Clinical Status and Optimal Use of Rituximab for B-Cell Lymphomas

ABSTRACT: Rituximab (IDEC-C2B8 [Rituxan]) is a chimeric anti-CD20 monoclonal antibody (MoAb) that was recently approved by the FDA for the treatment of patients with low-grade or follicular B-cell non-Hodgkin’s lymphoma. Its potential efficacy in other B-cell malignancies is currently being explored. This article reviews the mechanisms of action of rituximab, as well as preclinical data and results of the clinical trials that led to its approval. Also discussed are the mechanics of administering rituximab on the recommended weekly ´ 4 outpatient schedule. Finally, the article describes ongoing and planned trials of rituximab in other dosage schedules, in other B-cell neoplasms, and in conjunction with chemotherapy. As the first MoAb to gain FDA approval for the treatment of a malignancy, rituximab signals the beginning of a promising new era in cancer therapy. [ONCOLOGY 12(12):1763-1770, 1998]

Introduction

Monoclonal antibodies (MoAbs) have been used since the 1980s to treat both solid tumors and hematologic neoplasms.[1] Lymphoma was a ripe area for early MoAb trials, since extensive research on the normal immune system led to the characterization of many lymphocyte surface antigens that could serve as potential therapeutic targets.[2] These early trials yielded few responses, but many insights, including the following:

Some (but not all) surface proteins can be depleted from the cell surface by being shed into the serum, internalized into the cell, or modulated.

Murine antibodies have a short half-life in humans.

Human effector functions would be more effectively mediated by a human Fc portion of the antibody than by a murine Fc fragment.

Immunogenicity is a limitation of murine antibodies.

Even in these early trials, it was observed that MoAb therapy could be effective, and that it was both feasible and relatively nontoxic. The most common toxicity, which was noted to some extent in virtually all of the trials, was a symptom complex, probably cytokine-mediated, of fever, chills, sweats, and, occasionally, bronchospasm and hypotension.[1,3,4] However, even with murine antibodies, severe allergic or hypersensitivity reactions were quite infrequent, as were late effects, such as serum sickness.

The CD20 molecule is an appealing target for a therapeutic MoAb.[5-7] It is expressed on B-cells from the pre-B-cell stage to the activated B-cell stage but is not expressed on stem cells, normal plasma cells, or cells of other lineages. In addition, CD20 is expressed on most B-cell lymphomas and chronic lymphocytic leukemia cells and on 50% of pre-B-cell acute lymphoblastic leukemias.[2,6,8] It is not shed, internalized, or modulated. Evidence indicates that CD20 may play a role in cell-cycle entry and progression in B-lymphocytes,[9-11] suggesting that anti-CD20 MoAb therapy may have B-cell growth regulatory effects that are independent of human effector functions.

The chimeric human/mouse anti-CD20 antibody rituximab (IDEC-C2B8 [Rituxan]) was developed to minimize some of the drawbacks of murine antibodies. A chimeric antibody is expected to be less immunogenic than a murine MoAb, and to have a longer half-life. A chimeric MoAb should be more effective in terms of mediating human effector functions, such as complement- mediated cell lysis and antibody-dependent cell-mediated cytotoxicity. Also, accumulating evidence suggests that rituximab may induce apoptosis, as well as sensitize resistant human cell lines to the effects of chemotherapy.[12]

This theoretical background provided the basis for the development of rituximab. It also underlies the clinical success of this antibody, which led to its being the first MoAb to gain FDA approval for the treatment of a malignancy. In a real sense, rituximab represents the beginning of a promising new era in cancer therapy.

Specificity, Mechanism, and Preclinical Experience

Direct and competitive binding assays were used to compare rituximab to the murine 2B8 antibody from which it was derived; these assays showed rituximab to have comparable affinity and specificity for the CD20-positive SB cell line.[5] Flow cytometry experiments showed that normal peripheral blood B-cells bind to rituximab, whereas other lymphocyte subsets do not.

The tissue reactivity of rituximab was tested on a panel of 32 different human tissues. Only a subset of lymphoid tissues reacted, including those in the white pulp of the spleen, in lymphoid follicles of the tonsil, in some lymph node B-cells, and in lymphoid cells present in such organs as the intestine. Rituximab showed no reactivity with epithelial cells, fibroblasts, endothelial cells, or neuroectodermal cells, including cells of the brain and spinal cord.

