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Decrease of lethal infectious complications in the context of causes of death (COD) after hematopoietic cell transplantation: COD-2 and COD-1 study of the Infectious Diseases Working Party EBMT

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We previously analyzed trends in incidence and factors associated with lethal complications in ALL/AML/CML patients (causes of deaths; COD-1 study). The objective of this study was the analysis of incidence and specific causes of death after HCT, with focus on infectious deaths in two time periods, 1980–2001 (cohort-1) and 2002–2015 (cohort-2). All patients with HCT for lymphoma, plasma cell disorders, chronic leukemia (except CML), myelodysplastic/myeloproliferative disorders, registered in the EBMT-ProMISe-database were included (n = 232,618) (COD-2 study). Results were compared to those in the ALL/AML/CML COD-1 study. Mortality from bacterial, viral, fungal, and parasitic infections decreased in very early, early and intermediate phases. In the late phase, mortality from bacterial infections increased, while mortality from fungal, viral, or unknown infectious etiology did not change. This pattern was similar for allo- and auto-HCT in COD-1 and COD-2 studies, with a distinct and constant lower incidence of all types of infections at all phases, after auto-HCT. In conclusion, infections were the main cause of death before day +100, followed by relapse. Mortality from infectious deaths significantly decreased, except late phase. Post-transplant mortality has significantly decreased in all phases, from all causes after auto-HCT; it has decreased in all phases after allo-HCT except late phase.
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ARTICLE
Decrease of lethal infectious complications in the context of
causes of death (COD) after hematopoietic cell transplantation:
COD-2 and COD-1 study of the Infectious Diseases Working
Party EBMT
Jan Styczynski
1
, Gloria Tridello
2,3
, Linda Koster
3
, Nina Knelange
3
, Lotus Wendel
3
, Anja van Biezen
3
, Stefe van der Werf
3
,
Malgorzata Mikulska
4
, Lidia Gil
5
, Catherine Cordonnier
6
, Per Ljungman
7
, Diana Averbuch
8
, Simone Cesaro
2
,
Helen Baldomero
9
, Christian Chabannon
10
, Selim Corbacioglu
11
, Harry Dolstra
12
, Bertram Glass
13
, Raffaella Greco
14
,
Nicolaus Kröger
15
, Régis Peffault de Latour
16
, Mohamad Mohty
17
, Benedicte Neven
18
, Zinaida Peric
19
, John A. Snowden
20
,
Anna Sureda
21
, Ibrahim Yakoub-Agha
22
and Rafael de la Camara
23
© The Author(s), under exclusive licence to Springer Nature Limited 2023
We previously analyzed trends in incidence and factors associated with lethal complications in ALL/AML/CML patients (causes of
deaths; COD-1 study). The objective of this study was the analysis of incidence and specic causes of death after HCT, with focus on
infectious deaths in two time periods, 19802001 (cohort-1) and 20022015 (cohort-2). All patients with HCT for lymphoma, plasma
cell disorders, chronic leukemia (except CML), myelodysplastic/myeloproliferative disorders, registered in the EBMT-ProMISe-
database were included (n=232,618) (COD-2 study). Results were compared to those in the ALL/AML/CML COD-1 study. Mortality
from bacterial, viral, fungal, and parasitic infections decreased in very early, early and intermediate phases. In the late phase,
mortality from bacterial infections increased, while mortality from fungal, viral, or unknown infectious etiology did not change. This
pattern was similar for allo- and auto-HCT in COD-1 and COD-2 studies, with a distinct and constant lower incidence of all types of
infections at all phases, after auto-HCT. In conclusion, infections were the main cause of death before day +100, followed by
relapse. Mortality from infectious deaths signicantly decreased, except late phase. Post-transplant mortality has signicantly
decreased in all phases, from all causes after auto-HCT; it has decreased in all phases after allo-HCT except late phase.
Bone Marrow Transplantation (2023) 58:881–892; https://doi.org/10.1038/s41409-023-01998-2
INTRODUCTION
Improvement in outcome of hematopoietic cell transplantation
(HCT) is a key factor in this eld of medicine. Outcome of HCT is
most often presented as overall survival (OS), disease-free survival
(DFS), event-free survival (EFS), relapse-free survival (RFS) or graft-
versus-host disease (GVHD)-free, relapse-free survival (GRFS) and is
determined by a variety of factors. OS is dependent mainly on two
factors: relapse-related mortality and treatment-related mortality
(TRM). Main causes of TRM include GVHD (after allogeneic HCT
only), infections, toxicity, and other/unknown causes. In the
Infectious Diseases Working Party (IDWP) of the European Society
for Blood and Marrow Transplantation (EBMT) study on causes of
Received: 20 December 2022 Revised: 15 April 2023 Accepted: 19 April 2023
Published online: 6 May 2023
1
Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Torun, Bydgoszcz, Poland.
2
Pediatric Hematology Oncology,
Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
3
EBMT Leiden Study Unit, Leiden, The Netherlands.
4
Division of Infectious Diseases,
University of Genoa (DISSAL) and Ospedale Policlinico San Martino, Genoa, Italy.
5
Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical
Sciences, Poznan, Poland.
6
Hôpital Henri Mondor, Assistance Publique-Hopitaux de Paris (AP-HP) and Paris-Est-Créteil University, Creteil, France.
7
Deptartment of Cellular Therapy
and Allogeneic Stem Cell Transplantation, Karolinska Comprehensive Cancer Center, Karolinska University Hospital Huddinge, Department of Medicine Huddinge, Karolinska
Institutet, Stockholm, Sweden.
8
Faculty of Medicine, Hebrew University of Jerusalem, Pediatric Infectious Diseases, Hadassah Medical Center, Jerusalem, Israel.
9
EBMT Activity
Survey Ofce, Hematology, Department of Medicine, University Hospital, Basel, Switzerland.
10
Institut Paoli Calmettes Comprehensive Cancer Center and Inserm CBT-1409,
Centre dInvestigations Cliniques en Biothérapies, Marseille, France.
11
Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Regensburg,
Regensburg, Germany.
12
Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
13
Klinik für
Hämatologie und Stammzelltransplantation, HELIOS Klinikum Berlin-Buch, Berlin, Germany.
14
Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientic
Institute, Vita-Salute San Raffaele University, Milan, Italy.
15
Department of Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany.
16
BMT Unit, Department
of Hematology, Hospital St. Louis, Paris, France.
17
Department of Hematology, Hospital Saint Antoine, Sorbonne University, INSERM UMRs938, Paris, France.
18
Pediatric Immune-
Hematology Unit, Necker Children Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
19
School of Medicine, University of Zagreb, University Hospital Center Zagreb,
Zagreb, Croatia.
20
Department of Haematology, Shefeld Teaching Hospitals NHS Foundation Trust, Shefeld, UK.
21
Clinical Hematology Department, Institut Català dOncologia-
Hospitalet, Institut dInvestigació Biomèdica de Bellvitge (IDIBELL), University of Barcelona, Barcelona, Spain.
22
CHU de Lille, Université de Lille, INSERM U1286, Innite, Lille,
France.
23
Hematology Department, Hospital de la Princesa, Madrid, Spain. email: jstyczynski@cm.umk.pl
www.nature.com/bmt
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... Despite the well-known infection risk in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), the early posttransplant mortality rate progressively decreased in recent years, thanks to the development of new antimicrobial agents for infection prophylaxis and treatment. 1 Invasive fungal infections (IFIs) are still one of the leading causes of infection-related morbidity among allo-HSCT recipients, raising TherapeuTic advances in infectious disease interest in implementation of antifungal prophylaxis (AFP). [2][3][4] In allo-HSCT setting, both yeasts and molds are potentially responsible for serious IFIs; therefore, a mold-active primary AFP is strongly recommended, particularly for patients at high risk for IFI. 5 The third European Conference on Infections in Leukemia (ECIL-3) proposed phase-specific recommendations for allo-HSCT according to the different risk factors for IFI in the pre-and post-engraftment period, as described by Gruppo Italiano Trapianto Midollo Osseo (GITMO). ...
