Ruxolitinib in Myelofibrosis: 'Unprecedented' for Some Patients

Zosia Chustecka

February 29, 2012

February 29, 2012 — The first drug ever approved for myelofibrosis, ruxolitinib (Jakafi, Incyte/Novartis), has shown results that are "unprecedented" in the treatment of this disorder, according to one of the principal investigators, Claire Harrison, DM, from Guy's Hospital, London, United Kingdom.

Dr. Harrison headed 1 of the 2 pivotal trials (COMFORT-1 and COMFORT-2) that were filed for registration; both were published in the March 1 issue of the New England Journal of Medicine. However, an accompanying editorial questions some of the results.

Ruxolitinib was approved in the United States in November 2011; it is currently awaiting approval in Europe.

Dr. Harrison told Medscape Medical News that in her clinical experience, the "vast majority of patients" on ruxolitinib experience benefits in quality of life and symptom relief that are highly clinically meaningful and durable.

Researchers involved in the 2 studies (which were sponsored by the manufacturers) have been enthusiastic about the results, and there was considerable excitement among experts not involved in the trials when the results were first presented at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO), as reported at that time by Medscape Medical News. For example, Alessandro Vannucchi, MD, associate professor of hematology at the University of Florence, Italy, who was a principal investigator on COMFORT-2, said that "this therapy has the potential to change the treatment landscape."

In addition, ASCO described the results of these studies as a "notable" advance in its Clinical Cancer Advances 2011 report.

Now, however, comments from an expert not involved in either of the 2 pivotal studies, but who was involved in an earlier phase 1/2 study of the drug, temper some of this enthusiasm. In his editorial accompanying the 2 studies, and in an interview with Medscape Medical News, Ayalew Tefferi, MD, from the division of hematology at the Mayo Clinic Rochester, Minnesota, explained that ruxolitinib is suitable for only some patients with myelofibrosis, possibly only 25%. Even then it might not be the best option, he said.

Dr. Tefferi pointed out that ruxolitinib does not affect the underlying disease, and offers only transient palliation of some symptoms. In addition, he maintains that it does not improve survival, and points out that it has adverse effects, including myelosuppression, and is expensive.

"I don't believe that anyone doubts...that it is a useful addition to the treatment options [for myelofibrosis]. We don't just treat patients to prolong their lives, we also treat them to make them feel better," Dr. Tefferi explained to Medscape Medical News.

Useful in About 25% of Patients

Ruxolitinib is not the best treatment option for the majority of patients, he maintains. His team recently published their clinical experience with more than 1000 patients who had primary myelofibrosis — all at the Mayo Clinic, and most of them seen personally by Dr. Tefferi (Mayo Clin Proc. 2012;87:25-33). This review shows how patients present with this disease; it provides a glimpse of the "universe of myelofibrosis," he said.

"Nowadays, most patients are not very sick when they present," he continued. About 25% of patients present with low-grade disease that does not require immediate action. They can be followed with observation, and they will live for many years; average survival for this group is more than 20 years, he noted.

"In this group, treatment could kill the patients faster than the disease would."

Another 25% of patients present with high-grade disease, and are at risk of progressing very quickly to acute leukemia, "so there is no time to play around," Dr. Tefferi said, emphasizing that these patients need a stem cell transplant. "If they are not candidates for transplant, then you would want to enrol them in a clinical trial of an investigational agent that has the potential for disease-modification and prolonging of survival," he explained.

That leaves about 50% of patients with myelofibrosis in the middle-risk category. About half of these patients can be managed on hydroxyurea or other available treatment options, he said. But for the other half, ruxolitinib would be a reasonable option to consider.

However, ruxolitinib is not the only option, he emphasized. These patients could also be offered a transplant (with something like a 50% chance of kill or cure), or other available therapies such as hydroxyurea, or they could be offered investigational agents, including new and improved JAK inhibitors, which might be better than ruxolitinib, but which are free because they are research drugs that are in clinical trials. Why would a patient who is eligible for a clinical trial and for whom there is no impediment to participation (e.g., such as distance) want to take ruxolitinib, he asked.

"Physicians should, as much as possible, put patients into clinical trials where the drugs are free and [possibly] better," he said.

Dr. Harrison told Medscape Medical News that she disagrees with these estimates of the proportion of patients with myelofibrosis who could benefit from ruxolitinib. In her opinion, about half  the patient population would stand to benefit, if not slightly more. The pivotal studies were conducted in patients with intermediate-risk 2 disease; the drug could benefit patients with intermediate-risk 1 disease, although with adverse effects such as weight loss, fevers, and night sweats, "all of which would respond very nicely to ruxolitinib," she said.

