Dose Dense, High Intensity Therapy in Newly Diagnosed Elderly Patients with Acute Myeloid Leukemia Using Gemtuzumab Ozogamicin (Mylotarg™) and High Dose Cytarabine (HiDAC).

The failure to overcome drug resistance leads to a high rate of relapse in elderly patients with acute myeloid leukemia. We evaluated, in a Phase I study the feasibility of a dose dense regimen of HiDAC, and MylotargTM therapy for newly diagnosed elderly (≥60 years) patients with AML in terms of toxicity with two cycles of this regimen as the sole induction and consolidation therapy. HiDAC was administered in a dose escalation pattern: 3000mg/m2 intravenously given for 6, and 9 doses, and MylotargTM was administered at a dose of 6mg/m2 intravenously on days 1 and 8 of each cycle. Patients without unacceptable toxicity, defined as failure to recover counts to a minimum of ANC ≥ 500/ μl, platelets ≥ 30K and hematocrit ≥ 25%, received a second cycle of therapy, though not before day 28 following day 1 of induction. In addition, death within the first 30 days of induction (not related to disease progression) and life-threatening non-hematologic toxicity (such as cardiac or pulmonary arrest) was also considered dose-limiting. Patients with persistent disease but at least a 50% decrease in the marrow or peripheral blood blast count, or those with low blood counts and patients achieving CR without platelet recovery (CRp) at the 4–6 week examination received cycle 2 with a de-escalation of the Mylotarg dose (from 6 mg/m2 to 4 mg/m2). All patients received G-CSF 5mcg/kg/day subcutaneously from days 11–14. Eight patients (five male, three female) with a median age of 68 years (range 60–74) were enrolled. In cohort one (6 doses of HiDAC), four of six patients were able to complete both cycles of therapy and two of these have achieved CR. Two of the six patients achieved CRp with persistent thrombocytopenia and thus received a second cycle of chemotherapy off protocol. One patient in this cohort had progressive disease and persistent pancytopenia requiring transfusions and subsequently received chemotherapy using Etoposide and Cyclophosphamide. Five out of six patients are alive and remain disease free. In cohort two (9 doses of HiDAC), two patients have been enrolled thus far. One patient developed neurotoxicity after six doses of HiDAC and thus completed both cycles of therapy with six doses of HiDAC along with protocol dose of MylotargTM. The other patient was able to get all nine doses of HiDAC and both patients have achieved a CR. No unexpected hematologic toxicity was observed. All patients developed grade IV thrombocytopenia requiring platelet transfusions. One patient in cohort one died after developing aspergillus infection and multiorgan failure before he could be evaluated for response. Two patients in cohort one developed uncomplicated gram-positive bacteremia requiring antibiotics. In cohort two, one patient developed neurotoxicity and the other developed uncomplicated gram-positive bacteremia. At the time of submission of this abstract seven out of eight patients are alive with four CR and two CRp. No veno-occlusive disease was seen in these eight patients treated with two cycles of HiDAC and MylotargTM back to back. The high rate of CR and relatively good tolerance of this regimen remains encouraging.