In this clinical presentation, the speaker outlines the institution's experience with venetoclax‑based therapies for acute myeloid leukemia (AML). A prognostic model predicting early mortality guides the choice between intensive chemotherapy and low‑intensity approaches for older (≥70‑75 y) or unfit patients. For this group, azacitidine or decitabine combined with venetoclax is now FDA‑approved, delivering 70‑80 % marrow complete remission (CR) and ~40 % 2‑year survival, with higher survival in favorable‑risk karyotype. A 10‑day decitabine‑venetoclax schedule shows similar CR (80‑85 %) and 40‑50 % 2‑year survival. Building on a prior triple nucleoside analog low‑intensity regimen (cladribine, low‑dose cytarabine, azacitidine/decitabine), the addition of venetoclax in a pilot trial achieved ~90 % CR, <3 % 4‑week mortality, and 50‑60 % 2‑year survival, suggesting a potential new standard pending validation. For younger, fit patients, the institution piloted intensive FLAG‑IDA or CLLIA regimens (idarubicin, high‑dose cytarabine, fludarabine or cladribine) augmented with venetoclax, reporting 90 % CR, ~80 % MRD‑negative rates, and 60‑70 % 1.5‑year survival. The speaker emphasizes the need for larger, multi‑center comparative trials to confirm these promising results against established standards such as 3+7.
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Those sets of studies include innovative combination studies. Some of them are already accepted as FDA-approved studies, and some are somewhat novel. So if you look at acute myeloid leukemia, we usually look at the patients in terms of their tolerance to intensive chemotherapy, what we call older patients, that's usually patients over the age of 70, 75 years, or patients who are unfit for intensive chemotherapy where they have comorbidities. And where in our institution we use a prognostic model, a model that predicts for the early mortality. So that model tells us, well, with intensive chemotherapy, the early mortality can be over 10 to 20%. and therefore we do not use the intensive chemotherapy, or the mortality is low, and then we can use the intensive chemotherapy. So for the patients with acute myeloid leukemia who are older or unfit for intensive chemotherapy based on a high early mortality, we have used hypomethylating agents with venetoclax. The 2 hypomethylating agents that we use are azacitidine or decitabine. And within the context of Decitabine, we have used 5 days or 10 days. The mature experience from these studies has shown that Azacitidine Venetoclax in such patients is now a standard of care. It's an FDA approved dose schedule. If you give this combination, you can achieve a marrow CR rate close to 70 to 80%. And the estimated 2-year survival is close to about 40%. If you take patients who have a normal karyotype and favorable mutation features, then the estimated 2-year survival is over 50 to 60%. Now, when we use the decitabine for 10 days with the venetoclax, and this is a study that we conducted at MD Anderson, we find that the marrow CR rate is also very high in the range of 80 to 85%. And the estimated 2-year survival rate is close to 40 to 50%. Now, in addition, in those older people, we have asked the question, is the combination of hypomethylating agents, azacitidine or decitabine with venetoclax, the optimal combination schedules? So from historical experience, we had piloted what we call now the triple nucleoside analog regimen whereby we use cladribine with low-dose RRC and alternating, and alternate this with either decitabine or azacitidine. What we found was this triple low-intensity regimen produced a very high CR rate. And this was before incorporating venetoclax. We found that it produces a high CR rate and an estimated 2-year survival rate of about 35%. So then what we decided is to pilot that combination and add venetoclax to this. So we reported at the ASH meeting that in people who are older or unfit for intensive chemotherapy, when we give them the low-intensity regimen with the triple nucleoside analogs, namely cladribine, lodocytarabine, and azacitidine, and we add venetoclax, We have achieved the marrow CR rate of about 90%. The 4-week mortality was extremely low. Actually, in our hands, it was 2 to 3% or less. And we have an estimated 2-year survival rate of 50%. In patients with the normal karyotype, the estimated 2-year survival rate is over 60%. So we think that this may be in this pilot trial, a regimen that could beat the current standard of care. But this has to be, of course, reproduced in other centers, and also confirmed in comparative trials of this new regimen versus Azacitidine Venetoclax. Now, borrowing from this experience, we said, well, what about the younger people? who receive currently intensive chemotherapy. So in the younger people, most AML experts consider the 3+7 regimen as a standard of care. At our institution, we've piloted a more intensive approach with what we call the FLAG-IDA or the CLLIA regimens. So again, it's idarubicin with high-dose cytarabine during the induction and consolidation. and we add either fludarabine or cladribine. And then, in the more recent studies, we have added venetoclax to either FLAG-IDA or CLLIA. So we have reported at the ASH on 2 abstracts, and these are early and pilot trials, but with both the FLAG-IDA venetoclax and the CLLIA venetoclax, our marrow CR rate is 90%. the incidence of MRD negativity is close to 80%, which is incredible. And the estimated survival at 1.5 years is over 60 to 70%. So we think again that these new pilot trials combining FLAG, EIDA, or CLIA with venetoclax are producing very positive results, and they are safe when they are given in centers of leukemia expertise. And we would like to continue those studies once we have about 50 to 100 patients. If we can continue to show the same high efficacy, then I think these regimens should be compared to the standards of care, which are 3+7.
