西部单中心51例套细胞淋巴瘤患者临床特征及预后因素分析

目的:研究套细胞淋巴瘤（MCL)患者的临床特点及预后相关因素，进一步全面评估病情，探索个体化治疗。方法:回顾性分析2012年1 月至2016年12 月经我院病理科确诊的51例MCL 患者的临床特点、住院20例患者的预后分层和不同化疗方案的近期及远期疗效，并进行随访观察。结果:20例住院治疗患者中，R-Hyper-CVAD组及R-CHOP样组的ORR（分别为100%、100%）均高于其未联合美罗华组（分别为50%、40%）；MIPI评分中，低危组ORR为75.0%，明显高于中危组（16.6%）；CD5-患者CR、PR均高于CD5+患者；Ki67≥30%患者CR率（20%）大于Ki67＜30%组（11%），PR率则相反；Ki67＜30%患者3年OS明显高于Ki67≥30%患者，有统计学差异，而PFS无统计学差异；MIPI分组中，低危组3年OS明显高于中高危组，有统计学差异，PFS无统计学差异；美罗华组无论OS还是PFS均高于非美罗华组；Hyper-CVAD组与非Hyper-CVAD组OS、PFS均无统计学差异。结论:美罗华联合化疗治疗MCL的疗效是肯定的，绝大多数患者能够耐受减低剂量的Hyper-CVAD A及B方案化疗，但统计学显示与非Hyper-CVAD组无明显差异，可能与病例数偏少相关，需要更多大样本的循证医学的支持。     

靶向药物治疗套细胞淋巴瘤的研究进展

套细胞淋巴瘤(MCL)是一种少见的非霍奇金淋巴瘤亚型.MCL临床表现有两种类型:一种为惰性表现,病情进展缓慢;另一种为侵袭性表现,病程进展迅速.近年,一些用于MCL治疗的新靶向药物已经问世.这些靶向药物较常规化疗提高了对复发/难治性MCL的疗效,其治疗MCL的靶点为B细胞淋巴瘤表面抗原、B细胞受体信号和肿瘤细胞微环境等.文章介绍了MCL靶向药物的研究进展.     

Combined inhibition of Chk1 and Wee1 as a new therapeutic strategy for mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive, incurable disease, characterized by a deregulated cell cycle. Chk1 and Wee1 are main regulators of cell cycle progression and recent data on solid tumors suggest that simultaneous inhibition of these proteins has a strong synergistic cytotoxic effect. The effects of a Chk1 inhibitor (PF-00477736) and a Wee1 inhibitor (MK-1775) have been herein investigated in a large panel of mature B-cell lymphoma cell lines. We found that MCL cells were the most sensitive to the Chk1 inhibitor PF-00477736 and Wee1 inhibitor MK-1775 as single agents. Possible involvement of the translocation t(11;14) in Chk1 inhibitor sensitivity was hypothesized. The combined inhibition of Chk1 and Wee1 was strongly synergistic in MCL cells, leading to deregulation of the cell cycle, with increased activity of CDK2 and CDK1, and activation of apoptosis. In vivo treatment with the drug combination of mice bearing JeKo-1 xenografts (MCL) had a marked antitumor effect with tumor regressions observed at non-toxic doses (best T/C%=0.54%). Gene expression profiling suggested effect on genes involved in apoptosis. The strong synergism observed by combining Chk1 and Wee1 inhibitors in preclinical models of MCL provides the rationale for testing this combination in the clinical setting.     

Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma

The aggressive biological behavior of mantle cell lymphoma (MCL) and its short response to current treatment highlight a great need for better rational therapy. Herein, we investigate the ability of ABT-199, the Bcl-2-selective BH3 mimetic, to kill MCL cells. Among MCL cell lines tested (n = 8), only three were sensitive (LD₅₀ < 200 nM). In contrast, all primary MCL samples tested (n = 11) were highly sensitive to ABT-199 (LD₅₀ < 10 nM). Mcl-1 and Bcl-x_L both confer resistance to ABT-199-specific killing and BCL2/(BCLXL + MCL1) mRNA ratio is a strong predictor of sensitivity. By mimicking the microenvironment through CD40 stimulation, we show that ABT-199 sensitivity is impaired through activation of NF-kB pathway and Bcl-x_L up-regulation. We further demonstrate that resistance is rapidly lost when MCL cells detach from CD40L-expressing fibroblasts. It has been reported that ibrutinib induces lymphocytosis in vivo holding off malignant cells from their protective microenvironment. We show here for two patients undergoing ibrutinib therapy that mobilized MCL cells are highly sensitive to ABT-199. These results provide evidence that in situ ABT-199 resistance can be overcome when MCL cells escape from the lymph nodes. Altogether, our data support the clinical application of ABT-199 therapy both as a single agent and in sequential combination with BTK inhibitors.     

Inhibition of Lyn is a promising treatment for mantle cell lymphoma with bortezomib resistance

Although proteasome inhibition with bortezomib (BTZ) is a validated treatment for relapsed or refractory mantle cell lymphoma (MCL), many patients show resistance to BTZ. However, the molecular mechanism of BTZ resistance in MCL has not been elucidated. In the present study, we investigated BTZ-resistant MCL cells in vitro and in vivo. We demonstrate that BTZ-resistant MCL cells showed highly increased expression of the B-cell receptor (BCR) components CD79A and CD19. Activation of the BCR signaling pathway enhanced the activity of Src family kinases (SFKs), especially Lyn, and downstream kinases PI3K/AKT/mTOR in BTZ-resistant MCL cells. Depletion of CD79A and Lyn significantly reduced several kinase activities involved in PI3K signaling, leading to inhibition of proliferation. In addition, the SFKs inhibitor dasatinib inhibited the proliferation of BTZ-resistant cells, preventing the binding of CD19 with Lyn and PI3K p85. We also verified our findings with the mouse xenograft tumor model. Dasatinib treatment significantly decreased tumor size in the mouse bearing BTZ-resistant MCL cells, but not in the mouse bearing BTZ-sensitive MCL cells. Collectively, our data show that overexpression of the BCR and its activated signaling confers BTZ resistance in MCL cells. Thus, targeting BCR signaling with dasatinib could be a novel therapeutic approach for patients with MCL that has relapsed or is refractory to treatment with BTZ.     

Urinary tract involvement of mantle cell lymphoma diagnosed by urine cytology

Urinary tract lymphoma is unusual, with the kidney being the most commonly reported site of involvement. Urinary bladder involvement by lymphoma is rare. Mantle cell lymphoma (MCL) is a relatively uncommon type of lymphoma. Herein, we report a case of MCL of the urinary bladder diagnosed by urine cytology, with confirmatory immunocytochemical stains, which has not previously been reported in the literature.     

RB but not R‐HCVAD is a feasible induction regimen prior to auto‐HCT in frontline MCL: results of SWOG Study S1106

Aggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto‐HCT ) is effective for younger patients with mantle cell lymphoma (MCL ). However, the optimal induction regimen is widely debated. The Southwestern Oncology Group S1106 trial was designed to assess rituximab plus hyperCVAD /MTX /ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) (RH ) versus rituximab plus bendamustine (RB ) in a randomized phase II trial to select a pre‐transplant induction regimen for future development. Patients had previously untreated stage III , IV , or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB , followed by auto‐HCT . Fifty‐three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2‐year progression‐free survival (PFS ) was 81% vs. 82% and overall survival (OS ) was 87% vs. 88% for RB and RH , respectively. RH is not an ideal platform for future multi‐centre transplant trials in MCL . RB achieved a 2‐year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL .