High-Dose Cytarabine Induction Regimens Elicit High Responses in Transplant-Eligible MCL

Reid W. Merryman, MD

The addition of high-dose cytarabine to bendamustine and rituximab (Rituxan; BR) or rituximab were found to generate high response rates for transplant-eligible patients with mantle cell lymphoma (MCL), according to results of a pooled analysis that were published in Blood Advances.

Investigators pooled data from 2 phase II trials and an off-trial cohort, each of which evaluated 3 cycles of BR and 3 cycles of rituximab/high-dose cytarabine followed by autologous stem cell transplant (ASCT) in treatment-naïve, transplant-eligible patients with MCL.

Results showed that of 87 response-evaluable patients, the end-of-induction overall response rates (ORRs) and complete response (CR) rates were 97% and 90%, respectively. After a median follow-up of 33 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 83% and 92%, respectively.¹

These findings suggest that adding high-dose cytarabine to BR or rituximab alone as an induction regimen is an optimal frontline approach for patients with MCL, according to lead investigator Reid W. Merryman, MD.

“This has been our standard regimen for the last 6 years at Dana-Farber Cancer Institute and the outcomes look excellent. For patients who are treated outside of a clinical trial, this is a good option and it seems to be well-tolerated and is highly effective,” said Merryman.

In an interview with OncLive, Merryman, instructor of medicine, Harvard Medical School, and a medical oncologist at Dana-Farber Cancer Institute, discussed the impact of adding high-dose cytarabine to BR as an induction regimen for patients with MCL.

OncLive: Could you provide some background on the state of therapy for patients with treatment-naïve, transplant-eligible MCL?

Merryman: Treatment for patients with MCL has changed dramatically over the last decade. There were 2 randomized trials looking at the regimen of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) versus BR as a frontline treatment for patients with MCL. Both trials found that BR improved outcomes compared with R-CHOP. There have also been a few other methods trying to improve outcomes.

One is consolidating frontline treatment with autologous stem cell transplantation. There was a randomized trial done in the early 2000s, results of which found that consolidation with autologous stem cell transplant lengthens progression-free survival (PFS). Over the last 10 or 15 years, there have been a lot of different regimens that included high-dose cytarabine, which was studied as part of a randomized trial and suggested that its addition to induction therapy for patients with MCL improved outcomes.

The idea for this trial came from some of that earlier research. First, BR might be a better chemotherapy backbone than R-CHOP in this disease. Secondly, the addition of high-dose cytarabine might improve outcomes. At Dana-Farber Cancer Institute, we took these 2 ideas and came up with a regimen combining BR or rituximab with high-dose cytarabine. This was first studied in a phase II trial between 2012 and 2014. After that, we saw encouraging data from that initial trial and that regimen became the standard frontline regimen for all transplant-eligible patients.

Subsequently, investigators at Washington University School of Medicine in St. Louis looked at a very similar regimen combining BR or rituximab and high-dose cytarabine. This paper is a pooled analysis of all 3 of those patient cohorts. Historically, BR was used as the preferred induction regimen in transplant-eligible patients with MCL.

Could you discuss the use of these regimens in all-comers, irrespective of transplant eligibility?

BR was studied both in transplant-eligible and -ineligible patients. It is a potential induction regimen for either [patient subgroup]. There are 2 trials that looked at the addition of cytarabine to BR for transplant-ineligible patients and found encouraging outcomes. There is not a standard-of-care in terms of first-line therapy for MCL and there have been limited randomized trials in this space.

One randomized trial that was conducted in Europe a few years ago, which somewhat clarifies things, is that transplant-eligible patients do better if they have high-dose cytarabine as part of their induction regimen. Beyond that, there have not been any randomized trials comparing different high-dose cytarabine regimens; that is why you see a lot of different regimens being tested and used in clinical practice.

Could you discuss the research included in this pooled analysis that you conducted?

The first phase II trial that was conducted at Dana-Farber Cancer Institute from 2012 to 2014 involved 23 patients. We found that, since 2014, about 47 patients received that same regimen outside of the clinical trial. These patients received about 3 cycles of bendamustine or rituximab followed by 3 cycles of rituximab and high-dose cytarabine.

Washington University School of Medicine in St. Louis designed their trial slightly different, in that the cycles of BR or cytarabine were alternating, whereas the initial trial had BR for cycles 1 through 3 and rituximab for cycles 4 through 6. Their trial included BR for cycles 1, 3, and 5 and cytarabine and rituximab from cycles 2, 4, and 6. The dosing and patient eligibility criteria were very similar, so we opted to combine all 3 cohorts together. With this regimen, all of these patients were intended to go onto consolidative ASCT.

What were the results of your pooled analysis?

This was a representative sample among patients with MCL. The vast majority of patients had advanced-stage disease. About 20% of patients had a high Mantle Cell Lymphoma International Prognostic Index (MIPI) score, one-quarter of patients had a high Ki-67, and about 12% of patients had either blastoid or pleomorphic histology. All of those are clinical pathologic features that we know are associated with worse outcomes in general for MCL.

Results showed that the ORR was 97% and the CR rate was 90%. We saw high response rates across all cohorts. We even saw high response rates in the traditional poor-risk patient subgroups; patients with blastoid histology and high MIPI scores all had CR rates over 75%.

When we looked at progression-free survival (PFS), the median follow-up was about 33 months, so we looked at 3-year PFS rate and for the entire cohort, we found that it was 83%; the 3-year overall survival rate was 92%. You cannot compare directly across studies, but these results are encouraging in light of other clinical trials looking at up front regimens in transplant-eligible patients.

What were the most common adverse events (AEs) observed with this regimen?

We saw expected AEs, most of which were hematologic toxicities. There was a high rate of grade 3/4 cytopenias and overall neutropenia, although, not more than you would expect with this regimen. About 15% of patients had febrile neutropenia. There were no induction-related deaths, but there were 2 deaths related to posttransplant complications.

What should your colleagues take away from this study?

Transplant-eligible patients with MCL should receive a high-dose cytarabine induction regimen. Because there are no randomized studies comparing different high-dose cytarabine regimens one can choose which of these regimens they want to use. These data are encouraging, and this regimen should be considered an option for induction chemotherapy for patients who are eligible for transplantation.

It probably should be studied more and there is an ongoing study that is using BR and cytarabine as a chemotherapy backbone. They are testing whether the incorporation of acalabrutinib (Calquence) can improve outcomes; specifically, they are looking at minimal residual disease at the end of induction therapy as the primary endpoint.

Are there any next steps for this research?

The next steps are [for these regimens to be] studied in other trials that would hopefully confirm the results we found in this study. This field is moving quickly and there are a lot of trials incorporating some novel agents, such as BTK inhibitors and venetoclax (Venclexta) in the up front setting.

Merryman RW, Edwin N, Redd R, et al. Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma. Blood Adv. 2020;4(5):858-867. doi: 10.1182/bloodadvances.2019001355