Development of a drug–disease simulation model for rituximab in follicular non-Hodgkin's lymphoma

AIM

Rituximab has dramatically improved the survival of patients with non-Hodgkin''s lymphomas (NHL), but the dosing regimen currently used should be optimized. However, the concentration–effect relationship of rituximab has never been described by pharmacokinetic–pharmacodynamic (PK–PD) modelling, precluding the simulation of new dosing regimens. The aim of this study was to develop a PK–PD model of rituximab in relapsed/resistant follicular NHL (FL).

METHODS

A model describing the relationship between rituximab concentrations and progression-free survival (PFS) was developed using data extracted from the pivotal study, which evaluated 151 relapsed/resistant FL patients. The influence of FCGR3A genetic polymorphism on the efficacy of rituximab was quantified using data from 87 relapsed/resistant FL patients. The predictive performance of the model was analysed using two independent datasets: a study that evaluated rituximab combined with chemotherapy [rituximab, cyclophosphamide, vincristine, adriamycin and prednisone (R-CHOP)] in 334 relapsed/resistant FL patients and a study that evaluated rituximab monotherapy in 47 asymptomatic FL patients with known FCGR3A genotype.

RESULTS

For R-CHOP, observed and model-predicted PFS (90% confidence interval) at 24 months were 0.50 and 0.48 (0.40, 0.56), respectively, for the observation arm, and 0.62 and 0.59 (0.50, 0.65), respectively, for the rituximab maintenance arm. For rituximab monotherapy, observed and predicted PFS at 24 months were 0.67 and 0.63, respectively, for FCGR3A-V/V patients, and 0.41 and 0.36 (0.25, 0.49), respectively, for FCGR3A-F carriers.

CONCLUSIONS

Our model provides a satisfactory prediction of PFS at 24 months. It can be used to simulate new dosing regimens of rituximab in populations of FL patients and should improve the design of future clinical trials.     

Model-based design of rituximab dosage optimization in follicular non-Hodgkin's lymphoma

AIMS

Rituximab has dramatically improved the survival of patients with non-Hodgkin''s lymphoma (NHL). However, studies have suggested that the dose regimen currently used (i.e. 375 mg m⁻²) could be optimized. The aims of this study were to quantify the benefits of the new dose regimen for rituximab in follicular NHL (FL) patients using a previously validated PK–PD model and to design clinical trials investigating optimization of rituximab dosage.

METHODS

A PK–PD model was used to predict progression-free survival (PFS) of FL patients treated by rituximab alone in asymptomatic FL, and those treated by rituximab combined with chemotherapy (R-CHOP) in relapsed/resistant FL. This model accounts for the influence of a polymorphism in FCGR3A, the gene encoding the FcγRIIIa receptor, on clinical efficacy. Several induction and maintenance dose regimens using rituximab alone or in combination with conventional chemotherapy (CHOP) were tested. The benefits of rituximab dose adjustment for F carriers were investigated. The numbers of subjects required for the design of two-armed clinical trials were calculated using model-predicted PFS at a power of 80%.

RESULTS

The model predicted a potential benefit of 1500 mg m⁻² maintenance doses of rituximab for both rituximab monotherapy and R-CHOP. The model shows that the PFS of FCGR3A-F carriers remains lower than that of homozygous FCGR3A-VV patients, even with markedly increased rituximab doses.

CONCLUSION

Our results suggest a benefit of increasing doses of rituximab in FL, both during induction and maintenance. These results need to be confirmed in controlled clinical trials.     

