Rouslan Kotchetkov, MD, PhD, Simcoe Muskoka Regional Cancer Program, Barrie, ON, Canada, discusses results from a retrospective review exploring the efficacy and safety of bendamustine plus rituximab for the treatment of mantle cell lymphoma (MCL) in the real-world setting.

These results were presented at the virtual 2021 ASCO Annual Meeting.

Transcript:

Hello, I am Rouslan Kotchetkov. I'm a hematologist-oncologist at Simcoe Muskoka Regional Cancer Center. It's in Canada, north of Toronto. I work as a hematologist-oncologist with a lot of patients who need chemotherapy.

This study was inspired by patients and by my colleagues, trying to answer them. When you counsel the patients, the patients may ask you practical details. We were able, how can we answer it?

What's the prognosis? What to expect? We said we know there are clinical trials that investigated bendamustine plus rituximab but what's actually happening in the real-world, in a community setting, or in the real-world, the use of bendamustine plus rituximab in non-selected patients?

We started to use bendamustine in June 2013, so it's already 7 years. We said, let's look at what we have here. It's not my work. It's the work of our group. I want to acknowledge my colleagues, Dr. Nay, Dr. Gerard, Dr. DiMaria, for contributing and with the patients and with helping to prepare this abstract.

We submitted this abstract to ASCO and now, we're working on the paper. The main question for us was, first, how different are our patients from the clinical trials that were used? Is there any difference in the disease, as in the spectrum of disease, that was used in the clinical trials?

Of course, mainly, looking at the clinical trials StiL and BRIGHT that had two large trials that investigated bendamustine plus rituximab as a first-line chemoimmunotherapy. What we found was, first, the disease spectrum was comparable to the clinical trials for it.

Follicular lymphoma, we did these trials in all the indolent non-Hodgkin's lymphoma and mantle cell lymphoma. We found that patients with follicular lymphoma comprised approximately 50% of all the patients. It was comparable to the BRIGHT and the StiL clinical trials.

What we found was the rate of lymphoplasmacytic lymphoma was high. It was doubled in comparison to the StiL trial. It was 15% in our trial and 8% in StiL. The rate of mantle cell lymphoma was a little bit lower in our patients, 13% versus 18%. In general, the patient's disease spectrum was comparable.

In the real-world setting and in clinical trials, what we found is that we have more elderly patients. It's a question for real-world; what to do with them. For example, usually, in clinical trials, there is a cut-off for the age. In the StiL trial, 23% were over the age of 70. In our study, we had 56%. More than half of the patients were considered to be elderly.

The next question to answer was practicality. How long does it take from the diagnosis of the disease until you start treatment with B+R? B+R is the standard of care for all of these patients. We found that it's between 4 and 7 years that the patients are on active surveillance and don't require any treatment.

Next, we'll look at high-risk patients, particularly how many high-risk patients were there in general? We had 37 high-risk patients, exactly matching to the StiL trials. The proportion of patients with a high risk of follicular lymphoma was 48% in our trial compared to 46% in the StiL trial. That was practically perfectly matching it.

Then, we said we didn't really select any patients with ECOG status. We found in our patient's cohort, over 10% of patients had ECOG 3, which is an exclusion criteria for clinical trials. We also delivered chemoimmunotherapy to sicca patients.

We found that the treatment can be given in unselected patients, same as in the clinical trial. A median number of cycles of B+R, per patient, was six, same as before. The median dose of bendamustine was 90 mg/m2, same as in the clinical trial.

However, we found that compared to the StiL trial, less patients in our real-world setting received the full dose of bendamustine. It was only 66% versus 96% in the clinical trial. We found, actually, that said dose reduction was expected in approximately 40% of patients and therapy delays occurred in approximately 30 patients, an average of 1.8 weeks.

It's important to counsel the patients. We expect the dose can be adjusted due to the treatment and delays are also expected. When the patient asks, "How long would it take?" Me, I would say probably about 6 months but to expect about a two-week delay.

In terms of efficacy, we found that overall response rate didn't differ from the StiL trial. It was 95% in our trial and 93% in the StiL trial. However, what's interesting is that the rate of complete remission was high in our study compared to StiL, was 77% versus 40%.

