DE Tsai 1, HCF Moore 1, CL Hardy 2, DL Porter 1, EY Loh 1, DJ Vaughn 1, S Luger 1, SJ Schuster 1 and EA Stadtmauer 1

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1 Bone Marrow Transplantation, (1999) 24, Stockton Press All rights reserved /99 $ Rituximab (anti-cd20 monoclonal antibody) therapy for progressive intermediate-grade non-hodgkin s lymphoma after high-dose therapy and autologous peripheral stem cell transplantation DE Tsai 1, HCF Moore 1, CL Hardy 2, DL Porter 1, EY Loh 1, DJ Vaughn 1, S Luger 1, SJ Schuster 1 and EA Stadtmauer 1 1 Bone Marrow and Stem Cell Transplant Program, University of Pennsylvania Cancer Center, Philadelphia, PA; and 2 Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA Summary: We evaluated the response and toxicity of rituximab in the setting of progressive intermediate grade non-hodgkin s lymphoma (NHL) after autologous peripheral stem cell transplantation (PSCT). Seven patients with a median age of 59 years (45 62), ECOG performance status 0 1, and CD20-positive diffuse large cell lymphoma with progression after PSCT were treated. All patients initially received 4-weekly infusions of rituximab (375 mg/m 2 ). The maximum response was three CR and four PR. Median progression-free survival was 197 days (range ). With a median follow-up of 204 ( ) days, the patients disease status is classified as two CR, one PR, and four PD. Four of five patients with ECOG performance status of 1 prior to treatment showed improvement to status 0 after treatment with rituximab. While follow-up is short, these results suggest that rituximab has significant activity in intermediate-grade non-hodgkin s lymphoma that has relapsed after PSCT. Keywords: autologous bone marrow transplantation; autologous peripheral stem cell transplantation; non- Hodgkin s lymphoma; relapse; rituximab Autologous peripheral stem cell transplantation (PSCT) is an effective treatment for patients with chemotherapysensitive relapsed intermediate-grade non-hodgkin s lymphoma (NHL). Numerous trials show that 30 50% of patients with relapsed responding NHL experience longterm relapse-free survival after PSCT. 1 These results appear superior to those achieved with conventional salvage chemotherapy. Promising studies also suggest a role for PSCT in initial therapy for poor prognosis NHL. 1 3 Despite PSCT, a large percentage of patients treated in this manner will experience relapse. The prognosis of patients with progressive NHL after PSCT is poor. 4 In general, these patients have received multiple chemotherapy Correspondence: Dr DE Tsai, Bone Marrow and Stem Cell Transplant Program, 16 Penn Tower, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104, USA Received 15 October 1998; accepted 14 April 1999 regimens and radiation therapy and may no longer be sensitive to such treatments. Patients with HLA-compatible donors can be considered for allogeneic bone marrow transplantation with potential for long-term relapse-free survival. 5 Unfortunately, allogeneic bone marrow transplantation is not a realistic option for many patients due to the lack of a suitable donor, age, or poor general medical condition. Patients can be considered for various salvage therapies including further chemotherapy, biologic therapy, second autologous transplantation or investigational agents. 1,5,6 Extensive prior treatment and lack of hematopoietic reserve in these patients, however, often limit these options. Long-term survival is rarely achieved and the median survival of patients with relapsed intermediategrade NHL after PSCT is only 3 months. 4 Rituximab is a chimeric monoclonal anti-cd20 antibody composed of variable light and heavy chain murine regions plus human immunoglobulin (Ig) C1 heavy chain and kappa light chain constant regions. 7 It has affinity for the CD20 antigen that is present on more than 90% of all B cell NHL. 8,9 In clinical trials, rituximab has been shown to be an effective treatment for relapsed or refractory lowgrade NHL. In this context, up to 48% of patients can expect a response with a projected median time to progression of 13 months. 10 Patients who had previously undergone autologous bone marrow transplantation for low-grade NHL had a higher response rate of 78%. In newly diagnosed intermediate- or high-grade NHL, this drug in combination with CHOP chemotherapy resulted in a response in 29 of 30 patients. 11 While the mechanism of action has not been fully defined, the antibody binds C1q in vitro and induces both complement-mediated and antibodydependent cytotoxicity of CD20 positive cells. 7,12 The antibody has also been found to induce apoptosis and sensitize human B cell lymphoma cells to cytotoxic chemotherapy. 13 These mechanisms of action would be expected to be noncross-resistant with those of chemotherapy and radiation therapy. In addition, adverse events related to the therapy are mostly transient and infusion-related. 10 Previous experience with rituximab in intermediate-grade NHL is limited. However, the CD20 antigen is expressed on these lymphoma cells as well and therefore might make them susceptible to rituximab. Given the mild side-effects and the novel mechanism of tumor cell killing, we evaluated the clinical efficacy and toxicity of rituximab monotherapy in the set-

