Listen to Jeremy S. Abramson, MD, MMSc, discuss key findings from select studies in lymphomas presented at the ASH 2025 Annual Meeting, including perspectives on the clinical implications of the data for patients with CLL, FL, and DLBCL.
In this podcast episode, Jeremy S. Abramson, MD, MMSc, reviews data from select presentations in lymphomas at the ASH 2025 Annual Meeting and provides perspectives on the clinical implications of these data for patients with chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL), including:
Presenter:
Jeremy S. Abramson, MD, MMSc
Professor of Medicine
Harvard Medical School
Director, Center for Lymphoma
Mass General Brigham Cancer Ins
Boston, Massachusetts
Content based on an online CME program supported by educational grants from AstraZeneca, BeOne Medicines, Genentech, Geron Corporation, Incyte, Johnson & Johnson, Lilly, and Novartis Pharmaceuticals Corporation.
Link to full program:
https://bit.ly/4aqMobZ
Jeremy Abramson: We've just completed a very exciting annual meeting of the American Society of Hematology, with some very relevant and potentially practice-changing and practice-informing data that was presented across the spectrum of B-cell lymphomas and CLL.
One exciting presentation was actually the very first presentation in the plenary session, and it was the presentation from the German CLL study group of the CLL17 trial. The CLL17 trial was a randomized trial with 3 arms, comparing ibrutinib monotherapy to venetoclax obinutuzumab, or venetoclax ibrutinib.
The ibrutinib arm in the study was continuous therapy, as typically done with a single-agent BTK inhibitor, whereas the venetoclax obinutuzumab and venetoclax ibrutinib arms were both time-limited therapies. And today, we don't have any direct data comparing these two strategies until now.
These study results were important. Importantly, they showed that patients in all three studied arms did very well, with high response rates in all three arms.
If we look at depth of response, the MRD undetectable rate, defined as 10 to the negative 4th, was highest in the venetoclax obinutuzumab arm, followed by venetoclax ibrutinib, followed by ibrutinib.
The primary endpoint of the study was progression-free survival, and this was a non-inferiority trial to show that these agents administered in time-limited therapy were not inferior to ibrutinib given as continuous therapy, and that primary endpoint was met.
There was no difference in 3-year progression-free survival, which was 80%, approximately, in all 3 arms. And what these data show is that time-limited therapy with either their venetoclax or ibrutinib venetoclax were non-inferior to continuous therapy with ibrutinib alone.
Notably, the combination of venetoclax with a BTK inhibitor had also previously been studied with venetoclax in combination with acalabrutinib in the AMPLIFY trial.
Now, the Amplify trial did not include an arm for venetoclax or obinutuzumab, so these particular, data, help support that either a time-limited approach with venetoclax obinutuzumab or venetoclax with a single BTK inhibitor, either ibrutinib per CLL17 or acalabrutinib per Amplify are reasonable and appropriate, and importantly, highly effective and well-tolerated time-limited strategies.
There were also additional CLL studies, particularly looking at the non-covalent BTK inhibitor, pirtobrutinib.
As of today, in frontline therapy, patients can receive a BTK inhibitor with one of the fully FDA-approved covalent BTK inhibitors, ibrutinib, acalabrutinib, or zanubrutinib, with most providers preferring acalabrutinib or zanubrutinib, the next-generation covalent BTK inhibitors, due to more favorable safety profile compared to the first-generation ibrutinib.
However, until today, there were no frontline pirtobrutinib trials comparing pirtobrutinib with a covalent BTK inhibitor.
At this meeting, we saw the first Phase 3 trial doing just that. And it was a non-inferiority trial evaluating the non-covalent PTK inhibitor pirtobrutinib with the covalent first-generation BTK inhibitor, ibrutinib.
This was a non-inferiority trial designed to show that pirtobrutinib was not inferior to ibrutinib, but hopefully with less toxicity. As a matter of fact, however, the study actually appeared to show that pirtobrutinib appeared even more effective than ibrutinib.
The overall response rate favored pirtobrutinib at 87% compared to 78.5%, and the 18-month progression-free survival was 87% for pirtobrutinib and 82% for ibrutinib. So clearly, pirtobrutinib was not inferior to, ibrutinib in terms of progression-free survival, and in fact, pirtobrutinib was associated with a 43% reduction in risk of progression or death over ibrutinib.
Now, not surprisingly, pirtobrutinib did have a more favorable safety profile. It was particularly notable, that there were fewer dose reductions or dose discontinuations on the pirtobrutinib arm.
And additionally, there were a, significantly lower incidence of atrial fibrillation and other cardiac adverse events on preretinal compared with ibrutinib. And so these data would suggest, at least in the frontline setting, that we shouldn't be using ibrutinib as initial therapy.
And these data would suggest that pirtobrutinib might be added to our upfront treatment paradigm options, along with acalabrutinib and zanubrutinib, if selecting a continuous BTK inhibitor strategy for our patients.
