane): adjuvant Rx for post-meno; ↑ OS vs. tam. (Lancet 2015;386:1341); 7 y of Rx ↑ DFS vs. 5 y of Rx (NEJM 2021;385:395) Adding selective ER degrader (fulvestrant) to AI ↑ OS if mets
	Ovarian suppress.	LHRH agonists (eg, leuprolide) or oophorectomy: adjuvant Rx for high-risk pre-meno combined with tam. or AI (NEJM 2018;379:122)
	Cell prolif. (NEJM 2012;366: 520)	CDK 4/6 inhib (eg, palbociclib, abemaciclib, ribociclib): + AI (1st-line metastatic Rx) or fulvestrant ↑ PFS (& OS for ribociclib) in stage IV vs. AI alone (NEJM 2018;379:1926; JCO 2017;35:3638); + AI for adjuvant (Ann Onc 2021;32:1571) mTOR inhib (everolimus): + AI (exemestane) ↑ OS in stage IV
PIK3CA ⊕	PI3K inhib	Alpelisib + fulvestrant ↑ PFS in met HR⊕ (NEJM 2019;380:1929)
HER2 ⊕ (Lancet 2017;389: 2415)	HER2- targeted	Trastuzumab (anti-HER2): 1st-line Rx combined w/ chemo Trastuzumab emtansine (mAb linked to chemo): ↓ risk of recurrence/death if residual disease post neoadj. Rx (NEJM 2019;380:617); preferred 2nd line Rx for met. disease Trastuzumab deruxtecan (mAb linked to chemo): emerging data as 2nd line Rx for met disease, ↓ risk disease progression vs. trastuzumab emtansine, ↑ lung toxicity (NEJM 2022;386:1143) Margetuximab (anti-HER2): combined w/ chemo preferred after 2+ lines of Rx (JAMA Oncol 2021;7:573)
Stage I–III (above)	Chemo	Neoadjuvant: to conserve breast & evaluate Rx efficacy, equivalent OS as adjuvant (JCO 2008;26:778) Adjuvant: use anthracycline ± taxane. Nb, endocrine only for some ER/PR ⊕ based on oncotype Dx (see staging).
Triple ⊖	Immune	Pembrolizumab (anti-PD-1 mAb) + chemo 1st-line for early stage (NEJM 2020;382:810) & PD-L1 ⊕ met dis. (Lancet 2020;396:1817)
	Ab-drug conjugate	Sacituzumab govitecan: anti-trop-2 Ab linked to chemo ↑ PFS & OS in heavily pre-Rx’d metastatic disease (NEJM 2019;380:741)
BRCA ⊕	PARP inh	Olaparib & talazoparib (NEJM 2017;377:523 & 2018;379:753)

DFS, disease-free survival; OS, overall survival; PFS, progression-free survival

PROSTATE CANCER

Epidemiology and risk factors (NEJM 2003;349:366)

• Most common cancer in U.S. men; 2^nd most common cause of cancer death in men

• Lifetime risk of prostate cancer dx ~16%; lifetime risk of dying of prostate cancer ~3%

• ↑ risk with ↑ age (rare if <45 y), in African Americans, ⊕ FHx, BRCA mutations

Clinical manifestations

• Most prostate cancers (78%) are asymptomatic and localized at diagnosis

• Metastatic dis. sx primarily from bone mets: bone pain, spinal cord compression, cytopenias

Screening (JAMA 2014;311:1143; Lancet 2014;384:2027)

• PSA: 4 ng/mL cut point neither Se nor Sp; can ↑ with BPH, prostatitis, acute retention, after bx or TURP, and ejaculation (no significant ↑ after DRE, cystoscopy); 15% of men >62 y w/ PSA <4 & nl DRE have bx-proven T1 cancer (NEJM 2004;350:2239)

• Digital rectal exam no longer recommended due to limitations, no mortality benefit

• ACS rec: ≥50 y (or ≥45 y AA or ⊕ FHx) discuss PSA screening, informed decision making

• USPSTF (JAMA 2018;319:1901) rec discuss pros/cons w/ Pt (no ↓ in prostate ca-related mort.)

Diagnostic evaluation, staging, and treatment (NCCN Guidelines v1.2022)

• Transrectal ultrasound (TRUS) guided biopsy (6–12 cores)

• Multiparametric MRI (± endorectal coil): improves detection (NEJM 2018;378:1767)

• Gleason score & grade group (histology): Gleason score determines Grade Group. 1 = best → 5 = worst. Group 1: 3+3=6 (most common histologic pattern is 1^st #, next is 2^nd #), Group 2: 3+4=7, Group 3: 4+3=7, Group 4: 4+4=8, Group 5: all higher.

