Rituximab (Rituxan, MabThera) is under development by Biogen Idee and Genentech in collaboration with Roche, Chugai, and Zenyaku Kogyo. This antibody is in Phase III clinical trials in the United States and Europe.
Rituximab is a mouse/human chimeric MAb directed against the cluster of differentiation (CD) 20 molecule. CD20 is a calcium channel that interacts with the B-cell immunoglobulinreceptor complex and is expressed on both normal and malignant B cells, making it an ideal target for monoclonal antibodies therapy in B-cell disorders. After binding to CD20, rituximab is thought to deplete B cells in a number of ways, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and alteration of calcium flux and factors involved in apoptosis. This antibody has been launched for the treatment of relapsed or refractory low-grade or follicular, CD20-positive B-cell non-Hodgkin’ s lymphoma (B-NHL).
Rituximab is under investigation in many chronic lymphocytic leukemia clinical trials both as a single agent and in combination with chemotherapy as well as in first- and subsequent-line settings.
The role for rituximab as a single agent in chronic lymphocytic leukemia is controversial. Previous studies showed an overall response rate of only 11% and 25%, comparing poorly with the rate of 40-60% reported for follicular NHL. However, a recent Nordic multicenter study yielded improved results. Twenty-four chronic lymphocytic leukemia patients of median age 57 (47-72) with active disease (3 Binet A, 7 Binet B, 14 Binet C) who had previously been heavily treated with a variety of chemotherapy regimens were given the standard dose of 375 mg/m2 rituximab once weekly for four doses. The primary objectives this study addressed were response rate, quality, and duration; secondary objectives were to analyze the feasibility and tolerability of rituximab therapy.
Eight of 23 evaluable patients (35%) achieved a partial response (PR), with a median duration of 12.5 weeks. A drop of at least 50% in blood lymphocyte count occurred in 17/21 (81%) patients who had pretreatment lymphocytosis, and 10 patients achieved a normal blood lymphocyte count (< 3 x 109 L_1). Of the 15 patients who did not achieve a PR with rituximab, 9 had at least a 50% drop in lymphocyte count and 3 achieved a normal count.
TABLE. Emerging Therapies in Development for Chronic Lymphocytic Leukemia
|Rituximab (Rituxan, MabThera)|
|United States||III||Biogen Idec/Genentech|
|United States||II||Biogen Idee|
|United States||II||National Cancer Institute|
|United States||I/I I||Invitrogen (formerly with Xcyte Technology)|
|United States||II||Tragen/University of California at San Diego|
|Denileukin diftitox (Ontak)|
|United States||II||Ligand Pharmaceuticals|
|Motexafin gadolinium (Xcytrin)|
|Selective apoptotic antineoplastic drugs|
|United States||Ila||OSI Pharmaceuticals|
Seventy-five percent of patients experienced rituximab-related side effects, half of which were related to the first infusion only. The most common toxicities were World Health Organization (WHO) grade 1/2 chills and grade 2 fever. In previous studies, the severe infusion-related toxicities reported had been specifically linked to a high tumor burden. Mainly mild/moderate side effects were observed in this study, even in patients with extremely high lymphocytosis (223 x 109 L_1). This study demonstrates that single-agent rituximab does have some activity in heavily pretreated chronic lymphocytic leukemia patients, although the response is minor and of short duration.
The reasons rituximab is more effective in NHL than in chronic lymphocytic leukemia are unclear. Circulating soluble CD20 and a high tumor burden, both of which “mop up” rituximab, are potential mechanisms/states by which the antibody is rapidly cleared from the blood; this theory is supported by the observation of altered pharmacokinetics and increased response rates with higher doses of rituximab in chronic lymphocytic leukemia. In addition, chronic lymphocytic leukemia cells have a much lower density of surface CD20 than do NHL cells, although no correlation between density and response to therapy has been found.
