ASH 2022 | Limitations of current risk stratification systems in FL & treatment options for high-risk patients

That ASH educational section, I think the biggest takeaway from that is that to date we still do a very poor job, unfortunately, of identifying these high-risk patients, which are these early relapsing POD24 patients. A lot of the prognostic scores that we use, probably, at best, 50-60% accuracy in identifying these high-risk patients, which leaves out quite a bit. So that 20% of all FL patients who will get initial treatment, again, we still need to do a better identification of how to manage these patients. But, at least on the bright side, it looks like a lot of these non-chemotherapy-based agents seem to be agnostic to POD24.

The AUGMENT study, was very little difference between those who had a progression of disease at 24 months and those who did not. The MAGNIFY study was also a study looking at lenalidomide and rituximab. Again, we still had very good response rates and durable responses in patients who had POD24. The PI3 kinase delta inhibitors, even though there’s really only copanlisib left, also does appear to be agnostic to POD24. So the response rates, those with POD and without, seem to be about the same. The duration of response appears to be about the same. The biggest issue with the PI3 kinase delta inhibitors is tolerability, which is of a class effect. And then we look at tazemetostat. Tazemetostat is a little bit different in that those with the EZH2 mutation and have a POD24 tend to do better with tazemetostat than compared to wild-type patients. So there may be some rationale for looking for EZH2 mutations in that patient population.

CAR-T also appears to be very agnostic to POD24, at least with axi-cel. The data with tisa-cel is a bit more immature. The initial overall response rate and CR rate was a bit lower in the POD24 patients compared to non-POD24 patients with tisa-cel. But again, at least at last presentation, they did not necessarily give a true readout or duration of response between these two cohorts of patients. And then with mosunetuzumab having an indication in Europe, and it’s likely to have an indication in the US, also, it appears that the POD24 status won’t necessarily impact outcome to mosunetuzumab, which we would probably expect with the other bispecific antibodies if they get an indication in follicular lymphoma.

So, even though we do a very poor job as of right now of identifying these patients, I think, moving forward, at least we have options that may not necessarily depend on the POD24 status. And if we can do a better job of identifying these patients in the frontline setting, we could potentially improve some of the frontline treatment options we offer these patients to hopefully allow them to have more durable, first remission compared to the non-POD24 patients, which, in essence, would hopefully improve their overall survival and outcomes, which, as of right now, is still quite poor compared to the non-POD24 patients.