Rituximab therapy for indolent non-Hodgkin's lymphoma

Indolent non-Hodgkin's lymphomas (NHLs) are essentially incurable with current treatments. Rituximab is a specific anti-CD20 chimeric monoclonal antibody against the CD20 antigen, which is stably expressed on most B-cells (from the pre-B-cell stage). Compared with chemotherapy, rituximab has an excellent tolerability profile, making it a good therapeutic option for patients with indolent NHL. In the pivotal study for rituximab, patients with relapsed or refractory indolent or follicular lymphoma (FL) had an overall response rate of 50%. There is evidence that first-line rituximab therapy may be associated with better response rates; in previously untreated FL with a low tumor burden, rituximab monotherapy has produced an overall response rate of 73%. Attempts to improve response rates to rituximab by increasing the dose or frequency of dosing showed that the addition of four extra infusions of rituximab (in addition to the standard treatment schedule) resulted in an overall response rate of 76% in patients with FL. Augmenting rituximab with cytokines is also an option for increasing response rates in patients with indolent NHL. In a trial by the Nordic Lymphoma Study Group in patients with previously untreated or first-relapse indolent NHL, who had stable disease or a partial response after four doses of rituximab, 48% of the patients treated with rituximab plus interferon-alpha2a achieved a complete response. A further option is to combine rituximab with chemotherapy. Interim analyses from the East German Study Group have shown that rituximab plus mitoxantrone, chlorambucil and prednisolone (MCP) resulted in overall response rates of 89% in patients with untreated indolent lymphoma. Rituximab is therefore an excellent treatment option both as first-line and as salvage therapy for patients with indolent NHL.     

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)     

Rituxan immunotherapy and zevalin radioimmunotherapy in the treatment of non-Hodgkin's lymphoma

Immunotherapy with the anti-CD20 monoclonal antibody rituximab has been shown in clinical trials to be effective in the treatment of both indolent and aggressive non-Hodgkin's lymphomas (NHL). Recent studies have demonstrated improved clinical benefit with extended dose and maintenance therapies in patients with indolent lymphomas and chronic lymphocytic leukemia. Rituximab's label was recently expanded to include treatment of bulky disease, retreatment of patients previously treated with rituximab, and an eight-week extended treatment schedule. Rituximab has also been effectively combined with chemotherapy, resulting in higher response rates and longer response durations in randomized trials in patients with aggressive lymphoma. Studies continue to evaluate and expand the role of rituximab in the treatment of NHL, including its use in combined immunotherapy approaches and autologous stem cell transplant as well as in the treatment of autoimmune disorders. Radioimmunotherapy with the rituximab and ibritumomab tiuxetan (Zevalin) regimen was recently approved for the treatment of relapsed or refractory low-grade, follicular or CD20+ transformed NHL, including rituximab refractory follicular NHL. The regimen is delivered on an outpatient basis over the course of a week. Studies are currently exploring sequential dose therapy, radioimmunotherapy with rituximab maintenance, and ibritumomab tiuxetan radioimmunotherapy as part of autologous stem cell transplant. Current understanding of the mechanisms of action of rituximab and the use of rituximab and ibritumomab tiuxetan in patients with indolent and aggressive NHL will be discussed.     

Aggressive lymphoma: improving treatment outcome with rituximab

The standard therapy for patients with aggressive lymphoma is cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, which achieves a complete response in more than 60% of patients but is curative in only about 40-50%. More aggressive and/or dose-intensified chemotherapy regimens have failed to provide significant survival advantages compared with CHOP, and may have higher toxicity. Rituximab, a chimeric monoclonal antibody to the CD20 antigen, is effective as monotherapy in aggressive lymphoma and in combination with chemotherapy has demonstrated high response rates in phase II trials. A scheduled interim analysis of a randomized, prospective trial comparing rituximab plus CHOP with CHOP alone in elderly patients with untreated diffuse large B-cell lymphoma has shown significantly better response rates and survival with rituximab plus CHOP compared with CHOP alone. These results represent the first significant improvement in overall survival over CHOP in aggressive lymphoma for over 20 years. The addition of rituximab was not associated with significant additional toxicity over that seen with CHOP alone. Ongoing studies are underway to establish whether the survival benefit of rituximab plus CHOP is seen in younger patient populations. Rituximab in combination with chemotherapy is also being evaluated as salvage treatment for patients who relapse after initial chemotherapy. In a preliminary analysis of a study in 50 patients with refractory or relapsed aggressive lymphoma, rituximab plus etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (EPOCH) chemotherapy has demonstrated promising results when used as sole salvage therapy and as an induction therapy prior to autologous stem-cell transplantation, again without significant additional toxicity.     

