Allogeneic Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia In First Complete Remission: A Systematic Review and Meta-Analysis
Authors: Pidala Joseph , Djulbegovic Benjamin , Anasetti Claudio , Kharfan-Dabaja Mohamed A. , Kumar Ambuj 
Published: October 2019

Abstract
Abstract 3511

Background:
While multi-agent induction chemotherapy produces impressive complete remission rates, long term survival remains elusive for most patients with adult acute lymphoblastic leukemia (ALL). Consolidation chemotherapy, autologous hematopoietic cell transplantation (HCT), and allogeneic HCT represent potential treatment alternatives for post-remission therapy, but there is genuine uncertainty regarding the optimal approach.

Objectives:
To synthesize evidence from all existing randomized controlled trials with a donor vs. no donor comparison in adults with ALL in first complete remission. Our objectives were to determine whether or not there is a survival advantage with allogeneic HCT for ALL in CR1, and also to discern the benefit of this therapy according to disease risk subgroups. Search methods: A broad search of the Medline and Embase electronic databases was performed along with hand search of literature cited in relevant primary articles, search of abstracts from American Society of Hematology and American Society of Clinical Oncology meetings, as well as consultation with content experts in the field. Selection criteria: Include trials were those consisting of adults with ALL in CR1, and prospective randomized controlled trial (RCT) design with ‘genetic randomization' (i.e. based on availability of matched sibling donor vs. not). Data collection and analysis: Data from relevant trials was abstracted and reviewed by two investigators independently. We extracted data on benefits (OS, PFS) and harms (treatment related mortality, relapse) of compared treatments. Time-to-event data (OS, PFS) were reported as hazard ratios (HR) and dichotomous data (relapse and NRM) were reported as risk ratios (RR). The summary results from each study were pooled under a random effects model. Heterogeneity was assessed both by visual inspection of the forest plots for each outcome, as well as by formal statistical testing for heterogeneity using the chi square and I2 test. Subgroup analyses were performed for disease risk categories. Sensitivity analyses were performed according to domains of methodological quality.

Results:
A total of 14 relevant trials were identified, consisting of a total of 3215 patients. There was a statistically significant overall survival advantage in favor of the donor vs. no donor group HR of 0.79 (95% CI 0.7 – 0.90; p = 0.0003). The following was observed according to disease risk: standard risk ALL (HR of 0.62 (95% CI 0.46 – 0.84), p = 0.002); high risk ALL (HR of 0.8 (95% CI 0.63 – 1.01), p = 0.06). There was also a statistically significant improvement in disease-free survival in the donor vs. no donor group HR of 0.78 (95% CI 0.66 – 0.92), p = 0.003. Those in the donor group realized a statistically significant reduction in primary disease relapse, RR 0.54 (95% CI 0.4 – 0.73), p < 0.0001, but at the cost of statistically significant increase in non-relapse mortality, RR 2.8 (95% CI 1.66 – 4.73; p = 0.001). There were no significant subgroup differences or heterogeneity demonstrated in sensitivity analyses according to methodological quality domains.

Conclusion:
The results of this systematic review and meta-analysis support matched sibling donor allogeneic hematopoietic cell transplantation as the optimal post-remission therapy in adults age greater than or equal to 15. This therapy offers superior overall survival, disease-free survival, significantly reduces the risk of disease relapse, but does impose an increased risk of non-relapse mortality. These data importantly are based on adult ALL treated with largely total body irradiation-based myeloablative conditioning, and, therefore, can not be generalized to pediatric ALL, alternative donors including HLA mismatched or unrelated donors, or reduced toxicity or non-myeloablative conditioning regimens.
Forrest plot of overall survival according to donor vs. no-donor status.

Disclosures:
No relevant conflicts of interest to declare.