三氧化二砷联合ICE方案治疗难治性非霍奇金淋巴瘤的效果

目的探讨三氧化二砷联合ICE方案治疗难治性非霍奇金淋巴瘤的临床效果。方法选取2015年3月～2018年6月在我院治疗的难治性非霍奇金淋巴瘤患者88例为观察对象,随机分为对照组和研究组各44例,对照组使用ICE方案进行化疗,研究组在对照组治疗基础上给予三氧化二砷治疗,观察比较两组疗效、不良反应情况以及治疗前后血清乳酸脱氢酶的变化。结果研究组的总有效率为79.5%,显著高于对照组的52.3%,而且治疗后的血清乳酸脱氢酶含量明显低于对照组,组间比较差异均有统计学意义(P0.05);两组不良反应发生率比较,差异无统计学意义(P0.05)。结论三氧化二砷联合ICE方案治疗难治性非霍奇金淋巴瘤的效果较单独使用ICE方案的效果好,可明显降低患者的血清乳酸脱氢酶含量,安全性高。     

国产利妥昔单抗治疗弥漫大B细胞淋巴瘤的疗效及安全性

摘要 目的：探讨弥漫大B细胞淋巴瘤患者采用国产利妥昔单抗为基础的化疗方案的疗效及安全性。方法：回顾性分析2020年3月至2022年5月份在安徽省第二人民医院血液内科诊治的弥漫大B淋巴瘤患者31例,均接受国产利妥昔单抗为基础的联合方案化疗,其中非生发中心来源的弥漫大B细胞淋巴瘤患者25例,生发中心来源的弥漫大B细胞淋巴瘤患者6例。21~28 d为一个疗程,这些患者至少接受2~8个疗程的联合化疗,并且2个疗程以后进行疗效评估及不良反应监测。结果：①本研究31例弥漫大B细胞淋巴瘤患者接受利妥昔单抗为基础的联合化疗方案治疗后,疗效评估为完全缓解CR 16例（51.6%）,部分缓解PR 10例（32.3%）,疾病稳定SD 2例（6.5%）,疾病进展PD 3例（9.7%）,总体反应率ORR 83.9%。②31例弥漫大B细胞淋巴瘤患者接受国产利妥昔单抗治疗后,常见的不良反应发生率依次为：血液学毒性29.0%（9/31）,包括中性粒细胞减少、血小板减少等等。其次为感染19.4%（6/31）、消化道症状16.1%（5/31）,包括腹痛、腹泻、便秘等等。所有常见不良反应经过对症处理后均可好转。仅有1例患者发生过敏反应3.2%（1/31）,1例患者因病情严重而死亡。结论：国产利妥昔单抗在弥漫大B细胞淋巴瘤患者的治疗中具有良好的临床疗效及安全性,不良反应较少,值得进一步探讨和应用。     

Hyper-CVAD/MA治疗复发或难治性弥漫大B 细胞淋巴瘤的临床研究

目的:探讨Hyper-CVAD/MA方案治疗复发或难治弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)的疗效及安全性。方法:观察26例经系统化疗后复发或难治的DLBCL患者接受Hyper-CVAD/MA方案化疗,21-28天为1周期,连续2个周期评价疗效及安全性,分析生存情况。结果:全组26例患者中,总有效率为46.15%,其中完全缓解(complete remission,CR)3例(11.54%),部分缓解(partial remission,PR)9例(34.61%),全组患者中位生存时间为10(2-25)个月,1年和2年总生存率分别为28.57%、14.29%。不良反应主要表现为III-IV度骨髓抑制及继发的肺部感染,其他包括胃肠道反应、口腔炎、肝功能异常等。结论:Hyper-CVAD/MA治疗复发难治DLBCL有一定的疗效,且患者可耐受,可作为二线方案的一个选择。     

