General AML

ESH 2018 | Therapy of APL

Acute promyelocytic leukemia (APL) is characterized by a chromosomal translocation containing the retinoic acid receptor alpha (RARα or RARA) gene and by specific coagulopathy. APL is distinguished from other forms of acute myeloid leukemia (AML) by its responsiveness to anthracyclines, such as All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO) therapy. At the European School of Hematology (ESH) Clinical Updates in Acute Leukemia Meeting on 5 May 2018, in Budapest, Hungary., an educational talk was presented by Lionel Adès, Professor of Hematology at Hôpital Saint-Louis, Paris, France, on the prognostic factors and evolving chemotherapy-free therapy approach for APL.1

Prognostic factors

Pre-treatment factors such as older age and high white blood cell (WBC) count are highly associated with early death in APL. In addition, there are other pre-treatment factors associated with higher risk of relapse, for instance, FAB M3v morphology, short bcr3 transcript, expression of CD2, CD56, CD34, FLT3 internal tandem duplication, or high WBC count. The most important prognostic risk factor is treatment response after consolidation therapy, whether the patient achieved a complete remission or did not.

Early death (ED)

ED is defined as death within the first 30 days of diagnosis. Studies have shown that the ED rates remain high in APL despite the extensive accessibility of ATRA. Although the reasons for early deaths in APL are multiple, data suggest that delay of ATRA administration lead to ED.

Optimal treatment of coagulopathy

APL is highly associated with a complex coagulopathy. Regardless of recent therapy improvements, hemorrhagic death remains the main cause of induction failure. It is recommended that supportive treatment should be started as soon as the diagnosis of APL is assumed, even before it is confirmed by bone marrow samples or cytogenetics. Supportive care includes platelet transfusion to maintain the platelet count above 50 g/l. Fresh frozen plasma and fibrinogen are recommended if fibrinogen levels are under 150 mg/dl. During the coagulopathy period, all invasive procedures should be avoided.

First line treatment

ATRA in combination with anthracycline-based chemotherapy has characterized the standard of care in APL until very recently and still remains a commonly used option in front-line therapy, as ATRA monotherapy is characterized with a high incidence of relapse. Data from the APL91 trial, demonstrated that that treatment with ATRA followed by anthracycline-arabinosylcytosine (AraC) chemotherapy significantly decreased the incidence of relapse and improved survival in newly diagnosed APL, by comparison with chemotherapy alone. Furthermore, findings from the phase III randomized APL93 trial (NCT00591526) suggested that early addition of chemotherapy to ATRA and maintenance treatment with continuous low-dose chemotherapy and intermittent ATRA can decrease the incidence of relapse in APL. Based on the literature, ATRA in combination with anthracyclines should be administered immediately at first suspicion, because delays in ATRA administration appeared to contribute to early hemorrhagic death in patients with APL. The addition of cytarabine in high-risk APL should be considered to reduce the incidence of relapse. Prolonged maintenance with continuous low-dose 6-mercaptopurine, methotrexate and intermittent ATRA in high-risk APL is also recommended.

Arsenic derivatives

Arsenic trioxide (ATO) has been reported to be an effective and safe treatment option for relapsed APL patients. Thus, recent studies were investigating the role of ATO in newly diagnosed APL patients to decrease the use of chemotherapy.

ATO during consolidation

In 2004, a group of Chinese researchers reported data from a randomized trial which compared the effectiveness of three regimens (ATO + ATRA, ATO alone and ATRA alone) with newly diagnosed APL patients. Anthracycline therapy was administered to those who had achieved complete remission (CR). CR rates were equivalent in each cohort, relapse incidence and a decrease of fusion transcripts were significantly inferior in patients treated with ATO + ATRA.3 Another study in the USA demonstrated that the addition of two extra ATO courses to ATRA and anthracycline regimens as first-line post-remission therapy results in superior outcomes in terms of 3-year event-free and overall survival. An Iranian trial found the same results with ATO monotherapy without maintenance, nonetheless higher relapse rates were also observed.4

ATO during induction

Single-agent ATO induction therapy with or without low dose ATRA or chemotherapy was examined in an Indian study. Patients received ATO induction and consolidation, followed by maintenance therapy for 6 months (10 days/month).  The results showed higher CR rates, disease-free survival, and OS. In a study reported by a group of researchers from the M.D. Anderson demonstrated  ATRA plus ATO may serve as an alternative to chemotherapy in low-risk untreated APL and when combined with gemtuzumab ozogamicin, may improve outcome in high-risk patients.5,6

In a phase III randomized APL0406 study conducted by the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA), the Acute Myeloid Leukemia Study Group (AMLSG), and the Study Alliance Group (SAL), the combination of ATRA-ATO and ATRA-CHT was compared in newly diagnosed APL patients. Findings of this study demonstrated that ATRA-ATO combination significantly improved the survival and relapse risk of patients with newly diagnosed, low–intermediate-risk APL compared to ATRA-CHT. The long-term follow-up of this study showed that the advantages of ATRA-ATO over ATRA-chemotherapy increases over time and that there is significantly greater and more sustained antileukemic efficacy of ATRA-ATO compared with ATRA-chemotherapy in low- and intermediate-risk APL.7

References
  1. Adès L. Therapy of Acute Promyelocytic Leukemia. ESH Clinical Updates in Acute Leukemias. 2018 May 4–6. Budapest, Hungary.
  2. Adès L. et al. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010 Mar 4;115(9):1690-6. DOI: 10.1182/blood-2009-07-233387. Epub 2009 Dec 17.
  3. Shen Z. X. et al . All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA. 2004; 101(15): 5328–5335.
  4. Ghavamzadeh A. et al. Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol. 2011; 29: 2753–2757.
  5. Estey E. et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006; 107(9): 3469–3473.
  6. Cicconi L. and LeCoco F. Current management of newly diagnosed acute promyelocytic leukemia. Ann Oncol. 2016 Aug;27(8):1474-81. DOI: 10.1093/annonc/mdw171. Epub 2016 Apr 15.
  7. Platzbecker U. et al. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol. 2017 Feb 20; 35(6): 605–612. DOI: 1200/JCO.2016.67.1982.
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