The ability of rituximab to fix complement was demonstrated by showing the binding of fluorescent C1q to cells from the SB cell line that had been incubated with rituximab.[5] Complement-dependent cytotoxicity of ri-tuximab was characterized by using chromium-51–labeled SB cells that were exposed to antibody and human serum as a source of complement. Control studies were performed with the CD20-negative HSB cell line. Approximately 50% of the SB target cells were lysed in the presence of rituximab, but the CD20-negative HSB cells were not.[5] Thus, the lysis mediated by rituximab was antigen-specific.

Another study assessed the ability of rituximab to bind to human Fc receptors, which are found on effector cells, including monocytes, macrophages, and natural killer cells. Rituximab was found to bind to both the high-affinity Fc-gamma-RI receptor and the low-affinity Fc-gamma-RII and Fc-gamma-RIII receptors. The binding of rituximab to Fc-gamma-RI was equivalent to that of human immunoglobulin G1 (IgG1), and its binding to Fc-gamma-RII was stronger than that of IgG1. Thus, not surprisingly, rituximab was found to mediate antibody-dependent cell-mediated cytotoxicity; in the presence of rituximab, Fc receptor–positive effector cells killed ~50% of target cells that had adherent antigen-specific antibody.[5]

Cell line experiments showed that rituximab can inhibit growth of B-cell lines, including FL-18, Ramos, Raji, and DHL-4 cell lines.[11] Comparable growth inhibition was observed with IDEC-2B8, the murine anti-CD20 antibody from which the variable regions of rituximab are derived; this indicates that the human Fc region is not essential for the growth inhibition. Of five anti-CD20 antibodies tested, rituximab, IDEC-2B8 (IDEC Pharmaceuticals), and anti-B1 (Coulter) inhibited cell growth more strongly than 1F5 or 2H7, and also produced greater cell growth inhibition than did anti-CD19 or anti-HLA-DR (human leukocyte antigen–D-related) antibodies.[11] In studies of one of the cell lines (DHL-4), there was evidence that anti-CD20 MoAbs induce apoptosis. Rituximab can also sensitize resistant cell lines to the cytotoxicity of diphtheria toxin, ricin, cisplatin (Platinol), doxorubicin, and etoposide.[12]

In primate studies, rituximab was found to be nontoxic in cynomolgus monkeys, and to deplete B-cells effectively from peripheral blood, lymph nodes, bone marrow, and the spleen. In dose-ranging studies in monkeys, doses of up to 100 mg/kg (equivalent to 1,200 mg/m² in humans) were associated with only minor toxicity, including some vomiting and transient decreases in platelets and white blood cells.

Preclinical studies showed that rituximab has a relatively long serum half-life in cynomolgus monkeys. Anti-body was detectable up to 7 days after a single 10-mg/kg dose, and higher and more sustained serum levels were noted after higher doses (30 to 100 mg/kg).

Phase I Data and Pharmacokinetics

In single- and multiple-dose phase I trials, Maloney et al observed detectable antibody for up to 10 days after a single dose of rituximab. Higher and more sustained serum levels were seen after multiple doses (Table 1).[13-15]

The pivotal clinical trial leading to the approval of rituximab used a dose of 375 mg/m² weekly for 4 weeks. This trial showed a pattern similar to the multiple-dose phase I trial: a half-life of 59.8 hours after the first dose and 174 hours after the fourth dose.[16,17] Detectable serum rituximab levels were still present in patients for up to 3 to 6 months after the fourth dose. Despite a typically lower density of CD20 on small lymphocytic lymphoma (SL) cells than on follicular lymphoma cells,[18] patients with small lymphocytic lymphoma had more rapid depletion of rituximab than did patients with follicular lymphoma.

Ongoing studies are testing rituximab in a weekly × 8 schedule, including one trial that is using an escalated dose (500 mg/m²) for weeks 2 through 8.[19,20] Pharmacokinetic studies in these trials will address whether stepwise higher peak rituximab levels can be attained with repeat doses on the weekly × 8 schedule, and to what extent antibody levels can be prolonged further.

The phase I experience with rituximab did not define any dose-limiting toxicities (see “Side Effects” below). However, since tumor regressions were seen in the phase I trials, and the multiple-dose schedule achieved sus-tained antibody levels, the 375-mg/m²weekly × 4 schedule was pursued, and is the schedule approved by the FDA.

