利妥昔单抗治疗非霍奇金淋巴瘤20例

目的 探讨利妥昔单抗治疗B细胞非霍奇金淋巴瘤(NHL)的疗效、安全性.方法 共20例患者,初治18例,复治2例.利妥昔单抗单用1例;应用利妥昔单抗联合化疗19例,其中用于自体造血干细胞移植(APBSCT)体内净化治疗8例,维持治疗4例.结果 初治者单药治疗完全缓解1例,利妥昔单抗联合化疗完全缓解(CR)率82.4%(14/17),2例部分缓解(PR),总有效率94.1%;复治组中1例CR,1例PR;移植组中未观察到利妥昔单抗对采集的干细胞质量和数量以及移植后造血恢复有不良影响;维持治疗组4例全部生存,最长随访57个月.结论利妥昔单抗治疗NHL安全、有效,不论单用还是联合化疗对B细胞NHL均有良好疗效,可作为APBSCT的体内净化药物.     

抗CD20单克隆抗体联合自体外周血干细胞移植治疗非霍奇金淋巴瘤的临床研究

 目的　探讨抗CD20单克隆抗体（利妥昔单抗,商品名：美罗华）联合自体外周血干细胞移植（APBSCT）治疗B细胞非霍奇金淋巴瘤（NHL）的疗效。方法　21例CD20阳性的NHL患者,经过前期治疗,5例达完全缓解（CR）,难治性病例为16例,包括11例部分缓解（PR）和5例疾病进展（PD）。在自体造血干细胞动员的第1、8天及预处理的-1、＋7天每天应用利妥昔单抗375 mg／m2。结果　移植前疾病达到CR的5例患者,无一例复发;移植前处于PR的11例患者,仅1例在移植后6个月疾病复发,其余均无病生存;移植前处于PD的5例患者,2例无病生存。21例患者中位随访24（1～68）个月,复发、死亡4例（19 %）,其余17例均无病生存,2年无病生存（EFS）和总生存（OS）率均为81.0 %。未观察到利妥昔单抗对采集所得干细胞的质量和数量以及移植后造血恢复有不良影响。结论　APBSCT联合利妥昔单抗做体内净化治疗B细胞NHL疗效与移植前状态有关,作为巩固治疗,能使移植前达CR的患者获得长期生存,提高治愈率;作为强化治疗,可提高缓解率,延长PR患者的EFS及OS。利妥昔单抗的加入不影响造血干细胞采集和移植后造血重建。     

利妥昔单抗联合化疗治疗CD+20的B细胞型非霍奇金淋巴瘤27例

 目的 观察讨论利妥昔单抗（商品名：美罗华）联合化疗治疗CD+20 B细胞型非霍奇金淋巴瘤（NHL）的疗效。方法 对2001年6月至2005年8月收治的27例CD+20 B细胞型NHL患者,应用美罗华联合化疗（CHOP,BCHOP,VIP等方案）治疗。结果 有效（CR+PR）率93 %,治疗起效的中位时间30 d,中位缓解期22个月,半年生存率92 %,最长已存活42个月。结论 应用美罗华联合化疗治疗CD+20 B细胞型NHL,特别是对侵袭性或复发耐药的B细胞NHL有显著疗效,且全身毒副反应轻。     

美罗华联合CHOP治疗B细胞性非霍奇金淋巴瘤的临床研究

为了评价美罗华与CHOP联合治疗B细胞性非霍奇金淋巴瘤(non-Hodgkin’s lymphoma,NHL)的临床效果及不良反应,用同期对照的前瞻性研究方法,将22例B细胞性NHL患者分为研究组(美罗华组)和对照组,研究组11例用CHOP方案(环磷酰胺、多柔比星、长春新碱和泼尼松)联合美罗华治疗;对照组11例单用CHOP方案。结果美罗华组完全缓解率(CR)达72.7%(8/11),总有效率90.9%(10/11);对照组CR为36.4%(4/11),总有效率为54.6%(6/11),两组疗效差异有统计学意义,P=0.0018。初步研究结果提示,美罗华联合CHOP方案治疗CD20阳性的B细胞性NHL的疗效显著,不良反应与单纯化疗相似,可作为该病目前的首选方案。     