原发性肾上腺非霍奇金淋巴瘤（附9 例报告）

目的:探讨原发性肾上腺淋巴瘤(Primary Adrenal Lymphoma,PAL)的临床特点、提高对PAL的认识。方法:回顾分析解放军总医院1995年12月至2007年6月收治的9例PAL的临床表现、实验室检查、影像学特点、组织病理类型以及治疗方法等临床资料,并结合国内外文献进行分析。结果:9例患者中,1例因常规体检发现,8例因腹痛、腹胀或腰痛就诊发现;其中单侧3例,双侧6例,实验室检查无明显异常,影像学检查仅发现肾脏肿瘤,但术后病理组织学诊断为非霍奇金淋巴瘤(non-Hodgkin’s lymphoma,NHL),其中8例弥漫大B细胞淋巴瘤,1例T细胞淋巴瘤;7例患者术后均接受了CHOP或RCHOP方案化疗为主的综合治疗,2例常规治疗;随访至2010年2月,1例弥漫性大B细胞淋巴瘤患者存活4年,1例在术后3年2个月死亡,余7均在2年内死亡。结论:PAL是一种罕见的、恶性程度较高的肿瘤,临床表现和影像学检查缺乏特异性,组织病理学及免疫组织化学是明确诊断的好方法。术前确诊肾上腺原发性非霍奇金淋巴瘤可避免手术,联合化疗应为治疗首选。     

增强剂量的CTOP方案联合放疗治疗非何杰金氏淋巴瘤的疗效观察

目的:分析增强剂量CTOP方案联合放疗治疗非何杰金氏淋巴瘤的疗效.方法:我院从2005年5月至2008年5月期间初治43例非何杰金氏淋巴瘤患者,随机分成对照组和观察组,分别采用常规剂量(THP40mg/m2)和增强剂量(THP60mg/m2)CTOP方案治疗6-8个疗程,第4-6个疗程后放疗一次,观察疗效及不良反应.结果:对照组总有效率(CR+PR)为81.82%,观察组的总有效率(CR+PR)为85.71%,疗效有所提高.两组毒副作用差异无显著性.结论:增强剂量CTOP方案结合放疗治疗非何杰金氏淋巴瘤有较好的疗效,与常规剂量CTOP方案相比毒副作用相仿.     

EBV与非霍奇金淋巴瘤的相关性研究

目的探讨EBV与非霍奇金淋巴瘤的相关性。方法采用免疫荧光法检测62例非霍奇金淋巴瘤患者外周血血清中EBV-VCA-IGA,进而探讨EBV感染与非霍奇金淋巴瘤的相关性。结果92例非霍奇金淋巴瘤患者EBV-VCA-IGA阳性率为36%,B细胞来源非霍奇金淋巴瘤患者EBV-VCA-IGA阳性率为34%,T细胞来源非霍奇金淋巴瘤患者EBV-VCA-IGA阳性率为38%。结论EBV与非霍奇金淋巴瘤关系密切,监测EBV感染状况,对非霍奇金淋巴瘤的早期诊断及预后判断具有重要意义。     

利妥昔单抗联合CHOP化疗治疗感染乙肝病毒的非霍奇金淋巴瘤患者的安全性分析

目的:观察利妥昔单抗与CHOP化疗联合治疗感染乙肝病毒(HBV)的非霍奇金淋巴瘤(NHL)患者的有效性及安全性。方法:选取2010年6月至2013年6月35例B细胞NHL住院患者,分为两组,观察组(n=13)为感染HBV患者,接受利妥昔单抗-CHOP化疗方案;对照组(n=22)为非感染HBV的患者,单纯接受CHOP化疗方案,两组治疗4~6疗程,观察两组患者治疗的疗效及肝功能。结果:观察组完全缓解率(CR率)为76.92%,对照组CR率为40.91%(P0.05),两组差异有统计学意义。观察组肝功能损害I~Ⅱ级发生率为23.07%,对照组肝功能损害I~Ⅱ级发生率18.18%(P0.05),观察组毒副反应发生率为30.77%,对照组毒副反应发生率为22.72%(P0.05),两组在肝功能损害及毒副反应上差异无统计学意义。两组患者HBV均未再激活。结论:感染HBV的B细胞NHL患者用R-CHOP联合化疗方案治疗,以及在化疗时预防性、足疗程的抗病毒治疗,可以减少HBV再激活的发生,并且可以降低肝功损害率。     

美罗华联合CHOP方案与CHOP方案治疗老年复发性弥漫性大B细胞性淋巴瘤的临床研究

目的:探讨美罗华联合CHOP方案与CHOP方案治疗老年复发性弥漫性大B细胞性淋巴瘤的临床疗效和不良反应.方法:选择老年复发性弥漫性大B细胞性淋巴瘤60例,按治疗方案分成研究组(30例)和对照组(n＝30),研究组采用美罗华联合CHOP方案,对照组给予单纯CHOP方案.评估比较两组患者疗效和不良反应,并随访两组患者的生存时间.结果:两组患者均完成治疗及治疗效果评估,研究组CR为10例,PR为15例,总有效率为83.3％(25/30);对照组CR为3例,PR为6例,总有效率为30.0％(9/30),研究组有效率明显高于对照组(X2=8.42,P＜0.05).随访期间,研究组MST、PFS明显长于对照组(P＜0.05).研究组和对照组1年生存率、2年生存率比较,差异有统计学意义(P＜0.01).两组间抗癌药物毒性分度比较,差异无统计学意义(P＞0.05).结论:美罗华联合CHOP方案用于老年复发性弥漫性大B细胞淋巴瘤,能明显提高治疗有效率,延长无进展生存期和生存时间,且没有增加老年患者毒副作用,应用安全.     

EPOCH-L方案治疗复发难治性T细胞淋巴瘤的临床研究

目的:探讨EPOCH-L方案治疗复发难治性T细胞淋巴瘤的疗效及安全性。方法:回顾性分析解放军某医院2012年1月至2017年1月收治的12例复发难治性T细胞淋巴瘤患者的临床资料,均采用EPOCH-L方案化疗(依托泊苷50 mg/m2第1～4天、吡柔比星10 mg/m2第1～4天、长春地辛1 mg/d第1～4天、环磷酰胺750 mg/m2第5天、泼尼龙60 mg/m2第1～5天、培门冬酶2500 iu/m2第6天)3～6个周期,并随机选取同期进行异基因造血干细胞移植治疗的12例复发难治性T细胞淋巴瘤患者为对照组,比较两组的临床疗效及不良反应的发生情况。结果:随访至2018年1月,EPOCH-L方案组患者取得完全缓解4例(33.3%),部分缓解4例(33.3%),总有效率为66.7%,中位生存期为23.7(7～65)个月,随访期间总生存率为25%;对照组患者中位生存期为9.2(3～60)个月,无病生存率为41.7%,总体生存时间分布差异无统计学意义(P=0.683)。实验组没有患者死于化疗合并症(0.0%),对照组4例死于移植合并症(33.3%),差异有统计学意义(P=0.028)。结论:EPOCH-L方案治疗复发难治性T细胞淋巴瘤的临床效果与异基因造血干细胞移植治疗相当,且安全性较高。     

