G-CSF Priming, Clofarabine and High Dose Cytarabine (GCLAC) for Relapsed or Refractory Acute Myeloid Leukemia (AML).

Clofarabine is active in both relapsed and newly diagnosed AML. Clofarabine in combination with ara-C at a dose of 1 g/m² daily for 5 days resulted in 52% complete remission (CR) in newly diagnosed patients age 50 or older. (Faderl et al Blood 108:45, 2006), Addition of low dose cytarabine (ara-C) improved efficacy as compared to clofarabine alone in untreated patients age 60 or older (Faderl et al Blood 112:1638, 2008). As high dose ara-C has considerable efficacy in AML, we combined clofarabine with higher dose ara-C (HiDAc) and granulocyte colony-stimulating factor (G-CSF) priming for patients with relapsed AML or AML that failed to respond to initial therapy. GCLAC is based on the FLAG regimen, substituting clofarabine for fludarabine, given the former's greater anti-AML effect.

We initially conducted a phase 1 trial in 19 pts and identified 25 mg/m² daily days 1-5 as the MTD of clofarabine when combined with ara-C 2 g/m² daily days 1-5 and G-CSF 5 mcg/kg subcutaneously, beginning 1 day before chemotherapy and continuing daily until neutrophil recovery. A phase 2 expansion was then conducted at the MTD.

We have treated 38 patients (pts), age range 19-66 years, median 51, 22 at the MTD. Twenty pts received GCLAC as 1^st salvage, 15 at the MTD. Seven of the 20 had relapsed after a median 1^st CR duration of 6 mos while 13 had not responded to initial 3+7 induction therapy, including 4 who were refractory to > 1 course. The CR rate for all patients or all patients at the MTD was 45% and the CR +CRp rate at the MTD was 64%. These rates are 50% CR (95%CI 27-73%) and 65% CR+CRp among 1^st salvage pts (95% CI 41-85%), respectively, and 70% CR + CRp excluding pts who relapsed after allogeneic SCT. Median time to neutrophil recovery (ANC>500) was 21 days (range 13 to 39), and to platelet recovery (platelet count >100,000), 29 days (range 21-42). Four of 22 pts had serious infections and/or asymptomatic grade 3 LFT elevations, a rate not in excess of that seen with other ara-C-containing salvage therapies. Sixty percent of the first salvage patients had poor risk cytogenetics, and 80% of CRs were observed after the first course of therapy. Median overall survival was 7.4 months, and event free survival, 4.3 months. Using a prognostic model that derives expected CR rates with HiDAc or FLAG based on 1^st CR duration and number of prior salvage therapies (Blood 1996;88:756), the ratio of observed (with GCLAC) to expected CR was 2.5:1.

Based on its efficacy, formal comparisons of GCLAC with other salvage regimens are warranted and the combination should also be investigated in untreated pts.

Becker:Genzyme Oncology: Research Funding. Off Label Use: Clofarabine is approved for relapsed or refractory pediatric ALL .