Trials In Lymphoma Research Articles

A review of recruitment criteria, patient characteristics and results of CHOP chemotherapy in prospective randomized phase III clinical trials for aggressive non-Hodgkin's lymphoma.

It has frequently been questioned whether results of trials can be generalized to routine clinical practice. Results obtained with standard cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) chemotherapy for aggressive non-Hodgkin's lymphoma in the control arm of prospective randomized phase III clinical trials during the past 25 years appear to be comparable. As the possibility to generalize trial results is favored by such consistency, we tested this hypothesis and tried to indicate explanatory 'moderator variables' (inclusion and exclusion criteria, therapy characteristics, sample sizes, inequalities in the distribution of patients over prognostic categories across different trials) in the case of divergent trial results. Trial results on conventional CHOP chemotherapy were obtained from literature research. Overall response (OR), complete response (CR) and two-year overall survival (2YS) were considered as outcome measures. Although OR rates and 2YS rates were within acceptable limits of comparability, the absolute differences within the results were remarkably wide, particularly with regard to CR and 2YS. Divergent rates could not be properly explained by differences in the moderator variables. We conclude that absolute results obtained with CHOP in the control arm of trials appeared to be poorly generalizable to routine clinical practice, particularly in the case of elderly patients. This analysis underlines the need for the strict application of internationally agreed response criteria and the WHO classification system, large sample sizes and stratifying patients on the basis of prognostic factors, preferably in intergroup clinical trials. We expect those factors to lead to a better consistency of results in future trials and improved possibilities to generalize the results.

Childhood and adolescent large-cell lymphoma (LCL): a review of the Children's Cancer Group experience.

We reviewed the clinical characteristics, treatment, and outcome of 67 children with localized and 212 with disseminated large-cell lymphoma (LCL) treated during a 20-year period in 5 consecutive Children's Cancer Group (CCG) non-Hodgkin's lymphoma (NHL) trials. Clinical outcomes for patients treated on the four earlier studies with moderate-dose chemotherapy administered over 12-18 months were compared with patients treated most recently with short, intensive therapy. Median age at diagnosis was 12 years (range: 0-19 years). Male to female ratio was 1.8:1.0. Five-year event-free survival (EFS) was 92% +/- 3.3% and 50 +/- 3.5% for patients with localized LCL and disseminated LCL, respectively. After adjustment for lactate dehydrogenase (LDH), age at diagnosis, and BM involvement, short and intensive therapy as delivered on the most recent study, CCG-5911, was associated with an improved outcome (P< 0.05) compared to the four previous studies. Elevated LDH (> or = 500 IU/L) at diagnosis and young age (<5 years) were both significant independent predictors of poorer long-term EFS (P< 0.05). Long-term survival after relapse or other treatment failure was only 31% +/- 4.7%. In summary, more recent shorter and intense therapy appears to be associated with superior event-free survival for children and adolescents with disseminated LCL. Large numbers of patients treated with shorter and intense therapy are required to confirm these preliminary observations.

Current clinical trials for advanced Hodgkin's lymphoma in North America: history, design and rationale

Current clinical trials for advanced Hodgkin's lymphoma in North America: history, design and rationale

Differentiation of antigen-presenting cells (dendritic cells and macrophages) for therapeutic application in patients with lymphoma.

The recent clinical trial in lymphoma using tumor antigen-loaded DCs (Hsu et al, Nature Med 1996; 2: 52) demonstrates the efficiency of the use of professional antigen presenting cells (APCs) for taking up, processing and presenting tumor protein in a vaccine strategy in cancer. However, the production of large quantities of clinical grade APCs remains to be resolved. Here, we describe that both dendritic cells (DCs) and macrophages (MOs) can be efficiently differentiated in large numbers from lymphoma patients in spite of their disease and previous therapy. These cells were produced using the VAC and MAK cell processors according to standard operating procedures. DCs and MOs were differentiated from circulating monocytes in gas permeable hydrophobic bags, with 2% autologous serum and in the presence of GM-CSF and IL-13 or GM-CSF alone, respectively. DCs and MOs were then purified by counter flow centrifugation. Phenotypic, morphological and functional analysis showed that cells differentiated from patients with lymphoma present quite similar features to DCs and MOs produced from monocytes of healthy donors. Moreover, we show that MOs, when combined with CD20 antibody (Rituximab), can efficiently engulf tumor cells and propose that a such combination could be used for initiating a clinical trial in lymphoma. Thus, the possibility of producing functional DC and MOs in large amounts in conditions compatible with therapeutic application will allow the development of new immune strategies to eradicate lymphoma.

Helicobacter pylori in the upper gastrointestinal tract: medical or surgical treatment of gastric lymphoma?

The treatment of primary gastric lymphoma is controversial. The role of surgery has come to be questioned with increasing knowledge about the pathogenesis of gastric lymphoma and with new therapeutic approaches such as eradication of Helicobacter pylori. We review published clinical trials of primary gastric lymphoma, including preliminary results of our own prospective multicenter trial. The results of 7 trials of H. pylori eradication and 12 prospective therapeutic trials trial are discussed. On basis of these data it is concluded that surgery with intention of R0 resection is the treatment of choice in stages EI2 and EII1 of low-grade lymphoma. In high-grade lymphomas it is still unclear whether surgery or its primary combination with radio- or chemotherapy should be preferred. The eradication of H. pylori is a promising therapeutic approach for localized low-grade mucosa-associated lymphoid tissue lymphoma. A randomized trial is needed to clarify whether medical or surgical management of localized gastric lymphoma or a combination of two is the best treatment modality.

Non-Hodgkin's lymphoma in pediatric patients with chromosomal breakage syndromes (AT and NBS): Experience from the BFM trials

Lymphoma and leukemia are the commonest malignant diseases in patients with chromosomal breakage syndromes and immunodeficiency (Ataxia teleangiectasia (AT) and Nijmegen breakage syndrome (NBS)). With improved management of infections, malignant disease is more frequently diagnosed and has become one of the commonest causes of death in pediatric AT and NBS. In three consecutive multicenter therapy trials for pediatric non-Hodgkin's lymphoma (NHL) (NHL-BFM), 1569 patients with newly diagnosed NHL have been registered between 1986 and 1997. Nine patients with AT (n = 5) and NBS (n = 4) were identified and analysed. Median age of patients with AT and NBS at diagnosis of NHL was nine years. NHL-entities differed from non-AT/NBS-patients: diffuse large B-cell lymphomas, n = 7 (78%); ALCL, n = 1; lymphoblastic T-cell lymphoma, n = 1. Cervical nodes, paranasal sinuses and epipharynx were the sites most frequently involved. Stages were: I and II in three patients, III in five and IV in one patient. All patients received polychemotherapy according to tumor-entity and stage, none received radiation. Dose reductions according to individual tolerance concerned mainly ethotrexate, alkylating agents and epipodophyllotoxines. One patient died of toxic complications, two patients relapsed and died, one patient suffered from second malignancy. Five of nine patients are in 1. CCR after a median follow-up of five years. Patients with AT and NBS suffer from rare entities of pediatric NHL. Curative treatment is possible and should be attempted. Intensity of therapy should be adjusted to individual risk factors and tolerance. Alkylating agents, epipodophyllotoxines should be omitted, dose of MTX should be limited to 1 g/m2. Further cooperative trials using standardized approaches are required.

Osteolymphoma (primary bone lymphoma): an Australian review of 70 cases. Australasian Radiation Oncology Lymphoma Group (AROLG).

