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BACKGROUND: Bacteremia is a common complication in allogeneic hematopoietic cell transplant recipients (alloHCTr), especially during the pre-engraftment period. International guidelines recommend antibacterial prophylaxis (ABP), despite potential selection for multidrug-resistant organisms (MDRO). Limited contemporary data exist on the epidemiology of pre-engraftment bacteremia in alloHCTr, who do not receive ABP. METHODS: We performed a retrospective observational single-center cohort study including all consecutive adult alloHCTr (2015-2021), investigating the incidence, risk factors, and outcomes of bacteremia during the engraftment period. Primary fluoroquinolone (FQ) ABP is not routinely administered in our center. RESULTS: Among 421 patients identified, 124 bacteremia episodes were observed in 121/421 (29%) alloHCTr. The median time to the 1st bacteremia episode was 9 days (IQR 6-11). Most (105/124, 85%) episodes were monomicrobial, while >1 pathogens were identified in 19/124 (15%) episodes. Overall, 152 pathogens were isolated, with a predominance of Gram-positive (118/152, 78%), including coagulase-negative staphylococci (n:47), streptococci (n:46), and enterococci (n:15), followed by Gram-negative bacteria (GNB, 30/152, 20%), and anaerobes (4/152, 3%). There were 2/152 (1%) MDRO (extended-spectrum beta-lactamase producing) GNB. Multivariable analyses identified age >40-year-old (OR 2.4, P = 0.02), male gender (OR 1.8, P = 0.02), and a haploidentical/mismatched unrelated donor (OR 2.5, P < 0.001) as independent risk factors for bacteremia. All cause 30-day mortality among alloHCTr with bacteremia was 0.8% (1/121): one patient died due to an HCT-related complication. CONCLUSION: Despite lack of primary FQ ABP, low rates of bacteremia were observed during the pre-engraftment period, with low MDRO prevalence and mortality. Our findings may allow to revisit the need for primary universal FQ ABP in high-risk neutropenic hematology patients.

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Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for severe aplastic anemia (SAA). Existing guidance about HCT in SAA is primarily derived from expert reviews, registry data and societal guidelines; however, transplant-specific guidelines for SAA are lacking. A panel of SAA experts, both pediatric and adult transplant physicians, developed consensus recommendations using Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology employing a GRADE guideline development tool. The panel agrees with previous recommendations for the preferential use of bone marrow as a graft source and the use of rabbit over horse antithymocyte globulin (ATG) for HCT conditioning. Fludarabine containing regimens are preferred for patients at high risk of graft failure and those receiving matched unrelated or haploidentical donor transplant. Given advancements in HCT, the panel does not endorse the historical 40-year age cut-off for considering upfront HCT in adults, acknowledging that fit older patients may also benefit from HCT. The panel also endorses increased utilization of HCT by prioritizing matched unrelated or haploidentical donor HCT over immunosuppressive therapy in children and adults who lack a matched related donor. Finally, the panel suggests either calcineurin inhibitor plus methotrexate or post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis for matched related or matched unrelated donor recipients. These recommendations reflect a significant advancement in transplant strategies for SAA and highlight the importance of ongoing and further research to revisit current evidence in terms of donor choice, conditioning chemotherapy, GVHD prophylaxis and post-transplant immunosuppression.

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Relapse and graft-versus-host disease (GVHD) are currently the predominant causes of mortality post allogeneic hematopoietic stem cell transplantation (allo-HSCT). The contentious use of antithymocyte globulin (ATG) for preventing GVHD in matched sibling HSCT scenarios has been a topic of significant debate. A retrospective analysis was conducted on matched sibling HSCT cases with high-risk factors for GVHD in our center from January 2018 to June 2023. Our assessment revealed that the group administered with ATG exhibited a 30 % incidence of acute GVHD (aGVHD), in contrast to 81.8 % in the non-ATG cohort (P = 0.037) among matched sibling HSCT cases with high GVHD risk factors. Furthermore, chronic GVHD (cGVHD) occurred in 20 % of the ATG group and 72.7 % of the non-ATG group (P = 0.03). Notably, the administration of ATG did not significantly impact disease relapse (p = 0.149), infection rates (p = 0.64), granulocyte recovery time (p = 0.15), platelet recovery time (p = 0.12), overall survival (p = 0.889), or disease-free survival time (p = 0.787). The use of rabbit antithymocyte globulin (r-ATG) at a 5 mg/kg dosage demonstrated a notable reduction in aGVHD and cGVHD incidences within sibling matched HSCT cases with high-risk factors for GVHD, without increasing rates of disease recurrence or infections. These findings highlight the potential benefit of using low-dose r-ATG in high-risk of GVHD sibling matched allogeneic HSCTs, although further validation with a larger cohort is necessary.

