利妥昔单抗对于非霍奇金淋巴瘤的治疗及其药物经济学

目的:阐述利妥昔单抗对于非霍奇金淋巴瘤的疗效和药物的不良反应,并尝试探讨其药物经济学。方法:借鉴国外的研究并结合本院血液科对于这方面的探索,采用非传统的药物经济学模式来评价利妥昔单抗的治疗方案。结果:从药物经济学的角度而言,利妥昔单抗联合环磷酰胺 多柔比星(阿霉素) 长春新碱 泼尼松(CHOP)方案治疗非霍奇金淋巴瘤较传统单用CHOP方案优势明显。结论:利妥昔单抗具有较好的疗效和安全性,也是治疗非霍奇金淋巴瘤较经济的方法。     

Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia

Rituximab (MabThera, Rituxan) is an anti-CD20 monoclonal antibody that induces lysis and apoptosis of normal and malignant human B cells, and sensitises malignant B cells to the cytotoxic effect of chemotherapy. In phase III trials in patients with indolent or aggressive B-cell non-Hodgkin's lymphoma (NHL), intravenous rituximab in combination with chemotherapy was more effective as first- or second-line therapy than chemotherapy alone in providing tumour remission and patient survival. Likewise, in patients with chronic lymphocytic leukaemia (CLL), rituximab in combination with chemotherapy appeared more effective than chemotherapy alone as either first- or second-line treatment. In addition, rituximab maintenance therapy was shown to significantly prolong tumour remission and patient survival in patients with indolent B-cell NHL or CLL. The combination of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) was cost effective as first-line therapy for advanced-stage diffuse large B-cell NHL compared with CHOP alone. Rituximab, either alone or in combination with chemotherapy, was generally well tolerated in patients with NHL or CLL. Overall, rituximab in combination with chemotherapy, is a valuable option for first- and second-line therapy in patients with advanced-stage indolent or aggressive B-cell NHL, and possibly those with B-cell CLL, and is included in current treatment guidelines for these indications. The drug is also potentially useful as maintenance therapy in patients with indolent B-cell NHL or CLL.     

Combination chemotherapy and rituximab

Rituximab is a human-mouse chimeric monoclonal antibody that has demonstrated efficacy against non-Hodgkin's lymphoma (NHL). There is a powerful rationale for combining rituximab treatment with chemotherapeutic agents that have also shown efficacy in NHL, since the mechanisms of action are distinct and there is also evidence that rituximab may sensitize chemoresistant tumor cells to the actions of cytotoxic drugs. A study of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemoimmunotherapy has been carried out in 40 patients with low-grade NHL. In the 35 patients who completed the study, the overall response rate was 100%, with 63% achieving a complete response. Median time to progression has not yet been reached at 47.2+ months. Molecular analysis (polymerase chain reaction) showed that CHOP plus rituximab (unlike CHOP alone) could completely clear blood and bone marrow of cells containing the bcl-2 gene translocation, a molecular marker of NHL cells. Rituximab can therefore add to the efficacy of CHOP without significantly increasing toxicity. A further study is underway to determine whether similar efficacy with less overall toxicity can be achieved using rituximab in combination with fludarabine.     

Rituximab: new indication. In aggressive non Hodgkin lymphoma: benefits must be confirmed

The first-line treatment for diffuse large-B-cell non Hodgkin's lymphoma, a highly malignant lymphoma, is CHOP chemotherapy (cyclophosphamide + doxorubicin + vincristine + prednisone). Rituximab, a monoclonal antibody targeting certain B cells, has received a new indication in the treatment of this type of lymphoma, in combination with the CHOP protocol. In late 2002, the only available evaluation data came from one comparative, unblinded trial in patients over 60 years of age. Addition of rituximab to the CHOP protocol increased both the overall two-year survival rate (70% versus 57%), and the two-year event-free survival rate. Other trials are underway. In this trial, 9% of patients had major systemic reactions during the first rituximab infusion (respiratory disturbances, chills, fever and hypotension). These reactions did not occur during subsequent infusions. About 6% of patients had serious cardiac arrhythmias. In practice, the CHOP protocol remains the standard treatment for aggressive non Hodgkin's lymphoma. Pending further information, addition of rituximab to the CHOP protocol may be justified for patients who meet the inclusion criteria used in the only available clinical trial.     

