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Influential Factors and Efficacy Analysis of Tacrolimus Concentration After Allogeneic Hematopoietic Stem Cell Transplantation in Children with ß-Thalassemia Major
Li, C., Lu, J., Zhou, S., Wei, Y., Lv, C., Liu, T., Wu, Y., Wu, D., Qi, J., Cai, R.
Pharmacogenomics and personalized medicine. 2021;14:1221-1237
Abstract
PURPOSE To analyze factors influencing tacrolimus (TAC) trough concentration (C(0)) in ß-thalassemia major (ß-TM) pediatric patients after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and to investigate the effects of genotype polymorphism and drug-drug interactions on TAC trough concentration in children with ß-TM. Furthermore, to analyze the correlation between TAC C(0) and efficacy and adverse reactions. PATIENTS AND METHODS Prospectively collection of demographic information and details of combined treatment of patients with ß-TM receiving HSCT, and genotypes of CYP3A4, CYP3A5, and ABCB1 (rs1045642, rs1128503, rs2032582) were obtained for each patient. Univariate analysis and multiple linear regression analysis were used to investigate influencing factors on TAC C(0). The impact of different genotypes and the co-administration of azole antifungal drugs on ß-TM patients receiving TAC were evaluated, together with the correlation between acute graft-versus-host disease (aGVHD), infection, and liver injury of TAC C(0). RESULTS A total of 46 patients with 587 concentration data were included. The multiple linear regression results showed that the patient's sex, weight, postoperative time, hemoglobin, platelet count, serum cystatin C, and combined voriconazole were independent influencing factors of the infusion trough concentration/daily dose, C(0)/D(iv). Age, body surface area, postoperative time, co-administration of voriconazole, and CYP3A4*18B are independent influencing factors of C(0)/D(po). Group comparisons showed that voriconazole can affect TAC C(0) administered intravenously (IV) and orally in ß-TM pediatric patients, while patient genotype can affect TAC C(0) during oral administration. TAC C(0) does not correlate with aGVHD or liver injury, but infection may be associated with TAC C(0). CONCLUSION The concentration of TAC should be closely monitored when co-administered with voriconazole. It is worth considering that the influence of genotype on the trough concentration of oral TAC and individualized drug administration warrant investigation. Finally, this study indicated that C(0) is not suitable as an indicator of the efficacy of TAC.
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Abatacept is effective as GVHD prophylaxis in unrelated donor stem cell transplantation for children with severe sickle cell disease
Ngwube, A., Shah, N., Godder, K., Jacobsohn, D., Hulbert, M. L., Shenoy, S.
Blood advances. 2020;4(16):3894-3899
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Abstract
We report results of a phase 1 multicenter stem cell transplantation (SCT) trial from HLA-matched (n = 7) or one-antigen-mismatched (n = 7) unrelated donors (URD) using bone marrow or cord blood as stem cell source, following reduced-intensity conditioning (RIC) in severe sickle cell disease (SCD). Conditioning included distal alemtuzumab, fludarabine, and melphalan (matched donors), with thiotepa (mismatched donors). Abatacept, a selective inhibitor of T cell costimulation, was added to tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis to offset GVHD risks, and was administered for longer duration in bone marrow recipients than in cord blood recipients because of increased incidence of chronic GVHD with bone marrow. Median age at transplant was 13 years (range, 7-21 years). The incidence of grades II to IV and grades III to IV acute GVHD at day +100 was 28.6% and 7%, respectively. One-year incidence of chronic GVHD was 57% and mild/limited in all but 1 patient who received abatacept for a longer duration. Only 1 patient developed reversible posterior encephalopathy syndrome and recovered. With a median follow-up of 1.6 years (range, 1-5.5 years), the 2-year overall and disease-free survival was 100% and 92.9%, respectively. The encouraging results from the phase 1 portion of this RIC SCT trial, despite risk factors such as older age, URD, and HLA-mismatch, support further evaluation of URD SCT in clinical trial settings. The phase 2 portion of the trial is in progress. This trial was registered at www.clinicaltrials.gov as NCT03128996.
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Posterior Reversible Encephalopathy Syndrome after Hematopoietic Cell Transplantation in Children with Hemoglobinopathies
Gaziev, J., Marziali, S., Paciaroni, K., Isgro, A., Di Giuliano, F., Rossi, G., Marziali, M., De Angelis, G., Alfieri, C., Ribersani, M., et al
Biology of Blood & Marrow Transplantation. 2017;23(9):1531-1540
Abstract
Posterior reversible encephalopathy syndrome (PRES) is a serious adverse event associated with calcineurin inhibitors used for graft-versus-host disease (GVHD) prophylaxis. We compared the incidence of PRES in children with thalassemia (n=222, 1.4 to 17.8 years old) versus sickle cell disease (SCD; n=59, 2 to 17 years old) who underwent hematopoietic cell transplantation from HLA-matched siblings or alternative donors and analyzed the risk factors for PRES. Overall, 31 children developed calcineurin inhibitor-related PRES (11%), including 30 patients with seizures and 1 patient without seizures. PRES incidence was significantly higher in SCD patients (22%; 95% confidence interval [CI], 10% to 32%) than in thalassemia patients (8%; 95% CI, 5% to 12%;P=.002). In multivariate analysis, factors associated with PRES were hypertension (hazard ratio [HR], 5.87; 95% CI, 2.57 to 13.43; P=.0001), SCD (HR, 2.49; 95% CI, 1.25 to 4.99; P=.009), and acute GVHD (HR 2.27; 95% CI, 1.06 to 4.85; P=.031). In the entire cohort overall survival (OS) was significantly higher in patients without versus with PRES (90% versus 77%; P=.02). In a subgroup analysis that including matched sibling transplants, OS and disease-free survival (DFS) were similar in thalassemia patients without PRES (92% and 88%, respectively) and with PRES (82% and 73%, respectively), whereas SCD patients with PRES had significantly lower OS (67%) and DFS (67%) than patients without PRES (94% and 94%, respectively; P=.008). Thus, SCD patients had a significantly higher incidence of PRES than thalassemia patients, and hypertension and GVHD were the 2 main risk factors for PRES in patients with hemoglobinopathies. Although PRES did not significantly influence survival in patients with thalassemia, patients with SCD had significantly lower survival after PRES.
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Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT
Fitzhugh, C. D., Hsieh, M. M., Taylor, T., Coles, W., Roskom, K., Wilson, D., Wright, E., Jeffries, N., Gamper, C. J., Powell, J., et al
Blood Advances. 2017;1(11):652-661
Abstract
Peripheral blood stem cell transplantation (PBSCT) offers a curative option for sickle cell disease (SCD). Although HLA-matched sibling transplantation is promising, the vast majority of patients lack such a donor. We sought to develop a novel nonmyeloablative HLA-haploidentical PBSCT approach that could safely be used for patients with severe organ damage. Based on findings in our preclinical model, we developed a phase 1/2 trial using alemtuzumab, 400 cGy total body irradiation, and escalating doses of posttransplant cyclophosphamide (PT-Cy): 0 mg/kg in cohort 1, 50 mg/kg in cohort 2, and 100 mg/kg in cohort 3. A total of 21 patients with SCD and 2 with beta-thalassemia received a transplant. The mean hematopoietic cell transplant-specific comorbidity index of 6 reflected patients with cirrhosis, heart failure, and end-stage renal disease. The engraftment rate improved from 1 (33%) of 3 in cohort 1 to 5 (63%) of 8 in cohort 2 and 10 (83%) of 12 in cohort 3. Percentage of donor myeloid and CD3 chimerism also improved with subsequent cohorts. There was no transplant-related mortality, and overall survival was 87%. At present, 0% in cohort 1, 25% in cohort 2, and 50% in cohort 3 remain free of their disease. There was no grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD). Therefore, PT-Cy improves engraftment and successfully prevents severe GVHD after nonmyeloablative conditioning in patients with SCD who are at high risk for early mortality. Additional strategies are necessary to decrease the graft rejection rate and achieve a widely available cure for all patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT00977691. Conflict-of-interest disclosure: The authors declare no competing financial interests.