JAK Inhibitors to Treat Myelofibrosis Could Lead to Development of Lymphomas

Janus kinase (JAK) inhibitors being used to treat myelofibrosis may actually lead to the development of aggressive lymphomas, according to new findings. Myelofibrosis is a type of rare bone marrow cancer where too many blood cells are produced, which causes scarring and hardening of the bone marrow.

Researchers from Austria studied 626 patients being treated for myeloproliferative neoplasms—the larger umbrella under which myelofibrosis falls—in order to determine if the developing lymphomas were related to the treatment. Although recent reports have hinted at an increased risk for lymphomas in myelofibrosis patients using JAK inhibitors, the frequency and potential causes remain unclear.

In general, JAK inhibitors are not a cure for myelofibrosis, but they do offer effective symptom relief, the study authors noted. JAK inhibitors function by targeting the abundant production action of the JAK2 gene, which controls the production of red blood cells and is thought to be behind myelofibrosis and its related condition.

For the study, published in the journal Blood, there were 69 patients with myelofibrosis being treated with the JAK inhibitors; of those, 4 patients developed lymphomas. The study authors also noted for the sake of comparison that just 2 of the 557 patients who did not receive JAK inhibitors developed lymphomas. Thus, the investigators deduced a 16-fold increased risk for aggressive B-cell lymphoma in patients receiving the JAK inhibitor treatment.

The study authors described these lymphomas as “a rare but consistently occurring second malignancy sharing some clinicopathological features.”

The researchers then focused only on samples taken from myelofibrosis patients, which were found to have a preexisting B-cell clone in the bone marrow in 3 of those 4 patients who later developed lymphomas. The researchers determined that these clones were the same that later developed into the lymphoma. They were present as early as 6 years before developing into full-fledged lymphoma, which the researchers said offers a wide window to determine which patients are at risk.

The study authors also said that these 4 lymphoma patients were treated with ruxolitinib, though 1 had initially been treated with fedratinib. They did not determine if lymphoma development was linked solely to ruxolitinib or wider JAK inhibitor treatment.

“The most surprising finding is that cancer/lymphoma cells (or their precursors) can be found in the bone marrow of patients years before the lymphoma develops,” study co-author Ulrich Jaeger, MD, told Rare Disease Report^®. “They seem to be in a dormant or controlled state. This may be important for the selection of patients for this treatment (16% are affected).”

The researchers were also able to demonstrate this link between JAK inhibitors and the developing lymphomas in mouse models.

In their modeling, the researchers said the “common denominator between mice and men is immune-suppression, which is exerted in human patients by ruxolitinib.”

Another common feature between the mice and human myelofibrosis patients was that the lymphoma only became evident after the reduction of the myelofibrosis — in humans, that was via the ruxolitinib.

While there are “clear parallels” for the course of the disease in both mice and human patients, the underlying mechanisms for the diseases might be different, according to the researchers. JAK2 mutations are involved in human patients, but it may be something else in mice models.

“The next step would be to test larger series of patients particularly in prospective clinical trials for these dormant cells and to establish the clinical value on a bigger scale,” Dr Jaeger said.