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 European Society for Blood and Marrow Transplantation

Background This study was performed 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 We performed an outcome analysis of 28542 acute leukemia patients who underwent HSCT from 2000 to 2012. There were 347 patients with candidemia by day 100 and 28195 without candidemia or any other type of Candida infection. Results The incidence of candidemia by day 100 was 1.2% and occurred at a median of 22 days after HSCT. Higher 100-day nonrelapse mortality (NRM; hazards ratio [HR], 3.0, P < .0001) and lower 100-day overall survival (OS; HR, 2.5, P < .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 female gender, bone marrow or cord blood stem cell source, T-cell depletion, use of total body irradiation, and acute graft vs 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% confidence interval, 5.5 - 5.7) for patients with and without candidemia were 22.5% vs 13.5%, P < .0001 and 45.6% vs. 53.4%, P = .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 = .001) and lower OS (HR, 1.4, P = .001). Conclusions The early occurrence of candidemia after HSCT is still associated with higher NRM and lower short- and-long-term OS.

[1]  National Institute of Allergy and Infectious Disease , 2020, Definitions.

[2]  L. Pagano,et al.  Changes in the incidence of candidemia and related mortality in patients with hematologic malignancies in the last ten years. A SEIFEM 2015-B report , 2017, Haematologica.

[3]  E. Castagnola,et al.  Retrospective study on the incidence and outcome of proven and probable invasive fungal infections in high‐risk pediatric onco‐hematological patients , 2017, European journal of haematology.

[4]  L. Pagano,et al.  Risk stratification for invasive fungal infections in patients with hematological malignancies: SEIFEM recommendations. , 2017, Blood reviews.

[5]  L. Pagano,et al.  ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients , 2016, Haematologica.

[6]  M. Paesmans,et al.  Epidemiology and outcome of fungemia in a cancer Cohort of the Infectious Diseases Group (IDG) of the European Organization for Research and Treatment of Cancer (EORTC 65031). , 2015, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[7]  P. Chiusolo,et al.  Incidence and outcome of invasive fungal diseases after allogeneic stem cell transplantation: a prospective study of the Gruppo Italiano Trapianto Midollo Osseo (GITMO). , 2014, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[8]  N. Yapar Epidemiology and risk factors for invasive candidiasis , 2014, Therapeutics and clinical risk management.

[9]  E. Mylonakis,et al.  Systemic antifungal prophylaxis after hematopoietic stem cell transplantation: a meta-analysis. , 2014, Clinical therapeutics.

[10]  T. Calandra,et al.  ESCMID* guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT). , 2012, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[11]  A. Erbacher,et al.  Caspofungin as antifungal prophylaxis in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis , 2012, BMC Infectious Diseases.

[12]  C. Heussel,et al.  Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation , 2011, British journal of haematology.

[13]  A. Thiébaut,et al.  European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3—2009 Update , 2011, Bone Marrow Transplantation.

[14]  Thomas J Walsh,et al.  Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  Russell E. Lewis,et al.  Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001‐2007) , 2009, Cancer.

[16]  E. Anaissie,et al.  Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[17]  E. Anaissie,et al.  Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  Patricia Muñoz,et al.  Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[19]  D. Kontoyiannis,et al.  The changing epidemiology of invasive candidiasis , 2008, Cancer.

[20]  A. Kumar Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial , 2008 .

[21]  D. Kontoyiannis,et al.  Caspofungin as Primary Antifungal Prophylaxis in Stem Cell Transplant Recipients , 2007, Pharmacotherapy.

[22]  R. Betts,et al.  Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[23]  D. Pittet,et al.  Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial , 2007, The Lancet.

[24]  J. Lipton,et al.  Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. , 2007, The New England journal of medicine.

[25]  J. Lipton,et al.  Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[26]  ohn,et al.  COMPARISON OF CASPOFUNGIN AND AMPHOTERICIN B FOR INVASIVE CANDIDIASIS , 2002 .

[27]  R. Collins,et al.  Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group , 2000, Bone Marrow Transplantation.

[28]  T. C. White,et al.  Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole. , 2000, The Journal of infectious diseases.

[29]  B. Lebeau,et al.  Candidemia in cancer patients: a prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of Cancer (EORTC). , 1999, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[30]  D. Snydman,et al.  The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance. , 1996, The American journal of medicine.

[31]  M. Levenstein,et al.  Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation--a prospective, randomized, double-blind study. , 1995, The Journal of infectious diseases.

[32]  H. Horowitz,et al.  Fluconazole Prophylaxis of Fungal Infections in Patients with Acute Leukemia: Results of a Randomized Placebo-Controlled, Double-Blind, Multicenter Trial , 1993, Annals of Internal Medicine.

[33]  G. McDonald,et al.  Veno-occlusive Disease of the Liver and Multiorgan Failure after Bone Marrow Transplantation: A Cohort Study of 355 Patients , 1993, Annals of Internal Medicine.

[34]  J. L. Goodman,et al.  A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. , 1992, The New England journal of medicine.

[35]  M G Rinaldi,et al.  Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. , 1991, The New England journal of medicine.

[36]  K. Sullivan,et al.  Regimen-related toxicity and early posttransplant survival in patients undergoing marrow transplantation for lymphoma. , 1989, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  K. Sullivan Acute and chronic graft-versus-host disease in man. , 1986, International journal of cell cloning.