Radioimmunotherapy and Autologous Stem-Cell Transplantation in the Treatment of B-Cell Non-Hodgkin Lymphoma.

High-dose chemotherapy and autologous stem-cell transplantation (ASCT) is the standard therapy for patients with chemosensitive-relapsed or chemosensitive-refractory aggressive lymphoma. The use of rituximab, an anti-CD20 monoclonal antibody, has dramatically changed the outcome of patients with aggressive lymphoma, increasing both response and survival rates. However, despite this progress a significant proportion of patients are still refractory or relapse after frontline rituximab-containing therapy. Moreover, it is increasingly more difficult to rescue these patients with current salvage chemotherapy and ASCT approaches. Novel approaches are needed for these high-risk patients, especially in the rituximab era. Radioimmunotherapy (RIT) is a form of targeted therapy using the parent monoclonal antibody to deliver radiation emitted by a conjugated radioisotope, to the vicinity of antigen-positive tissues. Two radioimmunoconjugates--yttrium-90 ibritumomab tiuxetan (Zevalin) and iodine-131 tositumomab (Bexxar) have been in clinical use. There are multiple studies demonstrating the safety and efficacy of both agents in both indolent and aggressive lymphoma. Radiolabeled antibodies are ideal candidates to combine with high-dose chemotherapy and ASCT. RIT targets radiation to disease sites while limiting exposure of uninvolved critical organs, thus it can safely replace total-body irradiation during conditioning for ASCT. The major toxicity and limiting factor in RIT is myelotoxicity that is easily reversed by stem-cell rescue. RIT can be combined at standard doses with high-dose chemotherapy or can be given in escalated doses either alone or with high-dose chemotherapy before ASCT. Several phase II studies have shown the safety and potential efficacy of both agents using these approaches. A small randomized study comparing standard-dose Zevalin with combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) high-dose chemotherapy and BEAM alone suggested a survival advantage of Zevalin-BEAM. However, a large randomized study comparing Bexxar-BEAM and rituximab-BEAM did not show any advantage. More studies are needed to establish the role and the dose of RIT given for ASCT.

[Cutaneous lymphomas]. / Kutane Lymphome.

Cutaneous lymphomas are a heterogenous group of lymphoproliferative disorders of the T- and B-lymphocytes with a low incidence of approximately 1:100000/year. They belong to the Non-Hodgkin lymphoma. The skin is the second most abundant site of extranodal lymphoma formation (after the GI tract). The new WHO/EORTC classification of cutaneous T- and B-cell lymphomas provides a widely accepted nomenclature for primary cutaneous lymphomas based primarily on clinical, but also on histologic, cytologic and molecular features. It has already proven to be an invaluable tool for international prospective clinical studies. The clear distinction of primary cutaneous from secondary cutaneous lymphoma will also be important to prevent overtreatment of the frequently benign primary cutaneous lymphoma. Treatment of primary cutaneous lymphoma is skin-directed in early disease stages, and uses as systemic approach in advanced stages. Skin-directed therapies encompass UV-light treatment such as UVB311nm, or PUVA, topical steroids class III and IV, or bexaroten gel. Systemic treatment options may be immunomodulatory, such as treatment with interferon alpha injection, or biologic response modifiers such as bexarotene. We recommend that advanced stages of cutaneous lymphoma should be treated in centers that offer clinical studies in this field, because prognosis of late stages is still dismal and there is so far no therapeutic approach that has led to an increase in overall survival. Hence, inclusion of patients in prospective controlled clinical studies should always be considered in patients with primary cutaneous lymphoma.

Pretargeted radioimmunotherapy for B-cell lymphomas.

Relapsed or treatment refractory B-cell lymphomas are currently incurable with conventional chemotherapy and radiation treatments. High-dose chemoradiotherapy and stem cell transplantation can cure some patients with relapsed or refractory lymphoma, but the majority of such patients die of progressive disease. We have investigated the potential utility of pretargeted radioimmunotherapy using monoclonal antibody-streptavidin, immunoconjugates, and fusion proteins in combination with N-acetylgalactosamine dendrimeric clearing agent and radiometal-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid biotin for treatment of lymphomas using mouse and primate models. We have targeted a variety of cell surface antigens, including CD20, CD22, CD45, and HLA-DR, using conventional and pretargeted radioimmunotherapy. These studies showed the marked superiority of pretargeted radioimmunotherapy for each of the antigenic targets in terms of superior biodistributions, more complete tumor regressions, and longer survival. We are optimistic that this novel approach will provide a meaningful prolongation of survival for patients with relapsed or refractory lymphomas.

