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Matched unrelated donor transplantation versus haploidentical transplantation with post-transplant cyclophosphamide in children with acute myeloid leukemia: a PDWP-EBMT study
Ruggeri, A., Santoro, N., Galimard, J. E., Kalwak, K., Algeri, M., Zubarovskaya, L., Czyzewski, K., Skorobogatova, E., Sedlacek, P., Besley, C., et al
Haematologica. 2024
Abstract
In children with acute myeloid leukemia (AML) who lack an HLA identical sibling, the donor can be replaced with an HLA matched unrelated donor (MUD) or a haploidentical donor (haplo). We compared outcomes of patients <18 years with AML in first and second complete remission (CR1 and CR2) undergoing a hematopoietic stem cell transplantation (HCT) either with a MUD with anti-thymocyte globuline (ATG) (n=420) or a haplo HCT with PT-CY (n=96) after a myeloablative conditioning regimen (MAC) between 2011 and 2021, reported to EBMT. A matched pair analysis was performed to adjust for differences among groups. The final analysis was performed on 253 MUD and 95 haplo-HCTs. In the matched cohort, median age at HCT was 11.2 and 10 years and median year of HCT was 2017 and 2018, in MUD and haplo- HCT recipients, respectively. The risk of grade III-IV aGvHD was significantly higher in the haplo group (HR=2.33, 95%CI1.18-4.58, p=0.03). No significant differences were found in 2 years overall survival (OS; 78.4%vs71.5%; HR 1.39, 0.84-2.31, p=0.19), leukemia-free-survival (LFS; 72.7%vs69.5%; HR1.22, 0.76-1.95, p=0.41), CI of relapse (RI; 19.3%vs19.5%; HR=1.14, 0.62-2.08, p=0.68) non-relapse-mortality (NRM; 8%vs11%; HR=1.39, 0.66-2.93, p=0.39) and graft versus host free-relapse free survival (GRFS; 60.7%vs54.5%, HR=1.38, 0.95-2.02, p=0.09) after MUD and haplo-HCT respectively. Our study suggests that haplo-HCT with PT-CY is a suitable option to transplant children with AML lacking a matched related donor.
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Long-term complications after allogeneic hematopoietic stem cell transplantation for pediatric patients with acute leukemia or myelodysplastic syndrome given either a Treosulfan- or a Busulfan-based conditioning regimen: results of an AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) retrospective study
Saglio, F., Pagliara, D., Zecca, M., Balduzzi, A., Cattoni, A., Prete, A., Tambaro, F. P., Faraci, M., Calore, E., Locatelli, F., et al
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Patients given hematopoietic stem cell transplantation (HSCT) during their childhood for hematological malignancies have an increased risk of developing long-term sequelae that are in part attributable to the conditioning regimen. OBJECTIVE The present study aimed to assess the occurrence of long-term toxicities in a population of children undergone to HSCT for hematological malignancies using either Treosulfan or Busulfan in the conditioning regimen. STUDY DESIGN Cumulative Incidence of growth impairment, alteration of gonadal function, alteration of the thyroid function, cataract, incidence of secondary malignant neoplasia and alteration of pulmonary function were retrospectively evaluated by univariable and multivariable analysis in a population of 521 pediatric patients affected by acute leukemias and myelodysplastic syndromes treated in 20 Italian Transplant Centers affiliated to AIEOP (Associazione Italiana Ematologia ed Oncologia Pediatrica) RESULTS The median duration of the follow up of the entire study population was of 7,1 years (range 1 -16 years). Overall, patients given Busulfan developed long-term toxicities in a larger proportion of cases compared to patients treated with Treosulfan (34% versus 20% p=0.01). In univariable analysis, patients having received Treosulfan developed gonadal toxicity in 10% (95%CI: 3-15) of the cases compared with 38% (95%CI: 24-39) of Bu-treated patients (p=0,02) and this finding was confirmed by multivariable analysis (Relative Risk: 0,51 95%CI: 0,34-0,76 p=0.0009). For all the other long-term toxicities our study did not show a statistically significant association between their occurrence and the use of either Busulfan or Treosulfan. CONCLUSIONS This study provides evidence that the use of Treosulfan is correlated with a reduced incidence of gonadal toxicity in children undergoing HSCT for hematological malignancies.
