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The impact of donor type on the outcome of pediatric patients with very high risk acute lymphoblastic leukemia. A study of the ALL SCT 2003 BFM-SG and 2007-BFM-International SG
Dalle, J. H., Balduzzi, A., Bader, P., Pieczonka, A., Yaniv, I., Lankester, A., Bierings, M., Yesilipek, A., Sedlacek, P., Ifversen, M., et al
Bone marrow transplantation. 2020
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Editor's Choice
Abstract
Allogeneic HSCT represents the only potentially curative treatment for very high risk (VHR) ALL. Two consecutive international prospective studies, ALL-SCT-(I)BFM 2003 and 2007 were conducted in 1150 pediatric patients. 569 presented with VHR disease leading to any kind of HSCT. All patients >2 year old were transplanted after TBI-based MAC. The median follow-up was 5 years. 463 patients were transplanted from matched donor (MD) and 106 from mismatched donor (MMD). 214 were in CR1. Stem cell source was unmanipulated BM for 330 patients, unmanipulated PBSC for 135, ex vivo T-cell depleted PBSC for 62 and cord-blood for 26. There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years, median follow up of survivals was 4.88, range (0.01-11.72) years. The 4-year CI of extensive cGvHD was 13?±?2% and 17?±?4% (p?=?NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60?±?2% vs. 42?±?5%, p?0.001) for the whole cohort. This difference does not exist if considering separately patients treated in the most recent study. There was no difference in 4-year CI of relapse. The 4-year NRM was lower for patients transplanted from MD (9?±?1% vs. 23?±?4%, p?0.001). In multivariate analysis, donor-type appears as a negative risk-factor for OS, EFS, and NRM. This paper demonstrates the impact of donor type on overall results of allogeneic stem cell transplantation for very-high risk pediatric acute lymphoblastic leukemia with worse results when using MMD stem cell source.
PICO Summary
Population
Children with very high risk acute lymphoblastic leukaemia (n=569)
Intervention
Matched donor (MD) or matched sibling donor (MSD) transplantation (n=463)
Comparison
Mismatched donor transplantation (MMD, n=106)
Outcome
There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years,median follow up of survivals was 4.88 years. The 4-year CI of extensive cGvHD was 13± 2% and 17 ± 4% (p=NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60±2% vs. 42±5%) for the whole cohort. This difference does not exist if considering separately patients treated in the most recent study. There was no difference in 4-year CI of relapse. The 4-year NRM was lower for patients transplanted from MD (9±1% vs. 23±4%). In multivariate analysis, donor-type appears as a negative risk-factor for OS, EFS, and NRM.
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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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Editor's Choice
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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The increase of the global donor inventory is of limited benefit to patients of non-Northwestern European descent
van Walraven, S. M., Brand, A., Bakker, J. N., Heemskerk, M. B., Nillesen, S., Bierings, M. B., Bungener, L. B., Hepkema, B. G., Lankester, A., van der Meer, A., et al
Haematologica. 2017;102(1):176-183
Abstract
Between 2001 and 2012, the number of unrelated donors registered worldwide increased from 7 to 21 million, and the number of public cord blood units increased to over 500,000. We addressed the question of whether this expansion resulted in higher percentages of patients reaching transplantation. Unrelated donor searches were evaluated for 3,124 eligible patients in the Netherlands in two cohorts (2001-2006, n=995; 2007-2012, n=2129), comparing results for patients of Northwestern European and non-Northwestern European origin. Endpoints were 'donor found' and 'transplantation reached'. The substantial growth of the donor inventory over the period studied did not increase the median number of potential unrelated donors (n=7) for non-Northwestern European patients, but almost doubled the number for Northwestern European patients from 42 to 71. Before and after 2007, an unrelated donor or cord blood was identified for 91% and 95%, respectively, of Northwestern European patients and for 65% and 82% of non-Northwestern European patients (P<0.0001). Non-Northwestern European patients more often needed a cord blood transplant. The degree of HLA matching was significantly lower for non-Northwestern European patients (P<0.0006). The time needed to identify a donor decreased for both populations. The percentage of Northwestern European patients reaching transplantation increased from 77% to 83% and for non-Northwestern European patients from 57% to 72% (P=0.0003). The increase of the global inventory resulted in more transplants for patients lacking a family donor, although the quality and quantity of (potential) haematopoietic cell grafts for patients of a non-Northwestern European descent remained inferior, indicating the need for adaptation of recruitment.