Page 1243 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 68 The Polycythemias 1089

standard of care for high-risk PV patients. Nevertheless, as a caution- in members of the RAS pathway, SRSF2, and in ASXL1 were more
ary principle, it is wise to consider carefully the use of this agent in common in JAK2 WT post-MPN AML, and these mutations often
very young patients, in those carrying cytogenetic abnormalities, and were present as subclonal disease alleles at the time of transformation,
in patients previously exposed to alkylating agents. In a report in suggesting they are not rate limiting in the transformation from
which patients were treated exclusively with hydroxyurea with an MPN to AML.
average follow-up of 16.3 years, the cumulative incidence of AML/
MDS was 7.3%, 10.7%, and 16.6% at 10, 15, and 20 years, respec-
tively, and was significantly lower than in patients treated with the CLINICAL MANIFESTATIONS
22
alkylating agent piprobroman. However, patients treated with
hydroxyurea had a greater chance of developing MF (at 20 years, The principal clinical manifestations of PV can largely be attributed
31.6% vs. 21.3%). Whether hydroxyurea really is leukemogenic is to the excessive production of cells belonging to each of the myeloid
difficult to say from this study. The possibility exists that these rates lineages affected by the malignant process, including RBCs, platelets,
of evolution reported with hydroxyurea use merely reflect the natural and WBCs. With the implementation of laboratory tests during
history of the disease. annual physical examinations, increasing numbers of people are being
Genetic studies of paired samples before and after leukemic diagnosed with PV before the symptoms related to this neoplastic
transformation have suggested there are at least two distinct routes process become apparent. Symptomatic patients with PV may present
for leukemic transformation that are operational. Some patients who to a physician with a myriad of nonspecific complaints, including
present with a JAK2V617F/MPL mutation-positive MPN progress headaches, weakness, pruritus, dizziness, excessive sweating, visual
to JAK2V617F/MPL mutation-positive AML that is associated disturbances, paresthesias, joint symptoms, abdominal distress, a
with the acquisition of additional genetic alterations. A second, thrombotic or hemorrhagic episode, and weight loss. Thrombosis is
more complex, route to AML from MPN has been described in a frequent presenting event. Two-thirds of such thrombotic events
which a JAK2V617F/MPL mutation-positive MPN is followed by occur either at presentation or before diagnosis and the remainder
JAK2V617F/MPL mutation-negative AML. Clonality studies using most often during the first 10 years of follow-up. At diagnosis,
X-chromosome inactivation in informative females demonstrated that one-third of patients have already lost 10% of their body weight,
JAK2V617F/MPL mutation-positive MPN and JAK2V617F/MPL presumably secondary to the hypermetabolism associated with this
mutation-negative AML are clonally related, consistent with trans- disorder, and complaints of fatigue are common. Arthropathies are
formation of an antecedent, pre-JAK2V617F/MPL mutation mutant frequently observed and are largely caused by the clinical manifesta-
clone that can progress to AML. Patients with JAK2V617F-positive tions of gout. The hyperproliferative BM state characteristic of PV
MPN who developed JAK2V617F-negative leukemias had a shorter and the increased nucleoprotein degradation are contributory factors
time between the diagnosis of the original MPN and the leukemic in the development of hyperuricemia.
transformation (3 + 2 vs. 10 + 7 years, respectively) than patients The principal findings on physical examination of a patient with
with JAK2V617F-positive leukemias. SNP array analysis has shown PV include ruddy cyanosis, conjunctival plethora, hepatomegaly,
that genomic alterations occur at an increased frequency during the splenomegaly, and hypertension.
period of blastic transformation and that no single gene or molecular Untreated patients are at particularly high risk for thrombotic
pathway is sufficient to cause transformation. A surprising correla- and hemorrhagic events. In several large series of patients with
tion has been observed between the phenotype of the preceding PV, thrombosis was the cause of death in 30–40% of patients.
