Ruxolitinib Shines in New, Long-Term Myelofibrosis Data


Data shows ruxolitinib continues to work in patients with advanced myelofibrosis by maintaining spleen size reduction and overall survival improvements over the course of a 5 year study, according to data presented during the 57th Annual Meeting of the American Society of Hematology.

Ruxolitinib Long-Term Myelofibrosis Data

Ruxolitinib Long-Term Myelofibrosis Data

Claire Harrison, MD

Data shows ruxolitinib (Jakafi) continues to work in patients with advanced myelofibrosis by maintaining spleen size reduction and overall survival (OS) improvements over the course of a 5 year study, according to data presented during the 57th Annual Meeting of the American Society of Hematology.

Ruxolitinib, approved in 2011, improved and maintained reduction and OS, in the the COMFORT-II study. The study was one of the clinical trials that led to the treatment's approval. In the earlier COMFORT-II findings that led to the therapy’s approval, published in 2012, ruxolitinib significantly decreased spleen size in 28% of patients, but no decrease was seen in patients in the control arm, who were taking best available therapy (BAT).

In the longer-term study, ruxolitinib reduced splenomegaly at any time during treatment by at least 35% in 53.4% of enrolled patients. Of those who crossed over to the ruxolitinib arm from the BAT group, who were primarily treated with hydroxyurea, 42.2% experienced a significant reduction in splenomegaly.

The 5-year results also showed that the drug’s safety and tolerability profiles did not change over time, said Claire Harrison, MD, professor of hematology, Guy’s and St. Thomas’ NHS Foundation Trust, who presented the findings. Harrison said an OS benefit with the drug that was demonstrated after 3 years of study was also maintained, and would have reflected a more striking improvement had crossover by patients from the BAT arm to the ruxolitinib arm not confounded those results.

Ruxolitinib is an oral JAK1 and JAK2 inhibitor that slows or halts the cell-signaling process that causes myelofibrosis, a disease characterized by the replacement of healthy bone marrow with scar tissue. The spleen becomes enlarged when, in the absence of bone marrow, it takes over part of the job of producing new blood cells. Myelofibrosis can also bring on anemia, night sweats, and muscle and bone pain—as well as a reduction in life expectancy.

Harrison said that ruxolitinib, a tyrosine kinase inhibitor that is also approved to treat the rare blood disorder polycythemia vera, has made an enormous difference in the lives of tens of thousands of patients with myelofibrosis and has been “a great joy” to prescribe.

“For the first time, I was able to treat patients with a drug that made them feel better,” Harrison said of ruxolitinib. “A week or so later, they were smiling, and one patient was crying because he was able to take a bath for the first time in 5 years, because the disease causes dramatic water-induced pruritis (itching). These patients gained weight, were sleeping better, and were physically performing better. They’re able to enjoy life. They said, ‘I took a walk, I played golf, I went out with my wife, I didn’t feel a burden on my family anymore, I was able to work.’ There are patients I see now who’ve been on the study for 5 years who say, ‘I know I’m alive because of this drug.’”

Harrison noted that COMFORT-II provides a large amount of data for a population with a rare condition. Initially, 146 patients were randomized to ruxolitinib and 73 to BAT. Patients stayed on the study until they experienced progressive splenomegaly. In the ruxolitinib arm, 39 patients completed 5 years of follow-up; 11 in the BAT arm crossed over and also completed 5 years of treatment, with another 28 from the BAT arm dropping out.

The study found that the median duration of response for a significant reduction in spleen volume was 3.2 years, but Harrison said there was “a really strong suggestion of a plateau in response after that,” meaning that, for patients who stayed on the medication after hitting the 3.2-year mark, “there was hardly any dropoff” in control of their spleen size in the 2 years that followed.

She added that 32% of patients taking ruxolitinib experienced stabilization of fibrosis, and that nearly 16% saw an improvement in that area, including 4 patients who dropped down to a normal amount of fibrosis in their marrow. In 18.5% of patients, however, fibrosis worsened.

After a drop in the first 12 weeks, hemoglobin levels recovered to match those in the BAT arm and then stayed stable, which Harrison described as “very reassuring for patients and clinicians.” Reductions in JAK2 V617F allele burden, a speculative biological endpoint that may factor into research, were apparent with longer-term treatment.

As of April 2015, a median duration of OS had not yet been reached in patients in the ruxolitinib arm; the median was 4.1 years in the BAT arm, but, using an accepted statistical tool to consider what median OS would have been in the BAT arm without crossover, investigators suggested it would have been 2.7 years. The reduction in death in the intent-to-treat population was 33% in the ruxolitinib arm compared with the BAT arm.

Investigators found no relevant increase in the incidence of adverse events with longer exposure to ruxolitinib. The most commonly reported adverse events with ruxolitinib at any time were thrombocytopenia, anemia, diarrhea, and peripheral edema; grade 3/4 adverse events included anemia, thrombocytopenia, pneumonia, general physical health deterioration, and dyspnea. A total of 8 and 5 patients developed leukemia in the ruxolitininb and BAT arms, respectively. Overall, 40% of patients died in the ruxolitinib arm and 48% in the BAT arm.

Adverse events leading to drug discontinuation were reported in about one-quarter of patients, but there was no pattern of serious adverse events occurring after discontinuation that would suggest a withdrawal effect, which had been a potential concern about ruxolitinib based on the findings of earlier studies.

Harrison said that ruxolitinib will next be studied in earlier-stage myelofibrosis, based on findings from COMFORT-II that patients who received the drug later in the course of their disease experienced less benefit. It’s “biologically plausible” that this will work well for patients, Harrison said, since “the disease is more complex and harder to treat as it progresses.”

Scientists will also test ruxolitinib in combination with drugs that counteract anemia or thrombocytopenia, or with other cancer drugs, such as panobinostat or PI3K inhibitors. In patients eligible for bone marrow transplant, Harrison explained, ruxolitinib may be tested as a means of helping to control graft-versus-host disease after the procedure.

She added that a host of new drugs for myelofibrosis are expected to emerge over the next 5 to 10 years, including a new JAK inhibitor and a telomerase inhibitor. “It’s a massively exciting field, and it’s a great privilege to be working in it,” she said.


  1. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term efficacy and safety in comfort-ii, a phase 3 study comparing ruxolitinib with best available therapy for the treatment of myelofibrosis: 5-year final study results. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 59.
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