Effect of Busulfan and Treosulfan on Gonadal Function after Allogeneic Stem Cell Transplantation in Children and Adolescents with Nonmalignant Diseases Is Not Exposure-Dependent

Stoep, M Y E C van der; Bense, Joëll E; Kloet, Liselotte C de; Asmuth, Erik G J von; Pagter, Anne P J de; Hannema, Sabine; Guchelaar, Henk‐Jan; Zwaveling, J.; Lankester, Arjan C.

doi:10.1016/j.jtct.2023.05.003

Cited by 3 publications

(3 citation statements)

References 27 publications

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“…Overall, the detection of clinical/biochemical signs consistent with impaired Leydig cell function raised from 36.9% in the study population up to 84.5% in the TBI cohort. These findings are consistent with the data published by other authors ( 11 , 20 ).…”

Section: Discussionsupporting

confidence: 94%

“…When assessing patients who had achieved Tanner stage 5, statistically smaller median TV was found in patients who were prepubertal at the time of HSCT. These results, consistent with those reported by Wilhelmsson and colleagues and de Kloet and colleagues ( 20 , 22 ), seem to collide with the remarkable reduction of the risk of developing hypogonadism among patients prepubertal upon HSCT versus those peri-/post-puberal, as this supports the hypothesis of a protective role of younger age and prepubertal status on gonadal health following transplantation. This apparent paradox can be easily explained considering that most patients from the PostP cohort had already achieved a certain TV before undergoing transplantation.…”

Section: Discussionsupporting

confidence: 89%

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Pubertal attainment and Leydig cell function following pediatric hematopoietic stem cell transplantation: a three-decade longitudinal assessment

Cattoni,

Nicolosi,

Capitoli

et al. 2023

Front. Endocrinol.

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IntroductionImpaired testosterone secretion is a frequent sequela following hematopoietic stem cell transplantation (HSCT) in pediatrics, but long-term longitudinal trendlines of clinical and biochemical findings are still scanty.MethodsMonocentric, retrospective analysis. Male patients transplanted <18 years between 1992 and 2021, surviving ≥2 years after HSCT and showing, upon enrollment, clinical and biochemical signs consistent with pubertal onset and progression were included. Clinical and biochemical data collected every 6-12 months were recorded.ResultsOf 130 patients enrolled, 56% were prepubertal, while 44% were peri-/postpubertal upon HSCT. Overall, 44% showed spontaneous progression into puberty and normal gonadal profile, while the remaining experienced pubertal arrest (1%), isolated increase of FSH (19%), compensated (23%) or overt (13%) hypergonadotropic hypogonadism. Post-pubertal testicular volume (TV) was statistically smaller among patients still pre-pubertal upon HSCT (p 0.049), whereas no differences were recorded in adult testosterone levels. LH and testosterone levels showed a specular trend between 20 and 30 years, as a progressive decrease in sexual steroids was associated with a compensatory increase of the luteinizing hormone. A variable degree of gonadal dysfunction was reported in 85%, 51%, 32% and 0% of patients following total body irradiation- (TBI), busulfan-, cyclophosphamide- and treosulfan-based regimens, respectively. TBI and busulfan cohorts were associated with the lowest probability of gonadal event-free course (p<0.0001), while it achieved 100% following treosulfan. A statistically greater gonadotoxicity was detected after busulfan than treosulfan (p 0.024). Chemo-only regimens were associated with statistically larger TV (p <0.001), higher testosterone (p 0.008) and lower gonadotropin levels (p <0.001) than TBI. Accordingly, the latter was associated with a 2-fold increase in the risk of gonadal failure compared to busulfan (OR 2.34, CI 1.08-8.40), whereas being pre-pubertal upon HSCT was associated with a reduced risk (OR 0.15, CI 0.08-0.30).Conclusionsa) patients pre-pubertal upon HSCT showed a reduced risk of testicular endocrine dysfunction, despite smaller adult TV; b) patients showed downwards trend in testosterone levels after full pubertal attainment, despite a compensatory increase in LH; c) treosulfan was associated to a statistically lower occurrence of hypogonadism than busulfan, with a trend towards larger TV, higher testosterone levels and lower gonadotropins.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 89%

Pubertal attainment and Leydig cell function following pediatric hematopoietic stem cell transplantation: a three-decade longitudinal assessment

Cattoni,

Nicolosi,

Capitoli

et al. 2023

Front. Endocrinol.

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“…Strikingly, we also observed that in the high exposure group (>2,400 mg•hour/L), there were no graft rejections, lesser incidence of RRTs (one patient developed SOS), and one death (a patient died due to dengue) ( Figure ) . Our results indicate that TDM‐based dose escalation would benefit patients, especially in the underexposure group, minimizing graft rejection and early TRM without resulting in treatment‐related toxicities as reported previously 18,39 …”

Section: Discussionsupporting

confidence: 81%

Treosulfan Exposure Predicts Thalassemia‐Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation

Pai,

Mohanan,

Panetta

et al. 2023

Clin Pharma and Therapeutics

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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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Long-Term Complications after Allogeneic Hematopoietic Stem Cell Transplantation with Treosulfan- or Busulfan-Based Conditioning in Pediatric Patients with Acute Leukemia or Myelodysplastic Syndrome: Results of an Associazione Italiana Ematologia Oncologia Pediatrica Retrospective Study

Saglio,

Pagliara,

Zecca

et al. 2024

Transplantation and Cellular Therapy

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Effect of Busulfan and Treosulfan on Gonadal Function after Allogeneic Stem Cell Transplantation in Children and Adolescents with Nonmalignant Diseases Is Not Exposure-Dependent

Cited by 3 publications

References 27 publications

Pubertal attainment and Leydig cell function following pediatric hematopoietic stem cell transplantation: a three-decade longitudinal assessment

Pubertal attainment and Leydig cell function following pediatric hematopoietic stem cell transplantation: a three-decade longitudinal assessment

Treosulfan Exposure Predicts Thalassemia‐Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation

Long-Term Complications after Allogeneic Hematopoietic Stem Cell Transplantation with Treosulfan- or Busulfan-Based Conditioning in Pediatric Patients with Acute Leukemia or Myelodysplastic Syndrome: Results of an Associazione Italiana Ematologia Oncologia Pediatrica Retrospective Study

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