2 522 ting of relapsed diffuse large cell NHL after PSCT. We report here the results of this treatment in a retrospective series of seven patients. Materials and methods Patients From January 1998 to June 1998, seven patients with progressive intermediate-grade NHL after PSCT were treated with rituximab. Patient records were reviewed retrospectively for response and toxicity. Eligibility for this series consisted of documented progressive CD20 positive diffuse large cell NHL after PSCT that had not been treated with any other agents prior to or during the rituximab treatment and follow-up. Patients receiving anti-neoplastic agents or steroids during that time were excluded. Patients with a history of low grade, mixed or transformed NHL were not included in our series. The median age was 59 (range 45 62) and all patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 1. Patient demographics, initial presentation of NHL and status prior to rituximab treatment are noted in Table 1. All patients previously had undergone initial treatment with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy with initial responses of six complete responses (CR) and one progressive disease (PD). Median initial progression-free survival was 200 days (range ). All patients experienced relapse or progression of disease and were treated with various salvage chemotherapy regimens with or without radiation (Table 2). All patients achieved either a CR (one) or PR (six) with salvage chemotherapy and were then treated with high-dose therapy and PSCT. After PSCT, patients were observed by serial CT scans. No maintenance therapy, such as interferon or other chemotherapeutic agents, was used. Six of seven patients had undergone radiation therapy as part of their initial chemotherapy or PSCT. Each patient eventually relapsed or had progressive disease after PSCT. Rituximab was the first treatment administered after PSCT in all cases. Evaluation of the seven patients prior to rituximab showed that five of six had an elevated LDH and two had masses larger than 5 cm. The number of extranodal sites in these patients was 0 (n = 3), 1 (n = 3) and 2 (n = 1) (Table 1). No bone marrow evaluation or gallium scans were performed prior to treatment with rituximab. No patient had documented CNS lymphoma involvement. Median time to initiation of rituximab therapy from date of PSCT was 148 days (range ). No other therapy for NHL was attempted during the treatment with rituximab. Treatment regimen Initial post-transplant treatment for all patients consisted of rituximab (375 mg/m 2 ) given as a slow infusion over 3 5 h weekly for 4 weeks. Patients were premedicated with acetaminophen 650 mg and diphenhydramine 50 mg, 30 min prior to starting the infusion. After completion of the fourth treatment, patients entered an observation period. All patients were followed by serial history and physical examinations. Laboratory studies including CBC with differential and serum chemistries were performed at followup examinations. Serial CT scans were obtained starting approximately 1 month (median 52 days, range 29 79) after completion of the initial rituximab treatment course and then at intervals of 2 3 months. Retreatment On detection of disease progression, patients were considered for retreatment with rituximab. Two patients who developed progressive disease (days 60 and 75) received a second 4-week course of rituximab identical to the initial Table 1 Patient demographics Sex, male/female 5/2 Lymphoma histology 7 diffuse large cell lymphoma Stage at initial diagnosis I (n = 1), II (n = 2), III (n = 1), IV (n = 3) Patients with initial B symptoms 2 Response to initial CHOP chemotherapy 6 CR and 1 SD Relapse-free survival from initial chemotherapy in days (n = 6) 200 ( ) Radiation therapy utilized 6 Bone marrow involvement 0 Status at initiation of Rituximab therapy Age (years) 59 (45 62) Number of extranodal sites 0 (n = 3), 1 (n = 3), 2 (n = 1) Bulky disease ( 5 cm) 2 Elevated LDH (n = 6) 5/6 Performance status (ECOG) 0 (n = 2), 1 (n = 5) Median WBC ( 10 3 per l) 4.5 ( ) Median ANC (per l) 2900 ( ) Median hemoglobin (g/dl) 10.1 ( ) Median platelet count (THO/ l) 74 (37 174) Median time from transplant to initiation of Rituximab therapy (days) 148 (46 715) CR = complete remission; SD = stable disease; LDH = lactate dehydrogenase; ECOG = Eastern Cooperative Oncology Group.

