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Association Between the Magnitude of Intravenous Busulfan Exposure and Development of Hepatic Veno-Occlusive Disease in Children and Young Adults Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation
Bognàr, T., Bartelink, I. H., Egberts, T. C. G., Rademaker, C. M. A., Versluys, A. B., Slatter, M. A., Kletzel, M., Nath, C. E., Cuvelier, G. D. E., Savic, R. M., et al
Transplantation and cellular therapy. 2022;28(4):196-202
Abstract
Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg × h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg × h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk.
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Myeloablative Conditioning Regimen in Haploidentical Stem Cell Transplantation With Posttransplant Cyclophosphamide in Children With High-risk Hematologic Malignancies
Dufort, Y. Alvarez G.
Journal of pediatric hematology/oncology. 2022
Abstract
Limited information is available on outcomes of haploidentical stem cell transplantation (haploSCT) with posttransplant cyclophosphamide using myeloablative conditioning regimens in children and adolescents. We report the results of a single-institution retrospective study of myeloablative haploSCT in 36 children and adolescents (median age, 8 y; range, 9 mo to 22 y) with high-risk hematologic malignancies. Donor engraftment occurred in 31 of 33 evaluable patients (94%). Recovery of neutrophils and platelets occurred at a median of 15 and 20 days. Cumulative incidence of acute graft-versus-host-disease (GVHD) grades II to IV and grades III to IV at 100 days was 36±8.7% and 10±5.4% and of chronic GVHD at 1 year was 55±9.2%, with 31±8.6% moderate to severe. Nonrelapse mortality was 16±6.1% and 22±6.9% at 100 days and 1 year. The cumulative incidence of relapse at 4 years was 32±8.8%. With a median follow-up of 57 months (range, 8 to 89 mo), the overall survival and event-free survival at 4 years was 55.6±8.7% and 44.8±8.5%. Myeloablative conditioning T-replete haploSCT with posttransplant cyclophosphamide is a viable alternative to matched unrelated transplantation for children and adolescents with high-risk hematologic malignancies. The high rates of nonrelapse mortality and chronic GVHD is a concern and deserves careful consideration.
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Allogeneic hematopoietic stem cell transplantation with the modified myeloablative conditioning regimen for children with chronic active Epstein-Barr virus infection
Luo, Y., Wei, A., Wang, B., Zhu, G., Zhang, R., Jia, C., Yan, Y., Zhou, X., Yang, J., Qin, M., et al
Pediatric investigation. 2022;6(4):250-259
Abstract
IMPORTANCE Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the only effective treatment for chronic active Epstein-Barr virus infection (CAEBV). The clinical efficacy and safety of allo-HSCT with different conditioning regimens in children with CAEBV remain unclear. OBJECTIVE To evaluate the effectiveness and safety of allo-HSCT with the modified myeloablative conditioning (MAC) regimen for children with CAEBV and also the factors affecting the outcomes. METHODS We retrospectively analyzed children with CAEBV who underwent allo-HSCT with the modified MAC regimen at Beijing Children's Hospital, Capital Medical University from October 2016 to June 2021. Data related to the clinical manifestations, engraftment, and outcome were extracted from the medical records. RESULTS The cohort comprised 41 patients (24 males, 17 females) with a median transplantation age of 92.6 (60.4, 120.7) months and a median follow-up time of 28.2 (15.3, 40.2) months. Four patients (9.8%) died, among which three died from primary disease relapse, and one died from grade IV acute graft-versus-host diseases (aGVHD) after stopping treatment. The 3-year overall survival (OS) and 3-year event-free survival (EFS) rates were 88.8% ± 5.4% and 85.0% ± 5.7%, respectively. The 3-year OS and EFS did not significantly differ between the patients with hemophagocytic lymphohistiocytosis (HLH) and the patient without HLH (87.7% ± 6.8% vs. 91.7% ± 8.0%, P = 0.790; 85.0% ± 6.9% vs. 84.6% ± 10.0%, P = 0.921), or among the patients with complete remission, partial remission, and activity disease before HSCT (all P > 0.05). Multivariate analysis showed that grade III-IV aGVHD was a risk factor for mortality (Hazards ratio: 11.65, 95% confidence interval: 1.00, 136.06; P = 0.050). INTERPRETATION Allo-HSCT with the modified MAC regimen is safe and effective for pediatric CAEBV. This treatment benefits patients with HLH or active disease. Patients with Grade III-IV aGVHD may be associated with worse outcomes.