Article
Full-text available
Background Invasive fungal infections (IFIs) represent a major cause of morbidity among allogeneic hematopoietic stem cell transplantation (allo-HSCT). Isavuconazole (ISA) is a broad-spectrum triazole with favorable safety profile. Objectives and design Herein, we evaluate the real life coadministration of ISA and sirolimus in allo-HSCT recipients in a single-center retrospective analysis, describing clinical efficacy, safety, and therapeutic drug monitoring (TDM) of both drugs. Methods All consecutive allo-HSCT recipients who received the coadministration of ISA and sirolimus for at least 2 weeks between July 2017 and December 2022 were included in this retrospective analysis. TDM was longitudinally performed during treatment. IFIs were classified according to the revised European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus criteria. Results A total of 51 recipients were included in the analysis. A total of 17 patients received ISA as continuous antifungal treatment for IFI diagnosed before transplant: one patient experienced a probable invasive pulmonary aspergillosis, and one patient switched from ISA to liposomal amphotericin B for a possible IFI. A total of 34 patients started ISA as antifungal therapy for IFI diagnosed after transplant. Sixteen of 34 were treated for a proven/probable breakthrough IFI during mold-active prophylaxis: 6/16 patients died for IFI after a median of 51 days of ISA. Eighteen of 34 started ISA as empirical therapy for a possible IFI: 15/18 patients were alive with resolution of infection after 6 weeks, 1 died for disease progression, and 2 had empirically changed antifungal therapy due to pneumonia progression. Clinical and radiological response rate was 68% after 90 days from IFI diagnosis. No toxicities related to drug–drug interaction have been registered in patients reaching concomitant therapeutic levels of ISA and sirolimus. Conclusion The coadministration of ISA and sirolimus was safe and feasible in this cohort, confirming favorable clinical efficacy in patients with multiple-drug coadministration.
... Two prognostic factors were related to ADV infection: clinical form of ADV manifestation, and time from HCT to ADV infection. Other factors identified are well-known associations of OS after allo-HCT, including BM as a more frequent source of stem cells in children than in adults, which may have influenced better survival in children [24]. ...
Article
Full-text available
The objective of the study was the analysis of clinical types, outcomes, and risk factors associated with the outcome of adenovirus (ADV) infection, in children and adults after allo-HCT. A total number of 2529 patients (43.9% children; 56.1% adults) transplanted between 2000 and 2022 reported to the EBMT database with diagnosis of ADV infection were analyzed. ADV infection manifested mainly as viremia (62.6%) or gastrointestinal infection (17.9%). The risk of 1-year mortality was higher in adults (p = 0.0001), and in patients with ADV infection developing before day +100 (p < 0.0001). The 100-day overall survival after diagnosis of ADV infections was 79.2% in children and 71.9% in adults (p < 0.0001). Factors contributing to increased risk of death by day +100 in multivariate analysis, in children: CMV seropositivity of donor and/or recipient (p = 0.02), and Lansky/Karnofsky score <90 (p < 0.0001), while in adults: type of ADV infection (viremia or pneumonia vs gastrointestinal infection) (p = 0.0004), second or higher HCT (p = 0.0003), and shorter time from allo-HCT to ADV infection (p = 0.003). In conclusion, we have shown that in patients infected with ADV, short-term survival is better in children than adults. Factors directly related to ADV infection (time, clinical type) contribute to mortality in adults, while pre-transplant factors (CMV serostatus, Lansky/Karnofsky score) contribute to mortality in children.
... Despite advances in supportive care, infections remain a significant cause of morbidity and mortality in the setting of HSCT (33,34). The resultant injury on the gastrointestinal epithelial barrier by chemotherapy (CT) or radiotherapy (RT), and the extensive use of antibiotics during the neutropenic phase, may lead to gut microbiota dysbiosis (35). ...
Article
Full-text available
Autoimmune diseases (ADs) represent a heterogeneous group of conditions affecting 5–10% of the global population. In recent decades, hematopoietic stem cell transplant (HSCT), mainly autologous, has been successfully adopted to treat patients affected by severe/refractory ADs. In this context malnutrition has a detrimental impact on relapse, mortality, infection rate, engraftment, long-term survival, and prolongation of hospitalization. However, in this population, the management of nutrition should be improved since nutritional assessment is partially performed in routine clinical practice. A panel of nurses and physicians from the European Society for Blood and Marrow Transplantation (EBMT) reviewed all available evidence based on current literature and expert practices from centers with extensive experience in HSCT for ADs, on the nutritional management of ADs patients during HSCT procedure. In this context, adequate nutritional status predicts a better response to treatment and improves quality of life. Herein, a systematic and comprehensive monitoring of nutritional status before, during and after HSCT, with adequate nutritional support in the case of ADs patients, in addition to assessing the dietary requirements associated with HSCT has been covered. Moreover, given the singularity of each AD, the underlying disease should be considered for an appropriate approach. The management and evaluation of nutritional status must be carried out by a multidisciplinary team to assess the needs, monitor the effectiveness of each intervention, and prevent complications, especially in complex situations as patients affected by ADs.
