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Article Title: Polycythemia vera and essential thrombo- Servicess Policy on Activity Disclosure and Conict
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C 2011 Wiley-Liss, Inc.
MPN, myeloproliferative neoplasms; ET, essential thrombocythemia; PV, polycythemia vera; PMF, primary myelobrosis; MF includes both PMF and post-ET/PV myelo-
brosis; BP-MPN, blast phase MPN; CP-MPN, chronic phase MPN.
Major 1 Hgb > 18.5 g/dL (men) > 16.5 g/dL 1 Platelet count 450 3 109/L 1 Megakaryocyte proliferation and atypiab
criteria (women) or Hgb or Hct > 99th accompanied by either reticulin and/or
percentile of reference range for age, collagen brosis, or in the absence of
sex, or altitude of residence or red cell reticulin brosis, the megakaryocyte
mass > 25% above mean normal changes must be accompanied by
predicted or Hgb > 17 g/dL (men)/ increased marrow cellularity,
>15 g/dL (women) if associated with a granulocytic proliferation, and often
sustained increase of 2 g/dL from decreased erythropoiesis (i.e.,
baseline that can not be attributed to prebrotic PMF)
correction of iron deciency
2 Presence of JAK2V617F or JAK2 exon 2 Megakaryocyte proliferation with large 2 Not meeting WHO criteria for CML, PV,
12 mutation and mature morphology. MDS, or other myeloid neoplasm
3 Not meeting WHO criteria for CML, PV, 3 Demonstration of JAK2V617F or other
PMF, MDS, or other myeloid clonal marker or no evidence of
neoplasm reactive marrow brosis
4 Demonstration of JAK2V617F or other
clonal marker or no evidence of
reactive thrombocytosis
Minor 1 BM trilineage myeloproliferation 1 Leukoerythroblastosis
criteria 2 Subnormal serum Epo level 2 Increased serum LDH level
3 EEC growth 3 Anemia
4 Palpable splenomegaly
BM, bone marrow; Hgb, hemoglobin; Hct, hematocrit; Epo, erythropoietin; EEC, endogenous erythroid colony; WHO, World Health Organization; CML, chronic myeloge-
nous leukemia; PV, polycythemia vera; PMF, primary myelobrosis; MDS, myelodysplastic syndromes; LDH, lactate dehydrogenase.
a
PV diagnosis requires meeting either both major criteria and one minor criterion or the rst major criterion and two minor criteria. ET diagnosis requires meeting all
four major criteria. PMF diagnosis requires meeting all three major criteria and two minor criteria.
b
Small to large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering.
TABLE IV. International Working Group for Myeloproliferative Neoplasms complications as well as maternal thrombohemorrhagic
Research and Treatment (IWG-MRT) Recommended Criteria for Postpolycy- events are relatively infrequent and platelet count usually
themia vera and Postessential Thrombocythemia Myelobrosis [41] decreases substantially during the second and third trimes-
ters [72]. Neither platelet count nor cytoreductive therapy
Criteria for postpolycythemia vera myelobrosis
Required criteria appears to affect either maternal morbidity or pregnancy
Documentation of a previous diagnosis of polycythemia vera as dened by the outcome. Therefore, cytoreductive treatment is currently not
WHO criteria (see Table II) recommended for low-risk women with ET that are either
Bone marrow brosis grade 23 (on 03 scale) or grade 34 (on 04 scale)
(see footnote for details)
pregnant or wish to be pregnant.
Additional criteria (two are required): Pruritus occurs in the majority of patients with PV and is of-
Anemia or sustained loss of requirement for phlebotomy in the absence of ten exacerbated by hot bath [58]. In the low-risk disease set-
cytoreductive therapy ting, management should start with simple non-drug meas-
A leukoerythroblastic peripheral blood picture
Increasing splenomegaly dened as either an increase in palpable ures, such as avoidance of precipitating conditions, dry skin,
splenomegaly of 5 cm (distance of the tip of the spleen from the left costal and temperature control of ones environment and water used
margin) or the appearance of a newly palpable splenomegaly for bathing. Etiology of PV-associated pruritus remains to be
Development of 1 of three constitutional symptoms: >10% weight loss in 6
months, night sweats, unexplained fever (>37.58C) determined and treatment responses to antihistamines have
Criteria for postessential thrombocythemia myelobrosis been both unpredictable and variable [58]. In contrast, recent
Required criteria studies have suggested a greater than 50% response rate in
Documentation of a previous diagnosis of essential thrombocythemia as
dened by the WHO criteria (see Table II)
PV-associated pruritus treated with paroxetine (20 mg/day),
Bone marrow brosis grade 23 (on 03 scale) or grade 34 (on 04 scale) which is a selective serotonin reuptake inhibitor [73]. Other
(see footnote for details) treatment modalities that have been reported to be useful in
Additional criteria (two are required):
Anemia and a 2 g/dL decrease from baseline hemoglobin level
PV-associated pruritus include JAK inhibitors [74,75], IFN-a
A leukoerythroblastic peripheral blood picture [76], and narrow-band ultraviolet B phototherapy [77].
