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© 2001 American Society for Clinical Oncology Rituximab Using A Thrice Weekly Dosing Schedule in B-Cell Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Demonstrates Clinical Activity and Acceptable ToxicityFrom the Division of Hematology-Oncology, Department of Medicine and the Department of Clinical Investigation, Walter Reed Army Medical Center, Washington, DC; Division of Hematologic Malignancies, Johns Hopkins Oncology Center, Baltimore; Department of Critical Care Medicine, Uniformed Services University of Health Sciences, Bethesda, MD; Department of Medicine, The Ohio State University, Columbus, OH; IDEC Pharmaceuticals Inc, San Diego; and Genentech Pharmaceuticals, Inc, San Francisco, CA. Address reprint requests to John C. Byrd, MD, The Ohio State University, 320 West 10th Ave, Room 302 SL, Columbus OH 43210; email: byrd-2{at}medctr.osu.edu
PURPOSE: Rituximab has been reported to have little activity in small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) and to be associated with significant infusion-related toxicity. This study sought to decrease the initial toxicity and optimize the pharmacokinetics with an alternative treatment schedule. PATIENTS AND METHODS: Thirty three patients with SLL/CLL received dose 1 of rituximab (100 mg) over 4 hours. In cohort I (n = 3; 250 mg/m2) and cohort II (n = 7; 375 mg/m2) rituximab was administered on day 3 and thereafter three times weekly for 4 weeks using a standard administration schedule. Cohort III (n = 23; 375 mg/m2) administered rituximab similar to cohort II for the first two treatments and then over 1 hour thereafter. RESULTS: A total of 33 CLL/SLL patients were enrolled; only one patient discontinued therapy because of infusion-related toxicity. Thirteen patients developed transient hypoxemia, hypotension, or dyspnea that were associated with significant changes in baseline interleukin-6, interleukin-8, tumor necrosis factor alpha, and interferon gamma compared with those not experiencing such reactions. Infusion-related toxicity occurred more commonly in older (median age 73 v 62 years; P = .02) patients with no other pretreatment clinical or laboratory features predicting occurrence of these events. The overall response rate was 45% (3% CR, 42% PR; 95% CI 28% to 64%). Median response duration for these 15 patients was 10 months (95% CI, 6.8-13.2; range, 3 to 17+). CONCLUSION: Rituximab administered thrice weekly for 4 weeks demonstrates clinical efficacy and acceptable toxicity. Initial infusion-related events seem to be cytokine mediated and resolve by the third infusion making rapid administration possible. Future combination studies of rituximab with other therapies in CLL seem warranted.
CHRONIC LYMPHOCYTIC leukemia (CLL) is the most common adult leukemia that occurs in the western hemisphere and accounts for 25% of all leukemias. Despite the greater than 10-year life expectancy in patients with early stage leukemia, CLL remains an incurable illness.1,2 Patients whose disease progresses onto or are diagnosed with more advanced stage CLL have a median survival between 18 months to 3 years. However, unlike most of the other forms of acute and chronic leukemia, substantial therapeutic progress has not been made over the past 40 years in prolongation of survival and the introduction of curative therapy. Alkylator therapy with or without corticosteroids is effective in patients with symptomatic CLL. The addition of fludarabine early in the treatment of symptomatic CLL patients has led to a higher rate of complete responses compared with alkylator-based therapies.3,4 Both fludarabine and alkylator-based therapies can transiently increase the severity of pre-existing cytopenias and predisposition toward developing secondary infections before producing improvements in these important clinical parameters. As a consequence to this, attempts to improve both the treatment results and toxicity observed with fludarabine are currently ongoing.5 One such therapy being investigated in CLL is rituximab, a chimeric monoclonal antibody directed against CD20. The high expression of CD20 in B-cell Non-Hodgkin’s Lymphoma (NHL) and promising preclinical data led to several phase II studies in this disease that demonstrate activity in both low-grade and diffuse large cell NHL.6-10 These results led to a pivotal trial in low-grade NHL where a 48% overall response rate was noted with a median progression free survival of 1 year.11 When response was broken down by the International Working Formulation (IWF) classification, response was significantly lower in the 33 