Condensed versus standard schedule of high-dose cytarabine consolidation therapy with pegfilgrastim growth factor support in acute myeloid leukemia

The concept of intensive post-remission chemotherapy in acute myeloid leukemia (AML) is based on the observation that despite achievement of a first complete remission (CR) after intensive induction therapy virtually all patients relapse in the absence of further treatment. Moreover, randomized studies showed that intensive post-remission consolidation chemotherapy was superior to prolonged low-dose maintenance therapy in younger patients. Concerning consolidation therapy, the landmark study conducted by the Cancer and Leukemia Group B (CALGB) established the current standard for patients aged 60 years and younger with high-dose cytarabine (HDAC) 3 g/m² b.i.d. on days 1, 3 and 5. This study aimed to compare a condensed schedule of HDAC on days 1, 2 and 3 with the standard HDAC given on days 1, 3 and 5 as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in patients in first CR receiving repetitive consolidation cycles for AML. We included Patients aged 18 to 60 years between 2004 and 2009. They were randomized up-front 1:9 between the standard German AML Intergroup arm and the AMLSG 07 04 study (NCT00151242). Induction therapy in the 07 04 study consisted of two cycles of idarubicin, cytarabine and etoposide ± All-trans retinoic acid (ATRA) and ± valproic acid (VPA) in a 2 × 2 factorial design. After recruitment of 392 patients, due to toxicity, we stopped the randomization for VPA. For consolidation therapy, patients with high-risk AML, defined either by high-risk cytogenetics or induction failure, were assigned to receive allogeneic hematopoietic cell transplantation from a matched related or unrelated donor. All other patients were assigned to three cycles of HDAC from 2004 to November 2006 with cytarabine 3 g/m² b.i.d. on days 1, 3 and 5 and pegfilgrastim on day 10 (HDAC 135). From December 2006 to 2009 patients were treated with a condensed schedule with cytarabine 3 g/m² b.i.d. on days 1, 2 and 3 and pegfilgrastim on day 8 (HDAC 123). Patients randomized to the German AML Intergroup arm were treated for consolidation therapy with cytarabine 3 g/m² b.i.d. on days 1, 3 and 5 (HDAC 135) without prophylactic growth-factor support. Overall 568 patients receiving 1376 consolidation cycles were included in the study. According to up-front randomization 41 were treated with HDAC 135 without prophylactic growth factor support in the German AML Intergroup protocol, 135 with HDAC 135 and 392 with HDAC 123 with intended prophylactic pegfilgrastim at day 10 and 8, respectively, in the 07 04 protocol. Time from start to chemotherapy until hematological recovery (leukocytes > 1.0 × 109/l and neutrophils > 0.5 × 109/l) was significantly (p < 0.0001 each) and in median four days shorter in patients receiving HDAC 123 compared to HDAC 135. By adding pegfilgrastim, we were able to further reduce the hematologic recovery by two days (p < 0.0001). Treatment with ATRA and VPA according to initial randomization had no impact on hematological recovery times. Rates of infections were significantly reduced by HDAC 123 compared to HDAC 135 (p < 0.0001) and pegfilgrastim yes versus no (p = 0.002). Days in hospital and platelet transfusions were also significantly reduced in patients receiving HDAC 123 compared to HDAC 135. Relapse-free and overall survival were similar with HDAC 123 and HDAC 135 (p = 0.48 and p = 0.90 respectively).Data from this study suggest that consolidation therapy with a condensed schedule of HDAC 123 is superior to that of standard HDAC 135 regarding faster hematological recovery, lower infection rate and fewer days in hospital. In addition, the administration of one dose of pegfilgrastim after chemotherapy further shortened hematological recovery and reduced infection rate. Importantly, similar efficacy concerning relapse-free and overall survival rates after HDAC 123 and HDAC 135 was observed.