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Effect of Testicular Boost in Children With Leukemia Receiving Total Body Irradiation and Stem Cell Transplant: A Single-Institution Experience
Blomain, E. S., Jiang, A., Donaldson, S. S., Agarwal, R., Bertaina, A., Shyr, D., Eisenberg, M. L., Hoppe, R. T., Hiniker, S. M., Oh, J.
Advances in radiation oncology. 2023;8(1):101071
Abstract
PURPOSE Children with leukemia who receive fractionated total body irradiation (fTBI) with 12 to 13.2 Gy as part of conditioning for hematopoietic stem cell transplant are frequently treated with an additional 4 Gy testicular boost to reduce the risk of testicular relapse. While institutional practices vary, limited data exists regarding whether the 4-Gy testicular boost reduces the risk of relapse and whether it causes toxicity beyond that imparted by TBI. This study compared the survival and endocrine outcomes among the patients who were treated with and without a testicular boost as part of fTBI from 1990 to 2019 at our center. METHODS AND MATERIALS We retrospectively reviewed charts of male children with leukemia treated with fTBI as part of a conditioning regimen for stem cell transplant from 1990 to 2019. Reported outcomes included progression-free survival, testicular relapse rate, and overall survival. Gonadal dysfunction and fertility were assessed by comparing the rate of abnormally low testosterone or high luteinizing hormone or follicular stimulating hormone, number of offspring, fertility service use, and abnormal sperm count in the subsequent follow-up period between the testicular boost and nonboost subset. RESULTS Ninety-three male patients (63 acute lymphoblastic leukemia, 30 acute myeloid leukemia) with a median age of 9 years (range, 1-22) and follow-up of 3.3 years were included. In addition to 12- to 13.2-Gy fTBI, 51 male patients (54%) received a testicular boost to 4 Gy. There was 1 testicular relapse in the boost subset and none in the nonboost subset. Five-year progression-free survival for the boost and nonboost subset was 74% and 66%, respectively (P = .31). On multivariable analysis, boost was not associated with improved relapse-free survival or overall survival. More patients in the boost subset (35 of 51, 69%) had abnormal serum gonadal blood work compared with the nonboost subset (18 of 42, 43%) (P = .03). CONCLUSIONS Omission of testicular boost may be associated with comparable oncologic but improved gonadal endocrine outcomes and should be further studied.
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Volumetric modulated arc therapy total body irradiation in pediatric and adolescent/young adult patients undergoing stem cell transplantation: Early outcomes and toxicities
Marquez, C., Hui, C., Simiele, E., Blomain, E., Oh, J., Bertaina, A., Klein, O., Shyr, D., Jiang, A., Hoppe, R. T., et al
Pediatric blood & cancer. 2022;:e29689
Abstract
INTRODUCTION Total body irradiation (TBI) is an important component of many conditioning regimens for hematopoietic stem cell transplantation (HSCT), most commonly used in pediatric and adolescent/young adult (AYA) patients. We aimed to evaluate outcomes and toxicities among pediatric and AYA patients treated with TBI utilizing volumetric modulated arc therapy total body irradiation (VMAT-TBI). METHODS We reviewed pediatric and AYA patients treated with VMAT-TBI at our institution from 2019 to 2021. Data on patient and disease characteristics, treatment details, outcomes and toxicities were collected. Overall survival (OS) and relapse-free survival (RFS) were analyzed using the Kaplan-Meier method. RESULTS Among 38 patients, 16 (42.1%) were treated with myeloablative regimens and 22 (57.9%) with nonmyeloablative regimens. Median age was 7.2 years (range: 1-27) and median follow-up was 8.7 months (range: 1-21). Lungs D(mean) was 7.3 ± 0.3 Gy for myeloablative regimens (range: 6.8-7.8). Kidneys were spared to average mean dose of 71.4 ± 4.8% of prescription dose. Gonadal sparing was achieved for patients treated for nonmalignant diseases to D(mean) of 0.7 ± 0.1 Gy. No patient experienced primary graft failure; one (2.6%) experienced secondary graft failure. The most common grade 1-2 acute toxicities were nausea (68.4%) and fatigue (55.3%). Mucositis was the most common grade 3-4 acute toxicity, affecting 39.5% of patients. There were no cases of pneumonitis or nephrotoxicity attributable to TBI. CONCLUSION VMAT-TBI offers increased ability to spare organs at risk in pediatric and AYA patients undergoing HSCT, with a favorable acute/subacute toxicity profile and excellent disease control.
