JAC Advance Access originally published online on January 23, 2006
Journal of Antimicrobial Chemotherapy 2006 57(3):527-535; doi:10.1093/jac/dkl009
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Treatment with caspofungin in immunocompromised paediatric patients: a multicentre survey
1 Department of Paediatric Haematology/Oncology, Children's University Hospital, Muenster, Germany; 2 Children's University Hospital, Munich, Germany; 3 University Hospital Wuerzburg, Wuerzburg, Germany; 4 Children's Hospital, Medical School Hannover, Hannover, Germany; 5 Children's University Hospital, Hamburg-Eppendorf, Germany; 6 University Children's Hospital, Duesseldorf, Germany; 7 Department of Paediatric Haemotology, Children's University Hospital, Frankfurt, Germany; 8 St Anna Children's Hospital, Vienna, Austria
* Correspondence address. Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, Children's University Hospital, Albert-Schweitzer-Strasse 33, 48129 Muenster, Germany. Tel: +49-251-835-2801; Fax: +49-251-835-2804; E-mail: grollan{at}ukmuenster.de
Received 29 August 2005; returned 1 November 2005; revised 14 December 2005; accepted 2 January 2006
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Abstract |
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Objectives: Although a paediatric dosage has not been established, caspofungin is occasionally used in paediatric patients. We conducted a multicentre retrospective survey to obtain data on immunocompromised paediatric patients considered to require caspofungin therapy.
Methods: The survey identified 64 patients (median age: 11.5 years; 25 females, 39 males) with haematological malignancies (48), marrow failure (9), solid tumours (3), haematological disorders (2) and congenital immunodeficiency (2) who received caspofungin for proven (17), probable (14) and possible (17) invasive fungal infections or empirically (16). Caspofungin was administered until intolerance or maximum efficacy at dosages individually determined by the responsible physician for refractory infection (38), intolerance of other agents (10) or as best therapeutic option (16).
Results: The 64 patients received caspofungin for a median of 37 days (range 3–218) as single agent (20) or in combination (44). The median daily maintenance dosage was 1.07 mg/kg (95% CI 1.09–1.35; range 0.40–2.92) or 34.3 mg/m2 (95% CI 32.3–37.3; range 16.3–57.5). In none of the patients was therapy discontinued due to adverse events (AEs). Clinical AEs were mild to moderate and observed in 34 patients (53.1%). While mean glutamate pyruvate transaminase and glutamate oxalate transaminase values were slightly (P < 0.005) higher at the end of treatment (EOT), serum bilirubin, alkaline phosphatase and creatinine values were not different from baseline. Complete responses, partial responses or stabilization were observed in 5/7/3 of 17 patients with proven, in 3/4/3 of 14 patients with probable and in 7/6/1 of 15 evaluable patients with possible invasive infections. Thirteen of 16 patients on empirical therapy completed without breakthrough infection. Overall survival was 75% at the EOT and 70% at 3 months post-EOT, respectively.
Conclusions: Caspofungin displayed favourable safety and tolerance and may have useful antifungal efficacy in severely immunocompromised paediatric patients.
Keywords: echinocandins , mycoses , children , cancer , immunodeficiency
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Introduction |
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Caspofungin is the first licensed member of a novel class of antifungal lipopeptides, the echinocandins. The compound has broad spectrum activity against Candida and Aspergillus species, favourable pharmacokinetics and an excellent safety profile,1–3 and has been approved for primary treatment of oesophageal candidiasis and candidaemia, for second-line therapy of invasive aspergillosis, and for empirical antifungal therapy in individuals
18 years of age.4–8 Based on solid safety and efficacy data, the lack of cross-resistance to other antifungal classes, the absence of mechanism-based toxicities and relevant cytochrome P450-mediated metabolism, caspofungin can be considered as important innovation to the current antifungal armamentarium.9–12 Although a final paediatric dosage has not been established, caspofungin is occasionally being used in paediatric patients with refractory infections or intolerance to standard agents.13–15 In order to obtain data on clinical use, safety, tolerance and outcome in children and adolescents, we conducted a multicentre retrospective survey in immunocompromised paediatric patients who were considered to require therapy with caspofungin.
