High Dose Cytarabine (HiDAC) and Mitoxantrone (MITO) Is An Effective Induction Therapy for High-Risk Acute Myeloid Leukemia (AML).

Patients with high risk AML, including those with advanced age, relapsed or refractory disease, unfavorable cytogenetics, therapy-related myeloid neoplasm (t-MN), and multiple medical co-morbidities, carry a poor prognosis and outcomes after 7+3 induction chemotherapy are poor. Complete remission (CR) rates tend to be low and range from 12-63% and induction death rates range from 10-26%. We developed a novel, timed-sequential regimen that takes advantage of synergy when MITO follows cytarabine (VW Quinones et al. ASH 1996. abstr 849).

We performed a retrospective analysis of all AML patients, except those with t(15;17), who received HiDAC/MITO from 2001-2008 at our institution. Patients with high risk AML defined by age >60 and/or at least two adverse prognostic features (cytogenetics, co-morbid conditions, antecedent hematologic disorder) received cytarabine at 3gm/m2 over four hours (with dose reduction to 2gm/m2 for patients >60 years old) on days 1 and 5 plus mitoxantrone at 30mg/m2 (with dose reduction to 20mg/m2 for patients >60) over one hour immediately following the HiDAC on days 1 and 5. The primary endpoints of the study were CR and toxicity determined by induction death defined as death within 30 days of initiation of treatment.

78 consecutive patients received HiDAC/MITO for remission induction. The median age was 63 years (range 23-85); 27% of these patients had a Charlson comorbidity index (CCI) >2. The distribution of diagnoses is shown in the Table. 43 (56%) patients had poor-risk cytogenetics, 28 (37%) had intermediate-risk cytogenetics and 5 (7%) had good-risk cytogenetics. Overall CR rate was 45%, CRi rate 10%, refractory rate 36%, and induction death rate of 9%. Patients with AML with myelodysplasia related changes tended to have a lower CR rate (p=0.07) and were more likely to have a CRi. Notably, t-MN and relapsed/refractory patients had CR and induction death rates equivalent to de novo AML patients. Cytogenetics and CCI were also not associated with best response, p=0.7 and 0.94, respectively. Forty percent of patients proceeded to allogeneic stem cell transplantation (alloSCT) after receiving HiDAC/MITO. Overall survival at one year was 39%.

In this high risk AML population, HiDAC/MITO induction was well tolerated and demonstrated an overall response rate of 55% and low induction death rate of 9%, allowing a substantial number of patients to proceed to alloSCT. High risk cytogenetics and multiple medical co-morbidities did not affect CR rate, and the CR rate was similar among relapsed/refractory, t-MN and de novo AML patients, which highlights the utility of this regimen for both high risk newly diagnosed and relapsed/refractory patients with AML.

No relevant conflicts of interest to declare.