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1.
Cytogenetic abnormalities predict survival after allogeneic hematopoietic stem cell transplantation for pediatric acute myeloid leukemia: a PDWP/EBMT study
Sharma, A., Galimard, J. E., Pryce, A., Bhoopalan, S. V., Dalissier, A., Dalle, J. H., Locatelli, F., Jubert, C., Mirci-Danicar, O., Kitra-Roussou, V., et al
Bone marrow transplantation. 2024
Abstract
Poor-risk (PR) cytogenetic/molecular abnormalities generally direct pediatric patients with acute myeloid leukemia (AML) to allogeneic hematopoietic stem cell transplant (HSCT). We assessed the predictive value of cytogenetic risk classification at diagnosis with respect to post-HSCT outcomes in pediatric patients. Patients younger than 18 years at the time of their first allogeneic HSCT for AML in CR1 between 2005 and 2022 who were reported to the European Society for Blood and Marrow Transplantation registry were subgrouped into four categories. Of the 845 pediatric patients included in this study, 36% had an 11q23 abnormality, 24% had monosomy 7/del7q or monosomy 5/del5q, 24% had a complex or monosomal karyotype, and 16% had other PR cytogenetic abnormalities. In a multivariable model, 11q23 (hazard ratio [HR] = 0.66, P = 0.03) and other PR cytogenetic abnormalities (HR = 0.55, P = 0.02) were associated with significantly better overall survival when compared with monosomy 7/del7q or monosomy 5/del5q. Patients with other PR cytogenetic abnormalities had a lower risk of disease relapse after HSCT (HR = 0.49, P = 0.01) and, hence, better leukemia-free survival (HR = 0.55, P = 0.01). Therefore, we conclude that PR cytogenetic abnormalities at diagnosis predict overall survival after HSCT for AML in pediatric patients.
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2.
Molecular Measurable Residual Disease Assessment before Hematopoietic Stem Cell Transplantation in Pediatric Acute Myeloid Leukemia Patients: A Retrospective Study by the I-BFM Study Group
Benetton, M., Merli, P., Walter, C., Hansen, M., Da Ros, A., Polato, K., Tregnago, C., Abrahamsson, J., Strocchio, L., Sonneveld, E., et al
Biomedicines. 2022;10(7)
Abstract
Hematopoietic stem cell transplantation (HSCT) is a curative post-remission treatment in patients with acute myeloid leukemia (AML), but relapse after transplant is still a challenging event. In recent year, several studies have investigated the molecular minimal residual disease (qPCR-MRD) as a predictor of relapse, but the lack of standardized protocols, cut-offs, and timepoints, especially in the pediatric setting, has prevented its use in several settings, including before HSCT. Here, we propose the first collaborative retrospective I-BFM-AML study assessing qPCR-MRD values in pretransplant bone marrow samples of 112 patients with a diagnosis of AML harboring t(8;21)(q22; q22)RUNX1::RUNX1T1, or inv(16)(p13q22)CBFB::MYH11, or t(9;11)(p21;q23)KMT2A::MLLT3, or FLT3-ITD genetic markers. We calculated an ROC cut-off of 2.1 × 10(-4) that revealed significantly increased OS (83.7% versus 57.1%) and EFS (80.2% versus 52.9%) for those patients with lower qPCR-MRD values. Then, we partitioned patients into three qPCR-MRD groups by combining two different thresholds, 2.1 × 10(-4) and one lower cut-off of 1 × 10(-2), and stratified patients into low-, intermediate-, and high-risk groups. We found that the 5-year OS (83.7%, 68.6%, and 39.2%, respectively) and relapse-free survival (89.2%, 73.9%, and 67.9%, respectively) were significantly different independent of the genetic lesion, conditioning regimen, donor, and stem cell source. These data support the PCR-based approach playing a clinical relevance in AML transplant management.
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3.
Allogeneic hematopoietic stem cell transplantation for pediatric acute myeloid leukemia in first complete remission: a meta-analysis
Masetti, R., Muratore, E., Gori, D., Prete, A., Locatelli, F.
