Can Venetoclax-Based Strategies Be Used in Treating Patients With Secondary-Type AML Mutations?
In 2022, the European LeukemiaNet (ELN) updated their guidelines for the diagnosis and management of acute myeloid leukemia (AML), which included how health care professionals classify the genetic risk of AML.1 The guidelines introduced a class of mutations called secondary-type mutations. In this Q&A, Ian Bouligny, MD, answers questions about his team’s research2 that sought to determine the use of venetoclax-based strategies in patients with newly diagnosed secondary-type mutations of AML.
This Q&A is a transcription of a video interview. Watch the full video here.
Consultant360: Can you tell us more about how your study came about?
Ian Bouligny, MD: This study came about with the recent update in the European Leukemia Guidelines in 2022, which has changed how we classify the genetic risk of acute myeloid leukemia. The 2022 update introduced a class of mutations called the secondary-type mutations, named so because of how common they are in secondary AML. And these secondary-type mutations now comprise part of the adverse risk category. So one thing to keep in mind is that the ELN 2022 guidelines were built with data from patients treated with intensive chemotherapy. However, after the FDA approval of venetoclax, a small molecule BCL-2 inhibitor, the treatment of a AML with lower intensity strategies has changed dramatically. An excellent presentation at ASCO this past weekend3 showed that nearly half of patients with AML received venetoclax after it was approved. So given how impactful venetoclax has been, we're trying to explore if some of the risk stratifications proposed in ELN 2022 still apply to patients treated with lower-intensity strategies. So we set out to do that with the secondary-type mutations, which is how this study came about.
C360: How do your findings contribute to the existing literature about this topic?
Dr Bouligny: There is not an abundance of literature on the topic, which is why we were interested in doing the study. One of the big draws to performing this study is that there is a drive to perform outcomes-based analysis in molecularly selected cohorts of patients to move away from a one size fits all approach and individualize patient care in AML. The MD Anderson Group published a paper in Blood Advances in 20214 that looked at the impact of splicing mutations, which are a subset of secondary-type mutations in patients treated with venetoclax and a hypomethylating agent. They found similar rates of response, measurable residual disease negativity, and overall survival in patients that had a spliceosome mutation compared to those that did not have a spliceosome mutation. We aimed to build on this study by observing the remaining secondary-type mutations introduced in the ELN 2022 guidelines after the Blood Advances study was published.
When we observed outcomes in our molecularly expanded cohort where we included patients that had harbored spliceosome mutations in addition to BCOR, EZH2, STAG2, ASXL1, RUNX1, we found the same patterns of survival that the MD Anderson group did in the spliceosome cohort. We observed no differences in survival between patients treated with venetoclax and hypomethylating agent with secondary-type mutations and those without secondary-type mutations. We did notice that specific co-mutation pairs such as secondary-type mutations with RAS, FLT3-ITD or TP53 appear to have shorter survival.
On the other hand, patients with IDH mutations appear to be BCL-2 dependent, meaning that they are quite sensitive to venetoclax, and they tend to co-occur with certain secondary-type mutations. So we noted that in patients with IDH mutations and secondary-type mutations, for example, AML with co-mutations in IDH2 and SRSF2, the presence of a secondary-type mutation together with the favorably responding IDH mutation did not appear to worsen overall survival. So our findings make us rethink some of the concepts introduced in ELN 2022 in the context of lower-intensity strategies.
C360: How do the results of your study impact clinical practice?
Dr Bouligny: Our study impacts clinical practice because it adds to the growing literature that shows that genetic risk markers proposed in ELN 2022 may not apply to patients treated with venetoclax-based lower-intensity strategies. Our study is an important reminder for clinicians to remember the context in which we treat our patients. The risks may not necessarily be uniform across all treatment options. Additionally, mutational cooperation appears to be quite impactful, meaning that it is not just important to look at the secondary-type mutation, but also look at the mutations that they co-occur with, such as IDH or RAS. Looking at mutational cooperation gives a better idea of how likely patients are to do well with venetoclax-based regimens. So taken together, our study helps to individualize therapy for patients with AML to optimize response and survival.
C360: Do your findings impact the multidisciplinary care of acute myeloid leukemia and if so, how?
