Multivariate Analysis of Response and Survival After Treatment with Clofarabine, Cytarabine and G-CSF Priming (GCLAC) In Relapsed/Refractory Acute Myeloid Leukemia (AML): Comparison with Prior Experience Using Fludarabine and Cytarabine Combination Regimens.

Clofarabine is active in both relapsed and newly diagnosed AML, and combinations of clofarabine with low-dose cytarabine appear superior to clofarabine alone. Because high-dose ara-C (HiDAC) is often more effective than lower doses, we combined clofarabine with HiDAC, together with granulocyte colony-stimulating factor (G-CSF) priming in patients with relapsed AML or AML that failed to respond to initial therapy (refractory).

Beginning in 2008, a phase I dose-escalation trial was conducted using clofarabine at 15, 20, and 25 mg/m² daily × 5, in combination with cytarabine 2 g/m² daily × 5, and G-CSF 5 mcg/kg subcutaneously, beginning 1 day before chemotherapy and continuing daily until neutrophil recovery (GCLAC). The phase I study was followed by a phase II expansion at the maximum tolerated dose (MTD; 25 mg/m²). We used multivariate analyses to compare complete remission (CR) and survival rates in patients given GCLAC with those seen in 101 relapsed/refractory patients given fludarabine 30 mg/m² daily × 5 and cytarabine 2 g/m² daily × 5 with (FLAG, 20 patients) or without (FA, 81 patients) G-CSF at M.D. Anderson Cancer Center (MDA) before 2008. Independent analyses were done by statisticians at Fred Hutchinson Cancer Research Center (FHCRC) and MDA to examine whether outcomes were affected by treatment type after accounting for first CR duration, number of prior salvage therapies, cytogenetics, and age.

Fifty patients received GCLAC at the FHCRC including 34 using clofarabine at the 25 mg/m² MTD and 32 as first salvage therapy. Thirty-two patients had relapsed after a median 1^st CR (CR1) duration of 6 months, while 18 patients were refractory. The CR rate among the 46 evaluable patients was 46% (95% CI, 31–61%) and the CR + CRp rate was 61% (95% CI, 45–75%). Ninety percent of the CRs were observed after the first course of therapy. Twelve patients who had >5% blasts on day 14 of course 1 subsequently achieved CR without further therapy. The CR rate was 4/8 in patients given a second induction course. Median time to neutrophil count >500 was 21 days (range 17–39) and to platelet count >100,000 was 30 days (range 21–42). Grade ≥3 toxicity was similar to that seen with other HiDAC regimens, with infections and pulmonary toxicity (invariably associated with infection) being the most frequent adverse events, occurring in 40% and 46%of patients, respectively. Response rate was similar at all dose levels of clofarabine, and amongst all cytogenetics risk groups. The 30 day mortality from day 1 of salvage induction chemotherapy was 0%. In contrast, CR rates were 22/81 with FA (27%; 95% CI 18–38%) and 4/20 with FLAG (20%; 95%CI 6–44%) salvage. For the comparisons with FA and FLAG, both the FHCRC and MDA multivariate analyses indicated that after accounting for CR1 duration, salvage number, age, and cytogenetics, GCLAC was associated with a higher CR rate (p= 0.001 MDA, p<0.0001 FHCRC) and longer survival (p< 0.0001 GCLAC vs. FA and 0.09 GCLAC vs FLAG, MDA; p = 0.001 for FA vs GCLAC, p=0.08 for FA vs. FLAG, FHCRC). The apparent superiority of GCLAC reflected results in patients with primary refractory disease or with first CR duration <6 months, who typically had unfavorable cytogenetics.

This study indicates that GCLAC is active in relapsed and refractory AML, may be qualitatively different from regimens such as FLAG, and warrants prospective comparison with them.

Becker:Genzyme: Research Funding. Off Label Use: Clofarabine is approved for treatment of relapsed pediatric ALL. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.