In the case of donor/recipient rhesus (Rh)-incompatibility after allogeneic hematopoietic stem cell transplantation (alloHSCT), the transfusion policy in France is to transfuse red blood cells (RBC) in the donor's Rh phenotype from the day of transplantation, leading to a risk of allo-immunization, either of donor or recipient origin. In this single-center retrospective study, the incidence of donor/recipient Rh incompatibility was 7.1% over an 8-year period including 1012 alloHSCT. Six of 58 evaluable patients (10.3%) developed alloantibodies to RBC antigens within one year of alloHSCT. None of these allo-immunizations were directed against the donor-mismatched Rh antigens and none could have been prevented by the transfusion of recipient and donor Rh-compatible RBC units. None of these allo-immunizations led to immune-mediated hemolytic anemia. We observed a statistically significant higher incidence of chronic GVHD among patients with anti-RBC allo-immunization. In the context of donor/recipient Rh incompatibility, the transfusion of packed RBC units in the donor's Rh phenotype from the day of alloHSCT is feasible and not associated with a high risk of allo-immunization. The generalization of this strategy could be discussed even when donor and recipient Rh phenotypes could be respected, to allow the preservation of units of infrequent phenotypes for other indications.
Acute graft-versus-host disease (aGVHD) remains a barrier to successful allogeneic hematopoietic stem cell transplantation (HSCT) outcomes. Contemporary comprehensive analyses of real-world clinical outcomes among patients who develop aGVHD post-HSCT are needed to better understand the unmet needs of this patient population. This multicenter, retrospective chart review describes treatment patterns and clinical outcomes among patients (≥18 years old) from Finland, Sweden, and France who developed grades II-IV aGVHD after their first HSCT (January 2016-June 2017). From 13 participating centers, 151 patients were included. The median (Q1, Q3) age at HSCT was 56 (45, 62) years old. One line of aGVHD treatment was received by 47.7%, and the most common first-line treatment was methylprednisolone (alone or in a combination regimen, 74.2%; monotherapy, 25.8%). Among patients treated with methylprednisolone, 79.5% achieved a complete or partial response. The median (Q1, Q3) number of treatment lines was 2.0 (1.0, 3.0). The median (Q1, Q3) time to obtain an aGVHD diagnosis from transplant was 29.5 (21.0, 44.0) days, and 14.5 (7.0, 34.0) days to achieve the best response for 110 evaluable patients. At 6 and 12 months, 53.6% and 49.0%, respectively, achieved a complete response. Chronic GVHD occurred in 37.7% of patients, and aGVHD reoccurred in 26.5%. Following aGVHD diagnosis, mortality rates were 30.0% at 6 months and 37.3% at 12 months. Findings from this study demonstrate a continuing unmet need for new therapies that control aGVHD and improve mortality.
INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disease of hematopoietic cells with a variable clinical spectrum characterized by intravascular hemolysis, high risk of thrombosis, and cytopenias. To understand the biochemical shifts underlying PNH, this study aimed to search for the dysfunctional pathways involved in PNH physiopathology by comparing the systemic metabolic profiles of affected patients to healthy controls and the metabolomic profiles before and after the administration of eculizumab in PNH patients undergoing treatment. METHODS: Plasma metabolic profiles, comprising 186 specific annotated metabolites, were quantified using targeted quantitative electrospray ionization tandem mass spectrometry in 23 PNH patients and 166 population-based controls. In addition, samples from 12 PNH patients on regular eculizumab maintenance therapy collected before and 24 hours after eculizumab infusion were also analyzed. RESULTS: In the PNH group, levels of the long-chain acylcarnitines metabolites were significantly higher as compared to the controls, while levels of histidine, taurine, glutamate, glutamine, aspartate and phosphatidylcholines were significantly lower in the PNH group. These differences suggest altered acylcarnitine balance, reduction in the amino acids participating in the glycogenesis pathway and impaired glutaminolysis. In 12 PNH patients who were receiving regular eculizumab therapy, the concentrations of acylcarnitine C6:1, the C14:1/C6 ratio (reflecting the impaired action of the medium-chain acyl-Co A dehydrogenase), and the C4/C6 ratio (reflecting the impaired action of short-chain acyl-Co A dehydrogenase) were significantly reduced immediately before eculizumab infusion, revealing impairments in the Acyl CoA metabolism, and reached levels similar to those in the healthy controls 24 hours after infusion. CONCLUSIONS: We demonstrated significant differences in the metabolomes of the PNH patients compared to healthy controls. Eculizumab infusion seemed to improve deficiencies in the acyl CoA metabolism and may have a role in the mitochondrial oxidative process of long and medium-chain fatty acids, reducing oxidative stress, and inflammation.
