Nonmyeloablative Allogeneic Stem Cell Transplant Strategies and the Role of Mixed Chimerism

Abstract

Experimental and clinical experiences have demonstrated successsful donor engraftment following nonmyeloablative preparative regimens. These less toxic conditioning strategies may be better tolerated with diminished transplant-related morbidity and mortality. Importantly, the intentional induction of mixed chimerism can be established following nonmyeloablative conditioning. This approach has the potential advantages of inhibiting graft-versus-host disease, presumably secondary to the persistence of host immunoregulatory cells, and providing a platform for the delivery of adoptive cellular immunotherapy with donor leukocyte infusions for patients with an underlying malignancy. This review will describe the preclinical evolution of nonmyeloablative transplant strategies, the rationale for considering these approaches, and the preliminary clinical experience with this novel allogeneic stem cell therapy.

Allogeneic hematopoietic SCT in patients with non-malignant diseases, and importance of chimerism

“…4 Not surprisingly, we experienced more patients with MC after conditioning with RIC than with myeloablative conditioning, which has been described by others. [21][22][23] More importantly, however, high MC was no different using RIC than with myeloablative conditioning. High MC was correlated with graft failure and it is therefore undesirable.…”

Comparison of donor chimerism following myeloablative and nonmyeloablative allogeneic hematopoietic SCT

“…This perception may have developed from the purposeful establishment of 'mixed chimerism' in animal models and in humans following some NMA regimens, including low-dose TBI alone 3 or the combination of CY, anti-thymocyte globulin and thymic irradiation. 9 Stable mixed chimerism protects from GVHD and can be used as a platform for additional therapy including donor lymphocyte infusion to increase donor chimerism and augment antitumor effect. [9][10][11] This study demonstrates that Flu/TBI, the well-tolerated and most commonly used nonmyeloablative regimen, is similar to BU/CY and CY/TBI in achieving rapid lymphohematopoietic engraftment in most patients.…”

“…9 Stable mixed chimerism protects from GVHD and can be used as a platform for additional therapy including donor lymphocyte infusion to increase donor chimerism and augment antitumor effect. [9][10][11] This study demonstrates that Flu/TBI, the well-tolerated and most commonly used nonmyeloablative regimen, is similar to BU/CY and CY/TBI in achieving rapid lymphohematopoietic engraftment in most patients. Speed and extent of donor chimerism has been shown to be influenced by additional factors including primary diagnosis and previous treatment.…”

How and when should we monitor chimerism after allogeneic stem cell transplantation?

“…124 To convert mixed chimerism into complete chimerism, repetitive DLIs are performed. [128][129][130][131] While patients rapidly achieved high donor chimerism, the majority remained mixed chimeras during the first 6 months. 132,133 Pediatric patients with mixed chimerism in T-cell and NK-cell fraction at day þ 28 post transplant seemed to be more likely to reject the graft.…”