Maintenance Rituximab Improves Survival in Older Patients With MCL, But More Work Needed

Maintenance rituximab (Rituxan) was found to improve progression-free and overall survival (OS) in older patients with mantle cell lymphoma, according to results from an analysis presented during the 2020 ASCO Virtual Scientific Program. However, older patients with the disease still have inferior survival outcomes compared with their younger counterparts.

“Intensive chemoimmunotherapy, with or without an autologous stem cell transplantation, which many would argue is the standard of care for frontline treatment, is not feasible in such patients,” said lead study author Reem Karmali, MD. “We believe that this leads to poorer outcomes in this particular patient group.”

Karmali and colleagues set out to evaluate clinical outcomes and predictors of survival in this population in the era of rituximab. The study enrolled patients 65 years of age or older with newly diagnosed MCL who had received treatment between 2000 and 2015. Data were collected from 12 centers for a total of 1168 patients between the ages of 65 and 100; 465 patients were categorized as 65 years and older, and the median age was 70 years.

Of 407 older patients with initial treatment data available, 36% received bendamustine plus rituximab, 16% received a cytarabine-based regimen, 2% were given lenalidomide (Revlimid), and 23% received other treatments that did not include BTK inhibitors. Furthermore, 19% of patients were enrolled on a clinical trial for initial treatment, 24% underwent autologous transplantation in first remission, and just under half of patients (44%) received maintenance rituximab. Data were available for 157 patients who experienced relapse and 37% were treated with a BTK inhibitor alone or in combination.

Progression-free survival (PFS) and OS rates were compared across cohorts of younger and older patients. For patients aged younger than 65 years, 65 to 69 years, and 70 years or older, the 2-year PFS rates were 79%, 69%, and 66%, respectively; the 2-year OS rates were 92%, 87%, and 84%, respectively (P <.001).

In the older cohort, an ECOG performance status of 2 or higher, brain metastases, blastoid histology, more than 3 cytogenetic abnormalities, and lack of maintenance rituximab were all linked with inferior PFS and OS (P = .012 to <.001) in univariate analyses. Transplant in first remission did not impact survival. Multivariate analyses revealed that maintenance rituximab led to a significant improvement in OS and PFS (P <.001). Two-year PFS rates were 81% and 58%, and 2-year OS rates were 96% and 80% with and without maintenance rituximab, respectively (P <.001).

In an interview with OncLive, Karmali, an assistant professor of medicine at Northwestern University Feinberg School of Medicine, discussed survival outcomes in older patients with MCL with maintenance rituximab and highlighted other ongoing MCL research efforts to optimize maintenance strategies in this patient population.

OncLive: Could you discuss the current limitations of frontline treatment for older and medically unfit patients with MCL?

Karmali: As you know, MCL is a rare, aggressive B-cell non-Hodgkin lymphoma; that in and of itself poses an issue in terms of trying to identify novel therapeutics for these patients. The issue is, we see poor outcomes with this particular kind of lymphoma subset and one of the major challenges is that the majority of patients who are diagnosed with MCL are older. Some of the unique challenges that we see with this patient population, specifically, are that they have comorbidities, or they could be medically unfit.

Could you shed light on the methods used to conduct your analysis on practice patterns and predictors of survival in older patients with the disease?

For our study, we looked to assess clinical outcomes and predictors of survival in patients with MCL who were older. We defined “older” patients with MCL as 65 years of age or older. We collected data across 12 academic institutions, and we included over 1100 cases of MCL. Within this group, there were 465 patients over the age of 65 who were identified; these were the patients [who] were essentially used for the majority of our analyses.

Could you elaborate on the characteristics of those patients and the treatment course they received?

For our patients, we found that over 50% had a high-risk Mantle Cell Lymphoma International Prognostic Index with respect to treatment patterns. About one-third receive bendamustine/rituximab, which we know is a reasonably well-tolerated regimen for patients who are older. Notably, only 2% received lenalidomide (Revlimid) and none of our patients were treated with a BTK inhibitor up front. Despite their older age, about one-quarter received an autologous stem cell transplantation in first remission. About 44% of patients received maintenance rituximab. Interestingly, only 19% of these patients were enrolled on clinical trials.

How did this translate to outcomes?

We looked at survival outcomes. We followed these patients [and found that] within 6 months of completing their therapy, about one-quarter relapsed. Approximately one-third of these patients in the relapsed/refractory setting were treated with a BTK inhibitor or BTK inhibitor combination therapy. Then, we looked at how this translated over to PFS and OS.

The way we conducted this analysis was to examine patients based on age cohorts. To this end, we divided patients into 3 cohorts: the first was age under 65, the second cohort was 65 to 69 years of age, and the third cohort was age 70 or older. We were able to show that 2-year PFS and OS rates diminished with cohorts of increasing age.

We then went ahead and performed univariate and multivariate analyses. On univariate analysis, what we saw was the lack of use of maintenance rituximab along with a [progression of disease (POD)] of 6 months and a POD of 24 months, all predicted for poor OS. When we looked at multivariate analyses, we found that maintenance rituximab impacted OS significantly, as well as PFS. Interestingly, the use of an autologous stem cell transplantation, which was conducted in about one-quarter of our patients, did not seem to impact survival.

Was it surprising to find that transplantation didn't impact survival?

No, not so much, because the idea is that we probably ended up with some morbidity and mortality that contributed to and negated the potential positive effects of transplantation. However, that is a big question: “Is transplantation really needed?” That's where the cooperative group trial is specifically addressing that question, although it does exclude patients over the age of 70.

Do you believe the limited number of patients who received BTK inhibitors limit the application of the analysis to the current era?

Absolutely, that's an important point here. The data predates the widespread use of BTK inhibitors and even cellular therapies, such as CAR T-cell therapy. As such, [the analysis] doesn't really reliably reflect the potential advancements in survival that we've been able to achieve with these novel targeted therapies. However, some elements to this study are still useful.

The study points out that maintenance strategies do appear to have a place [in the treatment of these patients]. In younger patients who have undergone stem cell transplantation followed by rituximab maintenance, we know that approach offers a survival advantage, but we're seeing the same here in older patients. The key is going to be to serve to optimize maintenance strategies in older patients.

The second thing that our study has done is that it has showed us how survival is impacted in the rituximab era. As such, it serves as a historical reference for ongoing studies to which we can compare impact on survival with novel therapeutic strategies.

Where should future research efforts focus?

With respect to the future, the big question is how to optimize maintenance therapeutics for older patients. We, ourselves, have a trial that we accrued to in which we are examining ibrutinib (Imbruvica) maintenance therapy for up to 4 years. This trial includes patients who are older; it includes patients across all age groups. We may gain some insight into whether ibrutinib monotherapy as maintenance would be helpful in this particular population. 

Other trials are ongoing that hope to specifically [examine] therapeutic strategies in the older population. One of them is the SHINE study, in which investigators are looking at patients over the age of 65 and they are treating them with bendamustine/rituximab as a backbone with or without ibrutinib. They are also addressing whether ibrutinib with rituximab versus rituximab monotherapy as a maintenance strategy would be useful.

Another trial, the MCL R2 Elderly trial, is being conducted in Europe. Here, investigators will also examine whether lenalidomide is an appropriate strategy for the maintenance setting. A ton of trials are ongoing that will address optimization maintenance in elderly patients.

Reference

1. Karmali R, Switchenko JM, Goyal S, et al. Older patients with mantle cell lymphoma (MCL): Practice patterns and predictors of survival in the rituximab era. J Clin Oncol. 2020;38(suppl 15):e20064. doi:10.1200/JCO.2020.38.15_suppl.e20064.