HLA peptide-binding pocket diversity modulates immunological complications after cord blood transplant in acute leukaemia.

Pocket motifs and their amino acid positions of HLA molecules are known to govern antigen presentation to effector cells. Our objective was to analyse their influence on the risk of graft-versus-host disease (GVHD) and relapse after umbilical cord blood transplant (UCBT). The transplant characteristics of 849 patients with acute leukaemia were obtained from the Eurocord/EBMT database. Higher acute (a) GVHD was associated with homozygosity of UCB HLA-C amino acid positions 77 and 80 (NN/KK) (p = 0.008). Severe aGVHD was associated with HLA-A pocket B YSAVMENVHY motif (p = 0.002) and NN and RR genotypes of the HLA-C amino acid positions 77 and 156 (p = 0.006 and p = 0.002). Such risk was also increased in case of recipient and UCB mismatches in P4 (p < 0.0001) and P9 (p = 0.003) pockets of HLA-DQB1 alleles. For chronic GVHD, the pocket B YYAVMEISNY motif of the HLA-B*15:01 allele and the absence of mismatch between recipient and UCB in the P6 pocket of HLA-DRB1 were associated with a lower risk (p = 0.0007 and p = 0.0004). In relapse, both UCB pocket B YFAVMENVHY belonging to HLA-A*32:01 and recipient pocket B YDSVGENYQY motif of the HLA-C*07:01 allele were associated with higher risk (p = 0.0026 and p = 0.015). We provide clues on HLA-mediated cellular interactions and their role in the development of GVHD and relapse.

Matched unrelated donor transplantation versus haploidentical transplantation with post-transplant cyclophosphamide in children with acute myeloid leukemia: a PDWP-EBMT study.

In children with acute myeloid leukemia (AML) who lack a human leukocyte antigen (HLA) identical sibling, the donor can be replaced with an HLA-matched unrelated donor (MUD) or a haploidentical donor (haplo). We compared outcomes of patients <18 years with AML in first and second complete remission (CR1 and CR2) undergoing a hematopoietic stem cell transplantation (HCT) either with a MUD with anti-thymocyte globulin (ATG) (N=420) or a haplo HCT with post-transplant cyclophosphamide (PT-CY) (N=96) after a myeloablative conditioning regimen (MAC) between 2011 and 2021, reported to the European Society for Blood and Marrow Transplantation. A matched pair analysis was performed to adjust for differences among groups. The final analysis was performed on 253 MUD and 95 haplo-HCT. In the matched cohort, median age at HCT was 11.2 and 10 years and median year of HCT was 2017 and 2018, in MUD and haplo-HCT recipients, respectively. The risk of grade III-IV acute graft-versus-host disease (aGVHD) was significantly higher in the haplo group (hazard ratio [HR]=2.33, 95% confidence interval [CI]: 1.18-4.58; P=0.01). No significant differences were found in 2 years overall survival (OS; 78.4% vs. 71.5%; HR=1.39, 95% CI: 0.84-2.31; P=0.19), leukemia-free survival (LFS; 72.7% vs. 69.5%; HR=1.22, 95% CI: 0.76-1.95; P=0.41), CI of relapse (RI; 19.3% vs. 19.5%; HR=1.14, 95% CI: 0.62-2.08; P=0.68) non-relapse-mortality (NRM; 8% vs. 11%; HR=1.39, 95% CI: 0.66-2.93; P=0.39) and graft-versus-host free relapse-free survival (GRFS; 60.7% vs. 54.5%, HR=1.38, 95% CI: 0.95-2.02; P=0.09) after MUD and haplo-HCT respectively. Our study suggests that haplo-HCT with PT-CY is a suitable option to transplant children with AML lacking a matched related donor.

Current challenges in cell and gene therapy: a joint view from the European Committee of the International Society for Cell & Gene Therapy (ISCT) and the European Society for Blood and Marrow Transplantation (EBMT).

