Zeitschriftenaufsatz
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2018
Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy
Autor:in
Porpaczy, E.; Tripolt, Sabrina; Hoelbl-Kovacic, Andrea; Gisslinger, Bettina; BagoHorvath, Zsuzsanna; Casanova, Emilio; Clappier, Emmanuelle; Decker, Thomas; Fajmann, Sabine; Fux, Daniela; Greiner, G.; Gueltekin, Sinan; heller, gerwin; herkner, harald; Hoermann, Gregor; Kiladjian, Jean-Jacques; Kolbe, Thomas; Kornauth, Christoph; Krauth, Maria Theresa; Kralovics, Robert; Müllauer, Leonhard; Mueller, Mathias; Prchal-Murphy, Michaela; König, Eva; Raffoux, Emmanuel; Schiefer, Ana-Iris; Schmetterer, Klaus G.; Schneckenleithner, Christine; Simonitsch-Klupp, Ingrid; Skrabs, C.; Sperr, Wolfgang R.; Staber, Philipp; Strobl, Birgit; Valent, Peter; Jaeger, Ulrich; BERBEC, Nicoleta Mariana; Sexl, Veronika
Publikationen als Autor:in / Herausgeber:in der Vetmeduni
Journal
Abstrakt
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.
Schlagwörter
Animals; Cell Line, Tumor; Female; Humans; Janus Kinase 1antagonists & inhibitorsgeneticsmetabolism; Janus Kinase 2antagonists & inhibitorsgeneticsmetabolism; Lymphoma, B-Celldrug therapyenzymologygeneticspathology; Mice; Mice, Knockout; Neoplasm Proteinsantagonists & inhibitorsgeneticsmetabolism; Primary Myelofibrosisdrug therapyenzymologygeneticspathology; Protein Kinase Inhibitorspharmacology; Retrospective Studies
Dokumententyp
Originalarbeit
ISSN/eISSN
0006-4971 - 1528-0020
10.1182/blood-2017-10-810739
WoS ID
PubMed ID