Triplet Regimens Are New Frontier for AML Therapy

Courtney D. DiNardo, MD, MSCE

Treatment for acute myelocytic leukemia (AML) has evolved into finding the right approach based on a patient’s risk status and ability to tolerate high-intensity therapies. Triplet therapy regimens now are on the horizon for patients with AML, thanks to ongoing research into targeted therapies.

“When we talk about triplets, we’re talking about usually a hypomethylating agent [HMA], either azacitidine [Vidaza®; Bristol Myers Squibb] or decitabine, (Inquovi®; Taiho Oncology) in combination with venetoclax [Venclexta®; Genentech, AbbVie], which is the small molecule BCL2 inhibitor, with something else,” explained Courtney D. DiNardo, MD, MSCE, in an interview with The SOHO Daily News ahead of 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023) in Houston, Texas. “Whatever that something else is, [that] is what makes it the triplet.”

DiNardo, an associate professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, will give a presentation on the use of triplet therapies in AML at 4:25 pm on Wednesday, September 6, at SOHO 2023. She said in the interview that the combination of azacitidine and venetoclax is now the de facto standard of care for older, unfit patients who are not getting intensive chemotherapy and that various triplets are under investigation in clinical trials.

Targeted Therapies Lead to Triplet Approaches

Patients with AML are stratified for risk based on age, fitness, and genetic factors. Patients with favorable genetic factors including core binding factor leukemia, inversion 16, translocation 8/21, or who have NPM1 mutation or basic leucine zipper (bZIP) mutation in CEBPA, can be cured with intensive chemotherapy alone, according to DiNardo. Patients with poor risk factors, including TP53 mutation, deletion 17p, splicing factor mutations, and myelodysplastic syndrome–associated mutations, are unlikely to benefit from intensive chemotherapy alone. DiNardo said that intermediate-risk patients, who make up 40% to 50% of patients with AML, have a better likelihood of responding to chemotherapy, but their best curative option is stem cell transplant.

No triplet regimens are currently approved, but they are most likely to come into play with the addition of targeted therapies. DiNardo said that adding a FLT3 inhibitor or IDH1/IDH2 inhibitor for patients with these mutations is a promising approach. The combination of azacitidine, venetoclax, and gilteritinib (Xospata®; Astellas), an FLT3 inhibitor, has been investigated in a phase 1/2 trial (NCT04140487), where it showed an 87% overall response rate.¹ Meanwhile, DiNardo and her fellow investigators have presented data from a phase 1b/2 study (NCT03471260) of ivosidenib (Tibsovo®; Servier) plus venetoclax with or without azacitidine in patients with IDH1-mutated AML; the results showed high minimal residual disease negativity.²

“Both of these [trials], along with others, are showing that we’re seeing higher response rates and we’re seeing patients appear to have deeper remissions…when you look at those deeper levels of remission, like minimal residual disease, flow cytometry, or the specific mutation [clearance] itself following that,” DiNardo said.

Other triplet regimens are also being investigated, some which are mutation-agnostic. The CD47 inhibitor magrolimab, which has shown particular efficacy in patients with TP53 mutations, is being combined with azacitidine and venetoclax in the phase 3 ENHANCE-3 trial (NCT05079230). A phase 1b/2 trial (NCT04086264) of the antibody-drug conjugate IMGN632 with venetoclax and/or azacitidine for patients with CD123-positive AML showed manageable safety and antileukemia activity, and results from additional cohorts will show more about this combination.³

Other triplet approaches include the addition of menin inhibitors, which are effective in patients with NPM1 mutations and KMT2A rearrangements. Research into this triplet regimen could impact patients who are not in the poor-risk group. DiNardo’s presentation will incorporate the latest data from various trials that have been presented at meetings this year.

“These combinations really do appear to be effective and may have improved efficacy compared with the HMA-venetoclax backbone alone, which, of course, is what we’re needing to see,” DiNardo said.

More importantly, DiNardo said, triplets may offer better long-term outcomes. “The majority of patients will go into a remission with HMA-venetoclax, but do we get deeper remissions and does that remission lasts longer?” she asked. Helping patients survive longer to transition to stem cell transplant is a key end point, she said.

DiNardo said that safety is another key end point and it must be determined whether there are challenges in safe administration of an additional component in real-world patients. “We really have to make sure that not only are they providing more benefit to the patient, [but that] they’re also safe to do,” she said, noting that each triplet has a different safety profile because of each additional agent.

She explained that triplets generally have been found to be safe “with appropriate modifications to the HMA-venetoclax backbone.” Even with HMA and venetoclax alone, continuous 28-day treatment with venetoclax is commonly reduced to 21 days for best tolerability, and with triplet regimens, DiNardo said a 14-day cycle of venetoclax seems to be tolerated better. Reducing the dose of the third agent is also viable; she noted that reducing the dose of gilteritinib from the recommended single-agent dose of 120 mg to 80 mg improved myelosuppression in the combination trial.¹ As an investigator on the phase 3 VIALE-A study (NCT02993523), she observed that granulocyte colony-stimulating factors can be used with HMA-venetoclax safely and without impairing survival to mitigate neutropenia.⁴

Next Steps for Triplet Therapy

DiNardo hopes that the ongoing trials will lead to the use of an additional agent to HMA-venetoclax backbone in the appropriate patients in clinical practice. “I think the community will adapt and be very ready to initiate and use these triplets in their portfolio of AML treatment,” she said.

She identified several key mutations in AML that are associated with less-durable responses with azacitidine and venetoclax alone: TP53, FLT3-ITD, KRAS, and NRAS. Adding a third agent could promote longer-lasting responses leading to better survival outcomes.

As new agents and classes of drugs are approved, they can become candidates for addition to HMA-venetoclax, as is the case for menin inhibitors and magrolimab. DiNardo said she is monitoring the outcomes of studies of these drugs to see what their role could be in triplet therapies.

Unmet Needs Persist in AML

DiNardo said one of the biggest needs is better treatment for patients with a TP53 mutation, who don’t benefit sufficiently from intensive chemotherapy or venetoclax-based therapy. Also, for patients with inversion in chromosome 3 and 3q26/MECOM-rearranged AML, a rare subtype, no good treatment is available. The KMT2A rearrangements in leukemias are another challenging subpopulation that may be addressed by menin inhibitors.

For patients with poor-risk disease whose needs are not met by HMA-venetoclax alone, finding the right triplet therapy could dramatically improve their outcomes. “[There are] a lot of different risk groups and different patient populations that may benefit from the addition of something to the HMA-venetoclax backbone,” DiNardo said.

References

1. Ong F, Short N, Daver N, et al. A phase I/II study of combination of ASTX727, gilteritinib and venetoclax in patients with relapsed/refractory FLT3 mutated acute myeloid leukemia (AML) and frontline FLT3 mutated AML patients unfit for chemotherapy. Blood. 2022;140(suppl 1):9029-9031. doi:10.1182/blood-2022-159110

2. Lachowiez CA, Loghavi S, Zeng Z, et al. A phase Ib/II study of ivosidenib with venetoclax ± azacitidine in IDH1-mutated myeloid malignancies. Blood Cancer Discov. 2023;4(4):276-293. doi:10.1158/2643-3230.BCD-22-0205

3. Daver N, Aribi A, Montesinos P, et al. Safety and efficacy from a phase 1b/2 study of IMGN632 in combination with azacitidine and venetoclax for patients with CD123-positive acute myeloid leukemia. Blood. 2021;138(suppl 1):372. doi:10.1182/blood-2021-146503

4. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971