Hemoglobinuria, Paroxysmal , Thrombosis , Humans , Hemoglobinuria, Paroxysmal/drug therapy , Hemolysis , Oxidoreductases , Acyl Coenzyme A
BACKGROUND: Human parvovirus B19 (B19V) infection is associated with pure red cell aplasia (PRCA) in immunocompromised patients; however, the spectrum of manifestations associated with B19V in allogeneic hematopoietic stem cell transplantation recipients (alloHSCT) has rarely been reported. METHODS: In this study, we aimed to report clinical and immune features of B19V infection after alloHSCT. We retrospectively collected and analyzed clinical and microbiological data of all transplanted patients with B19V DNAmia or tissue infection detected by polymerase chain reaction (PCR) in our center from 2010 to 2021. RESULTS: We report 35 cases of B19V infections in 33 patients. Median time from transplant to B19V first PCR positivity was 6.9 months (interquartile range (IQR) [1.6-18.9]). No preferential immune profile, type of transplantation or conditioning was identified. Hematological impairment was the most frequent sign, followed by rash and fever. Unconventional clinical forms were also detected, such as acute myelitis and myositis. For some cases, the direct relationship between symptoms and B19V infection was difficult to prove but was suggested by targeted tissue PCR positivity. When hematological impairment was not at the forefront, reticulocytopenia helped to diagnose B19V infections. Treatment was mainly based on high dose intravenous immunoglobulin. CONCLUSION: Although hematological impairment was the most frequent sign, B19V can affect multiple targets and lead to atypical manifestations. Because of its heterogeneous clinical presentation, B19V infection is likely under-diagnosed. Diagnosis of unusual B19V organ involvement needs combination of arguments which can include targeted tissue PCR.
Erythema Infectiosum , Hematopoietic Stem Cell Transplantation , Parvoviridae Infections , Parvovirus B19, Human , Humans , Erythema Infectiosum/complications , Retrospective Studies , Parvovirus B19, Human/genetics , DNA, Viral/analysis , Hematopoietic Stem Cell Transplantation/adverse effects , Stem Cell Transplantation
Early administration of azithromycin after allogeneic hematopoietic stem cell transplantation was shown to increase the relapse of hematological malignancies. To determine the impact of azithromycin on the post-transplant gut ecosystem and its influence on relapse, we characterized overtime gut bacteriome, virome, and metabolome of 55 patients treated with azithromycin or a placebo. We describe four enterotypes and the network of associated bacteriophage species and metabolic pathways. One enterotype associates with sustained remission. One taxon from Bacteroides specifically associates with relapse, while two from Bacteroides and Prevotella correlate with complete remission. These taxa are associated with lipid, pentose, and branched-chain amino acid metabolic pathways and several bacteriophage species. Enterotypes and taxa associate with exhausted T cells and the functional status of circulating immune cells. These results illustrate how an antibiotic influences a complex network of gut bacteria, viruses, and metabolites and may promote cancer relapse through modifications of immune cells.
