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Incidence and impact of fungal infections in post-transplant Cyclophosphamide (PTCy)-based graft-versus-host disease prophylaxis and haploidentical hematopoietic cell transplantation: A CIBMTR analysis
Papanicolaou, G. A., Chen, M., He, N., Martens, M. J., Kim, S., Batista, M. V., Bhatt, N. S., Hematti, P., Hill, J. A., Liu, H., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Fungal infections (FI) after allogeneic hematopoietic cell transplant (HCT) are associated with increased morbidity and mortality. Neutropenia, HLA mismatch, graft versus host disease (GVHD), and viral infections are risk factors for FI. OBJECTIVES The objectives of this CIBMTR registry study were to compare the incidence and density of FI occurring within 180 days after HCT in matched sibling (Sib) transplants receiving either calcineurin inhibitor (CNI)-based or PTCy-based GVHD prophylaxis and related haploidentical transplants receiving PTCy, and to examine the impact of FI by day 180 on transplant outcomes. STUDY DESIGN Patients who received their first HCT between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndromes and received related haploidentical transplant with PTCy (HaploCy, N = 757) or Sib transplant with PTCy (SibCy, N = 403) or CNI (SibCNI, N = 1605) were analyzed. The incidence of FI by day 180 post-HCT was calculated as a cumulative incidence with death as the competing risk. The association of FI on overall survival (OS), non-relapse mortality (NRM), chronic GVHD, and relapse at 2 years post HCT were examined in Cox proportional hazards regression models. Factors significantly associated with the outcome variable at a 1% level were kept in the final model. RESULTS By Day 180 post HCT, 56 (7%) HaploCy, 24 (6%), SibCy, and 59 (4%) SibCNI developed ≥1 FI (<0.001). The cumulative incidence (99% confidence interval) of yeast FI was 5.2% (3.3-7.3), 2.2% (0.7-4.5), and 1.9% (1.1-2.9) (p=.001), and mold FI was 2.9% (1.5-4.7). 3.7% (91.7-6.6) and 1.7% (1.0-2.6) (p=0.040) for HaploCy, SibCy, and SibCNI, respectively. FI were associated with an increased risk of death with an adjusted hazard ratio [HR] (99% confidence interval) of 4.06 (2.2-7.6); 4.7(2.0-11.0) and 3.4 (1.8-6.4) for HaploCy; SibCy and SibCNI compared with SibCNI without FI, respectively (p<.0001; for all). Similar associations were noted for transplant-related mortality. FI did not impact relapse or chronic GVHD. CONCLUSIONS Rates of FI by Day 180 ranged between 1.9-5.2% for yeast and 1.7%-3.7% for molds across the 3 cohorts. Use of PTCy was associated with higher rates of yeast infections only in Haplo HCT and mold infections in Haplo and Sib HCT. Presence of FI by Day 180 was associated with increased risk for overall mortality and transplant-related mortality at 2 years regardless of donor or PTCy. While rates of FI were low with PTCy, FI were associated with increased risk of death, underscoring the need for improved management strategies.
