Micrograph showing myelofibrosis
New research indicates that JAK inhibitors may increase the risk of lymphoma in patients with myelofibrosis (MF).
The patients studied had a 15- to 25-fold higher risk of developing B-cell lymphoma if they received treatment with JAK inhibitors.
The researchers speculate that screening MF patients for a pre-existing B-cell clone before starting JAK inhibitor therapy may help prevent lymphoma development.
Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, and his colleagues conducted this research and reported the findings in Blood.
“[W]e 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,” Dr Gisslinger said.
Therefore, he and his colleagues assessed 626 patients receiving treatment for myeloproliferative neoplasms (MPNs) at the Medical University of Vienna.
The incidence of B-cell lymphoma was 5.8% (4/69) in patients treated with JAK inhibitors and 0.36% (2/557) in patients who did not receive JAK inhibitors. That amounts to a 16-fold increased risk of lymphoma in patients receiving JAK inhibitors.
When the researchers analyzed only patients with primary MF (n=216), the increased risk of B-cell lymphoma was even greater. The incidence of lymphoma was 9.68% (3/31) in patients treated with JAK inhibitors and 0.54% (1/185) in patients who did not receive JAK inhibitors.
That corresponds to a 19-fold increased risk of B-cell lymphoma in primary MF patients treated with JAK inhibitors. When the researchers adjusted for age, there was a 21-fold greater risk. When they adjusted for sex, the risk was 25 times higher.
In a second cohort of 929 MPN patients, the incidence of B-cell lymphoma was 3.51% (2/57) in patients who received JAK inhibitors and 0.23% (2/872) in patients who did not. This corresponds to a 15-fold increased risk of lymphoma in the JAK inhibitor recipients.
Lymphoma cases
In all, there were 6 patients who developed lymphoma after JAK inhibitor treatment. Five developed diffuse large B-cell lymphoma, and 1 had high-grade B-cell lymphoma not otherwise specified.
Four of the patients had primary MF, 1 had post-polycythemia vera MF, and 1 had post-essential thrombocythemia (ET) MF. Five patients had a JAK2V617F mutation, and 1 (the post-ET MF patient) had a CALR mutation.
All 6 patients had received treatment with ruxolitinib. One patient also received fedratinib.
B-cell clone
The researchers studied bone marrow samples from 54 of the 69 patients treated with JAK inhibitors in the first cohort. The team found a pre-existing B-cell clone in 3 of the 4 patients who developed lymphoma. Further investigation suggested this was the clone that later transformed into lymphoma.
The researchers also found an association between JAK inhibition and an increased frequency of aggressive B-cell lymphomas in mouse models.
“By replicating this link between this B-cell clone and aggressive lymphoma, we hope to speed the discovery of an alternative therapy for myelofibrosis,” said study author Veronica Sexl, MD, of the University of Veterinary Medicine in Vienna. “These findings are going to be valuable in clinical care.”
“We determined that patients with this pre-existing B-cell clone in their bone marrow are most at risk for developing aggressive lymphoma,” added study author Ulrich Jäger, MD, of the Medical University of Vienna.
“We also know that up to 16% of people with myelofibrosis have immunoglobulin gene rearrangements like this B-cell clone. Therefore, our findings suggest that all patients with myelofibrosis should be tested for such gene rearrangements before prescribing JAK inhibitors to treat their disease.”