Azithromycin , Hematologic Neoplasms , Humans , Ecosystem , Neoplasm Recurrence, Local , T-Lymphocytes
Human adenoviruses (HAdVs) of the F species are commonly responsible for acute gastroenteritis. A few cases of systemic infections have been described in adults or children who have received a hematopoietic stem cell transplant (HSCT), but with no report of liver cytolysis. Since January 2022, several countries have reported an increase in cases of acute hepatitis of unknown cause in children. Adenovirus species F type 41 (HAdV-F41) infection was predominantly identified. The objective of this study is to describe HAdV-F41 infections diagnosed since January 2022 in adult HSCT recipients in two French hospitals. All four patients had diarrhea and liver cytolysis at the time of diagnosis of infection. HAdV viremia was observed in three patients (#1, #3, and #4), but no disseminated disease was reported. HAdV whole genome sequencing and metagenomics characterization were performed on stool and blood samples. The complete HAdV-F41 genome sequence was obtained for three patients and phylogenetic analysis showed that the strains consisted of similar lineage (2b). We did not identify any new HAdV-F41 strains. Metagenomics analysis found adeno-associated virus 2 and torque-teno virus infection in patient #1 and Epstein-Barr virus in patient #4. This is the first case series reporting liver cytolysis during HAdV-F41 infection in adult HSCT patients.
Adenoviridae Infections , Adenoviruses, Human , Epstein-Barr Virus Infections , Hematopoietic Stem Cell Transplantation , Child , Adult , Humans , Phylogeny , Herpesvirus 4, Human , Hematopoietic Stem Cell Transplantation/adverse effects , Liver
BACKGROUND: Advanced-stage cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and fatal diseases. Case series have suggested that allogeneic haematopoietic stem cell transplantation (HSCT) might improve the prognosis of advanced-stage CTCLs. The objective of this study was to investigate the effect of allogeneic HSCT compared with non-HSCT therapy on the outcome of individuals with advanced-stage CTCLs. METHODS: In this prospective, multicentre, matched controlled trial, conducted at 30 hospitals, participants with advanced CTCLs were allocated treatment: if they had an available compatible related donor they were assigned to allogeneic HSCT, or if not they were allocated to non-allogeneic HSCT therapy. Key inclusion criteria were participants aged 18-70 years, with advanced stage mycosis fungoides or Sézary syndrome, and at least one poor prognostic criteria. Participants were excluded if they were not in complete or partial remission of the disease. Propensity score 1:1 matching with replacement (ie, that each participant treated with HSCT was matched to the participant with the closest propensity score treated with non-HSCT therapy, even if they had already been matched) was used to handle confounding factors, with the balance of covariate distribution between HSCT and non-HSCT groups assessed using standardised mean differences. The primary endpoint was progression-free survival in the matched intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02520908), and is currently active but not recruiting. FINDINGS: From June 1, 2016, to March 3, 2022, total of 99 participants were enrolled at 17 centres in France. Participants with a sibling or matched unrelated donor were assigned to allogeneic HSCT (HSCT group, n=55 [56%]) and participants without a donor were assigned to non-allogeneic HSCT treatment (non-HSCT group, n=44 [44%]). The median follow-up among survivors was 12·6 months (IQR 11·0-35·2). In the HSCT group, 51 participants (93%) were 1:1 matched to participants from the non-HSCT group. In the intention-to-treat analysis, median progression-free survival was significantly longer in the HSCT group (9·0 months [95% CI 6·6-30·5]) than in the non-HSCT group (3·0 months [2·0-6·3]), with a hazard ratio of 0·38 (95% CI 0·21-0·69; p<0·0001). In the per-protocol population, 40 participants (78%) in the HSCT group had 101 serious events and 29 participants (67%) in the non-HSCT group had 70 serious adverse events. The most common serious adverse event other than graft-versus-host disease in both groups was infections, occurring in 30 participants (59%) in the HSCT group and in 19 participants (44%) in the non-HSCT group. INTERPRETATION: Allogeneic HSCT was associated with significantly longer progression-free survival in participants with advanced-stage CTCLs. These results indicate that allogeneic HSCT treatment should be made available to individuals with high-risk, advanced-stage mycosis fungoides or Sézary syndrome who achieve pre-transplant disease remission. FUNDING: French Ministry of Health, National Cancer Institute, Programme Hospitalier de Recherche Clinique en Cancérologie.
