ONCAlert | Upfront Therapy for mRCC

Case 3: IDH2-Mutated AML

Targeted Oncology
Published Online:12:26 PM, Wed July 10, 2019


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Naval G. Daver, MD: Moving on to our third case, this is an IDH2-mutated acute myeloid leukemia [AML], and I’m going to ask Dr Gergis to discuss the case, please.

Usama Gergis, MD, MBA: Thank you very much. I think it’s very timely to discuss IDH2 and acute myeloid leukemia. Our case today is a 65-year-old woman who presented with some bruising and fatigue, and she’s very fit—much better than most of us around the table. She walks 3 miles every day. She has a past medical history of hypercholesterolemia that is controlled. She presents with pancytopenia, white [blood] count [WBC] of 2.8, hemoglobin of 9, and platelets of 40,000. She now is diagnosed with acute myeloid leukemia—blast percentage 48%, cytogenetics are diploid, next-generation sequencing mutations in IDH2, GATA2, and ECH2.

She was appropriately treated with 7+3 [cytarabine/daunorubicin]. Treatment course was complicated, as expected, by mucositis and febrile neutropenia. After resolution of her complications, she received 2 cycles of high dose Ara-C consolidation. In the midst of her consolidation 6 months after initial diagnosis, she presented with fatigue, body ache, and gum bleeding. She was pancytopenic—WBC 1.8, hemoglobin 8, and platelets 28,000—and she had circulating myeloblasts. The bone marrow biopsy was hypercellular with 80% blasts and normal cytogenetics. Next-generation sequencing was done again on relapse, and she has the same IDH2, but now she has RUNX1 and DNMT3A.

Naval G. Daver, MD: Well, thank you very much. We’re moving now more into the pure targeted therapies and salvage, which is where a lot of these drugs are initially getting approval. For IDH1/2, we have gilteritinib, recently, and others in review like quizartinib. Dr Weinberg, for the molecular testing, are you routinely seeing people check this in the relapsed setting? If they are, are they asking for targeted panels or are you repeating the whole panel? What do you do?

Olga K. Weinberg, MD: Yes, we run the same panel.

Naval G. Daver, MD: Same panel, OK.

Olga K. Weinberg, MD: It is approved in a relapse setting. It’s not approved in a day 30 kind of setting, so we don’t use it there.

Naval G. Daver, MD: Not in remission.

Olga K. Weinberg, MD: Our panel is not really meant to be a minimal residual disease [MRD] panel. There are other panels that you can use for that, but we don’t run those.

Naval G. Daver, MD: Since you brought it up, minimal residual disease, now we’re going to stop for 1 hour and discuss this. I’m not going to do that, but I would just like to ask, clinically, does anybody use MRD in treatment decision-making today? At what time point do you use it and for what? James?

James K. McCloskey II, MD: I think we use MRD mostly for risk stratification. We do MRD testing at the time of first remission. We do MRD testing before they proceed to transplant and then subsequently every 3 months from the peripheral blood. I think that everyone will probably comment on this. There are a lot of variables right now in terms of how we measure MRD and how we reliably interpret it even as 1 patient might have different results, depending on the laboratory or depending on the particular aspirate that we send. There’s a lot of variability, and in general, we do not alter treatment based on the MRD response at this time. I do think it adds something in terms of risk stratification and it is incorporated into some of our clinical trials.

Naval G. Daver, MD: Anything different, Dr Rizzieri, that you do with MRD?

David Alan Rizzieri, MD: I do it so I can understand if it’s going to interrupt my sleep pattern at night, like you said. We know when to worry. It doesn’t necessarily mean that I’m going to jump and offer an allotransplant sooner rather than later, though I’m inclined to have that discussion concerning that issue. You can see if Usama agrees.

Naval G. Daver, MD: What do you think? You use it at transplant?

Usama Gergis, MD, MBA: Sure.

Naval G. Daver, MD: Let’s say somebody is low MRD-positive. What is your discussion, as a leukemia doctor?

Usama Gergis, MD, MBA: It’s a tough discussion because a patient like this, at 65 years old, should come to transplant in CR1 [first complete remission]. Now, with the decision tree, we prefer if she’s MRD-negative. If it’s MRD-positive coming to transplant, the survival rate is in the range of 20%. That doubles if she’s MRD-negative. Transplant does not offer that much for MRD-positive patients. We talk to our leukemia colleagues, and you can only do too much, and sometimes your patient’s still MRD-positive after 2, 3, 4 cycles of chemotherapy. Then we have to bite the bullet and transplant, and be more vigilant with MRD monitoring after transplant. How does that really help? You reduce immune suppressive agents and cause more graft versus host disease. You get into another black hole.

Naval G. Daver, MD: Right. I think it will emerge with time. The big thing missing right now is a drug that will alter MRD, and while doing that, also alter the biology and the outcome of the disease. All of us are very familiar and happy about blinatumomab in ALL [acute lymphocytic leukemia], which is able to eradicate MRD, plus give you 3-year EFS [event-free survival] of 80%. I think in AML, we don’t have that. I kind of agree with Dr Rizzieri’s statement. It’s like a red light. It’s bad, but we don’t know what to do with that. It’s bad if you go to transplant; it’s bad if you don’t. It’s been a difficult situation. We won’t go into detailed discussion.

