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Excellent overall and chronic graft-versus-host-disease-free event-free survival in Fanconi anaemia patients undergoing matched related- and unrelated-donor bone marrow transplantation using alemtuzumab-Flu-Cy: the UK experience
Bernard, F., Uppungunduri, C. R. S., Meyer, S., Cummins, M., Patrick, K., James, B., Skinner, R., Tewari, S., Carpenter, B., Wynn, R., et al
British journal of haematology. 2021
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Editor's Choice
Abstract
Haematopoietic stem cell transplantation (HSCT) remains the only curative option in Fanconi anaemia (FA). We analysed the outcome of children transplanted for FA between 1999 and 2018 in the UK. A total of 94 transplants were performed in 82 patients. Among the donors, 51·2% were matched related donors (MRD) while the remainder were alternative donors. Most patients received a fludarabine-cyclophosphamide (Flu-Cy)-based conditioning regimen (86·6%) and in vivo T-cell depletion with alemtuzumab (69·5%). Five-year overall survival (OS) was 85·4% [70·4-93.2] with MRD, 95·7% [72·9-99.4] with matched unrelated donors (MUD), 44·4% [6·6-78.5] with mismatched unrelated donors (MMUD) and 44·4% [13·6-71.9] with mismatched related donors (MMRD) (P < 0·001). Other factors significantly impacting OS were pre-transplant bone marrow status, source of stem cells, cytomegalovirus (CMV) serostatus, preparation with Flu-Cy, use of total body irradiation (TBI) and alemtuzumab as serotherapy. In multivariate analysis, absence of myelodysplastic syndrome (MDS) or leukaemia, bone marrow as source of stem cells, cytomegalovirus (CMV) other than +/- (Recipient/Donor) and Flu-Cy were protective factors for five-year OS. Five-year chronic graft-versus-host-disease (cGVHD)-free event-free survival was 75·4% with the same risk factors except for CMV serostatus. Five-year non-relapse mortality was 13·8% [7·3-22.3]. Only five patients (6·1%) developed grade II-IV acute GVHD and two patients chronic GVHD. These data confirm the excellent outcome of matched related or unrelated HSCT in children with FA.
PICO Summary
Population
Children transplanted for fanconi anaemia (n=82)
Intervention
Matched related or alternative donor transplantation with fludarabine-cyclophosphamide conditioning
Comparison
None
Outcome
Five-year overall survival (OS) was 85·4% [70·4-93.2] with MRD, 95·7% [72·9-99.4] with matched unrelated donors (MUD), 44·4% [6·6-78.5] with mismatched unrelated donors (MMUD) and 44·4% [13·6-71.9] with mismatched related donors (MMRD) Other factors significantly impacting OS were pre-transplant bone marrow status, source of stem cells, cytomegalovirus (CMV) serostatus, preparation with Flu-Cy, use of total body irradiation (TBI) and alemtuzumab as serotherapy. In multivariate analysis, absence of myelodysplastic syndrome (MDS) or leukaemia, bone marrow as source of stem cells, cytomegalovirus (CMV) other than +/- (Recipient/Donor) and Flu-Cy were protective factors for five-year OS. Five-year chronic graft-versus-host-disease (cGVHD)-free event-free survival was 75·4% with the same risk factors except for CMV serostatus. Five-year non-relapse mortality was 13·8% [7·3-22.3]. Only five patients (6·1%) developed grade II-IV acute GVHD and two patients chronic GVHD.
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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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Modelling of neutrophil dynamics in children receiving busulfan or treosulfan for haematopoietic stem cell transplant conditioning
Solans, B. P., Chiesa, R., Doncheva, B., Prunty, H., Veys, P., Troconiz, I. F., Standing, J. F.
British journal of clinical pharmacology. 2020
Abstract
AIM: Busulfan and treosulfan are cytotoxic agents used in the conditioning regime prior to paediatric hematopoietic stem cell transplantation (HSCT). These agents cause suppression of myeloid cells leaving patients severely immunocompromised in the early post-HSCT period. The main objectives were: (i) to establish a mechanistic PKPD model for the treatment and engraftment effects on neutrophil counts comparing busulfan and treosulfan-based conditioning, and (ii) to explore current dosing schedules with respect to time to HSCT. METHODS data on 126 patients, 72 receiving busulfan (7 months-18 years, 5.1-47.0 Kg) and 54 treosulfan (4 months-17 years, 3.8-35.8 Kg), were collected. 8,935 neutrophil count observations were recorded during the study period in addition to drug concentrations to develop a mechanistic PKPD model. ANC profiles were modelled semi-mechanistically accounting for transplant effects and differing set points pre- and post-transplant. RESULTS Pharmacokinetics were best described by two-compartment models for both drugs. The Friberg semi-mechanistic neutropenia model was applied with a linear model for busulfan and an Emax model for treosulfan describing drug effects at various stages of neutrophil maturation. System parameters were consistent across both drugs. The HSCT was represented by an amount of progenitor cells enhancing the neutrophils' proliferation and maturation compartments. Alemtuzumab was found to enhance the proliferative rate under which the ANC begin to grow after HSCT. CONCLUSIONS A semi-mechanistic PKPD model linking exposure to either busulfan or treosulfan to the neutrophil reconstitution dynamics was successfully built. Alemtuzumab co-administration enhanced the neutrophil proliferative rate after HSCT. Treosulfan administration was suggested to be delayed with respect to time to HSCT, leaving less time between the end of the administration and stem cell infusion.