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Patients and methods |
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The study was a multicentre retrospective, non-comparative survey on immunocompromised paediatric patients who were considered to require therapy with caspofungin. Caspofungin was administered intravenously at dosages individually determined by the responsible physician, infused as recommended by the manufacturer and continued until occurrence of intolerance or maximum efficacy on the basis of refractory infection, intolerance of or contraindications to standard therapies, or as best individual therapeutic option as determined by the responsible physician.
Twelve paediatric haematology/oncology centres participated in the survey and committed to the requirement to report all eligible patients who had received treatment with caspofungin. Patients eligible for inclusion were <18 years of age, had received at least one dose of caspofungin and had begun caspofungin therapy from the time of licensure until July 2004, the cut-off date of the survey. Study design and data handling were reviewed and approved by the local ethics committees of Frankfurt and Muenster, the sites of the principal investigators of the study (A. H. G. and T. L.).
Data collection was accomplished with an anonymized, standardized case report form. Coding of invasive fungal infections and outcome was performed by the individual investigator and reviewed and jointly adjudicated as necessary by the principal investigators (A. H. G. and T. L.). The diagnostic validity of invasive fungal infections was classified according to the published EORTC/MSG criteria.16 Responses to treatment in cases of possible, probable and proven invasive fungal infections were evaluated according to efficacy end-points in clinical trials with caspofungin in invasive aspergillosis and candidiasis.7,17 A favourable response (‘success’) included either ‘complete response’ or ‘partial response’. The efficacy end-point in patients receiving caspofungin as empirical antifungal therapy (‘success’) was defined as the absence of a breakthrough fungal infection and survival at the time of discontinuation of caspofungin. Any fungal infection documented by imaging or microbiology during caspofungin therapy was considered as breakthrough fungal infection and graded as indicated above.
Clinical adverse events (AEs) were recorded and graded according to current Common Toxicity Criteria set forth by the US National Cancer Institute (NCI)18 and rated as possibly, probably or definitely related to treatment with caspofungin by the individual investigator. Laboratory parameters of renal and hepatic organ function were recorded at baseline and end of treatment (EOT). In addition, the most pathological value during treatment was recorded for each parameter and patient. As adjunct to the non-parametric comparison of baseline, maximum and EOT values, increases in laboratory parameters at the EOT were also graded as increased to 1.5 and 3.0 times their respective baseline value (alkaline phosphatase, creatinine) or as increased to 1.5 and 3.0 times their respective baseline value and being above a predefined upper cut-off value (hepatic transaminases and bilirubin), respectively.
For statistical comparisons of continuous data, the Mann–Whitney U-test or Kruskal–Wallis ANOVA was used as appropriate. Categorical data were evaluated by Fisher's exact test.
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Results |
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Seventy-one patients who received at least one dose of caspofungin were reported from 12 paediatric haematology/oncology centres. Seven patients who were
18 years of age were eliminated from the final dataset. The remaining 64 patients were considered evaluable and constitute the study population. Therapeutic indications and the types of presumed or documented invasive infections are summarized in Table 1. Sixteen (25%) of the 64 patients received caspofungin as empirical therapy, 17 (26.6%) for possible, 14 (21.8%) for probable and 17 (26.6%) for proven invasive infections. Among the 17 patients who started caspofungin for possible invasive fungal infections, two were later found to have pneumocystosis and recurrent lymphoma, respectively, and were therefore excluded from the efficacy analysis. However, since both received caspofungin for prolonged periods of time, they were included in the analysis of safety and tolerance. The overwhelming majority of patients receiving caspofungin for possible, probable and proven infections (n = 48) were treated for invasive pulmonary mould infection (n = 32; 66.6%), followed by invasive pulmonary and paranasal sinus mould infection and chronic disseminated candidiasis (n = 5 each; 10.4%), candidaemia (n = 3; 6.3%) and paranasal sinus-, central nervous system-, and disseminated invasive mould infections (n = 1 each; 2.1%).
