General AML

Outcomes of therapy-related APL patients treated with or without ATO

The use of Arsenic Trioxide (ATO) in combination with All Trans Retinoic Acid (ATRA) has been shown to be an effective therapy for patients with de novo Acute Promyelocytic Leukemia (APL).1 However, the clinical impact of ATO/ATRA combination has not been evaluated in patients with Therapy-related APL (tAPL), hence the rationale for this study.

Sabine Kayser from the University Hospital of Heidelberg, Heidelberg, Germany, and colleagues retrospectively compared the outcomes of t-APL patients who were treated with ATO/ATRA or Chemotherapy (CTX) either with ATRA alone or in combination with ATO. The results of the study were published ahead of print in Leukemia on 18th April 2017.2  

In total, 103 adult t-APL patients (median age = 59 years) diagnosed between 1991–2015 from 11 study centers in the US and Europe were enrolled in this study. Patients either received induction therapy with ATRA alone (n = 7) or in combination with ATO (n = 24) or CTX (n = 53) or CTX in combination with ATO and ATRA (n = 19). Response data were available for 100 patients (97%).

The key results of the study were:
  • Complete Remission Rate (CRR) in patients after induction therapy with ATRA, ATRA-ATO, CTX/ATRA and CTX/ATRA/ATO; 57% vs 100% vs 78% vs 95%
  • Early death (ED) rate in patients treated with ATRA, ATRA-ATO, CTX/ATRA and CTX/ATRA/ATO; 43% vs 0% vs 12% vs 5%
  • 2-year Overall Survival (OS) rate in patients treated with ATRA-ATO, CTX/ATRA and CTX/ATRA/ATO; 89% vs 84% vs 95%
  • 2-year Event Free Survival (EFS) rate in patients treated with ATO based therapy (ATO/ATRA and CTX/ATO/ATRA) and CTX/ATRA; 95% vs 78%; P = 0.042
  • Relapse (n = 3) and therapy-related Acute Myeloid Leukemia (n =2) in patients treated with CTX/ATRA
  • Grade ≥ 3 febrile neutropenia during induction therapy was less frequent in patients treated with ATO/ATRA compared to CTX/ATRA or CTX/ATRA/ATO; P = 0.03
  • Death occurred in thirteen patients due to relapse of prior malignancy (n = 7), infections (n = 3), development of Diffuse Large B-cell Lymphoma (n =1), cardiopulmonary arrest (n =1) and unknown reason (n = 1)

The ATO-based regimen for first line treatment of t-APL patients was “feasible and leads to better outcomes compared to CTX/ATRA”. Sabine et al., concluded by suggesting that the ATRA and ATO (Trisenox®)  approach, which was recently approved by the European Medicines Agency (EMA) for first line treatment of low to intermediate risk APL patients should be expanded  for the primary management of t-APL patients.

Abstract

Therapy-related acute promyelocytic leukemia (t-APL) is relatively rare, with limited data on outcome after treatment with arsenic trioxide (ATO) compared to standard intensive chemotherapy (CTX). We evaluated 103 adult t-APL patients undergoing treatment with all-trans retinoic acid (ATRA) alone (n=7) or in combination with ATO (n=24), CTX (n=53), or both (n=19). Complete remissions were achieved after induction therapy in 57% with ATRA, 100% with ATO/ATRA, 78% with CTX/ATRA, and 95% with CTX/ATO/ATRA. Early death rates were 43% for ATRA, 0% for ATO/ATRA, 12% for CTX/ATRA and 5% for CTX/ATO/ATRA. Three patients relapsed, two developed therapy-related acute myeloid leukemia and 13 died in remission including seven patients with recurrence of the prior malignancy. Median follow-up for survival was 3.7 years. None of the patients treated with ATRA alone survived beyond one year. Event-free survival was significantly higher after ATO-based therapy (95%, 95% CI, 82-99%) as compared to CTX/ATRA (78%, 95% CI, 64-87%; P=0.042), if deaths due to recurrence of the prior malignancy were censored. The estimated 2-year overall survival in intensively treated patients was 88% (95% CI, 80-93%) without difference according to treatment (P=0.47). ATO when added to ATRA or CTX/ATRA is feasible and leads to better outcomes as compared to CTX/ATRA in t-APL.

References
  1. Platzbecker U. et al. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol. 2017 Feb 20; 35(6): 605–612. DOI: 10.1200/JCO.2016.67.1982.
  2. Kayser S. et al. Characteristics and outcome of patients with therapy-related acute promyelocytic leukemia front-line treated with or without arsenic trioxide. 2017 Apr 18. Leukemia. DOI: 10.1038/leu.2017.92. [Epub ahead of print].