Bødker Julie Støve, Severinsen Marianne Tang, El-Galaly Tarec Christoffer, Brøndum Rasmus Froberg, Laursen Maria Bach, Falgreen Steffen, Nyegaard Mette, Schmitz Alexander, Jakobsen Lasse Hjort, Schönherz Anna Amanda, Due Hanne, Reinholdt Linn, Bøgsted Martin, Dybkær Karen, Johnsen Hans Erik
Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
Department of Hematology, Aalborg University Hospital, Aalborg, Denmark ; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 15, 9000 Aalborg, Denmark.
Exp Hematol Oncol. 2017 Jan 11;6:3. doi: 10.1186/s40164-016-0063-0. eCollection 2017.
The concept of precision medicine in cancer includes individual molecular studies to predict clinical outcomes. In the present N = 1 case we retrospectively have analysed lymphoma tissue by exome sequencing and global gene expression in a patient with unexpected long-term remission following relaps. The goals were to phenotype the diagnostic and relapsed lymphoma tissue and evaluate its pattern. Furthermore, to identify mutations available for targeted therapy and expression of genes to predict specific drug effects by resistance gene signatures (REGS) for R-CHOP as described at http://www.hemaclass.org. We expected that such a study could generate therapeutic information and a frame for future individual evaluation of molecular resistance detected at clinical relapse.
The patient was diagnosed with a transformed high-grade non-Hodgkin lymphoma stage III and treated with conventional R-CHOP [rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisone (P)]. Unfortunately, she suffered from severe toxicity but recovered during the following 6 months' remission until biopsy-verified relapse. The patient refused second-line combination chemotherapy, but accepted 3 months' palliation with R and chlorambucil. Unexpectedly, she obtained continuous complete remission and is at present >9 years after primary diagnosis. Molecular studies and data evaluation by principal component analysis, mutation screening and copy number variations of the primary and relapsed tumor, identified a pattern of branched lymphoma evolution, most likely diverging from an in situ follicular lymphoma. Accordingly, the primary diagnosed transformed lymphoma was classified as a diffuse large B cell lymphoma (DLBCL) of the GCB/centrocytic subtype by "cell of origin BAGS" assignment and R sensitive and C, H, O and P resistant by "drug specific REGS" assignment. The relapsed DLBCL was classified as NC/memory subtype and R, C, H sensitive but O and P resistant.
Thorough analysis of the tumor DNA and RNA documented a branched evolution of the two clinical diagnosed tFL, most likely transformed from an unknown in situ lymphoma. Classification of the malignant tissue for drug-specific resistance did not explain the unexpected long-term remission and potential cure. However, it is tempting to consider the anti-CD20 immunotherapy as the curative intervention in the two independent tumors of this case.
癌症精准医学的概念包括个体分子研究以预测临床结果。在本 N = 1 病例中，我们对一名复发后意外获得长期缓解的患者的淋巴瘤组织进行了外显子组测序和全基因表达的回顾性分析。目标是对诊断性和复发性淋巴瘤组织进行表型分析并评估其模式。此外，识别可用于靶向治疗的突变以及通过 http://www.hemaclass.org 所述的 R-CHOP 耐药基因特征（REGS）预测特定药物效应的基因表达。我们期望这样的研究能够产生治疗信息以及为临床复发时检测到的分子耐药性的未来个体评估提供一个框架。
该患者被诊断为转化型高级别非霍奇金淋巴瘤 III 期，并接受了传统的 R-CHOP [利妥昔单抗（R）、环磷酰胺（C）、阿霉素（H）、长春新碱（O）和泼尼松（P）] 治疗。不幸的是，她出现了严重的毒性反应，但在随后 6 个月的缓解期恢复，直至活检证实复发。患者拒绝二线联合化疗，但接受了 3 个月的 R 和苯丁酸氮芥姑息治疗。出乎意料的是，她获得了持续完全缓解，目前距离初次诊断已超过 9 年。通过主成分分析、突变筛查以及原发和复发肿瘤的拷贝数变异进行分子研究和数据评估，确定了一种分支状淋巴瘤演变模式，很可能源自原位滤泡性淋巴瘤。因此，根据“起源细胞 BAGS”分类，初次诊断的转化型淋巴瘤被归类为 GCB/中心细胞亚型的弥漫性大 B 细胞淋巴瘤（DLBCL），根据“药物特异性 REGS”分类，对 R 敏感而对 C、H、O 和 P 耐药。复发性 DLBCL 被归类为 NC/记忆亚型，对 R、C、H 敏感，但对 O 和 P 耐药。
对肿瘤 DNA 和 RNA 的深入分析记录了两种临床诊断的 tFL 的分支状演变，很可能源自未知的原位淋巴瘤。对恶性组织进行药物特异性耐药分类并不能解释意外的长期缓解和潜在治愈情况。然而，将抗 CD20 免疫疗法视为该病例中两个独立肿瘤的治愈性干预措施颇具吸引力。
