scholarly journals Pegylated Interferon Alpha-2b in Patients With Polycythemia Vera and Essential Thrombocythemia in the Real World

2021 ◽  
Vol 11 ◽  
Author(s):  
Yingxin Sun ◽  
Yifeng Cai ◽  
Jiannong Cen ◽  
Mingqing Zhu ◽  
Jinlan Pan ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Real World ◽  
Myeloproliferative Neoplasms ◽  
Pegylated Interferon ◽  
Molecular Response ◽  
The Real ◽  
Entire Cohort ◽  
Interferon Alpha 2B ◽  
Ifn Treatment

Several clinical trials have shown promising efficacy of pegylated interferon (Peg-IFN) in the first- and second-line polycythemia vera (PV) and essential thrombocythemia (ET). However, the efficacy and safety of Peg-IFN in the real world have rarely been reported. Hence, we conducted a prospective, single-center, single-arm, open exploratory study, which aimed to explore the hematologic response, molecular response, safety, and tolerability of patients with PV and ET treated with Peg-IFN in the real world. This study included newly diagnosed or previously treated patients with PV and ET, aged 18 years or older, admitted to the Department of Hematology of the First Affiliated Hospital of Soochow University from November 2017 to October 2019. The results revealed that complete hematological response (CHR) was achieved in 66.7% of patients with PV and 76.2% of patients with ET, and the molecular response was obtained in 38.5% of patients with PV and 50% of patients with ET after 48 weeks of Peg-IFN treatment. Peg-IFN is safe, effective and well tolerated in most patients. In the entire cohort, 4 patients (9.1%) discontinued treatment due to drug-related toxicity. In conclusion, Peg-IFN is a promising strategy in myeloproliferative neoplasms (MPNs), and Peg-IFN alone or in combination with other drugs should be further explored to reduce treatment-related toxicity and improve tolerability.

Pegifna Promotes Proliferation and Myeloid Differentiation In Human Hematopoietic Progenitors In Patients With Polycythemia Vera and Essential Thrombocythemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2843-2843
Author(s):  
Katherine King ◽  
Sabina Swierczek ◽  
Katie Matatall ◽  
Kimberly Hickman ◽  
Margaret A. Goodell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Pegylated Interferon ◽  
Hematopoietic Stem ◽  
Financial Compensation ◽  
Specific Differentiation ◽  
Allelic Burden

Abstract The myeloproliferative neoplasms, polycythemia vera (PV) and essential thrombocythemia (ET), are characterized by clonal hematopoiesis that is often associated with a JAK2V617F mutation, although this does not appear to be a disease-initiating event. Treatment of PV and ET with pegylated interferon-alpha (pegInfα) has been shown to lead to hematological remission, a decrease in the JAK2V617F allelic burden in many cases, and even a reversion to polyclonal hematopoiesis. Despite promising therapeutic results, the mechanism of pegInfα-induced remission remains elusive. There are several potential mechanisms through which pegInfα may be acting, which include stimulating the immune system in order to more effectively suppress the aberrant PV clones, enhancing the activation of normal hematopoietic stem cells (HSCs), or by selectively suppressing the mutant clones. It has been previously reported that PV patients on pegInfα have an increased number of CD4+CD25+Foxp3+ T regulatory cells (Tregs) in the peripheral blood as compared to untreated or hydroxyurea treated patients (Riley Blood, 2011), which suggests that PegIFNa maybe altering immunity against the mutated clone. However, we have found that interferon treatment leads to increased proliferation of HSCs and myeloid-specific differentiation in mice (Baldridge Nature, 2010). If this finding is also true in humans, it suggests the return to polyclonality after pegInfα could also involve an increase in normal HSC proliferation. In order to address this question, we are studying the effects of pegInfα treatment on the Tregs and HSCs of PV and EV patients, when compared to hydroxyurea or untreated patients. Previously we showed that pegInfα treatment reduced the JAK2V617F allelic burden in 17 out of 32 patients. Of the 13 female patients for which clonality could be assessed, one developed polyclonal hematopoiesis with three-fold reduction of JAK2V617F allelic burden, but one developed polyclonal hematopoiesis during therapy despite no reduction in the JAK2V617F allelic burden, suggesting that pegInfα treatment is able to affect both pre-JAK2V617F clones and JAK2V617F-positive PV clones. We have now assessed changes in the HSC population in response to pegInfα treatment. Upon analysis of bone marrow samples from these same pegInfα or hydroxyurea treated patients, we found that the number of HSCs (CD45+CD34+CD38-) was increased in patients treated with pegInfα. Further we saw a decrease in the percent of quiescent HSCs in the pegInfα treated samples, measured by the percentage of cells in G0, suggesting a more actively proliferating HSC population. In agreement with these data, our RNA analysis of the HSCs showed an increase in the expression of cell cycle genes in response to short-term pegInfα treatment. In addition to this apparent increase in HSC proliferation, we also saw an increase in the number of colonies formed in methocult media from the bone marrow samples of the pegInfα treated patients, suggesting an increase in myeloid specific differentiation. When we analyzed the RNA of patients who had received long-term pegInfα treatment, we saw a transcriptional profile that was indicative of cell death. Taken together, these data suggest a model in which pegInfα treatment is allowing for a return to polyclonal hematopoiesis by inducing cell division and differentiation of normal HSCs, while suppressing the pre-JAK2V617F or JAK2V617F-positive PV and ET clones, possibly by promoting apoptosis or inducing an immune-mediated cell death. Our findings do not exclude other potential mechanisms for salutary effects of pegInfα for treatment of PV and ET (see accompanying abstract by Swierczek et al). Disclosures: Swierczek: University of Utah: No financial compensation , No financial compensation Patents & Royalties.

