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Myelofibrosis symptom control takes ‘significant’ step forward with ruxolitinib approval
In mid-November, the FDA approved the JAK inhibitor ruxolitinib for the treatment of myelofibrosis.
Ruxolitinib (Jakafi, Incyte) is the first FDA-approved drug for symptom alleviation in myelofibrosis, and some clinicians suggest it could be the first in a series of breakthroughs that help alleviate the symptoms of the progressive and frequently debilitating bone marrow disease.
“The approval of ruxolitinib is such a significant medical advancement for patients suffering from myelofibrosis,” said Srdan Verstovsek, MD, PhD, associate professor in the leukemia department at The University of Texas MD Anderson Cancer Center. “It is fair to say that ruxolitinib has the potential to transform the way we treat myelofibrosis, and it is a starting point for developing combination therapies that would bring to patients additional benefits and, hopefully, eventually result in the elimination of the disease.”
Myelofibrosis, considered a type of chronic leukemia, is marked by an enlarged spleen, anemia, decreased blood counts and weight loss.
The condition disrupts the body’s production of blood cells, leading to the formation of scar tissue in the bone marrow and forcing blood cells to produce in the spleen and liver.
This can result in a severely enlarged spleen and liver, as well as anemia. Patients also may experience constitutional symptoms, weight loss, night sweats, fever and fatigue.
Ruxolitinib is an oral drug taken twice daily that inhibits the JAK1 and JAK2 enzymes that are involved in regulating blood and immunological functioning. Its approval was based on the results of two clinical trials, the COMFORT-I and COMFORT-II trials, which showed a greater reduction in spleen size with ruxolitinib compared with placebo or best available therapy.
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Photo by Juliana Thomas; courtesy of Memorial Sloan-Kettering Cancer Center |
In addition, the drug showed significant improvements in myelofibrosis-related symptoms that dramatically affect patients’ quality of life and performance status.
Furthermore, new longer-term follow-up data from COMFORT-I — scheduled to be presented at the 53rd ASH Annual Meeting and Exposition — indicate treatment with ruxolitinib also may prolong the survival of patients with myelofibrosis.
HemOnc Today spoke with several experts in the field about ruxolitinib’s approval, its clinical significance for the treatment of myelofibrosis and its potential benefits for patients.
Treating the symptoms
“Myelofibrosis is a difficult illness. Although fatal for some, there is a burden of suffering that is more universal with the illness,” said Ruben A. Mesa, MD, director of the Acute and Chronic Leukemias Program in the Division of Hematology-Oncology at Mayo Clinic in Arizona. “It also includes a massive enlargement of the spleen, sometimes to 20 times its normal size, where it can look like a full-term pregnancy.”
Patients have difficulty walking, and the enlarged spleen stretches out the stomach, resulting in constipation, diarrhea or other gastrointestinal problems. Additionally, patients have many symptoms independent of the enlarged spleen, including cachexia, fatigue, night sweats, pruritus and bone pain.
All of these symptoms combined lead to a general deterioration of the body and quality of life and ultimately can result in a slow death.
“Patients with myelofibrosis suffer greatly, particularly because of their spleen size, their systemic symptoms and general well-being,” said Ross Levine, MD, associate member at Memorial Sloan-Kettering Cancer Center. “We have been trying lots of different agents to treat the disease, but they have only modest effects.”
The only known curative treatment for myelofibrosis is bone marrow transplant.
However, given that most patients diagnosed with myelofibrosis are aged older than 60 years, bone marrow transplant only is a good option in about 5% to 10% of patients diagnosed with the condition, Mesa said.
Other treatment options are targeted at reducing the primary symptoms of myelofibrosis: enlarged spleen and anemia. Drugs such as thalidomide (Thalomid, Celgene), lenalidomide (Revlimid, Celgene) or hydroxyurea may help to reduce the size of the spleen, but their use and efficacy is debated among experts.
“We do not have good drugs to treat these patients, and some of the drugs we do have are leukemogenic in a disease where 20% of people will progress to and die of acute leukemia,” said Jerry Spivak, MD, director of the Center for the Chronic Myeloproliferative Disorders at Johns Hopkins Medicine.
