Pegylated interferon Alfa-2a and hydroxyurea in polycythemia vera and essential thrombocythemia: differential cellular and molecular responses.
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SUBMITTER: Tashi T
PROVIDER: S-EPMC6552660 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
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Pegylated interferon Alfa-2a and hydroxyurea in polycythemia vera and essential thrombocythemia: differential cellular and molecular responses.
Tashi Tsewang T Swierczek Sabina S Kim Soo Jin SJ Salama Mohamed E ME Song Jihyun J Heikal Nahla N King Katherine Y KY Hickman Kim K Litton Scott S Prchal Josef T JT
Leukemia 20180228 8
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Project description:Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 months were 69.2% (43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P = .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was -6% (range, -84% to 47%) in patients achieving a CR vs +4% (range, -18% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU. This trial was registered at www.clinicaltrials.gov as #NCT01259856.
| S-EPMC6839950 | biostudies-literature
Project description:PurposeWe conducted a phase II study of pegylated interferon alfa-2a (PEG-IFN-alpha-2a) in patients with essential thrombocythemia (ET) and polycythemia vera (PV).Patients and methodsSeventy-nine patients (40 with PV and 39 with ET) have been treated. Median time from diagnosis to PEG-IFN-alpha-2a was 54 months in patients with PV and 33 months in patients with ET. Eighty-one percent of patients had received prior therapy. The first three patients received PEG-IFN-alpha-2a at 450 microg weekly. As a result of poor tolerance, this dose was decreased in a stepwise manner to a current starting dose of 90 microg weekly. Seventy-seven patients are evaluable and have been observed for a median of 21 months.ResultsThe overall hematologic response rate was 80% in PV and 81% in ET (complete in 70% and 76% of patients, respectively). The JAK2(V617F) mutation was detected in 18 patients with ET and 38 patients with PV; sequential measurements by a pyrosequencing assay were available in 16 patients with ET and 35 patients with PV. The molecular response rate was 38% in ET and 54% in PV, being complete (undetectable JAK2(V617F)) in 6% and 14%, respectively. The JAK2(V617F) mutant allele burden continued to decrease with no clear evidence for a plateau. The tolerability of PEG-IFN-alpha-2a at 90 microg weekly was excellent.ConclusionPEG-IFN-alpha-2a resulted in remarkable clinical activity, high rates of molecular response, and acceptable toxicity in patients with advanced ET or PV. The ability of PEG-IFN-alpha-2a to induce complete molecular responses suggests selective targeting of the malignant clone.
| S-EPMC4881362 | biostudies-literature
Project description:BackgroundPegylated interferon alfa-2a (PEG-IFN-α-2a) is a potent immunomodulating agent capable of inducing high rate of hematologic and even complete molecular remission in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We recently reported results of a phase 2 trial of PEG-IFN-α-2a in 83 patients with ET and PV after a median follow-up of 83 months. Here we report an analysis of bone marrow (BM) responses in these patients.MethodsAmong 83 patients, 58 (70%, PV 25, ET 31) had evaluable BM samples. BM responses and fibrosis grading were defined according to the International Working Group for Myeloproliferative Neoplasms Research and Treatment, and the European Consensus on grading of BM fibrosis, respectively. BM was assessed prior to enrollment, and every 6-24 months while on therapy in all patients, and after therapy discontinuation in some patients.ResultsThe median age of analyzed 58 patients was 52 years, and 29% were males. After a median follow-up of 84 months, 32 patients are still on study. Hematologic (HR) and molecular responses (MR) were seen in 93 and 69% patients, respectively. Twenty-nine patients (50%) had a BM response, including 13 (22%) with a complete BM response (BM-CR). Moreover, 13 patients (22%) have experienced complete resolution of bone marrow reticulin fibrosis. Patients with BM response had higher duration of HR and MR, and lower discontinuation rate. Furthermore, patients with BM-CR had a higher probability of complete MR. The median duration of BM-CR was 30 months, and 9 patients have maintained their BM-CR (69%), including five who have maintained their response after discontinuation of therapy. Despite this observation, the pattern of HR, MR and BM response, their durability and interrelation was heterogeneous.ConclusionsOur results show the ability of PEG-IFN-α-2a to induce complete BM responses in a subset of ET and PV patients, but its correlation with durable clinically relevant treatment benefit warrants further investigation. Trial registration This study is registered with ClinicalTrials.gov (NCT00452023), and is ongoing but not enrolling new patients.