Cell and gene therapy poses evolving challenges. The current article summarizes the discussions held by European Regional Committee of the International Society for Cell & Gene Therapy and the European Society for Blood and Marrow Transplantation (EBMT) on the current challenges in this field, focusing on the European setting. This article emphasizes the imperative assessment of real-world cell and gene therapy activity, advocating for expanded registries beyond hematopoietic transplantation and chimeric antigen receptor-T-cell therapy. Accreditation's role in ensuring standardized procedures, as exemplified by JACIE (The Joint Accreditation Committee of ISCT-Europe and EBMT), is crucial for safety. Access to commercial products and reimbursement variations among countries underscore the need for uniform access to advanced therapy medical products (ATMPs). Academic product development and point-of-care manufacturing face barriers to patient access. Hospital Exemption's potential, demonstrated by some initial experiences, may increase patient accessibility in individual situations. Regulatory challenges, including the ongoing European ATMPs legislation review, necessitate standardized criteria for Hospital Exemption and mandatory reporting within registries. Efforts to combat unproven therapies and fraud involve collaboration between scientific societies, regulatory bodies and patient groups. Finally, is important to highlight the vital role of education and workforce development in meeting the escalating demand for specialized professionals in the ATMP field. Collaboration among scientific societies, academic institutions, industry, regulatory bodies and patient groups is crucial for overcoming all these challenges to increase gene and cell therapy activity in Europe.

Patterns and prognostic impact of CNS infiltration in adults with newly diagnosed acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is highly associated with central nervous system (CNS) infiltration and can be associated with higher risk of relapse. Conventional cytology (CC) is the traditional method for diagnosing CNS infiltration, although the use of immunophenotyping by flow cytometry (FC) has gained prominence in recent years due to its higher sensitivity. Also, some authors have proposed that CSF contamination by a traumatic lumbar puncture (TLP) could have a clinical impact. This retrospective study accessed the impact of CNS infiltration by CC or FC on overall survival, event-free survival, and relapse rate. In a cohort of 105 newly diagnosed ALL patients, CNS1, CNS2, and CNS3 status were found in 84%, 14%, and 2%, respectively. We found that extramedullary disease at the diagnosis, higher leukocyte counts, and higher blast percentage were associated with a positive CC. Sensitivity and specificity of CC were 53% and 98%, respectively. Three-year overall survival was 42.5%. Conversely, TLP was not associated with a positive CC nor had an impact on relapse rates. In multivariate analysis, a positive CC was associated with an increased relapse rate (HR 2.074, p = 0.037), while its detection by FC did not associate with this endpoint. Survival rates seem to be increasing over the last years by the adoption of a stratified CNS prophylaxis risk strategy. CSF contamination does not represent a major concern according to our report, as it did not increase CNS involvement or relapse rates.

Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: A global collaborative analysis.

Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis. We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9-12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse (p = .01), showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy. In conclusion, splenic irradiation immediately before HCT is a reasonable approach in patients experiencing JAK inhibition failure and is associated with a low incidence of relapse.

COVID-19 surveillance in a bone marrow transplantation unit: experience from a Brazilian tertiary-care teaching hospital.

PURPOSE: In this work, we aimed to describe the strategy of the weekly SARS-CoV-2 RT-PCR surveillance program that was implemented in our bone marrow transplantation (BMT) unit. METHODS: Our unit performed SARS-CoV-2 RT-PCR before admission and then weekly during hospitalization even if the patient was asymptomatic. From May 2021 to May 2022, we collected data from all patients that were admitted in the BMT unit to perform transplantation. The total of SARS-CoV-2 RT-PCR performed and the positive rate were described. RESULTS: During the study period, 65 patients were admitted for HSCT. A total of 414 SARS-CoV-2 RT-PCR were performed. Two cases were detected (positivity rate, 0.48%). After the positive test, both patients were isolated outside the BMT unit. CONCLUSION: We postulate that diagnosing these patients and isolating them outside the transplantation unit may have prevented secondary symptomatic cases.

Persistent hypofibrinolysis in severe COVID-19 associated with elevated fibrinolysis inhibitors activity.

