A Remission by Any Other Means May Smell as Sweet

In the second act of Shakespeare’s Romeo and Juliet, Juliet argues that despite Romeo being of Montague — and not Capulet — lineage, their burgeoning love affair should be afforded the opportunity to thrive. Similarly, recent advances in the treatment of acute myeloid leukemia (AML) have increasingly suggested that older, transplant-eligible patients who achieve remission — regardless of how the remission may have been induced — should be afforded the opportunity to proceed to potentially curative allogeneic hematopoietic cell transplantation (alloHCT).^1,2  It is well documented that patients with AML over the age of 60 have a lower likelihood of remission with 7+3-based chemotherapy and higher rates of treatment-related mortality, likely due to both patient-related and AML biology-related factors.^3,4,5  Even for patients who achieve remission with 7+3-based chemotherapy, the toxicity of standard induction therapy frequently prevents fit, older patients from proceeding to potentially curative transplant.

On behalf of the EORTC Leukemia Group, GIMEMA, and the German MDS Study Group, Lübbert and colleagues sought to determine whether a 10-day decitabine induction regimen could improve outcomes when compared with standard 7+3 induction in transplant-eligible patients with newly diagnosed AML aged 60 years and older. The study began enrolling in 2014, and patients were randomly assigned 1:1 to receive either 10-day decitabine or standard 7+3 induction, with patients in both groups strongly encouraged to proceed to alloHCT after achieving a response. The primary endpoint was overall survival in the intention-to-treat population.

Between 2014 and 2021, the study enrolled 606 patients across 54 centers, with 303 patients assigned to each arm. The median age was 67 in the decitabine group and 68 in the 7+3 group, with approximately one-third of patients in each group aged 70 years or older. Eastern Cooperative Oncology Group (ECOG) performance was ≤1 in more than 90% of patients in both groups.

At a median follow-up of four years, the analysis revealed no difference in overall survival between the decitabine and 7+3 groups (26% vs. 30%. respectively, p=0.68). Although remission rates were higher in the 7+3 group (61% vs. 48%, odds ratio: 0.57, 95% CI 0.42-0.80), the numbers of patients who proceeded to on-protocol HCT were similar (40% in the decitabine group vs. 39% in the 7+3 group), and the four-year incidence of relapse following HCT was also similar between groups (24% in the decitabine group vs. 22% in the 7+3 group).

Despite similar primary and key secondary outcomes between the decitabine and 7+3 groups, important differences in safety outcomes were noted. Overall, patients in the decitabine group experienced significantly fewer grade 3-5 adverse events, principally driven by fewer grade 3-5 infections and reductions in mucositis and diarrhea. The 30-day mortality rate was 3.6% for the decitabine group versus 6.3% in the 7+3 group. In a subset of patients (n=173), health economics also favored the decitabine group, with shorter hospital stays, less frequent use of intravenous antibiotics, and fewer units of blood products transfused.

Strengths of this trial include its large, prospective, multicenter nature, as well as the long duration of follow up and the prescient inclusion of key health care economic variables. The conclusions are particularly provocative given that this study was designed in the pre-venetoclax era, prompting us to consider what results might have been achieved if 7+3 had been compared with combination therapy involving a hypomethylating agent and venetoclax, the subject of a trial currently underway in the U.S.⁶