Annals of hematology. 2022
Abstract
Identification of pediatric patients with acute myeloid leukemia (AML) candidates to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) is still a matter of debate. Currently, transplantation is reserved to patients considered at high risk of relapse based on cytogenetics, molecular biology, and minimal residual disease (MRD) assessment. However, no randomized clinical trial exists in the literature comparing transplantation with other types of consolidation therapy. Here, we provide an up-to-date meta-analysis of studies comparing allo-HSCT in CR1 with chemotherapy alone as a post-remission treatment in high-risk pediatric AML. The literature search strategy identified 10 cohorts from 9 studies performing as-treated analysis. The quantitative synthesis showed improved overall survival (OS) (relative risk, 1.15; 95% confidence interval [CI], 1.06-1.24; P = 0.0006) and disease-free survival (relative risk, 1.31; 95% CI, 1.17-1.47; P = 0.0001) in the allo-HSCT group, with increased relapse rate in the chemotherapy group (relative risk, 1.26; 95% CI, 1.07-1.49; P = 0.006). Sensitivity analysis including prospective studies alone and excluding studies that reported the comparison only on intermediate-risk patients confirmed the benefit of allo-HSCT on OS. Further research should focus on individualizing allo-HSCT indications based on molecular stratification and MRD monitoring.
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4.
Outcome of children relapsing after first allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: a retrospective I-BFM analysis of 333 children
Uden, T., Bertaina, A., Abrahamsson, J., Ansari, M., Balduzzi, A., Bourquin, J. P., Gerhardt, C., Bierings, M., Hasle, H., Lankester, A., et al
British journal of haematology. 2020
Abstract
Outcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was 14%. 4y-pOS for 122 children receiving a second haematopoietic stem cell transplantation was 31% and 3% for those that did not (P = <0.0001). Achievement of a subsequent remission impacted survival (P = <0.0001). For patients receiving a second transplant survival with or without achieving a subsequent remission was comparable. Graft source (bone marrow vs. peripheral blood stem cells, P = 0.046) and donor choice (matched family vs. matched unrelated donor, P = 0.029) positively impacted survival after relapse. Disease recurrence and non-relapse mortality at four years reached 45% and 22%.
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5.
Clofarabine and Treosulfan as conditioning for matched related and unrelated HSCT: results from the phase II trial "Clo3o"
Peccatori, J., Mastaglio, S., Giglio, F., Greco, R., Crocchiolo, R., Patriarca, F., Forno, B., Deola, S., Assanelli, A., Stanghellini, M. T. L., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for patients with hematological malignancies. The ideal conditioning regimen before allogeneic HSCT has not been established. We conducted a phase II study to evaluate tolerability and efficacy of Clofarabine and Treosulfan as conditioning regimen before allo-HSCT. Primary objective was evaluation of the cumulative incidence of non-relapse mortality (NRM) on day +100. Forty-four patients (36 acute myeloid leukemias, 5 acute lymphoblastic leukemias, 3 myelodysplastic syndromes) were enrolled. Median age was 47 years. Median follow-up was 27 months. Conditioning regimen was based on Clofarabine 40 mg/m(2) (day -6 to -2) and Treosulfan 14 g/m(2) (day -6 to -4). Allogeneic haematopoietic stem cells were derived from a sibling (n=22) or a well-matched unrelated donor (n=22). Graft versus host disease (GvHD) prophylaxis consisted of Thymoglobuline, Rituximab, Cyclosporine and short course Methotrexate. The regimen allowed rapid engraftment and 100 days NRM of 18%, mainly because of bacterial infections. Grade 2-4 acute and chronic GvHD were 16% and 19% respectively. Overall survival (OS), progression free survival and relapse incidence at 2-year were 51%, 31% and 50%. A significantly different outcome was observed between patients with "low/intermediate" vs "high/very high" disease risk index (DRI; 1-year OS 78% and 24%). Treosulfan and Clofarabine as conditioning regimen for allo-HSCT is feasible, with 78% 1-year OS in low/intermediate DRI. However 1-year NRM was 18% and, despite the intensification of the conditioning regimen, relapse incidence is still a major issue in patients with poor prognostic risk factors.
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6.
Impact of Conditioning Regimen on Outcomes for Children with Acute Myeloid Leukemia Undergoing Transplantation in First Complete Remission. An Analysis on Behalf of the Pediatric Disease Working Party of the European Group for Blood and Marrow Transplantation
Lucchini, G., Labopin, M., Beohou, E., Dalissier, A., Dalle, J. H., Cornish, J., Zecca, M., Samarasinghe, S., Gibson, B., Locatelli, F., et al
Biology of Blood & Marrow Transplantation. 2017;23(3):467-474
Abstract
Hematopoietic stem cell transplantation (HSCT) represents the cornerstone of treatment in pediatric high-risk and relapsed acute myeloid leukemia (AML). The aim of the present study was to compare outcomes of pediatric patients with AML undergoing HSCT using 3 different conditioning regimens: total body irradiation (TBI) and cyclophosphamide (Cy); busulfan (Bu) and Cy; or Bu, Cy, and melphalan (Mel). In this retrospective study, registry data for patients>2 and <18 years age undergoing matched allogeneic HSCT for AML in first complete remission (CR1) in 204 European Group for Blood and Marrow Transplantation centers between 2000 and 2010 were analyzed. Data were available for 631 patients; 458 patients received stem cells from a matched sibling donor and 173 from a matched unrelated donor. For 440 patients, bone marrow was used as stem cell source, and 191 patients received peripheral blood stem cells. One hundred nine patients received TBICy, 389 received BuCy, and 133 received BuCyMel as their preparatory regimen. Median follow-up was 55 months. Patients receiving BuCyMel showed a lower incidence of relapse at 5 years (14.7% versus 31.5% in BuCy versus 30% in TBICy, P<.01) and higher overall survival (OS) (76.6% versus 64% versus 64.5%, P=.04) and leukemia-free survival (LFS) (74.5% versus 58% versus 61.9%, P<.01), with a comparable nonrelapse mortality (NRM) (10.8% versus 10.5% versus 8.1%, P=.79). Acute graft-versus-host disease (GVHD) grades III and IV but not chronic GVHD, was higher in patients receiving BuCyMel. Older age at HSCT had an adverse impact on NRM and the use of peripheral blood as stem cell source was associated with increased chronic GVHD and NRM as well as lower LFS and OS. Among pediatric patients receiving HSCT for AML in CR1, the use of BuCyMel conditioning proved superior to TBICy and BuCy in reducing relapse and improving LFS. Copyright © 2017 The American Society for Blood and Marrow Transplantation. All rights reserved.
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7.
Unrelated cord blood transplantation for childhood acute myelogenous leukemia: The influence of cytogenetic risk group stratification
Michel, G., Cunha, R., Ruggeri, A., O'Brien, T. A., Bittencourt, H., Dalle, J. H., Locatelli, F., Iori, A. P., Mauad, M., Oudin, C., et al
Leukemia. 2016;30(5):1180-3
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8.
Killer Cell Immunoglobulin-Like Receptor-Ligand Matching and Outcomes after Unrelated Cord Blood Transplantation in Acute Myeloid Leukemia
Rocha, V., Ruggeri, A., Spellman, S., Wang, T., Sobecks, R., Locatelli, F., Askar, M., Michel, G., Arcese, W., Iori, A. P., et al
Biology of Blood & Marrow Transplantation. 2016;22(7):1284-9
Abstract
The effect of killer cell immunoglobulin-like receptor (KIR)-ligand matching on outcomes after unrelated cord blood (CB) transplantation was studied in 461 patients with acute myeloid leukemia, categorizing KIR ligand for HLA-C groups C1 and C2 and Bw4. Donor-recipient HLA matching considered allele-level matching at HLA-A, -B, -C, and -DRB1. Separate analyses were conducted for 6-7/8 HLA-matched and 3-5/8 HLA-matched transplants because HLA matching confounded KIR-ligand matching (ie, KIR-ligand mismatching was less likely with better HLA matching). All patients received single CB unit and myeloablative conditioning. There were no significant differences in nonrelapse mortality (NRM), relapse, and overall mortality by KIR-ligand match status. However, among recipients of 3-5/8 HLA-matched transplants, NRM (HR, 2.26; P = .008) and overall mortality (HR, 1.78; P = .008) but not relapse were higher with KIR-ligand mismatched (host-versus-graft direction) compared with KIR-ligand matched transplants. These data do not support selecting CB units based on KIR-ligand match status for transplants mismatched at 1 or 2 HLA loci. Although transplants mismatched at 3 or more HLA loci are not recommended, avoiding KIR-ligand mismatching in this setting lowers mortality risks. Copyright © 2016 American Society for Blood and Marrow Transplantation. All rights reserved.