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

Harvard University, Cambridge, Massachusetts, United States
Blood (Impact Factor: 10.45). 12/2002; 100(13):4298-302. 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.

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    • "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 . "
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    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 · FEBS Open Bio
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    • "The treatment of APL with chemotherapy achieved complete remission (CR) in two-thirds of newly diagnosed patients, however, the 5-year disease-free survival (DFS) was still very poor [1]–[3]. The induction of all-trans retinoic acid (ATRA) in the treatment and optimization of the anthracycline-based regimens resulted in terminal differentiation of APL cells with a 90–95% CR and the 5-year DFS up to 74% [1], [4], [5], although approximately 5–30% of patients developed disease recurrence [6]. "
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    ABSTRACT: The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3, ATO) has been effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL), but the long-term efficacy and safety among newly diagnosed APL patients are unclear. In this retrospective study, total 45 newly diagnosed APL patients received ATRA/chemotherapy combination regimen to induce remission. Among them, 43 patients (95.6%) achieved complete remission (CR) after induction therapy, followed by ATO/ATRA/anthracycline-based chemotherapy sequential consolidation treatment with a median follow-up of 55 months. In these patients, the estimated overall survival (OS) and the relapse-free survival (RFS) were 94.4%±3.9% and 94.6±3.7%, respectively. The toxicity profile was mild and reversible. No secondary carcinoma was observed. These results demonstrated the high efficacy and minimal toxicity of ATO/ATRA/anthracycline-based chemotherapy sequential consolidation treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for APL.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "APL also known as AML, M3 subtype is characterized by the typical morphology and t(15;17) translocation that fuses the PML gene on chromosome 15 to the RARA gene on chromosome 17, which serves as a “clone specific” molecular marker for the diagnosis and monitoring.[1] Anthracycline and Cytosine arabinoside (Ara-C) based combination chemotherapy introduced in the 1960s, has yielded cure rates of 35-40% in APL, whereas combination of anthracycline-Ara C or anthracycline alone to ATRA, introduced in the early 1990s, has improved this cure rate to 65-70% because of its unique sensitivity to the differentiating action of ATRA.[2] We report a patient in remission after chemotherapy for APL who developed AML,M2 subtype with no evidence of APL. "
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    ABSTRACT: The use of all trans-retinoic acid (ATRA) and combination chemotherapy has made acute promyelocytic leukemia (APL) a potentially curable leukemia. Late sequelae of the treatment of APL have therefore become an important consideration in the overall treatment strategy. We report a patient with APL who achieved complete clinical and molecular remission after treatment with daunorubicin and ATRA. Three years later, she developed acute myeloid leukemia (AML), M2 subtype without any evidence of relapse of the APL clone. Karyotypic analysis showed a normal female karyotype.
    Full-text · Article · Oct 2013 · Indian journal of medical and paediatric oncology
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