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Data regarding the safety and efficacy of reduced-toxicity conditioning regimen (RTC) prior to allogeneic stem cell transplantation (allo-SCT) to treat hematological malignancies in pediatric patients are limited. This prospective multicenter, phase 2 trial investigated a RTC regimen based on the combination of intravenous busulfan (3.2 mg/kg/d x 4 days), fludarabine (30 mg/m 2 /d x 5 days) and antithymocyte globulin (Thymoglobulin®, Genzyme; 5 mg/kg total dose) with the aim of delivering high dose myeloablation that would allow optimal disease control while minimizing toxicity, in a subgroup of children at very high risk of non-relapse mortality (NRM). The primary endpoint was NRM at 1 year after allo-SCT. A total of 48 high risk patients were included (median age, 13 years; range, 3-24). At 1 year, the cumulative incidence of recurrence/disease progression and NRM were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively. We conclude that the RTC regimen used in this prospective trial is safe, with a < 10% NRM rate noted among high-risk children and adolescents, paving the way for larger phase 3 trials incorporating novel agents pre- and post-allo-SCT.(ClinicalTrials.gov Identifier: NCT01572181)., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

We included 255 patients from the L.E.A. French long-term follow-up cohort. All had received hematopoietic stem cell transplantation (HSCT) and/or testicular radiation for childhood acute leukemia and were older than 18 years at last L.E.A. evaluation. Total testosterone deficiency was defined as a <12 nmol/l level or by substitutive therapy, partial deficiency as normal testosterone with elevated luteinizing hormone (>10 UI/l). After myeloablative total body irradiation (n = 178), 55.6% had total deficiency, 15.7% partial deficiency, and 28.7% were normal. A 4-6 Gy testicular boost and a younger age at HSCT increased significantly the risk. After a Busulfan-containing myeloablative conditioning regimen (n = 53), 28.3% had total deficiency, 15.1% partial deficiency, 56.6% were normal (62.5% vs. 0% in patients without or with additional testicular radiation). A 24-Gy testicular radiation without HSCT induced total or partial deficiency in 71.4% and 28.6%, respectively (n = 21). Total testosterone deficiency increased the risk of metabolic syndrome: 25% vs. 12.1% in men with partial testosterone deficiency and 8.8% when Leydig cell function was normal (p = 0.031).

Data on post-transplant iron overload (IO) are scarce in pediatrics. We conducted a prospective multicenter cohort study (Leucémie de l'Enfant et de l'Adolescent cohort) to determine the prevalence and risk factors of IO in 384 acute leukemia survivors transplanted during childhood. Prevalence of IO (ferritin level ⩾350 ng/mL) was 42.2% (95%CI 37.2-47.2%). Factors significantly associated with IO were: 1) in univariate analysis: older age at transplant (P<0.001), allogeneic versus autologous transplantation (P<0.001), radiation-based preparative regimen (P=0.035) and recent period of transplantation (P<0.001); 2) in multivariate analysis: older age at transplant in quartiles (Odds Ratio (OR)=7.64, 95% CI: 3.73-15.64 for age >12.7 years and OR=5.36, 95% CI: 2.63-10.95 for age from 8.2 to 12.7 years compared to age < 4.7 years), acute myeloid leukemia (OR=3.23, 95% CI: 1.47-7.13), allogeneic graft (OR=4.34, 95% CI: 2.07-9.12 for alternative donors and OR=2.53, 95% CI: 1.2-5.33 for siblings, compared to autologous graft) and radiation-based conditioning regimen (OR=2.45, 95% CI: 1.09-5.53). Graft-versus-host disease was an additional risk factor for allogeneic graft recipients. In conclusion, IO is a frequent complication in pediatric long-term survivors after transplantation for acute leukemia, more frequently observed in older children, those transplanted from alternative donors or with graft-versus-host disease.

