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Finding a balance in reduced toxicity hematopoietic stem cell transplantation for thalassemia: role of infused CD3+ cell count and immunosuppression
Meissner, B., Lang, P., Bader, P., Hoenig, M., Müller, I., Meisel, R., Greil, J., Sauer, M. G., Metzler, M., Corbacioglu, S., et al
Bone marrow transplantation. 2024
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Editor's Choice
Abstract
We performed a retrospective analysis on 124 patients with transfusion-dependent thalassemia who were registered in the German pediatric registry for stem cell transplantation. All patients underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 2011 and 2020 and belonged mainly to Pesaro risk class 1-2. Four-year overall (OS) and thalassemia-free survival (TFS) were 94.5% ± 2.9% and 88.0% ± 3.4% after treosulfan-fludarabine-thiotepa- and 96.9% ± 3.1% (P = 0.763) and 96.9% ± 3.1% (P = 0.155) after busulfan-fludarabine-based conditioning. Mixed chimerism below 75% occurred predominantly in treosulfan-based regimens (27.5% versus 6.2%). OS and TFS did not differ significantly between matched sibling, other matched family and matched unrelated donor (UD) HSCTs (OS: 100.0%, 100.0%, 96.3% ± 3.6%; TFS: 96.5% ± 2.4%, 90.0% ± 9.5%, 88.9% ± 6.0%). However, mismatched UD-HSCTs performed less favorable (OS: 84.7% ± 7.3% (P = 0.029); TFS: 79.9% ± 7.4% (P = 0.082)). We generated a scoring system reflecting the risk to develop mixed chimerism in our cohort. The main risk-reducing factors were a high CD3+ cell count (≥6 × 10(7)/kg) in the graft, busulfan-conditioning, pre-conditioning therapy and low-targeted ciclosporin A trough levels. Acute GvHD grade III-IV in treosulfan-based concepts predominantly occurred in patients with UD and reduced GvHD prophylaxis but not in the context of high CD3+ cell doses. Taken together, this information might be used to develop more risk-adapted HSCT regimens for thalassemia patients.
PICO Summary
Population
Children and young adults with transfusion-dependent thalassemia who underwent first allogeneic transplant between 2011 and 2020 and were registered in the German pediatric registry for stem cell transplantation. (n=124)
Intervention
Treosulfan-fludarabine-thiotepa based conditioning (n=92)
Comparison
Busulfan-fludarabine-based conditioning (n=32)
Outcome
Four-year overall (OS) and thalassemia-free survival (TFS) were 94.5% ± 2.9% and 88.0% ± 3.4% after treosulfan-fludarabine-thiotepa- and 96.9% ± 3.1% and 96.9% ± 3.1% after busulfan-fludarabine-based conditioning. Mixed chimerism below 75% occurred predominantly in treosulfan-based regimens (27.5% versus 6.2%). OS and TFS did not differ significantly between matched sibling, other matched family and matched unrelated donor (UD) HSCTs (OS: 100.0%, 100.0%, 96.3% ± 3.6%; TFS: 96.5% ± 2.4%, 90.0% ± 9.5%, 88.9% ± 6.0%). However, mismatched UD-HSCTs performed less favorable (OS: 84.7% ± 7.3%; TFS: 79.9% ± 7.4%). We generated a scoring system reflecting the risk to develop mixed chimerism in our cohort. The main risk-reducing factors were a high CD3+ cell count (≥6 × 10(7)/kg) in the graft, busulfan-conditioning, pre-conditioning therapy and low-targeted ciclosporin A trough levels. Acute GvHD grade III-IV in treosulfan-based concepts predominantly occurred in patients with UD and reduced GvHD prophylaxis but not in the context of high CD3+ cell doses.
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Treosulfan Exposure Predicts Thalassemia-free Survival In Patients With Beta Thalassemia Major (TM) Undergoing Allogeneic Hematopoietic Cell Transplantation
Pai, A. A., Mohanan, E., Panetta, J. C., Kulkarni, U. P., Stallon Illangeswaran, R. S., Balakrishnan, B., Jayaraman, A., Edison, E. S., Kavitha, M. L., Devasia, A. J., et al
Clinical pharmacology and therapeutics. 2023
Abstract
A toxicity-reduced conditioning regimen with Treosulfan, Fludarabine, and Thiotepa in patients with high-risk β- thalassemia major has significantly improved HCT outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of Treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with β-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of Treosulfan is feasible. Plasma Treosulfan/S, S-EBDM levels were measured in seventy-seven patients using a validated LC-MS/MS method, and the PK parameters were estimated using nlmixr2. The influence of Treosulfan & S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year Overall Survival (OS), and Thalassemia Free Survival (TFS) were assessed. We observed that Treosulfan exposure was lower in patients with graft rejection than those without (1655 vs. 2037 mg*h/L, p=0.07). Pharmacodynamic modeling analysis to identify therapeutic cut-off revealed that Treosulfan exposure ≥1660 mg*hr/L was significantly associated with better 1-year TFS (97% vs. 81%, p=0.02) and a trend to better 1-year OS (90% vs. 69%, p=0.07). Further, multivariate analysis adjusting for known PreHCT risk factors also revealed Treosulfan exposure <1660mg*h/L (HR=3.23; 95% CI=1.12-9.34; p=0.03) and GSTA1*B variant genotype (HR=3.75; 95% CI=1.04-13.47; p=0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower Treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing Treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.
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Excellent outcome of stem cell transplantation for sickle cell disease
Vallée, T., Schmid, I., Gloning, L., Bacova, M., Ahrens, J., Feuchtinger, T., Klein, C., Gaertner, V. D., Albert, M. H.
Annals of hematology. 2023
Abstract
Many sickle cell disease (SCD) patients lack matched family donors (MFD) or matched unrelated donors (MUD), implying haploidentical donors (MMFD) as a logical donor choice. We used a reduced toxicity protocol for all donor types. We included 31 patients (2-22 years) with MFD (n = 15), MMFD (10), or MUD (6) HSCT and conditioning with alemtuzumab/ATG, thiotepa, fludarabine and treosulfan, and post-transplant cyclophosphamide for MMFD. After the initial six patients, treosulfan was replaced by targeted busulfan (AUC 65-75 ng*h/ml). After a median follow-up of 26 months (6-123), all patients are alive and off immunosuppression. Two MMFD patients experienced secondary graft failure with recurrence of SCD, both after treosulfan conditioning. Neither acute GVHD ≥ °III nor moderate/severe chronic GVHD was observed. The disease-free, severe GVHD-free survival was 100%, 100%, and 80% in the MFD, MUD, and MMFD groups, respectively (p = 0.106). There was a higher rate of virus reactivation in MMFD (100%) and MUD (83%) compared to MFD (40%; p = 0.005), but not of viral disease (20% vs 33% vs 13%; p = 0.576). Six patients had treosulfan-based conditioning, two of whom experienced graft failure (33%), compared to 0/25 (0%) after busulfan-based conditioning (p = 0.032). Donor chimerism was ≥ 80% in 28/31 patients (90%) at last follow-up. Reduced toxicity myeloablative conditioning resulted in excellent overall survival, negligible GVHD, and low toxicity among all donor groups in pediatric and young adult patients with SCD.
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Increased incidence of hematologic malignancies in SCD after HCT in adults with graft failure and mixed chimerism
Lawal, R. A., Mukherjee, D., Limerick, E. M., Coles, W., Hsieh, M. M., Dillon, L. W., Hourigan, C. S., Fitzhugh, C. D.
Blood. 2022;140(23):2514-2518
Abstract
Lawal et al report on a 45-fold increase in secondary hematologic malignancy in 120 patients following hematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD), comparable to what has been reported following gene therapy. Notably, the cohort is enriched for older patients and for haploidentical transplant recipients with mixed chimerism following HSCT. These data further support the idea that pre-existing premalignant myeloid clones undergo clonal selection in the setting of nonmyeloablative HSCT and contribute to secondary malignancy.
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Unrelated Donor Transplantation in Children with Thalassemia Using Reduced Intensity Conditioning - the URTH Trial
Shenoy, S., Walters, M. C., Ngwube, A., Soni, S., Jacobsohn, D., Chaudhury, S., Grimley, M., Chan, K., Haight, A., Kasow, K. A., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalassemia (TDT). In a multicenter trial, we investigated the efficacy of reduced intensity conditioning (RIC) before unrelated donor (URD) HSCT in children with TDT. Thirty-three children (1-17 years), received marrow or cord blood (UCB) allografts. Median time to neutrophil engraftment was 13 (range, 10-25) and 24 (range, 18-49) days; platelet engraftment was 23 (range, 12-46) and 50 (range, 31-234) days after marrow and UCB respectively. With median follow-up of 58 (range, 7-79) months, overall and thalassemia-free survival was 82% (95% CI, 0.64-0.92) and 79% (95% CI, 0.6-0.9) respectively. The cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) after marrow and UCB was 24% and 44%; the 2-year CI of chronic extensive GVHD was 29% and 21% respectively; 71% (marrow) and 91% (UCB) recipients discontinued systemic immunosuppression by 2 years. Six patients who had Pesaro risk class 2 (N=5) and class 3 (N=1) died of GVHD (N=3), viral pneumonitis (N=2) and pulmonary hemorrhage (N=1). Outcomes following this RIC compared favorably with URD HSCT outcomes for TDT and supported engraftment in 32 of 33 patients. Efforts to reduce GVHD and infectious complications are being pursued further.