Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia

Abstract

All-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combinationbased therapy has benefitted newly diagnosed acute promyelocytic leukemia (APL) in short-term studies, but the long-term efficacy and safety remained unclear. From April 2001, we have followed 85 patients administrated ATRA/ATO with a median follow-up of 70 months. Eighty patients (94.1%) entered complete remission (CR). Kaplan-Meier estimates of the 5-year event-free survival (EFS) and overall survival (OS) for all patients were 89.2% ؎ 3.4% and 91.7% ؎ 3.0%, respectively, and the 5-year relapse-free survival (RFS) and OS for patients who achieved CR (n ‫؍‬ 80) were 94.8% ؎ 2.5% and 97.4% ؎ 1.8%, respectively. Upon ATRA/ATO, prognosis was not influenced by initial white blood cell count, distinct PML-RAR␣ types, or FLT3 mutations. The toxicity profile was mild and reversible. No secondary carcinoma was observed, and 24 months after the last dose of ATRA/ATO, patients had urine arsenic concentrations well below the safety limit. These results demonstrate the high efficacy and minimal toxicity of ATRA/ATO treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for de novo APL.combination therapy ͉ 5-year EFS ͉ 5-year OS ͉ residual disease ͉ arsenic retention A cute promyelocytic leukemia (APL) is the M3 subtype of acute myeloid leukemia (AML) and is characterized by an accumulation of abnormal promyelocytes in the bone marrow and a severe bleeding tendency. Additionally, in the great majority of cases, APL is associated with the t(15,17) chromosomal translocation and resultant PML-RAR␣ transcripts that encode the leukemogenic PML-RAR␣ fusion protein (1). Five decades ago, APL was the most fatal type of acute leukemia and was considered essentially untreatable (2). The first breakthrough came with the use of anthracyclines, which improved the complete remission (CR) rate but provided a low 5-year overall survival (OS) (3). The introduction of all-trans retinoic acid (ATRA) therapy resulted in terminal differentiation of APL cells and a 90-95% CR rate in patients (1, 4), and subsequent combination of ATRA with chemotherapy raised the 5-year disease-free survival (DFS) rate up to 74% (5). In the 1990s, significant benefits of arsenic trioxide (ATO) were reported, which further improved the outcome of patients with APL (6, 7). ATO exerts dose-dependent dual effects on APL cells, with low concentrations inducing partial differentiation and relatively high concentrations triggering apoptosis. Of note, both ATRA and ATO induce catabolism of the PML-RAR␣ fusion protein, demonstrating a paradigm for rationally targeted therapy in leukemia. However, between 20% and 30% of newly diagnosed APL patients treated with regimens based on the use of ATRA or ATO as single agents will develop disease recurrence or drug resistance.To improve further the clinical outcome of APL, therapeutic strategies should be designed to include combinatorial use of drugs with distinct but convergent mechanisms that may amplify treatment effic...

How to manage acute promyelocytic leukemia

“…According to data from the SIH, Kaplan --Meier estimates that the 5-year EFS and OS in a group of 85 newly diagnosed APL patients were 89.2% and 91.7%, respectively, demonstrating the high efficacy of ATRA/ATO treatment for newly diagnosed APL. 67 Recent literature supports our data in that the CR rate and EFS were relatively higher in the working groups using ATO/ATRA combination 68,69 compared with the groups using ATO alone. 59,60,62 GIMEMA group carried out a randomized phase III study to compare ATO þ ATRA versus standard ATRA þ anthracycline-based chemotherapy (AIDA regimen) for newly diagnosed non high-risk APL.…”

“…28,61 In the past two decades, the frequency of DS in our patients has been very low, 67 with the exception of a few patients presenting hyperleukocytosis at the diagnosis of the disease.…”

“…Mathews et al 70 suggested that mutant FLT3 was not an adverse indicator of poor prognosis for APL with ATO-based therapy, which was supported by our group. 67 At present, our induction therapy program is as follows 61,67 ( Figure 2): 25 mg/m 2 ATRA orally per day, and 0.16 mg/kg As 2 O 3 i.v. per day until documentation of CR.…”

“…Notably, the 5-year relapse-free survival and OS of our patients who achieved CR were 94.8% and 97.4%, respectively. 67 Although it was usually a common practice to avoid CNS prophylaxis for patients without hyperleukocytosis, among whom the risk of CNS relapse is extremely low, 42 we still recommend 4 --6 times of CNS prophylaxis, methotrexate (10 --15 mg), dexamethasone (5 mg) (or Prednisolone 40 mg) and Ara-C (40 --50 mg), during maintenance therapy, in considering that the first site of relapse was exclusively the CNS in all of the total four relapses out of our recent series of 80 patients achieving complete remission, and most of the relapsed patients exhibited no hyperleukocytosis initially. 67 Nevertheless, for the patients with high WBC counts, the CNS prophylaxis should be carried out for at least 6 --8 times.…”

Chronic Myeloid Leukemia Developing After Successful Treatment of Acute Promyelocytic Leukemia

“…As ATO is used increasingly in APL patients and is a well known carcinogen, special attention should be paid to APL patients who received therapy with ATO. Hu et al recently reported that no secondary carcinoma was observed in 89 APL patients received ATRA and ATO combinational therapy with a median follow-up of 70 months [13]. However, there was initially observed an increased risk of second solid tumors subsequent to ATO treatment for APL [14], and there was a reported case that t-AML developed after APL receiving chemotherapy and arsenic agent as maintenance treatment [15].…”