Current treatment of follicular and low-grade non-Hodgkin's lymphoma

Patients with low-grade non-Hodgkin's lymphoma (NHL) have a median survival of 4-8 years from diagnosis and a cause-specific survival of about 10 years. Radiotherapy can be curative in a small proportion of patients with very localized disease, but the majority of patients have advanced disease at diagnosis and it is not clear that any current therapy is curative in this situation. While in many instances patients with high-grade NHL are cured by chemotherapy, those with low-grade NHL, despite impressive response rates, almost invariably relapse. A 'watch-and-wait' strategy can therefore delay the onset of chemotherapy by 2-3 years, without affecting survival. Results with autologous stem cell transplantation have been similarly disappointing to date. Rituximab is a human-mouse chimeric monoclonal antibody that represents a novel approach to treatment of low-grade NHL, targeting malignant cells without the side effects associated with chemotherapy. A pivotal study has demonstrated a response rate of 56% in relapsed or refractory low-grade NHL. The relatively benign side-effect profile means rituximab can be used early in the disease process, and in combination with chemotherapeutic regimens and autologous transplantation. Ongoing and future studies will define the optimal role of rituximab in treatment of low-grade NHL.     

Rituximab: as first-line maintenance therapy following rituximab-containing therapy for follicular lymphoma

Rituximab is a recombinant chimeric murine/human monoclonal IgG(1-κ) antibody. It binds specifically to the CD20 antigen on normal and malignant B lymphocytes and produces complement-dependent and antibody-dependent cytotoxicity and induces apoptosis in these cells. Prolonged treatment with rituximab in patients with follicular lymphoma results in a sustained reduction in circulating B lymphocytes. Two years of single-agent maintenance therapy with rituximab significantly prolonged progression-free survival (primary endpoint) compared with observation in patients with follicular lymphoma who were responsive to first-line induction therapy with rituximab plus chemotherapy. Furthermore, maintenance therapy with rituximab significantly delayed the time to the next antilymphoma treatment and the next chemotherapy compared with observation in these patients. Rituximab had an acceptable tolerability profile as single-agent maintenance therapy in patients with follicular lymphoma with no new or unexpected adverse events compared with induction therapy.     

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.     

Rituximab in B-cell disorders other than non-Hodgkin's lymphoma

Rituximab is a human/mouse chimeric monoclonal antibody that binds to the CD20 antigen and is expressed at all stages of B-cell development. Rituximab has demonstrated efficacy as monotherapy and in combination with chemotherapy in the treatment of both indolent and aggressive non-Hodgkin's lymphoma (NHL). Rituximab treatment results in rapid depletion of B-cells and this has led to the consideration of other B-cell disorders as candidates for rituximab therapy. Recent studies have demonstrated the efficacy of rituximab in a variety of such disorders, including chronic lymphocytic leukemia (CLL), post-transplant lymphoproliferative disorder (PTLD), Waldenstr?m's macroglobulinemia (WM), multiple myeloma (MM), idiopathic thrombocytopenic purpura (ITP), hairy-cell leukemia (HCL) and cold agglutinin disease (CAD). In patients with CLL, increasing the dose and/or frequency of rituximab treatment has given improved response rates compared with the standard dose schedule used in NHL, and combination immunochemotherapy has yielded an overall response rate of 92% (with a 60% complete response rate). Clinical trials have also demonstrated evidence of efficacy for rituximab in PTLD, WM and relapsed or refractory ITP. Efficacy of rituximab in CAD and relapsed or refractory HCL has also been demonstrated in small studies and case reports. Available data thus indicate that rituximab can be an effective therapy in a wide range of CD20+ lymphoid disorders.     

Rituximab maintenance therapy of relapsed or refractory follicular lymphoma, with longer follow-up: no proven impact on survival

Long-term follow-up data from a clinical trial including 334 patients that compared single-agent maintenance therapy with rituximab versus watchful waiting showed no statistically significant increase in survival time among patients with relapsed or refractory follicular lymphoma.     

