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1.
Influence of invasive aspergillosis during acute leukaemia treatment on survival after allogeneic stem cell transplantation: a prospective study of the EBMT Infectious Diseases Working Party
Penack, O., Tridello, G., Salmenniemi, U., Martino, R., Khanna, N., Perruccio, K., Fagioli, F., Richert-Przygonska, M., Labussière-Wallet, H., Maertens, J., et al
EClinicalMedicine. 2024;67:102393
Abstract
BACKGROUND Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed. METHODS We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints. FINDINGS 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n = 87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p = 0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p = 0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p = 0.01). INTERPRETATION Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure. FUNDING There was no external funding source for this study.
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2.
Predictors of outcomes in hematopoietic cell transplantation for Fanconi anemia
Cancio, M., Troullioud Lucas, A. G., Bierings, M., Klein, E., de Witte, M. A., Smiers, F. J., Bresters, D., Boelens, J. J., Smetsers, S. E.
Bone marrow transplantation. 2023
Abstract
Allogeneic hematopoietic cell transplantation (HCT) remains the only cure for the hematologic manifestations of Fanconi anemia (FA). We performed retrospective predictor analyses for HCT outcomes in FA for pediatric and young adult patients transplanted between 2007 and 2020 across three large referral institutions. Eighty-nine patients, 70 with bone marrow failure +/- cytogenetic abnormalities, 19 with MDS/AML, were included. Five-year overall survival (OS) was 83.2% and event-free survival (EFS) was 74%. Age ≥19, HLA mismatch and year of HCT were multivariable predictors (MVPs) for OS, EFS and treatment-related mortality (TRM). In the pediatric group, TCD was a borderline MVP (P = 0.059) with 5-year OS of 73.0% in TCD vs. 100% for T-replete HCT. The cumulative incidence of day 100 grade II-IV aGvHD and 5-year cGvHD were 5.6% and 4.6%, respectively. Relapse in the MDS/AML subgroup occurred in 4 patients (16%). Graft failure was seen in 9 patients (TCD 6/37 [16%]; T-replete 3/52 [5.7%]). Six patients developed malignancy after HCT. Survival chances after HCT for FA are excellent and associated with high engrafted survival and low toxicity. Age ≥19, HLA mismatch, year of transplant and 'TCD in the <19 years group' (although borderline) were found to be negative predictors for survival.
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3.
Use of eculizumab in children with allogeneic haematopoietic stem cell transplantation associated thrombotic microangiopathy - a multicentre retrospective PDWP and IEWP EBMT study
Svec, P., Elfeky, R., Galimard, J. E., Higham, C. S., Dalissier, A., Quigg, T. C., Bueno Sanchez, D., Han Lum, S., Faraci, M., Cole, T., et al
Bone marrow transplantation. 2022
Abstract
Terminal complement blockade by humanised monoclonal antibody eculizumab has been used to treat transplantation-associated thrombotic microangiopathy (TA-TMA) in recent years. This retrospective international study conducted by the Paediatric Diseases (PDWP) and Inborn Error Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) describes outcome and response of 82 paediatric patients from 29 centres who developed TA-TMA and were treated with eculizumab between January 2014 and May 2019. The median time from hematopoietic stem cell transplantation (HSCT) to TA-TMA manifestation was 92 days (range: 7-606) and from TA-TMA diagnosis to the start of eculizumab treatment 6 days (range: 0-135). Most patients received eculizumab weekly (72%, n = 55) with a standard weight (kg)-based dose (78%, n = 64). Six months from beginning of eculizumab therapy, the cumulative incidence of TA-TMA resolution was 36.6% (95% CI: 26.2-47) and the overall survival (OS) was 47.1% (95% CI: 35.9-57.5). All 43 patients with unresolved TA-TMA died. The cause of death was HSCT-related in 41 patients. This study also documents poor outcome of patients without aGvHD and their frequent concomitant viral infections. Considering recent publications, intensified eculizumab dosing and complement monitoring could potentially improve upon outcomes observed in this study.
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4.
