Characteristics and Outcome of Patients with Core Binding Factor Acute Myelogenous Leukemia Treated with Timed Sequential Chemotherapy.

Core-binding factor (CBF) leukemias represent 13% of adults with acute myeloid leukemia (AML). Favorable cytogenetic abnormalities encompassing t(8;21) and inv (16) achieve a complete remission (CR) rate of over 80% of the time with therapy. In general, CBF patients (pts) are reported to have a better disease free survival (DFS) than those without CBF alterations. Conventionally, postinduction outcome is improved with repetitive high dose cytarabine (HiDAC). The 5-year overall survival (OS) is reported at 45 to 76%. Timed sequential chemotherapy (TST) exploits augmented leukemic cell-cycle dependent killing by recruitment and synchronization of residual malignant clones and results in improved induction and postremission outcomes in poor-risk AML subtypes. We performed a retrospective study evaluating our single institutional experience on the outcome(s) of patients with CBF-AML treated with TST from 1984 to 2004.

We identified 66 previously untreated pts who underwent a single cycle of induction TST (AcD-VP16) consisting of daunorubicin 45 mg/m²/d (days 1–3) and cytarabine 667 mg/m²/d IV continuous infusion (days 1–3) followed by etoposide 400mg/m²/d (days 8–10). Patients in remission received a single cycle of consolidation TST (Ac-D-Ac) consisting of one of two regimens: (1) daunorubicin 45mg/m²/d (days 1–3) and cytarabine 2g/m²/d IV continuous infusion (days 1–3) followed by cytarabine 0.667g/m²/d IV continuous infusion (days 10–12) or (2) daunorubicin 45mg/m²/d (days 1–3) plus cytarabine 0.667g/m²/d IV continuous infusion (days 1–3) followed by cytarabine 0.667g/m²/d (days 10–12). CR rates per pre-treatment cytogenetics were examined as well as overall survival (OS) after post-remission treatment.

Among 66 patients (median age, 42 years; range 12–72 years) with CBF-AML treated with TST, 25(37.8%) and 41(62.1%) were t (8;21) and inv (16), respectively. CR was achieved with induction TST in 24/25(96%) of patients with t(8;21) and in 38/41(93%) of patients with inv(16). Refractory disease was seen in 1/66 pts (1.5%). CR rates of 94%, 95% and 89% were observed in pts treated with TST at (a) all ages, (b) age <60 years and (c) 60–75 years, respectively. The most common additional cytogenetic abnormality was loss of sex chromosome in the t(8;21) group in 10/29(34%) pts. For the inv (16) group, trisomy 8 was the most frequent associated additional abnormality and was present in 10/47(21%) of pts. The 5 year overall survival (OS) for the CBF cohort was 50%. Cox proportional hazards regression models for survival were performed using cytogenetic grouping as the main effect. OS was superior for pts with complex t(8;21) compared to simple t(8;21) (P=0.02); however, a trend for improved outcome was observed in pts with complex inv (16).

TST resulted in excellent CR rates for pts with CBF AML, and this is associated with a low incidence of refractory disease. Secondly, TST is associated with acceptable 5-year OS of about 50% and is comparable to historical data.

Gore:Celgene: Research Funding, Stock options.