All Trans Retinoic Acid in Primary and Relapsed Acute Promyelocytic Leukemia

Koller, Elisabeth; Krieger, O.; Reisner, Regina; Grill, Robert; Waldner, R; Lutz, D.

doi:10.1159/000217331

Cited by 5 publications

(4 citation statements)

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“…All patients received ATRA 45 mg/m2/day for induction treatment, six of them in combination with cytostatic therapy (patients 1, 5, and 10 received a standard chemotherapy, "3 + 7", i.e., daunorubicin 60 mg/m 2 day 1-3, cytosine arabinoside 100 mg/m 2 day 1-7; patients 4, 6, and 7 received high-dose cytosine arabinoside chemotherapy 3 g/m 2 every 12 h for 2 days, as previously reported for hyperleukocytosis [5]. All patients received ATRA 45 mg/m2/day for induction treatment, six of them in combination with cytostatic therapy (patients 1, 5, and 10 received a standard chemotherapy, "3 + 7", i.e., daunorubicin 60 mg/m 2 day 1-3, cytosine arabinoside 100 mg/m 2 day 1-7; patients 4, 6, and 7 received high-dose cytosine arabinoside chemotherapy 3 g/m 2 every 12 h for 2 days, as previously reported for hyperleukocytosis [5].…”

Section: Patientsmentioning

confidence: 87%

“…This rearrangement results in a functionally altered retinoic acid receptor, thus explaining the response of promyelocytic blasts to all-trans retinoic acid (ATRA) as a differentiating agent in vitro and in vivo [2,3]. ATRA gives a high complete remission rate in APL patients and reduces the incidence of fatal disseminated coagulopathy significantly [3][4][5]. Nevertheless, patients maintained with ATRA alone have a high relapse rate and therefore need chemotherapeutic consolidation [6].…”

Section: Introductionmentioning

confidence: 99%

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Early detection of minimal residual disease by reverse transcriptase polymerase chain reaction predicts relapse in acute promyelocytic leukemia

et al. 1995

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The PML/RAR alpha fusion RNA can be detected in acute promyelocytic leukemia (APL), cytogenetically characterized by the translocation t(15;17). Our study included ten newly diagnosed patients with APL who were investigated during the course of their diseases using reverse transcription polymerase chain reaction (RT-PCR). At diagnosis, aberrant fragments with a size heterogeneity due to alternative spliced products were detected in all patients, we observed breakpoints within bcr3 (short type) in two patients and bcr1 and 2 breakpoints (long type) in eight patients. Treatment consisted of all-trans retinoic acid (ATRA) in all patients; six patients received simultaneous cytostatic therapy during remission induction. At the time of complete hematological remission (CR), only two patients showed a negative RT-PCR result; eight of the ten patients were still PCR positive when nested primers were used. Subsequently, eight patients received consolidation chemotherapy and became PCR negative. Seven of eight patients are in continuous complete remission (median remission duration: 21 months, range: 11+ -26+ months). One patient of the chemotherapy group became PCR positive after 4 months in complete remission and relapsed after 6 months. The remaining two patients who were treated only with ATRA relapsed, received induction chemotherapy, and are in second and third complete remission, respectively. In conclusion. PCR negativity can be achieved only by chemotherapeutic consolidation; patients treated with ATRA alone remain PCR positive. Relapse is always preceded by a positive PCR result. Surprisingly, also patients without measurable PML/RAR alpha-mRNA in sequential analyses after cytostatic treatment became PCR positive and experienced relapse.

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Section: Patientsmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Early detection of minimal residual disease by reverse transcriptase polymerase chain reaction predicts relapse in acute promyelocytic leukemia

et al. 1995

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“…As occasionally reported in the literature, APL patients who enter remission after cytotoxic chemotherapy sometimes do so without experiencing marrow hypoplasia [21,33,51,56]. ATRA-induced remissions, however, consistently occur with out marrow hypoplasia [7,22,35,38,58]. Serial marrow sam ples taken from APL patients during ATRA treatment show progressive maturation of the abnormal promyelocytes, in cluding retention of Auer rods in granulocytes.…”

