Invasive fungal infections/disease (IFI/IFD) are a major cause of morbidity and mortality after hematopoietic stem cell transplants (HCT), but their incidence and risk factors are not well defined. We performed a retrospective review of 270 consecutive adults (152 M/118 F), median age 53 (18–75) years, with hematologic malignancy receiving allogeneic HCT at Massachusetts General Hospital between 2000 to 2010 to determine the incidence, risk factors and outcomes of patients that developed IFD. All patients received antifungal prophylaxis from the start of conditioning until Day +100; 90% received fluconazole 400 mg daily. We defined IFD using 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 definitions, defining proven cases as evidence of fungal elements in a sterile tissue, and probable as presence of fungal elements in non sterile tissue or positive Galactomannan antigen or β-D-Glucan test in patients with clinical features suggestive of IFI. Diagnoses were Acute Myeloid Leukemia (34%), Non Hodgkin's Lymphoma (24%), Myelodysplastic syndrome (15%), Acute Lymphoblastic Leukemia (8%), Chronic Lymphocytic Leukemia (5%), Myeloproliferative disorders, Hodgkin Lymphoma and Multiple Myeloma (4% each), and others (2%). 15% had a prior autologous transplant. Conditioning included reduced intensity (64%) or myeloablative (36%) regimens. Donor source was fully HLA matched (MRD) in 60%, matched unrelated (MUD) in 20%, Haploidentical in 12% and Cord Blood in 8%. 41% received ATG based aGVHD prophylaxis vs non ATG based in 59%. 11% were diabetic, while 6% had a history of IFD prior to transplant. 55% received systemic steroids for GVHD and 34% received TPN during transplant course. Median follow up was 28 (1.0–141.0) months. 49 distinct episodes of IFI were observed in 40 subjects (15%). Aspergillus spp (47%) was most frequently encountered, followed by Candida spp (43%). Mucor was isolated in 1 case. Among the Candida spp, the majority (52%) were non albicans- Candida glabrata (8) vs 1 each of Candida krusei, Candida tropicalis and Candida parapsilosis. Most frequently infected site was the lungs (69%), followed by the blood stream and paranasal sinuses (14% each), and GI tract (4%). Spleen (hepatosplenic candidiasis), kidneys and brain were affected in 1 patient each. In 6%, involvement of both the lungs and sinuses was observed. The estimated probability of early IFD (within 100 days post transplant) was 7%. Patients and transplant factors, including age, diagnosis, prior autologous transplant, type of conditioning regimen, type of aGVHD prophylaxis, donor type, CD34+ cell dose infused, history of diabetes or prior IFD, systemic use of steroids for GVHD and TPN administration, were examined to determine risk factors for developing IFD. In multivariable analysis, haploidentical donor transplants (HR 3.48, 95% CI 1.35–8.99, p=0.01) and the development of Grade III and IV aGVHD (HR 3.32, 95% CI 1.23–9.01, p=0.02) were risk factors for the development of IFD. Conversely, higher CD34+ cell dose infused was associated with a lower risk of IFD (HR 0.80, 95% CI 0.68–0.94, p=0.01, per 1×10⋀6 cells/kg increase). The overall mortality (OM) of patients with IFD was 41%. A higher non-relapse mortality (NRM) was observed for patients with IFD as compared to patients without IFD, 55% vs 18% (HR 3.76, 95% CI 2.03–6.97, p<0.001). In multivariable analysis, accounting for CD34+ cell count, donor type and Grade III-IV aGVHD, the effect of IFI on NRM remained significant (HR 3.32, 95% CI 1.65–6.67, p=0.001). Patients with IFD had lower overall survival (OS), 16 months as opposed to 50 months for patients without IFD. In summary, 1) The risk of IFD after allogeneic HCT was 15%; 2) Patients with IFD have a high mortality after allogeneic HCT; 3) Haploidentical donor type and development of Grades III-IV GVHD are risk factors for IFD; 4) A higher CD34+ cell dose may be protective against IFD; 5) Prior IFD did not predict for higher risk of IFD or higher mortality, suggesting these patients should not be excluded from allogeneic HCT. Further studies looking at alternate aGVHD prophylaxis regimens, strategies to increase cell dose infused and better antifungal prophylaxis for these high risk patients are needed to lessen this potentially life threatening complication.
Mylonakis:T2 Biosystems: Research Funding; Astellas inc : Research Funding.
Asterisk with author names denotes non-ASH members.