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HSCT may improve DFS, OS in older patients with AML
Reduced-intensity conditioning hematopoietic stem cell transplantation appeared well tolerated and associated with favorable outcomes in selected older patients with acute myeloid leukemia, according to phase 2 study results published in Journal of Clinical Oncology.
Further, the researchers observed lower rates of graft-versus-host disease and nonrelapse mortality than initially expected.
Older adults with newly diagnosed AML experience extremely poor long-term survival rates, according to study background. Previous observational studies have conjectured that HSCT may improve OS by producing lower relapse rates; however, the toxicity associated with HSCT has prohibited its use in an older population.
Thus, Steven M. Devine, MD, professor of internal medicine and director of the blood and marrow transplant program at The Ohio State University’s Wexner Medical Center, and colleagues sought to prospectively determine the value of HSCT among older patients with AML in first complete remission.
Devine and colleagues conducted a multicenter, phase 2 study of HSCT in patients aged 60 to 74 years.
DFS at 2 years after HSCT served as the primary endpoint. Secondary endpoints included nonrelapse mortality, graft-versus-host disease (GVHD), relapse and OS.
The study included data from 114 patients (median age, 65 years; 62% men) in first complete remission from AML. Fifty-two percent of patients received transplants from unrelated donors and antithymocyte globulin for GVHD prophylaxis.
The entire cohort had a 2-year DFS rate of 42% (95% CI, 33-52) and OS rate of 48% (95% CI, 39-58). Patients undergoing unrelated donor transplantation had a DFS rate of 40% (95% CI, 29-55) and OS rate of 50% (95%, 38-64).
The cohort had a 2-year nonrelapse mortality rate of 15% (95% CI, 8-21).
Twenty-eight percent of patients (95% CI, 19-36) reported chronic GVHD, with grade 2 to grade 4 acute GVHD occurring in 9.6% (95% CI, 4-15).
Although 68% of patients experienced at least one grade 3 to grade 5 toxicity, the incidences of grade 3 to grade 5 organ toxicity — including mucositis, gastrointestinal, hepatic, pulmonary, renal, cardiac and neurologic — were fewer than 5% for each category.
The researchers observed a 2-year cumulative incidence of relapse of 44% (95% CI, 35-53).
“Given multiple potential biases among leukemia therapists and their patients, a truly randomized study comparing transplantation to chemotherapy seems unlikely because of the lack of equipoise,” Devine and colleagues wrote. “The results of this trial create a platform on which future trials can build. Studies to more precisely define the physiologic characteristics that determine a patient’s suitability for transplantation are needed. … Studies are needed to better define the group of older patients with AML most likely to benefit from this approach.” – by Cameron Kelsall
Disclosure: Devine reports receiving research funding from Genzyme. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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It is well established that hematopoietic stem cell transplantation improves OS in younger patients with AML in first complete remission.
With a 2-year OS rate of 48%, the study by Devine and colleagues suggests that reduced-intensity conditioning followed by HSCT is an effective treatment for older patients with AML in first complete remission. However, this study also shows there still are many unanswered questions with regard to the approach to transplantation in this age group.
Older age often has been automatically prohibitive when considering donor transplantation as a treatment option for any hematologic malignancy. Although Devine’s study certainly supports use of allografting in the older population, the precise characteristics that constitute a favorable candidate need to be defined. The hematopoietic cell transplantation–comorbidity index (HCT-CI) was established in an effort to identify relevant comorbidities in patients being considered for allogeneic HSCT. A more recent version, called the HCT-CI/age index, takes into account the effect of comorbidities with advancing age.
This scoring system predicts 2-year nonrelapse mortality and stratifies patients into low, intermediate and high risk based on their score. After taking into consideration disease characteristics, the HCT-CI/age index can help with risk assessment and, thus, the decision of whether to offer donor transplant to an older patient.
Given the highly immunosuppressive effect of antithymocyte globulin, it is not surprising that the rate of graft-versus-host disease (GVHD) in this study was reported to be rather low and the rate of relapse was high. In the older population — in which the rate of relapse with conventional therapy is already quite high — those patients who are taken to transplant depend on the antileukemic effect of the graft. It then becomes a question of “how much is too much” with regard to immunosuppression/GVHD prophylaxis. Newer strategies for GVHD prevention that are less immunosuppressive — such as posttransplant cyclophosphamide — are likely needed to improve upon relapse rate. Further studies are clearly needed to better define the optimal conditioning regimen and method of GVHD prophylaxis for this population.
Despite these unanswered questions, it is clear there is a role for allogeneic HSCT in older patients with AML, and that these patients need not be automatically excluded as candidates for transplant simply because of their age.