Targeted Approaches to Treating AML

Transcript:

Naval G. Daver, MD: Ivosidenib is an IDH1 inhibitor. It was FDA approved about 1, 1-and-a-half-years ago in the relapsed/refractory setting based on a phase Ib, phase II study where the single agent ivosidenib showed about a 35% to 40% CR/CRh [complete response/complete response with partial hematologic recovery]. CR means there is a complete remission with a full recovery of counts. CRh is a relatively new term that the FDA has used that shows that you have less than 5% blasts in the marrow, and not full recovery, but platelets are above 50, neutrophils above 0.5, which most experts and treating physicians believe is sufficient for the patients to have good quality of life, be transfusion independent. That’s how the relapsed ivosidenib approval came about.

However, we also noted that there are frontline patients where we can document IDH mutations, and even with lower intensity therapies like azacitidine/venetoclax, although it’s a lower intensity, it’s not low, low intensity, you do see prolonged myelosuppression, cytopenia; there is a risk of infection. The azacitidine is injectable, so people do have to get laboratory tests 2 times a week at least for the first 4 to 8 weeks.

So if you have an 80-year-old patient who has comorbidities, performance status of 2, maybe is in a wheelchair, maybe has some organ dysfunction, for this patient even azacitidine or low-dose cytarabine/venetoclax is actually a difficult proposition and may have up to 20% early mortality. For these patients we are now looking at single-agent targeted therapies, and that’s where the first one to be approved is ivosidenib. This was based on a study that was presented by Dr Gail Roboz ,MD, etcetera, at ASH [American Society of Hematology] last year, as well as updated at the ASCO [American Society of Clinical Oncology] meeting this year. They treated about 36 patients and they saw that as a single agent in a newly diagnosed older AML [acute myeloid leukemia] patient who was unfit to receive even HMA/VEN [hypomethylating agent/venetoclax] or induction, they could get about a 40% to 45% CR/CRi [complete response with incomplete hematologic recovery]. So it’s not 70%, 75% like you would with [hypomethylating agent/venetoclax], but it was very well tolerated, very low early mortality, and these are the people where about half of them routinely would have been sent to hospice. What was also very encouraging is that the responses seemed to be durable, and they have a 1-year survival of about 50%.

I think that this is probably not going to be used widely across all patients. We think [hypomethylating agent]/venetoclax, or even [hypomethylating agent]/ivosidenib, which is showing good data, would be the general approach. But for the patients above 75, above 80 years old who are very fragile, who decide that they really want minimal oral therapy with not frequent visits that will give them a few years, I think this can be a very nice option. So it will probably be used in the United States.

Transcript Edited for Clarity