Outcome after failure of allogeneic hematopoietic stem cell transplantation in children with acute leukemia: a study by the société Francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in the case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent 10-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted of chemotherapy alone (n=108), chemotherapy followed by second SCT (n=70), supportive/palliative care (n=67), combination of chemotherapy and donor lymphocyte infusion (DLI; n=30), or isolated reinfusion of donor lymphocytes (DLI; n=13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy=385 days, second allograft=391 days, chemotherapy=174 days, DLI alone=140 days, palliative care=43 days. A second SCT or a combination of chemotherapy and DLI yielded similar outcome (hazard ratio (HR)=0.85, P=0.53) unlike chemotherapy alone (HR=1.43 P=0.04), palliative care (HR=4.24, P<0.0001) or isolated DLI (HR=1,94, P<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML.

Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI.

Graft failure remains a severe complication of hematopoietic stem cell transplantation (HSCT). Several risk factors have already been published. In this study, we re-evaluated them in a large cohort who had the benefit of the recent experience in HSCT (2006-2012). Data from 4684 unrelated donor HSCT from 2006 to 2012 were retrospectively collected from centers belonging to the French Society for Stem Cell Transplantation. Among the 2716 patients for whom HLA typing was available, 103 did not engraft leading to a low rate of no engraftment at 3.8%. In univariate analysis, only type of disease and status of disease at transplant for malignant diseases remained significant risk factors (P=0.04 and P<0.0001, respectively). In multivariate analysis, only status of disease was a significant risk factor (P<0.0001). Among the 61 patients who did not engraft and who were mismatched for 1 HLA class I and/or HLA-DP, 5 donor-specific antibodies (DSAs) were detected but only 1 was clearly involved in graft failure, for the others their role was more questionable. Second HSCT exhibited a protective although not statistically significant effect on OS (hazard ratio=0.57 [0.32-1.02]). In conclusion, only one parameter (disease status before graft) remains risk factor for graft failure in this recent cohort.

Suggestive evidence of a role of HLA-DRB4 mismatches in the outcome of allogeneic hematopoietic stem cell transplantation with HLA-10/10-matched unrelated donors: a French-Swiss retrospective study.

We have conducted a retrospective study on 251 patients from three centers in France and Switzerland between 2004 and 2010 with the goal to evaluate the impact of HLA-DRB3/B4/B5 allele mismatching after HLA-10/10-matched unrelated allogeneic hematopoietic stem cell transplantation (HSCT). Fourteen (5.5%) patients receiving HSCT from an HLA-10/10-matched unrelated donor had a mismatched DRB4 donor, 23 (9.5%) patients had a mismatched DRB3 donor and 214 (85%) had a fully matched unrelated donor (HLA-10/10) without DRB3- or DRB4-mismatched donor. We compared the outcomes of 37 patients with a DRB3 or DRB4 mismatch with the rest of the population. The median survival for a patient without DRB3/4 mismatch was 18 months (95% confidence interval (CI), 13-29), for DRB3-mismatched patients 32 months (95% CI, 13-NR) and for DRB4-mismatched patients 7 months (95% CI, 3-NR). The multivariate analysis showed a significant impact of DRB4 mismatching on survival (Hazards ratio (HR)=2.1 (95% CI, 1.01-4.67), P=0.045), acute GvHD (HR=2.66 (95% CI, 0.99-7.09) P=0.05) and on transplant-related mortality (HR=2.8; (95% CI, 1.7-4.4) P=0.024). In the view of an impact of DRB4 locus mismatch on clinical outcome, it would be important to confirm this observation in a prospective study as it may be worth considering DRB4 in the unrelated donor selection.

Is there any impact of HLA-DPB1 disparity in 10/10 HLA-matched unrelated hematopoietic SCT? Results of a French multicentric retrospective study.

We retrospectively analyzed the impact of HLA-DPB1 mismatches in a large cohort of 1342 French patients who underwent 10/10 HLA-matched unrelated HSCT. A significant impact of HLA-DPB1 allelic mismatches (2 vs 0) was observed in severe acute GVHD (aGVHDIII-IV) (risk ratio (RR)=1.73, confidence interval (CI) 95% 1.09-2.73, P=0.019) without impact on OS, TRM, relapse and chronic GVHD (cGVHD). According to the T-cell epitope 3 (TCE3)/TCE4 HLA-DPB1 disparity algorithm, 37.6% and 58.4% pairs had nonpermissive HLA-DPB1, respectively. TCE3 and TCE4 disparities had no statistical impact on OS, TRM, relapse, aGVHD and cGVHD. When TCE3/TCE4 disparities were analyzed in the graft-vs-host or host-vs-graft (HVG) direction, only a significant impact of TCE4 nonpermissive disparities in the HVG direction was observed on relapse (RR=1.34, CI 95% 1.00-1.80, P=0.048). In conclusion, this French retrospective study shows an adverse prognosis of HLA-DPB1 mismatches (2 vs 0) on severe aGVHD and of nonpermissive TCE4 HVG disparities on relapse after HLA-matched 10/10 unrelated HSCT.

