Therapy For Polycythemia Vera Research Articles

Real-life use of ropeg-interferon α2b in polycythemia vera: patient selection and clinical outcomes

Ropeginterferon-alfa2b (ropegIFNα2b) is a long-acting IFN formulation with broad FDA/EMA approval as a therapy of polycythemia vera (PV) with no symptomatic splenomegaly. There is currently lack of information on the real-world patient selection, including the impact of local reimbursement policies, and drug management, particularly: type/timing of screening and follow-up tests; absolute/relative contraindications to therapy; ropegIFNα2b dose and combinations with hydroxyurea. As a sub-analysis of the PV-ARC retrospective study (NCT06134102), we here report our monocenter experience with ropegIFNα2b in the period from January 2021, corresponding to drug availability outside clinical trial, and December 2023. Among the 149 patients with EMA/FDA indication, only 55 (36.9%) met the local reimbursement criteria and 18 (12.1%) received ropegIFNα2b. Thanks to appropriate screening, relative/absolute contraindications to ropegIFNα2b were detected and managed in a multidisciplinary manner. Efficacy and safety of ropegIFNα2b was confirmed, with 3 cases of early molecular response. General use of low ropegIFNα2b dose, with frequent need for hydroxyurea combinations, was noted. This real-world experience suggests a significant impact of local regulations on drug prescription and the need for greater real-world data collection on ropegIFNα2b in PV patients. Also, it describes appropriate multidisciplinary screening and monitoring procedures during ropegIFNα2b therapy.

Correlation of Quality of Life between Treatment Outcomes in the Majic Study Which Compared Ruxolitinib to Best Available Therapy in Polycythemia Vera

Correlation of Quality of Life between Treatment Outcomes in the Majic Study Which Compared Ruxolitinib to Best Available Therapy in Polycythemia Vera

Heterogeneity of Bone Marrow Morphology in Patients with Polycythemia Vera Resistant to First and Second Line Therapies - Impact of Hydroxyurea Dosage on MDS-like Progression

Background: First-line therapy in polycythemia vera (PV) generally consists of low-dose aspirin, phlebotomy, cytoreductive agents, and interferon. Hydroxyurea (HU) is the most frequently used cytoreductive agent, however, about 15-20% of patients (pts) become therapy resistant or intolerant. Resistance to HU is frequently associated with an aggressive disease course by increasing the risk of progression to post-PV myelofibrosis (PPMF). The clinical phenotype at this disease stage is very heterogeneous and often triggers a switch to second-line treatment options like JAK-inhibitor therapy.Design: A series of more than 500 consecutively collected cases with PV was screened in this observational study and analyzed with regard to inadequately controlled disease and resistance, intolerance or both to first-line cytoreductive agents. Only pts with available bone marrow (BM) trephine biopsies at this disease stage were finally selected. PPMF was defined according to the WHO 2016 criteria and HU resistance was assessed according to the European LeukaemiaNet (ELN). BM trephines were evaluated for grade of BM fibrosis (reticulin/collagen), cellularity, amount of CD34+ progenitors and morphology of megakaryocytes including the occurrence of myelodysplastic features associated with disease progression. Hematological and clinical data were collected at corresponding time points.Results: A total of 56 cases (31 males, 25 females, median age 67.5 years) with a representative BM trephine and uncontrolled disease or resistance to first-line cytoreductive agents was analyzed. Median time after diagnosis was 96.5 months (range 4 - 381 months), median treatment time with first-line cytoreductive agents (HU in 87.5%) was 48 months (range 12 - 240 months). Only 62.5% (35/56) of cases presented at this time point with a BM fibrosis grade ≥ 2 and thus fulfilled the WHO criteria for classical PPMF. 14 cases (25.0%) revealed a BM fibrosis grade of 1, whereas an uncontrolled myeloproliferation defined by increased platelet and/or leukocyte counts was found in 7 cases (12.5%). In 2 patients (3.5%) a blast phase was diagnosed at the time of treatment failure which was not associated with progressive fibrosis. In classical PPMF BM cellularity was heterogeneous but generally increased. Cases with grade 1 fibrosis or uncontrolled myeloproliferation had higher hemoglobin levels, lower leukocytes count, and higher platelet counts at time of treatment failure as compared to the PPMF group. On the other site, classical post-PV MF more often was presenting with relevant cytopenia and erythrocyte transfusion dependency. There was no difference in the amount of CD34+ progenitors between classical PPMF and cases presenting with either grade 1 fibrosis or uncontrolled myeloproliferation. MDS-like progression characterized by highly atypical megakaryocytes was observed in 12 pts (21.4%), all pts presented with classical PPMF. For all pts. treated with HU the total cumulative dosage, the average dosage per years, as well as the highest used dosage to control disease was calculated. Pts presenting with MDS-like BM features received a significantly higher total HU dosage (6,230 vs 721 gram, p=0.011) and showed a longer median treatment time with HU (72 vs 48 months), whereas the average annual dosage showed no significant difference.Conclusions: Progression of inadequately controlled PV represents a biological spectrum and is not restricted by degree of BM fibrosis as in classical WHO defined PPMF, but can also be defined by resistance to cytoreductive agents like HU. In clinical practice it is important to recognize that high dosages of HU and long treatment duration are more often seen in the important subgroup presenting with MDS-like features. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Germline genetic factors influence the outcome of interferon-α therapy in polycythemia vera

