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1.
Low rate of nonrelapse mortality in under 4-year-olds with ALL given chemo-conditioning for HSCT: Phase III FORUM study
Bader, P., Poetschger, U., Dalle, J. H., Moser, L. M., Balduzzi, A. C., Ansari, M., Buechner, J., Güngör, T., Ifversen, M., Kriván, G., et al
Blood advances. 2023
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). In young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of two TBI-free conditioning regimens in children with ALL <4 years old. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children were transplanted and observed for ≥6 months (median follow-up: 3 years). 3-year OS was 0.63 (95% confidence interval [95% CI]: 0.52-0.72) and 0.76 (95% CI: 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (p = 0.075), respectively. 3-year EFS was 0.52 (95% CI: 0.41-0.61) and 0.51 (95% CI: 0.39-0.62), respectively (p = 0.794). Cumulative incidence of non-relapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI: 0.02-0.12) versus 0.03 (95% CI: <0.01-0.09) (p = 0.406) and 0.42 (95% CI: 0.31-0.52) versus 0.45 (95% CI: 0.34-0.56) (p = 0.920), respectively. Grade >1 acute graft-versus-host disease (GvHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% receiving Flu/Thio/Treo (p = 0.049), while grade 3-4 occurred in 10% and 9% (p = 0.813). 3-year incidence of chronic GvHD was 0.07 (95% CI: 0.03-0.13) versus 0.05 (95% CI: 0.02-0.11), respectively (p = 0.518). In conclusion, both chemo-conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure.
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2.
Upper and/or lower respiratory tract infection caused by human metapneumovirus after allogeneic hematopoietic stem cell transplantation
Piñana, J. L., Tridello, G., Xhaard, A., Wendel, L., Montoro, J., Vazquez, L., Heras, I., Ljungman, P., Mikulska, M., Salmenniemi, U., et al
The Journal of infectious diseases. 2023
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Abstract
PATIENTS AND METHODS This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allogeneic stem cell transplantation (allo-HCT). RESULTS We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases. CONCLUSIONS These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases.
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Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan
Sobkowiak-Sobierajska, A., Lindemans, C., Sykora, T., Wachowiak, J., Dalle, J. H., Bonig, H., Gennery, A., Lawitschka, A.
Frontiers in pediatrics. 2022;10:808103
Abstract
Herein we review current practice regarding the management of chronic graft-vs.-host disease (cGvHD) in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukaemia (ALL). Topics covered include: (i) the epidemiology of cGvHD; (ii) an overview of advances in our understanding cGvHD pathogenesis; (iii) current knowledge regarding risk factors for cGvHD and prevention strategies complemented by biomarkers; (iii) the paediatric aspects of the 2014 National Institutes for Health-defined diagnosis and grading of cGvHD; and (iv) current options for cGvHD treatment. We cover topical therapy and newly approved tyrosine kinase inhibitors, emphasising the use of immunomodulatory approaches in the context of the delicate counterbalance between immunosuppression and immune reconstitution as well as risks of relapse and infectious complications. We examine real-world approaches of response assessment and tapering schedules of treatment. Furthermore, we report on the optimal timepoints for therapeutic interventions and changes in relation to immune reconstitution and risk of relapse/infection. Additionally, we review the different options for anti-infectious prophylaxis. Finally, we put forth a theory of a holistic view of paediatric cGvHD and its associated manifestations and propose a checklist for individualised risk evaluation with aggregated considerations including site-specific cGvHD evaluation with attention to each individual's GvHD history, previous medical history, comorbidities, and personal tolerance and psychosocial circumstances. To complement this checklist, we present a treatment algorithm using representative patients to inform the personalised management plans for patients with cGvHD after HSCT for ALL who are at high risk of relapse.
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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.
