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

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.

• Authors: Edit Porpaczy, Sabrina Tripolt, Andrea Hoelbl-Kovacic, Bettina Gisslinger, Zsuzsanna Bago-Horvath, Emilio Casanova-Hevia, Emmanuelle Clappier, Thomas Decker, Sabine Fajmann, Daniela A Fux, Georg Greiner, Sinan Gueltekin, Gerwin Heller, Harald Herkner, Gregor Hoermann, Jean-Jacques Kiladjian, Thomas Kolbe, Christoph Kornauth, Maria-Theresa Krauth, Robert Kralovics, Leonhard Muellauer, Mathias Mueller, Michaela Prchal-Murphy, Eva Maria Putz, Emmanuel Raffoux, Ana-Iris Schiefer, Klaus Schmetterer, Christine Schneckenleithner, Ingrid Simonitsch-Klupp, Cathrin Skrabs, Wolfgang R Sperr, Philipp Bernhard Staber, Birgit Strobl, Peter Valent, Ulrich Jaeger, Heinz Gisslinger, Veronika Sexl
• Journal: Blood (Blood) Vol. 132 Issue 7 Pg. 694-706 (08 16 2018) ISSN: 1528-0020 [Electronic] United States
• PMID: 29907599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society of Hematology.

Chemical References

• Neoplasm Proteins
• Protein Kinase Inhibitors
• JAK1 protein, human
• JAK2 protein, human
• Jak1 protein, mouse
• Jak2 protein, mouse
• Janus Kinase 1
• Janus Kinase 2

Topics

• Animals
• Cell Line, Tumor
• Female
• Humans
• Janus Kinase 1 (antagonists & inhibitors, genetics, metabolism)
• Janus Kinase 2 (antagonists & inhibitors, genetics, metabolism)
• Lymphoma, B-Cell (drug therapy, enzymology, genetics, pathology)
• Mice
• Mice, Knockout
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Primary Myelofibrosis (drug therapy, enzymology, genetics, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Retrospective Studies