Pocket Medicine: The Massachusetts General Hospital Handbook of Internal Medicine (69 page)

Hypoplastic MDS (rare) → can consider
immunosuppression
(CsA, ATG, prednisone)

• Prognosis: IPSS correlates with
survival
and
progression to AML

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; mastocytosis; 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 ✓ SaO
₂
or PaO
₂
, 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 B
₁₂

• 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 thrombocytosis (plt >1.5 × 10
⁶
/µL) • PEG IFNa-2a yields high response rate w/ limited toxicity (
Blood
2008;112:3065) • Supportive: allopurinol (gout), H
₂
-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 >10
⁶
/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