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Population-based studies and case reports suggest that there may be an increased risk of acute leukemia associated with sickle cell disease (SCD). Following the description of a new case report, an extensive review of the literature identified 51 previously described cases. Most cases study showed myelodysplastic features confirmed, when available, by genetic markers such as chromosome 5 and/or chromosome 7 abnormalities and TP53 gene mutations. The increased risk of leukemogenesis is certainly multifactorial and related to the pathophysiologic mechanisms of the clinical manifestations of SCD. Chronic hemolysis and secondary hemochromatosis may cause increased chronic inflammation, resulting in persistent marrow stress, which could potentially compromise the genomic stability of the hematopoietic stem cells generating genomic damage and somatic mutations over the course of SCD and its treatment, resulting in a clone that led to acute myeloid leukemia., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after conditioning with a sequential association of fludarabine, amsacrine, and cytosine arabinoside (FLAMSA) followed by a reduced-intensity conditioning regimen has emerged for patients with high-risk acute myeloid leukemia (AML), especially in refractory or relapsing patients. Here we aimed to address retrospectively the impact of pretransplantation minimal residual disease (MRD) by flow cytometry on the outcomes of high-risk AML patients who underwent allo-HSCT after sequential FLAMSA-busulfan (FLAMSA-Bu)-based conditioning regimens. We included 165 high-risk AML patients who underwent transplantation after FLAMSA-BU in this retrospective single-center "real life" study. All patients received in vivo T cell depletion with antithymocyte globulin (5 mg/kg). MRD detection was based on a leukemia-associated immunophenotype using the European LeukemiaNet recommendations, with a threshold of .1%. Univariate and multivariate analyses were performed using R version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria). With a median follow-up of 4.0 years post-transplantation, the median overall survival (OS) was 54.9 months. Overall, 41 patients (24.8%) relapsed post-transplantation, with a resulting cumulative incidence of relapse (CIR) of 26.7% at 2 years and 34.0% at 5 years. Detectable MRD preceding allo-HSCT and refractory status were associated with worse median OS and CIR rates compared with patients without detectable MRD; however, OS was not significantly different between pre-HSCT MRD-positive and refractory patients (median, .7 year versus 2.0 years; P = .3). Conversely, pre-HSCT MRD negativity was associated with a reduced 2-year CIR. Neither European LeukemiaNet risk stratification nor age had a significant influence on OS. In the multivariate analysis, only pre-HSCT MRD positivity and lower conditioning regimen intensity were significantly associated with a poorer OS. The cumulative incidence of extensive chronic graft-versus-host disease at 2 years was 26.15%. The estimated nonrelapse mortality (NRM) of the entire cohort at 2 years was 23.1%, with age and unrelated donor identified as risk factors for higher NRM. Our data ahow that FLAMSA-Bu conditioning did not reverse the pejorative effect of detectable pre-HSCT MRD, suggesting that such patients should be offered alternative strategies before HSCT to reach deeper remission., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Class I Human Leukocyte Antigen (HLA) evolutionary divergence (HED) is a metric which reflects immunopeptidome diversity and has been associated with immune checkpoint inhibitor responses in solid tumors. Its impact and interest in allogeneic hematopoietic stem cell transplantation (HCT) have not yet been thoroughly studied. This study analyzed the clinical and immune impact of class I and II HED in 492 acute myeloid leukemia (AML) recipients undergoing HCT. The overall cohort was divided into a training (n=338) and a testing (n=132) set. Univariate cox screening found a positive impact of a high class I HED and a negative impact of a high class II HED on both disease-free (DFS) and overall survival (OS). These results were combined in a unique marker, class I/class II HED ratio, and assessed in the testing cohort. The final multivariate cox model confirmed the positive impact of a high versus low class I/class II HED ratio on both DFS (Hazard Ratio (HR) 0.41 [95% CI 0.2-0.83]; p=0.01) and OS (HR 0.34 [0.19-0.59]; p<0.001), independently of HLA matching and other HCT parameters. No significant association was found between the ratio and graft-versus-host disease (GvHD) nor with neutrophil and platelet recovery. A high class I HED was associated with a tendency for an increase in NK, CD8 T-cell, and B cell recovery at 12 months. These results introduce HED as an original and independent prognosis marker reflecting immunopeptidome diversity and alloreactivity after HCT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Daull, Dubois, Labussière-Wallet, Venet, Barraco, Ducastelle-Lepretre, Larcher, Balsat, Gilis, Fossard, Ghesquières, Heiblig, Ader and Alcazer.)