AbstractInterferon-α (IFN-α)–based treatments can induce hematologic and molecular responses (HRs and MRs, respectively) in polycythemia vera (PV); however, patients do not respond equally. Germline genetic factors have been implicated in differential drug responses. We addressed the effect of common germline polymorphisms on HR and MR after treatment of PV in the PROUD-PV and CONTINUATION-PV studies in a total of 122 patients who received ropeginterferon alfa-2b. Genome-wide association studies using longitudinal data on HR and MR over a 36-month follow-up did not reveal any associations at the level of genome-wide statistical significance. Furthermore, we performed targeted association analyses at the interferon lambda 4 (IFNL4) locus, well known for its role in hepatitis C viral clearance and recently reported to influence HR during treatment of myeloproliferative neoplasms. We did not observe any association of IFNL4 polymorphisms with HR in our study cohort; however, we demonstrated a statistically significant effect of the functionally causative IFNL4 diplotype (haplotype pair, including the protein-coding variants rs368234815/rs117648444) on MR (P = 3.91 × 10−4; odds ratio, 10.80; 95% confidence interval, 2.39-69.97) as reflected in differential JAK2V617F mutational burden changes according to IFNL4 diplotype status. Stratification of patients with PV based on IFNL4 functionality may allow for optimizing patient management during IFN-α–based therapy.

P6. Abstract Title: Risks and Benefits of Antithrombotic Therapy in Polycythemia Vera: A Systematic Review