... Rituximab administered after HCT impacted the timing for vaccine administration, but did not modify responses to inactivated vaccines. Infections remain one of the most frequent direct causes for mortality and morbidity in HSCT recipients, and re-immunization is an useful strategy for vaccine-preventable diseases [23]. Reports of response rates in pediatric and adult HCT recipients after recommended primary vaccine series show high rates of protective titers for tetanus, diphteria, haemophilus influenzae type B, pertussis, and pneumococcus [24][25][26]. ...
Article
Full-text available
Myeloablative T cell depleted (CD34-selected) hematopoietic cell transplantation (HCT) is associated with less acute and chronic graft versus host disease (GVHD). We aimed to examine vaccine responses in relation to immune reconstitution and post HCT rituximab administration in this population. This single center retrospective study included 251 patients with hematological malignancies who received a first CD34-selected HCT between 2012 and 2015. Of 251 patients, 190 were alive 1 year after HCT. Among the entire population, 77 (30.7%) patients were vaccinated. After vaccine administration, 35/44 (80%), 30/75 (40%), 27/36 (75%), 33/65 (51%), 34/51 (51%), 22/28 (79%) and 20/34 (59%) of evaluable patients had protective antibody titers for haemophilus influenzae type B (Hib), Pneumococcus, Tetanus, Diphtheria, Pertussis, hepatitis A (HAV), and hepatitis B (HBV) respectively. Responders to the pneumococcal vaccine had a higher CD45RA T cell count than non responders, with 12/18 patients (66.7%) vs 11/32 (34.4%) p = 0.04. For pneumococcal vaccine, there was also a trend to higher total lymphocyte B cell count in responders vs non responders p = 0.06. Rituximab post HCT was given to 59/251 (23.5%) patients. No difference was found in immune reconstitution patterns for rituximab use between vaccine responders and not. Recipients of CD34-selected HCT may respond to vaccination, and T and B cell subsets could be useful to predict vaccine response.
Article
Background Prolonged periods of immunosuppression during hematopoietic stem cell transplant (HSCT) can result in serious infectious complications and contribute to transplant‐related morbidity and mortality. Adherence to standardized pre and postinfection screening guidelines, prescribed medications, and early identification of infectious symptoms through comprehensive patient and family education are crucial to minimizing infectious complications. Advanced practice nurses (APNs) are key members of the multidisciplinary care team in the HSCT specialty, maintaining a specialized skillset and scope of practice which includes a holistic based, preventative medicine and risk mitigation approach. Methods This review sought to describe the role of the APN in HSCT care and to further examine existing APN led models of care which focus on infection prevention and education throughout the HSCT treatment journey. Results No studies specifically examined the APN role in infectious diseases risk assessment, screening, and management throughout the HSCT journey were identified throughout our review, however, there was considerable evidence to demonstrate the benefits of APN led care in the oncology and solid organ transplantation specialty which led to improvements in continuity of care, overall patient outcomes, and multidisciplinary team collaboration. The key themes identified in our review, were the role of the APN in the delivery of comprehensive patient and family education, the role of the APN in supporting, mentoring, and educating junior medical and nursing teams, the collaboration between the APN and the multidisciplinary care team, and the role of the APN in prompt recognition, triage, and management of treatment related complications, such as infection.
