Journal of Clinical Oncology, Vol 17, Issue 1
(January), 1999: 268
© 1999 American Society for Clinical Oncology
Treatment of Patients With Low-Grade B-Cell Lymphoma With the Combination of Chimeric Anti-CD20 Monoclonal Antibody and CHOP Chemotherapy
M. S. Czuczman,
A. J. Grillo-López,
C. A. White,
M. Saleh,
L. Gordon,
A. F. LoBuglio,
C. Jonas,
D. Klippenstein,
B. Dallaire,
C. Varns
From the Roswell Park Cancer Institute, Buffalo, NY; IDEC Pharmaceuticals Corporation, San Diego, CA; Sidney Kimmel Cancer Center, San Diego, CA; University of Alabama, Birmingham, AL; and Northwestern University, Chicago, IL.
Address reprint requests to Myron S. Czuczman, MD, Department of Hematologic Oncology and Bone Marrow Transplantation, Roswell Park Cancer Institute, Elm and Carlton Sts, Buffalo, NY 14263
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ABSTRACT
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PURPOSE: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody, Rituxan (Rituximab, IDEC-C2B8; IDEC Pharmaceuticals Corporation, San Diego, CA), and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy.
PATIENTS AND METHODS: Forty patients with low-grade or follicular B-cell non–Hodgkin's lymphoma received six infusions of Rituxan (375 mg/m2 per dose) in combination with six doses of CHOP chemotherapy.
RESULTS: The overall response rate was 95% (38 of 40 patients). Twenty-two patients experienced a complete response (55%), 16 patients had a partial response (40%), and two patients, who received no treatment, were classified as nonresponders. Medians for duration of response and time to progression had not been reached after a median observation time of 29 + months. Twenty-eight of 38 assessable patients (74%) continued in remission during this median follow-up period. The most frequent adverse events attributable to CHOP were alopecia (38 patients), neutropenia (31 patients), and fever (23 patients). The most frequent events attributed to Rituxan were fever and chills, observed primarily with the first infusion. No quantifiable immune response to the chimeric antibody was detected. In a subset of 18 patients, the bcl-2 [t(14;18)] translocation was positive in eight patients; seven of these patients had complete remissions and converted to polymerase chain reaction (PCR) negativity by completion of therapy.
CONCLUSION: This is the first report demonstrating the safety and efficacy of Rituxan anti-CD20 chimeric antibody in combination with standard-dose systemic chemotherapy in the treatment of indolent B-cell lymphoma. The clinical responses suggest an additive therapeutic benefit for the combination with no significant added toxicity. The conversion of bcl-2 from positive to negative by PCR in blood and/or marrow suggests possible clearing of minimal residual disease not previously demonstrated by CHOP chemotherapy alone.
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INTRODUCTION
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THE NON–HODGKIN'S LYMPHOMAS (NHLs) are a diverse group of lymphoid neoplasms that collectively rank fifth in cancer incidence and mortality.1,2 The prevalence of NHL has been increasing during the last two decades, and it is estimated that approximately 55,400 new cases and 24,900 deaths will occur in 1998.2 Recognized since the 1950s as a distinct group of diseases, NHLs range from indolent malignancies (low-grade histologies) to rapidly growing and highly aggressive tumors (high-grade histologies). The overall median age at presentation is 42 years (58 years for low grade), and the incidence increases with advancing age.3 The majority of NHLs are of B-cell origin,4 with more than 90% of patients expressing the CD20 antigen.5
In general, low-grade or follicular NHL is assumed to have an indolent course when compared with intermediate- and high-grade NHL. Although treatment of low-grade follicular lymphomas with standard chemotherapeutic regimens is characteristically associated with a high initial response rate, the clinical course consists of a pattern of repeated relapse. Subsequent remissions occur, but at a progressively lower rate and with a shorter duration.6 Patients eventually succumb to the disease or its complications with a median survival of approximately 6.2 years.7,8 For these reasons, novel therapeutic agents and strategies need to be evaluated in this group of patients.