Acute myeloid leukemia (AML) intensive chemotherapy combined with broad-spectrum antibiotics, leads to gut microbiota dysbiosis promoting pathological conditions and an increased incidence of complications. Here we report findings from a phase II single-arm, multicenter study evaluating autologous fecal microbiota transfer (AFMT) in 25 AML patients treated with intensive chemotherapy and antibiotics (ClinicalTrials.gov number: NCT02928523). The co-primary outcomes of the study are to evaluate the efficacy of AFMT in dysbiosis correction and multidrug-resistant bacteria eradication. The main secondary outcomes are to define a dysbiosis biosignature, to evaluate the effect of dysbiosis correction on patient clinical status, to assess the short and mid-term safety of AFMT in this immunocompromised population, and to evaluate the feasibility of the AFMT procedure and acceptability by the patient. Intensive induction chemotherapy induces a dramatic decrease of α-diversity indices, and a microbial dysbiosis with a significant shift of the microbial communities and domination of pro-inflammatory families. After AFMT treatment, α-diversity indices return to their initial mean levels and the similarity index shows the restoration of microbial communities. The trial meets pre-specified endpoints. AFMT appears to be safe and may be effective for gut microbiota restoration in AML patients receiving intensive chemotherapy and antibiotics, with an excellent gut microbiota reconstruction based on both richness and diversity indices at the species level.

This study aims to evaluate the impact of implementing a specialized clinical pharmacy program in patients with allogeneic hematopoietic stem cell transplant (HSCT) on their adherence to the immunosuppression treatment after discharge. A prospective open interventional design using a retrospective control group was used. The intervention was based on pharmaceutical consultations: the first was performed the day before discharge of HSCT unit and the next consultations during day-care follow-up (weeks 2 and 4 after discharge). Proactive medication reconciliation was implemented with a complete list of medications before the discharge prescription. The discharge prescription summarized on a personalized drug schedule was explained to the patient. The importance of optimal adherence and the potential problems related to self-medication were explained to the patient. Immunosuppression drug adherence was assessed by a direct method using serum levels of calcineurin inhibitors. The potential impact on acute GvHD, and infection was investigated. Twenty-six patients were included in the specialized clinical pharmacy program and 35 patients were in the control group. Seventy-nine pharmaceutical consultations were conducted in the intervention group, lasting a mean 25 min and 16 min for the first and following consultations, respectively. Serum levels in the therapeutic target range were higher in the intervention group (61.5% versus 53.0%, p = 0.07), with greater intra-individual variation (p = 0.005). There was no significant intergroup difference in acute GvHD (53.8% versus 50.3%, p = 0.85) or infection (26.9 versus 22.8%, p = 0.72). The implementation of a specialized clinical pharmacy program for patients who have received allogeneic HSCT seems to be beneficial for immunosuppression drug adherence; this now needs to be confirmed in a multicenter study involving a larger number of patients.

Torque teno virus (TTV) has been proposed as a surrogate biomarker of T-cell function in allogeneic-haematopoietic-stem-cell transplantation (allo-HSCT). Conflicting data exists regarding the value of TTV to assess the degree of immunosuppression. The aim of the present study was to investigate the correlation between TTV viral load and immune function. Using samples from a prospective cohort composed of healthy-volunteers (HV) and allo-HSCT recipients at 6 months post-transplantation, we assessed the correlation between TTV viraemia and immune cell counts or T-cell proliferation capacity post-phytohaemagglutinin stimulation. TTV viraemia was detected in 68% of HV ( n = 80) and 100% of allo-HSCT recipients ( n = 41; p < 0.001); it was significantly higher in allo-HSCT recipients (3.9 vs. 2.1 Log copies/mL, p < 0.001). There was no correlation between T-cell function and CD3 + T-cell count (rho: 0.002) suggesting that T-cell count can normalise without full functional recovery. Furthermore, no significant correlation was observed between TTV viraemia and absolute total/subset lymphocyte counts (rho: <0.13). The highest correlation was observed between TTV viral load and T-cell proliferation capacity (rho: -0.39). We therefore report an inverse correlation between T-cell function and TTV viraemia that is independent of T-cell count. Monitoring of TTV viraemia could be a fast suitable option to objectively assess the competence of immune function in at-risk populations.