3 Table 2 Response to treatments 523 Patient No Age Previous 8/93 4/95 5/92 CHOP 6 8/96 8/94 8/96 4/97 chemotherapy and CHOP/XRT 8- XRT/CHOP 6- and CVVP 2-CR CHOP 6-SD CHOP 6-CR CHOP 3/XRT- CHOP 6-CR XRT CR CR 5/97 CVVP 2-SD 12/96 2/96 CR 1/98 9/97 5/96 7/97 ESHAP 3-PR ESHAP 2-PR 5/97 ESHAP 4-PR ESHAP 4-PR DHAP 4-PR XRT/ESHAP 4- ESHAP 2-CR 9/96 SD VP16 1, CY 1 10/97 MINE-PR PSCT 1/8/98 10/7/96 12/11/97 3/31/97 5/29/96 7/15/97 4/9/98 melphalan ICE melphalan CY/BCNU/VP16 CY/VP16/TBI melphalan/tbi melphalan/tbi Response to PSCT PR PR SD CR CR PD PD PSCT relapse 1/30/98 1/7/97 12/31/97 12/19/97 8/14/97 10/24/97 6/25/98 Rituxan initiated 2/23/98 2/11/98 1/19/98 1/30/98 5/14/98 2/10/98 6/26/98 Initial rituxan CR PR SD PR PR PR PR response Rituxan retreatment? No No Yes Yes No No No Current days of F/U Initial performance status Best performance status Current peformance status Maximum response CR PR CR PR PR CR PR Current disease status CR PD PD PD PD CR PR CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; ESHAP = cisplatin, cytarabine, prednisone, etoposide; DHAP = dexamethasone, cisplatin, cytarabine; CVVP = cyclophosphamide, etoposide, vincristine, prednisone; MINE = mitoxantrone, ifosfamide, etoposide, mesna; ICE = ifosfamide, carboplatin, etoposide; TBI = total body irradiation; PD = progresssive disease; SD = stable disease. treatment. One of these patients then continued on maintenance therapy receiving an additional five infusions every 2 to 3 weeks over a total of 10 weeks. Evaluation of tumor response All patients had measurable disease. Tumor response was evaluated by physical examination and by CT scan after the completion of the 4 week course of rituximab (day 29 79). Complete response was defined as lack of any radiographically measurable disease. Bone marrow analyses were not routinely performed. Partial response (PR) was defined as 50 99% reduction in the product of the bidimensional measurements. Stable disease (SD) corresponded to below 50% change in original volume. Progression at any site including mixed responses was classified as progressive disease (PD). Evaluation of toxicity Patients were evaluated for toxicity by history, physical examination and routine laboratory analysis at each treatment date and periodically during follow-up after completion of the course of rituximab. Performance status was defined as per ECOG standards. Statistical analysis Statistical analysis of these data was primarily descriptive. All variables were summarized by the mean, standard deviation, and the minimum and maximum values. The variables of interest included patient demographics, follow-up times, duration of initial remission after chemotherapy, time to treatment with rituximab after PSCT, and time to nadir blood counts after first treatment with rituximab. All days were calculated from the day of initial treatment with rituximab (day 1). WBC, ANC, hemoglobin and platelet counts at days 1, 21 and at the nadir were examined. The nadir count was defined as the date of lowest WBC during the course of follow-up. A Wilcoxon signed rank test was performed to determine whether significant changes were seen in this sample of seven patients. Power calculations were performed using PASS 6.0 software to determine statistical power for the one-sample t-test for a sample of seven patients, since the one-sample t-test is the parametric counterpart to the Wilcoxon test for this small sample cohort study. Sample sizes of seven and standard deviations of percentage change ranging from 30 to 60 were examined based on the sample standard deviations. These power calculations show that statistical power to detect a 50% change varies between 50% and 99% depending on the parameters of sample size and standard deviation of percentage change. Results Response Response to therapy was assessed by history, physical examination and CT scans. The earliest clinical response was seen in one patient by the third week with decreased lymphoma-associated symptoms. Objective evidence of

4 524 response was obtained by follow-up CT scans. At initial CT scan and follow-up after the completion of the 4-weekly infusions (day 29 79), the response rate was 86% with one CR, five PR and one SD. Two patients (No. 3 with SD and No. 4 with PR) later developed symptomatic and radiographic evidence of disease progression on days 60 and 75, respectively, and underwent retreatment with rituximab. Patient No. 3 had significant improvement in his lymphoma-associated symptoms after the initial 4-week treatment with rituximab, with complete resolution of severe lower extremity edema lasting for a period of 2 weeks. The edema was presumed to be based on venous obstruction from pelvic adenopathy. However, at the time of initial follow-up on day 