Dr Bouligny: Potentially, yes, it is a growing area of research. The more we use venetoclax-based combinations, the more we learn about them. Regarding multidisciplinary care, questions naturally arise when considering patients for allogeneic stem cell transplants. For example, for patients with secondary-type mutations and IDH mutations that respond favorably to venetoclax, do the favorable outcomes persist after transplant compared to those with no IDH mutations? We do not know. The second question also arises with post-transplant maintenance. If we transplant our patients with secondary-type mutations and co-mutations in FLT3, does the addition of a FLT3 inhibitor and venetoclax as maintenance improve survival in the post-transplant setting? Several trials are now looking at venetoclax-based combinations in the post-transplant setting. It is equally important that we try to stratify post-transplant outcomes to molecular cohorts as much as possible to better understand who is going to benefit from these evolving approaches. And these are areas of active study and answers to these questions will eventually come through further research.
Lastly, since lower-intensity venetoclax-based strategies are continued as maintenance, a team-based approach is even more critical, where we not only include our transplant colleagues, as I mentioned earlier, but also physical therapy, occupational therapy, our social workers. We have also noticed increased collaboration between our leukemia physicians here at academic centers and our oncologists in the community that refer patients on venetoclax to our center. So these are all the ways in which multidisciplinary care impacts patients with these mutations treated with venetoclax.
C360: What is the next step in this area of research?
Dr Bouligny: The next step in looking at more detailed outcomes of co-mutation pairs is going to be the most predictable thing, not just secondary-type mutations, but those mutations with FLT3, RAS, IDH, and many others. This is challenging for a few reasons. The first reason, first and foremost, is how rare these mutations are, especially the co-mutation pairs. It generally takes fairly sizable studies, which can be difficult when looking at rare mutation pairs in AML. Another challenge is with taking this study to the next step is addressing the variability in which venetoclax is dosed, so institutions can have different approaches for how to dose venetoclax, which our field is learning more and more about, particularly in maintenance. This is also an area of intense study.
The third challenge is addressing these questions at the pace in which these venetoclax-based combinations are evolving, so clinical trials are adding more drugs such as FLT3 inhibitors or IDH inhibitors to venetoclax and hypomethylating agent. We have to wonder, with more intensive therapy, what the outcomes of these patients with secondary-type mutations look like? Do they matter as much? We have a few exciting questions for the next steps.
C360: What is the overall take-home message from your study?
Dr Bouligny: The take-home message from this study is that when we discuss the prognosis in AML, particularly with our patients, we need to be mindful of the context in which patients are treated. This is because while the secondary-type mutations may confer adverse risk for patients treated with intensive chemotherapy, the same may not be true for patients treated with lower-intensity venetoclax-based combinations. Mutational cooperation will only complicate things further. If you'd like to learn more about secondary-type mutations in AML and the various new approaches that we could take, we will have a review article on this topic published shortly in the upcoming weeks.
Thank you very much for having me, and it's been a pleasure talking to you.
Michael Doyel is the first author of this study submitted to ASCO 20231 This study is presented by his mentor, Dr Bouligny, on behalf of the rest of the Virgina Commonwealth University (VCU) Leukemia Clinical Research Team: Graeme Murray, Tilak Patel, Josh Boron, Valerie Tran, Juhi Gor, Yiwei Hang, Thuy Ho, Kyle Zacholski, Chad Michael Venn, Yanal Mufeed Alnimer, Nolan Wages, Steven Grant, and Keri Renee Maher. This project is part of VCU Massey Cancer Center’s Project ERIS: Expanding Research in Induction and Salvage. We thank the patients and their caregivers for their involvement and contribution to the efforts of Project ERIS.
- Döhner H, Wei AH, Applebaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-377. doi:10.1182/blood.2022016867
- Doyel M, Bouligny IM, Murray G, et al. The impact of secondary-type mutations in newly diagnosed acute myeloid leukemia treated with venetoclax and decitabine or azacitidine. J Clin Oncol. Published online May 31, 2023. doi:10.1200/JCO.2023.41.16_suppl.e19048
- Zeiden AM, Donoso LH, Hodzic S, et al. Real-world (RW) use of venetoclax (VEN) in patients (pts) with acute myeloid leukemia (AML) in a US RWE database (COTA). Presented at: 2023 American Society of Clinical Oncology's Annual Meeting; May 31-June 4, 2023; Chicago, IL. Accessed June 14, 2023. https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.7044?af=R
- Lachowiez CA, Loghavi S, Furudate K, et al. Impact of splicing mutations in acute myeloid leukemia treated with hypomethylating agents combined with venetoclax. Blood Adv. 2021;5(8):2173-2183. doi:10.1182/bloddadvances.2020004173