Molecular research has identified the bcl-2 proto-oncogene as being associated with a t(14;18) chromosomal translocation, which has been reported to occur in approximately 50% of NHLs (80% low grade; 30% intermediate grade).3 This chromosomal translocation moves the bcl-2 gene from chromosome 18 to the immunoglobulin heavy-chain locus on chromosome 14 and results in bcl-2 activation. Resultant overexpression of bcl-2 protein localizes to the mitochondrial membrane, nuclear membrane, endoplasmic reticulum, and cell membrane.9 This results in inhibition of apoptosis (programmed cell death) and gives cells a survival advantage. B cells containing t(14;18) chromosomal translocation are believed to play a role in lymphomagenesis, possibly serving as the "first hit" in a "multi-hit" theory of carcinogenesis. By use of a sensitive, nested polymerase chain reaction (PCR) assay, cells containing the t(14;18) chromosomal translocation are detectable at an assay sensitivity of one bcl-2–positive cell in 105 to 106 normal cells.10 In patients with documented B-cell lymphoma, serial analyses of bcl-2 in blood and marrow by PCR could serve as a method for monitoring minimal residual disease.
Attempts to treat B-cell malignancies with monoclonal antibodies (mAbs) began more than a decade ago with monoclonal antibodies reactive with B-cell antigen idiotypes.11,12 Customized anti-idiotypic monoclonal antibodies were developed and used alone or in combination with interferon alfa or chlorambucil. Significant clinical activity was observed; however, this type of murine monoclonal antibody therapy was limited by the development of human anti-mouse antibody responses, the relative inability of mouse antibodies to induce human immune effector mechanisms, and the occurrence of idiotype-negative relapses. The technology to alter antibodies genetically by joining the variable region genes of murine antibodies to human immunoglobulin constant region genes allowed the development of a mouse/human chimeric antibody with the demonstrated advantages of reduced immunogenicity and an enhanced ability to interact with human effector cells.
Rituxan (IDEC Pharmaceuticals Corporation, San Diego, CA) is a chimeric monoclonal anti-CD20 antibody that can deplete malignant B cells through complement-dependent cell cytotoxicity, antibody-dependent cell-mediated cytotoxicity,13 and apoptotic mechanisms. It has also been shown to sensitize drug-resistant lymphoma cell lines to killing by cytotoxic drugs.14 The monoclonal antibody has shown single agent activity in patients with low-grade or follicular lymphomas. Two previous phase I/II single agent, dose-escalation studies of Rituxan have been conducted in patients with relapsed or recurrent NHL. Fifteen patients were enrolled onto a single dose study (10 to 500 mg/m2 of Rituxan), and 47 patients were enrolled onto a multiple dose study (125, 250, or 375 mg/m2 weekly for 4 weeks). Clinical activity was noted in seven of 15 patients in the single dose trial, with two partial responses lasting 8.1 and 8.5 months and five minor responses.15 In the phase II portion of the multiple dose (375 mg/m2) Rituxan study, three complete responses and 14 partial responses were noted in 34 assessable patients, with a median response duration of 8.6 months.16 Median time to progression (TTP) in these responders was 10.2 months; TTP exceeded 20 months in five patients and 30+ months in two patients. Adverse experiences were mostly grade 1 or 2 and consisted primarily of infusion-related events (fever, asthenia, chills, and, less commonly, bronchospasm, hypotension, and angioedema). Hematologic toxicity was usually mild and reversible.
Because of these encouraging results, a phase II open-label, single arm, multicenter study was designed to evaluate the safety and clinical activity of this new monoclonal antibody in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in the treatment of patients with low-grade B-cell lymphoma. CHOP chemotherapy was chosen because this cytotoxic regimen is an effective first-line therapy for low-grade or follicular NHL. The rationale for the combination of Rituxan and CHOP includes single agent efficacy, non–cross-resistant mechanisms of action, non-overlapping toxicities, and in vitro synergy with certain cytotoxic drugs, including doxorubicin.
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PATIENTS AND METHODS
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Eligibility
The patient population in this study consisted of newly diagnosed and relapsed/refractory patients at least 18 years of age with histologically documented low-grade or follicular B-cell NHL and measurable progressive disease. Tumors were required to be CD20 positive. Patients were to have an expected survival of 3 months or more; a prestudy performance status of 0, 1, or 2 according to the World Health Organization scale; recovery from any significant toxicity associated with anticancer therapy; and adequate hematologic, renal, and hepatic function within 7 days of initial therapy. The following exclusion criteria applied: "bulky" disease (defined as any single mass > 10 cm in its greatest diameter); prior therapy with anthracyclines, anthrapyrazoles, or drugs that were classified at the time as investigational phase I or II antineoplastic agents; prior radioimmunotherapy; cancer radiotherapy, immunotherapy, or chemotherapy within 3 weeks of the scheduled first study treatment; nitrosourea or mitomycin therapy within 6 weeks of the first scheduled study therapy; or presence of CNS lymphoma. Other exclusion criteria were as follows: significantly impaired organ function, as measured by a serum creatinine level greater than 2.0 mg/dL, a total bilirubin level greater than 2.0 mg/dL, or an AST or alkaline phosphatase level more than 2 times normal; serious nonmalignant disease; active opportunistic infection; major surgery within 4 weeks; and previous or concomitant malignancy other than basal cell or squamous cell carcinoma of the skin, carcinoma-in-situ of the cervix, or other malignancy for which the patient had not been disease-free for at least 5 years. Patients with a New York Heart Association class III or IV heart disease or myocardial infarction within the past 6 months and patients with a left ventricular ejection fraction of less than 45% within 1 month of study enrollment were disqualified from entering onto the study. Patients who had prior anti-CD20 therapy were excluded, except for patients who were previously enrolled onto a clinical trial of Rituxan with negative human anti–chimeric antibody (HACA) serum titers. Patients with a nondemonstrable CD20-positive neoplastic B-cell population in lymph nodes or bone marrow were not included. Pregnant or lactating women and patients of childbearing potential, unless using accepted birth control methods, were not allowed to enroll. Eligible patients signed a detailed written informed consent statement meeting the requirements of the institutional review board of the participating institution. Institutional review board approval was given for this study at each participating center.
PCR Assay for t(14;18)
The assay for the detection of cells with the t(14;18) chromosomal translocation by PCR uses a nested primer amplification specifically for either the major breakpoint region or the minor cluster region and was developed at Roswell Park Cancer Institute in collaboration with Dr. John Gribben. The PCR technique used in this study was essentially the same, with minor modifications, as that used and described by Gribben et al.10 The assay will detect one in 105 to one in 106 t(14;18)-containing cells for either breakpoint region among a normal background and will discriminate all t(14;18) translocations that occur within these regions. Major breakpoint region- and minor cluster region-positive and -negative cell lines were used as controls. A separate PCR reaction was performed to amplify a region within the bcl-2 gene to act as an internal DNA quality control.
Treatment Design
This study consisted of a single treatment group. Patients were to receive a total of six intravenous infusions of 375 mg/m2 of Rituxan and six cycles of CHOP, given every 3 weeks (Fig 1). Each CHOP cycle consisted of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (maximum dose, 2.0 mg), given intravenously on day 1, and oral prednisone 100 mg/m2 on days 1 through 5. Rituxan was produced and supplied as a 5-mg/mL saline solution of antibody in 10-mL glass syringes. The mAb was further diluted in normal saline to a final concentration of 1 mg/mL and administered intravenously through a low-protein-binding 0.22-µm in-line filter. Rituxan infusions 1 and 2 were administered on days 1 and 6 before the first CHOP cycle, which started on day 8. Rituxan infusions 3 and 4 were given 2 days before the third and fifth CHOP cycles, respectively, and infusions 5 and 6 were given on days 134 and 141, respectively, after the sixth CHOP cycle. This mAb schedule was chosen to take advantage of three different characteristics of Rituxan in addition to its known clinical activity in NHL: (1) in vitro data demonstrating its ability to sensitize chemoresistant cell lines; therefore, doses 1 and 2 could be viewed as a form of induction immunotherapy that could possibly render chemoresistant cells chemosensitive; (2) in vitro data demonstrating that possible synergy with cytotoxic agents would best be effected by interim doses 3 and 4; and (3) the generally well-accepted belief that monoclonal antibodies are extremely effective in a minimal residual disease setting; thus, doses 5 and 6 could be viewed as being used as a "mop up" of residual lymphoma after completion of systemic chemotherapy.
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Fig 1. Treatment schedule. Patients received a total of six intravenous infusions of 375 mg/m2 of Rituxan and six cycles of CHOP given every 3 weeks.
