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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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Full text
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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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Busulfan-Based and Treosulfan-Based Myeloablative Conditioning for Allogeneic Transplantation in Children with Thalassemia Major: a Single-Center Experience From Southern Turkey
Aygüneş, U., Karagun, B. S., Ay Tuncel, D., Sasmaz, H. I., Antmen, B.
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 2023;21(11):883-892
Abstract
OBJECTIVES Allogeneic hematopoietic stem cell transplant is the only curative treatment for patients with transfusion-dependent thalassemia major. In recent years, a number of novel approaches have improved patient outcomes and quality of life by minimizing the toxicity of conditioning regimens. The objective of this study was to compare the role of treosulfan- and busulfan-based conditioning in transfusion-dependent thalassemia. MATERIALS AND METHODS Data were collected retrospectively on 121 children with beta thalassemia major who underwent hematopoietic stem cell transplant using treosulfan-based (n = 37) or busulfan-based (n = 84) conditioning regimens between 2012 and 2022. RESULTS Two-year overall survival was 87.5% in the busulfan-based conditioning group and 91.1% in the treosulfan-based conditioning group.The group given the busulfan regimen compared with treosulfan regimen had significantly increased number of side effects (58.3% vs 21.6%, respectively; P < .001). When the busulfan-based regimen by level was evaluated, we observed no significant differences between the frequency of side effects according to drug serum levels. In addition, no significant differences were shown between the 2 regimen groups for cumulative incidence of acute and chronic graft-versus-host disease. CONCLUSIONS The safety and effectiveness of a treosulfan-based myeloablative conditioning regimen has been confirmed by ourretrospective investigation of pediatric patients with beta thalassemia.
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Busulfan-fludarabine- or treosulfan-fludarabine-based conditioning before allogeneic HSCT from matched sibling donors in paediatric patients with sickle cell disease: A study on behalf of the EBMT Paediatric Diseases and Inborn Errors Working Parties
Cseh, A., Galimard, J. E., de la Fuente, J., Isgro, A., Zecca, M., Garwer, B., Biffi, A., Aljurf, M., Sundin, M., Belendez, C., et al
British journal of haematology. 2023
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Editor's Choice
Abstract
How important is choice of conditioning regimen in allogeneic haematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD)? We compared HSCT outcomes by conditioning regimen in paediatric patients with SCD from the EBMT registry. In 2010-2020, 251 patients aged <18 years underwent a first matched sibling donor (MSD) HSCT with conditioning based on busulfan-fludarabine (bu-flu; n = 89) or treosulfan-fludarabine (treo-flu; n = 162). In the bu-flu and treo-flu groups, 51.7% and 99.4% of patients, respectively, received thiotepa. Median follow-up was 2.7 years. Two-year overall survival (OS) was 98.7% (95% confidence interval [CI]: 90.9-99.8) with bu-flu and 99.3% (95% CI: 95.2-99.9) with treo-flu (p = 0.63). Grade III-IV acute graft-versus-host disease (GVHD) at 100 days was 2.4% (95% CI: 0.4-7.5) and 0.6% (0.1%-3.2%) for bu-flu and treo-flu respectively (p = 0.25). The 2-year incidence of extensive chronic GVHD was 1.5% (95% CI: 0.1-7.3) with bu-flu and 8.0% (95% CI: 4.1-13.3) with treo-flu (p = 0.057). These multinational data confirm the excellent curative capacity of MSD HSCT with myeloablative conditioning. Both conditioning regimens yielded excellent OS, low rates of acute and chronic GVHD, and low rates of graft failure.
PICO Summary
Population
Children who underwent transplant for sickle cell disease, identified from the EBMT registry (n=251)
Intervention
Conditioning based on busulfan-fludarabine (bu-flu, n=89)
Comparison
Conditoning based on treosulfan-fludarabine (treo-flu, n=162).
Outcome
Median follow-up was 2.7 years. Two-year overall survival (OS) was 98.7% (95% confidence interval [CI]: 90.9-99.8) with bu-flu and 99.3% (95% CI: 95.2-99.9) with treo-flu. Grade III-IV acute graft-versus-host disease (GVHD) at 100 days was 2.4% (95% CI: 0.4-7.5) and 0.6% (0.1%-3.2%) for bu-flu and treo-flu respectively. The 2-year incidence of extensive chronic GVHD was 1.5% (95% CI: 0.1-7.3) with bu-flu and 8.0% (95% CI: 4.1-13.3) with treo-flu.
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Recent results of hematopoietic stem cell transplantation for thalassemia with busulfan-based conditioning regimen in France: improved thalassemia free survival despite frequent mixed chimerism. A retrospective study from the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)
Rossi, M., Szepetowski, S., Yakouben, K., Paillard, C., Sirvent, A., Castelle, M., Pegon, C., Piguet, C., Grain, A., Angoso, M., et al
Bone marrow transplantation. 2023
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Is Old (Fludrabine/Busulfan/Cyclophosphamide/rAntiThymocyteGlobulin) Conditioning Still Gold for Allogeneic Transplants in Transfusion Dependent Beta-Thalassemia of All Risk Categories in 21st Century?