^*In asx Pts w/ life expect ≤5 y & very low-to-intermed risk dis., no w/up or Rx until sx. NCCN Guidelines v1.2022

^†RP more short-term impotence (unless ADT) & incont than RT; over yrs → similar (NEJM 2016;375:1425)

Treatment of Metastatic Prostate Cancer (NCCN Guidelines v1.2022)
Androgen deprivation therapy (ADT)	Prostate ca requires androgen signaling for growth. ADT backbone of Rx. Med: 1. Luteinizing hormone-releasing hormone (LHRH) agonist (eg, leuprolide) ± 1st-gen anti-androgen (nilutamide, bicalutamide), or 2. LHRH antagonist (degarelix) Surgery: bilateral orchiectomy
Hormone- sensitive prostate cancer (HSPC)	Def: ADT sensitive (ie, PSA ↓ w/ Rx): all prostate ca initially sensitive Workup/testing: PEx & PSA q 3–6 mos; sx-guided imaging Rx: 1. ADT alone (only if minimal disease, eg, rising PSA); or 2. ADT + abiraterone/pred or enza/apalutamide (↑ OS vs. ADT alone); or 3. Docetaxel + ADT (↑ OS vs. ADT alone, espec. in high-volume disease)
Castration-resistant prostate cancer (CRPC) Always continue ADT	Def: All met. HSPC eventually becomes CRPC (ie, progression despite castration androgen levels on ADT), due to re-estab. of androgen signaling via other mech. ∴ more potent anti-androgens are needed. Rx: New-gen. anti-androgens: abiraterone (biosynth inhib.) + pred, or enza/daro/apalutamide (receptor blocker) ↑ PFS & OS Targeted: BRCA1/2, ATM (homologous recomb genes, ~20%): olaparib; MSI-H/Lynch syndrome (2–5%): pembro; Cancer vaccine: Sipuleucel-T Chemo: doce/cabazitaxel +pred/dex+Luetitium-177 (NEJM 2021;385:1091) Bone-active agents: 1. denosumab or zoledronic acid ↓ skeletal-related events (SREs); 2. radium-223 used in bone-only dis, ↓ SREs & ↑ OS

(NEJM 2017;377:338 & 352; 2019;381:121; 2019;381:13; Lancet 2016;387:1163)

Prognosis and monitoring

• PSA level, Gleason score/grade group and age are predictors of metastatic disease

• In surgically treated Pts, 5-y relapse-free survival >90% (excellent) if disease confined to organ, ~75% if extension through capsule, and ~40% if seminal vesicle invasion

• PSA q6mo for 5 y if curative Rx; consider PET Axumin scan if ↑ PSA ± equivocal bone scan

COLORECTAL CANCER (CRC)

Epidemiology and risk factors (CA Cancer J Clin 2018;68:7)

• 4^th most common cancer in U.S. men & women; 2^nd leading cause of all cancer death

• 90% of cases occur after age 50. ~75% are sporadic.

• IBD a/w ~0.3%/y ↑ risk of CRC. ↑ risk w/ ↑ extent and duration of disease.

Heritable Genetic Syndromes
Disorder	CRC risk	Pathophysiology	Assoc Cancers
Hereditary nonpolyposis colorectal cancer (HNPCC or Lynch)	~80% lifetime	Most common hered. CRC (~3%). Mismatch repair mut (eg, MSH2, MLH1). Dx: ≥3 family HNPCC cancer, 1 dx before 50 y, involves 2 gen. Typically right-sided.	Endometrial, ovarian, stomach, urothelial, small bowel & pancreas
Familial adeno polyposis (FAP)	100% lifetime	Mutation in APC gene → 1000s of polyps at young age	Thyroid, stomach, small bowel
MUTYH-assoc. polyposis (MAP)	40–100% lifetime	Autosomal recessive; consider if mult. polyps but ⊖ for FAP	Duodenal, ovarian, bladder, skin

• ASA rec for 1° prev. if 50–59 y & ≥10% 10-y CRC risk. Must take for at least 10 years.

Screening (JAMA 2021;325:1965)

• Average-risk Pts: start at age 45, repeat q1–10y based on screening modality

• ↑ risk Pts: ⊕ FHx: screen age 40 or 10 y before index dx, then q5y. IBD: colo 8–10 y after dx, then q1–2y. Suspect familial syndrome: genetic counsel, screen age 20–25, yearly.

• Colonoscopy: preferred; 90% Se for lesions >1 cm. If polyp, re ✓ in 3–5 y. Adenomatous polyp removal a/w ↓ CRC mortality (NEJM 2012;366:687). Adenoma: ↑ risk of malig. if >2.5 cm, villous, or sessile; can progress to CRC over ~10 y interval (sporadic & familial).

• Sigmoidoscopy: benefit w/ 1-time flex-sig (Lancet 2017;389:1299); less Se than colo or CTC

• CT colonography (CTC): ~90% Se for lesions ≥1 cm but less if smaller (NEJM 2008;359:1207). If high-risk, Se only 85% for neoplasia ≥6 mm (JAMA 2009;301:2453).

• Combo DNA + Hb immunoassay w/ ~90% Se & Sp (NEJM 2014;370:1287)

• Occult blood (FOBT): use 3-card home testing (Se 24%) yearly

Clinical manifestations

• Distal colon: Δ bowel habits/ caliber, obstruction, colicky abd. pain, hematochezia

• Proximal colon: iron defic. anemia, dull vague abd pain, liquid stool

• Associated with Streptococcus bovis bacteremia and Clostridium septicum sepsis

Cancer genetics (Nature 2014;513:382)

• Microsatellite stable (MSS) vs. high instability (MSI-H): latter sign of mismatch repair gene failure, accounts for 15% CRC, presents more often as early stage, ~5% of met dis.

