Mipletamig Combo Produces Robust Activity in Newly Diagnosed AML

Combining mipletamig with venetoclax (Venclexta) and azacitidine (Vidaza) demonstrated robust clinical benefits among patients with newly diagnosed acute myeloid leukemia (AML) who are older or unfit for intensive chemotherapy, according to a press release from the developer, Aptevo Therapeutics Inc.¹

Among 28 evaluable patients, including 24 from the phase 1b/2 RAINIER trial (NCT06634394) and 4 from a completed dose-expansion trial, the mipletamig regimen produced a clinical benefit rate (CBR) of 86%. Additionally, 79% of patients experienced a complete remission (CR) or CR with incomplete hematologic recovery (CRi), and 61% had a CR. Among those with a CR or CRi, 55% had blast reductions resulting in minimal residual disease (MRD) negativity.

Safety data revealed that 100% of patients treated in the frontline setting were free of cytokine release syndrome (CRS) following treatment with the mipletamig-based combination.

“The emerging mipletamig data in frontline AML are highly encouraging and highlight the differentiated profile we believe is needed to advance treatment in frontline AML. In this study we are observing strong remission rates in a growing number of evaluable patients together with a consistently favorable safety and tolerability profile, including the absence of [CRS],” Dirk Huebner, MD, chief medical officer of Aptevo Therapeutics, stated in the press release.¹ “Achieving meaningful clinical activity while maintaining this level of safety and tolerability is essential in the frontline AML setting, where therapies must be compatible with established regimens. These results reinforce our belief that mipletamig can be successfully combined with venetoclax and azacitidine, with the potential to enhance outcomes for older and/or unfit patients [with AML] who continue to [have] poor prognosis and limited treatment options.”

Investigators previously presented findings from the RAINIER trial in a poster session at the 2025 American Society of Hematology Annual Meeting & Exposition (ASH).² Among 15 evaluable patients with frontline AML as of the cutoff of October 6, 2025, 12 achieved a CR or CRi after the first cycle of treatment, and 1 experienced a partial response (PR) after the first cycle, before having a CRi after the second cycle. Of 10 patients with CR or CRi who had evaluable MRD status, 6 experienced MRD negativity.

The most common treatment-emergent adverse effects (TEAEs) observed in this population included infusion-related reactions (71%), constipation (62%), thrombocytopenia (62%), increased alanine aminotransferase (47%), increased aspartate aminotransferase (47%), and nausea (43%).

In the phase 1b/2 RAINIER study, investigators assessed the safety, tolerability, and anti-leukemia activity of mipletamig plus azacitidine/venetoclax. In the phase 1b dose-optimization portion of the trial, patients received mipletamig at 9 mcg, 18 mcg, or 27 mcg each week across 3 cohorts in combination with venetoclax and azacitidine.

The trial’s primary end points included grade 3/4 TEAEs, serious AEs, TEAEs of interest, the maximum tolerated dose, and recommended phase 2 dose. A secondary end point was efficacy based on CR rate.

Developers designed mipletamig to attack leukemic cells and stem cells expressing CD123, which is overexpressed on leukemic stem cells and AML blasts. Additionally, the agent may reduce the probability and severity of CRS by harnessing the CRIS-7–derived CD3 binding pathway.

“Our frontline data show that mipletamig has the potential to play a meaningful role in the future frontline AML treatment. From the outset, our objective has been to develop an AML drug capable of integrating into the current standard of care and improving outcomes for patients who continue to [have] poor prognoses. The data reported reinforces our conviction that mipletamig may represent a differentiated approach with the potential to complement existing frontline therapies in a practical and impactful way,” Marvin White, president and chief executive officer at Aptevo, concluded.¹

References

1. Mipletamig delivers compelling 86% clinical benefit rate and no CRS as evaluable AML patient data increases by nearly 50%. News release. Aptevo Therapeutics, Inc. March 10, 2026. Accessed March 11, 2026. https://tinyurl.com/3pv2rywd
2. Watts J, Borthakur G, Lin T, et al. A dose optimization phase 1b/2 study evaluating mipletamig (formerly APVO436), a novel bispecific CD123 x CD3 ADAPTIRÒ molecule in combination therapy for the treatment of frontline acute myeloid leukemia (AML) in patients unfit for intensive chemotherapy. Blood. 2025;146(suppl 1):5198. doi:10.1182/blood-2025-5198