Mipletamig Triplet Demonstrates Frontline Activity in TP53-Mutated AML

An investigational triplet regimen combining mipletamig (APVO436) with venetoclax (Venclexta) and azacitidine (Vidaza) produced clinical benefit in nearly all evaluable patients with TP53-mutated frontline acute myeloid leukemia (AML), according to updated data from the phase 1b/2 RAINIER trial (NCT06634394).¹

Of 14 evaluable patients with TP53-mutated AML who received the mipletamig triplet, including 2 patients carried over from a previously completed dose expansion trial, 13 patients (93%) experienced clinical benefit, defined as complete remission (CR), complete remission with incomplete hematologic recovery (CRi), partial response, or morphologic leukemia-free state. Eleven patients (79%) achieved CR or CRi, including 9 patients who achieved CR.

"TP53-mutated AML remains one of the most challenging AML subpopulations to treat," Dirk Huebner, MD, chief medical officer of Aptevo Therapeutics, stated in a news release. "Seeing this level of clinical benefit with the mipletamig triplet in a patient population that historically has not responded well to treatment is exciting. These results support mipletamig as a promising frontline treatment for one of the most difficult-to-treat forms of AML."

Mipletamig and the Unmet Need in TP53-Mutated AML

TP53 mutations are associated with increased resistance to standard therapies and are consistently linked to inferior remission rates and shorter survival relative to other AML molecular subgroups. Achieving deep, durable responses in this population has proven particularly difficult, underscoring the need for a regimen that can effectively overcome resistance.

Mipletamig is a CD123 x CD3 bispecific antibody designed to redirect a patient's T cells to recognize and destroy leukemic cells and leukemic stem cells that express CD123, an antigen overexpressed on AML blasts and leukemic stem cells. The agent uses a CD3-binding domain derived from CRIS-7, an approach that is intended to reduce the likelihood and severity of cytokine release syndrome relative to other CD3-engaging bispecific agents.

RAINIER Trial Design and Previous Data

The RAINIER study is a multicenter, open-label phase 1b/2 dose-optimization study being conducted in adults with newly diagnosed AML who are not eligible for intensive induction chemotherapy.² The phase 1b portion consists of sequential cohorts using 28-day treatment cycles and is intended to identify an appropriate dose for subsequent phase 2 evaluation.

The current findings build on earlier RAINIER data reported in May 2026, in which an 87% clinical benefit rate and an 81% remission rate were seen among 31 evaluable frontline AML patients treated with the mipletamig triplet, although those data included the broader frontline AML population rather than being restricted to patients with TP53 mutations.³

According to the sponsor, the ongoing dose-optimization phase is expected to be completed by the end of 2026, with regulatory discussions planned for the first half of 2027. Further evaluation of mipletamig in RAINIER will therefore focus on dose optimization, safety, and efficacy as the study advances toward phase 2.

REFERENCES

1. Aptevo Reports 93% Clinical Benefit Rate with Mipletamig Triplet in Difficult-to-Treat TP53-Mutated Frontline AML. News release. Aptevo Therapeutics. September 3, 2026. Accessed September 8, 2026. https://tinyurl.com/4emxthyx

2. APVO436 Phase 1b/​2 Study in Patients With Newly Diagnosed AML. ClinicalTrials.gov. Updated May 11, 2025. Accessed September 8, 2026. https://clinicaltrials.gov/study/NCT06634394

3. Aptevo Reports 87% Clinical Benefit and 81% Remission in 31 Evaluable Frontline AML Patients Through Cohort 5, Substantially Outperforming Benchmark; RAINIER on Track for 2026 Completion and Phase 2 Dose Selection. News release. Aptevo Therapeutics. May 6, 2026. Accessed September 9, 2026. https://tinyurl.com/yvc8k7su