乳腺恶性血液病的病理类型、临床特点及生存分析

目的:探讨乳腺恶性血液病的病理分型、患者的临床特征及预后。方法:回顾性分析2014年1月至2019年1月空军军医大学西京医院收治的33例乳腺恶性血液病患者的病理分型、临床特征及预后。结果:33例患者中,32例为女性,1例为男性,平均年龄为45.5岁(12-78岁)。经病理确诊29例(29/33,87.9%)为非霍奇金淋巴瘤,其中弥漫大B细胞淋巴瘤(18/29,62.1%)最为常见,其次是NK/T细胞淋巴瘤(3/29,10.3%),B淋巴母细胞白血病/淋巴瘤(2/29,6.8%),而伯基特淋巴瘤、滤泡淋巴瘤、原发皮肤间变大细胞淋巴瘤各1例(1/29,3.4%),其余3例未进一步分型。此外,1例(1/33,3.0%)霍奇金淋巴瘤,3例(3/33,9.1%)急性白血病复发累及乳腺。原发性乳腺恶性血液病为19例(57.6%),继发性为14例(42.4%),病变主要累及右侧乳腺(18例,54.5%),其次为左侧(10例,30.3%),双侧均累及的为少数(5例,15.2%)。19例原发性乳腺恶性血液病均为淋巴瘤,与14例继发性乳腺恶性血液病相比,其血小板计数明显升高(P=0.004),β2-MG显著降低(P=0.049),B症状少(P=0.017),Ann Arbor分期主要为Ⅰ-Ⅱ期(P<0.01),骨髓受累少(P<0.01)等特点。生存分析提示原发性乳腺恶性血液病患者比继发性患者生存期更长(HR=9.846,P=0.002)。恶性血液病累及骨髓可导致生存期显著缩短(HR=6.434,P<0.01)。结论:乳腺恶性血液病患者以中年女性为主,原发性乳腺恶性血液病比继发性发病率高(分别为57.5%和42.5%),最常见的病理类型为弥漫大B细胞淋巴瘤,病变主要累及右侧乳腺。与继发性乳腺恶性血液病相比,原发性乳腺恶性血液病患者具有血小板计数相对更高,β2-MG水平更低,往往不伴B症状,Ann Arbor分期主要为Ⅰ-Ⅱ期,骨髓不受累,且生存期显著延长等特点。此外,恶性血液病累及骨髓提示预后不良。     

Residential and occupational exposure to sunlight and mortality from non-Hodgkin's lymphoma: composite (threefold) case-control study.

OBJECTIVE: To determine whether non-Hodgkin''s lymphoma mortality is associated with sunlight exposure. DESIGN: Three case-control studies based on death certificates of non-Hodgkin''s lymphoma, melanoma, and skin cancer mortality examining associations with potential sunlight exposure from residence and occupation. SETTING: 24 states in the United States. SUBJECTS: All cases were deaths from non-Hodgkin''s lymphoma, melanoma, and non-melanotic skin cancer between 1984 and 1991. Two age, sex, and race frequency matched controls per case were selected from non-cancer deaths. MAIN OUTCOME MEASURES: Odds ratios for non-Hodgkin''s lymphoma, melanoma, and skin cancer from residential and occupational sunlight exposure adjusted for age, sex, race, socioeconomic status, and farming occupation. RESULTS: Non-Hodgkin''s lymphoma mortality was not positively associated with sunlight exposure based on residence. Both melanoma and skin cancer were positively associated with residential sunlight exposure. Adjusted odds ratios for residing in states with the highest sunlight exposure were 0.83 (95% confidence interval 0.81 to 0.86) for non-Hodgkin''s lymphoma, 1.12 (1.06 to 1.19) for melanoma, and 1.30 (1.18 to 1.43) for skin cancer. In addition, non-Hodgkin''s lymphoma mortality was not positively associated with occupational sunlight exposure (odds ratio 0.88; 0.81 to 0.96). Skin cancer was slightly positively associated with occupational sunlight exposure (1.14; 0.96 to 1.36). CONCLUSIONS: Unlike skin cancer and to some extent melanoma, non-Hodgkin''s lymphoma mortality was not positively associated with exposure to sunlight. The findings do not therefore support the hypothesis that sunlight exposure contributes to the rising rates of non-Hodgkin''s lymphoma.     

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

ONC201/TIC10 is a small molecule initially discovered by its ability to coordinately induce and activate the TRAIL pathway selectively in tumor cells and has recently entered clinical trials in adult advanced cancers. The anti-tumor activity of ONC201 has previously been demonstrated in several preclinical models of cancer, including refractory solid tumors and a transgenic lymphoma mouse model. Based on the need for new safe and effective therapies in pediatric non-Hodgkin''s lymphoma (NHL) and the non-toxic preclinical profile of ONC201, we investigated the in vitro efficacy of ONC201 in non-Hodgkin''s lymphoma (NHL) cell lines to evaluate its therapeutic potential for this disease. ONC201 caused a dose-dependent reduction in the cell viability of NHL cell lines that resulted from induction of apoptosis. As expected from prior observations, induction of TRAIL and its receptor DR5 was also observed in these cell lines. Furthermore, dual induction of TRAIL and DR5 appeared to drive the observed apoptosis and TRAIL expression was correlated linearly with sub-G1 DNA content, suggesting its potential role as a biomarker of tumor response to ONC201-treated lymphoma cells. We further investigated combinations of ONC201 with approved chemotherapeutic agents used to treat lymphoma. ONC201 exhibited synergy in combination with the anti-metabolic agent cytarabine in vitro, in addition to cooperating with other therapies. Together these findings indicate that ONC201 is an effective TRAIL pathway-inducer as a monoagent that can be combined with chemotherapy to enhance therapeutic responses in pediatric NHL.     

