Frontline Mipletamig Triplet Drives Clinical Benefit in TP53-Mutated AML

Treatment with the CD123 x CD3 bispecific antibody–like recombinant protein mipletamig (APVO436) in combination with venetoclax (Venclexta) and azacitidine yielded clinical benefit in the frontline treatment of patients with acute myeloid leukemia (AML) harboring TP53 mutations, according to data from the phase 1b/2 RAINIER trial.¹

Data announced by Aptevo Therapeutics showed that evaluable patients with TP53-mutated AML treated with the triplet (n = 14) experienced a clinical benefit rate (CBR) of 93%; notably, 79% of patients achieved a complete remission (CR) or CR with incomplete hematologic recovery (CRi), including 9 CRs.

“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.”

How is the RAINIER study being conducted and who is eligible?

Along with targeting CD123 on leukemia cells and CD3 on T cells, mipletamig leverages a CRIS-7–derived binding pathway for CD3, which is intended to reduce the incidence and severity of cytokine release syndrome (CRS).

RAINIER is an open-label, multicenter, phase 1b/2 trial enrolling patients at least 18 years of age.^1,2 Patients must have CD123-positive AML as confirmed by local flow cytometry and be ineligible for induction therapy due to at least 1 of the following criteria: 75 years of age or older; an ECOG performance status of 2 or 3; cardiac disorder; pulmonary disorder; a creatinine clearance of 30 to 45 mL/min; or hepatic disorder with total bilirubin level between 1.5 and 3 times the upper limit of normal.²

Investigators are excluding patients who received prior treatment with a hypomethylating agent, venetoclax, and/or chemotherapy for AML, myelodysplastic syndrome, chronic myelomonocytic leukemia, or a myelodysplastic/myeloproliferative neoplasm. Other key exclusion criteria comprise active participation in another interventional study; a history of myeloproliferative neoplasm including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia, or BCR:ABL1-mutated AML; acute promyelocytic leukemia; and active central nervous system involvement with AML.

The phase 1b portion of the study is evaluating 28-day treatment cycles distributed in 5 sequential cohorts. In cycle 1 only across all cohorts, each patient is receiving 4 priming doses of mipletamig to reduce the risk of cytokine release syndrome before being given in combination with venetoclax and azacitidine. Starting on day 15 of cycle 1, patients begin receiving mipletamig at the determined cohort dose level, with the agent administered via a 4-hour intravenous (IV) infusion. Venetoclax is given orally on days 1 through 22 of each 28-day cycle, and azacitidine is given via an IV infusion on days 1 to 8 on a fixed 28-day cycle.

The primary end point in this study is to assess the safety, tolerability, and maximum tolerated dose of increasing doses of mipletamig in combination with venetoclax/azacitidine. Secondary end points consist of efficacy outcomes with the combination, including CR rate.

The phase 1b portion of the study is expected to be completed by the end of 2026, and Aptevo Therapeutics plans to engage with regulatory authorities in the first half of 2027 to determine next steps for the development of mipletamig.¹

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 3, 2026. https://aptevotherapeutics.gcs-web.com/news-releases/news-release-details/aptevo-reports-93-clinical-benefit-rate-mipletamig-triplet
2. APVO436 phase 1b/​2 study in patients with newly diagnosed AML. ClinicalTrials.gov. Accessed September 3, 2026. Updated May 11, 2025. https://clinicaltrials.gov/study/NCT06634394