Two-Year OS Doubles for Patients With Philadelphia-Positive Relapsed ALL After HSCT

While acute lymphoblastic leukemia (ALL) was still the primary cause of death, researchers saw a steady increase in 2-year survival from 27.8% to 54.8% even as patient age at the time of relapse after allogeneic hematopoietic stem cell transplantation (HCST) increased.

Thanks to new treatment options and other strategies, the 2-year overall survival (OS) rate has doubled for patients with acute lymphoblastic leukemia (ALL) carrying the Philadelphia chromosome whose disease relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT), according to a new study published Wednesday.

The findings, which the authors said are the largest study to date on real-world trends over time for this population, were published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

ALL by itself is an aggressive blood cancer, but patients with the Philadelphia chromosome have a worse prognosis and relapse after allo-HSCT about 30% of the time.

With new knowledge about how to manage these patients and reduce the risk of relapse—such as through the use of tyrosine kinase inhibitor (TKI)-based maintenance therapy, regular monitoring for minimal residual disease, or a second allo-HSCT—researchers wanted to evaluate real-world data for this patient group over time.

The study was conducted by investigators from Acute Leukemia Working Party of the European Society of Blood and Marrow Transplantation (EBMT); the EBMT is a voluntary working group of more than 600 transplant centers that are required to report all consecutive HSCTs and follow-ups once a year.

The retrospective, registry-based, multicenter study included 899 patients 18 years and older with a first allo-HSCT for Philadelphia-positive B-cell ALL in their first complete remission and documented hematologic relapse after allo-HSCT between 2000 and 2019. Investigators divided the years into 4 time periods: 2000 to 2004, 2005 to 2009, 2010 to 2014, and 2015 to 2019.

The median ages at transplant and at relapse were 44 and 45.4 years, respectively, and there was a progressive increase in patient age at transplant (from 40.6 to 46.1 years; P = .007).

Over the 4 time periods, 116 patients relapsed between 2000 and 2004, 225 between 2005 and 2009, 294 between 2010 and 2014, and 264 between 2015 and 2019. There was also a statistically significant progressive increase in the use of matched unrelated donors, peripheral blood stem cells, reduced intensity conditioning (RIC), and in vivo T-cell depletion and a progressive decrease in total body irradiation (TBI).

For the entire group, the 2-year OS after relapse was 41.5% (95% CI, 38.0%-44.9%), but in univariate analysis, the 2-year OS after relapse jumped from 27.8% between 2000 and 2004 to 54.8% for 2015 to 2019 (P = .0001).

Overall, original disease was the cause of death in 68.5% of patients, followed by infections (14.3%) and graft-versus-host-disease. However, over time, original disease as the cause of death decreased, falling from 72.2% to 50% by 2019, while infections as the cause of death rose from 8.2% to 30.6%.

A second allo-HSCT within 2 years after relapse was performed in 13.9% of patients, resulting in a 2-year OS of 35.9%. In multivariate analysis, OS from relapse was positively affected by a longer time from transplant to relapse (P = .0006) and the year of relapse (HR, 0.71; P < .0033, for patients relapsing from 2005 to 2009; and HR, 0.37; P <.0001, for those relapsing from 2015 to 2019).

Explaining the improvements, the authors noted that RIC was used more often in recent years and TBI was used less frequently; with less-intense pretreatment, patients were likely able to withstand heavier treatments when they relapsed. In addition, these patients may have been more sensitive to later graft-versus-leukemia treatments at relapse, as they had received more T-cell–depleted grafts.

In addition, these improvements in OS came despite a significant increase in patient age at the time of relapse (from 44 to 56 years).

"This effect is likely due to the greater efficacy of the novel targeted therapies,” Ali Bazarbachi, MD, PhD, professor of medicine, associate dean for basic research, and director of the Bone Marrow Transplantation Program at the American University of Beirut, said in a statement. Besides newer TKIs, other strategies for therapy at relapse include monoclonal antibodies and chimeric antigen receptor T-cell therapy

"These large-scale real-world data can serve as a benchmark for future studies in this setting.”

The study had some limitations. There was a lack of detailed information on minimal residual disease status and on the treatment of posttransplant relapse and its impact on survival improvement. There was also a lack of information on maintenance therapy, once a second remission was achieved.

Reference

Bazarbachi A, Labopin M, Aljurf M, et al. 20-year steady increase in survival of adult patients with relapsed Philadelphia-positive acute lymphoblastic leukemia post allogeneic hematopoietic cell transplantation. Clin Cancer Res. Published online January 12, 2021. doi:10.1158/1078-0432.CCR-21-2675