Treatment Of Vera Research Articles

The efficiency of therapeutic erythrocytapheresis compared to phlebotomy: A mathematical tool for predicting response in hereditary hemochromatosis, polycythemia vera, and secondary erythrocytosis

Recently, therapeutic erythrocytapheresis (TE) was suggested to be more efficient in depletion of red blood cells (RBC) compared to manual phlebotomy in the treatment of hereditary hemochromatosis (HH), polycythemia vera (PV), and secondary erythrocytosis (SE). The efficiency rate (ER) of TE, that is, the increase in RBC depletion achieved with one TE cycle compared to one phlebotomy procedure, can be calculated based on estimated blood volume (BV), preprocedural hematocrit (Hct(B)), and delta-hematocrit (ΔHct). In a retrospective evaluation of 843 TE procedures (in 45 HH, 33 PV, and 40 SE patients) the mean ER was 1.86 ± 0.62 with the highest rates achieved in HH patients. An ER of 1.5 was not reached in 37.9% of all procedures mainly concerning patients with a BV below 4,500 ml. In 12 newly diagnosed homozygous HH patients, the induction phase duration was medially 38.4 weeks (medially 10.5 procedures). During the maintenance treatment of HH, PV, and SE, the interval between TE procedures was medially 13.4 weeks. This mathematical model can help select the proper treatment modality for the individual patient. Especially for patients with a large BV and high achievable ΔHct, TE appears to be more efficient than manual phlebotomy in RBC depletion thereby potentially reducing the numbers of procedures and expanding the interprocedural time period for HH, PV, and SE.

Are All Interferons the Same for Therapy in Polycythemia Vera?

The use of recombinant interferons (rIFNs) for myeloproliferative neoplasms (MPNs) has increased significantly in the past 20 years, especially for polycythemia vera (PV) and essential thrombocythemia (ET). In PV, substantial change in the JAK2V617F allele burden (found in virtually all cases of PV and in approximately half of patients with ET) has occurred. 1 Silver R.T. Kiladjian J.J. Hasselbalch H.C. Interferon and the treatment of polycythemia vera, essential thrombocythemia and myelofibrosis. Expert Rev Hematol. 2013; 6: 49-58 Crossref PubMed Scopus (83) Google Scholar This observation has not been consistently noted in patients treated with rIFN-α2b. 2 Jones A.V. Silver R.T. Waghorn K. et al. Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha. Blood. 2006; 107: 3339-3341 Crossref PubMed Scopus (100) Google Scholar The issue as to whether there is a qualitative or a quantitative difference is relevant for the treatment of ET and PV.

Overcoming AC220 resistance of FLT3-ITD by SAR302503

Overcoming AC220 resistance of FLT3-ITD by SAR302503

PHS33 - Resource use patterns and costs associated with the treatment of myelofibrosis, polycythemia vera and essential trombocythemia in the brazilian public health care system

To evaluate the resource use and associated costs of patients treated for polycythemia vera (PV), myelofibrosis (MF) and essential thrombocythemia (ET) in the Brazilian public health care system. DATASUS is a Brazilian comprehensive database that reports all outpatient and inpatient services provided by the Brazilian public health care system. Patients identified with the diagnosis of PV (ICD 10 D45), MF (D47.1) and ET (D47.3) in the Datasus database between January 2010 and December 2010 were included in the analysis, irrespective of the date of diagnosis. Patients’ profile was defined based on age, sex and geographical region. Costs and resource use patterns were analyzed for the year 2010 and characterized by the percentage of patients using each health resource, the average quantity per patient and the total associated cost. Analyses were segmented by outpatient (drugs and transport) and inpatient (hospitalization) costs. The number of patients identified with the diagnosis of PV, MF and ET were 1533, 2130 and 2413, respectively. Their average age was 65, 63 and 63 years, and the percentage of females equaled 55%, 55% and 66%, respectively. The majority of patients live in the southeast region of Brazil. The three diseases present a similar treatment pattern. The majority of outpatient costs are associated to first line and second line chemotherapy treatment (21.9% and 77.5% for PV; 12.6% and 86.9% for MF; 12.6% and 87.2% for ET, respectively). The average annual outpatient and inpatient costs per patient were: R$2,581.27 and R$15.27 for PV; R$3,341.02 and R$45.22 for MF; R$ 4,070.28 and R$15.92 for ET) (1 USD = R$2.04). The current treatment for PV, MFand ET in the Brazilian public health care system relies basically on the use of first and second line chemotherapy. These items are responsible for more than 90% of the annual treatment cost.

