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Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera.

ABSTRACT: We conducted a phase II study of pegylated interferon alfa-2a (PEG-IFN-alpha-2a) in patients with essential thrombocythemia (ET) and polycythemia vera (PV).Seventy-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.The 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.PEG-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.

SUBMITTER: Quintas-Cardama A

PROVIDER: S-EPMC4881362 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera.

Quintás-Cardama Alfonso A Kantarjian Hagop H Manshouri Taghi T Luthra Rajyalakshmi R Estrov Zeev Z Pierce Sherry S Richie Mary Ann MA Borthakur Gautam G Konopleva Marina M Cortes Jorge J Verstovsek Srdan S

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20091013 32

<h4>Purpose</h4>We conducted a phase II study of pegylated interferon alfa-2a (PEG-IFN-alpha-2a) in patients with essential thrombocythemia (ET) and polycythemia vera (PV).<h4>Patients and methods</h4>Seventy-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 4 ...[more]

PMID: 19826111

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Project description:Background:Pegylated interferon alfa-2a (PEG-IFN-?-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-?-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. Methods:Among 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. Results:The 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. Conclusions:Our results show the ability of PEG-IFN-?-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.

Project description:BACKGROUND:Pegylated-interferon alpha (PegINF?) treatment of patients with polycythemia vera (PV) and essential thrombocythemia (ET) has resulted in long-term clinical response, decreased JAK2V617F allelic burden and restoration of polyclonal hematopoiesis. The mechanisms of the beneficial effects of PegINF? are not clear, but available evidence suggests direct suppression of JAK2-mutated clone, induction of dormant stem cells to proliferation, and augmentation of an immune effect against PV and ET clones. METHODS:We analyzed the phenotype and frequency of peripheral blood lymphocytes (PBL) from PegINF? treated patients and compared them to patients treated with hydroxyurea (HU). Samples collected at various time points before and during treatment were analyzed using multicolor flow cytometry. RESULTS:We found that PegINF? increased the frequency of peripheral blood CD4+ Foxp3+ regulatory T cells (Treg). Highly suppressive Treg, characterized by co-expression of CD39 and HLA-DR, were also increased in PBL from PegINF? treated patients. We observed an augmentation of cycling CD8+ T cells, NK cells, and of poorly activated CD38+CD8+ T cells. Our results also suggest that PegINF? increased the frequency of PD-1+ CD4+ helper cells and PD-1+ CD4+ Foxp3+ Treg cells. None of these changes were present in HU treated patients. We analyzed the correlation between changes in different T cell populations in the peripheral blood with the changes in JAK2V617F allelic burden in clonal granulocytes. Augmentation of Ki-67+ Treg, HLA-DR+ CD39+ Treg, Helios+ Treg and HLA-DR+ CD38+ CD8+ T cells correlated with an increase in JAK2V617F allelic burden. We also found a positive correlation between PD-1+ Treg and JAK2V617F allelic burden; however, the number of available patients was small (n = 7). CONCLUSIONS:We report marked changes in frequencies of PBL subsets after PegINF? treatment, suggesting an immunomodulatory effect by PegINF?. Generation of a more suppressive immune response, as measured by an increase in highly suppressive Treg and poorly activated CD8+ T cells, correlated with a poor molecular response. In this study, we have not identified changes in the PBL that would indicate the presence of an effective anti-tumor response.Trial registration NCT01259856, December 7. 2010 and NCT01259817, December 6. 2010, Grant #1P01CA108671-O1A2, July 17. 2006, Sponsor: MPDRC/NIH, NCI-2012-00269, January 12. 2011 and NCI-2012-00268, January 12. 2011.

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Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera.

Publications

Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera.

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