When Less Is More: A Tough Way of Finding a Good Fit

by Maxim Norkin and John R. Wingard

Originally, myeloablative conditioning was considered as an essential part of hematopoietic cell transplantation (HCT) to ensure maximum anti-tumor effect. Its greater anti-tumor activity is usually offset by an increased risk of non-relapse mortality, making older patients and those with comorbid conditions poor candidates for such an effective but intense treatment. Obviously, alternatives to myeloablative conditioning are needed to allow greater proportions of patients to be considered for allogeneic HCT.

Observations of durable responses following donor lymphocyte infusions due to graft-versus-tumor (GVT) effect led to the development of reduced intensity conditioning (RIC) regimens. The rationale for RIC is to provide reliable donor stem cell engraftment with subsequent disease control via GVT. Introduction of RIC significantly expanded transplantation options to older patients, virtually eliminating age as a barrier for allogeneic transplantation and extending options to patients with comorbidities and nonmalignant conditions. Unfortunately, RIC provides less anti-tumor activity and increases the possibility for posttransplantation relapse and graft failure.

Many of these issues were addressed in the satellite symposium held in February 2011 at the Tandem BMT meeting in Honolulu, HI. Dr. Shaw focused on RIC regimens in pediatric transplant recipients, who differ from adults given a significantly higher prevalence of primary nonmalignant diseases, fewer comorbid conditions, and the desirability of fertility preservation. Prolonged posttransplantation survival is anticipated, so long-term adverse effects caused by the conditioning regimen should be strongly considered in the selection of the preparative regimen, particularly if total body irradiation (TBI) is considered. Dr. Forman reviewed radiation-based transplantation regimens for hematologic malignances and described options for decreasing their toxicities. TBI has high anti-tumor potency, but its benefit is frequently offset by increased toxicity. Novel approaches using non-myeloblative doses of TBI, radioimmunotherapy, or total marrow radiation instead of TBI have the potential of reducing side effects without a significant compromise of posttransplantation outcomes. Dr. Andersson described alternatives to radiation-based conditioning with a focus on the toxicity and efficacy of commonly used chemotherapy agents.

Despite its excellent anti-tumor activity, myeloablative conditioning does not necessarily translate into better posttransplantation outcomes than less intense conditioning because of its higher risk of complications. No prospective studies have ever compared myeloablative and RIC, and such studies will be difficult but important. Retrospective studies addressing this issue are subject to significant selection bias because RIC is typically offered to older and less fit patients, and questions remain about the utility of RIC in patients at high risk for relapse or in patients who are not in remission. In addition, the efficacy of RIC for malignancies that may be less susceptible to GVT effect requires further confirmation. Therefore, appropriate selection of the intensity of preparative regimen is not trivial and, for now, should be individualized based on patient and disease characteristics. Further study is needed to determine the optimal RIC regimen(s) and when RIC should be chosen over ablative regimens.

In this issue:

Introduction

When Less Is More: A Tough Way of Finding a Good Fit
Maxim Norkin, John R. Wingard

Membership Application

Symposium Report:

Impact of Conditioning Regimens on Transplantation Outcomes

CME Assessment Test

CME Answer Sheet

CME Evaluation Form

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