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Busulfan-fludarabine- or treosulfan-fludarabine-based conditioning before allogeneic HSCT from matched sibling donors in paediatric patients with sickle cell disease: A study on behalf of the EBMT Paediatric Diseases and Inborn Errors Working Parties
Cseh, A., Galimard, J. E., de la Fuente, J., Isgro, A., Zecca, M., Garwer, B., Biffi, A., Aljurf, M., Sundin, M., Belendez, C., et al
British journal of haematology. 2023
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Editor's Choice
Abstract
How important is choice of conditioning regimen in allogeneic haematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD)? We compared HSCT outcomes by conditioning regimen in paediatric patients with SCD from the EBMT registry. In 2010-2020, 251 patients aged <18 years underwent a first matched sibling donor (MSD) HSCT with conditioning based on busulfan-fludarabine (bu-flu; n = 89) or treosulfan-fludarabine (treo-flu; n = 162). In the bu-flu and treo-flu groups, 51.7% and 99.4% of patients, respectively, received thiotepa. Median follow-up was 2.7 years. Two-year overall survival (OS) was 98.7% (95% confidence interval [CI]: 90.9-99.8) with bu-flu and 99.3% (95% CI: 95.2-99.9) with treo-flu (p = 0.63). Grade III-IV acute graft-versus-host disease (GVHD) at 100 days was 2.4% (95% CI: 0.4-7.5) and 0.6% (0.1%-3.2%) for bu-flu and treo-flu respectively (p = 0.25). The 2-year incidence of extensive chronic GVHD was 1.5% (95% CI: 0.1-7.3) with bu-flu and 8.0% (95% CI: 4.1-13.3) with treo-flu (p = 0.057). These multinational data confirm the excellent curative capacity of MSD HSCT with myeloablative conditioning. Both conditioning regimens yielded excellent OS, low rates of acute and chronic GVHD, and low rates of graft failure.
PICO Summary
Population
Children who underwent transplant for sickle cell disease, identified from the EBMT registry (n=251)
Intervention
Conditioning based on busulfan-fludarabine (bu-flu, n=89)
Comparison
Conditoning based on treosulfan-fludarabine (treo-flu, n=162).
Outcome
Median follow-up was 2.7 years. Two-year overall survival (OS) was 98.7% (95% confidence interval [CI]: 90.9-99.8) with bu-flu and 99.3% (95% CI: 95.2-99.9) with treo-flu. Grade III-IV acute graft-versus-host disease (GVHD) at 100 days was 2.4% (95% CI: 0.4-7.5) and 0.6% (0.1%-3.2%) for bu-flu and treo-flu respectively. The 2-year incidence of extensive chronic GVHD was 1.5% (95% CI: 0.1-7.3) with bu-flu and 8.0% (95% CI: 4.1-13.3) with treo-flu.