Polycythemia vera revealed via a bladder tumor in a patient with erectile dysfunction: a case report

IntroductionPolycythemia vera is a polyglobular myeloproliferative syndrome related to the mutation of multipotent hemopoietic stem cells. This case report describes a patient whose bladder tumor was associated with polycythemia vera and erectile dysfunction. The association of bladder neoplasia with polycythemia vera and erectile dysfunction has not previously been reported in the literature.Case presentationA 40-year-old Moroccan man was followed up for a bladder tumor which manifested with coagulant hematuria and a facial erythrosis with a hemoglobin level of 20.3g/L suggesting polycythemia vera. The patient also suffered from an erectile disorder. Considering the anesthesia difficulty due to polyglobulia, the patient was treated by bleeding. This treatment enabled the patient’s sexual performance to be improved and adjustment of his hemoglobin to a level allowing anesthesia, and hence surgical resection of his bladder tumor.ConclusionErectile dysfunction associated with polycythemia vera is elucidated by rheological disorders. Bleeding contributed to satisfactory sexual performance and facilitated treatment of polycythemia vera because it enabled anesthesia to be performed and hence the surgical resection of the bladder tumor.

Interferon and the treatment of polycythemia vera, essential thrombocythemia and myelofibrosis

Recombinant IFN-α (rIFN-α) induces complete hematologic remissions in patients with myeloproliferative neoplasms (MPNs), but its use has been limited by side effects owing to the relatively high doses used. Now, low-dose rIFN-α is stressed, starting relatively early in the course of the MPNs. In polycythemia vera, this has resulted in a significant clinical, hematologic, morphologic and molecular response manifested by reduction in the JAK2V617F allele burden, sustained even after discontinuation of recombinant IFN. In essential thrombocythemia, platelet count reduction is prompt and durable without treatment for varying periods. In hypercellular primary myelofibrosis, rIFN-α has restored normal blood counts, reduced splenomegaly and induced morphologic marrow remissions. This article highlights our current use of rIFN-α in MPNs.

Homoharringtonine is an effective therapy for patients with polycythemia vera or essential thrombocythemia who have failed or were intolerant to hydroxycarbamide or interferon-α therapy

At present, the treatment of polycythemia vera (PV) and essential thrombocythemia (ET) is still largely supportive and symptomatic. Homoharringtonine (HHT), a valid drug for treating chronic myelogenous leukemia, has shown some effect on leukemic stem cells. The aim of this study was to observe the effect of HHT on patients with high-risk PV and ET. Patients with high-risk PV (n = 17) or ET (n = 18) who had failed or were intolerant to hydroxycarbamide or interferon-α therapy received HHT at a dose of 1.5 mg/m(2) daily by continuous infusion for 7 days every month. Hematological responses were evaluated at the 6th month after HHT therapy. After six courses of HHT therapy, the hematological response rates were 64.7 % (11/17) in PV and 72.2% (13/18) in ET. In PV, the single sign remission rates of constitutional symptoms, symptomatic splenomegaly, pruritus and bone pain were 70.0% (7/10), 77.8% (7/9), 50% (1/2) and 100% (3/3), respectively. The remission rates of constitutional symptoms and symptomatic splenomegaly in ET were 66.7% (6/9) and 71.4% (5/7), respectively. The rates of grade 1 granulocytopenia and thrombocytopenia were 1.8 and 0.9%, respectively. No grade 2 or over events, or pancytopenia were observed. Low-dose HHT alone has considerable short-term efficacy for high-risk PV/ET and may used as a second-line drug for PV/ET treatment in patients who have failed or were intolerant to hydroxycarbamide or interferon-α therapy.

