Efficacy of a Two Day Induction Regimen for De Novo and Secondary AML with Intermediate and Adverse Cytogenetic Profiles
Authors: Larson Melissa L. , Thomas Ann M. , Goyal Nitin , Shammo Jamile M. , Maciejewski John J. , Gregory Stephanie A. , Venugopal Parameswaran 
Published: April 2020

Abstract
Background: Cytogenetic data remains one of the most powerful prognostic factors for predicting response and survival in adult AML patients. The relationship between cytogenetics and induction response to the standard “7+3” regimen has been analyzed in the past. In a CALGB study, patients with favorable cytogenetics achieved a complete remission (CR) rate of 88%, those with intermediate cytogenetics achieved a 67% CR rate and those with adverse cytogenetics had a 32% CR rate (Byrd et al. Blood100: 4325, 2002). We present a retrospective analysis of the correlation between the hierarchical cytogenetic groups and complete remission rate following induction of AML using a novel induction regimen. This regimen was developed based on the concept of timed sequential therapy. The first pulse of chemotherapy recruits leukemic cells into the cell cycle while the second pulse is given at a time of peak cell recruitment. It utilizes two highly active anti-leukemic drugs: cytarabine, a cell cycle-specific drug, and mitoxantrone, which has a favorable cardiac toxicity profile.
Patients and Methods: One hundred four patients with AML were treated with two days of chemotherapy given 96 hours apart from April 1997 to April 2008. Each day consisted of two doses of cytarabine 2gm/m2 (at t=0 and t=12) followed by one dose of mitoxantrone 30 mg/m2 administered after the second cytarabine dose (t=15). Bone marrow biopsies were performed for assessment of leukemia-free state (day 14) and to document remission response. Cytogenetic results were classified into favorable, intermediate, and unfavorable categories based on CALGB data. Responses were defined per the Revised IWG Recommendations (Cheson et al, J Clin Onc21: 4642, 2003).
Results: Median age of the 104 patients was 57 years [range 17–79]. There were 47 males and 57 females. Forty-two patients (40%) were 60 years of age and older, and the remaining 62 patients (60%) were younger than 60. Sixty-four patients (61.5%) had de novo AML. Five patients had favorable cytogenetics with 100% of them achieving CR. All of the patients with favorable cytogenetics were less than 60 years of age. For the 61 patients with intermediate cytogenetics, the ORR was 83.6% with a CR of 61%. In patients younger than 60, the ORR was 83.8%% (26 CR, 3 CRi, 2 CRp) with CR of 70%. For patients 60 years and older, the ORR was 83.3% (11 CR, 3 CRi, 5 CRp, 1 RMDS). In the 38 patients with unfavorable cytogenetics, the ORR was 57.9% with CR of 37%. For patients younger than 60 and 60 years and older, the overall responses were 75% and 38.8%, respectively.
Of the 40 patients with secondary AML due to pre-existing MDS, the ORR was 65% with CR of 27.5%. In patients with de novo AML, the ORR was 81% with CR of 70%. Patients with prior MDS were more likely to have CRi (20% vs 1.5%), TF due to refractory disease (25% vs 15.6%) or aplasia (7.5% vs 1.5%) as compared to patients without MDS. The rates of CRp (10% vs 9%) were similar for both groups. MDS patients with intermediate cytogenetics had an ORR of 77.7% as compared to 54.5% in those with unfavorable cytogenetics. De novo patients with intermediate cytogenetics had ORR of 86% and those with unfavorable cytogenetics had ORR of 62.5%.
Conclusion: Our data reflects the overall effectiveness of high dose cytarabine and mitoxantrone for induction therapy of AML. In the favorable cytogenetic group, the CR rate was higher than previously reported response rates; however, the number of patients was small. In the intermediate and unfavorable cytogenetic groups, the response rates for de novo AML compare favorably to historic controls. Patients with secondary AML respond equally well as compared to those with de novo AML; though, the influence of cytogenetics was similar to that seen in de novo AML. This regimen is very effective in producing a high response rates across cytogenetic categories.