A large international phase 3 randomized controlled trial has found that 10-day decitabine treatment did not improve overall survival compared to standard 3+7 chemotherapy in older patients with acute myeloid leukemia (AML) who were eligible for intensive chemotherapy. However, decitabine showed a better safety profile and may be a reasonable alternative for some patients, particularly those aged 70 and older or with adverse genetics.
The open-label study, conducted by the European Organisation for Research and Treatment of Cancer (EORTC) Leukemia Group, GIMEMA, and German MDS Study Group, took place at 54 hospitals across 9 European countries. It was funded by Janssen Pharmaceuticals and published in The Lancet Haematology on November 1, 2023.
The purpose of the trial was to test whether replacing intensive induction chemotherapy with the hypomethylating agent decitabine could improve outcomes in older AML patients. The rationale was that decitabine may be better tolerated while still allowing patients to proceed to potentially curative allogeneic hematopoietic stem cell transplantation (HSCT).
Between December 2014 and August 2019, the study enrolled 606 patients aged 60 years and older (median age 68) with newly diagnosed AML who were eligible for intensive chemotherapy. Key inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less and eligibility for intensive chemotherapy. Patients with acute promyelocytic leukemia, blast crisis of chronic myeloid leukemia, active CNS leukemia, or severe cardiovascular disease were excluded. Those who had received prior hypomethylating agents or intensive chemotherapy for myelodysplastic syndromes or myeloproliferative neoplasms in the past 3 years were also excluded.
Patients were randomized 1:1 to receive either 10-day decitabine (20 mg/m2 for 10 days in 28-day cycles) or standard 3+7 induction chemotherapy (daunorubicin 60 mg/m2 for 3 days plus cytarabine 200 mg/m2 for 7 days). In both arms, allogeneic HSCT was strongly encouraged for eligible patients. The primary endpoint was overall survival.
Baseline characteristics were well-balanced between the two groups. About 70% of patients had de novo AML, while the rest had secondary or therapy-related AML. Approximately 25% had favorable-risk genetics by European LeukemiaNet 2017 criteria, 45% intermediate-risk, and 30% adverse-risk.
At a median follow-up of 4 years, there was no significant difference in overall survival between the decitabine and 3+7 groups. The 4-year overall survival rate was 26% with decitabine versus 30% with 3+7 (hazard ratio 1.04, 95% CI 0.86-1.26, p=0.68). Median overall survival was 15 months with decitabine and 18 months with 3+7.
The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was lower with decitabine (48% vs 61% with 3+7). However, the rate of allogeneic HSCT was similar between groups at around 40%. Among those who underwent transplant, 4-year overall survival from HSCT was also similar at 45% with decitabine versus 47% with 3+7.
Decitabine showed a more favorable toxicity profile. Grade 3-5 adverse events occurred in 84% of decitabine patients versus 94% of 3+7 patients. Rates of grade 3-5 infections (41% vs 53%), oral mucositis (2% vs 10%), and diarrhea (1% vs 8%) were all lower with decitabine. Treatment-related deaths occurred in 12% of decitabine patients versus 14% of 3+7 patients.
In exploratory subgroup analyses, patients aged 60-64 and those with favorable genetics, particularly NPM1 mutations, appeared to benefit more from 3+7 chemotherapy. In contrast, patients aged 70 and older and those with adverse genetics, including monosomal karyotype, tended to have better outcomes with decitabine.
The study had some important limitations. It was designed as a superiority trial for decitabine, so non-inferiority of decitabine cannot be conclusively established. The open-label design introduces potential for investigator bias, though this is mitigated by the objective primary endpoint of overall survival. Patients with white blood cell counts over 30 x 10^9/L that could not be controlled with hydroxyurea were excluded, so results may not apply to all patients with hyperleukocytosis. The study also did not allow use of FLT3 inhibitors, which are now standard for FLT3-mutated AML.
The authors concluded that 10-day decitabine did not improve overall survival compared to 3+7 chemotherapy in older fit AML patients, but showed a better safety profile. They suggest decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3+7 induction in fit older patients with AML without favorable genetics.
This study has several potential clinical implications. For older AML patients eligible for intensive therapy, it provides evidence that a less intensive decitabine-based approach can achieve similar long-term survival and transplant rates as standard induction, with less toxicity. This may be particularly relevant for patients aged 70 and above or those with high-risk genetics. The reduced toxicity and hospital stay with decitabine could translate to quality of life benefits, which are important considerations in this older population.
However, the results also suggest that standard intensive induction may remain preferable for fit patients aged 60-69 with favorable-risk AML. The lower initial CR/CRi rates with decitabine highlight the importance of proceeding to allogeneic HSCT when possible with this approach.
More broadly, this trial provides a strong rationale for further studies evaluating hypomethylating agent-based regimens as alternatives to intensive chemotherapy in fit older AML patients. Ongoing studies are now evaluating combinations like decitabine plus venetoclax compared to 3+7 induction. The favorable toxicity profile of decitabine monotherapy in this study suggests such combinations may be able to improve efficacy while maintaining tolerability.
The study also raises interesting questions about the mechanisms underlying the efficacy of decitabine in adverse-risk AML. The similar transplant outcomes despite lower CR rates hint at potential immunomodulatory effects that may enhance graft-versus-leukemia activity. This warrants further investigation.
From a health economics perspective, the reduced hospital stays and antibiotic use with decitabine could have significant cost implications if this approach is adopted more widely. However, drug costs would also need to be factored in.
In conclusion, this landmark phase 3 trial provides important data to help guide treatment decisions for older fit patients with AML. While not superior to standard induction, 10-day decitabine appears to be a reasonable alternative approach, particularly for those aged 70 and above or with adverse genetics. The results set the stage for further optimization of reduced-intensity approaches in this challenging patient population.
References
Lübbert M, Wijermans PW, Kicinski M, et al. 10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial. Lancet Haematol. 2023;10(11):e879-e889. doi:10.1016/S2352-3026(23)00273-9
