Long‐term follow‐up of European APL 2000 trial, evaluating the role of cytarabine combined with ATRA and Daunorubicin in the treatment of nonelderly APL patients

Abstract

All-trans retinoic acid (ATRA) combined to anthracycline-based chemotherapy is the reference treatment of acute promyelocytic leukemia (APL). Whereas, in high-risk patients, cytarabine (AraC) is often considered useful in combination with anthracycline to prevent relapse, its usefulness in standard-risk APL is uncertain. In APL 2000 trial, patients with standard-risk APL [i.e., with baseline white blood cell (WBC) count <10,000/mm 3 ] were randomized between treatment with ATRA with Daunorubicin (DNR) and AraC (AraC group) and ATRA with DNR but without AraC (no AraC group). All patients subsequently received combined maintenance treatment. The trial had been prematurely terminated due to significantly more relapses in the no AraC group (J Clin Oncol, (24) 2006, 5703-10), but follow-up was still relatively short. With long-term follow-up (median 103 months), the 7-year cumulative incidence of relapses was 28.6% in the no AraC group, compared to 12.9% in the AraC group (P 5 0.0065). In standard-risk APL, at least when the anthracycline used is DNR, avoiding AraC may lead to an increased risk of relapse suggesting that the need for AraC is regimen-dependent. Am. J. Hematol. 88:556-559, 2013. V C 2013 Wiley Periodicals, Inc. IntroductionIn spite of recent promising results obtained with arsenic trioxide (ATO) in this situation [1,2] the combination of alltrans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT) remains the reference first-line treatment of acute promyelocytic leukemia (APL), which leads to complete remission in 90-95% and prolonged calorie restriction (CR) in 75-80% of the patients [3]. Reducing the amount of CT in APL patients has been investigated in order to limit its toxicity. The PETHEMA and GIMEMA groups, in particular, reported very few relapses and deaths in CR with regimens combining ATRA and intercalating agents (idarubicin and mitoxantrone) without AraC, suggesting that AraC can be omitted from the treatment of APL, at least in standard-risk patients [i.e., with white blood cell (WBC) count <10,000/mm 3 ] [4,5].On the other hand, our APL 2000 trial randomizing AraC during induction and consolidation treatment, in patients aged 60 years with WBC count <10 G/l, was closed after the first interim analysis, made after a median follow-up of 24 months, due to significantly higher 2 year cumulative incidence of relapse (CIR) in the group without AraC [6,7].We present here long-term results of this trial, 7 years after the last patient inclusion, with a median follow-up of 103 months.

Autophagy and Ubiquitin-Mediated Proteolytic Degradation of PML/Rarα Fusion Protein in Matrine-Induced Differentiation Sensitivity Recovery of ATRA-Resistant APL (NB4-LR1) Cells: in Vitro and in Vivo Studies

“…The complete remission rate of APL exceeded 90% with the application of all-trans retinoic acid (ATRA), arsenic trioxide (ATO), and anthracycline-based chemotherapy [2]. However, the 7-year cumulative incidence of relapses was reported as 28.6% in APL maintenance with ATRA and daunorubicin [3] and even reached 33% in the ATRA maintenance treatment group [4]. The relapse/refractory patients showed resistance to ATRA and/or ATO, which has been identified as a clinically significant problem.…”

Computational fishing of new DNA methyltransferase inhibitors from natural products

“…Daunorubicin, an anthracycline produced by Streptomyces peucetius [92], has been extensively used for the treatment of acute promyelocytic leukemia by acting through epigenetic inactivation of genes in the INK4/CDK/RB cell cycle pathway [93,94], and other cancer therapies [95,96], as well as against unwanted intraocular proliferation [97]. However, its anticancer effects have been related to inhibition of DNA topoisomerase II [98].…”

Progress in the treatment of acute promyelocytic leukemia: optimization and obstruction

“…Patients \60 years and with standard risk (WBC count B 10 9 10 9 /L) were randomized into Ara-C and no Ara-C groups in induction and consolidation therapies. The results showed that DNR alone instead of the classic DNR-Ara-C combination led to a higher risk of relapse, with the 7-year cumulative incidence of relapses (CIR) 28.6 % in the non-Ara-C group, compared to 12.9 % in the Ara-C group (P = 0.0065) [47].…”