Rituximab Regimen Elicits High ORR in Relapsed MCL

Rory McCulloch, MD

Rituximab (Rituxan) in combination with bendamustine and cytarabine (R-BAC) demonstrated an 89.3% overall response rate (ORR) in patients with relapsed/refractory mantle cell lymphoma (MCL) who have previously relapsed on BTK inhibitor, according to retrospective findings presented at the 2019 European Hematology Association Congress.

In the analysis, 28 patients with relapsed/refractory MCL who previously relapsed on a BTK inhibitor were treated with R-BAC, which previously has shown promising antitumor activity in the first-line setting. Responses were analyzed using RECIST criteria and collected data retrospectively from hospital records.

The median number of prior therapies was 2 (range, 1-6), with the most common frontline regimen being rituximab plus high-dose cytarabine in 62.1% of patients. All 28 patients enrolled had stopped BTK inhibition therapy due to progressive disease or failure to respond to treatment; the BTK inhibitors that were previously used included ibrutinib (Imbruvica), acalabrutinib (Calquence), tirabrutinib, and M7583. The objective response rate (ORR) to BTK inhibition was 64.3%, and the complete response rate was 25.9%.

Results showed that in addition to the 89.3% ORR, the complete response rate with R-BAC was 55.2%, the estimated median progression-free survival (PFS) was 8.6 months, and the estimated median overall survival was 12.2 months. Moreover, 20% of patients went on to receive an allogenic stem cell transplant (SCT). These responses compared favorably with studies looking at other regimens in the post-BTK inhibition setting.

Nine patients required admission due to toxicity from the regimen, including 31.8% of patients who had neutropenic fever. Additionally, 77.8% of patients required transfusion support; however, there were no treatment-related deaths. Overall, the toxicity profile was manageable, and efficacy was maintained at attenuated doses; R-BAC was successful in getting disease under control before moving a patient to allogenic SCT.

In an interview with OncLive, Rory McCulloch, MD, of the Department of Hematology, University Hospital of Plymouth, United Kingdom, discussed the results from the retrospective analysis for R-BAC treatment following relapse on a BTK inhibitor in patients with MCL, as well as the necessary next steps in incorporating this combination into clinical practice.

OncLive: What is the likelihood for patients with MCL to relapse on a BTK inhibitor?

McCulloch: BTK inhibitors have revolutionized the treatment [landscape], but the figures show that ultimately, roughly half [of the patients] won’t have a durable response, and everybody will end up relapsing at some point. We’re now getting to the stage where there are enough patients who are on these [BTK inhibitors] and we are starting to be met with that difficult scenario of what to do next.

The early data that have come out have shown that it’s a very difficult point in the treatment algorithm, and there have been no satisfactory treatments that have surfaced. The average response [rate] is normally about 30%, and the PFS, in the best study which was with venetoclax (Venclexta), is only about 3 months. This is clearly a big unmet need.

What was the rationale to combining bendamustine and cytarabine in the R-BAC regimen for these patients?

The work had originally been done in Italy, so 1 of our collaborators, Carlo Visco, MD, has pioneered the treatment. We know that bendamustine works well in MCL, and we also know that cytarabine works well in MCL. When the 2 are given together, there are in vitro studies that have shown that there’s a synergistic effect. We’re not just getting 2 drugs that work well; there’s something about the combination that seems to improve the response rates.

What were the efficacy and safety results that you found in this trial?

Obviously, this is a retrospective study, so we are basically looking at how different physicians are going to interpret the use of this. Although there is a definition of what the standard treatment is, it is quite high in hematological toxicity, and it’s not going to be right for every patient. However, that doesn’t matter as long as we learn to attenuate the doses. Our oldest patient was 79-years-old and had a very short response to ibrutinib, so we just gave him 1 day of the bendamustine/cytarabine; he actually tolerated the combination pretty well. He had a response for over 2 years, so although there will be concerns about the hematologic toxicity, we have to weigh it out against the poor prognosis of the patient, and we also have to be sensible when trying to match the dosing regimen to the fitness of the patient.

What are the next steps for research regarding the R-BAC regimen?

It’s an area that, at the moment, is just starting to be studied. There are phase II trials that are looking at novel agents, but where will R-BAC fit into that? Obviously, it’s a chemotherapy regimen, and it will not be likely that there will be a lot of pharmaceutical companies backing for large clinical trials, so it’s probably going to be limited to more observational studies. However, we are hoping that we are going to get about 35 patients in our series before we put it to publication.

What would you like community oncologists to know about using this regimen in their patients with MCL that have relapsed on a BTK inhibitor?

The bottom line of R-BAC is that it seems to have a particularly impressive response rate; 85% of patients had some sort of response, and some of them had very durable responses that were going over a year. In the younger patients, this seems to be a very attractive option if you feel they are fit enough for an allograft. Because of that response rate, you can get the disease under as much control as you can before proceeding to allograft. For the older patients, you shouldn’t be deterred, but you should be sensible and attenuate your doses appropriately.

McCulloch R, Visco C, Frewin R, et al. Efficacy of R-BAC immunochemotherapy in patients with relapsed, refractory mantle cell lymphoma post BTK inhibitor therapy. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract PS1255.