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“Daunodouble” and the Dawn of Triplets in AML

December 13, 2022

Triplet therapy is now the norm for most hematologic malignancies, and it seems that the dawn of triplet therapy in acute myeloid leukemia (AML) has arrived (beyond the already established triplet of gemtuzumab with 7+3 in favorable-risk AML). We now have intriguing data presented on azacitidine with venetoclax and magrolimab in AML. These are early-phase data, with a small number of patients treated in the newly diagnosed (n=41, 80% response rate) and relapsed/refractory settings with limited follow-up; nevertheless, this remains something to keep an eye on as we await evaluation of this combination in randomized settings (ENHANCE 3).

Another promising triplet regimen was the combination of pivekimab sunirine, azacitidine, and venetoclax in high-risk relapsed/refractory AML. Pivekimab sunirine is a first-in-class antibody-drug conjugate (ADC) that targets CD123 (this is not the first CD123-targeting drug, but it is the first targeting ADC), with encouraging responses seen in a heavily pretreated AML population, including patients previously treated with hypomethylating agents and venetoclax. An additional triplet of interest, though a considerably myelosuppressive regimen, was azacitidine, venetoclax, and gilteritinib in FLT3-mutated AML, with a one-year overall survival of 80 percent in newly diagnosed patients with AML. However, to put this in context, the phase III LACEWING trial of azacitidine + gilteritinib versus azacitidine in newly diagnosed AML was negative, so it remains to be seen how this combination will play out in future studies. Larger, randomized studies with appropriate crossover will be needed to confirm the role of triplets, but in a few years perhaps, they might become the standard of care across the board for AML too.

Now, here is a thing we all struggled with as trainees on our hematology rotations: Why do some attendings and institutions insist on a day 14 bone marrow biopsy during induction and others do not? An interesting retrospective study presented Saturday, December 10 (session 613, abstract 60), may answer this question. Ultimately, there were no differences in outcomes between patients who underwent a day 14 bone marrow biopsy and those that did not. Obviously, many confounding factors cannot be accounted for in such a study, but these results provide us with much food for thought.

The data from Germany on AML have indeed been stunning this year (including the Plenary abstract on the ASAP Trial, covered in Monday’s ASH News Daily). The “Daunodouble” trial, aptly named to answer two important questions in a beautiful fashion, was presented on Saturday, December 10 (session 615, abstract 217). The debate between the 60 mg/m2 versus 90 mg/m2 dose of daunorubicin has long been an open question in the field, as has the value of a second cycle of induction chemotherapy in those who respond well to the first. Although powered for response rates and not for overall survival, this trial found that 60 mg/m2 is as efficacious as 90 mg/m2, and that for those who have fewer than 5 percent blasts after a first cycle of induction chemotherapy, a second cycle of induction chemotherapy does not offer additional survival benefit. Yet again, less is sometimes more. In the United States, we have already moved away from second inductions in responders, but many European centers still continue this practice. It looks like we may now have a more definitive answer.

Our abstract round-up would be incomplete without a plug for a new targeted therapy — menin inhibitors — in KMT2A-rearranged or NPM1-mutant AML. In a very heavily pretreated AML population, response rates of 53 percent with a median duration of response of nine months were seen with revumenib,  an orally bioavailable menin-MLL inhibitor. Another menin inhibitor, ziftomenib, also showed clinical activity, reinforcing the therapeutic potential of this new class of drugs.

If you were puzzled during your training by the fact that 19 percent blasts were labeled myelodysplastic syndrome (MDS) and 20 percent labeled AML, you were not the only one. Adding to the confusion, there has recently been much commotion about two new diagnostic classification systems (the 2022 World Health Organization Classification of Haematolymphoid Tumours and the International Classification System) for AML and MDS, and the implications of having two separate systems to diagnose and classify these diseases. We loved the fascinating oral presentation from Dr. Hoermann (abstract 228) discussing these new classification systems. The presentation highlighted that, while these two systems most often overlap, there is a still a small fraction of patients for whom different diagnoses are obtained, depending on which schema is used.

There were also several noteworthy presentations about the applicability and utilization of risk stratification systems. An analysis, presented by Dr. Hartmut Döhner (abstract 602), observed that the commonly used European Leukemia Network (ELN) classification may not as accurately prognosticate and predict outcomes in elderly patients treated with non-chemotherapeutic approaches.

While we highlight many of the positive findings, it is also important to note pertinent negatives. An effort to use nivolumab as maintenance therapy following initial chemotherapy in patients with AML who were not candidates for transplant proved inefficacious, but the investigators are to be commended for tackling an important question. Checkpoint inhibition has surely been transformative in many other fields, but its role in the setting of AML, other than in the post allogenic transplant setting, remains to be elucidated.

There are so many other studies we could sing the praises of, but, alas, there is not enough space or time. As this meeting has shown us, the landscape of AML continues to change rapidly, ranging from how we diagnose, classify, prognosticate, and best treat it. We hope for much change and progress in the years to come, so stay tuned for what is truly shaping up to be the dawn of a new era in AML!

Dr. Vardell and Dr. Mohyuddin indicated no relevant conflicts of interest.

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