Clinical and molecular genetic characteristics of B-cell acute lymphoblastic leukemia with PAX5 P80R
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摘要: 目的 分析伴PAX5 P80R突变的急性B淋巴细胞白血病(B-ALL)的临床和分子遗传学特征，探索该亚型患者治疗方案与预后的关系。方法 回顾性研究2019年9月—2024年11月苏州大学附属第一医院和苏州弘慈血液病医院收治的B-ALL患者中，伴PAX5 P80R突变患者的临床资料。结果 936例B-ALL患者中，10例(1.1%)伴PAX5 P80R。其中，男性占80%，初诊中位年龄为35.5(14.0~59.0)岁。10例患者均表达CD10、CD19，其中7例患者还表达CD34和CD38。4例患者合并染色体异常，所有患者融合基因均阴性。7例患者合并22个共突变，其中NRAS最为常见(5/7)。异常核型患者伴有2个以上共突变比例明显高于正常核型患者(100.0% vs 16.6%，P=0.02)。经过基于VP(长春地辛+地塞米松)方案的多药联合诱导化疗后，10例患者均达到形态学完全缓解(CR)，其中5例(50%)流式微小残留病(MFC-MRD)阴性(< 0.01%)；巩固治疗期间，4例在CR1期间行异基因造血干细胞移植(allo-HSCT)的患者存活，3例患者化疗期间出现复发(2例死亡，1例经移植、嵌合抗原受体T细胞治疗后存活)，2例化疗患者无复发生存[1例儿童患者已完成中国儿童白血病协作组-2015化疗方案(CCCG-ALL-2015)，1例拟行allo-HSCT]，其余1例患者失访。中位随访时间42(2~63)个月，5年总生存率(OS)及无复发生存率(PFS)分别为75%(95%CI 0.153~0.503)和62.5%(95%CI 0.171~0.365)，中位OS和PFS均未达到。结论 PAX5 P80R突变的B-ALL对诱导化疗敏感，总体预后良好，但合并其他高危遗传学异常对预后的影响有待进一步探索。Abstract: Objective To analyze the clinical and molecular genetic features of B-cell acute lymphoblastic leukemia(B-ALL) with PAX5 P80R and explore the correlation between treatment approaches and clinical outcomes.Methods A retrospective study was conducted on clinical data of B-ALL patients with PAX5 P80R mutation admitted to the First Affiliated Hospital of Soochow University and Soochow Hopes Hematology Hospital from September 2019 to November 2024.Results In a cohort of 936 patients diagnosed with B-ALL, 10 cases(1.1%) were identified PAX5 P80R mutation. Among these cases, 80% were male, with a median age of 35.5 years at diagnosis(range 14-59 years). All 10 patients expressed CD10 and CD19, with 7 of them also expressing CD34 and CD38. Four patients had chromosomal abnormalities, while all patients tested negative for fusion genes. Seven patients had 22 co-mutations, with NRAS being the most common(5/7). The proportion of patients with more than two co-mutations was significantly higher in those with abnormal karyotypes compared to those with normal karyotypes(100.0% vs 16.6%, P=0.02). Following induction chemotherapy based with VP regimen, all patients achieved complete remission(CR), with a 50% rate of minimal residual disease(MRD) negativity by flow cytometry. During consolidation therapy, 4 patients underwent allogeneic hematopoietic stem cell transplantation(allo-HSCT) in CR1. Of the remaining patients, 3 experienced relapse(2 deaths, 1 survived after allo-HSCT and chimeric antigen receptor T cell therapy), while 2 were still alive without recurrence(1 pediatric patient completed the CCCG-ALL-2015 protocol, and 1 was planning for allo-HSCT). One patient was lost to follow-up. The median follow-up was 42 months(range 2-63 months), with 5-year overall survival(OS) and progression-free survival(PFS) rates of 75%(95%CI 0.153-0.503) and 62.5%(95%CI 0.171-0.365), respectively. The median OS and PFS were not reached.Conclusion B-ALL with PAX5 P80R shows positive responses to induction chemotherapy, with an overall good prognosis. However, the impact of concomitant high-risk genetic abnormalities on prognosis remains to be further explored.