大剂量BEAC方案联合自体外周血干细胞移植治疗非霍奇金淋巴瘤临床分析

目的:观察BEAC方案作为预处理方案联合自体干细胞移植(autologous stem cell transplantation,ASCT)治疗非霍奇金淋巴瘤(non-Hodgkin’s lymphoma,NHL)的疗效。方法:选取2000-01-2011-12新疆医科大学附属肿瘤医院收治的NHL患者共45例,采用BEAC方案联合ASCT治疗,动员方案为依托泊苷(Vp-16)联合粒细胞集落刺激因子(G-CSF)。41例患者采用BEAC联合ASCT方案作为巩固治疗,4例采用BEAC联合ASCT方案作为挽救治疗。结果:45例患者均移植成功,重建造血功能。不良反应均可耐受,无移植相关死亡。移植前CR 53.3%(24/45),PR 46.7%(21/45),移植后CR 73.3%(33/45),PR 26.7%(11/45)。中位随访时间为41个月(8~139个月),至随访截止日期6例因疾病进展死亡,1例因第二原发肿瘤死亡。5年生存率为83.3%。结论:BEAC预处理方案联合ASCT方案治疗NHL安全性高,疗效较好。     

自体干细胞移植联合美罗华治疗非霍奇金淋巴瘤

经过自体干细胞移植(ASCT)治疗的非霍奇金淋巴瘤(NHL)患者仍有部分复发。复发的根源主要为体内的微小残留病变，包括体内残留的肿瘤细胞和移植物中的肿瘤细胞。单克隆抗体美罗华可通过清除CD20^ B细胞而达到体内净化，预防了移植物肿瘤细胞的污染，并可进一步清除体内残留病灶．ASCT联合美罗华有望进一步提高NHL的疗效。     

利妥昔单抗联合DHAP方案治疗复发性非霍奇金淋巴瘤的临床疗效

 目的 探讨利妥昔单抗（商品名：美罗华）联合DHAP方案治疗复发性非霍奇金淋巴瘤（NHL）的疗效及安全性。方法 16例复发的B细胞NHL患者，其中8例接受美罗华联合DHAP方案治疗者为治疗组；8例接受联合化疗者为对照组；治疗组患者接受美罗华+DHAP方案治疗4 ~ 6周期，每周期21 d，于化疗开始前1天予美罗华（375 mg／m2）静脉滴注，然后每隔1周重复上述治疗，共4 ~ 6次。对照组予CHOP方案基础上加用甲氨蝶呤（MTX）、阿糖胞苷（Ara-C）、依托泊苷（VP16），治疗4 ~ 6周期，每周期21 d。结果 治疗组完全缓解（CR）率75 %，总有效（OR＝CR＋PR）率100 %，平均无进展生存期（PFS）（18.3±5.4）个月；对照组CR率37.5 %，OR率62.5 %，PFS（4.7±2.8）个月；治疗组平均PFS明显高于对照组（P＜0.05）。结论 美罗华联合DHAP方案对复发性NHL患者有较好疗效，且化疗药物的毒副作用未见增加。     

利妥昔单抗体内净化造血干细胞移植治疗非霍奇金淋巴瘤

 目的 探讨利妥昔单抗（商品名：美罗华）体内净化造血干细胞移植治疗非霍奇金淋巴瘤（NHL）的疗效。方法 自体造血干细胞移植（AHSCT）-1、+8天运用利妥昔单抗375 mg／m2的体内净化。结果 7例患者移植后造血功能恢复,未观察到利妥昔单抗的严重毒副反应,移植后随访1～28个月（中位随访时间15个月）,均未见疾病进展或复发。结论 利妥昔单抗净化造血干细胞移植能提高CD+20 NHL的疗效,有助于清除微小残留病灶,延长NHL的生存期。     