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Project description:The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.
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Project description:AbstractWe report the 2-year end-of-study results from the phase 2 COMBI II clinical trial investigating the combination treatment of ruxolitinib and low-dose pegylated interferon alfa-2a in patients with newly diagnosed polycythemia vera (PV). The primary outcome was safety and key secondary endpoints were efficacy, based on hematologic parameters, quality-of-life measurements, and JAK2V617F variant allele frequency (VAF). We used the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research remission criteria. The remission criteria included remissions in symptoms, splenomegaly, peripheral blood counts, and bone marrow. We included 25 patients with PV with a median age of 70 years; 5 of those had prior thromboembolic events and 3 had computed tomography-verified splenomegaly. Two patients stopped both study drugs; 1 of these due to progression to post-PV myelofibrosis, the only one with a grade 3 infection. No events of herpes zoster infections were observed. None of the patients discontinued treatment due to psychiatric symptoms. The peripheral blood cell count remission rate was 92% at 24 months. Using the 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research remission criteria, 14 (56%) achieved remission at 24 months; 3 (12%) achieved complete remission and 11 (44%) achieved partial remission. The following items from the Myeloproliferative Neoplasm Symptom Total Symptom Score were significantly reduced: abdominal discomfort, night sweats, itching, and bone pain. The median JAK2V617F VAF decreased from 47% (95% confidence interval [CI], 35-59) to 7% (95% CI, 3-15), and 60% of patients achieved molecular remission. In conclusion, combination treatment improved cell counts; bone marrow cellularity, and fibrosis; and decreased JAK2V617F VAF; with acceptable toxicity in patients with PV. The trial was registered at www.clinicaltrialsregister.eu as #EudraCT2018-004150-13.
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Project description:Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells; these include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPNs are inflammatory cancers, wherein the malignant clone generates cytokines that sustain the inflammatory drive in a self-perpetuating vicious cycle. The course of MPNs follows a biological continuum, that is, from early cancer stages (ET/PV) to advanced myelofibrosis as well as impending leukemic transformation. MPN-related symptoms, e.g., fatigue, general weakness, and itching, are caused by inflammatory cytokines. Thrombosis and bleeding are also exacerbated by inflammatory cytokines in patients with MPN. Until recently, the primary objective of ET and PV therapy was to increase survival rates by preventing thrombosis. However, several medications have recently demonstrated the ability to modify the course of the disease; symptom relief is expected for most patients. In addition, there is increasing interest in the active treatment of patients at low risk with PV and ET. This review focuses on the ET/PV treatment strategies as well as novel treatment options for clinical development.
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Project description:Polycythemia vera (PV) is characterized by JAK2 and essential thrombocythemia (ET) by JAK2, calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) mutations; we describe the occurrence and prognostic relevance of DNA sequence variants/mutations other than JAK2/CALR/MPL. A myeloid neoplasm-relevant 27-gene panel was used for next-generation sequencing of bone marrow or whole blood DNA and conventional tools were used for analysis. "Adverse variants/mutations" were identified by age-adjusted multivariable analysis of impact on overall, leukemia-free, or myelofibrosis-free survival. Fifty-three percent of 133 Mayo Clinic patients with PV and 53% of 183 with ET harbored 1 or more sequence variants/mutations other than JAK2/CALR/MPL; the most frequent were TET2 and ASXL1. "Adverse variants/mutations" in PV included ASXL1, SRSF2, and IDH2 and in ET SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2; combined prevalence was 15% and 15%, respectively. Adverse variants/mutations were associated with inferior survival in both PV (median, 7.7 vs 16.9 years) and ET (median, 9 vs 22 years) and the effect was independent of conventional prognostic models with respective hazard ratio (95% confidence interval) of 2.8 (1.5-5.1) and 2.6 (1.4-4.8); these observations were validated in 215 Italian patients with PV and 174 with ET. In both Mayo Clinic and Italian cohorts, leukemic or fibrotic progression was also predicted by adverse variants/mutations. Number of mutations did not provide additional prognostic information. We conclude that targeted deep sequencing in PV and ET allows for genetic risk stratification that is independent of clinically derived prognostic models.