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Demographics and details of the underlying haematological/oncological conditions are shown in Table 2. Thirty-nine of the 64 patients were male and 25 were female; the median age was 11.5 years (range 0.4–17.9). Seventeen patients (26.6%) were <6, 18 (28.1%) were between 6 and 11, and 29 (45.3%) were from 12 to <18 years of age. As to be expected in the setting of antifungal therapy, most patients (75%) had a haematological malignancy as principal diagnosis, and more than half were post-allogeneic haematopoietic stem cell transplantation (HSCT). All but two patients (96%) had been exposed to therapeutic dosages of glucocorticosteroids and/or had undergone an episode of profound granulocytopenia within the 4 weeks prior to the start of caspofungin [mean ± SEM duration of granulocytopenia <500 granulocytes/mm3: 19.8 ± 1.2 days (median: 21 days) with granulocytopenia lasting for >28 days duration set to 28 days]. Graft-versus-host disease (GVHD) of any grade and distance from transplantation was present in seven (10.9%) patients of the study population or in 20% of the 34 patients post-allogeneic HSCT, respectively. Approximately half of the patients (51.5%) were profoundly granulocytopenic at the time of commencement of caspofungin therapy.
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Table 3 depicts the indication for antifungal treatment with caspofungin and prior antifungal therapy of the 64 patients. The majority (59.4%) was started on caspofungin because of fever or infection refractory to prior antifungal therapy. Fewer patients received the compound due to intolerance of other antifungal therapies (15.6%) or as best individual therapeutic option (25%). All patients had received systemic antifungal agents for prolonged periods of time (median: 19.5 days; range 1–94) prior to treatment with caspofungin, most commonly amphotericin B and/or itraconazole and/or voriconazole. Thirty-nine patients (60.9%) had received prior therapy with one antifungal agent (amphotericin B alone, 42.1%; itraconazole or voriconazole alone, 12.5%; fluconazole alone, 6.2%), and the remaining 25 patients had received two or more agents in combination or sequentially.
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The majority of patients (44/64; 68.7%), particularly those with possible, probable and proven infections, received caspofungin in combination with other systemic antifungal agents (Table 4). There were a total of 14 different concurrent or sequential combinatory regimens. Amphotericin B formulations were part of these regimens in 35 cases (79.5%), voriconazole in 18 (40.9%), fluconazole in 6 (13.6%), flucytosine in 4 (9.1%) and itraconazole in 3 (6.8%) cases. The median duration of treatment with caspofungin was 37 days, and the median daily maintenance dosage was 1.07 mg/kg or 34.3 mg/m2, respectively. Most patients (n = 35; 54.6%) received the adult maintenance dosage of 50 mg/day; only 5 (7.8%) were treated at 50 mg/m2, the dosage that has been selected for further paediatric development. While on therapy with caspofungin, 45/64 patients (70.5%) were granulocytopenic for a median duration of 12.0 days with granulocytopenia <500 cells/mm3 (range 1–120 days) (62.2, 76.4, 78.5, 64.7% and 11, 6, 18 and 8 days for patients receiving empirical therapy or treatment for possible, probable and proven infections, respectively).
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In none of the patients was treatment with caspofungin discontinued due to limiting clinical or laboratory AEs. A total of 62 clinical AEs were recorded in 34 patients (53.1%). All clinical AEs were rated as possibly related to caspofungin treatment. Most AEs were of Grade I or II; only 7 of the 62 recorded AEs were
Grade III (Table 5). The most commonly recorded AEs were fever, nausea and/or vomiting, and diarrhoea. AEs appeared to be more common in patients with proven infections (14/17; 82.3%) than in patients with probable infections (8/14; 57.1%), possible infections (7/17; 41.1%) and those receiving empirical therapy (5/16; 31.2%). However, there was no effect of exposure as a function of dose per body surface area on the occurrence and number of clinical AEs.
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Increases in laboratory hepatic and renal function parameters during therapy were frequent. However, while mean glutamate oxalate transaminase (GOT) and glutamate pyruvate transaminase (GPT) values were slightly elevated at the EOT (P = 0.0004 and 0.0015, respectively), mean bilirubin, alkaline phosphatase and creatinine values were not different from baseline (P
0.5) (Figure 1). This is also reflected in the proportion of patients who had increases of 3 times baseline (and an abnormal value in the case of GOT, GPT and bilirubin) at EOT: whereas 10.9 and 14% of patients had such parameter increases in GOT and GPT, the proportion of patients fulfilling these criteria with respect to bilirubin, alkaline phosphatase and creatinine did not exceed 5% per category (Table 5). No correlation was found between drug exposure as a function of dose per body surface area and abnormal laboratory values.