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Hematopoietic cell transplant (HCT) and chimeric antigen receptor T-cell (CAR-T) therapy recipients are susceptible to multiple pulmonary complications that are caused by infectious and noninfectious processes. Numerous variables can be associated with specific pulmonary diseases including time from transplantation, presence of graft versus host disease (GVHD), underlying disease, and prolonged neutropenia and lymphocytopenia. Most pulmonary complications are infectious in origin, with bacterial pneumonia remaining the most common pulmonary infection, particularly before neutrophil engraftment. Invasive fungal infections continue to affect this patient population even when antifungal prophylaxis is used. Noninfectious pulmonary complications include a wide differential of pathologies in this population, and as clinical presentations of these various pulmonary disorders often overlap, clinicians frequently will use a multidisciplinary approach in diagnosing these abnormalities. Radiography, particularly with chest computed tomography (CT) imaging, is an essential tool in identifying pulmonary pathology and potential sources. While standard microbiological cultures of respiratory specimens are still utilized, their role is limited by low sensitivity and diagnostic yield. The likelihood of obtaining a diagnosis can be improved by using other microbiological assays, including fungal antigen tests and molecular diagnostic methods, particularly if specimens are collected via bronchoscopy. This review will highlight the more common causes of pulmonary diseases encountered after HCT and CAR-T and will examine the different methods in their diagnosis.
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Infections are still one of the most common causes of death after hematopoietic cell transplantation (HCT). Antimicrobial prophylaxis plays a crucial role in decreasing non-relapse mortality after HCT. The objective of this guideline paper was the presentation of current recommendations of antimicrobial prophylaxis for children and adults after hematopoietic cell transplantation, prepared in cooperation with Polish scientific hematological societies. Recommendations were prepared by the working group and finally approved by all 23 Polish transplant centers for children and adults. Existing (European Conference on Infections in Leukemia (ECIL) and European Society of Blood and Marrow Transplantation (EBMT) guidelines, as well as the results of a survey performed among all Polish transplant centers, were the background material for the working group. Recommendations are presented in sections dedicated to antibacterial prophylaxis, antifungal prophylaxis, antiviral prophylaxis, as well as prophylaxis of toxoplasmosis and infections with Pneumocystis jiroveci. Recommendations on the principles of vaccination against COVID-19 are provided based on the state of knowledge in September 2021. A section on guidelines of environmental prophylaxis is also presented. © 2021 The Polish Society of Haematologists and Transfusiologists, Insitute of Haematology and Transfusion Medicine.
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The Worldwide Network of Blood and Marrow Transplantation (WBMT) pursues the mission of promoting hematopoietic cell transplantation (HCT) for instance by evaluating activities through member societies, national registries and individual centers. In 2016, 82,718 first HCTs were reported from 1662 HCT teams in 86 of the 195 World Health Organization member states representing a global increase of 6.2% in autologous and 7.0% in allogeneic HCT and bringing the total to 1,298,897 procedures. Assuming a frequency of 84,000/year, 1.5 million HCTs had been performed by 2019 from 1957. Slightly more autologous (53.5%) than allogeneic and more related (53.6%) than unrelated HCTs were reported. A remarkable increase was noted in haploidentical related HCT for leukemias and lymphoproliferative diseases, but even more in non-malignant diseases. Transplant rates (TR; HCT/10 million population) varied according to region reaching 560.8 in North America, 438.5 in Europe, 76.7 in Latin America, 53.6 in South East Asia/Western Pacific (SEA/WPR) and 27.8 in African/East Mediterranean (AFR/EMR). Interestingly, haploidentical TR amounted to 32% in SEA/WPR and 26% in Latin America, but only 14% in Europe and EMR and 4.9% in North America of all allogeneic HCT. HCT team density (teams/10 million population) was highest in Europe (7.7) followed by North America (6.0), SEA/WPR (1.9), Latin America (1.6) and AFR/EMR (0.4). HCTs are increasing steadily worldwide with narrowing gaps between regions and greater increase in allogeneic compared to autologous activity. While related HCT is rising, largely due to increase in haploidentical HCT, unrelated is plateauing and cord blood in decline.
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Information on incidence, and factors associated with mortality is a prerequisite to improve outcome after hematopoietic stem cell transplantation (HSCT). Therefore, 55′668 deaths in 114′491 patients with HSCT (83.7% allogeneic) for leukemia were investigated in a landmark analysis for causes of death at day 30 (very early), day 100 (early), at 1 year (intermediate) and at 5 years (late). Mortality from all causes decreased from cohort 1 (1980–2001) to cohort 2 (2002–2015) in all post-transplant phases after autologous HSCT. After allogeneic HSCT, mortality from infections, GVHD, and toxicity decreased up to 1 year, increased at 5 years; deaths from relapse increased in all post-transplant phases. Infections of unknown origin were the main cause of infectious deaths. Lethal bacterial and fungal infections decreased from cohort 1 to cohort 2, not unknown or mixed infections. Infectious deaths were associated with patient-, disease-, donor type, stem cell source, center, and country- related factors. Their impact varied over the post-transplant phases. Transplant centres have successfully managed to reduce death after HSCT in the early and intermediate post-transplant phases, and have identified risk factors. Late post-transplant care could be improved by focus on groups at risk and better identification of infections of “unknown origin”.