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表 1 10例伴PAX5 P80R阳性B-ALL患者的临床特征
例号 年龄 性别 临床表现 白细胞计数/(×109/L) 骨髓原始细胞比例/% 免疫表型 染色体核型 RT-PCR RNA-seq 伴随突变 1 14 男 胸闷，皮肤瘀点 42.30 94.0 CD34、CD10、CD19 46，XY 阴性 未做 无 2 59 男 乏力 48.54 41.5 CD34、CD10、CD19、CD38、CD22 46，XY 阴性 未做 NRAS 3 18 女 皮肤瘀点 30.68 94.0 CD10、CD19、CD38、CD34 46，XX，t(7；18)(p11；q23)[11]/46，XX[2] 阴性 阴性 NRAS、KMT2D、SOS1 4 43 男 腹痛 3.78 63.0 CD22、CD10、CD19、CD34、 46，XY 阴性 未做 KRAS 5 18 男 头晕乏力 11.21 80.0 CD34、DR、CD10、CD19、CD38 46，XY 阴性 未做 无 6 29 女 皮肤瘀点、瘀斑伴牙龈出血 26.23 87.0 CD34、DR、CD10、CD19、CD38 44，XX，-7，-9，20q-[9]/46，XX[1] 阴性 阴性 DNMT3A、ETV6、NF1、PTPN11、IL7R 7 52 男 体检发现血小板减少 10.73 80.0 CD10、CD19、CD38 45，XY，dic(7；9)(q10；q10)[10] 阴性 未做 NRAS、KRAS、CCND3、CREBBP 8 36 男 头晕，牙龈肿胀 17.70 95.5 CD10、CD19、CD38、CD20 46，XY 阴性 阴性 无 9 35 男 发热 10.21 92.5 CD34、DR、CD10、CD19、CD38 34-46，XY，-1，-2，-4，-5，-6，-8，-9，-10，-12，-12，-14，-15，-17，+18，-19，-20，-22[10] 阴性 未做 NRAS、KMT2D、GNAI2 10 58 男 发热伴乏力 41.00 83.5 CD10、CD19、CD22 46，XY 阴性 阴性 TP53、FLT3、PTPN11、NRAS、KRAS 注：RNA-seq：转录组测序。 
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表 2 10例伴PAX5 P80R阳性B-ALL患者的治疗、疗效及生存情况
例号 诱导化疗方案/疗效/流式MRD 巩固化疗方案/疗效 复发 再诱导化疗方案/疗效 移植 生存情况
(死亡原因)OS期/月 1 IVLP/CR/ < 3.4×10-4 CCCG-ALL-2015/CR 否 否 否 存活 63.0 2 IVLP/CR/1.20% Hyper-CVAD-B/A/B/CR；VP/复发 是 Hyper-CVAD-B/NR；FC/死亡 否 死亡
(多脏器功能衰竭)10.0 3 IVP/CR/ < 7.5×10-5 Hyper-CVAD-B/MD-MTX/CR 否 否 是(CR1) 存活 54.0 4 IVP /CR/ < 9.4×10-5 MD-MTX/IVP/CR 否 否 是(CR1) 存活 52.0 5 IVP/CR/9.0×10-5 MD-MTX/IVP/CR 否 否 是(CR1) 存活 46.0 6 IVP/CR/ < 3.2×10-4 MD-MTX+PEG-Asp/CR；MD-MTX/CNSL；Hyper-CVAD-A/复发 是 CDA+Ara-C+Vp16+Ven/NR；Blincyto/NR；CD19 CAR-T/NR 否 死亡
(感染)13.0 7 IVP/CR/ < 1.0×10-4 MD-Ara-C+IVP/CR 否 否 是(CR1) 存活 43.0 8 VDP/CR/7×10-5 VP/复发 是 EA/NR；VDCPP/CR2；Hyper-CVAD-B/CR2；移植后60 d复发，FC+ HD-MTX/CR3；AZA/复发；CD19/CD22 CAR-T(供体来源)/CR4 是(CR2) 存活 40.0 9 IVP+Blincyto/CR/6.4×10-4 失访 失访 失访 失访 失访 失访 10 IVP+Blincyto/CR/ < 1.8×10-4 Hyper-CVAD-A/CR 否 否 拟移植 存活 2.0 注：IVLP：伊达比星+长春地辛+培门冬酶+地塞米松；FC：氟达拉滨+环磷酰胺；IVP：伊达比星+长春地辛+地塞米松；CDA：克拉曲滨；Vp16：依托泊苷；Ven：维奈克拉；MD-Ara-C：中剂量阿糖胞苷；VDP：长春地辛+柔红霉素+地塞米松；EA：依托泊苷+阿糖胞苷；VDCPP：长春地辛+柔红霉素+环磷酰胺+培门冬酶+地塞米松；HD-MTX：高剂量甲氨蝶呤；AZA：阿扎胞苷。
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