Defect in Bone Marrow

Myelofibrosis involves a defect in the bone marrow, which results in scar tissue in the bone marrow that disrupts blood formation, causing anemia and thrombocytopenia. However, the scarred bone marrow also forms and accumulates in other organs, notably the spleen and liver, leading to distention of these organs and discomfort for these patients, Richard Stone, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, told Medscape Medical News in a  recent interview.

This distention of the spleen can lead to systemic symptoms, such as early satiety and weight loss, from the spleen crushing the stomach; the effects in the liver can lead to hepatic failure. The combined impact of all these effects is an abrupt shortening of life expectancy, Dr. Stone noted. The course of the disease is variable, but patients with high-risk myelofibrosis have a median survival of 5 to 8 years.

Ruxolitinib Relieves Symptoms

COMFORT-1 and 2, which formed the basis of the approval of ruxolitinib, showed that ruxolitinib reduces the size of the spleen and alleviates disease-related symptoms, such as fatigue, weight loss, abdominal pain, severe itching, night sweats, and bone pain.

The primary end point in both studies was a reduction in spleen volume of at least 35%, documented by magnetic resonance imaging, although the time period was different in the 2 trials (24 weeks in COMFORT-1 and 48 weeks in COMFORT-2). Both trials showed that ruxolitinib had a significant impact on this primary end point.

COMFORT-1, which compared ruxolitinib and placebo in 209 patients, showed that 41.9% of patients in the ruxolitinib group had a reduction in spleen volume of at least 35% at 24 weeks, compared with 0.7% in the placebo group (P < .001).

COMFORT-2, which compared ruxolitinib and best available therapy in 219 patients,  showed that 28% of patients had a reduction in spleen volume of at least 35% at 48 weeks, compared with 0% in the control group (P < .001). The corresponding percentages at week 24 were 32% and 0% (P < .001).

COMFORT-2, which was headed by Dr. Harrison, also showed that patients treated with ruxolitinib had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. However, the researchers report that the drug was associated with hematologic adverse effects, such as thrombocytopenia and anemia; these were managed with dose reduction, interruption of treatment, or transfusion. "Anemia was seen but was manageable, " Dr. Harrison said, noting that some patients reduced their reliance on transfusions, and a few became transfusion independent while on the drug.

Dr. Harrison and colleagues report that adverse effects of any grade requiring dose reductions or interruptions were seen in 63% of patients treated with ruxolitinib and 15% of those treated with best available therapy.

Ruxolitinib had "an unprecedented benefit in terms of quality-of-life concerns for patients," Dr. Harrison told Medscape Medical News. COMFORT-1 showed this against placebo, and COMFORT-2 showed this even more convincingly against the physician's choice of best available therapy, she said. "The spectrum of drugs that are currently available to treat these patients does not have anything like the quality-of-life responses that we saw with ruxolitinib."

One example of this is the intractable itching that a small proportion of these patients experience. It can "make their life awful.... Occasionally patients commit suicide because of it," she said. Many agents, including antihistamines, have been tried and have failed, but this symptom responds very well to ruxolitinib, she noted. One of her patients who was not able to bathe or shower for 6 years because of intractable itching and aquagenic pruritu is now able to with ruxolitinib; "this has transformed his life," she said.

The reduction in spleen size that was seen in both COMFORT studies has also not been seen previously, Dr. Harrison noted. There have been a few previous reports of spleen reduction with other agents, such as chemotherapy, but not of the same magnitude and durability, she said. One of her patients, a 63-year-old woman, had a spleen size of 30 cm and had lost 15 kg; after ruxolitinib treatment, her spleen was nearly normal (11 cm) and she had gained 20 kg.

She takes issue with Dr. Tefferi's statement that the benefits from ruxolitinib are transient, and pointed out that the primary end point in COMFORT-2 was 48 weeks, which is nearly a year, and the median duration of response for that benefit (spleen reduction) has not yet been reached. The results show that the response is durable, she emphasized.

Impact on Overall Survival

COMFORT-1, which was a placebo-controlled trial, also showed an improvement  in overall survival.

This point was highlighted by principal investigator Srdan Verstovsek, MD, PhD, in a press release issued by the University of Texas M.D. Anderson Cancer Center in Houston. At a median follow-up of 51 weeks, there were 13 deaths (8.4%) in the ruxolitinib group and 24 (15.7%) in the placebo group. At the time of the analysis, 111 of 154 patients in the placebo group had crossed over to the ruxolitinib group, another 38 had dropped out of the study, and 2 patients were still on placebo, according to the statement. Most patients in the placebo group experienced progressive spleen enlargement and a worsening of myelofibrosis-related symptoms.

