National Cancer Institute®
Last Modified: March 1, 2002
UI - 11843810
AU - Chau I; Webb A; Cunningham D; Hill M; Rao S; Ageli S; Norman A; Gill K;
TI - Howard A; Catovsky D An oxaliplatin-based chemotherapy in patients with relapsed or refractory intermediate and high-grade non-Hodgkin's lymphoma.
SO - Br J Haematol 2001 Dec;115(4):786-92
AD - Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK.
This study was designed to assess the efficacy and safety of substituting cisplatin with oxaliplatin in the DHAP (dexamethasone, cytarabine and cisplatin) regimen for patients with relapsed or refractory non-Hodgkin's lymphoma. Twenty-four evaluable patients with intermediate or high-grade non-Hodgkin's lymphoma were treated at 3-weekly intervals with oxaliplatin (130 mg/m2, d 1), cytarabine (2 g/m2 for two doses, d 2) and dexamethasone (40 mg, d 1-4). The median age of the patients was 58 (range 18-70). Histological subtypes were diffuse large B cell, 20; mantle cell, two; anaplastic large cell, one; and peripheral T cell, one. The overall objective response rate (RR) was 50% [95% confidence interval (CI) = 29-71%] including four complete responses and eight partial responses. RR for those patients treated at first relapse was higher than those treated at second and subsequent relapse (77% versus 29%). Grade 3 and 4 toxicity was mainly haematological: anaemia 17%, neutropenia 75% and thrombocytopenia 75%. No grade 4 non-haematological toxicity was reported. No significant renal and neurotoxicity was demonstrated. Median survival was 10.6 months. Probabilities of 1-year progression-free survival and overall survival were 47% (95% CI = 26-66%) and 50% (95% CI = 23-72%) respectively. In conclusion, dexamethasone, cytarabine and oxaliplatin (DHAX) is a novel combination in salvage therapy for relapsed or refractory non-Hodgkin's lymphoma. It has clinically significant activity with an acceptable toxicity profile. Lack of renal toxicity makes DHAX an attractive cytoreductive regimen before high-dose chemotherapy.
UI - 11806987
AU - Rambaldi A; Lazzari M; Manzoni C; Carlotti E; Arcaini L; Baccarani M;
TI - Barbui T; Bernasconi C; Dastoli G; Fuga G; Gamba E; Gargantini L; Gattei V; Lauria F; Lazzarino M; Mandelli F; Morra E; Pulsoni A; Ribersani M; Rossi-Ferrini PL; Rupolo M; Tura S; Zagonel V; Zaja F; Zinzani P; Reato G; Foa R Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma.
SO - Blood 2002 Feb 1;99(3):856-62
AD - Divisione di Ematologia, Ospedali Riuniti Bergamo, Largo Barozzi 1, 24100 Bergamo, Italy. email@example.com
Minimal residual disease (MRD) following sequential administration of CHOP and rituximab was studied in previously untreated patients with follicular lymphoma. At diagnosis, the presence of Bcl-2/IgH-positive cells in the peripheral blood (PB) and/or bone marrow (BM) was demonstrated in all patients (n = 128) by polymerase chain reaction (PCR) analysis. Patients who achieved a clinical response following CHOP but remained PCR-positive were eligible for rituximab (375 mg/m(2) intravenously, weekly for 4 weeks). After CHOP, 57% achieved a complete response (CR), 37% a partial response (PR), and 6% were nonresponders (NR). At this stage, patients proving PCR-negative (n = 41) or failing to achieve a clinical response (n = 8) were excluded from rituximab treatment. Seventy-seven patients received rituximab and entered a scheduled MRD follow-up program. At the first molecular follow-up (+12 weeks), 59% had converted to PCR negativity in the BM and PB, with a further increase documented at the second control (+28 weeks) with 74% PCR negative. At the last molecular follow-up (+44 weeks), 63% of the patients remained PCR negative. At 3 years, the estimated overall survival of all patients is 95% (95% confidence interval [CI], 86-98). For patients achieving PCR-negative status following CHOP and therefore excluded from rituximab treatment, freedom from recurrence (FFR) was 52% (95% CI, 28-71). For patients treated with rituximab, a durable PCR-negative status was associated with a better clinical outcome since FFR was 57% (95% CI, 23-81) compared with 20% (95% CI, 4-46) in patients who never achieved or lost the molecular negativity (P <.001).
UI - 11830549
AU - Vrana JA; Bieszczad CK; Cleaveland ES; Ma Y; Park JP; Mohandas TK; Craig
TI - RW An MCL1-overexpressing Burkitt lymphoma subline exhibits enhanced survival on exposure to serum deprivation, topoisomerase inhibitors, or staurosporine but remains sensitive to 1-beta-D-arabinofuranosylcytosine.
SO - Cancer Res 2002 Feb 1;62(3):892-900
AD - Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755-3835, USA.