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Reversible increases in hepatic transaminase values in healthy volunteers receiving concomitant ciclosporin A have been a safety issue in the clinical development of caspofungin. A comparison of hepatic function parameters of patients receiving ciclosporin A concomitantly with caspofungin with patients not receiving concomitant ciclosporin A revealed no differences overall between the two cohorts: similar proportions of patients had increased parameter values of GOT, GPT, bilirubin and alkaline phosphatase at EOT (Table 6).
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Responses to treatment with caspofungin are listed in Table 7. Ten of 16 patients (62.5%) receiving empirical therapy completed treatment with caspofungin without breakthrough fungal infection and survived; an additional three patients died on therapy from unrelated causes without fungal infection. Breakthrough infections occurred in three patients (18.7%): possible (1) and probable (1) pulmonary mould infection, and proven disseminated aspergillosis (1). All of these patients ultimately died. Among patients with possible, probable and proven invasive fungal infections, complete or partial responses were observed in 13/15 (86.7%), 7/14 (50%) and 12/17 (70.6%) of patients, respectively. Altogether, 42 of 62 patients (67.7%) evaluable for assessment of efficacy responded to treatment, and 20 (32.3%) were considered treatment failures. Overall survival was 75% at EOT (68, 88, 50 and 88% in patients with empirical therapy and treatment for possible, probable and proven infections). Survival at 3 months post-EOT was 70% (56, 88, 50 and 82% in patients with empirical therapy and treatment for possible, probable and proven infections, respectively).
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Relative to microbiological aetiology of the infection, 2/3 patients with candidaemia were cured and survived. The remaining patient became culture negative but died with presumed mitral valve endocarditis and disseminated adenoviral infection. Among the five patients with probable and proven chronic disseminated candidiasis, three had a complete (1) or partial (2) response and two stabilized; one patient (partial response) died on therapy from unrelated causes. Complete (2) and partial (3) responses or stabilization, respectively, were observed in 5/11 (45.5%) and 2/11 (18.2%) of patients with probable invasive aspergillosis; the overall survival rate was 45.5% at EOT and at 3 months post-EOT. Nine of 12 patients with proven invasive aspergillosis (75%) had a complete (3) or partial (6) response; one additional patient (8.3%) stabilized. The overall survival rate was 91.6% at EOT and 83.3% at 3 months post-EOT, respectively.
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Discussion |
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Cognizant of the limitations imposed by the retrospective nature of this survey, the lack of an appropriately validated paediatric dosage and the fact that approximately two-thirds of the patients received caspofungin as part of a combination regimen, we considered it important to analyse our collective clinical experience with this novel agent in children and adolescents judged to have no alternative therapeutic option. Indeed, caspofungin is being used worldwide in select paediatric patients with refractory infections or intolerance to standard agents who have similar demographic and therapeutic features as those accrued in our survey.13,14 While a paediatric programme has been initiated by the manufacturer of caspofungin and clinical trials are under way, their results, however, will not be available for some time.
In the interim, a sequential cohort, Phase I/II single and multiple dose pharmacokinetic trial of caspofungin in paediatric cancer patients aged from 2 to 17 years has been completed.19 Based on the faster clearance relative to adults in the subset of patients 2–11 years of age, a dosage of 50 mg/m2 has been selected for the further paediatric development. In our survey, the median daily maintenance dosage of caspofungin was 1.07 mg/kg or 34.3 mg/m2, respectively. More than half of the patients received the adult maintenance dosage of 50 mg/day; only five were treated at 50 mg/m2. Thus, in the absence of an established dosage, part of the patients may not have had the exposure documented to be effective in clinical trials performed in the adult population.6–8 The relevance of such differences in exposure to antifungal efficacy, however, is not entirely clear, since the concentration target of 1 mg/L at trough used in the development of the adult dosage is not based on pharmacokinetic/pharmacodynamic relationships but on the MIC90 value of a large set of Candida spp.2 and the assumption of exposure- and time-dependent pharmacodynamics.20,21
Most patients included in this survey received caspofungin in combination with other systemic antifungal agents. This may be reflective of current clinical practice in the salvage setting as observed in small sets of paediatric13,14 and in adult22,23 patients. Whereas there appear to be no fundamental safety issues, it is not clear to this date which combination may enhance therapeutic efficacy, and whether combination therapy is indicated upfront or whether it should be reserved for salvage therapy. Several retrospective14,22–24 and one prospective25 case series point to the potential usefulness of combination therapy. However, the ultimate answer to this important question can only be provided by randomized, comparative clinical trials that are currently being initiated.
