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General Updates | Management of ruxolitinib failure in myelofibrosis

John Mascarenhas, MD, Icahn School of Medicine at Mount Sinai, New York, NY, provides insights into the management of patients who fail ruxolitinib treatment. To begin with, patients treated with ruxolitinib who have residual transfusion burden can receive various agents in addition to ruxolitinib. Patients who have poorly controlled spleen and symptom burden and anemia should switch from ruxolitinib to another agent like fedratinib, and patients who are transplant-eligible should be referred for transplantation. In addition, patients also have the opportunity to enroll in clinical trials evaluating novel agents for MF, including pelabresib, navitoclax, parsaclisib, and navtemadlin. This interview took place virtually.

Transcript (edited for clarity)

The failure of ruxolitinib treatment, the definition can vary. So some patients fail because they never have a response to begin with. That’s a minority of patients. Other patients may fail because they are intolerant to the drug. They can develop significant cytopenias or non-hematologic toxicity, and I would say that that’s also a minority of patients, but they do exist. And then most patients don’t, because they have some degree of response, and it may be suboptimal and/or optimal, and then lose that response and start having progressive spleen symptom or both, or progressive cytopenias...

The failure of ruxolitinib treatment, the definition can vary. So some patients fail because they never have a response to begin with. That’s a minority of patients. Other patients may fail because they are intolerant to the drug. They can develop significant cytopenias or non-hematologic toxicity, and I would say that that’s also a minority of patients, but they do exist. And then most patients don’t, because they have some degree of response, and it may be suboptimal and/or optimal, and then lose that response and start having progressive spleen symptom or both, or progressive cytopenias. That’s often a reason for discontinuation.

So depending on what that looks like for any given individual, will inform the best treatment approach. For patients who have great spleen and symptom response but continue to have anemia, typically you check an erythropoietin level and then can dose an ESA if appropriate. Danazol, immunomodulatory drugs like thalidomide or lenalidomide, or even luspatercept off-label in the US is a possibility for those receiving ruxolitinib with residual transfusion burden, and a third of patients can respond to that. So there are various treatments to address anemia that can be added on to ruxolitinib.

If you have a poorly controlled spleen and symptom burden and anemia, for example, then I would advocate for totally changing therapy from ruxolitinib. And for spleen symptom control, I still think that fedratinib as a commercially available drug is a great option, and that should be considered.

Clinical trial options vary, and they could include pelabresib, the BET inhibitor, and navitoclax, the BCL-2 inhibitor, parsaclisib, the PI3 kinase inhibitor and navtemadlin, the MDM2 inhibitor. And there are a number of drugs that are moving into the space that would hopefully synergize with ruxolitinib and salvage those responses in patients who have a suboptimal response or have lost initial response. And then of course, if transplant is an option for the patient, patients who are losing response before they get even sicker or should be moved to transplant as quickly as possible.

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Disclosures

Research funding paid to Prof. Mascarenhas’ institution from Incyte, Novartis, Celgene, BMS, CTI Bio, Merck, Roche, Kartos, PharmaEssentia, Abbvie, and Geron. Consulting fees from Novartis, Incyte, CTI Bio, Constellation, Abbvie, Roche, Kartos, PharmaEssentia, Sierra Onc, Galecto, GSK, Karyopharm, Celgene, Geron and BMS.

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