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Association Between Candidemia and Noninfectious Interstitial Pneumonia After Allogeneic Hematopoietic Cell Transplantation: JSTCT Transplant Complications Working Group
Kimura, S. I., Akahoshi, Y., Shiratori, S., Okinaka, K., Harada, K., Uchida, N., Doki, N., Ikegame, K., Nakamae, H., Tanaka, M., et al
Open forum infectious diseases. 2023;10(4):ofad163
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Abstract
BACKGROUND α-mannan from Candida albicans reportedly induces Th17-mediated pulmonary graft-versus-host disease (GVHD) in mouse models. This study aimed to evaluate the association between candidemia and noninfectious interstitial pneumonia (IP) in allogeneic hematopoietic cell transplantation (HCT) recipients. METHODS Using a Japanese transplant registry database, we analyzed 9143 pediatric and adult patients with hematological malignancies who underwent their first (n = 7531) or second (n = 1612) allogeneic HCT between 2009 and 2019. RESULTS Noninfectious IP was observed in 694 patients at a median (range) of 63 (0-1292) days after HCT. Candidemia occurred in 358 patients at a median (range) of 31 (0-903) days after HCT. Candidemia treated as a time-dependent covariate was significantly associated with an increased incidence of noninfectious IP (hazard ratio [HR], 2.51; 95% CI, 1.48-4.25), along with total body irradiation (>8 Gy; HR, 1.57; 95% CI, 1.18-2.10) and malignant lymphoma (vs acute myeloid leukemia; HR, 1.30; 95% CI, 1.004-1.69). On the other hand, prompt platelet recovery (HR, 0.58; 95% CI, 0.45-0.75) and acute lymphoblastic leukemia (vs acute myeloid leukemia; HR, 0.68; 95% CI, 0.49-0.94) were associated with reduced incidence of noninfectious IP. The median survival after the development of noninfectious IP in patients with prior candidemia was significantly shorter than that in those without it (22 days vs 59 days; P < .001). CONCLUSIONS Candidemia was associated with an increased incidence of noninfectious IP. The prognosis of noninfectious IP after candidemia was extremely poor.
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Risk and predictive factors for candidemia after allogeneic hematopoietic cell transplantation: JSTCT Transplant Complications Working Group
Kimura, S. I., Kameda, K., Harada, K., Saburi, M., Okinaka, K., Shinohara, A., Uchida, N., Nishijima, A., Ozawa, Y., Tanaka, M., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Although antifungal prophylaxis that covers Candida species is a standard of care in allogeneic hematopoietic cell transplantation (HCT), candidemia mainly caused by non-albicans Candida species still occurs and is associated with a high mortality rate. OBJECTIVE This study aimed to evaluate the risk factors for candidemia after allogeneic HCT. Particularly, we evaluated the impact of patient factors such as hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and performance status (PS) in addition to well-recognized risk factors including donor type, delayed engraftment and graft-versus-host disease (GVHD). STUDY DESIGN By using data from a Japanese transplant registry database, we analyzed 26,236 pediatric and adult patients with hematological malignancies who underwent their first allogeneic HCT. The posttransplant period was divided into early (days 0-40), late (days 41-100) and very late (days 101-365) phases RESULTS The 1-year cumulative incidence of candidemia was 1.8%. When we analyzed pretransplant factors, age ≥ 40 years (hazard ratio [HR] 1.85), male (HR 1.34), HCT-CI (HCT-CI 1-2, HR 1.56; HCT-CI ≥ 3, HR 2.21), PS ≥ 2 (HR 2.01), high-risk disease (HR 1.78) and donor type including HLA-mismatched related donor (MMRD) (HR 1.96), HLA-mismatched unrelated donor (HR 2.05) and cord blood (CB) (HR 2.85) were significantly associated with an increased incidence of candidemia. Focusing on the early phase (days 0-40), HCT-CI, PS, high-risk disease and CB transplantation together with engraftment and severe acute GVHD significantly affected the development of candidemia. In the late phase (days 41-100), higher HCT-CI, male, and donor type including MMRD, and CB were associated with the occurrence of candidemia together with acute GVHD and disease relapse. In the very late phase (days 101-365), HCT-CI ≥ 3 and high-risk disease significantly affected the occurrence of candidemia together with acute and chronic GVHD, and disease relapse. CONCLUSIONS In addition to well-recognized risk factors including donor type, engraftment and GVHD, patient factors such as HCT-CI and PS were associated with the development of candidemia, which suggests that severely ill patients with transplantation-associated complications are more likely to develop candidemia.
