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To assess the role of Arsenic trioxide and/or ATRA during consolidation course in APL. It is hoped that the investigational arms will further increase the event-free survival at 2 years, with reduced toxicity and without increasing the relapse rate by comparison with a classical anthracycline-AraC consolidation regimen.
Definition: Extended description of the protocol, including information not already contained in other fields, such as comparison(s) studied.
APL is a specific type of acute myeloid leukemia (AML) characterized by its morphology (M3 or M3v in the FAB classification), t(15;17) translocation leading to PML-RARa fusion gene, and by a specific coagulopathy combining D.I.C., fibrinolysis and non specific proteolysis. ATRA can differentiate APL blasts in vitro and in vivo. The combination of ATRA and anthracycline based chemotherapy yields CR rates greater than 90% in newly diagnosed APL. With early introduction of anthracycline AraC chemotherapy during induction treatment, and maintenance combining continuous 6MP and MTX to intermittent ATRA, the relapse risk in APL therefore now appears to be in the range of 10 to 15%.
Nevertheless, 5 to 10% of the patients do not achieve CR and 10% to 15% still relapse. Another subset of patients (5 to 7% in APL 93 trial including 17% of patients aged greater than 65 years) die in CR, from complications of the consolidation treatment phase, mainly from infection during chemotherapy induced aplasia. Failure to achieve CR with current treatment approaches is almost exclusively due to early death during induction treatment. Causes of death are predominantly bleeding, ATRA syndrome and less often infection. Early deaths predominate in elderly patients and patients with high WBC counts. Reducing the amount of chemotherapy administered to newly diagnosed APL patients diminishes this toxicity. The Spanish PETHEMA group reported results of two successive phase II trials in newly diagnosed APL with ATRA and chemotherapy with intercalating agents (idarubicin and mitoxantrone) without AraC followed by maintenance combining ATRA and low dose chemotherapy (LPA96 and LPA99 trials). Results appeared similar to those of the best arm of APL 93 trial, but with less toxicity and only 2 to 3 % death in CR were seen, including in elderly patients.
Arsenic trioxide (As2O3 or ATO) is an effective agent in relapsing or refractory APL, which induced 85% hematological and 79% molecular CR rates in a pivotal US study. The interest of ATO in the front-line therapy of newly-diagnosed APL has been strongly suggested in three studies which showed high complete remission rate, low incidence of relapse and limited toxicity.
In this study, patients will be stratified based on age (≤ 70 years and > 70 years) and WBC count at diagnosis (WBC<10.000/mm3 and >10.000 /mm3).
-Patients aged 70 years or less with WBC<10.000/mm3.
In this population (about 70 % of APL) the best treatment group of APL2000 trial (ATRA with early introduction of anthracycline-AraC chemotherapy but where Idarubicin will be substituted for Daunorubicin, followed by 2 anthracycline-AraC consolidation courses and maintenance combining continuous chemotherapy and intermittent ATRA) will be compared to the same regimen, but without AraC during consolidation courses which will be replaced by:
- either ATO
- or ATRA It is hoped that the investigational arms will further increase the event-free survival at 2 years, with reduced toxicity and without increasing the relapse rate by comparison with a classical anthracycline-AraC consolidation regimen.
- Patients aged 70 years or less with WBC>10.000/mm3 Patients ages 70 years or less with initial WBC counts > 10000/mm3 (ie very high counts for APL), which represent about 20% of APL, remain at relatively high risk of relapse even with the current reference treatment. The main objective of the study will be to test the addition of ATO during consolidation courses to our current standard ATRA and chemotherapy regimen. Patients will receive the best treatment group of APL 2000 trial (but where Idarubicin will be substituted for Daunorubicin) with or without ATO during the 2 consolidation cycles.
- Patients older than 70 years with WBC<10.000 /mm3. Elderly patients with initial WBC ≤ 10000/m3 (about 8% of APL) and no contra indication to this treatment will receive a regimen with reduced cumulative dose of chemotherapy but addition of ATO during consolidation courses and during the first year of maintenance treatment. The main purpose of this non randomized part of the trial is to reduce the early death mortality and death in CR observed in elderly patients, without increasing the relapse rate.
- Patients older than 70 years with WBC>10.000 /mm3. Elderly patients with initial WBC > 10000/m3 (about 2 to 3% of APL) and no contra indication to intensive regimen will receive the same regimen as those with low WBC but with moderate doses of Aracytine during the induction and during the first consolidation course. The main purpose of this non randomized part of the trial is to reduce the early death mortality and death in CR observed in elderly patients, without increasing the relapse rate.
Allocation: Randomized, Control: Active Control, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Leukemia, Promyelocytic, Acute
Arsenic trioxide, ATRA
Assistance Publique - Hôpitaux de Paris
Published on BioPortfolio: 2014-08-27T03:42:27-0400
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An acute myeloid leukemia in which abnormal PROMYELOCYTES predominate. It is frequently associated with DISSEMINATED INTRAVASCULAR COAGULATION.
A tripartite motif protein that contains three ZINC FINGERS, including a RING FINGER DOMAIN, at its N-terminal. Several nuclear and one cytoplasmic isoforms result from alternative splicing of the PML gene; most nuclear isoforms localize to subnuclear structures (PML nuclear bodies) that are disrupted in ACUTE PROMYELOCYTIC LEUKEMIA cells.
An important regulator of GENE EXPRESSION during growth and development, and in NEOPLASMS. Tretinoin, also known as retinoic acid and derived from maternal VITAMIN A, is essential for normal GROWTH; and EMBRYONIC DEVELOPMENT. An excess of tretinoin can be teratogenic. It is used in the treatment of PSORIASIS; ACNE VULGARIS; and several other SKIN DISEASES. It has also been approved for use in promyelocytic leukemia (LEUKEMIA, PROMYELOCYTIC, ACUTE).
A promyelocytic cell line derived from a patient with ACUTE PROMYELOCYTIC LEUKEMIA. HL-60 cells lack specific markers for LYMPHOID CELLS but express surface receptors for FC FRAGMENTS and COMPLEMENT SYSTEM PROTEINS. They also exhibit phagocytic activity and responsiveness to chemotactic stimuli. (From Hay et al., American Type Culture Collection, 7th ed, pp127-8)
Disorders associated with acute or chronic exposure to compounds containing ARSENIC (ARSENICALS) which may be fatal. Acute oral ingestion is associated with gastrointestinal symptoms and an encephalopathy which may manifest as SEIZURES, mental status changes, and COMA. Chronic exposure is associated with mucosal irritation, desquamating rash, myalgias, peripheral neuropathy, and white transverse (Mees) lines in the fingernails. (Adams et al., Principles of Neurology, 6th ed, p1212)
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