Autologous and Allogeneic Stem-Cell Transplantation As Salvage Treatment of Acute Promyelocytic Leukemia Initially Treated With All-Trans-Retinoic Acid: A Retrospective Analysis of the European Acute Promyelocytic Leukemia Group

2005 ◽  
Vol 23 (1) ◽  
pp. 120-126 ◽  
Author(s):  
S. de Botton ◽  
A. Fawaz ◽  
S. Chevret ◽  
H. Dombret ◽  
X. Thomas ◽  
...  
Keyword(s):  
Stem Cell ◽  
Retinoic Acid ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Acute Promyelocytic Leukemia ◽  
Allogeneic Stem Cell Transplantation ◽  
Promyelocytic Leukemia ◽  
Free Survival ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Purpose To retrospectively determine the outcome of acute promyelocytic leukemia (APL) patients who underwent autologous or allogeneic stem-cell transplantation (SCT) during second complete remission. Patients and Methods Of 122 relapsing patients included in two successive multicenter APL trials who achieved hematological second complete remission (generally after a salvage regimen of all-trans-retinoic acid [ATRA] combined with chemotherapy), 73 (60%) received allogeneic (n = 23) or autologous (n = 50) SCT. Results Seven-year relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) in the autologous SCT group were 79.4%, 60.6%, and 59.8%, respectively, with a transplant-related mortality (TRM) of 6%. Of the 28 and two patients autografted with negative and positive, respectively, reverse transcriptase-polymerase chain reaction before auto SCT, three (11%) and one relapsed, respectively. In the allogeneic SCT group, 7-year RFS, EFS, and OS were 92.3%, 52.2%, and 51.8%, respectively, with 39% TRM. OS was significantly better in the autologous SCT group than in the allogeneic SCT group (P = .04), whereas RFS and EFS did not differ significantly (P = .19 and P = .11, respectively). In patients not receiving transplantation, 7-year RFS, EFS, and OS were 38%, 30.4%, and 39.5%, respectively. Conclusion These retrospective data suggest that autologous SCT is very effective in APL relapsing after treatment with ATRA if performed in molecular remission. Allogeneic SCT yields few relapses, but it is associated with high TRM when performed after salvage with very intensive chemotherapy. Salvage with arsenic trioxyde, which has lower toxicity, should further improve the outcome of relapsing APL, especially before allogeneic SCT.

scholarly journals PLZF-RARα, NPM1-RARα, and Other Acute Promyelocytic Leukemia Variants: The PETHEMA Registry Experience and Systematic Literature Review

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1313 ◽  
Author(s):  
Marta Sobas ◽  
Maria Carme Talarn-Forcadell ◽  
David Martínez-Cuadrón ◽  
Lourdes Escoda ◽  
María J. García-Pérez ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Complete Remission ◽  
Acute Promyelocytic Leukemia ◽  
Fusion Gene ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
High Relapse Rate ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Shed Light

It has been suggested that 1–2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RARα) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RARα being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RARα and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RARα and 2 NPM1-RARα), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 × 109/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far.

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.

scholarly journals Treatment With a New Synthetic Retinoid, Am80, of Acute Promyelocytic Leukemia Relapsed From Complete Remission Induced by All-trans Retinoic Acid

Blood ◽  
1997 ◽  
Vol 90 (3) ◽  
pp. 967-973 ◽  
Author(s):  
Tadasu Tobita ◽  
Akihiro Takeshita ◽  
Kunio Kitamura ◽  
Kazunori Ohnishi ◽  
Mitsuaki Yanagi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Complete Remission ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Major Advance ◽  
Synthetic Retinoid ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
First Choice

Differentiation therapy with all-trans retinoic acid (ATRA) has marked a major advance and become the first choice drug in the treatment of acute promyelocytic leukemia (APL). However, patients who relapse from ATRA-induced complete remission (CR) have difficulty in obtaining a second CR with a second course of ATRA therapy alone. We tested the efficacy of a new synthetic retinoid, Am80, in APL that had relapsed from CR induced by ATRA in a prospective multicenter study. Am80 is approximately 10 times more potent than ATRA as an in vitro differentiation inducer, is more stable to light, heat, and oxidation than ATRA, has a low affinity for cellular retinoic acid binding protein, and does not bind to retinoic acid receptor-γ. Patients received Am80, 6 mg/m2, orally alone daily until CR. Of 24 evaluable patients, 14 (58%) achieved CR. The interval from the last ATRA therapy was not different between CR and failure cases. The clinical response was well correlated with the in vitro response to Am80 in patients examined. Adverse events included 1 retinoic acid syndrome, 1 hyperleukocytosis, 9 xerosis, 8 cheilitis, 16 hypertriglyceridemia, and 15 hypercholesterolemia, but generally milder than those of ATRA, which all patients had received previously. Am80 is effective in APL relapsed from ATRA-induced CR and deserves further trials, especially in combination with 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 Proof of differentiative mode of action of all-trans retinoic acid in acute promyelocytic leukemia using X-linked clonal analysis

