Acute promyelocytic leukemia: Aparadigm for differentiation therapy with retinoic acid

Tallman, Martin S.; Rowe, Jacob M.

doi:10.1016/s0268-960x(05)80010-4

Cited by 13 publications

(15 citation statements)

References 84 publications

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“…[2]/46,XX [2] Precursor B-ALL MLL-ENL 47,XX,+X,inv(11)(p15q23) [10] Precursor T-ALL SIL-TAL 46,XY,der(9)del(9)(?q33q34)?inv(9)(q13q34) [4]/46,XY [10] Broad molecular screening and cytogenetic analysis S Meyer-Monard et al…”

Section: Precursor T-allmentioning

confidence: 99%

“…These have changed our approach to leukemic pathogenesis, 1 they have provided a basis for classification, as documented by the World Health Organization (WHO) Classification of Tumors of Haematopoietic and Lymphoid Tissues, 2 and they currently guide searches for targeted therapies. 3,4 Therapeutic decision making is based on various well-defined prognostic parameters, the most important being the genetic makeup of the leukemic cell. 5,6 The application of molecular analysis and cytogenetics for diagnosis and follow-up is controversial.…”

Section: Introductionmentioning

confidence: 99%

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Combination of broad molecular screening and cytogenetic analysis for genetic risk assignment and diagnosis in patients with acute leukemia

Meyer-Monard

Parlier²,

Passweg

et al. 2006

Leukemia

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We evaluated the impact of genetic analysis combining cytogenetics and broad molecular screening on leukemia diagnosis according to World Health Organization (WHO) and on genetic risk assignment. A two-step nested multiplex RT-PCR assay was used that allowed the detection of 29 fusion transcripts. A total of 186 patients (104 males (56%), 174 adults (94%), 12 children (6%), 155 AML (83%), 31 ALL (17%)) characterized by morphology and immunophenotyping were included. Of these 186 patients, 120 (65%) had a genetic abnormality. Molecular typing revealed a fusion transcript in 49 (26%) patients and cytogenetic analysis revealed an abnormal karyotype in 119 (64%). A total of 27 (14%) cases were genetically classified as favorable, 107 (58%) intermediate and 52 (28%) unfavorable. For 38 (20%) patients, there was a discrepancy in the genetic risk assignments obtained from broad molecular screening and cytogenetics. Cryptic fusion transcripts in nine (5%) patients changed the genetic risk assignment in four and the WHO classification in four patients. In 34 patients (18%), cytogenetics defined the risk assignment by revealing structural and numerical chromosomal abnormalities not detected by molecular screening. Broad molecular screening and cytogenetics are complementary in the diagnosis and genetic risk assignment of acute leukemia.

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Section: Precursor T-allmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combination of broad molecular screening and cytogenetic analysis for genetic risk assignment and diagnosis in patients with acute leukemia

Meyer-Monard

Parlier²,

Passweg

et al. 2006

Leukemia

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“…(1). Intracellularly, ATRA is bound by CRABP (2) which appears to facilitate its oxidation (3), via P450 cytochromes (4), to 4-oxo-metabolites. ATRA can also undergo isomerization to 9cRA and 13cRA (5).…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Acute promyelocytic leukemia (APL), M3 subtype in the French-American-British classification system, comprises 10% to 15% of patients with acute myeloid leukemia [1][2][3]. Over the last decade, our approach to the treatment of APL has changed dramatically, and, as a result, the long-term event-free survival for patients has improved significantly.…”

Section: Introductionmentioning

confidence: 99%

All-Trans-Retinoic Acid Pharmacology and Its Impact on the Treatment of Acute Promyelocytic Leukemia