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Iron overload following hematopoietic stem cell transplantation: Prevalence, severity and management in children and adolescents with malignant and non-malignant diseases
Cattoni, A., Capitoli, G., Casagranda, S., Corti, P., Adavastro, M., Molinaro, A., Gennaro, F. D., Bonanomi, S., Biondi, A., Galimberti, S., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Iron overload (IOL) is a frequently reported complication following hematopoietic stem cell transplantation (HSCT) which has been extensively assessed in the field of hemoglobinopathies, but has not been thoroughly characterized after HSCT in pediatric malignancies. OBJECTIVES Our aim was to assess prevalence, severity, risk factors and management of IOL, as defined by means of biochemical (serum ferritin) and radiological tools (T2*-MRI), in a cohort of pediatric patients transplanted for either malignant or benign diseases. STUDY DESIGN Monocentric, retrospective, observational study. All the 163 patients alive and in continuous remission 24 months after HSCT, out of the 219 consecutive children and adolescents transplanted at our Institution between 2012 and 2018, were included in the study. IOL was classified into four categories, i.e. absent, mild, moderate and severe. RESULTS Of the 163 patients, 73% had some degree of IOL, which was mild, moderate and severe in 37%, 29% and 7%, respectively. Moderate/severe IOL was more frequent among patients diagnosed with a malignant versus benign disease (43% vs 19%; p 0.0065). Ferritin trend lines showed a "bell-shaped" distribution, with the highest levels being recorded during the first 6 months after HSCT, followed by a spontaneous reduction. Both pre-HSCT (1659 versus 617 ng/mL, p<0.001) and maximum post-HSCT (2473 ng/mL versus 1591 ng/mL, p<0.001) median ferritin levels were statistically higher among patients with malignancies. Radiological assessment of IOL confirmed a more severe degree in malignant compared to benign disorders (median T2*-MRI 4.20 msec, IQ: 3.0-6.40 versus 7.40, IQ: 4.90-11.00, respectively - p 0.008). T2* levels were associated with the number of transfusions performed (p 0.0006), with a steeper drop in T2* values for the first 20 transfusions and a milder slope subsequently. T2* and ferritin values showed a statistically significant negative exponential relationship (p<0.0001), though ferritin levels ≥1000 ng/mL showed a poor specificity (48%) and positive predictive value (53%) in discriminating moderate-to-severe from absent-mild IOL as assessed by T2*-MRI, but high sensitivity (92%) and negative predictive value (91%). In a multivariable model, >20 transfusions (OR 4.07, 95% CI 1.61-10.68, p 0.003) and higher pre-HSCT ferritin levels (p<0.001) were associated with the risk of developing moderate-to-severe IOL. A sibling donor (OR 0.29, 95% CI 0.10-0.77, p 0.015) and a non-malignancy (OR 0.27, 95% CI 0.08-0.82, p 0.026) were protective factors. Phlebotomies (66%), low-dose oral chelators (9%) or a combined approach (25%) were started at a median of 12 months after HSCT in 78% of the patients with IOL. Six% of the patients treated exclusively with phlebotomies (median 14, significantly higher in patients >40 kg) discontinued them due to poor venous accesses, lack of compliance or hypotension, whereas 39% of patients treated with chelators developed mild renal or hepatic side effects which resolved upon tapering or discontinuation. CONCLUSIONS Patients with malignancies showed statistically higher pre- and post-HSCT ferritin levels and lower T2*. High ferritin recorded upon T2*-MRI showed unsatisfactory diagnostic accuracy in predicting IOL, thus, T2*-MRI should be regarded as a key element to confirm IOL after HSCT in patients with elevated ferritin levels. IOL treatment is feasible after HSCT.
