麻豆传媒

A small but significant proportion of patients with the rare bone marrow malignancy myelofibrosis (MFB) developed aggressive lymphomas during treatment with a Janus kinase (JAK) inhibitor, two large retrospective cohort studies showed.

In a study of 626 patients, 5.8% of those treated with JAK1/2 inhibitors developed aggressive B-cell lymphomas. By comparison, 0.36% of patients treated with other drugs developed developed B-cell lymphomas, reported Ulrich Jaeger, MD, of the Medical University of Vienna (MUV) in Austria, and colleagues. in .

A separate group of 929 patients with myeloproliferative neoplasms (MPNs), including MFB, had a similar disparity of B-cell lymphoma cases, 9.7% of patients with primary MFB treated with JAK inhibitors versus 0.54% of patients who received other therapies.

Most of the patients who developed lymphoma had a pre-existing B-cell clone that underwent transformation during treatment with JAK inhibitors. Using a mouse model, investigators replicated the associations between MFB, abnormal B-cell clones, JAK1/2 inhibitor treatment, and development of aggressive lymphomas.

"We determined that patients with this preexisting B-cell clone in their bone marrow are most at risk for developing aggressive lymphoma," Jaeger said in a statement. "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."

The findings were reported simultaneously at the European Hematology Association meeting in Stockholm.

The observation of lymphoma in patients with MFB treated with JAK inhibitors is not new, but the degree to which the association was documented, particularly the study in the mouse model, is new and reinforces previously reported data, said David Steensma, MD, of Dana-Farber Cancer Institute in Boston.

"This is something that we need to be counseling patients about when they start treatment with these drugs," said Steensma, a clinical expert for the American Society of Hematology. "It's a rare complication. That being said, we know about second malignancies with other types of treatments, and I think this is just another example. I think almost certainly that it's real."

Whether JAK inhibitors pose a similar risk when used to treat patients with other conditions, notably arthritis and psoriasis, remains unclear. Steensma, who was not involved in the research, said he is unaware of any reports of secondary lymphoma in those populations.

"There may be two reasons for that," he said. "Patients with those conditions have almost an inherent incidence of B-cell lymphomas, regardless of treatment. In the era of JAK inhibitors, I doubt anyone would make very much of a few more cases of lymphoma. The other difference is that the drugs most commonly used in those other settings are different -- tofacitinib (Xeljanz), for example, is a JAK3 inhibitor -- and JAK1 is what seems to be important in the lymphomas that develop in patients with myeloproliferative neoplasms."

MPNs arise from abnormalities in bone marrow stem-cell formation and development. The disease classification of MPN includes essential thrombocytopenia (ET) and polycythemia vera (PV), in addition to MFB. Both ET and PV can transform into MFB. Though the precise mechanisms underlying the evolution of MPNs remain unknown, the discovery of an association with the JAK2 V617F mutation led to development of JAK1/2 inhibitors, which have become a mainstay of treatment for MPNs.

Clinical experience with JAK1/2 inhibitors led to observations of sporadic B-cell non-Hodgkin lymphomas in patients with MPNs treated with JAK1/2 inhibitors, Jaeger's group noted. The frequency and potential causes of the lymphomas remained unclear.

To investigate the association between JAK1/2 inhibitor-treated MPNs and development of lymphomas, the authors reviewed medical records of 626 patients with MPNs treated at MUV from 1997 to 2016. The cohort included 69 patients treated with JAK1/2 inhibitors. Investigators also analyzed bone marrow samples from 54 of the 69 patients, all treated with ruxolitinib (Jakafi).

The results showed that four of the 69 patients treated with a JAK1/2 inhibitor developed aggressive lymphomas, as compared with two of the remaining 557 patients, all of whom received conventional therapies. The difference represented a 16-fold increase in lymphoma risk among patients who received a JAK1/2 inhibitor (P=0.0017). A separate analysis of 216 patients with primary MFB showed that three of 31 (9.7%) patients treated with a JAK inhibitor developed lymphoma versus one of 185 (0.54%) conventionally treated patients, a 19-fold increase in the odds ratio (P=0.01). The median time from start of JAK inhibitor treatment to lymphoma diagnosis was 25 months.

For comparison, the authors examined data for a French cohort of 929 patients with MPNs. The data showed a 0.23% incidence of lymphoma in 872 patients treated with conventional therapies versus 3.51% among 57 patients treated with JAK1/2 inhibitors, a 15-fold increase in the OR (P=0.0205).

Examination of the 54 bone marrow samples from the Vienna cohort showed that all three who subsequently developed aggressive lymphomas during treatment with a JAK inhibitor had a preexisting immunoglobulin rearrangement (IgR) before exposure to the JAK inhibitor. Comparison with the lymphoma samples confirmed the association between the abnormality and lymphoma transformation.

Overall, nine of the 54 patients (16.7%) tested positive for IgR. Additionally, seven of 44 (15.9%) age- and sex-matched control patients who received conventional therapy or none (15.9%) tested positive for IgR.

"This indicates the presence of clonal B cells in the bone marrow of approximately 15% of primary myelofibrosis patients, regardless of treatment," the authors noted.

As a final means of confirming the results, the authors studied JAK1/2 inhibition in Stat1 altered mice and found that 16 of 24 animals developed a spontaneous myeloid hyperplasia associated with the presence of aberrant B cells.

Representatives of Incyte, which markets ruxolitinib, said in a prepared statement, “We are aware of the recent analysis reviewing the development of aggressive B-cell lymphomas among patients treated with JAK1/2 inhibitors, including ruxolitinib.… We are continuing to evaluate the analysis, but would note that the analysis was not adequately controlled and did not account for factors such as prior treatment exposure, time since MPN diagnosis, or the point at which the JAK1/2 inhibitors were initiated in the patients’ disease course.”

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