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HEMATOLOGY-ONCOLOGY

MYELOPROLIFERATIVE NEOPLASMS (MPN)

General (NEJM 2006;355:2452; Nat Rev Clin Oncol 2009;6:627; Am J Hematol 2012;87:285)

•  Results from clonal expansion of multipotent hematopoietic stem cell

•  A type of myeloid neoplasm (see MDS for classification)

•  Different from MDS in that the cells are not dysplastic (ie, normally developed)

•  8 categories of MPN: polycythemia vera (PV); essential thrombocythemia (ET); primary myelofibrosis (PM); chronic myelogenous leukemia (CML), BCR-ABL1 ; chronic neutrophilic leukemia; chronic eosinophilic leukemia, not otherwise specified; masto- cytosis; myeloproliferative neoplasms, unclassifiable

•  Gain of fxn mutations in JAK2 V617F ( Janus kinase) present in many cases (PV ~95%, ET ~50%, PMF ~50%; NEJM 2005;352:1779) and BCR-ABL fusion in all cases of CML; KIT mutations in virtually all systemic mastocytosis; MPL and TET2 mutations w/ lower frequency; genetic lesions are useful as a clonal marker and dx tool

POLYCYTHEMIA VERA (PV)

Definition

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

Etiologies of erythrocytosis

•  Relative ↑ RBC (↓ plasma): dehydration; “stress” erythrocytosis (Gaisböck’s syndrome)

•  Absolute ↑ RBC: 1° (PV, other MPD) or 2° due to hypoxia; carboxyhemoglobinemia; inappropriate erythropoietin (renal, hepatic, cerebellar tumors); Cushing’s syndrome

Clinical manifestations (common between PV and ET)

•  Symptoms → often termed “vasomotor symptoms”

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

thrombosis (hyperviscosity, thrombocytosis): transient visual disturbances (amaurosis, ocular migraine); Budd-Chiari syndrome; erythromelalgia = intense burning, pain and erythema of extremities due to microvascular thrombi; ↑ risk of DVT, MI, stroke. Risk of thrombosis highly correlated with ↑ WBC in PV and ET (see below).

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

•  Hb >18.5 g/dL (men), >16.5 g/dL (women)

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

•  JAK2 V617F mutation screen on peripheral blood is positive in ~95% of PV and JAK2 exon 12 mutations are present in the remainder of Pts

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

•  Peripheral smear → no morphologic abnormalities

•  BM bx → hypercellular, megakaryocytic hyperplasia, ↓ iron, absence of Ph chromosome

Treatment

•  Phlebotomy to moderate degree of Fe defic., goal Hct <45% (NEJM 2013;368:22), consider <42% in 

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

•  Hydroxyurea if high risk of thrombosis (age ≥60, prior thrombosis) or sx throm- bocytosis (plt >1.5 × 10⁶/µL)

•  PEG IFNa-2a yields high response rate w/ limited toxicity (Blood 2008;112:3065)

•  Supportive: allopurinol (gout), H₂-blockers/antihistamines (pruritus)

Prognosis

•  Median survival w/ Rx 9–12 y. ↑ age, WBC predict ↓ survival (Br J 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%; higher if previous cytoreductive chemo)

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)

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

•  Of patients with plt >10⁶/µL, <1 in 6 will have ET

Clinical manifestations (see “Polycythemia Vera”)

•  Thrombosis with erythromelalgia (risk of thrombosis highest in Pts with WBC >8700), bleeding, pruritus; mild splenomegaly; migraine, TIA; early fetal loss

Diagnostic evaluation

•  Peripheral smear: large hypogranular platelets

•  BM bx: megakaryocytic hyperplasia; absence of Philadelphia chromosome and lack of collagen fibrosis; normal iron stores

•  JAK2 V617F present in ~50% of ET

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

Prognosis

•  Low-risk Pts have overall survival  control population. Risk of transformation into acute leukemia ~2–3%.

PRIMARY MYELOFIBROSIS (PMF)

Definition

•  Clonal myeloproliferation with reactive marrow fibrosis & extramedullary hematopoiesis

•  Formerly known as agnogenic myeloid metaplasia with myelofibrosis

Etiologies of myelofibrosis

•  Myeloproliferative neoplasm = primary myelofibrosis; post-PV/ET myelofibrosis

•  Other hematologic: eg, CML, AML, ALL, MDS

•  Metastatic malignancies: eg, breast, prostate

•  Autoimmune: eg, SLE and other collagen vascular disorders

•  Other: toxins (eg, benzene); radiation; granulomas from infection (eg, TB, fungal) or sarcoid; deposition diseases (eg, Gaucher’s disease)

Clinical manifestations (NEJM 2000;342:1255; 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 (NEJM 2006;355:2452; JAMA 2010;303:2513)

•  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 present in ~50% of PMF; MPL mutations in ~11% of JAK2  Pts

•  No BCR-ABL translocation; also does not meet criteria for PV or MDS

Treatment (Blood 2011;117:3494)

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

•  Allogeneic HSCT only potential cure → consider in young Pts with poor prognosis

•  Supportive care: transfusions; inconsistent benefit from androgens or Epo; splenectomy for blood counts refractory to transfusion or painful splenomegaly

•  Hydroxyurea for significant leukocytosis or thrombocytosis

•  Ruxolitinib (JAK1/JAK2 inhibitor) ↓ sx, ↓ splenomegaly, ↑ survival (NEJM 2012;366:787 & 799)

•  Thalidomide and lenalidomide (improve red cell count)

Complications and prognosis

•  Median survival ~5 y; transformation into AML occurs at a rate of ~8%/y

•  International Working Group (IWG) poor prognostic factors: age >65, WBC >25k, Hgb <10, blasts >1%,  symptoms (Blood 2009;113:2895). Stratification based on IWG factors allows prognostication at any point during clinical course (Blood 2010;115:1703).