Retrospective Cohort Analysis of Response and Survival of Children, Adolescents, and Young Adults (CAYA) with Relapsed and/or Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia (T-ALL) and Lymphoma (T-LL) Treated with Curative Intent: A TACL Consortium Study

Introduction: Less than a third of CAYA with R/R T-ALL and T-LL survive, and little progress has been achieved over the past two decades. Chemotherapy resistance and treatment related morbidity and mortality (TRM) are the main obstacles to achieve complete remission (CR) and proceed to hematopoietic stem cell transplant (HSCT). However, due to limited number of patients and few prospective clinical trials for patients with R/R T-ALL/LL, the impact of each factor on outcome is unclear. We conducted a retrospective study of CAYA patients with first and subsequent R/R T-ALL/LL treated with curative intent to estimate the 1) rates of CR following each cycle of therapy, 2) frequency of TRM, 3) proportion of patients proceeding to HSCT, 4) event free survival (EFS) and 5) overall survival (OS).

Methods: The TACL 2018-001 study enrolled R/R T-ALL/LL patients aged <21 years at the time of initial diagnosis who received treatment with curative intent between 2000 and 2018 at one of 22 participating institutions. Patients were identified through institutional patient databases; 112 patients are included in this analysis. Patient demographics, clinical characteristics, treatment details, response and survival data were abstracted from the medical record. The CR rate was determined sequentially by patients who reached CR after reinduction cycle(s). For T-ALL, CR was defined as a single bone marrow sample with <5% blasts by morphology and no evidence of extramedullary disease. For T-LL, CR was defined as resolution of disease from all sites. Differences in cause of mortality between T-ALL and T-LL were evaluated using Fisher’s exact test. The log-rank test was used to assess differences in EFS and OS.

Results: A total 342 cycles of therapy from 112 eligible patients, 93 with T-ALL (83%) and 19 with T-LL (17%), were included in this analysis. Median age for the entire cohort was 11.6 years (range 1.7-22.5 years) and 68% were males. Only 8 of 112 patients (7%) had primary refractory disease, all with T-ALL; 99 patients (88%) were in 1^st relapse at study entry. Of 93 patients with T-ALL, 81 were in 1^st relapse and 4 in 2^nd relapse while 18 of 19 patients with T-LL were in 1^st relapse and 1 in 3^rd relapse. Among the T-ALL patients at study entry, 40% and 31% had experienced isolated bone marrow or isolated central nervous system (CNS) relapse respectively; overall CNS involvement occurred in 52% of patients with T-ALL. In patients with T-ALL, CR rates diminished following each cycle attempt at 45% (49/109 first reinduction cycles), 30% (14/46 second reinduction cycles with no CR after the first cycle), and 17% (4/23 third reinduction cycles with no CR after the first 2 cycles). In patients with T-LL, the rates of CR were lower at 19% (4/21 first cycles), 14% (2/14 second cycles), and 25% (2/8 third cycles). When accounting only for 1^st relapse and refractory disease, 62/89 patients (70%) with T-ALL and 9/18 patients (50%) with T-LL achieved CR with a median of 1 and 2 cycles respectively. The proportion of patients proceeding to HSCT was similar between those with T-ALL and T-LL (52% and 47%) with a median time from study entry to HSCT of 3.3 and 4 months, respectively. Among those who proceeded to HSCT, 63% (30/48, median follow-up of 4.7 years) of patients with T-ALL and 44% (4/9, median follow-up of 6.3 years) of patients with T-LL were alive at last follow up. Overall, the EFS and OS were not statistically different between the two groups (p=0.13 and 0.07, respectively) with 3-year EFS of T-ALL vs T-LL of 39% (95% CI: 29%-49%) vs. 21% (7%-41%) and 3-year OS of 41% (31%-51%) vs. 21% (7%-41%). Among the patients who died, 74% (52/70) died from disease and 20% (14/70) died from treatment related causes. Death from TRM appeared more common in patients with T-ALL than T-LL (24% vs. 7%) but did not reach statistical significance (p=0.45).

Conclusion: This retrospective cohort study is the first to provide comprehensive post-relapse data on a large cohort of CAYA patients with R/R T-ALL and T-LL. While confirming the poor EFS and OS, we show that the response to the first reinduction cycle is unsatisfactory and declines with further attempts, only allowing approximately half of patients to proceed to HSCT. Failure to achieve CR and TRM remain significant challenges further supporting the need for novel therapies and improved supportive care measures to improve survival outcomes. This study provides a benchmark for future clinical trials for CAYA patients with R/R T-ALL/LL.