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FAQs: AML Emerging Data
Myeloid Malignancies Clinical Advances Journal Club on Emerging Data for AML: Answers to Frequently Asked Questions

Released: July 22, 2024

Expiration: July 21, 2025

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Key Takeaways
  • Although the FLAG-IDA/venetoclax regimen is appealing because of the potential for high composite remission rates, there is potential for treatment-related complications (eg, bacteremia typhlitis).
  • Decitabine/cedazuridine with venetoclax and gilteritinib is a promising new treatment option for patients with acute myeloid leukemia; however, the duration of venetoclax treatment that will minimize incidence of myelosuppression remains to be determined.
  • Patients with both NMP1- and IDH1/IDH2-mutated newly diagnosed disease tend to benefit from receipt of more venetoclax therapy, while patients who have TP53-mutant disease may not and may potentially receive less venetoclax therapy to minimize myelosuppression.

Assessing and integrating new clinical data for individualized care of patients with acute myeloid leukemia (AML) is increasingly becoming more important with the release of new data updates and emergence of novel treatment options. In this commentary, we share answers to frequently asked questions posed by a live audience of healthcare professionals on key emerging new data presented for AML at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and the 2024 European Hematology Association (EHA) Congress, including takeaways for practicing hematology/oncologist looking to stay up-to-date.

Do you foresee that community oncologists might be able to use agents like decitabine/cedazuridine with venetoclax as outpatient therapy for AML similar to oral venetoclax?

Eunice S. Wang, MD:
I anticipate that these regimens will continue to show efficacy for oral targeted therapy and they will most likely be adopted by community oncologists in the outpatient setting. I hope that this may allow more patients—particularly those who live at a distance from large medical cancer centers—to achieve similar outcomes as patients receiving treatment at the major medical centers.

In the FLAG-IDA/venetoclax trial conducted in patients with newly diagnosed or relapsed/refractory AML, approximately what percentage of patients went on to receive allo transplantation? 

Courtney DiNardo, MD, MSCE:
I was a senior author of that report for the FLAG-IDA/venetoclax trial presented at EHA by Dr Jen and colleagues. Most patients had newly diagnosed AML and were young/fit with a median age of 44 years (range: 20-67 years). I would say that the majority of patients on this study went on to receive a transplant. As a reminder for our readers, the FLAG-IDA/venetoclax regimen is a very effective yet very intensive regimen for most patients. Often, I would be asked whether this regimen is something that we should be using in the community, and I think it depends on the level of resources that you have at your disposal. This regimen is very appealing because of the potential for a composite remission rate ≥90% in the frontline setting with approximately 80% of patients achieving MRD-negative status. However, there is the potential for patients to get very sick. They may become bacteremic and have typhlitis issues during the nadir. Not everyone will experience that of course, but it can happen. If you want to pursue the FLAG-IDA/venetoclax regimen, you must ensure you are able to check on patients several times per week, preferably they live nearby, and if complications develop you can admit them and administer antibiotics as needed. Moreover, some patients may need transfusion support as well. In my view, the patients who benefit the most are the intermediate- and adverse-risk patients who would otherwise not benefit as much from intensive chemotherapy in the frontline setting as a bridge to transplant. The median number of FLAG-IDA/venetoclax cycles received in that study was only 2, because the vast majority of patients went on to transplant successfully.

Eunice S. Wang, MD:
I agree with Courtney that the FLAG-IDA/venetoclax regimen is not necessarily one we would consider for the majority of older or unfit patients. The median age of presentation for AML is typically in the late 60s to 70s. Approximately 15% of patients in that study were 60 years of age or older. Most patients who were older had relapsed/refractory disease. This regimen was quite effective with a complete response (CR) rate of approximately 80% and overall response rate approaching 100% in the newly diagnosed population and 68% in the relapsed/refractory population. Patients who did not do as well were those with a poor prognostic risk factor (eg, TP53 mutant and MECOM rearrangements). 

What about other therapies that look promising?