Hypercoagulability and reduced fibrinolysis are well-established complications associated with COVID-19. However, the timelines for the onset and resolution of these complications remain unclear. The aim of this study was to evaluate, in a cohort of COVID-19 patients, changes in coagulation and fibrinolytic activity through ROTEM assay at different time points during the initial 30 days following the onset of symptoms in both mild and severe cases. Blood samples were collected at five intervals after symptoms onset: 6-10 days, 11-15 days, 16-20 days, 21-25 days, and 26-30 days. In addition, fibrinogen, plasminogen, PAI-1, and alpha 2-antiplasmin activities were determined. Out of 85 participants, 71% had mild COVID-19. Twenty uninfected individuals were evaluated as controls. ROTEM parameters showed a hypercoagulable state among mild COVID-19 patients beginning in the second week of symptoms onset, with a trend towards reversal after the third week of symptoms. In severe COVID-19 cases, hypercoagulability was observed since the first few days of symptoms, with a tendency towards reversal after the fourth week of symptoms onset. A hypofibrinolytic state was identified in severe COVID-19 patients from early stages and persisted even after 30 days of symptoms. Elevated activity of PAI-1 and alpha 2-antiplasmin was also detected in severe COVID-19 patients. In conclusion, both mild and severe cases of COVID-19 exhibited transient hypercoagulability, reverted by the end of the first month. However, severe COVID-19 cases sustain hypofibrinolysis throughout the course of the disease, which is associated with elevated activity of fibrinolysis inhibitors. Persistent hypofibrinolysis could contribute to long COVID-19 manifestations.

Fatal hepatic mucormycosis in an allogeneic hematopoietic-stem cell transplanted patient: Case report of a rare presentation and review of the literature.

Hepatic mucormycosis is a rare condition. Our objective is to report a case in a HSCT patient and to perform a review of the literature. A 36-year-old man with acute myeloid leukemia, performed a haploidentical HSCT. In D+132, when treating acute GVHD with methylprednisolone and etanercept, a hepatic abscess was diagnosed. Puncture of the abscess was performed, and fungal hyphae were visualized. The culture of the aspirate identified Mucor sp. Sequencing confirmed the isolate as Mucor indicus. The patient died despite the use of Amphotericin B. Our search identified 24 hepatic mucormycosis reports. Fifteen (62.5 %) were male and 79.1 % were immunocompromised. Fever accompanied with abdominal pain was present in 41.6 %. Twelve (50.0 %) had multiple hepatic lesions. Mortality rate was 45.8 % (n = 11/24). In conclusion, the most common clinical presentation of hepatic mucormycosis in immunocompromised patients might be abdominal pain and fever, along with hepatic abscess findings in abdominal imaging exams.

Ponatinib vs Imatinib in Frontline Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.

Importance: In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I. Objective: To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL. Design, Setting, and Participants: Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022. Intervention: Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission. Main Outcomes and Measures: The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival. Results: Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%). Conclusions and Relevance: Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib. Trial Registration: ClinicalTrials.gov Identifier: NCT03589326.

Early Toxicity and Efficacy of Four Different Conditioning Regimens for Autologous Hematopoietic Cell Transplantation in Patients With Lymphoma: Impact of Drug Shortages in a Resource-Constrained Country.

High-dose therapy followed by autologous hematopoietic cell transplant (AHCT) remains a viable consolidation strategy for a subset of patients with relapsed or refractory (R/R) lymphomas. BEAM (carmustine, etoposide, cytarabine, and melphalan) is widely recognized as the predominant conditioning regimen due to its satisfactory efficacy and tolerability. Nevertheless, shortages of carmustine and melphalan have compelled clinicians to explore alternative conditioning regimens. The aim of this study was to compare the toxicity and transplant outcomes following BEAM, CBV (carmustine, etoposide, cyclophosphamide), BuMel (busulfan, melphalan), and BendaEAM (bendamustine, etoposide, cytarabine, melphalan). We retrospectively analyzed data from 213 patients (CBV 65, BuMel 42, BEAM 68, BendaEAM 38) with R/R lymphomas undergoing AHCT between 2014 and 2020. Multivariate models were employed to evaluate toxicity and transplant outcomes based on conditioning type. Among grade III to IV toxicities, oral mucositis was more frequently observed with BuMel (45%) and BendaEAM (24%) compared to BEAM (15%) and CVB (6%, P ≤ .001). Diarrhea was more common with BendaEAM (42%) and less frequent with BuMel (7%, P = .01). Acute kidney injury was only found after BendaEAM (11%). Febrile neutropenia and infectious complications were more frequent following BendaEAM. Frequencies of other treatment-related toxicities did not significantly differ according to conditioning type. BendaEAM (odds ratio [OR] 3.07, P = .014) and BuMel (OR 4.27, P = .002) were independently associated with higher grade III to IV toxicity up to D+100. However, there were no significant differences in relapse/progression, nonrelapse mortality, progression-free survival, or overall survival among the four regimens. BuMel and BendaEAM were associated with a higher rate of grade III to IV toxicity. Carmustine-based regimens appeared to be less toxic and safer; however, there were no significant differences in transplant outcomes. The utilization of alternative preparative regimens due to drug shortages may potentially lead to increased toxicity after AHCT for lymphoma.

