All-trans retinoic acid in acute promyelocytic leukemia: Long-term outcome and prognostic factor analysis from the North American Intergroup protocol

ArticleinBlood 100(13):4298-302 · December 2002with17 Reads
DOI: 10.1182/blood-2002-02-0632 · Source: PubMed
We previously reported a benefit for all-trans retinoic acid (ATRA) in both induction and maintenance therapy in patients with acute promyelocytic leukemia (APL). To determine the durability of this benefit and identify important prognostic factors, long-term follow-up of the North American Intergroup APL trial is reported. A total of 350 patients with newly diagnosed APL were randomized to either daunorubicin and cytarabine (DA) or ATRA for induction and then either ATRA maintenance or observation following consolidation chemotherapy. The complete remission (CR) rates were not significantly different between the ATRA and DA groups (70% and 73%, respectively). However, the 5-year disease-free survival (DFS) and overall survival (OS) were longer with ATRA than with DA for induction (69% vs 29% and 69% vs 45%, respectively). Based on both induction and maintenance randomizations, the 5-year DFS was 16% for patients randomized to DA and observation, 47% for DA and ATRA, 55% for ATRA and observation, and 74% for ATRA and ATRA. There was no advantage of either induction regimen among any subgroups when CR alone was considered. However, female sex, classical M3 morphology (vs the microgranular variant [M3v]), and treatment-white blood cell count (WBC) interaction (ATRA/WBC below 2 x 10(9)/L [2000/microL] best, DA/WBC above 2 x 10(9)/L worst) were each significantly associated with improved DFS (P <.05). Treatment with ATRA, WBC below 2 x 10(9)/L, and absence of bleeding disorder were each significantly associated with improved OS. Age more than 15 years, female sex, and treatment-morphology interaction (DA/M3v worst, ATRA best regardless of morphology) were each significantly associated with improved DFS based on maintenance randomization. The improvement in outcome with ATRA in APL was maintained with long-term follow-up.
    • "The oncogenic fusion proteins generated by translocations involving the RARa locus (Figure 5) can form homodimers, for example, through the PML moiety (Sternsdorf et al., 2006), which antagonize retinoid signaling and contribute to the epigenetic silencing of RARb2 expression through the aberrant recruitment of transcriptional silencing complexes (Di Croce et al., 2002; Zhou et al., 2006). Pharmacological treatment of APL patients with ATRA can induce differentiation and durable hematologic remission (Huang et al., 1988; Tallman et al., 2002; Wang and Chen, 2008). A role for NRs in cancer-associated gene translocations has recently emerged (Bastus et al., 2010; Lin et al., 2009; Mani et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Retinoids are natural and synthetic derivatives of vitamin A, also termed retinol. This article will address the current understanding of (i) the uptake, the metabolism, and storage of dietary retinoids; (ii) the molecular mechanisms whereby retinoids activate transcription via the retinoic acid receptor (RAR) and retinoid X receptor (RXR) and thereby effect the diverse actions of retinoids in vivo; and (iii) the physiological roles of retinoids in normal development and health. Finally, we will outline the current pharmacological uses of retinoids in the treatment and management of acute promyelocytic leukemia and potential future use of retinoids in cancer chemoprevention and treatment.
    Chapter · Jan 2016 · Blood Reviews
    • "Acute promyelocytic leukemia (APL) is a distinct form of acute myeloid leukemia (AML) that is characterized by an arrest of leukocyte differentiation at the promyelocyte stage. Standard treatment of APL to mitigate the block includes differentiation therapy with all trans-retinoic acid (RA) [1]. However, despite advances in differentiation induction therapy and purported complete remission rates of 80–85%, some APL patients develop either relapsed or refractory disease which no longer responds to RA therapy . "
    [Show abstract] [Hide abstract] ABSTRACT: In binary cell-fate decisions, driving one lineage and suppressing the other are conjoined. We have previously reported that aryl hydrocarbon receptor (AhR) promotes retinoic acid (RA)-induced granulocytic differentiation of lineage bipotent HL-60 myeloblastic leukemia cells. VAF347, an AhR agonist, impairs the development of CD14+CD11b+ monocytes from granulo-monocytic (GM) stage precursors. We thus hypothesized that VAF347 propels RA-induced granulocytic differentiation and impairs D3-induced monocytic differentiation of HL-60 cells. Our results show that VAF347 enhanced RA-induced cell cycle arrest, CD11b integrin expression and neutrophil respiratory burst. Granulocytic differentiation is known to be driven by MAPK signaling events regulated by Fgr and Lyn Src-family kinases, the CD38 cell membrane receptor, the Vav1 GEF, the c-Cbl adaptor, as well as AhR, all of which are embodied in a putative signalsome. We found that the VAF347 AhR ligand regulates the signalsome. VAF347 augments RA-induced expression of AhR, Lyn, Vav1, and c-Cbl as well as p47phox. Several interactions of partners in the signalsome appear to be enhanced: Fgr interaction with c-Cbl, CD38, and with pS259c-RafAhR, and AhR interaction with c-Cbl and Lyn. Thus, we report that, while VAF347 impedes monocytic differentiation induced by 1,25-dihydroxyvitamin D3, VAF347 promotes RA-induced differentiation. This effect seems to involve but not to be limited to Lyn, Vav1, c-Cbl, AhR, and Fgr.
    Full-text · Article · Apr 2015
    • "However, 2 more recent randomized trials have demonstrated substantial improvement in outcomes with ATRA-based maintenance. Tallman and colleagues for the North American Intergroup (E2491) reported lower relapse rates (22% vs. 39%) and improved 5-year DFS (61% vs. 36%) with ATRA mainte- nance [26,58]. The European APL (EAPL) group also demonstrated the benefit of ATRA-based maintenance when given with low-dose oral 6- mercaptopurine and methotrexate in a randomized study [29]. "
    [Show abstract] [Hide abstract] ABSTRACT: Acute promyelocytic leukemia (APL) is one of the most exciting stories of modern medicine. Once a disease that was highly lethal, the majority of patients are now cured with the advent of molecularly targeted therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). In many patients, chemotherapy can be omitted completely, particularly in patients with low- or intermediate-risk disease (white blood cell count ≤ 10,000/μl). Recent data show overall survival exceeding 90% with ATRA and ATO-based induction and consolidation strategies. In the uncommon patient in whom relapse does occur, most can still be cured with ATO and autologous hematopoietic cell transplantation. Remaining challenges in APL management include the rapid identification and treatment of newly diagnosed patients to decrease the early death rate, optimizing treatment strategies in high-risk patients (white blood cell count > 10,000/μl), and the role of maintenance therapy in lower risk patients.
    Article · Sep 2014
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