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Children with bone marrow failure syndromes and severe aplastic anemia (SAA) are treated with allogeneic blood or marrow transplantation (BMT). However, there is a paucity of studies examining late mortality risk after allogeneic BMT performed in childhood for bone marrow failure syndromes and SAA and evaluating how this risk differs between these diseases. We investigated cause-specific late mortality in 2-year survivors of allogeneic BMT for bone marrow failure syndromes and SAA performed before age 22 years between 1974 and 2010 at 2 US transplantation centers. Vital status information was collected from medical records, the National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. The standardized mortality ratio (SMR) was calculated using age- sex-, and calendar-specific mortality rates from the Centers for Disease Control and Prevention. Among the 2-year survivors of bone marrow failure syndromes (n = 120) and SAA (n = 147), there were 15 and 19 deaths, respectively, yielding an overall survival of 86.4% for bone marrow failure syndromes and 93.1% for SAA at 15 years post-BMT. Compared with the general population, patients with bone marrow failure syndromes were at a higher risk for premature death (SMR, 22.7; 95% CI, 13.1 to 36.2) compared with those with SAA (SMR, 4.5; 95% CI, 2.8 to 7.0) (P <.0001). The elevated relative risk persisted at ≥15 years after BMT for both diseases. The hazard of all-cause late mortality was 2.9-fold (95% CI, 1.1 to 7.3) higher in patients with bone marrow failure syndromes compared with those with SAA. The high late mortality risk in recipients of allogeneic BMT in childhood for bone marrow failure syndromes calls for intensified life-long follow-up.
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Background: We analyzed late fatal infections (LFI) in allogeneic stem cell transplant (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. Methods: We analyzed the incidence, infection types and risk factors contributing to LFI in 10336 adult and 5088 pediatric subjects surviving ≥2 years after first HCT without relapse. Results: Among 2245 adult and 377 pediatric subjects who died, infections were a primary or contributory cause of death in 687(31%) and 110(29%) subjects, respectively. At 12 years post-HCT cumulative incidence of LFIs was 6.4 % (95% confidence interval[CI]:5.8-7.0%) in adults as compared with 1.8% (95%CI:1.4-2.3%) in pediatric subjects, p<0.001. In adults, the two most significant risks for developing LFI were increasing age (20-39, 40-54 and ≥ 55 vs 18-19 years) with hazard ratio (HR) of 3.12 (95%CI:1.33-7.32), 3.86 (95%CI:1.66-8.95) and 5.49 (95%CI:2.32-12.99) and a history of chronic GVHD (cGVHD) with ongoing immunosuppression 2 years post-HCT as compared to no history of GVHD with HR 3.87 (95%CI:2.59-5.78), respectively. In pediatric subjects, the three most significant risks for developing LFI were a history of cGVHD with (HR 9.49, 95%CI:4.39-20.51) or without (HR 2.7,95%CI:1.05-7.43) ongoing immunosuppression 2 years post-HCT as compared to no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function as compared to diagnosis of acute myeloid leukemia (AML) (HR 2.30, 95%CI:1.19-4.42) and age >10 years (HR 1.92, 95%CI:1.15-3.2). Conclusion: This study emphasizes the importance of continued vigilance for late infections after HCT and support strategies aimed to decrease the risk of cGVHD.