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Unrelated cord blood transplantation with myeloablative conditioning for pediatric acute lymphoblastic leukemia in remission: prognostic factors
Kawahara, Y., Morimoto, A., Inagaki, J., Koh, K., Noguchi, M., Goto, H., Yoshida, N., Cho, Y., Hori, T., Hiwatari, M., et al
Bone Marrow Transplantation. 2021;56(2):357-367
Abstract
The number of individuals undergoing unrelated cord blood transplantation (UCBT) has increased in recent years; however, information on prognostic factors is limited. We retrospectively analyzed data from 475 children and adolescents receiving UCBT with myeloablative conditioning for acute lymphoblastic leukemia (ALL) in complete remission (CR), based on a nationwide registry. In the total patient cohort, 5-year leukemia-free survival (LFS) and overall survival (OS) rates after UCBT were 61.1% and 67.7%, respectively. UCBT at first CR and UCBT after 2007 were associated with good survival, while grade II-IV acute graft-versus-host disease (GVHD) was associated with low relapse rate but did not affect survival. Analysis according to human leukocyte antigen (HLA) disparity revealed that tacrolimus-based GVHD prophylaxis resulted in higher OS and lower relapse rate and nonrelapse mortality (NRM) than cyclosporine-based GVHD prophylaxis in patients transplanted with 6/6 and ≤4/6 HLA-matched umbilical cord blood. Furthermore, grade II-IV acute GVHD was associated with good LFS and low relapse rate, without high NRM, in patients receiving 5/6 HLA-matched UCBT. These data indicate that prognostic factors for ALL differ depending on HLA disparity in UCBT.
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Myeloablative haploidentical BMT with posttransplant cyclophosphamide for hematologic malignancies in children and adults
Symons, H. J., Zahurak, M., Cao, Y., Chen, A., Cooke, K., Gamper, C., Klein, O., Llosa, N., Zambidis, E. T., Ambinder, R., et al
Blood advances. 2020;4(16):3913-3925
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Abstract
Promising results have been reported for patients with high-risk hematologic malignancies undergoing HLA-haploidentical bone marrow transplantation (haploBMT) with posttransplantation cyclophosphamide (PTCy), but there are few data on outcomes with myeloablative conditioning in this context. We report the results of a single-institution, prospective phase 2 trial of myeloablative haploBMT using busulfan-based or total body irradiation-based conditioning in 96 children or adults (median age, 42 years; range, 1-65 years) with high-risk hematologic malignancies. Recovery of neutrophils and platelets occurred at a median of 24 and 29 days. Engraftment of donor cells with chimerism >95% was achieved in 91%. The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and grades III to IV at day 100 was 11% and 4%, and of chronic GVHD at 6 and 12 months was 4% and 15%, with 6% moderate to severe. The cumulative incidence of nonrelapse mortality was 6% at 100 days and 11% at 1 year (19% in those aged >55 years). The cumulative incidence of relapse at 1 year was 35%; at 3 years, it was 43%. In multivariable analysis, relapse was associated with increased age (P = .02 for age 20-55 years and P = .02 for age >55 years) and with minimal residual disease before transplantation (P = .05). The overall survival at 1 and 3 years is 73% and 54%, and event-free survival at 1 and 3 years is 57% and 49%. We show that haploBMT with PTCy after myeloablative conditioning is safe and efficacious for adult and pediatric patients with hematologic malignancies. Careful consideration must be given to using myeloablative conditioning in patients age >55 years. This trial was registered at www.clinicaltrials.gov as #NCT00796562.
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Late effects after ablative allogeneic stem cell transplantation for adolescent and young adult acute myeloid leukemia
Lee, C. J., Kim, S., Tecca, H. R., Bo-Subait, S., Phelan, R., Brazauskas, R., Buchbinder, D., Hamilton, B. K., Battiwalla, M., Majhail, N. S., et al
Blood advances. 2020;4(6):983-992
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Abstract
There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P < .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning.
