Treatment of myelofibrosis with JAK inhibitors may increase risk for aggressive lymphoma

Patients with pre-existing B-cell clone gene who underwent treatment for myelofibrosis with ruxolitinib or other JAK1/2 inhibitors appeared to have a 16-fold increased risk for developing aggressive B-cell lymphoma, according to study findings published in Blood.

“We determined that patients with this preexisting B-cell clone in their bone marrow are most at risk for developing aggressive lymphoma. We also know that up to 16% of people with myelofibrosis have immunoglobulin gene arrangements like this B-cell clone,” Ulrich Jaeger, MD, from the division of hematology and hemostaseology at Medical University of Vienna in Austria, and coauthor of the study, said in a press release. “Therefore, our findings suggest that all patients with myelofibrosis should be tested for such gene rearrangements before prescribing JAK inhibitors to treat their disease.”

JAK1/2 inhibitors interfere with the JAK-STAT signaling pathway — a driver of myeloproliferative neoplasms — through the inhibition of activity among janus kinase enzymes. Ruxolitinib (Jakafi, Incyte) — a first-in-class potent selective inhibitor of JAK1 and JAK2 — improves symptoms of myeloproliferative neoplasms and is widely used to treat myelofibrosis and polycythemia vera.

However, the JAK-STAT pathway also is linked to the development of malignant lymphoma. Previous research showed a slight increased risk for lymphoid neoplasms among patients with myeloproliferative neoplasms harboring JAK2 V617F mutations, as well as aggressive lymphomas found among patients with myeloproliferative neoplasms undergoing treatment with ruxolitinib.

“We started noticing sporadic cases of lymphomas developing in patients being treated for myeloproliferative neoplasms and wanted to know if this phenomenon was connected to treatment,” Heinz Gisslinger, MD, from the division of hematology and hemostaseology at Medical University of Vienna, another study coauthor, said in the press release.

Investigators evaluated data from 626 patients who received treatment for myeloproliferative neoplasms at Medical University of Vienna to identify 69 patients with myelofibrosis undergoing treatment with a JAK inhibitor — ruxolitinib, gandotinib (LY2784544, Eli Lilly), fedratinib ((TG101348, SAR302503; Impact Biomedicines, Celgene) or momelotinib (CYT387, Gilead Sciences) — since 2009.

Four patients (5.8%) who received a JAK inhibitor developed aggressive CD19-positive B-cell type lymphomas compared with two cases of lymphomas among the 557 patients (0.36%) not treated with a JAK inhibitor. Lymphoma cases were aggressive B-cell type, extra nodal or leukemic with high MYC expression in the absence of JAK2 V617F or other mutations associated with myeloproliferative neoplasms.

All four patients with lymphoma had JAK2 V617F mutation and a primary (n = 3) or post-polycythemia vera (n = 1) myelofibrosis diagnosis.

Median time to lymphoma diagnosis from initiation of JAK1/2 inhibitor treatment was 25 months (range, 13-35 months).

The number of developed cases of lymphoma corresponded to a 16-fold (95% CI, 3-87; P = .0017) increase in likelihood of developing an aggressive B-cell lymphoma while on JAK1/2 inhibitor therapy.

Researchers detected clonal immunoglobulin gene rearrangement in the bone marrow of 16.3% of patients during myelofibrosis. Of these, three cases of lymphoma developed during JAK1/2 inhibitor treatment and were preceded by a pre-existing B-cell clone.

Some patients in an independent cohort of 929 patients from Hôpital St. Louis in Paris developed lymphoma while on treatment with ruxolitinib. The frequency of lymphoma was 3.51% among 57 patients treated with JAK1/2 inhibitors compared with 0.23% among 872 patients not treated with JAK inhibitors, which confirmed a 15-fold (95% CI, 2-92; P = .0205) increased risk.

A subgroup analysis of 216 patients with primary myelofibrosis in a Viennese cohort revealed three of 31 patients (9.6%) treated with ruxolitinib developed lymphomas compared with one of 185 patients (0.5%) who did not, which indicated a 19-fold increased risk (95% CI, 2-196; P = .01).

Researchers also developed a mouse model to measure lymphoma development under myeloproliferative neoplasms among mice with the signal transducer and activator of transcription 1 (STAT1^-/-) gene.

The STAT1 gene — which acts downstream of JAK kinases — is considered a tumor suppressor, the researchers wrote. In JAK2 V617F-mutated disease, the level of activated STAT1 forms the characteristics of the disease.

In the mouse model, researchers also observed an association between JAK inhibition and increased frequency of B-cell lymphoma.

Sixteen of 24 mice developed spontaneous myeloid hyperplasia with a presence of aberrant B cells. Transplantations of bone marrow from afflicted mice showed malignant B-cell clone offshoot derived into aggressive B-cell leukemia-lymphoma.

Median survival was 13.1 months among Stat1-positive mice compared with 28 months in wild-type mice.

“By replicating this link between B-cell clone and aggressive lymphoma, we hope to speed the discovery of an alternative therapy for myelofibrosis,” Veronika Sexl, MD, from Institute of Pharmacology and Toxicology and University of Veterinary Medicine in Vienna, Austria, said in the release. “These findings are going to be valuable in clinical care.” – by Melinda Stevens

Disclosure s : Jaeger reports honoraria and research funding from Novartis and Roche. Gisslinger reports honoraria and research funding from Novartis. Sexl reports no relevant financial disclosures. Please see the study for a list of all other researchers’ relevant financial disclosures.