Targeting JAK
Ruxolitinib is the first myelofibrosis-specific treatment available, and it is the first in a line of several JAK2 inhibitors that were developed after the discovery of the JAK2 mutation in 2005.
The JAK2 mutation is present in about half of patients with myelofibrosis, but it is not the cause of the disease, and it is just one of many mutations these patients have.
“Not all JAK2 inhibitors are JAK2 mutation-specific,” said Verstovsek, a lead researcher on one of the phase 3 studies of ruxolitinib. “All the inhibitors we have are only JAK inhibitors. They inhibit mutated JAK2 and normal JAK2. Patients with or without JAK2 mutations are candidates for JAK2 inhibitors. The benefit is the same.”
This non-specificity means two things, according to Verstovsek.
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Clinicians do not have to test patients for JAK2 mutations before treating them with JAK2 inhibitors, and patients who have a mutation and are given a JAK2 inhibitor do not need to have periodic tests for JAK2 allele burden to see how many cells are still present with JAK2 mutations.
COMFORT trials
The results from two phase 3 trials examining ruxolitinib’s safety and efficacy were presented at the 2011 ASCO Annual Meeting.
The COMFORT I and II studies had a primary endpoint of at least 35% reduction in spleen volume and a secondary endpoint of symptom alleviation.
“This was the first time in malignant hematology that symptom improvement was a secondary endpoint, and it was assessed using a new tool developed in conjunction with the FDA — the myelofibrosis symptoms assessment form,” said Verstovsek, who presented the results of COMFORT-I.
COMFORT-I was a randomized, double blind, placebo-controlled study. It included 240 patients with myelofibrosis who were randomly assigned to treatment with 15 mg or 20 mg of ruxolitinib twice daily, based on baseline platelet count, or placebo.
“Almost all patients had some reduction in spleen size, and about 42% met the 35% or greater threshold,” said Mesa, who helped to develop and validate the myelofibrosis symptoms assessment form. These improvements occurred regardless of the presence or absence of the JAK2 mutation.
In addition, about 46% of patients on ruxolitinib had at least a 50% decrease in total symptom score as measured by the myelofibrosis symptoms assessment form. Measured symptom improvement occurred in areas such as abdominal discomfort, inactivity, early satiety, night sweats, itching, and bone or muscle pain.
Serious adverse events occurred in 6.1% of patients assigned to ruxolitinib and 5.6% of patients on placebo. Overall, 11% of patients on ruxolitinib and 11% of patients on placebo discontinued treatment due to adverse effects. The most common adverse events were thrombocytopenia and anemia, which were more common in those with higher baseline grade. However, these adverse effects rarely led to discontinuation of the drug. Only one patient in each treatment group discontinued due to anemia. Also, with continued time of study, thrombocytopenia and anemia decreased and approached that of placebo levels.
Results were similar in COMFORT-II. The study compared ruxolitinib with best available therapy, which was left up to physician choice.
After 48 weeks, 28.5% of patients on ruxolitinib achieved the primary endpoint compared with none of the patients assigned to best available treatment.
Clinical implications
Although these physicians said ruxolitinib is a treatment for symptoms rather than a cure, they do not downplay the effect this drug could have on those who have myelofibrosis.
“In their day-to-day life, patients will have more energy. They will gain weight,” Mesa said. “Having treated people on the clinical trial, I saw several patients who were able to go back to work who were previously medically disabled due to symptoms of their illness. People, overall, will have much greater enjoyment of life and greater quality of life.”
Despite the excitement about ruxolitinib, there are issues to which clinicians should pay attention as they begin to use this drug.
First, researchers do not fully understand why certain patients are benefiting more from treatment with ruxolitinib than others.
“There definitely remains, for reasons that are not fully understood, some heterogeneity in the response to ruxolitinib,” Levine said. “There are some patients who benefit a lot and others who benefit much less.”
Second, if patients have to stop treatment with ruxolitinib — either due to adverse effects or concurrent illness — symptoms of myelofibrosis will return within 7 days.