52, the edema had returned to baseline. CT scan at the time was essentially unchanged from the pretreatment assessment and he was classified as having SD. On day 60, he presented with progressive lower extremity edema and was felt to have clinical PD and was retreated. His retreatment regimen consisted of an identical 4-week induction course of rituximab followed by five additional infusions at 2 3 week intervals over 10 weeks. At initial follow-up, 6 weeks after completion of the retreatment regimen, this patient had attained a CR. Patient No. 4 had a mixed response after retreatment with a second 4-week course of rituximab. CT scans demonstrated a mixed response with progression of his pulmonary lesions and regression of his hepatic lesions and he was classified as having PD. On day 179, patient No. 4 was enrolled in another investigational protocol. At the time he was asymptomatic but had radiographic evidence of progressive pulmonary lymphoma. Two other patients (Nos 2 and 5) have developed progressive disease on days 204 and 200, respectively, but have not undergone retreatment with rituximab. Patient No. 2 has been enrolled in another investigational study. With a median follow-up of 204 days ( ) from initiation of therapy and with two patients undergoing retreatment, overall survival is 100%. The patients are currently classified as two CR, one PR and four PD (Table 2). Median progression-free survival after a single 4-week course of rituximab is 197 days (60 282) (Figure 1). Three patients (Nos 2, 5 and 7) had prolonged responses with continued radiologic decrease in adenopathy 182, 98 and 62 days after the initial treatment with rituximab. Symptomatic patients all reported improvement or resolution of lymphoma-associated complaints. Five of seven patients initially had symptoms which included fever, night sweats, pain, lower extremity edema and fatigue. These five patients were classified as having an ECOG performance status of 1. After rituximab treatment, four of five patients became asymptomatic with ECOG status of 0. Four of five patients with symptomatic disease had improvement prior to completion of their initial 4-week treatment with rituximab. At current follow-up, four patients have sought other treatments after developing progressive disease. Of the three patients who remain progression-free after rituximab, all have an ECOG status of 0. Probability of relapse free survival Figure 1 Adverse events Months Relapse-free survival with a median follow-up of 204 days. A total of 41 infusions were performed in the seven patients studied. Twenty-eight infusions comprised the initial induction course and 13 infusions were for retreatment purposes. There was no treatment-related mortality in our series of seven patients. Infusion-related complications consisted of rash and rigors in one patient during the initial infusion only. These symptoms resolved with a temporary pause in the drug infusion. The treatment was then completed at a slower infusion rate without further incident. Significant delayed adverse events included three episodes of transient leukopenia and granulocytopenia. On the date of the first rituximab infusion (day 1), patients 2, 3 and 4 had WBC of 5.8, 2.1 and per l and absolute neutrophil count (ANC) of 4800, 840, and 2025 per l, respectively. At initial follow-up on days 52, 63, and 39, patients 2, 3 and 4 had WBC of 3, 2.9 and per l and absolute neutrophil count (ANC) of 1230, 2117 and 2300 per l, respectively. During later follow-up, patients 2, 3, and 4 developed WBC nadirs of 2.3, 1.7 and per l and ANC nadirs of 644, 1394 and 48 per l on days 101, 112 and 74 from initial treatment, respectively. Patient 4 required hospital admission for febrile neutropenia. He was treated with G-CSF and achieved an ANC 500 in 4 days. A bone marrow biopsy was performed on patient 4 at the time of the ANC nadir. The biopsy showed a normocellular bone marrow with myeloid hyperplasia and left shift in maturation consistent with a recovering marrow. No lymphoma involvement was identified. Patients 2 and 3 recovered their counts without medical intervention. Statistical analysis of changes in WBC, ANC, hemoglobin and platelets was performed using a Wilcoxon signed rank test to determine if there was any overall significant change after treatment with rituximab. No statistically significant change in total WBC, ANC, hemoglobin, or platelet count was detected between the first infusion (day 1) and the fourth infusion (day 21) of rituximab, nor between day 1 and the day of WBC nadir. Although statistical power for these tests varies from 50 99%, a 50% decrease was determined to be significant, and no mean decreases in