利妥昔单抗联合CHOP方案治疗弥漫大B细胞性淋巴瘤的多中心临床研究(英文)

目的 :观察利妥昔单抗联合环磷酰胺、长春新碱、多柔比星及泼尼松 (CHOP方案 )治疗新诊断的弥漫性大B细胞性淋巴瘤 (DLBL)的临床疗效。　方法 :2 0 0 2年 4月至 2 0 0 3年 2月 ,共 5 2例病人进入本研究。化疗采用标准的CHOP方案 :d 1,环磷酰胺 6 0 0mg·m- 2 ,长春新碱 1.4mg·m- 2 ,多柔比星 2 5mg·m- 2 ,泼尼松 6 0mg·m- 2 × 5d ,每 3wk一个疗程 ,共 6个疗程。利妥昔单抗静脉滴注剂量为 375mg·m- 2 ,于化疗第一个疗程前 2d开始 ,每周输注 1次 (连续输注 ) ,连续 4次 (标准剂量 )或 6次 (增强剂量 ) ;或于每疗程的CHOP方案化疗前 2d输注 ,每 3周 1次 (间隔输注 ) ,输注 4次 (标准剂量 )或 6次 (增强剂量 )。结果 :5 0例病人进入临床疗效评估 ,6 0 %获得完全缓解 ,总有效率为 10 0 %。其中 ,34例AnnArbor分期为Ⅲ期或Ⅳ期的病人有15例获得完全缓解 ,完全缓解率为 4 4%。 5 0例病人共随访了 (8±s 5 )wk ,2～ 30wk ,病人 16wk的无病生存 (PFS)率为 87%。标准剂量组和增强剂量组疗效无显著差异 ,连续输注和间隔输注疗效差异亦无显著意义 (P >0 .0 5 )。所有病人在治疗过程中对本方案均能较好耐受 ,主要的不良反应为输注相关的不良反应 (32 % )和化疗相关的血液学不良反应 (2 0 % )。　结论 :利妥昔单?     

利妥昔单抗联合CHOP方案治疗弥漫大B细胞性淋巴瘤的多中心临床研究

目的:观察利妥昔单抗联合环磷酰胺、长春新碱、多柔比星及泼尼松(CHOP方案)治疗新诊断的弥漫性大B细胞性淋巴瘤(DLBL)的临床疗效. 方法:2002年4月至2003年2月,共52例病人进入本研究.化疗采用标准的CHOP方案:d 1,环磷酰胺600 mg·m-2,长春新碱1.4 mg·m-2,多柔比星25 mg·m-2,泼尼松60 mg·m-2×5 d,每3 wk一个疗程,共6个疗程.利妥昔单抗静脉滴注剂量为375 mg·m-2,于化疗第一个疗程前2 d开始,每周输注1次(连续输注),连续4次(标准剂量)或6次(增强剂量);或于每疗程的CHOP方案化疗前2 d输注,每3周1次(间隔输注),输注4次(标准剂量)或6次(增强剂量).结果:50例病人进入临床疗效评估, 60 %获得完全缓解,总有效率为 100 %.其中,34例Ann Arbor分期为Ⅲ期或Ⅳ期的病人有15例获得完全缓解,完全缓解率为44 %.50例病人共随访了(8±s 5) wk, 2～30 wk,病人16 wk的无病生存(PFS)率为87 %.标准剂量组和增强剂量组疗效无显著差异,连续输注和间隔输注疗效差异亦无显著意义(P>0.05).所有病人在治疗过程中对本方案均能较好耐受,主要的不良反应为输注相关的不良反应(32 %)和化疗相关的血液学不良反应(20 %). 结论:利妥昔单抗联合CHOP方案可有效用于治疗新诊断的弥漫性大B细胞性淋巴瘤,它具有较高的完全缓解率,而且在治疗中不良反应较小.     

Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia

Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin's lymphoma (NHL) and B-cell chronic lymphocytic leukaemia (CLL). While the optimal use of the drug in many clinical settings has yet to be clarified, two pivotal trials have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL, and as a standard first-line treatment option when combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (the most common type of aggressive NHL). The former was a noncomparative trial in relapsed indolent NHL (follicular and small lymphocytic subtypes) with clinical responses achieved in about half of patients treated with rituximab 375 mg/m(2) intravenously once weekly for 4 weeks, which was similar to some of the most encouraging results reported with traditional chemotherapeutic agents. The latter was a randomised comparison of eight cycles of CHOP plus rituximab 375 mg/m(2) intravenously (one dose per cycle) versus CHOP alone in previously untreated elderly patients (60 to 80 years of age) with diffuse large B-cell lymphoma. In this pivotal trial, 2-year event-free and overall survival were significantly higher with rituximab plus CHOP, and there was no increase in clinically significant adverse effects compared with CHOP alone. Treatment with rituximab is generally well tolerated, particularly in terms of adverse haematological effects and serious or opportunistic infections relative to standard chemotherapy. Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions. In approximately 10% of patients, however, severe infusion-related reactions develop (e.g. bronchospasm, hypotension). These reactions are usually reversible with appropriate interventions and supportive care but there have been rare reports of fatalities. CONCLUSIONS: Clinical trials with rituximab indicate that the drug has broad application to B-cell malignancies, although further clarification is needed to determine its optimal use in many of these clinical settings. Importantly, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated diffuse large B-cell lymphoma, at least in elderly patients. Compared with conventional chemotherapy, rituximab is associated with markedly reduced haematological events such as severe neutropenia, as well as associated infections. Rituximab may be particularly suitable for elderly patients or those with poor performance status, and its tolerability profile facilitates its use in combination with cytotoxic drugs. PHARMACODYNAMIC PROPERTIES: Rituximab is a mouse/human chimaeric IgG(1)-kappa monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal B lymphocytes. Although treatment with rituximab induces lymphopenia in most patients, typically lasting about 6 months, a full recovery of B lymphocytes in the peripheral blood is usually seen 9-12 months after therapy, as CD20 is not expressed on haematopoietic stem cells. CD20 is, however, expressed on >90% of B-cell non-Hodgkin's lymphomas (NHL) and to a lesser degree on B-cell chronic lymphocytic leukaemia (CLL) cells.Although not fully elucidated, the cytotoxic effects of rituximab on CD20-positive malignant B cells appears to involve complement-dependent cytotoxicity, complement-dependent cellular cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. In addition, in vitro data indicate that rituximab sensitises tumour cells to the effects of conventional chemotherapeutic drugs. PHARMACOKINETIC PROPERTIES: Serum rituximab concentrations increased in proportion to dose across a wide range of single- and multiple-dose intravenous regimens in patients with B-cell NHL. When administll NHL. When administered at a dose of 375 mg/m(2) once weekly for 4 weeks in a pivotal trial in patients with relapsed or refractory indolent B-cell NHL (follicular or small lymphocytic subtypes), peak serum concentrations essentially doubled from the first (239.1 mg/L) to the fourth (460.7 mg/L) infusion, while elimination half-life (t(1/2)) increased from 76.3 to 205.8 hours (3.2 to 8.6 days). The concomitant increase in serum rituximab concentrations and t(1/2) with each successive infusion may be due, at least in part, to the elimination of circulating CD20-positive B cells and reduction or saturation of CD20-binding sites after the initial infusions of rituximab. The pharmacokinetic properties of rituximab are also characterised by wide inter-individual variability, and serum drug concentrations that are correlated with clinical response. Although pharmacokinetic data are limited in patients with aggressive forms of NHL, such as diffuse large B-cell lymphoma, rituximab appears to have a similar pharmacokinetic profile in these patients to that in patients with indolent B-cell NHL. The pharmacokinetics of rituximab are also reported to be similar whether the drug is administered with or without cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy. THERAPEUTIC USE: A number of studies have demonstrated efficacy of intravenous rituximab in patients with various lymphoid malignancies of B-cell origin, including indolent (e.g. follicular lymphoma) and aggressive (e.g. diffuse large B-cell lymphoma) forms of NHL, and CLL, but the drug has not yet been approved for use in CLL, and approved indications in NHL vary between countries. In the US, for example, rituximab is available for the treatment of patients with low-grade or follicular, relapsed or refractory, CD20-positive B-cell NHL. In Europe, the drug has similar approval for relapsed or refractory follicular NHL as in the US, but has also been approved for use in combination with CHOP chemotherapy for the most common aggressive form of NHL (CD20-positive, diffuse large B-cell lymphoma). Rituximab was approved for these indications primarily on the basis of results from two pivotal trials. In Japan, rituximab has been approved for indolent B-cell NHL and mantle cell lymphoma (an aggressive form of B-cell NHL), primarily on the basis of results of a Japanese phase II trial. Indolent NHL: Results of several studies evaluating rituximab 375 mg/m(2) once weekly for 4 weeks in patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic lymphomas) showed objective response (OR) rates ranging from approximately 40-60% in those receiving the drug for relapsed or refractory indolent B-cell NHL, and slightly higher (50-70%) for those receiving rituximab as first-line therapy. In a pivotal trial in 166 patients with relapsed or refractory low-grade or follicular B-cell NHL, intent-to-treat (ITT) analysis showed an OR rate of 48%, and a projected median time to progression of 13 months.Encouraging data are also emerging on the use of rituximab in combination with chemotherapeutic agents (e.g. CHOP, fludarabine-containing regimens) or other drugs (e.g. interferon-alpha2a) in previously untreated patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic subtypes). Rates for OR were consistently around 95%, with the majority being complete responses (CRs). Follow-up data from a study in 40 patients with low-grade or follicular B-cell NHL treated with rituximab plus CHOP as first-line therapy showed that responses were durable with a progression-free survival and median duration of response >5 years.Bcl-2 gene rearrangement (t14;18) occurs in malignant cells in up to 85% of patients with follicular lymphoma, and minimal residual disease in peripheral blood and bone marrow can be monitored using polymerase chain reaction (PCR). In several studies assessing blood and/or bone marrow, rituximab has achieved molecular response (conversion from PCR-positive to PCR-negative bcl-2 status) in at least half of the patients. Aggressive NHL: Studies with rituximab as monotherapy in aggressive B-cell NHL, a potentially curable disorder, have generally been restricted to patients with relapsed or recurrent disease, since CHOP has traditionally been the standard first-line treatment regimen. However, promising results from phase II monotherapy studies prompted further clinical investigation of rituximab in conjunction with chemotherapy. Thus, most studies with rituximab in patients with aggressive forms of B-cell NHL have involved combination therapy, including a pivotal randomised trial comparing eight cycles of standard CHOP therapy plus rituximab 375 mg/m(2) (one dose per cycle) versus CHOP alone in 399 previously untreated elderly patients (60-80 years of age) with diffuse large B-cell lymphoma. Results of the pivotal trial showed a clear advantage for rituximab plus CHOP versus CHOP in terms of event-free survival (primary endpoint) at 2 years (57% vs 38%, p < 0.001). Overall survival at 2 years (70% vs 57%, p < 0.01) and CR rate (76% vs 63%, p < 0.01) were also higher with the rituximab-CHOP combination. Other, smaller trials with rituximab in combination with CHOP or other chemotherapeutic regimens, either as first-line therapy or for patients with relapsed or refractory aggressive B-cell NHL, have also shown promising results in terms of clinical response rates.CLL: In relatively small trials (n < 40) conducted primarily in patients with relapsed or refractory B-cell CLL, rituximab monotherapy (various regimens) achieved OR rates of 23-45%, with median duration of response ranging from approximately 3-10 months. (ABSTRACT TRUNCATED)     

Rituximab and other emerging monoclonal antibody therapies for lymphoma

The recent approval of rituximab, gemtuzumab ozogamicin, alemtuzumab and ibritumomab tiuxetan by the FDA in the US revealed clear evidence that monoclonal antibodies (mAbs) have significant roles in the current treatment of haematologic malignancies. Among the mAbs under clinical development, anti-CD20 mAbs have been most extensively investigated and have shown definitive clinical efficacy. Rituximab is a genetically engineered chimeric anti-CD20 mAb, with mouse variable and human constant regions. Consecutive clinical trials conducted in the US, Europe and Japan have revealed that rituximab is a highly effective agent with acceptable toxicities against indolent and aggressive B cell non-Hodgkin’s lymphomas (B-NHLs) as a single agent and in combination with cytotoxic drugs. A recent French Phase III study in elderly patients with untreated aggressive B-NHL suggested that the addition of rituximab to standard CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy increases the complete response rate and prolongs event-free and overall survival. Lymphoma cells are inherently sensitive to radiation. The aim of radioimmunotherapy is to use the mAb to target radiation to lymphoma tissue while minimising toxicity to normal cells. The clinical trials of ⁹⁰Y ibritumomab tiuxetan and ¹³¹I tositumomab showed they have definitive efficacy in relapsed indolent B-NHL with acceptable toxicities. A recent comparative study in relapsed indolent B-NHL showed that ⁹⁰Y ibritumomab tiuxetan produces higher response rates than rituximab. In addition, BL22, a recombinant anti-CD22 immunotoxin, showed significant efficacy in patients with chemotherapy-resistant hairy cell leukaemia. MAbs will have significant roles in the treatment of lymphoid malignancies in the future.     

Rituximab and other emerging monoclonal antibody therapies for lymphoma

The recent approval of rituximab, gemtuzumab ozogamicin, alemtuzumab and ibritumomab tiuxetan by the FDA in the US revealed clear evidence that monoclonal antibodies (mAbs) have significant roles in the current treatment of haematologic malignancies. Among the mAbs under clinical development, anti-CD20 mAbs have been most extensively investigated and have shown definitive clinical efficacy. Rituximab is a genetically engineered chimeric anti-CD20 mAb, with mouse variable and human constant regions. Consecutive clinical trials conducted in the US, Europe and Japan have revealed that rituximab is a highly effective agent with acceptable toxicities against indolent and aggressive B cell non-Hodgkin's lymphomas (B-NHLs) as a single agent and in combination with cytotoxic drugs. A recent French Phase III study in elderly patients with untreated aggressive B-NHL suggested that the addition of rituximab to standard CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy increases the complete response rate and prolongs event-free and overall survival. Lymphoma cells are inherently sensitive to radiation. The aim of radioimmunotherapy is to use the mAb to target radiation to lymphoma tissue while minimising toxicity to normal cells. The clinical trials of 90Y ibritumomab tiuxetan and (131)I tositumomab showed they have definitive efficacy in relapsed indolent B-NHL with acceptable toxicities. A recent comparative study in relapsed indolent B-NHL showed that 90Y ibritumomab tiuxetan produces higher response rates than rituximab. In addition, BL22, a recombinant anti-CD22 immunotoxin, showed significant efficacy in patients with chemotherapy-resistant hairy cell leukaemia. MAbs will have significant roles in the treatment of lymphoid malignancies in the future.     

