Cladribine in the Treatment of Acute Myeloid Leukemia

Abstract

Despite advances in supportive care and post-remission therapy, the outcome of elderly and relapsed/refractory AML patients (pts) remains poor. These pts commonly present with high risk features including antecedent myelodysplastic syndrome and unfavorable cytogenetics. In addition, such pts are often unable to tolerate standard induction chemotherapy (IC) or myelotoxic salvage chemotherapy (SC), limiting clinical options. Between 1/2007 and 5/2008, we treated 24 pts with two cladribine based regiments designed to limit hematologic and non-hematologic toxicities, while maintaining cytotoxic activity. Treatment consisted of Cladribine (5 mg/m2 d1–5) and Cytarabine (2 g/m2 d1–5) in combination with G-CSF (300mcg sc d0–5) (CLAG) or mitoxantrone (10mg/m2 d1–3) (CLAM). IC pts had a median age of 63 (range 23–80). SC pts had a median age of 56 (range 25–68). No pt had favorable cytogenetics. 40% (IC) and 56% (SC) of patients had unfavorable cytogenetics. Prior anthracycline/topoisomerase inhibitor therapy, myelodysplastic syndrome or other antecedent hematologic disorder was common (53% IC and 11% SC) and prior remission had been brief among SC pts (median 165 days). Complete response occurred in 53% of IC and 44% of SC patients lasting a median of 73 days (IC) and 222 days (SC). The median duration of neutropenia and thrombocytopenia in IC pts (CLAG/CLAM) was 22 and 24 days, respectively. The median duration of neutropenia and thrombocytopenia in SC pts (CLAG/CLAM) was 25 days and 21 days, respectively. Neutropenia and thrombocytopenia contributed to significant rates of documented infection (53% IC and 78% SC) and severe bleeding (33% IC and 11% SC). Significant cardiac, hepatic or renal toxicities were not noted in any group. Examining subgroups, those that received IC CLAG were elderly (median age 70) and fared poorly (14%CR, 43%PD, 43%TRM). In contrast the younger IC CLAM cohort did well with 7/8 pts achieving CR with a median duration of 126 days despite poor risk features (38% high-risk cytogenetics/63% AHD). This is the first report of front-line CLAM in AML. Both CLAG and CLAM performed similar to other salvage regimens reported in the literature though in a less favorable population than has been previously reported with CLAG and CLAM (median age 45 and 17–25% unfavorable cytogenetics in the Polish experience compared to median age 56 and 56% unfavorable cytogenetics in this report) (Wierzbowska A et al. Eur J Haematol 2007; 80: 115–26, Wrzesien-Kus A et al. Eur J Haematol 2003; 71: 155–62). CLAM warrants further study, especially in the context of other agents as both induction and salvage therapy for high-risk AML.New DiagnosisRelapsedPatients (CLAG/CLAM)15 (7/8)9 (5/4)Median Age63 (range 23–80) (70/56)56 (range 25–68) (56/53)Median WBC count18,000 (1000–157,600)15,400 (200–83,000)Favorable cytogenetics0%0%High risk cytogenetics or FLT3-ITD positive40% (43%/38%)56% (60%/50%)Prior tAML, MDS or AHD53% (43%/63%)11% (20%/10%)Duration of first remissionNA165 days (30–263)CR53% (14%/88%)44% (40%/50%$)PD27% (43%/12%)56% (60%/50%)Death during aplasia20% (43%/0%)0%CLAG/CLAM Duration of CR (days)73 (range 73)/126# (range 96–∞)222 (range 219–224)/164 (range 61@-267)% of CR going on to receive allogeneic transplant13% (0%/14%)11% (20%/0%)Median duration of neutropenia <500 (days)20 (range 11–33) (24*/18)25 (range 11–35)!Median duration of neutropenia <1000 (days)22 (range 12–33) (27*/22)25 (range 12–35)!Median duration of thrombocytopenia <50,00023 (range 7–27) (25*/20)15 (range 13–22)!Median duration of thrombocytopenia <100,00024 (range 13–35) (26*/24)21 (range 14–46)!Documented infection53% (57%/50%)78% (60%/100%)Severe bleeding33% (57%/13%)11% (0%/25%)(xx/xx)=data from CLAG and CLAM, respectively.