patients with small lymphocytic lymphoma (SLL) (12% v 58%; P < .001) compared with those with patients with International Working Formulation (IWF) B, C, or D histology.11,12 Three recent studies using a similar schedule of rituximab in previously treated patients with CLL/SLL noted similar response rates.13-15 Explanations for such poor response rates in patients with CLL/SLL include low density of CD20 expression on tumor cells or possibly altered pharmacokinetics, given the large intravascular tumor burden present in CLL/SLL. Pharmacokinetic studies performed on the pivotal NHL study demonstrated a strong correlation of mean plasma antibody concentration with response and SLL patients had significantly lower plasma trough concentrations of rituximab at most time points examined.11,12 Additionally, rapid clearance of antibody without substantial accumulation was observed in these nonresponding patients. These clinical data suggest that a once weekly schedule of rituximab in SLL (and related CLL) is sub-optimal and an alternative schedule with a shorter interval of rituximab administration might prove to be more effective for this patient subset. In addition to considering optimal schedule of administration, another important consideration for using immunotherapy in CLL is minimization of infusion-related events that can occur when tumor cells are circulating in the peripheral blood. Similar to other murine antibodies previously used in the treatment of CLL,16 several reports have noted increased, and sometimes life threatening, infusion-related events when rituximab was given to patients with this disease or those with prolymphocytic leukemia and mantle-cell lymphoma.13,17,18 Use of a stepped up dosing approach17 similar to that used with Campath-1H in CLL19 has been preliminarily noted to diminish such infusion-related events. In an attempt to determine if the lack of rituximab efficacy observed to date in CLL/SLL was due to a sub-optimal schedule of administration compared with a diminished tumor target antigen expression and if using a stepped up dosing approach might diminish infusion-related side effects, we performed a phase I/II study outlined herein.
Subjects Patients were enrolled onto this institutional review board approved multicenter trial at the Walter Reed Army Medical Center and Johns Hopkins Oncology Center. All patients gave written informed consent before participation. Patients were required to have histologically documented CLL as defined by the modified National Cancer Institute (NCI) criteria20 or SLL as defined by the International Working Formulation classification.21 All patients had either failed one or more prior therapy with no limitation on the number of prior treatments. Previously un-treated patients were allowed to enroll if they were direct antiglobulin test positive, had a previous history of auto-immune anemia, auto-immune thrombocytopenia, or were not appropriate candidates for chemotherapy based on comorbid illnesses. Required features included an Eastern Cooperative Oncology Group performance status of  3, life expectancy of 12 weeks or greater, having recovered from toxicity of previous therapy for CLL and not having an active infection that required treatment with oral or IV antibiotics. Laboratory requirements included tumor lymphocyte cells expressing surface CD20 of any detectable intensity and a serum creatinine of 3.0 mg/dL. Pregnant patients and those with a previous allergic reaction to rituximab were excluded from this study. Patients were considered alkylator or fludarabine refractory, respectively, if they did not attain a partial or complete response to treatment with the respective agent or relapsed within 6 months of the last treatment. Response was judged according to the modified NCI criteria.20
Pretreatment Evaluation
Treatment
Definition of Dose-Limiting Toxicity Dose-limiting toxicities for this study were defined as nonhematologic toxicity of grade 3 or greater severity (except transient bronchospasm in the absence of urticaria that was reversible with the interventions outlined previously). As any significant toxicity in Cohort III was viewed as unacceptable, dose-limiting toxicity for this cohort included transient bronchospasm. Grade 2 toxicity, which included irreversible renal, chronic pulmonary, neurologic, cardiac, and local toxicities, were also considered dose-limiting toxicities. Hematologic toxicity was not considered dose-limiting. Hematologic toxicity was graded according to the modified NCI criteria20 while non hematologic toxicity was graded according to the NCI Common Toxicity Criteria.
Cytokine and Complement Levels
Quantitative CD20 Expression
Pharmacokinetics
Disease Response
Statistics
Patient Characteristics A total of 33 patients were enrolled on this protocol from January 1999 to August 1999. The pretreatment features of these patients are summarized in Table 2. The median age of these patients was 66 years (range, 50 to 80) with 26 having typical chronic lymphocytic leukemia and seven having small lymphocytic lymphoma as classified by the Working Formulation Criteria. The median number of prior treatments was two (range, 0 to 6) with 17 (52%) of the patients being refractory to fludarabine. Using the modified Rai staging criteria, 24 (73%) of the patients were high-risk, with all meeting the criteria for initiation of treatment as outlined by the modified NCI criteria.20
Feasibility of Initial Rituximab Infusion All 33 patients enrolled on the study were assessable for initial infusion-related toxicity noted predominately within the first two infusions of rituximab. The details of the toxicities observed are specified in Table 3, including 20 patients experiencing one or more infusion-related side effects during the first infusion. Of these, 13 patients had transient hypoxemia, hypotension, or dyspnea that required cessation of the infusion and supportive intervention. Only two patients (7%) experienced grade 3 (n = 1) or grade 4 (n = 1) events. Only the patient who experienced the grade 4 event discontinued therapy. This patient, a 73 year-old-patient with alkylator and fludarabine refractory CLL, had a performance status of 3, thrombocytopenia, and was on low molecular weight heparin for a previous deep venous thrombosis before beginning therapy. He developed significant hypoxemia, dyspnea, and tachycardia during the first infusion for which treatment was discontinued. His symptoms improved after therapy was discontinued but he subsequently developed hemoptysis and progressive dyspnea on day 3 in the absence of further therapy. These pulmonary symptoms (eg, hemoptysis) ultimately lead to his death. The relationship of rituximab therapy to this patient’s death is probable. Infusion events were less frequent with the second rituximab treatment, with only 12 patients experiencing infusion-related events that were mild (grade 1, n = 8; grade 2, n = 3; and grade 3, n = 1). All patients who had reactions during the second infusion had previously experienced infusion-related events during the first treatment. Minimal infusion-related events (grade 1 chills, n = 2) were observed in the first nine patients who received nondisrupted rituximab administration after the second infusion. This lead to the hypothesis that rituximab could be administered rapidly in an attempt to facilitate shorter clinic visits for the patients. Of the next 23 patients enrolled using an hour infusion on the third and subsequent infusion, no infusion-related reactions were noted beyond the second treatment.
Hematologic toxicity was often observed during the first week despite the selectivity of rituximab for CD20 positive CLL cells as demonstrated in Table 4. These changes were generally transient and of no clinical significance. The exception to this was thrombocytopenia, where three of six patients who began treatment with a platelet count less than 50 x 109/L but more than 20 x 109/L had a decrease in platelets to less than 20 x 109/L with the first infusion. This decline was transient, as all three patients returned to their baseline platelet count by the 5th day of treatment despite continuation of rituximab therapy. Only one of these patients required a platelet transfusion. Similar transient anemia and neutropenia was observed during the 1st week of treatment. For the majority of patients, cytopenias either improved from baseline or returned to the pretreatment baseline value during treatment. Non-infusion-related toxicity was minimal. Hematologic toxicity after week 1 of therapy was minimal with rituximab as demonstrated in Table 5.
Inflammatory Cytokine Levels During Initial Rituximab Infusion After administration of rituximab in both CLL and NHL patients, it has been noted that inflammatory cytokines such as TNF-  and IL-6 increase.13 To assess if these cytokines (and others) increase in patients who receive rituximab and if these changes correlate with infusion-related events, we performed serial sequential testing for IL-6, IL-8, TNF-, and IFN- levels during the first two treatments with rituximab. Levels of these respective cytokines were correlated with patients having reactions that included hypotension, hypoxemia, or dyspnea during treatments 1 or 2 and required cessation of therapy and supportive intervention. These were chosen prospectively before examining the cytokine data because these events would always mandate a delay in the rituximab infusion and might require hospital admission. For the whole group, it is notable that each of the inflammatory cytokines measured increased significantly over time compared with the baseline measurement. Figure 1 demonstrates that the inflammatory cytokines TNF- (P = .007, IL-6 (P = .058), IL-8 (P = .02), and IFN- (P = .011) are significantly higher during treatment 1 and 2 for those patients having reactions compared with those without. In contrast, alterations in complement (CH50 and C3) were not associated with infusion-related reactions (data not shown). It is noteworthy that the six patients who developed similar infusion-related side effects during treatment 2 were noted to have increased levels of these same cytokines while those who did not have infusion-related events had diminished cytokine release relative to the first treatment. This is demonstrated with TNF- in Fig 1A and 1B.