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Experience with a Reduced Toxicity Allogeneic Transplant Regimen for Non-CGD Primary Immune Deficiencies Requiring Myeloablation
Chandra, S., Chandrakasan, S., Dávila Saldaña, B. J., Bleesing, J. J., Jordan, M. B., Kumar, A. R., Grimley, M. S., Krupski, C., Davies, S. M., Khandelwal, P., et al
Journal of clinical immunology. 2020
Abstract
PURPOSE A need exists for reduced toxicity conditioning regimens that offer less toxicity while maintaining myeloablation, especially for primary immune deficiencies where myeloablation or high donor myeloid chimerism is required to achieve cure. We adapted a busulfan and fludarabine regimen by Gungor et al. for children and young adults undergoing allogeneic HCT for non-CGD primary immune deficiencies requiring myeloablation or high donor myeloid chimerism, and herein report our experience. METHODS We retrospectively reviewed records of 41 consecutive patients who underwent allogeneic HCT for Wiskott-Aldrich syndrome (n = 12), primary HLH/XLP (n = 10), CD40L deficiency (n = 7), or other (n = 12) primary immune deficiencies with a conditioning regimen containing pharmacokinetic-guided busulfan dosing which achieved a cumulative AUC between 57 and 74 mg/L × h (65-80% of conventional myeloablative exposure), along with fludarabine and alemtuzumab or anti-thymocyte globulin at 3 transplant centers between 2014 and 2019. RESULTS Forty-one patients underwent a first (n = 33) or second (n = 8) allogeneic HCT. Median age was 2.3 years (range, 0.3 years-19.8 years). All but one patient (97.5%) achieved neutrophil recovery at a median of 14 days (range, 11-34 days). One patient developed sinusoidal obstruction syndrome and two patients developed diffuse alveolar hemorrhage. Four patients developed grades II-IV acute GVHD. Three patients developed chronic GVHD. One-year overall survival was 90% (95% confidence interval [CI] 81-99%) and event-free survival was 83% (95% CI 71-94%). CONCLUSIONS Our experience suggests that a reduced toxicity busulfan-fludarabine regimen offers low toxicity, low incidence of grades 2-4 GVHD, durable myeloid engraftment, and excellent survival, and may be considered for a variety of primary immune deficiencies where myeloablative HCT is desired.
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Immune recovery after in vivo T-cell depletion myeloablative conditioning hematopoietic stem cell transplantation in severe beta-thalassemia children
Qin, F., Shi, L., Li, Q., Zhang, Z., Liu, L., Li, J., Yang, G., Lai, Y.
European journal of haematology. 2019
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Editor's Choice
Abstract
BACKGROUND The clinical outcome of HSCT in those with severe beta-thalassemia (beta-TM) is closely related to post-transplantation immune reconstitution (IR). However, the data on the IR in these settings are scarce. METHODS A prospective analysis of the clinical outcome and IR in 47 children with severe beta-TM who underwent in vivo T-cell depletion myeloablative conditioning and matched sibling donor HSCT was performed. IR, including immune cell subset counts, as well as the generation of new T and B cells assays after HSCT, was measured. RESULTS In the first year after HSCT, bacterial infections, cytomegalovirus (CMV) reactivation were observed in 70.2% and 36.2% of the patients, respectively. In the same period, poor CD4(+) T cell recovery were observed. The B cells recovered within 6 months. NK cells recovered as early as 1 month, but their function was defective. Cord blood and bone marrow (CB+BM) group had slower T cell recovery, and higher B cells and NK cells in comparison to peripheral blood and bone marrow (PB+BM) group. CONCLUSION The high incidence of infection within 1 year after in vivo T-cell depletion myeloablative conditioning HSCT in severe beta-TM was consistent with poor IR. This article is protected by copyright. All rights reserved.
PICO Summary
Population
Children with severe beta-thalassaemia (n=47).
Intervention
In vivo T-cell depletion myeloablative conditioning and matched sibling donor HSCT.
Comparison
None.
Outcome
In the first year after HSCT, bacterial infections, cytomegalovirus (CMV) reactivation were observed in 70.2% and 36.2% of the patients, respectively. In the same period, poor CD4(+) T cell recovery were observed. The B cells recovered within 6 months. NK cells recovered as early as 1 month, but their function was defective. Cord blood and bone marrow (CB+BM) group had slower T cell recovery, and higher B cells and NK cells in comparison to peripheral blood and bone marrow (PB+BM) group.