Rituximab has been used as a first-line, single-agent therapy, and limited clinical data suggest it may be more effective than as second- or third-line therapy. In one trial, treatment-naive patients with stage II — IV small lymphocytic lymphoma or chronic lymphocytic leukemia received 375 mg/m2 rituximab weekly for four doses. Patients who achieved an objective response (PR or complete response [CR]) or stable disease at reevaluation after six weeks continued maintenance courses of rituximab using the standard four-week schedule every six months for a maximum of four courses. Twenty-two of forty-three patients (51%) had an objective response at week 6, and the remaining patients had stable disease.
Twenty-eight patients (65%) went on to receive maintenance rituximab therapy. With a median follow-up of 24 months, the response rate was 58% (9% CR). Median progression-free survival (PFS) was 19 months with a one- and two-year actuarial PFS of 63% and 49%, respectively. Two patients had a reversible grade 3 infusion-related toxicity with the first course of rituximab. The increase in overall response rate is encouraging, but the small CR indicates that single-agent rituximab will not result in long-term survival in chronic lymphocytic leukemia.
Treatment for chronic lymphocytic leukemia is generally reserved for patients with symptoms of advanced disease, although rituximab therapy may be effective in early-stage disease for those at risk of progression. The overall response rate in 21 evaluable patients with Rai stage 0-11 and beta-2 microglobulin levels >2 mg/dL was 90% (19% CR, 19% nodular PR [nPR], 48% PR). The clinical significance of these results is unclear because a longer follow-up is required to analyze time to progression and long-term survival.
The dose and schedule of administration for single-agent rituximab therapy as both first and subsequent lines of therapy are under investigation in dose-escalation studies in an attempt to increase response rates. Researchers have reported using doses of up to 2,000 mg/m2/week in four patients. Such studies are ongoing to optimize clinical responses.
The most active area of research involving rituximab is in combination with chemotherapy. A randomized Phase II study of fludarabine in combination with concurrent rituximab versus sequential rituximab was conducted in 104 previously untreated chronic lymphocytic leukemia patients. The treatment schedule for sequential therapy involved patients receiving 25 mg/m2 fludarabine for 5 days, repeated every 28 days for six cycles. Four weekly doses of 375 mg/m2 rituximab were administered to patients who achieved stable disease or better, following a two-month rest period and restaging. The concurrent schedule followed the same pattern as the sequential schedule, with the addition of rituximab to each fludarabine cycle. It is important to note that patients receiving concurrent administration received 11 doses of rituximab (seven in combination with fludarabine and four as consolidation after this therapy) compared with only 4 doses in the sequential arm.
Concurrent administration of these two agents demonstrated superior response rates when compared with the sequential arm (47% CR versus 28% CR, 43% PR versus 49% PR, respectively). Neutropenia was more common in the concurrent arm, but infectious complications occurred at similar frequencies in both schedules. Additional data presented at the American Society of Hematology (ASH) meeting in 2003 determined that adding rituximab to fludarabine did not significantly increase the risk of infection.
This encouraging study establishes that concurrent administration of rituximab and fludarabine produces CR rates superior to those achieved with fludarabine alone. To date, the impact of rituximab on improving progression-free survival and overall survival compared with fludarabine monotherapy has not been analyzed in a randomized trial. A retrospective comparison with data from 179 patients enrolled in the North American Intergroup Study CALGB 9011 who received fludarabine monotherapy showed that CR, PR, and two-year performance-free and overall survival rates were significantly superior in the fludarabine/rituximab group.
The triple-drug regimen fludarabine/cyclophosphamide/rituximab (FCR) is also under intense investigation. In one study, 202 previously untreated chronic lymphocytic leukemia patients received FCR (25 mg/m2/day F for three days; 250 mg/m2/day C for three days; 375-500 mg/m2 R on day 1). Results showed 68% CR, 18% nPR, and 14% PR. The study also analyzed patients for the presence of minimal residual disease (minimal residual disease) and found that the FCR regimen produced a high level of minimal residual disease-negative complete remissions. A longer follow-up will determine whether minimal residual disease-negative CR is more durable than minimal residual disease-positive CR.
At the 2003 ASH meeting, the results of a sequential FCR program also were presented. Thirty treatment-naive chronic lymphocytic leukemia patients received six cycles of standard fludarabine therapy, then 3 g/m2 cyclophosphamide every three weeks for three cycles, and finally standard rituximab therapy. CR and PR rates of 57% and 29% (10% nPR and 19% PR), respectively, were achieved.
The FCR regimen has also succeeded in patients with relapsed or refractory chronic lymphocytic leukemia. In one trial, 179 patients who had already received between one and three courses of therapy were treated with FCR and achieved responses of 25% CR, 16% nPR, and 32% PR. Minimal residual disease (analyzed by polymerase chain reaction) was absent in 33% of CR patients. Therapy was well tolerated, and 62% of patients completed four or more cycles of this regimen. Forty-one percent of patients experienced fever and chills with the first rituximab infusion, and a minority experienced hypotension, nausea, and dyspnea (6%, 9%, and 3%, respectively). Hematologic toxicities included neutropenia in 30% of cycles and thrombocytopenia in 12%.
A comparative, retrospective analysis of patients treated with fludarabine (plus or minus prednisone), fludarabine/cyclophosphamide, or FCR demonstrated increased CR, overall response, and median survival in patients treated with FCR.
The purine analogue pentostatin (SuperGen Warner-Lambert’s Nipent) has shown significant activity and minimal toxicity when combined with cyclophos-phamide in chronic lymphocytic leukemia patients. In one trial, rituximab was added to this combination (known as the PCR regimen) and administered to previously untreated chronic lymphocytic leukemia patients. Preliminary data on 15 patients presented at ASH 2003 revealed 40% CR, 13% complete clinical response, and 47% PR. Most toxicities were grade 1 or 2, although eight patients suffered grade 3 anemia and hypotension and one patient developed grade 4 sinus bradycardia.
In another trial, 20 patients with relapsed or refractory disease were treated with the PCR regimen; the response rates were 20% CR, 10% nPR, and 50% PR. Grade 3/4 neutropenia occurred in 45% of patients, grade 3/4 thrombocytopenia in 5%, and infections in 15%. Preliminary data suggest this regimen is well tolerated, but further analysis is needed to determine both response rates and toxicity profiles compared with those associated with fludarabine-containing regimens.
The combination of rituximab and another MAb, alemtuzumab is under investigation for relapsed and refractory chronic lymphocytic leukemia. Nine patients underwent treatment with this combination, and preliminary data showed a 44% CR and 23% PR rate. Nonhematologic toxicities were grade 2 or less, and infection occurred in 44% of patients. Another study presented at ASH 2003 failed to show any complete or partial remissions in 11 patients with relapsed or refractory chronic lymphocytic leukemia who were treated with alemtuzumab and rituximab in combination. Further investigation into the combination of these antibodies is needed to determine their potential efficacy.
In an attempt to improve upon the success seen in FCR, the M.D. Anderson Cancer Center is pioneering a trial examining a regimen consisting of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (known as the CFAR regimen). Only two relapsed/refractory patients have completed all courses, and both achieved PRs. Four patients on continuing therapy were evaluated after three courses, and responses included one CR, one nPR, and two PRs. Seven patients came off therapy because of treatment failure (n = 2), infection (n = 1), noncompliance (n = 1), or at their own request (n = 2); one death occurred as a result of disease-related liver failure. Early analysis indicates good response with substantial but expected toxicities.
Rituximab enjoys extensive off-label usage in the United States, mainly in the first- and second-line chronic lymphocytic leukemia settings in combination with chemotherapy. In Europe, however, the use of rituximab is restricted by a lack of reimbursement owing to its experimental status and high cost.