Impending anterior ischemic optic neuropathy with elements of retinal vein occlusion in a patient on interferon for polycythemia vera

We describe the course and likely pathophysiology of impending anterior ischemic optic neuropathy (AION) and retinal vein occlusion in a 56-year-old man with polycythemia vera managed with interferon alpha for 2 years. Our patient presented with decreased vision, scintillating scotomata, and floaters. Fundus examination findings and results of a fluorescein angiogram led to the diagnosis of impending AION and retinal vein occlusion. Considering that both polycythemia vera and interferon have possible influences on vascular occlusion and optic disc edema, we stopped interferon treatment and immediately attempted to treat the polycythemia vera empirically with pentoxifylline and any interferon-associated inflammation with prednisone. Our patient experienced complete resolution of fundus abnormalities and return of normal vision within 3 weeks, which may be attributed to our successful treatment of both etiologies. Thus, further study is warranted to elucidate the treatment of both polycythemia vera and interferon-induced impending AION.

Treatment of Polycythemia Vera With Hydroxyurea and Pipobroman: Final Results of a Randomized Trial Initiated in 1980

The overall impact of hydroxyurea (HU) or pipobroman treatments on the long-term outcome of patients with polycythemia vera (PV) has not been assessed in randomized studies. We report final analyses from the French Polycythemia Study Group (FPSG) study, which randomly assigned HU versus pipobroman as first-line therapy in 285 patients younger than age 65 years. The full methodology has been described previously. FPSG results were updated with a median follow-up of 16.3 years. Statistical analysis was performed by using competing risks on the intention-to-treat population and according to main treatment received. Median survival was 17 years for the whole cohort, 20.3 years for the HU arm, and 15.4 years for the pipobroman arm (P = .008) and differed significantly from that in the general population. At 10, 15, and 20 years, cumulative incidence of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) was 6.6%, 16.5%, and 24% in the HU arm and 13%, 34%, and 52% in the pipobroman arm (P = .004). Cumulative myelofibrosis incidence at 10, 15, and 20 years according to main treatment received was 15%, 24%, and 32% with HU versus 5%, 10%, and 21% with pipobroman (P = .02). Data from this unique randomized trial comparing HU with another cytoreductive drug in PV showed that (1) survival of patients with PV treated with conventional agents differed from survival in the general population, (2) evolution to AML/MDS is the first cause of death, (3) pipobroman is leukemogenic and is unsuitable for first-line therapy, and (4) incidence of evolution to AML/MDS with HU is higher than previously reported, although consideration should be given to the natural evolution of PV.

Aconitase Regulation of Erythropoiesis Correlates with a Novel Licensing Function in Erythropoietin-Induced ERK Signaling

BackgroundErythroid development requires the action of erythropoietin (EPO) on committed progenitors to match red cell output to demand. In this process, iron acts as a critical cofactor, with iron deficiency blunting EPO-responsiveness of erythroid progenitors. Aconitase enzymes have recently been identified as possible signal integration elements that couple erythropoiesis with iron availability. In the current study, a regulatory role for aconitase during erythropoiesis was ascertained using a direct inhibitory strategy.Methodology/Principal FindingsIn C57BL/6 mice, infusion of an aconitase active-site inhibitor caused a hypoplastic anemia and suppressed responsiveness to hemolytic challenge. In a murine model of polycythemia vera, aconitase inhibition rapidly normalized red cell counts, but did not perturb other lineages. In primary erythroid progenitor cultures, aconitase inhibition impaired proliferation and maturation but had no effect on viability or ATP levels. This inhibition correlated with a blockade in EPO signal transmission specifically via ERK, with preservation of JAK2-STAT5 and Akt activation. Correspondingly, a physical interaction between ERK and mitochondrial aconitase was identified and found to be sensitive to aconitase inhibition.Conclusions/SignificanceDirect aconitase inhibition interferes with erythropoiesis in vivo and in vitro, confirming a lineage-selective regulatory role involving its enzymatic activity. This inhibition spares metabolic function but impedes EPO-induced ERK signaling and disturbs a newly identified ERK-aconitase physical interaction. We propose a model in which aconitase functions as a licensing factor in ERK-dependent proliferation and differentiation, thereby providing a regulatory input for iron in EPO-dependent erythropoiesis. Directly targeting aconitase may provide an alternative to phlebotomy in the treatment of polycythemia vera.

JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations

The discovery of JAK2V617F has rejuvenated interest in Janus kinase (JAK)-signal transducer and activator of transcription (STAT), both as an oncogenic pathway and a drug target in BCR-ABL1-negative myeloproliferative neoplasms (MPN). However, the complexity of these diseases in terms of both clonal structure and mutation repertoire makes it unlikely that JAK inhibitor therapy will replicate what has been achieved with imatinib in chronic myeloid leukemia. Consistent with this view, JAK inhibitor therapy in myelofibrosis has not yet produced complete or partial remissions. However, most patients treated with a JAK2 (TG101348) or JAK1/2 (INCB018424) inhibitor experienced substantial improvement in constitutional symptoms and reduction in spleen size; the mechanism of action for INCB018424 includes anti-JAK1-mediated downregulation of proinflammatory cytokines. These observations complicate the choice of primary end points in clinical trials that would be robust enough to support regulatory approval. TG101348 and INCB018424 are the vanguard of JAK inhibitor therapy in myelofibrosis, but newer JAK inhibitors might have a broader spectrum of activity; preliminary results with CYT387 suggest responses in both anemia and splenomegaly. Outstanding issues regarding these drugs include identification of the optimal dosing strategy, their role (if any) in the treatment of polycythemia vera or essential thrombocythemia, and the potential for combining them with other therapeutic agents.

Treatment outcome in a cohort of young patients with polycythemia vera

The treatment of polycythemia vera in young adults is challenging, requiring one to run a balance between the increased risk of vascular complications, if left untreated, versus the potential of promoting secondary leukemia/myelodysplasia or cancer, if actively managed with chemotherapy. We report the results of a 20-year retrospective analysis in a cohort of 30 young adults with PV (median age 37 years, range 19-45) treated exclusively with phlebotomy, aspirin and hydroxyurea only in case of vascular complications occurring in the presence of thrombocytosis (platelet count > 600 × 10(9)/L). With this approach, vascular complications were no higher than in other published series, and secondary leukemia/myelodysplasia or cancer was not observed during a follow-up of 14 years.

Aconitase Modulates Erythroid Signaling through a Novel MEK-ERK Regulatory Pathway.

