Stem Cell Transplantation In Children Research Articles

Interest of the preventive and curative use of defibrotide on the occurrence and severity of sinusoidal obstruction syndrome after hematopoietic stem cell transplant in children.

Defibrotide (DF) is indicated for the treatment of severe sinusoidal obstruction syndrome (SOS) following hematopoietic stem cell transplantation (HSCT), but its prophylactic use against SOS is not recommended yet. This study describes the impact of the preventive and curative use of DF on reducing the incidence and severity of SOS in children. Patients aged 0–19 years, who received allogenic HSCT after myeloablative conditioning regimen with busulfan or total body irradiation in our comprehensive cancer center, between 2013 and 2017, were included. The Baltimore or modified Seattle criteria were used for SOS diagnosis. SOS was graded using the 2017 European Society for Blood and Marrow Transplantation classification defining severity criteria of SOS in children. SOS occurrence tended to decrease with prophylactic DF, but no significant difference was observed in terms of severity. When not treated with preventive DF, 50% (19/38) of the patients with SOS were graded severe to very severe, but only 37% (7/19) had organ dysfunction. Curative DF was administered at a median of 2 days post‐HSCT, for a median of 6.5 days. The absence of fatal SOS supports the use of early curative DF with acceptable toxicities and questions the optimal duration of DF treatment.

Gut Microbiome Suffers from Hematopoietic Stem Cell Transplantation in Childhood and Its Characteristics Are Positively Associated with Intra-Hospital Physical Exercise.

Simple SummaryGut microbiome research has rapidly advanced with good perspectives for the diagnostics and/or therapy of a plethora of diseases, including metabolic and neurodegenerative diseases and various types of cancer. In this study, we examined the composition of the fecal microbiota of eligible children with acute lymphoblastic leukemia (ALL) after hematopoietic stem cell transplantation (HSCT). We found a negative effect of HSCT treatment on microbiome bacterial diversity and richness with microbial monodominance by pathogenic bacteria in pediatric ALL patients after 3 months. The changes in the gut microbiota were associated with systemic inflammation on day + 28. However, promisingly, we have observed an association between bacterial diversity and physical exercise during HSCT treatment. Our findings provide additional support for the importance of investigating the gut microbiome in children with cancer.Gut microbiome impairment is a serious side effect of cancer treatment. The aim of this study was to identify the effects of hematopoietic stem cell transplantation (HSCT) treatment on gut microbiota composition in children with acute lymphoblastic leukemia (ALL). Fecal microbiotas were categorized using specific primers targeting the V1–V3 region of 16S rDNA in eligible pediatric ALL patients after HSCT (n = 16) and in healthy controls (Ctrl, n = 13). An intra-hospital exercise program was also organized for child patients during HSCT treatment. Significant differences in gut microbiota composition were observed between ALL HSCT and Ctrl with further negative effects. Plasma C-reactive protein correlated positively with the pathogenic bacteria Enterococcus spp. and negatively with beneficial bacteria Butyriccocus spp. or Akkermansia spp., respectively (rs = 0.511, p = 0.05; rs = −0.541, p = 0.04; rs = −0.738, p = 0.02). Bacterial alpha diversity correlated with the exercise training characteristics. Therefore, specific changes in the microbiota of children were associated with systemic inflammation or the ability to exercise physically during HSCT treatment.