A systematic review and meta-analysis of immune checkpoint therapy in relapsed or refractory non-Hodgkin lymphoma; a friend or foe?

Over the last decades, a revolution has occurred in oncology with the development of immune checkpoint inhibitors (ICIs). Following tremendous successes in solid tumors, interest has risen to explore these inhibitors in hematologic malignancies; while Hodgkin's lymphoma (HL) has shown overwhelming achievements, available data on different types of non-Hodgkin's lymphoma (NHL) vary considerably. To the best of our knowledge, no meta-analysis has assessed the efficacy and safety of ICI therapy in relapsed or refractory NHL patients. Meta-analysis of the included studies (n = 29) indicated PD-1 may probably be the more attractive ICI target rather than PD-L1 and CTLA-4 in NHL patients. Also, there is a plausible correlation between NHL subtypes and response to ICI therapy. While MF, ENKTL, RT, and PMBCL showed promising responses to ICI monotherapy, neither FL nor DLBCL had satisfactory responses; further necessitating novel strategies such as the application of ICIs in combination with other treatment strategies. Notably, among different combinations, BTK inhibitors showed an obvious improvement as compared to ICI monotherapy in both FL and DLBCL, however, the best results were obtained when ICI was combined with anti-CD20 monoclonal antibodies. Finally, while most NHL patients who received ICI treatment have experienced mild AEs, larger trials with long-term follow-up are required to confirm the safety, as well as the efficacy, of ICI therapy in NHL patients.     

Association between incidence of non-Hodgkin's lymphoma and solar ultraviolet radiation in England and Wales.

OBJECTIVES--To examine whether the incidence of non-Hodgkin''s lymphoma in different areas of England and Wales is associated with levels of solar ultraviolet radiation. DESIGN--Geographically based study examining the association between incidence of non-Hodgkin''s lymphoma and estimated levels of solar ultraviolet radiation, controlling for social class and employment in agriculture. SETTING--59 counties in England and Wales. SUBJECTS--All registered cases of non-Hodgkin''s lymphoma during the period 1968-85. MAIN OUTCOME MEASURE--Age and sex adjusted odds ratio for non-Hodgkin''s lymphoma in each county. RESULTS--Incidence of non-Hodgkin''s lymphoma was significantly associated with solar ultraviolet radiation levels (P < 0.001), even after social class and employment in agriculture were controlled for (P = 0.004). In a comparison of counties in the highest and lowest quarters of solar ultraviolet radiation, the relative risk of non-Hodgkin''s lymphoma was 1.27 (95% confidence interval 1.24 to 1.29), rising to 1.34 (1.32 to 1.37) after adjustment for social class and employment in agriculture. CONCLUSIONS--The incidence of non-Hodgkin''s lymphoma in different areas of England and Wales is positively associated with levels of solar ultraviolet radiation. These results are consistent with the hypothesis that exposure to solar ultraviolet radiation increases the risk of non-Hodgkin''s lymphoma.     