Cost-effectiveness analysis of the addition of rituximab to CHOP in young patients with good-prognosis diffuse large-B-cell lymphoma

BACKGROUND and objective: Diffuse large-B-cell lymphoma (DLBCL) is an aggressive form of lymphoma. It accounts for 30-40% of all new cases of non-Hodgkin's lymphoma and is the subtype with the highest overall incidence. Before the development of monoclonal antibodies, the standard treatment of newly diagnosed DLBCL was based on combination therapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Current treatment consists of the combination of CHOP and the monoclonal antibody rituximab (R-CHOP regimen), with recovery rates of 70%. The aim of this study was to compare the efficacy (survival) and direct medical costs of two chemotherapy regimens, R-CHOP and CHOP, in the treatment of DLBCL in young patients with a good prognosis. METHODS: A decision-analysis model with tree structure was used to compare R-CHOP and CHOP in the treatment of young patients with DLBCL from the perspective of the Italian National Health Service. Patients entered at the root of the tree and followed one of the six possible therapeutic pathways. After receiving one of the two chemotherapy treatments (R-CHOP or CHOP) for 5 months, patients could have a complete response or not. In the presence of no response, patients underwent rescue therapy. In the case of relapse after 3 years' follow-up (following an initial complete response at 5 months), patients were given rescue therapy. The model provided an estimate of mean survival (life-years gained [LYG]) and mean costs (direct medical costs) over a period of 3 years. Both survival and costs were discounted at a rate of 3%. Costs were in euro, year 2007 values. Several sensitivity analyses were carried out with varying clinical parameters. RESULTS: The LYG with the R-CHOP regimen was higher (2.697 LYG per patient) than with the CHOP regimen (2.517 LYG per patient). When taking into account the cost of rescue therapy, the overall mean treatment cost per patient was lower with the R-CHOP regimen (22,113.44 euro) than with the CHOP regimen (22,831.17 euro). Sensitivity analyses showed that the incremental cost-effectiveness ratios per LYG for complete response at 5 months (16,816.00 euro) and for relapse-free survival at 3 years (11,967.12 euro) were below the internationally accepted threshold (50,000 euro). Furthermore, for survival at 3 years, R-CHOP was confirmed as the dominant therapy (lower expected mean costs, higher number of LYG). CONCLUSIONS: Our study demonstrated the clinical and economic benefits of adding rituximab to a CHOP chemotherapy regimen in young patients who present with DLBCL with good prognosis. The higher costs associated with rituximab were offset by the significantly lower rescue therapy costs. Further studies that include patients with unfavourable prognosis are needed to confirm these findings.     

Mechanism of action of rituximab

Rituximab, the humanized chimeric anti-CD20 monoclonal antibody, represents a powerful tool for treating B-cell malignancies and is licensed for the treatment of relapsed or chemorefractory low-grade or follicular non-Hodgkin's lymphoma (NHL). It has a unique mode of action and can induce killing of CD20+ cells via multiple mechanisms. The direct effects of rituximab include complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity, and the indirect effects include structural changes, apoptosis, and sensitization of cancer cells to chemotherapy. In vitro studies have made a significant contribution to the understanding of these mechanisms of action and have led to the development of innovative and effective treatment strategies to optimize patient response. The most significant of these strategies is the combination of rituximab and CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone), which is proving a highly effective combination in the treatment of NHL. However, all patients do not respond equally well to rituximab, and in vitro studies have identified a possible mechanism of resistance involving the anti-complement inhibitors CD55 and CD59. Neutralizing antibodies to CD55 and CD59 can overcome resistance to rituximab-mediated complement-mediated cytotoxicity in vitro. This paper overviews our understanding of the mechanisms of action of rituximab and identifies how this knowledge could be applied in a clinical setting to maximize response in both sensitive and resistant patients.     

Monoclonal antibodies in the treatment of cancer, Part 2.

Monoclonal antibodies used in the treatment of cancer are discussed. Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to having direct cellular effects, antibodies can carry substances, such as radioactive isotopes, toxins, and antineoplastic agents, to the targeted cells. Five monoclonal antibodies--rituximab, trastuzumab, gemtuzumab ozogamicin, alemtuzumab, and ibritumomab tiuxetan--are available for clinical use. Rituximab is active against indolent lymphomas, providing a valuable alternative for patients with relapsed or refractory disease. Rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) increased survival over CHOP alone in patients with high-grade lymphomas. Trastuzumab has significant activity against HER-2-positive breast cancer, especially in combination with paclitaxel or an anthracycline and cyclophosphamide. Gemtuzumab ozogamicin is an active second-line therapy in older patients with acute myelogenous leukemia, but its role in combination regimens is unclear. Alemtuzumab is a valuable option for salvage therapy of patients with chronic lymphocytic leukemia. Ibritumomab tiuxetan delivers radioactive isotopes to tumor cells and is active against indolent lymphomas in patients who have relapsed after chemotherapy or rituximab therapy. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumor lysis syndrome, arrhythmias, and pulmonary dysfunction. Alemtuzumab causes immunosuppression, increasing the risk of infection. Gemtuzumab ozogamicin may cause hepatotoxicity, and trastuzumab may cause significant pulmonary or cardiac toxicity. Investigational monoclonal antibodies include edrecolomab and tositumomab. Monoclonal antibodies have a significant role in the management of patients with advanced refractory or relapsed lymphomas and leukemias.     

