Mismatched related donor allogeneic haematopoietic cell transplantation compared to other donor types for Ph+ chronic myeloid leukaemia: A retrospective analysis from the Chronic Malignancies Working Party of the EBMT.

Allogeneic haematopoietic cell transplantation (allo-HCT) remains an option for tyrosine kinase inhibitor-resistant chronic myeloid leukaemia (CML) in first chronic phase (CP1) and high-risk patients with advanced disease phases. In this European Society for Blood and Marrow Transplantation (EBMT) registry-based study of 1686 CML patients undergoing first allo-HCT between 2012 and 2019, outcomes were evaluated according to donor type, particularly focusing on mismatched related donors (MMRDs). Median age at allo-HCT was 46 years (IQR 36-55). Disease status was CP1 in 43%, second CP (CP2) or later in 27%, accelerated phase in 12% and blast crisis in 18%. Donor type was matched related (MRD) in 39.2%, MMRD in 8.1%, matched unrelated (MUD) in 40.2%, and mismatched unrelated (MMUD) in 12.6%. In 4 years, overall survival (OS) for MRD, MMRD, MUD and MMUD was 61%, 56%, 63% and 59% (p = 0.21); relapse-free survival (RFS) was 48%, 42%, 52% and 46% (p = 0.03); cumulative incidence of relapse (CIR) was 33%, 37%, 27% and 30% (p = 0.07); non-relapse mortality (NRM) was 19%, 21%, 21% and 24% (p = 0.21); and graft-versus-host disease (GvHD)-free/relapse-free survival (GRFS) was 16%, 18%, 22% and 15% (p = 0.05) respectively. On multivariate analysis, MMRD use associated with longer engraftment times and higher risk of graft failure compared to MRD or MUD. There was no statistical evidence that MMRD use associated with different OS, RFS and incidence of GvHD compared to other donor types.

Outcomes of allogeneic haematopoietic cell transplantation for myelofibrosis in children and adolescents: the retrospective study of the EBMT Paediatric Diseases WP.

This retrospective study evaluated 35 children (median age 5.2 years; range 0.4-18) with myelofibrosis (MF), including 33 with primary myelofibrosis and 2 with secondary myelofibrosis transplanted from matched sibling donor (MSD) (n = 17) or non-MSD (n = 18) between 2000 and 2022. Conditioning was usually chemotherapy-based (n = 33) and myeloablative (n = 32). Fifteen patients received bone marrow (BM), 14 haematopoietic cells (HC) from peripheral blood (PB), and 6 from cord blood (CB). Day +100 acute GvHD II-IV incidence was significantly lower after MSD-haematopoietic cell transplantation (MSD-HCT) than after non-MSD-HCT [18.8% (4.3-41.1) vs 58.8% (31-78.6); p = 0.01]. Six-year non-relapse mortality (NRM) was 18% (7.1-32.8), relapse incidence was 15.9% (5.6-30.9), progression-free survival (PFS) was 66.1% (47-79.7), GvHD-free relapse-free survival was 50% (30.6-66.7), and overall survival (OS) was 71.1% (51.4-84). Six-year PFS and OS were significantly higher after BM transplantation compared to HCT from other sources [85.1% (52.3-96.1) vs 50.8% (26.3-71), p = 0.03, and 90.9% (50.8-98.7) vs 54% (28.1-74.2), p = 0.01, respectively], whereas NRM was significantly lower [0% vs 32% (12.3-53.9); p = 0.02]. This first multicentre study on outcomes of allogeneic HCT in children with myelofibrosis proves feasibility and curative effect of transplantation in these children, suggests that bone marrow transplantation is associated with better outcomes, and indicates the need for further studies.

El paradigma de la irradiación corporal total en la leucemia linfoblástica aguda: efectividad terapéutica frente a los desafíos de toxicidad / The paradigm of total body irradiation in acute lymphoblastic leukemia: Therapeutic effectiveness against the challenges of toxicity