scholarly journals Pegylated Interferon Alfa-2a Yields High Rates of Hematologic and Molecular Response in Patients With Advanced Essential Thrombocythemia and Polycythemia Vera

2009 ◽  
Vol 27 (32) ◽  
pp. 5418-5424 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Taghi Manshouri ◽  
Rajyalakshmi Luthra ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Response Rate ◽  
Pegylated Interferon ◽  
Interferon Alfa ◽  
Clinical Activity ◽  
Molecular Response ◽  
Prior Therapy ◽  
Poor Tolerance ◽  
Pegylated Interferon Alfa

Purpose We conducted a phase II study of pegylated interferon alfa-2a (PEG-IFN-α-2a) in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Patients and Methods Seventy-nine patients (40 with PV and 39 with ET) have been treated. Median time from diagnosis to PEG-IFN-α-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-α-2a at 450 μg weekly. As a result of poor tolerance, this dose was decreased in a stepwise manner to a current starting dose of 90 μg weekly. Seventy-seven patients are evaluable and have been observed for a median of 21 months. Results The overall hematologic response rate was 80% in PV and 81% in ET (complete in 70% and 76% of patients, respectively). The JAK2V617F 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 JAK2V617F) in 6% and 14%, respectively. The JAK2V617F mutant allele burden continued to decrease with no clear evidence for a plateau. The tolerability of PEG-IFN-α-2a at 90 μg weekly was excellent. Conclusion PEG-IFN-α-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-α-2a to induce complete molecular responses suggests selective targeting of the malignant clone.

Use of pegylated interferon in young patients with polycythemia vera and essential thrombocythemia

2020 ◽  
Author(s):  
Nicole Kucine ◽  
Shayla Bergmann ◽  
Spencer Krichevsky ◽  
Devin Jones ◽  
Michael Rytting ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Young Patients ◽  
Pegylated Interferon

Pilot study of pegylated interferon-alpha 2b in patients with essential thrombocythemia

2003 ◽  
Vol 51 (1) ◽  
pp. 81-86 ◽  
Author(s):  
Yesid Alvarado ◽  
Jorge Cortes ◽  
Srdan Verstovsek ◽  
Deborah Thomas ◽  
Stephan Faderl ◽  
...  
Keyword(s):  
Pilot Study ◽  
Interferon Alpha ◽  
Essential Thrombocythemia ◽  
Pegylated Interferon ◽  
Pegylated Interferon Alpha ◽  
Interferon Alpha 2B

scholarly journals Clonal Dynamics of JAK2V617F and Non-Driver Mutations in Polycythemia Vera and Essential Thrombocythemia Patients Receiving Hydroxyurea Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3623-3623
Author(s):  
Lierni Fernández-Ibarrondo ◽  
Joan Gibert ◽  
Concepción Fernández-Rodríguez ◽  
Laura Camacho ◽  
Anna Angona ◽  
...  
Keyword(s):  
Dna Repair ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Evolutionary Dynamics ◽  
Driver Mutations ◽  
Molecular Response ◽  
Increased Risk ◽  
Cytoreductive Treatment ◽  
Allelic Burden

