Abstract

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).

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.

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo-HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre-HSCT cytoreductive therapies and related toxicities, disease status pre-HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5-year OS and EFS were 42% (30-53%) and 39% (27-51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48-95] vs 37% [24-50],P = .04), while none of the other variables considered had an impact. Twenty-two patients received pre-HSCT cytoreduction and 9/22 showed a grade 3-4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre-HSCT 48% [20-75%] vs no-toxicity 51% [25-78%],P = .98). The cumulative incidence of day-100 grade II-IV a-GvHD and of 5-year c-GvHD were 38% (26-50%) and 40% (28-52%). Non-relapse-related mortality and incidence of relapse at 5-years were 40% (29-52%) and 21% (11-30%) respectively, without any significant impact of the tested variables. Causes of death were transplant-related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre-HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre-HSCT should be considered if a donor have been secured. This article is protected by copyright. All rights reserved.

Abstract

INTRODUCTION Gonadal impairment is an important late effect having a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after Busulfan (Bu) or Treosulfan (Treo) conditioning regimens in pre and post-pubertal children. MATERIAL AND METHODS This is a retrospective, multicenter study including children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemo-radiotherapy before the transplant. RESULTS We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range 5-18); 89 patients were males and 48 were females. Eighty-nine patients were pre-pubertal at transplant, while 48 were post-pubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of females treated with Treo in pre-pubertal stage reached spontaneous puberty compared to those treated with Bu (p=0.02). Spontaneous menarche was more frequent after Treo than after Bu (p< 0.001). Post-pubertal males and females treated with Treo had significantly lower luteinizing hormone (LH) levels (p=0.03 and p=0.04, respectively) compared to the Bu group. CONCLUSIONS Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.

Abstract

Outcomes for adolescents and young adults (AYA) with leukemia differ from other age groups but are still underrepresented in clinical research. The aim of this study was to analyze outcomes of umbilical cord blood transplant (UCBT) in AYA with acute leukemia reported to Eurocord/EBMT. Patients (n=504) had acute lymphoblastic (59%) or myeloid leukemia (41%), were aged 15-25 years, and received UCBT after myeloablative conditioning regimens between 2004 and 2016. Primary endpoint was 3-year overall survival (OS). Median follow-up was 3.9 years. Transplant was single in 58% and double UCBT in 42%. Three-year OS was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIF) of non-relapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute GVHD grade II-IV at day-100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT (HR 2.74, p <0.001) and more recent UCBT (HR 1.43, p=0.01) were associated with increased OS and a similar effect of these factors was observed on LFS. Contrastingly, the use of ATG had a negative effect in LFS. The risk of acute GVHD grade II-IV increased with the use of double UCBT (HR 1.65, p =0.02) and decreased with more recent transplantation period (HR 0.65, p=0.02) and ATG use (HR 0.55, p =0.01). Outcomes of AYA UCBT improved in more recent years becoming comparable to pediatric results. Demonstrating the feasibility of UCBT in AYA facilitates stem cell source selection and provides the basis for future prospective studies.

Abstract

In this retrospective study, we evaluate long-term complications in nearly all beta-thalassemia-major patients who successfully received, in France, allogeneic hematopoietic stem cell transplantation. 99 patients were analysed with a median age of 5.9 years at transplantation. The median duration of clinical follow-up was 12 years. All conditioning regimen were myeloablative, most often based on busulfan combined with cyclophosphamide and more than 90% of patients underwent a transplant from a matched sibling donor. After transplantation, 11% of patients developed thyroid dysfunction, 5% diabetes and 2% heart failure. Hypogonadism was present in 56% of females and 14% of males. Female patients who developed normal puberty after transplant were significantly younger at transplantation than those who experienced delayed puberty (median age 2.5 versus 8.7 years). Fertility was preserved in 9/27 females aged 20 and above and 2 other patients became pregnant following oocyte donation. In addition to patient's age and higher serum ferritin levels at transplantation, time elapsed since transplant was significantly associated with decreased height growth in multivariate analysis. Weight growth increased after transplantation particularly in females, 36% of adults being overweight at last evaluation. A comprehensive long-term monitoring especially of endocrine late-effects is required after hematopoietic stem cell transplantation for thalassemia.

Abstract

We previously reported in a French prospective randomized study that transplantation of 2 unrelated cord blood (UCB) units instead of 1 does not decrease the risk of transplantation failure but may enhance alloreactivity. We present here the influence of pre-transplant minimal residual disease (MRD) on leukemia relapse and survival after single versus double-UCB transplantation. Among 137 children and young adults who were transplanted in the randomized study, 115 had available MRD assessment immediately before their conditioning regimen. MRD was considered positive when ≥ 10(-4), which was the case of 43 out of 115 patients. Overall, the 3-year survival probability was 69.1+/-4.4% and it was not significantly influenced by the MRD level: 70.7+/-5.4% in MRD- (<10(-4)) patients (n=72), 71.1+/-9.4% in MRD+ with 10(-4)≤MRD<10(-3) (n=26), and 58.8+/-11.9% in MRD+ ≥ 10(-3) patients (n=17). In the MRD+ group, we found a significantly lower risk of relapse in the double- versus single-unit arm (10.5+/-7.2% vs 41.7+/-10.4%; p=0.025) leading to a higher 3-year survival rate (82.6+/-9.3% vs 53.6+/-10.3%, p=0.031). This difference was only observed in patients who had not received anti-thymocyte globulin (ATG) during their conditioning regimen. In the MRD- group, no difference was found between the single- and the double-unit arms. We conclude that, even in case of positive pre-transplant MRD, UCB transplantation in children and young adults with acute leukemia results in a high cure rate and that a double-unit strategy may enhance graft-vs-leukemia effect and survival in these patients.

