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Blood. 2018 Aug 16;132(7):694-706. doi: 10.1182/blood-2017-10-810739. Epub 2018 Jun 14.

Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy.

Author information

1
Division of Hematology and Hemostaseology, Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
2
Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria.
3
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
4
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
5
Department of Physiology, Centre of Physiology and Pharmacology, Comprehensive Cancer Centre, Medical University of Vienna, Vienna, Austria.
6
INSERM/CNRS UMR 944/7212, Paris, France.
7
Institut Universitaire d'Hématologie, Paris Cancer Research Institute and.
8
Laboratory of Hematology, Hopital Saint Louis, Assistance Publique-Hopitaux de Paris, University Paris Diderot, Paris, France.
9
Max F. Perutz Laboratories.
10
Department of Laboratory Medicine.
11
Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center.
12
Department of Emergency Medicine, and.
13
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
14
Munich Leukemia Laboratory, Munich, Germany.
15
Centre d'Investigations Cliniques, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, INSERM, Université Paris 7, Paris, France.
16
Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria.
17
Department for Agrobiotechnology (IFA)-Tulln, University of Natural Resources and Life Sciences, Tulln, Austria.
18
Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria.
19
Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria; and.
20
Hematology Department, Hopital Saint Louis, Assistance Publique-Hopitaux de Paris, University Paris Diderot, Paris, France.

Abstract

Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 patients with MPN, including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4 (5.8%) of 69 patients receiving JAK1/2 inhibition compared with 2 (0.36%) of 557 with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 patients with MPN. Considering primary myelofibrosis only (N = 216), 3 lymphomas were observed in 31 inhibitor-treated patients (9.7%) vs 1 (0.54%) of 185 control patients. Lymphomas were of aggressive B-cell type, extranodal, or leukemic with high MYC expression in the absence of JAK2 V617F or other MPN-associated mutations. Median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months. Clonal immunoglobulin gene rearrangements were already detected in the bone marrow during myelofibrosis in 16.3% of patients. Lymphomas occurring during JAK1/2 inhibitor treatment were preceded by a preexisting B-cell clone in all 3 patients tested. Sequencing verified clonal identity in 2 patients. The effects of JAK1/2 inhibition were mirrored in Stat1-/- mice: 16 of 24 mice developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B cells. Transplantations of bone marrow from diseased mice unmasked the outgrowth of a malignant B-cell clone evolving into aggressive B-cell leukemia-lymphoma. We conclude that JAK/STAT1 pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. Detection of a preexisting B-cell clone may identify individuals at risk.

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