With Successor to R-CHOP on Horizon, Habermann Says DLBCL Treatment Choices Create “Complicated World”

Thomas M. Habermann, MD, is a hematologist with the Mayo Clinic in Rochester, Minnesota. A member of the Lymphoma Research Foundation Scientific Advisory Board, Habermann is well known as the lead investigator for the study that made R-CHOP—the combination of rituximab and the chemotherapy combination of cyclophosphamide, doxorubicin hydrochloride, vincristine [Oncovin], and prednisone—the standard of care in first-line treatment of diffuse large B-cell lymphoma (DLBCL).¹ In a conversation with The American Journal of Managed Care^®, Habermann discussed the explosion of new therapeutic options in DLBCL—including a new combination using polatuzumab vedotin that may soon be the successor to R-CHOP. This interview is lightly edited for clarity.

AJMC®: Can you discuss the differences between patients with DLBCL who relapse after frontline therapy and those who are refractory to it?

Habermann: Refractory disease is defined as disease progression, as per International Working Group response criteria showing less than a partial response, which means less than 50% reduction in size of nodes and masses or disease recurrence or progression within less than 6 months from the completion of first-line therapy, or [those] showing less than a partial response to the most recently administered systemic therapy.

If you then ask the question further about relapse, we had a 2019 paper from our molecular epidemiology research project in our SPORE grant (Specialized Programs of Research Excellence) on late relapses in patients with DLBCL.^2,3 And when looking at that information, the 5-year relapse rate from DLBCL alone, the late relapse rate was 6.3%. And then if it was indolent lymphoma alone, it was 5.2%, but the survival rates were very different. So, if you had a late relapse, the survival rate was 29.9 months, vs if it was indolent or low-grade lymphoma, it was unreached. And so that's what's important to understand about, and I think best defines the difference between what refractory disease is and relapses and latent relapse.

AJMC®: The POLARIX trial evaluated the use of a modified regimen of R-CHOP with polatuzumab vedotin, replacing vincristine in patients who had previously untreated DLBCL.⁴ What are the key takeaways from this study?

Habermann: This is an important trial, and we're waiting for regulatory bodies to review the data internationally to define which patients might be treated with this regimen. But to start out, 65% to 75% of patients with DLBCL are cured of their disease after treatment with R-CHOP–based regimens. And if you look at the data on groups of patients with limited-stage disease and in the PET [positron emission tomography] scan era, patients treated in the PET scan era with R-CHOP for 3 to 4 cycles, the 5-year progression-free survival rates were 87% to 88%. And these patients were included in this particular trial.

The second point about the trial is that the median time to treatment was 23 days. We reported that there's an important cutoff that the longer you go out, the better patients do—and so there were some more favorable patients included in this trial. This trial reports a 6.5% difference in the progression-free survival at 2 years, which is 24 months—it was 76.7% vs 70.2%. And there was no difference in the overall survival. As a fourth point—and I think it's important that we're all going to incorporate this regimen, and practices are different in Europe than in the United States—that the preplanned before randomization consolidation, radiation therapy was administered after treatment to initial sites of bulky disease that is greater than or equal to 7.5 centimeters. And the outcomes were reported in the paper of what happened to those patients, which I won't review.

The next point is that the number of screen failures was high in this series; 17% or 182—higher than we're used to seeing—and [there were] 18 patients who became ineligible due to signed informed consent, which is a little unusual. The next point is if you look at subgroups of the forest plots and in the supplementary tables that appeared to have the greatest benefit, those patients were aged over 60 and had ABC [activated B-cell] phenotype and an IPI [International Prognostic Index] of 3 to 5. And again, to achieve this difference in progression-free survival, the next point is that this will add significant costs because there will be the pola-R; secondly, growth factor [would be given] to all patients, and that would include patients under the age of 60. So, all patients received growth factor.

There are 2 additional doses of anti-CD20 and if added on as per the older German trials, and then everyone that was eligible got the radiation therapy, not all patients. And looking at the cost, they're not going to be insignificant, and there are different analyses that are ongoing at this time, which I won't allude to at this time. So again, the overall survival differences were not different to 88.7% vs 88.6%. The patients who had an [Eastern Cooperative Oncology Group] performance score of greater than 2 were excluded, which is characteristic in clinical trials. But then, should these patients be all treated with this regimen, [even if] they weren't included in this analysis? And I alluded to the limited-stage disease. Who should be treated I think will be decided on further reviews, but in looking at the data, I don't think there's convincing evidence to treat all patients with pola-R-CHP, and the data from the forest plots would suggest over the age of 60 [and] ABC. And those patients with IPI of 3 to 5 would benefit from this therapeutic intervention.

AJMC®: When we talk about moving polatuzumab up to the frontline setting, where it has traditionally been used in the relapsed refractory setting, how might its use in the front line impact decision-making in later settings?

Habermann: If we look at the initial polatuzumab vedotin trial, it was with bendamustine and rituximab. That regimen was approved in June of 2019, and looking at the response rates and the outcomes, the overall response rate was 45%.⁵ And the complete remission rates were 40% and the [polygenic risk score] of 5%. And so, it's an active regimen. I think that once a patient has received polatuzumab vedotin then to consider repeating that regimen in patients who have been refractory or who have relapsed, I think consideration might be given to other regimens rather than pursuing that direction next, but this will be institutional and investigator dependent. I think now we have some other opportunities and other regimens to incorporate at the time of relapse.

AJMC®: The combination of tafasitamab and lenalidomide was recently studied in patients with relapsed refractory DLBCL, who are ineligible for autologous stem cell transplant. What has been your experience if any, with this combination in practice?