We evaluated prospectively the incidence and risk factors of the metabolic syndrome (MS) and its components in 170 adult patients (mean age at evaluation: 24.8±5.4 years) who received an hematopoietic stem cell transplantation for childhood ALL, n=119, or AML, n=51. TBI was carried out in 124 cases; a busulfan-based conditioning was done in 30 patients. Twenty-nine patients developed a MS (17.1%, 95% confidence intervals: 11.7-23.6). The cumulative incidence was 13.4% at 25 years of age and 35.5% at 35 years of age. A higher body mass index (BMI) before transplantation and a growth hormone deficiency were associated with increased MS risk (P=0.002 and 0.01, respectively). MS risk was similar for patients who received TBI or busulfan-based conditioning. The TBI use increased the hyperglycemia risk (odds ratio (OR): 4.7, P=0.02). Women were at the risk of developing increased waist circumference (OR: 7.18, P=0.003) and low levels of high-density lipoprotein cholesterol (OR: 2.72, P=0.007). The steroid dose was not a risk factor. The MS occurs frequently among transplanted survivors of childhood leukemia. Its incidence increases with age. Both intrinsic (BMI, gender) and extrinsic factors (TBI, alkylating agents) contribute to its etiopathogenesis.

The purpose of this multicenter study was to compare the long-term impact of a preparative regimen with either BUBU or TBI on health status and quality of life (QoL) in childhood acute leukemia survivors treated with hematopoietic SCT (HSCT). Two-hundred and forty patients were included. Sixty-six had received BU, while 174 had received TBI. Median follow-up from HSCT was 10.1 years. Multivariate analyses were performed to assess the occurrence of late effects according to treatment. QoL was assessed in 130 adults using SF-36 questionnaires. Patients developed fewer late complications after BU (2.35 vs 3.01, P=0.03) while the risk to present with at least one complication was equivalent in both groups (87.9% after BU and 93.1% after TBI, P=0.66). Detailed multivariate analyses revealed a lower risk of height growth failure (OR=0.2), cataract (OR=0.1) and iron overload (OR=0.2) after BU, and an increased risk of overweight (OR=3.9) and alopecia (OR=11.2). SF-36 mental and physical composite scores were similar in both treatment groups and proved significantly lower than French norms. Late effects induced by BU might differ from those experienced after TBI. Although less frequent, they are still of considerable importance and may affect patients' QoL.

We report French prospective experience with reduced-intensity conditioning-allo-SCT in 46 patients (median age: 15.5 years, 4.8-20.2) presenting high-risk AL (n=11), Hodgkin's lymphoma (n=15) or solid tumors (n=20). Graft sources were BM (n=21), PBSC (n=20) and cord blood (CB; n=5) from related (n=20) or unrelated (n=26) donors. For CB grafts, only one patient out of five achieved sustained engraftment. For PBSC/BM grafts, engraftment rate was 95%, hematopoietic recovery times were not significantly different between BM, PBSC, sibling or unrelated grafts, day+100. Full donor chimerism was achieved in 94% of patients, and incidences of primary acute GVHD and chronic GVHD were 49% and 14%, respectively. Underlying disease was fatal in 39% of patients. TRM was 6.9%. Three-year OS was 49.15%. OS and EFS were not significantly different between patients transplanted with different grafts and with or without primary GVHD. Patients with solid tumor or measurable disease at transplant had poorer outcomes. Three-year EFS: 33.3% for ALL, 75.0% for AML, 51.8% for Hodgkin's lymphoma, 28.6% for neuroblastoma and 22.2% for sarcoma patients. This multicentre study concluded that Bu/fludarabine/anti-thymocyte globulin conditioning with PB or BM, related or unrelated grafts in patients with various malignancies at high-risk for transplantation toxicity results in high engraftment rates, low TRM and acceptable survival.