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Impact of treosulfan exposure on early and long-term clinical outcome in pediatric allogeneic HSCT recipients: a prospective multicenter study
van der Stoep, Myec, Bertaina, A., Moes, Djar, Algeri, M., Bredius, R. G. M., Smiers, F. J. W., Berghuis, D., Buddingh, E. P., Mohseny, A. B., Guchelaar, H. J., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
BACKGROUND Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favorable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationship between systemic treosulfan exposure, early and long term clinical outcome in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for non-malignant diseases is as yet unresolved. OBJECTIVE In this study we assessed the association between treosulfan exposure and early, and in particular, long term clinical outcomes. STUDY DESIGN We conducted a multicenter, prospective observational study and included 110 pediatric patients with non-malignant diseases transplanted between 2011 and 2019 in Leiden, The Netherlands and Rome, Italy. Blood samples were collected and treosulfan area under the curve (AUC(0-8)) was estimated as a measure of exposure. Cox proportional hazard survival analyses were performed to assess the relationship between treosulfan exposure, OS and EFS. The predictive value of systemic treosulfan exposure for the occurrence of toxicity within 28 days is evaluated using a multivariable logistic regression analysis. RESULTS In the overall cohort, overall survival (OS) and event-free survival (EFS) at 2 years were 89.0% and 75.3%, respectively, with an excellent OS of 97% in children under the age of 2 years. The occurrence of grade II-IV aGvHD, the level of 1-year whole blood chimerism, and 2-year OS and EFS were not correlated with treosulfan exposure. The occurrence of skin toxicity (odds ratio (OR) 3.97, 95% confidence interval (CI) 1.26-13.68, p=0.02) and all grade mucositis (OR 4.43, 95%CI 1.43-15.50, p=0.02), but not = grade 2 mucositis (OR 1.51, 95%CI 0.52-4.58, p=0.46) was related to high treosulfan exposure (>1750 mg*h/L). CONCLUSION Our study demonstrates that standardized treosulfan-based conditioning results in a favorable OS and EFS in infants and children with non-malignant diseases, independent of interindividual variation in treosulfan exposure. These outcomes can be achieved without the need for therapeutic drug monitoring (TDM), thereby emphasizing the advantage of treosulfan use in this category of patients. Although higher treosulfan exposure increases the risk of skin toxicity, there is no absolute necessity for therapeutic drug monitoring if proper preventive skin measures are taken. More research is needed to assess whether de-escalation of treosulfan doses is possible in order to minimize early and long term toxicity without compromising efficacy.
PICO Summary
Population
Children with non-malignant diseases who received allogeneic HSCT at two centres in the Netherlands and Italy (n=110)
Intervention
Treosulfan conditioning
Comparison
None
Outcome
In the overall cohort, overall survival (OS) and event-free survival (EFS) at 2 years were 89.0% and 75.3%, respectively, with an excellent OS of 97% in children under the age of 2 years. The occurrence of grade II-IV aGvHD, the level of 1-year whole blood chimerism, and 2-year OS and EFS were not correlated with treosulfan exposure. The occurrence of skin toxicity (odds ratio (OR) 3.97, 95% confidence interval (CI) 1.26-13.68, p=0.02) and all grade mucositis (OR 4.43, 95%CI 1.43-15.50, p=0.02), but not = grade 2 mucositis (OR 1.51, 95%CI 0.52-4.58, p=0.46) was related to high treosulfan exposure (>1750 mg*h/L).