Eunice S. Wang, MD:
In the older unfit patient population, venetoclax plus azacitidine has been our standard treatment option since the pivotal phase III VIALE-A trial. We have known for a little while now that FLT3 gene mutations predict for resistance to venetoclax plus azacitidine. At EHA 2024, a phase I/II study was presented evaluating oral decitabine/cedazuridine with venetoclax and gilteritinib in patients with newly diagnosed or relapsed/refractory FLT3-mutant AML. That report included a total of 26 patients, 84% of whom had seen prior hypomethylating agents, 79% had previous venetoclax, and 21% had had previous FLT3 inhibitor. In this patient population, the response rate in newly diagnosed AML was 86% and approximately 50% in relapsed/refractory patients. Duration of response was 7.6 in the relapsed/refractory population and was not reached in the newly diagnosed population. Many of the patients with relapsed/refractory disease would need to go on to subsequent allogeneic stem cell transplantation to attain full benefit from this regimen. 

Considering the side effect of myelosuppression with venetoclax in patients receiving decitabine/cedazuridine plus venetoclax and gilteritinib, how long should venetoclax be given to these patients?
This is a key practice question for all of us who have used this regimen, and I expect that this study is going to be looking at it in more detail. In patients receiving this regimen, even when venetoclax was held at Day 14 to Day 21 because of evidence of cytoreduction or blast elimination in the bone marrow, we still saw patients experience prolonged cytopenias. Absolute neutrophil count recovery after cycle 1 varied from 38 to 48 days, with platelet recovery taking between 26 and 38 days. Again, and although the regimen is leading to very high response rates, particularly in patients with newly diagnosed AML, we are still looking at this not being a standard of care until we can gain a better understanding of how much venetoclax to give these patients with minimal myelosuppression. 

A retrospective chart review study attempted to answer this very question. A few years ago, a French group reported data on older unfit patients who were not eligible per the VIALE-A regimen (standard azacitidine/venetoclax with a venetoclax dose of 21-28 days) but instead had received the 7+7 regimen (7 days of azacitidine and 7 days of venetoclax) at selected centers. At EHA 2024, a report by Bazinet and colleagues looked to compare, in a retrospective analysis, the French 7+7 outcomes in 82 patients vs 166 patients who were treated with 21 to 28 days of azacitidine/venetoclax. What we saw presented was very encouraging with similar response rates with standard azacitidine/venetoclax vs 7+7 (CR: 57% vs 55%; CR with incomplete marrow recovery: 15% vs 17%) with fewer 8-week mortality cases reported in patients who received 7+7 (6% vs 16%; P = .032). The rate of neutropenic fever was comparable between groups. Regarding the NPM1- and IDH1/2-mutant subgroups, there was a trend for improved overall survival (OS) and event-free survival (EFS) in the MD Anderson Cancer Center cohort, but no difference in outcomes for TP53-mutated patients. But overall, data appeared to substantiate the fact that patients who received the 7+7 had equivalent OS and EFS as patients who received the 21 to 28 days of venetoclax.

My takeaway from that study is that the patients who were more sensitive to venetoclax benefited from receiving more venetoclax, including those that had both NMP1-mutant and IDH1/IDH2-mutant disease in the newly diagnosed setting. In  patients who had TP53-mutant disease, which did not seem highly sensitive to venetoclax, there was no difference in outcomes.

I will also point out that patients who have AML with MDS-related changes who are receiving intensive chemotherapy and who are not able to undergo allogeneic stem cell transplantation can have their outcomes improved by receiving oral azacitidine maintenance based on the post-hoc analyses of AML outcomes from the phase III QUAZAR AML-001 study, based on data presented by Voso and colleagues at EHA 2024.

Your Thoughts?
What are your thoughts or questions on the emerging data for patients with AML? Answer the polling question and join the conversation by leaving a comment. Also, visit the program page to view an on-demand webcast from the live event, download the associated slides, read other clinical commentaries, or listen to podcasts on emerging data for MDS, AML, and MPNs.

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