Immunological recovery following HLA-matched CD3+ TCR αß+/CD19+ depleted hematopoietic stem cell transplantation in children.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for children with both malignant and nonmalignant diseases. T-cell depletion techniques may result in reduced transplant-related mortality compared with unmanipulated grafts due to a lower incidence of GvHD. Immune recovery and outcome were analyzed in a cohort of 23 patients with malignant and nonmalignant diseases who received CD3+TCRαβ+ T- and B-cell-depleted allografts from matched donors after reduced-intensity or myeloablative conditioning. The median number of CD34+, CD3+TCRαβ+, and CD19+B-cells infused was 12.7×106 /kg, 16.8×103 /kg, and 96×103 /kg bodyweight. With a median follow-up of 36 (range 1-73) months, overall survival and disease-free survival at 3years were 65.2% and 60.8%. Eight patients died, six due to the underlying disease and two of extended visceral cGvHD. Immune reconstitution, disease-free, and overall survivals were similar compared with a historical cohort of 23 patients transplanted with matched unmanipulated bone marrow. A significant lower rate of higher grade (III-IV) aGvHD was observed in the manipulated HSCT group (8.7% vs. 26%; p=0.001), whereas the incidence of cGvHD was equal. Our data suggest that this graft manipulation strategy could be a safe and effective alternative to conventional HSCT techniques in matched donors.

Высокодозная химиотерапия с аутологичной трансплантацией гемопоэтических стволовых клеток при ретинобластоме у детей. Обзор литературы и демонстрация клинических случаев

Высокодозная химиотерапия с аутологичной трансплантацией гемопоэтических стволовых клеток при ретинобластоме у детей. Обзор литературы и демонстрация клинических случаевHigh-dose chemotherapy with autologous hemopoietic stem cell transplantation in children with retinoblastoma. Literature review and case series

Metagenomic Next-Generation Sequencing vs. Traditional Pathogen Detection in the Diagnosis of Infection After Allogeneic Hematopoietic Stem Cell Transplantation in Children.

Infection is a severe complication of allo-HSCT in children, however, the accurate detection of the infection is hard. In this study, we traced the records of 101 pediatric recipients with allo-HSCT to investigate the pathogens of infection, and collected 54 bronchoalveolar lavage fluid, 32 blood, and 15 cerebrospinal fluid samples. In these samples, 87 was with post-transplant infection and 14 without infection. Using the metagenomic next-generation sequencing (mNGS) and traditional pathogen detection, we compared their sensitivity and specificity to detect pathogens of infection. Our results showed that mNGS was more sensitive (89.7%) than conventional pathogen detection (21.8%), with a difference of 67.9% (P < 0.001), However, mNGS was less specific (78.5%) than traditional methods (92.9%), with a difference of 14.4% (P = 0.596). The sensitivity of mNGS for diagnosing pulmonary infections, bloodstream infections or viremia, and CNS infections post-transplant were 91.7, 85.7, and 90.9%, respectively. In contrast, the sensitivity of conventional testing for diagnosing pulmonary infections, bloodstream infections or viremia, and CNS infections post-transplant were 22.9, 21.4, and 18.2%, respectively. There were significant differences in the sensitivity of mNGS and conventional testing in BALF, blood, and CSF samples, with P values of 0.000, 0.000, and 0.002 respectively. Among the patients with pulmonary infection, 11 pathogens were both identified by mNGS and conventional testing, and 33 by mNGS only. The percentage with the mNGS-positive result was 44/48 (91.7%), including viruses (n = 12), bacteria (n = 17), fungi (n = 9) and mixed infections (n = 6). Among the patients diagnosed with fungal pneumonia (n = 9), the most prevalent pathogenic fungi were Pneumocystis jiroveci (n = 6), which were also detected in 4 patients with mixed infectious pneumonia. In the 28 blood specimens of patients with bloodstream infections or viremia, five patients were positive by both mNGS and conventional testing, 19 were positive by mNGS, and 1 was positive by traditional testing only. The percentage with the mNGS-positive results was 24/28 (85.7%), including viruses (n = 12), bacteria (n = 4), fungi (n = 3), and mixed infections (n = 5). Of the 15 CSF specimens enrolled, 11 patients were eventually diagnosed with CNS infections. Ten pathogens were identified by mNGS in the 11 patients, including viruses (n = 8), bacteria (n = 1), and fungi (n = 1). These results suggest that mNGS is more sensitive than conventional pathogen detection for diagnosing infections post HSCT in children which may help the clinic diagnosis. Pneumocystis jiroveci was the most frequent pathogen of pulmonary infections post-transplant, while viruses were the most common pathogens of CNS infections in allo-HSCT recipients.

