Myelofibrosis: Beyond Ruxolitinib

Myelofibrosis: Beyond Ruxolitinib


Other JAK inhibitors, combinations, and novel therapies offer more hope for patients

by
Mike Bassett,

Staff Writer, MedPage Today

Up until fairly recently, ruxolitinib (Jakafi) was the only FDA-approved treatment for intermediate- and high-risk myelofibrosis, and thus has been the cornerstone of myelofibrosis treatment for more than a decade.

However, in the last 5 years, three other JAK inhibitors have been approved — fedratinib (Inrebic) in 2019, pacritinib (Vonjo) in 2022, and momelotinib (Ojjaara) in 2023. This led to the question, said Naveen Pemmaraju, MD, of the University of Texas MD Anderson Cancer Center in Houston, of “which one to use, why, and when?”

The National Comprehensive Cancer Network, along with other guidelines from other organizations, gave caregivers some direction, with the caveat that every case is different.

As the first approved agent and first widely used targeted agent for myelofibrosis, “ruxolitinib has the most experience and the strongest track record in treating myelofibrosis,” Pemmaraju said, and has led to improvements in spleen volume, symptom response, and even overall survival.

That said, there are some common adverse effects to look out for with ruxolitinib. For example, there have been reports in clinical trials of an association with non-melanoma skin cancers, as well as a higher incidence of herpes Zoster.

Fedratinib, like ruxolitinib, is approved for patients with myelofibrosis and platelet counts ≥50 × 109/L, and comes with a black box warning in the prescribing information regarding the risk of serious and fatal encephalopathy.

Pacritinib is indicated for the treatment of adults with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L, while momelotinib was specifically approved for the treatment of adults with anemia and intermediate- or high-risk myelofibrosis.

“So, you do have some guidance, and you’re looking at the patient in front of you and the comorbidities they have,” Pemmaraju said.

Sequencing Therapy

In a study in Cancer among 524 patients who received ruxolitinib for myelofibrosis, about 40.8% discontinued treatment at 3 years. The reasons for discontinuation included lack (22.9%) or loss (11.9%) of a spleen response, ruxolitinib-related adverse events (27.5%), progression to blast phase (23.4%), ruxolitinib-unrelated adverse events (9.2%), and allogeneic transplantation during response (5.1%).

“The supposition is that not many of these patients are taking these JAK inhibitors for 5, 8, 10, or 12 years,” said Pemmaraju.

The question then becomes — what next?

“If I have a patient on ruxolitinib and they do well on it for a while and the blood count picture starts to change, because — let’s face it — none of these drugs are going to be curative, the only chance for cure is a transplant, which, sadly, few patients are eligible for,” said James Rossetti, DO, of UPMC Hillman Cancer Center in Pittsburgh. “One of the nice things about having all these drugs would be if somebody has side effects from one drug, and because their side effect profiles are very different, sometimes you can switch for that reason.”

“Or maybe you’re losing your response, or the biology of the disease is now dropping the blood counts,” he added. “Then maybe we need to get away from ruxolitinib and go with one of the newer agents because it would potentially help.”

Pemmaraju pointed out that “the concept of switching therapies is a new one, because only in the last few years have we had the option to do that. So it is an ongoing emerging concept. Importantly — and sadly — we don’t have any biomarkers, so it’s an art of medicine, a clinical call involving a constellation of factors.”

Pemmaraju said reasons for switching therapies include:

  • A myeloproliferative neoplasm symptom burden “that’s persistent and progressive, despite maximizing the JAK inhibitor”
  • A reappearance of splenomegaly
  • Elevated blasts either in the bone marrow or peripheral blood
  • Lowering of blood counts and greatly progressing elevated white blood cell counts

In addition, Pemmaraju noted that physicians should be on the lookout for symptoms in the patient that may not be typical and not necessarily the ones they presented with.

“Communicate with your patients,” he said. “If something isn’t right, reassess, also ruling out other competing comorbidities, other cancers, or other entities that could be causing these symptoms.”

“It’s quite a difficult challenge,” he added. “Once you’ve assessed that the disease is progressing through the frontline JAK inhibitor, now you are screening and looking for second-line therapy — either another JAK inhibitor, clinical trial, and if a stem cell transplant hasn’t been used yet, possibly referring to that.”

Combinations and Novel Therapies

Another question, Pemmaraju said, is whether disease modification can be achieved “with more therapy upfront rather than waiting for relapses and progression and going for sequential monotherapy. Over the last 5 years, we and others have been working on combinations, first in the add-on relapse setting, and now moving into the frontline setting.”

Last year at the American Society of Hematology annual meeting, Pemmaraju and colleagues presented results from the phase III TRANSFORM-1 trial in which they evaluated ruxolitinib with the BCL-XL/BCL-2 inhibitor navitoclax in patients with intermediate- or high-risk myelofibrosis.

The trial randomized 252 patients to receive the combination of ruxolitinib and navitoclax or ruxolitinib plus placebo. Of the patients who received ruxolitinib and navitoclax, 63.2% achieved a spleen volume reduction of at least 35% within 24 weeks compared with 31.5% of patients receiving ruxolitinib plus placebo.

Results of the phase III MANIFEST-2 trial with the BET inhibitor pelabresib plus ruxolitinib were similar to those of TRANSFORM-1, with 66% of patients treated with the combination achieving a 35% or greater reduction in spleen volume at week 24 versus 35% of patients given ruxolitinib and placebo (P<0.001).

Another combination — ruxolitinib plus the oral XP01 inhibitor selinexor — was evaluated in the phase II XPORT-MF-034 trial, showing a tolerable and manageable adverse effect profile and demonstrating efficacy in patients with JAK inhibitor-naive myelofibrosis.

Many of these approaches are now in the advanced stages of clinical trial development, said Pemmaraju, “and we eagerly await to see if any of those combinations are in fact yielding any clinical benefit for our patients.”

He also noted that the pipeline for novel therapies in this space is rapidly expanding.

“When I look at the field in the 20 years prior to the last 5 years, there wasn’t a whole lot of unique myelofibrosis-specific development beyond JAK inhibitors,” Pemmaraju said. “Many of the developments were either borrowed from the other myeloid malignancies or were still in the JAK inhibitor class of drugs.”

“But when you look at these other pathways that are either essential or important in myelofibrosis, you are seeing a lot of drug development — and we’re seeing this development at a rapid rate,” he added. “A lot of that is because we are understanding more at the lab level. We’re finding new pathways of interest, and we’re finding that drugs that were used for another purpose can be repurposed in the field of myelofibrosis, and de novo drugs are being developed for the very first time that are myelofibrosis specific, but are based on older pathways that were already known, but not previously explored.”

“I believe we’re entering a hopeful, golden era for our patients,” he said.

  • author['full_name']

    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

Pemmaraju reported multiple relationships with industry, including research support from AbbVie, which sponsored the TRANSFORM-1 study.

Rossetti disclosed relationships with BeiGene, AstraZeneca, and CTI BioPharma.

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