High-Dose Caspofungin Combination Antifungal Therapy in Patients with Hematologic Malignancies and Hematopoietic Stem Cell Transplantation
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Bone Marrow Transplantation (2007) 39, 157–164 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00 www.nature.com/bmt ORIGINAL ARTICLE High-dose caspofungin combination antifungal therapy in patients with hematologic malignancies and hematopoietic stem cell transplantation A Safdar1, G Rodriguez1, KVI Rolston1, S O’Brien2, IF Khouri3, EJShpall 3, MJKeating 2, HM Kantarjian2, RE Champlin3, II Raad1 and DP Kontoyiannis1 1Department of Infectious Diseases, Infection Control, and Employee Health, MD Anderson Cancer Center, Houston, TX, USA; 2Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA and 3Department of Blood and Marrow Transplantation, MD Anderson Cancer Center, Houston, TX, USA Pneumocandins have concentration-dependent antifungal Introduction activity and higher dose of caspofungin (HD-CAP) in combination with other licensed antifungal therapy Invasive fungal infection (IFI) remains a serious complica- (OLAT) may improve response. Thirty-four patients tion in patients receiving antineoplastic therapy.1,2 Recent who received HD-CAP were compared with 63 patients advances in the treatment of invasive fungal infections who received standard dose (SD)-CAP. There were no include broad-spectrum triazoles and ecchinocandins, a differences between the groups in either patient or disease novel class of antimicrobials that inhibit fungal cell wall characteristics. Significantly more patients in the HD- synthesis.3 Caspofungin (CAP) given alone in patients with CAP arm had extrapulmonary infections (29 vs 8% in SD refractory aspergillosis has resulted in less than satisfactory group; P ¼ 0.0053), and non-Aspergillus species infection response rates.4,5 Furthermore, since laboratory tests have (21 vs 6%; P ¼ 0.05) and had received prior antifungal shown a possible therapeutic advantage with combinations therapy (71 vs 33%; P ¼ 0.0004). No serious adverse of CAP and other antifungal drugs,6–8 in recent years reactions were noted in patients receiving HD- or SD- combination antifungal therapy has been increasingly used CAP therapy. Twelve weeks after treatment commenced in severely immunosuppressed cancer patients with IFI who 44% had a complete or partial response compared with are considered at high risk of treatment failure.9–12 29% in SD-CAP group (P ¼ 0.1). Logistic regression In vitro antimicrobial susceptibility tests and studies of analysis showed a significant probability of a favorable experimentally induced invasive mycosis in immunosup- outcome at 12 weeks in patients who received HD-CAP pressed animals indicate that CAP has a concentration- (OR 3.066, 95% CI, 1.092–8.61; P ¼ 0.033). This may in dependent fungicidal effect,13 and dose-escalation studies in part reflect higher number of patients in HD group had healthy volunteers have shown no evidence of increased received granulocyte–macrophage colony-stimulating fac- dose-associated serious adverse events with CAP.14,15 tor (41 vs 14% in SD group; P ¼ 0.04) and/or interferon c However, the safety of higher doses of CAP in cancer (26 vs 5% in SD group; P ¼ 0.003) immune enhancement. patients and hematopoietic stem cell transplant recipients is Further studies are needed to evaluate efficacy of HD- not known. Although the efficacy of standard dose CAP CAP in severely immunosuppressed cancer patients with (SD-CAP) in combination with other agents has been invasive fungal infections. disappointing,11,12 the response to high-dose (HD)-CAP) in Bone Marrow Transplantation (2007) 39, 157–164. combination with other antifungal agents in patients with a doi:10.1038/sj.bmt.1705559 high risk of treatment failure is not known. We therefore Keywords: high-dose caspofungin; refractory fungal in- sought to evaluate the safety and efficacy of HD-CAP fection; allogeneic bone marrow transplantation; leukemia; therapy in combination with other classes of antifungal lymphoma; adverse events agents for invasive fungal infections in patients receiving care at a comprehensive cancer center. Materials and methods Study setting, patients and design A retrospective analysis of cancer patients with IFIs treated at The University of Texas MD Anderson Cancer Center Correspondence: Dr A Safdar, Department of Infectious Diseases, between December 2002 and December 2004 was under- Infection Control, and Employee Health, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. taken after obtaining Institutional Review Board approval; E-mail: [email protected] the requirement for patient consent was waived. Patients Received 24 July 2006; revised and accepted 12 September 2006 who had received CAP and at least one other antifungal High-dose caspofungin therapy A Safdar et