5 blood counts greater than 25% were observed. In addition, at current follow-up, no clinically meaningful changes from baseline have been observed in liver function tests, creatinine or serum electrolytes. Discussion The role of PSCT for intermediate-grade NHL is expanding. Once reserved for patients with relapsed or progressive disease after primary chemotherapy, this modality is now being investigated for use in high-risk patients in first remission. 2,3 While high-dose therapy with stem cell support may overcome chemotherapy resistance and cure some patients with relapsed or high-risk disease, a significant number of patients are destined to develop progressive disease despite these measures. Given the relatively low mortality rate currently associated with PSCT, the major cause of treatment failure and death in these patients is disease recurrence. Further therapy for patients who fail PSCT is difficult with limited treatment options. We have explored the use of rituximab as a therapy for patients with progressive intermediate-grade NHL after PSCT. Trials in low-grade NHL have suggested that patients with a history of autologous bone marrow transplantation have a high response rate of 78% to rituximab. 10 In our series of patients after PSCT, all (7/7) responded to one or two cycles of rituximab therapy with both symptomatic, as well as radiographic improvement. In this patient population with demonstrated tumor resistance to conventional, as well as high-dose chemotherapy, these results are remarkable when compared to what might be expected with further salvage chemotherapy. 1 It was logical to test rituximab as it has a different mechanism of action than chemotherapy and radiation therapy. Rituximab is a humanized anti-cd20 monoclonal antibody. 7 Unlike chemotherapy and radiation therapy, which depend on penetration into the tumor cell and production of free radicals or a toxic drug effect at critical steps in cell metabolism, rituximab s putative mechanisms include complement activation, antibodydependent cell-mediated cytotoxicity and induction of apoptosis. 7,13 These cytotoxic activities might remain intact even in NHL cells that have developed resistance to the effects of chemotherapy and radiotherapy. Thus, disease which is chemoradiotherapy resistant may be susceptible to rituximab. The relatively long time to maximum response is an important observation. Three patients showed continued decrease in their adenopathy months after the completion of treatment. Unlike conventional chemotherapeutic agents which frequently have half-lives measured in minutes to hours, rituximab has a prolonged serum half-life of 4.4 days (range ). 14 In addition, with repeated dosing the half-life increases. In one series, the mean serum half-life after the first infusion was 76 h vs 205 h after the fourth infusion. 10 The mechanism of action of rituximab in vivo is not clearly defined, but appears to involve the host immune system and apoptosis. Multiple factors may contribute to the long median time to response of 50 days (range ) and the prolonged median duration of remission of 13.0 months seen in low-grade NHL. 10 It is of note that this slow prolonged response seen in low-grade NHL is also seen with higher grade NHL. Two patients (Nos 3 and 4) underwent retreatment with rituximab after clinical or radiographic evidence of disease progression. In low-grade NHL, rituximab can have a delayed onset of action and it is often difficult to assess whether a maximum response has been reached or whether any response is destined to occur. Both these patients had evidence of clinical or radiographic response to the initial treatment course. At the time of retreatment, both had a reversal of their response and our judgement was that they had developed progressive disease after a short-lived initial response. We however cannot exclude the possibility that they may have had further response at a later date had we not retreated them. Given the relatively low toxicity and the lack of data on optimum dosing of rituximab, we decided on immediate retreatment with a result of one CR and one PD. We found the toxicities related to the use of rituximab in a heavily pretreated patient population after PSCT to be mild. The CD20 antigen is cell specific for B cells and is not found on early pre-b cells, stem cells, dendritic cells or plasma cells. 8,15,16 One would expect the hematologic toxicity to be minor with this treatment modality. Our patients, in general, had impaired performance status and were symptomatic from their progressive lymphoma prior to this therapy. Given their recent PSCT, most had limited hematopoietic reserves. We found acute adverse events related to rituximab infusion to be infrequent, occurring transiently in only one patient. While the overall change in white blood cell count, granulocyte count, hemoglobin and platelet count was not statistically significant, possibly due to our small number of subjects, three of seven patients experienced delayed decreases in their granulocyte count with two becoming neutropenic. This is a higher number than would be expected from the published data in which the rate of NCI grade 1 to 4 neutropenia is 4%. 