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Objective: To evaluate the efficacy of avatinib plus allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of recurrent/refractory RUNX1-RUNX1T1 positive acute myeloid leukemia (AML) with KIT mutations. Method: A retrospective study was conducted on the clinical data of seven relapsed/refractory AML patients containing the RUNX1-RUNX1T1 fusion gene and KIT mutation who received afatinib plus allo-HSCT treatment at the First Affiliated Hospital of Soochow University from June 2019 to June 2023. Results: The seven AML patients included one male and six females with a median age of 37 (18-56) years. All seven patients had KIT mutations (five positive for D816V and two positive for D816Y) . There were two refractory patients and five relapsed patients (all of whom had bone marrow recurrence) . All patients had to complete at least one course of treatment with afatinib before transplantation. Four patients achieved complete remission (CR) after treatment with afatinib, six patients had negative KIT gene mutations, and one had a decreased KIT gene mutational burden. There were three cases of unrelated identical transplantation and four cases of haploidentical transplantation. All patients received the modified Bu/Cy pretreatment regimen. After transplantation, all patients were successfully implanted and a bone marrow examination showed CR and minimal residual disease turned negative. Five patients exhibited negative fusion genes. Two patients died from infection following transplantation. Conclusion: Afatinib plus allo-HSCT may be an effective and safe new treatment strategy for RUNX1-RUNX1T1 positive AML patients with KIT-D816 mutation.

Asunto(s)

Subunidad alfa 2 del Factor de Unión al Sitio Principal , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Mutación , Proteínas Proto-Oncogénicas c-kit , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Estudios Retrospectivos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas Proto-Oncogénicas c-kit/genética , Adolescente , Adulto Joven , Proteína 1 Compañera de Translocación de RUNX1/genética , Trasplante Homólogo , Proteínas de Fusión Oncogénica/genética

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Objective: To investigate the efficacy and safety of avapritinib in the treatment of molecular biologically positive core binding factor-acute myeloid leukemia (CBF-AML) with KIT mutation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: We retrospectively analyzed the clinical data of six patients with molecular biologically positive CBF-AML with KIT mutation after allo-HSCT, who were treated with avapritinib at Henan Cancer Hospital from December 2021 to March 2023, and evaluated the efficacy and safety of avapritinib. Results: After 1 month of treatment with avapritinib, the transcription level of the fusion gene decreased in six patients, and the transcription level decreased by ≥1 log in five patients. In four patients who received avapritinib for ≥3 months, the fusion gene turned negative, and the median time to turn negative was 2.0 (range: 1.0-3.0) months. Up to the end of follow-up, four patients had no recurrence. The most common adverse reaction of avapritinib was myelosuppression, including neutropenia in two cases, thrombocytopenia in two cases, and anemia in one case. The non-hematological adverse reactions were nausea in two cases, edema in one case, and memory loss in one case, all of which were grades 1-2. Conclusion: Avapritinib was effective for molecular biologically positive CBF-AML patients with KIT mutation after allo-HSCT. The main adverse reaction was myelosuppression, which could generally be tolerated.

