Gallagher R E, Willman C L, Slack J L, Andersen J W, Li Y P, Viswanatha D, Bloomfield C D, Appelbaum F R, Schiffer C A, Tallman M S, Wiernik P H
Department of Oncology, Montefiore Medical Center and Albert Einstein Cancer Center, Bronx, NY 10467, USA.
Blood. 1997 Aug 15;90(4):1656-63.
In each case of acute promyelocytic leukemia (APL) one of three PML-RAR alpha mRNA types is produced, depending on the break/fusion site in the PML gene that is linked to a common RAR alpha gene segment: a short (S)-form type, PML exon 3 RAR alpha exon 3; a long (L)-form type, PML exon 6 RAR alpha exon 3; or a variable (V)-form type, variably deleted PML exon 6 RAR alpha exon 3. We evaluated whether PML-RAR alpha mRNA type is associated with distinct pretreatment clinical characteristics and therapeutic outcome in previously untreated adult APL patients registered to protocol INT 0129 by the Eastern Cooperative Oncology Group, the Southwest Oncology Group, and the Cancer and Leukemia Group B. Of 279 clinically eligible cases, 230 were molecularly evaluable, and of these, 111 were randomized to receive remission induction therapy with all-trans retinoic acid (ATRA) and 119 with conventional chemotherapy. Nine cases not excluded by central pathology review were PML-RAR alpha negative, and notably, none of five of these cases treated with ATRA achieved complete remission (CR). Among 221 PML-RAR alpha-positive cases, there were 82 S-form cases (37%), 121 L-form cases (55%), and 18 V-form cases (8%). Before any antileukemic therapy, the S-form type, compared with the L-form type, was associated with higher values for the white blood cell (WBC) count (median 2,500/microL v 1,600/microL; P = .009), the percentage of blood blasts plus promyelocytes (median 29% v 8.5%; P = .03), and the absolute blood blasts plus promyelocytes (884/microL v 126/microL; P = .019). Also, an increased percentage of S-form versus L-form cases had the M3 variant phenotype, 24% v 12% (P = .036). There were no differences between S-form and L-form cases in either CR rate (79% v 69%; P = .14) or disease free survival distribution (multivariate analysis adjusting for the association of S-form type and higher WBC count; P = .40). We conclude that the S-form type is associated with previously-identified adverse risk WBC parameters but that the identification of the S-form or L-form type of PML-RAR alpha mRNA, per se, does not predict clinical outcome or add to the value of an increased WBC count as a negative prognostic indicator in APL patients.
在每例急性早幼粒细胞白血病（APL）中，根据与常见的维甲酸受体α（RARα）基因片段相连的早幼粒细胞白血病（PML）基因中的断裂/融合位点，会产生三种PML-RARα mRNA类型之一：短（S）型，即PML外显子3-RARα外显子3；长（L）型，即PML外显子6-RARα外显子3；或可变（V）型，即PML外显子6可变缺失-RARα外显子3。我们评估了PML-RARα mRNA类型是否与东部肿瘤协作组、西南肿瘤协作组和癌症与白血病B组登记入INT 0129方案的初治成年APL患者的不同预处理临床特征及治疗结果相关。在279例临床符合条件的病例中，230例可进行分子评估，其中111例被随机分配接受全反式维甲酸（ATRA）诱导缓解治疗，119例接受传统化疗。经中心病理复查未排除的9例病例为PML-RARα阴性，值得注意的是，这5例接受ATRA治疗的病例中无一例达到完全缓解（CR）。在221例PML-RARα阳性病例中，有82例S型病例（37%）、121例L型病例（55%）和18例V型病例（8%）。在任何抗白血病治疗前，与L型相比，S型的白细胞（WBC）计数更高（中位数分别为2500/μL和1600/μL；P = 0.009），血原始细胞加早幼粒细胞的百分比更高（中位数分别为29%和8.5%；P = 0.03），血原始细胞加早幼粒细胞的绝对值更高（884/μL和126/μL；P = 0.019）。此外，S型病例中具有M3变异型表型的比例高于L型病例，分别为24%和12%（P = 0.036）。S型和L型病例在CR率（79%和69%；P = 0.14）或无病生存分布方面均无差异（多变量分析校正了S型与较高WBC计数的相关性；P = 0.40）。我们得出结论，S型与先前确定的不良风险WBC参数相关，但PML-RARα mRNA的S型或L型本身并不能预测临床结果，也不能增加WBC计数作为APL患者不良预后指标的价值。
