Ibrutinib continues to provide patients with relapsed or refractory mantle cell lymphoma (MCL) with durable responses and a manageable safety profile, according to longer-term follow-up from an international, multicenter, open-label, Phase II trial published in Blood (2015;126:739–745).
The drug already received accelerated approval in that group based on the results published two years ago in the New England Journal of Medicine (2013;369:507–516). “Ibrutinib is the best medicine for mantle cell lymphoma so far,” said Michael Wang, MD, the lead author of both studies and Professor in the Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center. “It is now used in almost every patient who has received frontline therapy and has relapsed.”
Ibrutinib for the treatment of mantle cell lymphoma is “a hot topic in terms of new therapeutics for our patients,” commented Paul Barr, MD, Director of the Clinical Trials Office at Wilmot Cancer Institute at the University of Rochester (NY) Medical Center. “Most lymphoma experts agree that the drug is very promising.”
Mantle cell lymphoma can be aggressive and incurable, as well as difficult to study because of the relatively low number of cases, he explained. “When we see agents like ibrutinib that provide promising results and are well tolerated, it gets everyone's attention.”
The new study—a follow-up to results reported at the most recent American Society of Hematology Annual Meeting—shows a sustained benefit beyond two years, with a well-tolerated side effects profile that is perhaps even better compared with other available drugs such as bortezomib and lenalidomide for patients with previously treated MCL, said Jack Jacoub, MD, a medical oncologist at MemorialCare Cancer Institute at Orange Coast Memorial Medical Center in Fountain Valley, California. Bruton tyrosine kinase, which ibrutinib inhibits, “is a very active and targetable” pathway.
The median follow-up time of the updated study was 26.7 months. Patients were a median 68 years old and had a median of three previous therapies.
Patients who had a response or stable disease were eligible for long-term extension, in which the median treatment was 8.3 months. Fifty-one individuals (46%) were treated for more than a year, and 22 (20%), took ibrutinib for more than two years. The most common reasons for discontinuation were disease progression (56%), adverse events (11%), withdrawing consent (5%), and a physician's recommendation (3%).
The overall response rate (ORR) was 67 percent, and 23 percent of patients had a complete response (CR). Similarly, in the original NEJM study, patients with MCL had an ORR of 68 percent and a CR of 21 percent.
In the updated analysis, the median duration of response was 17.5 months. The median time to initial response was 1.9 months, while the median time to CR was 5.5 months.
In 48 patients who had received prior bortezomib, ORR was 65 percent, and in 27 patients who had received previous lenalidomide, ORR was 59 percent. The 24-month progression-free survival (PFS) rate was 31 percent and overall survival was 47 percent.
In a subgroup analysis, patients who had less than two prior treatments had an ORR of 82 percent, while those with two or more had an ORR of 63 percent. While researchers did not observe differences in ORR when considering tumor volume, other outcomes, including CR, duration of response, overall survival, and PFS were generally higher for patients with tumors less than 10 centimeters in size.
Median overall survival was not reached in patients who responded to treatment, while it was 13 months in refractory patients. Moreover, median PFS was longer in non-refractory compared with refractory patients—16.6 versus 6.6 months, respectively.
The most common adverse events observed by researchers were diarrhea (which occurred in 54% of patients), fatigue (50%), nausea (33%), and dyspnea (32%). Grade 3 or higher infections included pneumonia (8%), urinary tract infections (4%), and cellulitis (3%). Grade 3 or higher bleeding events, including hematuria and subdural hematoma, were both reported in two percent of patients; and the most common grade 3 or higher hematologic adverse were neutropenia (17%), thrombocytopenia (13%), and anemia (11%).
Wang noted that in the past, the use of chemotherapy in MCL patients meant intravenous infusion and hospital admission due to side effects such as low blood counts, infections, dehydration, and liver toxicity. Ibrutinib allows patients to take a pill once daily with relatively few side effects.
Side effects such as diarrhea, infection, and bleeding were all fairly manageable, Jacoub noted, adding that oncologists have gained experienced in managing such side effects when using ibrutinib to treat other types of lymphoma.
