Over the years, there has been considerable progress in the understanding of the molecular pathogenesis of acute myeloid leukemia (AML) in adults. This progress helped in the identification of new options in AML management.1 Current management includes chemotherapy followed by several courses of consolidation chemotherapy or allogeneic stem-cell transplantation (SCT).2 The gold standard induction therapy since 1982 is “7 + 3”, which consists of 3 days of an anthracycline (mainly daunorubicin (DNR), at least 60 mg/m2) and 7 days of cytarabine (AraC) (100-200 mg/m2 continuous IV). Complete remission (CR) is achieved in 60% to 80% of younger adults with such regimen.1
There have been many attempts to improve remission with minimal toxicity. One possible way to intensify induction treatment is by adding a purine analog such as fludarabine or cladribine. The Polish Adult Leukemia Group (PALG) did a randomized clinical trial3 to determine whether the addition of a purine analogue to the standard induction regimen affects the outcome of adults with AML. It included 652 untreated AML patients with median age of 47 years (range 17 to 60 years). Patients were randomly assigned to receive one of three induction regimens: DA (daunorubicin plus cytarabine), DAC (DA plus cladribine), or DAF (DA plus fludarabine). Overall survival (OS) was the primary end point, and leukemia-free survivals (LFS), CR rate after the first induction, CR rate after one or two courses of induction, death from hypoplasia, and disease resistance to chemotherapy were secondary end points. The results were as follows: overall 3-year survival rates were 45% in the DAC arm, 33% in the DA arm, and 35% in those receiving the DAF regimen (P=0.02). CR rate was significantly higher in the DAC arm compared with the DA arm (67.5% vs. 56%; P=.01), but not in the DAF arm (59%), and LFS was comparable between groups. Authors observed a survival advantage of the DAC arm over the DA arm among patients whom are 50 years or older (P=0.005), those with initial leukocyte count above 50×109/L (P=0.03), and those with unfavorable karyotype (P=0.03). There was no significant difference in early outcome between the DAF and DA arms, and long-term outcome did not differ significantly for the comparison of the DAF and DA arms. For secondary endpoints, all patients experienced world health organization grade 4 neutropenia and thrombocytopenia. Additionally, the duration of hospital stay, the median number of RBCs and platelet transfusions as well as the use of granulocyte colony-stimulating factor were comparable among study groups.
The researchers concluded that the addition of cladribine, but not fludarabine, to the standard induction regimen, (DA), increased rate of CR and improves the survival of newly diagnosed AML patients aged 60 years or younger. They attributed the difference in outcome to the different features of both drugs, since cladribine acts against both proliferating and non-proliferating cells.
The results of this trial are promising and it will not be long enough until ...