A Randomized Comparison of All Transretinoic Acid (ATRA) Followed by Chemotherapy and ATRA Plus Chemotherapy and the Role of Maintenance Therapy in Newly Diagnosed Acute Promyelocytic Leukemia

Abstract

All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA→CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment]) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients ≤75 years of age and with newly diagnosed APL were included. Induction treatment was stratified on white blood cell (WBC) count and age: patients ≤65 years of age and with an initial WBC count of ≤5,000/μL (n = 208) were randomized between ATRA→CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/μL (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA →CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P = .0002) and close to significance in the elderly group (P = .086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA→CT group (P = .04, relative risk [RR] = .41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA→CT group (P = .1, RR = .62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P = .0002) and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P= .02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had relapsed. Overall survival was improved in patients who received maintenance CT (P = .01), and there was a trend for better survival in patients who received maintenance ATRA (P = .22). Our findings strongly suggest that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT and intermittent ATRA can reduce the incidence of relapse in APL. This effect already translates into significantly better survival for maintenance treatment with continuous CT.

The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia

“…This agent binds to the PML-RARA oncoprotein leading to its degradation, induces differentiation of APML cells which subsequently apoptose giving rise to achievement of clinical remission in the majority of patients (Grimwade et al, 2009b). Unfortunately, remissions are not sustained with ATRA used as single agent therapy, which led to the investigation of ATRA in conjunction with chemotherapy, with the combination shown in randomized studies to be superior to chemotherapy alone (Fenaux et al, 1999;Tallman et al, 2002). Induction regimens involving ATRA with anthracycline lead to complete remission rates of 90-95% (Sanz et al, 2004).…”

“…Notably, high doses were used (1.5-14 g/d TA, 12-48 g/d EACA and 800 000-2 000 000 u/d aprotinin). Many of the large trials (Table I) mention the use of antifibrinolytics as part of supportive care for patients included in these studies but information regarding doses or duration of use is sparse (Tallman et al, 1997;Fenaux et al, 1999;Avvisati et al, 2002). The PETHEMA group included use of TA in the LPA99 trial (Sanz et al, 2004;de la Serna et al, 2008).…”

Appearance of del(11q) in two patients with acute promyelocytic leukaemia treated with all‐trans retinoic acid and combination chemotherapy

“…The outcome for APL patients has been significantly improved by ATRA (Fenaux et al, 1999), which appears to overcome the block in myeloid differentiation by a variety of mechanisms including induction of PML/RARa fusion protein degradation (Grimwade, 1999). Unfortunately, longterm survivors of many cancers face a significant risk of developing therapy-related malignancies.…”

“…All-trans retinoic acid (ATRA) in conjunction with chemotherapy has become accepted as standard induction therapy for acute promyelocytic leukaemia (APL) (Fenaux et al, 1999). Few long-term sequelae of regimens including ATRA have been reported.…”

Carnosic Acid‐combined Arsenic Trioxide Antileukaemia Cells in the Establishment of NB4/SCID Mouse Model

“…Damage to the heart and liver often occurs even when the dose is lower than the therapeutic dose. Relapse also commonly occurs in patients with high-risk disease and ATO is the first choice to again gain remission [2]. In particular, high risk of death for older patients, which may in part be related to reaction against the agent, are uniformly higher when compared to younger age groups [3,4].…”