Clinical and Laboratory Features Predicting for Rituximab Infusion Toxicity In an attempt to identify factors predictive of serious initial infusion reactions with rituximab, we performed a univariate analysis examining clinical features previously associated as outlined in Table 6. Only increasing age (median, 73 v 62 years; P = .02) was noted to be more frequently associated with serious infusion-related toxicity. Other factors such as the disease type, prior therapy, absolute tumor blood count number, extensive nodal involvement, and tumor CD20 expression did not correlate with infusion-related reactions with the first rituximab treatment. A nonsignificant, but higher baseline level of plasma concentration of IFN- (88 pg/mL v 23 pg/mL; P = .39), TNF- (median, 28 pg/mL v 18 pg/mL; P = .15), and IL-8 (1.6 pg/mL v 0.1 pg/mL; P = .12) was noted in patients who developed infusion-related events.
Response to Treatment Of the 33 patients enrolled on this study, 4 patients were unassessable for efficacy due to the following reasons: one died on day 3 of treatment of pulmonary hemorrhage, one developed septic arthritis during week 2 of treatment, one died 1 month post therapy from septicemia and a gastrointestinal bleed, and one patient developed idiopathic thrombocytopenic purpura following week 4 of therapy that required alternative therapy. Of the 29 patients who were assessable, the overall response rate was 52% with 14 attaining a partial remission and one complete remission. Of the patients who did not respond to therapy, 11 had stable disease, and three had evidence of progressive disease at the time of the two-month posttreatment assessment. Using an intent to treat analysis, the overall response rate was 45% (95% CI, 28-64). The median response duration for the 15 responding patients was 10 months (95% CI, 6.8-13.2; range, 3 to 17+) as depicted in Fig 2. Responses are still ongoing in eight patients with durations of response being 4, 6, 7, 7, 9, 10, 12, and 17 months, respectively. Of the seven patients with fludarabine refractory CLL who responded to rituximab therapy, the median duration of response was 6 (range, 3 to 11) months. The median time to progression for the entire group of patients was 6 months (range, 0 to 18+) as depicted in Fig 3. The median time to progression was 11 months (95% CI, 7.8-14.2; range, 3 to 18+) for the 15 responding patients and 6 months (95% CI, 2.6-9.4; range, 0 to 14+) for those who did not respond. Six patients died after therapy as a consequence of the following: pulmonary hemorrhage (n = 1), myocardial infarction (n = 1), congestive heart failure (n = 1), subsequent therapy (n = 1), and infection (n = 2).
Clinical Features Predicting Response to Treatment We next performed an exploratory univariate analyses of preclinical and early treatment features predictive of eventual response to rituximab in CLL and SLL patients as partially demonstrated in Table 7. It is noteworthy that previously important prognostic factors for other therapies such as age, nodal involvement, stage (intermediate Rai versus advanced Rai) did not correlate with response to therapy. This observation, however, is limited by the small patient sample size. Other factors such as the density of CD20 on tumor cells, baseline cytokine level of IL-6, IL-8, IFN- , and TNF-, and development of infusion-related reactions (mild or severe) did not correlate with response to therapy. Although not significant, it is notable that patients who were previously untreated had a higher response rate (83%) than those who were treated with alkylator (30%) or who were refractory to fludarabine (41%).
Rituximab Treatment Causes Depletion of Complement As humanized monoclonal antibodies can work in vivo through a variety mechanisms, characterization of the in vivo events after treatment are important as this might lead to treatment modifications to further augment response. To determine if complement mediated lysis contributed to the efficacy of rituximab treatment, we serially assessed for changes in complement as measured by CH50 and C3 levels in 12 patients on treatments day 1 and 3. Plasma was obtained before and immediately after rituximab treatment. CH50 levels fell from a pretreatment level of 79.7 to 69.7 posttreatment on day 1 and pretreatment level of 74.9 to 64.2 on day 3 of therapy. Likewise, C3 levels fell from a pretreatment level of 41.9 to 32.2 post treatment on day 1 and pretreatment level of 37.5 to 24.2 on day of 3 of therapy. All of these changes were significant (P < .01). Decreases occurred in all patients irrespective of eventual response to therapy.
