ACTIVE Regimen Elicits High Response Rates in R/R NPM1-Mutated AML

The ACTIVE regimen (actinomycin D combined with low-dose cytarabine and venetoclax [Venclexta], with gilteritinib [Xospata] added for FLT3-mutated disease) produced an objective response rate (ORR) of 92% and a composite complete remission (CRc) rate of 81% among evaluable patients in a heavily pretreated cohort of patients with relapsed or refractory NPM1-mutated acute myeloid leukemia (AML; n = 26), according to findings from a retrospective, single-cohort, real-world study presented at the 2026 SOHO Annual Meeting.¹

Among the 21 evaluable patients who achieved CRc, 62% achieved measurable residual disease negativity. Moreover, 54% of patients in the overall cohort were bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT). At a median follow-up of 54.7 months (95% CI, 38.3-60.0), the median overall survival (OS) was 17.2 months (95% CI, 7.2-not reached [NR]), with OS data favoring patients who proceeded to transplant. No treatment-related deaths were recorded.

What was the rationale for investigating the ACTIVE regimen in relapsed/refractory NPM1-mutant AML?

Adding venetoclax to lower-intensity salvage therapy has been shown to improve response and survival outcomes in NPM1-mutated AML compared with wild-type disease; a retrospective analysis showed respective complete response CR/CR with incomplete count recovery (CRi) rates of 71% vs 32% and respective median OS values of 14.7 months vs 5.9 months.² However, the current study authors noted that venetoclax plus low-dose cytarabine is ineffective in many patients with relapsed/refractory AML, and responders often relapse quickly, a pattern linked to MCL-1–driven venetoclax resistance.¹

Actinomycin D monotherapy has generated responses in NPM1-mutated relapsed/refractory AML and inhibited MCL-1 synergistically with BCL-2 blockade in preclinical models, providing the rationale for combining it with a venetoclax-based backbone. Mechanistically, actinomycin D inhibits RNA polymerase I, inducing nucleolar stress that releases mutant NPM1 into the cytoplasm, stabilizes p53, and inhibits MCL-1. Venetoclax displaces BIM from BCL-2 to activate BAX/BAK-mediated apoptosis. Low-dose cytarabine adds replication stress and DNA damage that prepares leukemic cells for venetoclax-induced apoptosis. In unpublished in vitro synergy experiments, the 3-drug combination produced the highest ZIP and Bliss synergy scores, exceeding any 2-drug pairing.

How was the retrospective ACTIVE cohort treated and characterized?

Investigators retrospectively evaluated the efficacy and toxicity of the ACTIVE regimen in 28 patients with relapsed or refractory NPM1-mutated AML. In each 28-day induction cycle, patients received actinomycin D at 12.5 mcg/kg intravenously on days 1 through 3 (days 1-2 for those 65 years or older), cytarabine at 20 mg/m² subcutaneously on days 1 through 10, and venetoclax at 600 mg/day orally on days 1 through 14; gilteritinib at 80 to 120 mg/day was added for patients with FLT3-mutated disease. A day 14 bone marrow assessment was also conducted, with induction therapy extended if blast levels exceeded 5% on day 14. Responders received 1 to 2 additional cycles of the ACTIVE regimen before proceeding to allo-HSCT or maintenance.

The cohort had a median age of 64 years (range, 20-87), with 39% of patients ages 65 years or older. In total, 89% of patients had de novo AML. Patients had received a median of 1 prior line of therapy (range, 1-5), with 75% of patients having been previously exposed to intensive chemotherapy with or without midostaurin. Co-mutations were common, including FLT3-ITD or FLT3-TKD (64%), DNMT3A (57%), and IDH1 or IDH2 (39%); 96% of patients had normal or non-adverse karyotype. Most patients (57%) received the ACTIVE regimen plus gilteritinib.

What additional response and survival outcomes were observed with the ACTIVE regimen in relapsed/refractory NPM1-mutant AML?

Among 26 evaluable patients, best responses included CR in 61.5%, CRi in 19.2%, and morphologic leukemia-free state in 11.5%. The median time to best response was 28.5 days (range, 14-67). The 12-month, 24-month, and 36-month OS rates were 56% (95% CI, 36%-72%), 49% (95% CI, 29%-66%), and 49% (95 CI, 29%-66%), respectively. Additionally, the median relapse-free survival (RFS) among responders was 13.9 months (95% CI, 4.5-NR).

Patients who underwent allo-HSCT (n = 15) had a 3-year OS rate of 80% (95% CI, 50%-93%), and the median OS was not reached. Conversely, among patients who did not undergo allo-HSCT, the 3-year OS rate was 9% (95% CI, 1%-33%), and the median OS was 4.6 months (P < .001). The 3-year RFS rate was 67% (95% CI, 38%-85%) with transplant vs 13% (95% CI, 1%-44%) without (P = .026).

What is the safety profile of the ACTIVE regimen in relapsed/refractory NPM1-mutant AML?

The 30-day and 60-day mortality rates were 11% (n = 3/28) and 18% (n = 5/28), respectively. Infection-dominated toxicity was the primary safety signal, with infectious complications of any type occurring in 86% of patients, general weakness seen in 61% of patients, diarrhea reported in 46% of patients, sepsis observed in 43% of patients, and febrile neutropenia and septic shock seen in 36% of patients each; additionally, nausea was reported in 29% of patients, and invasive fungal infection and pneumonia or lung infection each occurred in 14% of patients.

The investigators concluded that the ACTIVE regimen demonstrated promising efficacy and acceptable tolerability in this heavily pretreated population, with the 2-year survival plateau largely driven by transplanted patients. The investigators also called for a prospective evaluation of this regimen in this patient population and noted that these findings may provide the rationale for combining the ACTIVE regimen with menin inhibitors.

References

1. Smalinskaitė T, Tamutytė-Jankauskė M, Mikalonytė M, Daukėlaitė G, Batiuškaitė R, Žučenka A. Actinomycin D in combination with low-dose cytarabine and venetoclax in relapsed or refractory NPM1-mutated acute myeloid leukemia. Presented at: 2026 SOHO Annual Meeting; September 9-12, 2026; Houston, Texas. Abstract AML-1299.
2. Issa GC, Bidikian A, Venugopal S, et al. Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML. Blood Adv. 2023;7(6):933-942. doi:10.1182/bloodadvances.2022008316