Induction Therapy with “3+7” Chemotherapy Plus ATRA Followed by Consolidations with Three Courses of Idarubicin Alone and Maintenance Therapy with ATRA in Newly Diagnosed Acute Promyelocytic Leukemia (APL) Has An Excellent Leukemia-Free Survival but Minimal Toxicity in Low and Intermediate Risk Groups.
Authors: Choi Moon-Young , Mun Yeung-Chul , Park Se Hoon , Cho Eun Kyung , Lee Jae Hoon , Jo Deog Yeon , Kim Inho , Bang Soo-Mee , Yoon Sung-Soo , Park Seonyang , Kim Byoung Kook , Kim Hawk , Min Young Joo , Park Jae Hoo , Seo Jong Jin , Moon Hyung Nam , Lee Moon Hee , Kim Cheol Soo , Lee Won Sik , Joo Young Don , Chung So Young , Oh Doyeun , Zang Dae Young , Lee Kyung Hee , Hyun Myung Soo , Song Hong Suk , Kim Heung Sik , Kim Sung Hyun , Kwon Hyuk Chan , Kim Hyo Jin , Park Kyung Tae , Ahn Jin Seok , Park Yeon Hee , Ahn Myung Ju , Bae Sung Hwa , Ryoo Hun-Mo , Choi Jung-Hye , Yoon Hwi-Joong , Nam Seung-Hyun , Kim Bong-Seog , Ghim Thad T. , Seong Chu-Myong 
Published: October 2019

Abstract
Abstract 2072
Poster Board II-49

Backgrounds
Currently, there are many efforts to design risk-adapted strategies in newly diagnosed acute promyelocytic leukemia (APL) by modulating treatment intensity and those seem to be an efficient approach to minimize treatment-related morbidity and mortality (TRM) while maintain the potential in cure for each relapse-risk group. We had postulated that maintaining of Ara-C during induction therapy might have acceptable toxicities yet obtaining good CR in newly diagnosed APL, and idarubicin alone during consolidation periods might have excellent LFS and OS with low relapse rate.

Patients and Methods
Eighty six patients with newly diagnosed APL were enrolled in the “multicenter AML-2000 trial” after informed consents were obtained during the period of January 2000 to July 2007. For remission induction therapy, patients received oral ATRA (45mg/m2/d, maintained until CR) combined with idarubicin (12mg/m2/d, D1-D3) plus Ara-C (100mg/m2/d, D1-D7). After CR achievement, patients received 3 monthly consolidation courses consisting of idarubicin (12mg/m2/d, D1-D3) alone and maintenance therapy with ATRA (45mg/m2/d, D1-D15, every 2 month) alone had continued for 2 years. Total patients were divided into low-risk, intermediate-risk and high-risk groups according to a predictive model for relapse risk (Sanz score) based on pretreatment WBC and platelet count and the treatment outcomes were compared in the different risk groups.

Results
The median age of our cohort was 40 years old (range; 6-80) and median follow-up was 27 months (range; 1-90). The distribution of patients in the 3 risk groups was as follows ; 28 (32.6%) patients in low-risk, 40 (46.5%) in intermediate-risk and 18 (20.9%) in high-risk. Overall, CR was achieved in 78 (90.7%) of 86 patients. The CR rate according risk groups was 96.4% in low-risk, 87.5% in intermediate-risk, and 88.9% in high-risk group and there was no significant statistical difference among the different risk groups. During induction therapy, 48 (55.8%) patients experienced grade 3-4 treatment-related toxicity (TRT), mostly fever and infection (38.8% of all patients) and 6 (7.0%) patients died of treatment-related complications. During 3 consolidation courses, 25 (29.1%) of 78 patients experienced grade 3-4 TRT in 1st course, 27 (36.0%) of 75 patients in 2nd course, and 14 (28.0%) of 50 patients in 3rd course. Overall, 3 (3.5%) patients died of treatment-related complications in CR. The incidence of TRT and treatment-related mortality (TRM) during induction or consolidation therapy showed no significant statistical difference among the different risk groups. The relapse occurred in 6 (7.0%) patients; 2 cases in intermediate-risk and 4 cases in high-risk. However, none had relapsed in low risk group, 5 patients of relapsed patients relapsed during consolidation courses and only one patient, however, relapsed during maintenance therapy. The overall survival (OS) and leukemia-free survival (LFS) rate at 7 years in all of patients was 76.7% and 83.5%, respectively. The OS rate at 7 years was 92.9% in low-risk, 78.6% in intermediate-risk and 53.6% in high-risk group (P:0.04) and the LFS rate at 7 years was 96.4%, 83.4% and 62.2% respectively, showing the significant difference between 3 different risk groups (P:0.046).

Conclusions
This study indicates that our protocol composed of induction therapy with “3+7” chemotherapy plus ATRA followed by consolidations with three courses of idarubicin alone and maintenance therapy with ATRA alone yields a high CR rate and low relapse rate but minimal acceptable toxicities. Despite of adding Ara-C during induction therapy, we did not find much significant toxicities but having good CR rates, and despite of not adding any additional low/intermediate dose chemotherapies(ie, 6MP), we were able to observe significantly high relapse rate in low and intermediate risk group with excellent LFS and OS. Meanwhile, in high-risk group, the relapse rate was significantly higher than other risk groups and most of the relapses occurred in the middle of consolidation courses. This data suggests that our consolidation therapy composed of anthracycline alone may be not enough to minimize risk of relapse in high-risk group in contrast with the low and intermediate-risk groups. More intensive consolidation therapy combined with other effective, but get tolerable chemotherapies or hematopoietic stem cell transplantation in first CR or the combination of arsenic trioxide or others in front-line therapy should be considered in the patients with high-risk of relapse.

Disclosures:
No relevant conflicts of interest to declare.