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Molecular responses and chromosomal aberrations in patients with polycythemia vera treated with peg-proline-interferon alpha-2b.

ABSTRACT: Fifty-one polycythemia vera (PV) patients were enrolled in the phase I/II clinical study PEGINVERA to receive a new formulation of pegylated interferon alpha (peg-proline-IFN?-2b, AOP2014/P1101). Peg-proline-IFN?-2b treatment led to high response rates on both hematologic and molecular levels. Hematologic and molecular responses were achieved for 46 and 18 patients (90 and 35% of the whole cohort), respectively. Although interferon alpha (IFN?) is known to be an effective antineoplastic therapy for a long time, it is currently not well understood which genetic alterations influence therapeutic outcomes. Apart from somatic changes in specific genes, large chromosomal aberrations could impact responses to IFN?. Therefore, we evaluated the interplay of cytogenetic changes and IFN? responses in the PEGINVERA cohort. We performed high-resolution SNP microarrays to analyze chromosomal aberrations prior and during peg-proline-IFN?-2b therapy. Similar numbers and types of chromosomal aberrations in responding and non-responding patients were observed, suggesting that peg-proline-IFN?-2b responses are achieved independently of chromosomal aberrations. Furthermore, complete cytogenetic remissions were accomplished in three patients, of which two showed more than one chromosomal aberration. These results imply that peg-proline-IFN?-2b therapy is an effective drug for PV patients, possibly including patients with complex cytogenetic changes.

SUBMITTER: Them NC

PROVIDER: S-EPMC4657499 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Molecular responses and chromosomal aberrations in patients with polycythemia vera treated with peg-proline-interferon alpha-2b.

Them Nicole C C NC Bagienski Klaudia K Berg Tiina T Gisslinger Bettina B Schalling Martin M Chen Doris D Buxhofer-Ausch Veronika V Thaler Josef J Schloegl Ernst E Gastl Guenther A GA Wolf Dominik D Strecker Karin K Egle Alexander A Melchardt Thomas T Burgstaller Sonja S Willenbacher Ella E Zagrijtschuk Oleh O Klade Christoph C Greil Richard R Gisslinger Heinz H Kralovics Robert R

American journal of hematology 20150302 4

Fifty-one polycythemia vera (PV) patients were enrolled in the phase I/II clinical study PEGINVERA to receive a new formulation of pegylated interferon alpha (peg-proline-IFNα-2b, AOP2014/P1101). Peg-proline-IFNα-2b treatment led to high response rates on both hematologic and molecular levels. Hematologic and molecular responses were achieved for 46 and 18 patients (90 and 35% of the whole cohort), respectively. Although interferon alpha (IFNα) is known to be an effective antineoplastic therapy ...[more]

PMID: 25545244

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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.

Project description:The first clinical trials of the safety and efficacy of interferon-alpha2 (IFN-alpha2) were performed about 30 years ago. Since then, several single-arm studies have convincingly demonstrated that IFN-alpha2 is a highly potent anti-cancer agent in several cancer types but unfortunately not being explored sufficiently due to a high toxicity profile when using non-pegylated IFN-alpha2 or high dosages or due to competitive drugs, that for clinicians at first glance might look more attractive. Within the hematological malignancies, IFN-alpha2 has only recently been revived in patients with the Philadelphia-negative myeloproliferative neoplasms-essential thrombocytosis, polycythemia vera, and myelofibrosis (MPNs)-and in patients with chronic myelogenous leukemia (CML) in combination with tyrosine kinase inhibitors. In this review, we tell the IFN story in MPNs from the very beginning in the 1980s up to 2018 and describe the perspectives for IFN-alpha2 treatment of MPNs in the future. The mechanisms of actions are discussed and the impact of chronic inflammation as the driving force for clonal expansion and disease progression in MPNs is discussed in the context of combination therapies with potent anti-inflammatory agents, such as the JAK1-2 inhibitors (licensed only ruxolitinib) and statins as well. Interferon-alpha2 being the cornerstone treatment in MPNs and having the potential of inducing minimal residual disease (MRD) with normalization of the bone marrow and low-JAK2V617F allele burden, we believe that combination therapy with ruxolitinib may be even more efficacious and hopefully revert disease progression in many more patients to enter the path towards MRD. In patients with advanced and transforming disease towards leukemic transformation or having transformed to acute myeloid leukemia, "triple therapy" is proposed as a novel treatment modality to be tested in clinical trials combining IFN-alpha2, DNA-hypomethylator, and ruxolitinib. The rationale for this "triple therapy" is given, including the fact that even in AML, IFN-alpha2 as monotherapy may revert disease progression. We envisage a new and bright future with many more patients with MPNs obtaining MRD on the above therapies. From this stage-and even before-vaccination strategies may open a new horizon with cure being the goal for some patients.

Dataset Information

Molecular responses and chromosomal aberrations in patients with polycythemia vera treated with peg-proline-interferon alpha-2b.

Publications

Molecular responses and chromosomal aberrations in patients with polycythemia vera treated with peg-proline-interferon alpha-2b.

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