Increasing splenomegaly dened as either an increase in palpable Recommendations. I recommend the use low-dose as-
splenomegaly of 5 cm (distance of the tip of the spleen from the left costal pirin (81 mg/day; range 40100 mg/day) in all patients with
margin) or the appearance of a newly palpable splenomegaly
Increased lactate dehydrogenase low-risk PV or ET, provided there are no major contraindi-
Development of 1 of three constitutional symptoms: >10% weight loss in 6 cations. In PV patients, I prefer a hematocrit target of 45%
months, night sweats, unexplained fever (>37.58C) but do not object to a higher target of as high as 50%, in
aspirin-treated patients. I manage, pregnant patients or
Grade 23 according to the European classication [42]: diffuse, often coarse
ber network with no evidence of collagenization (negative trichrome stain) or dif- women of child-bearing potential, in the same general man-
fuse, coarse ber network with areas of collagenization (positive trichrome stain). ner and I do not use platelet-lowering agents or heparin
Grade 34 according to the standard classication [43]: diffuse and dense therapy in the setting of low-risk disease. In the presence
increase in reticulin with extensive intersections, occasionally with only focal bun-
dles of collagen and/or focal osteosclerosis or diffuse and dense increase in reticu-
of aspirin-resistant symptoms, it is reasonable to utilize al-
lin with extensive intersections with coarse bundles of collagen, often associated ternative anti-platelet agents such as clopidogrel (75 mg/
with signicant osteosclerosis. day) alone or in combination with aspirin [78], as long as
patients are monitored closely for drug side effects. One
might also consider platelet-lowering agents (e.g. hydrox-
(>30%) [6870] is signicantly higher than the 15% rate yurea) in such aspirin-refractory cases, but the target plate-
expected in the control population and does not appear to let count in this instance should be the level at which relief
be inuenced by specic treatment [71]. Late obstetric of symptoms is observed, and not necessarily 400 3 109/L.
I no longer use anagrelide for the treatment of PV or ET developed large cell lymphoma and the incidence of gastro-
because of its reported association with increased risk of intestinal and skin cancer was increased in those patients
arterial thrombosis, major bleeding and brotic progression treated with either chlorambucil or radiophosphorus.
[79]. Based on preliminary data from ongoing anti-JAK2 The European Organization for Research on Treatment
clinical trials, I suspect that JAK inhibitors might become of Cancer (EORTC) randomized 293 patients between
the most effective agents for the treatment of MPN-associ- 1967 and 1978 to treatment with either radiophosphorus or
ated pruritus [74,75]. oral busulfan [101]. The results favored busulfan in terms of
Management of low-risk PV or ET patients with extreme both rst remission duration (median, 4 years vs. 2 years)
thrombocytosis or abnormal bleeding diathesis and overall survival (10-year survival rates of 70% vs.
Bleeding diathesis in ET or PV is currently believed to be 55%). At a median follow-up period of 8 years, there was
multi-factorial in etiology. Laboratory evidence of AvWS not signicant difference in the risk of leukemic transforma-
occurs in the majority of patients with ET or PV and is char- tion (2% vs. 1.4%), non-hematologic malignancy (2.8% vs.
acterized by the loss of large von Willebrand factor multi- 5%), vascular complications (27% vs. 37%), or transforma-
mers, linked to their increased proteolysis by the tion into post-PV MF (4.8% vs. 4.1%) between the two
ADAMTS13 cleaving protease, in a platelet count-depend- arms.
