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

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.

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

Blood ◽

10.1182/blood.v72.2.567.567 ◽

1988 ◽

Vol 72 (2) ◽

pp. 567-572 ◽

Cited By ~ 1563

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

Abstract 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.

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

Blood ◽

10.1182/blood.v90.3.967.967_967_973 ◽

1997 ◽

Vol 90 (3) ◽

pp. 967-973 ◽

Cited By ~ 7

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.

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A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients

Blood ◽

10.1182/blood.v78.6.1413.bloodjournal7861413 ◽

1991 ◽

Vol 78 (6) ◽

pp. 1413-1419 ◽

Cited By ~ 3

Author(s):

ZX Chen ◽

YQ Xue ◽

R Zhang ◽

RF Tao ◽

XM Xia ◽

...

Keyword(s):

Bone Marrow ◽

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Bone Marrow Cells ◽

Promyelocytic Leukemia ◽

Leukemic Cells ◽

Therapeutic Effects ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Fifty patients with acute promyelocytic leukemia (APL) have been treated with all-trans retinoic acid (RA). In vitro induced differentiation of primarily cultured bone marrow cells from the patients, colony-forming unit granulocyte-macrophage (CFU-GM) and L-CFU colony-forming assays, and karyotype analysis were performed over the treatment course. The very high bone marrow complete remission (CR) rate (94%) suggested that all-trans RA was superior to conventional chemotherapeutic regimens for the treatment of APL. The leukemic clone was reduced by RA-induced terminal differentiation and loss of proliferation capacity of leukemic cells. Relapse after CR in about 40% of patients was the major reason for the failure of the RA treatment. Patients who relapsed after a chemotherapy-maintained CR could be effectively reinduced to second CR by RA. However, if relapse occurred after a CR maintained by both RA and chemotherapy, the sensitivity of newly emerged leukemic clones to RA was greatly reduced. Therefore, it is suggested that RA should be replaced by conventional chemotherapy as soon as CR is achieved. Laboratory studies proved valuable in selecting cases for RA therapy and in predicting therapeutic effects and prognosis.

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

Blood ◽

10.1182/blood.v90.3.967 ◽

1997 ◽

Vol 90 (3) ◽

pp. 967-973 ◽

Cited By ~ 132

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

Abstract 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.

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A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients

Blood ◽

10.1182/blood.v78.6.1413.1413 ◽

1991 ◽

Vol 78 (6) ◽

pp. 1413-1419 ◽

Cited By ~ 275

Author(s):

ZX Chen ◽

YQ Xue ◽

R Zhang ◽

RF Tao ◽

XM Xia ◽

...

Keyword(s):

Bone Marrow ◽

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Bone Marrow Cells ◽

Promyelocytic Leukemia ◽

Leukemic Cells ◽

Therapeutic Effects ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract Fifty patients with acute promyelocytic leukemia (APL) have been treated with all-trans retinoic acid (RA). In vitro induced differentiation of primarily cultured bone marrow cells from the patients, colony-forming unit granulocyte-macrophage (CFU-GM) and L-CFU colony-forming assays, and karyotype analysis were performed over the treatment course. The very high bone marrow complete remission (CR) rate (94%) suggested that all-trans RA was superior to conventional chemotherapeutic regimens for the treatment of APL. The leukemic clone was reduced by RA-induced terminal differentiation and loss of proliferation capacity of leukemic cells. Relapse after CR in about 40% of patients was the major reason for the failure of the RA treatment. Patients who relapsed after a chemotherapy-maintained CR could be effectively reinduced to second CR by RA. However, if relapse occurred after a CR maintained by both RA and chemotherapy, the sensitivity of newly emerged leukemic clones to RA was greatly reduced. Therefore, it is suggested that RA should be replaced by conventional chemotherapy as soon as CR is achieved. Laboratory studies proved valuable in selecting cases for RA therapy and in predicting therapeutic effects and prognosis.

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Fucoidan enhances the therapeutic potential of arsenic trioxide and all-trans retinoic acid in acute promyelocytic leukemia, in vitro and in vivo

Oncotarget ◽

10.18632/oncotarget.10016 ◽

2016 ◽

Vol 7 (29) ◽

pp. 46028-46041 ◽

Cited By ~ 17

Author(s):

Farzaneh Atashrazm ◽

Ray M. Lowenthal ◽

Joanne L. Dickinson ◽

Adele F. Holloway ◽

Gregory M. Woods

Keyword(s):

Retinoic Acid ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Therapeutic Potential ◽

Promyelocytic Leukemia ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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

Cancers ◽

10.3390/cancers12051313 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1313 ◽

Cited By ~ 1

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.

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Characterization of acute promyelocytic leukemia cases with PML-RAR alpha break/fusion sites in PML exon 6: identification of a subgroup with decreased in vitro responsiveness to all-trans retinoic acid

Blood ◽

10.1182/blood.v86.4.1540.bloodjournal8641540 ◽

1995 ◽

Vol 86 (4) ◽

pp. 1540-1547 ◽

Cited By ~ 77

Author(s):

