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1.
Azithromycin use and increased cancer risk among patients with bronchiolitis obliterans after hematopoietic cell transplantation
Cheng, G. S., Bondeelle, L., Gooley, T., He, Q., Jamani, K., Krakow, E. F., Flowers, M. E. D., de Latour, R. P., Michonneau, D., Socie, G., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Azithromycin exposure during the early phase of allogeneic hematopoietic cell transplantation (HCT) has been associated with an increased incidence of hematological relapse. We assessed the impact of azithromycin exposure on the occurrence of relapse or new subsequent neoplasm (SN) in patients with bronchiolitis obliterans syndrome (BOS) after HCT, who are commonly treated with azithromycin alone or in combination with other agents. In a retrospective study of BOS patients from two large allograft centers, the effect of azithromycin exposure on the risk of relapse or SN was estimated from a Cox model with a time-dependent variable for treatment initiation. The Cox model was adjusted on time-fixed covariates measured at cohort entry, selected for their potential prognostic value. Similar models were used to assess the exposure effect on the cause-specific hazard of relapse, SN, and death free of those events. Sensitivity analyses were performed using propensity score matching. Among 316 patients, 227 (71.8%) were exposed to azithromycin after BOS diagnosis. The corresponding adjusted hazard ratio in patients exposed to azithromycin versus unexposed was HR=1.51 (95% CI, 0.90 to 2.55) for relapse or SN, 0.82 (95% CI, 0.37 to 1.83) for relapse, and 2.00 (95% CI, 1.01 to 3.99) for SN. Patients exposed to azithromycin had a significantly lower cause-specific hazard of death free of neoplasm and relapse (adjusted HR= 0.54, 95%CI, 0.34 to 0.89). In conclusion, exposure to azithromycin after BOS after HCT was associated with an increased risk of SN but not relapse.
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Management of growth failure and growth hormone deficiency after pediatric allogeneic HSCT: Endocrinologists are of importance for further guidelines and studies
Lawitschka, A., Schwarze, P., Rovelli, A., Badoglio, M., Socie, G., Tichelli, A., Bauer, D., Rovo, A., Basak, G., Schoemans, H., et al
Pediatric hematology and oncology. 2019;:1-10
Abstract
Growth failure (GF) is a frequent problem after pediatric allogeneic hematopoietic stem cell transplantation (HSCT). Growth hormone deficiency (GHD) occurs in 20 to 85%, but published data on the efficacy of growth hormone treatment (GHT) are conflicting. Currently, there are no recommendations on screening for and treatment of GHD after HSCT. We aimed to describe the management of endocrine follow-up (FU)and details of GHT within European Society for Blood and Marrow Transplantation (EBMT) centers. In a retrospective questionnaire study, all EBMT centers performing pediatric HSCT were invited. Results were evaluated in correlation with the structure of endocrine aftercare (HSCT-clinicians and endocrinologists). The majority of centers (80%) reported endocrine FU by an endocrinologist - either within the HSCT-center or in a separate endocrine clinic. Fifty-four percent reported FU outside of the HSCT-center. As diagnostic tests the insulin-like growth factor IGF-I and insulin-like growth factor binding protein IGFBP3, insulin tolerance test and arginine stimulation test were most frequently used. Sixty-four percent of centers performed GHT and endocrinologists were more likely to prescribe GH (74%) compared to HSCT-clinicians (33%). The most frequent indication for GHT was GHD in 60%, with a distinct different approach of endocrinologists in comparison with HSCT-clinicians. Our study reveals substantial variation in practice and emphasizes the need for endocrine aftercare performed by dedicated endocrinologists in close collaboration with the HSCT-center. Our results indicate that the management of GHT depends on the structure of endocrine aftercare, which is important for the future development and distribution of studies and guidelines.
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3.
