Kinetics of Molecular Response to Imatinib in Patients With Chronic Myeloid Leukemia May Predict Persistent Polymerase Chain Reaction Negativity After Imatinib Discontinuation

Carmen Fava, Stefano Ulisciani, Emilia Giugliano, Vanessa Brunetto, Enrico Gottardi, Lorena Giaretto, Giuseppe Saglio, Giovanna Rege-Cambrin
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引用次数: 0

Abstract

Four patients with a rapid clearance of leukemic cells maintained a molecular response after discontinuation of therapy. We adopted a new, more sensitive technique to detect minimal residual disease that can help to detect those patients who might be the most eligible for discontinuation when they achieve a complete molecular response.

Full Abstract

Only a restricted group of patients with Philadelphia chromosome—positive (Ph+) CML is able to achieve a complete molecular response (CMR) after treatment with imatinib. Clinical studies evaluating patients who discontinued treatment are ongoing, and initial reports have pointed out that approximately 50% of patients relapsed within 6 months. We report 4 cases of patients who stopped imatinib in sustained CMR, defined as BCR-ABL/ABL levels below a detection threshold of 5-log reduction and undetectable BCR-ABL transcript by qualitative polymerase chain reaction (PCR), either on BM and PB samples, in at least 2 samples. Cessation was due to some degree of toxicity. CCyR was reached within 3 months of imatinib therapy, and CMR was achieved after 12, 6 (2 cases), and 9 months. The duration of treatment before discontinuation was 43, 54, 16, and 51 months, respectively, while the median time of PCR negativity on imatinib was 36 months. Three patients did not relapse and are PCR-negative with a follow-up of 62, 47, and 41 months, respectively. The fourth patient stayed off of treatment in confirmed CMR for 28 months, until an RQ-PCR analysis on PB disclosed a BCR-ABL/ABL ratio of 0.0208%. She refused to restart imatinib, and she is currently off therapy after 1 year with an RQ-PCR still in the MMR range. Minimal residual disease was assessed with a new strategy with multiple PCR reactions on a 82-well plate, increasing the sensitivity to a 6-log reduction. Patients who remained persistently negative at standard PCR techniques behaved like the normal controls. The single patient who relapsed proved to be positive also in samples obtained during the PCR negativity at the standard methods. This report confirms that a molecular response can be sustained after discontinuation of imatinib. All patients were characterized by a rapid clearance of leukemic cells, suggesting that the kinetics of molecular response might predict prolonged remission after imatinib discontinuation. Furthermore, though in the literature all relapses occurred early, we observed a late molecular recurrence, not associated with progression. Finally we adopted a new, more sensitive technique to detect minimal residual disease that can help to detect those patients who can be the most eligible for discontinuation when they achieve a CMR.

慢性髓性白血病患者对伊马替尼的分子反应动力学可以预测伊马替尼停药后持续的聚合酶链反应阴性
4例白血病细胞快速清除的患者在停止治疗后仍保持分子反应。我们采用了一种新的、更灵敏的技术来检测最小残留疾病,这可以帮助发现那些在达到完全分子反应时可能最适合停药的患者。只有一小部分费城染色体阳性(Ph+) CML患者在伊马替尼治疗后能够达到完全分子缓解(CMR)。评估停止治疗患者的临床研究正在进行中,初步报告指出,大约50%的患者在6个月内复发。我们报告了4例在持续CMR中停止使用伊马替尼的患者,定义为BCR-ABL/ABL水平低于5-log降低的检测阈值,并且通过定性聚合酶链反应(PCR)在BM和PB样本中检测不到BCR-ABL转录物,至少有2个样本。戒烟是由于某种程度的毒性。伊马替尼治疗3个月内达到CCyR, 12个月、6个月(2例)和9个月后达到CMR。停药前治疗时间分别为43、54、16、51个月,而伊马替尼PCR阴性的中位时间为36个月。3例患者未复发,pcr阴性,随访时间分别为62,47和41个月。第4例确诊CMR患者停止治疗28个月,直到对PB的RQ-PCR分析显示BCR-ABL/ABL比率为0.0208%。她拒绝重新开始伊马替尼治疗,目前她在1年后停止治疗,RQ-PCR仍在MMR范围内。在82孔板上采用多重PCR反应的新策略评估最小残留疾病,增加了对6对数降低的灵敏度。在标准PCR技术中持续呈阴性的患者表现与正常对照一样。在标准方法PCR阴性期间获得的样本中,复发的单个患者也被证明为阳性。本报告证实,在停用伊马替尼后,分子反应可以持续。所有患者的特点都是白血病细胞的快速清除,这表明分子反应动力学可能预测伊马替尼停药后缓解时间的延长。此外,虽然在文献中所有的复发都发生在早期,但我们观察到晚期分子复发,与进展无关。最后,我们采用了一种新的、更灵敏的技术来检测最小残留疾病,这可以帮助发现那些在达到CMR时最适合停药的患者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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