Improving the Outcomes of Acute Promyelocytic Leukemia in a Limited Resources Setting: The Benefit of Early ATRA Administration in 30-Day Survival
Authors: Duarte Bruno Kosa Lino , Toreli Ana Carolina Mourão , Pastori Mariana Dos Santos , Peres Paulo Vittor Oliveira , Lamonica Andreza , Saraiva Camilla Maria de Alencar , Rego Eduardo Magalhães , Pagnano Katia B 
Published: October 2019

Abstract

INTRODUCTION:Acute promyelocytic leukemia (APL) is the most curable acute leukemia in adults. Advancements in therapeutics such as the use of tretinoin (ATRA) and arsenic trioxide (ATO) have led to an overall survival of over 90% in 5 years. Early mortality, however, remains a major component of overall mortality in this disease and prompt recognition and initiation of adequate treatment has always been considered the most effective strategy to prevent it. Recent reports, though, have failed to show the benefit of prompt ATRA ministration in early mortality, once APL is suspected. These reports come mainly from high-income countries with swift and widespread access to health care services that are capable of recognizing, diagnosing and treating APL in a timely manner.
We hypothesized, therefore, that in a lower income country, in a limited resources setting, prompt ATRA administration would improve early mortality in the setting of APL.
METHODS: This is a retrospective, single-center study. We included all patients with APL diagnosis, confirmed by molecular or cytogenetics analysis treated in our institution, from January 1999 to May 2018. Until 2006, patients were treated with a modified AIDA regimen (ATRA plus mitoxantrone). After 2006, patients were treated with the International Consortium on Acute Promyelocytic Leukemia - ICAPL protocol (ATRA plus daunorubicin). This was a combined effort of the American Society of Hematology and of healthcare institutions from Latin American countries to improve outcomes in APL through improvements in therapeutics, education of healthcare professionals and expanded access to molecular diagnosis.
We retrieved and reviewed patients' records for the time interval from disease presentation until the first hospital admission, and from hospital admission to the first dose of ATRA. We also looked for diagnostic variables that could be related with 30-day survival.
RESULTS:Between January 1999 and May 2018, 83 APL patients were evaluated. Table 1 summarizes patients' characteristics. Medical records were available for 81/83 patients; 4 of them did not receive ATRA and died less than 7 days after their presentation. At diagnosis, median age was 37 years, 51.9% of patients were female, 26% were high-risk, 77.8% had bleeding symptoms, 72.8% had abnormal coagulation tests, and 12.3% had an elevated serum creatinine. Seventy-five percent were treated under the IC-APL protocol. Median time from disease presentation to the first hospital admission was 14.3 days (1-64 days) and median time to administration of ATRA after hospital admission was 18.2 hours (0.47-95.47 hours). Time to ATRA administration was significantly higher in patients who died in the first 30 days after diagnosis (median 27.46 vs.15.52 hours p=0.037) and who were treated with the modified AIDA (median 25.04 hours for the modified AIDA vs. 15.2 hours for the IC-APL protocol, p=0.037).
Early administration of ATRA (less than 24 hours after the first hospital admission) was associated with a higher 30-day survival (89.4% vs. 63.3%, p=0.007; 75.3% for the whole cohort - Figures 1A and B). This benefit was seen mainly in patients with low or intermediate Sanz's risk score (Figures 1C and D). Serum creatinine, leukocytes count, and Sanz's risk were also predictive of 30-day survival in the whole cohort. There was no correlation between time from disease presentation to first hospital admission with 30-day survival.
CONCLUSIONS: Our data support the role of early ATRA administration in the reduction of 30-day mortality in patients with recently diagnosed APL. This contrasts with previous findings from high-income countries that did not support such a benefit. We should highlight that in these cohorts the median time for ATRA administration was longer, which could explain the conflicting results. Furthermore, patients in high-income countries access health services early in their disease course, which could hamper any benefit from early ATRA administration.
The correlation of early ATRA administration with the institution of IC-APL protocol underscores the importance of initiatives that promote the education of healthcare professionals and access to diagnostic tests of complex hematological diseases in low-income settings.

Disclosures
Pagnano: Abbvie: Consultancy; EMS: Other: Financial support for participation in congress; Novartis: Consultancy; Shire: Other: Lecture.