<h3>Background</h3> Thrombosis is the major cause of morbidity and mortality in patients with polycythemia vera (PV). Aspirin, and phlebotomy with or without cytoreductive therapy are key components of PV management to reduce thrombotic risk. However, patients with PV are also at risk for hemorrhagic complications, especially in the context of thrombocytosis and acquired Von Willebrand factor deficiency. The net benefit of antithrombotic therapy for primary and secondary thromboprophylaxis is uncertain. A systematic review conducted in 2013 identified 2 randomized control trials (RCTs) and concluded that low-dose aspirin does not increase the risk of major bleeding and is associated with a clinically but not statistically significant reduction in fatal thrombotic events. The risks and benefits of aspirin and other antithrombotics for primary and secondary thromboprophylaxis in PV remain uncertain. <h3>Objective</h3> To evaluate the benefits and harms of antithrombotic therapies in adult patients with PV. <h3>Methods</h3> MEDLINE, CENTRAL, and Pubmed were searched for relevant articles. Studies were included if they (i) were RCTs or observational studies, (ii) included adults (≥18 years of age) with PV, (iii) compared outcomes (thrombosis, bleeding or mortality) in patients receiving antithrombotic therapy versus control or no antithrombotic therapy, and (iv) were published in English. Case reports, abstracts, narrative reviews, and editorials were excluded. Screening, full text review, and data extraction were completed by two independent reviewers. The study protocol was developed according to PRISMA guidelines and registered on Prospero (PROSPERO 2017 CRD42017079688). Risk of bias was assessed using the Cochrane Risk of Bias Tool for RCTs and ROBINS-I Tool for observational studies. <h3>Results</h3> Out of 4523 studies identified, 12 studies (9 observational studies and 3 RCTs) were included in the analysis. Agreement by Cohen's kappa was excellent at the full text stage (0.89). Antithrombotics were associated with non-significant reductions in the risks of thrombosis (RR 0.83, CI 0.55 – 1.26, I2 72%) and all-cause mortality (RR 0.67, CI 0.44 – 1.01, I2 22%) and a non-significant increase in the risk of bleeding (RR 1.19, CI 0.87 – 1.63, I2 0%) compared to control/no antithrombotics. Most studies were judged to be at high risk of bias. There was insufficient data to conduct a subgroup analysis for heparin and the direct oral anticoagulants. <h3>Conclusion</h3> Our systematic review and meta-analysis is an updated comprehensive summary of available data regarding the benefits and harms of antithrombotic therapy in PV. In keeping with the findings of the previous meta-analysis, our results show non-significant reductions in thrombosis and death, and a non-significant increase in bleeding. However, this analysis is limited by heterogeneity and may be underpowered given the small sample sizes of included studies. Further, the included studies were at high risk of bias due to confounding. Prospective studies regarding anticoagulation in patients with PV are warranted.

Differential roles of STAT1 and STAT2 in the sensitivity of JAK2V617F- vs. BCR-ABL-positive cells to interferon alpha

BackgroundInterferon alpha (IFNa) monotherapy is recommended as the standard therapy in polycythemia vera (PV) but not in chronic myeloid leukemia (CML). Here, we investigated the mechanisms of IFNa efficacy in JAK2V617F- vs. BCR-ABL-positive cells.MethodsGene expression microarrays and RT-qPCR of PV vs. CML patient PBMCs and CD34+ cells and of the murine cell line 32D expressing JAK2V617F or BCR-ABL were used to analyze and compare interferon-stimulated gene (ISG) expression. Furthermore, using CRISPR/Cas9n technology, targeted disruption of STAT1 or STAT2, respectively, was performed in 32D-BCR-ABL and 32D-JAK2V617F cells to evaluate the role of these transcription factors for IFNa efficacy. The knockout cell lines were reconstituted with STAT1, STAT2, STAT1Y701F, or STAT2Y689F to analyze the importance of wild-type and phosphomutant STATs for the IFNa response. ChIP-seq and ChIP were performed to correlate histone marks with ISG expression.ResultsMicroarray analysis and RT-qPCR revealed significant upregulation of ISGs in 32D-JAK2V617F but downregulation in 32D-BCR-ABL cells, and these effects were reversed by tyrosine kinase inhibitor (TKI) treatment. Similar expression patterns were confirmed in human cell lines, primary PV and CML patient PBMCs and CD34+ cells, demonstrating that these effects are operational in patients. IFNa treatment increased Stat1, Stat2, and Irf9 mRNA as well as pY-STAT1 in all cell lines; however, viability was specifically decreased in 32D-JAK2V617F. STAT1 or STAT2 knockout and reconstitution with wild-type or phospho-deficient STAT mutants demonstrated the necessity of STAT2 for IFNa-induced STAT1 phosphorylation in BCR-ABL- but not in JAK2V617F-expressing cells. STAT1 was essential for IFNa activity in both BCR-ABL- and JAK2V617F-positive cells. Furthermore, ChIP experiments demonstrate higher repressive and lower active chromatin marks at the promoters of ISGs in BCR-ABL-expressing cells.ConclusionsJAK2V617F but not BCR-ABL sensitizes MPN cells to interferon, and this effect was dependent on STAT1. Moreover, STAT2 is a survival factor in BCR-ABL- and JAK2V617F-positive cells but an IFNa-sensitizing factor solely in 32D-JAK2V617F cells by upregulation of STAT1 expression.