Dosage and Administration

For administration, rituximab is diluted in normal saline (or 5% dextrose-in-water) to a concentration of 1 to 4 mg/mL. Use of a 0.22-µm in-line filter was required for some early lots but is no longer necessary, although a low-protein binding filter may be used.

Rituximab should not be administered as an intravenous (IV) push or bolus, as hypersensitivity reactions may occur. Premedication with acetaminophen and diphenhydramine 30 to 60 minutes before each rituximab infusion may attenuate infusion-related events. Medications for the treatment of hypersensitivity reaction (eg, epinephrine, antihistamines, and corticosteroids) should be available for immediate use in the event of a reaction during rituximab administration.

Since initial infusions are often associated with infusion-related events (see “Side Effects” below), the recommended initial rate for the first infusion is 50 mg/h. Anecdotal information suggests that patients with high circulating B-cell counts may be more prone to toxicity during the first infusion. Thus, it may be prudent to use an initial infusion rate of 25 mg/h in such patients. For patients with high white blood cell counts (eg, 75,000/mm³ or higher), it is probably also appropriate to anticipate possible tumor lysis, and, therefore, the use of allopurinol and careful attention to hydration and monitoring of electrolytes would also be appropriate in such patients.

If infusion-related events do not occur, the infusion rate can be increased in 50-mg/h increments every 30 minutes to a maximum of 400 mg/h. The mean duration of the first infusion was 5.2 hours in the pivotal trial. For second and later infusions, the initial rate can be 100 mg/h and rate increments can be 100 mg/h every 30 minutes to a maximum of 400 mg/h. The mean durations of the second, third, and fourth infusions were 3.5, 3.3, and 3.3 hours, respectively, in the pivotal trial.

If hypersensitivity or infusion-related events occur, the infusion should be slowed or interrupted. Upon improvement of symptoms, the infusion can be resumed at half the previous rate, with cautious rate increases thereafter.

In the single-agent trials of rituximab, steroids were specifically avoided, largely to ensure that the efficacy assessment of rituximab would not be confounded by concurrent steroid use. From this experience, it is clear that the vast majority of patients tolerate rituximab without the need for steroids. Thus, the routine use of steroids as a premedication is unnecessary.

Conceivably, steroids could compromise the efficacy of rituximab via their effects on host effector cells, but this is speculative. In the studies evaluating the combination of CHOP (cyclophosphamide, doxorubicin, Oncovin, and prednisone) chemotherapy and rituximab[21] (see “Efficacy” below), no antagonism was observed, but the steroid was not given concurrently with rituximab.

Contraindications and Undefined Areas

The specific FDA approval of rituximab is for relapsed or refractory low-grade or follicular CD20-positive B-cell lymphoma. Studies of rituximab in other B-cell malignancies are currently in progress; some preliminary positive data have been reported (see “Ongoing Trials and Future Directions” below).

Rituximab should not be administered to patients with a known hypersensitivity to murine proteins.

Trials of rituximab to date have not included children. Because human IgG is excreted in human milk and can cross the placenta, rituximab should not be given to a pregnant or nursing woman. No data are available on the effects of rituximab on fertility, carcinogenicity, or mutagenicity, and, therefore, individuals of childbearing potential should use effective contraception during therapy.

To date, trials of rituximab have focused on low-grade and follicular lymphoma (not chronic lymphocytic leukemia). Consequently, there is limited experience with the MoAb in patients with very high circulating B-cell counts. Since B-cell depletion can occur rapidly with rituximab, appropriate precautions and monitoring for the possibility of tumor lysis are prudent.

Clinical trials of rituximab have excluded patients with central nervous system (CNS), pleural, or peritoneal lymphoma; those with acquired immunodeficiency (AIDS)–related lymphoma; and those with serious nonmalignant diseases (eg, congestive heart failure, active uncontrolled infection). Entry criteria have also included adequate renal function (serum creatinine, < 2.0 mg/dL) and liver function (liver function tests, £ 2 × normal), as well as ade-quate hematologic status (hemoglobin, ³ 8 g/dL; platelet count, > 75,000/mm³; granulocyte count, > 1,500/mm³). Thus, the tolerance of such patients for ri-tuximab is not yet well defined.

Conversely, it is known that patients who have undergone bone marrow transplantation (BMT) and the elderly can tolerate rituximab well.[16,17,22]

Drug Interactions

To date, no drug interactions with rituximab have been observed.

Since transient hypotension may occur during infusion of rituximab, consideration should be given to withholding antihypertensive medications for 12 hours prior to rituximab infusion.

