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Keywords:

  • invasive aspergillosis;
  • galactomannan;
  • surrogate endpoint;
  • correlation;
  • galactomannan;
  • invasive aspergillosis;
  • outcome

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Determining the outcome of patients with aspergillosis can be particularly difficult because patients with aspergillosis are at risk for other conditions that mimic this infection. Galactomannan is an Aspergillus-specific antigen released during invasive aspergillosis and is detected by the quantitative serum galactomannan index (GMI) test.

METHODS.

Using a kappa correlation coefficient test (KCC), the strength of correlation was determined between GMI and survival outcome of aspergillosis among 56 adults with hematologic cancer (90% had myeloma) who underwent serial GMI monitoring until hospital discharge or death.

RESULTS.

All 56 patients received antineoplastic therapy (myeloablative followed by stem cell transplantation [autologous in 21 patients and allogeneic in 3 patients] or nonmyeloablative therapy [32 patients]). The overall correlation between survival outcome and GMI was excellent (KCC = 0.8609; 95% confidence interval [95% CI], 0.7093–1.000 [P < .0001]) and was comparable among neutropenic and nonneutropenic patients (KCC = 0.8271; 95% CI, 0.6407–1.000 [P < .0001] and KCC = 1.0; 95% CI, 1–1 [P = .0083], respectively).

CONCLUSIONS.

The survival outcome of patients with aspergillosis strongly correlated with serum GMI. These findings have important implications for patient care and clinical trials of mold-active antifungal agents. Cancer 2007; 110:830–4. © 2007 American Cancer Society.

Despite the availability of active antifungal agents, invasive aspergillosis among patients with hematologic cancers continues to cause high morbidity, mortality, and resource utilization.1–6 Assessing aspergillosis outcome can be particularly difficult because patients with aspergillosis are at risk for other infections and conditions that may mimic this infection. Precise outcome evaluation is critical because of its implications for managing patients, such as the need for invasive diagnostic procedures and/or alternative therapies. Because repeat microbiologic and histopathologic sampling is difficult in these critically ill patients, conventional outcome evaluation of aspergillosis frequently relies on subjective and nonspecific variables such as signs and symptoms and nonstandardized operator-dependent radiologic findings. A noninvasive Aspergillus-specific, objective, reproducible, measurable, and quantitative endpoint is clearly needed. Galactomannan is an Aspergillus-specific antigen that is hematogenously released during invasive aspergillosis and is detectable by a commercially available test.7

We herein analyze the strength of correlation between serum galactomannan index (GMI) values and survival among 56 patients with cancer with aspergillosis.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The study was conducted at the University of Arkansas for Medical Sciences between November 2003 and January 2007 and was approved by the Institutional Review Board.

Inclusion Criteria

Patients with hematologic cancer and proven or probable aspergillosis was as defined by the European Organisation for Research and Treatment of Cancer/Mycology Study Group (EORTC)/MSG8: ≥2 consecutive positive serum GMI (optical density [OD] of ≥0.5) and sequential (at least weekly) serum galactomannan testing after diagnosis of aspergillosis, including within 1 week of outcome evaluation (discharge or death, whichever occurred first). Patients receiving piperacillin-tazobactam or amoxicillin-clavulanate during the infectious episode were excluded.

Testing

Serum galactomannan testing was performed and reported according to the manufacturer's instructions (Platelia Aspergillus EIA; Bio-Rad, Redmond, Wash). Sera with an index ≥0.5 were retested the following day and considered positive if the GMI was ≥0.5.

All patients were prospectively followed by 1 of the investigators (E.A.). The frequency of GMI testing was at the discretion of the primary physician until January 2005, after which testing was performed daily when serum galactomannan was ≥0.5. Testing was continued until death or discharge. The date of diagnosis of aspergillosis was defined as the date of the first of 2 consecutive positive serum galactomannan.

