Jakafi (ruxolitinib), a drug approved in 2011 to reduce the volume of enlarged spleens in patients with myelofibrosis, continues to work in this population when taken long-term.
Data showing that spleen size reduction and overall survival (OS) improvements were maintained in patients with advanced myelofibrosis who took the targeted drug over five years were shared when final results of the COMFORT-II study — one of the clinical trials that led to Jakafi's approval — were presented during the 57th Annual Meeting of the American Society of Hematology.
In the earlier COMFORT-II findings that led to the therapy’s approval, published in 2012, Jakafi significantly decreased spleen size in 28 percent 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, Jakafi reduced splenomegaly at any time during treatment by at least 35 percent in 53.4 percent of enrolled patients. Of those who crossed over to the Jakafi arm from the BAT group, which primarily took hydroxyurea, 42.2 percent experienced a significant reduction in splenomegaly.
The five-year results also showed that the drug’s safety and tolerability profiles did not change over time, noted Claire Harrison, a professor of hematology at Guy’s and St. Thomas’ NHS Foundation Trust in London, who presented the findings. Importantly, Harrison said, an OS benefit with the drug that was demonstrated after three years of study was also maintained, and would have reflected a more striking improvement had crossover by patients from the BAT arm to the Jakafi arm not confounded those results.
Jakafi 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 Jakafi, 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 Jakafi. “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 five 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 five 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 Jakafi and 73 to BAT. Patients stayed on the study until they experienced progressive splenomegaly. In the Jakafi arm, 39 patients completed five years of follow-up; 11 in the BAT arm crossed over and also completed five 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 two years that followed.
She added that 32 percent of patients taking Jakafi experienced stabilization of fibrosis, and that nearly 16 percent saw an improvement in that area, including four patients who dropped down to a normal amount of fibrosis in their marrow. In 18.5 percent 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 Jakafi 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 percent in the Jakafi arm compared with the BAT arm.
Investigators found no relevant increase in the incidence of adverse events with longer exposure to Jakafi. The most commonly reported adverse events with Jakafi 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 eight and five patients developed leukemia in the Jakafi and BAT arms, respectively. Overall, 40 percent of patients died in the Jakafi arm and 48 percent 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 Jakafi based on the findings of earlier studies.
Harrison said that Jakafi 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 Jakafi 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, Jakafi 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 five 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.