Roberts Kathryn G, Gu Zhaohui, Payne-Turner Debbie, McCastlain Kelly, Harvey Richard C, Chen I-Ming, Pei Deqing, Iacobucci Ilaria, Valentine Marcus, Pounds Stanley B, Shi Lei, Li Yongjin, Zhang Jinghui, Cheng Cheng, Rambaldi Alessandro, Tosi Manuela, Spinelli Orietta, Radich Jerald P, Minden Mark D, Rowe Jacob M, Luger Selina, Litzow Mark R, Tallman Martin S, Wiernik Peter H, Bhatia Ravi, Aldoss Ibrahim, Kohlschmidt Jessica, Mrózek Krzysztof, Marcucci Guido, Bloomfield Clara D, Stock Wendy, Kornblau Stephen, Kantarjian Hagop M, Konopleva Marina, Paietta Elisabeth, Willman Cheryl L, Mullighan Charles G
Kathryn G. Roberts, Zhaohui Gu, Debbie Payne-Turner, Kelly McCastlain, Deqing Pei, Ilaria Iacobucci, Marcus Valentine, Stanley B. Pounds, Lei Shi, Yongjin Li, Jinghui Zhang, Cheng Cheng, and Charles G. Mullighan, St Jude Children's Research Hospital, Memphis, TN; Richard C. Harvey, I-Ming Chen, and Cheryl L. Willman, University of New Mexico Cancer Center, Albuquerque, NM; Alessandro Rambaldi, Manuela Tosi, and Orietta Spinelli, Ospedale Papa Giovanni XXIII, Bergamo, Italy; Jerald P. Radich, Fred Hutchinson Cancer Research Center, Seattle, WA; Mark D. Minden, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Jacob M. Rowe, Shaare Zedek Medical Center, Jerusalem, Israel; Selina Luger, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Mark R. Litzow, Mayo Clinic, Rochester, MN; Martin S. Tallman, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York; Peter H. Wiernik, Cancer Research Foundation of New York; Elisabeth Paietta, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Ravi Bhatia, The University of Alabama at Birmingham, Birmingham, AL; Ibrahim Aldoss and Guido Marcucci, City of Hope, Duarte, CA; Jessica Kohlschmidt, Krzysztof Mrózek, and Clara D. Bloomfield, Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Wendy Stock, University of Chicago Medical Center, Chicago, IL; and Stephen Kornblau, Hagop M. Kantarjian, and Marina Konopleva, The University of Texas MD Anderson Cancer Center, Houston, TX.
J Clin Oncol. 2017 Feb;35(4):394-401. doi: 10.1200/JCO.2016.69.0073. Epub 2016 Nov 21.
Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non-Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.
目的 费城染色体（Ph）样急性淋巴细胞白血病（ALL）是儿童ALL的一种高危亚型，其特征为激酶激活改变，可用酪氨酸激酶抑制剂治疗。我们试图确定成人Ph样ALL的患病率和基因组格局，并评估其对传统化疗的反应。
患者与方法 通过对798例年龄在21至86岁的B细胞ALL患者进行基因表达谱分析，评估Ph样ALL的频率。确定Ph样ALL患者与非Ph样ALL患者的无事件生存期和总生存期。对194例Ph样ALL患者中的180例进行了详细的基因组分析。
结果 Ph样ALL患者占成人ALL患者的20%以上，其中年轻成人（21至39岁）占27.9%，成人（40至59岁）占20.4%，老年人（60至86岁）占24.0%。总体而言，Ph样ALL患者的5年无事件生存期低于非Ph样ALL患者（分别为22.5%[95%CI，14.9%至29.3%；n = 155]和49.3%[95%CI，42.8%至56.2%；n = 247]；P <.001）。我们在88%的Ph样ALL患者中发现了激酶激活改变，包括CRLF2重排（51%）、ABL类融合（9.8%）、JAK2或EPOR重排（12.4%）、其他JAK-STAT序列突变（7.2%）、其他激酶改变（4.1%）和Ras途径突变（3.6%）。鉴定出11种新的激酶重排，包括4种涉及新的激酶或细胞因子受体基因，7种涉及先前鉴定基因的新伙伴。
结论 Ph样ALL是成人ALL中高度流行的亚型，且与不良预后相关。Ph样ALL中多种激酶激活改变具有重要的治疗意义。需要进行比较在传统治疗中添加酪氨酸激酶抑制剂的试验，以评估这些药物在治疗Ph样ALL中的临床效用。