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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Mutación , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Estudios Retrospectivos , Proteínas Proto-Oncogénicas c-kit/genética , Trasplante Homólogo , Masculino , Adulto , Femenino , Persona de Mediana Edad , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Pirazoles , Pirroles , Triazinas

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BACKGROUND: Primary mediastinal germ-cell tumors (PMGCTs) account for 1%-3% of all germ-cell tumors (GCTs). Non-seminoma have a poorer prognosis compared to their gonadal counterpart and, according to the International Germ Cell Cancer Collaborative Group, they are considered 'poor risk' disease. Medical treatment is the same, with overall survival (OS) being ∼40%, declining to 10%-15% at 3 years in case of lung and non-visceral metastases. Patients failing first-line chemotherapy have a dismal prognosis, with only 5%-10% of cases being cured in the salvage setting. High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been successfully used to treat patients with relapsed or refractory gonadal GCTs. PATIENTS AND METHODS: This retrospective study aimed to investigate the value of HDC with ASCT in the whole population and define primary mediastinal non seminoma germ cell tumor (PMNSGCT) patient subgroups, who were registered in the European Society for Blood and Marrow Transplantation database from January 2000 to January 2018. Sixty-nine adult male patients with PMNSGCT were included. HDC consisted mainly of carboplatin/etoposide doublet, and most patients received HDC as part of a multiple sequential HDC program. RESULTS: OS was 43.3% at 2 years, and 34.7% at 5 and 10 years for the entire cohort. Analysis of outcomes showed that patients undergoing HDC as upfront therapy had a better progression-free survival (PFS) and OS compared to those treated in subsequent relapses (5-year PFS 51.8% versus 26.8% and 5-year OS 51.3% versus 25.9%). Better remission status before transplantation was predictive of the benefit of HDC. Three treatment-related deaths were recorded. CONCLUSIONS: To our knowledge, this is the most extensive retrospective study of HDC in PMNSGCTs patients and the first to thoroughly investigate potential predictors of benefit from this treatment. HDC with ASCT may well represent a therapeutic option in patients with PMNSGCTs after the first relapse or even as a front-line program.

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INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) comprises one of the two main treatment regimens for patients with mucopolysaccharidoses (MPS). There is a scarcity of literature concerning the process of growth in children with Mucopolysaccharidosis type I (MPS I) and Mucopolysaccharidosis type I (MPS II) after HSCT. The aim of this manuscript was to evaluate the therapeutic effect of HSCT on the heights of patients with MPS I and MPS II. MATERIAL AND METHODS: It was an observational, single-center study on patients with MPS I and II treated with HSCT. RESULTS: 6 MPS patients, including 4 MPS I and 2 MPS II, underwent HSCT at a median age of 2 years. All patients are alive to date, with a median age of 7.7 years (range 5.5-12 years) at the last follow-up. In both (MPS I and MPS II) groups of patients treated with HSCT, the growth rate was higher than in untreated patients and was found to be in line with the population norm. In both MPS I and MPS II patients who were treated with HSCT, normalization of urinary GAG excretion was observed. Additionally, no bands of DS and HS in GAG electrophoresis were visible. CONCLUSIONS: Both MPS I and MPS II patients presented height gain after HSCT compared to the curves of untreated patients. The absence of dermatan sulphate after HSCT could lead to normal growth in bone length.

RESUMEN

LRBA deficiency is an inborn error of immunity defined by autoimmunity, lymphoproliferation, recurrent infections, cytopenia, and inflammatory bowel disease. Despite recent advances in managing this disease with targeted biologic therapy, haematopoietic stem cell transplant (HSCT) remains the only cure. However, great variability exists between protocols used to transplant patients with LRBA deficiency. We describe a cohort of seven patients with LRBA deficiency who underwent HSCT using a myeloablative, reduced toxicity regime of fludarabine, treosulfan, and thiotepa at two transplantation centres from 2016 to 2019. Data were collected both retrospectively and prospectively, measuring time to engraftment, infectious complications, incidence of graft versus host disease, and post-transplantation chimerism. Six of seven patients survived transplantation, and four of six surviving patients achieving treatment-free survival. We thus recommend that HSCT with fludarabine, treosulfan, and thiotepa-based conditioning be considered in patients with LRBA deficiency.