Strategies for Success With Umbilical Cord Haematopoietic Stem Cell Transplantation in Children With Malignant and Non-Malignant Disease Indications.

Umbilical Cord blood is an intuitively attractive stem cell source, but its use has declined since it is associated with an increased procedure-related morbidity and transplant related mortality. Some of this reflects that cord blood transplants are more often HLA-mismatched compared to other unrelated donor transplants. The ability to transplant in such a setting, indeed without high rates of chronic Graft versus Host Disease (GVHD), constitutes an advantage compared to other unrelated donor cell sources and there are other advantages specifically associated with cord blood as a donor cell source. These advantages must be weighed against its disadvantage, and we have utilised cord blood preferentially as a donor cell source in certain clinical situations in paediatric medicine. In non-malignant diseases, outcomes in metabolic disease are critically dependent on age at transplant and the enzyme delivered by that transplant, and in cord blood transplantation then the time to transplant can be minimised and the engrafted recipients have higher chimerism that delivers higher enzyme levels. In malignant diseases, studies have described reduced relapse rate and better GVHD-free survival, and so we have prioritised cord as a donor cell source where the risk of relapse is highest, and the effects of higher transplant related mortality is most clearly offset by the reduced relapse rates.

Clinical characteristics and risk factors of pericardial effusion after hematopoietic stem cell transplantation in children with thalassemia major

Objective: To investigate the characteristics, risk factors and outcomes of thalassemia major (TM) children with pericardial effusion (PE) after allo-geneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Clinical data of 446 TM children received allo-HSCT at Shenzhen Children's Hospital between January 2012 and December 2020 were analyzed retrospectively. Patients were divided into PE and non-PE group according to the occurrence of PE. Chi-square tests were used to investigate the risk factors that were associated with the development of PE. Kaplan-Meier method was used for survival analysis of the 2 groups. Results: Twenty-five out of 446 patients (5.6%) developed PE at a time of 75.0 (66.5, 112.5) days after allo-HSCT. Among these patients, 22 cases (88.0%) had PE within 6 months after allo-HSCT and 19 patients (76.0%) had PE within 100 days after allo-HSCT. The diagnoses of PE were confirmed using echocardiography. Pericardial tamponade was observed in only 1 patient, who later undergone emergency pericardiocentesis. The rest of patients received conservative managements alone. PE disappeared in all patients after treatment. Risk factors that were associated with the development of PE after allo-HSCT included the gender of patients, the type of transplantation, the number of mononuclear cells (MNC) infuse, pulmonary infection after HSCT and transplantation associated thrombotic microangiopathy (TA-TMA) (χ²=3.99, 10.20, 14.18, 36.24, 15.03, all P<0.05). In 239 patients that received haploidentical HSCT, the development of PE was associated with the gender of patients, pulmonary infection after HSCT and TA-TMA (χ²=4.48, 20.89, 12.70, all P<0.05). The overall survival rates of PE and non-PE groups were 96.0% (24/25) and 98.6% (415/421). The development of PE was not associated with the overall survival of TM children after allo-HSCT (χ²=1.73, P=0.188). Conclusions: PE mainly develop within 100 days after allo-HSCT in pediatric TM recipients. Haploidentical grafts, female gender, pulmonary infection after HSCT and TA-TMA are the main risk factors associated with PE development after transplant. However, the presence of PE don't have a significant impact on the outcomes of pediatric TM patients after allo-HSCT.