Clinical and Preclinical Pharmacology of Liposomal Vincristine

Abstract

Vincristine is one of the most commonly administered anticancer drugs and is active in a wide range of indications including non-Hodgkin's lymphomas, acute lymphocytic leukemias and lung cancer. Administration of vincristine in long-circulating liposomes may be expected to result in increased accumulation of drug at tumor sites due to “passive targeting” or “disease-site targeting” effects arising from the more permeable vasculature in these regions. Further, for liposomes with appropriate drug release characteristics, extended exposure of tumor cells to vincristine would result from liposomal delivery. The combination of increased drug delivery and extended duration of drug exposure may be expected to result in increased efficacy, particularly because vincristine is a cell-cycle specific drug. It is shown that vincristine can be encapsulated in large unilamellar vesicles (diameter β 100 nm) using a pH gradient (interior acidic) approach. Further, the efficacy of liposomal formulations of vincristine in animal models is highly sensitive to the drug release rate in vivo. A liposomal formulation with drug retention characteristics such that more than 50% of the vincristine is retained in the carrier 24 h following i.v. injection exhibits significantly improved antitumor efficacy in A431 xenograft and P388 murine tumor models in comparison to either free drug or leakier liposomal formulations. The clinical activity of liposomal vincristine has been investigated in relapsed or refractory non-Hodgkin's lymphoma patients at a dose level of 2 mg/m² every two weeks. Of 83 registered patients, there were 24 responses in 68 evaluable patients. The responses according to histology are: Indolent-13%; Transformed-42%; Aggressive-45%. There were no serious cases of myelosuppression or any toxic deaths. It is concluded that liposomal vincristine can be given at high doses, is active and well tolerated and is rarely neurotoxic or myelosuppressive in these heavily pretreated patients. It appears that the benefits of low toxicity and enhanced efficacy noted in the tumor models are also observed in the clinical setting. A multicenter pivotal Phase II trial of liposomal vincristine in relapsed and refractory non-Hodgkin's lymphoma has been approved by the US FDA and is ongoing.     

Paternal preconceptional radiation exposure in the nuclear industry and leukaemia and non-Hodgkin's lymphoma in young people in Scotland.

OBJECTIVE--To determine if a relation exists between paternal exposure to relatively high levels of radiation in the Scottish nuclear industry and the risk of leukaemia and non-Hodgkin''s lymphoma is subsequently conceived children. DESIGN--Matched case-control study with three controls for each case. SETTING--The whole of Scotland. SUBJECTS--The fathers of 1024 children with leukaemia and 237 children with non-Hodgkin''s lymphoma diagnosed in Scotland below the age of 25 among those born in Scotland since nuclear operations began (in 1958) and the fathers of 3783 randomly chosen controls. The fathers of 80 children with leukaemia and 16 with non-Hodgkin''s lymphoma in north Cumbria were also covered since some workers at one Scottish nuclear site live over the border in that area. Details of all fathers were then matched against records of the nuclear industry. MAIN OUTCOME MEASURES--Paternal preconceptional radiation exposures, particularly relatively high levels, both lifetime and in the six and three months before conception. RESULTS--No significant excess was observed in any subgroup and there was no significant trend: fathers of three controls but no cases were exposed to lifetime preconceptional levels of 100 mSv or greater (Fisher''s exact p value 0.84). In the six months before conception, fathers of two cases and three controls received 10 mSv or more, odds ratio 2.3 (95% confidence interval 0.31 to 17.24). In the three months before conception the fathers of one case and two controls received 5 mSv or more, odds ratio 1.7 (0.10 to 30.76). The results for leukaemia and non-Hodgkin''s lymphoma combined were similar. CONCLUSIONS--No significant excess of leukaemia or of leukaemia and non-Hodgkin''s lymphoma was found at any radiation level in any preconceptional period.     