al 158 agent were identified using a pharmacy database. A or lipid-based polyenes for a minimum of 7 days before matched case–control analysis of patients who received diagnosis of the IFI. Refractory-relapsed cancer was HD-CAP (100 mg daily) and SD-CAP (70 mg followed by defined as stage IV disease in patients with solid-organ 50 mg daily) was performed to assess the responses to malignancies, first cancer relapse following hematopoietic therapies and the infection-associated mortality rate. stem cell transplantation, or second relapse after antineo- Patient and disease data were retrieved from patients’ plastic therapy in patients with hematologic malignancies. charts and computerized hospital data systems and Neutropenia prior to and during antifungal therapy was included age, sex, race, duration of hospitalization, under- defined as an absolute neutrophil count lower than 500/ml. lying malignancy, stem cell transplantation, graft-versus- Corticosteroid use was defined as 4600 mg of prednisone host disease, immunosuppressive therapy, systemic corti- or an equivalent dose of another corticosteroid given costeroid use, antineoplastic therapy, neutrophil counts 4 during the immediate 7 days before diagnostic samples week before infection diagnosis, at the time antifungal were obtained. Acute Physiology and Chronic Health therapy commenced, and during the course of antifungal Evaluation (APACHE) II scores, which could signal the therapy, complications of fungal infection, treatments for presence of multiorgan dysfunction, were calculated by IFI, and outcome. Comorbid conditions such as diabetes, standard methods.21 renal failure, structural lung disease including chronic For this study, we evaluated the response to antifungal obstructive pulmonary disease, hepatic dysfunction, con- therapy 4 weeks and 12 weeks after combination therapy gestive heart failure, ischemic heart disease, and APACHE commenced. Complete response was defined as a major II score, corticosteroid use were also recorded. improvement in symptoms and signs and radiographic All patient samples obtained from patients in whom IFI findings associated with IFI, and the discontinuation of was suspected were evaluated at MD Anderson, and fungal systemic antifungal therapy or the reduction of doses for species were identified by standard methods.16 secondary prophylaxis. Partial response was defined as improvement in symptoms and signs and incomplete radiographic disease resolution on X-rays or computed Definitions tomography scans, when available. Progressive disease was Invasive fungal infection was defined as proven, probable, defined as deterioration in signs and symptoms and or disseminated according to the guidelines of the Invasive radiographic findings associated with IFI in patients who Fungal Infections Cooperative Group of the European had received at least 7 days of systemic antifungal therapy. Organization for Research and Treatment of Cancer and Stable disease was modest improvement in signs and of the Mycoses Study Group of the National Institute of symptoms and unchanged radiographic features associated Allergy and Infectious Diseases.17 For probable IFIs, we with IFI. considered host factors and major and minor criteria as Serious drug toxicity were adverse events including grade strength of evidence for diagnosis of IFI. The demonstra- 3, 4 and grade 5 according to standard criteria described tion of tissue-invasive mold on histological examination or elsewhere.22 Invasive fungal infection was considered the the presence of fungemia in patients with clinical and principal contributor to a patient’s death if there was radiographic evidence of deep-tissue infection was consi- evidence of progressive fungal disease despite 7 days of dered evidence of definite infection. Isolation of Aspergillus combination antifungal therapy and either a post-mortem and Penicillium species in blood cultures alone in patients examination was consistent with organ dysfunction asso- with no evidence of deep-tissue infection was regarded as ciated with invasive mycosis or an antemortem diagnosis of pseudofungemia.18 Isolation of Fusarium and Scedosporium progression of fungal disease with organ failure that was species from sterile blood culture isolates obtained from known to be affected by fungal disease was established and separate body sites and/or more than 24 h apart even in the other causes of death, such as intracranial hemorrhage, absence of known deep-tissue infection was also considered myocardial infarction, or pulmonary embolism, were not definite infection.17–20 Disseminated fungal infection was present. Sepsis, septic shock-related multiorgan failure, defined as infection involving two noncontiguous body disseminated intravascular coagulation, and respiratory sites; the presence of fungemia was not required to establish