Members of the BCL2 gene family influence cell viability and can, therefore, affect the susceptibility of cancer cells to multiple chemotherapeutic agents. Thus, it is a challenge to devise approaches for inducing the death of tumor cells in which the expression of prosurvival family members is elevated or deregulated. BL41-3, a spontaneously derived subline of BL41 Burkitt lymphoma cells, was found to have amplified the prosurvival MCL1 gene (3-fold) and overexpressed the MCL1 protein. The level of MCL1 protein was 5-fold elevated compared with ML-1 cells expressing maximal MCL1 on exposure to phorbol-12-myristate-13- acetate. To assess whether this increase in MCL1 expression was associated with enhanced protection from cell death, cells were exposed to conditions of growth factor deprivation or to various cytotoxic agents. Whereas BL41-3 and BL41 cells exhibited similar growth rates in logarithmic phase, BL41-3 cells remained largely viable on reaching saturation phase in contrast to BL41 cells, which began to die. Similarly, the BL41-3 subline remained viable for an extended period under conditions of reduced serum. BL41-3 cells were also more resistant to the apoptosis-inducing effects of etoposide, camptothecin, and staurosporine (>3-fold more than BL41 cells). Unexpectedly, these cells exhibited enhanced sensitivity to 1-beta-D-arabinofuranosylcytosine, but only on exposure for an extended period (>10-fold more sensitive than BL41 cells with a 24-h but not a 6-h exposure). Thus, whereas cells expressing prosurvival BCL2 family members are frequently resistant to a variety of chemotherapeutic agents, the findings presented here, using a cell line exhibiting amplification and overexpression of MCL1, indicate that such cells may exhibit increased sensitivity to certain chemotherapeutic regimens.
UI - 11773279
AU - Esteller M; Gaidano G; Goodman SN; Zagonel V; Capello D; Botto B; Rossi
TI - D; Gloghini A; Vitolo U; Carbone A; Baylin SB; Herman JG Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma.
SO - J Natl Cancer Inst 2002 Jan 2;94(1):26-32
AD - Division of Cancer Biology, The Johns Hopkins Oncology Center, Baltimore, MD 21231, USA.
BACKGROUND: The gene encoding the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is transcriptionally silenced by promoter hypermethylation in several human cancers, including diffuse large B-cell lymphoma (B-DLCL). MGMT promoter hypermethylation is a favorable prognostic marker in patients with brain tumors treated with alkylating agents. METHODS: In a retrospective cohort study, we used methylation-specific polymerase chain reaction to analyze the MGMT promoter methylation status in tumor DNA of B-DLCL patients receiving cyclophosphamide as part of multidrug regimens. Molecular data were compared with patient response with the use of Student's t test. Disease-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the use of the log-rank test. Multivariable survival analyses were performed with the Cox proportional hazards model. All statistical tests were two-sided. RESULTS: Thirty (36%) of 84 B-DLCL patients showed MGMT promoter hypermethylation in their lymphomas. The presence of MGMT methylation was associated with a statistically significant increase in overall survival (hazard ratio for time to death for nonmethylation versus methylation = 2.8; 95% confidence interval (CI) = 1.2 to 7.5; P =.01) and progression-free survival (hazard ratio for time to progression for nonmethylation versus methylation = 2.6; 95% CI = 1.3 to 5.8; P =.02). MGMT promoter hypermethylation was both independent of and stronger than established prognostic factors, such as age, disease stage, serum lactic dehydrogenase level, and performance status. CONCLUSION: MGMT promoter hypermethylation appears to be a useful marker for predicting survival in patients with B-DLCL treated with multidrug regimens including cyclophosphamide.
UI - 11823692
AU - Briggs JH; Algan O; Miller TP; Oleson JR
TI - External beam radiation therapy in the treatment of patients with extranodal stage IA non-Hodgkin's lymphoma.
SO - Am J Clin Oncol 2002 Feb;25(1):34-7
AD - Department of Radiation Oncology, University of Arizona Cancer Center, 1501 North Campbell Avenue, Tucson, AZ 85724, U.S.A.
The purpose of this report was to study the results of external beam radiotherapy for patients with extranodal stage IA non-Hodgkin's lymphoma (NHL). A retrospective review was carried out on 27 patients seen between 1984 and 1998 with stage IA NHL of extranodal sites, and followed up for a minimum of 1 year. Sites involved included eye/orbit (seven), parotid (five), breast (four), Waldeyer ring (four), thyroid (three), other head and neck (two), stomach (one), and prostate (one). All patients had biopsy-proven disease and underwent staging workup to rule out other sites of disease. Histologic analysis revealed 16 patients with low-grade NHL, 9 with intermediate-grade, and 2 with high-grade. Ten patients received chemotherapy before radiation therapy, and eight of them had a complete response. The remaining 17 patients were treated with external beam radiation therapy alone. Radiation was directed to the involved field at 1.8 Gy to 2.0 Gy per fraction to a median dose of 40 Gy (range: 20-50.4 Gy). The median patient age was 71 years (range: 39-85 years); 55% were female, and 45% were male. A complete response was attained in all 27 patients after radiation therapy. There were five failures (all in uninvolved distant sites), and two deaths during the follow-up. Median disease free survival (DFS) and overall survival (OS) have not been reached. The 5-year DFS and OS are 85% and 94%, respectively. Older age at presentation showed a trend toward worse outcome (p = 0.07), but because of the relatively few events, other factors (radiation dose, grade of disease, sex, or the use of chemotherapy) showed no statistical differences among the patients. External beam radiation therapy is a highly effective treatment for stage IA NHL found in extranodal sites.
UI - 11876162
AU - Anonymous
TI - Current and ongoing clinical development of immunotherapy in B-cell Hawaii, USA.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):1-112; quiz 113-21
UI - 11842397
AU - Grillo-Lopez AJ; Hedrick E; Rashford M; Benyunes M
TI - Rituximab: ongoing and future clinical development.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):105-12
AD - Antonio J. Grillo-Lopez, Consultant Clinical Research and Regulatory Strategy, Genentech, Inc, South San Francisco, CA 94080-4990, USA.
Monoclonal antibodies have been used as therapeutic agents for many years. In 1997, rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) became the first monoclonal antibody to be approved by the US Food and Drug Administration for a cancer indication. The use of rituximab in the treatment of low-grade or follicular, relapsed, or refractory CD20-positive B-cell non-Hodgkin's European Union countries under the trade name MabThera as therapy for patients with stage III/IV, follicular, chemoresistant, or relapsed (> or = 2 relapses) non-Hodgkin's lymphoma. To date, rituximab has been approved in 56 countries. Over 125,000 patients have been treated with this antibody in the United States alone. Rituximab served to heighten interest in the therapeutic applications of monoclonal antibodies. Literally dozens of antibodies are currently under investigation for a variety of malignant and non-neoplastic indications. The US Food and Drug Administration approved a new (revised) package insert in early 2001. These revisions have been communicated to physicians via a "Dear Doctor Letter" and will appear in the 2002 edition of the Physicians' Desk Reference. A significant amount of clinical research has been performed over the past 9 years, which has served to further our understanding of the potential clinical applications for this novel therapeutic agent. Ongoing and future clinical trials are reviewed in this article. However, much remains to be accomplished in key areas such as combinations with chemotherapy, biologics (including other antibodies), and radiotherapy/radioimmunotherapy; its role within multimodality regimens; and other malignant (beyond low-grade non-Hodgkin's lymphoma) and nonmalignant applications. Copyright 2002 by W.B. Saunders Company.
UI - 11842385
AU - Hainsworth JD
TI - Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin's lymphoma: interim follow-up of a multicenter phase II trial.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):25-9
AD - Sarah Cannon Cancer Center, Centennial Medical Center, Nashville, TN.
The purpose of this study is to evaluate the activity of rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) in the first-line treatment of patients with indolent non-Hodgkin's lymphoma, and to evaluate the role of scheduled maintenance courses of rituximab in prolonging duration of remission. Sixty-two patients with stages II to IV indolent non-Hodgkin's lymphoma (follicular or small lymphocytic) who had received no previous systemic therapy entered this multicenter, community-based trial. All patients received rituximab 375 mg/m(2) weekly for 4 consecutive weeks, and were evaluated for response at week 6. Patients who had an objective response or stable disease continued treatment every 6 months with repeat 4-week courses of rituximab for a total of four treatment courses. Interim results of this ongoing trial are available. When evaluated at week 6, 28 of 60 evaluable patients (47%) had objective response and 27 patients (45%) had minor response or stable disease. With further follow-up and repeat courses of rituximab, the major response rate increased from 47% to 65% and the complete response rate increased from 7% to 27%. Response rates were similar in patients with follicular lymphoma and small lymphocytic lymphoma (63% and 66%, respectively). Median progression-free survival has not been reached, but will be greater than 24 months. There has been no cumulative toxicity observed with repeat courses of rituximab. Rituximab is highly effective as a first-line single agent for the treatment of indolent non-Hodgkin's lymphoma. The initial response rate can be improved by using scheduled maintenance courses of rituximab administered every 6 months. Final information regarding duration of response and time to progression awaits further follow-up. Copyright 2002 by W.B. Saunders Company.
UI - 11842386
AU - Coiffier B
TI - Rituximab in the treatment of diffuse large B-cell lymphomas.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):30-5
AD - Hospices Civils de Lyon and Universite Claude Bernard, Lyon, France.
A review of the use of rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) in diffuse large B-cell lymphomas is presented, focusing on the recent presentation of the combination of CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) plus rituximab in elderly patients. This combination increased the response rates, event-free survival, and overall survival of patients older than 60 years in comparison with CHOP alone. The toxic events observed with the combination were not more numerous or severe than those observed with CHOP alone. Rituximab is a chimeric anti-CD20 antibody that increases the treatment options in patients with B-cell lymphomas. Copyright 2002 by W.B. Saunders Company.
UI - 11842387
AU - Czuczman MS; Fallon A; Mohr A; Stewart C; Bernstein ZP; McCarthy P;
TI - Skipper M; Brown K; Miller K; Wentling D; Klippenstein D; Loud P; Rock MK; Benyunes M; Grillo-Lopez AJ; Bernstein SH Rituximab in combination with CHOP or fludarabine in low-grade lymphoma.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):36-40
AD - Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Non-Hodgkin's lymphoma (NHL) is composed of a group of lymphoid malignancies that has been increasing in incidence at an annual rate of 4% to 7% over the last 20 years in both the United States and Europe. The reasons for this rise in incidence in NHL are not yet defined but most likely involve environmental exposures. Low-grade and follicular lymphomas account for approximately 40% of the incidences of NHL in the United States. While patients with intermediate- and high-grade lymphomas are potentially curable with combination chemotherapy, low-grade and follicular lymphomas are still considered to be essentially incurable with standard therapy. Although low-grade lymphomas characteristically respond well to treatment with chemotherapeutic agents, the disease typically follows a course of recurrent relapse and progressively shorter remissions, and ultimately death from lymphoma. Median survival for patients with low-grade lymphoma is 6.2 years from diagnosis and just 5 years from time of first relapse. Therefore, novel therapeutic strategies are urgently needed for these patients. One approach to the development of innovative strategies for treatment of NHL has been the generation of monoclonal antibodies to specific B-cell antigens expressed on NHL cells. Copyright 2002 by W.B. Saunders Company.
UI - 11842388
AU - Wilson WH; Gutierrez M; O'Connor P; Frankel S; Jaffe E; Chabner BA;
TI - Grossbard ML The role of rituximab and chemotherapy in aggressive B-cell lymphoma: a preliminary report of dose-adjusted EPOCH-R.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):41-7
AD - Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Accumulating evidence suggests that the ability to activate apoptotic pathways may be an important determinant of chemotherapy sensitivity and presents a potentially important new therapeutic strategy. Monoclonal antibodies against the CD20 antigen directly induce apoptosis and may serve to modulate the threshold for chemotherapy-induced apoptosis. Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA), a monoclonal antibody against CD20, was combined with dose-adjusted EPOCH (infusional etoposide/vincristine/doxorubicin/bolus cyclophosphamide/prednisone) chemotherapy and tested in 38 untreated or relapsed poor-prognosis aggressive lymphomas. Twenty-three patients were untreated. Of these patients, all had large B-cell histologies, a median age of 52 years, Eastern Cooperative Oncology Group performance status > or = 2 in 30%, and high-intermediate or high International Prognostic Index scores in 61%. Fifteen patients had relapsed or refractory lymphomas. These patients had received a median of two (range, one to four) prior regimens, 67% had aggressive histologies, and 60% had high-intermediate or high International Prognostic Index scores. Complete remissions were achieved in 85% and 64% of untreated and previously treated patients, respectively; additionally 42% of patients with disease refractory before therapy achieved complete remission. At a median follow-up of 12 months, progression-free and overall survival in the previously untreated group was 85% and 79%, respectively, and no patient in complete remission has relapsed. These results suggest that rituximab may modulate the sensitivity of B-cell lymphomas to chemotherapy.
UI - 11842389
AU - Sarris AH; Jiang Y; Tsimberidou AM; Thomaides A; Rassidakis GZ; Ford RJ;
TI - Medeiros LJ; Cabanillas F; McLaughlin P Quantitative real-time polymerase chain reaction for monitoring minimal residual disease in patients with advanced indolent lymphomas treated with rituximab, fludarabine, mitoxantrone, and dexamethasone.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):48-55
AD - Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Fludarabine and rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) are active against indolent lymphomas. We have previously shown the safety and efficacy of the combination of FND (fludarabine/mitoxantrone/dexamethasone) in relapsed and subsequently untreated patients with stage IV indolent lymphomas. Currently, we treat patients with stage IV indolent lymphomas who are previously untreated, younger than 60 years, human immunodeficiency virus-negative, and have adequate organ and marrow function with FND and random assignment to concurrent or delayed administration of rituximab. We have developed a quantitative real-time polymerase chain reaction assay for t(14;18). With 1 microg of DNA, this assay detects 0.6 copies in 55% of reactions, as expected for the Poisson distribution. When 1microg of DNA was analyzed in duplicate, cells with the t(14;18) were detected in peripheral blood of 22% of 152 volunteer blood donors. Quantitation showed that numbers of t(14;18) cells were higher than the statistical upper normal limit (mean of all volunteer values plus standard deviations) in 2% of volunteer blood donors. By contrast, 36% of blood or marrow specimens from follicular lymphoma patients were positive, and the number of cells with t(14;18) was higher than the normal upper limit in 26%. The presence of cells with t(14;18) and their numbers are prospectively quantitated in blood and marrow of patients treated with FND plus rituximab to determine their clinical significance both at presentation and during therapy. Copyright 2002 by W.B. Saunders Company.
UI - 11842393
AU - Leonard JP; Link BK
TI - Immunotherapy of non-Hodgkin's lymphoma with hLL2 (epratuzumab, an anti-CD22 monoclonal antibody) and Hu1D10 (apolizumab).
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):81-6
AD - Center for Lymphoma and Myeloma and Division of Hematology/Oncology, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY 10021, USA.
Clinical activity of anti-CD20 monoclonal antibodies both in the unlabeled (rituximab [Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA]) and radiolabeled forms, as well as radioimmunoconjugates targeting other antigens, has resulted in the exploration of alternative targets for immunotherapeutic strategies in lymphoma. We report on the rationale for and initial efforts in the development of two unlabeled, humanized monoclonal antibodies directed against molecules commonly expressed in B-cell malignancies. hLL2 (epratuzumab; Immunomedics, Inc, Morris Plains, NJ) binds to the CD22 antigen, while Hu1D10 (apolizumab; Protein Design Labs, Inc, Fremont, CA) reacts with a polymorphism on the HLA-DR beta chain. Preclinical studies and early clinical evaluations suggest that these agents have a potential role as novel therapeutic targets for lymphoma with acceptable toxicity profiles. Further efforts will explore optimal clinical settings for their use, as well as define treatment regimens either as single agents or in combination with chemotherapy or other biologics. Copyright 2002 by W.B. Saunders Company.
UI - 11842394
AU - Gordon LI; Witzig TE; Wiseman GA; Flinn IW; Spies SS; Silverman DH;
TI - Emmanuolides C; Cripe L; Saleh M; Czuczman MS; Olejnik T; White CA; Grillo-Lopez AJ Yttrium 90 ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory low-grade non-Hodgkin's lymphoma.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):87-92
AD - Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611-2927, USA.
The treatment of malignant lymphoma has improved over the past 20 years, but the majority of patients are not cured. New modalities using targeted therapy based on new information in molecular biology and immunology hold promise for better outcomes with less toxicity. We review data on the use of radiolabeled monoclonal antibodies directed against the CD20 antigen on malignant B cells. We discuss the major radionuclides available, iodine 131 ((131)I), tositumomab, and yttrium 90 ((90)Y) ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San Diego, CA) and present data on new approaches in labeling antibodies that have facilitated their use. Clinical trial data with the yttrium-labeled antibodies are discussed. The use of dosimetry as a means for predicting toxicity is discussed, and the questions of long-term toxicity (late effects) are addressed. These targeted approaches to the treatment of malignancy, and lymphoma in particular, hold great promise. Copyright 2002 by W.B. Saunders Company.
UI - 11842396
AU - Kipps TJ
TI - Advances in classification and therapy of indolent B-cell malignancies.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):98-104
AD - Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
Advances in our understanding of normal B-cell differentiation have allowed for improved classification and therapy of B-cell malignancies. B-cell neoplastic diseases may be classified more accurately according to the differentiation stages of presumed normal B-cell counterparts. These advances have challenged the notion that chronic lymphocytic leukemia represents a malignancy of naive CD5 B cells. Analyses of immunoglobulin genes and gene expression patterns through microarray have defined at least two types of chronic lymphocytic leukemia that differ in their tendency toward disease progression. Nevertheless, these types still share more in common than they do with other lymphoid malignancies, and both may be derived from memory-type B cells. Advances in immune therapy are revolutionizing the approach to therapy. B-cell surface differentiation antigens constitute tissue-specific targets for passive immune therapy. Since the US Food and Drug Administration approval of rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) for use in the treatment of follicular lymphoma, monoclonal antibody therapy is being considered for all types of B-cell malignancies. The ability to transform leukemia and lymphoma B cells into effective antigen-presenting cells through CD40 ligation allows for autologous immune recognition of neoplastic cells. Together, active and passive immune approaches have potential for effective treatment of patients with these diseases. Copyright 2002 by W.B. Saunders Company.
UI - 11857288
AU - Seymour JF; Grigg AP; Szer J; Fox RM
TI - Cisplatin, fludarabine, and cytarabine: a novel, pharmacologically designed salvage therapy for patients with refractory, histologically aggressive or mantle cell non-Hodgkin's lymphoma.
SO - Cancer 2002 Feb 1;94(3):585-93
AD - Department of Hematology, The Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia. firstname.lastname@example.org
BACKGROUND: Based on in vitro synergism, the combination of cytarabine (ara-C) and cisplatin is the basis of many salvage regimens for patients with aggressive non-Hodgkin lymphoma (NHL). However, patients with previously refractory disease are significantly less likely to respond, stimulating the search for novel salvage regimens. In vitro, fludarabine enhances the cytotoxicity of both ara-C and cisplatin, increasing ara-C incorporation into DNA and inhibiting repair of platinum/DNA adducts, suggesting that the combination of cisplatin, fludarabine, and ara-C (PFA) may have clinical utility. METHODS: A Phase-II study of a 96 hour continuous infusion of cisplatin with two timed-sequential couplets of fludarabine and ara-C together with granulocyte colony stimulating factor was performed in 45 patients with previously refractory, histologically aggressive or mantle cell NHL. RESULTS: Patients had predominantly diffuse large cell and/or immunoblastic NHL or its variants (80%), or they had mantle cell lymphoma (18%). Overall, 93% of patients had previously refractory disease, with a median International Prognostic Index score of 3. A median of 2 cycles per patient were delivered (range, 1-4 cycles) with significant myelosuppression; there were medians of 2 days of neutropenia < 0.5 x 10(9)/L (range, 0-12 days) and 3 days of thrombocytopenia < 20 x 10(9)/L (range, 0-24 days). This was more severe in older patients and was cumulative with successive cycles. Thirty-five percent of cycles were complicated by infections, nausea and emesis were prominent, but other nonhematologic toxicity was mild. Peripheral blood progenitor cells were mobilized adequately after the first cycle, but collections were impaired after more prolonged therapy. The overall response rate was 48% (7% of patients had complete responses, and 41% of patients had partial responses), with one toxic death due to tumor-lysis syndrome. Patients with mantle cell lymphoma were more likely to respond than patients with other histologies (88% vs. 39%, respectively; P = 0.019), although three of eight patients had relapsed rather than refractory disease. The median remission duration was 4 months, with 28% of potentially eligible patients able to proceed to subsequent high dose therapy. The actuarial 2 year survival rates were 20% +/- 6% overall and 50 +/- 18% for patients with mantle cell lymphoma. CONCLUSIONS: Given the adverse outlook for these patients, the results are promising, particularly for patients with mantle cell lymphoma, and suggest that the addition of fludarabine as a potential biochemical modulator may enhance the activity of cisplatin and ara-C. This is associated with significant cumulative (but manageable) myelosuppression. This paradigm, in which a nucleoside analogue is used to inhibit the repair of platinum/DNA adducts, also may be applicable for the treatment of patients with other types of platinum-sensitive tumors. Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10240
UI - 11857289
AU - Sugiyama K; Omachi K; Fujiwara K; Saotome T; Mizunuma N; Takahashi S;
TI - Ito Y; Aiba K; Horikoshi N Irinotecan hydrochloride for the treatment of recurrent and refractory non-Hodgkin lymphoma: a single institution experience.
SO - Cancer 2002 Feb 1;94(3):594-600
AD - Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
BACKGROUND: Irinotecan hydrochloride (CPT-11) has a broad range of antitumor activity and has demonstrated little cross-resistance with doxorubicin or vincristine. In the current study, the authors investigated the efficacy and adverse effects of irinotecan in the treatment of recurrent and refractory non-Hodgkin lymphoma, for which current therapies appear to be unsatisfactory. METHODS: Irinotecan was administered by intravenous infusion at a dose of 40 mg/m(2)/day for 3 days, and this regimen was repeated 2-3 times at weekly intervals, followed by 2 weeks off therapy. The subjects were 48 patients with recurrent or refractory non-Hodgkin lymphoma. The histologic classification (Working Formulation) was low grade in 8 patients, intermediate grade in 36 patients, high grade in 1 patient, and other (angiocentric lymphoma, Ki-1 lymphoma, and unidentified) in 3 patients. RESULTS: Forty-five patients were determined to be evaluable. Therapy resulted in a complete disease remission in 2 patients and a partial remission in 15 patients. The response rate was 37.8%. The median duration of response was 64 days and the median time to disease progression was 77 days. The median survival time was 422 days. Major adverse reactions included myelosuppression and gastrointestinal toxicity. Leukopenia, anemia, and thrombocytopenia of Grade 3 or 4 (according to the National Cancer Institute Common Toxicity Criteria) was observed in 63.0%, 30.4%, and 6.5% of the patients, respectively, and Grade 3 or 4 diarrhea occurred in 30.4% of patients. Treatment was withdrawn because of diarrhea in three patients. Because of myelosuppression and diarrhea, approximately 67% of the patients required changes to the regimen, including dose reduction, prolongation of the interval between treatments, and reducing the number of days of consecutive treatment. CONCLUSIONS: The results of the current study suggest the activity of irinotecan as salvage therapy for patients with recurrent and refractory non-Hodgkin lymphoma. However, the optimum dosing schedule remains to be determined. Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10266
UI - 11857290
AU - Wilder RB; Romaguera JE; Tucker SL; Ha CS; Hess MA; Cabanillas F; Cox JD
TI - Results with chemotherapy comprised of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by radiotherapy with or without prechemotherapy surgical debulking for patients with bulky, aggressive lymphoma.
SO - Cancer 2002 Feb 1;94(3):601-5
AD - Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA. email@example.com
BACKGROUND: The authors performed a case-control analysis of local control, progression free survival, and overall survival in patients with Stage I-II aggressive lymphomas measuring > or = 7 cm in greatest dimension who were treated initially with or without surgical debulking: All patients then received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) based chemotherapy followed by involved field treated with (n = 25 patients) or without (n = 25 patients) resection of > 80% of their bulky lymphomas. Chemotherapy consisted of 3-12 cycles of CHOP. In general, patients who underwent debulking received three cycles of chemotherapy, whereas patients who did not undergo debulking received at least six cycles of chemotherapy. The total radiotherapy dose was 40.8 grays (Gy) +/- 4.2 Gy (mean +/- standard deviation). RESULTS: The median follow-up was 62 months. Patients who underwent debulking were similar prognostically to patients who did not. There was a trend toward improved local control (5 year rates: 96% vs. 80%; P = 0.10) and overall survival (5 year rates: 83% vs. 71%; P = 0.18) in patients who underwent debulking compared with patients who did not, respectively. Progression free survival was significantly better for patients who underwent debulking compared with patients who did not (5 year rates: 88% vs. 62%, respectively; P = 0.04). CONCLUSIONS: Because this study was retrospective, selection bias may account for the observed difference in progression free survival. Because it is unlikely that a trial randomizing patients with bulky, aggressive lymphoma to surgery will be conducted, the authors' current efforts are focused on escalation of the total radiotherapy dose as a possibly less costly and less morbid approach toward improving progression free survival for these patients. Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10260
UI - 11877754
AU - Koral KF; Francis IR; Kroll S; Zasadny KR; Kaminski MS; Wahl RL
TI - Volume reduction versus radiation dose for tumors in previously untreated lymphoma patients who received iodine-131 tositumomab therapy. Conjugate views compared with a hybrid method.
SO - Cancer 2002 Feb 15;94(4 Suppl):1258-63
AD - University of Michigan Medical Center, Ann Arbor, Michigan 48109-0552, USA. firstname.lastname@example.org
BACKGROUND: A Phase II study of previously untreated patients with malignant low grade follicular lymphoma given a combination of unlabeled tositumomab and tositumomab labeled with iodine-131 has recently been completed. The responses of these patients have been characterized, and for some of them tumor dosimetry during therapy has been estimated not only by pretherapy tracer conjugate views but also by a hybrid method. METHODS: Available patients were studied if they had had a pelvic or abdominal tumor evaluation by single photon emission computed tomography (SPECT) and achieved a partial response. A tumor outlined on the iodine-131 conjugate-view images was called a composite tumor. Its volume estimate came from multiple, not necessarily contiguous, regions of interest (ROI) on the pretherapy computed tomography (CT) scan. Its radiation dose was estimated from the weeklong series of pretherapy images and standard Medical Internal Radiation Dose methods. Computed tomography ROI were also grouped into smaller, contiguous volumes that defined individual tumors. Their radiation doses were estimated by the hybrid method. This method employed the activity measured for each individual tumor by a single intratherapy SPECT scan, as well as the tumor's volume, to individually normalize the composite time-activity curve as appropriate. The individual normalization factors then converted the composite radiation dose to radiation doses for individual tumors. Reduction in tumor volume was calculated for both composite and individual tumors at 12 weeks posttherapy. RESULTS: For 14 composite tumors in 10 patients, the median pretherapy volume was 170 cm(3). Application of a sigmoidal curve function to the plot of volume reduction versus radiation absorbed dose resulted in degeneration of the curve into a straight line with a negative slope. There was no statistical significance in the relationship (P = 0.73). For 43 individual tumors, the median pretherapy tumor volume was 26 cm(3). The plot of volume reduction versus dose was fairly well fit by a sigmoidal curve, and the relationship approached statistical significance (P = 0.06). The representation assigned 56% of the shrinkage to the effects of unlabeled tositumomab. For the subset of individual tumors with a pretherapy volume less than 10 cm(3) from 6 patients (n = 15), the relationship was significant (P = 0.03). The sigmoidal representation assigned only 12% of the shrinkage to unlabeled tositumomab, as contrasted with 72% for tumors with pretherapy volume greater than 10 cm(3). CONCLUSIONS: For patients who attained a partial response, analysis of individual tumors by a hybrid dosimetric method led to a dependence between volume reduction at 12 weeks and radiation dose that tended to be significant. The same was not true with dosimetry of composite tumors based on pretherapy conjugate views alone. It appeared that volume reductions from both unlabeled antibody and radiation dose were important in tositumomab therapy of lymphoma patients, with unlabeled antibody relatively more important for larger tumors. Copyright 2002 American Cancer Society.
UI - 11877765
AU - Wiseman GA; Leigh B; Erwin WD; Lamonica D; Kornmehl E; Spies SM;
TI - Silverman DH; Witzig TE; Sparks RB; White CA Radiation dosimetry results for Zevalin radioimmunotherapy of rituximab-refractory non-Hodgkin lymphoma.
SO - Cancer 2002 Feb 15;94(4 Suppl):1349-57
AD - Division of Nuclear Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. email@example.com
BACKGROUND: Zevalin consists of a murine anti-CD20 monoclonal antibody (ibritumomab) conjugated to the linker-chelator tiuxetan, which securely chelates indium-111 ((111)In) for imaging and dosimetry and yttrium-90 ((90)Y) for radioimmunotherapy (RIT). Previous trials involving rituximab-naive patients have demonstrated excellent targeting of Zevalin to CD20+ B-cell non-Hodgkin lymphoma with minimal uptake in normal organs. The purpose of this trial was to perform (111)In-Zevalin imaging in patients with rituximab-refractory tumors to determine normal organ dosimetry. METHODS: Twenty-seven patients were given an imaging dose of 5 mCi (185 MBq) (111)In-Zevalin on Day 0, evaluated with dosimetry, and then given a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) (90)Y-Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B cells and improve Zevalin biodistribution. Residence times for (90)Y in blood and major organs were estimated from (111)In biodistribution, and the MIRDOSE3 computer software program was used to calculate absorbed radiation doses to organs and red marrow. RESULTS: Median estimated absorbed radiation doses from (90)Y-Zevalin were 8.1 Gray (Gy) (range, 4.2-23.0 Gy) to the spleen, 5.1 Gy (range, 2.6-12.0 Gy) to the liver, 2.0 Gy (range, 1.4-5.3 Gy) to the lungs, 0.22 Gy (range, < 0.01-0.66 Gy) to the kidneys, and 0.74 Gy (range, 0.29-1.2 Gy) to the red marrow. These results are consistent with those from earlier Zevalin trials in rituximab-naive patients. Hematologic toxicity was manageable and did not correlate with estimates of red marrow or total-body absorbed radiation dose. CONCLUSIONS: Zevalin treatment of rituximab-refractory follicular NHL patients at 0.4 mCi/kg resulted in acceptable estimates of absorbed radiation dose to organs, similar to those observed in other Zevalin-treated populations. Copyright 2002 American Cancer Society.
UI - 11877766
AU - Harwood SJ; Gibbons LK; Goldner PJ; Webster WB; Carroll RG
TI - Outpatient radioimmunotherapy with Bexxar. Closed, clean air reservoir minimizes personnel radiation exposure.
SO - Cancer 2002 Feb 15;94(4 Suppl):1358-62
AD - Department of Nuclear Medicine, Veterans Affairs Medical Center (VAMC) Bay Pines, Bay Pines, Florida 33744, USA. Steven_J@Bay-Pines.va.gov
BACKGROUND: Radioimmunotherapy (RIT) with Bexxar (tositumomab and iodine-131 tositumomab; Coulter Pharmaceutical, South San Francisco, CA) has been shown to be effective in the treatment of low-grade and transformed low-grade non-Hodgkin lymphoma (NHL). METHODS: Patient-specific dosimetry with 5 mCi of iodine-131 tositumomab preceded by 450 mg of tositumomab was utilized to calculate the radionuclide dose needed to deliver 75 cGy whole-body radiation (65 cGy for platelet counts of 100,000-149,000/mm(3)). To safely infuse the approximately 95 mCi (range, 52-211mCi) of iodine-131 needed for this treatment, a shielded, closed system was developed to minimize radiation exposure for personnel administering the treatment infusions and to eliminate possible release of aerosolized iodine-131. RESULTS: Twenty-five patients who could be evaluated were infused with a single course of iodine-131 tositumomab therapy and achieved a 76% total response rate at 3 months (32% complete response [CR], 44% partial response [PR]); 59% total response at 6 months (40% CR, 18% PR); and 38% total response at 12 months (31% CR, 6% PR). Administration of RIT using our unique, totally closed system significantly reduced personnel exposure and potential for radioactive spills. The sum of all individuals who administered and monitored the infusions was < 120 mRem whole body exposure over 22 months, well within the ALARA (as low as reasonably achievable) Level I guideline limits. No radioiodide was detectable in the thyroid of any staff member. CONCLUSIONS: In NHL patients who had experienced failure with conventional therapy, RIT with iodine-131 tositumomab therapy was safe and effective. Response rates obtained were equivalent to those obtained at the university medical centers where the Phase I-III clinical trials were performed. Copyright 2002 American Cancer Society.
UI - 11877767
AU - Behr TM; Griesinger F; Riggert J; Gratz S; Behe M; Kaufmann CC; Wormann
TI - B; Brittinger G; Becker W High-dose myeloablative radioimmunotherapy of mantle cell non-Hodgkin lymphoma with the iodine-131-labeled chimeric anti-CD20 antibody C2B8 and autologous stem cell support. Results of a pilot study.
SO - Cancer 2002 Feb 15;94(4 Suppl):1363-72
AD - Department of Nuclear Medicine, Georg-August-University of Gottingen, Gottingen, Germany. firstname.lastname@example.org
BACKGROUND: CD20 has been used successfully as a target molecule for conventional low-dose, as well as high-dose, myeloablative radioimmunotherapy (RIT) of B-cell non-Hodgkin lymphoma (NHL). Mantle cell lymphoma (MCL) is an especially aggressive, prognostically unfavorable subtype of B-cell NHL, associated with an overall 5-year survival rate of less than 20%. Recent evidence has failed to show convincing therapeutic efficacy of conventional, nonmyeloablative RIT in patients with MCL. The aim of this pilot study was to investigate whether high-dose, myeloablative RIT with the iodine-131 ((131)I)-labeled chimeric anti-CD20 antibody C2B8 (rituximab, obtained as Mabthera from Roche Pharma, Reinach, Switzerland) is therapeutically effective in MCL patients. METHODS: A total of seven patients with chemorefractory or relapsed MCL were studied in this pilot trial. All had relapsed after high-dose chemotherapy with autologous stem cell transplantation (four of them combined with 12 grays (Gy) total-body irradiation). A diagnostic-dosimetric study was performed with approximately 10 mCi of (131)I-labeled C2B8 at a protein dose of 2.5 mg per kg body weight, in order to assess its biodistribution and dosimetry. If splenic pooling was observed, as is typically the case in patients with splenomegaly, the protein dose was doubled in additional studies until a "favorable" biodistribution was obtained. Therapy was performed with myeloablative doses of 261-495 mCi of (131)I-labeled C2B8 at the previously optimized protein dose, aiming at lung doses less-than-or-equal 27 Gy. Homologous stem cell support was provided. Clinical follow-up was obtained at 3-month intervals for up to 38 months (median observation time, 25 months). Overall, in six patients the 2.5 mg/kg protein dose was used, whereas in one patient with splenomegaly, 10 mg/kg was necessary to overcome the splenic antigenic sink. RESULTS: Blood cell nadirs were reached at 2-3 weeks after therapy infusion, but all patients reengrafted at 7-10 days after stem cell reinfusion. Nonhematologic toxicity was restricted to mild-to-moderate nausea, fever, transient bilirubin, or liver enzyme elevations. One patient with preexisting alcoholic cirrhosis experienced a deterioration of liver function. Despite thyroid blocking, 5 of 7 patients developed hypothyroidism, requiring thyroxine substitution at 6-18 months after RIT. Six patients experienced a complete and one a good partial remission. Five patients were still in CR at the time this article was written, and six are still alive for more than 3 years; one patient relapsed locally at 3 months and one systemically at 26 months after RIT. CONCLUSIONS: High-dose myeloablative radioimmunotherapy with (131)I-labeled anti-CD20 antibodies seems to be associated with a high response rate and moderate toxicity in patients with MCL. Further follow-up to monitor the long-term outcome as well