Introducción: La irradiación corporal total (ICT) forma parte del acondicionamiento mieloablativo del trasplante de progenitores hematopoyéticos (TPH) en hemopatías malignas. Esta terapia ha demostrado recientemente mayor supervivencia en leucemia linfoblástica aguda (LLA) frente a regímenes basados en quimioterapia. Sin embargo, los efectos secundarios son una limitación importante, especialmente en la población pediátrica.Pacientes y métodosAnalizamos retrospectivamente la supervivencia de pacientes con LLA que recibieron un TPH en un hospital terciario entre los años 1996 a 2009 (N=69 TPH en 57 pacientes). Diferenciamos una cohorte que había recibido ICT (N=44) y otra que no (N=25). Posteriormente entrevistamos a los supervivientes del grupo ICT con un mínimo de 10 años de seguimiento (N=18), preguntando acerca de la presencia de efectos secundarios.ResultadosLa supervivencia global (SG) a los 2 y 5 años fue del 79,1 y 65,2%, respectivamente para el grupo ICT y del 66,2 y 55,8% para el grupo no ICT, aunque esta diferencia no fue significativa (p=0,31). La supervivencia libre de evento (SLE) a los 2 y 5 años fue del 77,3 y 63,6%, respectivamente para el grupo ICT y del 56 y 32% para el grupo no ICT (p=0,02). La probabilidad de recidiva (PR) a los 2 años habiendo recibido ICT fue del 10% y sin haber recibido ICT del 28,6% (p=0,005). Los supervivientes que recibieron ICT desarrollaron neoplasias secundarias (39%), dislipemia (67%), alteraciones cognitivas (44%), infecciones respiratorias de repetición (39%), alteraciones tiroideas (45%), insuficiencia ovárica precoz (89%), cataratas (22%) y problemas psicológicos (44%), aunque la calidad de vida, valorada por ellos mismos, fue considerada como buena para el 83% de los encuestados.ConclusionesLos pacientes que recibieron ICT tuvieron significativamente mayor SLE y menor PR. Sin embargo, los efectos adversos son frecuentes e importantes, aunque no afectan subjetivamente a la calidad de vida. (AU)

Introduction: Total body irradiation (TBI) is part of the myeloablative conditioning for hematopoietic stem cell transplantation (HSCT) in malignant hematologic disorders. This therapy has recently shown improved survival in acute lymphoblastic leukemia (ALL) compared to chemotherapy-based regimens. However, side effects are a significant limitation, especially in the pediatric population.Patients and methodsWe retrospectively analyzed the survival of patients with ALL who underwent an HSCT at a tertiary hospital between 1996 and 2009 (N=69 HSCT in 57 patients). We differentiated a cohort that received TBI (N=44) from another that did not (N=25). Subsequently, we interviewed the survivors from the TBI group with a minimum of 10 years of follow-up (N=18), asking about the presence of side effects.ResultsThe overall survival (OS) at 2 and 5 years was 79.1% and 65.2% respectively for the TBI group and 66.2% and 55.8% for the non-TBI group, although this difference was not significant (P=.31). The event-free survival (EFS) at 2 and 5 years was 77.3% and 63.6% respectively for the TBI group and 56% and 32% for the non-TBI group (P=.02). The probability of relapse (PR) at 2 years for those who received TBI was 10% compared to 28.6% for those who did not receive TBI (P=.005). Survivors who received TBI developed secondary neoplasms (39%), dyslipidemia (67%), cognitive impairments affecting memory (44%), recurrent respiratory infections (39%), thyroid abnormalities (45%), premature ovarian failure (89%), cataracts (22%), and psychological problems (44%). However, the quality of life, as self-assessed by the patients, was considered good for 83% of the participants.ConclusionsPatients who received TBI had significantly higher EFS and lower PR. However, adverse effects are frequent and significant, although they do not subjectively affect quality of life. (AU)

The paradigm of total body irradiation in acute lymphoblastic leukaemia: Therapeutic effectiveness versus the challenges of toxicity.

INTRODUCTION: Total body irradiation (TBI) is part of the myeloablative conditioning for hematopoietic stem cell transplantation (HSCT) in malignant hematologic disorders. This therapy has recently shown improved survival in acute lymphoblastic leukemia (ALL) compared to chemotherapy-based regimens. However, side effects are a significant limitation, especially in the pediatric population. PATIENTS AND METHODS: We retrospectively analyzed the survival of patients with ALL who underwent an HSCT at a tertiary hospital between 1996 and 2009 (N = 69 HSCT in 57 patients). We differentiated a cohort that received TBI (N = 44) from another that did not (N = 25). Subsequently, we interviewed the survivors from the TBI group with a minimum of 10 years of follow-up (N = 18), asking about the presence of side effects. RESULTS: The overall survival (OS) at 2 and 5 years was 79.1% and 65.2% respectively for the TBI group and 66.2% and 55.8% for the non-TBI group, although this difference was not significant (P=.31). The event-free survival (EFS) at 2 and 5 years was 77.3% and 63.6% respectively for the TBI group and 56% and 32% for the non-TBI group (P=.02). The probability of relapse (PR) at 2 years for those who received TBI was 10% compared to 28.6% for those who did not receive TBI (P=.005). Survivors who received TBI developed secondary neoplasms (39%), dyslipidemia (67%), cognitive impairments affecting memory (44%), recurrent respiratory infections (39%), thyroid abnormalities (45%), premature ovarian failure (89%), cataracts (22%), and psychological problems (44%). However, the quality of life, as self-assessed by the patients, was considered good for 83% of the participants.. CONCLUSIONS: Patients who received TBI had significantly higher EFS and lower PR. However, adverse effects are frequent and significant, although they do not subjectively affect quality of life.

Neuropsychological and biopsychosocial evolution, therapeutic adherence and unmet care needs during paediatric transplantation: study protocol of a mixed-methods design (observational cohort study and focus groups) - the TransplantKIDS mental health project.

The present article describes the protocol of a mixed-methods study (an observational cohort design and focus groups), aimed to examine neuropsychological functioning and other biopsychosocial outcomes, therapeutic adherence and unmet care needs in paediatric population undergoing solid organ or allogeneic hematopoietic transplant during the pre- and post-transplant phases. Following a multi-method/multi-source approach, neuropsychological domains will be comprehensively measured with objective tests (SDMT, K-CPT 2/CPT 3, TAVECI/TAVEC, WISC-V/WAIS-IV Vocabulary and Digit Span subtests, Verbal Fluency tests, Stroop, ROCF, and TONI-4); ecological executive functioning, affective and behavioral domains, pain intensity/interference, sleep quality and therapeutic adherence will be assessed through questionnaires (parent/legal guardians-reported: BRIEF-2 and BASC-3; and self-reported: BASC-3, BPI, PROMIS, AIQ and SMAQ); and blood levels of prescribed drugs will be taken from each patient's medical history. These outcomes will be measured at pre-transplant and at 4-weeks and 6-months post-transplant phases. The estimated sample size was 60 patients (any type of transplant, solid organ, or hematopoietic) from La Paz University Hospital (Madrid, Spain). Finally, three focus group sessions will be organized with patients, parents/guardians, and transplant clinicians (n = 15, with 5 participants per group), in order to qualitatively identify unmet care needs during the pre-, and post-transplant stages of the process. The study protocol was registered at ClinicalTrials.gov (NCT05441436).

Corrigendum: Impact of disease burden and late loss of B cell aplasia on the risk of relapse after CD19 chimeric antigen receptor T Cell (Tisagenlecleucel) infusion in pediatric and young adult patients with relapse/refractory acute lymphoblastic leukemia: role of B-cell monitoring.

[This corrects the article DOI: 10.3389/fimmu.2023.1280580.].

The challenge of standardizing CAR-T cell monitoring: A comparison of two flow-cytometry methods and correlation with qPCR technique.

Chimeric antigen receptor (CAR) T-cell therapy is a breakthrough in hematologic malignancies, such as acute B lymphoblastic leukemia (B-ALL). Monitoring this treatment is recommended, although standardized protocols have not been developed yet. This work compares two flow cytometry monitoring strategies and correlates this technique with qPCR method. CAR-T cells were detected by two different flow-cytometry protocols (A and B) in nine blood samples from one healthy donor and five B-ALL patients treated with Tisagenlecleucel (Kymriah®, USA). HIV-1 viral load allowed CAR detection by qPCR, using samples from seven healthy donors and nine B-ALL patients. CAR detection by protocol A and B did not yield statistically significant differences (1.9% vs. 11.8% CD3 + CAR+, p = 0.07). However, protocol B showed a better discrimination of the CD3 + CAR+ population. A strong correlation was observed between protocol B and qPCR (r = 0.7, p < 0.0001). CD3 + CAR+ cells were detected by flow cytometry only when HIV-1 viral load was above 104 copies/mL. In conclusion, protocol B was the most specific flow-cytometry procedure for the identification of CAR-T cells and showed a high correlation with qPCR. Further efforts are needed to achieve a standardized monitoring approach.

Hematopoietic stem cell transplantation in children with chronic granulomatous disease: the Spanish experience.