Incidence and outcome of Kaposi sarcoma after hematopoietic stem cell transplantation: a retrospective analysis and a review of the literature, on behalf of infectious diseases working party of EBMT
Cesaro, S., Tridello, G., van der Werf, S., Bader, P., Socie, G., Ljungman, P., McQuaker, G., Giardino, S., Uckan-Cetinkaya, D., Anagnostopoulos, A., et al
Bone marrow transplantation. 2019
Abstract
The incidence, the clinical characteristics, and the outcome of Kaposi sarcoma (KS) in patients after hematopoietic stem cell transplantation (HSCT) were assessed. During the period 1987-2018, 13 cases of KS were diagnosed, 3 females and 10 males, median age of 50 years, median time from HSCT of 7 months. KS had an incidence of 0.17% in allogeneic and 0.05% in autologous HSCT. HHV-8 was documented in eight of nine tumor tissue samples assessed. The organ involvement was: skin in nine, lymph nodes in six, oral cavity in four, and visceral in three patients, respectively; seven patients had >1 organ involved. Five patients had immunosuppression withdrawn, whereas four and three patients received radiotherapy and chemotherapy, respectively. Eight patients are alive (median follow-up 48 months, range 5-128), whereas five patients died after a median time of 8 months from the diagnosis of KS. However, no death was caused by KS. We conclude that the incidence of KS after HSCT is very low. Although KS can be managed with the reduction of immunosuppression, visceral forms may require chemotherapy and/or radiotherapy. The low prevalence of KS indicates that screening for HHV-8 serology and surveillance for HHV-8 viremia are not indicated in HSCT patients.
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Utility and safety of liver biopsy in patients with undetermined liver blood test anomalies after allogeneic hematopoietic stem cell transplantation, a monocentric retrospective cohort study
Ruggiu, M., Bedossa, P., Rautou, P. E., Bertheau, P., Plessier, A., de Latour, R. P., Robin, M., de Fontbrune, F. S., Pagliuca, S., Villate, A., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Liver blood test anomalies are common after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but their cause often remains difficult to identify. Our objective was to evaluate the safety and utility of liver biopsies in patients who underwent allo-HSCT. In a retrospective single center cohort study, we reviewed all cases of patients who underwent liver biopsy between June 2005 and July 2017. During this period, 54 biopsies were performed in 45 patients; 38 patients underwent allo-HSCT for malignant and seven for non-malignant hematological disorders. Median time between allo-HSCT and liver biopsy was 213 days. Seven biopsies were percutaneous and 47 transjugular. No adverse event related to the biopsy procedure occurred; 94.5% biopsies (51/54) led to identify a histological diagnose. Cholestatic graft versus host disease was histologically demonstrated in 16 biopsies (30%), hepatitis-like GvHD in nine biopsies (17%), non-alcoholic steatohepatitis in six biopsies (9%), regenerative nodular hyperplasia in four biopsies (5%), and drug-induced liver injury, sinusoidal obstruction syndrome and viral hepatitis each in three biopsies (5%). Association between clinical, laboratory, imaging and pathological features was poor. Only 34% of physicians' pre-biopsy hypotheses were confirmed by pathological findings. Patient management was influenced by liver biopsy results in 65% of cases, allowing us to identify a new diagnosis (n=13), rule out a differential diagnosis (n=14) or confirm the main hypothesis (n=6). In conclusion, liver biopsy is a safe and useful technique to investigate liver blood test anomalies following allo-HSCT.
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5.