Mehta, D. M. P., Khushoo, V.
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion. 2023;:1-9
Abstract
Allogeneic stem cell transplant (allo-SCT) is the only curative option for transfusion dependent thalassemia (TDT) until the gene therapy could bring paradigm shift. We analysed TDT allo-SCTs performed with Flu/Bu/Cy/rATG conditioning between October 2018 and April 2022 at our center. A retrospective analysis of 55 consecutive HLA matched alloSCT for TDT and was approved by hospital's Institutional Review Board. Median age was 7(2-13) years. On presentation, number of patients with Class I, II, III were 18 (32.7%), 14(25.4%) and 23(41.8%) respectively {ClassIIIA = 14(25.4%),ClassIIIB = 9(16.3%)}. After downstaging, Class I, II, III were 22(40%), 15(27.2%) and 18(32.7%) patients respectively {ClassIIIA = 15(27.2%),ClassIIIB = 3(5.4%)}. Graft was bone marrow in 53(96.4%) and peripheral blood stem cell in 2(3.6%) patients. Mean CD34 stem cell dose was 3.28(1.2-6.5) × 10(6)/kg. Neutrophils and platelets engrafted at a median of 16(12-32) and 17(12-48) days. Median duration of follow-up was 20.7(1.8-43.9) months. There was no primary rejection. Although, mixed chimerism was common {17(30.9%)}, there was only one secondary rejection (1.8%). Venoocclusive disease was seen 12(21.8%) patients {mild = 9(75%), moderate = 2(16.6%) and severe = 1(8.3%)}. Acute and Chronic graft versus host disease was observed in 4(7.2%) and 4(7.2%) patients respectively. There was no treatment related mortality. Overall survival and Thalassemia Free Survival were 100% ± 0% and 98% ± 2% respectively. Flu/Bu/Cy/rATG conditioning with BM graft is a safe and effective regimen even in higher risk. It also highlights the importance of pretransplant downstaging of risk class in improving the outcomes.
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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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Alemtuzumab clearance, lymphocyte count, and T-cell chimerism after hematopoietic stem cell transplant in sickle cell disease
Furstenau, D., Peer, C. J., Hughes, T. E., Uchida, N., Tisdale, J., Hall, O. M., Figg, W. D., Hsieh, M.
Pharmacotherapy. 2022;42(1):14-22
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Free full text
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Abstract
STUDY OBJECTIVE Alemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such as chronic lymphocytic leukemia, and incorporated into many hematopoietic stem cell transplant (HSCT) conditioning regimens, few studies have evaluated the pharmacology of alemtuzumab in adult patients with sickle cell disease (SCD). We therefore examined the pharmacokinetics (PK) and pharmacodynamics (PD) of alemtuzumab in adults with SCD who received a matched related donor HSCT to determine if the clearance of alemtuzumab affects transplant outcomes. DESIGN PK and PD analysis of patient data from a single-center clinical trial. SETTING Clinical research center. PATIENTS Twenty-two adult patients with SCD who received one of two nonmyeloablative allogeneic HSCT regimens: alemtuzumab and total body irradiation (Alem-TBI) or pentostatin, cyclophosphamide, alemtuzumab, and total body irradiation (Pento-Cy-Alem-TBI). MEASUREMENTS AND MAIN RESULTS Alemtuzumab serum concentrations, absolute lymphocyte counts, T-cell (CD3), and myeloid (CD14/15) chimerism were collected at distinct time points and analyzed. A semi-mechanistic PK population model was built to understand inter-individual differences in pharmacology. Alemtuzumab was detectable up to 28 days post-HSCT. The mean alemtuzumab level 7 days after transplant for patients on Alem-TBI was 818 ng/ml, significantly lower than the mean level of 1502 ng/ml for patients on Pento-Cy-Alem-TBI (p < 0.001), but this difference decreased as time progressed. The clearance of alemtuzumab was linear, and the half-life was longer in the Pento-Cy-Alem-TBI group (average half-life = 61.1 h) compared to the Alem-TBI group (average half-life = 44.1 h) (p < 0.001). The CD3 chimerism at 2 and 4 months after transplant positively correlated with alemtuzumab levels collected on day 14 after transplant (R(2) = 0.40 and p = 0.004 at 2 months, R(2) = 0.36 and p = 0.005 at 4 months), but this significance was lost by 6 months after HSCT. No correlation was seen between alemtuzumab levels and CD14/15 chimerism. CONCLUSION Between 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment, suggesting more lymphodepletion may be needed to reduce graft failure in these two non-myeloablative matched related donor HSCT regimens.
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HLA-matched related-donor hematopoietic stem cell transplantation is a suitable treatment in adolescents and adults with sickle cell disease: comparison of myeloablative and non-myeloablative approaches
Dhedin, N., Chevillon, F., Castelle, M., Lavoipière, V., Vasseur, L., Dalle, J. H., Joseph, L., Beckerich, F., Buchbinder, N., Coman, T., et al
American journal of hematology. 2022