Abstract

Allogeneic haematopoietic stem cell transplantation is still the only available curative option for Familial Haemophagocytic Lymphohistiocytosis (FHLH). Most studies report outcomes after bone marrow or peripheral blood stem cell transplantation. We analysed the outcomes of 118 children with FHLH undergoing single-unit umbilical cord blood transplantation performed from 1996 to 2014. Myeloablative conditioning regimen was given to 90% of the patients, and was mostly busulfan-based (n = 81, 76%), including anti-thymocyte globulin or alemtuzumab (n = 102, 86%). The cumulative incidence of Day 60 neutrophil engraftment was 85%; and that of non-relapse mortality and acute graft-versus-host disease (GvHD) was 21% and 33% at 100 days, respectively. The 6-year cumulative incidence of chronic GvHD was 17% and the 6-year probability of overall survival was 55%. In multivariate analysis, children receiving a graft with a total nucleated cell dose greater than 9.9 x 10(7) /kg had a better overall survival (hazard ratio [HR]: 0.49, 95% CI: 0.27-0.88, P = 0.02). Degree of human leucocyte antigen (HLA) matching was associated with improved disease-free survival (5/6 vs. 6/6 HR: 2.11, 95% confidence interval [CI]: 1.01-4.4, P = 0.05 and ≤4/6 vs. 6/6, HR: 2.82, CI: 1.27-6.23, P = 0.01). Umbilical cord blood transplantation with a high cell dose and good HLA match is a suitable alternative option to haematopoietic stem cell transplantation in children with FHLH who lack a HLA-matched donor.

Abstract

Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal, neurodegenerative disease caused by mutations in the ABCD1 gene resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). A large, multicenter, retrospective chart review to characterize the natural history of CALD, describe outcomes after HSCT, and identify predictors of treatment outcomes was conducted. Major Functional Disabilities (MFDs) were identified as having the most significant impact on CALD patients' abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes MRI score were assessed. Data were collected on 72 CALD patients who did not undergo HSCT (Untreated cohort) and 65 who were transplanted (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) rates from time of CALD diagnosis were 55% (95% CI, 42.2%-65.7%) for the Untreated cohort and 78% (95% CI, 64%-86.6%) for the HSCT cohort overall (p=0.01). KM-estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE+) were 29% (95% CI, 11.7%-48.2%) for Untreated patients (N=21). For patients transplanted with GdE+ at baseline, with an NFS ≤1 and Loes 0.5 to ≤9 (N=27), 2-year MFD free survival was 84% (95% CI, 62.3%-93.6%). Mortality rates post-HSCT were 8% (100-day, 5/65) and 18% (1-year, 12/65), with disease progression (44%, 7/16) and infection (31%, 5/16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%, 19/65), acute grade II-IV graft-versus-host disease (GVHD; 31%, 18/58), and chronic GVHD (7%, 4/58). Eighteen percent (12/65) of patients experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor/recipient human leukocyte antigen-matching and lack of GVHD, and early disease treatment was a predictor of MFD-free survival. GdE+ is a strong predictor of disease progression in untreated patients. This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than only assessing overall survival as an indicator of treatment success.

Abstract

Leukodystrophies (LD) are devastating inherited disorders leading to rapid neurological deterioration and premature death. Hematopoietic stem cell transplantation (HSCT) can halt disease progression for selected LD. Cord blood is a common donor source for transplantation of these patients because it is rapidly available and can be used without full HLA matching. However, precise recommendations allowing care providers to identify patients who benefit from HSCT are lacking. In this study, we define risk factors and describe the early and late outcomes of 169 patients with globoid cell leukodystrophy, X-linked adrenoleukodystrophy, and metachromatic leukodystrophy undergoing cord blood transplantation (CBT) at an European Society for Blood and Marrow Transplantation center or at Duke University Medical Center from 1996 to 2013. Factors associated with higher overall survival (OS) included presymptomatic status (77% vs 49%; P = .006), well-matched (<=1 HLA mismatch) CB units (71% vs 54%; P = .009), and performance status (PS) of >80 vs <60 or 60 to 80 (69% vs 32% and 55%, respectively; P = .003). For patients with PS<=60 (n = 20) or 60 to 80 (n = 24) pre-CBT, only 4 (9%) showed improvement. Of the survivors with PS >80 pre-CBT, 50% remained stable, 20% declined to 60 to 80, and 30% to <60. Overall, an encouraging OS was found for LD patients after CBT, especially for those who are presymptomatic before CBT and received adequately dosed grafts. Early identification and fast referral to a specialized center may lead to earlier treatment and, subsequently, to improved outcomes.