• Mutations: APC (~80%); KRAS (~40%); TP53 (50–70%); DCC, SMAD4, BRAF (~15%), HER2 amplification (<5%)

Staging and treatment (NCCN Clin Pract Guidelines; version 3.2021)

• TNM staging, including CT chest and abdomen/pelvis with contrast ± MRI pelvis for rectal

• Baseline CEA: monitor post resection or follow response; not for screening

• Chemo options (Lancet 2014;383:1490): 5-FU/leucovorin (LV) foundation. 5-FU/LV + oxaliplatin &/or irinotecan (FOLFOX, FOLFIRI, FOLFOXIRI, resp). Capecitabine oral 5-FU prodrug. TAS102 (trifluridine + tipiracil) in progressive disease (NEJM 2015;372:1909).

Anti-VEGF (bevacizumab) added to chemo ↑ OS in all subsets of mCRC.

• Targeted therapy: anti-EGFR mAb (cetuximab or panitumumab) in unmutated KRAS/NRAS/BRAF (NEJM 2013;369:1023), better for L-sided disease; encorafienib + cetuximab + binimetinib in BRAF V600E (NEJM 2019;381:1632)

• ImmunoRx: anti PD-1 (NEJM 2020;383:2207) ± CTLA-4 in MSI-H/ MMRd met CRC

• Radiation: loc. adv. rectal (T3/N+) & colon (unresectable); consider for oligo-mets

TNM	Path. Criteria	5-y Surv.	Treatment
I	Submucosa/muscularis	94–97%	Surgery alone (resect & analyze ≥12 LN)
IIA	Serosa	83%	Surgery. Consider adjuvant chemo for high-risk Stage II: obstruction, perf, adherence, inadequate LN sampling (<12 LNs).
IIB	Peritoneum	74%
IIC	Direct invasion	56%
IIIA	≤6 ⊕ LNs	86%	Surgery + FOLFOX (6 mo) or CAPOX (3–6 mo) (NEJM 2018;378:13) Pre RT ± chemo if rectal (NEJM 2006;355:1114)
IIIB	Varying # ⊕ LNs & local invasion	51–77%
IIIC		15–47%
IV	Distant metastases* (NEJM 2014;371:1609)	5%	Chemo (FOLFOXIRI if high-risk) ± anti-PD-1 (MSI-H only) ± resect isolated mets

^*Oligometastatic dis (few, limited mets) sometimes still curable w/ chemo + metastatectomy/radiation

PANCREATIC TUMORS

Genetics and path (Nat Rev Dis Primers 2016;2:16022)

• Histologic types: adenocarcinoma (~85%), acinar cell carcinoma, endocrine tumors, cystic neoplasms (<10%); rarely, mets to pancreas (eg, lung, breast, renal cell)

• Location: ~60% in head, 15% in body, 5% in tail; in 20% diffuse infiltration of pancreas

• Adeno. mut.: KRAS (>90%), p16 (80–95%), p53 (50–75%), SMAD4 (~55%), BRCA (10%)

Epidemiology and risk factors (Lancet 2016;388:73)

• 4^th leading cause of cancer death in U.S.; 80% panc adeno in ages 60–80 y; M>F (1.3:1)

• Acquired risk factors: smoking (RR ~1.5; 25% cases), obesity, chronic pancreatitis, T2DM

• Hereditary (5–10%): familial breast/ovarian CA (BRCA2); hereditary chronic pancreatitis (mutation in cationic trypsinogen gene (PRSS1, SPINK1); familial cancer syndromes: atypical multiple mole melanoma (CDKN2A/p16), Peutz-Jeghers (LKB1), ataxia-telang.

Clinical manifestations

• Painless jaundice (w/ pancreatic head mass), pain radiates to back, ↓ weight & appetite

• New-onset atypical DM (25%); migratory thrombophlebitis (Trousseau’s syndrome)

• Exam: jaundice, RUQ/epigastric nontender mass, palpable gallbladder (Courvoisier’s sign); hepatomegaly; ascites; L supraclavicular node (Virchow’s)

• Laboratory tests may show ↑ bilirubin, ↑ alk phos, anemia

Diagnostic and staging evaluation (NCCN Guidelines v.2.2021)

• Pancreatic protocol CT scan (I⁺ w/ arterial & venous phase imaging) or MRI w/ contrast

• If no lesion seen but concerning signs & sx as above → EUS, ERCP, or MRCP

• Biopsy pancreatic lesion via EUS-guided FNA (pref. for surgical candidates) or CT-guided (risk of seeding); if possible metastases, biopsy those for staging and dx.

• ✓ CA19-9 preop (nb, can be ↑ in benign liver/biliary dis.); may be useful to trend postop

• Germline genetic testing for all Pts with pancreatic cancer

Clinical (Radiologic) Staging Pancreatic Adenocarcinoma
Resectable	No extrapanc. dis. or bulky LAN; no arterial tumor contact [celiac axis (CA), SMA, common hepatic (CHA)]; and no venous contact [SMV, portal vein (PV)] or ≤180° + patent veins (ie, no tumor thrombus)
Borderline resectable	No extrapanc dis. or bulky LAN. Head/uncinate: contact w/ CHA (no extension to CA or HA bifurcation), SMA contact ≤180°, variant anatomy. Body/tail: contact CA ≤180° or >180° but w/o gastro-duodenal art. or aortic. Venous: SMV & PV contact ≤180° w/ contour irreg; contact w/ IVC.
Unresect.	Distant mets; or head/uncinate: contact >180° SMA, CA; or Body/tail: contact >180° SMA or CA; CA & aortic involvement; or Venous: SMV/PV involvement/not reconstructible

Treatment of pancreatic adenocarcinoma (Lancet 2016;388:73)

• Resectable: pancreaticoduodenectomy (Whipple procedure) + adjuvant chemo:

modified FOLFIRINOX (5-FU + leucovorin, irinotecan, oxaliplatin) if ECOG 0-1

(NEJM 2018;379:2395), o/w gemcitabine + capecitabine (Lancet 2017;389:1011). Gemcitabine

monoRx recently standard, but now w/ ↓ role. Role of RT is controversial.

