Chemo-Free Quadruplet Promising as Initial Treatment in DLBCL

Initial treatment with lenalidomide (Revlimid), tafasitamab (Monjuvi), rituximab, and acalabrutinib (Calquence) led to complete responses (CRs) in 64% of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), according to results from cohort 1 of the Smart Stop study. The phase II findings, presented at the recent American Society of Hematology (ASH) annual meeting, tested a response-adapted approach, with only two cycles of chemotherapy given to those in CR after initial treatment with the quadruplet regimen alone.

In this second of four exclusive episodes, MedPage Today brought together three expert leaders in the field, all from The Ohio State University Wexner Medical Center in Columbus — moderator Kami J. Maddocks, MD, is joined by Yazeed Y. Sawalha, MD, and David A. Bond, MD — for a virtual roundtable discussion on the Smart Stop results.

You can watch the first video in the series here.

Following is a transcript of their remarks:

Maddocks: Let’s move on to the next study, it was a little bit different study, frontline study in diffuse large B-cell lymphoma considering at least part non-chemo-therapy based. So the Smart Stop study was presented — lenalidomide, tafasitamab, rituximab, and acalabrutinib alone and with combination chemotherapy for the treatment of newly diagnosed diffuse large B-cell lymphoma.

So as a setup to this trial, we had the Smart Start study presented by Dr. Westin, which looked at the combination of rituximab, lenalidomide, and ibrutinib [Imbruvica] as a lead-in in patients with diffuse large B-cell lymphoma. And then the plan was for those patients to go on and receive all six cycles of chemoimmunotherapy, so non-chemo lead-in, but still receive the six cycles of chemotherapy. This showed very promising outcomes with a 2-year progression-free survival of a little over 90% in patients and really kind of set up this Smart Stop trial. So thoughts on this trial?

Sawalha: Yeah, I think very exciting data, very interesting concept potentially paving the way to hopefully one day chemo-free approach to diffuse large B-cell lymphoma and other aggressive B-cell lymphomas as well.

So 19 out of the 30 patients were able to receive only two cycles of CHOP [cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone], and with the limited follow-up to date, remained in remission. I think that’s very exciting. It looks like most patients are able to tolerate this regimen, so most patients were able to maintain more than 90% of the dose intensity of the targeted agents. Thirty percent of the patients were 70 years or older. I think that’s encouraging to see that older patients are included in this patient population, the overall high-risk patient population. I think it’s also important to note that most patients (83%) had non-GCB [non-germinal center B-cell] DLBCL or large B-cell lymphoma.

One kind of interesting side effect, which I don’t think is surprising to us to see, is rash in more than 40%, including grade 3 in 13%, which we know can be seen especially when we combine lenalidomide with a BTK inhibitor.

But overall, as you mentioned, Dr. Maddocks, very high response rate, a CR rate of 93% by the end of the second of two cycles of CHOP in combination with the targeted agents and then a CR rate of a 100% at the end of treatment for a subset of patients; only 22 patients that reached that point. So very encouraging. I would like to see these data also be… see similar responses in a multicenter hopefully setting rather than a single-center study.

Bond: Yeah, and I think it’s exciting to see the BTK [Bruton’s tyrosine kinase] inhibitors still being looked at in diffuse large B-cell lymphoma. I think there’s a lot going on in diffuse large B-cell lymphoma, a lot of classes of drugs being developed when we just spoke about bispecifics and we’ll be speaking about CAR-T. But I think that there was other data as well trying to look at the role of BTK inhibitors.

I think this is one potential path forward where you have a targeted combination therapy that has a time-limited approach frontline. And so I think with acalabrutinib, the earlier stage in diffuse large B-cell lymphoma with ibrutinib, which we know has more side effects, at least cardiovascular side effects compared to acalabrutinib, tends to be a little bit harder to tolerate. So I think looking at acalabrutinib in combination and these newer second generation BTK inhibitors is an attractive option.

I think it’s promising and I think we hope we see more in the frontline with the BTK inhibitors or in other settings that we’re able to bring these to patients, because I think right now in clinical practice, for the most part, BTK inhibitors have really fallen out of practice in large B-cell lymphoma, but there may be a path to bring them back in if we have effective combination regimens like this that really show more definitive efficacy.

Maddocks: Yeah, I think this is really interesting too because they plan on looking at not just response-adapted [reduction], but potentially receiving no chemoimmunotherapy with this non-chemotherapy approach. So we’ll look forward to longer follow-up on this study and further results. As you mentioned Dr. Sawalha, hopefully in larger populations of patients in a multicenter fashion.

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