European experience and risk factor analysis of donor cell-derived leukaemias/MDS following haematopoietic cell transplantation
Engel, N., Rovo, A., Badoglio, M., Labopin, M., Basak, G. W., Beguin, Y., Guyotat, D., Ljungman, P., Nagler, A., Schattenberg, A., et al
Leukemia. 2018
Abstract
Donor cell leukaemia (DCL) is a rare complication of allogeneic haematopoietic cell transplantation (HCT). We have investigated the prevalence and outcome of donor cell haematology malignancies within centres registered with the European Society of Blood and Marrow transplantation (EBMT). We have sought to identify risk factors to shed light on the pathogenesis of DCL as a model for leukaemogenesis. DCL cases were identified by questionnaire and a follow-up questionnaire requested detailed data. Control subjects from the EBMT registry who had not developed DCL were used for a matched pair analysis to identify risk factors. We identified 38 patients with DCL; the estimated prevalence was 80.5/100,000 transplants. Patients were predominantly treated for haematological malignancy. A clone was retrospectively identified in 7/25 (28%) donors for whom data was available. Overall survival was poor with 29/38 patients dead a median of 11 (range 0-91) months after DCL diagnosis. Matched case-pair analysis identified three factors on multivariate analysis as significantly associated with an increased risk for DCL: use of growth factors within the first 100 days after transplantation, in vivo T-cell depletion and multiple allografts. The risk factors identified, support reduced immune surveillance and replicative stress as pathogenic in the development of DCL.
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6.
Noninfectious lung complications after allogeneic haematopoietic stem cell transplantation
Bergeron, A., Chevret, S., de Latour, R. P., Chagnon, K., de Margerie-Mellon, C., Riviere, F., Robin, M., Mani, J., Lorillon, G., Socie, G., et al
The European respiratory journal. 2018
Abstract
Epidemiological data on late noninfectious pulmonary complications (LONIPCs) following allogeneic haematopoietic stem cell transplantation (HSCT) are derived exclusively from retrospective studies and conflicting. We aimed to evaluate prospectively their incidence, risk factors and outcomes.All consecutive patients scheduled to receive allogeneic HSCT between 2006 and 2008, at the university-teaching Saint Louis Hospital (Paris, France) were screened for inclusion. Eligible patients were those surviving at day 100. Among 243 screened patients, 198 patients were included in the analysis. The median follow-up was 72.3 months [IQR: 15.2-88.5]. Fifty-five LONIPCs were diagnosed in 43 patients. Bronchiolitis obliterans syndrome (n=22) andinterstitial lung disease (n=12) were the most common LONIPC. At 36 months after inclusion, the estimated cumulative incidence of LONIPCs was 19.8% (95% CI: 14.2-25.3%). The estimated median survival after the diagnosis of LONIPCs was 78.5 months (95% CI: 20.0-not reached). Based on a multivariable Cox model, a history of chest irradiation anytime prior to HSCT, a history of pneumonia within the 100 days post-HSCT and a low mean forced expiratory flow between 25% and 75% of forced vital capacityat day 100 were associated with the development of LONIPCs.Our data provide clues to identify patients at high risk of LONIPCs. These patients should be targeted for close monitoring to provide earlier LONIPC treatment or prophylactic treatment.
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7.
Evaluation of Second Solid Cancers After Hematopoietic Stem Cell Transplantation in European Patients
Tichelli, A., Beohou, E., Labopin, M., Socie, G., Rovo, A., Badoglio, M., van Biezen, A., Bader, P., Duarte, R. F., Basak, G., et al
JAMA oncology. 2018
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Abstract
Importance: Incidence and risk factors of second solid cancers (SSCs) that occur after hematopoietic stem cell transplantation (HSCT) are well documented. However, clinical outcome data of patients who developed an SSC after HSCT are limited. Objective: To assess the outcome of patients with an SSC occurring after HSCT from the time of SSC diagnosis. Design, Setting, and Participants: This cohort study used data of 4065 patients from 26 countries registered with the European Society for Blood and Marrow Transplantation, which has maintained clinical data since 1977 of patients who received a transplant. Information from all patients who underwent a transplant in Europe and had an SSC diagnosis between January 1, 2000, and December 31, 2014, was extracted. The cohort included patients with 18 different cancers. Data analysis was conducted from September 3, 2017, to March 17, 2018. Main Outcomes and Measures: Median and 5-year age-standardized overall survival, causes of death, risk factor multivariate analysis using a clustered Cox proportional hazard regression model, and standardized mortality ratio were calculated for each of the 18 types of SSC. Results: In total, 220 617 patients underwent a transplant, of whom only 4065 (1.8%) patients with a second solid cancer after HSCT were included in the study. Among the 4065 patients, 2321 (57.1%) were men and 1744 (42.9%) were women, with a mean (range) age of 59.1 (3.2-82.3) years at diagnosis of second solid cancer. The 5-year age-standardized overall survival was 47% (95% CI, 45%-49%). The 5-year overall survival rate after SSC diagnosis was poor for pancreas, lung, hepatobiliary, esophageal, brain, and gastric cancers, with a median survival between 0.6 and 1 year. The 5-year overall survival was intermediate for endometrial, colorectal, sarcomas, ovarian, bladder, oropharyngeal, and kidney cancers, with a median survival between 2 and 10 years. The 5-year overall survival was more favorable for melanoma, breast, prostate, cervix, and thyroid cancers, with a median survival of 10 or more years. Additional transplant-associated factors for mortality for patients treated with allogeneic HSCT were age at transplant, donor type, conditioning regimen, and graft-vs-host disease. In total, 1777 patients (43.7%) died, of which 1256 (74.8%) were from SSC, 344 (20.5%) from primary disease, and 79 (4.7%) from other causes. Standardized mortality ratio was higher, compared with de novo solid cancers, for melanoma, prostate, breast, kidney, bladder, colorectal, and endometrial cancers but not for the other cancers. Conclusions and Relevance: The outcome of SSC is mainly dependent on the type of second cancer; thus, future studies should investigate the reasons the standardized mortality ratio is higher for some cancers to identify whether patients with these cancers should be treated differently and to help in screening and counseling patients who developed an SSC after HSCT.
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Late effects after hematopoietic stem cell transplantation for beta-thalassemia major: the French national experience
Rahal, I., Galambrun, C., Bertrand, Y., Garnier, N., Paillard, C., Frange, P., Pondarre, C., Dalle, J. H., Peffault de Latour, R., Michallet, M., et al
Haematologica. 2018
Abstract
In this retrospective study, we evaluate long-term complications in nearly all beta-thalassemia-major patients who successfully received, in France, allogeneic hematopoietic stem cell transplantation. 99 patients were analysed with a median age of 5.9 years at transplantation. The median duration of clinical follow-up was 12 years. All conditioning regimen were myeloablative, most often based on busulfan combined with cyclophosphamide and more than 90% of patients underwent a transplant from a matched sibling donor. After transplantation, 11% of patients developed thyroid dysfunction, 5% diabetes and 2% heart failure. Hypogonadism was present in 56% of females and 14% of males. Female patients who developed normal puberty after transplant were significantly younger at transplantation than those who experienced delayed puberty (median age 2.5 versus 8.7 years). Fertility was preserved in 9/27 females aged 20 and above and 2 other patients became pregnant following oocyte donation. In addition to patient's age and higher serum ferritin levels at transplantation, time elapsed since transplant was significantly associated with decreased height growth in multivariate analysis. Weight growth increased after transplantation particularly in females, 36% of adults being overweight at last evaluation. A comprehensive long-term monitoring especially of endocrine late-effects is required after hematopoietic stem cell transplantation for thalassemia.
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9.
Late treatment-related mortality versus competing causes of death after allogeneic transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia
Schetelig, J., de Wreede, L. C., van Gelder, M., Koster, L., Finke, J., Niederwieser, D., Beelen, D., Mufti, G. J., Platzbecker, U., Ganser, A., et al
Leukemia. 2018
Abstract
The causes and rates of late patient-mortality following alloHCT for myelodysplastic syndromes or secondary acute myeloid leukemia were studied, to assess the contribution of relapse-related, treatment-related, and population factors. Data from EBMT on 6434 adults, who received a first alloHCT from January 2000 to December 2012, were retrospectively studied using combined land-marking, relative-survival methods and multi-state modeling techniques. Median age at alloHCT increased from 49 to 58 years, and the number of patients aged ≥65 years at alloHCT increased from 5 to 17%. Overall survival probability was 53% at 2 years and 35% at 10 years post-alloHCT. Survival probability at 5 years from the 2-year landmark was 88% for patients <45-year old and 63% for patients ≥65-year old at alloHCT. Cumulative incidence of nonrelapse mortality (NRM) for patients <45-year old at transplant was 7% rising to 25% for patients aged ≥65. For older patients, 31% of NRM-deaths could be attributed to population mortality. Favorable post-alloHCT long-term survival was seen; however, excess mortality-risk for all age groups was shown compared to the general population. A substantial part of total NRM for older patients was attributable to population mortality, information which aids the balanced explanation of post-HCT risk and helps improve long-term care.
