Interferon α-2b gains high sustained response therapy for advanced essential thrombocythemia and polycythemia vera with JAK2V617F positive mutation

doi:10.1016/j.leukres.2014.06.019

Leukemia Research

Volume 38, Issue 10, October 2014, Pages 1177-1183

https://doi.org/10.1016/j.leukres.2014.06.019 Get rights and content

Highlights

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IFNα made ET with JAK2V617F⁺ have better hematologic response than JAK2V617F⁻.
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For PV patients with JAK2V617F⁺, IFN gained better molecular response than HU.
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ET patients with JAK2V617F⁺ demonstrated a definite advantage in PFS.
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For PV patients with JAK2V617F⁺, IFN α-2b was superior to HU in PFS.
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IFN improved vasomotor symptoms, especially distal paresthesias and erythromelalgia.

Abstract

Objective

This open-label, prospective, observational study aimed to evaluate treatment response, efficacy therapy and safety to IFN α-2b for the essential thrombocythemia (ET) and polycythemia vera (PV) with JAK2V617F positive mutation.

Method

A total of 123 ET patients received IFNα-2b therapy with JAK2V617F positive or negative mutation; and 136 PV patients with JAK2V617F⁺ received IFNα-2b or hydroxyurea (HU) therapy according to random number assignment (ages 18–65 years old).

Result

ET patients receiving IFN α-2b with JAK2V617F⁺ had a greater advantage in overall hematologic response (OHR) than JAK2V617F⁻ (83.3% versus 61.4%, P < 0.01). For PV patients with JAK2V617F⁺, IFN had no OHR superiority to HU (70.3% versus 70.8%, P > 0.05), but which gained a greater satisfactory molecular response than HU (54.7% versus 19.4%, P < 0.01). IFN significantly decreased the phlebotomy rate, which was better than HU for MPDs patients with OHR than HU (3.6% versus 65.7%, P < 0.01). Furthermore, ET patients with JAK2V617F⁺ demonstrated a definite advantage over JAK2V617F⁻ in five-year PFS (75.9% versus 47.6%, P < 0.05). For PV patients with JAK2V617F⁺, IFN α-2b was superior to HU in five-year PFS (66.3% versus 46.7%, P < 0.01). Moreover, IFN α-2b also contributed to improved vasomotor symptoms in MPDs, and especially significantly decreased the incidence of distal paresthesias (14.1% versus 37.5%) and erythromelalgia (9.4% versus 29.2%) better than HU (P < 0.01). Meanwhile, IFN did not observe the severe hematological adverse events in patients with PV or ET.

Conclusion

The data confirmed that IFN α-2b benefited the patients with ET or PV, particularly for JAK2V617F⁺ mutation.

Introduction

Chronic myeloproliferative disorders (MPDs) constitute one of five categories of myeloid malignancies, according to the World Health Organization (WHO) classification system for hematopoietic tumors [1]. Essential thrombocythemia (ET) and polycythemia vera (PV) are sub-categories of MPDs [2]. For a long time, the absence of specific genetic or molecular markers caused problems in the differential diagnosis in MPDs. Recently, the acquired gain-of-function V617F mutation in the Janus Kinase 2 (JAK2V617F) has been found to be the major mutation involved in BCR/ABL negative classical MPDs. It is present in the mutational frequency of 96% in PV, 55% of ET patients [3], [4].

The risk of thrombosis, in both ET and PV, exceeds 20% and a substantial proportion of patients experience vasomotor disturbances [5]. Risk factors for shortened survival in both ET and PV include history of thrombosis, leukocytosis, advanced age and anemia. Accordingly, the goal of current therapy in PV and ET is primarily to prevent thrombohemorrhagic complications.

The related treatment for patients with ET and PV should aim at avoiding thromboembolic complications by bone marrow-suppressive therapy. Such treatments ideally should not increase the risk of acute leukemia [6]. Hydroxyurea (HU) generally is considered the treatment of choice for MPDs-associated thrombocythemia [7] and recently showed superior activity over anagrelide. On the other hand, the clinical effectiveness of interferon α-2b (IFN α-2b) had been demonstrated nearly a quarter of a century ago in PV in the US, and almost simultaneously in ET patients by French and Austrian groups [8].

At present, it is still not determined whether IFN α-2b gains the therapy superiority for the PV and ET with or without positive JAK2V617F mutation. The study represents the multicenter study reviews to evaluate efficacy and adverse events of IFN α-2b for advanced ET or PV adult patients (hematocrit >45% or extreme thrombocytosis >1000 × 10⁹/L) or thrombosis history related to JAK2V617F mutation.

Section snippets

Study population

This open-label, observational, multicenter clinical assessment enrolled participants from February 2009 to March 2014. All adult patients (ages 18–65 years old) were diagnosed according to the WHO 2008 classification and fit a composite assessment of clinical and laboratory features [9]. Enrolled advanced patients with extreme thrombocytosis risks or thrombosis history gave written informed consent before entering the study. This study was approved by the institution review board at each of

Enrolled patients with clinical characteristics

The median age of 123 patients with ET was 49 years old. Two treatment groups JAK2V617F⁺ versus JAK2V617F⁻) were well balanced in age (median: 47 versus 50 years old), WBC (median: 26 versus 22 × 10⁹/L), hemoglobin (median: 161 versus 166 g/L), and platelet (median: 1125 versus 1127 × 10⁹/L) counts (P > 0.05) at the time of random assignment (Table 1).

The median age of 136 PV patients with JAK2V617F⁺ was 47 years old. Two treatment groups (IFN α-2b versus HU) were well balanced in age (median: 47

Discussion

PV and ET are chronic MPDs characterized by clonal expansion of an abnormal hematopoietic stem/progenitor cell. Patients with MPDs have a clinical course characterized by a thrombophilic state, which results in arterial and venous thromboses that greatly impacts morbidity and mortality. For ET and PV patients with extreme thrombocytosis risks or thrombosis history, the agent of choice to manage hyperviscosity is HU or IFN. HU provides effective control of the hematocrit in approximately 80% of

Conflict of interest statement

All authors discussed the results and commented on the manuscript. I would like to declare on behalf of my co-authors that this work is original research that has not been published previously and is not under consideration for publication elsewhere, either in part of in whole. All the authors listed have approved the manuscript that is enclosed.

Acknowledgments

We would like to thank all the patients and the clinicians from the participating sites. This work was supported by grants from the Natural Science Foundation of Inner Mongolia (2013MS1157) and Inner Mongolia Autonomous Region Health and Family Planning health research projects (201302059).

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¹: These authors contributed equally to this work.

View full text

Interferon α-2b gains high sustained response therapy for advanced essential thrombocythemia and polycythemia vera with JAK2V617F positive mutation

Highlights

Abstract

Objective

Method

Result

Conclusion

Introduction

Section snippets

Study population

Enrolled patients with clinical characteristics

Discussion

Conflict of interest statement

Acknowledgments

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood Rev

Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms

Leukemia

Annual clinical updates in hematological malignancies: a continuing medical education series: polycythemia vera and essential thrombocythemia: 2011 update on diagnosis, risk-stratification, and management

Am J Hematol