Successful allogeneic stem cell transplantation with nonmyeloablative conditioning in patients with relapsed hematologic malignancy following autologous stem cell transplantation

Abstract

The use of myeloablative preparative therapy and allogeneic stem cell transplantation (alloSCT) as salvage therapy for adult patients with relapsed hematologic malignancy after autologous stem cell transplantation (autoSCT) is generally unsuccessful due to very high treatment-related mortality rates. We evaluated the outcome of HLA-matched related donor alloSCT following nonmyeloablative preparative therapy in 13 patients (median age, 38 years) with relapsed hematologic malignancies (Hodgkin's disease, n = 4; Hodgkin's disease and advanced myelodysplastic syndrome, n = 1; non-Hodgkin's lymphoma, n = 6; multiple myeloma, n = 2) after initial autoSCT. Median time from autoSCT to alloSCT was 12 months (range, 3-24 months); 6 patients had chemotherapy-refractory disease following autoSCT, 6 were in untreated relapse, and 1 had a partial response from salvage chemotherapy. Preparative therapy consisted of cyclophosphamide, 150-200 mg/kg; peritransplantation anti-thymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal irradiation); and a very short course of cyclosporine as GVHD prophylaxis. All patients achieved initial mixed chimerism as defined by greater than 1% donor peripheral white blood cells. Seven patients, who had no evidence of GVHD, received prophylactic DLI beginning 5 to 6 weeks after transplantation for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-tumor effect. Six patients showed conversion to full donor chimerism and 1 lost the graft. Grade II or greater acute GVHD occurred in 9 patients. Seven patients achieved a complete response; 6 had no response. The median survival time of the 13 patients is currently 10 months (range, 3-39 months), with an overall survival probability at 2 years of 45% (95% confidence interval [CI], 19%-73%) and a disease-free survival probability at 2 years of 37.5% (95% CI, 12%-65%). Thus, this novel nonmyeloablative alloSCT strategy followed by prophylactic DLI was well tolerated and can result in durable disease-free survival among patients with advanced hematologic malignancies after a failed autoSCT. Further follow-up and evaluation of additional patients are required to conclusively establish the role of this strategy in the treatment of hematologic malignancies after an autologous transplantation.

Progressive disease following autologous transplantation in patients with chemosensitive relapsed or primary refractory Hodgkin's disease or aggressive non-Hodgkin's lymphoma

“…In the setting of disease progression after ASCT, nonmyeloablative allogeneic transplantation appears to have lower rates of transplant-related mortality compared to conventional transplantation, with long-term diseasefree survival rates reported to be between 20 and 35%. [42][43][44] These encouraging results warrant prospective studies of this approach.…”

Second hematopoietic SCT for lymphoma patients who relapse after autotransplantation: another autograft or switch to allograft?

“…[48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] The rationale behind this strategy is to decrease the high TRM observed after myeloablative allo-SCT, though preserving the GVT effect. In addition, RIC allo-SCT allows patients with significant coexistent medical problems to undergo allo-SCT.…”

Low T-cell chimerism is not followed by graft rejection after nonmyeloablative stem cell transplantation (NMSCT) with CD34-selected PBSC

“…One out of six patients (17%) experienced grade X2 acute GVHD only after abrupt cyclosporin discontinuation and a interferon therapy for life-threatening tumor progression. T-cell chimerism was 23% (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) on day 28, 32% (10-35) on day 100, 78% (49-95) on day 180 and 99.5% (99-100) on day 365. Three out of four patients who had measurable disease before the transplant experienced a complete response.…”

“…DLI given early (around day 40) after a T-cell depleted NMSCT have been previously reported to convert mixed into complete donor chimerism. 23,24 Thus, we hypothesized that CD8-depleted pre-emptive DLI given in our patients on days 40 and 80 after the transplant were critical to avoid transplant rejection. Similarly, it has been shown that extending the duration of CyA from 35 to 100 days after the transplant favorably influenced stable donor engraftment in dogs conditioned with 100 cGy TBI and post grafting immunosuppression combining CyA and MMF.…”