552 - Haploidentical Stem Cell Transplantation in Children with Acquired Severe Aplastic Anemia. Experience in a Pediatric Bone Marrow Transplant Facility in Bogota, Colombia, South America

552 - Haploidentical Stem Cell Transplantation in Children with Acquired Severe Aplastic Anemia. Experience in a Pediatric Bone Marrow Transplant Facility in Bogota, Colombia, South America

148 - Venetoclax-Based Combination Therapy As a Bridge to Allogeneic Hematopoietic Stem Cell Transplant in Children with Relapsed/Refractory AML

148 - Venetoclax-Based Combination Therapy As a Bridge to Allogeneic Hematopoietic Stem Cell Transplant in Children with Relapsed/Refractory AML

Current Prophylaxis and Treatment Approaches for Acute Graft-Versus-Host Disease in Haematopoietic Stem Cell Transplantation for Children With Acute Lymphoblastic Leukaemia.

Acute graft-versus-host disease (aGvHD) continues to be a leading cause of morbidity and mortality following allogeneic haematopoietic stem cell transplantation (HSCT). However, higher event-free survival (EFS) was observed in patients with acute lymphoblastic leukaemia (ALL) and grade II aGvHD vs. patients with no or grade I GvHD in the randomised, controlled, open-label, international, multicentre Phase III For Omitting Radiation Under Majority age (FORUM) trial. This finding suggests that moderate-severity aGvHD is associated with a graft-versus-leukaemia effect which protects against leukaemia recurrence. In order to optimise the benefits of HSCT for leukaemia patients, reduction of non-relapse mortality—which is predominantly caused by severe GvHD—is of utmost importance. Herein, we review contemporary prophylaxis and treatment options for aGvHD in children with ALL and the key challenges of aGvHD management, focusing on maintaining the graft-versus-leukaemia effect without increasing the severity of GvHD.

Long term outcomes of allogeneic hematopoietic stem cell transplantation in children with X-linked adrenoleukodystrophies

Long term outcomes of allogeneic hematopoietic stem cell transplantation in children with X-linked adrenoleukodystrophies

Allogeneic hematopoietic stem cell transplantation in children and adolescents: ethical problems faced by the multidisciplinary team

RESUMO Objetivo: Identificar os problemas éticos enfrentados pela equipe multidisciplinar no transplante de células-tronco hematopoiéticas alogênico na criança e no adolescente. Método: Pesquisa qualitativa inspirada na Pesquisa Convergente Assistencial realizada em uma Unidade de Transplante de Células-Tronco Hematopoiéticas em hospital geral do Sul do Brasil. Participaram 15 profissionais da equipe multidisciplinar selecionados de modo intencional. As informações foram coletadas por meio de entrevistas semiestruturadas e analisadas à luz do Modelo da Bioética Complexa. Resultados: A equipe de saúde enfrenta dois problemas éticos no cotidiano de trabalho: a decisão de realizar o transplante, e o momento de estabelecer os cuidados paliativos. Nesta situação vulnerável, as crianças e os adolescentes necessitam ser acolhidos, escutados e respeitados. Conclusão: Os profissionais imbuem-se de coragem moral para advogar pelo paciente no processo terapêutico, a partir da reflexão sobre os direitos da criança e do adolescente e do respeito à voz nas decisões sobre o seu cuidado.

Allogeneic hematopoietic stem cell transplantation in children and adolescents: ethical problems faced by the multidisciplinary team.

To identify the ethical problems faced by the multidisciplinary team in allogeneic hematopoietic stem cell transplantation in children and adolescents. Qualitative research inspired by the Convergent Care Research carried out in a Hematopoietic Stem Cell Transplantation Unit in a general hospital in southern Brazil. Fifteen professionals from the multidisciplinary team, intentionally selected, participated. The information was collected through semi-structured interviews and analyzed in the light of the Complex Bioethics Model. The health team faces two ethical problems in their daily work: the decision to perform the transplant, and the moment to establish palliative care. In this vulnerable situation of life, children and adolescents need to be welcomed, listened to and respected. Professionals are imbued with moral courage to advocate for the patient throughout the therapeutic process, based on reflection on the rights of children and adolescents and respect for the voice in decisions about their care.

