EARLY MORTALITY AND THE RETINOIC ACID SYNDROME IN ACUTE PROMYELOCYTIC LEUKEMIA - IMPACT OF LEUKOCYTOSIS, LOW-DOSE CHEMOTHERAPY, PMN/RAR-ALPHA ISOFORM, AND CD13 EXPRESSION IN PATIENTS TREATED WITH ALL-TRANS-RETINOIC ACID
EARLY MORTALITY AND THE RETINOIC ACID SYNDROME IN ACUTE PROMYELOCYTIC LEUKEMIA - IMPACT OF LEUKOCYTOSIS, LOW-DOSE CHEMOTHERAPY, PMN/RAR-ALPHA ISOFORM, AND CD13 EXPRESSION IN PATIENTS TREATED WITH ALL-TRANS-RETINOIC ACID
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DOI：
10.1182/blood.v84.11.3843.bloodjournal84113843
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发表时间：
1994-12-01
期刊：
影响因子：
20.3
通讯作者：
WARRELL, RP
中科院分区：
文献类型：
--
作者：
VAHDAT, L;MASLAK, P;WARRELL, RP
全反式维甲酸(RA)已被证明在治疗急性早幼粒细胞白血病(APL)方面取得了重大进展。然而，在全反式HA诱导缓解期间出现或发展为白细胞增多症的患者的适当处理尚未建立，也没有明确的白细胞增多与维甲酸综合征的发生之间的关系。我们回顾了我们接受全反式维甲酸诱导的患者的病程，以确定可能预测这种综合征发展的潜在因素，并确定哪些患者(如果有的话)可能特别受益于细胞毒性化疗的额外治疗。78个疗程的全反式维甲酸治疗被用于APL的分子诊断。分析了初始和峰值白细胞计数、它们的上升速率、欧洲制定的白细胞计数标准和细胞表面标记表达与RA综合征的后续发展以及早期死亡的所有原因的关系。接受维甲酸诱导的白细胞增多症的特殊治疗的患者的结果也被检查。没有发现一致的因素可以预测RA综合征的发展。虽然综合征的发生与外周血白细胞计数的峰值呈正相关(P=.001)，但无论是初始白细胞计数还是发病前几天白细胞计数的上升速度都没有足够好的相关性来用于临床(P=.21)。欧洲制定的白细胞计数标准的敏感度为62%，特异度为69%，阳性预测值仅为44%至72%。然而，我们意外地发现，CD13(氨基肽酶N)的基础表达与急性髓系白血病患者的综合征的发展高度相关(P<；.051)以及白细胞计数的升高(P=0.006)。CD13是一种细胞表面酶，以前与肿瘤细胞侵袭和急性髓系白血病患者的不良预后有关。小剂量化疗和白细胞分离术都不能阻止综合征的发展，也不能改善其效果。事实上，在接受这些干预的11名患者中，有9名患者发生了致命或接近致命的事件，其中大部分是由于出血。然而，在大多数情况下，早期使用短疗程的大剂量皮质类固醇可以阻止综合征的发展。最后，我们发现PML/RAR-Alpha型‘’A‘’亚型(也称为bcr3或‘’Short‘)的表达与显著缩短的无复发持续时间和总生存期有关(P=0.005)。我们的数据表明，白细胞增多与呼吸窘迫综合征的发生几乎没有直接关系。CD13的表达提示了一种机制联系，并提供了进一步治疗调节的可能性，但需要进一步的研究来确定这种联系的重要性。大多数接受全反式维甲酸治疗的APL患者在诱导期间不需要额外的化疗，尽管几乎一半的患者需要皮质类固醇预防。迫切需要进一步的研究来确定和优化早期致死性出血风险最高的患者的治疗，并降低表达PML/RAR-αA型亚型的患者晚期复发的风险。(C)1994年由美国血液病学会主办。
All-trans retinoic acid (RA) has proven a major advance in the treatment of acute promyelocytic leukemia (APL). However, the proper management of patients who present with or develop leukocytosis during remission induction with all-trans HA is not established, nor is there a clear relation between leukocytosis and the development of the retinoic acid syndrome. We reviewed the course of our patients who underwent induction with all-trans RA to identify potential factors that might predict for the development of this syndrome and to identify which patients, if any, might specifically benefit from additional treatment with cytotoxic chemotherapy Seventy-eight courses of all-trans RA therapy were administered to patients with a molecular diagnosis of APL. initial and peak leukocyte counts, their rate of rise, leukocyte count criteria developed in Europe, and cell surface marker expression were all analyzed relative to subsequent development of both the RA syndrome as well as all causes of early mortality. The outcome of patients who received specific treatment for retinoid-induced leukocytosis was also examined. No factor was found to consistently predict for the development of the RA syndrome. Although the occurrence of the syndrome was positively associated with the peak value of the peripheral blood leukocyte count (P = .001), neither the initial leukocyte count nor the rate of rise in leukocyte counts on days preceding onset of the syndrome were sufficiently well-correlated to be clinically useful (P = .21). The leukocyte count criteria developed in Europe had a sensitivity of 62%, a specificity of 69%, and a positive predictive value that ranged from only 44% to 72%. However, we unexpectedly found that basal expression of CD13 (aminopeptidase N), a cell surface enzyme previously linked to tumor cell invasion and an inferior outcome in patients with acute myeloid leukemia, was highly associated with both development of the syndrome (P < .051 as well as an elevated leukocyte count (P = .006). Neither low-dose chemotherapy nor leukapheresis prevented development of the syndrome nor ameliorated its effects. In fact, 9 of 11 patients who received these interventions sustained fatal or near-fatal events, most of which were due to hemorrhage. However, early treatment with a short-course of high-dose corticosteroids halted progression of the syndrome in most cases. Finally, we found that expression of the type ''A'' isoform of PML/RAR-alpha (also known as bcr3 or ''short'') was associated with a significantly shorter duration of relapse-free and overall survival (P = .005). Our data indicate that leukocytosis has little direct relationship to the development of this respiratory distress syndrome. CD13 expression suggests a mechanistic link and offers a possibility of further therapeutic modulation, but additional study is required to determine the importance of this association. The majority of patients with APL treated with all-trans RA do not require additional chemotherapy during induction although almost half wilt need corticosteroid prophylaxis. Further studies are critically needed to identify and optimize the management of patients who are at highest risk for early fatal hemorrhage and to reduce the risk of late relapse in patients who express the type A isoform of PML/RAR-alpha. (C) 1994 by The American Society of Hematology.