Exploring Non-Chemotherapy Options for the Frontline Treatment of Patients With Mantle Cell Lymphoma

At the 2024 Great Debates & Updates (GDU) in Hematologic Malignancies meeting in Los Angeles, California, Tycel Phillips, MD, City of Hope, Duarte, California, participated in a debate about the role of non-chemotherapy regimens for the treatment of patients with newly diagnosed mantle cell lymphoma (MCL).

Transcript:

Hi, I'm Dr Tycel Phillips from City of Hope in Duarte, California. I’m here at Great Debates 2024 in Los Angeles. In debate, I was tasked with debating the role of non-chemotherapeutic regimens in the treatment of patients with newly diagnosed mantle cell lymphoma.

Mantle cell lymphoma is a very rare non-Hodgkin lymphoma, which has been mainly treated with chemotherapeutic agents for the last 20 years. But with the advent of novel treatments until the relapsed/refractory setting, we have begun to explore these agents and how beneficial they would be for our patients in the frontline setting, mainly based on efficacy that we've seen in the improved toxicity profile. In this discussion we've reviewed several non-chemotherapeutic regimens.

The main one we started with was a study looking at lenalidomide and rituximab that came out of Cornell in New York. This was the first study that looked at a sort of a non-cytotoxic chemotherapy regimen in patients who were technically considered to be ineligible for a autologous stem cell transplantation, or refused a stem cell transplantation. What we saw from this regimen initially was very high overall response rate but more encouraging with 5 and 9-year follow-up, we are seeing prolonged and durable progression for survival.

I believe the more 9-year follow -up showed about half the patients were still in remission. What supports the avoidance again of chemotherapy in this regimen is this sort of treatment regimen compares very favorably to what we see with chemotherapy regimens, including those with autologous stem cell transplantation.

As the offspring of that study, we have 2 trials, one that looked at acalibrutinib with lenalidomide and rituximab that showed a very high overall response rate, with an ORR of 100% and 24 patients, very short follow -up, but the majority of these patients are under complete response.

We also developed a study that looked at venetoclax with lenalidomide and rituximab, again in 28 patients. In this study, we had a very high overall and complete response rate, with almost 90% of the patients being in complete response. What we've seen thus far with longer follow-up is that we've had all of the patients who got into remission, that lack the P53 mutation. All those patients have remained in remission going on 4 years of follow-up. Next we looked at the Brutus tyrosine kinase inhibitors, the BTK inhibitors, which have become a mainstay in second-line treatment and have moved into the frontline setting.

There was a couple studies from MD Anderson.The first one looked at ibrutinib and rituximab in this patient population who were considered ineligible for an auto-transplant. This study showed a very high overall response rate, but did have some cardiac toxicities. So they looked at a second generation BTK inhibitor called acalabrutinib and rituximab in a very similar study, which again showed a very high overall response rate, but improved safety and toxicity. This regimen has been added to our national guidelines, the NCCN guidelines, as an option for patients who are unfit or ineligible for an autologous stem cell transplantation.

Moving forward, we have several regimens that are looking in all comers, young and old patients, with these novel regimens. There is an acalabrutinib-venetoclax-rituximab study that has been sponsored by AstraZeneca. Again, looking to see if we can avoid chemotherapy in all patients with a fixed duration of treatment for patients who are considered to be minimal residual disease undetectable by the adaptive ClonoSEQ assay.

Then we have the BOVen trial, which was designed out of Memorial Sloan Kettering. This was presented by Dr Anita Kumar. This study looked at obinutuzumab, which is a CD-20 antibody that seems to be a bit more effective in mantle cell lymphoma versus rituximab versus zanubrutinib, which is another second-generation BTK inhibitor. They added venetoclax after 3 cycles of that doublet combination of zanubrutinib and obinutuzumab.

What they saw was that improvement in overall response rate with the addition of venetoclax, and overall they had about 80% of the patients at a complete remission of the early study of 20-some odd patients that they enrolled. They had very few progressions in this patient population. And again, they had very overall response rate in that P53-mutated study, so that 24 patients with those with just P53 mutations. They did have another study looking at older patients with the same regimen, they had about 43 response-evaluable patients. And again in this situation they showed even higher overall response rate and durability of response with shorter follow-up only 11 months, but again suggests that we could avoid chemotherapy in all these patient populations.

Lastly we had the SYMPATICO study which looked that patients with P53 mutations, which is a very high-risk feature that does not respond very well to chemotherapy. They looked at the study of ibrutinib, rituximab, and venetoclax. Again in this situation, they had a very impressive complete response rate of over 50 percent and a median PFS of about 22 months in this patient population, which is substantially longer than what we have seen with most of the chemotherapy studies that are looking at patients with through mutations.

All in all, we have older patients, we have younger patients even with high-risk features, that are shown to be highly responsive and have a durability of response with these non-chemotherapy regimens. This supports us as we continue to move forward into the future of continuing to explore these non-chemotherapeutic regimens, and will likely, I would suspect in the next 3 to 5 years lead to elimination of  these of chemotherapy in these patients in the frontline setting.

Source:

Phillips T. Debate - Novel, Non-chemotherapy Approaches are Best for Initial Therapy for Mantle Cell Lymphoma. Presented at the Great Debates and Updates in Hematologic Malignancies Meeting; July 27-28, 2024; Los Angeles, California.