Neutropenia was defined as an absolute neutrophil count (ANC) <1000 cells/μL; severe neutropenia was defined as an ANC <100 cells/μL. High-dose steroids were defined as the receipt of dexamethasone at a dose ≥80 mg.

Outcome Definitions

Success

Success was defined as repeatedly negative serum GMI values in the absence of new extrapulmonary lesions of aspergillosis (eg, a skin lesion that was culture positive and/or with hyphal tissue invasion consistent with aspergillosis) for at least 2 weeks after the first negative GMI.

Failure

Failure was defined as persistently positive serum GMI. Patients who died within 2 weeks after normalization of GMI values were considered failures unless autopsy examination failed to reveal aspergillosis.

We selected serum GMI as an outcome variable because the test is Aspergillus-specific, objective, quantitative, and shown to be an accurate measure of fungal load9 and a validated surrogate endpoint for aspergillosis outcome.10–12 We also evaluated survival because it is an important and objective clinical outcome.

Death within 2 weeks of the first negative serum GMI was considered failure in the absence of autopsy examination, even when other conditions contributed to or were the primary apparent cause of death (eg, progressive cancer). Patients with aspergillosis have significant mortality, frequently from causes other than aspergillosis, particularly when death occurs later during the course of aspergillosis.13 To account for this late nonfungal mortality, we selected a 2-week cutoff period for mortality after the first negative GMI.

Statistical Analysis

The kappa correlation coefficient (KCC) test was used to assess the correlation between GMI values and survival. Concordance was considered to be perfect when the kappa was 1.0, excellent when ≥0.75, good if between 0.4 and 0.75, and marginal if ≤0.4.14 Statistical significance was defined as P ≤ .05. Survival functions for different galactomannan levels (OD <0.5 and ≥0.5) were further estimated using the Kaplan-Meier product-limit method and compared by log-rank test. For patients who failed, the survival time was the actual number of days from the date of the first positive GMI until death. For patient who succeeded, the survival time was censored at 2 weeks after the first negative GMI and computed as 14 days plus the interval between the first positive and first negative GMI. SAS software (version 9.1; SAS Institute Inc, Cary, NC) was used for this study.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Fifty-six patients had proven/probable aspergillosis (myeloma [51 patients; 91%], non-Hodgkin lymphoma [3 patients], and aplastic anemia and acute myeloid leukemia [1 patient each]); 19 were in remission of their underlying disease. The median age of the patients was 59 years (range, 27–76 years) and 32 patients were male. All 56 patients received antineoplastic therapy within 90 days of the diagnosis of aspergillosis (myeloablative followed by stem cell transplantation [autologous in 21 patients and allogeneic in 3patients] or nonmyeloablative [32 patients]).

Forty-six patients (82%) were severely neutropenic at the time of diagnosis (mean, 10 days; range, 1–69 days) and 45 had received high-dose steroids within 60 days of aspergillosis (mean, 20 days; range, 1–57 days). All patients but 1 were not receiving mold-active antifungal prophylaxis. A mean of 9 serum GMI tests per patient were positive (range, 2–60 tests). Time to first positive serum GMI test after myeloablative and nonmyeloablative chemotherapy was 14 days (range, −2 to 44 days) and 23 days (range, 5–74 days), respectively.

Respiratory tract cultures (sputum, bronchoalveolar lavage fluid, sinus drainage, and/or tracheal aspirate) yielded Aspergillus species in 11 patients, whereas septate hyphae, consistent with Aspergillus species, were identified in biopsy specimens of 4 patients (lungs [2 patients] and sinuses and esophagus [1 patient each]). Thirty patients died at a mean of 72 days after diagnosis (range, 2–400 days) and serum GMI at death was persistently positive in 12. Eighteen patients died without evidence of aspergillosis at a mean of 92 days (range, 2–393 days) after normalization of serum GMI. In 4 of these patients, Aspergillus antigenemia had resolved within 14 days of death; these patients were therefore considered as failures of therapy. One patient underwent autopsy examination that revealed invasive aspergillosis.