Introduction: Hematopoietic stem cell transplantation (HCT) can cure chronic granulomatous disease (CGD). However, transplant-associated morbidity or mortality may occur, and it is still controversial which patients benefit from this procedure. The aim of this retrospective study was to evaluate the outcome of pediatric patients who received HCT in one of the Spanish pediatric transplant units. Results: Thirty children with a median age of 6.9 years (range 0.6-12.7) were evaluated: 8 patients received a transplant from a sibling donor (MSD), 21 received a transplant from an unrelated donor (UD), and 1 received a haploidentical transplant. The majority of the patients received reduced-intensity conditioning regimens based on either busulfan plus fludarabine or treosulfan. Relevant post-HCT complications were as follows: i) graft failure (GF), with a global incidence of 28.26% (CI: 15.15-48.88), 11.1% in patients with MSD (1.64-56.70) and 37.08% in unrelated donors (19.33-63.17); and ii) chronic graft-versus-host disease (GVHD), with an incidence of 20.5% (8.9-43.2), 11.1% in patients with MSD (1.64-56.70) and 26.7% in unrelated donors (10.42-58.44). Post-HCT infections were usually manageable, but two episodes of pulmonary aspergillosis were diagnosed in the context of graft rejection. The 2-year OS was 77.3% (55.92-89.23). There were no statistically significant differences among donor types. Discussion: HCT in patients with CGD is a complex procedure with significant morbidity and mortality, especially in patients who receive grafts from unrelated donors. These factors need to be considered in the decision-making process and when discussing conditioning and GVHD prophylaxis.

An artificial intelligence-driven predictive model for pediatric allogeneic hematopoietic stem cell transplantation using clinical variables.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a procedure with high morbidity and mortality. Identifying patients for maximum benefit and risk assessment is crucial in the decision-making process. This has led to the development of predictive risk models for HSCT in adults, which have limitations when applied to pediatric population. Our goal was to develop an automatic learning algorithm to predict survival in children with malignant disorders undergoing HSCT. METHODS: We studied allogenic HSCTs performed on children with malignant disorders at a third-level hospital between 1991 and 2021. Survival was analyzed using the Kaplan-Meier method, log-rank test for the univariate analysis, and Cox regression for the multivariate analysis. A prognostic index was constructed based on these findings. Lastly, we constructed a predictive model using a random forest algorithm to forecast 1-year survival after HSCT. RESULTS: We analyzed 229 HSCTs in 201 patients with a median follow-up of 1.64 years. Variables that impacted on the multivariate analysis were older age (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.12-1.76, p = .003), oldest period of HSCT (HR 0.46, 95% CI 0.29-0.73, p < .001), and mismatched donor (HR 2.65, 95% CI 1.51-4.65, p = .001). Our prognostic index was associated with 3-year overall survival (OS; p < .001). A random forest was developed using as variables: diagnosis, age, year of HSCT, time from diagnosis to HSCT, disease stage, donor type, and conditioning. This achieved 72% accuracy in predicting 1-year OS. CONCLUSIONS: Our index and random forest was effective in predicting 1-year survival. However, further validation in diverse populations is necessary to establish their generalizability.

Results of phase 2 randomized multi-center study to evaluate the safety and efficacy of infusion of memory T cells as adoptive therapy in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia and/or lymphopenia (RELEASE NCT04578210).

BACKGROUND AIMS: There are currently no effective anti-viral treatments for coronavirus disease 2019 (COVID-19)-hospitalized patients with hypoxemia. Lymphopenia is a biomarker of disease severity usually present in patients who are hospitalized. Approaches to increasing lymphocytes exerting an anti-viral effect must be considered to treat these patients. Following our phase 1 study, we performed a phase 2 randomized multicenter clinical trial in which we evaluated the efficacy of the infusion of allogeneic off-the-shelf CD45RA- memory T cells containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells from convalescent donors plus the standard of care (SoC) versus just the SoC treatment. METHODS: Eighty-four patients were enrolled in three Spanish centers. The patients were randomized into the infusion of 1 × 106/kg CD45RA- memory T cells or the SoC. We selected four unvaccinated donors based on the expression of interferon gamma SARS-CoV-2-specific response within the CD45RA- memory T cells and the most frequent human leukocyte antigen typing in the Spanish population. RESULTS: We analyzed data from 81 patients. The primary outcome for recovery, defined as the proportion of participants in each group with normalization of fever, oxygen saturation sustained for at least 24 hours and lymphopenia recovery through day 14 or at discharge, was met for the experimental arm. We also observed faster lymphocyte recovery in the experimental group. We did not observe any treatment-related adverse events. CONCLUSIONS: Adoptive cell therapy with off-the-shelf CD45RA- memory T cells containing SAR-CoV-2-specific T cells is safe, effective and accelerates lymphocyte recovery of patients with COVID-19 pneumonia and/or lymphopenia. TRIAL REGISTRATION: NCT04578210.