• Borderline: goal to ↓ tumor to allow complete resection (R0 – neg margin at histology) using neoadjuvant Rx (various approaches tested). General schema: chemo ± RT → restage & potential resection depending on response. May need vasc. reconstruction during resection. Regimens include: FOLFIRINOX; gemcitabine + nab-paclitaxel.

• Locally advanced (ie, unresectable): Rx is typically palliative. However, in highly select Pts recent trend toward Rx w/ FOLFIRINOX plus XRT followed by laparotomy for response assessment (imaging can be unreliable) and potential resection.

• Metastatic: clinical trials preferred; Rx based on performance status (PS)

Good PS: FOLFIRINOX, gemcitabine + nab-paclitaxel (NEJM 2013;369:1691); germline BRCA1/2 mut: maintenance olaparib (NEJM 2019;381:317) also ↑ response to platinum combination chemo (eg, cisplatin w/ gemcitabine), ICI for MSI-high.

Poor PS: gemcitabine; capecitabine; continuous infusion 5-FU

• Palliative care: Biliary/gastric outlet obstruct.: endoscopic stenting, IR drain, surg bypass. Pain: opiates, celiac plexus neurolysis, XRT. Wt loss: enzyme replacement.

Prognosis

• Resectable: if Rx’d w/ adjuvant FOLFIRINOX, 50+ mos, o/w ~30 mos

• Unresectable: if locally advanced ~1–2 y; if metastatic, ~1 y

Cystic lesions of the pancreas (Am J Gastroenterol 2018;113:464)

• Serous cystadenoma: usually benign; central scar or honeycomb appearance on imaging

• Mucinous cystic neoplasm (MCN): predominantly young females; multiloculated tumors in body or tail w/ ovarian-type stroma and mucin-rich fluid w/ ↑ CEA levels; precancerous

• Intraductal papillary mucinous neoplasm (IPMN): arises in main panc duct or branch

OTHER SOLID TUMORS

HEPATOCELLULAR CARCINOMA (HCC)

Risk factors (globally, 3^rd leading cause of cancer death, espec. in Africa & Asia)

• Cirrhosis: present in 70–90% HCC cases

• Infectious: HCV & HBV (~75%), HBV/HDV coinfection; HBV can cause HCC w/o cirrhosis

• Toxic: EtOH (⅓ cases in U.S.), tobacco, aflatoxin from Aspergillus

• Metabolic disorders: NASH, DM, autoimmune hepatitis, hemochromatosis

Screening (screen high-risk Pts: cirrhosis, chronic HBV)

• Ultrasonography (U/S) + AFP q 6 mos; if high-risk may alternate U/S w/ MRI

• If lesion found or increasing AFP, perform 3-phase contrast CT or MRI

Clinical manifestations

• Exam: nonspec. c/w liver dysfxn (eg, hepatomegaly, ascites, jaundice, encephalopathy)

• Labs: coagulopathy, low albumin, elevated LFTs; r/o other etiologies of liver dysfxn

Diagnosis

• Can diagnose w/o biopsy in high-risk Pts with 3-phase contrast CT or MRI

• Only 15% of liver masses are HCC; liver metastases from other 1° more common

Treatment (NEJM 2019;380:1450)

• Localized disease (goal = cure) → resection if feasible (preferred), ablation, transarterial chemoembolization, or radiotherapy (SBRT) also options. Inadequate hepatic reserve → liver transplant if able (NEJM 1996;334:693); non-surgical local and/or systemic Rx if not.

• Systemic Rx: atezolizumab (anti-PD-L1) + bevacizumab preferred (NEJM 2020;382:1894), 2^nd line: kinase (lenvatinib, sorafenib) or PD-(L)1 inhib (Lancet 2017;389:2492 & 2018;391:1163)

GASTRIC/ESOPHAGEAL CANCER

Epidemiology (Lancet 2017;390:2383 & 2020;29:635)

• Esophageal: Predominantly adenocarcinoma in U.S. (>60%), squamous cell (SCC) more common globally. Risk factors: GERD → Barrett’s esoph (adeno), smoking/EtOH (SCC)

• Gastric: Predominantly adenocarcinoma. Risk factors include H. pylori, FHx & cancer syndromes (eg, Lynch syndrome), nitrosamines in diet, smoking/EtOH.

Screening

• Esophageal: screen for Barrett’s w/ endoscopy if multiple risk factors (eg, hiatal hernia, age ≥50, male, chronic GERD, obese, smoking, FHx). Repeat q3–5y if Barrett’s.

• Gastric: typically not screened in U.S. More common in regions w/ higher incidence (eg, Japan, Korea, Chile) w/ endoscopy or barium radiographs.

