scholarly journals Efficacy and Safety of Daily All-Trans Retinoic Acid Monotherapy As Maintenance Therapy for Acute Promyelocytic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3898-3898
Author(s):  
Yoo Jin Lee ◽  
Seo-Yeon Ahn ◽  
Jae-Cheol Jo ◽  
Yunsuk Choi ◽  
Ji Hyun Lee
Keyword(s):  
Retinoic Acid ◽  
Maintenance Therapy ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Significant Difference ◽  
Ecog Ps

Introduction Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia with a unique chromosomal translocation t(15;17), causing promyelocytic leukemia gene fusion with the retinoic acid receptor α gene (PML-RARα). Therapeutic All-trans retinoic acid (ATRA) converts PML-RARα into transcriptional activator, induces APL differentiation. ATRA added during all treatment period have been reported to improve the outcomes of newly diagnosed APL. However, the benefits of maintenance therapy for patients with acute promyelocytic leukemia (APL) who achieved molecular complete remission (CRmol) are uncertain. In this study, we evaluated the efficacy and toxicity of daily ATRA monotherapy comparing with ATRA for 15 days with or without additional chemotherapy. Materials and Methods A retrospective data on 129 patients with newly diagnosed APL was conducted between February 2007 and August 2014. Induction and consolidation therapy were based on PETHEMA protocol. Among 113 patients (87.6%) who achieved CRmol following induction and 3 cycles of consolidation chemotherapy, 35 patients were treated daily with ATRA monotherapy (ATRAdaily), 39 with intermittent ATRA monotherapy for 15 days every 3 months (ATRA15), and 39 with ATRA plus continuous low-dose 6 mercaptopurine and methotrexate chemotherapy (ATRA/CT) for 2 years as a maintenance therapy. Event-free survival was defined as the time of CRmol to the development of events, which were defined by relapse, death, and toxicity that required hospitalization or dose reduction. Results The median age of patients was 46 years (range, 18-80 years). There was no significant difference among the three groups (ATRAdaily, ATRA15, and ATRA/CT) in terms of age, sex, ECOG PS, WBC count, platelet count, fibrinogen, prothrombin time, and Sanz risk score. Among the 12 relapsed patients during maintenance therapy, 3 presented molecular relapse and 9 hematologic relapse. Six (15.4%) relapses were observed in the ATRA15 group, whereas 2 (5.7%) and 4 (10.3%) relapses were observed in the ATRAdaily and ATRA/CT groups, respectively. At a median follow-up of 75.3 months (range: 9.0-140.4 months) from CRmol, the 5-year relapse free survival (RFS) for patients receiving maintenance therapy with ATRAdaily was higher than that of the patients in the ATRA15 or ATRA/CT groups without a statistically significant difference, 93.0 ± 4.8%, 84.6 ± 5.8%, and 88.0 ± 5.7%, respectively (P = 0.447). The 5-year overall survival (OS) rate was 92.7 ± 5.1%, 94.6 ± 3.7%, and 91.2 ± 5.0% for the ATRAdaily, ATRA15, and ATRA/CT groups, respectively (P = 0.601). However, ATRA/CT group frequently had myelosuppression (n = 11, 28.2%). The 5-year EFS rate was 81.5 ± 7.6%, 86.4 ± 5.7%, and 51.7 ± 8.2% for the ATRAdaily, ATRA15, and ATRA/CT groups, respectively (P < 0.001). In the multivariate analysis, maintenance therapy in the ATRA/CT group compared to ATRAdaily showed a significantly lower EFS (HR = 2.14, 95% CI = 1.06-4.31, P = 0.023). ECOG PS ≥ 2 was also associated with lower EFS (P = 0.033). Sanz risk score was the only adverse prognostic factor for RFS, and OS (HR = 6.20, 95% CI = 1.29-29.90, P = 0.023; HR=5.30, 95% CI = 1.10-25.63, P = 0.038). Conclusions In conclusion, in the present study, ATRAdaily as a maintenance therapy for patients with newly diagnosed APL who achieved CRmol showed non-inferiority compared with ATRA/CT in terms of RFS and OS. In addition, ATRAdaily maintenance therapy can be a feasible and effective choice in terms of myelosuppression or hepatotoxicity. In the future, well-conducted systematic studies of long term survivorship, quality of life, and treatment-related complications are needed to confirm these observations. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Japan Adult Leukemia Study Group [see comments]

Blood ◽  
1995 ◽  
Vol 85 (5) ◽  
pp. 1202-1206 ◽  
Author(s):  
A Kanamaru ◽  
Y Takemoto ◽  
M Tanimoto ◽  
H Murakami ◽  
N Asou ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Mortality Rate ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Early Mortality ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Significant Difference

