In 2005, the JAK2 V617F driver mutation was identified as the most common molecular abnormality in myeloproliferative neoplasms (MPNs), prompting the subsequent identification of other mutations that activate the JAK pathway in these diseases, and spurring the development of JAK1/2-inhibitor therapies.1-4 In a subset of patients with MPNs, JAK1/2 inhibitors reduce counts and improve disease-related symptoms and splenomegaly, thus decreasing disease-associated morbidity.5-8 In addition to the well-recognized risk of developing myeloid malignancies, patients with MPNs seem to additionally face a slightly higher risk of developing solid tumors and lymphoid malignancies.9-12 The JAK-STAT pathway is implicated in the development of some malignant lymphomas. Additionally, a coincidence of B-cell non-Hodgkin lymphomas in patients with MPNs receiving JAK1/2 inhibitors has been observed.13 Together, these observations raise the question of whether JAK1/2-inhibitor therapy in patients with MPNs alters the risk of lymphoma development.
To address this question, Dr. Edit Porpaczy and colleagues 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, and investigators accessed an MPN database to obtain data on secondary malignancies. During treatment with a JAK1/2 inhibitor, four (5.8%) of 69 patients developed an aggressive B-cell lymphoma. All four patients had primary (grade 3) or postessential (grade 1) thrombocytosis or post–polycythemia vera (grade 1) myelofibrosis characterized by a JAK2 V617F mutation and were treated with ruxolitinib. Three of the four patients had been pretreated with alkylating agents, and one patient had also received a second JAK2 inhibitor (fedratinib). The median time from starting therapy to lymphoma diagnosis was 25 months (range, 13-35 months). Among patients who did not receive JAK1/2 inhibitor therapy, two (0.36%) of 557 developed lymphoma. This equates to a 16-fold increase in the probability of developing an aggressive B-cell lymphoma with JAK1/2 inhibitor therapy (95% CI, 3-87; p=0.0017). The authors then analyzed an independent cohort of 929 MPN patients treated at the Hôpital St. Louis in Paris. JAK1/2 inhibition conferred a similar increase in lymphoma development in this cohort (3.51% of 57 patients treated with a JAK1/2 inhibitor vs. 0.23% of 872 patients treated with conventional therapy; OR, 15.0; 95% CI, 2-92; p=0.0205). All lymphomas were of aggressive CD19+ B-cell type (5 diffuse large B-cell lymphomas and 1 high-grade B-cell lymphoma not otherwise specified), with the majority occurring at extranodal sites.
Among the 54 patients in the Vienna cohort of patients with bone marrow samples available prior to JAK1/2 inhibitor therapy, nine harbored clonal immunoglobulin gene rearrangements (16.7%). This incidence was comparable to an age- and sex-matched control cohort of MPN patients who had not received JAK1/2 inhibitor therapy (15.9%), indicating that clonal B cells are present in the bone marrow of MPN patients regardless of treatment. Pretreatment bone marrow samples were available from three of the individuals treated with JAK1/2 inhibitors who subsequently developed lymphoma. All three patient samples tested positive for a B-cell clone as early as 47 to 70 months before lymphoma diagnosis and when the patient had an MPN. Notably, the investigators demonstrated that the pretreatment B-cell clone likely gave rise to the subsequent lymphoma. In contrast, an antecedent B-cell clone was present in only six (5.9%) of 50 patients who did not develop lymphoma during JAK1/2 inhibitor therapy. This equates to a 15-fold increase in risk of developing a B-cell lymphoma upon JAK1/2 inhibition in patients with a detectable B-cell (95% CI, 2-128; p=0.0124), suggesting that the detection of a preexisting B-cell clone may identify individuals at risk.
The authors then demonstrated this association between JAK inhibition and an increase in the frequency of aggressive B-cell lymphomas in a mouse model. They found that Stat1 knockout in mice caused myeloid hyperplasia and B-cell transformation with subsequent development of lymphoma after bone marrow transplantation, recapitulating the clinical observation in patients. The transcription factor STAT1 acts downstream of JAK-kinases. Distinct phenotypes in JAK2 V617F–positive MPN cases reflect differential STAT1 signaling.14
In Brief
While JAK inhibitors have proven to be an effective treatment for patients with myelofibrosis, this work provides compelling evidence that treatment may come at a cost of increased risk of aggressive B-cell lymphoma development. While the authors speculate that the mechanism of disease may potentially reflect the ability of ruxolitinib to reduce T-cell function and numbers with lymphoma developing in the context of immune deficiency, additional mechanistic studies are needed to decipher the pathobiology, including whether JAK1 or JAK2 inhibition accounts for the lymphoma risk. Notably, detection of a pre-existing B-cell clone may identify individuals at risk, potentially providing an opportunity to integrate this testing in the risk-benefit analysis when considering these therapies. Whether JAK1/2 inhibitors pose a similar risk when used to treat patients with other conditions, such as arthritis and psoriasis, remains unknown.
References
Competing Interests
Dr. Keel indicated no relevant conflicts of interest.