The Real-World Treatment of Polycythemia Vera: Adherence to Treatment Guidelines and Outcomes

Background The aim of therapy for polycythemia vera (PV), a myeloproliferative neoplasm, is to reduce cardiovascular risk without increasing the risk of bleeding or hematological transformation. Current consensus guidelines suggest low dose aspirin and phlebotomy for patients at low-risk for thrombosis ( Methods We performed a retrospective cohort study of newly diagnosed JAK2V617F positive PV patients over the age of 18 between January 1, 2005 and January 1, 2017 in Hamilton, Ontario, Canada. The primary outcome was all-cause mortality. Secondary outcomes were non-fatal cardiovascular events, major bleeding, and hematological progression. Statistical analysis was performed in STATA using Cox proportional hazard models, and Poisson regression. Results A total of 112 patients (58.0% female) met inclusion criteria. The mean (SD) age at diagnosis was 70 (14) years. Median follow-up was 3.38 years (Range = 0.04-11.89). At diagnosis, 82.1% of patients were classified as high risk for thrombosis. At diagnosis cardiovascular risk factors were present in 69.6% of patients including previous thrombotic events in 27.5%. Symptoms of PV (e.g. pruritus, vasomotor, fatigue) were found in 52.7% of patients at diagnosis. Patients received treatment with phlebotomy (90.2%), aspirin (87.5%), and hydroxyurea (74.1%). Monotherapy was used in 6 (24%) of the non-guideline patients and was not found in the guideline group. Anticoagulants were used in 17.2% of patients. Overall, only 77.7% of patients received treatment that was consistent with guidelines regarding aspirin and hydroxyurea use. A total of 22 (19.6%) of patients died during follow-up; increasing white blood cell count at diagnosis, increasing age at diagnosis, history of diabetes and history of congestive heart failure were associated with higher risk of death (Table 1). Patients who were not treated according to the guideline recommendations at any point during follow-up had an increased risk of death (HR, 2.88; 95% CI, 1.03-8.05; P Conclusion This contemporary North American PV patient cohort study showed that the majority of newly diagnosed PV patients were older adults at high risk of thrombosis consistent with previous studies. The presence of cardiovascular comorbidities at diagnosis appeared to increase the risk of death. About three-quarters of patients in our cohort received treatment according to consensus guideline recommendations. Although the reasons for discordance with guidelines are uncertain, those who did not receive recommended therapy appeared to have an increased risk of death. The results of this study should be interpreted with caution due to the possibility of confounding by other factors that influence mortality. Future research regarding the barriers and facilitators of PV treatment guideline use, and the optimal strategy for assessment and management of cardiovascular risk factors may provide opportunities to improve care and patient outcomes. Disclosures Siegal: Novartis: Other: Focus Group; Bayer: Other: Focus group; BMS-pfizer: Other: Presentation; Servier: Other: Focus Group; Portola Pharmaceuticals: Other: Presentation. Hillis: Celgene: Other: Personal fees; Novartis Oncology: Research Funding; Bristol-Myers Squibb: Other: Personal Fees.

A reappraisal of the benefit-risk profile of hydroxyurea in polycythemia vera: A propensity-matched study.