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Pubertal attainment and Leydig cell function following pediatric hematopoietic stem cell transplantation: a three-decade longitudinal assessment
Cattoni, A., Nicolosi, M. L., Capitoli, G., Gadda, A., Molinari, S., Louka, S., Buonsante, A., Orlandi, S., Salierno, G., Bellani, I., et al
Frontiers in endocrinology. 2023;14:1292683
Abstract
INTRODUCTION Impaired 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. METHODS Monocentric, 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. RESULTS Of 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). CONCLUSIONS a) 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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Thyroid disorders following hematopoietic stem cell transplantation in childhood: the impact of the conditioning regimen on thyroid dysfunction, volume changes and occurrence of nodules
Cattoni, A., Molinari, S., Gaiero, A., De Lorenzo, P., Fichera, G., Riva, B., Di Marco, S., Tommesani, C., Mariani, E., Medici, F., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Thyroid late effects are among the most frequent sequelae reported after pediatric hematopoietic stem cell transplantation (HSCT). Though the detrimental effects of radiotherapy on the developing thyroid gland have been extensively assessed, the role of chemotherapy-only conditioning regimens is still controversial. OBJECTIVE We aimed at describing the occurrence, monitoring and management of thyroid function disorders (i.e. Graves' disease, Hashimoto thyroiditis and non-autoimmune hypothyroidism), nodules and volumetric changes over a 20-year observation period in a single pediatric transplant unit. In addition, we assessed the impact of different conditioning regimens on thyroid health. STUDY design Retrospective observational analysis. The study population included 244 patients transplanted for pediatric malignant or non-malignant diseases between 1999 and 2018 and for whom at least four thyroid function tests and one or more thyroid ultrasound(s) assessed sequentially after HSCT were available. RESULTS The 15-year cumulative incidence (CI) of either autoimmune or non-autoimmune thyroid dysfunctions (34%, SE 5.3%) did not statistically differ between total body irradiation- (TBI-) and chemo-based regimens (p 0.23). Indeed, the CI after busulfan (BU) was overall superimposable to that recorded after TBI (10-year CI: 22.2% versus 25.9%, respectively). Nevertheless, the CI of non-autoimmune hypothyroidism was statistically higher after BU- (12.4%, SE 3.7%) than after other chemotherapy only-based-conditionings (3.1%, SE 3.1%; p 0.02, 5-year CI), treosulfan included. The overall CI of nodules was low for the first 5 years after HSCT (1.9%, SE 0.9%), but it showed a subsequent steep increase over time, with a 15-year CI as high as 52.1% (SE 7.5%). TBI-conditioned patients experienced a higher 15-year CI of nodules (66.8%, SE 9.1%) compared to those receiving chemo-only regimens (33.6%, SE 9.5%; p 0.02), whereas age > 10 years upon transplantation showed a protective effect (HR 0.42, 95% confidence interval 0.2-0.88). Finally, a systematic sonographic follow-up highlighted a progressive statistically significant reduction in thyroid antero-posterior diameter among patients conditioned with TBI (p 0.005), but not after chemo-only regimens. CONCLUSIONS TBI and younger age upon HSCT play a remarkable and statistically demonstrated detrimental role on the occurrence of thyroid nodules, both benign and malignant. TBI and BU expose patients to a higher cumulative incidence of thyroid dysfunctions than other chemo-only regimens, treosulfan included. Accordingly, BU can be regarded as the most thyrotoxic agent among those administered as a part of a chemo-only conditioning regimen. Finally, patients conditioned with TBI, but not with other regimens, show a progressive decrease in thyroid volume over time, as assessed by sequential ultrasounds.
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Occurrence of long-term effects after hematopoietic stem cell transplantation in children affected by acute leukemia receiving either busulfan or total body irradiation: results of an AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) retrospective study
Saglio, F., Zecca, M., Pagliara, D., Giorgiani, G., Balduzzi, A., Calore, E., Favre, C., Faraci, M., Prete, A., Tambaro, F. P., et al
Bone marrow transplantation. 2020
Abstract
Patients given allogeneic hematopoietic stem cell transplantation (alloHSCT) present an increased incidence of long-term toxicities that can be attributed to the preparative regimen. We retrospectively analyzed in a population of 670 children receiving allo-HSCT for acute leukemia the occurrence of different late effects in function of the choice made between total body irradiation (TBI) and busulfan, as part of the preparative regimen. In univariable analysis, we found that patients treated with TBI developed cataract in 24% of the cases compared with 4% in patients treated with BU (p = 0.0001) and that the incidence of secondary malignant neoplasia (SMN) was higher in patients treated with TBI (18%) as compared with those prepared to the allograft with a Bu-based regimen (0%) (p = 0.019). Conditioning regimen did not show a statistically significant correlation with the occurrence of all the other investigated late effects. In multivariable analysis, TBI remained associated with the occurrence of cataracts (Relative Risk: 0.33 p = 0.012) and secondary malignancies (Relative Risk 3.96 x 10e-6 p < 0.001); however, other variables, as GvHD and disease type, were also correlated with these long-term sequels, indicating that in our study population the preparative regimen is not the only factor influencing the incidence of these complications.
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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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Pediatric acute graft-versus-host disease prophylaxis and treatment: Real-life approach reveals dissimilarities compared to published recommendations
Lawitschka, A., Lucchini, G., Strahm, B., Dalle, J. H., Balduzzi, A., Gibson, B., Diaz De Heredia, C., Wachowiak, J., Dalissier, A., Vettenranta, K., et al
Transplant international : official journal of the European Society for Organ Transplantation. 2020
Abstract
Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable non-malignant diseases and the lower incidence of Graft-versus-Host-Disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with ≥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: single-agent cyclosporine A (CsA) was used for matched-sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in non-malignant diseases. Most centers used additional anti-thymocyte globulin for matched-unrelated and mismatched donor HCT, but not for matched-siblings. Regarding prophylaxis in non-myeloablative conditioning (mainly for non-malignant diseases) responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches towards aGVHD prophylaxis/treatment differentiated for malignant and non-malignant underlying diseases.
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The impact of donor type on the outcome of pediatric patients with very high risk acute lymphoblastic leukemia. A study of the ALL SCT 2003 BFM-SG and 2007-BFM-International SG
Dalle, J. H., Balduzzi, A., Bader, P., Pieczonka, A., Yaniv, I., Lankester, A., Bierings, M., Yesilipek, A., Sedlacek, P., Ifversen, M., et al
Bone marrow transplantation. 2020
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Editor's Choice
Abstract
Allogeneic HSCT represents the only potentially curative treatment for very high risk (VHR) ALL. Two consecutive international prospective studies, ALL-SCT-(I)BFM 2003 and 2007 were conducted in 1150 pediatric patients. 569 presented with VHR disease leading to any kind of HSCT. All patients >2 year old were transplanted after TBI-based MAC. The median follow-up was 5 years. 463 patients were transplanted from matched donor (MD) and 106 from mismatched donor (MMD). 214 were in CR1. Stem cell source was unmanipulated BM for 330 patients, unmanipulated PBSC for 135, ex vivo T-cell depleted PBSC for 62 and cord-blood for 26. There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years, median follow up of survivals was 4.88, range (0.01-11.72) years. The 4-year CI of extensive cGvHD was 13?±?2% and 17?±?4% (p?=?NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60?±?2% vs. 42?±?5%, p?0.001) for the whole cohort. This difference does not exist if considering separately patients treated in the most recent study. There was no difference in 4-year CI of relapse. The 4-year NRM was lower for patients transplanted from MD (9?±?1% vs. 23?±?4%, p?0.001). In multivariate analysis, donor-type appears as a negative risk-factor for OS, EFS, and NRM. This paper demonstrates the impact of donor type on overall results of allogeneic stem cell transplantation for very-high risk pediatric acute lymphoblastic leukemia with worse results when using MMD stem cell source.
PICO Summary
Population
Children with very high risk acute lymphoblastic leukaemia (n=569)
Intervention
Matched donor (MD) or matched sibling donor (MSD) transplantation (n=463)
Comparison
Mismatched donor transplantation (MMD, n=106)
Outcome
There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years,median follow up of survivals was 4.88 years. The 4-year CI of extensive cGvHD was 13± 2% and 17 ± 4% (p=NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60±2% vs. 42±5%) for the whole cohort. This difference does not exist if considering separately patients treated in the most recent study. There was no difference in 4-year CI of relapse. The 4-year NRM was lower for patients transplanted from MD (9±1% vs. 23±4%). In multivariate analysis, donor-type appears as a negative risk-factor for OS, EFS, and NRM.