Daunorubicin, Cytarabine and Fludarabine (DAF) for the Treatment of Relapsed/Refractory Acute Myeloid Leukemia. Phase II Study by the Polish Adult Leukemia Group (PALG).

In 1992–93 a synergistic interaction of ribonucleotide reductase inhibitors (fludarabine, cladribine) and cytarabine (AraC) resulting in increase of Ara-CTP concentration in myeloblasts was proved. In the previous study by the Polish Adult Leukemia Group (PALG 1999 Study) we demonstrated that addition of cladribine to standard daunorubicin + cytarabine induction potentiates antileukemic activity of the regimen in acute myeloid leukemia (AML).

The goal of the current study was to assess the safety, tolerance and antileukemic activity of a new DAF regimen consisting of daunorubicin 60 mg/m2/d iv 1–3, AraC 200 mg/m2 ci 1–7, and fludarabine 25 mg/m2/d 1–5.

Twenty-five AML patients aged 40 (range 19–62) years with primary refractoriness 60% (n=15) or in relapse 40% (n=10) were included in the study between 2003–2004. DAF was administered as a second (n=24) or as a third line of induction treatment (n=1).

Twelve patients (48%) achieved complete remission (CR), 1 (4%) had partial remission (PR), and 10 (40%) did not respond (NR, leukemia regrowth). Two patients died in aplasia from infectious complications (8%).

All patients developed severe thrombocytopenia and granulocytopenia (WHO grade III or IV). Median time to neutrophil >0.5 G/L recovery and platelet >50 G/L recovery equaled 21 d. (11–30) and 20 d. (11–27), respectively.

Eleven (44%) patients exerienced severe (WHO grade III or IV) neutropenic infections (bacterial n=9, fungal n=2). Other serious adverse events were infrequent: vomiting 24% (n=6), mucositis 24% (n=6). Severe hepatotoxicity, nephrotoxicity and cardiotoxicity was not observed.

Median hospital stay lasted 28 (11–41) days. Patients required 5.5 (0–13) PRBC transfusions and 5.5 (1–14) platelet transfusions. Hematopoietic growth factors were not administered.

Results of this phase II study indicate that DAF is a relatively well-tolerated and safe regimen with high anti-leukemic potency in relapsed/refractory AML. Based on these findings a randomized, multicenter study comparing DAF to the standard DA induction has been designed for newly diagnosed AML patients.