利妥昔单抗联合沙利度胺维持治疗老年弥漫大B细胞淋巴瘤的疗效评价

目的 评价利妥昔单抗联合沙利度胺维持治疗老年弥漫大B细胞淋巴瘤(Diffuse large B cell lymphoma,DLBCL)的有效性及安全性.方法 回顾性分析甘肃省武威肿瘤医院血液科使用R-CHOP方案化疗后完全缓解的≥60岁的DLBCL患者86例,按其治疗方案分为2组.对照组患者在完全缓解后单用利妥昔单抗...     

Treatment strategies for relapsed and refractory aggressive non-Hodgkin's lymphoma

The aggressive non-Hodgkin's lymphomas (NHL) are a clinically heterogeneous group of lymphomas with disparate responses to standard chemotherapy regimens. Aggressive NHL includes diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and peripheral T-cell lymphomas (PTCL), among others. Significant advances have been made in the last decade in the initial treatment of DLBCL and MCL, but the treatment of relapsed or refractory disease remains difficult. The addition of rituximab to the treatment of DLBCL and MCL has improved clinical outcomes and is now a critical component of initial therapy and treatment of relapsed disease. The PTCLs, not having a similar agent to significantly change the treatment approach to these diseases, remain a difficult therapeutic problem. This review examines recent advances in the treatment of relapsed or refractory aggressive NHL and discusses novel approaches currently under investigation.     

Semi-extended, six weekly rituximab infusions in pre-treated advanced low-grade B cell non-Hodgkin's lymphoma: a phase II study

Either four or eight weekly rituximab infusions in relapsed or refractory low-grade or follicular B cell non-Hodgkin's lymphoma (NHL) are well tolerated and efficacious. This phase II trial investigated the safety and efficacy of six weekly rituximab doses in chemotherapeutically pre-treated relapsed or refractory low-grade NHL patients. Sixty-eight patients (median age 64 years) received six i.v. rituximab infusions 375 mg/m2 weekly. All patients had received one or more prior therapies (median 2; range 1-18). Forty-two patients had progressive disease and were evaluated for toxicity and efficacy; 12 of these required re-treatment with six weekly rituximab infusions. Twenty-six patients received rituximab as remission consolidation therapy and were assessed for toxicity only. No patients discontinued because of adverse events. Most adverse events were National Cancer Institute grade 1 (2-9%) or 2 (3-5%) and usually occurred during the first infusion. No hematological abnormalities were observed. Overall response rate was 59% (median time to response 2 weeks) and 10 of 12 re-treated patients responded. Median time to progression for all patients was 14 months and for responders 21 months. More than half the 42 patients evaluated for efficacy and more than 70% of the 25 responding patients still survived longer than 3 years after treatment. The safety profile and efficacy achieved in this study compare favorably with those seen with four or eight weekly doses in pre-treated low-grade NHL.     

Rituximab: an innovative therapy for non-Hodgkin's lymphoma.

The epidemiology, etiology, classification, and treatment of non-Hodgkin's lymphoma (NHL) are reviewed, and rituximab, a newly available therapy, is discussed. NHL comprises a group of lymphoproliferative disorders the frequency of which continues to rise. Although many classification systems exist for identifying specific histological subtypes, NHL is generally divided into indolent (low-grade) and aggressive (intermediate- and high-grade) forms. Low-grade NHL is characterized by a slowly progressive, continually relapsing course, with eventual transformation to a more rapidly progressive form that is usually fatal. Several options are available for the management of indolent NHL; none is curative. Rituximab, a human-mouse monoclonal antibody that targets the CD20 antigen expressed in over 90% of B-cell NHLs, provides an alternative to conventional chemotherapy that is relatively safe and effective. In a Phase III trial involving 166 patients with relapsed or refractory low-grade B-cell NHL, rituximab produced an overall response of 48%, with 20 of 80 responders still in remission more than 36 months after treatment. Study results in patients with bulky disease and those requiring retreatment have also been encouraging. Most adverse effects associated with rituximab are mild to moderate. Infusion-related reactions occur more commonly during initial infusions and in patients with evidence of increased tumor burden but can be effectively managed with premedication, supportive care, and adjusted infusion rates. Hematologic effects are generally mild and transient, and adverse immune responses are rare. Rituximab is an alternative to conventional chemotherapy for the treatment of relapsed or refractory low-grade or follicular CD20-positive B-cell NHL.     

