ONCAlert | 2018 ASCO Annual Meeting

Mesa Provides Tips for Treating Myelofibrosis After Ruxolitinib

Darcy Lewis
Published Online: 3:56 PM, Sat September 17, 2016

Ruben A. Mesa, MD

According to Ruben A. Mesa, MD, developing a treatment plan for myelofibrosis (MF) patients who fail ruxolitinib requires an understanding of both current treatment options and those that are expected to become available within the next several years.

“Now that we’re five years out from FDA approval, we know that front line therapy for myelofibrosis with ruxolitinib has been very impactful for splenomegaly, symptom improvement and survival,” said Mesa, deputy director at the Mayo Clinic Cancer Center and chair of hematology/oncology at Mayo Clinic Arizona. “But we should think of MF as a chronic, long-term illness with progression-free survival as the goal.” He made the remarks during a "How I Treat" session at the second annual ASH Meeting on Hematologic Malignancies in Chicago, noting that the process of identifying which patients have failed ruxolitinib can be open to interpretation.

Mesa said to decide whether a patient is failing treatment, he assesses the stability of four key indicators: symptomology, splenomegaly, anemia status and progression toward acute myeloid leukemia (AML). Worsening of any of these is cause for reassessment, he said. Presenting a case study with these variables, he noted that one exception to this would be a persistent JAK2-V617F allele burden. “Remember, improvement here is not an expectation of ruxolitinib therapy,” he said.

Mesa characterized the current footprint of ruxolitinib in myelofibrosis as being the front line therapy for patients with low-risk MF via the RETHINK trial and for those with intermediate and high-risk disease. It is also the front line treatment for those with accelerated MF in the form of trials of ruxolitinib in combination with other agents. These combination trials also present an appropriate second line option if needed.

In considering the issue of why myeloproliferative neoplasms progress, Mesa referred to what he called “our classic hypothesis” of MF being a stepwise prelude to AML as mutations accumulate. He also posited that the microenvironment might not only be involved in the fibrosing process but also a stimulant for progressive disease. “I suspect there is some level of truth in both of these,” he said.

To determine whether to continue ruxolitinib, Mesa considers the drug’s effect on the patient’s symptoms, splenic status and hematological toxicity. “If the patient is getting clear benefits without toxicity, of course you continue ruxolitinib. If the patient is getting no benefit and is experiencing toxicity, stopping is an easy decision,” he said. “For those between the extremes, you can consider continuing ruxo, but ask yourself what is the alternative.”

One alternative would typically be allogeneic stem cell transplantation. Mesa identified four key questions to consider: timing, what pre-transplant therapy to use, if alternative donor models are an option, and what post-transplant therapy to use.

Mesa acknowledges this can be a difficult decision due to the likelihood of diminishing returns if allotransplant is postponed too long. “Frankly, the ideal time is probably sooner than we’d all like,” he said. “When I reflect back, there have probably been patients who ended up going to transplant later than they should have.”

Alternative JAK inhibitors are another option. “Pacritinib, momelotinib and NS-018 may play a role as JAK inhibitors with different profiles than ruxolitinib for cytopenias,” Mesa noted. “They give us a range of choices, but they are all still on trial.”

Trial participation with ruxolitinib combinations can also be considered, he said. “The combo agents are all active in terms of symptom control and splenomegaly, but it’s difficult to know if there are any incremental benefits beyond what the ruxo provides,” he said. “Until we get more data, the combinations are not ready for prime time yet.”

Finally, Mesa discussed new drugs such as PRM-151 and imetelstat. “Even though they’re in Phase II trials they are already showing intriguing activity and mechanism of action,” he said.

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