RE Gallagher ◽

YP Li ◽

S Rao ◽

E Paietta ◽

J Andersen ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

High Sensitivity ◽

Promyelocytic Leukemia ◽

Reaction Products ◽

Reading Frame ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Fusion Site

Of 113 acute promyelocytic leukemia cases documented to have diagnostic PML-RAR alpha hybrid mRNA, 10 cases (8.8%) had fusion sites in PML gene exon 6 (V-forms) rather than in the two common hybrid mRNA configurations resulting from breaksites in either PML gene intron 6 (L- forms) or intron 3 (S-forms). In 4 V-form cases, a common break/fusion site was discovered at PML gene nucleotide (nt) 1685, abutting a 3′ cryptic splice donor sequence. The fusion site was proximal to the common site in 1 case and more distal in 5 cases. The open reading frame encoding a PML-RAR alpha gene was consistently preserved, either by an in-frame fusion site or by the insertion of 3 to 127 unidentified nts. In 2 V-form cases, hybridization analysis of the reverse transcriptase-polymerase chain reaction products with a PML-RAR alpha juction probe was required for discrimination from L-form cases. Two V- form subgroups were defined by in vitro sensitivity to all-trans retinoic acid (tRA)-induced differentiation: 4 of 4 cases tested with fusion sites at or 5′ to nt 1685 (subgroup E6S) had reduced sensitivity (EC50 > or = 10(-7) mol/L), whereas 4 of 4 cases with fusion sites at or 3′ to nt 1709 (subgroup E6L) had high sensitivity (EC50 < 10(-8) mol/L) indistinguishable from that of L-form and S-form cases. These results provide the first link between PML-RAR alpha configuration and tRA sensitivity in vitro and support the importance of subclassifying APL cases according to PML-RAR alpha transcript type.

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Targeted removal of PML-RARα protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid differentiation resistance in acute promyelocytic leukemia

Blood ◽

10.1182/blood.v100.3.1008 ◽

2002 ◽

Vol 100 (3) ◽

pp. 1008-1013 ◽

Cited By ~ 27

Author(s):

Yongkui Jing ◽

Lijuan Xia ◽

Samuel Waxman

Keyword(s):

Retinoic Acid ◽

Histone Deacetylase ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Dominant Negative ◽

Gene Expressions ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Nitroblue Tetrazolium Reduction ◽

A Cell

Abstract All-trans retinoic acid (tRA)–induced differentiation in NB4 cells, a cell line derived from an acute promyelocytic leukemia patient with t(15;17) translocation, is markedly facilitated by sodium butyrate (NaB), a histone deacetylase inhibitor (HDACI), or by hexamethylene bisacetamide (HMBA), a non–HDACI tRA-differentiation inducer, as determined by nitroblue tetrazolium reduction. The tRA-induced expression of RIG-G, Bfl-1/A1, and p21waf1 and, to a lesser extent, of CCAAT/enhancer binding protein–ε (C/EBPε) are also enhanced by such combined treatments. Both responses are associated with a facilitated diminution of the leukemogenic PML-RARα protein and retained ΔPML-RARα, a cleavage product. Treatment with tRA in tRA differentiation–resistant NB4 subclones R4 and MR-2 does not result in PML-RARα diminution and the tested gene expressions. Moreover, the addition of HMBA or NaB with tRA results in only minimal increase of differentiation in the tRA differentiation–resistant subclones. The increases in acetylated histone H3 (AcH3) and AcH4 in NaB-treated NB4, R4, and MR-2 cells are similar and do not correlate with the extent of differentiation induction when NaB and HMBA are given in combination with tRA. Arsenic trioxide (As2O3) treatment results in the total degradation of PML-RARα without increasing AcH3 or AcH4 or inducing differentiation in R4 cells. As2O3 in combination with tRA induces gene (Bfl-1/A1 and C/EBPε) expression and partial differentiation. Both NaB and HMBA addition to As2O3-plus-tRA–treated R4 cells further enhances differentiation. These results suggest that elimination of the dominant negative PML-RARα protein is required prior to inhibition of histone deacetylase to fully overcome tRA-differentiation resistance in APL cells.

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Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells [see comments]

Blood ◽

10.1182/blood.v82.7.2175.2175 ◽

1993 ◽

Vol 82 (7) ◽

pp. 2175-2181 ◽

Cited By ~ 127

Author(s):

L Delva ◽

M Cornic ◽

N Balitrand ◽

F Guidez ◽

JM Miclea ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Induction Therapy ◽

Binding Protein ◽

Promyelocytic Leukemia ◽

Leukemic Cells ◽

Differentiation Induction ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract All-trans retinoic acid (ATRA) induces leukemic cell differentiation and complete remission (CR) in a high proportion of patients with acute promyelocytic leukemia (AML3 subtype). However, relapses occur when ATRA is prescribed as maintenance therapy, and resistance to a second ATRA-induction therapy is frequently observed. An induced hypercatabolism of ATRA has been suggested as a possible mechanism leading to reduced ATRA sensitivity and resistance. CRABPII, an RA cytoplasmic binding protein linked to RA's metabolization pathway, is induced by ATRA in different cell systems. To investigate whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed, we studied the CRABP levels and in vitro sensitivity to ATRA of AML3 cells before and at relapse from ATRA. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with “virgin”-AML3 cells (n = 31; P < .05). Dose-response studies were performed in 2 cases at relapse and showed decreased sensitivity to low ATRA concentrations. CRABPII levels and in vitro differentiation characteristics of AML3 cells before and at relapse from ATRA therapy were studied concomittantly in 4 patients. High levels of CRABPII (median, 20 fmol/mg of protein) were detected in the cells of the 4 patients at relapse but were not detected before ATRA therapy. Three of these patients showed a decrease in differentiation induction of their leukemic cells, and a failure to achieve CR with a second induction therapy of ATRA 45 mg/m2/day was noted in all patients treated (n = 3). Results from this study provide evidence to support the hypothesis of induced-ATRA metabolism as one of the major mechanisms responsible for ATRA resistance. Monitoring CRABPII levels after ATRA withdrawal may help to determine when to administer ATRA in the maintenance or relapse therapy of AML3 patients.

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