Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.
“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.
Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.
Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”
“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.
Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.
HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.
However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.
To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.
Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.
In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.
In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.
In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.
The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.
In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).
In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).
Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).
Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).
In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.
An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).
Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).
The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.
They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).
However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.
“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.
“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.
“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.
In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.
“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.
“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.
Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
