Evaluating the Utilization of All-Trans Retinoic Acid and Arsenic Trioxide during Consolidation Therapy for Patients Receiving Treatment for Acute Promyelocytic Leukemia
Authors: Bowers Laura A , Hibino Maho , Hunt Rebecca Garcia , Ellis Leslie Renee , Bhave Rupali , Howard Dianna S. , Lyerly Susan , Dralle Sarah , Manuel Megan , Pardee Timothy S. , Powell Bayard L 
Published: November 2019

Background. Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) accounting for approximately 10% of AML cases. Advancements in the management of APL have led to complete remission (CR) rates of 90-100% and 5-year overall survival (OS) rates between 86-97%. Standard treatment of APL consists of induction and consolidation, with or without post-consolidation therapy, which is directed by risk group, age, and cardiovascular risk. A standard consolidation option consists of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) (NCCN Guidelines, AML Version 3.2019). Frequently patients are unable to obtain consolidation with ATRA due to the high prescription co-pay and limited financial assistance. This study assessed the efficacy, safety, and financial impact of APL consolidation therapy with ATRA/ATO compared to ATO monotherapy at a single institution.

Methods. This single-center, retrospective, chart-review study assessed adult patients with APL who received ATRA/ATO induction, followed by consolidation with ATRA/ATO or ATO monotherapy between November 2012 to January 2018. The primary efficacy endpoint was OS. Secondary endpoints included event-free survival (EFS), relapse-free survival (RFS), hematologic CR or molecular CR (CRm), incidence of adverse drug events, and outpatient accessibility of ATRA. Numerical data were expressed as medians and interquartile range (IQR) and categorical data were evaluated using the Fisher Exact test. The Log-rank test was used for time to event data and analyzed using the Kaplan-Meier method. A P-value of < 0.05 was defined as statistically significant.

Results. The final analysis included 31 patients, 25 patients received standard ATRA/ATO and 6 patients received ATO monotherapy. Patients in the ATRA/ATO group had a median age of 47 years (range 19 - 72); 8 had low risk and 15 had intermediate risk APL. Patients in the ATO monotherapy group had a median age of 73 years (range 70 - 83); 4 had low risk and 1 had intermediate risk APL. Patients in the ATO monotherapy group had more comorbidities, with all patients having a Charlson Comorbidity Index of 4 or higher compared to only 44% of the ATRA/ATO group (p=0.02). A dose reduction for ATO was required for 50% and 28% of patients in the ATO monotherapy and ATRA/ATO groups, respectively due to peripheral neuropathy. During consolidation, patients in the ATO monotherapy group received a median of 5.4 mg/kg of ATO over 2 cycles compared to 11.6 mg/kg over 4 cycles in the ATRA/ATO group (Table 1). Five of six patients (83.3%) and 24 of 25 patients (96%) were alive at last follow-up in the ATO monotherapy and ATRA/ATO groups with a median follow-up of 33.3 months and 35.5 months, respectively (Graph 1). Secondary endpoints are provided in Table 2. There was 1 death in each group, both due to unknown causes. All adverse events occurred in a higher proportion of patients in the ATRA/ATO group (Graph 2). The incidence of headache was significantly higher in the ATRA/ATO group, occurring in 68% of patients and leading to ATRA discontinuation for 1 patient (Table 3), compared to 0 events in the ATO monotherapy group (p=0.004). Barriers to access occurred in 19.4% (6 of 31) of all patients. In addition to the 4 patients who required omission of ATRA upfront due to cost, 2 additional patients discontinued ATRA during consolidation due to affordability (Table 3).

Conclusions. Patients in the ATO monotherapy group were on average older, had more comorbid conditions, and received a lower cumulative dose of ATO during consolidation. The standard dose of ATO during consolidation is 12 mg/kg administered over 4 cycles. In our study, patients in the ATO monotherapy group received a median of 5.4 mg/kg of ATO over 2 cycles compared to 11.6 mg/kg over 4 cycles in the ATRA/ATO group. Despite discrepancies in age, comorbidities, and total dose of ATO received, outcomes were similar in the ATRA/ATO and ATO monotherapy groups. Although limited by a small sample size and retrospective design, this study suggests that elimination of ATRA from consolidation may be an acceptable option for patients that are unable to obtain ATRA or that experience intolerable side effects. These findings also suggest that lower cumulative doses of ATO during consolidation may produce similar efficacy with lesser toxicity. Future large, multicenter studies are necessary to confirm the efficacy and safety of these findings.

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Disclosures

Manuel: Novartis: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Pardee:Rafael Pharmaceuticals: Consultancy, Research Funding; Karyopharm: Research Funding; Pharmacyclics/Janssen: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees; Spherix Intellectual Property: Research Funding. Powell:Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Janssen: Research Funding.