De Benedittis Caterina, Papayannidis Cristina, Venturi Claudia, Abbenante Maria Chiara, Paolini Stefania, Parisi Sarah, Sartor Chiara, Cavo Michele, Martinelli Giovanni, Soverini Simona
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Via Massarenti, 9-40138, Bologna, Italy.
BMC Cancer. 2017 Aug 5;17(1):523. doi: 10.1186/s12885-017-3511-2.
The treatment of Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) patients who harbor the T315I BCR-ABL1 mutation or who have two or more mutations in the same BCR-ABL1 molecule is particularly challenging since first and second-generation Tyrosine Kinase Inhibitors (TKIs) are ineffective. Ponatinib, blinatumomab, chemotherapy and transplant are the currently available options in these cases.
We here report the case of a young Ph+ ALL patient who relapsed on front-line dasatinib therapy because of two independent T315I-positive subclones, resulting from different nucleotide substitutions -one of whom never reported previously- and where additional mutant clones outgrew and persisted despite ponatinib, transplant, blinatumomab and conventional chemotherapy. Deep Sequencing (DS) was used to dissect the complexity of BCR-ABL1 kinase domain (KD) mutation status and follow the kinetics of different mutant clones across the sequential therapeutic approaches.
This case presents several peculiar and remarkable aspects: i) distinct clones may acquire the same amino acid substitution via different nucleotide changes; ii) the T315I mutation may arise also from an 'act' to 'atc' codon change; iii) the strategy of temporarily replacing TKI therapy with chemo or immunotherapy, in order to remove the selective pressure and deselect aggressive mutant clones, cannot always be expected to be effective; iv) BCR-ABL1-mutated sub-clones may persist at very low levels (undetectable even by Deep Sequencing) for long time and then outcompete BCR-ABL1-unmutated ones becoming dominant even in the absence of any TKI selective pressure.
对于携带T315I BCR-ABL1突变或在同一BCR-ABL1分子中有两个或更多突变的费城染色体阳性急性淋巴细胞白血病（Ph+ ALL）患者，其治疗极具挑战性，因为第一代和第二代酪氨酸激酶抑制剂（TKIs）均无效。波纳替尼、博纳吐单抗、化疗和移植是这些情况下目前可用的治疗选择。
我们在此报告一名年轻的Ph+ ALL患者的病例，该患者因两个独立的T315I阳性亚克隆导致一线达沙替尼治疗失败而复发，这两个亚克隆由不同的核苷酸替换产生——其中一个此前从未报道过——并且尽管接受了波纳替尼、移植、博纳吐单抗和传统化疗，额外的突变克隆仍生长并持续存在。深度测序（DS）用于剖析BCR-ABL1激酶结构域（KD）突变状态的复杂性，并跟踪不同突变克隆在连续治疗方法中的动力学变化。
该病例呈现出几个独特且显著的方面：i）不同的克隆可能通过不同的核苷酸变化获得相同的氨基酸替换；ii）T315I突变也可能由“act”到“atc”密码子的变化引起；iii）用化疗或免疫疗法暂时替代TKI治疗以消除选择性压力并淘汰侵袭性突变克隆的策略，并非总能有效；iv）BCR-ABL1突变的亚克隆可能长时间以极低水平持续存在（即使通过深度测序也检测不到），然后在没有任何TKI选择性压力的情况下超过BCR-ABL1未突变的亚克隆并成为主导。
