High-dose therapy and autologous hematopoietic cell transplantation as front-line consolidation in chronic lymphocytic leukemia: a systematic review

Abstract

High-dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT) is offered to patients with chronic lymphocytic leukemia (CLL) both as front-line consolidation and in the relapsed setting. The role of HDT in the front-line consolidation setting in CLL is uncertain. Literature search of PUBMED and Cochrane until 14 November 2014 and the last 2 years of abstracts from relevant conferences was undertaken. End points included benefits (overall survival; OS, PFS, event-free survival; EFS) and harms (adverse events, secondary malignancies, treatment-related mortality). The search identified 495 references of which four studies met inclusion criteria. Altogether, 301 patients were randomized to the HDT/auto-HCT arm and 299 patients to the control arm. Offering front-line HDT/auto-HCT did not result in statistically significant improvement in OS (Hazard ratio (HR) = 0.91; 95% confidence interval (CI) = 0.62, 1.33) or PFS (HR = 0.70; 95% CI = 0.32, 1.52). There was a statistically significant advantage favoring HDT/auto-HCT for EFS (HR = 0.46; 95% CI = 0.26, 0.83). Moreover, HDT/auto-HCT did not result in higher rate of secondary malignancy (risk ratio = 1.06; 95% CI = 0.55, 2.05) or treatment-related mortality (risk ratio = 1.32; 95% CI = 0.43, 4.06). Offering HDT/ auto-HCT as front-line consolidation in patients with CLL does not improve OS. At present this approach should not be offered outside the context of a clinical trial.

Clinical Practice Recommendations for Use of Allogeneic Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation

“…Emergence of ibrutinib, a BCR inhibitor, and other targeted therapies that have proved to be effective treatment options for CLL even in high-risk disease has undoubtedly challenged the appropriateness of the 2007 EBMT consensus recommendations [19,20]. Several randomized controlled trials (RCT) and a meta-analysis have shown that high-dose chemotherapy and autologous HCT do not offer an overall survival (OS) advantage compared with conventional chemotherapy or chemoimmunotherapy; accordingly, relapsed CLL after an autologous HCT is not considered, today, as a prerequisite for an allo-HCT [21-25]. Moreover, autologous HCT has been abandoned from current treatment algorithms for CLL [21-25].…”

“…Several randomized controlled trials (RCT) and a meta-analysis have shown that high-dose chemotherapy and autologous HCT do not offer an overall survival (OS) advantage compared with conventional chemotherapy or chemoimmunotherapy; accordingly, relapsed CLL after an autologous HCT is not considered, today, as a prerequisite for an allo-HCT [21-25]. Moreover, autologous HCT has been abandoned from current treatment algorithms for CLL [21-25]. Recognizing the pressing need to incorporate the new realities of treating CLL in this modern treatment era [19], the American Society for Blood and Marrow Transplantation convened a group of experts to develop clinical practice recommendations related to the role of allo-HCT for CLL.…”

Hematopoietic Cell Transplantation for Richter Syndrome

“…In CLL, allo-HCT induces durable remissions and an OS rate exceeding 50% at 3 years (with a plateau in survival curves), whereas auto-HCT has failed to demonstrate a survival advantage when compared with chemotherapy or chemoimmunotherapy as a consolidative strategy [29][30][31][32][33]. In our opinion, this represents an advantage for allo-HCT over auto-HCT in RS, especially when considering that 35% of cases who receive an auto-HCT for RS relapsed with CLL [35].…”

“…One particular challenge is the presence of residual CLL disease in RS cases. Several randomized controlled trials and a meta-analysis comparing HDT/ auto-HCT versus conventional chemotherapy (or chemoimmunotherapy) in patients with CLL failed to show an OS benefit for HDT/auto-HCT in CLL [29][30][31][32][33]. On the other hand, offering an allo-HCT to patients with RS (with residual CLL) might prove to be a more beneficial strategy aimed at eradicating both diseases, but certainly at the expense of higher nonrelapse mortality (NRM).…”