We conducted a multicenter trial of treatment with all-trans retinoic acid (ATRA) for newly diagnosed acute promyelocytic leukemia (APL) in the AML-92 study and compared it with our previous study with standard intensive chemotherapy, the AML-89 study, in the view of complete remission (CR) rate, incidence of early death, and event-free survival (EFS). Patients were scheduled to receive oral ATRA 45 mg/m2 daily until CR. If patients had leukocyte counts above 3 x 10(9)/L at the start of therapy, they received daunorubicine (DNR) 40 mg/m2 for 3 days and behenoyl cytosine arabinoside (BHAC) 200 mg/m2 for 5 days in addition to ATRA. During the ATRA therapy, if patients showed myeloblast plus promyelocyte counts higher than 1 x 10(9)/L in the peripheral blood, they received additional DNR and BHAC in the same schedule, as well. A total of 110 patients were entered into the study. Median age was 43 years (range, 16 to 74). Twenty-eight (26%) of 109 patients (one died before the start of therapy) received ATRA alone. Ninety-seven patients (89%) achieved CR; 48 of 49 (98%) aged less than 40 years, 44 of 52 (84%) aged between 40 and 69, and 5 of 8 (63%) aged above 70 achieved CR, respectively; 25 of 28 (89%) with ATRA alone, 46 of 51 (90%) with ATRA plus initial chemotherapy and 26 of 30 (87%) with ATRA plus later chemotherapy attained CR, respectively. Nine (8%) patients died within 28 days after the start of therapy. In contrast, 44 of 62 patients (71%) attained CR, and 13 (21%) died within 28 days in the AML-89 study with the combination of DNR, BHAC, 6-mercaptopurine and prednisolone. Seven developed retinoic acid syndrome and one died of it in the present study. Other toxicities associated with this drug included cheilitis, desquamation, muscle pain, and hypertriglyceridemia. Predicted 23 months EFS for all ATRA-treated patients and disease-free survival (DFS) in the CR cases were 75% and 81%, respectively, in a median follow-up period of 21 months. Compared to the AML-89 study, there was a highly significant difference in remission rate (P = .004), EFS (P = .0007), and also early mortality rate (P = .02). Present results demonstrated that ATRA with or without chemotherapy gives a statistical improvement in CR rate and early mortality rate, as well as superior survival in newly diagnosed APL.

scholarly journals All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4)

Blood ◽  
2012 ◽  
Vol 120 (8) ◽  
pp. 1570-1580 ◽  
Author(s):  
Harry J. Iland ◽  
Ken Bradstock ◽  
Shane G. Supple ◽  
Alberto Catalano ◽  
Marnie Collins ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Substantial Reduction ◽  
Initial Therapy ◽  
Promyelocytic Leukemia ◽  
Free Survival ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Clinical Trials Registry

Abstract The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.

Treatment with All-Trans Retinoic Acid and Anthracycline Monochemotherapy in Children with Acute Promyelocytic Leukemia: Analysis of Three Sequential Multicenter Trials of the PETHEMA Group

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 137-137
Author(s):  
Luis Madero ◽  
Pau Montesinos ◽  
Pilar Bastida ◽  
Amparo Verdeguer ◽  
Javier De la Serna ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
High Risk ◽  
Maintenance Therapy ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Consolidation Therapy ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Risk Patients ◽  
High Degree

Abstract The combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy has been adopted as the standard treatment for children and adults with acute promyelocytic leukemia (APL). However, information about therapy results in pediatric APL patients is scarce, particularly on long-term outcomes. A previous report of the PETHEMA Group (Ortega et al, JCO 2005) showed that a risk-adapted strategy combining a reduced dose of ATRA (25 mg/m2/d) and anthracycline monochemotherapy for induction and consolidation, followed by ATRA and low dose methotrexate and mercaptopurine for maintenance therapy, produced high antileukemic efficacy, moderate toxicity, and a high degree of compliance. We have now performed an updated analysis of a significantly enlarged cohort of 107 consecutive children (younger than 19 years) with APL who were enrolled in three sequential trials of the PETHEMA Group (LPA96, LPA99 and LPA2005) and followed up for a median of 71 months (range, 3–139). Induction consisted of 25 mg/m2 ATRA daily until CR and 12 mg/m2 idarubicin on days 2, 4, 6 and 8. In the LPA96 trial, patients in CR received three monthly chemotherapy courses: idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 5 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3). Since November 1999 (LPA99 trial), for patients with intermediate or high risk of relapse (Sanz et al, Blood 2000), consolidation was slightly intensified by increasing idarubicin doses in courses #1 and #3, and by simultaneously administering 25 mg/m2 ATRA together with chemotherapy in all three courses. Since July 2005, consolidation therapy in the ongoing LPA 2005 trial included the following modifications: the administration of ATRA for all patients; for low- and intermediate-risk patients, mitoxantrone has been reduced from five to three days in the second course; and for high-risk patients, cytarabine has been added to idarubicin in the first and third course. Maintenance therapy consisted of 50 mg/m2/d mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and 25 mg/m2/d ATRA for 15 days every three months. Of 1031 patients enrolled in three subsequent PETHEMA trials between November 1996 and July 2008, 107 (10%) from 43 Institutions were aged less than 19 years. WBC counts were &gt;10×09/l and &gt;50×109/l in 36 (34%) and 10 (9%), respectively; morphologically, 22 (22%) cases were hypergranular; PML/RARA isoform type was BCR1 or BCR2 in 47 (57%), and BCR3 in 35 (43%). One-hundred and one patients achieved CR (94%). In general, toxicity was manageable during consolidation and maintenance therapy. One patient died in CR during consolidation due to hepatic failure. At the end of consolidation, only 2 patients of 86 patients tested had molecular persistence (defined by positive RT-PCR of PML/RARA at 10−4 sensitivity). Ten additional relapses were observed, 5 molecular and 5 clinical relapses. Apart from 2 clinical relapses and 2 molecular relapses, all these events occurred among high risk patients. The 5-year Kaplan-Meier estimates of overall, disease-free and relapse-free survival were 89%, 86% and 86%, respectively. These results show a higher incidence of hyperleucocytosis in pediatric patients than in adults with genetically proven APL (p=0.05) and confirm the high antileukemic efficacy, low toxicity and high degree of compliance of three subsequent PETHEMA trials using a risk-adapted strategy with ATRA and anthracycline-based chemotherapy for induction and consolidation therapy.

Potential curability of newly diagnosed acute promyelocytic leukemia without use of chemotherapy: the example of liposomal all-trans retinoic acid

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1366-1367 ◽  
Author(s):  
Elihu Estey ◽  
Charles Koller ◽  
Apostolia M. Tsimberidou ◽  
Susan O'Brien ◽  
Miloslav Beran ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Newly Diagnosed ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid
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