Clinical manifestations

• Dysphagia, wt loss, early satiety, nausea, typically occult GI bleed, vague abd discomfort

• Exam: diffuse seborrheic keratoses (Leser-Trélat sign, though non-specific)

Diagnosis and staging

• Both diagnosed w/ endoscopic biopsy. CT chest/abd/pelvis for staging. If no mets → PET/CT (occult mets). If neg → endoscopic ultrasound for locoregional assessment.

• Staging laparoscopy needed for gastric cancer

• Molecular: ✓ HER2, PD-L1, microsatellite instability & mismatch repair

Treatment (NCCN Guidelines v5.2021 Gastric & v4.2021 Esophageal)

• If localized disease and good performance status/fit, goal is cure with surgery

• Localized: resection. Periop or neoadjuvant chemo/chemoRT if stage IB or higher (NEJM 2012;366:2074). Adjuvant nivolumab (NEJM 2021;384:1191).

• Advanced: sequential chemo w/ platinum/fluoropyrimidine (+ trastuzumab if HER2⊕, + nivolumab if PD-L1⊕), ramucirumab (VEGF, 2^nd line), nivolumab/pembrolizumab (PD-1, 3^rd line)

• Supportive care: pain/nausea mgmt. Consider G/G-J tube if obstruction, IVF prn.

MELANOMA

Clinical presentation and workup (NCCN Guidelines v1.2022)

• Suspicious skin lesion (ABCDE: asymm, border, color, diameter >6 mm, evolution) → bx

• Staging: I & II = no regional/distant mets. III = regional LN ⊕ or in-transit/satellite mets. Ulceration & thickness confer substage within I–III. IV = distant mets.

• Prognosis: excellent if localized dis., ≤1 mm thickness. Varies widely stage IIIA–IIID based on nodal burden (5yr OS 20–70%; ulceration, mitotic rate, & invasion depth predictive).

• Molecular diagnostics: check for BRAF V600E (present in ~50% of melanomas)

Treatment (NCCN Guidelines v1.2022; NEJM 2021;384:2229)

• Wide surgical excision + sentinel node mapping (unless in situ or low risk of node ⊕).

If sentinel node ⊕, nodal dissection vs. observation. No difference in survival w/ observation (Lancet Oncol 2016;17:757, NEJM 2017;376:2211).

• Checkpoint inhibitors (CPI = pembrolizumab, nivolumab, nivolumab/ipilimumab)

• BRAF/MEK inhibitors (dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib) if activating BRAF V600E mutation present

• Adjuvant for high-risk node ⊕ disease: CPI (↑ RFS, Lancet Onc 2020;21:1465 & JCO 2020;38:3925) or dabrafenib/trametinib (BRAF ⊕, ↑ OS, NEJM 2020;383:1139)

• Metastatic: CPI mono vs. dual (ipi+nivo a/w improved response rate especially for intracranial mets, NEJM 2018;379:722). Consider targeted Rx if BRAF ⊕.

OVARIAN CANCER

Histopathology

• Epithelial ovarian carcinoma (EOC, 95%): high-grade serous (most common, often dx at late stage, poor prognosis), low-grade serous, endometroid, clear cell, mucinous

• Non-epithelial (~5%): germ cell, sex cord-stromal. Rare: small cell, sarcoma.

Risk factors for EOC (Nat Rev Dis Primers 2016;2:16061)

• Nulliparity, early menarche, late menopause; EOC risk ↑ 2–7% each additional ovulatory yr

• Genetics: germline testing / genetics referral for all Pts (25% w/ heritable mutation), can inform Rx (eg, PARPi maintenance, JCO 2020;38:1222). 5% risk if one 1^st-degree relative w/ ovarian cancer, 3.5% risk if one 2^nd-degree relative (Obstet Gynecol 1992;80:700). ↑↑ risk w/ hereditary syndromes: BRCA1/2 (lifetime risk 17%/44%), Lynch syndrome (non-serous).

• History of pelvic radiation, endometriosis, or obesity (risk association less clear)

Clinical manifestations

• Nonspecific history of bloating, pelvic/abdominal pain, bowel sx, urinary sx

• Exam may reveal palpable pelvic mass, abdominal distention, or ascites

Diagnosis

• No screening modalities have shown survival benefit; no data to support at this time

• If concerning signs/sx (above), obtain pelvic U/S and/or CT A/P or pelvic MRI, CA-125

• Pathologic dx based on biopsy of lesion or sampling of ascitic fluid

Treatment

• Cytoreductive surgery: survival benefit even for stage IV and relapsed disease (Gynecol Oncol 2013;130:493; NEJM 2021;385:2123). Consider neoadj. chemo to ↑ likelihood of maximal cytoreduction at surgery and reduce surgical morbidity.

• Chemo: 1^st line (neoadj., adj., adv.): carboplatin+paclitaxel (CP). PARPi maintenance (olaparib, niraparib, rucaparib; esp if homologous recombination deficient [eg, BRCA1/2]) or bevacizumab maintenance if homologous recombination proficient.

• Recurrence at >6 mos = platinum sensitive → Rx w/ platinum doublet. If <6 mos = platinum resistant → single agent chemo (eg, liposomal doxorubicin, gemcitabine) ± bevacizumab.

PRIMARY CNS TUMORS AND BRAIN METASTASES

Presentation and diagnosis

• Suspect if new focal neurologic deficits, seizure, memory or balance issues, or evidence of ↑ intracranial pressure (HA, n/v, vision change)

• MRI brain for suspected CNS tumors; CT less Se. Consider LP if c/f CNS lymphoma.