Monoclonal antibodies in the treatment of cancer, Part 1.

Monoclonal antibodies used in the treatment of cancer are discussed. Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to having direct cellular effects, antibodies can carry substances, such as radioactive isotopes, toxins, and antineoplastic agents, to the targeted cells. Five monoclonal antibodies--rituximab, trastuzumab, gemtuzumab ozogamicin, alemtuzumab, and ibritumomab tiuxetan--are available for clinical use. Rituximab is active against indolent lymphomas, providing a valuable alternative for patients with relapsed or refractory disease. Rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) increased survival over CHOP alone in patients with high-grade lymphomas. Trastuzumab has significant activity against HER-2-positive breast cancer, especially in combination with paclitaxel or an anthracycline and cyclophosphamide. Gemtuzumab ozogamicin is an active second-line therapy in older patients with acute myelogenous leukemia, but its role in combination regimens is unclear. Alemtuzumab is a valuable option for salvage therapy of patients with chronic lymphocytic leukemia. Ibritumomab tiuxetan delivers radioactive isotopes to tumor cells and is active against indolent lymphomas in patients who have relapsed after chemotherapy or rituximab therapy. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumor lysis syndrome, arrhythmias, and pulmonary dysfunction. Alemtuzumab causes immunosuppression, increasing the risk of infection. Gemtuzumab ozogamicin may cause hepatotoxicity, and trastuzumab may cause significant pulmonary or cardiac toxicity. Investigational monoclonal antibodies include edrecolomab and tositumomab. Monoclonal antibodies have a significant role in the management of patients with advanced refractory or relapsed lymphomas and leukemias.     

GLD 与 CHOP 方案一线治疗外周 T 细胞淋巴瘤的疗效分析

目的 探讨GLD(吉西他滨+奥沙利铂+地塞米松)与CHOP(环磷酰胺+多柔比星/表柔比星+长春新碱+泼尼松)方案一线治疗外周T细胞淋巴瘤的疗效与安全性。方法 回顾性分析2010年1月—2015年4月诊治的外周T细胞淋巴瘤患者35例。17例采用GLD方案,18例采用CHOP方案。对比两组的疗效与不良反应。结果 GLD组与CHOP组客观有效率(ORR)分别为64.7%和50.0%,差异无统计学意义(P>0.05)。但NK/T细胞淋巴瘤亚型的ORR分别为100%和50%,差异有统计学意义(P<0.05)。GLD组与CHOP组中位无进展生存期(PFS)(12月 vs 4月)及2年生存率(73.2% vs 36.1%)的差异均有统计学意义(P<0.05)。两组不良反应主要为骨髓抑制,差异无统计学意义(P>0.05)。 结论 GLD方案治疗外周T细胞淋巴瘤近期疗效与CHOP方案相似(NK/T细胞亚型疗效优于CHOP方案),远期疗效优于CHOP方案,不良反应可耐受,是值得推广的一线治疗方案。     

Treatment of AIDS Related Non-Hodgkin's Lymphoma with Combination Mitoguazone Dihydrochloride and Low Dose Chop Chemotherapy: Results of a Phase II study

PURPOSE: To evaluate the response and side effects of combination therapy with low dose CHOP chemotherapy and mitoguazone dihydrochloride in patients with non-Hodgkin's lymphoma associated with the acquired immunodeficiency syndrome (AIDS-NHL). METHODS: Eighteen patients newly diagnosed with intermediate or high-grade AIDS-NHL were treated with low dose CHOP as follows: day 1, cyclophosphamide 350 mg/m(2), intravenously (IV); doxorubicin 25mg/m(2) IV; vincristine 2mg IV; and prednisone 100mg given orally on days 1 through 5. In addition, mitoguazone dihydrochloride was given at a dose of 600 mg/m(2) IV on days 1 and 15 of each 28-day treatment cycle. RESULTS: Seventeen males and one female patient were accrued. Twelve patients had high-grade pathologies while the remainder had an intermediate grade pathology (diffuse large cell). The median CD4+ lymphocyte count was 98/dl (range 1-924). Three patients (17%) reported an AIDS-defining illness prior to lymphoma diagnosis. Of 14 evaluable patients, 6 (43%) achieved a complete remission and 5 (35%) a partial remission. The median failure free and overall survival times were 6.5 and 8.4 months, respectively. Major toxicity was hematologic with grade 3 or 4 neutropenia in 72%; two patients died of neutropenic sepsis. CONCLUSIONS: Mitoguazone in combination with low dose CHOP is a safe regimen, associated with a response rate of 79% (CR 43%, PR 36%, 95% CI=49-95%). These preliminary results suggest no major improvement in terms of response over use of CHOP without mitoguazone.     