Abstract 75Erythropoiesis is a complex developmental program regulated in part by erythropoietin (EPO) and iron levels. We have previously shown that erythroid iron deprivation causes diminished enzymatic activity of the multifunctional aconitase proteins (Bullock et al., ASH 2007 #707). In addition, pharmacological inhibition of aconitase impairs erythroid growth and maturation in a lineage-selective manner without compromising ATP levels, suggesting a novel, non-metabolic regulatory role for aconitase in erythropoiesis (Talbot et al., ASH 2008 #3865). The nature of this regulatory role was addressed in the present study by examining the connection between aconitase activity and erythroid signal transduction. The impact of aconitase inhibition by fluoroacetate (FA) on several candidate pathways was assessed in primary human erythroid progenitors by standard immunoblotting. This approach consistently implicated the mitogen activated protein kinases (MAPKs) ERK1/2, whose phosphorylation was strongly induced both at early (30 minutes) and late (4 days) time points. In addition, phosphorylation of the other MAPKs p38 and JNK was unchanged, ruling out a non-specific stress response. To determine why aconitase inhibition augmented ERK1/2 phosphorylation, the effects of FA were determined on the upstream kinases MEK1/2. Surprisingly, phosphorylation of MEK1/2 showed no changes at earlier time points (up to 24 hours) and decreases at later time points (2–4 days). Activation of ERK/1/2 in the absence of MEK1/2 activation suggests an unconventional pathway in which aconitase regulates dephosphorylation, scaffolding, or subcellular localization. The inhibition of erythropoiesis by FA could result from increased ERK1/2 activity or diminished MEK1/2 activity. The first mechanism predicts phenotypic rescue by addition of MEK inhibitor (U0126), whereas the second mechanism predicts increased inhibition. In fact, U0126 alone recapitulated the anti-proliferative and anti-differentiative effects of FA on primary erythroid cultures, and the combination of U0126 and FA caused increased inhibition of growth and differentiation, arguing in favor of MEK1/2 repression as a mechanism for FA. Our findings establish that aconitase modulates signaling through the MEK-ERK pathway, perturbation of which may block erythropoiesis. To expand our studies on the in vivo role of aconitase in erythropoiesis, the impact of aconitase blockade was assessed in two additional murine models: phenylhydrazine (PHZ)-induced stress erythropoiesis and Polycythemia vera (PV). In both systems, erythropoiesis was found to be extremely sensitive to aconitase blockade. In the first system, adult C57Bl/6 female mice were treated with continuous FA infusion plus bolus intraperitoneal PHZ. FA-treated mice developed a much more severe anemia in response to PHZ than did non-FA-treated mice despite receiving 50% less PHZ. Their anemia showed a lower nadir (red cell count of 3.56 M/ul vs. 4.75 M/ul, p=0.0013, n=6) and a more prolonged trough. Their reticulocytosis was delayed and diminished. In the second system, PV female mice carrying one copy of the JAK2 V617F allele were treated with continuous FA infusion. Decreased red indices were observed by day 11 of treatment, with a decline in hematocrit from 51.3% to 42.5% in PV mice (p=0.0002, n=4), compared with a decline from 44.6% to 37.9% in wild type mice (p=0.04, n=4). No effects were observed on platelet and leukocyte counts. Interestingly, the rate of decrease of the red cell parameters was greater in the PV mice, suggesting that erythropoiesis driven by JAK2 V617F is highly responsive to changes in aconitase activity levels. We conclude that aconitase functions as a modifier of erythroid signaling to regulate proliferation and differentiation. Indeed, our results indicate that aconitase activity regulates steady state, stress, and JAK2 V617F-driven erythropoiesis, most likely through its novel modulation of MEK-ERK signaling. This novel function may provide an alternate targeting strategy in the treatment of Polycythemia vera. Disclosures:No relevant conflicts of interest to declare.

Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera

AbstractInterferon-α (IFN-α) is a nonleukemogenic treatment of polycythemia vera (PV) able to induce cytogenetic remissions. Its use is limited by toxicity, leading to treatment discontinuation in approximately 20% of patients. We completed a phase 2 multicenter study of pegylated IFN-α-2a in 40 PV patients. Objectives included evaluation of efficacy, safety, and monitoring of residual disease using JAK2V617F quantification (%V617F). Median follow-up was 31.4 months. At 12 months, all 37 evaluable patients had hematologic response, including 94.6% complete responses (CRs). Only 3 patients (8%) had stopped treatment. After the first year, 35 patients remained in hematologic CR, including 5 who had stopped pegylated IFN-α-2a. Sequential samples for %V617F monitoring, available in 29 patients, showed %V617F decrease in 26 (89.6%). Median %V617F decreased from 45% before pegylated IFN-α-2a to 22.5%, 17.5%, 5%, and 3% after 12, 18, 24, and 36 months, respectively. Molecular CR (JAK2V617F undetectable) was achieved in 7 patients, lasting from 6+ to 18+ months, and persisted after pegylated IFN-α-2a discontinuation in 5. No vascular event was recorded. These results show that pegylated IFN-α-2a yields high rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutated clone in selected cases. Available at www.clinicaltrials.gov as #NCT00241241.

Diagnosis and treatment of polycythemia vera: Brazilian experience from a single institution.

Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by predominant proliferation of erythroid precursors. Few data are available concerning Brazilian patients with this condition. The aim of this study was to describe clinical and demographic characteristics of PV patients at diagnosis and analyze their long-term outcomes. Retrospective study at the Division of Hematology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo. All consecutive patients with PV diagnosed according to World Health Organization criteria were eligible for this study. Clinical and demographic characteristics, thrombotic events, transformation to acute leukemia, myelofibrosis and survival were evaluated. Sixty-six patients were evaluated. Thirty-six (54.5%) were females, with a median age at diagnosis of 61 years. At diagnosis, the median hemoglobin concentration was 18.8 mg/dl and the median platelet count was 593,000/mm(3). Fifty-eight patients (88.0%) were treated with hydroxyurea with or without phlebotomy. During a median follow-up of 77 months, 22 patients (33.3%) had new thrombotic events, mainly of arterial type. The overall incidence of leukemia and myelofibrosis was 0.42% per patient-year and 1.06% per patient-year, respectively. Median overall survival was not reached and the seven-year survival rate was 77.8%. The PV patients described here had long survival and arterial thrombotic events were the most important and common complication among this population.

Advances in the molecular characterization of Philadelphia-negative chronic myeloproliferative disorders

The identification and characterization of somatic disease alleles have greatly improved our understanding of the molecular pathogenesis of myeloproliferative disorders. This review focuses on recent studies investigating the role of activated tyrosine kinase signaling in the Philadelphia chromosome negative myeloproliferative disorders. Previously identified tyrosine kinase mutations in chronic myeloid leukemia and other myeloproliferative disorders suggested the possibility that polycythemia vera, essential thrombocythemia and primary myelofibrosis are also caused by activated tyrosine kinases. Recent studies identified an activating mutation in the JAK2 tyrosine kinase (JAK2V617F) in most patients with polycythemia vera and in approximately half of those with essential thrombocythemia and primary myelofibrosis. More recently, activating mutations in the thrombopoietin receptor and in JAK2 exon 12 have been identified in JAK2V617F negative myeloproliferative disorders. The discovery of activated tyrosine kinases in the majority of patients with polycythemia vera, essential thrombocythemia and primary myelofibrosis has diagnostic and pathogenetic implications. Subsequent studies are needed to elucidate the cause of myeloproliferative disorders without known disease alleles and to determine if inhibition of JAK2 signaling has therapeutic efficacy in the treatment of polycythemia vera, essential thrombocythemia and primary myelofibrosis.

In the Forefront of Basic and Translational Cancer Research: Seventh Joint Conference of the American Association for Cancer Research and the Japanese Cancer Association

The Seventh Joint Conference of the American Association of Cancer Research and the Japanese Cancer Association, “In the Forefront of Basic and Translational Cancer Research,” held in Waikoloa, HI, on January 21 to 25, 2007, was designed to showcase the latest advances in all major areas of

The treatment of polycythaemia vera: an update in the JAK2 era

The clinical course of polycythaemia vera is marked by a high incidence of thrombotic complications, which represent the main cause of morbidity and mortality. Major predictors of vascular events are increasing age and previous thrombosis. Myelosuppressive drugs can reduce the rate of thrombosis, but there is concern that their use raises the risk of transformation into acute leukaemia. To tackle this dilemma, a risk-oriented management strategy is recommended. Low-risk patients should be treated with phlebotomy and low-dose aspirin. Cytotoxic therapy is indicated in high-risk patients, with the drug of choice being hydroxyurea because its leukaemogenicity is low. The recent discovery of JAK2 V617F mutation in the vast majority of polycythaemia vera patients opens new avenues for the treatment of this disease. Novel therapeutic options theoretically devoid of leukaemic risk, such as alpha-interferon and imatinib, affect JAK2 expression in some patients. Nevertheless, these drugs require further clinical experience and, for the time being, should be reserved for selected cases.

