Post-ibrutinib management in MCL unclear, speaker says
NEW YORK—Despite an “unprecedented” single-agent response rate and progression-free survival (PFS) in previously treated mantle cell lymphoma (MCL) patients, those with multiple risk factors have a dismal outcome following ibrutinib failure.
So after ibrutinib, what’s next in MCL? That was the question asked at Lymphoma & Myeloma 2015.
Peter Martin, MD, of Weill Cornell Medical College in New York, New York, discussed some possibilities.
Ibrutinib (Imbruvica) was approved by the US Food and Drug Administration for MCL based on the PCYC-1104 trial, which showed an overall response rate of 68%. In the MCL2001 trial, the overall response rate was 63%.
The median PFS for MCL was 13 months in PCYC-1104 and 10.5 months in MCL2001. The median overall survival (OS) was close to 2 years in PCYC-1104 and 18 months in MCL2001.
“So this is where I think it starts to get interesting,” Dr Martin said. “People were able to live for several months after progressing on ibrutinib. [However,] our experience at Cornell was not necessarily consistent with that.”
Cornell investigators, along with colleagues from Ohio State University, compiled data on patients who had been treated in clinical trials at their institutions and reviewed their survival after progression on ibrutinib. These patients had a median OS of 4 months.
In reviewing the patients’ Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, Dr Martin said they were arguably a higher-risk population.
Dr Martin collected data on 114 relapsed/refractory MCL patients from centers around the world and found they had a lower response rate (50%) with ibrutinib overall and a lower duration of ibrutinib therapy (4.7 months).
The median OS after stopping ibrutinib was 2.9 months for the entire group. For patients who did not receive any subsequent therapy after failure, it was 0.8 months. Patients who received treatment after ibrutinib failure had a median OS of 5.8 months.
“And it didn’t seem to matter what we gave,” Dr Martin said. “Those treatments were pretty short-lived.”
The median time to next treatment with the first subsequent therapy was 2.4 months. These therapies included bendamustine, cytarabine, and lenalidomide.
“There was no statistical association between survival and choice of therapy,” Dr Martin said.
What was significant, by univariate Cox regression analysis, was the patients’ MIPI prior to ibrutinib therapy (P=0.0002) and the duration of ibrutinib treatment (P=0.0465).
“So at this point in time, I think it’s fair to say that there is insufficient data to recommend any specific treatment following ibrutinib failure,” Dr Martin said.
However, he did make a few suggestions for treating high-risk patients.
Treatment suggestions after ibrutinib failure
Dr Martin’s first suggestion is to focus on symptom management rather than active therapy for the older, frailer patients. Second, consider allogeneic stem cell transplant in any high-risk patient responding to ibrutinib.
Third, consider continuing ibrutinib therapy while starting the next therapy. And fourth, consider some form of continuous therapy that does not depend on TP53.
Dr Martin admitted that what to do following ibrutinib failure remains cloudy.
“Conducting a clinical trial will be tricky,” he said, “because the median time from ibrutinib failure to the next therapy was 9 days, and we’re targeting a very high-risk patient population.”
In addition, on average 80% have expression of Ki67.
Currently, a phase 2 trial of copanlisib (NCT02455297) is the only post-ibrutinib clinical trial in MCL open. Copanlisib is a potent and reversible phosphatidylinositol-3-kinase (PI3K) inhibitor with activity against both alpha and delta isoforms of PI3K. Preliminary results of the trial demonstrated response in 5 of 7 MCL patients.