Section: Differentiating Agentsmentioning

confidence: 99%

Treatment of Acute Promyelocytic Leukemia

Runde¹,

Aul²

1992

Oncol Res Treat

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With the availability of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL), a subtype of acute myelogenous leukemia (AML), has gained a new and exemplary importance. So far, therapeutic strategies in oncology have been directed against the increased proliferative activity of the neoplastic cell clone. Treatment of APL with ATRA is a good example for successful ‘tumor differentiating therapy’. Under the influence of ATRA, immature leukemic cells differentiate into more mature leukemic cells which lack mitotic activities. Due to the physiological death of these maturing leukocytes, indirect reduction of tumor cell burden is achieved, and the majority of APL patients enter complete remission. It is of particular interest that bone marrow aplasia which is the main side effect of conventional chemotherapy can be avoided. Nevertheless, treatment of APL with ATRA is not devoid of clinical problems. Treatment with ATRA leads to a ‘washout’ of maturing promyelocytic blast cells which may cause hyperleukocytosis. Particularly during the early phases of treatment, this may contribute to the occurrence of severe thromboembolic events. Thus, the clinical picture of APL may change from hemorrhagic complications to leukostasis and thromboembolism. Evaluation of risk factors for the development of hyperleukocytosis is of critical importance for the patient. In order to avoid life-threatening complications, an effective prophylaxis of thromboembolism and in some cases additional chemotherapy may be necessary.

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“…The all-trans retinoic acid (ATRA) therapy of acute promyelocytic leukemia has become a prototype of differentiationinducing oncotherapy [1], yet maintaining remissions remains a challenge [2]. Muindi et al [3] reported that 'Relapsed patients showed a clinical resistance to ATRA due to progressive re duction of plasma concentrations, whereas the leukemic cells obtained at the time of relapse retained their in vitro sensiti vity ...…”

Section: Introductionmentioning

confidence: 99%

Oral Liarozole as a Catabolic Inhibitor Potently Increases Retinoic Acid in vivo: First Experience from an Ongoing Therapeutic Trial in Highly Malignant Primary Brain Tumors

Westarp

Bruynseels

et al. 1993

Oncol Res Treat

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Background: Retinoic acid, the intracellular metabolite of vitamin A, induces differentiation in glioblastoma cultures and recognizes nuclear retinoic acid (RA) receptors in human glial cells. Its degradation can be inhibited by the oral steroid synthesis modulator liarozole or R75251 (5-[(3-chlorophenyl) (lH-imidazole-l-yl)methyl]-lH-benzimidazole HC1). Measured by ³H-thymidine incorporation, liarozole also exhibits an intrinsic attenuating effect on glioblastoma growth in vitro. Patients and Method: Ten patients with primary malignant brain tumors have entered an open oral therapeutic pilot study with 13-cis-retinoic acid (isotre-tinoin^INN; Roaccutan® Roche) and the catabolic inhibitor liarozole. Results: Side effects such as cheilitis, conjunctivitis, and desquamation dose-depend-ently correlated with plasma levels and could be regularly used for dose adjustments. The combined therapy produced and maintained elevated plasma concentrations and clinical retinoid effects with fractions of formerly necessary 13-cis-RA doses. In vivo, 75-150 mg liarozole combined with 5-20 mg 13-cis-RA daily increased plasma 13-cis-RA and 4-oxo-13-cis-RA levels more than threefold. Long-term all-trans-RA therapy without liarozole leads to a progressive downregulation of plasma RA levels. Such a decrease may be prevented by combining all-trans-RA with its catabolic inhibitor liarozole (Janssen). Conclusion: First clinical experience recommends liarozole for either 13-cis-or all-trans RA therapy in retinoid-sensitive malignancies such as neuro-ectodermal glioma or acute promyelocytic leukemia.

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All Trans Retinoic Acid in Primary and Relapsed Acute Promyelocytic Leukemia

Cited by 5 publications

References 4 publications

Early detection of minimal residual disease by reverse transcriptase polymerase chain reaction predicts relapse in acute promyelocytic leukemia

Early detection of minimal residual disease by reverse transcriptase polymerase chain reaction predicts relapse in acute promyelocytic leukemia

Treatment of Acute Promyelocytic Leukemia

Oral Liarozole as a Catabolic Inhibitor Potently Increases Retinoic Acid in vivo: First Experience from an Ongoing Therapeutic Trial in Highly Malignant Primary Brain Tumors

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