Long‐term effects of the treatment of polycythemia vera with recombinant interferon‐α

Patients with polycythemia vera (PV) are most often treated with phlebotomy-only (PHL-O) or phlebotomy plus hydroxyurea (PHL + HU). Such treatment is often unsatisfactory because of persistent susceptibility to thrombosis owing to inadequate control of abnormal erythropoiesis and thrombopoiesis. Recombinant interferon-alpha (rIFN alpha) inhibits erythroid progenitors and affects megakaryocyte function and thus may be a more effective treatment, but reports of its use have been of relatively short duration. The long-term use (median, 13 years) of rIFN alpha in 55 patients previously treated with PHL alone or with PHL + HU was studied. Data pertaining to the natural history of the disease were also examined. Patients achieved partial response of their disease by 6 months, and complete response by 1-2 years (phlebotomy-free, HCT < or =45%, platelets < or =600,000/microL); spleen size was reduced in 27 of 30 patients with prior splenomegaly. The initial dose of rIFN alpha was 1 mega unit 3 times a week (1 MU/tiw) for the majority of patients, with periodic dose increases as required and as tolerated. The maintenance dose, usually 3 MU/tiw, could be decreased after the second year of treatment in half the patients. Toxicity was acceptable. Disease-free survival was marked by no thrombohemorrhagic complications reflecting both the effect of rIFN alpha and total patient care. Evidence is presented indicating that rIFN alpha effectively reduces PHL requirements, thrombocythemia, splenomegaly, and thrombohemorrhagic events. It is an effective drug for treating PV with acceptable toxicity.

Imatinib mesylate is effective in the treatment of polycythemia vera: A multi-institutional clinical trial

6532 Background: We previously reported that the erythrocytosis of polycythemia vera (PV) was controlled with imatinib mesylate in a cohort of patients. This effect may involve inhibition of tyrosine phosphorylation of c-Kit, the stem cell factor receptor essential for erythroid progenitor cell proliferation. Methods: We report treating an expanded cohort of 37 PV patients with imatinib in a multi-institutional phase II trial. All patients had an increased 51Cr RBC mass determination at diagnosis and fulfilled the stipulated criteria for the diagnosis of PV. Men were initially phlebotomized to a hematocrit (HCT) ≤ 45%; women to HCT ≤ 42%. Imatinib was started at 400 mg qd escalating 100 mg every 2 weeks to a maximum of 800 mg for persistent phlebotomy (PHL) requirements or for platelet counts &gt; 600 × 109/L. All patients received 81 mg of aspirin qd. Results: There were 21 men, 16 women, median age 51 years, range 29–83. Prior to imatinib, mean disease duration was 60.2 mos; average number of PHLs per year ranged from 0–23 (mean=9). After 1 year of imatinib, PHLs ranged from 0 to 9 (mean=2). There were 9 complete remissions (PHL-free, platelets ≤ 600 × 109/L, no splenomegaly) and 10 partial remissions (PHL and/or splenomegaly decreased by 50% of initial values with platelets ≤ 600 × 109/L, or platelets &gt; 600 × 109/L but no PHL requirements or splenomegaly); 1 patient, protocol violation. Thus, of 36 evaluable patients, 19 (53%) responded. Of the remaining 17, 10 failed due to disease progression: myelofibrosis (n=2); platelets &gt; 1,000 × 109/L with PHL and/or splenomegaly (n=2); repeated PHLs (n=1); cytogenetic abnormalities (n=1); increasing thrombocytosis (n=1); and a TIA (n=1). Seven of 17 with no remission developed toxicity: grade 3 dermatologic (n=2); grade 3 diarrhea (n=2); grade 3 bone pain (n=1), liver (n=1); heart failure (n=1). Median treatment duration: 17.2 months. Conclusions: We conclude that imatinib is useful for treating erythrocytosis and controlling splenomegaly in a significant proportion of PV patients, but is less effective for controlling thrombocytosis or splenomegaly in others. These data suggest heterogeneity of hematopoietic stem cell proliferation in PV or patient variability with respect to imatinib metabolism. [Table: see text]