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TCRaß/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different non-malignant disorders
Merli, P., Pagliara, D., Galaverna, F., Li Pira, G., Andreani, M., Leone, G., Amodio, D., Pinto, R. M., Bertaina, A., Bertaina, V., et al
Blood advances. 2021
Abstract
Several non-malignant disorders (NMDs), either inherited or acquired, can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Between January 2012 and April 2020, 70 consecutive children affected by primary immunodeficiencies, inherited/acquired bone marrow failure syndromes, red blood cell disorders or metabolic diseases, lacking a fully-matched donor or requiring urgent transplantation, underwent TCRaß/CD19-depleted haploidentical HSCT from an HLA-partially matched relative as part of a prospective study (#NCT01810120). Median age at transplant was 3.5 years (range 0.3-16.1); median time from diagnosis to transplant was 10.5 months (2.7 for SCID patients). Primary engraftment was obtained in 51 patients, while 19 and 2 patients experienced either primary or secondary graft failure (GF), the overall incidence of this complication being 30.4%. Most GFs were observed in children with disease at risk for this complication (e.g., aplastic anemia, thalassemia). All but 5 patients experiencing GF were successfully retransplanted. Six patients died of infectious complications (4 had active/recent infections at time of HSCT), the cumulative incidence of transplant-related mortality (TRM) being 8.5%. Cumulative incidence of grade I-II acute GvHD was 14.4% (no patient developed grade III-IV acute GVHD). Only one patient at risk developed mild chronic GvHD. With a median follow-up of 3.5 years, the 5-year probability of overall and disease-free survival was 91.4% and 86.8%, respectively. In conclusion, TCRaß/CD19-depleted haploidentical HSCT from an HLA-partially matched relative is confirmed to be an effective treatment for children with NMDs. Prompt donor availability, low incidence of GvHD and TRM make this strategy an attractive option in NMDs patients.
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Impact of Testicular Boost on Oncologic Outcomes and Late Effects in Pediatric Patients With Leukemia Receiving Fractionated Total Body Irradiation (TBI): A Single-Institution Experience
Blomain, E., Jiang, A., Donaldson, S. S., Agarwal, R., Bertaina, A., Shyr, D., Shin, D. H., Hoppe, R. T., Hiniker, S. M.
International journal of radiation oncology, biology, physics. 2021;111(3s):e177
Abstract
PURPOSE/OBJECTIVE(S): Late toxicity of treatment remains a major consideration among survivors of childhood leukemia. Pediatric patients with leukemia who receive fractionated total body irradiation (fTBI) as conditioning prior to stem cell transplantation (SCT) are frequently treated with a 4 Gy testicular boost in addition to fTBI to 12-13.2 Gy to reduce the risk of testicular relapse in this "sanctuary site." However, total body irradiation can be associated with risk of impaired hormonal function; it is unclear if the 4 Gy testicular boost is needed to reduce risk of testicular relapse, and whether it contributes to the toxicity beyond that imparted by fTBI. This study investigated patients both with and without a boost for risk of recurrence, hormonal function, and fertility. MATERIALS/METHODS We retrospectively reviewed records of boys treated for leukemia with fTBI as part of conditioning for SCT at our institution from 1989-present. We included patients with both AML and ALL in our analysis. We excluded patients who died in the peri-transplant period. Cumulative incidence was tested using Gray's Test for Equality of Cumulative Incidence Functions. Endocrine outcomes were tested using chi square test. RESULTS We identified 91 boys (age range 9 months - 22 years), 62 with ALL and 29 with AML. Median follow up was 43.4 months. In addition to fTBI to 12-13.2 Gy, 52 patients received a midplane testicular dose of 4 Gy (49 with ALL, 3 with AML), while 39 patients did not receive the testicular boost (13 with ALL, 26 with AML). There was no difference in time to first relapse or cumulative incidence of relapse between the boost and no-boost groups. There were 2 testicular relapses, one ALL patient who received boost and one AML patient who did not receive boost. The risk of abnormal luteinizing hormone (LH) was 65% in the boost group vs 26% in the non-boost group, P?=?0.0063. Serum follicle-stimulating hormone, total testosterone, free testosterone, abnormal sperm studies did not differ between groups, nor did the percentage of patients who required endocrine or fertility treatments. We further investigated the subset of patients with ALL and similarly found no difference in risk of relapse between patients who had received a testicular boost and those who had not boost. CONCLUSION Omission of boost was associated with comparable risk of recurrence and improved endocrine outcomes, specifically LH levels. Our data suggest that omission of testicular boost in the fTBI program is oncologically safe and results in improved hormonal function.
