Ibrutinib Plus Rituximab Demonstrates Promising Efficacy in Older Patients With Previously Untreated MCL

Preetesh Jain, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, discusses results from a phase 2 trial exploring the efficacy and safety of ibrutinib plus rituximab for the first-line treatment of older patients with mantle cell lymphoma (MCL).

Transcript:

Good morning, everyone. My name is Preetesh Jain. I'm an assistant professor and faculty in the department of lymphoma and myeloma at MD Anderson Cancer Center, and I focus on patients with MCL. It's my pleasure to be able to meet and talk to you today.

Oncology Learning Network (OLN): What existing data led you and your coinvestigators to conduct this research?

Dr Jain: Dr Michael Wang started this study in 2014 and the main reason is that MCL is a disease of the elderly, and the median patient age is around 68 to 71 years. These patients have generally some other comorbidities that would preclude them from getting intensive chemoimmunotherapy. The standard chemoimmunotherapy approach, bendamustine and rituximab, is also commonly used in this patient population. But the side effects from this therapy, particularly with respect to cytopenia, risk of infections, as well as second cancers are notable and that's the reason that the effort is being made to introduce chemotherapy–free treatment options.

Ibrutinib was already approved in MCL in the relapsed setting. Subsequently, the plan was to introduce this in the frontline setting with only rituximab to provide a chemotherapy–free treatment option. That's the main reason—to provide patients an alternate option—we introduced this regimen with ibrutinib and rituximab.

OLN: Please briefly describe the study and its findings.

Dr Jain: In this study, we enrolled 50 patients, previously untreated. And these patients were a median age of 71 years. All the patients were ≥65 years of age. Patients with controlled comorbidities were allowed to participate in this study. ECOG performance status was also 0 to 2, and also these patients had no blastoid or pleomorphic, which are the high-risk MCL variants. All patients were Ki-67% <50%, only those patients were included in this study.

Then we looked at these patients after we reported the results after a median of 45 months of follow-up. You see that the response rate has been excellent. It's around 96% response rate with the CR rate of around 71% and that was very interesting that with the chemotherapy–free treatment option, you got to get such type of response rate.

Subsequently, we also look at the median overall survival and PFS, and that has also been very nice, around 87% to 90% of 3-year PFS and OS is very interesting with this study. The other thing which was noticeable after a couple of years was that almost 30% of patients were taken off study because of adverse events. With ibrutinib, one of the concerns that was most noticeable was around 22% of patients had atrial fibrillation.

That is a major concern. At the time in 2014, when the study was introduced, we did not have quite a stringent criterion, we did not have much experience with ibrutinib and atrial fibrillation and therefore we did not have specific cardiovascular screening criteria at that time before enrollment. But subsequently, we noted those who developed atrial fibrillation versus those who did not develop atrial fibrillation.

Patients who developed atrial fibrillation, those patients had a higher number of cardiovascular risk factors. They had some baseline conduction blocks or baseline some other cardiac abnormalities. And that's the reason that these patients probably developed the propensity of getting atrial fibrillation.

Other side effects were also noticeable with Ibrutinib, a couple of patients with bleeding risks so because these patients were already receiving anticoagulants or antiplatelets because of their other comorbidities. Now we have learned that, although it is a very effective treatment and it is very impactful, patient selection is important. The gist is that we would like to screen these patients for cardiac issues beforehand, to make sure that these patients don't develop this.

We also, interestingly, identified with whole-exome sequencing and RNA sequencing patients who were partial responders vs those who were complete responders. Patients who were partial responders had over expression of B-cell receptor signaling pathway genes. Those patients who were partial responders, they also had over preponderance of the mutations in cyclin D1, mutations in NSD2, mutations in NOTCH1, mutations in KMT2D and FAT1.

These are the genes which we are noticing also in ibrutinib-resistant MCL. So, clearly, we are able to identify a pattern of gene signatures, which could predict which patients are going to respond, which patients are not going to have a great response to ibrutinib. That's another interesting piece of information from this study.

Another thing we noticed is that a fraction of patients who are taken off study, but then subsequently after a couple of years were also rechallenged with Ibrutinib. They were also able to tolerate the drug. And so far, we have almost 40% patients who are remaining in the study and couple of them more than 7 years. Clearly, patient selection is very important. Overall, it is a very good chemotherapy–free alternative treatment option for elderly patients with MCL.

OLN: Are there any real-world applications of these findings in clinical practice?

Dr Jain: Absolutely. It is now in the NCCN guidelines that ibrutinib and rituximab preinduction, prior to chemotherapy, are included in induction therapy, but not for elderly patients. They have not specified it yet. I would say that if patients are having comorbidities and if the patient cardiac status is good, then it would be a very interesting and very good treatment option for these patients over bendamustine-rituximab.

OLN: Do you and your coinvestigators intend to expand upon this research? If so, what are the next steps?

Dr Jain: We have already started another study, which is acalabrutinib and rituximab and we started it in October 2020. We are nearing completion of this study with only 10 patients left and this trial is open at MD Anderson. Acalabrutinib is a newer generation of BTK inhibitor. That is going on at this time and it is showing fantastic results without any cardiac issues. That study is an important one.

The second study is the Mangrove study. This study is actually comparing directly head to head—It's very interesting because it's a randomized study between zanubrutinib and rituximab, which is a newer version of BTK inhibitor, directly with the bendamustine and rituximab. This is a randomized study with 500 patients and it's an international global study. That makes it a more impactful phase 3 clinical trial. And that study, we have enrolled the highest number of patients in the world in MCL. It is specifically designed for patients who are 70 years and above, patients who are stem cell transplant ineligible, and those patients with controlled comorbidities. That study readout is going to be very impactful and may be a treatment-changing paradigm for patients with MCL.

OLN: Is there anything else pertaining to your research and findings that you would like to add?

Dr Jain: We are introducing more drugs and more agents. Pirtobrutinib is another new molecule, so we are going to introduce that in the frontline setting as well. That study is going to be open. And we are also trying to combine these BTK inhibitors with CAR T-cell therapy for the untreated patient, but only for the high-risk cohort. We will see how those pan out.

We are very excited that the field of MCL has significantly changed. Therefore, the treatment options are continuously moving and moving for the benefit of the patients. After introduction of BTK inhibitors, the patient survival is improved, especially impacting the patients who are elderly 60, 70 years. We are very excited to be in this era of treating MCL.

Source:

Jain P, Zhao S, Lee HJ, et al. Ibrutinib With Rituximab in First-Line Treatment of Older Patients With Mantle Cell Lymphoma. J Clin Oncol. 2022;40(2):202-212. doi:10.1200/JCO.21.01797.