Extracellular vesicles are a late marker of inflammation, hypercoagulability and COVID-19 severity.

Exacerbated inflammation and coagulation are a hallmark of COVID-19 severity. Extracellular vesicles (EVs) are intercellular transmitters involved in inflammatory conditions, which are capable of triggering prothrombotic mechanisms. Since the release of EVs is potentially associated with COVID-19-induced coagulopathy, the aim of this study was to evaluate changes in inflammation- and hypercoagulability-related EVs during the first month after symptom onset and to determine whether they are associated with disease severity. Blood samples of patients with mild or severe forms of the disease were collected on three occasions: in the second, third and fourth weeks after symptom onset for the quantification by flow cytometry of CD41A (platelet glycoprotein IIb/IIIa), CD162 (PSGL-1), CD31 (PECAM-1) and CD142 cells (tissue factor). Analysis of variance (ANOVA) with repeated measures, Kruskal-Wallis and correlation tests were used. Eighty-five patients were enrolled, 71% of whom had mild disease. Seventeen uninfected individuals served as controls. Compared to controls, both mild and severe COVID-19 were associated with higher EV-CD31+, EV-CD41+ and EV-CD142+ levels. All EV levels were higher in severe than in mild COVID-19 only after the third week from symptom onset, as opposed to C-reactive protein and D-dimer levels, which were higher in severe than in mild COVID-19 earlier during disease progression. EV levels were also associated with C-reactive protein and D-dimer levels only after the third week of symptoms. In conclusion, EVs expressing CD41A, CD31, TF, and CD162 appear as late markers of COVID-19 severity. This finding may contribute to the understanding of the pathogenesis of acute and possibly long COVID-19.

Unsupervised Clustering Analysis of Regimen and HLA Characteristics in Pediatric Umbilical Cord Blood Transplantation.

HLA matching is a critical factor in allogeneic unrelated hematopoietic cell transplantation (HCT) because of its impact on post-transplantation survival and quality of life. Umbilical cord blood transplantation (UCBT) offers unique advantages, but determining the optimal approach to graft selection and immunosuppression remains challenging. Unsupervised clustering, a machine learning technique, has potential for analyzing transplantation outcomes, but its application in investigating leukemia outcomes has been limited. This study aimed to identify optimal combinations of HLA/ killer immunoglobulin receptor (KIR) donor-patient pairing, conditioning, and immunosuppressive regimens in pediatric patients with acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML) undergoing UCBT. Outcome data for single, unmanipulated UCBT in pediatric AML (n = 708) and ALL (n = 1034) patients from the Eurocord/EBMT registry were analyzed using unsupervised clustering. Resulting clusters were used to inform post hoc competing risks and Kaplan-Meier analyses. In AML, single HLA-C mismatches with other loci fully matched (7/8) were associated with poorer relapse-free survival (RFS) (P = .039), but a second mismatch at any other locus counteracted this effect. In ALL, total body irradiation (TBI) effectively prevented relapse mortality (P = .007). KIR/HLA-C match status affected RFS in AML (P = .039) but not in ALL (P = .8). Administration of antithymocyte globulin (ATG) substantially increased relapse, with no relapses occurring in the 85 patients who did not receive ATG. Our unsupervised clustering analyses generate several key statistical and mechanistic hypotheses regarding the relationships between HLA matching, conditioning regimens, immunosuppressive therapies, and transplantation outcomes in pediatric AML and ALL patients. HLA-C and KIR combinations significantly impact RFS in pediatric AML but not in ALL. ATG use in fully matched pediatric patients is associated with late-stage relapse. TBI regimens appear to be beneficial in ALL, with efficacy largely independent of histocompatibility variables. These findings reflect the distinct genetic and biological profiles of AML and ALL.