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Impact of early candidemia on the long-term outcome of allogeneic hematopoietic stem cell transplant in non-leukemic patients: an outcome analysis on behalf of IDWP-EBMT
Cesaro, S., Tridello, G., Knelange, N. S., Blijlevens, N., Martin, M., Snowden, J. A., Malladi, R., Ljungman, P., Deconinck, E., Gedde-Dahl, T., et al
Bone marrow transplantation. 2021
Abstract
We assessed the incidence and outcome of early candidemia after hematopoietic stem cell transplant (HSCT). The analysis included all first HSCTs performed from 2000 to 2015 in adult and pediatric patients with a non-leukemic disease and recorded in the EBMT registry. Overall survival (OS), non-relapse mortality (NRM), and relapse mortality (RM) were evaluated. Candidemia was diagnosed in 420 of 49,852 patients at a median time of 17 days post HSCT (range 0-100), the cumulative incidence being 0.85%. In 65.5% of episodes, candidemia occurred by day 30 after HSCT. The mortality rate by day 7 was 6.2%, whereas 100-day NRM was higher (HR 3.47, p?0.0001), and 100-day OS was lower (HR 3.22, p?0.0001) than that of patients without candidemia. After a median follow-up of 4.3 years, 5-year OS, NRM, and RM for patients with and without candidemia were 50.5% vs. 60.8%, p?0.0001, 28.2% vs.18.8%, p?0.0001, and 25.3% vs. 27.2%, p?=?0.4, respectively. In conclusion, in non-leukemic transplant patients, the occurrence of an early episode of candidemia is rare but it is still associated with a negative effect on the outcome.
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Mainly post-transplant factors are associated with invasive aspergillosis after allogeneic stem cell transplantation. A study from the SAIF and SFGM-TC
Robin, C., Cordonnier, C., Sitbon, K., Raus, N., Lortholary, O., Maury, S., de la Tour, R. P., Bretagne, S., Bastuji-Garin, S.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Invasive aspergillosis (IA) occurs in up to 23% of allogeneic hematopoietic stem cell transplantation (HSCT) patients. While transplant procedures have changed over time, more late cases of IA are being observed. The objective of this study was to identify the pre- and post-transplant factors of IA in a large cohort of HSCT patients mainly transplanted with reduced-intensity conditioning. This multicenter, case-control study was carried out using data collected between 2005-2010 by the Surveillance des Aspergilloses Invasives en France (SAIF) program (Institut Pasteur, Paris) and the EBMT ProMISe registry. Four controls without IA were individually matched to each case based on the center, patient's age, and year of the transplant. We identified 185 cases of probable and proven IA and 651 controls. The median date of IA after the transplant was 133 days, with 35 (19%) cases of early IA (before day 40), 33 (18%) cases of late IA (day 40 to day 100), and 117 (63%) cases of very late IA (after day 100). In the multivariate analysis, early IA was significantly associated with a lack of engraftment, while late and very late IA were significantly associated with > grade 2 acute graft-versus-host disease (GvHD); very late IA was also significantly associated with relapse and secondary neutropenia. Two thirds of IA cases occurred more than 100 days after HSCT with different risk factors than those occurring earlier. Prophylactic strategies should consider the specific risk factors for late and very late IA, especially GvHD, relapse after transplant, and secondary neutropenia.
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Incidence, Risk Factors and Long-Term Outcome of Acute Leukemia Patients with Early Candidemia after Allogeneic Stem Cell Transplantation. A Study by the Acute Leukemia and Infectious Diseases Working Parties of EBMT
Cesaro, S., Tridello, G., Blijlevens, N., Ljungman, P., Craddock, C., Michallet, M., Martin, A., Snowden, J. A., Mohty, M., Maertens, J., et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018
Abstract
Objectives: To assess the incidence of, and risk factors for, Candida infection in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT) and the impact on long-term survival. Methods: outcome analysis of 28,542 acute leukemia patients who underwent HSCT from 2000 to 2012: 347 with candidemia by day +100, and 28,195 without candidemia or any other type of Candida infection. Results: The incidence of candidemia by day +100 was 1.2% (347/28542) and occurred at a median of 22 days after HSCT (range 1-100). A higher 100-day non-relapse-mortality (NRM) (HR 3.0, p <0.0001), and a lower 100-day overall-survival (OS) (HR 2.5, p<0.0001) were observed in patients with candidemia. The case fatality rate by day +100 in patients with candidemia was 22% (76/347). Factors associated with candidemia occurrence were: gender female, bone marrow or cord blood stem cell source, T-cell depletion, use of total body irradiation, and acute graft versus host disease. Among the patients alive at day +100, the 5-year NRM and OS after a median follow-up of 5.6 years (95% CI 5.5 - 5.7) for patients with and without candidemia were 22.5% vs. 13.5%, p <0.0001, and 45.6% vs. 53.4%, p=0.0003, respectively. In multivariate analysis, the occurrence of a candidemia episode by day +100 was an independent risk factor for higher NRM, HR 1.7, p=0.001, and lower OS, HR 1.4, p=0.001. Conclusions: despite the general improvements in prophylaxis and treatment, the early occurrence of candidemia after HSCT is still associated with higher NRM and lower short-and-long-term OS.
