Since its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea ...resistant or intolerant polycythemia vera (PV) is steadily increasing. Several other JAK2 inhibitors have entered clinical testing, but none have been approved and many have been discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, in which survival is short. Many such combinations are being explored, as are other novel agents, some of which could successfully be combined with JAK2 inhibitors in the future. In addition, new JAK2 inhibitors with the potential for less myelosuppression continue to be investigated. Given the proven safety and efficacy of ruxolitinib, it is likely that ruxolitinib-based combinations will be a major way forward in drug development for MF. If approved, less myelosuppressive JAK2 inhibitors such as pacritinib or NS-018 could prove to be very useful additions to the therapeutic armamentarium in MF. In PV, inhibitors of histone deacetylases and human double minute 2 have activity, but their role, if any, in the future treatment algorithm is uncertain, given the availability of ruxolitinib and renewed interest in interferons. Ruxolitinib is in late-phase clinical trials in essential thrombocythemia, in which it could fill an important void for patients with troublesome symptoms.
The genetic landscape of classical myeloproliferative neoplasm (MPN) is in large part elucidated. The MPN-restricted driver mutations, including those in JAK2, calreticulin (CALR), and ...myeloproliferative leukemia virus (MPL), abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors, more particularly the STATs. The most frequent mutation, JAK2V617F, activates the 3 main myeloid cytokine receptors (erythropoietin receptor, granulocyte colony-stimulating factor receptor, and MPL) whereas CALR or MPL mutants are restricted to MPL activation. This explains why JAK2V617F is associated with polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis (PMF) whereas CALR and MPL mutants are found in ET and PMF. Other mutations in genes involved in epigenetic regulation, splicing, and signaling cooperate with the 3 MPN drivers and play a key role in the PMF pathogenesis. Mutations in epigenetic regulators TET2 and DNMT3A are involved in disease initiation and may precede the acquisition of JAK2V617F. Other mutations in epigenetic regulators such as EZH2 and ASXL1 also play a role in disease initiation and disease progression. Mutations in the splicing machinery are predominantly found in PMF and are implicated in the development of anemia or pancytopenia. Both heterogeneity of classical MPNs and prognosis are determined by a specific genomic landscape, that is, type of MPN driver mutations, association with other mutations, and their order of acquisition. However, factors other than somatic mutations play an important role in disease initiation as well as disease progression such as germ line predisposition, inflammation, and aging. Delineation of these environmental factors will be important to better understand the precise pathogenesis of MPN.
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by clonal expansion of a hematopoietic progenitor, erythrocytosis, often leukocytosis and/or thrombocytosis, and nearly ...always an activating mutation in
Janus kinase 2
(
JAK2
). The PV symptom burden can be considerable, in part driven by small or large vessel thrombotic tendency, splenomegaly, fatigue, pruritus, and a chronic risk of disease transformation to myelofibrosis or acute myeloid leukemia. In addition, patients with PV have an increased risk of mortality compared with the general population that often results from cardiovascular complications or disease transformation. Further, healthcare utilization and costs are higher in patients with PV than noncancer controls. First-line therapy options for high-risk patients may effectively manage PV in some instances; however, some patients do not receive adequate benefit from current treatment options and experience a more severe disease burden as a result. This may be especially true for those patients who are resistant to or intolerant of hydroxyurea or interferon-based therapies. New treatments currently being investigated in phase 3 clinical trials may alleviate disease burden in this patient population.
