2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Table 2. WHO Criteria for Diagnosis of Polycythemia Vera a
Major Criteria
Hemoglobin � 18.5 g/dL in men, � 16.5 g/dL in women, or other evidence of
increased red cell volume
Presence of JAK2 V617F or other functionally similar mutation (JAK2 exon 12
mutation)
Minor Criteria
Bone marrow biopsy showing hypercellularity for age with trilineage
myeloproliferation
Serum erythropoietin level below the normal reference range
Endogenous erythroid colony formation in vitro
Abbreviations: WHO, World Health Organization; PV, polycythemia vera.
a Diagnosis of PV requires meeting either both major criteria and one minor
criterion or the first major criterion and two minor criteria.
disease-specific model, many investigators are more confident
applying prognostic systems developed in PMF in this
patient subset. 13,14
Evolution to AML is a rare event, and the predictors
include advanced age (sign of genomic instability) and a high
leukocyte count (sign of myeloproliferation). Concerning the
role of chemotherapy, a recent population-based study on
11,039 MPNs proved that 25% of patients with post-MPN
AML were never exposed to cytotoxic drugs and that hydroxyurea
at any dose is not associated with an increased
risk of AML, whereas an increasing cumulative dose of
alkylators is. 15
Specific Clinical Situations in PV and ET
A retrospective study on the outcome of 311 surgical
interventions for patients with PV and ET showed that 7.7%
of them were complicated by fatal arterial or venous thromboses
and 7.3% by fatal major hemorrhage within 3 months
from the procedure. 16 Although no prognostic factors could
be identified to predict postsurgery outcome, these data
should mandate watchfulness in the surgical management
of these patients.
When treating patients with ET (generally younger than
those with PV and PMF), a potential issue is the approach to
pregnancy. A study on 103 pregnancies in 62 women with
ET reported a 64% live birth rate, with 51% of pregnancies
being uneventful. 17 Maternal complications occurred in 9%
of cases, while fetal complications occurred in 40% of them.
Fetal loss was 3.4-fold higher than that of the general
population. The JAK2 V617F mutation was an independent
predictor of pregnancy complications.
Prognostication in MF
Among MPNs, PMF has the most heterogeneous clinical
presentation, which may encompass anemia, splenomegaly,
Table 3. WHO Criteria for Diagnosis of Essential
Thrombocythemia a
Sustained platelet count over 450 � 10 9 /L
Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic
lineage with increased numbers of enlarged, mature megakaryocytes; no
significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis
Not meeting WHO criteria for PV or PMF, BCR–ABL1-positive CML, MDS, or other
myeloid neoplasm
Demonstration of JAK2 V617F or other clonal marker or, in the absence of JAK2
V617F, no evidence of reactive thrombocytosis
Abbreviations: WHO, World Health Organization; PV, polycythemia vera; PMF,
primary myelofibrosis; CML, chronic myelogenous leukemia; MDS, myelodysplastic
syndrome.
a The diagnosis of ET requires meeting all four criteria.
422
FRANCESCO PASSAMONTI
Table 4. WHO criteria for Diagnosis of Primary Myelofibrosis a
Major Criteria
Presence of megakaryocyte proliferation and atypia, accompanied by either
reticulin or collagen fibrosis or—in the absence of significant reticulin
fibrosis—the megakaryocyte changes must be accompanied by an increased
marrow cellularity characterized by granulocytic proliferation and often
decreased erythropoiesis (i.e., prefibrotic cellular-phase disease)
Not meeting WHO criteria for PV, CML, MDS, or other myeloid disorders
Demonstration of JAK2 V617F or other clonal marker (e.g., MPLW515K/L) or—
in the absence of the above clonal markers—no evidence of secondary bone
marrow fibrosis
Minor Criteria
Leukoerythroblastosis
Increased serum lactate dehydrogenase level
Anemia
Splenomegaly
Abbreviations: WHO, World Health Organization; PV, polycythemia vera; CML,
chronic myelogenous leukemia; MDS, myelodysplastic syndrome.
a Diagnosis of PMF requires all three major criteria and two minor criteria.
leukocytosis or leukopenia, thrombocytosis or thrombocytopenia,
and constitutional symptoms. Median survival in
PMF is estimated at 6 years, but it can range from a few
months to many years. 13,14,18,19 Causes of death in MF
include bone marrow failure (severe anemia, bleeding from
thrombocytopenia, and infections from leukopenia) in 25%
to 30% of patients, AML transformation in 10% to 20% of
patients, cardiovascular complications in 15% to 20%, and
portal hypertension in 10%.
Risk Factors for Survival
The following were shown to be associated with poor
outcome in patients with PMF: advanced age, anemia, red
blood cell transfusion need, leukopenia, leukocytosis, thrombocytopenia,
peripheral blast count, constitutional symptoms,
hepatic myeloid metaplasia, decreased marrow
cellularity with higher degree of fibrosis, higher degree of
microvessel density, high number of circulating CD34positive
cells, cytogenetic abnormalities, mutational profile,
and high level of proinflammatory cytokines (IL-8 and IL-
2R). Among these, some parameters require a more detailed
discussion.
Molecular Abnormalities. Within a large international
database, 345 patients had an available JAK2 mutational
status and no association was observed between the JAK2
status and survival. 14 This result parallels other studies
including 199, 186, and 174 patients each that showed
no significant correlation between the presence of the
JAK2 V617F mutation and survival or leukemic transformation.
20-22 However, there is no a general agreement on
this matter. Data seem to indicate that having a lower JAK2
V617F allele burden implies a worse survival. 21,22 The
explanation for this association, however, differs as patients
mostly died from infections secondary to myelodepletion in
one study and from AML evolution in the other. 21,22 A study
on 139 patients with MF receiving allogenic stem cell transplantation
(ASCT) reported very intriguing results on the
association between allele burden reduction and post-ASCT
Table 5. Risk Categories in Essential Thrombocythemia
and Polycythemia Vera
Low risk Age � 60 and no history of thrombosis
High risk Age � 60 or history of thrombosis