Timed Sequential Therapy Induction and Consolidation in Newly Diagnosed AML: Achievement of Leukemia-Free Survival in Patients Using Two Cycles of Therapy Alone

Long term outcomes for patients with AML are unsatisfactory following induction and consolidation chemotherapy alone except in patients with favorable–risk cytogenetics. The additional administration of the same or different agents starting 8–10 days after start of initial chemotherapy (timed sequential therapy, TST) may enable the killing of leukemic cells synchronized into cell cycling by the initial chemotherapy. However, it is unclear if patients with intermediate and unfavorable cytogenetics achieve improved outcomes using this approach. Sixty-nine unselected patients with AML (42M, 27F; median age = 53, range 16–74; cytogenetic risk group favorable =2, intermediate = 37, unfavorable = 23; 10 with an antecedent hematologic disorder) referred to a tertiary leukemia center received initial chemotherapy with a regimen of cytarabine 667mg/m2/d by 24 hour infusion on d1–3, idarubicin 12mg (age <60) or 8 mg (age >60)/m2/d on d1–3 and etoposide 100mg/m2 on d 8–10. Induction death occurred in 7 patients (10%). Complete remission was achieved following one cycle of induction therapy in 30 patients (43.5%). The corresponding complete response (CR) rates by cytogenetic subgroup were100%, 48.6% and 26% in the favorable, intermediate and unfavorable cytogenetic groups respectively. In patients who achieved CR, median time to ANC > 1000/mm3 and platelets > 100,000/mm3 were 29 d (range 21–76d) and 26d (range 17–83d). Mucositis was the most common non-hematologic toxicity. Of the 69 patients treated, 30 (43%) and 4 (6%) patients proceeded to allogeneic and autologous hematopoietic stem cell transplantation respectively. Of the patients who did not receive stem cell transplantation, eleven patients (median age 54, range 23–72; median WBC 27.1, range 1–250; cytogenetics -9 normal, 1 t(9;22); 1 11q23 abnormality) underwent consolidation with TST–consisting of a single cycle of cytarabine 667mg/m2/d (continuous infusion) on d1–3 and 10–12, and idarubicin (same dose as induction). Two year estimated probabilities of overall survival and relapse in this group were 65% and 26% respectively. In summary, TST as administered in these patients can be safe in patients with newly diagnosed AML, including those patients aged between 60 and 70. However, the regimen does not appear to improve CR rates over that seen using conventional induction regimens. Patients with intermediate risk cytogenetics who achieve CR and are not candidates for stem cell transplantation may receive consolidation with a single additional cycle of TST.