Hematopoietic Stem Cell Transplantation , Lymphoma, T-Cell, Cutaneous , Mycosis Fungoides , Sezary Syndrome , Skin Neoplasms , Humans , Prospective Studies , Sezary Syndrome/therapy , Sezary Syndrome/etiology , Propensity Score , Lymphoma, T-Cell, Cutaneous/therapy , Lymphoma, T-Cell, Cutaneous/etiology , Transplantation, Homologous , Hematopoietic Stem Cell Transplantation/methods , Mycosis Fungoides/etiology , Mycosis Fungoides/pathology , Skin Neoplasms/therapy , Skin Neoplasms/etiology
Debates on the role and timing of allogeneic hemtopoietic stem cell transplantation (HSCT) in acute myelogenous leukemia (AML) have persisted for decades. Time to transplant introduces an immortal time and current treatment algorithm mainly relies on the European LeukemiaNet disease risk classification. Previous studies are also limited to age groups, remission status and other ill-defined parameters. We studied all patients at diagnosis irrespective of age and comorbidities to estimate the cumulative incidence and potential benefit or disadvantage of HSCT in a single center. As a time-dependent covariate, HSCT improved overall survival in intermediate- and poor-risk patients (hazard ratio =0.51; P=0.004). In goodrisk patients only eight were transplanted in first complete remission. Overall, the 4-year cumulative incidence of HSCT was only 21.9% but was higher (52.1%) for patients in the first age quartile (16-57 years old) and 26.4% in older patients (57-70 years old) (P<0.001). It was negligible in patients older than 70 years reflecting our own transplant policy but also barriers to transplantation (comorbidities and remission status). However, HSCT patients need to survive, be considered eligible both by the referring and the HSCT physicians and have a suitable donor to get transplantation. We, thus, comprehensively analyzed the complete decision-making and outcome of all our AML patients from diagnosis to last followup to decipher how patient allocation and therapy inform the value of HSCT. The role of HSCT in AML is shifting with broad access to different donors including haploidentical ones. Thus, it may (or may not) lead to increased numbers of allogeneic HSCT in AML in adults.
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Adult , Humans , Aged , Adolescent , Young Adult , Middle Aged , Transplantation, Homologous , Leukemia, Myeloid, Acute/therapy , Remission Induction , Proportional Hazards Models , Retrospective Studies
The real-world clinical and economic burden of graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation has not been comprehensively studied in France. Clinical outcomes, healthcare resource utilization and costs associated with acute GVHD (aGVHD), chronic GVHD (cGVHD), acute plus chronic GVHD (a+cGVHD) versus no GVHD were compared using French administrative claims data. After propensity score matching, 1934, 408, and 1268 matched pairs were retained for the aGVHD, cGVHD, and a+cGVHD cohorts, respectively. Compared with patients with no GVHD, odds of developing severe infection were greater in patients with aGVHD (odds ratio: 1.7 [95% confidence interval: 1.4, 2.1]). Compared with patients with no GVHD, mortality rates were higher in patients with aGVHD (rate ratio (RR): 1.6 [1.4, 1.7]) and with a+cGVHD (RR: 1.1 [1.0, 1.2]) but similar in patients with cGVHD (RR: 0.9 [0.7, 1.1]). Mean overnight hospital admission rates per patient-year were significantly higher in patients with aGVHD and a+cGVHD compared with no GVHD. Total direct costs (range 174,482-332,557) were 1.2, 1.5, and 1.9 times higher for patients with aGVHD, cGVHD, and a+cGVHD, respectively, versus patients with no GVHD. These results highlight the significant unmet need for effective treatments of patients who experience GVHD.