含美罗华联合方案治疗复发耐药B细胞性非霍奇金淋巴瘤

背景与目的:复发或耐药的B细胞性非霍奇金淋巴瘤(non-Hodgkin slymphoma,NHL)预后不良,二线方案化疗远期生存差;抗CD20单克隆抗体美罗华(rituximab)与CHOP或类似方案联合作为一线方案治疗初治侵袭性淋巴瘤可提高远期生存率,但在二线治疗中的作用尚未确定。本研究初步探讨含美罗华联合方案治疗复发耐药B细胞性NHL的近期疗效和不良反应的情况。方法:中山大学肿瘤防治中心近年应用含美罗华方案治疗35例复发耐药NHL患者,其中男性19例,女性16例,中位年龄53.5岁。PS评分0～1分33例(94.3%)。IPI评分0～1分20例(57.1%),2分7例(20.0%),3分4例(11.4%),4～5分4例(11.4%);病理类型以弥漫大B细胞性为主(23例,占65.7%)。所有患者都接受含美罗华的治疗,每疗程前1天应用,剂量375mg/m2,二、三线挽救化疗方案包括EPOCH、CHOP、DHAP、DICE、IMVP-16和FND等。结果:35例患者中单用美罗华治疗者5例,美罗华联合化疗30例,共化疗102疗程。32例可评价客观疗效,有效率68.8%(22/32),完全缓解(CR)13例(40.6%),3例患者在含美罗华方案治疗后接受局部放疗获CR,3例患者在挽救方案治疗后加用造血干细胞移植获CR。主要不良反应为胃肠道反应、骨髓抑制、脱发等,加用美罗华治疗主要增加畏寒、发热等输注相关反应(5例)。中位随访时间12.5个月(3～69个月),失访2例,全组死亡10例(9例死于疾病进展,1例死于重症乙型性肝炎),中位无进展生存期(PFS)11.8个月(3～33个月)。总的1、2、3年生存率分别为72.9%、62.8%和62.8%。结论:含美罗华方案治疗复发耐药的B细胞NHL有效率高、不良反应可以耐受,值得在更大宗病例中作进一步研究。     

自体干细胞移植联合美罗华治疗非霍奇金淋巴瘤

经过自体干细胞移植(ASCT)治疗的非霍奇金淋巴瘤(NHL)患者仍有部分复发.复发的根源主要为体内的微小残留病变,包括体内残留的肿瘤细胞和移植物中的肿瘤细胞.单克隆抗体美罗华可通过清除CD20+B细胞而达到体内净化,预防了移植物肿瘤细胞的污染,并可进一步清除体内残留病灶.ASCT联合美罗华有望进一步提高NHL的疗效.     

Feasibility of High-Dose Chemotherapy without Stem Cell Support as a First-Line Treatment for Non-Hodgkin's Aggressive Lymphoma: A Pilot Study

A regimen which incorporates cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) is the standard treatment for patients with non-Hodgkin's lymphoma (NHL), but it has not been effective in patients with aggressive NHL who are at high risk. The aim of the present trial was to investigate the feasibility of high-dose chemotherapy (HDC) without stem cell support as a first-line treatment. The primary endpoint was a complete remission rate. The second endpoint was survival. Fourteen patients with aggressive NHL entered the study and were treated according to the K93 protocol (3 cycles of CHOP, high-dose etoposide and ifosfamide, and high-dose methotrexate) Eleven patients (79%) achieved complete remission (CR) and two (14%) achieved partial remission (PR). Overall survival (OS) after five years was 79%. The actuarial five year disease free survival (DFS) for the eleven cases of CR was 75%. During chemotherapy, grade IV hematologic toxicity was observed in all patients and grade IV non-hematologic toxicity in only one patient, who experienced oral ulcers. Peripheral blood stem cell (PBSC) apheresis was performed in eight cases. One harvesting was enough to provide an adequate number of CD34+ cells for the subsequent PBSC transplantation (PBSCT).

In conclusion our study confirmed the efficacy of the K93 protocol in obtaining a good response (CR + PR) rate and a very good DFS rate in most cases of aggressive NHL, with acceptable toxicity. This regimen may improve the outcome in cases of aggressive NHL without stem cell support. It seems worthwhile to conduct a randomized controlled study comparing the K93 protocol with the standard CHOP regimen.     

Feasibility of high-dose chemotherapy without stem cell support as a first-line treatment for non-Hodgkin's aggressive lymphoma: a pilot study

A regimen which incorporates cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) is the standard treatment for patients with non-Hodgkin's lymphoma (NHL), but it has not been effective in patients with aggressive NHL who are at high risk. The aim of the present trial was to investigate the feasibility of high-dose chemotherapy (HDC) without stem cell support as a first-line treatment. The primary endpoint was a complete remission rate. The second endpoint was survival. Fourteen patients with aggressive NHL entered the study and were treated according to the K93 protocol (3 cycles of CHOP, high-dose etoposide and ifosfamide, and high-dose methotrexate) Eleven patients (79%) achieved complete remission (CR) and two (14%) achieved partial remission (PR). Overall survival (OS) after five years was 79%. The actuarial five year disease free survival (DFS) for the eleven cases of CR was 75%. During chemotherapy, grade IV hematologic toxicity was observed in all patients and grade IV non-hematologic toxicity in only one patient, who experienced oral ulcers. Peripheral blood stem cell (PBSC) apheresis was performed in eight cases. One harvesting was enough to provide an adequate number of CD34+ cells for the subsequent PBSC transplantation (PBSCT). In conclusion our study confirmed the efficacy of the K93 protocol in obtaining a good response (CR + PR) rate and a very good DFS rate in most cases of aggressive NHL, with acceptable toxicity. This regimen may improve the outcome in cases of aggressive NHL without stem cell support. It seems worthwhile to conduct a randomized controlled study comparing the K93 protocol with the standard CHOP regimen.     

