Older, fit patients with acute myeloid leukemia (AML) pretreated with a 10-day regimen of decitabine (Dacogen) prior to allogeneic hematopoietic stem cell transplantation had similar overall survival compared with those receiving conventional intensive chemotherapy, according to results from a phase 3 study.
Notably, those who received decitabine experienced significantly fewer severe adverse events.
Together, these findings suggest that some patients may safely forgo intensive chemotherapy prior to transplantation without affecting survival.
António Almeida, MD, president-elect of the European Hematology Association (EHA), called the results potentially “practice-changing.” He was not involved with the study.
“What is really exciting about this is that, for the first time, we actually have a head-to-head [trial] of a hypomethylating agent [decitabine] compared with intensive chemotherapy before proceeding to allogeneic transplant,” said Almeida, of the Hospital da Luz, in Lisbon, Portugal. “With the results, we see that we can take patients on hypomethylating agents to stem cell transplantation with less toxicity, so more patients can get to the transplant option.”
The study was presented at this week’s 2022 EHA Annual Meeting in Vienna, Austria.
Older patients with AML often have poor survival without hematopoietic stem cell transplantation, yet these patients have lower tolerance to induction chemotherapy treatment, which is standard for most prior to transplantation.
Treatment with milder DNA-hypomethylating agents such as decitabine is an alternative, but patients may fail to achieve complete remission on decitabine, which can rule them out for transplantation.
To evaluate whether decitabine is a viable substitute for induction chemotherapy before stem cell transplantation in fit patients, investigators enrolled 606 patients with newly diagnosed AML from 54 centers between December 2014 and August 2019 who were eligible for induction chemotherapy.
Patients were then randomly assigned 1:1 in the open-label study to receive treatment prior to hematopoietic stem cell transplantation either with a 10-day regimen of decitabine (n = 303) or conventional induction chemotherapy (n = 303), consisting of daunorubicin 60 mg/m2 for 3 days, cytarabine 200 mg/m2 for 7 days, followed by 1 to 3 additional chemotherapy cycles.
The patients were a mean age of 68 years; 21% had a good rating on the European LeukemiaNet (ELN) 2017 risk profile and 32% had adverse profiles.
As expected, patients who received decitabine had a lower rate of complete response or complete response with incomplete count recovery (48%) compared with those in the induction chemotherapy arm (61%). A similar proportion of patients went on to receive stem cell transplantation — 40% in the decitabine group and 39% in the induction chemotherapy group.
After a median follow-up of 4 years, the rates of overall survival between the groups were similar — 26% in the decitabine group and 30% in the induction chemotherapy group (hazard ratio [HR], 1.04; P = .68).
Median overall survival was 15 months in the decitabine group and 18 months in the induction chemotherapy group. And the 30-day mortality rate was 3.6% in the decitabine group vs 6.4% in the induction chemotherapy group.
Survival rates varied by patient subgroups. The estimated overall survival in the decitabine arm was lower in the 60-64 age group (HR, 1.34) and among those with NPM1 mutations (HR, 2.0); however, overall survival was higher for patients aged 70 or older who received decitabine (HR, 0.84).
Importantly, major toxicities were lower for those receiving decitabine prior to transplantation, including febrile neutropenia (37% vs 57%), a decrease in platelets (24% vs 32 %), diarrhea (1% vs 8%), and a decrease in neutrophils (19% vs 13%).
Those treated with decitabine also spent significantly less time in the hospital, needed fewer intravenous antibiotics, and fewer red blood cell and platelet transfusions.
The incidence of grade 5 treatment-related adverse events following hematopoietic stem cell transplantation was comparable between the groups — 25% for decitabine vs 22% for chemotherapy.
“These findings are very important because there is this dogma that a patient cannot receive transplantation until a complete response is achieved [first with chemotherapy],” first author Michael Lübbert, MD, of the Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Germany, told Medscape Medical News.
“The [remission] rate in our study before transplantation was indeed lower after decitabine, but since the survival outcomes after transplant were similar, this is proof that complete remission is not an absolute prerequisite for successful transplantation,” Lübbert said. In other words, even without complete remission, “curative chances are still very high” following transplantation.
The study was supported by an educational grant from Janssen. Lübbert is on the advisory boards of AbbVie, Astex Pharmaceuticals, Imago Biosciences, Janssen, Otsuka, and Syros, and receives research support from Janssen and Cheplapharm. Almeida reported no relevant financial relationships.
EHA 2022, the European Hematology Association Annual Meeting:
Abstract S125. Presented June 10, 2022.