Meta-Analysis Evaluating Efficacy of High-Dose Therapy and Autologous Hematopoietic Cell Transplantation As Front-Line Consolidation in Chronic Lymphocytic Leukemia: Results Do Not Justify This Treatment Approach

Background: High-dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT) has been offered to patients with chronic lymphocytic leukemia (CLL), both as front-line consolidation and in the relapsed setting. Uncertainty remains in regards to the role of HDT in the front-line consolidation setting in CLL. Accordingly, we performed a systematic review and meta-analysis aiming at evaluating the totality of evidence pertaining to the efficacy (or lack thereof) of HDT and auto-HCT as front-line consolidation in subjects with CLL.

Materials and methods: A total of 475 references were identified through a systematic search of PUBMED/MEDLINE and Cochrane through June 26, 2014. Only four randomized controlled trials which included a total of 600 subjects were eligible for inclusion in this meta-analysis. Data was meta-analyzed for benefits: progression-free survival (PFS) (data from 2 studies (total n=178)), event-free survival (EFS) (data from 2 studies (total n=422)), PFS or EFS (data from 4 studies (total n=600)), and overall survival (OS) (data from 4 studies (total n=600)); and harms: treatment related mortality (TRM) (data from 2 studies (total n=276)), development of any secondary malignancy ((data from 4 studies (total n=581)), or development of secondary MDS/AML in particular (data from 4 studies (total n=581)).

Results: These results are reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Four studies enrolled a total of 301 subjects in the HDT/auto-HCT arm and 299 subjects in the control arm. Offering front-line HDT/auto-HCT did not improve PFS [Hazard ratio (HR)=0.70 (95%CI= 0.32, 1.52), p=0.37] or OS [HR=0.91 (95%CI= 0.62, 1.33), p=0.64]. An advantage favoring HDT/auto-HCT was observed in terms of EFS (HR=0.46 (95%CI= 0.26, 0.83), p=0.01] or when analysis included PFS or EFS [HR=0.54 (95%CI= 0.35, 0.82), p=0.004]. Moreover, HDT/auto-HCT did not result in higher TRM (Risk ratio (RR)=1.32 (95%CI= 0.43, 4.06), p=0.63]. When analyzing development of any secondary malignancy, no difference was observed whether subjects were offered HDT/auto-HCT or not [RR=1.06 (95%CI=0.55, 2.05), p=0.86]. A two-fold higher incidence of secondary MDS/AML, albeit not statistically significant, was observed with the HDT/auto-HCT approach [RR=1.95 (95%CI=0.60, 6.34), p=0.27].

Conclusion: Offering HDT/auto-HCT as front-line consolidation in patients with CLL does not improve OS. At the present time, this approach should be offered only in the context of a clinical trial.