Transcript edited for clarity.


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Naval G. Daver, MD: Moving on to our third case, this is an IDH2-mutated acute myeloid leukemia [AML], and I’m going to ask Dr Gergis to discuss the case, please.

Usama Gergis, MD, MBA: Thank you very much. I think it’s very timely to discuss IDH2 and acute myeloid leukemia. Our case today is a 65-year-old woman who presented with some bruising and fatigue, and she’s very fit—much better than most of us around the table. She walks 3 miles every day. She has a past medical history of hypercholesterolemia that is controlled. She presents with pancytopenia, white [blood] count [WBC] of 2.8, hemoglobin of 9, and platelets of 40,000. She now is diagnosed with acute myeloid leukemia—blast percentage 48%, cytogenetics are diploid, next-generation sequencing mutations in IDH2, GATA2, and ECH2.

She was appropriately treated with 7+3 [cytarabine/daunorubicin]. Treatment course was complicated, as expected, by mucositis and febrile neutropenia. After resolution of her complications, she received 2 cycles of high dose Ara-C consolidation. In the midst of her consolidation 6 months after initial diagnosis, she presented with fatigue, body ache, and gum bleeding. She was pancytopenic—WBC 1.8, hemoglobin 8, and platelets 28,000—and she had circulating myeloblasts. The bone marrow biopsy was hypercellular with 80% blasts and normal cytogenetics. Next-generation sequencing was done again on relapse, and she has the same IDH2, but now she has RUNX1 and DNMT3A.

Naval G. Daver, MD: Well, thank you very much. We’re moving now more into the pure targeted therapies and salvage, which is where a lot of these drugs are initially getting approval. For IDH1/2, we have gilteritinib, recently, and others in review like quizartinib. Dr Weinberg, for the molecular testing, are you routinely seeing people check this in the relapsed setting? If they are, are they asking for targeted panels or are you repeating the whole panel? What do you do?

Olga K. Weinberg, MD: Yes, we run the same panel.

Naval G. Daver, MD: Same panel, OK.

Olga K. Weinberg, MD: It is approved in a relapse setting. It’s not approved in a day 30 kind of setting, so we don’t use it there.

Naval G. Daver, MD: Not in remission.

Olga K. Weinberg, MD: Our panel is not really meant to be a minimal residual disease [MRD] panel. There are other panels that you can use for that, but we don’t run those.

Naval G. Daver, MD: Since you brought it up, minimal residual disease, now we’re going to stop for 1 hour and discuss this. I’m not going to do that, but I would just like to ask, clinically, does anybody use MRD in treatment decision-making today? At what time point do you use it and for what? James?

James K. McCloskey II, MD: I think we use MRD mostly for risk stratification. We do MRD testing at the time of first remission. We do MRD testing before they proceed to transplant and then subsequently every 3 months from the peripheral blood. I think that everyone will probably comment on this. There are a lot of variables right now in terms of how we measure MRD and how we reliably interpret it even as 1 patient might have different results, depending on the laboratory or depending on the particular aspirate that we send. There’s a lot of variability, and in general, we do not alter treatment based on the MRD response at this time. I do think it adds something in terms of risk stratification and it is incorporated into some of our clinical trials.

Naval G. Daver, MD: Anything different, Dr Rizzieri, that you do with MRD?

David Alan Rizzieri, MD: I do it so I can understand if it’s going to interrupt my sleep pattern at night, like you said. We know when to worry. It doesn’t necessarily mean that I’m going to jump and offer an allotransplant sooner rather than later, though I’m inclined to have that discussion concerning that issue. You can see if Usama agrees.

Naval G. Daver, MD: What do you think? You use it at transplant?

Usama Gergis, MD, MBA: Sure.

Naval G. Daver, MD: Let’s say somebody is low MRD-positive. What is your discussion, as a leukemia doctor?

Usama Gergis, MD, MBA: It’s a tough discussion because a patient like this, at 65 years old, should come to transplant in CR1 [first complete remission]. Now, with the decision tree, we prefer if she’s MRD-negative. If it’s MRD-positive coming to transplant, the survival rate is in the range of 20%. That doubles if she’s MRD-negative. Transplant does not offer that much for MRD-positive patients. We talk to our leukemia colleagues, and you can only do too much, and sometimes your patient’s still MRD-positive after 2, 3, 4 cycles of chemotherapy. Then we have to bite the bullet and transplant, and be more vigilant with MRD monitoring after transplant. How does that really help? You reduce immune suppressive agents and cause more graft versus host disease. You get into another black hole.

Naval G. Daver, MD: Right. I think it will emerge with time. The big thing missing right now is a drug that will alter MRD, and while doing that, also alter the biology and the outcome of the disease. All of us are very familiar and happy about blinatumomab in ALL [acute lymphocytic leukemia], which is able to eradicate MRD, plus give you 3-year EFS [event-free survival] of 80%. I think in AML, we don’t have that. I kind of agree with Dr Rizzieri’s statement. It’s like a red light. It’s bad, but we don’t know what to do with that. It’s bad if you go to transplant; it’s bad if you don’t. It’s been a difficult situation. We won’t go into detailed discussion.

Transcript edited for clarity.
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