An additional randomized trial evaluated the non-covalent BTK pirtobrutinib versus bendamustine rituximab in patients with treatment-naive chronic lymphocytic leukemia.
As with many randomized trials that have come before this study, which have shown superiority of novel agents over chemoimmunotherapy, so too was the case here, with pirtobrutinib showing substantially better efficacy than BR in previously untreated CLL patients.
The 24-month progression-free survival for pirtobrutinib was 93%, compared with 71% for BR which correlates with an 80% reduction in risk of progression or death favoring pirtobrutinib.
Now, if we turn our attention to tolerance, I'll note that there were more infections in the pirtobrutinib arm, and that likely reflects the fact that pirtobrutinib in the study was given as continuous therapy rather than time-limited therapy with chemoimmunotherapy. And so there's a longer exposure to drug therapy.
I'll note, importantly, as well, that there was no difference in the incidence of atrial fibrillation, highlighting that pirtobrutinib as a next-generation non-covalent PTK inhibitor has less atrial fibrillation than the first generation covalent BTK inhibitors that have come before.
And these data, along with the data presented at this meeting of pirtobrutinib versus ibrutinib in previously untreated CLL, highlight pirtobrutinib, a non-covalent BTK inhibitor, as a promising upfront treatment strategy for patients with previously untreated CLL when selecting a continuous BTK inhibition strategy.
If we turn our attention to follicular lymphoma. The standard of care for many patients with follicular lymphoma has really been similar now for several years.
Patients with high tumor burden symptomatic follicular lymphoma typically receive chemoimmunotherapy in the frontline setting. And patients needing second-line management for follicular lymphoma have most often received the lenalidomide rituximab regimen.
Now, more recently, we've had two randomized trials that have looked at a triplet with rituximab lenalidomide compared to rituximab lenalidomide alone.
Previously, and at the last ASH meeting, we saw data for the addition of tafasitamab to rituximab lenalidomide, showing superiority of adding that anti-CD19 monoclonal antibody.
At this ASH meeting, we saw a result of the EPCOR follicular lymphoma, or FL1, study.
And the EPCOR FL1 study compared standard rituximab lenalidomide to the triplet of rituximab lenalidomide plus the anti-CD20-CD3 bispecific antibody, epcoritamab. Patients in both arms receive time-limited therapy with either R-squared alone or R-squared plus epcoritamab.
And importantly, this study showed a fairly impressive improvement in efficacy, favoring the inclusion of the bispecific antibody. Patients on R-squared epcoritamab achieved a CR in 83% of cases, compared to 50% with R-squared alone.
And this correlated, to a 16-month progression-free survival of nearly 86% for R-squared epcoritamab, compared to only 40% on R-squared alone, which is a nearly 80% reduction in risk of progression or death favoring erenumab R-squared over R-squared alone.
These are the first data in follicular lymphoma that bring bispecific antibody therapy into the second-line treatment for follicular lymphoma and show that it can be done with superb efficacy.
The side effects of this approach show that when you add epcoritamab, you do add some side effects related to the bispecific antibody, notably the low risk of cytokine release syndrome, which is quite manageable, along with more immune suppression, B-cell depletion, and hypogammaglobulinemia.
But this is consistent with the known side effects of the relevant drugs that are included, with no new or amplified toxicity signal, and thus have resulted in a new highly effective second-line follicular lymphoma regimen with R-squared epcoritamab.
And then finally, I'll highlight one additional bispecific antibody story, and that's in relapsed refractory diffuse large B-cell lymphoma.
I presented 3-year follow-up data of the STARGLOW trial, which is a randomized trial evaluating the addition of the CD20-CD3 bispecific antibody glofitamab to gemcitabine oxaliplatin compared to our Gemox.
This randomized trial was conducted in second-line and later diffuse large B-cell lymphoma patients who were considered ineligible or without access to autologous stem cell transplant.
Now, with 3 years of follow-up, we see ongoing marked benefit for glofitamab Gemox over RGEMOX, with a median progression-free survival of 14 months compared to only 3 months, and a median overall survival of 26 months for glofitamab Gemox compared with only 13 months of overall survival for our Gemox.
At this meeting, we broke out the second-line patients who represented 63% of patients on the STARGLOW trial, and the results were even more impressive. Among second-line DLBCL patients not eligible for transplant, we see a median progression-free survival of 20.4 months compared to 5.5 months for RGEMOX. The median overall survival has not been reached for second-line GloFit Gemox patients compared to 14 months for RGEMOX. And at 3 years, the progression-free survival rate was nearly 42%.
For GloFit GEMOX treated patients, compared to only 26% on our Gemox patients. And at 3 years, we do see a plateau on the survival curve, suggesting that approximately 40% of patients treated with an off-the-shelf bispecific antibody regimen like low-fit Gemox, might in fact be cured. And these are patients who may not be able to travel or have access to either stem cell transplant or CAR T-cell therapy, thus potentially widening the availability for curative intent, highly active immunotherapy regimens for second-line DLBCL.