Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group.

1998 ◽  
Vol 16 (1) ◽  
pp. 78-85 ◽  
Author(s):  
N Asou ◽  
K Adachi ◽  
J Tamura ◽  
A Kanamaru ◽  
S Kageyama ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Retinoic Acid ◽  
Leukocyte Count ◽  
Promyelocytic Leukemia ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

PURPOSE We conducted a multicenter study of differentiation therapy with all-trans retinoic acid (ATRA) followed by intensive chemotherapy in patients with newly diagnosed acute promyelocytic leukemia (APL) and analyzed the prognostic factors for predicting complete remission (CR), event-free survival (EFS), and disease-free survival (DFS). PATIENTS AND METHODS All patients received ATRA until CR. If patients had an initial leukocyte count greater than 3.0 x 10(9)/L, they received daunorubicin (DNR) and behenoyl cytarabine (BHAC). During therapy, if patients showed blast and promyelocyte counts greater than 1.0 x 10(9)/L, they received additional DNR and BHAC. After achieving CR, patients received three courses of consolidation and six courses of maintenance/intensification chemotherapy. RESULTS Of 198 registered, 196 were assessable (age range, 15 to 86 years; median, 46) and 173 (88%) achieved CR. Multivariate analysis showed that no or minor purpura at diagnosis (P = .0046) and age less than 30 years (P = .0076) were favorable factors for achievement of CR. Predicted 4-year overall survival and EFS rates were 74% and 54%, respectively, and the 4-year predicted DFS rate for 173 CR patients was 62%. Multivariate analysis showed that age less than 30 years (P = .0003) and initial leukocyte count less than 10 x 10(9)/L (P = .0296) were prognostic factors for longer EFS, and initial leukocyte count less than 10.0 x 10(9)/L was a sole significant prognostic factor for longer DFS (P = .0001). CONCLUSION Our results show that age, hemorrhagic diathesis, and initial leukocyte count are prognostic factors for APL treated with ATRA followed by intensive chemotherapy.

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.

Retinoic Acid Syndrome in Patients with Acute Promyelocytic Leukemia Treated with All-Trans Retinoic Acid and Anthracycline Monochemotherapy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2010-2010
Author(s):  
Pau Montesinos ◽  
Juan Bergua ◽  
Guillermo Martin ◽  
Javier de la Serna ◽  
Edo Vellenga ◽  
...  
Keyword(s):  
Renal Failure ◽  
Prognostic Factors ◽  
Retinoic Acid ◽  
Weight Gain ◽  
High Risk ◽  
Pleural Effusion ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Retinoic Acid Syndrome

Abstract Retinoic acid syndrome (RAS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid (ATRA). Incidence of RAS has been reported ranging from 2% to 30%. It has been suggested that patients with leukocytes >5 x109/L at presentation are at high risk for the development of RAS. The impact of RAS on long term outcome is still a matter of controversy. We analyze the incidence, prognostic factors and outcome of RAS in 733 patients with newly diagnosed APL enrolled in the PETHEMA LPA96 and LPA99 trials (175 and 558 patients, respectively). Induction therapy consisted of ATRA and idarubicin, followed by three consolidation courses of anthracycline monochemotherapy. In the LPA99 trial, ATRA was added in each cycle of consolidation, except for low-risk patients. In the LPA99 trial, all patients received RAS prophylaxis with oral prednisone (0.5 mg/kg). Temporary discontinuation of ATRA and treatment with intravenous dexamethasone were recommended at the first signs of suspected RAS, in both trials. Definite RAS was defined as the presence of at least four of the following criteria: unexplained fever, respiratory distress, radiological pulmonary infiltrates, pericardial/pleural effusion, hypotension, renal failure, and weight gain over 5 kg. Overall, 87 patients (12%) experienced RAS, after a median of 6 days of ATRA (range, 0 to 46). Forty-seven cases (54%) occurred from days 0 to 7, 4 (5%) from days 8 to 14, 32 (36%) from days 15 to 30, and 4 (5%) from days 31 to 46. The main clinical signs were pulmonary infiltrates (83%), fever (80%), weight gain (74%), pleural effusion (63%) and renal failure (49%). ATRA was discontinued in 63% of patients. RAS was associated with age >50 years (41% vs 29%, p=0.02), serum level of creatinine >1.4 mg/dl (9% vs 3%, p<0.01) and leukocytes at presentation >5x109/L (46% vs 32%, p=0.01). Leukocytes >5x109/L and creatinine >1.4 mg/dl remained as independent prognostic factors in multivariate analysis. The incidence of RAS was not statistically different between the LPA96 (without prednisone prophylaxis) and LPA99 trials (15% vs 11%, p=0.16). RAS was associated with induction death (26% vs 7%, p<0.01) and was the main cause of death in 10 patients (1.4%). Age >60 years, leukocytes >10x109/L, RAS, male gender and serum creatinine level >1.4 mg/dl at presentation were independent prognostic factors for induction death. Patients developing RAS had a higher cumulative incidence of relapse (CIR) in the LPA96 trial (40% vs 15%, p<0.01), but there were no significant differences in the LPA99 trial (12% vs 13%). In conclusion, we have observed a bimodal peak incidence of RAS during the induction phase, with the first peak from days 0 to 7 and the second peak from days 15 to 30. Patients with leukocytes >5x109/L and serum creatinine level >1.4 mg/dl are at high risk for development of RAS, which is an adverse prognostic factor for induction death. The negative impact of RAS on CIR among patients treated with the LPA96 trial was not observed in the LPA99, in which patients received additional doses of ATRA for consolidation therapy.

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.

Sign in / Sign up

Export Citation Format

Share Document