clinical topic updates

Drugs in Development and Ongoing Clinical Trials in MDS and AML

by David Sallman, MD


Hypomethylating agents are the foundation of treatment for patients with myelodysplastic syndrome (MDS), but many individuals do not achieve durable responses, particularly those with TP53 mutations. Preliminary data from clinical trials evaluating combination regimens are promising in patients with MDS and acute myeloid leukemia (AML).

Expert Commentary

David Sallman, MD

Assistant Member, Department of Malignant Hematology
H. Lee Moffitt Cancer Center & Research Institute
Assistant Professor, Department of Oncologic Sciences
University of South Florida
Tampa, FL

When evaluating novel combinations for high-risk MDS and AML in the frontline setting, a thorough understanding of resistance mechanisms and therapeutic synergy at the biological level can help to optimize treatment strategies.”

David Sallman, MD

Although hypomethylating agents remain the mainstay of therapy for patients with MDS, response rates are suboptimal, treatment effects are often short lived, and most patients cannot achieve durable responses. To address these limitations, multiple doublet regimens with azacitidine are under clinical investigation. Updated results from the phase 2 P-2001 trial showed that the complete remission (CR) rate with azacitidine plus pevonedistat was nearly double the rate with azacitidine alone (52% vs 27%). We are eagerly awaiting results from the phase 3 trial, which has a primary end point of event-free survival. While azacitidine plus venetoclax has been shown to be effective in AML, data from a phase 1b study in 57 treatment-naive high-risk patients who received the combination showed that only 42% achieved CR. However, myelosuppression associated with venetoclax may have had an impact on these preliminary response rates. In the above trials, responses have been observed in TP53 patients, but these cohorts have been relatively small.

In patients with TP53 mutations, restoring the function of p53 can promote malignant cell death. Eprenetapopt (APR-246) restores p53 function through stabilization and an overall shift toward a wild-type confirmation, allowing p53 to perform its proapoptotic tumor-suppressive function. In phase 2 studies, eprenetapopt demonstrated impressive CR and overall survival rates, which led to the only phase 3 trial in patients with high-risk MDS with TP53 mutations to date. Unfortunately, preliminary data showed that, while the CR rate was higher in the eprenetapopt-plus-azacitidine arm, this did not reach statistical significance. While this is a setback, we will have more information once the data mature from patients who received treatment with eprenetapopt in combination with azacitidine. Furthermore, there are ongoing trials with eprenetapopt in AML (in combination with azacitidine and venetoclax) as well as a maintenance trial with azacitidine post allogeneic stem cell transplantation.

Although there is evidence that doublet regimens with novel immunotherapies or targeted therapies improve response rates in select patients, triplet-based regimens may be necessary to achieve durable responses, particularly in patients with TP53 mutations. For example, planned and ongoing trials of triplet therapy with azacitidine, venetoclax, and novel therapies will evaluate whether synergy among these agents improves outcomes.

When evaluating novel combinations for high-risk MDS and AML in the frontline setting, a thorough understanding of resistance mechanisms and therapeutic synergy at the biological level can help to optimize treatment strategies. In my opinion, the goal of therapy is not only to achieve CR but also to eradicate the underlying clones that drive the disease. Importantly, we need to ensure safety with multidrug combinations in this elderly group of patients. As treatment strategies continue to evolve, the hope is that we can improve the depth of remission, quality of life, and, ultimately, survival in patients with MDS/AML.


Aprea Therapeutics announces results of primary endpoint from phase 3 trial of eprenetapopt in TP53 mutant myelodysplastic syndromes (MDS). Press release. Aprea Therapeutics, Inc; December 28, 2020.

Bewersdorf JP, Zeidan AM. Following in the footsteps of acute myeloid leukemia: are we witnessing the start of a therapeutic revolution for higher-risk myelodysplastic syndromes? Leuk Lymphoma. 2020;61(10):2295-2312. doi:10.1080/10428194.2020.1761968

Cluzeau T, Sebert M, Rahmé R, et al. Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the Groupe Francophone des Myélodysplasies (GFM). J Clin Oncol. 2021 Feb 18;JCO2002342. doi:10.1200/JCO.20.02342

Garcia JS, Wei AH, Borate U, et al. Safety, efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: a phase 1b study [abstract 656]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Jiang L, Zawacka-Pankau J. The p53/MDM2/MDMX-targeted therapies-a clinical synopsis. Cell Death Dis. 2020;11(4):237. doi:10.1038/s41419-020-2445-9

Sallman DA, DeZern AE, Garcia-Manero G, et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol. 2021 Jan 15;JCO2002341. doi:10.1200/JCO.20.02341

Sallman DA. The problem of TP53-mutant MDS/AML. Clin Lymphoma Myeloma Leuk. 2020;20 suppl 1:S65-S66. doi:10.1016/S2152-2650(20)30465-1

Saygin C, Carraway HE. Current and emerging strategies for management of myelodysplastic syndromes. Blood Rev. 2020 Dec 27;100791. doi:10.1016/j.blre.2020.100791

Sekeres MA, Watts JM, Radinoff A, et al. Efficacy and safety of pevonedistat plus azacitidine vs azacitidine alone in higher-risk myelodysplastic syndromes (MDS) from study P-2001 (NCT02610777) [abstract 653]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

More in MDS & AML



Update on Actionable Targets in the MDS and AML Disease Spectrum

clinical topic updates by David Sallman, MD

Mutations in FLT3 and IDH1/IDH2 are among those that are currently actionable in acute myeloid leukemia (AML). Trials of novel agents and combinati...READ MORE



Genomic Landscape of MDS and AML: Current Perspectives

clinical topic updates by Harry Paul Erba, MD, PhD

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are part of a disease spectrum that is beginning to enter into the precision medici...READ MORE



Higher-Risk MDS and AML: Need for Treatment Without Intensive Chemotherapy

patient care perspectives by Guillermo Garcia-Manero, MD

The US Food and Drug Administration approval of lower-intensity treatments, including hypomethylating agents (HMAs) and targeted and/or immunomodul...READ MORE

More In Oncology


Advances in the Diagnosis and Treatment of Gastrointestinal Stromal Tumors

expert roundtables
by Michael C. Heinrich, MD; Arun Singh, MD; and Jonathan C. Trent, MD, PhD


Differential Diagnosis of Gastrointestinal Stromal Tumors

patient care perspectives
by Jonathan C. Trent, MD, PhD


Immunotherapy and Gastrointestinal Stromal Tumors

clinical topic updates
by Arun Singh, MD