Primary CNS tumors

• Meningioma: histopath. grading (WHO grades). Grade 1 = benign, asx/small → observe. Large or sx → resection if able, radiation if not. Grade 2–3 → resection + adjuvant RT (defer if risk of RT complication high and tumor totally resected).

• Glioma: histopath. grading, Grade 1/2/3: astrocytoma, oligodendroglioma most common; Grade 4: glioblastoma. Grade 3/4 = “high grade” (Neuro Oncol 2021;23:1231).

• Notable testing: 1p/19q, IDH, MGMT methylation (predicts sensitivity to temozolomide)

• Treatment: max resection as feasible → adjuvant RT + temozolomide → surveillance. Steroids if neuro sx, hold until biopsy if c/f 1° CNS lymphoma. Anti-epileptics if seizures.

• Prognosis based on grade & histology. For glioblastoma, overall survival 12–15 mos, based on extent of tumor resection (J Neurosurg 2014;120:31).

Metastatic CNS Lesions

• ↑ incidence than 1° CNS. Most common: lung, breast, melanoma, RCC, gastro-esoph.

• Surgery if oligomet disease or symptomatic & resectable, steroids if neuro sx

• Radiation particularly if multiple mets or inoperable. Consider WBRT if many mets.

• Some systemic therapies (checkpoint inhibitors, targeted Rx in NSCLC) have CNS activity

IMMUNOTHERAPY & CELLULAR THERAPY

IMMUNE CHECKPOINT INHIBITORS (ICI)

Overview (Science 2018;359:1350)

• Immune checkpoints: co-inhibitory signaling molecules that limit immune responses

• Cytotoxic T-lymphocyte-assoc. protein 4 (CTLA-4): ↓ T cell activation via negative signals and ligand competition w/ CD28 (activating co-stim. molecule).

• Programmed cell death protein 1 (PD-1): on activated T cells, turns off T cell responses

• Prog. death-ligand 1 (PD-L1): PD-1 ligand expressed on tumor and/or immune cells

ICIs (Annals of Oncol 2017;28:2377)
Target	Drugs	Select Indications	Common Adverse Events (approx. incidence, any grade)
PD-1	Nivolumab Pembrolizumab Cemiplimab Dostarlimab	Melanoma, NSCLC, RCC, HNSCC, esoph., endometrial, MSI-high tumors	Rash (12%); hypothyroid (5%); pneumonitis (2%); colitis (<1%); hepatitis (<1%); type 1 DM (<1%)
PD-L1	Atezolizumab Avelumab Durvalumab	Urothelial carcinoma, NSCLC, SCLC, HCC (atezo)	Rash (5%); hypothyroid (2%); adrenal insufficiency (<1%); colitis (<1%); pneumonitis (<1%)
CTLA-4	Ipilimumab	Melanoma, RCC (w/ PD1), mesothelioma (w/ PD1)	Rash (21%); colitis (5%); hypophysitis (1%); hypothyroid (1%); pneumonitis (<1%); hepatitis (<1%)

ICI toxicities (Nat Rev Dis Primers 2020;6:38; Curr Cardiol Rep 2021;23:98)

• ICIs can cause inflammation of any tissue (lungs, liver, colon, joints, skin, etc.)

• Common immune-related adverse events (IRAEs) above; ↑ incidence w/ combinations.

• Rare: myocarditis (can be fulminant), myositis, myelitis, uveitis, diabetes

• Workup: CT chest for dyspnea; colonoscopy and infectious workup for colitis; TSH, FT4, a.m. cortisol, glucose. Trend comprehensive metabolic panel and TSH while on ICI.

• IRAEs graded 1 (mild) to 4 (severe) (NCCN Guideline v4.2021)

ICI toxicity treatment (multidisciplinary care)

• Most IRAEs reversible with steroids

• Mild symptoms (grade 1): supportive care, can often continue Rx; moderate symptoms (grade 2): hold ICI, consider steroids; severe symptoms (grades 3–4): often requires admission to hospital, hold ICI, IV steroids, targeted therapies (eg, enteracept)

• Endocrinopathies (hypophysitis, hypothyroid) are not reversible, Rx hormone replacement

• Managing IRAEs with steroids likely does not reduce ICI efficacy (J Clin Oncol 2019;37:1927)

• If ICI is restarted, Pts at increased risk for recurrent IRAE

CHIMERIC ANTIGEN RECEPTOR (CAR)-T CELLS

Overview (Nat Rev Cancer 2021;21:145)

• Autologous T cells w/ chimeric receptor: antibody variable region fused to T cell co-stimulatory intracellular signaling domains → MHC independent Ag recognition

• CAR-T cells targeting CD19 used for ALL, DLBCL, FL, MCL. Targeting B-cell maturation antigen (BCMA) for MM. Strategies for solid tumors in development.

Toxicities

• Cytokine release syndrome (CRS): fever, HoTN, shock secondary to overwhelming cytokine release from proliferating T cells

• Immune effector cell-associated neurotoxicitiy synd. (ICANS): cerebral edema → HA, aphasia, delirium, lethargy/obtundation. Graded using ICE score (vide infra).