Biweekly CHOP therapy improves therapeutic effect in the non-GCB subtype of diffuse large B-cell lymphoma

CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) is accepted as the best available standard treatment for diffuse large B-cell lymphoma (DLBCL) patients; however, the therapeutic efficacy seems unsatisfactory. Additional rituximab will improve the cure rate, but it is not popular in China because of its increased medical cost. Germinal center B-cell (GCB) and non-GCB subtypes distinction have been described as independent prognostic factors, and provides likelihood for cure with chemotherapy. The aim of the study is to explore the association between Immunophenotype and treatment regimen. Between August 2003 and May 2006, 66 patients with DLBCL were enrolled, according to immunohistochemistry results (GCB and non-GCB phenotype), randomly assigned to receive either six to eight cycles of CHOP every 2 weeks or standard CHOP every 3 weeks. After a median follow-up duration of 32 months (range of 4 to 42 months), an estimated 3-year overall survival (OS) rate for the GCB patients were 68.2% and 55.6% for the biweekly CHOP regimen and standard CHOP regimen respectively, while the data were 62.8% and 37.9% respectively for the non-GCB cases. The biweekly CHOP therapy showed higher efficacy than standard treatment, and its superiority was more obvious with the non-GCB subgroup. All rights reserved.     

Pixantrone: a novel aza-anthracenedione in the treatment of non-Hodgkin's lymphomas

Pixantrone (BBR-2778) is a novel mitoxantrone-like drug, which lacks the 5,8-dihyroxy substitution groups thought to be responsible for the cardiac toxicity associated with mitoxantrone. In Phase I/II single-agent pixantrone clinical trials, neutropenia was the dose-limiting toxicity and the maximum tolerated dose was 150 mg/m(2)/week for 3 weeks every 4 weeks. In relapsed aggressive non-Hodgkin's lymphomas, weekly single-agent pixantrone 85 mg/m(2) for 3 weeks every 4 weeks was associated with a 27% overall response and a 15% complete response. When intensively pretreated patients with relapsed aggressive non-Hodgkin's lymphoma were treated with a cyclophosphamide, pixantrone, vincristine and prednisolone regimen (pixantrone substituted for doxorubicin in standard regimen [cyclophosphamide, doxorubicin, vincristine and prednisolone regimen (CHOP)]), the overall response was 74% and complete response 57%. In the BBR-2778, methylprednisolone, cisplatin and cytosine arabinoside (BSHAP) regimen, 58% overall response and 37% complete response were achieved. A number of randomised studies of pixantrone (BBR-2778) in patients with relapsed indolent or aggressive lymphomas are ongoing.     

Complete remission of primary bilateral adrenal lymphoma achieved by Rituximab-CHOP chemotherapy

Primary adrenal lymphoma (PAL) is an exceedingly rare disease. Because of its rareness, uncertain etiology, variable duration of survival, unremarkable clinical presentations and unsatisfied therapeutic strategies, its treatment has always been unsatisfactory. Here we report a 50-year-old male patient with primary bilateral adrenal diffuse large B-cell lymphoma. He was treated with surgery followed by combined chemotherapy using R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). He achieved complete remission after 3 cycles of chemotherapy. At present, he is considered free of tumor at 3 years after chemotherapy. Our case report demonstrates that patients with primary bilateral adrenal diffuse large B-cell lymphoma may achieve a good outcome using R-CHOP chemotherapy. To the best of our knowledge, our patient who achieved complete remission after R-CHOP chemotherapy has had the longest survival as published in the literature.     