Pre-transplantation risk factors to develop sclerotic chronic GvHD after allogeneic HSCT: a multicenter retrospective study from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Sclerotic chronic GvHD (cGvHD) is one of the most severe complications after allo-hematopoietic stem cell transplantation (HSCT). Risk factors associated with this complication remain not very well defined. With the aim to define a pre-transplantation risk profile, we have conducted a French retrospective analysis in 705 consecutive patients between 2005 and 2010. Analyses to determine pre-transplantation risk factors included as variables: patient and donor age, kind of donor, HLA matching, ABO matching, sex-matching, diagnosis, stem cell source, gender, GvHD prophylaxis and antithymocyte globulin (ATG) in the conditioning regimen. The cumulative incidence of sclerotic cGvHD was 18% (95% CI, 16.6-19.6) 3 years after onset of cGvHD. In univariate analysis, we found a significantly lower number of sclerotic cGvHD form in patients transplanted from cord blood cells (P=0.0021), in patients with a one mismatched donor (P=0.041) and in patients who had received ATG in the conditioning regimen (P=0.002). In multivariate analysis, factors associated with an increased risk of sclerotic cGvHD were young patient age, multiple myeloma and PBSC as the stem cell source. ATG in conditioning regimen and cord blood unit as the stem cell source were associated with a lower risk.

Outcomes of adults with active or progressive hematological malignancies at the time of allo-SCT: a survey from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Previous data suggested that allo-SCT might be an effective therapy in the setting of chemo-refractory/relapsed diseases because of the potent long-term immune-mediated tumor control. This retrospective study aimed to analyze the outcome of adult patients who received allo-SCT in a chemo-refractory/relapsed status. The series included 840 patients with active or progressive disease at the time of transplant. Median age was 50 years. With a median follow-up of 40 months, 3-year OS, disease-free survival (DFS), and non-relapse mortality rates were 29±2, 23±2, and 30±2%, respectively. At the last follow-up, 252 patients (30%) were still alive (of whom 201 were in CR (24%). In a Cox multivariate analysis, the use of a reduced-intensity conditioning (RIC) before allo-SCT and use of an HLA-identical sibling donor remained independently associated with a better OS (hazard ratio (HR)=0.82; 95% confidence interval (CI), 0.69-0.98, P=0.03; and HR=0.79; 95% CI, 0.66-0.93, P=0.006, respectively). Also, a diagnosis of myelodysplastic syndrome/myeloproliferative disorder, Hodgkin lymphoma and non-Hodgkin lymphoma compared with acute leukemia had a favorable impact on OS (HR=0.55; 95% CI, 0.45-0.68, P<0.0001; HR=0.49; 95% CI, 0.31-0.75, P=0.001; and HR=0.47; 95% CI, 0.35-0.63, P<0.0001, respectively). In conclusion, this study suggests that allo-SCT may be of benefit in some subgroups of patients with active or progressive hematological malignancies at the time of allo-SCT.

Treatment of adult ALL with central nervous system involvement at diagnosis using autologous and allogeneic transplantation: a study from the Société Française de Greffe de Moelle et de Thérapie Cellulaire.

To assess the role of hematopoietic SCT (HSCT) in adult ALL patients with central nervous system involvement at diagnosis, we retrospectively analyzed 90 patients who underwent autologous HSCT (auto-HSCT group; n=27) or allogeneic HSCT (allo-HSCT group; n=63) and reported to the Société Française de Greffe de Moelle et de Thérapie Cellulaire registry between 1994 and 2008. At the time of transplantation, 67 patients (74%) were in first CR, 15 (17%) in CR2 and 8 (9%) with progressive disease. The 5-year probabilities of overall survival (OS) and disease-free survival (DFS) were 52% and 46% for the allo-HSCT and 37% and 33% for the auto-HSCT groups, respectively (P=NS). The TRM at 5 years was 29.8% for the allo-HSCT group and 3.7% for the auto-HSCT group. Using univariate analysis, a time for transplantation of <12 months, the remission status at transplantation, the use of high-dose TBI and the number of the transplant were all determined to be prognostic factors for improved DFS and OS probabilities. Using multivariate analysis, we demonstrated that both the use of high-dose TBI and the remission status had a favorable impact on OS. Although the DFS and OS were better in the allo-HSCT group, the differences were not statistically significant.

Allogeneic hematopoietic stem-cell transplantation after nonmyeloablative preparative regimens: impact of pretransplantation and posttransplantation factors on outcome.

PURPOSE: To analyze the impact of pre- and posttransplantation factors on the outcome of allogeneic transplantation after nonmyeloablative conditioning regimens. PATIENTS AND METHODS: Ninety-two allogeneic transplantations after nonmyeloablative preparative regimens were reported to the Société Française de Greffe de Moelle Registry registry. Initial diagnoses were lymphoid diseases (n = 22), myeloma (n = 14), acute leukemia and myelodysplasia (n = 41), chronic myelogenous leukemia (n = 12), and solid tumors (n = 3). Forty-six patients had previously received a transplant, and 49 had progressive disease before transplantation. Three types of conditioning regimens were used with fludarabine or antithymocyte globulins. Eighty-nine patients underwent transplantation, 60 from peripheral-blood progenitor cells. Eighty-six patients received graft-versus-host disease (GHVD) prophylaxis for a median duration of 53 days. RESULTS: Seventy-nine patients engrafted, with 40 complete and 21 mixed chimerisms. The acute GHVD rate at 3 months was 50% +/- 11%. Fifty-two patients achieved complete remission and 12, partial remission. At 18 months after transplantation, the overall survival (OS) and the transplant-related mortality (TRM) were 32% +/- 12% and 38% +/- 14%, respectively. Initial diagnosis and disease status before transplantation significantly influenced survival. Age and GHVD prophylaxis type significantly influenced TRM. We also showed an impact of GHVD prophylaxis duration on OS and TRM. In multivariate analysis, three factors remained of prognostic value on OS: initial diagnosis, disease status at transplantation, and GHVD prophylaxis duration. CONCLUSION: This series shows encouraging results from nonmyeloablative conditioning regimens before allotransplantation and demonstrates the impact of some pre- and posttransplantation factors on outcome after transplantation.