CAR-T Toxicity (Biol Blood Marrow Transplant 2019;25:625)
Type	Grade	Mechanism & Manifestations	Treatment
CRS	1	Fever (≥38°C) ± other sx	Supportive (fluids, O2), ± steroids ± anti-IL-6 (tocilizumab or siltuximab), depending on severity
	2	Fever + HoTN not needing pressors ± O2 by nasal cannula
	3	Fever + pressor ± O2 > nasal cannula
	4	Fever + >1 pressor ± ⊕ pressure vent
ICANS	1	ICE 7–9 pts	Steroids, anticonvulsants for seizures
	2	ICE 3–6 pts
	3	ICE 0–2 pts
	4	Unarousable & unable to perform ICE

ICE score: orientation (4 pts), name 3 objects (3 pts), follow commands (1 pt), write sentence (1 pt), count backward from 100 by 10 (1 pt)

ONCOLOGIC EMERGENCIES

FEVER AND NEUTROPENIA (FN) (NCCN Guidelines v.1.2021)

Definition

• Fever: single oral temp ≥38.3°C (101°F) or ≥38°C (100.4°F) for ≥1 h

• Neutropenia: ANC <500 cells/µL or <1000 cells/µL with predicted nadir <500 cells/µL

Pathophysiology and microbiology

• Predisposing factors: catheters, skin breakdown, GI mucositis, obstruction (lymphatics, biliary tract, GI, urinary tract), immune defect associated with malignancy

• Often thought due to seeding of bloodstream by GI flora, eg, GNRs (esp. P. aeruginosa)

• Neutropenic enterocolitis (typhlitis): RLQ pain, watery/bloody diarrhea, cecal wall thickening

• Gram ⊕ infections have recently become more common (60–70% of identified organisms)

• Fungal superinfection often results from prolonged neutropenia & antibiotic use

Prevention (only if intermediate or high-risk)

• Bacterial: consider FQ if neutropenic esp steroids+ALL; ↓ mortality (Cochrane 2012 CD004386)

• Fungal: consider during neutropenia in blood cancers (posa/fluconazole, micafungin)

• Viral: consider during active Rx in blood cancers (acyclovir, famciclovir, valacyclovir)

Role of hematopoietic growth factors (NCCN Guidelines v.4.2021)

• Granulocyte (G-CSF) and granulocyte-macrophage (GM-CSF) colony-stimulating factors can be used (but not in AML) as 1° Ppx when expected FN incidence >20% or as 2° Ppx after FN has occurred in a prior cycle (to maintain dose-intensity for curable tumors)

• CSFs ↓ rate of FN but have not been shown to affect mortality (Cochrane 2014 CD003039)

Diagnostic evaluation

• Exam: skin, oropharynx, lung, perirectal area, surgical & catheter sites; avoid rectal exam

• Studies: U/A, blood (periph & through each indwelling catheter port), urine, & sputum cx; for localizing s/s → ✓ stool (C. diff, cx), peritoneal fluid, CSF (rare source)

• Imaging: CXR; for localizing s/s → CNS, sinus, chest or abdomen/pelvis CT

• Caveats: neutropenia → impaired inflammatory response → exam and radiographic findings may be subtle; absence of neutrophils by Gram stain does not r/o infection

Risk stratification (factors that predict lower risk)

• History: outPt, ECOG 0–1, age <60 y, solid tumor, no sx, no major comorbidities, no h/o fungal infection, MASCC Risk Index ≥21 (Support Care Cancer 2013;21:1487)

• Exam: temp <39 °C, no tachypnea, no HoTN, no Δ MS, no dehydration

• Labs: ANC >100 cells/µL, anticipated duration of neutropenia ≤100 cells/µL <7 d

Initial antibiotic therapy (NCCN Guidelines v.1.2021)

• Empiric regimens should include antipseudomonal activity; consider VRE coverage if ⊕

• Low risk: PO abx or home IV abx may be considered in select Pts (JCO 2013;31:1149)

PO options: cipro+amoxicillin-clavulanate; levofloxacin; moxifloxacin (avoid if FQ Ppx)

• High risk: hospital admission & IV abx; monotherapy preferred

options: cefepime, imipenem, meropenem, piperacillin/tazobactam, ceftazidime

• Antifungal Rx added for neutropenic fever ≥4 d despite abx: micafungin, liposomal amphotericin B, caspofungin, anidulafungin, voriconazole, & posaconazole are options

Modification to initial antibiotic regimen based on site-specific evaluation

• Vancomycin only if HoTN, PNA, clinically apparent catheter-related or soft-tissue infxn, gram ⊕ BCx, mucositis + on quinolone Ppx; d/c when BCx ⊖ × 48 h for GPCs

• Mouth/esoph (ulcer, thrush): anaerobic (if necrotizing), anti-HSV and/or antifungal Rx

• Sinus/nasal: add vanc if periorbital cellulitis, ampho if concern for Aspergillus/Mucor

• Abd pain/diarrhea: PO vanc if concern for C. diff; ensure adequate anaerobic coverage

• Lung infiltrates: consider atypical coverage; vanc/linezolid if c/f MRSA; TMP/SMX if c/f PCP

• CNS: ID consult; empiric meningitis Rx (incl. Listeria), high-dose acyclovir for encephalitis

Duration of therapy

• Known source: complete standard course (eg, 14 d for bacteremia)

• Unknown source: continue antibiotics until afebrile and ANC >500 cells/µL

• Less clear when to d/c abx when Pt is afebrile but prolonged neutropenia

SPINAL CORD COMPRESSION

Clinical manifestations (Lancet Neuro 2008;7:459)

• Metastases located in vertebral body extend and cause epidural spinal cord compression

• Prostate, breast, and lung cancers are most common, followed by RCC, NHL, myeloma

• Site of involvement: thoracic (60%), lumbar (25%), cervical (15%)

• Signs and symptoms: pain (>95%, precedes neuro Δs), weakness, autonomic dysfunction (urinary retention, ↓ anal sphincter tone), sensory loss

Diagnostic evaluation

• Always take back pain in Pts w/ cancer seriously. Urgent whole-spine MRI; CT if unable.