To examine prognostic factors, treatment outcomes and design future studies for Osteolymphoma (OL)--also known as primary bone lymphoma. Between 1979 and 1993, 70 patients with OL were treated in nine Australian centres. The effect of patient-, tumour-, and treatment-related factors on local control, distant disease-free survival and overall survival were assessed by multivariate analysis. Most patients (94%) received radiotherapy (RT) (median dose 40 Gy) and 56% received chemotherapy. Multifocal disease was present in 20% of patients. The five year rates of overall survival and local control were 59% and 82%. Although there was a trend towards better results with the addition of chemotherapy, on multivariate analysis, there were no factors identified which appeared to impact upon overall and disease-free survival. Among the distant recurrences, there was a high proportion in bone (33%). Six patients suffered pathological fractures after treatment. High rates of local control were achieved by RT, but the overall survival remains relatively poor, worse than nodal lymphoma. The natural history of the disease suggests that OL may be a distinct entity, different to nodal lymphomas, so the results of clinical trials in nodal lymphoma may not be relevant to OL. Prospective studies could define the outcome of combined modality therapy and set a benchmark for testing further proposals, as well as improving our knowledge of the clinical features of OL.

Large Scale Manufacturing of B43(Anti-CD19)-Genistein for Clinical Trials in Leukemia and Lymphoma

We have conjugated the murine monoclonal anti-CD 19 antibody B43 to the tyrosine kinase inhibitor genistein to construct an effective immunoconjugate against CD 19 antigen positive hematologic malignancies. The scaled-up production and purification of B43 antibody, genistein, and B43-Genistein immunoconjugate permitted the manufacturing of a highly purified clinical-grade B43-Genistein preparation. In clonogenic assays, B43-Genistein elicited selective and potent cytotoxicity against CD 19 antigen positive human leukemia cells. To our knowledge, this work represents the first effort of producing a clinical-grade genistein immunoconjugate for treatment of B-lineage leukemia and lymphoma.

Monoclonal Antibodies in the Treatment of Human B-Cell Malignancies

Monoclonal antibody technology emerged in the 1970′s and was greeted by a wave of optimism. Many believed this new form of therapy would be effective in the treatment of human cancers. Early clinical trials in B-cell lymphomas demonstrated both the potential and limitations of unlabeled murine monoclonal antibody therapy, and taught us valuable lessons regarding the importance of the antibody structure, and nature of the targeted antigen. Since that time modifications in antibody structure and careful selection of target antigen have improved the clinical efficacy of these agents. Clinical trials using humanized antibodies have demonstrated that human/mouse chimeric antibodies and humanized antibodies have enhanced anti-tumor activity, decreased immunogenicity, and a very favorable toxicity profile. Radiolabeled monoclonal antibodies can induce durable remissions in lymphoma with toxicity limited largely to bone marrow suppression. Clinical trials with immunotoxins have demonstrated anti-tumor activity but also have been associated with significant toxicity. Standard treatment options for B-cell lymphoma will soon include antibody-based therapies. Further basic and clinical research is needed so we can understand more thoroughly the mechanisms responsible for the observed anti-tumor effects, and explore more extensively the best approach to their clinical use.

Burkitt's lymphoma presenting with jaw lesions in a young white girl

We report a case of Burkitt's lymphoma that presented with jaw lesions in a 5-year-old white girl, an extremely rare occurrence. She was treated according to the protocol of the UK Children's Cancer Study Group B-cell non-Hodgkin's lymphoma trial and was still in remission after 2 years.

