Diverio D, Rossi V, Avvisati G, De Santis S, Pistilli A, Pane F, Saglio G, Martinelli G, Petti M C, Santoro A, Pelicci P G, Mandelli F, Biondi A, Lo Coco F
Dipartimento di Biotecnologie Cellulari ed Ematologia, Università "La Sapienza", Rome, Italy.
Blood. 1998 Aug 1;92(3):784-9.
Although the majority of patients with acute promyelocytic leukemia (APL) are potentially cured by treatments combining all-trans retinoic acid (ATRA) and chemotherapy (CHT), a sizable proportion (around 30%) will relapse during follow-up. Retrospective molecular monitoring studies using reverse transcriptase-polymerase chain reaction (RT-PCR) for the specific PML/RARalpha fusion gene, have shown that a positive test usually precedes the occurrence of hematologic relapse. Prospective RT-PCR analyses were performed since 1993 at diagnosis and at preestablished time intervals during follow-up in bone marrow (BM) samples of 163 patients with PML/RARalpha+ APL enrolled in the multicenter Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA) trial AIDA (All-trans retinoic acid plus Idarubicin). Treatment consisted of ATRA and idarubicin for induction followed by three polychemotherapy courses as consolidation. The sensitivity level of the RT-PCR assay for PML/RARalpha, as assessed by serial dilution experiments, was 10(-4). All patients were in hematologic remission and tested PCR- at the end of consolidation. Of 21 who converted to PCR-positive thereafter, 20 underwent hematologic relapse at a median time of 3 months (range, 1 to 14) from the first PCR+ result. Seventeen of these 21 (81%) PCR+ conversions were recorded within the first 6 months postconsolidation. Of 142 who tested persistently PCR- in >/=2 tests after consolidation, 8 had hematologic relapse and 134 remained in complete remission (CR) after a median follow-up of 18 months (range, 6 to 38) postconsolidation. Using a time-dependent Cox model, the relative risk of hematologic relapse of patients who converted to PCR+ was 31.8 (confidence limits 95%, 12.9 to 78.3). Our results indicate that conversion to PCR positivity for PML/RARalpha during remission is highly predictive of subsequent hematologic relapse and highlight the prognostic value of stringent molecular monitoring during the early postconsolidation phase in APL. As a result of the present study, salvage treatment in patients enrolled in the GIMEMA trial AIDA is now anticipated at the time of molecular relapse, defined as the conversion to PCR positivity in two successive BM samplings during follow-up.
尽管大多数急性早幼粒细胞白血病（APL）患者可通过全反式维甲酸（ATRA）与化疗（CHT）联合治疗实现潜在治愈，但仍有相当比例（约30%）的患者在随访期间会复发。利用逆转录酶 - 聚合酶链反应（RT-PCR）对特定的PML/RARα融合基因进行回顾性分子监测研究表明，阳性检测结果通常先于血液学复发的发生。自1993年起，对参加多中心意大利成人恶性血液病研究组（GIMEMA）AIDA（全反式维甲酸加伊达比星）试验的163例PML/RARα+ APL患者的骨髓（BM）样本在诊断时以及随访期间预先设定的时间间隔进行前瞻性RT-PCR分析。治疗包括诱导期使用ATRA和伊达比星，随后进行三个多药化疗疗程作为巩固治疗。通过系列稀释实验评估，RT-PCR检测PML/RARα的灵敏度水平为10^(-4)。所有患者在巩固治疗结束时均处于血液学缓解状态且PCR检测为阴性。此后转为PCR阳性的21例患者中，20例在首次PCR+结果后的中位时间3个月（范围1至14个月）出现血液学复发。这21例PCR+转换病例中有17例（81%）在巩固治疗后6个月内记录到。巩固治疗后≥2次检测持续PCR阴性的142例患者中，8例出现血液学复发，134例在巩固治疗后中位随访18个月（范围6至38个月）后仍处于完全缓解（CR）状态。使用时间依赖性Cox模型，转为PCR+的患者血液学复发的相对风险为31.8（95%置信区间，12.9至78.3）。我们的结果表明，缓解期PML/RARα转为PCR阳性高度预示随后的血液学复发，并突出了APL巩固治疗后早期严格分子监测的预后价值。由于本研究的结果，参加GIMEMA试验AIDA的患者现在预计在分子复发时进行挽救治疗，分子复发定义为随访期间连续两次BM样本检测转为PCR阳性。