Data on immunogenicity and safety of the recommended revaccination schedule against diphtheria, tetanus, poliomyelitis, pertussis, Haemophilus influenzae type b (Hib), and hepatitis B in adult allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are limited. This prospective single-center cohort study (April 2014 to March 2018) included adult allo-HSCT recipients referred to a dedicated vaccinology consultation and vaccinated with the pediatric combined diphtheria, tetanus, acellular pertussis, hepatitis B virus, inactivated poliovirus, and Haemophilus influenzae type b (DTaP(±HB)-IPV-Hib) vaccine (3 doses 1 month apart, booster dose 1 year later). The proportion of responders to tetanus, diphtheria, Hib, and hepatitis B vaccine and geometric mean concentrations (GMCs) of antibodies were assessed before and up to 24 months after vaccination. A total of 106 patients were vaccinated at a median (interquartile range) time of 12.4 (10 to 18.4) months post-transplant. At 5.3 (4.8 to 6.6) and 23.1 (21.1 to 25.1) months after vaccine initiation, high and sustained rates of protective antibody titers were achieved for tetanus (97.8% [95% confidence interval (95% CI), 92.4% to 99.7%], n = 91/93 and 100% [95% CI, 92% to 100%], n = 44/44), diphtheria (94.6% [95% CI, 87.9% to 98.2%], n = 88/93 and 90.9% [95% CI, 78.3% to 97.5%], n = 40/44), Hib (96.6% [95% CI, 90.4% to 99.3%], n = 85/88 and 93% [95% CI, 80.9% to 98.5%], n = 40/43), and hepatitis B (83.5% [95% CI, 73.5% to 90.9%], n = 66/79 and 81.1% [95% CI, 64.8% to 92%], n = 30/37). Underlying disease, stem cell source, chronic graft-versus-host-disease, and extracorporeal photopheresis differentially influenced GMCs of tetanus, diphtheria, and hepatitis B antibodies after 3 doses but not in the long term (24 months). Six (5.7%) patients experienced mild side effects. The pediatric DTaP(±HB)-IPV-Hib vaccine was safe and effective in eliciting a sustained protective humoral response in adult allo-HSCT recipients. Hepatitis B revaccination might be optimized by using higher antigen doses., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Ninety-four adults with newly diagnosed or relapsed/refractory acute myeloid leukemia (AML) were treated with fractionated doses of gemtuzumab ozogamicin (GO) at one-single French center over ten years. We attempted to define predictive factors for response and survival. The overall response rate was 70% (86% in newly diagnosed and 65% in relapsed/refractory AML). Mortality during induction was 6%. Disease-free survival (DFS) and overall survival at three years after GO treatment was 36% and 31%, respectively. Median DFS in relapsed/refractory patients was eight months with a 3-year DFS at 34%. Among remitters, allogeneic hematopoietic stem cell transplantation (HSCT) can be performed in 28 cases (42%), including two patients in first-line therapy and 26 in further line. In relapsed/refractory patients undergoing allogeneic HSCT after responding to GO therapy, the median DFS was not reached. Incidences of transplant-related mortality, grade ≥ 3 acute graft-versus-host (GvH) disease, and extensive chronic GvH disease were 11%, 14%, and 25%, respectively. No sinusoidal obstruction syndromes were reported among allografted patients as among the other patients in the studied cohort. GO-based chemotherapy is a viable option for the treatment of relapsed/refractory AML patients and is a feasible schedule as a bridge to allogeneic transplant., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Programmed fork pausing is a complex process allowing cells to arrest replication forks at specific loci in a polar manner. Studies in budding yeast and other model organisms indicate that such replication fork barriers do not act as roadblocks passively impeding fork progression but rather elicit complex interactions between fork and barrier components. In this issue of Genes & Development , Shyian and colleagues (pp. 87-98) show that in budding yeast, the fork protection complex Tof1-Csm3 interacts physically with DNA topoisomerase I (Top1) at replication forks through the C-terminal domain of Tof1. Fork pausing at the ribosomal DNA (rDNA) replication fork barrier (RFB) is impaired in the absence of Top1 or in a tof1 mutant that does not bind Top1, but the function of Top1 can be partially compensated for by Top2. Together, these data indicate that topoisomerases play an unexpected role in the regulation of programmed fork pausing in Saccharomyces cerevisiae ., (© 2020 Larcher and Pasero; Published by Cold Spring Harbor Laboratory Press.)