ESTRO ACROP and SIOPE recommendations for myeloablative total body irradiation in children
Hoeben, B. A. W., Pazos, M., Seravalli, E., Bosman, M. E., Losert, C., Albert, M. H., Boterberg, T., Ospovat, I., Mico Milla, S., Abakay, C. D., et al
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2022
Abstract
BACKGROUND AND PURPOSE Myeloablative total body irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children with high-risk acute lymphoblastic leukemia (ALL). TBI practices are heterogeneous and institution-specific. Since TBI is associated with multiple late adverse effects, recommendations may help to standardize practices and improve the outcome versus toxicity ratio for children. MATERIAL AND METHODS The European Society for Paediatric Oncology (SIOPE) Radiotherapy TBI Working Group together with ESTRO experts conducted a literature search and evaluation regarding myeloablative TBI techniques and toxicities in children. Findings were discussed in bimonthly virtual meetings and consensus recommendations were established. RESULTS Myeloablative TBI in HSCT conditioning is mostly performed for high-risk ALL patients or patients with recurring hematologic malignancies. TBI is discouraged in children <3-4 years old because of increased toxicity risk. Publications regarding TBI are mostly retrospective studies with level III-IV evidence. Preferential TBI dose in children is 12-14.4 Gy in 1.6-2 Gy fractions b.i.d. Dose reduction should be considered for the lungs to <8 Gy, for the kidneys to ≤10 Gy, and for the lenses to <12 Gy, for dose rates ≥6 cGy/min. Highly conformal techniques i.e. TomoTherapy and VMAT TBI or Total Marrow (and/or Lymphoid) Irradiation as implemented in several centers, improve dose homogeneity and organ sparing, and should be evaluated in studies. CONCLUSIONS These ESTRO ACROP / SIOPE recommendations provide expert consensus for conventional and highly conformal myeloablative TBI in children, as well as a supporting literature overview of TBI techniques and toxicities.
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5.
Clinical Features, Treatment, and Outcome of Pediatric Steroid Refractory Acute Graft-Versus-Host Disease: A Multicenter Study
Verbeek, A. B., Jansen, S. A., von Asmuth, E. G. J., Lankester, A. C., Bresters, D., Bierings, M., Mohseny, A. B., Lindemans, C. A., Buddingh, E. P.
Transplantation and cellular therapy. 2022;28(9):600.e1-600.e9
Abstract
Steroid-refractory acute graft-versus-host disease (SR-aGvHD) is a severe complication in pediatric allogeneic hematopoietic stem cell transplantation (HSCT). We aimed to assess clinical course and outcomes of pediatric SR-aGvHD. We performed a retrospective nationwide multicenter cohort study in the Netherlands. All patients aged 0 to 18 years who underwent transplantation between 2010 and 2020 with SR-aGvHD were included. For each patient, weekly clinical aGvHD grade and stage, immunosuppressive treatment and clinical outcomes were collected. The primary study endpoint was the clinical course of SR-aGvHD over time. As a secondary outcome, factors influencing overall survival and SR-aGvHD remission were identified using a multistate Cox model. 20% of transplanted children developed grade II-IV aGvHD, of which 51% (n = 81) was SR-aGvHD. In these patients, second-line therapy was started at a median of 8 days after initial aGvHD-diagnosis. Forty-nine percent of SR-aGvHD patients received 3 or more lines of therapy. One year after start of second-line therapy, 34 patients (42%) were alive and in remission of aGvHD, 14 patients (17%) had persistent GvHD, and 33 patients (41%) had died. SR-aGvHD remission rate was lower in cord blood graft recipients than in bone marrow (BM) or peripheral blood stem cell (PBSC) recipients (hazard ratio [HR] = 0.51, 0.27-0.94, P = .031). Older age was associated with higher mortality (HR = 2.62, 1.04-6.60, P = .04, fourth quartile [aged 13.9-17.9] versus first quartile [aged 0.175-3.01]). In BM/PBSC recipients older age was also associated with lower remission rates (HR = 0.9, 0.83-0.96, P = .004). Underlying diagnosis, donor matching or choice of second-line therapy were not associated with outcome. Respiratory insufficiency caused by pulmonary GvHD was a prominent cause of death (26% of deceased). Our study demonstrates that SR-aGvHD confers a high mortality risk in pediatric HSCT. Older age and use of CB grafts are associated with an unfavorable outcome. Multicenter studies investigating novel treatment strategies to prevent pediatric SR-aGvHD and inclusion of children in ongoing trials, together with timely initiation of second-line interventions are pivotal to further reduce GvHD-related mortality.
