Novel Strategies in Acute Myeloid Leukemia Management

Matthew Davids, MD, MMSc:As we look more toward the future of venetoclax in AML [acute myeloid leukemia], we were talking a bit about the younger patients and those who have curative intentions. I know there is an interesting 7-plus-3 approach combined with venetoclax, so maybe talk a little bit about that.

Harry Erba, MD, PhD:Unlike CLL [chronic lymphocytic leukemia], chemotherapy is not dead in AML. We still cure patients with chemotherapy, and we have to remember that as we’re looking at these, treatment regimens that are being developed. Doesn’t it make sense, then, in a disease that does tend to be sensitive to chemotherapy, to use something that might sensitize the cells to cell death after that chemotherapy trigger? And so I think it makes perfect sense to combine venetoclax with 7 and 3, to combine it with other myelosuppressive regimens, like liposomal daunorubicin-cytarabine.

The concern here is the overlapping toxicity of myelosuppression, the definite need in intensively treated patients of using azole antifungals. This has to be done cautiously. But the phase I studies have already started. Richard Stone, MD, at Dana-Farber Cancer Institute, your institution, in combination with collaboration with The University of Texas MD Anderson Cancer Center are doing a phase I study of 7 and 3 with venetoclax. The venetoclax is being given for only 14 days to try to limit the myelosuppression. So we’ll see if it can be done safely, if counts will recover. Because that may be a way of improving not only CR [complete remission] rates but also the depth of remission, which clearly seems also to be important in AML in predicting prognosis and outcomes after transplant. It is being done. I think we have to be very cautious about just doing it outside the context of a clinical trial.

Matthew Davids, MD, MMSc:We were also talking in CLL about some of the novel agent combinations with venetoclax. You’ve been fortunate with the AML count. A number of other drugs were approved recently for specifically targeting different mutations, in particular in combinations with those agents with venetoclax that are being explored.

Harry Erba, MD, PhD:Absolutely. There are preclinical data of synergy with FLT3 inhibitors, with IDH inhibitors, and those combination trials are in progress right now. Courtney DiNardo, MD, at MD Anderson was asked an interesting question at the poster discussion today at the American Society of Clinical Oncology Annual Meeting. And that was, we see activity of the HMA [hypomethylating agent] in theIDH-mutated group, according to DiNardo, who has presented results of a phase Ib study in Munich, Germany. And at this meeting in a poster of HMA, azacitidine with ivosidenib forIDH1-mutated patients, and 80% response rate, there are very high and very quick responses.

And so the pointed question from the audience is, do you wait for the mutational analysis, and how do you choose between these 2? Do you use 1 or the other? And I congratulated her answer afterward on her answer. She said, “What I do is I put them on a clinical trial with all 3 drugs,” which is the right answer, right? We need to learn how to use all 3 drugs together. She has a study of an HMA with time-limited venetoclax, 14 days, and continuous ivosidenib or enasidenib for theIDH1- andIDH2-mutated patients. We’ll wait to see if we’re going to see acceptable toxicity.

I think the challenge that we will have with just that experience is whether it is safe to do; we’ll see. But if it is safe to do, the response rates are already so high with the doublets, 80% response rates, the only way we’re really going to know if we’re doing some good will be event-free and overall survival, maybe quality of life would be nice to look at. And then of course the question is we’re going to be back in the same boat that you might be in some day, which is, what do you do when those drugs fail?

Personally, right now I’m still following the sequential way of doing this in theIDH-mutated patients. The label indication is an HMA venetoclax. I’ll start with that. The initial label for ivosidenib and enasidenib is relapse-refractory, so I’ll use those in the second-line setting. The approval moving ivosidenib up front— and the NCCN [National Comprehensive Cancer Network] is saying you can move either of those up front—makes it a little more complicated in choosing between these 2 regimens.

Matthew Davids, MD, MMSc:The data for these other newer targeted agents are mainly after chemotherapy-based regimens. How confident are you of the activity of ivosidenib, for example, after HMA plus venetoclax?

Harry Erba, MD, PhD:Oh, I’m not confident at all. We have very little experience with that. Now in those phase I studies, some patients received FLT3 inhibitors or IDH inhibitors, some patients may have been just treated with HMAs. And they had relapsed-refractory disease and then went on to the study. The question is, can you extrapolate that to an HMA venetoclax failure? We don’t know yet. These are the things that we’re going to have to learn. So 1 of the big questions is, as we both alluded to, is it combinations or is it sequential therapy that’s going to be the best option for patients?

Thank you, Dr Davids, for this insightful discussion, and thank you to our audience for watching thisTargeted Oncology™ presentation on the use of BCL2 inhibitor in CLL and AML.