However, Dr. Tefferi takes issue with this finding of improved overall survival. He questions the ethics of offering a placebo to such patients, and told Medscape Medical News that although placebo-controlled trials are often required for registration, "this is controversial, and I would not offer a placebo to such sick patients."

In his editorial, Dr. Tefferi writes that the apparent survival advantage over placebo "was confounded by the lack of risk stratification during randomization and the possibility that withholding the best available therapy enabled occult or overt progression of disease and negatively influenced coexisting conditions."

He told Medscape Medical News that "if you do nothing, obviously the disease is going to progress faster than if you do something."

Countering these comments, Dr. Harrison pointed out that the patients in COMFORT-1 had already tried and failed best available therapies, and noted that the placebo-controlled trial was required for registration.

However, in the phase 3 COMFORT-2 study, which compared ruxolitinib and best available therapy, there was no effect on overall survival.

An earlier phase 1/2 trial  conducted by Dr. Tefferi and colleagues also demonstrated no effect on survival (N Engl J Med. 2011;365:1455-1457). This was a retrospective study, in which patients were compared with historic controls, but they were matched temporally and according to their disease grade, and "we were very careful to make sure that we were comparing oranges with oranges," he said. "This shows clearly that there was absolutely no difference [in survival]."

Mechanism of Action

Ruxolitinib is the first JAK inhibitor to be marketed, and it acts to inhibit both JAK1 and JAK2. When it was determined that JAK is involved in myeloproliferative neoplasms, there was hope that a JAK inhibitor would act as a specific targeted agent and stop the disease, like imatinib (Gleevec) for chronic myeloid leukemia acting through the BCR-ABL1 mutation. However, it turns out that JAK is not disease-specific, and inhibition of this system does suppress the leukemia clone that drives the disease, Dr. Tefferi explained.

However, the JAK system is important in myelofibrosis; it plays a role in the production and activity of proinflammatory cytokines, which appear to contribute to disease symptoms. "Ruxolitinib induces a rapid and marked suppression of these cytokines, in conjunction with the salutatory effects on constitutional symptoms," Dr. Tefferi notes in his editorial. He suggests that this cytokine modulation is the drug's primary mode of action, although nonspecific myelosuppression probably contributes to the drug's ability to reduce spleen size and to the adverse hematologic effects.

This cytokine suppression might lead to a rebound effect if the drug is stopped suddenly, Dr. Tefferi noted. "All the symptoms come back with [a vengeance]," he said, adding that 2 of his patients ended up in intensive care for a while. "Doctors need to be aware of this," he added.

Dr. Harrison disagreed with these comments on ruxolitinib's mode of action. She argued that ruxolitinib does have some effect on the malignant clone, and that is why it reduces the spleen size and normalizes the blood count. This is not a mutation-specific effect, she said — patients with and without the JAK2 mutation benefit from ruxolitinib — but there is an effect on JAK downstream signaling, and she believes that the drug does have some disease-modifying effect. Other drugs that dampen cytokine release have been used previously in myelofibrosis and have not shown benefits similar to ruxolitinib, she pointed out.

The lessons learned during the development of ruxolitinib have already stimulated research, and several new JAK inhibitors are under development.

What happened with ruxolitinib was unexpected, Dr. Tefferi writes. The drug turned out to have a primarily anticytokine rather than a selective anticlonal effect; this in turn has broadened the insight into the pathogenesis of the disease, and will hopefully lead to new and potentially better therapies, he notes.

COMFORT-1 was funded by Incyte Pharmaceuticals.  COMFORT-2 was supported by Novartis. Dr. Harrison reports receiving grants and speaker payments from Novartis; acting as a consultant for S*BIO and YM BioSciences; and receiving payments for lectures from sanofi-aventis and Pfizer. Several coauthors report receiving funding from Novartis, 2 coauthors are employees of Novartis, and 2 are employees of Incyte. Dr. Verstovsek reports receiving a research grant from Incyte, and that his institution receives grants from many pharmaceutical companies. Several coauthors report receiving payments from Incyte, and 3 coauthors are employees of Incyte. Dr. Tefferi has disclosed no relevant financial relationships.

N Engl J Med. 2012;366:787-798, 799-807, 844-846.  COMFORT-2 Abstract,  COMFORT-1 Abstract,  Editorial

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