Treatment of myelofibrosis, a rare type of blood cancer, with Jakafi (ruxolitinib) gives a patient 16 times the risk of developing aggressive B-cell lymphoma, through the activation of a pre-existing “dormant” lymphoma, according to a recent study.
The results suggest that the detection of this “dormant” lymphoma may be useful to identify myelofibrosis patients at risk.
The study, “Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy,” was published in the journal Blood.
Myelofibrosis belongs to the group of myeloproliferative neoplasms, in which the bone marrow stem cells that produce the body’s blood cells develop and function abnormally, resulting in increased numbers of specific types of blood cells.
The six types of myeloproliferative neoplasms are defined by the type of blood cell abnormally produced, in which myelofibrosis results in an increased number of immature white and red blood cells.
Jakafi, a suppressor of JAK1 and JAK2 — two proteins involved in the production of blood cells —became the first FDA-approved therapy for myelofibrosis and is widely used to treat this and other types of myeloproliferative neoplasms.
However, some patients with myeloproliferative neoplasms have developed aggressive lymphomas under Jakafi treatment, suggesting a potential association.
Researchers in Vienna, Paris, and Munich evaluated the frequency of lymphoma in patients with myeloproliferative neoplasms treated or not with JAK1/2 suppressors.
They analyzed the data of 626 patients (347 women and 279 men) with myeloproliferative neoplasms diagnosed and treated at the Medical University of Vienna between 1997 and 2016.
Among myeloproliferative neoplasms, 216 patients had primary myelofibrosis, 168 had polycythemia vera (an increased number of red blood cells), 232 had thrombocythemia (excessive platelets), and 10 had unclassified myeloproliferative neoplasm.
Of the 69 patients treated with JAK1/2 suppressors, four (5.8%) developed aggressive B-cell lymphoma. Only two (0.36%) of the 557 patients treated with other therapies developed lymphoma.
The data suggest that treatment with JAK1/2 suppressors is associated with 16 times the risk of developing lymphoma. This was corroborated by observation of a similar increased risk (15-fold) in a group of 929 patients with myeloproliferative neoplasms treated at a Paris hospital.
All four patients who developed lymphoma had myelofibrosis (one after having polycythemia vera) and were being treated with Jakafi at the time. One was receiving Jakafi as first-line treatment, and another had received a JAK2 suppressor called fedratinib.
These patients were found to carry a specific mutation (called V617F) in the JAK2 gene, and lymphoma developed after a median of 25 months of Jakafi treatment.
When looking only at patients with primary myelofibrosis, three (9.7%) of the 31 patients treated with JAK1/2 suppressors developed a B-cell lymphoma, compared with one (0.54%) in 185 patients receiving other therapies.
Analysis of bone marrow samples of 44 patients with myelofibrosis collected before initiation of JAK1/2 suppressors showed that seven of them (16%) had pre-existing “dormant” aggressive B-cell lymphoma. In patients who later developed lymphoma, this “dormant” form was there as long as six years before. Additional studies in a mouse model confirmed these results.
“Our study indicates that in humans and mice, the aggressive B-cell lymphomas arise from pre-existing [malignant] B-cell clones that are detectable at early stages of [myeloproliferative neoplasms],” the researchers said.
“This is therefore the best predictive tool. It enables us to filter out the relevant 16%, categorize them and identify them as high-risk patients prior to treatment with JAK2 inhibitors,” Heinz Gisslinger, one of the study’s senior authors from the Medical University of Vienna, said in a press release.
The team noted that additional studies are needed to clarify whether lymphoma development is only associated with Jakafi treatment or with all JAK1/2 suppressors, and with suppression of JAK1, JAK2, or both.
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