美罗华对CD20 阳性NHL患者血清LDH、beta2- 微球蛋白及预后的影响*

目的：分析美罗华对CD20 阳性非霍奇金淋巴瘤(NHL)患者血清乳酸脱氢酶（LDH）、beta2- 微球蛋白（beta2-MG）水平及预后的影 响。方法：对2004 年1 月-2011 年6 月在我院收治的86 例NHL患者,分别采用CHOP（对照组,n=48）与RCHOP（治疗组,n=48）2 种不同的方案进行化疗,每21 天为一个周期,共6 个周期。比较两组临床疗效、不良反应、LDH和beta2-MG 水平变化及预后。结果： 治疗组的ORR 和DCR 分别为77.1 %和89.6 %,均显著高于对照组56.3 %和72.9 %（P<0.05）;化疗后,两组血清LDH、beta2-MG 均 较化疗前明显下降,而治疗组化疗后血清LDH、beta2-MG 均显著低于对照组(P<0.05);治疗组白细胞减少、恶心呕吐的并发症高于 对照组(P<0.05);化疗后1、2 年生存率两组之间均无显著性差异（P>0.05）,而治疗组化疗后3 年生存率明显升高(P<0.05)。结论：美 罗华联合CHOP方案治疗CD20 阳性NHL患者疗效明显,且耐受性好,可有效调节血清LDH、茁2-MG 水平,提高缓解率,改善患 者预后。     

Quelques perspectives concernant le traitement des lymphomes par Zevalin® à partir de l’évaluation de l’expérience niçoise

Zevalin^® (yttrium-90 ibritumomab-tiuxetan) is the first radioimmunotherapy authorized in France for non-Hodgkin's lymphoma (NHL) treatment. It is indicated for clinical use in adults for recurrent or refractory follicular NHL including those refractory to rituximab. Treatment responses are between 70 and 80%. Since three years, 13 patients were treated in Nice by Zevalin^®. From this retrospective study, we discuss the various perspectives of this treatment. The majority of our patients in this study were evaluated by 18-FDG–PET and we also evaluated our results in this regard. Even if our follow-up is short, our experience confirms the efficacy and tolerance of Zevalin^® treatment in multirecurrent follicular NHL including those refractory to rituximab. The treatment is of interest in elderly patients and in case of autologous stem cell transplant. The proposed « Autorisation de Mise sur le Marché » (AMM) indication is probably not the best one since efficacy seems better in smaller tumour volumes and when used earlier in the therapeutic course. Zevalin^® will probably be more beneficial in first line treatment, for immunochemotherapy consolidation and for autologous stem cell transplant conditioning. We pointed out the prognostic value of FDG–PET for early post-treatment evaluation, one to two months after Zevalin^® administration. However, larger scale studies are necessary to confirm these findings.     

Human Bone Marrow Mesenchymal Stem Cells Display Anti-Cancer Activity in SCID Mice Bearing Disseminated Non-Hodgkin's Lymphoma Xenografts

Background

Although multimodality treatment can induce high rate of remission in many subtypes of non-Hodgkin''s lymphoma (NHL), significant proportions of patients relapse with incurable disease. The effect of human bone marrow (BM) mesenchymal stem cells (MSC) on tumor cell growth is controversial, and no specific information is available on the effect of BM-MSC on NHL.

Methodology/Principal Findings

The effect of BM-MSC was analyzed in two in vivo models of disseminated non-Hodgkin''s lymphomas with an indolent (EBV⁻ Burkitt-type BJAB, median survival = 46 days) and an aggressive (EBV⁺ B lymphoblastoid SKW6.4, median survival = 27 days) behavior in nude-SCID mice. Intra-peritoneal (i.p.) injection of MSC (4 days after i.p. injection of lymphoma cells) significantly increased the overall survival at an optimal MSC∶lymphoma ratio of 1∶10 in both xenograft models (BJAB+MSC, median survival = 58.5 days; SKW6.4+MSC, median survival = 40 days). Upon MSC injection, i.p. tumor masses developed more slowly and, at the histopathological observation, exhibited a massive stromal infiltration coupled to extensive intra-tumor necrosis. In in vitro experiments, we found that: i) MSC/lymphoma co-cultures modestly affected lymphoma cell survival and were characterized by increased release of pro-angiogenic cytokines with respect to the MSC, or lymphoma, cultures; ii) MSC induce the migration of endothelial cells in transwell assays, but promoted endothelial cell apoptosis in direct MSC/endothelial cell co-cultures.

Conclusions/Significance

Our data demonstrate that BM-MSC exhibit anti-lymphoma activity in two distinct xenograft SCID mouse models of disseminated NHL.     

Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies

ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1–8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.