10 While these results may be due to the small series, they may also reflect a different patient population being treated. The patients in our series had extensive treatment histories often including radiation and high-dose chemotherapy with PSCT. The prior treatments resulted in a patient population with poor hematopoietic reserves and a particularly high risk for hematologic complications. It should be pointed out that the observed rate of granulocytopenia, while higher than the anticipated rate, is still lower than would be expected with most salvage chemotherapy regimens used in this setting. The granulocytopenia in our cases resolved spontaneously or responded promptly to G-CSF treatment. In addition, no significant changes were noted in the patients platelet counts and hemoglobin during our follow-up. While our follow-up is short and patient number small, we observed a high response rate to rituximab in patients with relapsed diffuse large cell lymphoma after high-dose therapy and PSCT. The treatment was well tolerated in this patient population. Transient granulocytopenia occurred at a higher rate than expected, but compared favorably to rates expected with current conventional chemotherapy regimens. Rituximab should be considered as a therapeutic option for progressive intermediate-grade NHL after PSCT. 525

6 526 The non-cross-resistant mechanisms of action allow for significant activity with a low adverse event profile even in patients with significant resistance to previous chemoradiotherapy. In addition to providing palliation, rituximab therapy may allow time for hematopoietic recovery after PSCT and may help improve performance status so patients may become candidates for other therapeutic modalities such as salvage chemotherapy, allogeneic bone marrow transplantation or other investigational therapies. References 1 Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-hodgkin s lymphoma. New Engl J Med 1995; 333: Gianni AM, Bregni M, Siena S et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. New Engl J Med 1997; 336: Verdonck LF, Van Putten WL, Hagenbeek A et al. Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-hodgkin s lymphoma. New Engl J Med 1995; 332: Vose JM, Bierman PJ, Anderson JR et al. Progressive disease after high-dose therapy and autologous transplantation for lymphoid malignancy: clinical course and patient follow-up. Blood 1992; 80: de Lima M, van Besien KW, Giralt SA et al. Bone marrow transplantation after failure of autologous transplant for non- Hodgkin s lymphoma. Bone Marrow Transplant 1997; 19: Vandenberghe E, Pearce R, Taghipour G et al. Role of a second transplant in the management of poor-prognosis lymphomas: a report from the European Blood and Bone Marrow Registry. J Clin Oncol 1997; 15: Reff ME, Carner K, Chambers KS et al. Depletion of B cells in vitro by a chimeric mouse human monoclonal antibody to CD20. Blood 1994; 83: Anderson KC, Bates MP, Slaughenhoupt BT et al. Expression of human B cell associated antigens on leukemia and lymphomas. A model of human B cell differentiation. Blood 1984; 63: Nadler IM, Ritz J, Hardy R et al. A unique cell surface antigen indentifying lymphoid malignancies of B cell origin. J Clin Invest 1981; 67: McLaughlin P, Grillo-Lopez AJ, Link BK et al. Rituximab chimeric anti-cd20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16: Link BK, Grossbard ML, Fisher RI et al. Phase II pilot study of the safety and efficacy of rituximab in combination with CHOP chemotherapy in patients with previously untreated intermediate- or high-grade NHL. Proc ASCO 1998; 17: 3a. 12 Maloney D, Smith B, Appelbaum FR. The anti-tumor effect of monoclonal anti-cd20 antibody therapy includes direct antiproliferative activity and induction of apoptosis in CD20 positive non-hodgkin s lumphoma cell lines. Blood 1996; 88: 637a. 13 Demidem A, Lam T, Alas S et al. Chimeric anti-cd20 (IDEC- C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother Radiopharm 1997; 12: Maloney DG, Liles TM, Czerwinski DK et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti- CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994; 84: Stashenko P, Nadler LM, Hardy R et al. Characterization of a human B lymphocyte-specific antigen. J Immunol 1980; 125: Schriever F, Freedman AS, Freeman G et al. Isolated human follicular dendritic cells display a unique antigenic phenotype. J Exp Med 1989; 169: