Clinical use of rituximab in haematological malignancies

Rituximab is a chimeric human/mouse monoclonal antibody that is approved for the treatment of relapsed and refractory non-Hodgkin's lymphoma (NHL) and in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy as first-line therapy for diffuse large B-cell NHL, where it has shown the first survival advantage over CHOP alone in more than 20 years. Strategies to help define the optimal therapeutic usage of rituximab are being assessed, including first-line and maintenance or extended therapy, and the combination of rituximab with chemotherapy in indolent NHL. Emerging data suggest that earlier use may yield higher response rates, extended therapy can prolong remission, and the addition of rituximab to chemotherapy can increase clinical and molecular remission rates when compared with those achieved using chemotherapy alone. Studies in the peritransplant setting suggest a role for rituximab in vivo purging prior to transplant and/or maintenance rituximab as a means of clearing minimal residual disease. Rituximab has also shown activity in other B-cell disorders such as chronic lymphocytic leukaemia. The full potential of this immunotherapeutic agent remains to be defined in ongoing and future clinical trials.     

Rituximab Maintenance Versus Radioimmunotherapy Consolidation in Follicular Lymphoma: Which, When, and for Whom?

Follicular lymphoma (FL), the most common indolent lymphoma, typically presents in advanced-stage disease. Currently available therapy does not generally result in a curative outcome, but survival in FL has improved since the introduction of anti-CD20 monoclonal antibody immunotherapy. The goals of treatment include prolongation of survival and effective palliation of symptoms while limiting the duration of therapy to minimize adverse effects and reduce costs. Multiple rounds of treatment over many years characterize the clinical course for most patients with FL. Rituximab in combination with chemotherapy has been shown to improve overall survival in patients with FL compared with chemotherapy alone. Rituximab maintenance further improves disease control in patients with FL after a successful induction therapy in both first-line treatment and relapse. Consolidation with radioimmunotherapy is an innovative treatment approach to increase rates of complete remission and duration of remission. Here we summarize the data from actual trials and the resulting treatment indications.     

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。     

Monoclonal antibodies in the treatment of chronic lymphocytic leukemia

Traditional therapy for chronic lymphocytic leukemia (CLL) has consisted of alkylating agents, purine analogs, or a combination of these drugs. These agents are effective at producing remissions but are not curative. Thus, new drugs are still needed to improve the outcome of patients with CLL. The introduction of monoclonal antibodies, such as rituximab and alemtuzumab, provides a novel therapeutic modality. Rituximab is an active agent in CLL. Standard doses of rituximab result in higher response rates in previously untreated than in relapsed patients but low complete response (CR) rates. Rituximab is most effective in combination with chemotherapy, especially fludarabine-based regimens in the first-line and salvage setting. Rituximab is also useful in the treatment of complications of CLL, such as pure red cell aplasia, autoimmune thrombocytopenia, and autoimmune hemolytic anemia. Alemtuzumab has impressive activity in patients with refractory CLL and may play an important role in the consolidation treatment of CLL. Alemtuzumab is most efficacious at clearing disease in the peripheral blood and bone marrow. Bulky lymphadenopathy is less sensitive to therapy. Because of the significant lymphopenia associated with alemtuzumab, antibacterial and antiviral prophylaxis should always be used.     

Rituximab zur Therapie des Non-Hodgkin-Lymphoms

Rituximab is the first monoclonal antibody to be approved for the treatment of non-Hodgkin’s lymphoma. Compared to chemotherapy alone, the combination of rituximab and chemotherapy is superior for all indications so far tested. For the primary therapy of follicular lymphoma with rituximab and chemotherapy, there are now four large, randomized studies available, all of which show a statistically significant and clinically relevant prolongation of life due to the combination therapy. Thus, rituximab is today the standard primary therapy for this form of lymphoma. In addition, two other phase III studies show that treatment with rituximab also leads to a prolongation of life in patients suffering from recurrent follicular lymphoma. This is the case for both combined rituximab/chemotherapy induction treatment, as well as for rituximab maintenance therapy, which is also highly effective after the rituximab/chemotherapy and is well tolerated. The risk of dying is halved by the use of rituximab maintenance therapy, indicating that rituximab is the best available therapy for recurrent follicular lymphoma, as well as for the induction of remission of the disease and as a maintenance therapy. In cases of diffuse large B-cell lymphoma, rituximab combined with chemotherapy is the therapeutic standard, with four large, randomized studies showing a clear improvement in cure rate. This applies to all age groups and risk categories, which may, however, differ in the number of therapy cycles and the dose rate.     

Lymphocyte-predominant Hodgkin lymphoma—clinical features and treatment outcomes from a 30-year experience

Background: Lymphocyte-predominant Hodgkin disease (LPHD) is a rare subtype of Hodgkin lymphoma, for which there is limited evidence regarding the presentation, natural history and treatment outcomes.Patients and methods: We conducted a single-institution retrospective review all of patients diagnosed with LPHD over a 30-year period.Results: Eighty-eight patients were included. Median follow-up was 13 years. Local radiotherapy or chemoradiotherapy resulted in durable disease control in patients with stage I or II disease. Advanced stage at presentation, presence of B symptoms, low albumin, and either partial response or stable disease to first treatment were associated with worse treatment outcomes. Relapse rate for the entire cohort was 44%, with an 8% rate of transformation to large-cell lymphoma. Rituximab in combination with chemotherapy resulted in durable remission in a heavily pretreated subgroup. Outcomes with autologous transplant are discussed.Conclusion: Our series has the longest follow-up of any report, includes the only series of patients treated with autologous transplant, and has the largest group of patients treated with rituximab and chemotherapy in this indication.     

Rituximab

CHOP has been the standard chemotherapy for aggressive non-Hodgkin's lymphoma (NHL). However, indolent NHL remains largely an incurable diseases, with nearly static overall survival, and only 40% of patients with aggressive NHL are cured by CHOP. Monoclonal antibodies are an exciting advance in the treatment of lymphoma. Rituximab is a mouse/human chimeric monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal cells of the B-cell lineage, but not on primitive stem cells or mature plasma cells. Rituximab is safe and well-tolerated, and exhibit little cross-resistance with conventional chemotherapeutic agents. Clinical trials with rituximab indicate that the drug has broad application to NHL, although further clarification is needed to determine its optimal use in many of these clinical settings. In indolent NHL, rituximab has shown useful response rates, both as first-line therapy in relapsed disease. In aggressive lymphomas, diffuse large B-cell lymphoma is the most common form, the addition of rituximab to CHOP chemotherapy significantly lengthens disease-free and overall survival compared to CHOP alone as first line therapy, at least in elderly patients. These included combination with chemotherapy, prolonged or increased dosing regimens, and maintenance therapy, in which rituximab is administered to patients in remission to eliminate minimal residual disease and reduce the risk of relapse. Rituximab in vivo purging and maintenance is also being evaluated in autologous transplantation setting. Newer agents, including radiolabelled antibodies, Immunotoxin-linked antibodies and antibodies against novel target antigens are being tested in on-going clinical trial.     

Gastrointestinal stromal tumors in kidney transplant recipients: Report of two cases and literature review

Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal gastrointestinal neoplasms. However, GISTs occurring in kidney transplant recipients, including their treatment and outcome, are rarely described in literature. We hereby report two kidney transplant recipients with GISTs. Our first patient was diagnosed with high‐risk epithelioid gastric GIST 2 years after kidney transplant. He received everolimus after resection and remained disease‐free for 2 years before liver metastasis was confirmed. Imatinib therapy was planned but he died of fulminant pneumonia shortly. Our second patient was diagnosed with spindle cell GISTs in the mesentery 1 year after kidney transplant. Only partial response was obtained with imatinib as new lesions continued to develop. Withdrawal of cyclosporine and introduction of sirolimus resulted in complete shrinkage of existing tumors and no new lesions. He remained disease‐free for more than 10 years. Combination therapy consisting of imatinib and inhibitors of mammalian target of rapamycin (mTORi) seems to be safe and effective in kidney transplant recipients. However, therapeutic drug monitoring of mTORi is essential to avoid nephrotoxicity. Further trials addressing the optimal dosage of imatinib and mTORi in kidney transplant recipients are recommended.     

Rituximab anti-CD20 monoclonal antibody induces marked but transient reductions of peripheral blood lymphocytes in chronic lymphocytic leukaemia patients

Rituximab has been recently proposed as an effective non-chemotherapeutic option for patients with follicle centre lymphoma (FCL). However, less is known on its role in chronic lymphocytic leukaemia (CLL). We thus decided to assess its effectiveness on a panel of 7 patients with refractory or relapsed CLL. Mild (5 patients) or severe (1 patient) adverse reactions were observed during the first hours of Rituximab infusion, almost exclusively at the first course. Symptoms rapidly subsided with temporary drug withdrawal and low dose steroids. All patients could receive the whole scheduled treatment. A striking reduction of peripheral blood (PB) lymphocyte counts was observed in all patients (median 93%; range 57–99%). However, Rituximab was poorly effective towards nodal and splenic disease. Patients required additional treatment after a median time of 70 d (range: 20–180 d). Our data show that Rituximab delivery in CLL patients is feasible and has an acceptable toxicity, although it probably does not represent an ideal treatment option when delivered using schedules originally designed for FCL patients. However, responses observed at PB level suggest that Rituximab has an activity which is not negligible and deserves further investigation in CLL. Future approaches will be directed to the development of alternative schedules which may include dose intensification, combination of Rituximab and chemotherapy, andin vivo purging of periphral blood progenitor cell harvests for autografting procedures.     

Radiolabeled and native antibodies and the prospect of cure of follicular lymphoma

Advanced-stage follicular lymphoma is incurable by conventional treatment. Rituximab has been introduced in various combinations with chemotherapy and has resulted in a significantly superior treatment outcome compared with chemotherapy alone. Multiple studies have also shown the efficacy of radioimmunotherapy (RIT) both as a single agent and in combination with chemotherapy. Rituximab and RIT have clearly distinct mechanisms of action, the first acting exclusively as a biological treatment, while the second acts by a combination of biologic mechanisms and radiation effects. Despite the therapeutic efficacy of both approaches, the potential exists to further improve both modalities. Repeat administrations of RIT using appropriate radioisotopes for treatment of residual disease or new targeting strategies might afford additional benefits. Unlabeled antibody treatment could potentially benefit from the combination of antibodies directed against different target antigens or combination therapy with cytokines capable of further mobilizing patients' cellular defenses. In this review, we hypothesize that the combination of an optimized biological treatment together with radiolabeled antibodies and chemotherapy early in the disease course of advanced-stage follicular lymphoma may represent the best approach to achieve prolonged disease-free survival and eventually cure.     

Cisplatin-based chemotherapy in a renal transplant recipient

Cisplatin-based chemotherapy is the treatment of choice for metastatic testicular cancer; however, the safety of conventional regimens in renal transplant recipients has been questioned. The authors report the course of a renal transplant recipient successfully treated with a cisplatin-based chemotherapy regimen for testicular seminoma and review three additional cases that have been reported in the English language literature to date. Emphasis is placed on review of the safety, optimal administration, and appropriate monitoring of cisplatin and controversy regarding the need for continued administration of immunosuppressive therapy.     

Incidence and management of colorectal cancer in liver transplant recipients

Liver transplant recipients are at an increased risk of developing de novo malignancies because of the prolonged immunosuppression necessary to avoid acute and chronic rejections. Skin cancers and lymphoproliferative diseases are the most common malignancies, but the overall incidence of colon cancer in this patient population does differ from that of the general population. Therefore, colorectal cancer (CRC) is a major health concern in liver transplant recipients. Furthermore, there are unique subsets of liver transplant recipients, such as those with primary sclerosing cholangitis and inflammatory bowel disease, who are at an increased risk for developing CRC after liver transplantation and might require special screening/surveillance strategies. The similar principles for management of colon cancer can be applied to transplant recipients if the adjustment to maintain the need for the long-term immunosuppression is made. Colectomy can be performed safely during the posttransplantation period. Prophylactic colectomy at the time of liver transplantation has been performed in some patients at high risk or with known premalignant conditions. Chemotherapy with 5- fluorouracil and oxaliplatin has been used in transplant recipients for the treatment of metastatic CRC; however, further research is required to examine the safety, tolerability, and efficacy of combination chemotherapy and biologic agents in this patient population. This review summarizes the incidence, risk factors, diagnosis, and management of de novo CRC in liver transplant recipients.     