Multiple myeloma and Chagas disease: qPCR as a marker for preemptive antiparasitic therapy: a case reports series and review.

Multiple myeloma (MM) associated with Chagas disease is rarely described. This disease and its therapy suppress T cell and macrophage functions and increase regulatory T cell function, allowing the increase of parasitemia and the risk of Chagas Disease Reactivation (CDR). We aimed to analyze the role of conventional (cPCR) and quantitative Polymerase Chain Reaction (qPCR) for prospective monitoring of T. cruzi parasitemia, searching for markers of preemptive antiparasitic therapy in MM patients with Chagas disease. Moreover, we investigated the incidence and management of hematological diseases and CDR both inside and outside the transplant setting in the MEDLINE database. We found 293 studies and included 31 of them. Around 1.9-2.0% of patients with Chagas disease were reported in patients undergoing Stem Cell Transplantation. One case of CDR was described in eight cases of MM and Chagas disease. We monitored nine MM and Chagas disease patients, seven under Autologous Stem Cell Transplantation (ASCT), during 44.56±32.10 months (mean±SD) using parasitological methods, cPCR, and qPCR. From these patients, three had parasitemia. In the first, up to 256 par Eq/mL were detected, starting from 28 months after ASCT. The second patient dropped out and died soon after the detection of 161.0 par Eq/mL. The third patient had a positive blood culture. Benznidazole induced fast negativity in two cases; followed by notably lower levels in one of them. Increased T. cruzi parasitemia was related to the severity of the underlying disease. We recommend parasitemia monitoring by qPCR for early introduction of preemptive antiparasitic therapy to avoid CDR.

Prevalence and clinical consequences of Hepatitis C virus infection in patients undergoing hematopoietic stem cell transplantation.

Hepatitis C virus (HCV) infection is a significant cause of morbidity and mortality among hematopoietic stem cell transplant (HCT) recipients. In Brazil, its occurrence in HCT recipients remains undetermined. We now report on HCV prevalence in HCT recipients and its clinical consequences. The medical records of all HCT recipients seen at Hospital das Clinicas, Sao Paulo University Medical School, from January 2010 to January 2020 were reviewed to determine HCV serostatus. A retrospective analysis of medical charts was undertaken on all seropositive cases to determine HCV genotype, presence of liver fibrosis, co-infections with other viruses, previous treatments, and clinical evolution of liver pathology after HCT. Of the 1,293 HCT recipients included in the study, seven (0.54%) were HCV antibody-positive and five (0.39%) were also viremic for HCV-RNA. Four of these individuals had moderate to severe liver fibrosis (METAVIR F2/F3) and one was cirrhotic. Two of the viremic patients developed acute liver dysfunction following transplantation. All patients had their acute episode of liver dysfunction resolved with no further complications. Four of the viremic patients were treated for HCV infection with direct acting agents (DAA). Information regarding HCV treatment was lacking for one of the viremic HCV patients due to loss of follow up. Sustained anti-virologic responses were observed in three cases after the use of DAA. The detection of HCV in hematological adults undergoing HCT and its successful treatment with DAA highlight the necessity of testing for HCV both prior to and following transplantation.

