Phase II Trial Of Cladribine and Low-Dose AraC (LDAC) Alternating With Decitabine In Older Patients With Acute Myeloid Leukemia (AML)

Treatment of AML in older patients is often complicated by poor tolerance to intensive chemotherapy, high early mortality, and resistant disease. Lower intensity approaches employing more active combinations are needed. Cladribine has been shown to have single-agent activity in AML, and to modulate deoxycytidine kinase, making ara-C more effective. Cladribine has recently been shown to improve survival when combined with standard-dose araC (Holowiecki JCO 2012).

We designed a low-intensity, prolonged-maintenance program investigating the combination of cladribine and low-dose araC (LDAC) alternating with decitabine in patients aged > 60. Patients with adequate organ function and newly diagnosed AML (except APL), including secondary- (s-AML) and therapy-related AML (t-AML), and high risk MDS were eligible. Induction consisted of cladribine 5 mg/m² IV over 1-2 hours on days 1-5 followed by araC 20mg SQ BID on days 1-10. Consolidation/maintenance consisted of 2 cycles of cladribine 5 mg/m² IV over 1-2 hours on days 1-3 + araC 20 mg SQ BID on days 1-10 alternating with 2 cycles of decitabine 20 mg/m² on days 1-5, for a maximum of 18 cycles. One cycle was 4 weeks and up to 2 cycles of induction were allowed.

Forty-five patients have been enrolled thus far with a median age of 69 years (range, 60-85), including 20 pts (44%) ≥ age 70. 20 pts (44%) had secondary- (s-AML) or therapy related AML (t-AML), 8 pts (18%) had therapy for an antecedent hematologic disorder, and 4 pts (9%) had a concurrent active second malignancy while on study. Patient characteristics are listed in table 1. Of the 36 pts evaluable for response, there were 21 CR (58%), 1 CRi (3%), and 2 PR (6%) for an overall response rate of 67% (24/36). 38% of patients (5/13) with an abnormal karyotype at the start of therapy achieved a complete cytogenetic response (CyR) and 1 (8%) had partial CyR at the time of CR. MRD negativity by flow cytometry was achieved in 12/23 pts (52%) in whom it was measured at the time of CR. All 5 patients (100%) with FLT3+ AML achieved a CR/CRi (4CR, 1CRi). With a median followup of 3.2 months, median OS and median CR duration have not been reached. (Figure 1) The 1-year OS estimate is 51%. The regimen was very well tolerated, with 0% 4-week mortality. There were no treatment-related grade 3/4 non-hematologic adverse events (AEs). Most common non-heme AEs were elevated bilirubin, constipation, nausea/vomiting, mucositis, diarrhea and rash.

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The low intensity induction/consolidation/maintenance program of cladribine+LDAC alternating with decitabine is a highly effective, well-tolerated ambulatory regimen for older patients, including those with unfavorable-risk features. The study continues enrollment and updated data will be presented.

No relevant conflicts of interest to declare.