Decitabine Low-Dose Schedule (100 mg/m²/course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.

Decitabine, a hypomethylating agent, has shown activity in MDS, acute myeloid leukemia (AML), and chronic myeloid leukemia. In this study, we investigated optimizing the dose schedule. Patients with IPSS intermediate 1–2 and high risk were randomized to one of 3 schedules of decitabine: 1) 20 mg/m² IV over 1 hour daily x 5; 2) 10 mg/m² IV over 1 hour daily x 10; or 3) 10 mg/m² subcutaneously (SQ) BID x 5. A total of 90 patients are to be treated. Randomization is equal until the 45^th patient after which a Bayesian (play by the winner) randomization is implemented based on CR rates. Courses were given every 28 days regardless of counts, as long as counts recovered to pretreatment + evidence of disease on repeat marrow + no significant myelosuppression complications. Delays to allow for recovery of counts were permitted every 3 courses, or in the presence of myelosuppression without disease or severe myelosuppression-related complications. Patients were allowed to receive erythropoietin 40,000 units weekly for anemia, or GCSF if needed during febrile neutropenia. Response criteria for CR and PR were as for AML (PR requiring also decrease blasts by >50%). Clinical benefit (CB) referred to one or more of the following: platelets increase by 50% and above 30 x 10⁹/L, or granulocytes increase by 100% and to above 10⁹/L, or hemoglobin increase by 2 g/dl or transfusion independence, or splenomegaly decrease by 50% or more, or monocytes decrease by 50% or more (pretreatment >5 x 10⁹/L). 43 patients have been treated; median age 63 years (range 39 to 90); 60 (26%) were ≥ 60 years old. IPSS risk: intermediate 1 –13 (30%); intermediate 2–13 (30%); high-(23%); CMML-7(16%). Cytogenetic abnormalities were present in 56%; secondary MDS in 23%; marrow blasts ≥ 10% in 30%. 22 patients had prior erythropoietin; 9 had prior GCSF; 12 had other prior therapies (thalidomide 6, azacytidine 2, other 4). Presently, 36 patients have received at least 1 course of therapy. Results were: 10 CR (28%); 3 PR (9%); 18 CB (50%); overall response 31/36=86%. 22(51%) patients required hospitalizations for fever and neutropenia. Median courses to CR was 1 (range 1 to 3); 5 patients (50%) needed 2 or more courses to achieve CR. With a median follow-up of 4 months, 5 have evolved into AML; 4 have died (2 AML; 2 MDS); 35 patients continue on decitabine therapy. Compared with a historical group of 54 patients with MDS who received intensive chemotherapy (2000–2003) and matched for age, cytogenetics and IPSS/FAB, the CR rate was lower with decitabine (28% vs 47%), but the overall response rate was favorable; the 8-week mortality was also lower with decitabine (7% vs 26%); and estimated survival favorable (6-month rates 80% vs 67%). CR rates by schedule were: 5 days IV 6/15 (40%); 5 days SQ 2/11 (18%); 10 day IV 2/10 (20%). There was more myelosuppression with the 10 day IV schedule. We conclude that 1) decitabine at this low-dose schedule has major anti- MDS activity in the setting of poorer risk MDS; 2) the optimal dose schedule is being defined; 3) side effects are acceptable; 4) timely and repeated courses of decitabine therapy is required for optimal response results.