Safety and efficacy of combination therapy of interferon-α2 and ruxolitinib in polycythemia vera and myelofibrosis

Stine Ulrik Mikkelsen; Lasse Kjaer; Mads Emil Bjørn; Trine Alma Knudsen; Anders Lindholm Sørensen; Christen Bertel Lykkegaard Andersen; Ole Weis Bjerrum; Nana Brochmann; Daniel El Fassi; Torben A Kruse; Thomas Stauffer Larsen; Hans Torben Mourits-Andersen; Claus Henrik Nielsen; Niels Pallisgaard; Mads Thomassen; Vibe Skov; Hans Carl Hasselbalch

doi:10.1002/cam4.1619

Safety and efficacy of combination therapy of interferon-α2 and ruxolitinib in polycythemia vera and myelofibrosis

Stine Ulrik Mikkelsen, Lasse Kjaer, Mads Emil Bjørn, Trine Alma Knudsen, Anders Lindholm Sørensen, Christen Bertel Lykkegaard Andersen, Ole Weis Bjerrum, Nana Brochmann, Daniel El Fassi, Torben A Kruse, Thomas Stauffer Larsen, Hans Torben Mourits-Andersen, Claus Henrik Nielsen, Niels Pallisgaard, Mads Thomassen, Vibe Skov, Hans Carl Hasselbalch

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Abstract

Interferon-α2 reduces elevated blood cell counts and splenomegaly in patients with myeloproliferative neoplasms (MPN) and may restore polyclonal hematopoiesis. Its use is limited by inflammation-mediated toxicity, leading to treatment discontinuation in 10-30% of patients. Ruxolitinib, a potent anti-inflammatory agent, has demonstrated benefit in myelofibrosis (MF) and polycythemia vera (PV) patients. Combination therapy (CT) with these two agents may be more efficacious than monotherapy with either, potentially improving tolerability of interferon-α2 as well. We report the preliminary results from a phase II study of CT with pegylated interferon-α2 and ruxolitinib in 50 MPN patients (PV, n = 32; low-/intermediate-1-risk MF, n = 18), the majority (n = 47) being resistant and/or intolerant to interferon-α2 monotherapy. Objectives included remission (2013 revised criteria encompassing histologic, hematologic, and clinical responses), complete hematologic response (CHR), molecular response, and toxicity. Follow-up was 12 months. Partial remission (PR) and sustained CHR were achieved in 9% and 44% of PV patients, respectively. In MF patients, complete or partial remission was achieved in 39%, and sustained CHR in 58%. The median JAK2V617F allele burden declined significantly in both groups. Hematologic toxicity was the most common adverse event and was managed by dose reduction. Thirty-seven serious adverse events were recorded in 23 patients; the discontinuation rate was 20%. We conclude that CT with interferon-α2 and ruxolitinib is efficacious in patients with low-/intermediate-1-risk MF and, to a lesser extent, in patients with PV. These preliminary results encourage phase III studies as well as a study with CT in newly diagnosed MPN patients.

Original language	English
Journal	Cancer Medicine
Volume	7
Issue number	8
Pages (from-to)	3571-3581
Number of pages	11
ISSN	2045-7634
DOIs	https://doi.org/10.1002/cam4.1619
Publication status	Published - Aug 2018

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Safety and efficacy of combination therapy of interferon‐α2 and ruxolitinib in polycythemia vera and myelofibrosisFinal published version, 532 KBLicence: CC BY

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Mikkelsen, S. U., Kjaer, L., Bjørn, M. E., Knudsen, T. A., Sørensen, A. L., Andersen, C. B. L., Bjerrum, O. W., Brochmann, N., Fassi, D. E., Kruse, T. A., Larsen, T. S., Mourits-Andersen, H. T., Nielsen, C. H., Pallisgaard, N., Thomassen, M., Skov, V., & Hasselbalch, H. C. (2018). Safety and efficacy of combination therapy of interferon-α2 and ruxolitinib in polycythemia vera and myelofibrosis. Cancer Medicine, 7(8), 3571-3581. https://doi.org/10.1002/cam4.1619