Efficacy

Rituximab Alone

Even in the single- and multiple-dose phase I trials, responses to rituximab were seen (Table 2). [13,14] In the first phase II trial, which used a dose of 375 mg/m² weekly × 4 in 37 patients at seven institutions, responses were noted in 17 (46%), including 3 complete and 14 partial responses.[15]

In a larger, confirmatory, pivotal phase III trial, which involved 166 patients at 31 centers, a 48% response rate was observed, including a 6% rate of complete responses and a 42% rate of partial responses.[16,17,22,23] This trial used stringent response criteria and a blinded third-party review of all responses. The results of this pivotal trial, conducted between April 1995 and April 1996, provided the definitive data that led to the FDA approval of rituximab in November 1997.

Rituximab Plus CHOP

In parallel with the trial confirming the activity of rituximab alone, a pilot trial was conducted between 1994 and 1995 in which rituximab was combined with CHOP chemotherapy.[21] Six doses of rituximab were integrated with six courses of standard CHOP chemotherapy. The study population consisted of 40 patients, 31of whom were previously untreated.

Tolerance of this regimen was good, with only modest infusion-related symptoms attributed to the MoAb (see “Side Effects” below) and an overall pattern of toxicity comparable to that of CHOP alone. There was one death related to reactivation of a preexisting hepatitis B infection.

The efficacy results of this CHOP plus rituximab trial are quite encouraging: All 35 evaluable patients responded, 63% of whom had complete and 37% partial responses. The size of the study and short follow-up preclude one from making broad conclusions or comparisons with CHOP alone, at least with respect to traditional long-term end points, such as failure-free or overall survival.

The possible superiority of CHOP plus rituximab over CHOP alone was suggested by an analysis of a subset of patients monitored by the polymerase chain reaction (PCR) for bcl-2 rearrangements, however. Of eight patients with known pretreatment bcl-2 rearrangement and positive PCR in the peripheral blood and bone marrow, PCR reverted to negative in seven. This is a higher fraction of reversion to PCR-negativity than would be expected with CHOP alone, suggesting that a better quality of remission can be attained with chemotherapy plus rituximab than with chemotherapy alone.

Side Effects

Infusion-Related Effects

Like other monoclonal antibodies, rituximab produces an infusion-related symptom complex in most patients. This symptom complex typically occurs during the first infusion, usually within the first 2 hours, and consists primarily of fever and chills. Other less frequent infusion-related symptoms include nausea, headache, angioedema (a sensation of tongue or throat swelling), rhinitis, pruritus, urticaria, rash, mild hypotension, and dyspnea or bronchospasm (Table 3).

As mentioned above (see “Dosage and Administration”), these symptoms can be attenuated by premedication with acetaminophen and diphenhydramine and usually resolve when the rituximab infusion is slowed or interrupted. Infrequently, IV saline and/or bronchodilators are required. Once the symptoms subside, the infusion can be restarted at half the rate and then escalated as tolerated. Most often, symptoms do not occur during the remainder of the infusion or during subsequent infusions.

Other Side Effects

Some patients have experienced symptoms related to preexisting cardiac conditions, including arrhythmia and, less frequently, angina, during rituximab therapy. Bronchospasm has occurred in 8% of patients, but only 2% have required bronchodilators.

Hematologic abnormalities have occurred in a minority of patients and were usually mild and reversible. During the treatment period, platelet counts < 25,000/mm³ were observed in < 1% of patients, granulocyte nadirs of < 500/mm³ in 1.3%, and hemoglobin levels < 8.0 g/dL in 2.6%.

The tumor lysis syndrome was not observed in the 166 patients in the pivotal trial, so it is expected to be a rare event, at least in patients with indolent lymphoma who are not leukemic. But since tumor lysis has been observed in patients with high circulating B-cell counts, attention is appropriate in such patients for the possibility of tumor lysis.

Immune Responses

Human antimouse antibody (HAMA) or human antichimeric antibody (HACA) responses to rituximab have been rare, occurring in only 3 of 237 patients treated; this contrasts with the experience with murine monoclonal antibodies.[24] The three rituximab-treated patients who developed HACA responses had no associated symptoms or laboratory abnormalities. Thus, the hope has been realized that a chimeric, predominantly human, MoAb is less likely to evoke a host immune response than are murine MoAbs. By virtue of the lack of immunogenicity of rituximab, retreatment is feasible (see “Ongoing Trials and Future Directions” below).