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Busulfano , Trasplante de Células Madre Hematopoyéticas , Tiotepa , Acondicionamiento Pretrasplante , Vidarabina , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Tiotepa/uso terapéutico , Masculino , Femenino , Lactante , Preescolar , Enfermedad Injerto contra Huésped/etiología , Niño , Estudios Retrospectivos , Resultado del Tratamiento , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/terapia

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Background/Objectives: Graft-versus-host disease (GVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) resulting from histocompatibility differences between donor and host cells leading to inflammation, tissue damage, and compromised patient outcome. Extracorporeal photopheresis (ECP) is considered as a second-line treatment administered to patients with GVHD who do not respond to corticosteroid treatment or who experience a relapse after an initial response and are therefore classified as steroid refractory (SR). The aim of this study is to evaluate the clinical response rates in both pediatric and adult patients with acute (a) or chronic (c) GVHD and to assess the effectiveness of ECP using the real-world data from a single center. Methods: We performed a retrospective study on 30 patients, including 11 pediatric and 19 adult patients who were treated with ECP as a second-, third-, or fourth-line therapy for (a) and (c) GVHD, alongside corticosteroids and other immunomodulatory medications. The median time from aGVHD onset to ECP was 11.5 days (range: 3 days-9 months), while for cGVHD, the median time was 90 days (range: 2 days-9 months). Results: The overall response rate (ORR) in the aGVHD patient population was 60% with a median of 9 procedures (range: 2-20). For cGVHD patients, the ORR was 70% after a median of 23.5 ECP procedures (range: 8-43). Most patients had skin involvement, with ECP achieving an ORR of 81.8% in aGVHD and 77.7% in cGVHD cases. Conclusions: ECP is a beneficial therapy for patients with (a) and (c) GVHD who have not responded to corticosteroids and other forms of immunosuppressive therapy. Specifically, ECP demonstrated efficacy in improving skin and oral symptoms and permitted reductions in or the elimination of their corticosteroid usage. The study found that extending the duration of ECP treatment was associated with better outcomes, and no detectable complications were observed over a 38-week period.

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INTRODUCTION/AIM: Vitamin D plays a crucial role in immune modulation, which may influence the development of graft-versus-host disease (GvHD) in patients undergoing hematopoietic stem cell transplantation (HSCT). This study aims to evaluate the impact of vitamin D levels and supplementation on the incidence of GvHD in HSCT patients. METHODS: A narrative review was conducted across PubMed/Medline, Cochrane Library, CINAHL, and Embase databases. RESULTS: The reviewed studies indicated widespread vitamin D deficiency among HSCT patients, with baseline levels ranging from 12.8 to 29.2 ng/mL. Supplementation protocols varied significantly, with dosages ranging from 1000 IU/day to 60,000 IU/week. Post-supplementation levels improved in some studies. Studies exploring the relationship between vitamin D and GvHD showed mixed results. Lower baseline vitamin D levels were associated with an increased risk of acute GvHD in some studies, while others found no significant correlation. However, a significant association between low levels of vitamin D and the incidence of chronic GvHD was observed. CONCLUSION: Vitamin D deficiency is prevalent in HSCT patients and may influence the risk of developing chronic GvHD. Future research should focus on larger and more rigorous studies to determine the optimal role of vitamin D as an adjuvant therapy in the context of HSCT.

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Suplementos Dietéticos , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Deficiencia de Vitamina D , Vitamina D , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/sangre , Vitamina D/sangre , Vitamina D/administración & dosificación , Deficiencia de Vitamina D/sangre , Femenino , Incidencia , Masculino

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The benefit of high-dose melphalan followed by autologous hematopoietic stem cell transplantation (HDM-ASCT) for multiple myeloma (MM) patients with renal insufficiency (RI) is debated. A systematic review and meta-analysis were conducted to assess the safety and efficacy of HDM-ASCT in MM patients with RIs, and the findings were compared with real-world data. The study included 26 articles, 13 of which were pooled for meta-analysis. We compared three different types of MM patients with RI against MM patients with normal renal function (NRF). These patients were: MM patients with RI at the time of transplantation; MM patients with RI at the time of diagnosis; MM patients with RI at diagnosis but with NRF at transplantation. The meta-analysis indicated that MM patients with RIs conditioned with melphalan ≤ 140 mg/m2 followed by ASCT had transplant-related mortality rates comparable to those without RIs. The complete response rates post-ASCT were similar between MM patients with RIs and those with NRF. Although progression-free survival (PFS) was statistically similar between the groups, MM patients with RIs had significantly poorer overall survival (OS) than those with NRF. The real-world data supported these findings. With a reduced dose of melphalan, ASCT is safe and effective for MM patients with RI. MM patients with RI have similar complete response rates and PFS after ASCT compared to MM patients with NRF. The lower OS in MM patients with RI indicates the need for further research to improve OS in these patients.

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Trasplante de Células Madre Hematopoyéticas , Melfalán , Mieloma Múltiple , Insuficiencia Renal , Trasplante Autólogo , Mieloma Múltiple/terapia , Mieloma Múltiple/mortalidad , Humanos , Melfalán/administración & dosificación , Melfalán/uso terapéutico , Insuficiencia Renal/terapia , Análisis de Supervivencia , Resultado del Tratamiento , Acondicionamiento Pretrasplante/métodos

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BACKGROUND AND OBJECTIVES: Stem cell mobilization is a well-known procedure to harvest hematopoietic stem cells for autologous stem cell transplantation in certain hematologic diseases. Numerous studies have been conducted to identify risk factors for poor mobilization but there are no studies that identify good mobilizers. In our hospital, we decided to explore good mobilizers, defining them as those with ≥40 CD34+ cells/µL on Day +4 in order to start early apheresis. MATERIAL AND METHODS: A descriptive retrospective study was performed at Hospital Universitari Son Espases. A total of 198 patients mobilized with doses of around 10 µg/kg of granulocyte colony-stimulating factor (G-CSF) every 12 h were analyzed for autologous collection between January 2015 and September 2022. Fifty patients who had ≥40 CD34+ cells/µL on Day +4 started early apheresis; the rest continued mobilization as planned. Success was defined as obtaining over 2.5 × 106 CD34+ cells/kg in a single apheresis. RESULTS: The necessary number of CD34+ cells/kg to perform an autologous stem cell transplantation was reached in a single apheresis session in 62 % of patients with ≥40 CD34+ cells/µL in peripheral blood. A cutoff of 102 CD34+ cells/µL on Day +4 was shown to have the best success rate (94 %). In an analysis of success, age, previously failed mobilization and having one or more adverse factors for bad mobilization were statistically significant. CONCLUSION: Patients considered as good mobilizers were matched with our factors of poor mobilization, revealing that most patients (79 %) had none or only one risk factor for poor mobilization. Apheresis on Day +4 in good mobilizers was shown to be an effective alternative to reduce mobilization duration and decrease the amount of granulocyte-colony stimulating factor administered.

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BACKGROUND: Whole brain radiotherapy (WBRT) is commonly used as consolidation therapy in primary central nervous system lymphoma (PCNSL). However, high-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) has emerged as an alternative approach for PCNSL. This systematic review aims to assess the efficacy and safety of both treatment modalities. METHODS: The systematic review follows PRISMA guidelines. A comprehensive search strategy identified relevant studies from PubMed, Europe PMC, and Cochrane Library. The following search terms were used: "primary central nervous system lymphoma", "Autologous Stem Cell Transplantation", and "whole-brain radiotherapy". We included randomized controlled trials (RCTs) cohort studies evaluating the use of whole-brain radiotherapy and high-dose chemotherapy followed by autologous stem cell transplantation in the treatment of histologically-confirmed PCNSL. Publications included were limited to English language full texts that were published in the past 10 years. Data extraction & manuscript quality assessment was done by two independent reviewers with a third reviewer to resolve any discrepancy. Primary outcomes include overall survival (OS), progression-free survival (PFS) & treatment related toxicity (TRT). Secondary outcomes were clinical neurological function and performance score assessments. Individual studies were assessed using the Jadad Scale and the Newcastle-Ottawa Scale for observational studies. RESULTS: We identified 5 studies, consisting of 2 RCTs and 3 cohort studies. After all studies considered, analysis revealed that consolidation therapy with HD-ASCT had a better overall PFS and OS compared to whole-brain radiotherapy (P<0.005). Both groups showed similar TRT with mostly haematological toxicity. Holistically clinical cognitive functions are found to be improved in HD-ASCT Patients and poorer results are exhibited by WBRT patients primarily in executive functions. Performance statuses are scored differently across all studies with slightly preferable results shown in patients treated with HDC-ASCT. CONCLUSIONS: Based on the findings of this systematic review, HDC-ASCT might be a preferable choice of consolidative therapy as shown with better OS, PFS with similar TRT. While WBRT are more feasible and cost-efficient, risks of cognitive impairment and reduced performance status after WBRT should be considered for further treatment choices. Further randomized clinical trials with a similar scoring system are needed.