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 1916-1919 ◽  
Author(s):  
S Elliott ◽  
K Taylor ◽  
S White ◽  
R Rodwell ◽  
P Marlton ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Complete Remission ◽  
Acute Promyelocytic Leukemia ◽  
Mechanism Of Action ◽  
Clonal Analysis ◽  
Promyelocytic Leukemia ◽  
Atra Treatment ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Using X-linked clonal analysis, mechanism of action of all-trans retinoic acid (ATRA) was sought in a 16-year-old female with relapsed clonally evolved acute promyelocytic leukemia (APL), who achieved complete remission. On ATRA, metamorphosis of peripheral blood leukemic promyelocytes to mature neutrophils was observed, despite the persistence of t(15;17) in 100% of bone marrow metaphases. DNA was extracted from fractionated serial blood specimens, collected at diagnosis, in first complete remission (CR), relapse, and during ATRA treatment. Using a phosphoglycerokinase (PGK) probe, the patient was heterozygous for both Bgl I and Bst XI PGK polymorphisms. Methylation analysis showed monoclonal leukemic promyelocytes with a polyclonal first CR achieved by standard chemotherapy. Subsequent examination, in relapse, of granulocytes appearing during ATRA treatment showed these to be monoclonal, proving these were derived from the neoplastic clone. The X-linked clonal analysis methodology has provided in vivo evidence of cellular differentiation as the mechanism of action of ATRA. Parallel studies of cytogenetic and clonal analysis showed a regression of the t(15;17) cytogenetic abnormality and return of a polyclonal PGK methylation pattern in 5 weeks, indicating a repopulation of marrow by normal stem cells. As standard cytogenetic techniques are inappropriate for nondividing cells, X-linked clonal analysis provides a marker system to allow insight into mechanism of drug action in malignant hematologic disease.

scholarly journals Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 567-572 ◽  
Author(s):  
ME Huang ◽  
YC Ye ◽  
SR Chen ◽  
JR Chai ◽  
JX Lu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Complete Remission ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Nitroblue Tetrazolium Reduction ◽  
Morphological Maturation

Twenty-four patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (45 to 100 mg/m2/day). Of these, eight cases had been either nonresponsive or resistant to previous chemotherapy; the other 16 cases were previously untreated. All patients attained complete remission without developing bone marrow hypoplasia. Bone marrow suspension cultures were studied in 15 of the 24 patients. Fourteen of these patients had morphological maturation in response to the retinoic acid (1 mumol/L). Chloroacetate esterase and alpha-naphthyl acetate esterase staining as well as electronmicroscopic examination confirmed that retinoic acid-induced cells differentiated to granulocytes with increased functional maturation (as measured by nitroblue tetrazolium reduction, NBT). The single nonresponder to retinoic acid in vitro was resistant to treatment with retinoic acid but attained complete remission after addition of low-dose cytosine arabinoside (ara-C). During the course of therapy, none of the patients showed any abnormalities in the coagulation parameters we measured, suggesting an absence of any subclinical disseminated intravascular coagulation. The only side effects consisted of mild dryness of the lips and skin, with occasional headaches and digestive symptoms. Eight patients have relapsed after 2 to 5 months of complete remission. The others remain in complete remission at 1+ to 11+ months and are still being followed up. We conclude that all-trans retinoic acid is an effective inducer for attaining complete remission in APL.

Proteome Analysis of Apoptotic MR2 Cells, Acute Promyelocytic Leukemia Cell Line with All-Trans Retinoic Acid Resistance, Induced by Arsenic Trioxide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4726-4726
Author(s):  
Pengcheng He ◽  
Mei Zhang ◽  
Xiaoning Wang ◽  
Huaiyu Wang ◽  
Jieying Xi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Complete Remission ◽  
Cell Line ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Molecular Mechanisms ◽  
Promyelocytic Leukemia ◽  
Beta Tubulin ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Although all-trans retinoic acid(ATRA) provides complete remission in 90% patients with untreated acute promyelocytic leukemia(APL), it becomes ineffective to quite a few APL patients who have received ATRA before when their disease relapsed and used ATRA again. Arsenic trioxide(ATO) can make APL patients with ATRA-resistance obtain complete remission again by inducing APL cells apoptosis. However, the molecular mechanisms of apoptosis in ATRA-resistance APL cells induced by ATO remain unclear. For this reason, we take the apoptotic MR2 cells (APL cell line with ATRA-resistance) induced by ATO as a model, to screen and identify the proteins related with ATO-induced apoptosis by comparative proteomics. After MR2 cells were dyed with annexin V and PI staining, the percentage of the apoptotic MR2 cells induced by 1.0μmol/L ATO for 0h, 6h, 12h, 24h and 48h respectively was detected by Flow cytometry. The results showed that the majority of the apoptotic cells were in the earlier and later stage of apoptosis respectively, when MR2 cells were treated with ATO for 24 and 48 hours in sequence. The total proteins of MR2 cells of the control group, the earlier stages apoptosis group and the later stages apoptosis group were separated by two-dimensional electrophoresis(2-DE) respectively. Then, the differences in proteome profile among three groups were analyzed by ImageMaster™ 2D Platinum software. 14 protein pots were selected to be identified by Matrix-assisted laser desorption/ionization time of flight-mass spectrometry(MALDI-TOF-MS), in which the quantity of the protein differentially expressed was more than two times(≥2 or ≤0.5) among MR2-0h, MR2-24h and MR2-48h cells’ 2-DE map. However, only 11 proteins were successfully identified and their definite information was obtained. Among them, there were 8 proteins that were all probably involved in the mechanisms of apoptosis in MR2 cells and they were Calreticulin(CRT), Heat shock 70 kDa protein(HSP70), High mobility group protein B1(HMGB1), Ran-specific GTPase-activating protein(RanGAP1), Elongation factor 1-beta(EF-1β), Beta-tubulin, Cofilin-1, and Prolyl 4-hydroxylase(P4H) respectively. CRT was probably related with the early stage of apoptosis in MR2 cells, while RanGAP1 and HSP70 might related with the late stage of apoptosis in MR2 cells. Moreover, so far there was no related report on the roles of CRT, HMGB1, RanGAP1, cofilin-1 and beta-tubulin in the mechanisms of APL cells apoptosis. These differential proteins identified provide the new clues for further researching the molecular mechanisms of apoptosis in the ATRA-resistance APL cells induced by ATO.

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