High Response Rate in Patients with De-Novo or Relapsed/Refractory Acute Myeloid Leukemia Using a Novel Strategy of Low-Dose, Prolonged Administration of Cytarabine and Thioguanine in Combination with Filgrastim in the Ambulatory Setting: A Single-Center, Retrospective Study

Abstract 2624

The incidence of acute myeloid leukemia (AML) increases with age and outcomes for elderly patients remain poor. Furthermore, intensive induction chemotherapy is often unsuitable for elderly patients and can result in significant periods of inpatient care. Recent understanding of leukemia stem cell cycling suggests that prolonged cytotoxic exposure, e.g. >14–21 days, could provide a more effective anti-leukemic effect than the typical 5–7 days schedules during which time very few leukemic stem cells would be likely to undergo cell division. We have been using prolonged low-dose cytarabine schedules as reported 20 years ago (Hellstrom-Lindberg, Brit J Haem,1992;81:503), however we have combined this with oral thioguanine, a purine analogue that may synergize with cytarabine. Concomitant filgrastim or pegfilgrastim was given to minimize neutropenia and for its possible synergizing anti-leukemic effect when combined with cytotoxic agents. Encouraging experience with this schedule in a few relapsed/refractory elderly AML patients prompted us to use this strategy in elderly de-novo patients unsuitable for standard induction. Surprisingly good results prompted us to report our preliminary experience with this novel strategy. This report is a retrospective, single-center analysis of outcomes in elderly patients with AML managed as outpatients in an ambulatory care day unit. Between April 2009 and March 2011, 14 patients with either relapsed/refractory AML (n=5) or de novo AML (n=9) unsuitable for intensive therapy were treated using prolonged, low-dose cytarabine 20mg/m²/day subcutaneously and thioguanine 80mg/day orally. Treatment was given for 21 days followed by a 14 day break after which the schedule was repeated until remission. After obtaining remission, patients received a maintenance schedule consisting of 14 days on treatment with rest periods increasing from 14 to 28 days according to tolerance and time on therapy, with an intention to continue maintenance for 2 years. All patients received the treatment in an ambulatory care unit with supportive care including filgrastim or pegfilgrastim, blood and platelet transfusion as required, regular clinical review and prophylactic antibiotics and antifungal agents. Patient age ranged from 52 to 89 years (median 75y). All patients had intermediate or poor risk cytogenetics. A morphologic remission according to bone marrow aspirate was obtained in 8 patients (57.1%), with relapse seen in 1 patient at 2.6 months follow-up. Remission was maintained in 7 patients (50%) with follow-up ranging from 4.7 to 26.6 months (median 9.7 months), including 1 patient who was refractory to standard first and second-line induction chemotherapy. Refractoriness to treatment occurred in 5 patients (35.7%). Mortality relating to disease progression occurred in 3 patients (21.4%) and 1 patient died secondary to infection. All patients developed grade 3/4 neutropenia and thrombocytopenia but severe mucositis was not seen. The infection rate was low and hospital admission was uncommon. Nausea was common but manageable and significant liver toxicity was not observed. This study demonstrates that effective management of AML in elderly patients can be achieved in the outpatient setting. The data suggests a surprising efficacy for this strategy, with a remission rate comparable to that reported using standard induction chemotherapy but with a potentially favorable toxicity profile. A prospective study is now underway to further evaluate this protocol.