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Outcomes of pediatric patients with therapy-related myeloid neoplasms
Sharma, A., Huang, S., Li, Y., Brooke, R. J., Ahmed, I., Allewelt, H. B., Amrolia, P., Bertaina, A., Bhatt, N. S., Bierings, M. B., et al
Bone marrow transplantation. 2021
Abstract
Long-term outcomes after allogeneic hematopoietic cell transplantation (HCT) for therapy-related myeloid neoplasms (tMNs) are dismal. There are few multicenter studies defining prognostic factors in pediatric patients with tMNs. We have accumulated the largest cohort of pediatric patients who have undergone HCT for a tMN to perform a multivariate analysis defining factors predictive of long-term survival. Sixty-eight percent of the 401 patients underwent HCT using a myeloablative conditioning (MAC) regimen, but there were no statistically significant differences in the overall survival (OS), event-free survival (EFS), or cumulative incidence of relapse and non-relapse mortality based on the conditioning intensity. Among the recipients of MAC regimens, 38.4% of deaths were from treatment-related causes, especially acute graft versus host disease (GVHD) and end-organ failure, as compared to only 20.9% of deaths in the reduced-intensity conditioning (RIC) cohort. Exposure to total body irradiation (TBI) during conditioning and experiencing grade III/IV acute GVHD was associated with worse OS. In addition, a diagnosis of therapy-related myelodysplastic syndrome and having a structurally complex karyotype at tMN diagnosis were associated with worse EFS. Reduced-toxicity (but not reduced-intensity) regimens might help to decrease relapse while limiting mortality associated with TBI-based HCT conditioning in pediatric patients with tMNs.
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Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study
Willasch, A. M., Peters, C., Sedlacek, P., Dalle, J. H., Kitra-Roussou, V., Yesilipek, A., Wachowiak, J., Lankester, A., Prete, A., Hamidieh, A. A., et al
Bone marrow transplantation. 2020
Abstract
Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.
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Outcome of children relapsing after first allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: a retrospective I-BFM analysis of 333 children
Uden, T., Bertaina, A., Abrahamsson, J., Ansari, M., Balduzzi, A., Bourquin, J. P., Gerhardt, C., Bierings, M., Hasle, H., Lankester, A., et al
British journal of haematology. 2020
Abstract
Outcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was 14%. 4y-pOS for 122 children receiving a second haematopoietic stem cell transplantation was 31% and 3% for those that did not (P = <0.0001). Achievement of a subsequent remission impacted survival (P = <0.0001). For patients receiving a second transplant survival with or without achieving a subsequent remission was comparable. Graft source (bone marrow vs. peripheral blood stem cells, P = 0.046) and donor choice (matched family vs. matched unrelated donor, P = 0.029) positively impacted survival after relapse. Disease recurrence and non-relapse mortality at four years reached 45% and 22%.
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Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Nava, T., Ansari, M., Dalle, J. H., de Heredia, C. D., Gungor, T., Trigoso, E., Falkenberg, U., Bertaina, A., Gibson, B., Jarisch, A., et al
Bone marrow transplantation. 2020
Abstract
Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.
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Population pharmacokinetics of treosulfan in pediatric patients undergoing hematopoietic stem cell transplantation
van der Stoep, Myec, Zwaveling, J., Bertaina, A., Locatelli, F., Guchelaar, H. J., Lankester, A. C., Moes, Djar
British journal of clinical pharmacology. 2019
Abstract
AIMS: Treosulfan is an alkylating agent increasingly used prior to hematopoietic stem cell transplantation (HSCT). The aim of this study was to develop a population pharmacokinetic model of treosulfan in pediatric HSCT recipients and to explore the effect of potential covariates on treosulfan pharmacokinetics (PK). Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting. METHODS In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42 g/m(2) treosulfan, administered over 3 consecutive days, were enrolled. A population pharmacokinetic model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients. RESULTS A two-compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model-based dosing table is presented to target an exposure of 1650 mg*hr/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7 hours after start of infusion resulted in the best limited sampling strategy. CONCLUSIONS This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3-point LSM allows for accurate and precise estimation of treosulfan exposure.