Polycythemia vera (PV) is a chronic myeloproliferative neoplasm associated with JAK2 mutations (V617F or exon 12) in almost all cases. The World Health Organization has defined the criteria for ...diagnosis, but it is still unclear which parameter (hemoglobin or hematocrit) is the most reliable for demonstrating increased red cell volume and for monitoring response to therapy; also, the role of bone marrow biopsy is being revisited. PV is associated with reduced survival because of cardiovascular complications and progression to post-PV myelofibrosis or leukemia. Criteria for risk-adapted treatment rely on the likelihood of thrombosis. Controlled trials have demonstrated that incidence of cardiovascular events is reduced by sustained control of hematocrit with phlebotomies (low-risk patients) and/or cytotoxic agents (high-risk patients) and antiplatelet therapy with aspirin. Hydroxyurea and interferon may be used as first-line treatments, whereas busulfan is reserved for patients that are refractory or resistant to first-line agents. However, there is no evidence that therapy improves survival, and the significance of reduction of JAK2 mutated allele burden produced by interferon is unknown. PV is also associated with a plethora of symptoms that are poorly controlled by conventional therapy. This article summarizes my approach to the management of PV in daily clinical practice.
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm. Virtually all PV patients are iron deficient at presentation and/or during the course of their disease. The co-existence of iron ...deficiency and polycythemia presents a physiological disconnect. Hepcidin, the master regulator of iron metabolism, is regulated by circulating iron levels, erythroblast secretion of erythroferrone, and inflammation. Both decreased circulating iron and increased erythroferrone levels, which occur as a consequence of erythroid hyperplasia in PV, are anticipated to suppress hepcidin and enable recovery from iron deficiency. Inflammation which accompanies PV is likely to counteract hepcidin suppression, but the relatively low serum ferritin levels observed suggest that inflammation is not a major contributor to the dysregulated iron metabolism. Furthermore, potential defects in iron absorption, aberrant hypoxia sensing and signaling, and frequency of bleeding to account for iron deficiency in PV patients have not been fully elucidated. Insufficiently suppressed hepcidin given the degree of iron deficiency in PV patients strongly suggests that disordered iron metabolism is an important component of the pathobiology of PV. Normalization of hematocrit levels using therapeutic phlebotomy is the most common approach for reducing the incidence of thrombotic complications, a therapy which exacerbates iron deficiency, contributing to a variety of non-hematological symptoms. The use of cytoreductive therapy in high-risk PV patients frequently works more effectively to reverse PV-associated symptoms in iron-deficient relative to iron-replete patients. Lastly, differences in iron-related parameters between PV patients and mice with JAK2 V617F and JAK2 exon 12 mutations suggest that specific regions in JAK2 may influence iron metabolism by nuanced changes of erythropoietin receptor signaling. In this review, we comprehensively discuss the clinical consequences of iron deficiency in PV, provide a framework for understanding the potential dysregulation of iron metabolism, and present a rationale for additional therapeutic options for iron-deficient PV patients.
Here we critically evaluate the role of elevated hematocrit as the principal determinant of thrombotic risk in polycythemia and erythrocytosis, defined by an expansion of red cell mass. Since red ...cell volume determination is no longer readily available, in clinical practice, polycythemia and erythrocytosis are defined by elevated hemoglobin and hematocrit. Thrombosis is common in Chuvash erythrocytosis and polycythemia vera. Although the increased thrombotic risk is assumed to be due to the elevated hematocrit and an associated increase in blood viscosity, thrombosis does not accompany most types of erythrocytosis. We review studies indicating that the occurrence of thrombosis in Chuvash erythrocytosis is independent of hematocrit, that the thrombotic risk is paradoxically increased by phlebotomy in Chuvash erythrocytosis, and that, when compared to chemotherapy, phlebotomy is associated with increased thrombotic risk in polycythemia vera. Inherited and environmental causes that lead to polycythemia and erythrocytosis are accompanied by diverse cellular changes that could directly affect thrombotic risk, irrespective of the elevated hematocrit. The pressing issue in these disorders is to define factors other than elevated hematocrit that determine thrombotic risk. Defining these predisposing factors in polycythemia and erythrocytosis should then lead to rational therapies and facilitate development of targeted interventions.
JAK2 617V>F mutation occurs in a homozygous state in 25% to 30% of patients with polycythemia vera (PV) and 2% to 4% with essential thrombocythemia (ET). Whether homozygosity associates with distinct ...clinical phenotypes is still under debate. This retrospective multicenter study considered 118 JAK2 617V>F homozygous patients (104 PV, 14 ET) whose clinical characteristics were compared with those of 587 heterozygous and 257 wild-type patients. Irrespective of their clinical diagnosis, homozygous patients were older, displayed a higher leukocyte count and hematocrit value at diagnosis, and presented larger spleen volume. Aquagenic pruritus was significantly more common among homozygous PV patients. JAK2 617V>F homozygosity associated with more frequent evolution into secondary myelofibrosis in both PV and ET. After adjustment for sex, age, leukocyte count, and previous thrombosis in a multivariate analysis, homozygous ET patients displayed a significantly higher risk of cardiovascular events (hazard ratio HR 3.97, 95% confidence interval CI 1.34–11.7; P = .013) than wild-type (HR = 1.0) or heterozygous patients (HR = 1.49). No significant association of JAK2 617V>F homozygosity with thrombosis risk was observed in PV. Finally, JAK2 617V>F homozygous patients were more likely to receive chemotherapy for control of disease. We conclude that JAK2 617V>F homozygosity identifies PV or ET patients with a more symptomatic myeloproliferative disorder and is associated with a higher risk of major cardiovascular events in patients with ET.
RESPONSE is an open-label phase 3 study evaluating the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib versus best available therapy for efficacy/safety in hydroxyurea-resistant or intolerant ...patients with polycythemia vera. This preplanned analysis occurred when all patients completed the Week 80 visit or discontinued. Objectives included evaluating the durability of the primary response (Week 32 phlebotomy-independent hematocrit control plus ≥35% spleen volume reduction), its components, and that of complete hematologic remission; and long-term safety. Median exposure was 111 weeks; 91/110 (82.7%) patients randomized to ruxolitinib remained on treatment. No patients continued best available therapy (98/112 87.5% crossed over to ruxolitinib, most at/soon after Week 32). At Week 32, primary response was achieved by 22.7% vs. 0.9% of patients randomized to ruxolitinib and best available therapy, respectively (hematocrit control, 60.0% vs. 18.8%; spleen response, 40.0% vs. 0.9%). The probability of maintaining primary and hematocrit responses for ≥80 weeks was 92% and 89%, respectively; 43/44 spleen responses were maintained until Week 80. Complete hematologic remission at Week 32 was achieved in 23.6% of ruxolitinib-randomized patients; the probability of maintaining complete hematologic remission for ≥80 weeks was 69%. Among ruxolitinib crossover patients, 79.2% were not phlebotomized, and 18.8% achieved a ≥35% reduction from baseline in spleen volume after 32 weeks of treatment. New or worsening hematologic laboratory abnormalities in ruxolitinib-treated patients were primarily grade 1/2 decreases in hemoglobin, lymphocytes, and platelets. The thromboembolic event rate per 100 patient-years was 1.8 with randomized ruxolitinib treatment vs. 8.2 with best available therapy. These data support ruxolitinib as an effective long-term treatment option for hydroxyurea-resistant or intolerant patients with polycythemia vera. This trial was registered at clinicaltrials.gov identifier: 01243944.
Transformation from chronic myeloproliferative neoplasm to acute leukemia is a feature of myeloproliferative neoplasm; however, the rate is not high. Transformation to acute promyelocytic leukemia is ...rare. Here, we report a case of transformation of polycythemia vera to acute promyelocytic leukemia and describe a process of clonal evolution that has not yet been reported.
In this case, a 51-year-old woman was diagnosed with polycythemia vera and concomitant JAK2/V617F mutations in July 2019. She underwent intermittent phlebotomy and oral hydroxyurea irregularly. After 2 years, the patient complained of fatigue and poor sleep quality for 2 months.
Further examination revealed marked hypercellularity and grade 1 bone marrow fibrosis with the PML/RARαV variant (23.85% mutation load), WT1-Exon1 (37.8%), WT1-Exon9 (4.1%), JAK3-Exon7 (49.3%), and RELN-Exon55 (45.8%). According to the World Health Organization classification of tumors of hematopoietic and lymphoid tissues, the patient was ultimately diagnosed with a rare transformation of polycythemia vera to acute promyelocytic leukemia.
The patient underwent dual induction therapy with all-trans-retinoic acid and arsenic trioxide.
After 28 days of induction therapy, the patient achieved complete remission, was compliant and the treatment was well tolerated.
Polycythemia vera can transform into acute promyelocytic leukemia; therefore, it is important to review bone aspiration and other tests to perform a comprehensive assessment and monitor the disease status, to detect disease progression and intervene early when it transforms into acute promyelocytic leukemia.
Several observations have shown that patients with polycythemia have iron deficiency. Our objectives were to report the prevalence of iron deficiency and to evaluate the diagnostic performance of ...serum ferritin in polycythemia vera.
This is a retrospective descriptive and analytical study carried out in the internal medicine department of the Henri Mondor Hospital, Aurillac, France. The study involved 114 patients with polycythemia, followed in the department from January 1, 2010 to December 31, 2021. To evaluate the diagnostic performance, the JAK2 mutation was considered as the gold standard of diagnosis.
Thirty-three patients had polycythemia vera and 76 patients had secondary polycythemia. The mean age of the patients was 61.79 years (±15.44) with a sex ratio of 4.43. The overall prevalence of iron deficiency was 21.05%. The prevalence was 53% in polycythemia vera group and 1.32% in secondary polycythemia group. The risk of iron deficiency was high in polycythemia vera (OR =
115
; 95% CI 14.4-918.2, p < 0.0001) and the sensitivity and specificity of serum ferritin were 52.63% and 100% respectively.
Assessment of iron deficiency should be part of the initial evaluation of polycythemia. Iron deficiency had a high specificity during polycythemia vera.
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