Naqvi Kiran, Cortes Jorge E, Luthra Raja, O'Brien Susan, Wierda William, Borthakur Gautam, Kadia Tapan, Garcia-Manero Guillermo, Ravandi Farhad, Rios Mary Beth, Dellasala Sara, Pierce Sherry, Jabbour Elias, Patel Keyur, Kantarjian Hagop
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
Int J Hematol. 2018 Jun;107(6):689-695. doi: 10.1007/s12185-018-2422-6. Epub 2018 Feb 20.
Kinase domain (KD) mutations of ABL1 represent the most common resistance mechanism to tyrosine kinase inhibitors (TKI) in CML. Besides T315I, mutations in codon 255 are highly resistant mutations in vitro to all TKI. We aimed to study the incidence, prognosis, and response to treatment in patients with E255K/V. We evaluated 976 patients by sequencing of BCR-ABL1 fusion transcript for ABL1 KD mutations. We identified KD mutations in 381 (39%) patients, including E255K/V in 48 (13% of all mutations). At mutation detection, 14 patients (29%) were in chronic phase (CP), 12 (25%) in accelerated phase (AP), and 22 (46%) in blast phase (BP). 9/14 CP patients responded to treatment (best response complete hematologic response-CHR-4; complete cytogenetic response-CCyR-1; major molecular response-MMR-4); only 4/12 AP patients (CHR 3; MMR 1) and 7/22 BP patients responded (CCyR 2; MMR 2; partial cytogenetic response-PCyR-3). After a median follow-up of 65 months from mutation detection, 36 patients (75%) died: 9/14 (64%) in CP, 9/12 (75%) in AP, and 18/22 (82%) in BP (p = 0.003); median overall survival was 12 months. Patients with E255K/V mutation have a poor prognosis, regardless of the stage of the disease at detection.
ABL1激酶结构域（KD）突变是慢性粒细胞白血病（CML）中对酪氨酸激酶抑制剂（TKI）最常见的耐药机制。除T315I外，密码子255处的突变在体外对所有TKI均具有高度耐药性。我们旨在研究E255K/V患者的发病率、预后及治疗反应。我们通过对BCR-ABL1融合转录本进行测序来评估976例患者的ABL1 KD突变情况。我们在381例（39%）患者中检测到KD突变，其中E255K/V突变有48例（占所有突变的13%）。在检测到突变时，14例（29%）患者处于慢性期（CP），12例（25%）处于加速期（AP），22例（46%）处于急变期（BP）。14例CP患者中有9例对治疗有反应（最佳反应：完全血液学缓解-CHR-4例；完全细胞遗传学缓解-CCyR-1例；主要分子学缓解-MMR-4例）；12例AP患者中只有4例（CHR 3例；MMR 1例）有反应，22例BP患者中有7例有反应（CCyR 2例；MMR 2例；部分细胞遗传学缓解-PCyR-3例）。从检测到突变起，经过中位65个月的随访，36例（75%）患者死亡：CP期9/14例（64%），AP期9/12例（75%），BP期18/22例（82%）（p = 0.003）；中位总生存期为12个月。无论检测时疾病处于何阶段，E255K/V突变患者的预后均较差。