Mikkelsen, SU, Kjaer, L, Bjørn, ME, Knudsen, TA, Sørensen, AL, Andersen, CBL, Bjerrum, OW, Brochmann, N, Fassi, DE, Kruse, TA, Larsen, TS, Mourits-Andersen, HT, Nielsen, CH, Pallisgaard, N, Thomassen, M, Skov, V & Hasselbalch, HC 2018, 'Safety and efficacy of combination therapy of interferon-α2 and ruxolitinib in polycythemia vera and myelofibrosis', Cancer Medicine, vol. 7, no. 8, pp. 3571-3581. https://doi.org/10.1002/cam4.1619

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title = "Safety and efficacy of combination therapy of interferon-α2 and ruxolitinib in polycythemia vera and myelofibrosis",

abstract = "Interferon-α2 reduces elevated blood cell counts and splenomegaly in patients with myeloproliferative neoplasms (MPN) and may restore polyclonal hematopoiesis. Its use is limited by inflammation-mediated toxicity, leading to treatment discontinuation in 10-30% of patients. Ruxolitinib, a potent anti-inflammatory agent, has demonstrated benefit in myelofibrosis (MF) and polycythemia vera (PV) patients. Combination therapy (CT) with these two agents may be more efficacious than monotherapy with either, potentially improving tolerability of interferon-α2 as well. We report the preliminary results from a phase II study of CT with pegylated interferon-α2 and ruxolitinib in 50 MPN patients (PV, n = 32; low-/intermediate-1-risk MF, n = 18), the majority (n = 47) being resistant and/or intolerant to interferon-α2 monotherapy. Objectives included remission (2013 revised criteria encompassing histologic, hematologic, and clinical responses), complete hematologic response (CHR), molecular response, and toxicity. Follow-up was 12 months. Partial remission (PR) and sustained CHR were achieved in 9% and 44% of PV patients, respectively. In MF patients, complete or partial remission was achieved in 39%, and sustained CHR in 58%. The median JAK2V617F allele burden declined significantly in both groups. Hematologic toxicity was the most common adverse event and was managed by dose reduction. Thirty-seven serious adverse events were recorded in 23 patients; the discontinuation rate was 20%. We conclude that CT with interferon-α2 and ruxolitinib is efficacious in patients with low-/intermediate-1-risk MF and, to a lesser extent, in patients with PV. These preliminary results encourage phase III studies as well as a study with CT in newly diagnosed MPN patients.",

author = "Mikkelsen, {Stine Ulrik} and Lasse Kjaer and Bj{\o}rn, {Mads Emil} and Knudsen, {Trine Alma} and S{\o}rensen, {Anders Lindholm} and Andersen, {Christen Bertel Lykkegaard} and Bjerrum, {Ole Weis} and Nana Brochmann and Fassi, {Daniel El} and Kruse, {Torben A} and Larsen, {Thomas Stauffer} and Mourits-Andersen, {Hans Torben} and Nielsen, {Claus Henrik} and Niels Pallisgaard and Mads Thomassen and Vibe Skov and Hasselbalch, {Hans Carl}",

note = "{\textcopyright} 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.",

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language = "English",

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T1 - Safety and efficacy of combination therapy of interferon-α2 and ruxolitinib in polycythemia vera and myelofibrosis

