General AML

Outcomes of older APL patients treated with ATRA plus anthracycline

Front-line therapy with All Trans Retinoic Acid (ATRA) and a reduced dose of anthracycline monotherapy improved the outcomes of older patients with Acute Promyelocytic Leukemia (APL) according to a study published in Leukemia on 7th July 2017 by David Martínez-Cuadrón from the Hospital Universitari i Politècnic La Fe, Valencia, Spain, and colleagues.1

Previous reports from two consecutive Programa Espanol de Tratamientos en Hematologica (PETHEMA) trials have demonstrated that older APL patients can be treated using ATRA plus anthracycline, however outcomes are poorer than those observed in younger patients due to the high mortality rate related to toxicity of the treatment.2 This observation led to the design of the age- and risk-adapted LPA2005 trial (NCT00408278), in which the anthracycline dose in second consolidation was reduced and administered over three days rather than five days as per previous protocols in PETHEMA trials (LPA96 and LPA99 [LPA96&99]).

Martínez-Cuadrón et al., aimed to compare the long-term outcomes of older APL patients who were treated with the less intense protocol used in the LPA2005 trial and those who were included in the more intense protocol used in precedent LPA96&99 trials.

Overall, 268 older APL patients (median age = 68 years) who were enrolled in the LPA96&99 (n = 135) and the LPA2005 (n = 133) trials were analyzed in this study. The primary endpoint of the study was to compare the Disease Free Survival (DFS) between patients treated with a non-age- and risk- adapted protocol (LPA96 & LPA99) and those treated with an age- and risk adapted protocol (LPA2005).

The key results of the study were:
  • 5-year Overall Survival (OS) in patients in the LPA96&99 and LPA2005 were 60% and 74% respectively; P = 0.06
  • 5-year Disease Free Survival (DFS) in patients in the LPA96&99 and LPA2005 were 69% and 87% respectively; P = 0.04
  • 5-year Non-Relapse Mortality (NRM) in patients in the LPA96&99 and LPA2005 were 18% and 5% respectively; P = 0.15
  • 5-year Cumulative Incidence of Relapse (CIR) in patients in the LPA96&99 and LPA2005 were 12% and 7% respectively; P = 0.23

Dose reduction of anthracycline during consolidation for older APL patients treated in the LPA2005 trial resulted in a lower NRM, high antileukemic activity and improved survival compared to patients in the more intensive LPA96&99 trials.

Martínez-Cuadrón et al., concluded by highlighting that the results from their study demonstrates that a “less intensive front-line regimen with ATRA and anthracycline monochemotherapy resulted in an improved outcome in older patients with newly diagnosed APL”. They further proposed that “future studies with even less intense chemotherapy regimens or with arsenic trioxide plus ATRA” for older APL patients are warranted.

Abstract

Treatment outcome in older patients with acute promyelocytic leukemia (APL) is lower compared with younger patients, mainly because of a higher induction death rate and postremission non-relapse mortality (NRM). This prompted us to design a risk- and age-adapted protocol (Programa Español de Tratamientos en Hematología (PETHEMA)/HOVON LPA2005), with dose reduction of consolidation chemotherapy. Patients aged ⩾60 years reported to the PETHEMA registry and were treated with all-trans retinoic acid (ATRA) plus anthracycline-based regimens according to three consecutive PETHEMA trials that were included. We compared the long-term outcomes of the LPA2005 trial with the preceding PETHEMA trials using non-age-adapted schedules (LPA96&LPA99). From 1996 to 2012, 389 older patients were registered, of whom 268 patients (69%) were eligible. Causes of ineligibility were secondary APL (19%), and unfit for chemotherapy (11%). Median age was 67 years, without relevant differences between LPA2005 and LPA96&LPA99 cohorts. Overall, 216 patients (81%) achieved complete remission with no differences between trials. The 5-year NRM, cumulative incidence of relapse, disease-free survival and overall survival in the LPA2005 vs the LPA96&99 were 5 vs 18% (P=0.15), 7 vs 12% (P=0.23), 87 vs 69% (P=0.04) and 74 vs 60% (P=0.06). A less intensive front-line regimen with ATRA and anthracycline monochemotherapy resulted in improved outcomes in older APL patients.

References
  1. Martínez-Cuadrón D. et al. Long-term outcome of older patients with newly diagnosed de novo acute promyelocytic leukemia treated with ATRA plus anthracycline-based therapy. Leukemia. 2017 Jun 6. DOI: 10.1038/leu.2017.178. [Epub ahead of print].
  2. Sanz M. A. et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009 Feb 26; 113(9): 1875–1891. DOI: 10.1182/blood-2008-04-150250. Epub 2008 Sep 23.