Impact of Pegfilgrastim and Dosing Schedule of Cytarabine on Hematological Reconstitution Times, Incidences of Severe Infection and Duration of Hospitalization after Consolidation Therapy with High-Dose Cytarabine in Acute Myeloid Leukaemia - Interim Results from AMLSG 07-04 Trial.

Introduction: Therapy using high-dose cytarabine (HiDAC) according to the CALGB scheme (3g/m² bid. days 1,3,5) is recognized as a standard consolidation treatment for younger adult patients (pts) with AML. Pegfilgrastim (PF) has been shown to be effective in reducing the duration of neutropenia in treatment of solid tumors and it seems to be even more effective than Filgrastim in reducing the incidence of infection.

Methods: The AMLSG 07-04 trial (NCT00151242) was initiated in September 2004 (age 18–60 yrs). Consolidation therapy for cytogenetic favorable- and intermediate-risk groups consists of 3 cycles of HiDAC (3g/m² bid. days 1,3,5) with PF 6mg given at day 10 (1-3-5 schedule) or after amendment no. 2 of HiDAC (3g/m² bid. days 1,2,3) with PF 6mg given at day 8 (1-2-3 schedule). As a control group, pts randomized from AMLSG into the German AML Intergroup protocol using the standard 1-3-5 schedule for consolidation therapy with allowed interventional application of G-CSF were used.

Results: Data from 251 pts and a total of 584 cycles are available (137 pts and 324 cycles, 1-3-5 schedule; 78 pts and 185 cycles, 1-2-3 schedule; 36 pts and 75 cycles, German AML Intergroup standard arm). Data from all three consolidation cycles were pooled for the comparison between the AMLSG 07-04 1-3-5 schedule and the German AML Intergroup standard arm. The duration of leukopenia (LP) and neutropenia (NP) were significantly shorter in pts receiving PF within the AMLSG 07-04 trial compared to pts within the German AML Intergroup standard arm (intention-to-treat, p=0.08 and p=0.03; as-treated, p=0.01 and 0.008, respectively). This beneficial effect of PF on LP and NP increased with the number of cycles. This was paralleled by a lower incidence of infection ≥CTC grade 3 with 40% in the 1-3-5 schedule and 67% in the German AML Intergroup standard arm (p<0.0001). The comparison of the 1-2-3 schedule with the 1-3-5 schedule within the AMLSG 07-04 protocol revealed significantly shorter LP and NP in favor for the 1-2-3 schedule (p=0.03 and p=0.004, respectively). In median, pts after the 1-3-5 and the 1-2-3 schedule achieved a leukocyte count above 1.0/μl and a neutrophil count above 0.5/μl at day 20 and day 22 as well as 16 and 17, respectively. In a single center experience using out patient platelet and red blood cell support, the median time of hospitalization for the 1-3-5 (n=32 cycles) and the 1-2-3 (n=25) schedule could be reduced to 7.5 and 5 days with incidences for readmission of 33% and 12.5%, respectively.

Conclusion: The administration of PF after HiDAC-based consolidation therapy in AML significantly shortened the duration of leuko- and neutropenia, reduced the rate of severe infections, and reduced the period of hospitalization.