Overall, a strong correlation was present between serum GMI and outcome of aspergillosis (KCC = 0.8609; 95% confidence interval [95% CI], 0.7093–1.000 [P < .0001]), regardless of neutrophil status at diagnosis (KCC = 0.8271 [95% CI, 0.6407–1.000; P < .0001] and KCC = 1 [95% CI, 1–1; P = .0083]) for neutropenic and nonneutropenic patients, respectively).

The survival of patients whose serum GMI titers normalized was significantly better compared with those whose titers remained persistently positive (P < .0001) (Fig. 1).

thumbnail image

Figure 1. Survival of 56 patients with hematologic cancer and invasive aspergillosis monitored with serum Aspergillus galactomannan. GMI indicates galactomannan index.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Our results indicate that serum GMI values correlate strongly with aspergillosis outcome in both neutropenic and nonneutropenic adults with hematologic cancer receiving various antineoplastic therapies. The power of this correlation would have been stronger had autopsy been performed on patients who died within 2 weeks of their first negative GMI.

Persistently elevated GMI values were associated with failure and death in contrast to survival and success among patients whose Aspergillus antigenemia resolved. To our knowledge, this is the first study to evaluate the correlation between serum GMI and aspergillosis outcome using an established statistical test of correlation and the first to correlate serum GMI results with survival. To our knowledge, this study is also the largest to date to include serial and frequent serum GMI monitoring until outcome evaluation.

That serum galactomannan values correlate with clinical outcome is supported by our findings among 19 neutropenic patients with aspergillosis (6 in this series) who developed transient deterioration during neutrophil recovery. Because deterioration coincided with rapid normalization of daily serum GMI and neutrophil recovery, we interpreted the transient deterioration as an immune reconstitution and inflammatory syndrome and continued the same antifungal therapy (with the addition of methylprednisone in 2 patients) with complete aspergillosis response and survival.12

A correlation between the kinetics of serum GMI and aspergillosis outcome was suggested in 2 previous reports.15, 16 Boutboul et al.15 reported that 37 patients with aspergillosis, serum GMI values increased in the treatment failure group compared with the group of responders (P = .002) and that a GMI increase ≥1.0 over baseline value during the first week of monitoring was predictive of treatment failure (sensitivity of 44% and specificity of 87%). Among patients with aspergillosis who had sequential serum GMI, Herbrecht et al.16 reported that a significantly higher response rate was observed among patients whose GMI normalized (<0.5) between 5 to 9 days after therapy.

In contrast to these 2 studies, we included survival, an important and unambiguous outcome endpoint, and evaluated the correlation between serum GMI and outcome using an established statistical test of correlation. Using the same statistical test, we have also previously shown strong correlation between survival outcome in aspergillosis and serum GMI in 228 patients reported in the literature.11 Our current findings further support the strength of this correlation and imply that frequent GMI monitoring after diagnosis of aspergillosis is important to evaluate treatment response. Persistently positive GMI values imply unresolved infection requiring treatment modifications in contrast to aspergillosis response among those who antigenemia resolves.

These results support our previous findings that established GMI is a validated surrogate endpoint for aspergillosis outcome and that the test should be considered both as an enrollment criterion and an outcome measure in clinical trials of aspergillosis. Incorporating surrogate endpoints in clinical trials offers several benefits including decreasing trial duration and costs and improving trial accuracy, all of which likely expedite approval of therapies against aspergillosis.

Our findings are limited by the very small number of allogeneic hematopoietic stem cell transplantation recipients and should be confirmed and expanded into other patient populations at risk for aspergillosis.

We conclude that serum GMI values strongly correlate with survival outcome among adults with hematologic cancer and aspergillosis. This strong correlation has significant implications for patient care and for the design of trials of novel antifungal strategies.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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