Dexa-BEAM is not effective in patients with relapsed or resistant aggressive high-grade non-Hodgkin's lymphoma

The aim of the present study was to evaluate the feasibility and response of the Dexa-BEAM regimen as a salvage therapy followed by high-dose chemotherapy (HDCT) with peripheral blood stem cell transplantation (PBCST) in responding patients with high-grade relapsed or resistant aggressive non-Hodgkin's lymphoma (NHL). Sixteen pretreated patients (mean age 44, range 26-59) with relapsed (8) or resistant (8) NHL were treated with 1-4 cycles of Dexa-BEAM (dexamethasone, BCNU, etoposide, cytarabine, melphalan) in order to attain maximal response. Patients achieving complete response (CR) or partial response (PR) received HDCT with PBSCT. The conditioning regimen used was BEAM. Three patients achieved CR and one patient PR, resulting in an overall response rate of 25%. Three of four responding patients underwent high-dose chemotherapy and were successfully transplanted with autologous blood stem cells. Progressive disease developed in one patient after transplantation. Myelosuppression (WHO grade III- grade IV), the major side effect, was observed in all courses of Dexa-BEAM. Myelosuppression-related infection WHO grade IV occurred in four patients. The protocol was not well tolerated in this heavily pretreated group of patients with four severe myelosuppression-related infections WHO grade IV and one treatment-related death. The overall response rate in this study is not comparable to other salvage regimens published and led to the discontinuation of the trial. In conclusion Dexa-BEAM was only effective in a minority of patients with refractory or relapsed aggressive NHL and was not useful as a cytoreductive regimen prior to HDCT.     

High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study.

BACKGROUND: Combination chemotherapy can cure patients with non-Hodgkin's lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course. PATIENTS AND METHODS: Inclusion criteria were age 18-65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1-4), high-dose cytarabine 2 g/m2 12q (day 2), cisplatin 100 mg/m2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m2 (day 1) plus vincristine 1.4 mg/m2 (day 51); and etoposide 500 mg/m2 (day 58-62). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 81-84), etoposide 150 mg/m2 12q (day 81-84), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT. RESULTS: Fifty-seven patients (median age 43 years, range 24-65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1-76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively. CONCLUSIONS: We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL.     

Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma

Background: Rituximab is a chimeric monoclonal antibody directed against the B-cell CD20 antigen which has been utilized for therapy of B-cell non-Hodgkin's lymphoma. A previous clinical trial demonstrated that treatment with four weekly doses of 375 mg/m² of Rituximab in patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) was well tolerated and had significant clinical activity.Patients and methods: To assess the safety and efficacy of Rituximab treatment, an open-label, single-arm, multi-center, phase II study of eight consecutive weekly infusions of 375 mg/m² Rituximab in patients with low-grade or follicular B-cell NHL who had relapsed or had failed primary therapy was conducted. Thirty-seven patients with a median age of 55 years were treated.Results: Grade 1 or 2 adverse events were the majority of reported toxicities and occurred most frequently with the first infusion, decreasing with subsequent infusions. No patients developed a host antibody response (HACA) to Rituximab. The mean serum immunoglobulin levels for IgG, IgA, and IgM stayed within the normal range throughout the study. The majority of patients who were bcl-2 positive at baseline in peripheral blood became bcl-2 negative during treatment and remained negative at the time of B-cell recovery. In the 37 intent-to-treat patients, 5 (14%) had a complete response and 16 (43%) had a partial response for an overall response rate of 57%. Of 35 evaluable patients, 21 (60%) responded to treatment (14% CR and 46% PR). In responders, the median time to progression (TTP) and the median response duration have not been reached after 19.4+ months and 13.4+ months, respectively.Conclusions: The safety profile and efficacy achieved in this pilot study of extended treatment with Rituximab compares favorably with that seen with four weekly doses. Further studies are warranted to investigate whether this or other extended Rituximab schedules will result in increased efficacy in all or in certain subgroups of patients with low-grade or follicular NHL.     

