Nonmyeloablative Transplantation

Transplantation with nonmyeloablative or reduced-intensity conditioning regimens eliminates much of the morbidity and mortality associated with high-dose transplantation.37 38 As such, this approach has been used widely in older individuals, in individuals with comorbid illnesses, and in those who have undergone prior high-dose therapy approaches. Without highdose chemoradiotherapy, this approach to transplantation relies exclusively on the development of a potent graft-versus-leukemia (GVL) reaction. While GVL reactions are prominent in some hematologic malignancies, they may be less pronounced in aggressive lymphoid malignancies, such as ALL. However, after ablative transplantation, the presence of GVHD has been shown to be protective against relapse, invoking the power of a potent GVL response.26'39-41

No single study has prospectively accrued sufficient subjects to make reliable conclusions on the role of nonmyeloablative transplant for ALL; however, investigators from four large trials42-46 have pooled their results and reported outcomes on 27 patients.47 The median age of the patients was 50 years, and most had advanced disease (only four were in first remission while 12 were chemorefractory or in relapse at the time of transplant) or adverse cytogenetic features (Philadelphia chromosome in 11). In this study, multiple conditioning regimens, GVHD prophylaxis regimens, stem cell donor types, and stem cell sources were used. Despite this, donor-derived hematopoiesis occurred in all patients, with a 63% incidence of Grade II-IV acute GVHD and a 72% rate of chronic GVHD among evaluable patients. Treatment-related mortality was 23%. Eight of 27 patients are alive without disease at a median of

816 days from transplantation (range 381-1375 days), which is considered a promising result, given the otherwise poor prognosis of these patients without transplantation. In this study, a correlation between the incidence of acute GVHD and protection from relapse was noted (hazard rate for relapse prevention 3.3, p = 0.05), invoking an active GVL reaction.

A more uniform cohort of 22 high-risk ALL patients enrolled in a multicenter German trial has been reported.48 The majority of these patients received a fludarabine-busulfan conditioning regimen followed by an infusion of peripheral blood stem cells (PBSC) from matched related (13), unrelated (8), and mismatched related (1) donors. Despite similar rates of acute GVHD as reported in the pooled analysis, the overall survival in this cohort was 18% at a median follow-up of 16.5 months for survivors (range 5-30 months). In summary, at the present time, there remains insufficient data to routinely recommend nonmyeloablative transplant outside of a clinical trial.

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