Translational Aspects of Epithelioid Sarcoma - Current Consensus.

Epithelioid sarcoma (EpS) is an ultra-rare malignant soft-tissue cancer mostly affecting adolescents and young adults. EpS often exhibits an unfavorable clinical course with fatal outcome in ~50% of cases despite aggressive multimodal therapies combining surgery, chemotherapy, and irradiation. EpS is traditionally classified in a more common, less aggressive distal (classic) type, and a rarer aggressive proximal type. Both subtypes are characterized by a loss of nuclear INI1 expression, most often following homozygous deletion of its encoding gene SMARCB1 - a core subunit of the SWI/SNF chromatin remodeling complex. In 2020, the EZH2 inhibitor tazemetostat was the first targeted therapy approved for EpS, raising new hopes. Still, the vast majority of patients did not benefit from this drug or relapsed rapidly. Further, other recent therapeutic modalities, including immunotherapy, are only effective in a fraction of patients. Thus, novel strategies, specifically targeted to EpS, are urgently needed. To accelerate translational research on EpS and eventually boost the discovery and development of new diagnostic tools and therapeutic options, a vibrant translational research community has formed in past years and held two international EpS digital expert meetings in 2021 and 2023. This review summarizes our current understanding of EpS from the translational research perspective and points to innovative research directions to address the most pressing questions in the field, as defined by expert consensus and patient advocacy groups.

NKG2D-CAR memory T cells target pediatric T-cell acute lymphoblastic leukemia in vitro and in vivo but fail to eliminate leukemia initiating cells.

Introduction: Refractory/relapsed pediatric acute leukemia are still clinically challenging and new therapeutic strategies are needed. Interactions between Natural Killer Group 2D (NKG2D) receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), which are upregulated in leukemic blasts, are important for anti-leukemia immunosurveillance. Nevertheless, leukemia cells may develop immunoescape strategies as NKG2DL shedding and/or downregulation. Methods: In this report, we analyzed the anti-leukemia activity of NKG2D chimeric antigen receptor (CAR) redirected memory (CD45RA-) T cells in vitro and in a murine model of T-cell acute lymphoblastic leukemia (T-ALL). We also explored in vitro how soluble NKG2DL (sNKG2DL) affected NKG2D-CAR T cells' cytotoxicity and the impact of NKG2D-CAR T cells on Jurkat cells gene expression and in vivo functionality. Results: In vitro, we found NKG2D-CAR T cells targeted leukemia cells and showed resistance to the immunosuppressive effects exerted by sNKG2DL. In vivo, NKG2D-CAR T cells controlled T cell leukemia burden and increased survival of the treated mice but failed to cure the animals. After CAR T cell treatment, Jurkat cells upregulated genes related to proliferation, survival and stemness, and in vivo, they exhibited functional properties of leukemia initiating cells. Discussion: The data here presented suggest, that, in combination with other therapeutic approaches, NKG2D-CAR T cells could be a novel treatment for pediatric T-ALL.

Therapeutic strategies and clinical evolution of patients with infantile fibrosarcoma: a unique paediatric case series

Background Infantile fibrosarcoma is the most frequent soft tissue sarcoma in newborns or children under one year of age. This tumour often implies high local aggressiveness and surgical morbidity. The large majority of these patients carry the ETV6–NTRK3 oncogenic fusion. Hence, the TRK inhibitor larotrectinib emerged as an efficacious and safe alternative to chemotherapy for NTRK fusion-positive and metastatic or unresectable tumours. However, real-world evidence is still required for updating soft-tissue sarcoma practice guidelines. Objective To report our experience with the use of larotrectinib in pediatric patients. Methods Our case series shows the clinical evolution of 8 patients with infantile fibrosarcoma under different treatments. All patients enrolled in this study received informed consent for any treatment. Results Three patients received larotrectinib in first line. No surgery was needed with larotrectinib, which led to the rapid and safe remission of tumours, even in unusual anatomical locations. No significant adverse effects were observed with larotrectinib. Conclusion Our case series supports that larotrectinib may be a therapeutic option for newborn and infant patients with infantile fibrosarcoma, especially in uncommon locations (AU)

Rationale for combined therapies in severe-to-critical COVID-19 patients.