AU - Mikkelsen, Stine Ulrik

AU - Kjaer, Lasse

AU - Bjørn, Mads Emil

AU - Knudsen, Trine Alma

AU - Sørensen, Anders Lindholm

AU - Andersen, Christen Bertel Lykkegaard

AU - Bjerrum, Ole Weis

AU - Brochmann, Nana

AU - Fassi, Daniel El

AU - Kruse, Torben A

AU - Larsen, Thomas Stauffer

AU - Mourits-Andersen, Hans Torben

AU - Nielsen, Claus Henrik

AU - Pallisgaard, Niels

AU - Thomassen, Mads

AU - Skov, Vibe

AU - Hasselbalch, Hans Carl

PY - 2018/8

Y1 - 2018/8

N2 - Interferon-α2 reduces elevated blood cell counts and splenomegaly in patients with myeloproliferative neoplasms (MPN) and may restore polyclonal hematopoiesis. Its use is limited by inflammation-mediated toxicity, leading to treatment discontinuation in 10-30% of patients. Ruxolitinib, a potent anti-inflammatory agent, has demonstrated benefit in myelofibrosis (MF) and polycythemia vera (PV) patients. Combination therapy (CT) with these two agents may be more efficacious than monotherapy with either, potentially improving tolerability of interferon-α2 as well. We report the preliminary results from a phase II study of CT with pegylated interferon-α2 and ruxolitinib in 50 MPN patients (PV, n = 32; low-/intermediate-1-risk MF, n = 18), the majority (n = 47) being resistant and/or intolerant to interferon-α2 monotherapy. Objectives included remission (2013 revised criteria encompassing histologic, hematologic, and clinical responses), complete hematologic response (CHR), molecular response, and toxicity. Follow-up was 12 months. Partial remission (PR) and sustained CHR were achieved in 9% and 44% of PV patients, respectively. In MF patients, complete or partial remission was achieved in 39%, and sustained CHR in 58%. The median JAK2V617F allele burden declined significantly in both groups. Hematologic toxicity was the most common adverse event and was managed by dose reduction. Thirty-seven serious adverse events were recorded in 23 patients; the discontinuation rate was 20%. We conclude that CT with interferon-α2 and ruxolitinib is efficacious in patients with low-/intermediate-1-risk MF and, to a lesser extent, in patients with PV. These preliminary results encourage phase III studies as well as a study with CT in newly diagnosed MPN patients.

AB - Interferon-α2 reduces elevated blood cell counts and splenomegaly in patients with myeloproliferative neoplasms (MPN) and may restore polyclonal hematopoiesis. Its use is limited by inflammation-mediated toxicity, leading to treatment discontinuation in 10-30% of patients. Ruxolitinib, a potent anti-inflammatory agent, has demonstrated benefit in myelofibrosis (MF) and polycythemia vera (PV) patients. Combination therapy (CT) with these two agents may be more efficacious than monotherapy with either, potentially improving tolerability of interferon-α2 as well. We report the preliminary results from a phase II study of CT with pegylated interferon-α2 and ruxolitinib in 50 MPN patients (PV, n = 32; low-/intermediate-1-risk MF, n = 18), the majority (n = 47) being resistant and/or intolerant to interferon-α2 monotherapy. Objectives included remission (2013 revised criteria encompassing histologic, hematologic, and clinical responses), complete hematologic response (CHR), molecular response, and toxicity. Follow-up was 12 months. Partial remission (PR) and sustained CHR were achieved in 9% and 44% of PV patients, respectively. In MF patients, complete or partial remission was achieved in 39%, and sustained CHR in 58%. The median JAK2V617F allele burden declined significantly in both groups. Hematologic toxicity was the most common adverse event and was managed by dose reduction. Thirty-seven serious adverse events were recorded in 23 patients; the discontinuation rate was 20%. We conclude that CT with interferon-α2 and ruxolitinib is efficacious in patients with low-/intermediate-1-risk MF and, to a lesser extent, in patients with PV. These preliminary results encourage phase III studies as well as a study with CT in newly diagnosed MPN patients.

U2 - 10.1002/cam4.1619

DO - 10.1002/cam4.1619

M3 - Journal article

C2 - 29932310

SN - 2045-7634

VL - 7

SP - 3571

EP - 3581

JO - Cancer Medicine

JF - Cancer Medicine

IS - 8

ER -

Safety and efficacy of combination therapy of interferon-α2 and ruxolitinib in polycythemia vera and myelofibrosis

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