Effective Remission Induction for AML Using Two Days of Chemotherapy: Older Patients Tolerate and Respond Equally Well
Authors: Shah Neel B. , Larson Melissa L. , Goyal Nitin , Thomas Ann M. , Shammo Jamile M. , Maciejewski John J. , Gregory Stephanie A. , Venugopal Parameswaran 
Published: April 2020

Abstract
Background: The remission induction regimen used for treatment of adult AML has traditionally been the “7+3” regimen, which has not changed significantly since 1981. CR rates have been in the 55–60% range, historically. We present a single institution, retrospective analysis of a regimen consisting of two pulses of chemotherapy 96 hours apart with high-dose cytarabine and mitoxantrone. It is based on the concept of timed sequential therapy where the first pulse of chemotherapy recruits leukemic cells into the cell cycle and is followed by the second pulse at the time of peak cell recruitment. Cytarabine is a cell cycle-specific drug, and mitoxantrone was chosen because of its resistance to the effects of the gene MDR1, which is commonly expressed in adult leukemia, as well as its favorable cardiac toxicity profile.
Patients and Methods: One hundred four patients with AML were treated with timed sequential chemotherapy from April 1997 to April 2008. Each pulse of chemotherapy consisted of 2 doses of cytarabine 2gm/m2 given 12 hours apart (at t=0 and t=12) followed by one dose of mitoxantrone 30 mg/m2 administered after the second cytarabine dose (t=15) given on days 1 and 5. Bone marrow biopsies were performed to assess for leukemia free-state (day 14) and subsequently for remission documentation. Responses were defined per the Revised IWG Recommendations (Cheson, J Clin Onc21: 4642, 2003). Toxicities, response rates, relapse rates, and preexisting conditions were also recorded.
Results: Median age of the 104 patients was 57 y [range 17–79]. There were 47 males and 57 females. Forty-two patients (40%) were 60 years of age or older with 17 (16%) of them older than 70 years. Forty patients (38%) had preexisting MDS. Five patients (4.8%) had favorable cytogenetics, 61 (58.7%) had intermediate cytogenetics, and 38 (36.5%) had unfavorable cytogenetics. Seventy-four patients (71%) achieved a leukemia free state based on the day 14 bone marrow biopsy. At the time of the remission documentation bone marrow biopsy, the IWG-defined responses seen are the following: 56 CR (53.8%), 9 CRi (8.6%), and 10 CRp (9.6%). Three additional patients (2.9%) had a return to MDS (RMDS). Twenty patients (19.2%) had refractory disease. Overall, 78 patients had a response, (ORR=75%). The 30-day mortality rate was 2.8% (3/104). In the 62 patients under 60 years of age, 51 (82%) responded to chemotherapy. In the 42 patients age 60 and older, 27 had a response (64%). Thirteen of the seventeen patients age 70 and older had a response (10 CR, 2 CRp, 1 CRi) for an ORR of 76.4%. The remaining 4 patients in this age group had refractory disease.
Conclusion: This remission induction regimen of high dose cytarabine and mitoxantrone produces very high response rates, even in the older AML patients. The response rates in both younger patients and older patients compare favorably with the rates historically seen with the standard 7 + 3 regimen. The 30-day mortality rate of less than 3% is less than that previously reported with the 7 + 3 regimen. This may be attributable to improvements in supportive care; although, this could also represent the favorable toxicity profile of this effective, novel regimen.