Abstract Introduction : Hydroxyurea (HU) is the most widely used cytoreductive treatment for patients with essential thrombocythemia (ET) and polycythemia vera (PV) at high risk of thrombosis. It remains unknown whether long-term HU therapy modulates or promotes the acquisition of mutations in non-driver (ND) genes, especially, when assessing hematological (HR) and molecular (MR) response. The objective of the study was to analyze the clonal dynamics of ND genes in HR and MR with HU in a cohort of JAK2V617F-mutated PV and ET patients. Method s: The study included 144 JAK2V617F positive patients (PV n = 73, TE n = 71) receiving HU as first-line cytoreductive treatment. The baseline sample (before HU treatment) and at the timepoint of best molecular response to JAK2V617F were analyzed. The allelic burden of J AK2V617F was assessed by allele-specific PCR and the mutational profile of ND genes was analyzed by next generation sequencing with a custom panel including 27 myeloid-associated genes. HR was defined according to the criteria of the European LeukemiaNet 2009 and MR of JAK2V617F was defined as complete, major, partial and no response (Table I). Results : Median molecular follow-up was 54.1 months for PV and 55.5 months for ET. Patients with PV were more likely to be males (p<0.001), and displayed higher leukocyte count (p<0.001) compared to those with ET. The respective numbers of deaths, leukemic transformations and fibrotic progressions were: 22 (30%), 4 (5%), 6 (8%) for PV cases, and 19 (27%), 1 (1%), 0 (0%) for ET patients. At baseline, a total of 62 somatic mutations in ND genes were detected in 42/73 (57%) PV patients while 58 were detected in 36/71 (51%) ET patients. Complete HR was observed in 102 patients: 44 (60%) PV and 58 (81%) ET. Partial MR in 67 cases: 35 (48%) PV and 32 (45%) ET and major or complete MR in 21 cases: 8 (11%) PV and 13 (18%) ET. The median duration of HU treatment was 45.8 months (range: 17.5-189.5) for PV and 45.6 months (range: 14.6-168.6) for ET. The most frequently mutated genes detected at pre-therapy samples were TET2 (34%), ASXL1 (12%), SF3B1 (7%) and EZH2 (5%) in PV patients, and TET2 (34%), ASXL1 (13%), DNMT3A (13 %) and SRSF2 (5%) in ET patients. No significant differences were observed in the MR (p=0.358) or HR (p=0.917) according to the presence or absence of mutations in ND genes at baseline. Clonal dynamics of DNMT3A, ASXL1, and TET2 (DAT) genes were not modulated by HU therapy to the same extent as JAK2V617F. Disappearance and emergence of additional mutations in DAT genes were observed independently of the molecular response achieved by the JAK2V617F clone. These findings suggest the existence of clones with mutations in ND genes independent from the pathogenic driver clone, and the lack of modulation by HU treatment. Finally, an increase of allelic burden or the appearance of mutations in TP53, a gene related to progression, and in other DNA repair genes (PPM1D and CHEK2) was observed in 14 (19.1%) PV patients and 9 (12.6%) ET cases during HU treatment. However, no increased risk of myelofibrotic transformation or progression to acute myeloid leukemia was observed in these patients. Conclusion s: Pre-treatment ND mutations are not associated with HR and MR to HU in JAK2V617F-mutated patients. 2. The clonal dynamics of ND mutations (decrease, increase, appearance, disappearance) are not related to the evolutionary dynamics of JAK2V617F. 3. An increase or appearance of progression-related mutations in TP53 and/or other genes of the DNA repair pathway such as CHEK2 and PPM1D is observed during HU treatment. Acknowledgments : Instituto de Salud Carlos III-FEDER, PI16/0153, PI19/0005, 2017SGR205, PT20/00023 and XBTC. Figure 1 Figure 1. Disclosures Salar: Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Research Funding; Celgene: Consultancy, Speakers Bureau. Besses: Gilead: Research Funding. Bellosillo: Thermofisher Scientific: Consultancy, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau.

scholarly journals Germline Genetic Factors Influence Outcome of Interferon Alpha Therapy in Polycythemia Vera

Blood ◽  
2020 ◽  
Author(s):  
Roland Jäger ◽  
Heinz Gisslinger ◽  
Elisabeth Fuchs ◽  
Edith Bogner ◽  
Jelena D. Milosevic Feenstra ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Interferon Alpha ◽  
Genetic Factors ◽  
Myeloproliferative Neoplasms ◽  
Association Studies ◽  
Study Cohort ◽  
Molecular Response ◽  
Genome Wide Association Studies ◽  
Association Analyses ◽  
Genome Wide

