ASH 2025 | The risk of Richter’s transformation in the era of targeted therapy

This is certainly an evolving and open question. To contextualize this, we go back a number of years when the targeted agents and initially BTK was first entering the scene and it’s in the very heavily pre-treated relapsed refractory setting, many prior lines of therapy, much prior chemoimmunotherapy, and the progression events that occurred in those patients when they had disease progression were enriched for Richter’s events. And so there was actually an initial concern, are we going to see more Richter’s? Now, we’ve seen lower rates, certainly when you’re using these targeted drugs in the first line setting, the concern or the hypothesis is that we’ll see these later. And I think that it’s too early to tell. In this work that we published in Leukemia this year, we found a statistically significant lower rate just when looking at patients from the time of diagnosis by era, but also then actually looking within treatment subgroups. Treatment with chemoimmunotherapy is associated with an increased risk of Richter transformation; we’ve previously shown that, and others as well. Treatment with a targeted agent was not; importantly, it didn’t do what would be the best case scenario, which is actually decrease it compared to the non, you know, the treatment-free period patients who were never requiring therapy. It’s simply that the rate wasn’t increased above that. So, treatment itself, when targeted agent therapy, did not increase the risk of Richter transformation in the study compared to chemoimmunotherapy, when compared to no treatment at all. Certainly, now we need much longer follow-up because these drugs work very well; you’re talking about median progression-free survival, you know, eight or nine years with a BTK inhibitor. We certainly may see that these are suppressing and controlling bad clones that ultimately, in enough time, would grow out, but also, you know, and that may be the case. It is too early to say, but I think that inevitably you’re going to still reduce the overall incidence of this, even if you are, you know, quote-unquote, “”kicking it down the road.”” Simply because if you kick it down the road long enough, fortunately, our goal, people die from something else, not an infection or another cancer, but something, you know, natural causes. So, I think if we, even if you are deferring a bad clone for long enough, you would ultimately see the rates come down a little bit. Now, is it, in fact, just like truly reducing it altogether? That, I think, remains to be seen. But one other point on Richter’s is just this remains overall a rare, devastating but rare event, and not one that the, you know, typical newly diagnosed patient should be wringing their hands over and losing sleep over. That’s something that we fear that they fear, but, but fortunately, is rare and not something that needs to be on the top of everybody’s mind per se, right from the time that you’re diagnosed, saying, “”When’s the other shoe going to drop? I’m going to get Richter transformation.”” This is fortunately a rare event. If you have Richter transformation, this really shifts the path that we’re on, and that’s probably where it’s important to get to a tertiary center and start thinking about this again differently than de novo large cell lymphoma. R-CHOP is not going to suffice here, and trial and accrual and enrollment is really most key for those people. But fortunately, a very small sliver of the overall CLL patient population is going to have to worry about this.

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