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Rare variants in complement system genes associate with endothelial damage after pediatric allogeneic hematopoietic stem cell transplantation
Leimi, L., Koski, J. R., Kilpivaara, O., Vettenranta, K., Lokki, A. I., Meri, S.
Frontiers in immunology. 2023;14:1249958
Abstract
INTRODUCTION Complement system has a postulated role in endothelial problems after hematopoietic stem cell transplantation (HSCT). In this retrospective, singlecenter study we studied genetic complement system variants in patients with documented endotheliopathy. In our previous study among pediatric patients with an allogeneic HSCT (2001-2013) at the Helsinki University Children´s Hospital, Finland, we identified a total of 19/122 (15.6%) patients with vascular complications, fulfilling the criteria of capillary leak syndrome (CLS), venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS) or thrombotic microangiopathy (TMA). METHODS We performed whole exome sequencing (WES) on 109 patients having an adequate pre-transplantation DNA for the analysis to define possible variations and mutations potentially predisposing to functional abnormalities of the complement system. In our data analysis, we focused on 41 genes coding for complement components. RESULTS 50 patients (45.9%) had one or several, nonsynonymous, rare germline variants in complement genes. 21/66 (31.8%) of the variants were in the terminal pathway. Patients with endotheliopathy had variants in different complement genes: in the terminal pathway (C6 and C9), lectin pathway (MASP1) and receptor ITGAM (CD11b, part of CR3). Four had the same rare missense variant (rs183125896; Thr279Ala) in the C9 gene. Two of these patients were diagnosed with endotheliopathy and one with capillary leak syndrome-like problems. The C9 variant Thr279Ala has no previously known disease associations and is classified by the ACMG guidelines as a variant of uncertain significance (VUS). We conducted a gene burden test with gnomAD Finnish (fin) as the reference population. Complement gene variants seen in our patient population were investigated and Total Frequency Testing (TFT) was used for execution of burden tests. The gene variants seen in our patients with endotheliopathy were all significantly (FDR < 0.05) enriched compared to gnomAD. Overall, 14/25 genes coding for components of the complement system had an increased burden of missense variants among the patients when compared to the gnomAD Finnish population (N=10 816). DISCUSSION Injury to the vascular endothelium is relatively common after HSCT with different phenotypic appearances suggesting yet unidentified underlying mechanisms. Variants in complement components may be related to endotheliopathy and poor prognosis in these patients.
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Early vascular toxicity after pediatric allogeneic hematopoietic stem cell transplantation
Leimi, L., Jahnukainen, K., Olkinuora, H., Meri, S., Vettenranta, K.
Bone marrow transplantation. 2022
Abstract
Treatment-related mortality and morbidity remain a challenge in hematopoietic stem cell transplantation (HSCT). In this retrospective, single-center study, we analyzed endothelial damage as a potential, common denominator and mechanism for the adverse effects. We evaluated the prevalence of key vascular complications and graft-versus-host disease among 122 pediatric patients with an allogeneic HSCT between 2001 and 2013. The spectrum and frequency of acute adverse events emerging ≤100 days post transplant were graded according to the CTCAE 4.03 and analyzed. We identified a total of 19/122 (15.6%) patients with vascular complications, fulfilling the criteria of capillary leak syndrome, veno-occlusive disease/sinusoidal obstruction syndrome or thrombotic microangiopathy. The patients had a poorer overall survival (77% versus 26%, p < 0.001). Nearly one half (56/122, 45.9%) had at least one, severe (grade 3 or 4) adverse event. Patients with vascular complications had more often edema/effusions (p = 0.023), thrombocytopenia (p = 0.001), gastrointestinal bleeding (p < 0.001), acute kidney injury (p < 0.001), ascites (p < 0.001) or bilirubin increase (p = 0.027). These endotheliopathy-related adverse events appeared early post HSCT, varied in their clinical phenotype and predicted a poor outcome. An unrelated donor but not previous exposure to leukemia or irradiation-based conditioning was identified as a risk factor for vascular complications and endotheliopathy.
