Validation Of a Brief Arsenic Trioxide (ATO)-Based Consolidation Chemotherapy In The Upfront Management Of Acute Promyelocytic Leukemia (APL): Less Anthracycline Exposure and Faster Completion Of Consolidation Therapy With Equivalent Survival
Authors: Leech Mindy , Stewart Moshe , Zhang Xu , Bashey Asad , Holland H. Kent , Solomon Scott R. , Carraway Hetty E , Smith B. Douglas , Morris Lawrence E. , Gore Steven D. , Zeidan Amer M. 
Published: October 2019

Abstract

Background
Although anthracyclines have significant proven activity in APL, their use is associated with significant cardiac toxicity and risk of secondary malignancy. Therefore there has been an increased interest in minimizing anthracycline exposure without compromising outcomes. All-trans retinoic acid (ATRA)-ATO combination has been shown to be an active and less toxic regimen in APL, but the experience with this regimen is largely limited to patients (pts) without high-risk (HR) disease (White cell count [WBC]<10,000/µL) (Lo-Coco et al. NEJM 369: 111-121). Moreover, this regimen requires ≥8 months of therapy. We have previously reported that a single cycle of ATO- based consolidation chemotherapy is effective in the primary management of APL while significantly minimizing anthracycline exposure (Gore et al. JCO, 2010; 28:1047-1053). We sought to evaluate the “real-life” performance of this approach in patients treated following completion of protocol accrual.

Methods
We identified and screened all APL pts who received ATO-based consolidation at Johns Hopkins University (JHU), Baltimore, Maryland and Northside hospital (NSH), Atlanta, Georgia. We excluded pts who were enrolled on the original trial and pts who were diagnosed after August 1st 2012 to allow for adequate follow-up. Induction therapy used ATRA 45mg/m2/day (d) x 60d and daunorubicin 60mg/m2 on d 4, 6, and 8. Consolidation consisted of one course of therapy that included continuous infusion cytarabine 667 mg/m2/d, intravenous daunorubicin 60 mg/m2/d on d1-3, and ATO 0.15 mg/kg given for 5d per week for 30 doses beginning d8. Pts received 2 years of risk-adapted maintenance therapy: all patients received ATRA alone for 15d every 3 months, with the addition of mercaptopurine daily and oral methotrexate weekly for HR pts (WBC >10,000/µL). Descriptive statistics were used to summarize data and Kaplan-Meier methodology was used to calculate survivals. Event free survival (EFS) was defined as time from diagnosis till relapse or death, leukemia-free survival (LFS) was defined as time from remission to relapse (censoring for death in remission), and overall survival (OS) was defined as time from diagnosis to death.

Results
We identified 63 pts (30 JHU, 33 NSH) who were treated according to the study protocol but not enrolled on the original trial. 14 pts (8 JHU, 6 NSH) were diagnosed after August first, 2012 and therefore were excluded. Forty-nine pts (22 JHU and 27 NSH) were included in the analysis. The median age was 55 years (range, 21-73). Twenty-seven were males and 22 were females, and 14 had HR disease while 35 had low-risk disease. The median follow-up of survivors was 2.4 years (95% confidence interval [95%CI], 1– 8.8). Two patients died during induction (one with HR and one with low risk disease); all other pts achieved complete remission (CR). Two pts died during maintenance therapy while in CR (both low-risk disease, one died due to graft failure in a cardiac transplant recipient, and the other due to recurrent metastatic breast cancer). One patient relapsed during the follow-up period, but is currently in CR after autologous transplant. The EFS was 86.1% (95%CI, 74 – 100%), the LFS 97.6% (95%CI, 92-100%), and OS was 88.5% (95%CI, 76-100%). Among the 14 HR patients, the estimated OS and EFS were both 93 % (95%CI, 86-100%).

Conclusion
These data confirm the outcomes of the original clinical trial. While ATRA-ATO combination is an attractive non-chemotherapy approach for APL pts, its efficacy in HR pts is not yet documented and it requires prolonged intensive therapy (≥8 months). ATO-based chemotherapy consolidation is typically completed within 3-4 months and is effective in HR pts. This approach may be preferable in selected patients with HR APL or if a shorter period of intensive therapy is preferred.

Disclosures:
No relevant conflicts of interest to declare.