To What Extent Have Post-Transplant Outcomes Improved Following the Introduction of Tyrosine Kinase Inhibitors in Elderly Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia? a Retrospective Nationwide Survey in Japan

The advent of BCR-ABL tyrosine kinase inhibitors (TKIs) has markedly improved remission rates, transplantation rates and post-transplant survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL). The use of reduced intensity conditioning regimens for allogeneic haematopoietic stem cell transplantation (HSCT) and advances in supportive care have expanded the indications for transplantation. While HSCT offers the potential for cure in elderly patients, it carries a high risk of complications and non-relapse mortality. Hence, clinical studies in Ph+ALL often set the upper age limit for HSCT at 60 or 65 years. On the other hand, the development of new combination therapies, including next-generation TKIs and novel antibodies, has been reported to have the potential to prolong survival without HSCT in older patients. However, there are few reports on transplantation outcomes by age group in elderly patients. This study aims to clarify transplantation outcomes by age group in patients with Ph+ALL using actual data from Japan. We utilized transplant characteristics and post-transplant outcomes for patients with Ph+ALL using a large dataset from the Transplant Registry Unified Management Program. The study included 1,951 patients who underwent HSCT between 1989 and 2018, with 1,612 treated with TKIs before HSCT (TKI cohort) and 339 not treated with TKIs before HSCT (non-TKI cohort). The 5-year overall survival (OS) in the TKI cohort was 65% (95% CI, 62-68%), significantly higher than the 45% (95% CI, 40-51%) in the non-TKI cohort (P < 0.001). The 5-year relapse rate (RR) in the TKI cohort was 23% (95% CI, 21-25%), significantly lower than the 37% (95% CI, 32-44%) in the non-TKI cohort (P < 0.001). The 5-year non-relapse mortality (NRM) rate was significantly lower in the TKI cohort at 23% (95% CI, 21-25%) compared to 27% (95% CI, 22-33%) in the non-TKI cohort (P = 0.0271). In the TKI cohort, the 5-year OS and NRM were significantly inferior in patients above 50 years compared to those under 50 years, with OS at 56% (95% CI, 51-60%) vs. 71% (95% CI, 67-74%) (P < 0.001) and NRM at 32% (95% CI, 28-37%) vs. 17% (95% CI, 15-20%) (P < 0.001), respectively. A multivariate analysis for patients in the TKI cohort identified age at HSCT (over 50 years) (HR, 1.94; 95% CI, 1.50-2.50), donor type (unrelated donor) (HR, 1.43; 95% CI, 1.11-1.85), and year of HSCT (after 2010) (HR, 0.66; 95% CI, 0.52-0.83) as prognostic factors for NRM. In the non-TKI cohort, the 5-year OS for patients aged 50-59 years was 42% (95% CI, 30-53%), declining to 24% (95% CI, 6-48%) for those aged 60-64 years (P = 0.0152). In contrast, in the TKI cohort, there were no significant differences between age groups (50-59, 60-64, and 65+ years), with survival rates of 56% (95% CI, 50-61%), 55% (95% CI, 46-63%), and 59% (95% CI, 42-71%), respectively. For the 5-year NRM in the non-TKI cohort, it increased from 35% (95% CI, 24-49%) in the 50-59 age group to 53% (95% CI, 28-82%) in the 60-64 age group (P = 0.042). However, in the TKI cohort, the 5-year NRM was not significantly different among those aged 50-59 years, 60-64 years, and 65 years and older, with rates of 31% (95% CI, 26-37%), 34% (95% CI, 26-44%), and 34% (95% CI, 22-49%), respectively. In the post-2010 cohort, the 5-year OS rate for patients aged 50 years or older was 61% (95% CI, 55-66%), significantly better than in the pre-2010 cohort (45%; 95% CI, 37-53%; P < 0.001). The 5-year NRM rate was significantly improved in cases transplanted after 2010 compared to pre-2010, with rates of 28% (95% CI, 24-34%) versus 43% (95% CI, 35-52%) (P = 0.0017). In conclusion, post-transplant NRM and OS have improved significantly in elderly patients (>50 years) with Ph+ALL compared to the pre-TKI era. In the post-TKI era, OS and NRM were no longer significantly different between age groups (50-59, 60-64, and 65+ years). Furthermore, HSCT outcomes in elderly patients have improved significantly since 2010 compared to pre-2010, mainly due to a decrease in NRM. With the advent of TKIs and advancements in transplantation procedures, the clinical outcome of HSCT in elderly patients has markedly improved in recent years. These real-world clinical data provide new insights for future research on HSCT eligibility and the development of personalized treatment for elderly patients with Ph+ALL.