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Clinically relevant germline variants in allogeneic hematopoietic stem cell transplant recipients
Lahtinen, A. K., Koski, J., Ritari, J., Hyvärinen, K., Koskela, S., Partanen, J., Vettenranta, K., Koskenvuo, M., Niittyvuopio, R., Salmenniemi, U., et al
Bone marrow transplantation. 2022
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) provides patients with severe hematologic disease a well-established potential for curation. Incorporation of germline analyses in the workup of HSCT patients is not a common practice. Recognizing rare harmful germline variants may however affect patients' pre-transplantation care, choice of the stem cell donor, and complication risks. We analyzed a population-based series of germline exome data of 432 patients who had undergone HSCT. Our aim was to identify clinically relevant variants that may challenge the outcome of the HSCT. We focused on genes predisposing to hematological diseases, or solid tumors, and genes included in the American College of Medical Genetics secondary findings list v3.0. As population-specific controls, we used GnomAD non-cancer Finns (n = 10,816). We identified in our population-based analysis rare harmful germline variants in disease-predisposing or actionable toxicity-increasing genes in 17.8% of adult and pediatric patients that have undergone HSCT (15.1% and 22.9%, respectively). More than half of the patients with a family member as a donor had not received genetic diagnosis prior to the HSCT. Our results encourage clinicians to incorporate germline genetic testing in the HSCT protocol in the future in order to reach optimal long-term outcome for the patients.
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Hematopoietic cell transplant in pediatric acute myeloid leukemia after similar upfront therapy; a comparison of conditioning regimens
Versluys, A. B., Boelens, J. J., Pronk, C., Lankester, A., Bordon, V., Buchner, J., Ifversen, M., Jackmann, N., Sundin, M., Vettenranta, K., et al
Bone marrow transplantation. 2021
Abstract
The impact of conditioning regimen prior to hematopoietic cell transplant (HCT) in pediatric AML-patients is not well studied. We retrospectively analyzed the impact of Busulfan-Cyclophosphamide (BuCy), Busulfan-Cyclophosphamide-Melphalan (BuCyMel) and Clofarabine-Fludarabine-Busulfan (CloFluBu) in pediatric AML-patients, with similar upfront leukemia treatment (NOPHO-DBHconsortium), receiving an HCT between 2010 and 2015. Outcomes of interest were LFS, relapse, TRM and GvHD. 103 patients were included; 30 received BuCy, 37 BuCyMel, and 36 CloFluBu. The 5-years LFS was 43.3% (SE?±?9.0) in the BuCy group, 59.2 % (SE?±?8.1) after BuCyMel, and 66.7 % (SE?±?7.9) after CloFluBu. Multivariable Cox regression analysis showed a trend to lower LFS after BuCy compared to CloFluBu (p?=?0.07). BuCy was associated with a higher relapse incidence compared to the other regimens (p?=?0.06). Younger age was a predictor for relapse (p?=?0.02). A strong correlation between Busulfan Therapeutic Drug Monitoring (TDM) and lower incidence of aGvHD (p?0.001) was found. In conclusion, LFS after BuCyMel and CloFluBu was comparable, lower LFS was found after BuCy, due to higher relapse incidence. CloFluBu was associated with lower incidence of aGvHD, suggesting lower toxicity with this type of conditioning. This finding is also explained by the impact of Busulfan monitoring.
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Hematopoietic cell transplantation in severe combined immunodeficiency: the SCETIDE 2006-2014 European cohort
Lankester, A. C., Neven, B., Mahlaoui, N., von Asmuth, E. G., Courteille, V., Alligon, M., Albert, M. H., Serra, I. B., Bader, P., Balashov, D., et al
The Journal of allergy and clinical immunology. 2021
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Editor's Choice
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. OBJECTIVE To perform a comprehensive multicenter analysis of genotype-specific HSCT outcome including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. METHODS HSCT outcome was studied in 338 patients with genetically confirmed SCID, transplanted in 2006-2014 and registered in the SCETIDE registry. In a representative subgroup of n=152 patients data on IR and long-term clinical outcome were analyzed. RESULTS 2-years OS was similar with matched family and unrelated donors and superior to mismatched donor HSCT (p < 0.001). The 2-year EFS was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (p < 0.001). Genetic subgroups did not differ in 2-year OS (p=0.1) and EFS (p=0.073). In multivariate analysis, pretransplant infections and use of MMRD were associated with less favorable OS and EFS. With a median follow-up of 6.2 years [range 2.0-11.8 years], 73/152 IR cohort patients were alive and well without immunoglobulin dependency. IL2R?-JAK3-IL7R deficient SCID, myeloablative conditioning, matched donor HSCT, and naïve CD4 T lymphocytes > 0.5x10e3/µL at +1-year were identified as independent predictors of favorable clinical and immunological outcome. CONCLUSION Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long term outcome, treatment strategies should aim for optimal naïve CD4 T lymphocyte regeneration.
