Outcomes for allogeneic hematopoietic cell transplantation (alloHCT) for acute lymphoblastic leukemia (ALL) have improved in the past 30 years, according to study findings published in Blood Advances.
The retrospective study of a registry database verified the efficacy of evolving treatments by examining trends in alloHCT outcomes. The Japanese Transplant Registry Unified Management Program included 8,467 adult patients with ALL who underwent their first alloHCT between 1990 and 2019. The investigators divided this period into three 10-year intervals for the analysis. Karyotype data were available for 70.7% of patients in decade one, 92.6% of patients in decade two, and 96.5% of patients in decade three.
The researchers found that non-relapse mortality (NRM) improved in each disease stage: first complete remission (CR1), subsequent CR, and non-CR. However, the relapse rate across the decades only improved in CR1 (CR1 = 26.3% to 15.9%, subsequent CR = 33.4% to 32.8%, and non-CR = 53.6% to 54.8%). Patients with known high-risk abnormalities such as t(4; 11), t(8; 14), t(14; 18), or haplodiploidy showed no continuous improvement over the 30 years, whereas outcomes for patients with other chromosomal abnormalities improved every year.
The study revealed continual improvements in adjusted survival and relapse rate for Philadelphia-chromosome-positive (Ph+) patients. The most significant improvements in relapse rate were observed among Ph+ patients transplanted in CR1, with a five-year adjusted relapse rate of 39.9% during decade one, 21.4% during decade two, and 14.6% during decade three. According to the authors, these gains were made possible with the use of tyrosine kinase inhibitors (TKIs) that target BCR-ABL and are most effective in patients with Ph+ disease during CR1.
“As expected, the alloHCT outcomes improved steadily over the past 30 years, but I was surprised that improvement tendency between NRM and relapse was different,” said corresponding author Satoshi Nishiwaki, MD, PhD, of Nagoya University Hospital in Japan. He added that “despite changes such as the expansion of alloHCT indications for elderly patients due to the development of reduced-intensity conditioning, introduction of pediatric-inspired intensive chemotherapy to adult ALL, and the increase in the number of alloHCT to intractable cases due to the expansion of donor sources (i.e., cord blood and HLA-haploidentical donors), NRM was steadily improved over the past 30 years. Improvements happened even though these changes can lead to an increase in NRM.”
This continuous decline in NRM appears to have played a major role in improving alloHCT outcomes.
The authors listed several study limitations, including that the indication for alloHCT has changed over time for patients with non-Ph+ disease, making it probable that some cases with good prognoses were included in earlier decades and would no longer be indicated for alloHCT in CR1. Another limitation is the retrospective nature of this study, which was performed using a database. Additionally, a certain number of karyotype data were missing, and the options for numerical chromosomal abnormalities in the database were only hypodiploid and hyperdiploid. Lastly, the development of therapeutics such as bispecific antibodies and cellular therapies may affect the application of these results to today’s patients.
Yet, according to Dr. Nishiwaki, these study results confirm the maturity of the alloHCT method and its role as a curative treatment for ALL in adults. This is especially the case since inotuzumab, ozogamicin, and blinatumomab were approved in 2018, and tisaglenlecleucel was approved in 2019 in Japan for the treatment of relapsed/refractory ALL. As these drugs are effective as a bridge to alloHCT, transplantation outcomes for ALL should improve when they are used beforehand.
Dr. Nishiwaki emphasized, however, that the improvement in relapse rate was largely for patients with Ph+ ALL and who were transplanted in CR1. The difference likely stems from the fact that non-Ph+ patients lack specific molecular targeting drugs, he said, calling for more research to develop targeted agents to improve outcomes in patients with high-risk ALL.
Any conflicts of interest declared by the authors can be found in the original article.
Nishiwaki S, Akahoshi Y, Morita-Fujita M, et al. Improvements in allogeneic hematopoietic cell transplantation outcomes for adults with ALL over the past 3 decades [published online 2022 June 23]. Blood Adv. doi: 10.1182/bloodadvances.2022008032.