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If toxicity occurred during the mAb infusion, the infusion was to be slowed or temporarily discontinued and the patients were to be medicated as necessary with acetaminophen (for fever) or diphenhydramine (for rash, mucosal congestion, or other infusion-related reactions) and other medications as needed. Once the adverse events abated, the antibody infusion could be resumed at 50% of the previous rate and then escalated as tolerated. CHOP was to be administered according to the standard preparation and infusion procedures for each institution. If grade 3 neurotoxicity occurred at any time during the treatment period, vincristine could be discontinued at the investigator's discretion. Cyclophosphamide dose modification for hematologic toxicities was to be carried out according to an algorithm provided in the protocol. A patient whose treatment was interrupted for more than 3 weeks for either hematologic or nonhematologic toxicity was to be removed from the study. As stated in the informed consent, patients were allowed to withdraw from the study at any time. Furthermore, treatment was discontinued if disease progression was noted or if, in the opinion of the investigator, it was not in the patient's best interest to continue.
Oral premedication with 650 mg of acetaminophen and 50 to 100 mg of diphenhydramine hydrochloride could be administered 30 to 60 minutes before each mAb infusion. No concurrent antineoplastic therapy was allowed except for localized brain radiotherapy for CNS lymphoma. Surgery that did not affect any sentinel lesions was allowed, and surgery on sentinel lesions was allowed only to detect mAb tumor penetration.
Evaluation
All patients were assessable for the intent-to-treat analysis of tumor response and toxicity. The primary efficacy measure was the response of B-cell lymphoma to treatment as determined by the investigator and confirmed by the sponsor. Lesion evaluations occurred at baseline, before the third cycle of CHOP, after the completion of therapy, and every 4 months thereafter until disease progression (PD) was observed. Any evaluation indicating the onset of a partial response (PR) or complete response (CR) (Table 1) was followed by a confirmatory evaluation no sooner than 28 days later. Ninety-five percent confidence intervals for the response rates were calculated.
Secondary efficacy variables were the TTP and the response duration (PD-free interval). The TTP was measured from the date of the first Rituxan infusion to the date of PD or the date of last contact, whichever was earlier. Response duration was measured from the date of the first observation of response to the date of PD or the date of last contact, whichever was earlier.
Patients were monitored for the development of an HACA response (samples assayed at the Clinical Immunology Laboratory, IDEC Pharmaceuticals Corporation). Quantitative immunoglobulin levels were also measured at the individual treatment sites.
Each patient's NHL was classified histologically at baseline using International Working Formulation (IWF) criteria, and the stage of each patient's disease was assigned according to the Ann Arbor classification.
Pretreatment bcl-2 [t(14;18)] analysis by PCR was performed in the Laboratory of Molecular Diagnostics at Roswell Park Cancer Institute on peripheral blood and separately pooled bilateral bone marrow aspirate and biopsy samples from 18 patients enrolled onto the study at Roswell Park Cancer Institute. Serial samples for PCR analysis were obtained in those patients testing bcl-2 positive at baseline.
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RESULTS
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Patient Demographics and Disposition
The clinical features of the 40 patients (31 previously untreated) enrolled onto this study are listed in Table 2. Thirty-five of the 40 patients received all six infusions of Rituxan and six cycles of CHOP. Two patients were withdrawn from the study before treatment initiation (one patient withdrew for personal reasons, and one patient was withdrawn by the treating physician because of the discovery of lymphomatous involvement of the central nervous system). Three patients discontinued study treatment early (one patient withdrew for personal reasons, one patient withdrew owing to the development of an epidural abscess, and one patient died from reactivation of hepatitis B infection). All 40 patients are included in the intent-to-treat analysis.
Treatment Dose-Intensity
The Rituxan dose was not modified in the 38 patients who received treatment. Doses of one or more chemotherapy agents of the CHOP regimen were adjusted in only 13 patients at some time during the course of the study. In addition, the administration of at least one cycle of CHOP was delayed in six patients by 1 to 3 weeks. Dose-intensity was calculated for cyclophosphamide, doxorubicin, vincristine, and prednisone in each patient as the actual dose received in milligrams per meters squared per week, divided by the calculated total dose in milligrams per meters squared per week. This analysis revealed an average dose-intensity of 0.95 for cyclosphophamide, 0.97 for doxorubicin, 0.95 for vincristine, and 0.95 for prednisone. The average dose- intensity for all of the agents in the CHOP regimen was 0.96 in this chemoimmunotherapy study.