Honestly, I'm still working to find out what happened but it's a good thing. Increased interest in that we looked at the patients with lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia. We saw a higher rate of complete remission and a lower rate of partial remission compared to the StiL trial, as well as the presentation of Dr. Ramel. He did it at the 2019 ASH.

We actually had a grade of PR 37% versus 89% in the StiL trial. But what we noticed was that when patients received rituximab maintenance, the amount of monoclonal protein and the total amount of IgM continues to decline significantly.

When we looked at event-free survival, in our cohort, it was higher than reported in the StiL trial. We have a median event-free survival of 88% versus 69.5% in the StiL trial. It's actually good but taking into account the difference may be due to shorter median follow-up. We have only a 35-month follow-up and the StiL trial was 45%.

This additional 10 months may have mitigated this difference but we think, in general, yes, it's not lower than in the StiL trial. It's important that a majority of our patients were able to proceed with rituximab maintenance. When we looked at why patients didn't go, it was mainly sicca patients who progressed or those who just didn't want to do rituximab maintenance.

As a parameter, it's important to know that while delivering the chemotherapy, it's safety and particularly supportive for therapy. Granulocyte colony-stimulating factor, that is medications that increase the rate of neutrophils in patients, was significant.

The rate of the patients who needed it in our cohort was significantly higher than in the StiL trial. Although, 17% of patients need it compared to 4% in the B+R arm of the StiL trial. That could be attributed to either the patients were sicker or they were more cytopenic or maybe just a difference in clinical practice between Europe and North America.

It's important that in our real-world patients, we did not identify any new adverse events. We looked at the rate of hematological serious adverse events like a grade 3 to 4 neutropenia was 38% in our study versus 29% in the StiL trial.

The rate of anemia was significantly higher. It was 14.5 % in our trial versus 3% in the StiL trial. The rate of thrombocytopenia was comparable, 5% versus 7%.

It's interesting that 16 patients in our trial, 8%, had febrile neutropenia, and 6 patients, like 3%, had CV infectious complications with a fatal outcome compared to less than 1%, actually only 1 patient, in the StiL trial.

Next, we found that 27 patients to 101 patients, it's 13.5 %, developed a secondary malignancy, including 8% hematological, and 5.5% of non-hematological malignancies. It's as high as in the previously reported in the StiL trial where the rate of secondary malignancy was 7.66%.

When we look at the death of these patients, the cause of death, in 13 patients, like 48%, the cause of death was actually a secondary malignancy, including 8 patients with aggressive lymphoma, and 2 patients with MD, myelodysplastic syndrome, and 5 patients died from non-hematological malignancy.

It's also interesting that the rate of cumulative fatigue was increasing, going up to 20% in cycle 6 from 10% in cycle 1. That's kind of expected but we now really showed that cumulative fatigue is real and something that the patient needs to know that from cycle 1 to 6, to expect fatigue.

Finally, we looked at the rate of rituximab-associated infusion reactions. Traditionally, historically, the infusion reactions with rituximab happened in the first cycle. We looked at patients who got it in cycle 1 only. The rate of rituximab-associated infusion reactions sparked to 75% to 85% in the first cycle.

In our study, it was reported only in 34 patients. It's way less. It’s interesting that in 2017, we implemented enhanced premedication protocols for patients who go in for first rituximab, including montelukast rupatadine and we published our study and found that if the patients get these enhanced premedications package, then the rate of the reactions go down to 20 to 21%, and the reactions that happen are less severe.

We looked to see approximately when we started to see the decrease in the rate of rituximab-associated reactions was from 2018, so kind of a response to what we did. It's nice to see additional confirmation to our studies that we did in the past.

I think, in summary, we can say that bendamustine and rituximab can be safely given to patients in the real world, including sicca patients, and elderly patients, and patients with comorbidities.

Those reductions and delays, I expected. But, in spite of the fact that those that bendamustine was reduced and treatment was delayed, still, this combination maintains great efficacy in terms of event-free survival.

We didn't notice any new adverse events. I think the rate of secondary malignancies are more attributed to the advanced age of patients and comorbidities.

Interestingly, none of the secondary malignancies happened during the bendamustine and rituximab treatment. Like 99% of those cases happened after the completion of a treatment, so they're probably not related to that.

I would say that's a great combination. It can be certainly delivered in the real world with some specific features. It can be given to all types of patients and unselected patients with a great response and no unpredicted problems with safety. Thank you very much.