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Neoplasias del Sistema Nervioso Central , Linfoma , Trasplante Autólogo , Humanos , Trasplante Autólogo/métodos , Neoplasias del Sistema Nervioso Central/terapia , Linfoma/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre/métodos

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OBJECTIVE AND BACKGROUND: Sinusoidal obstruction syndrome (SOS) is a life-threatening complication in hematopoietic stem cell transplantation (HSCT) patients. However, the related risk factors in pediatric and young adult HSCT recipients remain unclear. Thus, we conducted this meta-analysis to identify potential risk factors for SOS in children and young adults undergoing HSCT. METHOD: We acquired related articles through searching PubMed, EMBASE, and the Cochrane Library up to May 31, 2024. We calculated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to identify potential risk factors. RESULTS: A total of 12 studies with 7644 HSCT recipients were included. Bone marrow transplantation (OR = 1.35, 95% CI: 1.03-1.77, I2 = 0%), busulfan (BU) (OR = 3.63, 95% CI: 1.78-7.38, I2 = 70%), and fludarabine (FLU) (OR = 1.55, 95% CI: 1.09-2.21, I2 = 16%) were risk factors for SOS after HSCT in children and young adults. CONCLUSION: Bone marrow transplantation and the use of BU or FLU might be risk factors for SOS after HSCT in children and young adults.

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Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática , Humanos , Enfermedad Veno-Oclusiva Hepática/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Factores de Riesgo , Pronóstico , Niño , Adulto Joven , Acondicionamiento Pretrasplante/efectos adversos , Adolescente

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Philadelphia chromosome (Ph)-like acute lymphoblastic leukaemia (ALL) is a high-risk subtype with a gene expression profile similar to Ph-positive ALL, due to activation of tyrosine kinase signalling. To understand the clinical implications of Ph-like ALL, this single-centre retrospective study evaluates outcomes in 268 adults, largely Hispanic ALL patients treated between 2013 and 2024, with a subgroup analysis of 139 haematopoietic stem cell transplantation (HSCT) patients. ALL subtypes included 68 (25.4%) Ph-like, 89 (33.2%) Ph-positive, and 111 (41.4%) Ph-negative. Ph-like patients were the youngest age at diagnosis (p = 0.007), most likely to have refractory disease (p < 0.001), and least likely to achieve minimal residual disease (MRD) negativity after induction (p = 0.031). Relative to Ph-negative ALL, Ph-like achieved worse event-free survival (EFS) (HR = 1.66; 95% CI 1.12-2.46; p = 0.012), whereas Ph-positive had improved EFS (HR = 0.60; 95% CI 0.38-0.93; p = 0.024) and cumulative incidence of relapse (CIR) (HR = 0.59; 95% CI 0.35-0.99; p = 0.046). Within the transplant subgroup, Ph status did not impact disease-free survival (DFS), CIR, or overall survival (OS). However, patients who received blinatumomab within 1-year pre-HSCT had improved DFS (HR = 0.43; 95% CI 0.20-0.94; p = 0.034) and CIR (HR = 0.26; 95% CI 0.09-0.75; p = 0.13). In conclusion, our data suggest that Ph-like is less likely to respond to standard induction therapy and HSCT may result in similar survival outcomes to Ph-negative ALL.

