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 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 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.

B‐cell frequencies and immunoregulatory phenotypes in myeloproliferative neoplasms: Influence of ruxolitinib, interferon‐α2, or combination treatment

“…The potentially tumorigenic effect of this could be counteracted by a decrease in PD‐L1 + B cells. However, in a study including 626 patients with MPNs from an Austrian cohort, the risk of developing aggressive B‐cell lymphoma was 16‐fold higher in patients receiving JAK inhibitor treatment . This finding was validated in a French validation cohort including 929 patients, and in a murine model where STAT‐1 deficiency resulted in a malignant B‐cell clone along with dysfunctional cytotoxic T cells and natural killer cells .…”

“…RUX markedly reduces the levels of circulating inflammatory cytokines . Their effects on B cells are mostly unknown, but a recent study reports an increased risk of aggressive B‐cell lymphomas after treatment with RUX …”

Myeloproliferative and lymphoproliferative disorders: State of the art

“…This notion that has been recently exploited from a therapeutic standpoint sheds light on a delicate interplay between physiological processes, such as immunocompetence and immune responses, and pathological derangements, as extreme inflammation, myeloid neoplasms, and lymphoid proliferation. Though not confirmed in other cohorts, data from Porpaczy et al may warrant the collection of larger data sets and/or implementation of screening procedures in future clinical trials with JAK‐inhibitors …”

“…In this regard, we should acknowledge that long‐term data on patients treated with other JAK‐inhibitors are quite limited compared with the well‐established clinical experience with ruxolitinib, so that our observations may be biased. This is particularly true since the median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months in the study from Porpaczy et al…”

“…During treatment, in fact, NK cells are notably reduced, dendritic cells are quantitatively and functionally impaired, secretion of inflammatory cytokines by CD4+ T lymphocytes is notably decreased, and Tregs are significantly reduced . The interest for the potential role of drugs in lymphomagenesis has been strengthened in the last year after the publication in August 2018 of an Austrian study that raised the possibility that JAK inhibitor treatment for myelofibrosis was associated with an increased risk for aggressive B‐cell lymphomas . Notably, lymphomas developed in the Austrian cohort shared some common phenotypic and genotypic features; they were all negative for the JAK2 V617F mutation (that was present in their MPN counterpart), developed from a preexisting B‐cell clone detectable at early stages of MPN and showed extranodal involvement and high MYC and BCL2 expression, thus resembling those lymphoproliferative diseases occurring in immunocompromised hosts.…”