難治性リンパ系腫ように対する新たな治療研究の動向

There are some refractory lymphomas those 5-year overall survival rate is less than 50%, including relapsed or chemotherapy-resistant aggressive NHL, high-intermediate-, or high-risk group of aggressive NHL categorized by International Prognostic Index, mantle cell lymphoma, advanced NK/T cell lymphoma, adult T-cell leukemia/lymphoma (ATL) and advanced and refractory follicular lymphoma. We report here the results of three clinical trials for these refractory lymphomas, as follows; (1) phase I/II trial of cure-oriented high-dose chemoradiotherapy with transplantation of CD34+ peripheral blood stem cells purified by the immunomagnetic bead method for refractory hematological malignancies. (2) phase I study of cladribine (2-chlorodeoxyadenosine) in lymphoid malignancies. (3) clinical trial of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma.(1) Nine patients with relapsed or refractory hematological malignancies including 8 NHL patients were enrolled and treated by high-dose chemoradiotherapy with transplantation of CD34+ peripheral blood stem cells purified by the immunomagnetic bead method. In each patient, a median of 1.75×106cells/kg purified CD34+ PBSCs (purity; 92%) were infused. Median times to hematopoietic recovery were as same as those in non-purged PBSCT. Most patients experienced only transient toxicities previously observed with the preparative chemotherapy regimens used. Seven patients are alive in remission. This phase I/II trial showed PBSCT with the immunomagnetic bead method to be an active and safe therapy. (2) To clarify the toxicity profiles of cladribine, we conducted a phase I and pharmacological study of cladribine with a schedule of seven-day continuous intravenous infusion every 28 days up to a maximun of three cycles. Anti-tumor effect was observed in the patients with ATL, cutaneous T-cell lymphoma and mantle cell lymphoma. The encouraging results prompted us to plan subsequent phase II studies of cladribine against ATL, hairy cell leukemia and indolent lymphoma. (3) A phase I/II trial of a chimeric mouse human monoclonal antibody to CD20 for CD20 positive recurrent indolent B-cell lymphoma in USA showed a response rate of 50%. A phase II trial has been started for recurrent or relapsed mantle cell lymphoma and indolent B-cell lymphoma in Japan. These three clical trials showed that CD34+ PBSCT by the immunomagnetic bead method, cladribine and IDEC-C2B8 are safe and active therapy or drugs, and suggested promising method or agents for refractory lymphomas.

Non-Hodgkin's lymphoma.

Attention is being directed at increasing the intensity of therapy as a means of improving the results of primary therapy for non-Hodgkin's lymphoma. There is increasing evidence that the use of high-dose consolidation therapy followed by autologous hematopoietic rescue in first remission improves survival in high-risk patients. There is also evidence from randomized trials that transplantation for relapsed patients improves survival compared with conventional salvage chemotherapy. Phase II trials of radiolabeled antibody therapy are providing promising results. There is still no definitive evidence that any treatment of advanced low-grade lymphoma prolongs survival, although the use of allogeneic bone marrow transplantation is under investigation. Treatment designed to eradicate Helicobacter pylori can cause regression in approximately 50% of patients with gastric lymphomas of mucosa-associated lymphoid tissue, although long-term follow-up information is lacking. The results of treatment for mantle cell lymphoma are poor and there is no consensus on management. Most trials of primary central nervous system lymphoma are employing systemic chemotherapy with drugs that penetrate the blood-brain barrier in addition to radiation.

Expression of mdr-1 in Refractory Lymphoma: Quantitation by Polymerase Chain Reaction and Validation of the Assay

Measurement of P-glycoprotein and the gene that encodes it, mdr-1, is an important tool for assessing the impact of multidrug resistance in clinical cancer. We evaluated mdr-1 expression by a quantitative polymerase chain reaction (PCR) assay in 78 biopsy samples from 48 patients with refractory lymphoma enrolled on a trial of infusional chemotherapy (EPOCH) in which R-verapamil was added as an antagonist of P-glycoprotein in a subset of patients whose tumors were unresponsive to treatment. Expression of mdr-1 was detectable in all biopsies at the time of enrollment on study, and a fourfold or greater increase in mdr-1 expression was noted in 42% of patients at the time of treatment failure. Expression of mdr-1 was also detectable in biopsies from patients at the time of diagnosis of lymphoma. An endogenous control gene, beta 2-microglobulin, was quantitated for normalization of the mdr-1 values. The use of beta 2-microglobulin expression for normalization was validated in a subset of samples by comparing Northern blots detecting beta 2-microglobulin, beta actin, and GAPDH gene expression. Immunoblot analysis suggested that no major discrepancy was present between mRNA expression and protein level. Immunophenotyping of lymphomatous lymph nodes showed that infiltration of tumor cells ranged from 8% to 95% and of normal T cells from 1% to 83%. Expression of mdr-1 in normal T cells and monocytes was also shown to be low. The mdr-1 levels in patient samples were independent of T-cell contamination, suggesting that the presence of normal cells has at best a small impact on mdr-1 measurements. Expression of mdr-1 in lymphoma can be quantitated by PCR, and wide variations in expression can be observed. Increased expression in patients with refractory disease supports an important role for Pgp in drug resistance in lymphoma. These studies will aid in the design and interpretation of clinical trials in lymphoma.