Antibodies for the treatment of diffuse large cell lymphoma

The development of monoclonal antibodies has significantly affected the therapy of B-cell non-Hodgkin's lymphomas (NHLs). Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, has activity in both indolent and aggressive B-cell lymphomas. Perhaps the greatest change has occurred in first-line therapy of advanced stage, diffuse large cell lymphoma (DLCL), where rituximab combined with conventional chemotherapy has improved both overall survival (OS) and progression-free survival (PFS) over combination chemotherapy alone. Further studies are needed assessing the role of rituximab in salvage therapy, as part of the conditioning regimen prior to autologous stem cell transplant, and as maintenance therapy for large cell lymphoma. Several novel monoclonal antibodies are in development and may also be active in DLCL. These agents may be most promising when combined with either chemotherapy or with rituximab. This review will summarize the use of rituximab in the therapy of diffuse large B-cell lymphoma and briefly describe antibodies in development.     

Central Nervous System Atypical Teratoid Tumor/Rhabdoid Tumor: Response to Intensive Therapy and Review of the Literature

Central nervous system atypical teratoid/rhabdoid tumor (ATT/RT) of infancy and childhood is a unique histologic entity with an extremely aggressive natural history. Standard therapy for infant and childhood medulloblastoma, for which this entity is often mistaken, has been ineffective; most children survive less than 12 months after diagnosis. Intensified therapy has been recently used for children with this disease, with promising results [1,2].We report four cases of ATT/RT in young children; all had subtotal resections and localized disease at diagnosis. One child treated prior to bone marrow transplant availability died of progressive disease 9 months after diagnosis. Another child, treated with high-dose chemotherapy and radiotherapy in preparation for bone marrow transplant, had a recurrence and died 20 months after diagnosis, without undergoing the transplant. Two children received high-dose chemotherapy and autologous bone-marrow transplant and had a good response to treatment; one survived 19 months, the other child is free of disease 46 months from diagnosis. Intensified therapy has altered the natural history of central nervous system ATT/RT.     

Use of rituximab in patients with follicular lymphoma

Advanced stage symptomatic follicular non-Hodgkin's lymphoma (NHL) is rarely, if ever, curable with conventional chemotherapy. Patients classically experience a pattern of remission and relapse, eventually dying of their disease. Data from a number of large-scale randomised phase III trials, both as first-line therapy and in relapsed/refractory patients, comparing rituximab plus chemotherapy with chemotherapy alone indicate that the addition of rituximab to a number of different chemotherapy regimens increases response rates and progression-free survival (PFS), without significantly increasing toxicity. Moreover, in four trials, three in first-line and one in relapsed disease, a significant overall survival benefit has been observed for rituximab combination therapy. These data indicate that patients with follicular NHL who require therapy should now receive rituximab plus chemotherapy as first-line treatment. Additionally, a strong case remains for offering rituximab-based therapy to patients with relapsed disease who have not previously received it, and in those who have previously responded well to this agent. Rituximab maintenance therapy has also been shown to significantly prolong PFS after rituximab in combination with chemotherapy in patients with relapsed disease and in newly diagnosed patients who have not received rituximab during induction, and the benefit of maintenance after immunochemotherapy in relapsed patients may yet be mirrored by ongoing studies in the first-line setting. This overview considers the most recently published clinical trials of rituximab and their potential effect on clinical practice in the treatment of follicular NHL.     

Successful treatment of gastrointestinal follicular lymphoma with rituxan and combination chemotherapy

The clinical course of follicular lymphoma (FL) is well known. Although it is a chemosensitive disease, thereby allowing substantial palliation, recurrence is the rule; only a small subset who presents with limited stage disease is cured. Multiple attempts have been made over the past two decades to improve the survival of patients with FL, and a large number of phase III trials have been reported. These have included a variety of different therapeutic interventions, such as combination chemotherapy, recombinant interferons, new cytotoxic drugs, and immunologic agents. Most studies have not demonstrated that the use of a particular therapy convincingly prolongs survival. Follicular lymphoma cells express CD20 and are associated in most cases with the t(14:18) chromosomal translocation. Rituximab is a chimeric monoclonal antibody directed against the B-cell CD20 antigen, which has been utilized for the therapy of B-cell non-Hodgkin's lymphoma. Rituximab was shown to be active in FL, and studies of its effectiveness in combination with cytotoxic chemotherapy to increase the response rate are forthcoming.     