An unprecedented global social and economic impact as well as a significant number of fatalities have been brought on by the coronavirus disease 2019 (COVID-19), produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute SARS-CoV-2 infection can, in certain situations, cause immunological abnormalities, leading to an anomalous innate and adaptive immune response. While most patients only experience mild symptoms and recover without the need for mechanical ventilation, a substantial percentage of those who are affected develop severe respiratory illness, which can be fatal. The absence of effective therapies when disease progresses to a very severe condition coupled with the incomplete understanding of COVID-19's pathogenesis triggers the need to develop innovative therapeutic approaches for patients at high risk of mortality. As a result, we investigate the potential contribution of promising combinatorial cell therapy to prevent death in critical patients.

Treosulfan-Based Conditioning Regimen In Pediatric Hematopoietic Stem Cell Transplantation: A Retrospective Analysis on Behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC).

Increasing data on treosulfan-based conditioning regimens before hematopoietic stem cell transplantation (HSCT) demonstrate the consistent benefits of this approach, particularly regarding acute toxicity. This study aimed to describe the results of treosulfan-based conditioning regimens in children, focusing on toxicity and outcomes when used to treat both malignant and nonmalignant diseases. This retrospective observational study of pediatric patients treated in Spain with treosulfan-based conditioning regimens before HSCT was based on data collection from electronic clinical records. We studied a total of 160 treosulfan-based conditioning HSCTs to treat nonmalignant diseases (n = 117) or malignant diseases (n = 43) in 158 children and adolescents. The median patient age at HSCT was 5.1 years (interquartile range, 2 to 10 years). The most frequent diagnoses were primary immunodeficiency (n = 42; 36%) and sickle cell disease (n = 42; 36%) in the nonmalignant disease cohort and acute lymphoblastic leukemia (n = 15; 35%) in the malignant disease cohort. Engraftment occurred in 97% of the patients. The median times to neutrophil engraftment (17 days versus 14 days; P = .008) and platelet engraftment (20 days versus 15 days; P = .002) were linger in the nonmalignant cohort. The 1-year cumulative incidence of veno-occlusive disease was 7.98% (95% confidence interval [CI], 4.6% to 13.6%), with no significant differences between cohorts. The 1-year cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) was higher in the malignant disease cohort (18% versus 3.2%; P = .011). Overall, the malignant cohort had both a higher total incidence (9% versus 3%; P < .001) and a higher 2-year cumulative incidence (16% versus 1.9%; P < .001) of total chronic GVHD. The 2-year cumulative transplantation-related mortality was 15%, with no difference between the 2 cohorts. The 5-year overall survival was 80% (95% CI, 72% to 86%) and was higher in the nonmalignant cohort (87% versus 61%; P = .01). The 2-year cumulative incidence of relapse was 25% in the malignant cohort. The 5-year cumulative GVHD-free, relapse-free survival rate was 60% (95% CI, 51% to 70%) and was higher in the nonmalignant cohort (72% versus 22%; P < .001). A treosulfan-based radiation-free conditioning regimen is feasible, achieving a high engraftment rate and 5-year overall survival, and is an emerging option for the first HSCT in nonmalignant diseases.

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Haploidentical Hematopoietic Stem Cell Transplantation in Pediatric Patients with Acquired Hypocellular Bone Marrow Failure.

Children with acquired hypocellular bone marrow failure of unknown cause (AHBMF) are usually diagnosed either with severe aplastic anemia (SAA) or refractory cytopenia of childhood (RCC). Patients with AHBMF who lack a matched donor and who failed or relapsed after immunosuppressive therapy (IST) need alternative therapies. Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) offers a curative treatment for these patients. We report a multicenter Spanish experience with haplo-HSCT in pediatric patients with AHBMF. Eleven pediatric patients (SAA, n = 9; RCC, n = 2) underwent haplo-HSCT with different lymphodepletion strategies. Most patients (10 of 11) had previously failed to respond or relapsed after IST. The conditioning regimen was reduced intensity in SAA and myeloablative in RCC. Patients with SAA received low-dose radiotherapy as part of their conditioning regimen. All patients engrafted. Viral reactivation was common (8 of 11). Acute GVHD grade ≥II was seen in 5 patients. Chronic GVHD was diagnosed in 4 of the long-term survivors. Transplantation-associated microangiopathy was a frequent complication in SAA patients and was related to worse outcome. Two patients died of transplantation-related complications. Overall survival was 81%, with a median follow-up of 36 months. Haplo-HSCT can be a successful salvage curative treatment for pediatric patients with AHBMF, but with significant toxicities that must be addressed. Transplantation-associated microangiopathy was the most critical complication.