Habermann: Tafasitamab and lenalidomide is an active regimen; the FDA approval was in July of 2020, and this is an Fc-enhanced anti-CD19 monoclonal antibody. And the other group excluded not only were not eligible for transplant, but [they were] also primary refractory patients were to be excluded in that regimen. And if you look at the response rates, the overall response rates were 60% and the complete remission rate was 42.5% and the PR [partial response] 17.5% in the paper by Gilles Salles in 2020 in Lancet Oncology.⁶ And looking at the median duration of response, it was 21.7 months. And in the median duration of response for [complete response] patients was not reached vs PR patients, 4.4 months. And so, our lymphoma group has utilized this approach. And this I think is a next approach in patients with relapse.

AJMC®: How do you sequence treatment options for patients who have relapsed or refractory DLBCL who are not candidates for transplant? What are some of those factors that play into that decision?

Habermann: There has never been a more complicated time. I had the privilege of chairing the North American and R-CHOP trial back in the 90s. And we've then gone through looking at autologous stem cell transplant. And now we have CAR [chimeric antigen receptor] T-cell therapy, then we have the pola+BR, tafasitamab/lenalidomide, selinexor, and [loncastuximab tesirine]. We have the bispecific antibodies—none of which are FDA approved at this time—are regulatory body-approved internationally, and that with the CAR T makes all of this very complicated. And I don't think anyone has the answer. I think it's going to come to the investigator and institutional dependent within referral centers, and the lymphoma groups will attempt to make their approaches more uniform.

I think the way we looked at things—with an R-CHOP regimen with the response rates I talked about—then if you think about second-line therapy, about half of patients would potentially be eligible for an auto stem cell transplant. Now, that's going to be auto stem cell transplant vs CAR T, and there's a lot of discussion and debate going on there about what approaches might be the most optimal. For those who are not transplant eligible, there also could be CAR T opportunities. The tafa/lenalidomide approach is an approach. And then as I mentioned, the pola+BR, selinexor, loncastuximab/tesirine, and then other therapies. What you come up against is looking at [a patient’s] age. We [must] be careful how we define that age performance score, and then patients who are or are not transplant or CAR T candidates and may not want those approaches. So, for the elderly with multiple comorbidities, the tafasitamab/lenalidomide approach is a reasonable one for older patients with medical problems, but not a transplant candidate but possibly CAR T. Then, the pola+BR is an approach, and then [we can] use one of the CD19 targeted approaches, most of which are CAR T. And then the bispecifics that are coming.

For patients with a good performance score progressing after CAR T, loncastuximab, tafasitamab/lenalidomide, pola+BR, selinexor would all be reasonable approaches in patients with a good performance score, failing rise with a planned CAR T or transplant, then pola+BR as a reasonable approach. In patients who have relapsed after R-CHOP and who are potential transplant or CAR T candidates, but do not wish to pursue [these options], they can then try tafasitamab/lenalidomide and selinexor and some of the others that I mentioned.

So, in summary, I've kind of rattled off several things, but it's the way things are in 2022. And we now have many different options—and it’s going to be a complicated world. In some ways that's a good thing because there are more opportunities for patients.

AJMC®: With that in mind, I'd like to ask, do you have any closing thoughts when we talked about DLBCL?

I think that from a patient perspective, the times are unprecedented. Secondly, and I didn't allude to this, but in all options, we try to put clinical trials at the forefront, whether patients are untreated, previously treated, and if they’ve relapsed, regardless of what other modalities they've received. That is what is really moving the field right now. And if patients don't participate in the clinical trials, then we're not going to be able to move the field forward.

Secondly, we haven't talked about the genomics world. We've had the privilege of being involved in different genomics papers and so forth since the 2000s and the hope was that we were going to be a lot further than we are today. In DLBCL, if you have FISH studies—fluorescence in situ hybridization—that are positive for MYC and BCL-2 with or without BCL-6 but BCL-6 with MYC is not as unfavorable. Then we consider other approaches because standard R-CHOP is not as effective upfront.

Everyone's looking for the master randomized trial. The United States and the cooperative groups are attempting to arrange something up front, a basket-type trial where different drugs would be combined depending upon what your genomic studies were. But unfortunately, the key genomics papers that were done were designed to study the science. They weren't designed to adapt to clinical trials, and everybody's trying to work on this question.

Prior to the pola+CHP trial, there were over 25 clinical trials that essentially did not change R-CHOP as the standard of care. And so now we're getting more sophisticated….We’re going to get much further along…it's a very exciting time for patients; if they have questions or concerns, they can reach out to referral institutions for a second opinion; in relapsed refractory disease, they can reach out to referral institutions that might have clinical trials open. Last year at this time we had 48 clinical trials open in lymphoma alone, whether it'd be phase 1, 2, or 3. So from the standpoint of disease management, which is really important.

References

1. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(19):3121-3127. doi:10.1200/JCO.2005.05.1003.

2. Wang Y, Faroog Y, Link BK, et al. Late relapses in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol. 2019;37(21):1819-1927. doi:10.1200/JCO.19.00014

3. Cerhan JR, BK Link, Habermann TM, et al. Cohort profile: the lymphoma specialized program of research excellence (SPORE) molecular epidemiology resource (MER) cohort study. Int J Epidemiol. 2017;46(6):1753-1754i. doi:10.1093/ije/dyx119.

4. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304

5. FDA approves first chemoimmunotherapy regimen in patients with relapsed or refractory diffuse large B-cell lymphoma. News release. FDA. June 10, 2019. Accessed July 17, 2022. https://bit.ly/3ATSDm

6. Salles G, Duell J, Barca EG, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4.