Response to Therapy
Median time to response was 47 days (range, 15 to 236 days). The overall response rate to the combination of CHOP and Rituxan treatment was 95% (95% confidence interval, 88% to 100%) in the intent-to-treat patient population (Table 3). Twenty-two patients (55%) experienced a CR, and 16 patients (40%) had a PR. Thus, only the two patients who were withdrawn from the study before the initiation of trial therapy were classified as nonresponders (one with an IWF histologic classification of A and the other, B). Response rates were also evaluated for patient subpopulations, including those with extranodal disease, an elevated serum lactate dehydrogenase concentration, bone marrow involvement, an age of 60 years or more, or bulky disease (Table 3). Combination Rituxan and CHOP therapy achieved at least a partial response in all of the patients, and the complete response rate was less than 45% only for those patients with bulky disease. Twenty-eight (74%) of 38 assessable patients continued in remission after a median observation time of 29 months (Fig 2).
There were 24 assessable (plus one unassessable) newly diagnosed patients with follicular histology, and they all responded to therapy (16 CR and eight PR). The median duration of response was yet to be reached at 27.8+ months. There was no significant difference in duration of response between naive and previously treated patients. There were nine patients with IWF type A histology. Of these, one patient was unassessable, and the other eight patients were responders (three CR and five PR). The median duration of response for the IWF type A patients had not been yet reached at 17+ months. Five of the eight patients were in ongoing remissions. At that time, there was no significant difference in rate or duration of response when these patients were compared with the rest of the study patients.
Eight of the nine patients who had received chemotherapy treatments before study entry responded to therapy with Rituxan and CHOP (Table 4). Five of these responses were complete; two of the complete responses occurred in patients who had experienced either progressive disease or a partial response with their last prior chemotherapy regimen (cyclophosphamide, vincristine, prednisone and chlorambucil, prednisone, respectively).
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Table 4. Tumor Response and Duration in Nine Previously Treated Patients: Last Chemotherapy Versus CHOP + Rituxan
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Safety
The most frequently experienced adverse events in this trial were neutropenia (31 patients), alopecia (30 patients), nausea (27 patients), and fever (23 patients). Adverse events that occurred in more than 10% of patients and grade 3 or 4 events are listed in descending order in Table 5. Eight patients were hospitalized with febrile neutropenia and two patients with neutropenia and a documented infection. Most (75%) of the adverse events were attributed to CHOP chemotherapy by the treating physicians. The one death that occurred on study was secondary to reactivation of hepatitis B with resultant hepatic failure and hepatorenal syndrome. Rapid deterioration of liver function tests followed the fifth cycle of CHOP chemotherapy. The most frequent events attributed to mAb treatments were infusion-related events. These events (19% overall) were all grade 1 or 2 in severity and included fever (12 patients), chills (nine patients), and pruritus (six patients). The infusion-related events occurred most frequently with the initial Rituxan infusion and decreased in frequency with subsequent infusions.
A quantifiable immune response to the chimeric antibody HACA was not detected in any patient (limit of detection, 0.57 µg/mL). The mean serum immunoglobulin (Ig) levels for IgG, IgA, and IgM remained within the normal range throughout the trial. Immunoglobulin levels decreased by 50% from baseline and fell below the normal range in 13 patients. Two patients experienced a drop in IgG levels of more than 50% from baseline at days 88 and 146; one (patient no. 27) recovered to normal levels or to within 20% of baseline at day 175. Four patients reported greater than 50% drop from baseline in IgA at days 162, 51, 169, and 97; two recovered to normal levels or to within 20% of baseline at days 92 and 98. Seven patients experienced a drop in IgM levels of more than 50% below baseline; two patients recovered to normal values or to within 20% of baseline at day 176. The immunoglobulin levels for the remaining nine patients had not recovered by the time of the last follow-up examination.