Safety of rituximab maintenance therapy in follicular lymphomas

The human/mouse chimeric monoclonal antibody rituximab has been used extensively in treatment of hematologic malignancies, and its efficacy and safety are well established, both as single-agent therapy and when used in combination with chemotherapy. Mild-to-moderate, transient infusion-related reactions are the most common adverse event, and rituximab does not add significantly to the toxicity of chemotherapy. Rituximab maintenance therapy has now emerged as an effective treatment for follicular lymphoma. Patients on rituximab maintenance therapy receive regular doses of rituximab for periods up to 2 years after initial induction therapy and are completely depleted of B-cells throughout this time, although B-cells eventually recover when maintenance treatment is stopped. In randomized trials of rituximab maintenance therapy versus observation after induction with single-agent rituximab, standard chemotherapy or rituximab plus chemotherapy, patients receiving rituximab maintenance therapy did not experience significantly greater toxicity than those in the observation arms, and no cumulative or unexpected toxicities were observed. Findings to date thus indicate that rituximab maintenance therapy is well tolerated, but further assessment of the long-term effects of prolonged B-cell depletion is still required.     

Management options for follicular lymphoma: observe; R-CHOP; B-R; others?

Treatment results are improving for patients who have advanced-stage follicular lymphoma; this progress is in large part related to the inclusion of anti-CD20 monoclonal antibody therapy in front-line therapy programs. Rituximab has been combined successfully in chemo-immunotherapy regimens with several standard chemotherapy combinations, and with bendamustine. Post-remission treatment strategies, including radioimmuotherapy consolidation and rituximab maintenance, have had a favorable impact on duration of remission. Thus, although traditional palliative strategies can still have a role in many situations, such approaches must now be placed in perspective with options that have the potential to achieve durable disease control. Recent therapeutic advances have renewed the hope that potentially curative treatment options may be forthcoming for these patients.     

Treatment of non-Hodgkin's lymphoma: a look over the past decade

The past decade has seen enormous changes in our understanding of lymphomas with a better classification (World Heath Organization) and identification of better prognostic factors; however, important genetic prognostic factors have not been completely analyzed. The appearance of rituximab and other monoclonal antibodies has completely revolutionized the treatment of this disease. If monoclonal antibodies have activity when used alone, most patients experienced relapse after such a treatment, even after maintenance therapy. The combination of rituximab with chemotherapy has now been shown in several randomized studies to increase the response rate, decrease the relapse rate, and prolong progression-free survival and overall survival. Rituximab plus CHOP (cyclophosphamide/doxorubicin/prednisone/vincristine; R-CHOP) has become the standard for patients with diffuse large B-cell lymphoma. Rituximab chemotherapy, probably with the CHOP regimen, is slowly gaining importance as the standard for patients with follicular lymphoma. Although little is known for other indolent lymphomas and mantle cell lymphoma, progress has been made there, too. Several questions remain for future randomized studies to continue our search toward cure.     

Prolymphocytic leukemia

Opinion statement Prolymphocytic leukemia is a rare chronic lymphoproliferative disorder that includes two subtypes, B cell and T cell, each with its own distinct clinical, laboratory and pathological features. T-cell prolymphocytic leukemia has an aggressive course with short median survival and poor response to chemotherapy. With the use of the purine analogue pentostatin more than half of patients will have a major response and a minority will have a complete remission, usually lasting months. With the introduction of alemtuzumab, most patients who progressed despite treatment with pentostatin had a major response with a complete remission rate higher than that obtained with pentostatin when used as a first line. Unfortunately, progression still follows shortly. We recommend alemtuzumab as initial therapy and offer stem cell transplant (SCT) to selected young, healthy patients who respond. Although B-cell prolymphocytic leukemia is also a progressive disease, some patients can achieve a prolonged progressionfree-survival with fludarabine. Patients presenting with massive splenomegaly may be effectively palliated with splenic irradiation or splenectomy. Rituximab is a promising agent and further investigations are warranted to better define its role in treatment of this disorder.