Vangsted Annette J, Klausen Tobias W, Gimsing Peter, Andersen Niels F, Abildgaard Niels, Gregersen Henrik, Vogel Ulla
Department of Oncology and Haematology, Roskilde Hospital, Copenhagen University, Køgevej 9-13, Roskilde, Denmark.
Haematologica. 2009 Sep;94(9):1274-81. doi: 10.3324/haematol.2008.004572.
Maintenance therapy with interferon-alpha after high-dose treatment with stem cell support in multiple myeloma has been intensively debated. In this study, we evaluated the response to treatment with interferon-alpha in relation to genetic variation in genes related to inflammation.
In a retrospective study of 296 patients with multiple myeloma undergoing high-dose therapy between 1994 and 2004, 146 patients were treated with interferon-alpha as maintenance therapy. We tested the polymorphisms IL1B T-31C, IL6 G-174C, NFKB1-94ins/delATTG, CD3EAP G-21A and PPP1R13L IVS1 A4364G for associations with time to treatment failure and overall survival with and without interferon-alpha treatment.
The wild type ins-allele of polymorphism NFKB1-94 ins/delATTG was, by multivariate Cox analysis, associated with longer time to treatment failure (p=0.01) and overall survival (p=0.0084) when tested between treatment arms and in the subgroup of patients treated with interferon-alpha the wild type ins-allele was associated with longer overall survival (p=0.002). In the absence of interferon-alpha treatment, there was no association between the polymorphisms and treatment outcome, except for patients homozygous for the wild type G allele of IL6 G-174C who survived longer (p= 0.0074) than variant allele carriers. There was no association between the polymorphisms IL1B T-31C, CD3EAP G-21A and PPP1R13L IVS1 A4364G and treatment outcome for interferon-alpha.
Patients who are homozygous carriers of the wild type ins-allele of the NFKB1 -94ins/delATTG polymorphism may benefit from treatment with interferon-alpha, in contrast to patients carrying the variant allele. This result may indicate that the effect of interferon-alpha treatment is dependent on the availability of nuclear factor-kappaB and the polymorphism in NFKB1 may, therefore, be a good prognostic marker for multiple myeloma patients on maintenance treatment with interferon-alpha after high-dose therapy. A prospective study of interferon-alpha treatment in relation to NFKB1 -94ins/delATTG is highly warranted.
多发性骨髓瘤患者在接受干细胞支持的大剂量治疗后使用α干扰素进行维持治疗一直存在激烈争论。在本研究中，我们评估了与炎症相关基因的遗传变异对α干扰素治疗反应的影响。
对1994年至2004年间接受大剂量治疗的296例多发性骨髓瘤患者进行回顾性研究，其中146例患者接受α干扰素作为维持治疗。我们检测了白细胞介素1B（IL1B）基因T-31C、白细胞介素6（IL6）基因G-174C、核因子κB1（NFKB1）基因-94ins/delATTG、CD3ε相关蛋白（CD3EAP）基因G-21A和蛋白磷酸酶1调节亚基13L（PPP1R13L）基因IVS1 A4364G的多态性与治疗失败时间及总体生存的相关性，包括使用和未使用α干扰素治疗的情况。
通过多变量Cox分析，在不同治疗组间检测时，NFKB1基因-94ins/delATTG多态性的野生型插入等位基因与较长的治疗失败时间（p=0.01）和总体生存时间（p=0.0084）相关；在接受α干扰素治疗的患者亚组中，野生型插入等位基因与较长的总体生存时间相关（p=0.002）。在未使用α干扰素治疗的情况下，除了IL6基因G-174C野生型G等位基因纯合的患者比变异等位基因携带者生存时间更长（p=0.0074）外，多态性与治疗结果之间无关联。IL1B基因T-31C、CD3EAP基因G-21A和PPP1R13L基因IVS1 A4364G的多态性与α干扰素治疗结果之间无关联。
与携带变异等位基因的患者相比，NFKB1基因-94ins/delATTG多态性野生型插入等位基因的纯合携带者可能从α干扰素治疗中获益。这一结果可能表明，α干扰素治疗的效果取决于核因子κB的可用性，因此，NFKB1基因的多态性可能是大剂量治疗后接受α干扰素维持治疗的多发性骨髓瘤患者的一个良好预后标志物。非常有必要对α干扰素治疗与NFKB1基因-94ins/delATTG的关系进行前瞻性研究。