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6.
Population pharmacokinetics of clofarabine for allogeneic hematopoietic cell transplantation in pediatric patients
Nijstad, A. L., Nierkens, S., Lindemans, C. A., Boelens, J. J., Bierings, M., Versluys, A. B., van der Elst, K. C. M., Huitema, A. D. R.
British journal of clinical pharmacology. 2021
Abstract
AIM: Clofarabine has recently been evaluated as part of the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HCT) in children. Pharmacokinetic (PK) exposure of different agents commonly used in conditioning regimens is strongly related to HCT outcome. Consequently, the PK of clofarabine may be important for outcome. This report describes the population PK of clofarabine in pediatric patients and one adult. METHODS From 80 pediatric (0.5-18 years) and 1 adult patient (37 years), 805 plasma concentrations were included in pharmacokinetic analyses using non-linear mixed effects modelling. RESULTS A two-compartment model adequately described the PK of clofarabine. Body weight and estimated glomerular filtration rate (eGFR) were included as covariates. Clearance was differentiated into non-renal and renal clearance (approximately 55% of total clearance), resulting in population estimates of 24.0 L/h (95% confidence interval (CI) 13.7-34.4) and 29.8 L/h (95% CI 23.9-36.1) for a patient of 70 kg with normal renal function, respectively. Unexplained interindividual variability in clearance was 17.8% (95% CI 14.6%-22.4%). A high variability in exposure was observed (range area under the curve(T0-inf) 1.8-6.0 mg/L*h) after body surface area (BSA) based dosing. Interestingly, children with low body weight had a lower exposure than children with a higher body weight, which indicates that the currently practiced BSA based dosing is not adequate for clofarabine. CONCLUSION A clofarabine dosing algorithm based on this PK model, using body weight and eGFR, results in a more predictable exposure than BSA based dosing. However, the exact target exposure needs to be further investigated.
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7.
Clofarabine-fludarabine-busulfan in HCT for pediatric leukemia: an effective, low toxicity, TBI-free conditioning regimen
Versluijs, B., De Koning, C. C. H., Lankester, A. C., Nierkens, S., Kollen, W. J., Bresters, D., Lindemans, C. A., Boelens, J. J., Bierings, M.
Blood advances. 2021
Abstract
We prospectively studied CloFluBu-conditioning in allogeneic Hematopoietic Cell Therapy (HCT) for lymphoid- and myeloid malignancies, and hypothesized that CloFluBu provides a less toxic alternative to conventional conditioning regimens, with adequate anti-leukemic activity. All patients receiving their first HCT, from 2011-2019, were included and received CloFluBu. Primary endpoint was Event Free Survival (EFS). Secondary endpoints were Overall Survival (OS), Graft-versus-Host-Disease (GvHD)-Relapse-Free Survival (GRFS), Treatment Related Mortality (TRM), Cumulative Incidence of Relapse (CIR), acute and chronic GvHD, and veno-occlusive disease (VOD). Cox Proportional Hazard- and Fine and Gray competing-risk models were used for data analysis. 155 Children were included; 60 acute lymphoid leukemia (ALL), 69 acute myeloid leukemia (AML), and 26 other malignancies (mostly MDS-EB). Median age was 9.7 (0.5-18.6) years. Estimated 2-yr EFS was 72.0% ± 6.0 in ALL, and 62.4% ± 6.0 in AML patients. TRM in the whole cohort was 11.0% ± 2.6, incidence of aGvHD III-IV at 6 months was 12.3% ± 2.7, extensive chronic GvHD at 2-yr was 6.4% ± 2.1. Minimal residual disease-positivity prior to HCT was associated with higher CIR, both in ALL and AML. CloFluBu showed limited toxicity and encouraging EFS. CloFluBu is a potentially less toxic alternative to conventional conditioning regimens. Randomized prospective studies are needed.
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8.
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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9.
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.
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10.
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%.