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Second-line therapy for myelofibrosis remains ‘active area of research’
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NEW YORK — Ruxolitinib has dramatically improved the care of patients with myelofibrosis, but new treatment strategies for patients who progress on the drug or discontinue therapy are desperately needed, according to a presenter at Chemotherapy Foundation Symposium.
The average life expectancy for patients with myelofibrosis is 5 to 6 years, but it can vary from a few months to longer than a decade, according to Marina Kremyanskaya, MD, PhD, assistant professor of internal medicine in the division of hematology/medical oncology at Tisch Cancer Institute at Mount Sinai.
The disease can manifest itself in several ways, and treatment typically depends on clinical need.
“The only treatment modality that has been shown to improve survival and offer potential for cure is allogeneic stem cell transplant,” Kremyanskaya said during a presentation. “Ruxolitinib has been shown to improve survival, though most of us believe it is due to improvements in patients’ quality of life.”
Ruxolitinib (Jakafi, Incyte) — a JAK1 and JAK2 inhibitor approved for treatment of patients with intermediate- or high-risk myelofibrosis — has shown benefit for patients with symptomatic splenomegaly, extramedullary hematopoiesis and constitutional symptoms.
However, approximately 50% of patients treated with ruxolitinib stop therapy after 3 years because they experience disease progression, develop significant cytopenias or otherwise cannot tolerate the drug.
No standard second-line therapy is available, and outcomes for patients who discontinue ruxolitinib are poor.
A single-institution retrospective study evaluated outcomes for patients who stopped ruxolitinib therapy. Median follow-up was 40 months.
Results showed median OS of 4.9 months for those who underwent no further treatment or observation and 15 months for those who underwent salvage therapy with other agents, such as immunomodulatory agents or hypomethylating agents. Median OS had not been reached for patients who underwent transplant.
“The best outcome for patients who progress on ruxolitinib or cannot tolerate it is to receive allogeneic stem cell transplant,” Kremyanskaya said. “Over the years, this has been difficult because a lot of patients did not have great donor options. Also, a lot of patients were not eligible for transplant because of age or comorbidities.”
Advances in transplantation approaches in recent years have helped many more patients become eligible for transplant.
A retrospective study that assessed outcomes of patients who underwent transplant between 2011 and 2014 showed no significant difference in outcomes between patients who had human leukocyte antigen identical sibling donors and those who had alternative donors.
“When patients stop doing well on ruxolitinib — or even show a hint of not doing well — transplantation should be strongly considered,” Kremyanskaya said. “This should really happen before they get too sick on current therapy to be able to undergo transplant.”
Multiple second-generation JAK inhibitors are in late-phase development, with the goal to fill the niche as second-line treatment after ruxolitinib discontinuation or as upfront therapy for patients with cytopenias.
These agents include pacritinib (CTI BioPharma), fedratinib (Impact Biomedicines) and momelotinib (Gilead).
The randomized phase 3 PERSIST-2 study compared the tyrosine kinase inhibitor pacritinib with best available therapy — including ruxolitinib — for 311 patients with myelofibrosis, all of whom had thrombocytopenia.
The percentages of patients who achieved at least 35% spleen volume reduction and at least 50% reduction in total symptom score from baseline to week 24 served as co-primary endpoints.
Researchers randomly assigned patients 1:1:1 to 200 mg of pacritinib twice daily, 400 mg of pacritinib daily or best available therapy. Best available therapy could include ruxolitinib.
Patients in both pacritinib treatment groups achieved superior spleen reduction volume compared with best available therapy; however, the twice-daily dose appeared more effective, with 21.6% achieving spleen response and 32.4% having total symptom score response.
The SIMPLIFY-2 trial included 156 patients previously treated with, but not refractory to, ruxolitinib. Researchers randomly assigned patients 2:1 to momelotinib or best available therapy for 24 weeks.
The trial did not meet its primary endpoint of momelotinib superiority for splenic response rate at week 24 compared with best-available therapy (6.7% for momelotinib vs. 5.8% for best-available therapy).
However, a significantly higher percentage of patients assigned momelotinib achieved 24-week symptom response (26% vs. 6%; P = .0006).
In addition, a significantly higher percentage of patients assigned momelotinib achieved red blood cell transfusion independence (P = .012).
“[Although] the trial did not meet its primary endpoint, the significant increase in transfusion independence and improvement in symptoms has resulted in the likely continued development of momelotinib in myelofibrosis,” Kremyanskaya said.
The JAKARTA-2 study assessed spleen response — defined as 35% or greater reduction in spleen volume — and change in total symptom score among 90 patients with intermediate- or high-risk myelofibrosis treated with fedratinib after ruxolitinib failure. All patients had palpable splenomegaly.
Results showed 47% of patients had spleen response at the end of cycle 3, and 55% had spleen response at the end of cycle 6. Also, 26% of patients achieved 50% or greater reduction in total symptom score at the end of cycle 6.
More than a dozen other trials are underway to assess the combination of ruxolitinib with other agents or therapeutic approaches, including intracellular signaling inhibitors, immunomodulating agents, epigenetic modulating agents and various transplantation options.
“New treatment options and strategies remain an active area of research in myelofibrosis; however, ruxolitinib remains our only currently approved therapy,” Kremyanskaya said. “I hope in the not-so-distant future we may have as many options as our colleagues who specialize in [other malignancies, such as] multiple myeloma.” – by Mark Leiser
For more information:
Kremyanskaya M. Second-line therapy after JAK inhibition in MF. Presented at: Chemotherapy Foundation Symposium; Nov. 7-9, 2018; New York.
Disclosure:
Kremyanskaya reports grant or research support from Constellation Pharmaceuticals and Incyte, as well as a consultant role with La Jolla Pharmaceutical Company.