Clinical Challenges: Treating TP53-Mutated Acute Myeloid Leukemia

— "It's of paramount importance that we do better for these patients," expert notes

MedpageToday

While advances in acute myeloid leukemia (AML) research have led to the development of a variety of novel treatments for the disease, finding optimal strategies to treat AML patients with TP53 mutations remains a critical unmet need.

About 10% of newly diagnosed AML patients have TP53 mutations, and it is even more common in older patients and those with therapy-related AML.

However, TP53 is associated with dismal responses to chemotherapy, making patients with that mutation particularly challenging to treat, noted Farhad Ravandi-Kashani, MD, of the University of Texas MD Anderson Cancer Center in Houston.

"Our essential focus with cancer therapy has been the use of chemotherapy," he told MedPage Today. "And because TP53-mutated disease has been highly resistant to chemotherapy, we need different treatment approaches."

Considering the poor response with traditional chemotherapy, allogeneic stem cell transplant continues to remain the only potential curative therapy. However, according to Asmita Mishra, MD, of the Moffitt Cancer Center and Research Institute in Tampa, Florida, the data suggest that outcomes for TP53-mutant AML patients after transplant are poor, with 1-year relapse-free survival rates of around 30% and median overall survival of 5 to 8 months.

"This is despite curative-intent allogeneic transplantation," Mishra told MedPage Today. "So these poor patients are coming in for a cure, and within months of presumably receiving curative-intent therapy, they are succumbing to disease. So, it's of paramount importance that we do better for these patients, and a maintenance strategy is just one potential mechanism to accomplish that."

One drug that has shown promise and has been studied in both the pre-transplant and post-transplant setting is eprenetapopt (APR-246), a small-molecule agent that can restore the activity of mutant p53 and induce cell apoptosis.

For example, a 2021 study by David Sallman, MD, also of Moffit, and colleagues evaluated the drug in 55 patients with TP53-mutant myelodysplastic syndromes (MDS) and oligoblastic AML, groups with a complete remission (CR) rate of less than 20% with standard-of-care azacitidine therapy.

The team found that the combination of eprenetapopt plus azacitidine resulted in an overall response rate (ORR) of 71%, with 44% achieving a CR. Of the 40 patients with MDS, 73% responded, 58% had a cytogenetic response, and 50% achieved CR. The ORR and CR rate among the 11 patients with AML were 64% and 36%, respectively.

The researchers said the data suggest that the combination may be significantly better than current treatment with hypomethylating agents like single-agent azacitidine or decitabine.

The results in that study were confirmed in a parallel phase II study by the Groupe Francophone des Myélodysplasies, which included 52 patients with TP53 mutations (34 with MDS and 18 with AML, including seven with more than 30% blasts). In MDS patients, the ORR was 62%, including 47% with a CR, with a median duration of response of 10.4 months. In the AML patients, the ORR was 33%, including 17% with a CR (27% and 0% in those with less than and more than 30% marrow blasts, respectively).

In another study, Mishra and colleagues evaluated the combination of eprenetapopt and azacitidine as maintenance therapy after transplantation in 14 AML patients and 19 MDS patients. Median relapse-free survival was 12.5 months, and the median overall survival was 20.6 months.

"Given these extremely exciting and encouraging results, we believe pursing this combination therapy as an additional maintenance paradigm targeting TP53 is warranted and needed," Mishra said. "We are currently working towards a randomized study to further investigate the efficacy of this combination in the post-transplant setting."

She emphasized that treating TP53-mutated AML patients in the post-transplant setting is challenging and there has been little else in the way of drug development. However, she added, "other therapies are showing promise in the pre-transplant setting."

One is the anti-CD47 antibody magrolimab. In a report on 29 evaluable TP53-mutant AML patients with previously untreated disease who were ineligible for intensive chemotherapy, 69% responded to treatment, 45% achieved a CR, and 14% had a CR with incomplete count recovery. The median duration of response was 7.6 months in this cohort.

Mishra noted that there are also several inhibitors of the mouse double minute 2 homolog (MDM2) protein currently in phase I/II trials, such as alrizomadlin (APG-115), which has shown antitumor activity in preclinical AML models. PD-1 and CTLA-4 checkpoint inhibitors, and even arsenic trioxide, are also being evaluated in this space, she added.

"So it will be exciting to see what happens with these drugs, and what their toxicity profiles are, and whether any of them can be branched into the post-transplant space," Mishra said.

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    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

Ravandi-Kashani reported relationships with Bristol Myers Squibb and Celgene.

Mishra reported research funding from Novartis.