MPN and the JAK2 mutational status of the leukemic blasts after Arterial thrombotic events account for two-thirds of such events, with
transformation. In contrast to JAK2 WT AML in this setting, venous thrombotic events representing the remainder. Ischemic
evolution to JAK2V617F-positive leukemia is invariably preceded stroke, myocardial infarction, and TIAs are the most common arterial
by a myelofibrotic transformation of ET/PV or JAK2V617F-positive thrombotic events. Patients may also present with deep venous
PMF. Because of these observations, myelofibrotic transformation of thrombosis in the lower extremities, pulmonary embolism, or periph-
ET or PV is thought by many to represent an accelerated phase of eral vascular occlusions. The cumulative rate of thrombosis ranges
the initial MPN preceded by genetic changes that result in evolution from 2.5% to 5% per patient per year. The prevalence of thrombosis
to MF and eventually leukemia. JAK2 WT leukemia, by contrast, at diagnosis ranges from 34% to 39%. It is not unusual for patients
usually arises in patients with chronic-phase PV or ET that do not with PV to develop thromboses at unusual anatomic sites; in particu-
undergo evolution to MF. Some have suggested that these leukemias lar, thromboses are relatively frequent in the splanchnic veins, includ-
are therapy related. The reversion from JAK2V617F to WT JAK2 in ing the splenic, hepatic, portal, and mesenteric vessels or cerebral
these leukemias has been shown not to be caused by homologous sinus veins, thrombosis of the vena cava, and intraventricular throm-
recombination. Two models have been proposed to account for the bosis. A particularly serious thrombotic event associated with PV is
clonal relationship between JAK2 WT AML and its preceding MPN: BCS, which results from hepatic venous or inferior vena caval throm-
(1) both the chronic MPN and the AML arise from a shared pre- bosis and obstruction. These events lead to hepatic venous outflow
JAK2V617F founder clone; and (2) the chronic MPN and the AML obstruction, increased hepatic sinusoidal pressure, and portal hyper-
arise from two independent stem cells. It remains possible that each tension. Portal venous perfusion of the liver is frequently reduced,
model is viable and operates in different individual patients. Muta- leading to portal venous thrombosis and hypoxic damage of liver
tions in CALR, JAK2, TP53, IDH2, and ASXL1 are frequent events in parenchymal cells. This cascade of events results in centrilobular
AML, which evolves from a prior MPN, while mutations in NPM1, hepatic necrosis, centrilobular fibrosis, and nodular regenerative
cohesin complex members, FLT3, and CEBPA, which are common fibrosis, which culminates in the development of cirrhosis of the liver.
events in de novo AML, are rarely, if ever, observed in post-MPN The cause of BCS can be identified in 75% of cases, including
AML. These data provide genetic evidence that post-MPN AML is a hereditary and acquired prothrombotic disorders, trauma, and infec-
distinct disease from classical AML with a unique mutational profile tion. PV account for 10–40% of all cases of BCS. Paroxysmal noc-
and molecular pathogenesis and that lack of response to AML chemo- turnal hemoglobinuria is also a frequent cause of BCS. Because BM
therapy regimens reflects the divergent biology of post-MPN AML. cells from 87% of patients with idiopathic BCS form erythroid colo-
Important differences in the mutational spectrum of JAK2V617F nies in the absence of EPO, such patients were in the past believed
and JAK2-WT in post-MPN AML have been observed. TP53 muta- to have a forme fruste of an MPN. The identification of these latent
tions are frequent, cooccurring events in patients with JAK2V617F MPNs, without elevated blood counts, has been facilitated by screen-
mutations but not in patients with CALR mutations. In patients ing for JAK2V617F. These patients tend to be younger and female,
with cooccurring JAK2V617F and TP53 mutations, the JAK2/Tp53 and to have normal blood counts caused by hemodilution and
mutant clone dominates, consistent with potent cooperativity in hypersplenism, which mask an elevated RBC mass. Many of these
vivo and with a dominant role in inducing transformation from the patients (37%) also have another predisposing factor for thrombosis
chronic JAK2V617F-positive MPN to AML. By contrast, mutations such as exposure to oral contraceptives, antiphospholipid antibodies,