Gene therapy offers new hope for children with metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is a rare, progressive lysosomal storage disease caused by mutations in the gene encoding arylsulfatase A (ARSA), causing disease in the central and peripheral nervous systems. MLD presents in toddlers (late infantile disease) or in children (juvenile disease) with gait disturbances, loss of developmental milestones, and cognitive decline, leading to death in childhood. It is frequently not diagnosed until the later symptomatic phase when it is too late to intervene. Haematopoietic stem-cell transplantation (HSCT) from allogeneic donors has been used with mixed results. Although HSCT can slow progression of disease in the central nervous system, it does not prevent progression in the peripheral nervous system. HSCT is also associated with risks of graft-versus-host disease and treatment-related toxicity. 1 Boucher AA Miller W Shanley R et al. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report. Orphanet J Rare Dis. 2015; 10: 94 Crossref PubMed Scopus (66) Google Scholar , 2 Wolf NI Breur M Plug B et al. Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction. Ann Clin Transl Neurol. 2020; 7: 169-180 Crossref PubMed Scopus (11) Google Scholar , 3 Beschle J Döring M Kehrer C et al. Early clinical course after hematopoietic stem cell transplantation in children with juvenile metachromatic leukodystrophy. Mol Cell Pediatr. 2020; 7: 12 Crossref PubMed Google Scholar , 4 Vander Lugt MT Chen X Escolar ML et al. Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders. Blood Adv. 2020; 4: 3041-3052 Crossref PubMed Scopus (3) Google Scholar Additionally, small trials of intrathecal gene therapy in mice or humans did not result in improvement in symptoms of clinical disease. 5 Miyake N Miyake K Sakai A Yamamoto M Suzuki H Shimada T Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A. Sci Rep. 2021; 1120513 Crossref PubMed Scopus (1) Google Scholar Thus, new therapeutic approaches are desperately needed. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded accessTreatment with arsa-cel resulted in sustained, clinically relevant benefits in children with early-onset MLD by preserving cognitive function and motor development in most patients, and slowing demyelination and brain atrophy. Full-Text PDF Open Access

Allogeneic Hematopoietic Stem Cell Transplantation for Children With Acute Lymphoblastic Leukemia: Shifting Indications in the Era of Immunotherapy.

Pediatric acute lymphoblastic leukemia generally carries a good prognosis, and most children will be cured and become long-term survivors. However, a portion of children will harbor high-risk features at the time of diagnosis, have a poor response to upfront therapy, or suffer relapse necessitating more intensive therapy, which may include allogeneic hematopoietic stem cell transplant (HSCT). Recent advances in risk stratification, improved detection and incorporation of minimal residual disease (MRD), and intensification of upfront treatment have changed the indications for HSCT over time. For children in first complete remission, HSCT is generally reserved for those with the highest risk of relapse. These include patients with unfavorable features/cytogenetics who also have a poor response to induction and consolidation chemotherapy, usually reflected by residual blasts after prednisone or by detectable MRD at pre-defined time points. In the relapsed setting, children with first relapse of B-cell ALL are further stratified for HSCT depending on the time and site of relapse, while all patients with T-cell ALL are generally consolidated with HSCT. Alternatives to HSCT have also emerged over the last decade including immunotherapy and chimeric antigen receptor (CAR) T-cell therapy. These novel agents may spare toxicity while attempting to achieve MRD-negative remission in the most refractory cases and serve as a bridge to HSCT. In some situations, these emerging therapies can indeed be curative for some children with relapsed or resistant disease, thus, obviating the need for HSCT. In this review, we seek to summarize the role of HSCT in the current era of immunotherapy.