Monoclonal antibodies in the treatment of non-Hodgkin's lymphoma

Antibody-based therapeutic approaches have had a significant impact in the treatment of non-Hodgkin's lymphoma (NHL). Rituximab's development as an anti-CD20 antibody heralded a new era in treatment approaches for NHL. While rituximab was first shown to be effective in the treatment of relapsed follicular lymphoma, it is now standard monotherapy for front-line treatment of follicular lymphoma, and is also used in conjunction with chemotherapy for other indolent, intermediate and aggressive B-cell lymphomas. The development of rituximab has led to intense interest in this type of therapeutic approach and to development and approval of the radioimmunoconjugates of rituximab, (90)Y-ibritumomab tiuxetan and (131)I-tositumomab, which have added to the repertoire of treatments for relapsed follicular lymphoma and increased interest in developing other conjugated antibodies. Since rituximab is a chimeric antibody, there is a need to develop fully humanised antibodies, such as IMMU-106 (hA20), in order to minimise infusion reactions and eliminate the development of human antibodies against the drug. Further clinical evaluation of antibodies has been based largely on our knowledge of antigen expression on the surface of lymphoma cells and has led to the development of antibodies against CD22 (unconjugated epratuzumab and calicheamicin conjugated CMC-544 [inotuzumab ozogamicin]), CD80 (galiximab), CD52 (alemtuzumab), CD2 (MEDI-507 [siplizumab]), CD30 (SGN-30 and MDX-060 [iratumumab]), and CD40 (SGN-40). Furthermore, the VEGF (vascular endothelial growth factor) inhibitor bevacizumab, which was first approved for the treatment of colon cancer is currently under investigation in NHL, and agonists rather than antibodies to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) [rApo2L/TRAIL, HGS-ETR1{mapatumumab}, HGS-ETR2] are currently being investigated as treatments for both advanced solid tumours and NHL. Knowledge of the ability of cancer cells to become resistant to a targeted therapy by activating an alternative pathway to evade apoptosis has driven studies that combine antibodies such as epratuzumab plus rituximab (ER) or ER plus chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) [ER-CHOP], inotuzumab ozogamicin plus rituximab, alemtuzumab plus CHOP (CHOP-C), bevacizumab plus rituximab, and now the combination of rApo2L/TRAIL plus rituximab. As a result of the expansion of research in this area, several treatment-specific adverse effects have been noted, including infusion-related reactions for rituximab, myelosuppression secondary to (90)Y-ibritumomab tiuxetan and (131)I-tositumomab, and immunosuppression leading to infectious complications for alemtuzumab. Also, soluble forms of the antigens (sCD30) are now being investigated as potential mechanisms of resistance to antibody treatments by binding the antibody before the drug can bind to the lymphoma cell. In addition, it has also become apparent that these antibodies often have a dose-dependent half-life (rituximab) or long half-lives of up to 2-3 weeks (epratuzumab and galiximab) with a consequent delay to a response, thus influencing how long we should wait for a response before declaring an antibody to be ineffective. Antibody-based therapeutic approaches have already had a profound impact on the treatment of NHL, and it is almost certain that, as their clinical development progresses, we will continue to refine the optimum methods of incorporating these drugs in NHL treatment in order to offer our patients the best clinical benefits.     

Influence of amifostine on toxicity of CHOP in elderly patients with aggressive non-Hodgkin's lymphoma--a phase II study

Due to concerns about toxicity, many elderly patients with aggressive non-Hodgkin's lymphoma (NHL) are not considered candidates for standard chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). The cytoprotective agent amifostine has the potential to reduce toxicity when added to chemotherapy. The purpose of the current study was to examine the toxicity of CHOP combined with amifostine in elderly patients with aggressive NHL. A prospective phase II study was performed in patients aged 60 years and older. Patients with stage I/II disease received 4 cycles of CHOP followed by involved-field irradiation. Patients with stage III/IV received 6-8 cycles of CHOP. Amifostine (740 mg/m(2)) was administered as a 15-min i.v. infusion immediately before chemotherapy. Forty-one (median age 69.5 years, range 60-87) of 49 consecutive previously untreated patients, aged 60 years and older, with aggressive NHL seen in our center were included in the study. Twenty-one patients had stage I/II disease and 20 had stage III/IV disease. The patients received a total of 207 cycles of amifostine-CHOP. Infusion of amifostine caused mild to moderate transient side effects, including a drop of systolic blood pressure >20 mmHg in 54 cycles and nausea/vomiting in 36 cycles. Hematotoxicity of CHOP consisted of leukopenia grade 4 in only 15.4% of cycles. There were two cases of grade 3 anemia. No thrombocytopenia higher than grade 2 occurred. Febrile neutropenia was rare, occurring in 4.3% of cycles. One patient died after the first CHOP administration because of anthracycline-related acute cardiomyopathy (corresponding to a toxic death rate of 2.4%). The complete response rates were 85 and 75% in stage I/II and stage III/IV patients, respectively. After median follow-up of 33 months (range 17-50 months) the median overall survival was not reached in patients with stage I/II and was found to be 32 months in patients with stage III/IV. At 2 years, 76% of patients with stage I/II and 70% with stage III/IV were alive. Twelve of the 15 patients who died were aged older than 70. Amifostine pre-treatment was associated with a low toxicity of CHOP in elderly patients with aggressive NHL treated with curative intent. Treatment outcomes appeared not to be impaired by the addition of amifostine to CHOP. This schedule merits further testing in a randomized trial.