DIFFERENTIATION THERAPY OF ACUTE PROMYELOCYTIC LEUKEMIA WITH TRETINOIN (ALL-TRANS-RETINOIC ACID)
DIFFERENTIATION THERAPY OF ACUTE PROMYELOCYTIC LEUKEMIA WITH TRETINOIN (ALL-TRANS-RETINOIC ACID)
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DOI：
10.1056/nejm199105163242002
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发表时间：
1991-05-16
影响因子：
158.5
通讯作者：
DMITROVSKY, E
中科院分区：
文献类型：
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作者：
WARRELL, RP;FRANKEL, SR;DMITROVSKY, E
研究背景和方法。急性早幼粒细胞白血病患者有一个特征的(15；17)易位，在17号染色体维甲酸受体-α(RAR-α)区域有一个断裂点。由于该受体在体外与髓系细胞的生长和分化有关，而且最近的临床研究报道了维甲酸(全反式维甲酸)诱导急性早幼粒细胞白血病患者完全缓解，我们研究了维甲酸对用该药诱导缓解的患者细胞成熟和分子异常的影响。11例急性早幼粒细胞白血病患者口服维甲酸，每天每平方米体表面积45 mg。11例患者中有9例完全缓解。在两名患者中，在完全缓解之前，出现了显著的白细胞增多症，尽管继续药物治疗，但症状消失了。细胞形态特征、细胞表面免疫表型分析和17号染色体探针荧光原位杂交的一系列研究表明，临床反应与白血病克隆的成熟有关。所有对治疗有反应的患者在Northern印迹分析中都有RAR-α的异常表达。随着患者进入完全缓解，RAR-α异常信息的表达明显减少，但在部分患者的形态和细胞遗传学完全缓解后仍可检测到RAR-α的表达。维甲酸是一种安全高效的诱导急性早幼粒细胞白血病患者完全缓解的药物。对这种药物的临床反应与白血病细胞分化有关，并与RAR-α核受体的异常表达有关。该异常受体的分子检测可作为该病患者残留白血病的有用标志物。
Background and Methods. Patients with acute promyelocytic leukemia have a characteristic (15;17) translocation, with a breakpoint on chromosome 17 in the region of the retinoic acid receptor-alpha (RAR-alpha). Since this receptor has been shown to be involved with growth and differentiation of myeloid cells in vitro, and since recent clinical studies have reported that tretinoin (all-trans-retinoic acid) induces complete remission in patients with acute promyelocytic leukemia, we studied the effects of tretinoin on cellular maturation and molecular abnormalities in patients undergoing the induction of remission with this agent.Results. Eleven patients with acute promyelocytic leukemia were treated with tretinoin administered orally at a dose of 45 mg per square meter of body-surface area per day. Nine of the 11 patients entered complete remission. In two patients, complete remission was preceded by striking leukocytosis that then resolved despite continued drug treatment. Serial studies of cellular morphologic features, cell-surface immunophenotypic analysis, and fluorescence in situ hybridization with a chromosome 17 probe revealed that clinical response was associated with maturation of the leukemic clone. All patients who responded to treatment who were tested by Northern blot analysis had expression of aberrant RAR-alpha. As patients entered complete remission,the expression of the abnormal RAR-alpha message decreased markedly; however, it was still detectable in several patients after complete morphologic and cytogenetic remission had been achieved.Conclusions. Tretinoin is a safe and highly effective agent for inducing complete remission in patients with acute promyelocytic leukemia. Clinical response to this agent is associated with leukemic-cell differentiation and is linked to the expression of an aberrant RAR-alpha nuclear receptor. Molecular detection of the aberrant receptor may serve as a useful marker for residual leukemia in patients with this disease.