[Radioimmunotherapy for non-Hodgkin lymphoma: historical development and current status]. / Radioinmunoterapia en los linfomas no Hodgkin: desarrollo histórico y estado actual.

Radioimmunotherapy treatment for lymphoma is a novel targeted therapeutic approach. Several years of development of radioimmunotherapeutic compounds came to fruition in February of 2002 when 90Y-ibritumomab tiuxetan (Zevalin, Y2B8) was approved in the USA and later in Europe, for the treatment of relapsed or refractory, low grade or transformed B-cell lymphoma in the USA. 90Y-ibritumomab tiuxetan utilizes a monoclonal anti-CD20 antibody to deliver beta-emitting yttrium-90 to the malignant B-cells. Clinical trials have demonstrated its efficacy, with observed clinical responses in the 80 % range. This product has become available in Europe, with simplified administration, for the treatment of relapsed follicular lymphoma. A similar anti-CD20 radiotherapeutic compound, 131I-tositumomab, was subsequently approved in the USA. Promising studies exploring expanded applications of radioimmunotherapy as consolidation, as part of transplant, or in other histologic types have been recently completed or are under way. Radioimmunotherapy has been shown to be an effective and clinically relevant complementary therapeutic approach for patients with lymphoma, bringing the Nuclear Medicine into lymphoma therapeutics.

[A case of malignant lymphoma of the prostate].

We report a case of primary malignant lymphoma of the prostate. A 76-year-old man was refer to our clinic with a chief complaint of dysuria. Based on a benign prostatic hypertrophy, transurethral resection of the prostate was performed. Histological findings showed diffuse, large cell type malignant lymphoma. His clinical stage was 1 A prostate (+) according to the Ann Abor classification. The combination chemotherapy with THP-COP was performed for 3 courses, followed by irradiation at 30 Gy. His prostate has showed no recurrence for 10 month after treatment. Primary malignant lymphoma of the prostate is rare. About 30 cases have been reported in the japanese literature. Preoperative diagnosis of malignant lymphoma of the prostate is difficult. All cases have been diagnosed after prostatic surgery or biopsy.

Coexistent rearrangements of c-MYC, BCL2, and BCL6 genes in a diffuse large B-cell lymphoma.

We present a patient with stage III de novo diffuse large B-cell lymphoma. The lymphoma cells showed mature B-cell immunophenotype but lacked surface immunoglobulin (Ig) expression. Long-distance and long-distance inverse polymerase chain reaction assays to detect the oncogene/Ig gene rearrangement revealed that the cells carried 3 independent fusion genes, namely, c-MYC/Ig heavy chain gene (IgH), BCL2/IgH, and Ig lambda light chain gene/BCL6. Thus, the lymphoma cells concurrently carried t(8;14)(q24;q32), t(14;18)(q32;q21), and t(3;22)(q27;q11), which developed in association with class switching, V/D/J recombination, and somatic hypermutation, respectively. The lymphoma responded to chemoradiotherapy, and the patient has been well for 2 years, suggesting that multiple oncogene rearrangements may not necessarily be associated with poor clinical outcome.

[Long-term results with MACOP-B and radiation therapy for aggressive lymphomas]. / Langzeitergebnisse mit MACOP-B und Strahlentherapie bei aggressiven Non-Hodgkin-Lymphomen.

BACKGROUND: Long-term results are needed to evaluate chemotherapy regimens and prognostic factors in non-Hodgkin's lymphomas (NHL). We report the 10-year follow-up data of aggressive NHL classified according to the Kiel classification and treated with MACOP-B. PATIENTS AND METHODS: Between 1985 and 1991, 71 patients with aggressive NHL were treated in a single institution with MACOP-B and adjuvant radiotherapy as first-line therapy. NHL subtypes were classified according to the updated Kiel classification. Follow-up data were available until 1998. RESULTS: The overall survival (OS) at 10 years is 45% (confidence interval 33-57%), the progression-free survival 42% (30-54%), and the relapse-free survival of the 59 patients (82%) in complete remission is 52% (39-65%). The Kiel classification combined with the International Prognostic Index (IPI) identified diffuse large B-cell and anaplastic large T-cell lymphomas with IPI 0-2 as subgroups with very favorable prognosis after MACOP-B (OS 84% and 80% at 10 years). Late relapses (>2 years after therapy) did occur in these patients but had a good prognosis after second remission. Only 3 of 24 relapses were in the radiation field. Three patients died of toxicity, 1 during MACOP-B (1.3%). Risk factors for therapy-related death were age and pulmonary toxicity. Most patients suffered from chemotherapy-associated mucositis. Osteoporosis was a common late toxicity (39%). Three second cancers but no leukemias or myelodysplastic syndromes were observed during follow-up. CONCLUSIONS: MACOP-B in combination with adjuvant radiotherapy is highly effective in diffuse large B-cell or anaplastic large T-cell-lymphomas with IPI 0-2. Patients with IPI >2 or with centrocytic or secondary centroblastic B-cell or non-anaplastic T-cell lymphomas need more intensive therapy or novel approaches. Regarding the toxicity profile, MACOP-B should be replaced by VACOP-B.

Radiolabeled antibody therapy of B-cell lymphomas.

Patients with relapsed B-cell lymphomas are currently incurable with conventional doses of chemotherapy or radiotherapy. In recent years, new treatment options have become available for these patients, including the use of chimeric mouse-human anti-CD20 antibodies and radiolabeled anti-CD20 antibodies. The nonradioactive rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA) antibody induces remissions in 60% of patients with relapsed follicular lymphomas, including 5% to 10% complete remissions. Anti-CD20 antibodies radiolabeled with iodine 131 and yttrium 90 given at nonmyeloablative doses yield remissions in 75% to 80% of cases, including 35% to 40% complete remissions. High-dose (131)I-anti-B1 antibody with stem cell transplantation generates objective responses in 85% to 90% of cases, including 75% to 80% complete remissions. Although more patients need to be evaluated with a longer follow-up period, radioimmunotherapy appears to be an effective and well-tolerated addition to the oncologists' armamentarium for relapsed lymphomas.

Short intensive primary chemotherapy and radiotherapy in sporadic primary CNS lymphoma (PCL).

PURPOSE: To assess the efficacy and toxicity of combined modality therapy with short intensive primary chemotherapy in the treatment of primary CNS lymphoma (PCL). METHODS AND MATERIALS: Prospective study of 31 nonimmunodeficient patients with PCL treated with initial chemotherapy (13 shortened MACOP-B; and 18 modified MACOP with high dose methotrexate) followed by radiotherapy (whole brain and a boost). Patients were aged 18-72 years (median 51 years). Eight patients had positive CSF cytology of which one had spinal meningeal disease; one patient had vitreous involvement. RESULTS: The overall complete response (CR) rate after chemotherapy and radiotherapy was 69% (95% Confidence Interval: 49-84%). At a median follow-up of 24 months (4 months to 10 years) median survival was 23 months and 5-year survival 34%. Age, sex, performance status, number of lesions, CSF cytology, and extent of surgery were not of prognostic significance for survival on univariate analysis. Eleven patients developed mucositis (Grade 3+) and 21 hematological toxicity (Grade 3+) with 22 septicemic episodes in 15 patients. Three patients developed dementia, one assumed to be treatment related, and two due to recurrent disease. CONCLUSION: The survival results of short intensive primary chemotherapy followed by radiotherapy are similar to the results of chemotherapy in Stage IV aggressive systemic non-Hodgkin's lymphoma, although the treatment was associated with high morbidity. The apparently favorable results when compared to radiotherapy alone may at least in part be due to selection of patients with good prognostic factors. To confirm the benefit of combined chemotherapy and radiotherapy over either of the two modalities alone requires evaluation in large prospective and ideally randomized studies.

Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support.

