Emerging Therapies May Offer Fresh Options for TP53-Mutated MDS

Oncology Live®Vol. 21/No. 24
Volume 21
Issue 24

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Two novel treatments options may shake up the landscape for treating patients with myelodysplasia syndrome.

Rami Komrokji, MD

Two novel treatment options may shake up the landscape for treating patients with myelodysplasia syndrome (MDS). Eprenetapopt (APR-246) and magrolimab have the potential to be game changers for patients with high-risk MDS, according to Rami Komrokji, MD. Both agents received breakthrough therapy designations from the FDA in 2020 and have demonstrated efficacy in patients with TP53 mutations.

“It’s exciting that we finally have so many options to offer our patients,” Komrokji said in an interview with OncLive®. “It [has been] more than a decade where we did not get new drugs approved after azacitidine and decitabine.” Komrokji is a professor of medicine and oncologic sciences at the College of Medicine of the University of South Florida, section head of leukemia and MDS, and vice chair of the Moffitt Cancer Center in Tampa, Florida.

“The most promising front-runners [include] APR-246 and, hopefully down the road, the oral formulation of that and magrolimab,” he said.

Komrokji said that eprenetapopt modulates the mutated TP53, thereby restoring wide function to the gene. Furthermore, the agent has showed an additive effect with azacitidine (Vidaza) in prior trials.

A French phase 2 study (NCT03588078) conducted by Groupe Francophone des Myélodysplasies enrolled patients with TP53-mutated MDS or acute myeloid leukemia (AML) who were treated with eprenetapopt plus azacitidine. Participants received 4500 mg per day of intravenous eprenetapopt on days 1 to 4 and 75 mg/m2 of subcutaneous azacitidine on days 4 to 10 every 28 days for 6 cycles. Those who responded to the combination continued on therapy until relapse.

In findings presented at the 2020 European Hematology Association Congress, response rate in the intention-to-treat (ITT) population was 62% among patients with MDS (n = 34), including a 47% complete remission (CR) rate; 64% among those with AML with 20% to 30% blasts (n = 11), including a 27% CR rate; and 29% for those with AML with greater than 30% blasts (n = 7), with no CRs.1

The median OS was 12.1 months (95% CI, 8.9-15.3) for both the entire group (n = 52) and for the MDS cohort after a median follow-up of 9.7 months. For patients who remained on treatment for 3 or more cycles, the median OS was higher at 13.7 months (95% CI, 11.7-15.7) versus 2.8 months (95% CI, 1.2-4.4) for patients who were on treatment for fewer than 3 cycles (P < .0001).

Enrollment for a randomized, controlled phase 3 trial (NCT03745716) evaluating eprenetapopt/azacitidine versus azacitidine alone as frontline therapy in intermediate-, high-, and very high–risk patients with TP53-mutant MDS finished in June. Investigators plan to have topline results by the end of this year.

“If those data are positive, I think that will lead to approval of the drug to be available for patients with a TP53 mutation,” Komrokji said.

Magrolimab Outperforms Azacitidine

Magrolimab is a first-in-class, investigational anti-CD47 monoclonal antibody for the treatment of newly diagnosed MDS. Data from an ongoing phase 1b trial (NCT03248479) evaluating magrolimab in combination with azacitidine in treatment-naïve patients with high- and very high–risk MDS showed that the regimen was well tolerated and effective in this patient population.

A total of 91% (30 of 33) of evaluable patients had an objective response to the combination; 42% had a CR, and 24% experienced a CR in the bone marrow. The median time to initial response was reported to be 1.9 months, which is faster than what is expected with azacitidine alone.2 Komrokji noted that azacitidine monotherapy typically induces CR rates of approximately 20%.

Additionally, those who responded to the treatment experienced deeper responses over time; the CR rate in those with 6 months of follow-up or longer was 56%. Investigators observed cytogenetic CRs in 35% of patients evaluable for response. Moreover, 22% of patients with CR or CR with incomplete hematologic recovery in the bone marrow also had minimal residual disease negativity per multiparameter flow cytometry.

Based on these results, investigators will assess the magrolimab/azacitidine combination versus azacitidine alone for patients with intermediate- to very high–risk untreated MDS in the phase 3 ENHANCE trial (NCT04313881).

Komrokji added that patients with TP53- mutated AML up front also had high responses with the magrolimab and that the monoclonal antibody appeared to be agnostic to all somatic mutations.

“If [the phase 3 data are] positive, it will lead to an approval [of magrolimab],” he said. “[Magrolimab] is also is going into a randomized, phase 3 trial in patients with TP53-mutant AML compared with azacitidine because, even with azacitidine/venetoclax [Venclexta] becoming the standard of care for patients with AML, the group that did not do well were [those who had a] TP53 mutation—magrolimab had shown promising activity even among that group. I think the drug looks very promising and is well tolerated. Hopefully that will translate to another option for our patients.”

“I think the next step down the road will be integrating all these promising drugs,” Komrokji said. “You have venetoclax, you have APR-246 and magrolimab. Maybe we’ll be talking about the combination of those drugs, as well.”


  1. Cluzeau T, Sebert M, Rahmé R, et al. APR-246 with azacitidine in TP53 mutated myelodysplastic syndromes (MDS) and acute myeloid leukemia. A phase 2 study by the Groupe Francophone Des Myélodysplasies (GFM). Abstract presented at: 2020 European Hematology Association Virtual Congress; June 11-21, 2020. Accessed November 25, 2020. https://bit.ly/3fsqKVz
  2. Sallman D, Malki MA, Asch A, et al. The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well-tolerated and effective in MDS patients: phase 1b results. Abstract presented at: 2020 European Hematology Association Virtual Congress; June 11-21, 2020. Accessed November 25, 2020. https://bit.ly/2FyqI1p
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