The use of hydroxyurea (HU) as first line therapy in polycythemia vera (PV) has been criticized because no solid demonstration that this drug prevents thrombosis or prolongs survival has been so far produced. Here we present the outcomes of a large cohort of patients with PV included in the European Collaborative Low-dose Aspirin (ECLAP) study. We selected 1,042 patients who, during the follow-up, had received only phlebotomy (PHL) or HU to maintain the hematocrit level < 45%. To assure comparability, we conducted a propensity score matching analysis. The two groups (PHL n = 342 and HU n = 681) were well balanced for the parameters included in the propensity score (overall balance: χ2 = 2.44, P = 0.964). Over a comparable period of follow-up (PHL = 29.9 vs. HU = 34.7 months), we documented an advantage of HU over PHL consistently significant with respect to the incidence of fatal/non-fatal cardiovascular (CV) events (5.8 vs. 3.0 per 100 person-years in PHL vs. HU group, P = 0.002) and myelofibrosis transformation that was only experienced by patients of PHL group. Evolution to acute leukemia was registered in three patients (two in PHL and one in HU group). The excess of mortality and total CV events in the PHL patients was restricted to the high-risk group, and, compared with HU cases, was significant higher in the PHL patients who failed to reach the hematocrit target < 0.45% (P = 0.000). In conclusion, this analysis provides reliable and qualified estimates of the therapeutic profile of HU and PHL treatments for future experimental studies and for the management of PV in clinical practice.

Individualizing Care for Patients With Myeloproliferative Neoplasms: Integrating Genetics, Evolving Therapies, and Patient-Specific Disease Burden.

Individualized medicine is important for patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, which are heterogeneous in terms of genetic mutation profile, prognosis, disease burden, and symptoms. Status of MPN driver mutations in JAK2, CALR, and MPL (or lack of one of these mutations) and other myeloid mutations (ASXL1, SRSF2, CBL, and IDH1/2, among others) affects diagnosis and prognosis. Management begins with estimating the prognosis, disease burden including MPN symptoms, and prevention of vascular events. Allogeneic stem cell transplantation is the definitive therapy in a subset of patients with myelofibrosis, the majority of whom receive JAK inhibition with ruxolitinib to relieve splenomegaly and symptoms and to prolong survival. Ruxolitinib is now a second-line therapy in polycythemia vera, with pegylated interferon being evaluated as a potential front-line therapy compared with hydroxyurea. The therapeutic landscape is evolving to include new JAK inhibitors, which may affect cytopenias (pacritinib and momelotinib), combination therapies including ruxolitinib, and novel targets such as pentraxin and telomerase. Assessing the therapeutic efficacy (including symptom impact) and toxicity of these new approaches is necessary to determine longitudinal management of MPNs in clinical practice and is a key component of "individualizing" care for patients with MPNs.

Individualizing Care for Patients With Myeloproliferative Neoplasms: Integrating Genetics, Evolving Therapies, and Patient-Specific Disease Burden

Individualized medicine is important for patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, which are heterogeneous in terms of genetic mutation profile, prognosis, disease burden, and symptoms. Status of MPN driver mutations in JAK2, CALR, and MPL (or lack of one of these mutations) and other myeloid mutations (ASXL1, SRSF2, CBL, and IDH1/2, among others) affects diagnosis and prognosis. Management begins with estimating the prognosis, disease burden including MPN symptoms, and prevention of vascular events. Allogeneic stem cell transplantation is the definitive therapy in a subset of patients with myelofibrosis, the majority of whom receive JAK inhibition with ruxolitinib to relieve splenomegaly and symptoms and to prolong survival. Ruxolitinib is now a second-line therapy in polycythemia vera, with pegylated interferon being evaluated as a potential front-line therapy compared with hydroxyurea. The therapeutic landscape is evolving to include new JAK inhibitors, which may affect cytopenias (pacritinib and momelotinib), combination therapies including ruxolitinib, and novel targets such as pentraxin and telomerase. Assessing the therapeutic efficacy (including symptom impact) and toxicity of these new approaches is necessary to determine longitudinal management of MPNs in clinical practice and is a key component of individualizing care for patients with MPNs.