Limited Pharmacokinetic Studies
CLL is one of the most common types of leukemia, remains incurable, and has only limited therapeutic options available including alkylator or fludarabine-based therapy. The identification of new, selective, and nontoxic forms of therapy for patients with CLL is therefore a high priority. The data described herein represent one of the largest cohorts of CLL/SLL patients treated with rituximab and establishes this agent as another potential useful therapy for patients with this disease. Specifically, we demonstrate that with a modified pharmacokinetic derived schedule of rituximab administration, rapid clearance of antibody and subsequent low serum trough levels is not observed. This pharmacokinetic optimization improved the response rate from the 5% to 14% range11,13-15 observed when rituximab is administered once weekly in relapsed CLL patients to a 45% response rate. Responses were noted in all groups of patients including the elderly, those with bulky lymphadenopathy, and those for which alkylator and/or fludarabine-based therapy had failed. For responders, the clinical response as measured by the modified NCI response criteria translates into a median response duration of 10 months that is similar to that noted in the pivotal trial of patients who received the rituximab once weekly.11 Furthermore, using a stepped up dosing approach of this agent similar to that used with other monoclonal antibodies, we have minimized the serious infusion-related events previously noted with rituximab therapy. When infusion events were noted, our data substantiated the role of inflammatory cytokines but not complement depletion being temporally related to significant clinical events that mandate medical attention. With this larger group of patients, we were able to establish that age, but no other factor including baseline leukocyte (or lymphocyte count), predicted who would develop this toxicity. These clinical data both substantiate the activity of rituximab in CLL/SLL and provide justification for further trials to optimize its use through effective combination strategies.
The etiology of infusion-related side effects noted in non-Hodgkin’s lymphoma or CLL patients after the administration of rituximab to this point has not been extensively studied. Winkler et al13 performed serial sampling of cytokines during the first treatment of rituximab in 10 CLL patients and noted that TNF-
The relevance of the observation that increases in inflammatory plasma cytokines correlates with development of infusion-related reactions are potentially significant to the future trials with rituximab (and other antibodies) in CLL. The sequence of cytokine release after administration of rituximab provides insight into a possible therapeutic intervention to diminish such reactions. This sequence seems similar to that observed with sepsis where TNF- With our findings and that of another group using weekly dosing of rituximab at much higher doses than used in NHL patients,29 it is clear that this agent has activity in CLL. Indeed, our limited pharmacokinetic data derived from the first 12 patients enrolled on this study demonstrate that responses can be obtained in the CLL/SLL subset when adverse pharmacokinetic parameters are removed. The observation of only partial responses is similar to that observed in relapsed follicular lymphoma.11 The only exception to this is minimal clearance of bone marrow disease in the majority of CLL patients who were examined posttreatment. Reasons for this are unclear, although it is well known that stromal and contact factors are important in protecting CLL cells from spontaneous apoptosis.30,31 Rituximab and other monoclonal antibodies work via a variety of mechanisms, including antibody dependent cellular cytotoxicity (ADCC), inducing apoptosis, and complement mediated lysis.32,33 In this study we have demonstrated that decreases in complement are observed in all patients which suggests that complement mediated cell lysis may contribute to the initial clearance of tumor cells in vivo. Although the presence of stromal effects might not protect CLL cells from complement mediated lysis or ADCC, it is quite feasible that the apoptotic pathway could be blocked. Advances in the treatment of CLL will likely require effective combination therapies. Rituximab has been demonstrated to sensitize lymphoma cell lines to the effects of chemotherapy34 and combination studies with fludarabine and fludarabine/cyclophosphamide combinations are ongoing. Rituximab has absolute selectivity for B-lymphocytes and should not augment fludarabine-induced cellular immune dysfunction.35,36 However, it is possible that the cellular immune suppression induced by fludarabine may limit application of rituximab and other immune based therapies. Because rituximab induced apoptosis in CLL cells requires F.C receptor ligation in vitro,33 strategies that involve increasing the absolute effector cell number with cytokines (GM-CSF, IL-2) is currently being studied by several groups. This and other cytokines currently in the clinic also may upregulate CD20 expression on CLL cells37 thus possibly augmenting clinical responses. Nonetheless, our data presented herein document the efficacy of rituximab in the treatment of CLL and provide justification for further study of this antibody in combination with other therapies for the treatment of this disease.
Supported in part by a clinical grant for data management by Genentech Inc (J.C.B. and I.W.F.) and the Sidney Kimmel Foundation for Cancer Research (J.C.B.). We thank Joseph Flynn, DO, and Charlotte Shinn, MS, for reviewing the final manuscript and the nursing team at both The Johns Hopkins Oncology Center and the Walter Reed Army Medical Center for supporting this trial.
J.C.B. and I.W.F. contributed equally to the design, implementation, and analysis of this study.
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ABSTRACT
INTRODUCTION
