JAK1/2 Inhibitors Linked to Lymphoma Risk in Myelofibrosis

Roxanne Nelson, BSN, RN

June 20, 2018

Drugs that target the Janus-kinase 1/2 (JAK1/2) pathway have become a mainstay of treatment for myeloproliferative neoplasms (MPNs), but new research suggests that their use may be associated with an increased risk for B-cell non-Hodgkin lymphomas.

A retrospective review found that patients treated with these drugs are at a 16-fold increased risk for aggressive B-cell lymphoma.

The study authors also found that a preexisting B-cell clone, detected in the bone marrow in three of the four patients who later developed lymphoma, appears to be associated with the risk for subsequent lymphoma.

The study was published online June 15 in Blood.

Study coauthor Ulrich Jäger, MD, head of the Division of Hematology and Hemostaseology at the Medical University of Vienna, Austria, noted that the patients in whom this preexisting B-cell clone was present in bone marrow are most at risk for developing aggressive lymphoma.

"We think that, indeed, the next step should be screening of patients in larger clinical trials by PCR [polymerase chair reaction]," he told Medscape Medical News.

"At this step, I would not exclude patients who had a B-cell clone from JAK1/2 inhibitor therapy as long as there is no better alternative. In our center, we will screen all patients and monitor those at risk closely," he added.

Increased Risk Reported

The authors note that previous reports have suggested a slightly increased risk for lymphoid neoplasms in MPN patients with JAK2 V617F mutations and that sporadic cases of aggressive lymphomas have been reported in patients being treated with ruxolitinib (Jakafi, Incyte).

In the current study, Jager and colleagues evaluated 626 patients with MPNs who had been diagnosed and treated at the Medical University of Vienna during a 20-year period. Of this cohort, 69 patients received JAK1/2 inhibitors.

Four of 69 patients (5.8%) developed an aggressive B-cell lymphoma after being treated with a JAK1/2 inhibitor, as compared to only 2 of 557 patients (0.36%) who developed lymphomas after receiving other types of treatment.

This corresponds to a 16-fold increase in the probability of developing an aggressive B-cell lymphoma after treatment with JAK1/2 inhibitor therapy (95% confidence interval [CI], 3 - 87; P = .0017). The four patients who developed lymphomas all had primary (n = 3) or postprimary polycythemia vera myelofibrosis (n = 1) with a JAK2 V617F mutation.

A subgroup analysis of 216 patients with primary myelofibrosis included 31 treated with JAK1/2 inhibitor therapy. Three of these patients (9.68%) developed lymphomas.

Among the 185 patients treated with other therapies, there was one case of lymphoma (0.54%) (odds ratio [OR], 19; 95% CI, 2 - 196; P = .01). The OR for developing lymphomas with JAK1/2 inhibitor therapy remained unchanged after adjustments for age (OR, 21; 95% CI, 2 - 218) and sex (OR, 25; 95% CI, 2 - 266).

In a second independent cohort (n = 929) at Hôpital St. Louis in Paris, France, two patients developed lymphoma following ruxolitinib treatment. Lymphomas in this cohort developed in 0.23% of patients treated with other therapies (n = 872), compared with 3.51% of patients who received JAK1/2 inhibitors (n = 57), thus confirming the increased risk (OR, 15; 95% CI, 2 - 92; P = .0205).

Presence of B-Cell Clone

The authors also investigated bone marrow samples of 54 of 69 patients before treatment with JAK1/2 inhibitors. A clonal immunoglobulin rearrangement (IgR) was detected in nine of these patients (16.7%).

Of the four patients in the Vienna cohort who subsequently developed aggressive B-cell lymphoma during treatment with ruxolitinib, three displayed a clonal IgR in the bone marrow, which occurred as early as 47 to 70 months before a lymphoma was diagnosed (no information was available for the fourth patient).

The authors also found an association between JAK inhibition and an increase in the frequency of aggressive B-cell lymphomas in mouse models. They found that Stat1 knockout in mice resulted in a disease course that was strikingly similar to the disease course of myeloproliferative disease. A clonal aggressive B-cell malignancy subsequently developed.

Screening Needed

Mikkael Sekeres, MD, director of the Leukemia Program at the Cleveland Clinic Taussig Cancer Institute, Ohio, commented that this is a "remarkable" study in which the investigators noticed a clinical complication of treatment for myelofibrosis and were able to replicate this complication in mice.

"Many patients had evidence of the potential to develop lymphoma prior to being treated with these drugs," he told Medscape Medical News. "In other words, patients with myelofibrosis are at risk of developing aggressive lymphomas, particularly when receiving the class of drugs similar to ruxolitinib."

The authors state that patients with myelofibrosis should be screened for this proclivity to develop B-cell lymphomas prior to undergoing treatment for their myelofibrosis, Sekeres noted. A question remains as to what to do for patients who are at risk.

"No other therapy is approved by the FDA for the treatment of myelofibrosis," he pointed out. "Should patients have an underlying B-cell clone, I would consider other off-label treatment options."

The study was supported by the Austrian Science Fund, the Anniversary Fund of the Austrian National Bank, and the Precision Medicine Program of the Vienna Science and Technology Fund. Dr Jager has disclosed no relevant financial relationships. Several coauthors have reported relationships with industry, which are noted in the original article. Dr Sekeres has financial relationships with Celgene Corp and Sandoz.

Blood. Published online June 15, 2018. Abstract

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