Under the auspices of an International Working Group, seven centers submitted diagnostic and follow-up information on 1545 patients with World Health Organization-defined polycythemia vera (PV). At ...diagnosis, median age was 61 years (51% females); thrombocytosis and venous thrombosis were more frequent in women and arterial thrombosis and abnormal karyotype in men. Considering patients from the center with the most mature follow-up information (n=337 with 44% of patients followed to death), median survival (14.1 years) was significantly worse than that of the age- and sex-matched US population (P<0.001). In multivariable analysis, survival for the entire study cohort (n=1545) was adversely affected by older age, leukocytosis, venous thrombosis and abnormal karyotype; a prognostic model that included the first three parameters delineated risk groups with median survivals of 10.9-27.8 years (hazard ratio (HR), 10.7; 95% confidence interval (CI): 7.7-15.0). Pruritus was identified as a favorable risk factor for survival. Cumulative hazard of leukemic transformation, with death as a competing risk, was 2.3% at 10 years and 5.5% at 15 years; risk factors included older age, abnormal karyotype and leukocytes ≥15 × 10(9)/l. Leukemic transformation was associated with treatment exposure to pipobroman or P32/chlorambucil. We found no association between leukemic transformation and hydroxyurea or busulfan use.
Background
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm associated at times with debilitating symptoms and a significant mortality rate. Understanding the demographics, ...epidemiology, and geography of this disease may provide further insight into important risk factors associated with its development. The objective of this study was to analyze patient demographics, incidence, and mortality rates, as well as the geographic distribution of PV patients in Canada between 1992 and 2010.
Methods
This study was achieved by analyzing the Canadian Cancer Registry, Le Registre Québécois du Cancer, and the Canadian Vital Statistics patient databases.
Results
A total of 4645 patients were diagnosed with PV between 1992 and 2010. While the annual incidence rate of this cancer fluctuated in Canada, mortality rate analysis indicated a decreasing trend. Geographically, PV incidence rates were notably elevated in the province of Quebec compared with the Canadian average. Further analysis of high‐incidence forward sortation areas indicated a striking clustering of cases in the H4W region encompassing the Côte‐Saint‐Luc borough of Montreal, with an incidence of 102.97 (95% confidence interval, 75.11‐137.79) cases per million per year, which is >13 times the national average.
Conclusion
The residential area of Côte‐Saint‐Luc is an important PV cluster in Canada, with high concentration of retirement homes and geriatric hospices. Also, Jewish residents comprise >60% of the population in this neighborhood. These findings suggest that an older age and, potentially, an inherent genetic predisposition may be implicated in the pathogenesis of this malignancy. This study provides a comprehensive overview of PV burden/geographic distribution of cases in Canada.
This study provides a comprehensive overview of polycythemia vera burden and geographical distribution in Canada. These findings suggest that older age and, potentially, an inherent genetic predisposition may be implicated in the pathogenesis of this malignancy.
Monocytosis (absolute monocyte count, AMC ≥ 1 × 109/L) might accompany a spectrum of myeloid neoplasms, other than chronic myelomonocytic leukemia (CMML). In the current study, we examined the ...prevalence, laboratory and molecular correlates, and prognostic relevance of monocytosis in polycythemia vera (PV). Among 267 consecutive patients with World Health Organization (WHO)‐defined PV, 55 (21%) patients displayed an AMC of ≥1 × 109/L and 18 (7%) an AMC of ≥1.5 × 109/L. In general, PV patients with monocytosis were significantly older and displayed higher frequencies of leukocytosis (81% vs. 50% at AMC ≥1 × 109/L) and TET2/SRSF2 mutations (57%/29% vs. 19%/1% at AMC ≥ 1.5 × 109/L). In univariate analysis, AMC ≥1.5 × 109/L adversely affected overall (OS; P = .004; HR 2.6, 95% CI 1.4‐4.8) and myelofibrosis‐free (MFFS; P = .02; HR 4.4, 95% CI 1.3‐15.1) survival; during multivariable analysis, significance was borderline sustained for OS (P = .05) and MFFS (P = .06). Other independent risk factors for OS included unfavorable karyotype (P = .02, HR 3.39, 95% CI 1.17‐9.79), older age (P < .0001, HR 3.34 95% CI 1.97‐5.65), and leukocytosis ≥15 × 109/L (P = .004, HR 2.04, 95% CI 1.26‐3.29). In conclusion, in the current study, we encountered a higher than expected prevalence of monocytosis in patients with PV and the mutation profile and age distribution of PV patients with monocytosis is akin to those of patients with CMML and might partly contribute to their worse prognosis.
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