PICO Summary
Population
Patients with severe combined immunodeficiency (SCID) transplanted in the years 2006-2014 and reported to the SCETIDE registry (n=338) Long-term outcomes were assessed in a representative subgroup (n=152)
Intervention
Assessment of the impact of donor source and SCID genetic diagnosis on transplant outcomes
Comparison
None
Outcome
2-years OS was similar with matched family and unrelated donors and superior to mismatched donor HSCT. The 2-year EFS was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT. Genetic subgroups did not differ in 2-year OS and EFS. In multivariate analysis, pretransplant infections and use of MMRD were associated with less favorable OS and EFS. With a median follow-up of 6.2 years [range 2.0-11.8 years], 73/152 IR cohort patients were alive and well without immunoglobulin dependency IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor–deficient SCID, myeloablative conditioning, matched donor HSCT, and naïve CD4 T lymphocytes > 0.5x10e3/µL at +1-year were identified as independent predictors of favorable clinical and immunological outcome.
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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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Acute toxicity and outcome among pediatric allogeneic hematopoietic transplant patients conditioned with treosulfan-based regimens
Huttunen, P., Taskinen, M., Vettenranta, K.
Pediatric hematology and oncology. 2020;:1-10
Abstract
Treosulfan-based regimens constitute a feasible and increasingly used, but still myeloablative, conditioning in pediatric allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed the acute toxicity and outcome of all consecutive (2004-2015) pediatric HSCT patients prepared for HSCT with treosulfan in a single-center setting. We included HSCTs performed for both nonmalignant (n = 23) and malignant diseases (n = 11). The controls were patients with nonmalignant diseases or hematological malignancies conditioned with cyclophosphamide (Cy)-total body irradiation (TBI)-based (39 patients) or busulfan-based regimens (11 patients). The major toxicities of the treosulfan-based regimens were limited to oral mucosa and skin. 50% of the patients needed IV morphine for severe mucositis compared to 31% in patients conditioned with Cy-TBI (P = 0.02). Other toxicities were rare. The disease-free survival (DFS) of patients transplanted for nonmalignant disorders was 88.9 +/- 7.5% at 2 years. The event-free survival (EFS) at 2 years in this small cohort for those with a malignant disease and a treosulfan-based conditioning was 54.5 +/- 1.5%. We conclude that a treosulfan-based conditioning regimen gives excellent DFS in pediatric HSCT performed for a nonmalignant disorder but with substantial mucosal toxicity. In a malignant disorder a treosulfan-based regimen looks promising but larger, preferably randomized, studies are needed to prove efficacy.
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Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Nava, T., Ansari, M., Dalle, J. H., de Heredia, C. D., Gungor, T., Trigoso, E., Falkenberg, U., Bertaina, A., Gibson, B., Jarisch, A., et al
Bone marrow transplantation. 2020
Abstract
Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.
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Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study
Peters, C., Dalle, J. H., Locatelli, F., Poetschger, U., Sedlacek, P., Buechner, J., Shaw, P. J., Staciuk, R., Ifversen, M., Pichler, H., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;:Jco2002529
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Editor's Choice
Abstract
PURPOSE Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients = 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). RESULTS Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
Clinical Commentary
Dr. Julia Wolf, University Hospitals Bristol and Weston NHS Foundation Trust
What is known?
Allogeneic haematopoietic stem cell transplantation (HSCT) provides a potential curative treatment option for paediatric patients with high risk acute lymphoblastic leukaemia (ALL). Pre-transplant conditioning regimes with total body irradiation (TBI) have resulted in encouraging overall and relapse-free survival but may cause serious long-term side effects. As a result, several studies have investigated TBI-free regimes. A large meta-analysis (1) which included seven randomised controlled trials comparing TBI-based with chemoconditioning regimes demonstrated significantly lower treatment related mortality (TRM) but no overall survival (OS) advantage with TBI-based regimes. A further small randomised study (2) found significantly higher event-free survival (EFS) with TBI-based regimes in patients with unrelated donors, but a non-significant difference only in patients with matched sibling donors. Concerns about late effects of TBI on growth, cognitive function and secondary malignancy however remain. A single centre retrospective study (3) in paediatric ALL concluded that triosulphan based regimes were safe and efficacious while a similar review (4) in adult patients suggested that busulphan and clofarabine could provide an alternative to TBI. This paper reports on the FORUM study. It compares TBI with chemoconditioning regimes to investigate whether optimal chemoconditioning regimens could replace TBI in paediatric patients with high-risk ALL.
What did this paper set out to examine?
This is the largest randomised, controlled, open-label, international, multicentre, phase III trial comparing TBI plus etoposide with chemoconditioning (fludarabine, thiotepa and busulfan or triosulfan) in paediatric ALL to date. It investigates whether chemoconditioning is non-inferior to TBI-based regimes with the primary endpoint of OS. It is also the first study to directly and prospectively compare these regimes in terms of disease-free survival and short- and long-term adverse events. The study aimed to recruit 1000 patients.
What did they show?
Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. Patients ≤18 years old at diagnosis and aged 4-21 at HSCT with high risk ALL in complete morphological remission with HLA compatible related or unrelated donor were included in the study. Patients were randomised 1:1 to 12Gy TBI with etoposide versus fludarabine, thiotepa and busulfan or triosulphan conditioning. Patients were well matched for baseline characteristics and demographics. Randomisation was stopped early due significant inferiority of chemoconditioning compared with TBI-based regime.
Results
Following randomisation of 417 patients, a futility stopping rule was applied because patients receiving chemoconditioning with fludarabine, thiotepa, and busulfan or treosulfan had inferior OS to those receiving TBI plus etoposide. Two-year OS was 0.91 (95% CI, P <.0001) following TBI versus 0.75 (95% CI) following chemoconditioning. Median follow up was 2.1 years. Relapse was the commonest reason for treatment failure and out of 67 patients who relapsed, there was no difference in OS between conditioning regimes. There was no difference in serious adverse events or GvHD rates between the groups.
What are the implications for practice and for future work?
While TBI is associated with potentially serious long-term side effects, this study supports growing evidence demonstrating improved outcomes for patients undergoing TBI-based conditioning. Here patients receiving TBI-based conditioning had a significantly lower risk of relapse and TRM than those given chemoconditioning.
Of note, TRM in this trial was low compared to previously reported studies. FOCUS reported a 2-year OS and EFS rate of 0.91 and 0.91 respectively, which is the lowest documented TRM in HSCT for high-risk paediatric ALL to date. Additionally, other risk factors thought to impact on outcomes (e.g. leukaemia phenotype, MRD pre-transplant, donor type, etc) were not found to be significant in FOCUS. Only remission status (CR1 vs CR2) and conditioning regime influenced OS and EFS. This may be in part explained by the strong attempts within this study to reduce MRD prior to HSCT in all patients.
This was a noninferiority study which required a sample size of 1000 patients with 2-year minimum follow-up to make analysis of primary outcomes feasible. As the majority of relapses in paediatric ALL occur in the first 24 months, it is unlikely that longer follow up would result in dramatic changes to outcomes.
Non-randomised recruitment in FORUM to assess long-term side effects of TBI, such as secondary malignancy, in FORUM is ongoing. However, no difference in adverse events or incidence of GvHD was found between study groups. The study reports a composite end point of 2-year GVHD-free, relapse-free survival of 72% (95% CI) following TBI plus etoposide and 51% (95% CI, p= .0003) following chemoconditioning which might be a benchmark for future investigations.
PICO Summary
Population
Patients diagnosed with acute lymphoblastic leukaemia at or before 18 years of age, who underwent HSCT aged 4-21 years (n=413)
Intervention
TBI conditioning (n=212)
Comparison
Chemoconditioning: fludarabine, thiotepa, and either busulfan or treosulfan (n=201)
Outcome
The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91) versus chemoconditioning (0.75). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 and 0.02 following TBI and 0.33 and 0.09 following chemoconditioning, respectively.