Bispecific Monoclonal Antibody Therapy of B-Cell Malignancy

Bispecific monoclonal antibodies (bsAbs) that recognize CD3 with one arm and a tumor associated antigen with the other arm can retarget T-cells toward tumor cells in an MHC independent manner, thereby combining the specificity of monoclonal antibodies with the power of the cellular immune system. B-cell malignancies are particularly attractive as targets for anti-CD3-based bsAb therapy because of their sensitivity to other forms of antibody therapy, and the extent to which B-cells and T-cells communicate at the molecular level. BsAbs that recognize CD3 and a number of antigens on malignant B-cells have been shown in vitro to be capable of retargeting T-cells. In animal models of B-cell malignancy, bsAb can eliminate tumor loads that are resistant to unmodified monoclonal antibody therapy. Ongoing early clinical trials in advanced B-cell lymphoma indicate CD3-based bsAbs have significant biologic effects, and suggest they have anti-tumor activity as well. A number of significant questions relating to bsAb therapy of B-cell malignancies remain. It is unclear what role both endogenously produced and exogenously administered cytokines are likely to play. Further exploration of whether bsAb can induce T-cells to target to tumor will also be required before the true promise of this novel form of immunotherapy can be determined.

Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy.

We reviewed survival data of patients with low-grade lymphoma entered on Southwest Oncology Group (SWOG) lymphoma trials in 1972 to 1983 to determine the utility of doxorubicin-containing therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) in such patients. We identified all patients with low-grade lymphoma, no prior therapy, and stage III or IV disease who were treated with full-dose CHOP induction therapy on any arm of SWOG studies 7204, 7426, or 7713. Survival data for this group of patients were correlated with pretreatment prognostic factors, including histology, patient age, sex, symptom status, performance status, bone marrow or extranodal involvement, and the number of disease sites. The effect of maintenance treatment was also assessed. Four hundred fifteen patients met criteria for inclusion in the study group. With median follow-up periods of 12.8 years (maximum, 19.8 years), the median survival duration was 6.9 years. Survival was significantly shorter in patients with follicular mixed or small lymphocytic histology, age greater than 40 years, male sex, B-symptom status, and SWOG performance status greater than 1. Multivariate regression analysis showed histology, age, and sex to be independent predictors of survival. There was no definite survival plateau of cured patients in any subgroup, although the survival curve for follicular mixed histology patients showed long-term survival of approximately 25%. Maintenance therapy did not prolong survival. Doxorubicin-containing treatment did not prolong the overall median survival of low-grade lymphoma patients compared with results with less-aggressive programs.

Treatment of leukemia with radiolabeled monoclonal antibodies.

In contrast to radioimmunotherapy of solid disease, wherein the primary obstacle to success is access of radiolabeled antibody to antigen-positive cells, in the treatment of leukemia delivering a lethal absorbed dose to the isolated cell appears to be the primary obstacle. The isolated cell is defined as one that is exposed only to self-irradiation (from internalized or surface-bound radiolabeled antibody) and to irradiation from free antibody in the blood. It is isolated in the sense that the particulate (beta, electron, alpha) emissions from its nearest neighboring antigen-positive cell do not contribute to its absorbed dose. Disease in the bone marrow and other tissues, since it is confined to a smaller volume, is more easily eradicated because the absorbed dose to a given cell nucleus is enhanced by emissions from adjacent cells (a smaller fraction of the emission energy is 'wasted'). The optimization simulations presented above for the M195 antibody suggest that the optimum dose of antibody that should be administered is that required to yield a concentration within the distribution volume of the antibody that is approximately equal to the concentration of antigen sites as determined by the tumor burden. Although not specifically considered in the modeling example presented above, antibody internalization and catabolism may be expected to play an important role in radioimmunotherapy treatment planning of leukemia. Depending upon the kinetics of internalization and catabolism, the absorbed dose to the red marrow and to antigen-positive cells may be reduced considerably, since catabolism, assuming that it is followed by rapid extrusion of the radioactive label, would decrease the cells' exposure time considerably. The recently demonstrated effectiveness of radioimmunotherapy in certain cases of B-cell lymphoma and in reducing tumor burden in acute myelogenous leukemia suggests that radioimmunotherapy is beginning to fulfill the promise held when it was initially conceived. The long delay in achieving reproducible success has, in large part, been the result of the conceptual simplicity of using agents that specifically 'target' tumor cells and they may thus selectively deliver cytotoxic agents. Emboldened by this apparent simplicity, early trials of radioimmunotherapy failed to consider the many variables involved in its implementation. As has been recently demonstrated using mathematical models of antibody delivery to solid tumor, chief among these may have been the failure to select the appropriate tumor type. By significantly reducing the problems associated with antibody delivery, hematopoietic malignancies offer the optimum conditions for successful radioimmunotherapy. As evinced by the wide range of antibody and radioactivity doses administered in the B-cell lymphoma trials, the case-specific nature of radioimmunotherapy requires an understanding of the relationship between the various input parameters and patient response. The complexity and interrelationship of these parameters precludes an experimental trial-and-error approach to their optimization. A stepwise approach to radioimmunotherapy treatment planning is proposed in which a model of antibody kinetics is developed and validated.(ABSTRACT TRUNCATED AT 400 WORDS)

Radioimmunotherapy of B-cell lymphoma

Radioimmunotherapy has evolved from an attractive concept to implementation in clinical trials for evaluation of toxicity and efficacy. Non-Hodgkin's lymphoma is a useful setting for evaluation of this novel form of therapy. Groups investigating radioimmunotherapy for non-Hodgkin's lymphoma are implementing single high doses and multiple smaller doses of beta emitters I-131 and Y-90 attached to antibodies. All groups giving multiple small doses observe partial responses to treatment with variable hematopoietic toxicity. Single very high doses have yielded complete responses with hematologic toxicity requiring reinfusion of stored bone marrow. A review of radioimmunotherapy trials for non-Hodgkin's lymphoma with a discussion of pertinent related issues is presented.

Cooperative trials of Hodgkin's lymphoma in the Federal Republic of Germany

Cooperative trials of Hodgkin's lymphoma in the Federal Republic of Germany

Interpretation of clinical trials in diffuse large-cell lymphoma.

Diffuse large-cell lymphoma is one of the neoplasms curable with chemotherapy in an appreciable percentage of patients. However, all patients are not cured and the best combination of agents is not certain. This reflects the lack of completed comparative trials using the regimens that appear most effective. Despite this uncertainty, several principles for the therapy of diffuse large-cell lymphoma can be identified that allow an analysis of the results reported in the literature. These principles include the following: (1) for a regimen to be curative in a substantial number of patients it must achieve a high rate of complete remissions; (2) cure must be accomplished with frontline therapy; (3) drugs must be delivered at curative doses; (4) rapidity of achieving a complete response might be related to chance for cure; (5) prolonged treatment for diffuse large-cell lymphoma is unnecessary; and (6) aggressive therapy is toxic. In analyzing the results with any regimen it is important to have long follow-up since late relapses do occur and initial very positive results tend to decay with greater numbers of patients treated. Applying these principles to the reported chemotherapy studies in patients with diffuse large-cell lymphoma suggest that no one of the new regimens is clearly superior to the others. Also, it is not clear that cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) delivered at full doses to comparable patients is inferior to the newer regimens. The results of ongoing studies comparing these regimens might help resolve these questions.

Guidelines for reporting outcomes of lymphoma trials.

Guidelines for reporting outcomes of lymphoma trials.