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DISCUSSION
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Treatment choices for advanced stage low-grade or follicular NHL (IWF type A, B, C, D) have included radiotherapy, single agent chemotherapy, combination chemotherapy, immunotherapy, and combined modalities. Early studies of combination chemotherapy regimens containing anthracyclines resulted in complete response rates of 30% to 40% but with no difference in survival as compared with other treatment modalities.17 The CHOP chemotherapy regimen has been studied extensively in NHL, and high response rates have been reported.18-24 In 1976, the Southwest Oncology Group18 (SWOG) reported on 204 stage III and IV assessable patients treated with CHOP chemotherapy that was repeated every 2 to 3 weeks (for six or more cycles), followed by maintenance with cyclophosphamide, vincristine, prednisone or vincristine, cytarabine, prednisone every 3 to 4 weeks for a total of 18 months in patients achieving CR status. A 78% complete response rate was reported in the subpopulation of 73 patients with nodular lymphoma and a 61% response rate in the subpopulation of 23 patients with well-differentiated lymphocytic lymphoma.
Jones et al19 reviewed the SWOG experience with CHOP from 1997 to 1983 in patients with no prior chemotherapy, advanced stage (III or IV), or recurrence after chemotherapy (any stage). Treatment was administered every 3 weeks for eight cycles. In 281 patients with favorable histology, the CR rate was 57% to 64%, without significant differences between CHOP or CHOP plus levamisole with or without BCG vaccine. Subsequently, Dana et al20 reviewed these two SWOG studies, as well as an additional SWOG lymphoma study, and identified 415 stage III or IV low-grade lymphoma patients who had no prior therapy and were treated with full-dose CHOP. A CR rate of 64% and a median survival duration of 6.9 years was observed in these patients. Overall, chemotherapy or levamisole-BCG maintenance treatment did not increase the overall survival of patients achieving a CR with CHOP.
McLaughlin et al22 added bleomycin and radiotherapy to the CHOP regimen for treatment of 74 patients with stage III follicular lymphoma. Chemotherapy was administered every 3 weeks for 10 cycles, with radiotherapy given after two cycles of chemotherapy. All patients were previously untreated. These investigators reported a 97% CR rate for follicular small-cleaved NHL, a 73% CR rate for follicular-mixed NHL, and a 57% CR rate for patients with follicular large-cell NHL. The overall survival rate was 71% at 5 years and 56% at 7 years; 5-year relapse-free survival was 52%. Survival was influenced by histology, with follicular small-cleaved cell (n = 38) and follicular-mixed (n = 15) (91% and 84% survival at 5 years, respectively) more successful than follicular large-cell (n = 21) (40% survival at 5 years).
It should be noted that many of these early published CHOP response data were determined at a time when computed tomographic scanning was not available and/or a variety of restaging studies were performed that were less stringent than the ones used in the current trial. In a more recent study,25 in which 83 patients with previously untreated follicular lymphoma (IWF types B and C) received six to eight cycles of CHOP chemotherapy, staging studies included computed tomographic scans, flow cytometric analysis of peripheral blood and bone marrow samples in every patient, and gallium scanning as needed to determine the extent of disease. In contrast to the high response rates reported in earlier studies, only 28 patients (36%; 90% confidence interval, 27% to 46%) achieved a CR25 with more stringent clinical staging evaluations. The 55% CR rate in the 40 intent-to-treat patients (including nine patients with prior chemotherapy) on our current study compares favorably with this more recent CHOP study and strongly suggests that Rituxan contributes additional antitumor activity to patients treated with six cycles of CHOP chemotherapy, as evaluated by similar staging studies.
