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Donor chimerism early after reduced-intensity conditioning hematopoietic stem cell transplantation predicts relapse and survival.

ABSTRACT: The impact of early donor cell chimerism on outcomes of T cell-replete reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) is ill defined. We evaluated day 30 (D30) and 100 (D100) total donor cell chimerism after RIC HSCT undertaken between 2002 and 2010 at our institution, excluding patients who died or relapsed before D30. When available, donor T cell chimerism was also assessed. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), relapse, and nonrelapse mortality (NRM). We evaluated 688 patients with hematologic malignancies (48% myeloid and 52% lymphoid) and a median age of 57 years (range, 18 to 74) undergoing RIC HSCT with T cell-replete donor grafts (97% peripheral blood; 92% HLA-matched), with a median follow-up of 58.2 months (range, 12.6 to 120.7). In multivariable analysis, total donor cell and T cell chimerism at D30 and D100 each predicted RIC HSCT outcomes, with D100 total donor cell chimerism most predictive. D100 total donor cell chimerism <90% was associated with increased relapse (hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.83 to 3.51; P < .0001), impaired PFS (HR, 2.01; 95% CI, 1.53 to 2.65; P < .0001), and worse OS (HR, 1.50; 95% CI, 1.11 to 2.04, P = .009), but not with NRM (HR, .76; 95% CI, .44 to 2.27; P = .33). There was no additional utility of incorporating sustained D30 to D100 total donor cell chimerism or T cell chimerism. Low donor chimerism early after RIC HSCT is an independent risk factor for relapse and impaired survival. Donor chimerism assessment early after RIC HSCT can prognosticate for long-term outcomes and help identify high-risk patient cohorts who may benefit from additional therapeutic interventions.

SUBMITTER: Koreth J

PROVIDER: S-EPMC4477288 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Donor chimerism early after reduced-intensity conditioning hematopoietic stem cell transplantation predicts relapse and survival.

Koreth John J Kim Haesook T HT Nikiforow Sarah S Milford Edgar L EL Armand Philippe P Cutler Corey C Glotzbecker Brett B Ho Vincent T VT Antin Joseph H JH Soiffer Robert J RJ Ritz Jerome J Alyea Edwin P EP

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20140604 10

The impact of early donor cell chimerism on outcomes of T cell-replete reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) is ill defined. We evaluated day 30 (D30) and 100 (D100) total donor cell chimerism after RIC HSCT undertaken between 2002 and 2010 at our institution, excluding patients who died or relapsed before D30. When available, donor T cell chimerism was also assessed. The primary outcome was overall survival (OS). Secondary outcomes included progress ...[more]

PMID: 24907627

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Project description:Different types of graft-versus-host disease prophylaxis have been proposed in the setting of reduced intensity and non-myeloablative allogeneic stem cell transplantation. An alternative combination with sirolimus and tacrolimus has recently been tested although comparative studies against the classical combination of a calcineurin inhibitor and mycophenolate mofetil or methotrexate are lacking. We describe the results of a prospective, multicenter trial using sirolimus + tacrolimus as immunoprophylaxis, and compare this approach with our previous experience using cyclosporine + mycophenolate in the setting of unrelated donor transplantation setting after reduced-intensity conditioning. Forty-five patients received cyclosporine + mycophenolate between 2002 and mid-2007, while the subsequent 50 patients, who were transplanted from late 2007, were given sirolimus + tacrolimus. No significant differences were observed in terms of hematopoietic recovery or acute graft-versus-host disease overall, although gastrointestinal acute graft-versus-host disease grade ? 2 was more common in the cyclosporine + mycophenolate group (55% versus 21%, respectively, P=0.003). The 1-year cumulative incidence of chronic graft-versus-host disease was 50% versus 90% for the patients treated with the sirolimus- versus cyclosporine-based regimen, respectively (P<0.001), while the incidence of extensive chronic disease was 27% versus 49%, respectively (P=0.043). The 2-year non-relapse mortality rate was 18% versus 38% for patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively (P=0.02). The event-free survival and overall survival at 2 years were 53% versus 29% (P=0.028) and 70% versus 45% (P=0.018) among patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively. In conclusion, in the setting of reduced intensity transplantation from an unrelated donor, promising results can be achieved with the combination of sirolimus + tacrolimus, due to a lower risk of chronic graft-versus-host disease and non-relapse mortality, which translates into better event-free and overall survival rates, in comparison with those achieved with cyclosporine + mycophenolate.

Project description:Allogeneic hematopoietic stem cell transplantation for patients with a hemoglobinopathy can be curative but is limited by donor availability. Although positive results are frequently observed in those with an HLA-matched sibling donor, use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity, and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced-intensity conditioning and mesenchymal stromal cells (MSCs). Six patients were enrolled, including 4 with high-risk sickle cell disease (SCD) and 2 with transfusion-dependent thalassemia major. Conditioning consisted of fludarabine (150 mg/m(2)), melphalan (140 mg/m(2)), and alemtuzumab (60 mg for patients weighing > 30 kg and .9 mg/kg for patients weighing <30 kg). Two patients received HLA 7/8 allele matched bone marrow and 4 received 4-5/6 HLA matched umbilical cord blood as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in 1 patient and from an unrelated third-party donor in the remaining 5 patients. GVHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil. One patient had neutropenic graft failure, 2 had autologous hematopoietic recovery, and 3 had hematopoietic recovery with complete chimerism. The 2 SCD patients with autologous hematopoietic recovery are alive. The remaining 4 died either from opportunistic infection, GVHD, or intracranial hemorrhage. Although no infusion-related toxicity was seen, the cotransplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. Although poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSCs had any positive impact on engraftment. Because of the lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated. Further investigations into understanding the mechanisms of graft resistance and development of strategies to overcome this barrier are needed to move this field forward.

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Donor chimerism early after reduced-intensity conditioning hematopoietic stem cell transplantation predicts relapse and survival.

Publications

Donor chimerism early after reduced-intensity conditioning hematopoietic stem cell transplantation predicts relapse and survival.

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