Levis Mark J, Hamadani Mehdi, Logan Brent R, Jones Richard J, Singh Anurag K, Litzow Mark R, Wingard John R, Papadopoulos Esperanza B, Perl Alexander E, Soiffer Robert J, Ustun Celalettin, Oshima Masumi Ueda, Uy Geoffrey L, Waller Edmund K, Vasu Sumithira, Solh Melhem, Mishra Asmita, Muffly Lori S, Kim Hee-Je, Stelljes Matthias, Najima Yuho, Onozawa Masahiro, Thomson Kirsty, Nagler Arnon, Wei Andrew H, Marcucci Guido, Chen Caroline, Hasabou Nahla, Rosales Matt, Hill Jason, Gill Stanley C, Nuthethi Rishita, King Denise, Mendizabal Adam, Devine Steven M, Horowitz Mary M, Chen Yi-Bin
Division of Hematologic Malignancies and Bone Marrow Transplant, Department of Oncology, Johns Hopkins University, Baltimore, MD.
Division of Hematology and Oncology, Department of Medicine, Center for International Blood and Marrow Transplant Research/Medical College of Wisconsin, Milwaukee, WI.
Blood. 2025 May 8;145(19):2138-2148. doi: 10.1182/blood.2024025154.
BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 1506 ("MORPHO") was a randomized study of gilteritinib compared with placebo as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary end point was to determine the impact on survival of before and/or after HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively affected RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared with 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild-type clones (assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multiclonal disease. These data demonstrate the potential of FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML. This trial was registered at www.clinicaltrials.gov as #NCT02997202.
血液与骨髓移植临床试验网络（BMT CTN）1506号研究（“MORPHO”）是一项随机研究，比较了吉瑞替尼与安慰剂作为FLT3-ITD突变的急性髓系白血病（AML）患者造血细胞移植（HCT）后维持治疗的效果。一个关键的次要终点是确定使用高灵敏度FLT3-ITD突变检测方法测定的HCT前后可测量残留病（MRD）对生存的影响。总体而言，吉瑞替尼维持治疗与HCT期间可检测到MRD的参与者无复发生存期（RFS）改善相关，而对于那些未检测到MRD的参与者则无明显益处。我们对数据进行了事后分析，发现用这种方法检测到的MRD水平与RFS和复发风险显著相关，并且任何水平可检测到的MRD都会对RFS产生负面影响。在安慰剂组中，可检测到FLT3-ITD MRD的参与者中有42.2%复发，而未检测到MRD的参与者中这一比例为13.4%。我们发现14.8%的参与者检测到多个FLT3-ITD克隆作为MRD，且无论治疗组如何，其生存情况都较差。最后，我们研究了FLT3-ITD克隆复发或清除的动力学，发现安慰剂组中可检测到MRD的参与者在HCT后很快复发，通常在几周内。吉瑞替尼组中MRD阳性的参与者要么复发为FLT3野生型克隆（通过毛细管电泳评估），要么在吉瑞替尼停药且MRD持续存在后复发，要么在多克隆疾病进展时复发。这些数据证明了FLT3-ITD MRD在指导吉瑞替尼治疗这种AML亚型方面的潜力。该试验已在www.clinicaltrials.gov上注册，编号为#NCT02997202。