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Differences in major and minor histocompatibility antigens between donor and recipient trigger powerful graft-versus-host reactions after allogeneic hematopoietic stem cell transplantation (HSCT). The clinical effects of alloreactivity present a Janus face: detrimental graft-versus-host disease increases non-relapse mortality, beneficial graft-versus-malignancy may cure the recipient. The ultimate consequences on long-term outcome remain a matter of debate. We hypothesized that increasing donor-recipient antigen matching would decrease the negative effects, whilst preserving antitumor alloreactivity. We analyzed retrospectively a predefined cohort of 32 838 such patients and compared it to 59 692 patients with autologous HSCT as reference group. We found a significant and systematic decrease in non-relapse mortality with decreasing phenotypic and genotypic antigen disparity, paralleled by a stepwise increase in overall and relapse-free survival (Spearman correlation coefficients of cumulative excess event rates at 5 years 0.964; P<0.00; respectively 0.976; P<0.00). We observed this systematic stepwise effect in all main disease and disease-stage categories. The results suggest that detrimental effects of alloreactivity are additive with each step of mismatching; the beneficial effects remain preserved. Hence, if there is a choice, the best match should be donor of choice. Data support an intensified search for predictive genomic and environmental factors of 'no-graft-versus-host disease'.Leukemia accepted article preview online, 08 March 2017. doi:10.1038/leu.2017.79.
Article
The Worldwide Network of Blood and Marrow Transplantation (WBMT) pursues the mission of promoting hematopoietic cell transplantation (HCT) for instance by evaluating activities through member societies, national registries and individual centers. In 2016, 82,718 first HCTs were reported from 1662 HCT teams in 86 of the 195 World Health Organization member states representing a global increase of 6.2% in autologous and 7.0% in allogeneic HCT and bringing the total to 1,298,897 procedures. Assuming a frequency of 84,000/year, 1.5 million HCTs had been performed by 2019 from 1957. Slightly more autologous (53.5%) than allogeneic and more related (53.6%) than unrelated HCTs were reported. A remarkable increase was noted in haploidentical related HCT for leukemias and lymphoproliferative diseases, but even more in non-malignant diseases. Transplant rates (TR; HCT/10 million population) varied according to region reaching 560.8 in North America, 438.5 in Europe, 76.7 in Latin America, 53.6 in South East Asia/Western Pacific (SEA/WPR) and 27.8 in African/East Mediterranean (AFR/EMR). Interestingly, haploidentical TR amounted to 32% in SEA/WPR and 26% in Latin America, but only 14% in Europe and EMR and 4.9% in North America of all allogeneic HCT. HCT team density (teams/10 million population) was highest in Europe (7.7) followed by North America (6.0), SEA/WPR (1.9), Latin America (1.6) and AFR/EMR (0.4). HCTs are increasing steadily worldwide with narrowing gaps between regions and greater increase in allogeneic compared to autologous activity. While related HCT is rising, largely due to increase in haploidentical HCT, unrelated is plateauing and cord blood in decline.
Article
Background Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic-cell transplantation. Letermovir is an antiviral drug that inhibits the CMV–terminase complex. Methods In this phase 3, double-blind trial, we randomly assigned CMV-seropositive transplant recipients, 18 years of age or older, in a 2:1 ratio to receive letermovir or placebo, administered orally or intravenously, through week 14 after transplantation; randomization was stratified according to trial site and CMV disease risk. Letermovir was administered at a dose of 480 mg per day (or 240 mg per day in patients taking cyclosporine). Patients in whom clinically significant CMV infection (CMV disease or CMV viremia leading to preemptive treatment) developed discontinued the trial regimen and received anti-CMV treatment. The primary end point was the proportion of patients, among patients without detectable CMV DNA at randomization, who had clinically significant CMV infection through week 24 after transplantation. Patients who discontinued the trial or had missing end-point data at week 24 were imputed as having a primary end-point event. Patients were followed through week 48 after transplantation. Results From June 2014 to March 2016, a total of 565 patients underwent randomization and received letermovir or placebo beginning a median of 9 days after transplantation. Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 [60.6%], P<0.001). The frequency and severity of adverse events were similar in the two groups overall. Vomiting was reported in 18.5% of the patients who received letermovir and in 13.5% of those who received placebo; edema in 14.5% and 9.4%, respectively; and atrial fibrillation or flutter in 4.6% and 1.0%, respectively. The rates of myelotoxic and nephrotoxic events were similar in the letermovir group and the placebo group. All-cause mortality at week 48 after transplantation was 20.9% among letermovir recipients and 25.5% among placebo recipients. Conclusions Letermovir prophylaxis resulted in a significantly lower risk of clinically significant CMV infection than placebo. Adverse events with letermovir were mainly of low grade. (Funded by Merck; ClinicalTrials.gov number, NCT02137772; EudraCT number, 2013-003831-31.)