Lengfelder E, et al. APL 2017:CO027

Front-line therapy of APL: Randomized comparison of ATRA and intensified chemotherapy including high dose cytosine-arabinoside versus ATRA and anthracyclines — a prospective, multicentre, randomized clinical trial of the German Acute Myeloid Leukemia Cooperative Group

Background

The APL-2005 study was started as an Acute Myeloid Leukemia Cooperative Group (AMLCG) trial with the intention to be part of an acute promyelocytic leukemia (APL) intergroup study with the PETHEMA LPA99 protocol as a common standard arm. Results from this study were presented at the 2017 International Symposium on APL.1

Study design

  • Patients with genetically confirmed, newly diagnosed APL were randomized to receive either the AMLCG protocol or the PETHEMA LPA99 study protocol between November 2005 and December 2015.
  • Primary endpoint was comparison of the kinetics of minimal residual disease.
    • This was defined as the first negative reverse transcription polymerase chain reaction (RT-PCR) of promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) after induction or consolidation.
  • Secondary endpoints included toxicity, overall survival (OS), event-free survival, relapse-free survival, and cumulative incidence of relapse (CIR).

Study design

Key findings

Baseline characteristics and disposition

  • A total of 102 patients were assessed for eligibility.
    • Fifteen patients were excluded prior to randomization for death (n = 3), no informed consent (n = 2), medical contraindication (n = 5), APL diagnosed after the start of acute myeloid leukemia therapy (n = 4), and secondary APL (n = 1).
  • Eighty-seven patients were randomized to the AMLCG (n = 44) or PETHEMA (n = 43) groups.
    • Six patients were excluded after randomization to the AMLCG group for protocol violation (n = 1), withdrawn consent (n = 1), or incorrect diagnosis of APL (n = 4).
    • One patient was excluded after randomization to the PETHEMA group for protocol violation.
  • Of the 38 evaluable patients in the AMLCG group, 14 were low risk, 18 were intermediate risk, and six were high risk.
  • Of the 42 evaluable patients in the PETHEMA group, 14 were low risk, 19 were intermediate risk, and nine were high risk.
    • The numbers of patients in each risk group were statistically similar to those in the AMLCG group (p = 0.875).
  • Baseline patient characteristics were similar between groups.
    • Median age was 56 years in the AMLCG group and 49.5 years in the PETHEMA group (p = 0.391).
    • The majority of patients were male (58% and 50% in the AMLCG and PETHEMA groups, respectively; p = 0.509), had an L/V transcript type (54% vs. 69%; p = 0.339), and had translocation between chromosomes 15 and 17 (62% vs. 60%; p = 1).
    • White blood cell counts were similar between groups (23 x 109/L in the AMLCG group and 12 x 109/L in the PETHEMA group; p = 0.583).

Efficacy

  • Complete hematological remission was observed in 33 patients (87%) in the AMLCG group and in 35 patients (83%) in the PETHEMA group (p = 0.76).
  • After induction, significantly more patients in the AMLCG group achieved RT-PCR negativity (p = 0.0124). (Table 1)
  • Following consolidation, RT-PCR negativity was similar between groups. (Table 1)
  • Cumulative incidence of RT-PCR conversion from positive to negative was also similar between groups (p = 0.12). (Figure 1)
  • Long-term outcomes were similar between groups with the exception of CIR, as there were no incidences of relapse in the AMLCG group compared to a 12% relapse rate in the PETHEMA group (p = 0.04). (Table 2)

Figure 1. Cumulative incidence of RT-PCR conversion from start of induction until bone marrow control after consolidation

Table 1. RT-PCR results for patients with complete response

Table 2. Long-term outcomes

Safety

  • Toxicities during induction therapy were similar between groups with the exception of the median duration of critical cytopenia, which was longer in the AMLCG group (p = 0.02). (Table 3)
  • Events during follow-up are summarized in Table 4.

Table 3. Results of induction therapy

Table 4. Events during follow-up

Key conclusions

  • The randomized comparison of AMLCG and PETHEMA regimens shows similar OS and indicates the limitations of ATRA and chemotherapy.
  • A lower relapse rate was seen with the more intensive regimen (AMLCG), but this was associated with more toxicity.
  • In comparison with the literature, the results indirectly support the application of ATRA plus arsenic trioxide in standard-risk APL.
  • Small patient number is a limitation of this study.

Reference: 1. Lengfelder E, Görlich D, Nowak D, et al. Frontline therapy of acute promyelocytic leukemia: randomized comparison of ATRA and intensified chemotherapy including high dose cytosine-arabinoside versus ATRA and anthracyclines — a prospective multicenter randomized clinical trial of the German Acute Myeloid Leukemia Cooperative Group (AMLCG). Intl. Symposium on APL Abstracts 2017:CO027.