Objectives: We previously reported the prognostic value of serum ferritin in younger patients with intermediate-risk acute myeloid leukemia (AML). The aims of this study were to confirm this finding in a larger cohort regardless of age and prognostic subgroups, to explore the expression and functional role of ferritin in AML cells as well as the regulation of serum ferritin levels in AML patients., Patients/materials/methods: Serum ferritin levels at diagnosis were collected in a cohort of 525 patients treated by intensive chemotherapy. In silico, in vitro, and in vivo analyses were conducted to assess the pattern of expression and functional role of FTH1 and FTL in AML., Results: We confirmed the independent prognostic value of serum ferritin. In transcriptomic databases, FTH1 and FTL were overexpressed in AML and leukemic stem cells compared to normal hematopoietic stem cells. The gene signature designed from AML patients overexpressing FTH1 revealed a significant enrichment in genes of the immune and inflammatory response including Nf-KB pathway, oxidative stress, or iron pathways. This gene signature was enriched in cytarabine-resistant AML cells in a patient-derived xenograft model. FTH1 protein was also overexpressed in patient's samples and correlated with the in vitro cytotoxic activity of cytarabine. Lastly, we demonstrated that chemotherapy induced an inflammatory response including a significant increase in serum ferritin levels between day 1 and 8 of induction chemotherapy that was blocked by dexamethasone., Conclusion: Ferritin is deregulated in most AML patients likely through inflammation, associated with chemoresistance, and could represent a new therapeutic target., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Carmustine shortage has led to an increase use of alternative conditioning regimens prior to autologous stem cell transplantation for the treatment of lymphoma, including Bendamustine-based (BeEAM). The aim of this study was to evaluate the safety of the BeEAM regimen in a large cohort of patients. A total of 474 patients with a median age of 56 years were analyzed. The majority of patients had diffuse large B-cell lymphoma (43.5%). Bendamustine was administered at a median dose of 197 mg/m 2 /day (50-250) on days-7 and -6. The observed grade 1-4 toxicities included mucositis (83.5%), gastroenteritis (53%), skin toxicity (34%), colitis (29%), liver toxicity (19%), pneumonitis (5%), and cardiac rhythm disorders (4%). Nonrelapse mortality (NRM) was reported in 3.3% of patients. Acute renal failure (ARF) was reported in 132 cases (27.9%) (G ≥2; 12.3%). Organ toxicities and death were more frequent in patients with post conditioning renal failure. In a multivariate analysis, pretransplant chronic renal failure, bendamustine dose >160 mg/m 2 and age were independent prognostic factors for ARF. Pretransplant chronic renal failure, hyperhydration volume, duration of hyperhydration, and etoposide dose were predictive factors of NRM. A simple, four-point scoring system can stratify patients by levels of risk for ARF and may allow for a reduction in the bendamustine dose to avoid toxicity. Drugs shortage may have dangerous consequences. Prospective, comparative studies are needed to confirm the toxicity/efficacy extents from this conditioning regimen compared to other types of high dose therapy., (© 2018 Wiley Periodicals, Inc.)

Introduction: Secondary acute myeloid leukemia (sAML) remains a therapeutic challenge. In elderly patients with AML, it is unclear whether sAML displays an inferior outcome compared with de novo AML., Patients and Methods: We studied AML with an antecedent of hematologic disease, treatment-related AML, or AML occurring concurrently to another malignancy in a single-center cohort of patients aged 70 and older with AML. The study included 169 patients who were compared with a cohort of patients with de novo AML, without any prior history of malignant disorders, seen during the same period of time., Results: Hematologic antecedents or presence of prior/concurrent solid malignancy did not impact complete remission rates and overall survival. In multivariate analysis, sAML appeared without independent prognostic value in the elderly., Conclusion: Our results support that sAML and de novo AML in elderly patients are not prognostically distinct entities. They should therefore not be considered separately when investigating outcomes and new treatment strategies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The Ku complex binds non-specifically to DNA breaks and ensures repair via NHEJ. However, Ku is also known to bind directly to telomeric DNA ends and its presence there is associated with telomere capping, but avoiding NHEJ. How the complex discriminates between a DNA break and a telomeric extremity remains unknown. Our results using a tagged Ku complex, or a chromosome end capturing method, in budding yeast show that yKu association with telomeres can occur at sites distant from the physical end, on sub-telomeric elements, as well as on interstitial telomeric repeats. Consistent with previous studies, our results also show that yKu associates with telomeres in two distinct and independent ways: either via protein-protein interactions between Yku80 and Sir4 or via direct DNA binding. Importantly, yKu associates with the new sites reported here via both modes. Therefore, in sir4Δ cells, telomere bound yKu molecules must have loaded from a DNA-end near the transition of non-telomeric to telomeric repeat sequences. Such ends may have been one sided DNA breaks that occur as a consequence of stalled replication forks on or near telomeric repeat DNA. Altogether, the results predict a new model for yKu function at telomeres that involves yKu binding at one-sided DNA breaks caused by replication stalling. On telomere proximal chromatin, this binding is not followed by initiation of non-homologous end-joining, but rather by break-induced replication or repeat elongation by telomerase. After repair, the yKu-distal portion of telomeres is bound by Rap1, which in turn reduces the potential for yKu to mediate NHEJ. These results thus propose a solution to a long-standing conundrum, namely how to accommodate the apparently conflicting functions of Ku on telomeres., Competing Interests: The authors have declared that no competing interests exist.