Bronchiolitis Obliterans Syndrome , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Humans , Financial Stress , Hematopoietic Stem Cell Transplantation/adverse effects , Treatment Outcome , Retrospective Studies
Weekly blood Toxoplasma gondii DNA screening using real-time quantitative polymerase chain reaction (qPCR) has been implemented in all allogeneic hematopoietic stem cell transplantation (alloHSCT) recipients at our hospital. We retrospectively analyzed the consequences of a positive blood qPCR in the management of Toxoplasma infection (TI) and disease (TD).From 2011 to 2020, 52 (4.13%) of 1 257 alloHSCT recipients had at least one positive qPCR, 45 (3.5%) with TI and seven (0.56%) with TD (central nervous system involvement). Forty-four patients were qPCR-positive before day 100, 30 without and 14 with anti-Toxoplasma prophylaxis. Twenty-five of them (56.8%) started or continued prophylactic dosage treatment: all became qPCR-negative, including 20 (80%) receiving only prophylactic dosage treatment. Twenty-four of them (54.5%) received non-prophylactic dosage treatment: qPCR became negative in 22/24 (91.7%), while TI contributed to death in two cases. Six of the eight patients diagnosed after D100 had breakthrough TI or TD. No death was attributable to TI or TD. qPCR kinetics available for 24 patients increased until anti-Toxoplasma treatment began, then decreased with all treatment regimens.Clinical follow-up and qPCR monitoring with quantification of the parasitic load appears a reasonable strategy to avoid TD and to use minimal effective dosage of anti-Toxoplasma treatments.
Hematopoietic Stem Cell Transplantation , Toxoplasma , Toxoplasmosis , Humans , Toxoplasma/genetics , Toxoplasmosis/diagnosis , Retrospective Studies , Real-Time Polymerase Chain Reaction
The coronavirus disease 2019 (COVID-19) pandemic indirectly resulted in missed therapeutic opportunities for many diseases. Here we focus on community-acquired respiratory viruses other than severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) [respiratory syncytial virus, parainfluenza and influenza A], and highlight the pandemics impact on clinical trials to develop novel therapies for other severe respiratory viral infections. We retrospectively reviewed inclusion rates within respiratory antiviral clinical trials in comparison with all other clinical trials in our clinical investigations center, before and during the COVID-19 pandemic. As opposed to the remaining clinical trials developed within our unit, respiratory antiviral trials inclusion rates did not recover after the initial recruitment decrease observed across all trials during the first pandemic wave. These results were discussed in the context of non-COVID-19 respiratory viral infection rates within our center, showing a general decline in seasonal respiratory viruses spread since the COVID-19 pandemic onset. Virus epidemiology changes upon the wide SARS-CoV-2 expansion as well as the lifestyle changes globally adopted to prevent SARS-CoV-2 transmission could have therefore contributed to the negative impact of the COVID-19 pandemic on antiviral drug development. Our study highlights the peculiarity of respiratory antiviral drug development during the COVID-19 pandemic era and describes potential explanations for such drug development halting.
COVID-19 , Respiratory Tract Infections , Viruses , Humans , COVID-19/epidemiology , Antiviral Agents/therapeutic use , Pandemics , SARS-CoV-2 , RNA, Viral , Retrospective Studies , Drug Development , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/epidemiology
Bronchiolitis obliterans syndrome (BOS) after allogeneic HSCT is the only formally recognized manifestation of lung chronic graft-versus-host disease (GVHD). Other lung complications were reported, including interstitial lung diseases (ILDs). Whether ILDs belong to the spectrum of lung cGVHD remains unknown. We compared characteristics and specific risk factors for both ILD and BOS. Data collected from consecutive patients diagnosed with ILD or BOS from 1981-2019 were analyzed. The strength of the association between patient characteristics and ILD occurrence was measured via odds ratios estimated from univariable logistic models. Multivariable models allowed us to handle potential confounding variables. Overall survival (OS) was estimated using the Kaplan-Meier method. 238 patients were included: 79 with ILD and 159 with BOS. At diagnosis, FEV1 was lower in patients with BOS compared to patients with ILD, while DLCO was lower in ILD. 84% of ILD patients received systemic corticosteroids, leading to improved CT scans and pulmonary function, whereas most BOS patients were treated by inhaled corticosteroids, with lung-function stabilization. In the multivariable analysis, prior thoracic irradiation and absence of prior treatment with prednisone were associated with ILD. OS was similar, even if hematological relapse was more frequent in the ILD group. Both complications occurred mainly in patients with GVHD history.
