Timed sequential therapy for AML

On 30^th August 2017, in an article published in Leukemia Research, Kelly J. Norsworthy from John Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, USA, et al. reported results of their retrospective study of Acute Myeloid Leukemia (AML) patients who were treated with Timed Sequential Therapy (TST) based induction therapy followed by consolidation chemotherapy or Blood and Marrow Transplant (BMT).

TST is a therapeutic strategy that exploits the leukemia cell cycle kinetics by administering a second drug in close approximation with the leukemia proliferation induced by the first drug.

In total, 301 newly diagnosed non-trial AML patients (median age = 52 years) who were treated at John Hopkins Hospital between 2004–2013 were enrolled in this study. Patients were treated with TST with cytarabine, daunorubicin or idarubicin, and etoposide (AcDVP16 or AcIVP16) followed by consolidation chemotherapy alone or BMT. Consolidation chemotherapy consisted of either High Dose cytarabine (HiDAC) or cytarabine and daunorubicin (AcDAC).

The key results of the study were:

• Complete Remission (CR); 68% (205/301)
• 60-day induction mortality rate; 8%
• Most common grade 4 adverse events include mucositis, febrile neutropenia, and cytopenias
• 5-year Overall Survival in all patients; 32%
• 5-year Disease Free survival (DFS) in CR patients (n = 205); 37%
• Better OS was significantly associated with younger age (P < 0.0001), favorable cytogenetics (P < 0.0001) and de novo AML (P = 0.02)
• Consolidation with TST AcDAc trended toward lower DFS (HR = 1.9, P = 0.08) and Post Remission Survival (PRS [HR = 1.6, P = 0.23]) compared to HiDAC alone

In summary, TST was feasible and offers favorable CR rate, OS and DFS in a “non-clinical trial population with manageable toxicities which is also comparable to rates seen in clinical trials”.

Additionally, “TST can provide long-term survival when followed by consolidation chemotherapy using either HiDAC or AcDAC”.

 Abstract

Timed sequential therapy (TST) aims to improve outcomes in acute myelogenous leukemia (AML) by harnessing drug-induced cell cycle kinetics of AML, where a second drug is timed to coincide with peak leukemia proliferation induced by the first drugs. We analyzed outcomes in 301 newly diagnosed AML patients treated from 2004–2013 with cytarabine, anthracycline, and etoposide TST induction. Median age was 52 (range 20–74) and complete remission rate 68%. With median follow-up 5.8 years, 5-year DFS and overall survival (OS) were 37% (95% CI 31–45%) and 32% (95% CI 27–38%), respectively. In multivariate analysis, older age, unfavorable cytogenetics, and WBC ≥ 50 × 109/L resulted in worse OS. Among patients not undergoing blood and marrow transplant, a propensity score analysis, which reduces imbalance in baseline characteristics, showed consolidation with TST compared with 1 or more cycles high-dose cytarabine trended toward lower DFS and post-remission survival with hazard ratio (HR) 1.9 (95% CI 0.9–4.0), and 1.6 (95% CI 0.7–3.6), respectively. Our results demonstrate the efficacy and feasibility of TST induction for newly diagnosed patients with AML, with results comparable to that seen in clinical trials with other TST therapies and 7 + 3.