Predictors of Survival, Treatment Modalities, and Clinical Outcomes of Diffuse Large B-Cell Lymphoma in Patients Older Than 70 Years Still an Unmet Medical Need in 2024 Based on Real-World Evidence.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) especially affects the older population. Old (≥60 years) and very old age (≥80 years) DLBCL patients often present high-risk molecular alterations, lower tolerability to conventional immunochemotherapy, and poor clinical outcomes. In this scenario, attenuated therapeutic strategies, such as the R-MiniCHOP and R-MiniCHOP of the elderly regimens, have emerged for this particularly fragile population. However, the responses, clinical outcomes, and toxicities of these regimens currently remain poorly understood, mainly because these individuals are not usually included in controlled clinical trials. METHODS: This retrospective, observational, and single-center real-world study included 185 DLBCL, NOS patients older than 70 years treated at the largest oncology center in Latin America from 2009 to 2020. We aimed to assess the outcomes, determine survival predictors, and compare responses and toxicities between three different primary therapeutic strategies, including the conventional R-CHOP regimen and the attenuated R-MiniCHOP and R-MiniCHOP of the elderly protocols. RESULTS: The median age at diagnosis was 75 years (70-97 years), and 58.9% were female. Comorbidities were prevalent, including 19.5% with immobility, 28.1% with malnutrition, and 24.8% with polypharmacy. Advanced clinical stage was observed in 72.4%, 48.6% had bulky disease ≥7 cm, 63.2% had B-symptoms, and 67.0% presented intermediate-high/high-risk IPI. With a median follow-up of 6.3 years, the estimated 5-year OS and PFS were 50.2% and 44.6%, respectively. The R-MiniCHOP of the elderly regimen had a lower ORR (p = 0.040); however, patients in this group had higher rates of unfavorable clinical and laboratory findings, including hypoalbuminemia (p = 0.001), IPI ≥ 3 (p = 0.013), and NCCN-IPI ≥ 3 (p = 0.002). Although associated with higher rates of severe neutropenia (p = 0.003), the R-CHOP regimen promoted increased OS (p = 0.003) and PFS (p = 0.005) in comparison to the attenuated protocols. Additionally, age ≥ 75 years, high levels of LDH, B-symptoms, advanced clinical stage (III/IV), neutrophilia, and low lymphocyte/monocyte ratio were identified as poor prognostic factors in this cohort. CONCLUSIONS: In this large and real-life Latin American cohort, we demonstrated that patients with DLBCL, NOS older than 70 years still do not have satisfactory clinical outcomes in 2024, with half of cases not reaching 5 years of life expectancy after diagnosis. Although the conventional R-CHOP offers response and survival advantages over attenuated regimens, its myelotoxicity is not negligible. Therefore, the outcomes reported and the prognostic factors here identified may assist clinicians in the appropriate selection of therapeutic strategies adapted to the risk for old and very old DLBCL patients.

COVID-19 in hematopoietic stem cell transplant recipients during three years of the pandemic: a multicenter study in Brazil.

Hematopoietic stem cell transplant (HSCT) recipients are at -increased risk for severe COVID-19. The aim of this study was to evaluate the burden of COVID-19 in a cohort of HSCT recipients. This retrospective study evaluated a cohort of adult hospitalized HSCT recipients diagnosed with COVID-19 in two large hospitals in São Paulo, Brazil post-HSCT, from January 2020 to June 2022. The primary outcome was all-cause mortality. Of 49 cases, 63.2% were male with a median age of 47 years. Allogeneic-HSCT (51.2%) and autologous-HSCT (48.9%) patients were included. The median time from HSCT to COVID-19 diagnosis was 398 days (IQR: 1211-134), with 22 (44.8%) cases occurring within 12 months of transplantation. Most cases occurred during the first year of the pandemic, in non-vaccinated patients (n=35; 71.4%). Most patients developed severe (24.4%) or critical (40.8%) disease; 67.3% received some medication for COVID-19, primarily corticosteroids (53.0%). The probable invasive aspergillosis prevalence was 10.2%. All-cause mortality was 40.8%, 51.4% in non-vaccinated patients and 14.2% in patients who received at least one dose of the vaccine. In the multiple regression analyses, the variables mechanical ventilation (OR: 101.01; 95% CI: 8.205 - 1,242.93; p = 0.003) and chest CT involvement at diagnosis ≥50% (OR: 26.61; 95% CI: 1.06 - 664.26; p = 0.04) remained associated with all-cause mortality. Thus, HSCT recipients with COVID-19 experienced high mortality, highlighting the need for full vaccination and infection prevention measures.

Colonization by Extended-Spectrum ß-Lactamase-Producing Enterobacterales and Bacteremia in Hematopoietic Stem Cell Transplant Recipients.