Interferon alpha (IFNα) based therapies can induce hematologic and molecular responses in polycythemia vera (PV); however, patients do not respond equally. Germline genetic factors have previously been implicated in differential drug response. We addressed the effect of common germline polymorphisms on hematologic and molecular response (HR/MR) in PV therapy within the PROUD-PV and CONTINUATION-PV studies including 122 patients with PV receiving ropeginterferon alfa-2b. Genome-wide association studies using longitudinal data on HR and MR over 36 months follow-up did not reveal any associations at genome-wide significance. Further, 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 therapy of myeloproliferative neoplasms. While we did not observe any association of IFNL4 polymorphisms with HR in our study cohort, we demonstrated a statistically significant effect of the functionally causative IFNL4 diplotype (haplotype pair including the protein-coding variants rs368234815/rs117648444) on MR (p=3.91x10-4; OR=10.80; 95%CI:[2.39-69.97]) as reflected in differential JAK2V617F mutational burden changes according to IFNL4 diplotype status. Stratification of PV patients based on IFNL4 functionality may allow for optimizing patient management during IFNα treatment.

scholarly journals Leukocytosis and thrombosis in essential thrombocythemia and polycythemia vera: a systematic review and meta-analysis

2019 ◽  
Vol 3 (11) ◽  
pp. 1729-1737 ◽  
Author(s):  
Alessandra Carobbio ◽  
Alberto Ferrari ◽  
Arianna Masciulli ◽  
Arianna Ghirardi ◽  
Giovanni Barosi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Blood Cell ◽  
Polycythemia Vera ◽  
White Blood Cell ◽  
Essential Thrombocythemia ◽  
Recurrent Events ◽  
Myeloproliferative Neoplasms ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Cell Counts

Abstract In the last years, a growing amount of evidence has been produced regarding the role of leukocytosis as a risk factor for thrombosis in patients with myeloproliferative neoplasms, predominantly in polycythemia vera (PV) and essential thrombocythemia (ET). Results from epidemiologic studies on this issue, however, are inconclusive. We conducted a systematic review and meta-analysis of articles published in the last 12 years addressing the issue, according to a predefined protocol. Forty-one articles analyzing >30 000 patients met our inclusion criteria and were deemed of acceptable methodologic quality. In addition to data on thrombosis, data were collected on bleeding, hematologic evolution, secondary cancer, and death. The relative risk (RR) of thrombosis in the presence of leukocytosis was 1.59 (95% CI, 1.40-1.80), mainly accounted for by ET (RR, 1.65; 95% CI, 1.43-1.91) and arterial thrombosis (RR, 1.45; 95% CI, 1.13-1.86) subgroups; the effect was not significant in venous thrombosis alone. Sensitivity analyses considering recurrent events as well as white blood cell estimates adjusted or unadjusted for confounding factors confirmed the primary results. In addition, the pooled RR of studies that tested white blood cell counts in time-dependent models suggested a causative effect of leukocytes in the mechanism that triggers thrombosis. The effect of leukocytosis on bleeding (RR, 1.87; 95% CI, 1.26-2.77) and death (RR, 1.89; 95% CI, 1.59-2.23) was confirmed, whereas conclusions on hematologic evolutions and solid tumors were uncertain. To confirm the accuracy of these results, an investigation on individual patient data in a large collective archive of homogeneous patients is warranted.

scholarly journals Outcome of Pregnancy in the Era of Pegylated Interferon Alpha 2a in Females with Essential Thrombocythemia: An Experience from Qatar

2020 ◽  
Vol 13 (1) ◽  
pp. 336-340
Author(s):  
Mohammad Abu-Tineh ◽  
Nancy Kassem ◽  
Mohammad Abdul-Jaber Abdulla ◽  
Omar Mohammad Ismail ◽  
Rola Ghasoub ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Pegylated Interferon ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Pegylated Interferon Alpha ◽  
Pregnant Females ◽  
Increased Risk ◽  
Hemorrhagic Complications

Myeloproliferative neoplasms are a diversified group of diseases of the hematopoietic stem cell, such as essential thrombocythemia (ET) and polycythemia vera. They are mainly caused by mutations in the following genes: JAK2, CALR, and MPL. All carry an increased risk to transform into acute leukemia or chronic myelogenous leukemia along with thrombosis and hemorrhagic complications. Treatment of such disorders during pregnancy is a challenging footstep, given the high risk of complications for both the mother and the fetus. Here, we report about two pregnant females with ET that has been treated with pegylated interferon alpha with safe and effective outcome.

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