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Promising frontline triplet regimen for TP53-mutated AML

Presented by
Dr Naval Daver, MD Anderson Cancer Center, TX, USA
ASH 2021
Phase 1/2
A triplet combination of 5-azacitidine, venetoclax, and magrolimab displayed promising response rates in newly diagnosed older, unfit, or TP53-mutated patients with acute myeloid leukaemia (AML). Moreover, the phase 1b/2 study showed a favourable safety profile of this regimen. Phase 3 trials investigating this triplet combination are ongoing [1].

“Older or unfit patients with AML treated with 5-azacitidine plus venetoclax show overall survival (OS) rates of 40% after 2 years,” said Dr Naval Daver (MD Anderson Cancer Center, TX, USA). “Moreover, patients with TP53-mutated AML treated with hypomethylating agents (HMA) plus venetoclax as first-line therapy display median OS rates of only 5–7 months. Therefore, there is an obvious unmet need in these patients,” Dr Daver argued. The current phase 1/2 trial included 48 patients divided over 3 cohorts:

  • Cohort 1: frontline therapy for older (≥75 years), unfit, or TP53-mutated patients;
  • Cohort 2: relapsed/refractory venetoclax-naïve patients;
  • Cohort 3: relapsed/refractory patients with prior venetoclax therapy.

Patients received cycles (21 days per cycle) of 5-azacitidine (75 mg/m2, once daily, day 1 to 7), venetoclax (400 mg, once daily, day 1 to 21/28), and magrolimab (ramped up to 30 mg/kg, at day 1 and day 11).

The overall response rate in older, unfit, or TP53-mutated patients (n=14) was 86%, with a complete response (CR) rate of 64%. In patients with TP53 wildtype (n=11) the overall response rate was 100%, with a CR of 64%. Furthermore, TP53 variant allele frequency (VAF) levels were significantly decreased in TP53-mutated patients who displayed a CR. This indicates biologic activity at the TP53 level. Among venetoclax-naïve patients and patients with prior venetoclax therapy, the CR rates were 38% and 0%, respectively. Notably, absolute neutrophil count and platelet recovery were robust after 28 days, which is an encouraging result in triplet therapy for AML.

According to Dr Daver, the safety profile of the current triplet regimen was similar to the safety of an HMA plus venetoclax regimen, with febrile neutropenia and lung infections as the most common serious adverse events (SAEs). In addition, increased bilirubin levels were reported. Dr Daver argued that this adverse event may be related to extravascular haemolysis, which can be observed with magrolimab. Anaemia due to haemolysis in the magrolimab arm was manageable with close monitoring and did not lead to SAEs or treatment interruption or discontinuation. No immune-related adverse events were reported.

Thus, the triplet combination of azacitidine, venetoclax, and magrolimab showed promising results as frontline therapy for newly diagnosed older, unfit, and TP53- mutated patients with AML in this phase 2 study. Larger trials are currently running to validate the efficacy and safety of this novel regimen.

  1. Daver NG, et al. Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML. Abstract 371, ASH 2021 Annual Meeting, 11–14 December.


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