Managed Care - July 2008 - (Page H6) whose serum EPO level is below 500 mU/mL. Some patients may derive additional benefit when EPO is combined with growth factors that stimulate the bone marrow to produce WBCs; this combination may result in a synergistic erythroid effect. The combination of EPO and G-CSF appears to be most beneficial for patients in the IPSS low-risk or intermediate-1 risk group. Darbepoetin. A major change to the NCCN guidelines in 2007 involved the addition of darbepoetin alfa (Aranesp) as a recommended alternative to EPO for anemic patients with low/intermediate-1 risk MDS. Darbepoetin is a related but longer-acting form of EPO; it requires only once-weekly dosing, compared with EPO, which may require dosing as often as three times a week. As with EPO, darbepoetin is most effective in patients with low-risk MDS who have low blood serum EPO levels (<500 mU/mL). A number of studies indicate that darbepoetin is a relatively safe and well-tolerated treatment for anemia. Combined major and minor ER rates of 40 to 60 percent that were demonstrated in studies that used the IWG response criteria suggest that darbepoetin is an effective agent that may offer patients a significant QoL improvement (Musto 2005, Mannone 2004). Clinical trials have suggested that overall response rates to darbepoetin are similar to and, in some cases, higher than response rates to EPO (Musto 2005, Stasi 2005). A meta-analysis of clinical trial results also found that higher initial doses of either agent and lower baseline serum EPO levels correlated with higher response rates among patients (Table). Findings from these studies suggest that appropriate patient selection is an important issue with regard to the use of ESAs. Neither EPO nor darbepoetin is recommended in patients with serum EPO levels above 500 mU/mL because such patients are unlikely to respond to either agent. In addition, all patients receiving ESAs should be monitored appropriately to ensure that these agents are discontinued in a timely fashion when they prove to be ineffective; currently, many patients continue to receive these TABLE agents even when they fail to produce a meaningful response. Lenalidomide. Lenalidomide, an analogue of thalidomide, is part of a proprietary class of drugs called immunomodulatory drugs. It has both immunologic and pharmacologic effects that include cytokine- and immune-modifying properties, modulation of signals in the microenvironment that surrounds diseased clonal cells, and anti-angiogenesis. Lenalidomide’s multiple mechanisms of action result in effective activity in patients with multiple myeloma as well as those with MDS. In the latter group, lenalidomide has additional effects, including enhanced EPO receptor signaling that restores effective erythropoiesis in normal and malignant stem cells. In patients with deletion of chromosome 5q, lenalidomide is directly cytotoxic and thus highly effective in suppressing aberrant precursor cells. Although lenalidomide has proven to be an effective agent for the treatment of MDS, its studies have generally focused on low and intermediate-1 risk MDS; conclusive data on lenalidomide’s effectiveness in intermediate-2 or high-risk patients is not available. Patients with chromosome 5q deletion. In 2005, the FDA approved the use of lenalidomide for the treatment of transfusion-dependent anemia in patients with IPSSranked low or intermediate-1 risk MDS with chromosome 5q deletion. This approval was based upon the results of a multicenter phase 2 study. This pivotal safety and efficacy study involved 148 patients with transfusion-dependent anemia and the 5q deletion, either with or without additional cytogenetic abnormalities (List 2006). The primary study endpoint was RBC-transfusion independence (TI) after completion of 24 weeks of treatment. Response was assessed using modified IWG response criteria. Lenalidomide was initially administered at an oral dose of 10 mg every 21 days in a 28-day cycle, and later was administered on a continuous dosing schedule. Secondary endpoints in the study included duration of ER, neutrophil and platelet responses, and cytogenetic response; data regarding safety also was obtained. Comparative meta-analysis of erythroid response rates for EPO and darbepoetin Parameter Erythroid response (%) (95% CI) Standard versus higher dose erythroid response rates (%)* Darbepoetin studies 59.4 (49.0–69.9) 47.8 vs. 63.3 EPO studies 57.6 (45.1–70.0) 52.6 vs. 71.1 P =.8282 150 mcg. Source: Mundle 2006 6 MANAGED CARE / SUPPLEMENT
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