Front-line therapy in polycythemia vera and essential thrombocythemia

Because the current therapy in polycythemia vera (PV) and essential thrombocythemia (ET) is aimed at lowering the risk of thrombosis, the risk classification system in these disorders is shaped according to thrombotic risk. Patients with either PV or ET can be stratified in a “high-risk” or “low-risk” category according to their age and previous history of thrombosis. Whether novel risk factors such as leukocytosis and JAK2 mutation may be included in the prognostic stratification requires confirmation in prospective future clinical studies. The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in chronic myeloproliferative neoplasms (MPN), as in the general population, should be considered a cornerstone of vascular prevention. Blood hyperviscosity in PV is a major cause of vascular disturbances which severely impact on morbidity and mortality. An aggressive target of hematocrit lower than 45% in males and 42% in females has been advised by the European LeukemiaNet (ELN) group, although no convincing evidence of this recommendation is currently available. The efficacy and safety of low-dose aspirin (100mg daily) in PV has been assessed in the European Collaboration on Low-dose Aspirin in Polycythemia (ECLAP) double-blind, placebo-controlled, randomized clinical trial. Translating evidence from the positive results of ECLAP to ET may be questionable. The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea and alpha-interferon at any age while anagrelide is recommended as second line-therapy in resistant and intolerant ET patients. Busulphan is a front-line therapy in the elderly. By definition, children with ET are a population with low vascular risk unless a major thrombotic or hemorrhagic event has occurred. ELN recommends to prescribe cytoreductive drugs in children as a last resort. No results of clinical trials with JAK-2 inhibitor drugs in PV and ET are so far available.

Decrease in JAK2V617F allele burden is not a prerequisite to clinical response in patients with polycythemia vera

Although reduction in the JAK2(V617F) allele burden (%V617F) has been suggested as a criterion for defining disease response to cytoreductive therapy in polycythemia vera, its value as a response monitor is unclear. The purpose of this study is to determine whether a reduction in %V617F in polycythemia vera is a prerequisite to achieving hematologic remission in response to cytoreductive therapy. We compared the clinical and hematologic responses to change in %V617F (molecular response) in 73 patients with polycythemia vera treated with either interferon (rIFNα-2b: 28, Peg-rIFNα-2a: 18) or non-interferon drugs (n=27), which included hydroxyurea (n=8), imatinib (n=12), dasatinib (n=5), busulfan (n=1), and radioactive phosphorus (n=1). Hematologic response evaluation employed Polycythemia Vera Study Group criteria, and molecular response evaluation, European Leukemia Net criteria. Of the 46 treated with interferon, 41 (89.1%) had a hematologic response, whereas only 7 (15.2%) had a partial molecular response. Of the 27 who received non-interferon treatments, 16 (59.3%) had a hematologic response, but only 2 (7.4%) had a molecular response. Median duration of follow up was 2.8 years. Statistical agreement between hematologic response and molecular response was poor in all treatment groups. Generally, hematologic response was not accompanied by molecular response. Therefore, a quantitative change in %V617F is not required for clinical response in patients with polycythemia vera.

198 INVITED Acute lymphoblastic leukaemia

Because the current therapy in polycythemia vera (PV) and essential thrombocythemia (ET) is aimed at lowering the risk of thrombosis, the risk classification system in these disorders is shaped according to thrombotic risk. Patients with either PV or ET can be stratified in a “high-risk” or “low-risk” category according to their age and previous history of thrombosis. Whether novel risk factors such as leukocytosis and JAK2 mutation may be included in the prognostic stratification requires confirmation in prospective future clinical studies. The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in chronic myeloproliferative neoplasms (MPN), as in the general population, should be considered a cornerstone of vascular prevention. Blood hyperviscosity in PV is a major cause of vascular disturbances which severely impact on morbidity and mortality. An aggressive target of hematocrit lower than 45% in males and 42% in females has been advised by the European LeukemiaNet (ELN) group, although no convincing evidence of this recommendation is currently available. The efficacy and safety of low-dose aspirin (100 mg daily) in PV has been assessed in the European Collaboration on Low-dose Aspirin in Polycythemia (ECLAP) double-blind, placebo-controlled, randomized clinical trial. Translating evidence from the positive results of ECLAP to ET may be questionable. The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea and alpha-interferon at any age while anagrelide is recommended as second line-therapy in resistant and intolerant ET patients. Busulphan is a front-line therapy in the elderly. By definition, children with ET are a population with low vascular risk unless a major thrombotic or hemorrhagic event has occurred. ELN recommends to prescribe cytoreductive drugs in children as a last resort. No results of clinical trials with JAK-2 inhibitor drugs in PV and ET are so far available.