Rituximab: the first monoclonal antibody approved for the treatment of lymphoma

Rituximab, a genetically engineered monoclonal chimeric antibody, targets the CD20 antigen expressed on B cells. It was approved by the US Food and Drug Administration on November 26, 1997, for the indication of relapsed or refractory, CD20-positive, B-cell, low-grade or follicular non-Hodgkin's lymphoma (LG/F NHL), and by the European Agency for the Evaluation of Medicinal Products on June 2, 1998, for therapy of patients with Stage III/IV, follicular, chemoresistant or relapsed NHL. Eight Phase II or II clinical trials in LG/F NHL patients have been completed: five single-agent studies and three combination studies. Rituximab has a favorable safety profile: most adverse events (AEs) are Grade 1 or 2, and the frequency of AEs decrease with subsequent infusions. AEs in the combination studies are consistent with those seen with individual agents. For evaluable patients in the single-agent studies, overall response rates (ORR) ranged from 40% to 60%, median duration of response (DR) ranged from 5.9 to 15.0+ months, and median time to progression (TTP) ranged from 8.1 to 19.4+ months. For evaluable patients in the combination studies, the ORR ranged from 45% to 100%, median DR ranged from 11.7+ to 39.1+ months, and median TTP ranged from 12.9+ to 40.5+ months. Studies in intermediate- and high-grade NHL are ongoing. Long-term development plans include evaluating the safety and efficacy of rituximab in various types of lymphoma and in combination with other lymphoma regimens. Future studies may explore ways to increase rituximab efficacy by upregulating CD20 or increasing effector function with different cytokines.     

继发性B细胞型非霍奇金淋巴瘤患者的临床特征分析

目的　探讨继发于非血液系统恶性肿瘤的B细胞型非霍奇金淋巴瘤（sNHL）患者的临床特征及预后情况。方法　2007年1月—2018年5月就诊于我院的NHL患者中,1.65%（47/2 853）以第二恶性肿瘤的形式出现,其中44例为B细胞型sNHL。44例中第一原发恶性肿瘤治疗情况：29例为手术切除治疗,10例为手术联合化疗,2例为手术联合放疗,3例接受手术联合化疗及放疗。继发肿瘤的治疗情况：34例患者接受化疗,5例患者接受化疗+手术切除,4例患者因结外病变或巨大包块接受放疗,1例结外边缘区B细胞淋巴瘤,黏膜相关淋巴组织型淋巴瘤（胃型）患者仅接受抗幽门螺杆菌治疗。中位化疗时间为6（2,8）个月。CD20+的弥漫大B细胞淋巴瘤（DLBCL）或CD20+Ⅲ～Ⅳ期滤泡淋巴瘤（FL）患者在化疗前1 d静脉滴注利妥昔单抗（375 mg/m2）。中位随访时间11.4（4.2,28.8）个月。结果　44例sNHL患者最常见的第一原发恶性肿瘤疾病类型为乳腺癌（10例）,最常见的sNHL病理类型为DLBCL（29例）。65.9%（29/44）的患者第一原发肿瘤诊断年龄＜60岁,59.1%（26/44）的患者sNHL诊断年龄≥60岁。中位sNHL发生时间为63.4（25.2,146.9）个月。平均无疾病进展时间为9.6（4.1,26.0）个月。3年总生存率为73.5%。一线治疗后完全缓解率为38.6%,总缓解率为63.6%。利妥昔单抗组与未利用利妥昔单抗组的3年总生存率分别为81.1%和66.5%（Log-rank χ2=2.026,P＞0.05）。单因素分析显示第一原发恶性肿瘤诊断年龄≥60岁（Log-rank χ2=7.562,P＜0.05）,sNHL诊断年龄≥60岁（Log-rank χ2=4.887,P＜0.05）均提示预后不良;多因素分析显示第一原发恶性肿瘤发病年龄≥60岁（HR=4.745,95%CI：1.405～16.020）是影响sNHL患者生存率的独立危险因素。结论　第一原发恶性肿瘤的诊断年龄≥60岁会增加sNHL患者的死亡风险。     

Rituximab maintenance therapy for follicular lymphoma: no better than watchful waiting

Chemotherapy is the first-choice treatment for patients with advanced follicular lymphoma (Ann Arbor stage III or IV) who qualify for therapy, but there is no consensus protocol. Adding rituximab (Mabthera, Roche) to chemotherapy moderately improves survival time. Rituximab is now authorised for long-term maintenance therapy in patients with follicular lymphoma in whom first-line chemotherapy induces a response. Clinical evaluation of rituximab in this setting is based on two unblinded randomised trials comparing rituximab maintenance therapy with watchful waiting in 1193 and 401 patients. Neither trial showed that rituximab had an impact on mortality or quality of life. Rituximab prolonged progression-free survival, based on unblinded assessment of radiological, laboratory or clinical criteria. These trials suffer from biases that make it difficult to interpret the results, including the lack of blinding, premature termination and too short follow-up in the larger trial, and in the other trial, heterogeneous patient recruitment and use of a different dose regimen from that recommended in the summary of product characteristics. Both trials confirmed the adverse effect profile of rituximab, which includes haematological disorders, infections, and cardiac and digestive disorders. These adverse effects are severe in about 7% of patients. There is also a riskof musculoskeletal and neuropsychiatric disorders. Questions still persist abouta possible oncogenic effect. In practice, the benefits of long-term rituximab maintenance therapy after a first line of chemotherapy remain to be demonstrated in terms of the length or quality of survival in patients with follicular lymphoma, while adverse effects are noteworthy. Pending further data, rituximab should only be used in clinical trials in this specific setting.     

Maintenance Strategies After Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) is an essential component of potentially curative therapy for patients with hematologic malignancies. High-dose chemotherapy with autologous (auto) stem cell rescue is used to overcome chemoresistance in multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Alternatively, poor-risk acute leukemias rely on the graft versus leukemia effect of allogeneic (allo) products. Long-term remissions are feasible with both auto- and allo-HCT; however, disease relapse is the leading cause of death after HCT for many patients. In recognition of this, novel therapies are being investigated in the upfront, relapsed/refractory, and post-HCT maintenance settings to deepen response and maintain disease control. To date, the most robust data to support this approach are in multiple myeloma, where post-transplant maintenance therapy has improved clinical outcomes. In Hodgkin lymphoma, patients with high-risk features may benefit from post–auto-HCT vedotin (BV) regardless of pre-HCT BV exposure. Apart from mantle cell lymphoma, where rituximab maintenance is generally accepted, post–auto-HCT maintenance in other forms of NHL is less established. In patients who undergo allo-HCT, the utilization of maintenance therapy is an important component of improving post-HCT outcomes, however, an individualized approach that considers patient factors such as residual toxicity from HCT, an immature graft with poor graft function, infection, and graft-versus-host disease create a complex environment for aggressive interventions. Initiation of directed agents in patients with identified mutations prior to allo-HCT, including FLT3 in acute myeloid leukemia and Philadelphia chromosome in acute lymphoid leukemia have generally improved post-HCT outcomes. Ongoing studies are exploring the safety and efficacy of additional maintenance strategies post–allo-HCT in an effort to further improve post-HCT outcomes.     

ICE方案治疗复发和难治性非霍奇金淋巴瘤

目的探讨ICE方案（异环磷酰胺、卡铂、依托泊苷）治疗复发和难治性非霍奇金淋巴瘤（NHL）的近期疗效和不良反应。方法25例复发和难治性NHL采用ICE方案治疗,21d为1个周期。观察疗效和不良反应。结果25例均能评价疗效,总有效率76．0％（19／25）,总缓解率（RR）为60．0％（15／25）,毒副反应主要为白细胞和血小板减少,但均为可逆,未出现因化疗毒性而死亡患者。结论ICE方案是治疗复发和难治性NHL安全有效的解救方案,缓解率高,化疗耐受性好。