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On The Right Track: Established Combinations and Investigational Therapies in Acute Myeloid Leukemia

December 12, 2023
Diego Adrianzen Herrera, MD, MSc, (@diegoah66) 
Division of Hematology & Oncology, Larner College of Medicine, U of Vermont Medical Ctr, Burlington

Targeted therapies have transformed the treatment landscape for acute myeloid leukemia (AML), particularly in older and unfit patients, as the field turns to the so-called “low intensity” strategies. The study Treatment Patterns and Outcomes of Patients With Acute Myeloid Leukemia (AML) from 2013 to 2022: A Connect® Myeloid Registry Study” presented real-world data from the U.S. CONNECT Myeloid Registry, highlighting a shift toward venetoclax-based regimens, with encouraging results. We talked to author David Grinblatt, MD, who described the study as “an analysis of … a large U.S. multicenter observational cohort study on the changes in outcome in patients with newly diagnosed AML, comparing those diagnosed between 2013-2016 [and] 2017-2022.” His takeaway message: “There was a statistically significant improvement in median overall survival over time,” correlating with “an increase in the use of transplant, targeted therapies and molecular testing.” Dr. Grinblatt said “the majority of patients on this registry were enrolled at community sites,” adding that “the rapidity with which new agents altered the outcome of patients is notable.” 

As clinicians favor venetoclax combinations in older AML patients, can we further improve on them? “A Phase 2 Study of the Fully Oral Combination of ASTX727 (Decitabine/Cedazuridine) Plus Venetoclax for Older and/or Unfit Patients With Acute Myeloid Leukemia,” presented by Alexandre Bazinet, MD, strives to do that. Dr. Bazinet described results from this phase II study of a “fully oral combination composed of decitabine/cedazuridine plus venetoclax,” saying “[it] was effective in an older and very high-risk chemotherapy-ineligible AML population.” 

“In the frontline setting, the combination yielded a composite complete remission (CR) rate of 57% and median overall survival of 11.5 months,” he added. Furthermore, he pointed out that “20% of the frontline patients had previously failed an HMA.” He said the results were “comparable to standard azacitidine plus venetoclax.” 

Farhad Ravandi, MD, MBBS, senior author, summed it up this way: “The all oral combination … is active and without unexpected side effects, and can provide a convenient strategy for treating older and unfit patients.” Indeed, a fully oral regimen may be an exciting new paradigm that can further improve quality of life for patients without compromising response. 

In the relapsed and refractory (R/R) setting, a common strategy consists of adding novel agents to these “low intensity” regimens. Can triplet combinations be the answer for unfit patients with R/R AML? Early Results of the Phase I/II Study Investigating the All-Oral Combination of the Menin Inhibitor Revumenib (SNDX-5613) With Decitabine/Cedazuridine (ASTX727) and Venetoclax in Acute Myeloid Leukemia (SAVE)focused on the addition of the menin inhibitor revumenib in patients harboring KMT2A or NUP98 rearrangements, or NPM1 mutations. The study only included eight patients; however, with a 71% CR rate among those with evaluable disease, the fact that this is an all-oral regimen represents an auspicious option. Similarly, Phase I/II Study of Quizartinib, Venetoclax, and Decitabine Triple Combination in FLT3-ITD Mutated AML focused on results from the addition of quizartinib, a FLT3 inhibitor, in patients with R/R AML harboring FLT3-ITD mutations. The trial included forty R/R patients, 85% of whom had previously received FLT3 inhibitors. Responses were achieved in 68% of patients, including a CR rate of 33%. Rounding out this exciting list, “Overcoming Venetoclax (Ven) Resistance through Glutamine (Gln) Depletion: Final Analysis of the Phase 1 Trial of Ven and Pegcrisantaspase (PegC) Combination in Relapsed and Refractory (R/R) Acute Myeloid Leukemia (AML)” showed the addition of pegcrisantaspase, a long-acting Erwinia asparaginase that enhances venetoclax activity in vitro and in vivo, to venetoclax combinations, which yielded an overall response rate (ORR) of 47%, including a 29% CR.  While these are early studies and mature data are needed, we must highlight the remarkable effort to build non-chemotherapeutic approaches that can reach a larger number of patients. 

Outside these combinations, two noteworthy abstracts highlighted novel agents with promising efficacy in R/R AML. “A First-in-Human Phase 1 Study of the Menin-KMT2A (MLL1) Inhibitor JNJ-75276617 in Adult Patients With Relapsed/Refractory Acute Leukemia Harboring KMT2A or NPM1  Alterations” focused on a selective inhibitor of the interaction between menin and KMT2A with an ORR of 40% in KMT2A-rearranged or NPM1-mutant R/R AML. “Tuspetinib Myeloid Kinase Inhibitor Safety and Efficacy As Monotherapy and Combined With Venetoclax in Phase 1/2 Trial of Patients With Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)” detailed a myeloid multi-kinase inhibitor that achieved CR in 29.4% of treated patients, with notable responses in those with TP53 and coexisting NPM1 and FLT3 mutations.  

The landscape of AML treatment is rapidly changing. In addition to the studies highlighted here, many other combinations and promising agents were presented at #ASH23, auguring a bright new era. While the road ahead may be winding and tortuous at times, we can take a moment to proudly acknowledge we are on the right track.

Dr. Adrianzen Herrera indicated no conflicts of interest.   

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