FDA Approves Revlimid and Dacogen for the Treatment of Myelodysplastic Syndromes

The FDA granted Sub-part H approval for Revlimid® (Celgene Corporation) on December 28, 2005, for the treatment of transfusion-dependent anemia in patients with IPSS Low or Intermediate-1 risk MDS with chromosome 5q deletion. This was based upon the results of a multicenter phase-II study and the initial phase I experience. The pivotal safety and efficacy study included 148 patients with transfusion-dependent anemia and the 5q deletion either with or without additional cytogenetic abnormalities. Eligibility was restricted to patients who received two or more units of red blood cells every eight weeks, with a primary study endpoint of red blood cell (RBC)-transfusion independence after completion of 24 weeks of treatment. Response was assessed using a modified International Working Group (IWG) response criterion in which transfusion independence was sustained for eight weeks or longer with a concordant minimum 1 g/dL rise in hemoglobin. Revlimid® was administered at a dose of 10 mg every 21 days in a 28-day cycle, and later changed to a continuous dosing schedule. Secondary objectives in the study included central review of both cytogenetic and pathologic response. In an intention-to-treat analysis, 112 patients (76 percent; 95 percent confidence interval, 68 percent to 82 percent) achieved a transfusion response by week 24, and 99 patients (67 percent; 95 percent confidence interval, 59 percent to 74 percent) achieved transfusion-independence which was independent of karyotype complexity. The time to response was rapid (median, 4.6 weeks), and durable, with a majority of patients remaining transfusion-free beyond one year. Overall, 90 percent of responding patients demonstrated evidence of response within three months of initiating Revlimid® treatment. Unlike cytokine therapy, erythroid response in this karyotypically-defined disease subset was closely associated with cytogenetic response. Seventy-three percent of the patients experienced cytogenetic improvement, which included a complete cytogenetic response in 45 percent of patients. Overall, all cytogenetic responders achieved transfusion independence - indicating strong concordance with hematologic improvement.

Myelosuppression, characterized as moderate-to-severe neutropenia (55 percent) or thrombocytopenia (44 percent), was the most common adverse event requiring treatment interruption and dose reduction to either 5mg daily or 5mg every other day. Other less common adverse events were generally of mild severity and included diarrhea (49 percent), pyrexia (42 percent), rash (36 percent), and fatigue (31 percent). Overall, 80 percent of patients required treatment interruption and dose reduction for management of myelosuppression or other toxicities during this study. Although recent trials conducted in multiple myeloma reported a significantly increased risk of thromboembolic events when lenalidomide was combined with dexamethasone, thromboembolic events were rare in the lenalidomide studies involving patients with MDS. Because of its structural resemblance to thalidomide, the FDA approved lenalidomide with a special restricted distribution program, termed RevAssist, in which women of childbearing age must be advised to avoid pregnancy while taking lenalidomide since animal studies cannot exclude a potential for teratogenic effect in humans. Given its action to suppress the deletion 5q clone and restore erythropoiesis, the label recommends close observation in the first two months of treatment, with weekly complete blood counts when the majority of patients may experience limiting myelosuppression. Because lenalidomide is predominately excreted by the kidney, dose adjustments should be considered for patients with renal dysfunction. Only prescibers and pharmacists that are registered under the RevAssist program can prescribe or dispense the agent. The high frequency of cytogenetic and erythroid response in patients with either isolated chromosome 5q deletion or additional cytogenetic abnormalities suggest that this agent may impact the natural history of the disease in higher-risk patients with greater karyotype complexity. New studies are now underway to explore the agent's potential in both higher-risk MDS and elderly acute myeloid leukemia (AML) harboring deletion 5q.

On May 2 of this year, the FDA approved injectable decitabine (Dacogen®, MGI Pharma, Inc.) for the treatment of MDS patients of all morphologic subtypes according to the French-American-British (FAB) classification system with IPSS Intermediate-1, Intermediate-2, or High-risk disease. After extensive phase II experience, the pivotal study reviewed by the FDA was an open-label multicenter randomized trial involving 170 patients. Eighty-nine patients were randomized to receive decitabine as an intravenous three-hour infusion at a dose of 15 mg/m² every eight hours for three consecutive days, and 81 patients received supportive measures only. Decitabine treatment was repeated every six weeks depending upon clinical response, recovery, and toxicities. Supportive measures included blood product transfusions, recombinant hematopoietic growth factors, and prophylactic antibiotics. The dual primary endpoints included the overall frequency of complete and partial response in the intent-to-treat population, and time to AML progression or death. Responses were classified using the IWG criteria in which hematologic improvements were sustained for a minimum of eight weeks and complete pathologic response required elimination of cytologic dysplasia. The overall response rate (complete and partial) was 17 percent in decitabine-treated patients (complete, 9 percent), compared to 0 percent in the supportive care arm (P<0.001). Hematologic improvement according to standard IWG criteria was reported in an additional 13 percent of decitabine-treated patients compared to 7 percent of patients in the supportive care arm. The median duration complete and partial response in the decitabine-treated patients was 288 days, with a corresponding median time to response of 93 days, or approximately three cycles of therapy. Overall, all but one of the decitabine-responders achieved complete or partial remission by the fourth cycle of therapy. Although decitabine did not significantly delay the median time to acute myeloid leukemia or death (p=0.160, L-rank analysis), patients with high risk IPSS category (N=44) experienced a significant prolongation in the interval to AML or death from 2.8 months to 9.3 months (p=0.010).

Results from two additional open-label multicenter phase II studies (which included 164 patients with all FAB subtypes) supported the pivotal study findings. Using a similar dosing schedule, the overall frequency of complete and partial response in these studies was 26 percent (n=66) and 24 percent. The major toxicity of decitabine in each of these studies included neutropenia, thrombocytopenia, anemia, and febrile neutropenia. Overall, 23 percent of patients treated with decitabine experienced febrile neutropenia compared to 4 percent of patients with supportive care. Moderate to severe thrombocytopenia was reported in 85 percent of the treated patients compared to 43 percent of controls. There was no significant difference in the overall frequency of study deaths in the decitabine compared to supportive care treatment groups (14 percent vs. 22 percent). Other adverse effects of generally mild severity included nausea, vomiting, diarrhea, constipation and edema, and hyperglycemia.

With the approval of decitabine, the MDS community has a second agent that may benefit patients with higher-risk disease by impacting AML progression and may possibly alter the natural history of the disease. Alternate schedules and doses of decitabine are currently under investigation, which may offer improved response rate and lower toxicity. The full impact that these new agents may have for patients with MDS will take some time to be realized. Nonetheless, these are welcome additions for the treatment of MDS, allowing for greater choices of active therapeutics with increasing probability of benefit.