The kinetics of peripheral blood progenitor cell (PBPC) release induced by G-CSF-alone at 10 microg/kg/day were monitored daily in 42 children with solid tumors and leukemias. Median 16- and 27-fold enrichment of circulating CD34+ cells and granulocyte-macrophage colony-forming units (CFU-GM) was noted with peak values occurring after the 4th or the 5th G-CSF dose. Individual values of PBCD34+ cell levels in patients with solid tumors were not significantly different after the 4th and after the 5th dose. The day-of-collection PBCD34+ cell concentration was related to the harvested CD34+ cell (P = 0.0001) and CFU-GM numbers (P = 0.0001). No correlations were found between PBPC enrichment and either patient age, body weight, diagnosis or pre-mobilization treatment duration. The median numbers of 1.1 x 10(6) CD34+ cells/kg and 28.1 x 10(4) CFU-GM/kg were derived from one patient's blood volume processed. Nineteen patients received G-CSF-alone primed grafts and had successful engraftment. Our data indicate that in 88% of children a single standard leukapheresis is sufficient to obtain a minimum graft (2 x 10(6) CD34+ cell and/or 10 x 10(4) CGU-GM per kg) whether undertaken after the 4th dose of G-CSF or the 5th.

To evaluate the feasibility and efficacy of CD34+ cell immunoselection from routine peripheral blood stem cell (PBSC) harvests in very small children a prospective study was performed in 15 children with advanced neuroblastoma weighing 20 kg or less. Products of two consecutive leukaphereses carried out on a COBE Spectra separator after G-CSF alone mobilization were pooled for immunoselection on Ceprate column. The median number of CD34+ cells and total CFU-GM collected were respectively 5.9 x 10(6)/kg (range 2.3-23.4) and 126.9 x 10(4)/kg (range 52.9-559.9). After separation the median number of CD34+ cells in the adsorbed fraction was 2.6 x 10(6)/kg (range 1-9.8) with a median purity of 54% (range 21-82) and a median of 95.7-fold (range 35-250) enrichment. Thirteen patients underwent autografts with CD34+ PBSCs after a busulfan 600 mg/m2 + melphalan 180 mg/m2 preparative regimen. The median number of days to achieve an absolute granulocyte count of 0.5 x 10(9)/l and a platelet count of 20 x 10(9)/l were respectively, 12 (range 10-24) and 35 (range 25-43). The median number of platelet transfusions was nine (range 2-15). We conclude that safe and effective immunoselection and transplantation of CD34+ PBSC can be accomplished in children with low body mass.

The purpose of the study was to determine the maximum tolerated dose of continuous infusion of high-dose VP-16 in combination with high-dose melphalan (HDM) for conditioning before autologous bone marrow transplantation (ABMT). Thirteen children (median age 27 months) with stage IV neuroblastoma were treated with high-dose VP-16 and HDM followed by ABMT as consolidation treatment. All had previously received conventional chemotherapy with a mean number of six drugs. Surgery of the primary tumor had been performed in 12/13. We performed a dose-escalating study of VP-16 from 1800 mg/m2/72 h with 300 mg/m2/72 h dose increments according to toxicity. VP-16 was administered as a 72-h i.v. infusion. Melphalan (140 mg/m2/day) was administered once as an i.v. push. VP-16 pharmacokinetics were analyzed in 12 patients. Five children received 1800 mg/m2/72 h of VP-16, five received 2100 mg/m2/72 h and three, 2400 mg/m2/72 h. The mean duration of granulocytopenia (< 0.5 x 10(9)/1) was 24 days and thrombocytopenia (< 50 x 10(9)/1) was 36 days. No major infectious complications occurred. Gastrointestinal (GI) toxicity was the dose-limiting toxicity. Five severe manifestations of GI toxicity in three patients led us to consider 2400 mg/m2/72 h as the MTD. The mean VP-16 clearance rate was 17.3 ml/min/m2 with continuous infusion. A mean steady-state plasma concentration of 24.2 micrograms/ml (s.d. = 2) and 28.3 micrograms/ml (s.d. = 1.9) was achieved at the 1800 mg/ml and 2100 mg/m2 dose levels, respectively, GI toxicity is dose limiting when VP-16 at 2400 mg/m2/72 h, is associated with HDM. When given as a continuous i.v. infusion, at 2100 mg/m2/72 h, VP-16 associated with HDM is well tolerated before ABMT in young heavily pre-treated children.