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Project description:Data on the efficacy and safety of interferon (IFN)-α for the treatment of essential thrombocythemia (ET) and polycythemia vera (PV) are inconsistent. We conducted a systematic review and meta-analysis and searched MEDLINE and EMBASE via Ovid, Scopus, COCHRANE registry of clinical trials, and Web of Science from inception through 03/2019 for studies of pegylated IFN (peg-IFN) and non-pegylated IFN (non-peg-IFN) in PV and ET patients. Random-effects models were used to pool response rates for the primary outcome of overall response rate (ORR) defined as a composite of complete response, partial response, complete hematologic response (CHR) and partial hematologic response. Peg-IFN and non-peg-IFN were compared by meta-regression analyses. In total, 44 studies with 1359 patients (730 ET, 629 PV) were included. ORR were 80.6% (95% confidence interval: 76.6-84.1%, CHR: 59.0% [51.5%-66.1%]) and 76.7% (67.4-84.0%; CHR: 48.5% [37.8-59.4%]) for ET and PV patients, respectively. In meta-regression analyses results did not differ significantly for non-peg-IFN vs. peg-IFN. Annualized rates of thromboembolic complications and treatment discontinuation due to adverse events were low at 1.2% and 8.8% for ET and 0.5% and 6.5% for PV patients, respectively. Both peg-IFN and non-peg-IFN can be effective and safe long-term treatments for ET and PV.
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Project description:Polycythemia vera (PV) and essential thrombocythemia (ET) are both driven by JAK-STAT pathway activation and consequently much of the recent research efforts to improve the management and outcomes of patients with these neoplasms have centered around inhibition of this pathway. In addition to newer JAK inhibitors and improved interferons, promising novel agents exploiting a growing understanding of PV and ET pathogenesis and disease evolution mechanisms are being developed. These agents may modify the disease course in addition to cytoreduction. Histone deacetylase, MDM2 and telomerase inhibitors in patients with PV/ET have demonstrated clinically efficacy and serve as chief examples. Hepcidin mimetics, limiting iron availability to red blood cell precursors, offer an exciting alternative to therapeutic phlebotomy and have the potential to revolutionize management for patients with PV. Many of these newer agents are found to improve hematologic parameters and symptom burden, but their role in thrombotic risk reduction and disease progression control is currently unknown. The results of larger, randomized studies to confirm the early efficacy signals observed in phase 1/2 trials are eagerly awaited.
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Project description:Polycythemia vera (PV) and essential thrombocythemia (ET) are both classic, relatively indolent, chronic Philadelphia-chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) characterized by elevated blood counts, thrombotic as well as hemorrhagic tendencies, a variety of symptoms, cumulative risks of progression to myelofibrosis and transformation to acute myeloid leukemia over time, and long survival. Molecularly, PV is more homogenous, being driven by JAK2 mutations in virtually all cases, while ET can be JAK2-, CALR-, or MPL-mutated, as well as 'triple negative'. Recent targeted next-generation sequencing efforts have identified other, nondriver gene mutations, some with prognostic relevance. Prevention of thrombotic and hemorrhagic complications continues to be the major focus of management, although symptoms are increasingly being recognized as a relatively unmet need, particularly in ET. Thrombotic risk stratification in PV is still based on age and history of thrombosis, while in ET, the additional contribution of JAK2 V617F to thrombotic risk is now well established. The associations of leukocytosis with clotting risk (in both conditions) and mortality (in PV) have drawn increased attention with the availability of ruxolitinib as a second-line treatment in PV. Similarly, there is a renewed interest in interferons with the emergence of ropeginterferon alfa-2b as a potential new frontline treatment option in PV. Drug development is more difficult in ET, the most indolent of the classic Ph- MPNs, but ruxolitinib is being studied. Triggering apoptosis via the p53 pathway through pharmacologic inhibition of human double minute 2 (and synergism with interferon) is a new, promising therapeutic strategy.
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