“Clinicians have to be aware that whatever symptoms were there before the patient went on ruxolitinib are going to come back, and they have to be prepared to deal with those sequelae,” Levine said.
Finally, research still is being conducted to examine whether ruxolitinib had any effect on anemia, another severe adverse effect of myelofibrosis.
“We observed a total of 40% response rate in those individuals who were transfusion-dependent for anemia, but we also observed a similar response rate in those individuals who were on placebo,” Mesa said. “We are analyzing the data in a variety of ways to try to get a better idea of anemia response.”
Possible survival benefit
Several abstracts were presented at the 53rd American Society of Hematology Annual Meeting and Exposition that will provide details on a survival advantage seen with ruxolitinib in the COMFORT-I trial and provide more details on the long-term follow-up of patients taking ruxolitinib.
Abstract No. 278 includes a longer-term follow-up analysis that evaluated the efficacy of ruxolitinib in COMFORT-I across patient subgroups and examined whether a survival advantage is associated with treatment with the drug.
In the analysis, the researchers examined the two primary endpoints of COMFORT-I — reduction in spleen volume and improvement in myelofibrosis-related symptoms — across a variety of subgroups, including myelofibrosis disease subtype, age, International Prognosis Scoring System risk group, presence or absence of JAK mutation, baseline hemoglobin, baseline spleen size and baseline total symptom score.
Results indicated that ruxolitinib had a consistent benefit vs. placebo for both spleen volume reduction and symptom alleviation across all of the subgroups.
In the survival analysis, researchers found that 13 patients taking ruxolitinib had died compared with 24 on placebo (HR=0.499; 95% CI, 0.254-0.98).
“It is likely that [ruxolitinib] may have an effect on slowing down the disease or helping patients live longer by helping to alleviate the significant debilitation and morbidity associated with their illness,” Mesa said. “It is a significant moment indeed. Ruxolitinib does not cure the illness, but it represents the most significant incremental benefit over anything we have had in the past.”
Verstovsek said he was satisfied to learn from longer follow-up of the randomized, phase 3 COMFORT-1 study that ruxolitinib therapy not only improved myelofibrosis-related symptoms, reduced patients’ enlarged spleen and liver, improved patients’ weight and ability to walk, but that better control of disease signs and symptoms resulted in the prolongation of life of patients with advanced myelofibrosis.
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Verstovsek and colleagues also were scheduled to present two additional abstract that help to illustrate ruxolitinib’s potential.
Abstract No. 793 includes data that compares patients treated with ruxolitinib with 310 patients with myelofibrosis with patient characteristics that would have allowed them to be enrolled in the phase 1/2 trial of ruxolitinib.
When comparing OS between ruxolitinib-treated patients and the historical controls, treatment with the JAK inhibitor resulted in a significant survival difference (P=.022). After a median follow-up of 32 months, 30.8% of patients in the ruxolitinib group had died vs. 60.9% of historical control patients after 22 months of follow-up. Among high-risk patients, the survival difference was even greater (P=.006). At follow-up, 33.3% of ruxolitinib patients had died vs. 67.9% of historical controls.
Abstract No. 3851 includes an analysis of the longest treated patients on ruxolitinib, those at The University of Texas MD Anderson Cancer Center who were enrolled in the phase 1/2 trial.
Verstovsek and colleagues provided details on the 2-year survival of these patients. The updated data involved 107 patients — 63 at high risk, 34 at intermediate-2 risk, and 10 at intermediate-1 risk.
After 32 months of follow-up, 54% of patients were still receiving treatment with ruxolitinib and 69% of patients were still alive.
However, among patients who remained on the drug, 2-year survival was 92% among those at intermediate-2 risk and 88% among those at high risk. Among patients who discontinued therapy, 2-year survival was 32% among those at intermediate-2 risk and 21% among those at high risk.
In addition, data indicated that the degree of reduction in spleen size was an indicator of survival.
Patients who had at least a 50% reduction in palpable spleen length while on ruxolitinib had significantly longer survival than those with a less than 25% reduction in spleen size (P<.0001).