Barr said that to date he has prescribed ibrutinib to at least 50 patients and the rate of discontinuation or dose modification is the lowest he has seen one of any available oral chemotherapy agent: “Ibrutinib is one of the easiest treatments to give to patients compared with other therapies we use for MCL,” and while diarrhea is fairly common, none of his patients have needed to stop treatment or have a change in dosage.
“Diarrhea usually improves after the first month or two,” said another expert on the topic, Leo Gordon, MD, the John & Abbey Friend Professor of Cancer Research at Robert H. Lurie Comprehensive Cancer Center of Northwestern University Feinberg School of Medicine.
Infection, Bleeding, Atrial Fibrillation
Additionally, some of the opportunistic infections observed in the study may not be related to ibrutinib but rather to prior treatment, Gordon noted. “While the authors did not address this issue, everyone who has been heavily and previously treated and on ibrutinib should stay on prophylactic antibiotics. Infection has not been a major limiting feature thus far.”
Barr said that although the risk of serious bleeding is rare in patients with MCL who are taking ibrutinib, oncologists can take precautions when prescribing the drug. “We have to be careful when giving ibrutinib to patients who are already at risk of bleeding such as those on anticoagulants or those with low platelet counts to begin with.”
Jacoub said that in his experience, although bleeding can occur, it has been minor, and there has not been a need to change therapy.
Atrial fibrillation (AF) occurs in about 10 percent of patients, Gordon noted, but being aware of a prior history of irregular heartbeat or underlying pulmonary or cardiac disease can help hematologists/oncologists address the problem. Physicians need to be aware of how to manage anticoagulation, which is often a part of treating AF, he said.
And Barr said that rashes and headaches, which may occur in a small percentage of patients, are manageable.
Other Ibrutinib Research
Wang and his colleagues at MD Anderson have also studied ibrutinib in combination with rituximab (ASH 2014, Abstract 627) in 50 patients with relapsed MCL, with the results showing an overall response rate of 88 percent and a complete response rate of 40 percent. If kI-67 was less than 50, which was the case in 66 percent of patients, the ORR was 100 percent. The duration of response with the addition of rituximab was also longer, and side effects were manageable.
In addition, the SPARK study of ibrutinib in MCL patients with disease progression after bortezomib therapy and who had received at least one prior rituximab-containing chemotherapy regimen has also generated responses, he noted, adding that the data are currently being prepared for publication.
Barr noted that the Blood study includes a large international cohort with a long follow-up, so it provides hematologist/oncologists with a lot of information about ibrutinib. But single-arm, Phase II studies are difficult to compare with other trials: “MCL is a heterogeneous disease, and we need additional randomized studies to directly compare different treatments,” he said. “We also need additional studies to better inform us about the best time to use ibrutinib in the course of treatment.”
Gordon said that while the researchers noted that tumor bulk and the number of prior treatments could help to predict response, the study did not address whether blastoid MCL was present and whether it helped predict outcomes, which would have been useful. There may not have been enough cases to address this issue, though, he added. In future trials, knowing the effect of ibrutinib in combination with other treatments in high-risk groups, such as those with blastoid morphology, would be valuable.
Another question to address, he noted, is whether treatment with ibrutinib can replace either autologous or allogeneic stem cell transplant in these patients, or whether the agent provides a bridge to ultimately performing a transplant, said Gordon.
Wang said he anticipates that once further clinical trials are completed, that ibrutinib will be a first-line treatment in combination with other therapies for MCL. Notably, the SHINE trial, NCT01776840, is evaluating the safety of ibrutinib in combination with bendamustine and rituximab in patients age 65 or older with newly diagnosed MCL. Wang and his colleagues are also studying ibrutinib plus rituximab as a frontline therapy in MCL patients younger than 65.
Jacoub confirmed that ibrutinib in combination with other drugs in the frontline setting is an area of ongoing research. With MCL, while researchers want a cure to be attainable, they have been struggling to find an effective therapy, he said.
Barr summed up: “Frankly, we're still not curing any of these patients. While survival has improved and ibrutinib is a part of this improvement, we still need to develop better treatments and use the ones that we have in a better fashion.”