Analysis of Peripheral Blood Mononuclear Cells Gene Expression Highlights the Role of Extracellular Vesicles in the Immune Response following Hematopoietic Stem Cell Transplantation in Children

Hematopoietic stem cell transplantation (HSCT) is an effective treatment method used in many neoplastic and non-neoplastic diseases that affect the bone marrow, blood cells, and immune system. The procedure is associated with a risk of adverse events, mostly related to the immune response after transplantation. The aim of our research was to identify genes, processes and cellular entities involved in the variety of changes occurring after allogeneic HSCT in children by performing a whole genome expression assessment together with pathway enrichment analysis. We conducted a prospective study of 27 patients (aged 1.5–18 years) qualified for allogenic HSCT. Blood samples were obtained before HSCT and 6 months after the procedure. Microarrays were used to analyze gene expressions in peripheral blood mononuclear cells. This was followed by Gene Ontology (GO) functional enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein–protein interaction (PPI) analysis using bioinformatic tools. We found 139 differentially expressed genes (DEGs) of which 91 were upregulated and 48 were downregulated. “Blood microparticle”, “extracellular exosome”, “B-cell receptor signaling pathway”, “complement activation” and “antigen binding” were among GO terms found to be significantly enriched. The PPI analysis identified 16 hub genes. Our results provide insight into a broad spectrum of epigenetic changes that occur after HSCT. In particular, they further highlight the importance of extracellular vesicles (exosomes and microparticles) in the post-HSCT immune response.

Neurological complications post allogenic hematopoietic stem cell transplantation in children

Neurological complications post allogenic hematopoietic stem cell transplantation in children

Impact of next generation sequencing in hematopoietic stem cell transplantation in children with non-DNA breakage defect inherited bone marrow failure syndromes

Impact of next generation sequencing in hematopoietic stem cell transplantation in children with non-DNA breakage defect inherited bone marrow failure syndromes

Association of Donor and Recipient Interleukin-1 Gene Single Nucleotide Polymorphisms with Outcome after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment approach for hematological malignancies, genetic diseases, and severe immune deficiencies. Despite the matching of the human leucocyte antigens (HLA), HSCT is still associated with a considerable rate of morbidity and mortality caused by infections, relapse, and graft-versus-host disease (GVHD). Therefore, non-HLA polymorphisms like cytokines and their receptors are considered as important contributing factors. Interleukin-1 (IL-1) is a cytokine that initiates and maintains the immune response as well as the development of GVHD in the recipient. Single nucleotide polymorphisms (SNPs) of the IL-1 gene are associated with a higher risk of malignancies, an elevated death rate because of infections, and a higher chance to suffer from autoimmune or chronic diseases. This study aimed to analyze the association of IL-1 gene SNPs with outcome in a pediatric population undergoing allogeneic HSCT.Methods: We included 270 pediatric patients with a median age of 9 years who underwent an allogeneic HSCT and their respective donors. We used TaqMan real-time polymerase chain reaction to analyze the SNPs IL-1-alpha rs1800587 (-889, A/T), IL-1-beta rs1143627 (-31, A/T), and IL-1-beta rs16944 (-511, A/T). The underlying diseases were acute lymphoblastic leukemia (n=89), acute myeloid leukemia (n=63), chronic myeloid leukemia (n=10), juvenile myelomonocytic leukemia (n=9), myelodysplastic syndrome (n=29), lymphoma (n=7), solid tumor (n=11), genetic disease (n=41), and aplastic anemia (n=11). The stem cell sources were bone marrow (n=178), peripheral blood (n=90) or umbilical cord blood (n=2). Two hundred donors were HLA-matched, and 70 donors were HLA-mismatched. Conditioning regimen was myeloablative in all cases and based on chemotherapy in 180 children or total body irradiation in 90 children. The predominant post-transplant immunosuppression was cyclosporine A and methotrexate in 148 patients or cyclosporine A alone in 55 patients. The genotyped SNPs were compared using the Kaplan-Meier method for event-free survival (EFS) and overall survival (OS) and the Gray test for acute GVHD, chronic GVHD, relapse rate (RR), and transplant-related mortality (TRM).Results: We observed a significant association between the SNP IL-1-alpha rs1800587 (-889, A/T) of the donor and the rate of acute GVHD. The genotypes of IL-1-alpha rs1800587 had the following distributions in the donor: CC genotype n=132 (49%), CT genotype n=114 (42%), and TT genotype n=24 (9%). Overall, 63 children (23%) suffered from moderate to severe acute GVHD (grade II-IV). We found a significantly increased incidence of moderate to severe acute GVHD (grade II-IV) if the patient was transplanted from a donor with the CC/CT genotype compared to the TT genotype (25% versus 4%; p=0.028). We found no significant associations of the SNP IL-1-alpha rs1800587 (-889, A/T) for chronic GVHD, RR, TRM, EFS, and OS. In addition, we observed no significant associations of the other studied genotypes IL-1-beta rs16944 (-511, A/T) and rs1143627 (-31, A/T) in either donors or recipients for acute and chronic GVHD, RR, TRM, EFS, and OS.Conclusion: Our study identified the IL-1-alpha rs1800587 CC/CT genotype of the donor as a genetic risk factor for the development of moderate to severe acute GVHD (grade II-IV) in pediatric allogeneic HSCT recipients. After confirmation in further studies, these findings could implicate the adjustment of prophylactic measures to reduce the risk of acute GVHD in children. DisclosuresGruhn: AmgenGmbh: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel costs; Bellicum Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees, Other: travel costs; EUSA Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Other: travel costs; Novartis Pharma Inc.: Honoraria, Other: travel costs; pfizer: Honoraria; servier: Honoraria, Other: travel costs; Neovii Biotech GmbH: Other: travel costs; medac GmbH: Other: travel costs.