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Myeloablative unrelated cord blood transplantation in adolescents and young adults with acute leukemia
Hayashi, H., Volt, F., Sanz, J., Petersen, E., Dhedin, N., Hough, R., Milpied, N., Angelucci, E., Yakoub-Agha, I., Michallet, M., 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
Outcomes for adolescents and young adults (AYA) with leukemia differ from other age groups but are still underrepresented in clinical research. The aim of this study was to analyze outcomes of umbilical cord blood transplant (UCBT) in AYA with acute leukemia reported to Eurocord/EBMT. Patients (n=504) had acute lymphoblastic (59%) or myeloid leukemia (41%), were aged 15-25 years, and received UCBT after myeloablative conditioning regimens between 2004 and 2016. Primary endpoint was 3-year overall survival (OS). Median follow-up was 3.9 years. Transplant was single in 58% and double UCBT in 42%. Three-year OS was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIF) of non-relapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute GVHD grade II-IV at day-100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT (HR 2.74, p <0.001) and more recent UCBT (HR 1.43, p=0.01) were associated with increased OS and a similar effect of these factors was observed on LFS. Contrastingly, the use of ATG had a negative effect in LFS. The risk of acute GVHD grade II-IV increased with the use of double UCBT (HR 1.65, p =0.02) and decreased with more recent transplantation period (HR 0.65, p=0.02) and ATG use (HR 0.55, p =0.01). Outcomes of AYA UCBT improved in more recent years becoming comparable to pediatric results. Demonstrating the feasibility of UCBT in AYA facilitates stem cell source selection and provides the basis for future prospective studies.
PICO Summary
Population
Adolescents and young adults with acute leukaemia (n=504)
Intervention
Unrelated cord blood transplantation after myeloablative conditioning
Comparison
None
Outcome
Three-year overall survival (OS) was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIF) of non-relapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute GVHD grade II-IV at day-100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT and more recent UCBT were associated with increased OS and a similar effect of these factors was observed on LFS. Contrastingly, the use of ATG had a negative effect in LFS. The risk of acute GVHD grade II-IV increased with the use of double UCBT and decreased with more recent transplantation period and ATG use.
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Comparison of conditioning regimens for autologous stem cell transplantation in children with acute myeloid leukemia: A nationwide retrospective study in Japan
Sakaguchi, H., Muramatsu, H., Hasegawa, D., Kudo, K., Ishida, H., Yoshida, N., Koh, K., Noguchi, M., Shiba, N., Tokimasa, S., et al
Pediatric blood & cancer. 2018;:e27459
Abstract
BACKGROUND Indications for hematopoietic stem cell transplantation (HSCT) have decreased with the improvement in chemotherapy for pediatric acute myeloid leukemia (AML) in the last decade. We conducted reevaluation of autologous HSCT (AHSCT) to compare myeloablative conditioning (MAC) regimens for pediatric AML without the need for consideration of toxicities caused by allogeneic immune reactions. PROCEDURE This retrospective study analyzed the clinical outcomes of 220 children with AML who underwent consecutive AHSCT between 1989 and 2002 in Japan by the national prospective registry. The transplantation outcomes of various conditioning regimens were compared. RESULTS The median follow-up period of the survivors was 160 months. The clinical outcomes of busulfan + cyclophosphamide +/- etoposide or busulfan + melphalan regimens were significantly superior compared with other busulfan-based and total body irradiation-based regimens (leukemia-free survival [LFS]: 68% vs 42% and 55%, P = 0.001; overall survival [OS]: 74% vs 49% and 61%, P < 0.001). Multivariate analysis showed that busulfan + cyclophosphamide +/- etoposide and busulfan + melphalan regimens were independent favorable factors for LFS (hazard ratio: 0.46; P < 0.001) and OS (hazard ratio: 0.40; P < 0.001) compared with the other busulfan-based regimen, and both age 2 years or older and advanced stage at AHSCT were independent poor predictors for LFS and OS, simultaneously. CONCLUSION Busulfan + cyclophosphamide +/- etoposide and busulfan + melphalan regimens exhibited superior antileukemic effects compared with other BU-based myeloablative regimens.