ASH 2023 | Improving upon the standard of care for patients with Richter’s transformation

So Richter’s transformation is a is a tough disease to treat. So it refers to the transformation of patients with CLL to aggressive lymphoma, largely diffuse large B-cell lymphoma. And unfortunately patients with Richter’s transformation have poor prognosis, even with contemporary therapy. The standard of care is chemoimmunotherapy with R-CHOP, but the median overall survival after this is fairly disappointing at around 12 months. 

There have been many attempts made to improve on this in recent years, and people have tried combining R-CHOP with BTK inhibitors, for instance, and there’s now a Phase III study ongoing with R-CHOP plus or minus acalabrutinib and we’re waiting for a readout from that. And people have also looked at things like venetoclax, and there are a couple of Phase II study designs combining either dose-adjusted EPOCH or R-CHOP with venetoclax, but it seems to add quite a lot of hematologic toxicity. And maybe there’s a bit of an improvement in efficacy signal, but we haven’t seen Phase III data there. Last year we saw some encouraging abstracts about pirtobrutinib, which is a non-covalent BTK inhibitor, and as a single agent actually has a very promising response rate of about 50-55% from memory with a relatively short PFS, but suggesting that it could potentially be combined with other agents to provide an interesting regimen. And we also saw preliminary data from the other CD20xCD3 bispecific antibody, epcoritamab, which resulted in the first ten patients treated with a CR rate of 50%, which we’re all really impressed with, but clearly we’re going to need more of a sample size and longer follow-up to know how durable those are. 

So I presented data on mosunetuzumab in Richter’s transformation, and there are about 20 patients presented there. We saw an overall response rate of 40% with a CR rate of 20%. And you might think, well, you know, that’s not that high when you compare it to the other abstracts that I mentioned, but the patients treated on this particular study were actually quite heavily pretreated in comparison to those treated on the epcoritamab study, for instance, where half of them were actually treatment-naive. And so I think that the efficacy seen was actually quite reasonable and a handful of patients had quite durable responses.

So again, thinking back to the theme, one of the themes of the meeting for me was seeing novel combinations with bispecifics. I think last year was all about bispecific agents as monotherapy and seeing how impressed we were with their activity, and this year’s meeting, I think the theme is seeing how bispecifics can be combined with other novel agents like polatuzumab and seeing, because of the non-overlapping toxicity profiles, we’re seeing potentially higher response rates, higher CR rates and potentially more durable PFS. And I think that it really speaks to the way that we’re going to be developing combinations, novel combinations, for people with diseases like Richter’s transformation in the future.