Phase II Study of Timed Sequential Therapy (TST) with Topotecan, Cytosine Arabinoside (ARA-C), and Mitoxantrone (TAM) Induction Therapy Followed by Non-Cross-Resistant Consolidation Chemotherapy for Adults with Newly Diagnosed Acute Myelogenous Leukemia (AML).
Authors: Gojo Ivana , Morris Lawrence , Guo Chuanfa , Heyman Meyer , Tidwell Michael , Greer Jackie , Klein Maureen , Irani Marianne , Karp Judith 
Published: October 2019

Abstract
Clinical results in AML continue to need improvement, particularly for age ≥60, prior MDS or secondary AMLs, and AMLs with adverse cytogenetics (CG) where complete remission (CR) rates are <50% and cure rates are <10%. In an attempt to improve these outcomes, we developed a TST regimen of the topoisomerase I inhibitor Topotecan with ara-C and Mitoxantrone (TAM) as induction therapy for adults with newly diagnosed AML: T, 4.5 mg/m2 IV continuous infusion (CI) over 72 hrs days (d) 1-3; A, 2 gm/m2 IV CI over 72 hrs d 3-5; and M, 40 mg/m2 IV d 10. CR patients with poor risk features received consolidation TST with T, 4.5 mg/m2 CI over 72 hrs d 1-3; A, 2 gm/m2 IV CI over 72 hrs d 3-5; and etoposide (E), 300 mg/m2 IV CI over 72 hrs d 10-12 (TAE); CR patients without poor risk features received consolidation TST with A, 2 gm/m2 CI over 72 hrs d 1-3 and 10-12; and idarubicin (I) 12 mg/m2 IV d 1,2,3 (AIA). From 04/02-2/04, 60 newly diagnosed AML patients (median age 49 yrs, 21–79) received TAM induction chemotherapy. Of 60 pts, 47 (78.5%) had at least one poor prognostic feature: age ≥60, 16 (27%); adverse CG, 28 (47%); MDS/AML, 10 (17%); secondary AML, 3 (5%); and/or WBC >25,000/μl, 23 (38.5%). Of the 41 (68.5%) pts who achieved CR, 32 (78%) received consolidation TST (22 TAE; 10 AIA). The remaining 9 pts received alloBMT (2), alternate therapy (5), or no consolidation (2) due to incomplete reversal of organ damage. Furthermore, 8 pts who finished 2 cycles of TST subsequently received alloBMT (3), autoBMT (2) and maintenance Zarnestra (3). Median overall survival (OS) for all pts is 10.1 mos, with 1yr survival 45.7% (95% CI; 32.5%–58.9%). On multivariate analysis, only antecedent MDS was a significant risk factor for poor OS (HR=2.5, 95% CI 1.13–5.65; p=0.02). For patients who achieved CR, median disease free survival (DFS) was 9.9 mos (95% CI; 5.8–18.2) with 1yr DFS 45.9% (95% CI; 29.4%–62.4%). Preceding MDS (p=0.02), adverse CG (p=0.04) and age ≥50 (p=0.06) were associated with low CR. Induction and consolidation mortality were <10%. Median time for ANC >100/μl was 28 days (22–56) and platelets >50,000/μl was 30 days (22–81) following TAM. For consolidation, median time to ANC >100/μl was 27.5 days (19–48) for TAE and 39 days (26–43) for AIA, and plts >50,000/μl 34 days (19–87) for TAE and 54 days (33–79) for AIA. Toxicities during induction and consolidation were generally ≤grade 3 and consisted of infection (bacteremias, pneumonias), oral and/or GI mucositis, transient elevation in liver function tests, reversible renal insufficiency. Pulmonary hemorrhage (1), GI bleed (3), CNS bleed/infarct (2) and decreased ejection fraction (2) occured during induction/consolidation but resolved. Causes of death during induction were sepsis/multiorgan failure (3), progressive fungal pneumonia (1), grade 5 marrow aplasia (1); during consolidation multiorgan failure (1), renal failure/sepsis (1), pulmonary hemorrhage (1). In summary, TAM induction for AML is associated with significant CR rates and acceptable toxicity, but did not appear to overcome the poor DFS and OS in a high-risk group of adults.