Both the pattern and extent of potentially drug-related AEs observed in this paediatric survey do not appear to be substantially different from those reported for caspofungin in adults.3,6–8 Withdrawals due to AEs in adults were generally <5%3,6–8 and the most commonly observed adverse experiences observed in controlled studies included fever, increased liver transaminases, headache, gastrointestinal symptoms and skin rashes.3,6,8 In our survey, clinical AEs were mostly mild to moderate in nature and limited to possibly drug-related events. The most commonly recorded events occurring in five or more per cent of patients included fever, nausea and/or vomiting, diarrhoea, headache and skin eruptions. Mean bilirubin, alkaline phosphatase and creatinine values at the EOT were not different from baseline, and the proportion of patients with relevant increases in these values was <5%. There was, however, a slight increase in mean GPT and GOT values at the EOT with 14 and 11% of patients, respectively, displaying relevant increases in these values. Nevertheless, in none of the patients was therapy discontinued prematurely due to AEs. This overall favourable safety profile is in agreement with the favourable tolerance and safety in an earlier report on 25 paediatric cancer patients receiving caspofungin mostly in combination with liposomal amphotericin B for proven and suspected invasive fungal infections13 and the thus far limited experience with other echinocandins in paediatric patients.26,27
Due to transient elevations of hepatic transaminases not exceeding 2–3 times the upper limit of normal observed in early, single-dose Phase I interaction studies in healthy volunteers,28 the concomitant use of ciclosporin A is currently not recommended in patients receiving caspofungin unless the potential benefits outweigh the risk to the patient.29 Recently published retrospective analyses, however, suggest the absence of significant risks of clinically relevant transaminase elevations with the concomitant use of caspofungin and ciclosporin A in adults.30–32 Of note, the comparison of liver function tests of the 19 patients in our survey who received concomitant ciclosporin A to the remaining 45 patients who did not revealed no differences overall between the two cohorts. Similar proportions of patients had increased parameter values of GOT, GPT, bilirubin and alkaline phosphatase at the end of therapy.
Despite the obvious limitations of this survey, reporting of outcome is mandatory in the context of patient safety. Possible, probable or proven breakthrough infections occurred in 3/16 patients receiving empirical therapy (18.7%). Among patients with probable and proven infections, 19/31 (61.3%) evaluable for assessment of efficacy had either a complete (8) or partial (11) response. Overall survival was 75% at the EOT and 70% 3 months thereafter. Considering underlying illnesses, risk factors at baseline and the comparatively large percentage of patients who were granulocytopenic at start of treatment and during therapy, the outcome of patients included in our survey appears to compare well to that reported contemporaneously for antifungal salvage therapies in adults7,33,34 as well as in children.35–37
In conclusion, the results of this retrospective survey indicate that caspofungin, given as a single agent or in combination with other antifungal compounds for prolonged periods of time, is safe and may have useful efficacy in the management of invasive fungal infections in immunocompromised paediatric patients. While most patients received an individualized dosage, based on a recently completed pharmacokinetic study, a dosage of 50 mg/m2 with careful clinical and laboratory monitoring may be recommended if caspofungin is used in patients considered to have no alternative therapeutic option.
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Transparency declarations |
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A. H. G. has served as consultant to Merck, Sharp & Dohme, Munich, Germany; A. H. G., H. G. L. and T. L have served as clinical investigators for Merck & Co., Inc., Whitehouse Station, NJ, USA. All other authors: none to declare.
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Acknowledgements |
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We thank our colleagues Claudia Dannenberg (Leipzig), Claus Doerfel (Jena), Angelika Eggert (Essen), Matthias Pfeiffer (Tuebingen) and Marta Wnorowski (Vienna) for participating in this study. The study was supported by Merck, Sharp & Dohme, Munich, Germany. Merck, Sharp & Dohme, Munich, Germany and Merck & Co., Inc., Whitehouse Station, NJ, USA had no role in data analysis or submission of this article. The results of this survey were presented in part at the Forty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2004.
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References |
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