Recent Advances in Treatment of Acute Myeloid Leukemia - Episode 7
Harry Erba, MD, PhD: Let’s talk about the use of venetoclax, the BCL2 inhibitor, with hypomethylating agents, LoDAC [low-dose decitabine], in older, unfit patients with AML [acute myeloid leukemia]. Dan, do you want to walk us through those?
Dan Pollyea, MD, MS: This has been around for a little while now, and we probably have a fair amount of comfort with it. Published large phase I studies have led to the approval of venetoclax plus a backbone therapy: either low-dose cytarabine or a hypomethylating agent, azacitidine or decitabine, in the setting of a newly diagnosed unfit patient or an older AML patient.
For the responses, at least with the hypomethylating therapy, the expectation is a response rate of somewhere in the order of 70%. We’re still a little bit in evolution on the durability and survival, but right now, they look fairly good and promising. These are pretty safe therapies. The concern for tumor lysis syndrome is pretty low when the tumor lysis syndrome mitigation techniques that were employed in the studies are used, and the early death rates are very low. Of course, this led to approval a little over a year ago. The venetoclax-based therapies for this population are a significant advancement and have worked their way into the standard of care, and there are lots of things that we could do to improve it.
Harry Erba, MD, PhD: Naval, how about combinations of venetoclax with intensive chemotherapy, like FLAG-IDA [fludarabine, cytarabine, granulocyte colony-stimulating factor—idarubicin hydrochloride]?
Naval Daver, MD: This is, of course, a much earlier study development. This is compared with the HMA [hypomethylating agent] venetoclax or low-dose araC [cytarabine]—venetoclax, which have more established track records of publication follow-up. This is a study that was presented from our center, The University of Texas MD Anderson Cancer Center. One of our fellows, Iman Abou Dalle, working with Dr Courtney DiNardo, presented results of a FLAG-IDA [fludarabine, cytarabine, granulocyte colony-stimulating factor–idarubicin hydrochloride], so fludarabine, cytarabine, idarubicin–intensive induction with venetoclax in relapsed population; initially in the phase Ib safety portion and now moving to both frontline and relapsed cohorts.
I have to say, with this study, it’s very important that the study has evolved quite a bit in dosing. It initially started with standard UK [United Kingdom] MRC [Medical Research Council] FLAG-IDA [fludarabine, cytarabine, granulocyte colony-stimulating factor—idarubicin hydrochloride] dosing with venetoclax and only 14 days of venetoclax. In the first 8 or 9 patients, we had 4 patients during the first cycle of myelosuppression who had severe infections, which required ICU [intensive care unit] treatment. They recovered and came back, and eventually 2 of them went to transplant and are still doing well. That made us very concerned, so we dropped the dosage of IDA [idarubicin hydrochloride] to 6 mg/m2 for 2 days and araC [cytarabine] to 1.5 g/m2 for 4 days. And that modified regimen, which was a small change, changed the myelosuppression infection.
Then the relapsed cohort is continued. We’ve treated about 20 patients. The response rate, CR [complete response] or CRI [complete response with incomplete blood recovery] rate is 75%, which in relapsed AML is amazing. It’s a small number, so we have to see if this will continue, and more than half of them went to transplant. It’s looking good. At the end of the day, the survival, unfortunately, is not that great. It’s about 8 months in relapsed patients, which is not bad, but it’s not comparing with what we were hoping when we saw the high response.
The frontline arm is ongoing. It’s showing a 100% response rate, but we do get high responses in the frontline setting. MRD [minimal residual disease] negativity is being achieved in everybody, so there is excitement for this, but I have to be cautious. This is not something to do at home at all.
Harry Erba, MD, PhD: No, it’s not for the faint of heart.
Naval Daver, MD: That’s why I mentioned ICU stays, etc. This is a great option if you have a 35-year-old, failed 3+7, and you want to call your large academic center and say, “Would you do this? Can you do this?” This could be something that could take them to transplant and get the patient through. If you do this at home, the mortality could be extremely, extremely high. It’s being evaluated and expanded, and we will have more data, but 75% is a very good number in relapse.
Transcript Edited for Clarity