• Do not wait for neurologic signs to develop before initiating evaluation b/c duration & severity of neuro dysfunction before treatment are best predictors of neurologic outcome

Treatment (NEJM 2017;376:1358)

• Dexamethasone (10 mg IV × 1 STAT, then 4 mg IV or PO q6h)

initiate immediately while awaiting imaging if back pain + neurologic deficits

• Emergent RT or surgical decompression if confirmed compression/neuro deficits

• Surgery + RT superior to RT alone for neuro recovery in solid tumors (Lancet 2005;366:643)

• If pathologic fracture causing compression → surgery; if not surgical candidate → RT

TUMOR LYSIS SYNDROME

Clinical manifestations (NEJM 2011;364:1844)

• Large tumor burden or a rapidly proliferating tumor → spontaneous or chemotherapy-induced release of intracellular electrolytes and nucleic acids

• Most common w/ treatment of high-grade lymphomas (Burkitt’s) and leukemias (ALL, AML, CML in blast crisis). Very rare w/ solid tumors; rarely due to spont. necrosis.

• Electrolyte abnormalities: ↑ K, ↑ uric acid, ↑ PO₄ → ↓ Ca; renal failure (urate nephropathy)

Prophylaxis

• Allopurinol 300 mg qd to bid PO or 200–400 mg/m² IV (adjusted for renal fxn) & aggressive hydration prior to beginning chemotherapy or RT

Treatment

• Avoid IV contrast and NSAIDs; treat hyperK, hyperPO₄, and only symptomatic hypoCa

• Allopurinol + aggressive IV hydration ± diuretics to ↑ UOP for goal 80–100 cc/h

• Rasburicase (0.1–0.2 mg/kg or 6 mg IV fixed dose) for ↑↑ uric acid esp. in aggressive malig (JCO 2003;21:4402; Acta Haem 2006;115:35). Avoid in G6PD def (hemolytic anemia). Consider G6PD testing in Jehovah’s Witnesses especially if Black (12% prevalence).

• Hemodialysis may be necessary; early renal consultation for renal insufficiency or ARF

CHEMO SIDE EFFECTS

Nausea & vomiting common (NEJM 2016;374:1356; 375:134 & 177)

Select Adverse Effects from Chemotherapy*
Toxicity	Common Agents	Comments
Cardiotoxicity (NEJM 2016;375;1457)	Anthracyclines	Dose-dependent CMP; ✓ EF pre-Rx
	5-FU	Spasm → ischemia; CCB may prevent
	Trastuzumab	CMP, esp w/ anthracycline, TTE’s for EF
	Tyrosine kinase inhib (TKI)	QTc prolongation, CMP, angina
	Cyclophosphamide	Myopericarditis (esp. in BMT)
	Cisplatin	AKI → HypoMg / HyperK → arrhythmia
Pulmonary (Sem Oncol 2006;33:98)	Busulfan	~8% fibrosis or DAH; if severe → steroids
	Bleomycin	~10% IPF; ✓ PFTs pre-Rx; Rx: steroids
	TKI (esp. dasatinib)	Pleural effusion
	Cyclophosphamide	Pneumonitis, progressive fibrosis; Rx: d/c
	Bevacizumab	Pulm. hemorrhage (esp. lung SCC)
Nephrotoxicity/ urologic toxicity	Platinum Rx (cisplatin)	Esp. proximal tubule; pretreat w/ IV saline
	Methotrexate	Via deposition; Rx: alkalinize urine, IVF
	Cyclophosphamide	Hemorrhagic cystitis; Rx: Mesna
Neurotoxicity (Sem Oncol 2006;33:324)	Platinum Rx (cisplatin)	“Stocking-glove” neuropathy; ototoxicity
	Cytarabine	Cerebellar toxicity (irreversible 5–10%)
	Methotrexate (esp. intrathecal)	Late leukoenceph, meningitis; reverse w/ intrathecal glucarpidase, leucovorin
	Ifosfamide	Enceph; Rx: methylene blue, thiamine
	Taxanes, vincristine	Sensorimotor long fiber neuropathy
Hepatotoxicity (Sem Oncol 2006;33:50)	TKI (eg, imatinib, nilotinib)	↑ LFTs, rarely necrosis; Rx: d/c ± steroids
	Gemcitabine	Common ↑ ALT/AST; ↓ dose if ↑ bili
	Methotrexate	↑ ALT/AST, rarely fibrosis
Dermatologic	TKI (eg, imatinib)	Dermatitis, can be severe (eg, SJS)

^*See “ImmunoRx” section for cytokine release and immune effector cell-associated neurotoxicity syndromes