200 INVITED What is known about HPV natural history? Current trends and variation in incidence, mortality and relation to screening programmes in Europe

Because the current therapy in polycythemia vera (PV) and essential thrombocythemia (ET) is aimed at lowering the risk of thrombosis, the risk classification system in these disorders is shaped according to thrombotic risk. Patients with either PV or ET can be stratified in a “high-risk” or “low-risk” category according to their age and previous history of thrombosis. Whether novel risk factors such as leukocytosis and JAK2 mutation may be included in the prognostic stratification requires confirmation in prospective future clinical studies. The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in chronic myeloproliferative neoplasms (MPN), as in the general population, should be considered a cornerstone of vascular prevention. Blood hyperviscosity in PV is a major cause of vascular disturbances which severely impact on morbidity and mortality. An aggressive target of hematocrit lower than 45% in males and 42% in females has been advised by the European LeukemiaNet (ELN) group, although no convincing evidence of this recommendation is currently available. The efficacy and safety of low-dose aspirin (100 mg daily) in PV has been assessed in the European Collaboration on Low-dose Aspirin in Polycythemia (ECLAP) double-blind, placebo-controlled, randomized clinical trial. Translating evidence from the positive results of ECLAP to ET may be questionable. The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea and alpha-interferon at any age while anagrelide is recommended as second line-therapy in resistant and intolerant ET patients. Busulphan is a front-line therapy in the elderly. By definition, children with ET are a population with low vascular risk unless a major thrombotic or hemorrhagic event has occurred. ELN recommends to prescribe cytoreductive drugs in children as a last resort. No results of clinical trials with JAK-2 inhibitor drugs in PV and ET are so far available.

Therapy for Polycythemia Vera and Essential Thrombocythemia Is Driven by the Cardiovascular Risk

The clinical course of polycythemia vera (PV) and essential thrombocythemia (ET) is characterized by an increased incidence of thrombotic and hemorrhagic complications and an inherent tendency to progress into myelofibrosis or acute myeloid leukemia. Major predictors of vascular events are increasing age and previous thrombosis. Myelosuppressive drugs can reduce the rate of thromboses and hemorrhages, but there is concern that their use accelerates the rate of leukemic transformation. Thus, a risk-oriented management strategy is recommended. Low-risk patients with PV should be treated with phlebotomy and low-dose aspirin, whereas those with ET can be left untreated. Cytotoxic agents are recommended in high-risk cases and hydroxyurea is the drug of choice in most patients. Interferon alpha or anagrelide could be considered in selected young patients or as second-line therapy in those refractory or intolerant of hydroxyurea. The recent identification of JAK2V617F mutation in a substantial proportion of patients with PV and ET raises new questions regarding both risk classification and management, but additional studies on these issues are required.

A phase II trial of pegylated interferon α‐2b therapy for polycythemia vera and essential thrombocythemia

Conventional interferon-alpha (IFN) is an effective treatment for patients with myeloproliferative disorders. However, many patients discontinue therapy because of side effects. In this 24-month, Phase II feasibility study of pegylated interferon alpha-2b (PEG-IFN) treatment, a starting dose of 0.5 microg/kg per week was received by 21 patients with polycythemia vera (PV) and 21 patients with essential thrombocythemia (ET). The treatment objective, a complete platelet response (CR), was a platelet count<400x10(9)/L in symptomatic patients and <600 in asymptomatic patients. Neutrophil polycythemia rubra vera-1 (PRV-1) messenger RNA expression was analyzed prior to and during therapy. Quality of life (QoL) was investigated by using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. At 6 months, 29 of 42 patients (69%) had achieved a CR after a median of 83 days. The CR rate was not related to diagnosis, gender, or previous therapy. Nineteen patients completed the planned 2-year treatment in CR. No thromboembolic or bleeding complications were observed. Phlebotomy requirements were reduced in the majority of patients with PV. Five of 14 patients (36%) who initially were positive for PRV-1 achieved normalized PRV-1 expression under PEG-IFN treatment. Side effects were the cause of therapy failure in 16 of 23 patients. However, only 8 of 19 patients reported any side effects at 2 years. The QLQ-C30 revealed clinically significant impairments in several aspects of QoL at 6 months; however, at 2 years, QoL measurements were not different from baseline. PEG-IFN effectively reduced platelet counts in 29 of 42 patients, but only 19 patients maintained a CR at 2 years. The reversal of PRV-1 positivity noted in a subset of patients suggested that PEG-IFN may have an effect on the malignant clone. PEG-IFN is a valuable therapeutic alternative for patients who tolerate its initial side effects.