The toxicity of CHOP chemotherapy has been described in studies of low-, intermediate-, and high-grade lymphoma. In a randomized study comparing CHOP with other aggressive regimens, 1% of patients experienced fatal toxicity in the CHOP group and an additional 31% developed grade 4 life-threatening toxicities.26 SWOG19 reported fatal toxicities in 3% of patients and grade 3 and 4 toxicities in an additional 28% of patients. Hematologic toxicity with secondary infection and anemia were the most prominent adverse effects. In one study, six of 20 patients (30%) developed pancytopenia (absolute granulocyte count < 500/mm3 and platelets < 50,000/mm3). The Eastern Cooperative Oncology Group (ECOG) reported that 17 of 19 patients (89%) developed grade 3 and 4 leukopenia, two of 19 patients (11%) had grade 3 thrombocytopenia, and 14 of 19 patients (74%) had grade 3 anemia. Sixty-three percent of patients who received CHOP required at least one admission to the hospital. Most hospitalizations were due to neutropenic fevers (nine of 19 patients [47%] had a total of 13 admissions).27 In another study, six of 20 patients developed documented infections.28 Furthermore, reactivation of hepatitis B has been attributed to immunosuppression secondary to cytotoxic drugs, corticosteroids, etc, in other studies.29-31 Grade 1 neurologic disorders32 developed in 59% of patients in one study, and ECOG reported that two (11%) of 19 patients had developed grade 3 neurologic adverse events related to vincristine. Sixty percent of patients developed grade 1 and another 30% developed grade 2 gastrointestinal toxicity. One hundred percent of patients developed alopecia. Forty percent of patients developed a decrease in left ventricular ejection fraction, and 20% experienced cardiac arrhythmias. One of 20 patients developed congestive heart failure after a cumulative doxorubicin dose of 294 mg/m2. CHOP has also been associated with anxiety, rash, and decreased sexual interest.33
In the present study of 31 patients with untreated NHL and nine patients with relapsed low-grade or follicular NHL, the combination of Rituxan and CHOP chemotherapy yielded an overall response rate of 95% (38 of 40 patients) in the intent-to-treat population, with a median time to progression that had not yet been reached at a median observation time of 29+ months. Patients with poor prognostic factors, such as extranodal disease, elevated serum lactate dehydrogenase levels, bone marrow involvement, advanced age, and bulky disease, responded to the combination of Rituxan and CHOP.
The bcl-2 proto-oncogene is associated with a t(14;18) chromosomal translocation and has been reported in approximately 80% of low-grade NHL and 30% of intermediate-grade NHL.3 The resultant bcl-2 activation leads to overexpression of bcl-2 protein, which inhibits apoptosis and is believed to play an important role in lymphomagenesis. Gribben et al10,34 have previously demonstrated that the presence of bcl-2 translocation-positive cells in marrow after autologous bone marrow transplantation, as measured by a sensitive PCR assay, has prognostic value in predicting relapse. In the CHOP-Rituxan study, serial bcl-2 analysis was not planned by protocol but was evaluated prospectively at one center (Roswell Park Cancer Institute) using essentially the same PCR assay as that used by Gribben et al. Eight of 18 tested patients were found to be bcl-2 positive in blood and/or marrow pretreatment. Seven of eight patients converted to PCR negativity after the completion of therapy. Six of these patients underwent elective autologous bone marrow collection posttreatment, with pooled buffy coat specimens confirming PCR negativity in all six patients. Unpurged stem cells were cryopreserved and are available for future autologous bone marrow transplantation if needed in those patients requiring dose-intensive therapy of refractory disease. The seven patients becoming bcl-2 negative also had documented complete remissions by standard restaging evaluations and were considered to have achieved molecular complete remissions. Six patients remained in CR, and five of seven patients remained PCR negative by serial analysis for at least 24 months or longer. Standard-dose CHOP alone is incapable of converting bcl-2–positive bone marrow to PCR negativity.35 The potential impact of achieving and maintaining a posttreatment molecular CR with respect to disease-free and overall survival in bcl-2–positive NHL patients in a non–autologous bone marrow transplantation setting will be studied prospectively in large cohorts of patients in future Rituxan trials.
These clinical findings suggest that Rituxan adds therapeutic benefit to CHOP therapy without causing significant additional toxicity. Owing to the promising results from this chemoimmunotherapy trial, a multicenter study of this combination in previously untreated intermediate- and high-grade NHL patients has recently been completed and a single institution study in previously untreated mantle-cell lymphoma patients is ongoing at Dana-Farber Cancer Institute. Many other clinical trials for the study of Rituxan in combination with a variety of other cytotoxic agents for the treatment of CD20-positive neoplasms in a variety of clinical settings are being planned for the future.
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ACKNOWLEDGMENTS
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Supported by clinical grants from IDEC Pharmaceuticals Corp, San Diego, CA
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accepted September 23, 1998.
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TOP
ABSTRACT
INTRODUCTION
