Significance of Measurable Residual Disease in Adult Philadelphia Chromosome-Positive ALL: A GRAAPH-2014 Study.

IF 42.1 1区医学 Q1 ONCOLOGY Journal of Clinical Oncology Pub Date : 2024-09-10 Epub Date: 2024-07-19 DOI:10.1200/JCO.24.00108

Rathana Kim, Yves Chalandon, Philippe Rousselot, Jean-Michel Cayuela, Françoise Huguet, Marie Balsat, Marie Passet, Patrice Chevallier, Yosr Hicheri, Emmanuel Raffoux, Thibaut Leguay, Sylvain Chantepie, Sébastien Maury, Sandrine Hayette, Françoise Solly, Thorsten Braun, Bernard De Prijck, Victoria Cacheux, Celia Salanoubat, Laure Farnault, Isabelle Guibaud, Mathilde Lamarque, Lauris Gastaud, Emilie Lemasle, Eolia Brissot, Emmanuelle Tavernier, Karine Bilger, Alban Villate, Jean Soulier, Carlos Graux, Véronique Lhéritier, Hervé Dombret, Nicolas Boissel, Emmanuelle Clappier

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Abstract

Purpose: BCR::ABL1 quantification is widely regarded as the standard for monitoring measurable residual disease (MRD) in Philadelphia chromosome-positive (Ph+) ALL. However, recent evidence of BCR::ABL1 multilineage involvement questions the significance of BCR::ABL1 MRD. We aimed to define the prognostic role of MRD as assessed by BCR::ABL1 or lymphoid-specific immunoglobulin/T-cell receptor (IG/TR) gene markers.

Patients and methods: We conducted BCR::ABL1 and IG/TR quantification after each treatment cycle in 264 patients treated in the GRAAPH-2014 trial, which used four cycles of reduced-intensity chemotherapy with nilotinib, followed by hematopoietic stem-cell transplantation (HSCT).

Results: Comparing BCR::ABL1 and IG/TR MRD revealed residual BCR::ABL1-positive non-ALL cells in 98 (43%) of 228 patients, defining multilineage Ph+ ALL. Despite poorer BCR::ABL1 responses, patients with multilineage Ph+ ALL had similar disease-free survival (DFS; hazard ratio [HR], 0.83 [95% CI, 0.49 to 1.41]; P = .50). Although BCR::ABL1 response failed to predict outcomes, IG/TR positivity (≥0.01%) was strongly associated with lower DFS (after cycle 2, HR, 2.49 [95% CI, 1.40 to 4.40]; P = .002; after cycle 4, HR, 4.13 [95% CI, 1.82 to 9.38]; P = .001). In multivariable analysis, both IG/TR positivity after cycle 2 and initial WBC count ≥30 × 10⁹/L predicted poorer DFS, enabling to define a high-risk group having a 4-year DFS of 56.5% compared with 87.6% (HR, 3.72 [95% CI, 1.93 to 7.15]; P < .001). Moreover, allogeneic HSCT significantly improved DFS in the high-risk group (HR, 0.33 [95% CI, 0.18 to 0.60]; P < .001), whereas the standard-risk group had favorable outcomes regardless of allogeneic HSCT.

Conclusion: Our findings challenge the significance of BCR::ABL1 monitoring in adult Ph+ ALL and demonstrate the prognostic role of IG/TR MRD. This study provides a framework for using MRD to guide treatment strategies in adults with Ph+ ALL.

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成人费城染色体阳性 ALL 中可测残留疾病的意义：GRAAPH-2014 研究。

目的：BCR::ABL1定量被广泛认为是监测费城染色体阳性（Ph+）ALL可测量残留疾病（MRD）的标准。然而，最近有证据表明BCR::ABL1多系受累，这对BCR::ABL1 MRD的意义提出了质疑。我们旨在明确BCR::ABL1或淋巴细胞特异性免疫球蛋白/细胞受体（IG/TR）基因标记物评估的MRD的预后作用：在GRAAPH-2014试验中，我们对264名患者在每个治疗周期后进行了BCR::ABL1和IG/TR定量分析，该试验使用尼洛替尼进行了四个周期的减毒化疗，随后进行了造血干细胞移植（HSCT）：比较BCR::ABL1和IG/TR MRD发现，228例患者中有98例（43%）残留BCR::ABL1阳性的非ALL细胞，定义为多系Ph+ ALL。尽管BCR::ABL1反应较差，但多系Ph+ ALL患者的无病生存期（DFS；危险比[HR]，0.83[95% CI，0.49至1.41]；P = .50）相似。虽然BCR::ABL1反应不能预测结果，但IG/TR阳性（≥0.01%）与较低的DFS密切相关（第2周期后，HR，2.49 [95% CI，1.40至4.40]；P = .002；第4周期后，HR，4.13 [95% CI，1.82至9.38]；P = .001）。在多变量分析中，第2周期后IG/TR阳性和初始白细胞计数≥30×109/L都预示着较差的DFS，从而确定了一个高危组别，其4年DFS为56.5%，而对照组为87.6%（HR，3.72 [95% CI，1.93至7.15]；P < .001）。此外，异基因造血干细胞移植能显著改善高风险组的 DFS（HR，0.33 [95% CI，0.18 至 0.60]；P <.001），而标准风险组无论是否进行异基因造血干细胞移植都能获得良好的结果：我们的研究结果对成人 Ph+ ALL 中 BCR::ABL1 监测的重要性提出了质疑，并证明了 IG/TR MRD 的预后作用。这项研究为使用MRD指导成人Ph+ ALL的治疗策略提供了一个框架。

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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来源期刊

Journal of Clinical Oncology 医学-肿瘤学

CiteScore

41.20

自引率

2.20%

发文量

8215

审稿时长

2 months

期刊介绍： The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.