Ruxolitinib in Combination with Orally Etoposide and Corticosteroids (REC) Is Safe and Effective in Heavily Pretreated Hodgkin and Non-Hodgkin Lymphomas
Ruxolitinib in Combination with Orally Etoposide and Corticosteroids (REC) Is Safe and Effective in Heavily Pretreated Hodgkin and Non-Hodgkin Lymphomas
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鲁索替尼联合口服依托泊苷和皮质类固醇 (REC) 对经过大量预处理的霍奇金淋巴瘤和非霍奇金淋巴瘤安全有效
DOI：
10.1182/blood.v126.23.3962.3962
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
J. Marolleau
中科院分区：
文献类型：
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作者：
Anne Parcelier;P. Morel;B. Royer;C. Delette;I. Leduc;H. Sevestre;J. Marolleau
目的在霍奇金淋巴瘤（HL）和原发性纵隔大B细胞淋巴瘤（PMBL）中JAK/STAT通路失调（Scott et al，2015; Younes et al，2014; Shipp et al，2010）。在弥漫性大B细胞淋巴瘤（DLBCL）中，特别是在ABC亚型中，MYD 88基因的LP 265突变通过允许JAK/STAT途径活化的微环境增强IL 6和IL 10分泌。（Gandhi等人，2015年）。JAK 2的过表达刺激DLBCL中STAT 3和PMBL中STAT 6的磷酸化，随后激活NF κ B信号传导途径的靶基因。JAK 2的治疗性抑制降低了体外和鼠异种移植模型中淋巴肿瘤的生长。(Hao等，2014年）。尽管Younes等报道了15例接受pacritinib单药治疗的难治性或复发性（R/R）滤泡性或套细胞淋巴瘤患者中有3例出现缓解，但尚无关于ruxolitinib（Jakavi®）（首个获批的JAK 1/JAK 2抑制剂）在淋巴瘤患者中作用的数据。在这里，我们报告的效果和安全性的口服联合连续鲁索替尼，依托泊苷和皮质类固醇的患者与R/R淋巴瘤。患者和方法自2014年12月起，对6例（DLBCL：4例，HL：1例，浆母细胞性淋巴瘤：1例）难治/复发DLBCL、HL或浆母细胞性淋巴瘤患者每日给予鲁索利替尼10 mg × 2或5 mg × 2（以防止中性粒细胞减少）。所有患者在开始REC之前都有疾病进展。中位年龄为57.5岁（范围30-87）。DLBCL表型为非老年中心（non-GC）2例，老年中心（GC）1例。1例患者接受了自体干细胞移植（ASCT），1例接受了同种异体干细胞移植（HSCT）; 3个月后，他出现了严重的巨噬细胞激活综合征（MAS）。中位既往治疗为5（范围1-12）。6例患者中有4例缓解：1例部分缓解（PR）和3例疾病稳定（SD）（包括MAS控制3个月）。2例患者发生疾病进展（PD）。无进展生存期（PFS）为82.5天（范围30-129天）。未报告副作用，仅住院1天进行输血（表1）。免疫组化显示pSTAT 3和pSTAT 5在肿瘤细胞上表达，但在微环境中不表达。与pSTAT 5的表达（范围0-50%）相比，pSTAT 3的表达水平（范围0-70%）更高;两者均不能预测治疗反应。（表1）结论REC是据我们所知的第一个在R/R淋巴瘤患者中报告的与Ruxolitinib口服组合。前6例预后不良的淋巴瘤患者已达到疾病稳定或PR，无毒性反应。这项正在进行的试验的这些初步结果表明，Ruxolitinib联合化疗可能是R/R HL或DLBCL淋巴瘤患者的一种有前途的方法。JAK/STAT“特征”的生物学分析，包括pSTAT 3和pSTAT 5的表达以及MYD 88和SOCS-1等激活基因的突变，将在ASH会议上发表。没有相关的利益冲突需要申报。
Purpose The JAK/STAT pathway is deregulated in Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBL) (Scott et al, 2015; Younes et al, 2014; Shipp et al, 2010). In Diffuse large B cell lymphoma (DLBCL), especially in ABC subtype, the LP265 mutation of the MYD88 gene enhances IL6 and IL10 secretion by the microenvironment permitting the activation of the JAK/STAT pathway. (Gandhi et al, 2015). The overexpression of JAK2 stimulates the phosphorylation of STAT3 in DLBCL and STAT6 in PMBL with a subsequent activation of target genes of the NFKB signaling pathway. Therapeutic inhibition of JAK2 decreases the growth of lymphoid tumors in vitro and in murine xenograft models. (Hao et al, 2014). Although Younes et al reported response in 3 of 15 patients with refractory or relapsed (R/R) follicular or mantle cell lymphoma who received pacritinib alone, no data are available on the effect of ruxolitinib (Jakavi®), the first approved JAK1/JAK2 inhibitor, in lymphoma patients. Here we report the effect and safety of the oral combination of continuous Ruxolitinib, Etoposide and Corticosteroids in patients with R/R lymphoma. Patients and Methods Since December 2014, patients with multirefractory/relapsed DLBCL, HL or plasmablastic lymphoma received Ruxolitinib 10mg X 2 or 5mg X 2 daily (in case of neutropenia Results Six patients (DLBCL: 4, HL: 1, plasmablastic lymphoma: 1) were treated between December 2014 and May 2015. All patients had a progressive disease before starting REC. Median age was 57,5 years (range 30-87). DLBCL Phenotype was non Germinal Center (non-GC) in 2 patients and Germinal Center (GC) in 1 patient. One patient had received autologous stem cell transplantation (ASCT) and one allogenic (HSCT); 3 months later he developed a severe macrophagic activation syndrome (MAS). Median prior treatment was 5 (range 1-12). Four of six patients had a response: 1 partial response (PR) and 3 stable disease (SD) (including control of MAS for 3 months). Two patients had a disease progression (PD). Progression-free survival (PFS) was 82.5 days (range 30-129). There were no side effects reported and only one day hospitalization for transfusion (Table 1). Immunostaining showed expression of pSTAT3 and pSTAT5 on tumoral cells but not in the microenvironment. There was a higher level of pSTAT3 expression (range 0-70%) compared with expression of pSTAT5 (range 0-50%); both were not predictive of the treatment response. (Table 1) Conclusion REC is the first orally combination with Ruxolitinib reported to our knowledge in R/R lymphoma patients. Stable disease or PR has been achieved without toxicity in the first 6 patients with poor prognosis lymphoma. These preliminary results of this ongoing trial suggest that Ruxolitinib chemotherapy combination may be a promising approach for R/R HL or DLBCL lymphoma patients. Biological analysis of the JAK/STAT "signature" including expression of pSTAT3 and pSTAT5 and mutations of activating genes like MYD 88 and SOCS-1 will be presented at the ASH meeting. Disclosures No relevant conflicts of interest to declare.