Rituximab consistently produces B-cell depletion, although this is associated with decreased immunoglobulin levels in only a minority of patients. The incidence of infection does not appear to be greater than expected in this patient population, and serious infections were considerably less common than have been reported with conventional chemotherapy. Infections occurred in 15% to 20% of patients, either during or for up to 1 year following rituximab therapy, and were usually of the upper respiratory tract, due to common pathogens, and mild.[22]

Comparison With Conventional Chemotherapy and BMT

The toxicity profile of rituximab is clearly superior to the profiles of both conventional chemotherapy and autologous bone marrow transplantation (BMT). Treatment-related toxicity with oral alkylating agents is typically modest, but myelosuppression can occur.[25,26] Grade 3 or 4 hematologic toxicities have developed in about 15% of patients treated with the purine nucleoside analogs fludarabine (Fludara) or cladribine (2-CdA [Leustatin]), and there is a 10% to 20% or higher rate of infections (including opportunistic ones), some of which have proven fatal.[27-29]

Combination chemotherapy typically produces even higher rates of myelosuppression and infection.[25,30-33] Autologous marrow transplant results in major myelosuppression in virtually 100% of recipients and is associated with a definite risk of treatment-related mortality (approximately 5% in most trials).[34]

Put in this perspective, the toxicity of rituximab is minimal. In addition, the brevity of treatment (four doses over 22 days) and the outpatient schedule are extremely appealing.

Ongoing Trials and Future Directions

Ongoing studies are exploring the efficacy of rituximab as retreatment, in other categories of B-cell malignancy besides low-grade or follicular lymphoma, and in other dose schedules besides the weekly × 4 schedule. In addition, based on the modest toxicity of rituximab, as well as its novel mechanism of action, nonoverlapping toxicity with most chemotherapeutic agents, and potential synergy with chemotherapy, the integration of rituximab with other antilymphoma therapies is another focus of current research.

Retreatment

Based on the lack of immunogenicity of rituximab, it is anticipated that retreatment will be feasible. In a preliminary analysis of retreatment of patients who had previously responded to rituximab, 40% showed responses when retreated with the same weekly × 4 schedule to which they had previously responded.[35]. Treatment of patients with bulky nodal disease with the weekly × 4 schedule is also being assessed. There is concern, with this or any antibody, about the penetration of antibody into mass lesions in such patients.

Other Schedules

A weekly × 8 schedule is being explored in both the United States and Europe.[19,20] Since infusion-related adverse events lead to slowing of the infusion only for the first dose in most patients, the European trial of the weekly × 8 schedule is exploring an escalation of the dose to 500 mg/m² for weeks 2 through 8. Preliminary data from this trial indicate that the escalated dose has a safety profile similar to that seen with the standard 375-mg/m² dose.

Other B-cell Malignancies

The efficacy of rituximab as a single agent on the weekly × 4 schedule is being tested in Europe in patients with mantle cell lymphoma, Waldenström’s macroglobulinemia, and lymphoplasmacytoid lymphoma. The European trial of the weekly × 8 schedule is being conducted in patients with intermediat- grade lymphomas, including mantle cell lymphoma; a 31% response rate has been observed.[20] Also, US trials of CHOP plus rituximab are being performed in previously untreated patients with intermediate-grade and mantle cell lymphoma.

Early results indicate that single-agent rituximab has efficacy in mantle cell lymphoma (3 responses in 11 patients) and large cell lymphoma.[20] Mantle cell lymphoma is a particularly frustrating entity for which new treatment approaches are needed.

In Combination With Other Agents

Ongoing studies of rituximab in combination with other antitumor agents include a trial of rituximab plus interferon-alfa (Intron A, Roferon-A) in low-grade lymphoma,[36] and a trial of CHOP plus rituximab in intermediate-grade lymphoma.[37] Additional trials of chemotherapy plus rituximab are planned. For example, investigators at UT M. D. Anderson plan to explore the FND (fludarabine, Novantrone, and dexamethasone) regimen[32] given with either concurrent or adjuvant rituximab in patients with previously untreated stage IV indolent lymphoma.

Conclusions

The approval and availability of rituximab are major steps in the treatment of B-cell lymphoma. Ongoing and future studies should provide further insights into how best to use rituximab, both alone and in combination with other antitumor drugs. The information provided by these studies should pave the way for future MoAb therapies for hematologic and other neoplasms.

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