“Looking at data from patients in the phase 1/2 study, at this point, many patients remain on the drug and continue to benefit from the drug,” Mesa said. “It means that the drug leads to a rapid response and then a plateau, but patients are stable with improvement in spleen [size] and symptoms, and we have not witnessed any demonstration of a sign of any long-term toxicity.”
‘A new standard of care’
All of the experts interviewed said ruxolitinib is the initial step in what they hope will be a series of advances in the coming years for patients with myelofibrosis.
“It is the first of a family of drugs that will come on the market because this one drug will not be the right fit for everybody with the disease,” Spivak said. “It is a tremendous advance. We have a drug that can alleviate symptoms and reduce splenomegaly without long-term marrow toxicity.”
Ruxolitinib, ultimately, will likely now be combined in clinical trials with other agents in patients with myelofibrosis, Levine said.
“It is my hope that this will not just lead to a new standard of care for our patients but, more importantly, lead to the next set of trials where we try to build on this and add to the benefit for our patients,” Levine said. – by Leah Lawrence
For more information:
- Mesa RA. Cancer. 2011;117:4869-4977.
- Vannucchi A. Abstract #LBA6501. Presented at: 2011 ASCO Annual Meeting; June 3-7; Chicago.
- Verstovsek S. Abstract #6500. Presented at: 2011 ASCO Annual Meeting; June 3-7; Chicago.
- Verstovsek S. Abstracts #278, #793 and #3851. Presented at: 53rd ASH Annual Meeting and Exposition; Dec. 10-13, 2011; San Diego.
Disclosure: Dr. Levine has received research support from Novartis and has served on an advisory board for Incyte. Drs. Mesa and Verstovsek report no relevant financial disclosures. Dr. Spivak is a consultant for Incyte.
Does hydroxyurea still have a role in the treatment of primary myelofibrosis?
Yes, it does.
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Primary myelofibrosis is characterized by bone marrow fibrosis, extramedullary hematopoiesis with splenomegaly, leukoerythroblastosis in peripheral blood and presence of the JAK2 V617F mutation in half of the patients.
Because the median age at diagnosis of primary myelofibrosis is 64 years, many elderly patients currently are managed with supportive care only. A 2011 international consensus by the European LeukemiaNet recommended the use of hydroxyurea as first-line therapy for patients with hyperproliferative features of primary myelofibrosis, such as marked leukocytosis, thrombocytosis, symptomatic splenomegaly or constitutional symptoms.
Hydroxyurea — an oral and usually well-tolerated, non-alkylating, myelosuppressive drug — is widely used in practice. It is clinically familiar, inexpensive, safe and effective, and it has had few side effects at the dose received by most patients.
Thus, in a recent series of 40 patients with myelofibrosis, hydroxyurea was particularly effective to control constitutional symptoms, bone pain, pruritus, symptomatic splenomegaly, leukocytosis and thrombocytosis.
According to International Working Group for Myelofibrosis Research and Treatment criteria, clinical improvement was observed in 40% of patients, including a reduction in spleen size of 50% or more in 30% of patients, with the median duration of the response being 13 months.
Worsening of pre-existing anemia — often requiring erythropoiesis-stimulating agents or danazol — and pancytopenia were the most frequent side effects. A few patients developed oral or leg ulcers.
In a phase 1/2 study, ruxolitinib (Jakafi, Incyte) — an oral JAK1/JAK2 inhibitor — was effective in controlling splenomegaly and constitutional symptoms in half of myelofibrosis patients refractory to hydroxyurea or other previous therapies, but it was associated with cytopenias and had limited activity in improving the anemia.
Two recent phase 3 trials comparing ruxolitinib with either placebo or best-available therapy have shown similar outcomes. However, a recently published study reported high rates of treatment discontinuation — due to disease progression, loss or lack of response, or toxicity — and the appearance of serious withdrawal symptoms at ruxolitinib discontinuation.
Do the results reported in these trials presage the retirement of hydroxyurea from myelofibrosis therapy? Despite the superiority of ruxolitinib in obtaining deeper responses in the splenomegaly and the constitutional symptoms, it is important to note that — given its palliative nature, presumable cost, discrete effect on the anemia, short follow-up, adverse events and severe withdrawal symptoms — concerns remain about its widespread routine use in myelofibrosis.