Polycythemia vera and other primary polycythemias

Diagnosis and therapy of polycythemia vera are controversial since the molecular basis of polycythemia vera remains unknown. Distinguishing between polycythemia vera and other polycythemic disorders can be very challenging. The purpose of this review is to discuss the recent progress in this area and critically review the published data in context of our knowledge of other polycythemic disorders. Erythropoietin is the principal regulator of regulator of erythropoiesis; its production is regulated by the degree of hypoxia. Our knowledge of cellular responses to hypoxia has recently exploded and led to the elucidation of the molecular basis of a polycythemia caused by augmentation of hypoxic sensing, Chuvash polycythemia. Similar progress in understanding the molecular basis of polycythemia vera has been elusive. A simple, readily available laboratory test to establish a diagnosis of polycythemia vera would be highly desirable; however, none exists. The value of quantization of neutrophil PRV-1 mRNA, platelet c-mpl expression, in vitro assays of erythroid progenitor cells, serum erythropoietin levels, establishing clonality in female subjects using assays employing X-chromosome-based polymorphism assays, and the progress in the chromosomal location of the gene is discussed. Integration of this information underlies the complexity of the molecular biology of polycythemia vera and indicates likely interaction of multiple genetic events in the genesis of polycythemia vera. The existence of family clustering of PV may facilitate the search for PV molecular basis. Only collaborative interaction of clinical researchers and laboratory scientists will lead to meaningful progress in determining the molecular basis of PV.

Lymphoma in Primary Chronic Cold Hemagglutinin Disease Treated With Chlorambucil

Two patients with primary chronic cold hemagglutinin disease (CHAD) were treated with chlorambucil for ten and 7 1/2 years, with cumulative doses of 14 and 6.6 g, respectively. Both responded favorably, and malignant lymphoma eventually developed in both of them. An attempt to assess the incidence of lymphoma as part of the natural course of untreated CHAD failed for want of proof. Literature since 1970 reported no chlorambucil-associated lymphoma. Of 77 responses to a questionnaire mailed to 135 US hematology-oncology programs, 76 reported no examples of chlorambucil-associated lymphoma. One response, however, did relate that diffuse histiocytic lymphoma developed in three of 141 patients receiving prolonged chlorambucil therapy for polycythemia vera. Alkylating-agent therapy for CHAD might be associated with development of lymphoma.

Therapy of Polycythemia Vera with Myleran

Abstract Myleran was used in the therapy of nine relapses of polycythemia vera in five patients. Clinical examinations, blood studies, and, in three instances, radioisotope tracer tests before and after treatment demonstrated the effectiveness, safety and simplicity of the treatment. Further trial of Myleran therapy in polycythemia vera seems warranted.

RADIO-PHOSPHORUS—AN AGENT FOR THE SATISFACTORY TREATMENT OF POLYCYTHEMIA AND ITS ASSOCIATED MANIFESTATIONS; A REPORT OF A CASE OF POLYCYTHEMIA SECONDARY POSSIBLY TO THE BANTI'S SYNDROME

Excerpt Polycythemia is a disease of unknown etiology characterized by a chronic course and a marked increase in total blood volume over the normal, with an absolute increase in the total number of...