ent fashion [8084]. This results in a functionally more rele- Other randomized studies in PV have compared hydrox-
vant defect that may not be apparent when measuring yurea against pipobroman (a signicant difference favoring
VWF:Ag and FVIII levels alone [80,85] and requires the pipobroman in the incidence of transformation into post-PV
use of assays that assess VWF function (e.g., ristocetin MF but no difference in survival, incidence of thrombosis, or
cofactor activity; VWF:RCoA) [8688]. Other causes of pla- the rate of leukemic conversion) [102], radiophosphorus
telet dysfunction in ET or PV include acquired storage pool alone or with HU (no difference in survival, incidence of
deciency, increased platelet activation, decreased adrener- thrombosis, or risk of transformation into post-PV MF but
gic receptor expression, impaired response to epinephrine, radiophosphorus alone was associated with signicantly less
and decreased platelet membrane glycoprotein receptor incidences of both acute leukemia and other cancers) [103],
expression [8997]. and radiophosphorus plus phlebotomy against phlebotomy
Based on the above, the use of aspirin in both PV and plus high-dose aspirin (900 mg/day) in combination with di-
ET requires caution, especially in the presence of extreme pyridamole (225 mg/day) (the addition of antiplatelet agents
thrombocytosis (platelet count >1,000 3 109/L), which pro- provided no benet in terms of thrombosis prevention but
motes the development of AvWS. However, clinically rele- increased the risk of gastrointestinal bleeding) [104].
vant AvWS can occur even when the platelet count is well The lack of anti-thrombotic value from anti-platelet agents
below 1,000 3 109/L, and that laboratory evaluation of in the above-mentioned PVSG-aspirin study may have
AvWS must be performed in the presence of abnormal been inuenced by the fact that 27% of the patients
bleeding, regardless of platelet count [98]. randomized to the phlebotomy-aspirin-dipyridamole arm
Recommendations. In patients with PV or ET and had a prior history of thrombosis compared to 13% in the
extreme thrombocytosis, the use of aspirin can lead to other arm. This contention was conrmed by the most
bleeding complications because of AvWS; therefore, in the recent study from the European collaboration study on low-
presence of platelets >1,000 3 109/L, screening for risto- dose aspirin in polycythemia (ECLAP) [60]. The study en-
cetin cofactor activity is advised and consideration be given rolled 518 patients with PV in a double-blind randomized
to withhold aspirin therapy if the result shows <30% activ- trial to low-dose aspirin (100 mg daily) or placebo. Treat-
ity. On the other hand, extreme thrombocytosis neither ment with aspirin did not increase the incidence of major
denes high-risk disease nor warrants the use of cytore- bleeding and instead reduced the risk of combined end-
ductive therapy. points for nonfatal myocardial infarction, nonfatal stroke, or
Management of high-risk PV or ET death from cardiovascular causes and nonfatal myocar-
Summary of randomized studies in PV. In the rst con- dial infarction, nonfatal stroke, pulmonary embolism, major
trolled study in PV, the PV study group (PVSG) randomized venous thrombosis, or death from cardiovascular causes
431 patients, between 1967 and 1974, to treatment with ei- [105].
Summary of randomized studies in ET. Unlike the
ther phlebotomy alone or phlebotomy with either oral chlor-
case with PV, the PVSG did not carry out large scale
ambucil or intravenous radioactive phosphorus (radiophos-
randomized studies in ET. In one of the very few controlled
phorus) [99]. The results signicantly favored treatment studies in ET, Cortelazzo et al. randomized 114 mostly
with phlebotomy alone with a median survival of 12.6 years high-risk patients to hydroxyurea (n 5 56) or not (n 5 58)
compared to 10.9 and 9.1 years for treatment with radio- [106]. After 27 months of follow-up, the incidences of
phosphorus and chlorambucil, respectively. The difference thrombotic complications were 3.6% for hydroxyurea and
in survival was attributed to an increased incidence of AML 24% for no hydroxyurea, although the thrombotic epi-
in patients treated with chlorambucil or radiophosphorus sodes in two patients in the non-hydroxyurea arm consti-
compared to those treated with phlebotomy alone (13.2% tuted supercial thrombophlebitis. This is the only study, to-
vs. 9.6% vs.1.5% over a period of 1319 years) [100]. Fur- date, which randomized patients with ET to a drug versus
thermore, 3.5% of the patients treated with chlorambucil no drug.