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.

Improved outcome for Chinese children with acute promyelocytic leukemia: A comparison of two protocols

“…Several studies have shown that ATRA and anthracycline-based therapy for induction and consolidation followed by maintenance with MTX, 6MP, and ATRA reduced relapse risk of APL [5,9,10], however, the role of AraC in APL remains controversial. Some study groups employed intensive regimen including high-dose AraC and anthracycline for consolidation therapy [11,12] and obtained a relapsed-free survival of 82% [12].…”

Arsenic Trioxide (Trisenox®) Therapy for Acute Promyelocytic Leukemia in the Setting of Hematopoietic Stem Cell Transplantation

“…Patient age at diagnosis appears to be an important clinical prognostic factor, as demonstrated in several trials [9,13,31]. For example, in a large European trial, survival at 2 years was 67% for patients older than 65 years compared with 82% for younger patients [9].…”

“…At the time of initial diagnosis of APL, a WBC of >10,000/µl and a platelet count of <40,000/µl have been shown to be adverse prognostic features in a number of studies [8,9,11,13,[30][31][32][33]. Multivariate analyses [11] of the PETHEMA trial and the trial of the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) using these two variables indicated that risk of relapse can be stratified accordingly, into low-risk (WBC ≤10,000/µl, platelet count >40,000/µl), intermediate-risk (WBC ≤10,000/µl, platelet count ≤40,000/µl), and high-risk (WBC >10,000/µl) groups.…”

“…In the late 1980s, however, investigators from China demonstrated that treatment with all-trans retinoic acid (ATRA) was highly effective in inducing remission [5]. The incorporation of ATRA into anthracycline-based APL treatment regimens since 1990 has more than doubled the number of survivors, compared with the results from chemotherapy alone [6][7][8][9][10].…”

IL-18-induced interaction between IMP3 and HuR contributes to COX-2 mRNA stabilization in acute myeloid leukemia

“…The treatments for AML include chemotherapy, radiation therapy, stem cell transplantation, and other drug therapies. Differentiation therapy, which includes treatment with arsenic trioxide [1], all-trans-retinoic acid [2], or VitD3 [3], or targeted therapy with a mAb [4] has been applied to treat AML patients by forcing malignant cells to undergo differentiation instead of killing the cancer cells through cytotoxicity [3]. However, AML patients treated with differentiation therapy still face the problem of drug resistance [5,6].…”