Reduced-intensity conditioned allogeneic hematopoietic stem-cell transplantation (HSCT) yielded “better than expected” survival outcomes for adults with high-risk acute lymphoblastic leukemia (ALL) in first complete remission, a prospective British trial found.
In the study of nearly 250 older adults, reduced-intensity conditioned HSCT with fludarabine, melphalan, and alemtuzumab resulted in event-free survival (EFS) and overall survival (OS) rates of 46.8% (95% CI 40.1-53.2) and 54.8% (95% CI 48.0-61.2) at 4 years, respectively, reported David Marks, MBBS, PhD, of the University Hospital Bristol NHS Trust in England, and colleagues.
Furthermore, these survival rates were achieved with relatively low rates of chronic graft-versus-host disease (GVHD) and transplant-related mortality, the investigators noted in Lancet Haematology.
The study “provides practice-informing evidence for the role of reduced-intensity conditioned allogeneic HSCT in older adults with acute lymphoblastic leukaemia in first complete remission,” Marks and colleagues concluded.
In an accompanying commentary, Anjali Advani, MD, of the Cleveland Clinic Taussig Cancer Institute in Ohio, noted that outcomes are worse for adults with ALL as they age, and that while one strategy has been to pursue allogeneic HSCT in first complete remission for suitable patients, there are concerns about the use of fully myeloablative regimens.
However, “few trials have systemically studied the question of non-myeloablative transplantation prospectively in a large scale fashion,” Advani wrote. “This trial was impressive given the number of patients and sites, follow-up, and results.”
In this study — a single arm substudy embedded in the UKALL14 trial — Marks and colleagues assessed the activity of reduced-intensity conditioned HSCT with fludarabine, melphalan, and alemtuzumab in all patients over 40 years with a suitable matched sibling or unrelated donor. UKALL14 was conducted in 46 centers in the U.K., and the substudy included 249 patients (median age 50, 55% men), considered unfit for a myeloablative allograft who received the reduced-intensity conditioned HSCT from February 2011 to July 2018.
After a median follow-up of 48.9 months, there were 128 EFS events and 112 deaths. Eighty patients relapsed (median of 9.5 months to relapse) for a cumulative incidence of 33.6% at 4 years, the authors said. Of the patients who died, 63 relapsed beforehand.
In BCR-ABL1-positive B-cell patients (25% of the cohort), the EFS rate was 41.7% and the OS rate was 57.6% at 4 years. These rates were 45.4% and 51.5%, respectively, for the BCR-ABL1-negative B-cell group.
In multivariable analysis, minimal residual disease (MRD)-positivity was associated with a significant decrease in EFS (HR 2.40, 95% CI 1.46-3.93, P=0.0005), with 4-year rates of 27.3% versus 60.8% for MRD-negative patients.
Transplant-related mortality occurred in 48 patients (median time 10.5 months), with infection being the most common cause of death. Cumulative incidence of transplant-related mortality was 3.6% at 100 days and 19.6% at 4 years.
Acute GVHD grade 2-4 occurred in 12% of patients and grade 3/4 GVHD occurred in 5%. Chronic GVHD occurred in 37% of patients analyzed, while 22% had extensive chronic GVHD.
The 4-year cumulative incidence of a second cancer was 4.0%, suggesting “that continued cancer surveillance after allogeneic HSCT is warranted, especially in this older population,” Marks and colleagues wrote.
This study was funded by Cancer Research UK.
Marks disclosed support from Pfizer, Amgen, Kite, and Novartis.
Other co-authors disclosed support from Incyte, Cyclacel, Novartis, Pfizer, Astellas, Jazz, Gilead, and Daiichi-Sankyo.
Advani disclosed support from Amgen, OBI, Pfizer, Immunogen, Seattle Genetics, Macrogenics, Kite, Servier, Glycomimetics, Kura, Beam, Jazz, and Taiho.