Tembhare Prashant R, Narula Gaurav, Khanka Twinkle, Ghogale Sitaram, Chatterjee Gaurav, Patkar Nikhil V, Prasad Maya, Badrinath Yajamanam, Deshpande Nilesh, Gudapati Pratyusha, Verma Shefali, Sanyal Mahima, Kunjachan Florence, Mangang Gunit, Gujral Sumeet, Banavali Shripad, Subramanian Papagudi G
Hematopathology Laboratory, ACTREC, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India.
Department of Pediatric Oncology, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India.
Front Oncol. 2020 Apr 24;10:577. doi: 10.3389/fonc.2020.00577. eCollection 2020.
Measurable/minimal residual disease (MRD) status is suggested as a powerful indicator of clinical-outcome in T-cell lymphoblastic leukemia/lymphoma (T-ALL). Contrary to B-cell ALL, reports on T-ALL MRD are limited and mostly based on molecular methods, mainly from developed countries. Multicolor flow cytometry (MFC)-based T-ALL studies are very few. Clinically relevant cut-off levels and ideal time-point for MRD assessment are still inconclusive. In view of lack of T-ALL MRD data from the developing world, we evaluated the prognostic value of MFC-based post-induction (PI)-MRD assessment in T-ALL in the context of standard practice. We included 256 childhood-T-ALL patients (age < 15 years) treated with a modified-MCP841 protocol, which uses high-dose cytarabine during consolidation, as a part of standard hospital practice. MRD was studied using 10-color 11-antibody MFC with any level of detectable disease being considered positive. Post-induction (PI)-MRD was available in all patients, and post-consolidation (PC) MRD was available mostly in PI-MRD-positive patients ( = 88). Three years cumulative-incidence-of-relapse (3years-CIR) in PI-MRD-positive patients was inferior to negative patients (46.3% vs. 18.4%). The median relapse-free-survival (RFS), event-free-survival (EFS) and overall-survival (OS) with hazard ratio (HR) of PI-MRD-positive patients were 21.4 months vs not reached ( < 0.0001, HR-4.7), 21.6 months vs. not-reached ( = 0.0003, HR-2.01) and 37.3 months vs. not reached ( = 0.026, HR-1.64) respectively. RFS, EFS and OS of patients with PI-MRD<0.01% ( = 17) were as inferior as PI-MRD ≥ 0.01% in comparison with MRD-negative patients with HR of 4.7 ( < 0.0001), 2.45 ( = 0.0003), and 2.5 ( = 0.029), respectively. Three-years-CIR of patients with hyperleukocytosis (≥100 × 109/L) was also higher (50.5 vs. 27.6%) with inferior RFS, EFS, and OS. Among PI-MRD-positive patients, 3years-CIR, RFS, EFS, and OS of PC-MRD-positive were also inferior to that of negative patients. On multivariate analysis any-level detectable PI-MRD and hyperleukocytosis remained independently associated with inferior RFS, EFS, and OS. A combination of PI-MRD-positive status and hyperleukocytosis identified the patients with the worst clinical outcomes. Detectable PI-MRD using MFC was found to be the strong predictive factor of inferior clinical outcome in T-ALL patients. The combination of PI-MRD status and hyperleukocytosis provides the most influential tool for the management of T-ALL in resource constrained settings from developing world.
可测量/微小残留病（MRD）状态被认为是T细胞淋巴母细胞白血病/淋巴瘤（T-ALL）临床结局的有力指标。与B细胞急性淋巴细胞白血病相反，关于T-ALL MRD的报告有限，且大多基于分子方法，主要来自发达国家。基于多色流式细胞术（MFC）的T-ALL研究非常少。MRD评估的临床相关临界值水平和理想时间点仍无定论。鉴于发展中国家缺乏T-ALL MRD数据，我们在标准治疗背景下评估了基于MFC的诱导后（PI）-MRD评估在T-ALL中的预后价值。我们纳入了256例接受改良MCP841方案治疗的儿童T-ALL患者（年龄<15岁），该方案在巩固期使用高剂量阿糖胞苷，作为标准医院治疗的一部分。使用10色11抗体MFC研究MRD，任何可检测到的疾病水平均被视为阳性。所有患者均有诱导后（PI）-MRD数据，巩固后（PC）MRD数据大多见于PI-MRD阳性患者（n = 88）。PI-MRD阳性患者的三年累积复发率（3年-CIR）低于阴性患者（46.3%对18.4%）。PI-MRD阳性患者的无复发生存期（RFS）、无事件生存期（EFS）和总生存期（OS）的中位数及风险比（HR）分别为21.4个月对未达到（P<0.0001，HR-4.7）、21.6个月对未达到（P = 0.0003，HR-2.01）和37.3个月对未达到（P = 0.026，HR-1.64）。与MRD阴性患者相比，PI-MRD<0.01%（n = 17）患者的RFS、EFS和OS同样较差，HR分别为4.7（P<0.0001）、2.45（P = 0.0003）和2.5（P = 0.029）。白细胞增多症（≥100×10⁹/L）患者的三年累积复发率也更高（50.5%对27.6%），RFS、EFS和OS较差。在PI-MRD阳性患者中，PC-MRD阳性患者的3年-CIR、RFS、EFS和OS也低于阴性患者。多因素分析显示，任何可检测到的PI-MRD水平和白细胞增多症仍与较差的RFS、EFS和OS独立相关。PI-MRD阳性状态和白细胞增多症的组合确定了临床结局最差的患者。发现使用MFC检测到的PI-MRD是T-ALL患者临床结局较差的强有力预测因素。PI-MRD状态和白细胞增多症的组合为发展中国家资源受限环境下的T-ALL管理提供了最具影响力的工具。
