How Often Should GPA Patients Be Tested for Leukopenia?

By Atul Khasnis, MD

Treatment with high-dose glucocorticoids and cyclophosphamide (CYC) is an effective therapy for patients with severe granulomatosis with polyangiitis (GPA) (Wegener’s). However, CYC use is associated with several adverse effects, including infection, malignancy and hematologic or bladder toxicities. Leukopenia is one of the most common adverse effects of CYC and typically occurs 10 to 14 days after the oral CYC dose. Patients may be more predisposed to leukopenia from CYC use if they have been subjected to multiple previous courses of CYC therapy or have been exposed to CYC for prolonged periods in the past. Concomitant glucocorticoids can confound the quantitative as well as immunologic assessments of WBCs in patients with GPA.

Severe infection is the most dreaded consequence of leukopenia (especially neutropenia). Notably, a recent meta-analysis of the trials conducted by the European Vasculitis Group showed that 50 percent of the reported first-year mortality in patients with GPA was attributable to infection vs. only 14 percent attributable to active vasculitis.1 Half of these infections occurred in the first two months, which is when patients are most likely to be on induction therapy with a combination of CYC and high-dose glucocorticoids.

How Often to Monitor for Leukopenia?

Serious adverse outcomes of leukopenia, including sepsis and potentially death, can very likely be prevented with appropriate monitoring. However, there are no standardized recommendations for WBC monitoring while patients are on CYC therapy. In addition to the serious medical implications of suboptimal WBC monitoring, there are serious potential cost implications of missing the opportunity to intervene for leukopenia. These cost implications range from development of non-life-threatening infection requiring treatment with antibiotics to life-threatening sepsis requiring intensive care and with a serious impact on quality of life.

At Cleveland Clinic’s Center for Vasculitis Care and Research, we check the CBC weekly for the entire time that patients are on CYC. To assess the potential merits and drawbacks of this approach, we undertook a study to compare the cost-effectiveness of two CBC monitoring strategies ‒ weekly vs. monthly ‒ for surveillance of leukopenia and its consequences in patients treated with CYC for severe GPA.

Cost-Effectiveness Methodology

For the weekly CBC monitoring arm, we used Cleveland Clinic’s GPA database, which includes patients with GPA referred to and managed at Cleveland Clinic between 1992 and 2004. For the monthly arm, we used published studies from the literature involving patients with GPA who received oral CYC or both oral and intravenous CYC. For studies with patients on both oral and intravenous CYC, only data regarding the oral CYC group were used for analysis.

The two CBC monitoring approaches were compared using a decision analysis model (TreeAge Pro™ software) (Figure 1) and a societal perspective. The willingness-to-pay threshold was set at $50,000. The selected studies were screened carefully for the following: strategy for monitoring CBC, incidence of leukopenia (severe and nonsevere), incidence of infectious complications (severe and nonsevere) and mortality attributable to infection. For our analysis, leukopenia was defined as a WBC count less than 4,000/mm3 and severe leukopenia as a WBC count less than 2,000/mm3. The prevalences of leukopenia, infections and outcomes were obtained from an existing registry and published reports. Costs were in 2010 dollars, and effectiveness was defined as quality-adjusted life-years (QALYs) gained, which is a measure of disease burden reflecting both the quantity and quality of life lived.

Figure 1. Decision tree used for the cost-effectiveness analysis.

After the probabilities, costs and estimates of QALYs were entered into the decision tree, an initial rollback analysis was performed, followed by a cost-effectiveness analysis and then by a one-way deterministic sensitivity analysis for each variable in the decision tree. Finally, a probabilistic sensitivity analysis (Monte Carlo simulation) was performed.

Results: Weekly Dominates Monthly

Demographic data were available for 131 patients ‒ 62 females (47 percent) and 69 males (53 percent) ‒ from Cleveland Clinic’s GPA database (weekly CBC arm). The frequencies for variables in the monthly CBC arm were derived from a literature review. The frequency of severe infection given severe leukopenia was 3 percent in the weekly CBC arm compared with 10 percent in the monthly CBC arm. Our results showed that the expected utility of weekly CBC monitoring for leukopenia in these patients was 18.74 QALYs, as compared with 18.52 QALYs for monthly CBC monitoring (Figure 2).

Figure 2. Quality-adjusted life-year (QALY) outcomes among 131 Cleveland Clinic patients with GPA undergoing weekly CBC monitoring and a literature review-based comparator group undergoing monthly CBC monitoring. The weekly monitoring group achieved a gain in QALYs, as shown, while incurring a lower average cost per patient (see text).

Weekly CBC monitoring yielded an expected gain of 0.22 QALYs and incurred $489 less in cost per patient compared with monthly monitoring. We therefore concluded that weekly CBC monitoring is cost-effective for prevention of severe leukopenia and severe infections in patients on daily CYC for severe GPA.

Although measuring WBC counts allows us to assess only one facet of the effects of CYC on leukocytes, it is a practical and economically feasible testing strategy. It is important to remember that glucocorticoid use also should be factored into the analysis, since glucocorticoids have qualitative and quantitative effects on leukocytes and patients are also on high doses of glucocorticoids during the induction phase of treatment for GPA. Likewise, it is important to remember that there are indirect consequences of severe infections beyond hospitalization, such as the morbidity that can occur after such events, and that these can have significant impact on patients’ quality of life.

Reference

1. Little MA, Nightingale P, Verburgh CA, et al. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. Ann Rheum Dis. 2010;69(6):1036-1043.

Dr. Khasnis is a member of the Center for Vasculitis Care and Research. His interests include vasculitis and general rheumatology.