Therefore, for the time being, it remains unclear whether ruxolitinib should be given to all myelofibrosis patients or could be restricted to second-line therapy for patients resistant or intolerant to hydroxyurea.
Eduardo Arellano-Rodrigo, MD, is a consultant hematologist in the hemotherapy and hemostasis department of the Hospital Clínic in Barcelona, Spain. References: Arellano-Rodrigo E. N Engl J Med. 2010;363:2464. Barbui T. J Clin Oncol. 2011;29:761-770. Harrison CN. J Clin Oncol. 2011;29(Suppl) abstract LBA6501. Mart?nez-Trillos A. Ann Hematol. 2010;89:1233-1237. Tefferi A. Mayo Clin Proc. 2011 (Published online ahead of print Oct. 27). Tefferi A. N Engl J Med. 2011;365:1455-1457. Verstovsek S. J Clin Oncol. 2011;29(Suppl) abstract 6500. Verstovsek S. N Engl J Med. 2010;363:1117-1127. Disclosure: Dr. Arellano-Rodrigo reports no relevant financial disclosures.
No, it does not.
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Myelofibrosis — an uncommon hematological malignancy — has a median prognosis of 5 years, although in the lowest-risk asymptomatic patients, this increases to 14 years.
The cardinal features are abnormalities of the blood count, ranging from myeloproliferation to pancytopenia; splenomegaly, which often is massive; severe impairment of quality of life; and a tendency to progressive marrow failure and acute myeloid leukemia.
Quality-of-life concerns are a dominant feature for these patients, with previous studies demonstrating quality-of-life scores equivalent to those of patients with metastatic malignancy.
A wide variety of current treatments are used to address this disease, ranging from observation and blood transfusion to blunt, nontargeted and possibly leukemogenic agents such as hydroxyurea.
Patients typically receive many different therapies, as response is infrequent and often not durable. Potentially curative stem cell transplantation rarely is appropriate and is associated with 30% to 50% mortality. None of these treatments has, until recently, been evaluated in a randomized trial in myelofibrosis.
The discovery of JAK2 activation and the highly prevalent JAK2 V617F mutation in myelofibrosis provided a target for therapy, and two phase 3 trials with a JAK inhibitor — ruxolitinib (Jakafi, Incyte) — recently have been reported. One was a placebo-controlled trial in patients refractory to hydroxyurea. In the second, the drug was compared with physicians’ choice of best available therapy — the most common of which being hydroxyurea.
In both trials, regardless of whether patients had the JAK2 V617F mutation, there was a highly significant advantage for ruxolitinib in controlling splenomegaly and constitutional symptoms. The median duration of response has not been reached, and most patients continue the drug.
The mechanism for control of symptoms is suggested to be reduction of inflammatory cytokines via JAK1 inhibition. Thus, on drug withdrawal, these symptoms will return, as is seen with other drugs that have anti-inflammatory capability.
In the large phase 3 trials, no new adverse effects were documented and there were no new events related to withdrawal.
All therapies have limitations and should be used with due caution. However, well-established routes of drug development and safety testing demonstrate unprecedented benefits for myelofibrosis patients treated with ruxolitinib.
In comparison, hydroxyurea causes similar rates of myelosuppression, is less effective at control of symptoms and splenomegaly, and never has been tested in a phase 3 trial, apart from that compared with ruxolitinib, where it was clearly inferior.
The FDA approved ruxolitinib for the treatment of patients with myelofibrosis on Nov. 16, and it undoubtedly will improve the lives of those suffering with myelofibrosis.
Claire Harrison, MD, is a consultant hematologist with Guy’s and St. Thomas’ NHS Foundation Trust in London. References: Harrison CN. J Clin Oncol. 2011;29(Suppl) abstract LBA6501. Mart?nez-Trillos A. Ann Hematol. 2010;89:1233-1237. Verstovsek S. J Clin Oncol. 2011;29(Suppl) abstract 6500. Disclosure: Dr. Harrison is an investigator with the COMFORT-II trial.