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Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study
Willasch, A. M., Peters, C., Sedlacek, P., Dalle, J. H., Kitra-Roussou, V., Yesilipek, A., Wachowiak, J., Lankester, A., Prete, A., Hamidieh, A. A., et al
Bone marrow transplantation. 2020
Abstract
Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.
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Transplantation in children and adolescents with acute lymphoblastic leukemia from a matched donor versus an hla-identical sibling: Is the outcome comparable? Results from the international bfm all sct 2007 study
Balduzzi, A., Dalle, J. H., Wachowiak, J., Yaniv, I., Yesilipek, A., Sedlacek, P., Bierings, M., Ifversen, M., Sufliarska, S., Kalwak, K., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Abstract
INTRODUCTION Eligibility criteria for hematopoietic stem cell transplantation (SCT) in acute lymphoblastic leukemia (ALL) vary according to disease characteristics, response to treatment and type of available donor; as the risk profile of the patient worsens, a wider degree of HLA mismatching is considered acceptable. METHODS A total of 138 children and adolescents transplanted from HLA-identical siblings (MSD) and 210 from matched donors (MD) (median 9 years, 68% male) in 10 countries were enrolled within the International-BFM ALL SCT 2007 prospective study to assess the impact of donor type in pediatric ALL. RESULTS The 4-year event-free survival (65%+/-5 vs 61%+/-4; p-value 0.287), overall survival (72%+/-4 vs 68%+/-4; p-value 0.235), cumulative incidence of relapse (24%+/-4 vs 25%+/-3; p-value 0.658) and non-relapse mortality (10%+/-3 vs 14%+/-3; p-value 0.212) were not significantly different between MSD and MD graft recipients. The risk of extensive chronic (cGVHD) was lower in MD than in MSD recipients (HR 0.38, p-value 0.002) and the risks of severe acute GVHD (aGVHD) and cGVHD were higher in peripheral blood than in bone marrow recipients (HR 2.06, p-value 0.026). Compared with the absence of aGVHD, grade I-II was associated with a lower risk of failure (HR 0.63, p-value 0.042) and grade III-IV with a higher risk of failure (HR 1.85, p-value 0.020) and non-leukemic death (HR 8.76, p-value <0.0001), despite a lower risk of relapse (HR 0.32, p-value 0.021). Compared with the absence of cGVHD, extensive cGVHD was associated with a higher risk of non-leukemic death (HR 8.12, p-value <0.0001). CONCLUSIONS Since the outcome of transplantation from a matched donor was not inferior to transplantation from an HLA-identical sibling, eligibility criteria for transplantation might be reviewed in pediatric ALL and, possibly, in other malignancies. Bone marrow should be the preferred stem cell source and the addition of MTX should be considered in MSD recipients.
PICO Summary
Population
Children with acute lymphoblastic leukaemia, receiving allo-transplantation in 10 countries. (n=348).
Intervention
HLA-identical sibling donor (MSD) (n=138).
Comparison
Matched donor (MD) (n=210).
Outcome
The 4-year event-free survival, overall survival, cumulative incidence of relapse and non-relapse mortality were not significantly different between MSD and MD graft recipients. The risk of extensive chronic (cGVHD) was lower in MD than in MSD recipients and the risks of severe acute GVHD (aGVHD) and cGVHD were higher in peripheral blood than in bone marrow recipients. Compared with the absence of aGVHD, grade I-II was associated with a lower risk of failure and grade III-IV with a higher risk of failure and non-leukemic death, despite a lower risk of relapse. Compared with the absence of cGVHD, extensive cGVHD was associated with a higher risk of non-leukemic death.
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Allogeneic Stem Cell Transplantation From HLA-Mismatched Donors for Pediatric Patients with Acute Lymphoblastic Leukemia Treated According to the 2003 BFM and 2007 International-BFM Studies: Impact of Disease Risk on Outcomes
Dalle, J. H., Balduzzi, A., Bader, P., Lankester, A., Yaniv, I., Wachowiak, J., Pieczonka, A., Bierings, M., Yesilipek, A., Sedlacek, P., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
RATIONAL Allogeneic HSCT is beneficial for pediatric patients with relapsed or (very) high-risk ALL in remission. A total of 1115 consecutive patients were included in the ALL SCT 2003 BFM study and the ALL SCT 2007-International study and were stratified according to relapse risk (Standard vs. High vs. Very High Risk of Relapse) and donor type (Matched Sibling vs. Matched Donor vs. Mismatched Donor). PATIENTS AND METHODS A total of 148 patients (60% male, median age 8.7 years; B-cell precursor ALL: 75%) were transplanted from MMD, which was defined as either less than 9/10 HLA-compatible donors or less than 5/6 unrelated cord blood after myelo-ablative conditioning regimen (TBI-based: 67%) for HRR (n=42) or VHRR disease (n=106). The stem cell source was either BM (n=31), unmanipulated PBSCs (n=28), T-cell ex vivo depleted PBSCs (n=59) or cord blood (n=25). The median follow-up was 5.1 years. RESULTS The 4-year OS and EFS was 56+/-4% and 52+/-4%, respectively, for the entire cohort. Patients transplanted from MMD for HRR disease obtained remarkable 4-y OS and EFS values of 82+/-6% and 80+/-6%, respectively, while VHRR patients obtained values of 45+/-5% and 42+/-5% (p<0.001), respectively. The cumulative incidence of relapse was 29+/-4%, and that of NRM was 19+/-3%. The cumulative incidence (CI) of limited and extensive cGVHD was 13+/-3% and 15+/-4%, respectively, among the 120 patients living beyond D100. Multivariate analysis showed that OS was lower for transplanted VHRR disease patients (p=0.002, HR 3.62, 95%CI 1.60-8.20) and for patients beyond CR2 vs CR1 (p<0.001; HR: 3.68, 95%CI: 1.79-7.56); relapse occurred more frequently in patients with VHRR disease (p=0.026; HR: 3.30, 95% CI: 1.16-9.60) and for those beyond CR2 (p=0.005; HR: 4.16, 95% CI: 1.52-10.59). NRM was not significantly higher for CMV-positive recipients receiving CMV-negative grafts (p=0.12; HR: 1.96, 95% CI: 0.84-4.58). CONCLUSION HSCT with a mismatched donor is feasible in pediatric ALL patients but leads to inferior results compared to HSCT with better matched donors, at least for patients transplanted for VHRR. The results are strongly affected by disease status. The main cause of treatment failure is still relapse, highlighting the urgent need for interventional strategies after HSCT for patients with residual leukemia before and/or after transplantation.
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Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial
Kuhlen, M., Willasch, A. M., Dalle, J. H., Wachowiak, J., Yaniv, I., Ifversen, M., Sedlacek, P., Guengoer, T., Lang, P., Bader, P., et al
British Journal of Haematology. 2017
Abstract
Relapse remains the major cause of treatment failure in children with high-risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem-cell transplantation (allo-SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo-SCT enrolled in the Berlin-Frankfurt-Munster (BFM) ALL-SCT-BFM 2003 and ALL-SCT-BFM international 2007 studies. Median time from allo-SCT to relapse was 7.7 months; median follow-up from relapse after allo-SCT until last follow-up was 3.4 years. The 3-year event-free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86.5%). The majority of children (48%) received salvage therapy without second allo-SCT, 26% of the children underwent a second allo-SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo-SCT hold promise to improve outcome in children with post allo-SCT relapse.