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Background: Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma (MM) progression. Simultaneously, previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upon stimulation with common γ-chain family cytokines in vitro and during homeostatic proliferation. The aim of the present work was to study the impact of homeostatic proliferation on the expansion of certain T cell subsets up-regulating PD-1 and TIM-3 checkpoint molecules. Methods: The expression of CD25, CD122, CD127 common γ-chain cytokine receptors, phosphorylated signal transducer and activator of transcription-5 (pSTAT5) and eomesodermin (EOMES) was comparatively assessed with flow cytometry in PD-1- and TIM-3-negative and positive T cells before the conditioning and during the first post-transplant month in peripheral blood samples of MM patients. Results: Substantial proportions of PD-1- and TIM-3-positive T lymphocytes expressed common γ-chain cytokine receptors and pSTAT5. Frequencies of cytokine receptor expressing cells were significantly higher within TIM-3+ T cells compared to PD-1+TIM-3- subsets. Considerable proportions of both PD-1-/TIM-3-negative and positive CD8+ T cells express EOMES, while only moderate frequencies of CD4+ PD-1+/TIM-3+ T cells up-regulate this transcription factor. Besides, the surface presence of CD25 and intranuclear expression of EOMES in CD4+ T cells were mutually exclusive regardless of PD-1 and TIM-3 expression. The stimulation with common γ-chain cytokines up-regulates PD-1 and TIM-3 during the proliferation of initially PD-1/TIM-3-negative T cells but fails to expand initially PD-1+ and TIM-3+ T cell subsets in vitro. Conclusions: Both PD-1 and TIM-3 expressing T cells appear to be able to respond to homeostatic cytokine stimulation. Differences in common γ-chain cytokine receptor expression between PD-1+ and TIM-3+ T cells may reflect functional dissimilarity of these cell subsets. Checkpoint blockade appears to alleviate lymphopenia-induced proliferation of PD-1+ T cells but may raise the possibility of immune-mediated adverse events.

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Receptor 2 Celular del Virus de la Hepatitis A , Mieloma Múltiple , Receptor de Muerte Celular Programada 1 , Humanos , Mieloma Múltiple/inmunología , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Persona de Mediana Edad , Masculino , Femenino , Anciano , Interleucina-7/metabolismo , Interleucina-15/farmacología , Interleucina-15/metabolismo , Regulación hacia Arriba , Adulto , Receptores de Citocinas/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo

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Background: Iron overload, as indicated by evaluated serum ferritin (SF) level, occurs commonly in patients with hematological diseases. To evaluate the association between pre-transplant SF level and outcomes of hematopoietic stem cell transplantation (HSCT), we performed this systematic review and meta-analysis. Methods: PubMed, Embase, Web of Science and the Cochrane Library electronic database were searched from inception to August 2023, and 56 studies with 14149 patients were found to be eligible. Results: An elevated pre-transplantation SF level was associated with inferior overall survival (hazard ratio [HR],1.77; 95 % confidence interval [CI],1.61-1.96) and disease-free survival (HR, 1.86; 95 % CI, 1.58-2.19), and increased risk of non-relapse mortality (HR, 1.73; 95 % CI, 1.49-2.02), and relapse (HR, 1.46; 95 % CI, 1.29-1.65). However, no meaningful association was observed between SF levels and acute graft-versus-host disease (GVHD) (risk ratio [RR], 1.09; 95 % CI, 0.96-1.24), or chronic GVHD (RR, 0.95; 95 % CI, 0.79-1.16). Furthermore, an elevated pre-transplantation SF level was associated with a higher risk of fungal infection (RR, 1.56; 95 % CI, 1.16-2.10), but not with bacterial infection (RR, 1.09; 95 % CI, 0.80-1.50). Moreover, an elevated pre-transplantation SF level was related to a higher risk of death due to relapse/disease progression (RR, 1.72; 95 % CI, 1.33-2.23) and infection (RR, 2.21; 95 % CI, 1.55-3.15), but not death due to GVHD (RR, 1.18; 95 % CI, 0.79-1.77). Conclusions: A higher pre-transplantation SF level was significantly associated with a higher risk of relapse/disease progression and infections, which contributed to worse survival in patients undergoing HSCT. In particular, a higher SF level was related to a higher risk of fungal infection, indicating that patients with a higher pre-transplantation SF level require more attention regarding the risk of fungal infection after HSCT.

RESUMEN

A 20-year-old male patient with a history of celiac disease came to medical attention after developing profound fatigue and pancytopenia. Evaluation demonstrated pan-hypogammaglobulinemia. There was no history of significant clinical infections. Bone marrow biopsy confirmed hypocellular marrow consistent with aplastic anemia. Oncologic and hematologic evaluations were unremarkable for iron deficiency, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndromes, T-cell clonality, and leukemia. A next generation genetic sequencing immunodeficiency panel revealed a heterozygous variant of uncertain significance in CTLA4 c.385T >A, p.Cys129Ser (C129S). Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor important in maintaining immunologic homeostasis. To determine the functional significance of the C129S variant, additional testing was pursued to assess for diminished protein expression, as described in other pathogenic CTLA4 variants. The results demonstrated severely impaired CTLA-4 expression and CD80 transendocytosis, consistent with other variants causing CTLA-4 haploinsufficiency. He was initially treated with IVIG and cyclosporine, and became transfusion independent for few months, but relapsed. Treatment with CTLA-4-Ig fusion protein (abatacept) was considered, however the patient opted for definitive therapy through reduced-intensity haploidentical hematopoietic stem cell transplant, which was curative.

RESUMEN

The optimal treatment for patients with severe aplastic anemia (SAA) who fail an initial course of antithymocyte globulin (ATG) plus cyclosporine has not yet been established. We compared the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n = 36) with repeated immunosuppressive therapy (IST) (n = 33) for relapsed/refractory SAA between 2007 and 2022. In the IST group, patients were retreated with ATG (n = 16) or high-dose cyclophosphamide (n = 17). The overall response rate was 57.6% at 6 months and 60.6% at 12 months. In the allo-HSCT group, patients received a transplant from a matched sibling donor (n = 6), matched unrelated donor (n = 7), or haploidentical donor (n = 23). All patients achieved neutrophil engraftment, and there were no cases of primary graft failure. The cumulative incidences (CIs) of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 36.1% ± 0.7% and 13.9% ± 0.3% at day +100, respectively. The 4-year CI of chronic GVHD (cGVHD) was 36.2% ± 0.7%, with moderate to severe cGVHD at 14.9% ± 0.4%. Compared with IST, HSCT recipients showed much higher hematologic recovery rate at 3, 6, and 12 months (63.9%, 83.3%, and 86.1%, respectively, p < 0.001). The estimated 4-year overall survival (OS) (79.8% ± 6.8% vs. 80.0% ± 7.3%, p = 0.957) was similar; however, the failure-free survival (FFS) was significantly better in the HSCT group (79.8% ± 6.8% vs. 56.6% ± 8.8%, p = 0.049). Of note, children in the HSCT cohort were all alive without treatment failures, exhibiting superior OS (100% vs. 50.0% ± 17.7%, p = 0.004) and FFS (100% vs. 50.0% ± 17.7%, p = 0.004) than children in the IST cohort. Subgroup analysis revealed that younger patients (age ≤ 35 years), especially children, and those with refractory SAA benefited more from HSCT. Therefore, for these patients, salvage HSCT may be more preferable than a second course of IST.

Asunto(s)

Anemia Aplásica , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores , Recurrencia , Humanos , Anemia Aplásica/terapia , Anemia Aplásica/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Femenino , Adolescente , Adulto , Enfermedad Injerto contra Huésped/etiología , Niño , Inmunosupresores/uso terapéutico , Inmunosupresores/administración & dosificación , Adulto Joven , Preescolar , Persona de Mediana Edad , Resultado del Tratamiento , Suero Antilinfocítico/uso terapéutico , Suero Antilinfocítico/administración & dosificación , Trasplante Homólogo , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Terapia de Inmunosupresión/métodos , Estudios Retrospectivos , Ciclosporina/uso terapéutico , Ciclosporina/administración & dosificación

RESUMEN

Severe aplastic anemia (SAA) is a life-threatening disorder with high mortality. The only curative treatment is hematopoietic stem cell transplantation (HSCT), but it is mainly for young patients with suitable donors. The alternative is immunosuppressive therapy (IST), which can improve blood counts in about 58% of patients, but many relapse after discontinuation. Recently, eltrombopag, a thrombopoietic receptor agonist, was tested. As a single drug, it improved blood counts in 40-50% of patients. However, combining eltrombopag and IST proved more effective and safer. A review of 20 randomized controlled trials with 2,469 patients showed that the group receiving eltrombopag and IST had a significantly higher overall response rate (86% vs. 74%) after six months. After two years, 54% of the experimental group had relapsed compared to 39% in the control group. Despite this, eltrombopag tends to increase relapse rates over time. In conclusion, combining eltrombopag with IST is a superior treatment for SAA.