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Risks and outcomes of invasive fungal infections in pediatric allogeneic hematopoietic stem cell transplant recipients receiving fluconazole prophylaxis: a multicenter cohort study by the Turkish Pediatric Bone Marrow Transplantation Study Group
Hazar, V., Karasu, G. T., Uygun, V., Ozturk, G., Kilic, S. C., Kupesiz, A., Daloglu, H., Aksoylar, S., Atay, D., Ince, E. U., et al
Medical mycology. 2018
Abstract
Invasive fungal infections (IFIs) are a major cause of infection-related morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Data from pediatric settings are scarce. To determine the incidence, risk factors and outcomes of IFIs in a 180-day period post-transplantation, 408 pediatric patients who underwent allogeneic HSCT were retrospectively analyzed. The study included only proven and probable IFIs. The cumulative incidences of IFI were 2.7%, 5.0%, and 6.5% at 30, 100, and 180 days post-transplantation, respectively. According to the multivariate analysis, the factors associated with increased IFI risk in the 180-day period post-HSCT were previous HSCT history (hazard ratio [HR], 4.57; 95% confidence interval [CI] 1.42-14.71; P = .011), use of anti-thymocyte globulin (ATG) (HR, 2.94; 95% CI 1.27-6.80; P = .012), grade III-IV acute graft-versus-host-disease (GVHD) (HR, 2.91; 95% CI 1.24-6.80; P = .014) and late or no lymphocyte engraftment (HR, 2.71; 95% CI 1.30-5.62; P = .007). CMV reactivation was marginally associated with an increased risk of IFI development (HR, 1.91; 95% CI 0.97-3.74; P = .063). IFI-related mortality was 1.5%, and case fatality rate was 27.0%.The close monitoring of IFIs in pediatric patients with severe acute GVHD who receive ATG during conditioning is critical to reduce morbidity and mortality after allogeneic HSCT, particularly among those with prior HSCT and no or late lymphocyte engraftment.
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Influence of pre-existing invasive aspergillosis on allo-HSCT outcome: a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties
Penack, O., Tridello, G., Hoek, J., Socie, G., Blaise, D., Passweg, J., Chevallier, P., Craddock, C., Milpied, N., Veelken, H., et al
Bone Marrow Transplantation. 2016;51(3):418-23
Abstract
Historically, invasive aspergillosis (IA) has been a major barrier for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The influence of invasive IA on long-term survival and on transplant-related complications has not been investigated in a larger patient cohort under current conditions. Our aim was to analyze the long-term outcome of patients undergoing allo-HSCT with a history of prior IA. We used European Society for Blood and Marrow Transplantation database data of first allo-HSCTs performed between 2005 and 2010 in patients with acute leukemia. One thousand one hundred and fifty patients with data on IA before allo-HSCT were included in the analysis. The median follow-up time was 52.1 months. We found no significant impact of IA on major transplant outcome variables such as overall survival, relapse-free survival, non-relapse mortality, cumulative incidence of acute GvHD grade II-IV, chronic GvHD, pulmonary complications and leukemia relapse. However, we found a trend toward lower overall survival (P=0.078, hazard ratio (HR) (95% confidence interval (CI)): 1.16 (0.98, 1.36)) and higher non-relapse mortality (P=0.150, HR (95% CI): 1.19 (0.94, 1.50)) in allo-HSCT recipients with pre-existing IA. Our data suggest that a history of IA should not generally be a contraindication when considering the performance of allo-HSCT in patients with acute leukemia.