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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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Risk Factors for Transplant Outcomes in Children and Adolescents with Non-Malignant Diseases Following Allogeneic Hematopoietic Stem Cell Transplantation
Zaucha-Prazmo, A., Sadurska, E., Pieczonka, A., Gozdzik, J., Debski, R., Drabko, K., Zawitkowska, J., Lejman, M., Wachowiak, J., Styczynski, J., et al
Annals of transplantation. 2019;24:374-382
Abstract
BACKGROUND The objective of this study was the analysis of transplant outcomes and survival in children treated with allogeneic hematopoietic cell transplantation (alloHCT) for non-malignant disorders, with a focus on risk factor analysis of transplant-related mortality (TRM). MATERIAL AND METHODS The treatment outcome was analyzed retrospectively in 10 consecutive years in 4 pediatric transplant centers in Poland. To compare the outcomes, patient data were analyzed according to the diagnosis, age at transplant, donor type, stem cell source, conditioning regimens, transplanted CD34+ cells dose, and pediatric TRM score. RESULTS From 183 analyzed patients, 27 (14.8%) died, all of them due to transplant-related complications. TRM occurred more frequently in matched unrelated donor (MUD) transplant recipients vs. matched sibling donor (MSD) transplant recipients (p=0.02); in peripheral blood (PB) recipients vs. bone marrow (BM) recipients (p=0.004); and in patients receiving >5x10(6)/kg CD34+ cells (p<0.0001). OS differed significantly according to underlying disease comparing to other diagnoses. Lower survival was found in patients transplanted from MUD (p=0.02). OS was higher in patients receiving BM (p=0.001) and in those receiving ≤5x10(6)/kg CD34+ cells (p<0.001). Multivariate analysis showed lower probability of TRM in BM recipients (p=0.04). The probability of TRM was higher in SCID patients (p=0.02) and in patients receiving >5x10(6)/kg CD34+ cells (p=0.0001). CONCLUSIONS Underlying disease, stem cell source, and CD34+ dose higher than 5x10(6)/kg were the most important risk factors for TRM, and they all affected OS.
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Infection profile in children and adolescents with bone marrow failures treated with allogeneic hematopoietic stem cell transplantation
Zaucha-Prazmo, A., Zawitkowska, J., Lejman, M., Kowalczyk, J. R., Czyzewski, K., Dziedzic, M., Pieczonka, A., Zajac-Spychala, O., Gozdzik, J., Fraczkiewicz, J., et al
Pediatric transplantation. 2019;:e13592
Abstract
BACKGROUND The objective of the study was to analyze the profile of infections in children with BMF following alloHCT. METHODS Data of 169 consecutive children with inherited and acquired BMF treated with alloHCT between 2012 and 2017 in Polish pediatric transplant departments were analyzed in registry-based retrospective study, with respect to the type of infection, and clinical outcome. RESULTS At least 1 infection was diagnosed in 107/169 patients (60.4%). In total, 182 infections were diagnosed. The most common were VI (96; 52.7%), followed by BI (71; 39.0%), and FI (15; 8.2%), P < .001. The most common etiological factors of VI were as follows: CMV (38.5%), EBV (22.9%), and BK virus (24%); while of BI were as follows: Staphylococcus spp. (17; 23.9%), Enterococcus faecium (10; 14.1%), and Klebsiella pneumoniae (9; 12.7%). No difference was found between the occurrence of infections with respect to donor type, graft source, and conditioning type. GvHD had no impact on the incidence of VI, BI, and FI. Fifteen FI were diagnosed in 12 patients, of which 14 FI were diagnosed in children transplanted for FA. Of total 107 children, 9 died (8.4%), of which 4 (3.7%) due to infections: bacterial sepsis (2) and invasive FI (2). CONCLUSION Infections in children with BMF following alloHCT remain an important cause of morbidity. Children with FA had high incidence of FI. In our analysis, aGvHD had no impact on the occurrence on infections, although the study was not strong enough to prove such a difference.
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HLA-inferred extended haplotype disparity level is more relevant then the level of HLA mismatch alone for the patients survival and GvHD in T cell-replate hematopoietic stem cell transplantation from unrelated donor
Nowak, J., Nestorowicz, K., Graczyk-Pol, E., Mika-Witkowska, R., Rogatko-Koros, M., Jaskula, E., Koscinska, K., Madej, S., Tomaszewska, A., Nasilowska-Adamska, B., et al
Human immunology. 2018
Abstract
Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N=889 patients by the population-based detection of HLA allele phase mismatch. We found increased graft versus host disease (GvHD) incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p=0.000037, HR=10.68, 95%CI 5.50-32.5) and extended chronic GvHD (p<0.000001, HR=15.51, CI95% 5.36-44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5-year overall survival (45% vs. 56%, p=0.00065, HR=4.05, CI95% 1.69-9.71) and non-relapse mortality (40% vs. 31%, p=0.00037, HR=5.63, CI95% 2.04-15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT.