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1.
Low rate of nonrelapse mortality in under 4-year-olds with ALL given chemo-conditioning for HSCT: Phase III FORUM study
Bader, P., Poetschger, U., Dalle, J. H., Moser, L. M., Balduzzi, A. C., Ansari, M., Buechner, J., Güngör, T., Ifversen, M., Kriván, G., et al
Blood advances. 2023
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). In young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of two TBI-free conditioning regimens in children with ALL <4 years old. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children were transplanted and observed for ≥6 months (median follow-up: 3 years). 3-year OS was 0.63 (95% confidence interval [95% CI]: 0.52-0.72) and 0.76 (95% CI: 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (p = 0.075), respectively. 3-year EFS was 0.52 (95% CI: 0.41-0.61) and 0.51 (95% CI: 0.39-0.62), respectively (p = 0.794). Cumulative incidence of non-relapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI: 0.02-0.12) versus 0.03 (95% CI: <0.01-0.09) (p = 0.406) and 0.42 (95% CI: 0.31-0.52) versus 0.45 (95% CI: 0.34-0.56) (p = 0.920), respectively. Grade >1 acute graft-versus-host disease (GvHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% receiving Flu/Thio/Treo (p = 0.049), while grade 3-4 occurred in 10% and 9% (p = 0.813). 3-year incidence of chronic GvHD was 0.07 (95% CI: 0.03-0.13) versus 0.05 (95% CI: 0.02-0.11), respectively (p = 0.518). In conclusion, both chemo-conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure.
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2.
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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3.
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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4.
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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5.
Development of a Limited Sampling Strategy for the Estimation of Exposure to High-Dose Etoposide After Intravenous Infusion in Pediatric Patients
Danielak, D., Sobiak, J., Wachowiak, J., Glowka, F., Chrzanowska, M.
Therapeutic Drug Monitoring. 2017;39(2):138-144
Abstract
BACKGROUND Etoposide (VP-16), a podophyllotoxin derivative, is used in conditioning regimens before allogeneic hematopoietic stem cell transplantation in children with acute lymphoblastic leukemia. The aim of this study was to develop a limited sampling strategy (LSS) suitable for the prediction of exposure to VP-16 defined as area under time-concentration curve (AUC). METHODS The study included 28 pediatric patients with acute lymphoblastic leukemia, who were administered a 4-hour infusion of 60 mg/kg VP-16. VP-16 concentrations were determined in samples collected 4-124 hours after the beginning of infusion. On obtaining the pharmacokinetic (PK) profiles, a population PK model was developed in NONMEM (ICON Development Solutions, Hanover, MD) with first-order conditional estimation with interaction algorithm. LSSs were chosen by means of a multivariate regression analysis and cross-validated with a leave-one-out approach. Predictive performance of LSSs was assessed by calculating relative prediction error (PE), mean PE, mean absolute PE, and root mean squared PE for model-predicted and observed AUC. RESULTS VP-16 PKs was best described by a 2-compartment first-order model, and a large variability in the PK parameters was observed. A 3-sample strategy allowed the estimation of VP-16 with highest accuracy and precision (mean relative PE = 0.18%, 95% confidence interval, 1.73%-2.09%; mean absolute relative PE = 3.47%, 95% confidence interval, 2.28%-4.66%; root mean squared PE = 4.43%). The final equation was AUC = 6.85 x C6 h + 3.88 x C12 h + 46.11 x C28 h + 282.0 (adjusted R = 0.9540). CONCLUSIONS In conclusion, developed LSS allows accurate and precise estimation of VP-16 AUC and might be useful for therapeutic drug monitoring.
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6.
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.
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7.
European Society for Blood and Marrow Transplantation Analysis of Treosulfan Conditioning Before Hematopoietic Stem Cell Transplantation in Children and Adolescents With Hematological Malignancies
Boztug, H., Sykora, K. W., Slatter, M., Zecca, M., Veys, P., Lankester, A., Cant, A., Skinner, R., Wachowiak, J., Glogova, E., et al
Pediatric Blood & Cancer. 2016;63(1):139-48
Abstract
BACKGROUND Standard myeloablative conditioning regimens for children with hematological malignancies undergoing allogeneic HSCT are based mainly on total body irradiation or busulfan. Their serious short- and long-term side effects warranted the exploration of less toxic alternatives. Treosulfan is increasingly used for adults and children before HSCT due to its potent immunosuppressive and cytotoxic effects combined with low organ toxicity. PROCEDURE To further investigate the role of treosulfan conditioning in children, the EBMT Pediatric diseases working party performed a retrospective analysis of 193 children with hematological malignancies (ALL n=71, AML n=47, MDS/MPS n=40, other leukemia/lymphoma n=25) undergoing allogeneic HSCT following treosulfan between January 2005 and July 2010. RESULTS Early regimen-related toxicity was low and mainly gastrointestinal. Veno-occlusive disease and neurological toxicity were rare. There was no association of toxicity with type of disease or treosulfan dose. High-grade early toxicity was not higher in infants or patients undergoing second or later transplantation. Treatment related mortality was low at 14%. Three-year event-free survival was 45+/-4% and not significantly influenced by number of transplants, however it appeared to be significantly better for infants (P=0.022). When compared to treosulfan plus fludarabine, the combination of treosulfan, fludarabine and an alkylator (either thiotepa or melphalan) resulted in significantly better overall survival (OS, P=0.048) and a trend toward better EFS. CONCLUSIONS Treosulfan based conditioning is a safe and effective approach for children with hematological malignancies, including and importantly for infants and those patients undergoing second or later transplantation. Copyright © 2015 Wiley Periodicals, Inc.