Oral arsenic trioxide, all‐ trans retinoic acid, and ascorbic acid maintenance after first complete remission in acute promyelocytic leukemia: Long‐term results and unique prognostic indicators

Cancer ◽  
2020 ◽  
Vol 126 (14) ◽  
pp. 3244-3254 ◽  
Author(s):  
Harinder S. Gill ◽  
Rita Yim ◽  
Cyrus R. Kumana ◽  
Eric Tse ◽  
Yok‐Lam Kwong
Keyword(s):  
Ascorbic Acid ◽  
Retinoic Acid ◽  
Complete Remission ◽  
Promyelocytic Leukemia ◽  
Long Term Results ◽  
Prognostic Indicators ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
First Complete Remission

Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience

Blood ◽  
2010 ◽  
Vol 115 (9) ◽  
pp. 1690-1696 ◽  
Author(s):  
Lionel Adès ◽  
Agnes Guerci ◽  
Emmanuel Raffoux ◽  
Miguel Sanz ◽  
Patrice Chevallier ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Cumulative Incidence ◽  
Maintenance Treatment ◽  
Promyelocytic Leukemia ◽  
Long Term Results ◽  
Long Term Outcome ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

AbstractAcute promyelocytic leukemia (APL) is highly curable with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.2% to 33%, 23.4%, and 13.4% with no maintenance, maintenance using intermittent ATRA, continuous 6 mercaptopurine plus methotrexate, and both treatments, respectively (P < .001). Maintenance particularly benefited patients with white blood cell (WBC) count higher than 5 × 109/L (5000/μL). Early addition of CT to ATRA significantly improved 10-year event-free survival (EFS), but without significant effect on overall survival (OS). The 10-year cumulative incidence of deaths in complete response (CR), resulting mainly from myelosuppression, was 5.7%, 15.4%, and 21.7% in patients younger than 55, 55 to 65, and older than 65 years, respectively, supporting the need for less myelosuppressive treatments, particularly for consolidation therapy. This study is registered at http://clinicaltrials.gov as NCT00599937.

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 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 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.

DNA vaccination with all-trans retinoic acid treatment induces long-term survival and elicits specific immune responses requiring CD4+ and CD8+ T-cell activation in an acute promyelocytic leukemia mouse model

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 653-656 ◽  
Author(s):  
Kouichi Furugaki ◽  
Katerina Pokorna ◽  
Carole Le Pogam ◽  
Masayuki Aoki ◽  
Murielle Reboul ◽  
...  
Keyword(s):  
T Cells ◽  
Retinoic Acid ◽  
Mouse Model ◽  
Immune Responses ◽  
Dna Vaccination ◽  
Interferon Γ ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract DNA vaccination and all-trans retinoic acid (ATRA) result in a survival advantage in a mouse model of acute promyelocytic leukemia (APL). Depletion of CD4+ or CD8+ cells abolished this effect. CD4+ depletions of long-term survivors resulted in relapse and death within 3 months, thus demonstrating the need of both CD4+ and CD8+ subsets for the generation of DNA-driven antileukemic immune responses and underscoring a crucial role of CD4+ cells in the maintenance of durable remissions. Degranulation and cytotoxic carboxyfluorescein diacetate succinimidyl ester–based assays showed major histocompatibility complex–restricted APL-specific T cell–mediated immune responses. Sorted APL-specific CD8+CD107a+ T cells showed an increase of antileukemic activity. Effectors from ATRA + DNA–treated mice were shown to secrete interferon-γ when stimulated with either APL cells or peptides from the promyelocytic leukemia-RARα vaccine-derived sequences as detected by ELISpot assays. Our results demonstrate that DNA vaccination with ATRA confers the effective boosting of interferon-γ–producing and cytotoxic T cells in the leukemic mice.

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.

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