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10.
Effect of Azithromycin on Airflow Decline-Free Survival After Allogeneic Hematopoietic Stem Cell Transplant: The ALLOZITHRO Randomized Clinical Trial
Bergeron, A., Chevret, S., Granata, A., Chevallier, P., Vincent, L., Huynh, A., Tabrizi, R., Labussiere-Wallet, H., Bernard, M., Chantepie, S., et al
JAMA. 2017;318(6):557-566
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Abstract
Importance: Bronchiolitis obliterans syndrome has been associated with increased morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). Previous studies have suggested that azithromycin may reduce the incidence of post-lung transplant bronchiolitis obliterans syndrome. Objective: To evaluate if the early administration of azithromycin can improve airflow decline-free survival after allogeneic HSCT. Design, Setting, and Participants: The ALLOZITHRO parallel-group trial conducted in 19 French academic transplant centers and involving participants who were at least 16 years old, had undergone allogeneic HSCT for a hematological malignancy, and had available pretransplant pulmonary function test results. Enrollment was from February 2014 to August 2015 with follow-up through April 26, 2017. Interventions: Patients were randomly assigned to receive 3 times a week either 250 mg of azithromycin (n=243) or placebo (n=237) for 2 years, starting at the time of the conditioning regimen. Main Outcomes and Measures: The primary efficacy end point was airflow decline-free survival at 2 years after randomization. Main secondary end points were overall survival and bronchiolitis obliterans syndrome at 2 years. Results: Thirteen months after enrollment, the independent data and safety monitoring board detected an unanticipated imbalance across blinded groups in the number of hematological relapses, and the treatment was stopped December 26, 2016. Among 480 randomized participants, 465 (97%) were included in the modified intention-to-treat analysis (mean age, 52 [SD, 14] years; 75 women [35%]). At the time of data cutoff, 104 patients (22%; 54 azithromycin vs 50 placebo) had experienced an airflow decline; 138 patients (30%) died (78 azithromycin vs 60 placebo). Two-year airflow decline-free survival was 32.8% (95% CI, 25.9%-41.7%) with azithromycin and 41.3% (95% CI, 34.1%-50.1%) with placebo (unadjusted hazard ratio [HR], 1.3; 95% CI, 1.02-1.70; P=.03). Of the 22 patients (5%) who experienced bronchiolitis obliterans syndrome, 15 (6%) were in the azithromycin group and 7 (3%) in the placebo group (P=.08). The azithromycin group had increased mortality, with a 2-year survival of 56.6% (95% CI, 50.2%-63.7%) vs 70.1% (95% CI, 64.2%-76.5%) in the placebo group (unadjusted HR, 1.5; 95% CI, 1.1-2.0; P=.02). In a post hoc analysis, the 2-year cumulative incidence of hematological relapse was 33.5% (95% CI, 27.3%-39.7%) with azithromycin vs 22.3% (95% CI, 16.4%-28.2%) with placebo (unadjusted cause-specific HR, 1.7; 95% CI, 1.2-2.4; P=.002). Conclusions and Relevance: Among patients undergoing allogeneic HSCT for hematological malignancy, early administration of azithromycin resulted in worse airflow decline-free survival than did placebo; these findings are limited by early trial termination. The potential for harm related to relapse requires further investigation. Trial Registration: clinicaltrials.gov Identifier: NCT01959100.