This prospective multicentre trial evaluated the safety and the efficacy of a thiotepa/melphalan-based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) in children and adolescents with chronic myeloid leukaemia (CML) in chronic phase (CP). Thirty-two patients were transplanted from matched siblings or matched unrelated donors. In 22 patients, HSCT was performed due to insufficient molecular response or loss of response to first- or second-generation tyrosine kinase inhibitor (TKI), with pretransplant BCR::ABL1 transcripts ranging between 0.001% and 33%. The protocol included a BCR::ABL1-guided intervention with TKI retreatment in the first year and donor lymphocyte infusions (DLI) in the second-year post-transplant. All patients engrafted. The 1-year transplant-related mortality was 3% (confidence interval [CI]: 0%-6%). After a median follow-up of 6.3 years, 5-year overall survival and event-free survival are 97% (CI: 93%-100%) and 91% (CI: 79%-100%) respectively. The current 5-year leukaemia-free survival with BCR::ABL1 <0.01% is 97% (CI: 88%-100%) and the current TKI- and DLI-free survival is 95% (CI: 85%-100%). The incidence of chronic graft-versus-host disease (GvHD) was 32%, being severe in four patients (13%). At last follow-up, 31 patients are GvHD-free and have stopped immunosuppression. RIC HSCT following pretreatment with TKI is feasible and effective in children and adolescents with CP-CML with an excellent disease-free and TKI-free survival.
- Klíčová slova
- allogeneic stem cell transplantation, children and adolescents, chronic myeloid leukaemia, reduced intensity conditioning,
- Publikační typ
- časopisecké články MeSH
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: We performed 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 who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. RESULTS: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P < .001). The 2-year event-free survival (EFS) was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (P < .001). Genetic subgroups did not differ in 2-year OS (P = .1) and EFS (P = .073). In multivariate analysis, pretransplantation infections and use of MMRDs were associated with less favorable OS and EFS. With a median follow-up of 6.2 years (range, 2.0-11.8 years), 73 of 152 patients in the IR cohort were alive and well without Ig dependency. IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor-deficient SCID, myeloablative conditioning, matched donor HSCT, and naive CD4 T lymphocytes >0.5 × 10e3/μL at +1 year were identified as independent predictors of favorable clinical and immunologic 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 naive CD4 T lymphocyte regeneration.
- Klíčová slova
- SCID, conditioning, genetic subgroups, immune reconstitution, pretransplantation infections,
- MeSH
- kohortové studie MeSH
- lidé MeSH
- nepříbuzný dárce MeSH
- příprava pacienta k transplantaci metody MeSH
- těžká kombinovaná imunodeficience * genetika terapie MeSH
- transplantace hematopoetických kmenových buněk * metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival (events include death, graft failure, and severe chronic GVHD) of 81.7%. Overall survival and chronic GVHD-free survival were not significantly affected by conditioning regimen (busulfan- vs treosulfan-based), donor type (matched sibling donor/matched family donor vs matched unrelated donor/mismatched unrelated donor vs mismatched family donor), or period of HSCT (2006-2013 vs 2014-2017). Patients aged <5 years at HSCT had a significantly better overall survival. The overall cumulative incidences of grade III to IV acute GVHD and extensive/moderate/severe chronic GVHD were 6.6% and 2.1%, respectively. Patients receiving treosulfan-based conditioning had a higher incidence of graft failure and mixed donor chimerism and more frequently underwent secondary procedures (second HSCT, unconditioned stem cell boost, donor lymphocyte infusion, or splenectomy). In summary, HSCT for WAS with conditioning regimens currently recommended by IEWP results in excellent survival and low rates of GVHD, regardless of donor or stem cell source, but age ≥5 years remains a risk factor for overall survival.
- MeSH
- busulfan terapeutické užití MeSH
- dárci tkání MeSH
- lidé MeSH
- nemoc štěpu proti hostiteli * etiologie MeSH
- předškolní dítě MeSH
- příprava pacienta k transplantaci metody MeSH
- retrospektivní studie MeSH
- transplantace hematopoetických kmenových buněk * škodlivé účinky MeSH
- výsledek terapie MeSH
- Wiskottův-Aldrichův syndrom * terapie MeSH
- Check Tag
- lidé MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- busulfan MeSH
Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children.
- MeSH
- analýza jednotlivých buněk MeSH
- buňky kostní dřeně metabolismus MeSH
- dítě MeSH
- HEK293 buňky MeSH
- intracelulární signální peptidy a proteiny genetika MeSH
- Kaplanův-Meierův odhad MeSH
- klonální evoluce genetika MeSH
- klonální hematopoéza genetika MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- myelodysplastické syndromy genetika patologie MeSH
- nádorové supresorové proteiny genetika MeSH
- předškolní dítě MeSH
- transkripční faktor GATA2 genetika MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- zárodečné mutace genetika MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- GATA2 protein, human MeSH Prohlížeč
- intracelulární signální peptidy a proteiny MeSH
- nádorové supresorové proteiny MeSH
- SAMD9 protein, human MeSH Prohlížeč
- SAMD9L protein, human MeSH Prohlížeč
- transkripční faktor GATA2 MeSH
Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.
- Klíčová slova
- allogeneic hematological stem cell transplantation, antibiotic prophylactic therapy, children, infection precaution, vaccination,
- Publikační typ
- časopisecké články MeSH
Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients.
- Klíčová slova
- Bone Marrow Failure, Congenital disorder, Diamond-Blackfan Anemia, Stem Cell Transplantation,
- MeSH
- aplastická anemie * terapie MeSH
- Diamondova-Blackfanova anemie * terapie MeSH
- dítě MeSH
- kostní dřeň MeSH
- lidé MeSH
- retrospektivní studie MeSH
- transplantace hematopoetických kmenových buněk * MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
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.
- MeSH
- akutní lymfatická leukemie patologie terapie MeSH
- busulfan aplikace a dávkování analogy a deriváty MeSH
- celotělové ozáření mortalita MeSH
- chemoradioterapie mortalita MeSH
- dítě MeSH
- etoposid aplikace a dávkování MeSH
- hodnocení ekvivalence jako téma MeSH
- lidé MeSH
- mezinárodní agentury MeSH
- míra přežití MeSH
- mladiství MeSH
- následné studie MeSH
- předškolní dítě MeSH
- prognóza MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- thiotepa aplikace a dávkování MeSH
- vidarabin aplikace a dávkování analogy a deriváty MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- busulfan MeSH
- etoposid MeSH
- fludarabine MeSH Prohlížeč
- thiotepa MeSH
- treosulfan MeSH Prohlížeč
- vidarabin MeSH
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.
- MeSH
- dítě MeSH
- infekční nemoci * MeSH
- kostní dřeň MeSH
- lidé MeSH
- transplantace hematopoetických kmenových buněk * MeSH
- výzkum MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