BACKGROUND: Assessing the risk of multidrug-resistant colonization and infections is pivotal for optimizing empirical therapy in hematopoietic stem cell transplants (HSCTs). Limited data exist on extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) colonization in this population. This study aimed to assess whether ESBL-E colonization constitutes a risk factor for ESBL-E bloodstream infection (BSI) and to evaluate ESBL-E colonization in HSCT recipients. METHODS: A retrospective analysis of ESBL-E colonization and BSI in HSCT patients was conducted from August 2019 to June 2022. Weekly swabs were collected and cultured on chromogenic selective media, with PCR identifying the ß-lactamase genes. Pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing (WGS) assessed the colonizing strains' similarities. RESULTS: Of 222 evaluated HSCT patients, 59.45% were colonized by ESBL-E, with 48.4% at admission. The predominant ß-lactamase genes were blaTEM (52%) and blaSHV (20%). PFGE analysis did not reveal predominant clusters in 26 E. coli and 15 K. pneumoniae strains. WGS identified ST16 and ST11 as the predominant sequence types among K. pneumoniae. Thirty-three patients developed thirty-five Enterobacterales-BSIs, with nine being third-generation cephalosporin-resistant. No association was found between ESBL-E colonization and ESBL-BSI (p = 0.087). CONCLUSIONS: Although the patients presented a high colonization rate of ESBL-E upon admission, no association between colonization and infection were found. Thus, it seems that ESBL screening is not a useful strategy to assess risk factors and guide therapy for ESBL-BSI in HSCT-patients.

High Dose Chemotherapy With Autologous Stem Cell Transplant for Patients With Advanced Germ Cell Tumors: Real-World Evidence From a Tertiary Cancer Center in Brazil.

BACKGROUND: High-dose chemotherapy followed by stem cell transplant (HDCT) is potentially curative for patients with refractory germ cell tumors (rGCT). There is scarce real-world data supporting its implementation in low- and middle-income countries. We described the experience of our tertiary cancer center in Sao Paulo, Brazil. METHODS: We identified male patients ≥18 years-old with rGCT referred to HDCT after board discussion. Clinical data, including delays in HDCT protocol, were extracted from medical records, and survival outcomes were estimated using the Kaplan-Meier method. The log-rank test and Cox proportional hazard were used to determine effects on overall survival (OS). RESULTS: From January 2013 to January 2023, 34 patients were referred and considered eligible to receive 2 cycles of HDCT. Most patients had primary testicular tumors (82%), nonseminomatous histology (88%), and poor International Germ Cell Collaborative Group (IGCCCG) (79%). Twenty-three patients received HDCT (1 cycle, n = 8; 2 cycles, n = 15). Main reasons for not receiving any HDCT were death due to progressive disease (n = 1), performance deterioration (n = 7), and failure of stem cell mobilization (n = 3). OS at 2 years was 36.7% for the eligible population, 56.1% for patients who underwent at least 1 HDCT, and 77.1% for those who had ≥2 cycles. The 2-year OS rate for patients not given HDCT was 0%. All patients had delays in protocol, and poor-risk patients had longer intervals from referral to protocol initiation (0.7 vs. 1.8 month, P < .01). CONCLUSION: Outcomes of patients who received ≥1 HDCT were encouraging; however, only 15 from 34 eligible patients were able to receive the planned 2 cycles of HDCT. Further strategies to minimize treatment delays in low- and middle-income countries are needed.

Immunological signatures unveiled by integrative systems vaccinology characterization of dengue vaccination trials and natural infection.

Introduction: Dengue virus infection is a global health problem lacking specific therapy, requiring an improved understanding of DENV immunity and vaccine responses. Considering the recent emerging of new dengue vaccines, here we performed an integrative systems vaccinology characterization of molecular signatures triggered by the natural DENV infection (NDI) and attenuated dengue virus infection models (DVTs). Methods and results: We analyzed 955 samples of transcriptomic datasets of patients with NDI and attenuated dengue virus infection trials (DVT1, DVT2, and DVT3) using a systems vaccinology approach. Differential expression analysis identified 237 common differentially expressed genes (DEGs) between DVTs and NDI. Among them, 28 and 60 DEGs were up or downregulated by dengue vaccination during DVT2 and DVT3, respectively, with 20 DEGs intersecting across all three DVTs. Enriched biological processes of these genes included type I/II interferon signaling, cytokine regulation, apoptosis, and T-cell differentiation. Principal component analysis based on 20 common DEGs (overlapping between DVTs and our NDI validation dataset) distinguished dengue patients by disease severity, particularly in the late acute phase. Machine learning analysis ranked the ten most critical predictors of disease severity in NDI, crucial for the anti-viral immune response. Conclusion: This work provides insights into the NDI and vaccine-induced overlapping immune response and suggests molecular markers (e.g., IFIT5, ISG15, and HERC5) for anti-dengue-specific therapies and effective vaccination development.