Matthew Davids, MD, MMSc:As we look more toward the future of venetoclax in AML [acute myeloid leukemia], we were talking a bit about the younger patients and those who have curative intentions. I know there is an interesting 7-plus-3 approach combined with venetoclax, so maybe talk a little bit about that.

Harry Erba, MD, PhD:Unlike CLL [chronic lymphocytic leukemia], chemotherapy is not dead in AML. We still cure patients with chemotherapy, and we have to remember that as we’re looking at these, treatment regimens that are being developed. Doesn’t it make sense, then, in a disease that does tend to be sensitive to chemotherapy, to use something that might sensitize the cells to cell death after that chemotherapy trigger? And so I think it makes perfect sense to combine venetoclax with 7 and 3, to combine it with other myelosuppressive regimens, like liposomal daunorubicin-cytarabine.

The concern here is the overlapping toxicity of myelosuppression, the definite need in intensively treated patients of using azole antifungals. This has to be done cautiously. But the phase I studies have already started. Richard Stone, MD, at Dana-Farber Cancer Institute, your institution, in combination with collaboration with The University of Texas MD Anderson Cancer Center are doing a phase I study of 7 and 3 with venetoclax. The venetoclax is being given for only 14 days to try to limit the myelosuppression. So we’ll see if it can be done safely, if counts will recover. Because that may be a way of improving not only CR [complete remission] rates but also the depth of remission, which clearly seems also to be important in AML in predicting prognosis and outcomes after transplant. It is being done. I think we have to be very cautious about just doing it outside the context of a clinical trial.

Matthew Davids, MD, MMSc:We were also talking in CLL about some of the novel agent combinations with venetoclax. You’ve been fortunate with the AML count. A number of other drugs were approved recently for specifically targeting different mutations, in particular in combinations with those agents with venetoclax that are being explored.

Harry Erba, MD, PhD:Absolutely. There are preclinical data of synergy with FLT3 inhibitors, with IDH inhibitors, and those combination trials are in progress right now. Courtney DiNardo, MD, at MD Anderson was asked an interesting question at the poster discussion today at the American Society of Clinical Oncology Annual Meeting. And that was, we see activity of the HMA [hypomethylating agent] in theIDH-mutated group, according to DiNardo, who has presented results of a phase Ib study in Munich, Germany. And at this meeting in a poster of HMA, azacitidine with ivosidenib forIDH1-mutated patients, and 80% response rate, there are very high and very quick responses.

And so the pointed question from the audience is, do you wait for the mutational analysis, and how do you choose between these 2? Do you use 1 or the other? And I congratulated her answer afterward on her answer. She said, “What I do is I put them on a clinical trial with all 3 drugs,” which is the right answer, right? We need to learn how to use all 3 drugs together. She has a study of an HMA with time-limited venetoclax, 14 days, and continuous ivosidenib or enasidenib for theIDH1- andIDH2-mutated patients. We’ll wait to see if we’re going to see acceptable toxicity.

I think the challenge that we will have with just that experience is whether it is safe to do; we’ll see. But if it is safe to do, the response rates are already so high with the doublets, 80% response rates, the only way we’re really going to know if we’re doing some good will be event-free and overall survival, maybe quality of life would be nice to look at. And then of course the question is we’re going to be back in the same boat that you might be in some day, which is, what do you do when those drugs fail?

Personally, right now I’m still following the sequential way of doing this in theIDH-mutated patients. The label indication is an HMA venetoclax. I’ll start with that. The initial label for ivosidenib and enasidenib is relapse-refractory, so I’ll use those in the second-line setting. The approval moving ivosidenib up front— and the NCCN [National Comprehensive Cancer Network] is saying you can move either of those up front—makes it a little more complicated in choosing between these 2 regimens.

Matthew Davids, MD, MMSc:The data for these other newer targeted agents are mainly after chemotherapy-based regimens. How confident are you of the activity of ivosidenib, for example, after HMA plus venetoclax?

Harry Erba, MD, PhD:Oh, I’m not confident at all. We have very little experience with that. Now in those phase I studies, some patients received FLT3 inhibitors or IDH inhibitors, some patients may have been just treated with HMAs. And they had relapsed-refractory disease and then went on to the study. The question is, can you extrapolate that to an HMA venetoclax failure? We don’t know yet. These are the things that we’re going to have to learn. So 1 of the big questions is, as we both alluded to, is it combinations or is it sequential therapy that’s going to be the best option for patients?

Thank you, Dr Davids, for this insightful discussion, and thank you to our audience for watching thisTargeted Oncology™ presentation on the use of BCL2 inhibitor in CLL and AML.

Transcript edited for clarity.