A prospective evaluation of pegylated interferon alfa-2a therapy in patients with polycythemia vera and essential thrombocythemia with a prior splanchnic vein thrombosis

Mascarenhas, John; Kosiorek, Heidi E.; Prchal, Josef T.; Yacoub, Abdulraheem; Berenzon, Dmitriy; Ritchie, Ellen K.; Silver, Richard T.; Kessler, Craig M.; Winton, Elliott F.; Finazzi, Maria Chiara; Vannucchi, Alessandro M.; Leibowitz, D; Rondelli, Damiano; Arcasoy, Murat O.; Catchatourian, Rosalind; Vadakara, Joseph; Rosti, Vittorio; Hexner, Elizabeth O.; Kremyanskaya, Marina; Sandy, Lonette; Tripodi, Joseph; Najfeld, Vesna; Farnoud, Noushin; Salama, M.; Weinberg, Rona Singer; Rampal, Raajit K.; Goldberg, Judith D.; Mesa, Ruben A.; Dueck, Amylou C.; Hoffman, Ronald

doi:10.1038/s41375-019-0524-7

Cited by 22 publications

(18 citation statements)

References 15 publications

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“…We previously showed that treatment with IFN-a reduces tumor necrosis factor a expression levels, 63 which is 1 of the target genes of NF-kB, 64 and IRAK1 regulates the NF-kB signaling pathway. 65 These data are supported by the multicenter phase 3 trials 66,67 and by our previous study, 63 which failed to confirm the expected superiority of IFN-a over hydroxyurea. Antiinflammatory agents, aspirin, and statin treatment may change these gene transcript levels.…”

Section: Discussionmentioning

confidence: 79%

Thrombotic, inflammatory, and HIF-regulated genes and thrombosis risk in polycythemia vera and essential thrombocythemia

et al. 2020

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Thrombosis is a major cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET). The pathophysiology of thrombosis in these disorders remains unclear, and we hypothesized that upregulation of thrombotic, inflammatory, and hypoxia-inducible factor (HIF)–regulated genes may play a role in it. We performed unbiased RNA sequencing in granulocytes and platelets of PV patients and found differential expression of several thrombotic, inflammatory, and HIF-regulated genes. The expression of many of these genes positively correlated with JAK2 expression and JAK2V617F allelic burden. We then validated these findings by quantitative polymerase chain reaction analyses of selected gene transcripts in a larger number of PV and ET granulocytes and platelets (58 patients) and in 28 controls, and we compared these findings in patients with and without thrombosis. The study included 29 females and 29 males; of these, 28 had a history of thrombosis. We found that transcripts of several selected genes were upregulated in patients with PV or ET compared with controls. In granulocytes, the expression levels of F3, SELP, VEGFA, and SLC2A1 were significantly higher in patients with a history of thrombosis compared with those who did not have thrombosis. Patients with a history of thrombosis have significantly higher expression of IL1RAP (P < .05) in platelets compared with those without thrombosis. Our study confirms the presence of a thrombo-inflammatory state and augmented HIF activity in PV and ET and its role in thrombosis. These data may provide the background for targeted therapies in PV and ET.

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Section: Discussionmentioning

confidence: 79%

Thrombotic, inflammatory, and HIF-regulated genes and thrombosis risk in polycythemia vera and essential thrombocythemia

et al. 2020

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“…In the subset of ET and PV patients with splanchnic vein thrombosis, Mascerenhas et al recently showed in a prospective phase II study of 20 ET and PV patients with prior splanchnic vein thrombosis treated with peg-IFN alfa-2a that 15% and 55% of patients achieved a CR and PR, respectively, after 12 months of therapy and none of the patients developed a recurrent splanchnic vein thrombosis. 66 However, it is important to note that 18 out of 20 patients received either ASA, anticoagulation (coumadin or low molecular weight heparin), or a combination of both, as well. 66 Therefore, the effect of IFN on thrombosis risk and its role in combination with ASA or anticoagulation warrants further studies.…”

Section: Discussionmentioning

confidence: 99%

“… 66 However, it is important to note that 18 out of 20 patients received either ASA, anticoagulation (coumadin or low molecular weight heparin), or a combination of both, as well. 66 Therefore, the effect of IFN on thrombosis risk and its role in combination with ASA or anticoagulation warrants further studies.…”

Section: Discussionmentioning

confidence: 99%

Interferon alpha therapy in essential thrombocythemia and polycythemia vera—a systematic review and meta-analysis

et al. 2020

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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 (CENTRAL), 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. 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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“…A cohort of patients in this trial included 20 PV or essential thrombocythemia patients who had a history of SVT and who were required not to have had prior therapy with hydroxyurea. After 12 months of peginterferon therapy, the overall response rate was 70%, and none of the patients had a recurrence of SVT after a median follow-up of 2.2 years 31 . In a phase 3 randomized trial of peginterferon versus hydroxyurea in 168 high-risk patients with PV and essential thrombocythemia, peginterferon complete response rates were similar for the two treatment groups at 12 and 24 months, and peginterferon had a higher rate of grade 3/4 toxicity 32 .…”

Section: Novel Therapeutic Avenues In Polycythemia Veramentioning

confidence: 94%

Recent advances in prognostication and treatment of polycythemia vera

Marcellino¹,

Hoffman²

2021

Fac Rev

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Polycythemia vera (PV) is a BCR-ABL –negative myeloproliferative neoplasm marked by acquisition of an activating mutation of JAK2 , which leads to not only erythrocytosis but also frequently to leukocytosis and thrombocytosis, and is associated with a high symptom burden and increased thrombotic risk. PV has the potential to progress to myelofibrosis or an aggressive form of acute myeloid leukemia. Mutational profiling of patients with PV has led to the development of risk stratification tools to determine an individual’s risk of developing progressive disease. Although the current goals of PV treatment are to alleviate symptoms and reduce thrombotic risk, there are growing efforts to identify disease-modifying agents which will also prevent progression of disease. Here, we give an overview of the developing prognostic tools and therapeutic landscape for PV, focusing on four drug classes: pegylated interferon-alpha 2, MDM2 antagonists, hepcidin mimetics, and histone deacetylase inhibitors.

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A prospective evaluation of pegylated interferon alfa-2a therapy in patients with polycythemia vera and essential thrombocythemia with a prior splanchnic vein thrombosis

Cited by 22 publications

References 15 publications

Thrombotic, inflammatory, and HIF-regulated genes and thrombosis risk in polycythemia vera and essential thrombocythemia

Thrombotic, inflammatory, and HIF-regulated genes and thrombosis risk in polycythemia vera and essential thrombocythemia

Interferon alpha therapy in essential thrombocythemia and polycythemia vera—a systematic review and meta-analysis

Recent advances in prognostication and treatment of polycythemia vera

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