The Future of BCL2i Combination Therapies

Transcript:Naval G. Daver, MD: BCL2 inhibitors are becoming a major player, we would even go as far as to say the backbone potentially of future AML [acute myeloid leukemia] therapies. BCL2 is important in AML, but I actually think it’s going to become important in many other diseases. CLL [chronic lymphocytic leukemia] of course we know it has a great history and track record. We’re also seeing activity in ALL, acute lymphoblastic leukemia. CML [chronic myeloid leukemia], there’s a lot of preclinical synergy with dasatinib and other TKIs [tyrosine kinase inhibitors], and these trials are being looked at. Lymphomas, there’s activity. Myeloma in a particular subset. So I think this is going to become, for the hematologic malignancies, a very important treatment strategy.

AML specifically, we are hoping that the BCL2 to AML will be what the IMIDs [immunomodulatory drugs] were for myeloma. We think that the azacitidine/venetoclax combination can become a new backbone. But on its own we don’t think it’s enough to get away from chemotherapy. You know, response rates are high, 70%, but if you look at the 3-year survival, it’s 45%. Whereas with induction, like chemotherapy, especially in the favorable intermediate groups, reports have shown somewhere between 50% and 65%. So I think we need to do more work, but I think we can get to this point where we could replace induction chemotherapy with [hypomethylating agent/venetoclax].

Some of the approaches that are looking at this are combining the new FLT3 inhibitors with [hypomethylating agent] and venetoclax, adding gilteritinib and quizartinib to the backbone of azacitidine/venetoclax. We actually have both of these studies open at The University of Texas MD Anderson Cancer Center. Initially they’re going to look at the doublets of venetoclax with quizartinib, venetoclax with gilteritinib in the relapse, and then the hope is to move it into the frontline using azacitadine, venetoclax, quizartinib, gilteritinib in the FLT3-mutated. If we can hit 70%, 3 to 4 year survival, then of course, the big question is: Why do we want to do induction chemotherapy with FLT3? Let’s do the lower intensity with the powerful FLT3 inhibitor.

The same approach with IDH1/2. In fact, at the EHA [the European Hematology Association] this year, my colleague Dr Courtney DiNardo ,MD, MSCE, will be presenting data combining IDH inhibitor with venetoclax, showing even in relapse setting we could get up to 70%, 80% response rate without chemotherapy, without [hypomethylating agent], which again, 5 years ago people would think would be impossible. So that also is moving to the frontline adding IDH inhibitor to hypomethylating/venetoclax for IDH mutated. And for those who are not FLT3 or IDH where we don’t have this kind of targeted triplet with [hypomethylating agent]/venetoclax, we’re looking at either idasanutlin or some of the immune therapies—PD-1 [programmed cell death protein 1] inhibitors, monoclonals—to add these to the [hypomethylating agent]/venetoclax. These studies are ongoing. So we think in the future for maybe not all the AMLs, there are some AMLs that still benefit from chemotherapy like the core binding factor and others. But for a large proportion, maybe 70%, 80%, 90%, we hope that there will be triplets that will further improve azacitidine or decitabine/venetoclax to the point where they’re equal to chemotherapy. And if that’s the case, we would definitely prefer those; so will the patients. They’re much more tolerable, they’re outpatient, less early mortality.

I think it’s going to be very much like the myeloma field has gone where they used to do VAD—vincristine/Adriamycin/[dexamethasone]—only 12, 13 years ago; it’s not ancient history. And today nobody talks about it. It’s about the new molecular targeted immune therapy. I think finally AML is going to move in that direction.

Transcript Edited for Clarity