Chemotherapy with rituximab followed by high-dose therapy and autologous stem cell transplantation in patients with mantle cell lymphoma

BACKGROUND: The authors evaluated the efficacy of chemotherapy combined with rituximab followed by high-dose therapy (HDT) plus autologous stem cell transplantation in patients with mantle cell lymphoma (MCL). METHODS: This was a retrospective analysis of 34 patients who were treated in 2 departments of hematology, including 29 patients (85%) who received first-line treatment. Rituximab was administered as 4 injections just before harvest in 25 patients (73%) or simultaneously with chemotherapy in 9 patients (27%). HDT included total body irradiation in 26 patients (77%). RESULTS: After induction therapy, all patients except one reached a response: There were 14 (41%) complete responses (CR) and 19 (56%) partial responses (PR). Stem cell harvest was successful in all patients but 2, with a median number of 5.9 CD34-positive cells per 10(6)/kg. Three months after transplantation, 24 patients (71%) were in CR, and 7 patients (21%) were in PR. At 3 years from the day of transplantation, the estimated overall survival was 87%. With a median follow-up at 2.6 years, the estimated median time to disease progression was 3.4 years. Rituximab treatment before harvest did not delay hematopoietic reconstitution: The median time it took patients to recover absolute neutrophil count to > 0.5 G/L was 10 days. CONCLUSIONS: Chemotherapy combined with rituximab followed by HDT improved the overall survival and progression-free survival in patients MCL without adding toxicities.     

Dexa-BEAM as salvage therapy in patients with primary refractory aggressive non-Hodgkin lymphoma

Although aggressive NHL in relapse after remission can still be cured by second-line treatment followed by high-dose therapy and autologous stem cell transplantation, the long-term prognosis of patients who fail to obtain remission after first-line therapy remains extremely poor. We retrospectively evaluated a series of 29 consecutive patients with primary refractory high-grade NHL who were treated with Dexa-BEAM (DB) as uniform salvage therapy at a single institution. Twenty-nine patients with aggressive NHL primary refractory to CHOP or CHOP-like induction therapy with a median age of 47 (range, 22 - 64) years received 1 - 2 cycles of DB and were candidates for subsequent autologous stem cell (PBSC) mobilization and transplantation (PBSCT). Follow-up of all patients was updated in March 2004. Eight of 29 patients (28%) responded to one cycle of DB (1 complete/7 partial remissions); 2 of whom are alive after PBSCT (1 autologous/1 matched unrelated donor), 1 patient died after autologous PBSCT. Reasons for failure to proceed to high-dose therapy in spite of response to DB were recurrent progressive disease (n = 2), septicemia (n = 1), and allogeneic transplant-related mortality after mobilization failure to DB (n = 2). Twenty-one patients failed to respond to DB and died of progressive disease. Overall survival was 7% after 41 months. We conclude that Dexa-BEAM salvage therapy is not effective in patients with truly primary refractory high-grade NHL. The efficiency of rituximab combined with Dexa-BEAM or novel chemotherapeutic strategies needs to be established.     

The role of complement in the mechanism of action of rituximab for B-cell lymphoma: implications for therapy

Rituximab, a genetically engineered chimeric monoclonal antibody specifically binding to CD20, was the first antibody approved by the U.S. Food and Drug Administration for the treatment of cancer. Rituximab significantly improves treatment outcome in relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL). However, there are also some challenges for us to overcome: why approximately 50% of patients are unresponsive to rituximab in spite of the expression of CD20, and why some responsive patients develop resistance to further treatment. Although the antitumor mechanisms of rituximab are not completely understood, several distinct antitumor activities of rituximab have been suspected, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), apoptosis, and direct growth arrest. To counteract resistance to rituximab therapy, several strategies have been developed to: (a) augment the CDC effect by increasing CD20 expression, heteroconjugating rituximab to cobra venom factor and C3b, and inhibiting membrane complement regulatory protein, especially CD59, function; (b) enhance the ADCC effect through some immunomodulatory cytokines and CR3-binding beta-glucan; and (c) reduce the apoptotic threshold or induce apoptotic signaling on the tumor. Extensive studies indicate that rituximab combined with these approaches is more effective than a single rituximab approach. Herein, the mechanism of action of and resistance to rituximab therapy in B-cell NHL, in particular, the involvement of the complement system, are extensively reviewed.