BACKGROUND: Radiolabeled monoclonal antibodies recognizing B-lymphocyte surface antigens represent a potentially effective new therapy for lymphomas. We assessed the biodistribution, toxicity, and efficacy of anti-CD20 (B1 and 1F5) and anti-CD37 (MB-1) antibodies labeled with iodine-131 in 43 patients with B-cell lymphoma in relapse. METHODS: Sequential biodistribution studies were performed with escalating doses of antibody (0.5, 2.5, and 10 mg per kilogram of body weight) trace-labeled with 5 to 10 mCi of 131I. The doses of radiation absorbed by tumors and normal organs were estimated by serial gamma-camera imaging and tumor biopsies. Patients whose tumors were estimated to receive greater doses of radiation than the liver, lungs, or kidneys (i.e., patients with a favorable biodistribution) were eligible for therapeutic infusion of 131I-labeled antibodies according to a phase 1 dose-escalation protocol. RESULTS: Twenty-four patients had a favorable biodistribution, and 19 received therapeutic infusions of 234 to 777 mCi of 131I-labeled antibodies (58 to 1168 mg) followed by autologous marrow reinfusion, resulting in complete remission in 16, a partial response in 2, and a minor response (25 to 50 percent regression of tumor) in 1. Nine patients have remained in continuous complete remission for 3 to 53 months. Toxic effects included myelosuppression, nausea, infections, and two episodes of cardiopulmonary toxicity, and were moderate in patients treated with doses of 131I-labeled antibodies that delivered less than 27.25 Gy to normal organs. CONCLUSIONS: High-dose radioimmunotherapy with 131I-labeled antibodies is associated with a high response rate in patients with B-cell lymphoma in whom antibody biodistribution is favorable.

[Lymphomas of the skin].

Malignant lymphoma of the skin is a type of extranodal lymphoma, in which the main organ involved is the skin, and 80-90% of cases in Japan show a T-cell phenotype. Mycosis fungoides (MF) and Sézary syndrome (SS) are common T-cell lymphomas of the skin with a benign prognosis. Therefore, various forms of topical therapy, such as topical steroid, photochemotherapy (PUVA) and interferons, have been indicated for the low-risk group (stages I A, I B and II A), whereas electron-beam irradiation, retinoid plus interferon (IFN), photopheresis and deoxycoformycin (DCF) plus IFN have been indicated for intermediate-risk group (stages II B and III). The cutaneous involvement of B-cell lymphoma has been considered an unmistakable sign of progression and dissemination of lymphoid disease, and is thus associated with a poor prognosis. However, some primary cutaneous B-cell lymphomas (CBCLs) show a benign prognosis, and electron-beam irradiation has been indicated for early-stage CBCL (stages I and II). However, the prognosis of high-risk group CTCL (stage IV) and cutaneous B-cell lymphoma (CBCL) (stages III and IV) is poor. Therefore, an effective multiagent combination chemotherapy, such as MACOP-B, M-BACOD or ProMACE-Cyta BOM is required for patients with advanced-stage CTCL and CBCL. With regard to age at the time of the first medical examination, patients with CTCL or CBCL at an advanced stage have a tendency to be older. Therefore, a mild but effective therapy, such as DCF plus IFN is recommendable.

Combined modality clinical trials for favorable B-cell neoplasms: lonidamine plus whole body hyperthermia and/or total body irradiation.

Favorable B-cell neoplasms provide an excellent clinical model to evaluate the use of systemic multimodality therapy as an approach to the problem of tumor cell heterogeneity. Inherent in this concept is the use of multiple antineoplastic agents to produce supra-additive cytotoxicity without sacrificing therapeutic index. The results of three completed clinical studies and complementary laboratory investigations are reviewed to illustrate an innovative approach to the nodular lymphomas and chronic lymphocytic leukemia. The clinical trials summarized include: A) the combination of 41.8 degrees C whole body hyperthermia (WBH) and the chemotherapeutic drug lonidamine; B) the use of total body irradiation (TBI) (12.5 cGy twice a week, every other week--total planned dose 150 cGy) and daily oral lonidamine; C) the juxtapositioning of TBI (with the same fraction schema) and 41.8 degrees C WBH x 75 min--initiated 10 min after TBI. Also presented is the laboratory rationale and early clinical results for combining lonidamine, TBI, and WBH.