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Targeted busulfan-based reduced-intensity conditioning and HLA-matched HSCT cure hemophagocytic lymphohistiocytosis
Felber, M., Steward, C. G., Kentouche, K., Fasth, A., Wynn, R. F., Zeilhofer, U., Haunerdinger, V., Volkmer, B., Prader, S., Gruhn, B., et al
Blood advances. 2020;4(9):1998-2010
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Abstract
Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation-approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti-T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L x h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15+ neutrophils, CD3+ T cells, and CD16+56+ natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.
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Proposed therapeutic range of treosulfan in reduced toxicity pediatric allogeneic hematopoietic stem cell transplant conditioning: results from a prospective trial
Chiesa, R., Standing, J. F., Winter, R., Nademi, Z., Chu, J., Pinner, D., Kloprogge, F., McLellen, S., Amrolia, P. J., Rao, K., et al
Clinical pharmacology and therapeutics. 2019
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Abstract
Treosulfan is given off-label in pediatric allogeneic hematopoietic stem cell transplant. This study investigated treosulfan's pharmacokinetics (PK), efficacy and safety in a prospective trial. Pediatric patients (n=87) receiving treosulfan-fludarabine conditioning were followed for at least 1 year post-transplant. PK were described with a two compartment model. During follow-up 11/87 patients died and 12/87 had low engraftment (≤ 20% myeloid chimerism). For each increase in treosulfan AUC(0-infinity) of 1000 mg.h/L the hazard ratio (95% CI) for mortality increase was 1.46 (1.23, 1.74), and the hazard ratio for low engraftment was 0.61 (0.36, 1.04). A cumulative AUC(0-infinity) of 4800 mg.h/L maximised the probability of success (>20 % engraftment and no mortality) at 82%. Probability of success with AUC(0-infinity) between 80 and 125% of this target were 78% and 79%. Measuring PK at the first dose and individualizing the third dose may be required in non-malignant disease.
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Long-term outcome following cyclosporine-related neurotoxicity in paediatric allogeneic haematopoietic stem cell transplantation
Straathof, K., Anoop, P., Allwood, Z., Silva, J., Nikolajeva, O., Chiesa, R., Veys, P., Amrolia, P. J., Rao, K.
Bone Marrow Transplantation. 2017;52(1):159-162
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Treosulfan, Fludarabine Conditioning for HSCT in Children with Primary Immunodeficiency: UK Experience
Slatter, M. A., Rao, K., Abd Hamid, I. J., Nademi, Z., Chiesa, R., Elfeky, R., Pearce, M. S., Amrolia, P., Worth, A., Flood, T., et al
Biology of Blood & Marrow Transplantation. 2017
Abstract
We previously published results of 70 children who received treosulfan with cyclophosphamide (30) or fludarabine (40) before haematopoietic stem cell transplantation (HSCT) for Primary Immunodeficiency (PID). Toxicity was lower and T cell chimerism better in those receiving fludarabine, but numbers were relatively small and follow-up short. We now report outcome of 160 children who received homogeneous conditioning with treosulfan, fludarabine mostly with alemtuzumab (n=124). Median age at transplant was 1.36 years (0.09-18.25). Donors were: matched unrelated, 73; 1-3 antigen mismatched unrelated, 54; matched sibling, 12; other matched family, 17; haploidentical, 4. Stem cell source was: peripheral blood stem cells (PBSCs), 70; Bone marrow, 49; Cord Blood, 41. Median follow up was 4.3 years (0.8-9.4). Overall survival was 83%. There was no veno- occlusive disease. Seventy-four (46%) had acute GVHD, but only 14(9%) greater than grade II. Four patients were successfully retransplanted for graft loss or poor immune reconstitution. One further patient who rejected the graft, died. There was no association between T cell chimerism > 95% and stem cell source, but a significant association with myeloid chimerism > 95% and use of PBSC without an increased risk of significant GVHD compared to other sources. All 11 patients with severe combined immunodeficiency diagnosed at birth are alive with up to 8.7 years follow up. Long-term studies are required to determine late gonadotoxic effects and pharmacokinetic studies are needed to identify whether specific targeting is advantageous. The combination of treosulfan, fludarabine and alemtuzumab gives excellent results in HSCT for PID. Copyright © 2017. Published by Elsevier Inc.
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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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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.
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Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience.[Erratum appears in Blood. 2016 Nov 24;128(21):2585; PMID: 27884839]
Morillo-Gutierrez, B., Beier, R., Rao, K., Burroughs, L., Schulz, A., Ewins, A. M., Gibson, B., Sedlacek, P., Krol, L., Strahm, B., et al
Blood. 2016;128(3):440-8
Abstract
Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR alphabeta/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan-containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility. Copyright © 2016 by The American Society of Hematology.