JAK1/2 inhibitors have been used as standard and experimental treatment of myeloproliferative neoplasms (MPNs) for years, but according to research published in Blood, their use was associated with a greater likelihood of patients developing aggressive B-cell lymphomas. The study authors also observed that patients with preexisting B-cell clones in their bone marrow (BM; detected on polymerase chain reaction [PCR]–testing) are at the highest risk for a secondary malignancy.
“The most intriguing finding of our study was that dormant clonal B-cells could be identified by PCR in the BM of patients during their myeloproliferative disease, and up to 70 months before the development of overt lymphoma,” study co-author Ulrich Jäger, MD, of the Medical University of Vienna in Austria, told ASH Clinical News. “These clones were identical to the lymphoma, which gives us a possibility to screen for a premalignant state before starting JAK1/2 inhibitors.”
Additionally, Dr. Jäger described how the study researchers found a “fairly uniform type of aggressive B-cell lymphoma with unusual BM infiltration or extranodal disease, which also was similar to two other cases reported in the literature.”
The researchers initiated this study based on sporadic observations of aggressive lymphomas that have been reported in patients with MPNs receiving ruxolitinib treatment. To understand the frequency and potential causes of lymphoma in this population, the authors identified 626 patients with MPNs treated between 1997 and 2016 at the Medical University of Vienna.
Sixty-nine of these patients received JAK1/2 inhibitors (including ruxolitinib, gandotinib, fedratinib, and momelotinib) since 2009. The investigators used an MPN database to access data regarding secondary malignancies and analyzed samples of peripheral blood and BM collected from 54 patients who were treated with ruxolitinib.
During treatment with a JAK1/2 inhibitor, four patients (5.8%) developed an aggressive B-cell lymphoma. Three of these patients were treated with alkylating agents plus ruxolitinib and one received ruxolitinib only; one of the patients also received fedratinib. The median time between inhibitor therapy initiation to lymphoma diagnosis was 25 months (range 13-35 months).
In the other 557 patients who had not received JAK1/2 inhibitors, two patients (0.36%) developed lymphomas.
This translated to a 16-fold higher risk of aggressive B-cell lymphoma for patients who received JAK1/2 inhibitors (odds ratio [OR] = 16.0; 95% CI 3-87; p=0.0017). This risk remained elevated for JAK1/2 inhibitor–treated patients in age- and sex-adjusted analyses, the authors added.
In a subgroup analysis of 216 patients with primary myelofibrosis, more patients treated with ruxolitinib developed a lymphoma, compared with patients treated with conventional therapy (9.68% vs. 0.54%), which translated to a 19-times higher risk for secondary lymphoma (OR=19.0; 95% CI 2-196; p=0.01).
To validate these results, the researchers also conducted an independent retrospective analysis of another cohort of patients with MPNs (n=929) who were treated at Hôpital Saint-Louis in Paris. Of the 57 receiving JAK1/2 inhibitors, two developed an aggressive B-cell lymphoma during ruxolitinib treatment (3.51%). Again, JAK1/2 inhibition conferred a significantly higher risk of secondary lymphoma, compared with conventional therapy (3.51% vs. 0.23%; OR=15.0; 95% CI 2-92; p=0.0205).
Researchers also tested clonality by using PCR, followed by the MiSeq System for genome sequencing, in 54 ruxolitinib-treated patients from the Vienna cohort. Nine patients (16.7%) had JAK1/2-associated clonal immunoglobulin gene rearrangements in their BM samples prior to JAK1/2 inhibitor exposure. Sequencing also determined that there was a preexisting B-cell clone in patients who developed lymphomas during therapy.
The small number of enrolled patients and the study’s retrospective design represent two potential limitations of this analysis. The study also was not designed to determine the mechanism behind this increased lymphoma risk.
“Ruxolitinib has the ability to reduce the function of T-cells and the frequency of circulating regulatory T-cells and is used as an immunosuppressive agent,” the authors noted. “It is attractive to speculate that the immunosuppressive properties of JAK1/2 inhibitors contribute to lymphoma development.”
For future trials, Dr. Jäger recommends incorporating PCR screening for immunoglobulin rearrangements into study protocols. “It also is unclear if this is a phenomenon related to ruxolitinib only, or if this is a drug-class effect,” he added. “Novartis has kindly agreed to recheck their databases. We also urge colleagues who have seen similar cases to report them to the respective companies or to us.”
The authors report financial relationships with Novartis, Roche, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Teva, and Jazz Pharmaceuticals.
Porpaczy E, Tripolt S, Hoelbl-Kovacic A, et al. Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy. Blood. 2018 June 14. [Epub ahead of print]