Adamson

1996

The Oncologist

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The approach to the treatment of acute promyelocytic leukemia (APL) has changed dramatically over the past decade and, as a result, the long-term event-free survival for patients has improved significantly. The addition of the vitamin A derivative, all-trans-retinoic acid (ATRA), to treatment regimens has been responsible for this improvement in survival. Although ATRA is a potent remission induction agent in APL, continuous administration of ATRA as a single agent does not maintain patients in remission. Although lower plasma concentrations were initially noted at the time of relapse in patients with APL, subsequent studies have demonstrated that the decline in plasma drug concentrations occurs within one to two weeks of initiation of treatment, and possibly as early as three days. The inability to maintain adequate plasma concentrations of ATRA because of rapid upregulation of its catabolism is an attractive hypothesis to explain the inevitable recurrences in patients with initially responsive disease, but more recent data suggest that this mechanism alone is unlikely to be responsible for drug resistance. Cellular retinoic acid binding proteins (CRABPs) play a critical role in regulating the amount of free retinoic acid capable of reaching and activating nuclear receptors. Recent studies using leukemic blasts obtained at the time of relapse have demonstrated a shift in the ATRA doseresponse curve in vitro. In addition, there is an upregulation in the expression of CRABP in leukemic blasts obtained at relapse. These observations suggest that ATRA resistance is not simply an inability to maintain therapeutic plasma concentrations of drug, but rather may be linked to the intracellular regulation of drug. The intricate nature of the homeostatic mechanisms that maintain tight control over retinoids, combined with the multiplicity of retinoid receptors and signaling pathways, leave open the possibility of a yet-to-be-defined mechanism of resistance that is independent of the clinical pharmacology of ATRA. HISTORICAL OVERVIEWThe history of ATRA in promyelocytic leukemia only dates back to 1980 when Breitman et al. described the effects of retinoic acid on the human leukemic cell line HL-60 [4]. These in vitro studies demonstrated that ATRA could induce a dose-dependent differentiation of HL-60 promyeloblasts to mature, functioning neutrophils. The Oncologist 1996;1:305-314 Adamson 306Exposure to ATRA at a concentration of 1 µM resulted in 95% of cells differentiating, with a concomitant loss of their capacity to proliferate.The first reports of the clinical use of ATRA in patients with APL came from Shanghai and were published in 1987 and 1988 [5, 6]. All 24 patients treated by Huang and colleagues attained a complete remission without experiencing marrow hypoplasia. These dramatic results were subsequently confirmed by investigators from Paris [7,8] and New York [9]. Since then, more than 3,000 patients with APL worldwide have been treated with ATRA [10], and complete remission rates exceed 80% to 90% in most series...

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“…1,242 11,899 NOTE: Platelet counts are shown in thousands per mm 3 . For designation of neutrophil response, a patient had to have had pre-bexarotene ANC <1,500/mm 3 with at least a 100% improvement or absolute increase of >500/mm 3 , whichever was greater.…”

mentioning

confidence: 99%

A Phase I Study of Bexarotene, a Retinoic X Receptor Agonist, in Non-M3 Acute Myeloid Leukemia

Tsai¹,

Luger²,

Andreadis³

et al. 2008

Clinical Cancer Research

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Purpose: Bexarotene is a retinoic X receptor agonist that has been shown in vitro to inhibit growth and induce differentiation of myeloid leukemic cell lines.We therefore conducted a phase I dose escalation study to assess the maximum tolerated dose, toxicities, and activity of bexarotene in patients with non-M3 acute myeloid leukemia (AML). Experimental Design: We enrolled patients with active non-M3 AML who had either relapsed or refractory disease or were not eligible for standard cytotoxic chemotherapy. Cohorts of three to six patients received escalating doses of daily oral bexarotene ranging from 100 to 400 mg/m 2 until evidence of disease progression or unacceptable adverse events occurred. Results: Twenty-seven patients, with median age of 69 years (range, 51-82 years), were treated. Twenty-four (89%) patients had undergone prior chemotherapy. At the highest dose level tested (400 mg/m 2 ), three of six patients had to reduce their dose of bexarotene due to grade 3 adverse events. The maximum tolerable dose of bexarotene was determined to be 300 mg/m 2 . Clinical activity was manifested by 4 (15%) patients with reduction in bone marrow blasts to V5%, 11 (41%) patients with improved platelet counts, and 7 (26%) patients with improved neutrophil counts. Three patients with relapsed AML survived >1 year while taking bexarotene. Leukemic blast differentiation was suggested by the presence of the leukemic cytogenetic abnormality in mature circulating granulocytes and the occurrence of differentiation syndrome. Conclusions: The recommended dose of bexarotene for future studies is 300 mg/m 2 /d. Bexarotene is well tolerated in patients with non-M3 AML and has evidence of antileukemic activity.

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Acute promyelocytic leukemia: Aparadigm for differentiation therapy with retinoic acid

Cited by 13 publications

References 84 publications

Combination of broad molecular screening and cytogenetic analysis for genetic risk assignment and diagnosis in patients with acute leukemia

Combination of broad molecular screening and cytogenetic analysis for genetic risk assignment and diagnosis in patients with acute leukemia

All-Trans-Retinoic Acid Pharmacology and Its Impact on the Treatment of Acute Promyelocytic Leukemia

A Phase I Study of Bexarotene, a Retinoic X Receptor Agonist, in Non-M3 Acute Myeloid Leukemia

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