Minimal Residual Disease Prior to and After Haematopoietic Stem Cell Transplantation in Children and Adolescents With Acute Lymphoblastic Leukaemia: What Level of Negativity Is Relevant?

Minimal residual disease (MRD) assessment plays a central role in risk stratification and treatment guidance in paediatric patients with acute lymphoblastic leukaemia (ALL). As such, MRD prior to haematopoietic stem cell transplantation (HSCT) is a major factor that is independently correlated with outcome. High burden of MRD is negatively correlated with post-transplant survival, as both the risk of leukaemia recurrence and non-relapse mortality increase with greater levels of MRD. Despite growing evidence supporting these findings, controversies still exist. In particular, it is still not clear whether multiparameter flow cytometry and real-time quantitative polymerase chain reaction, which is used to recognise immunoglobulin and T-cell receptor gene rearrangements, can be employed interchangeably. Moreover, the higher sensitivity in MRD quantification offered by next-generation sequencing techniques may further refine the ability to stratify transplant-associated risks. While MRD quantification from bone marrow prior to HSCT remains the state of the art, heavily pre-treated patients may benefit from additional staging, such as using 18F-fluorodeoxyglucose positron emission tomography/computed tomography to detect focal residues of disease. Additionally, the timing of MRD detection (i.e., immediately before administration of the conditioning regimen or weeks before) is a matter of debate. Pre-transplant MRD negativity has previously been associated with superior outcomes; however, in the recent For Omitting Radiation Under Majority age (FORUM) study, pre-HSCT MRD positivity was associated with neither relapse risk nor survival. In this review, we discuss the level of MRD that may require pre-transplant therapy intensification, risking time delay and complications (as well as losing the window for HSCT if disease progression occurs), as opposed to an adapted post-transplant strategy to achieve long-term remission. Indeed, MRD monitoring may be a valuable tool to guide individualised treatment decisions, including tapering of immunosuppression, cellular therapies (such as donor lymphocyte infusions) or additional immunotherapy (such as bispecific T-cell engagers or chimeric antigen receptor T-cell therapy).