Managed Care - July 2008 - (Page H7) In an intent-to-treat (ITT) analysis, 112 patients (76 percent) had a reduced need for transfusion by week 24, and 99 patients (67 percent) achieved TI, regardless of complexity of cytogenetic abnormalities (List 2006). The time to response was rapid (median, 4.6 weeks) and durable, with the majority of patients remaining transfusion-free after 1 year. Overall, 90 percent of patients who responded to treatment demonstrated evidence of response within 3 months of beginning lenalidomide treatment. ER among patients was closely associated with cytogenetic response. A complete cytogenetic response occurred in 45 percent of patients, and 73 percent of patients experienced cytogenetic improvement. Most patients with cytogenetic response achieved TI, indicating a strong correlation between cytogenetic response and hematologic improvement. The most common adverse event in this study was myelosuppression, which required treatment interruption or dose reduction in patients with moderate-tosevere neutropenia (55 percent) or thrombocytopenia (44 percent). Less common adverse events, including diarrhea, pyrexia, rash, and fatigue, were generally mild. Patients without chromosome 5q deletion. Recent published results from a multicenter, phase 2 trial with a similar study design provided eagerly awaited information about the use of lenalidomide in patients without chromosome 5q deletion (Raza 2008). As with the previous trial, these participants were low/intermediate-1 risk, transfusion-dependent patients. The primary endpoint was TI (2 months without transfusions) and an increase in hemoglobin level. Eligible patients had 50,000/mm3 or more platelets and required two or more units of RBCs within the previous 8 weeks; 214 patients received either 10 mg oral lenalidomide daily or 10 mg on days 1 to 21 of a 28-day cycle with 7-day breaks. Using an ITT analysis, 56 (26 percent) patients achieved TI after a median of 4.8 weeks of treatment, with a median TI duration of 41.0 weeks; thus, as with patients with the 5q-deletion, the time to initial response was rapid. In patients who achieved TI, the median rise in hemoglobin was 3.2 g/L from baseline. A 50 percent or greater reduction in transfusion requirement occurred in 37 additional patients, resulting in an overall 43 percent rate of hematologic improvement. As with the previous trial, the most common grade 3/4 adverse events were neutropenia (25 percent) and thrombocytopenia (20 percent). Although TI occurred in a smaller number of patients compared with the previous trial, patient responses were rapid and durable. These studies, which demonstrate that lenalidomide has clinically meaningful activity in transfusion-dependent patients with low- or intermediate 1-risk MDS, either with or without the 5q deletion, have prompted trials of lenalidomide in higher-risk patients with greater kary- otype complexity. New studies are currently exploring the agent’s potential in both higher-risk MDS and in elderly patients with AML, both with and without chromosome 5q deletion. Hypomethylating agents. Hypomethylating agents have been a major focus of clinical research during the past few years. The two best-studied hypomethylating agents are the structurally similar analogs decitabine and azacitidine, both of which have been evaluated and approved for use in patients with advanced or high-risk MDS. Although these agents are typically used in patients who are not candidates for high-intensity therapy, the NCCN panel recently determined that they also are appropriate for patients with intermediate-2/high-risk MDS who may be candidates for intensive therapy but who lack an available donor for hematopoietic stem cell transplantation (NCCN 2008). Hypomethylating agents work by restoring the inactivation of tumor suppressor genes caused by aberrant DNA methylation in patients with MDS. These agents have been proven to inhibit DNS methylation, reactivate tumor suppressor genes, and trigger apoptosis in aberrant cells. Azacitidine. Azacitidine, the first hypomethylating agent approved specifically to treat MDS, is administered by subcutaneous injection. In clinical trials, intermediate-2/high-risk patients treated with azacitidine had longer overall survival compared with patients who received best supportive care or conventional treatment (Fenaux 2007). In most trials, one subcutaneous injection of azacitidine was given daily for 7 days every 4 weeks. Patients had durable hematologic improvements, including increases in RBC counts and TI, increases in hemoglobin, increases in WBC or platelet numbers, and/or decreases in the percentage of bone marrow blasts (Silverman 2006). In some clinical trials, the time to onset of AML was significantly delayed in patients who were treated with azacitidine compared with patients who did not receive the agent (Silverman 2006). All patients in these clinical trials received supportive care regardless of whether they received azacitidine. Alternative dosing of azacitidine has been explored both in clinical settings and in a number of clinical trials (Lyons 2008). Despite disease improvement with azacitidine, many patients with MDS find the frequent dosing schedule to be inconvenient. To determine whether alternative azacitidine regimens resulted in efficacy and safety comparable to 7-day regimens, Lyons conducted a phase 2, prospective, multicenter, openlabel study to evaluate three different dosing schedules. Patients were randomized to receive 1 of 3 regimens for six 28-day cycles. A 2-day, no-treatment period was used in two arms to test the possibility of eliminating weekend dosing. In the first regimen, AZA-5, patients received azacitidine 75 mg/m2/day for 5 days (n=50). In the second regimen, AZA-5-2-2, patients received azacitidine SUPPLEMENT / HEMATOLOGIC CANCER 7
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