Quantifying the available capacity and resource needs for provision of CAR-T therapies in the National Health Service in Spain: a survey-based study.

OBJECTIVES: To estimate the readiness of Spanish National Health Service (NHS) hospitals to provide chimeric antigen receptor T cell (CAR-T), and to identify and quantify the different resources needed to provide CAR-T considering three scenarios defined by 10, 25 and 50 patients per centre per year. DESIGN: Targeted literature review and quantitative study using a questionnaire and telephone interviews. An algorithm was created to determine hospitals' readiness based on their capacity and capability. All the requirements for quantification were assessed and validated by the steering committee, formed by members of the Spanish Group of Haematopoietic Transplantation and Cell Therapy. A weighting system (from 0 to 1) was established for capability quantification. For resources quantification, a scoring system was established, with 0 points representing the minimum and 3 points the maximum of additional resources that a hospital indicated necessary. SETTING: 40 Spanish hospital centres that perform allogeneic haematopoietic stem cell transplantation were invited to complete the questionnaire for capacity quantification, 28 of which provided valid responses. Nine hospitals participated in the interviews for resource quantification, eight of which had previously been designated by the Ministry of Health (MoH) to provide CAR-T. OUTCOME MEASURE: Current capacity of NHS Spanish sites to administer CAR-T under different theoretical scenarios with varying numbers of procedures, and the potential healthcare resources that would be needed to realise the theoretical capacity requirements. RESULTS: Four hospitals were optimally ready, 17 were somewhat ready and 7 were not ready. The actual extrapolated capacity of the currently designated MoH CAR-T sites would allow treatment of approximately 250 patients per year. Regarding healthcare resource needs, the numbers of haematologists, nurses and beds were the most important limiting factors, and those requiring further growth as patient numbers increased. CONCLUSIONS: Increasing the number of CAR-T-qualified centres and/or increasing resources in the current designated sites are two potential strategies that should be considered to treat CAR-T-eligible patients in Spain.

Sarcopenia as a Prognostic Factor in Patients with Hepatoblastoma: Does It Influence Surgical Outcomes and Survival? Preliminary Retrospective Study.

AIM: Sarcopenia is associated with poor prognosis in adult oncologic patients, with little evidence of this association in pediatric population, including hepatoblastoma. METHODS: Retrospective study in patients with hepatoblastoma, divided into those with or without sarcopenia. Sarcopenia was assessed by measuring psoas muscle area (PMA) at L4-L5 level on the CT/MR and defined as z-score values ≤ 2. Relapse and mortality were analyzed. RESULTS: Twenty-one patients (57.1% male) were included, with median age 35.7 months (IQR: 23.5-58.5). Seven (33.3%) had sarcopenia on initial studies compared to 14 (66.7%) who did not. No differences were found between groups in age, weight, PRETEXT, surgical treatment or. α-fetoprotein levels. Sarcopenia was associated with a higher rate of metastases at diagnosis (49.2% vs 0.0%; p = 0.026) and surgical complications (57.1% vs 21.4%, p = 0.047). After a median follow-up of 65.1 months (1.7-144.8), 2 patients (28.6%) had tumor relapse in sarcopenic group compared to 1 (7.1%) in non-sarcopenic group. Two patients died in sarcopenic group and 1 in non-sarcopenic group. Median event-free survival (EFS) was lower in sarcopenic group (100.38 ± 25.63 vs 118.91 ± 11.52 months) as well as overall survival (OS) (101.72 ± 24.86 vs 121.78 ± 8.75 months) with no statistical significance. Five-year EFS was also lower in sarcopenic group (71% vs 93%) as well as 5-year OS (71% vs 87%). CONCLUSIONS: Sarcopenia at diagnosis was associated with a higher rate of metastases and surgical complications in hepatoblastoma. Our data shows the first evidence of its role as a possible poor prognostic factor, influencing survival and risk of relapse. LEVEL OF EVIDENCE: II. TYPE OF STUDY: Original article. Retrospective study.