New Chemotherapy-Free Option May Be Identified for Elderly Patients With MCL

Preetesh Jain, MBBS, MD, DM, PhD

Patients with mantle cell lymphoma (MCL) who are aged 65 years or older are a population with a poor prognosis who tend to be unfit for chemotherapy with immunotherapy as well as for stem cell transplant. Researchers hypothesized, though, that use of a Bruton’s tyrosine kinase (BTK) inhibitor may trigger responses in elderly patients with MCL.

In an analysis presented during the 2020 American Society of Hematology (ASH) Annual Meeting, 50 patients with MCL with Ki-67 ≥50%, blastoid or pleomorphic histology, and clinically uncontrolled comorbidities were assessed on treatment with ibrutinib (Imbruvica) 560 mg plus rituximab (Rituxan) 375 mg/m2. The coprimary end points of the study were safety and response to the combination.

Findings from the analysis showed ibrutinib to be an effective chemotherapy-free option for older patients with MCL. The objective response rate (ORR) was 90% with complete responses in 62% of patients and partial response in 28%. The study also assessed best response in patients with minimal residual disease negativity and showed an ORR of 86%. Survival in this study was not reached at a median follow-up of 36.2 months (range, 6-48).

Many of the toxicities observed with ibrutinib plus rituximab in the study were manageable with dose reductions, which were required for 58% of patients. The cardiac toxicities, namely atrial fibrillation and development of cardiac arrhythmias were difficult for the high-risk population, although none led to death. The conclusion was that baseline cardiac evaluation and cardiovascular risk factor modification should be performed before starting patients on ibrutinib.

In an interview with Targeted Oncology, Preetesh Jain, MBBS, MD, DM, PhD, assistant professor, The University of Texas MD Anderson Cancer Center, reviewed the results seen with ibrutinib added to rituximab in older patients with MCL, and provided insight on how to manage the interesting toxicity profile observed with the combination.

TARGETED ONCOLOGY: What was the rationale for this study?

Jain: The rationale for this clinical trial was to develop chemotherapy-free treatment strategies for frontline elderly patients who are transplant ineligible. The focus has been shifting towards chemotherapy-free therapies in MCL, considering the long-term toxicities from the chemotherapy, and the [adverse] effects of the chemotherapy, particularly second cancers, infections,myelosuppression, and secondary myelodysplasia. Considering that and the excellent response from ibrutinib and rituximab, which we have noted in the last study of MCL, we planned to study elderly patients who are treatment naive, and who have low-risk MCL.

TARGETED ONCOLOGY: What did you find in the study?

Jain: The response rate has been excellent. Ninety-six percent of patients have responded, and if you consider the intent-to-treat population, then the response rate is 90% with a 60% to 66% complete response rate. That is very significant, considering this was an elderly population with a median age of 71 years and multiple patients had comorbidities and were transplant ineligible.

TARGETED ONCOLOGY: Are there any specific predictors of response to ibrutinib?

Jain: We have noted that patients who had low Ki-67 had better response rates. But when you compare the progression-free survival (PFS) and overall survival (OS), there was no significant difference between patients with low Ki-67 and high Ki-67.

Of course, the study is limited by the number of patients. We already preselected low-risk patients, so we cannot clearly determine this finding. But based on the data that we have, patients who had low-risk disease or low Ki-67, were noted to have better response compared with patients who had Ki-67 of 30% to 50%.

TARGETED ONCOLOGY: Was the toxicity profile of the combination favorable?

Jain: Ibrutinib is a BTK inhibitor, which has off-target effects, particularly on atrial fibrillation and bleeding. We found that patients who had prior EKG abnormalities or prior history of atrial fibrillation, even though it was controlled, those patients had a tendency to develop cardiac arrhythmias. That was a limiting factor. Seventeen patients out of 50 developed atrial fibrillation and when you look at the history, 6 of these patients had prior EKG abnormalities. This means that adequate screening of the patients for cardiac risk factors is very important before we planned for this therapy.

Looking at the rate of discontinuation, if you consider the total number of patients being 50, 27 patients came off study, only 4 of them came out of the study because of disease progression, but the other had intolerance-related effects or reached follow-up or withdrew due to patient choice. Considering these data, we believe that this a significant advance, because only 4 patients progressed after 43 months of follow-up.

TARGETED ONCOLOGY: Based on the finding of cardiac arrhythmia development, would you say this combination is safe for all comers or just for select patients?

Jain: The combination is suitable for all comers. Patients who had significant cardiac history or patients who have ongoing atrial fibrillation or prior history of cardiac arrhythmia must be very carefully and critically screened by the cardiologist. Also, their EKG evaluation and other parameters like their left ventricular and systolic volume need to be clearly clarified before planning for this therapy.

TARGETED ONCOLOGY: Was there anything about this analysis that surprised you?

Jain: Seeing atrial fibrillation even in patients who did not have a prior history of atrial fibrillation was surprising. There were also some minor EKG abnormalities like left anterior fascicular block that led to cardiac arrhythmias. That was kind of surprising and happened at a higher incidence compared with other studies.Here we have to consider that this population is elderly with prior history and had already taken medications. Those patients have a propensity to develop atrial fibrillation. But, considering this excellent response rate, we believe that with adequate cardiac screening, this combination is highly effective.

TARGETED ONCOLOGY: Regarding atrial fibrillation, is that an adverse event that is typically observed with BTK inhibitors?

Jain: It is seen with other BTK inhibitors, but with ibrutinib, it is more common, as seen in the chronic lymphocytic leukemia, MCL, and Waldenström macroglobulinemia studies. This is because ibrutinib has more off-target effects. Cardiomyocytes also have the TEK tyrosine kinase and other enzymes that are inhibited by ibrutinib. There are more selective inhibitors like acalabrutinib (Calquence), zanubrutinib (Brukinsa), and from ASH we have data for LOXO-305, which is going to be a very beneficial and significant advance.

We already have ongoing phase 3 trials of zanubrutinib and rituximab in transplant-ineligible elderly patients and we are also doing an investigators-initiated study of acalabrutinib with rituximab in elderly patients. So, based on the learning experience, we are propagating newer BTK inhibitors that are more selective, and we expect that the toxicity and this type of adverse event profile would be mitigated with the use of these BTK inhibitors.

TARGETED ONCOLOGY: What else is important to note about this study or the treatment of elderly patients with MCL in general?

Jain: We are also conducting a lot of deep molecular sequencing and molecular studies, particularly with respect to MRD, using ctDNA. We are working on deep molecular sequencing on these patients with MCL who progressed. We are also trying to identify mechanisms of resistance to ibrutinib in frontline elderly patients with MCL.

_Reference:

_{Jain P, Yao Y, Zhao S, et al. Combination of ibrutinib with rituximab (IR) in previously untreated older patients with mantle cell lymphoma (MCL) – a phase ii clinical trial. Blood. 2020;136(suppl 1):41-42. doi:10.1182/blood-2020-137167}