Bronchiolitis Obliterans Syndrome , Bronchiolitis Obliterans , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Lung Diseases, Interstitial , Lung Transplantation , Humans , Bronchiolitis Obliterans/etiology , Bronchiolitis Obliterans/diagnosis , Lung , Lung Diseases, Interstitial/complications , Graft vs Host Disease/therapy , Adrenal Cortex Hormones/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Lung Transplantation/adverse effects , Retrospective Studies
In the past 65 years, over 25 000 referenced articles have been published on graft-versus-host disease (GVHD). Although this included clinically orientated papers or publications on chronic GVHD, the conservative estimate of scientific publications still contains several thousands of documents on the pathophysiology of acute GVHD. Thus, summarizing what we believe are prominent publications that can be considered milestones in our knowledge of this disease is a challenging and inherently biased task. Here we review from a historical perspective what can be regarded as publications that have made the field move forward. We also included several references of reviews on aspects we could not cover in detail.
Bronchiolitis Obliterans Syndrome , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Humans , Publications
Reproducibility crisis urge scientists to promote transparency which allows peers to draw same conclusions after performing identical steps from hypothesis to results. Growing resources are developed to open the access to methods, data and source codes. Still, the computational environment, an interface between data and source code running analyses, is not addressed. Environments are usually described with software and library names associated with version labels or provided as an opaque container image. This is not enough to describe the complexity of the dependencies on which they rely to operate on. We describe this issue and illustrate how open tools like Guix can be used by any scientist to share their environment and allow peers to reproduce it. Some steps of research might not be fully reproducible, but at least, transparency for computation is technically addressable. These tools should be considered by scientists willing to promote transparency and open science.
Background & Aims: Liver sinusoidal obstruction syndrome (SOS) is a well-established complication of myeloablative conditioning regimens used in hematopoietic stem cell transplantation. Hepatic venous pressure gradient (HVPG) >10 mmHg was described as an accurate diagnostic tool for SOS in the 1990s. However, epidemiology and presentation of SOS have dramatically changed. Moreover, elementary histological lesions influencing HVPG are unknown. Methods: We retrospectively analyzed the charts of all patients who underwent transjugular liver biopsy with HVPG measurement for a clinical suspicion of SOS at our center. Two expert pathologists unaware of the presence or absence of SOS reviewed all liver samples and graded elementary histological lesions according to a semi-quantitative scoring defined a priori. Results: Out of the 77 included patients, the 30 patients with SOS had higher HVPG than the 47 patients without SOS (median 14 mmHg [IQR 10-18], vs. 6 mmHg [3-9], respectively p <0.001). HVPG >10 mmHg had a specificity of 78% and a positive predictive value of 66% for the diagnosis of SOS. However, almost 40% of the patients with SOS had an HVPG ≤10 mmHg. HVPG correlated with sinusoidal congestion (r = 0.57; p = 0.001) and hepatocyte necrosis (r = 0.42; p = 0.02), but not with other lesions. Conclusion: Even though HVPG is higher in patients with SOS, low HVPG values do not rule out SOS. Thus, HVPG cannot be used alone, and should be combined with transjugular liver biopsy, for the diagnosis of SOS. Lay summary: Hepatic venous pressure gradient >10 mmHg has been described as an accurate tool for the diagnosis of liver sinusoidal obstruction syndrome after hematopoietic stem cell transplantation. This study shows that the sensitivity and specificity of hepatic venous pressure gradient measurement for sinusoidal obstruction syndrome are insufficient, so that liver pressure measurement should be combined with a liver biopsy in this setting.
