Monoclonal Antibody Therapy in Lymphoid Malignancies. The Sarah Cannon Cancer Center, Centennial Medical Center, Nashville, Tennessee, USA

Transcription

1 The Oncologist Promising New Drugs and Combinations Monoclonal Antibody Therapy in Lymphoid Malignancies JOHN D. HAINSWORTH The Sarah Cannon Cancer Center, Centennial Medical Center, Nashville, Tennessee, USA ABSTRACT Key Words. Indolent lymphoma Large-cell lymphoma Monoclonal antibodies Rituximab Radioimmunoconjugates The concept of targeted therapy for patients with advanced cancer has intrigued researchers for many years. The lymphoid malignancies are particularly good candidates for this therapeutic approach, due to the identification of multiple lymphocyte-specific antigens. The recent introduction of rituximab marks the beginning of a new era in the treatment of lymphoid malignancies. Rituximab is one of the most active single agents for patients with refractory indolent lymphoma, producing response rates of approximately 50%, with low toxicity and a brief duration of treatment. Additional uses of rituximab are being evaluated in ongoing clinical trials, and are briefly reviewed. As a first-line agent, responses of approximately 70% are produced in patients with indolent lymphoma, with minimal toxicity. A substantial percentage of patients can be successfully retreated with rituximab, with second remission durations longer than the first remission (14-16 months versus 12 months). Multiple The concept of targeted therapy for cancer has intrigued researchers for many years. However, it was not until the development of the hybridoma technology for producing monoclonal antibodies to specific targets that this type of cancer treatment became a real possibility. Even with the ability to produce monoclonal antibodies, numerous clinical problems have delayed their introduction into clinical medicine (Table 1) [1]. These problems have centered around identification of tumor-specific antigens, safe delivery of the antibody and/or attached toxin, and the induction of cancer cell death after antibody attachment to the target antigen. combination regimens using rituximab plus chemotherapy are also being evaluated. Although the role of these combined approaches is incompletely defined, high complete response rates can be obtained, with a higher rate of molecular complete remission (i.e., eradication of detectable bcl-2 rearrangements) than has been observed in patients receiving chemotherapy alone. Rituximab is also being evaluated in other CD20 + lymphoid malignancies including large-cell lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom s macroglobulinemia. Within the next 12 months, several additional monoclonal antibodies will be available for the treatment of lymphoid malignancies. These include the radioimmunoconjugates tositumomab (Bexxar) and ibritumomab (Zevalin), as well as Campath-1H (anti-cd52) monoclonal antibody. Early clinical data with each of these agents are also briefly reviewed. The Oncologist 2000;5: Table 1. Obstacles to the development of successful therapeutic monoclonal antibodies Identification of tumor-specific antigens Varying expression/density of antigen on tumor cells Reversible binding of antibody to antigen Internalization of antigen-antibody complex Poor access of antibody to bulky or hypoxic tumors Rapid clearance of antibody by circulating tumor cells Inability to produce cell death after antibody binding Toxicity from host humoral response (HAMA, HACA) Correspondence: John D. Hainsworth, M.D., The Sarah Cannon Cancer Center, th Avenue North, Suite 412, Nashville, Tennessee 37203, USA. Telephone: ; Fax: ; jhainsworth@tnonc.com Received June 29, 2000; accepted for publication July 27, AlphaMed Press /2000/$5.00/0 The Oncologist 2000;5:

2 377 Monoclonal Antibodies for NHL The identification of several lymphocyte-specific surface antigens has improved the possibility of developing effective and relatively specific targeted therapy for non-hodgkin s lymphoma (NHL). The pioneering work of Miller et al. in the early 1980s demonstrated the therapeutic efficacy of monoclonal antibodies raised against the unique surface immunoglobulin produced by a specific clonal B-cell proliferation [2]. However, the development of a unique ( antiidiotype ) antibody for each patient was too cumbersome and expensive to be clinically feasible. In addition, most responses were temporary, in part due to internalization of the target antigen by the malignant lymphocytes. Nevertheless, these early experiments provided proof that targeted monoclonal antibody therapy was potentially effective in the treatment of lymphoma, and led to the development of antibodies to additional lymphocyte-specific antigens. After an interval of almost 20 years, therapeutic monoclonal antibody therapy for lymphoma has become a reality, with the introduction of rituximab. Several additional antibodies are in late stages of clinical development and seemed poised to radically alter the therapy of this disease during the next 10 years. In this review, current and developing data with rituximab are summarized, and recommendations for its current and possible future uses in the treatment of lymphoma are given. In addition, other monoclonals that are likely to be available within the next twelve months are briefly reviewed. CURRENT TREATMENT OF NHL For purposes of determining therapy, lymphomas have traditionally been separated into indolent (low-grade) and aggressive (intermediate, high-grade) subtypes. The paradigms for treatment of these two lymphoma subgroups, as well as the outcome of treatment, differ markedly. Most patients with indolent lymphoma remain incurable, although many have prolonged survival. Most patients receive treatment at the time symptoms develop; since treatments are palliative, treatment-related toxicity as well as efficacy are of major importance. Most patients receive intermittent treatment with a series of different systemic agents during their course of this disease. Remission duration decreases with each retreatment. Intensive combination chemotherapy produces higher complete remission (CR) rates, but has not consistently been associated with improved survival. Therefore, in developing an active new drug for the treatment of indolent NHL, pertinent questions include the following: Where should the drug be positioned in the sequential treatment that these patients receive? Should the drug be used as a single agent, or in combination with other active agents? Is curative therapy possible when the new drug is added to the most effective existing treatment? In contrast to this strategy of sequential treatment, the treatment of aggressive lymphoma involves the use of combination chemotherapy, initiated at the time of diagnosis. First-line combination chemotherapy is curative in 30%-40% of such patients; another group of patients (approximately 15%-20%) can be cured with high-dose therapy at the time of first relapse. The value of any new drug is therefore determined by its ability to improve survival and increase the cure rate. Although multiple cytotoxic agents introduced during the last 20 years have single-agent activity against aggressive NHL, none have improved the result of first-line treatment when compared to the traditional CHOP regimen. The contribution of monoclonal antibodies to the first-line therapy of aggressive NHL will need to be assessed in randomized trials in which standard CHOP chemotherapy is compared to new treatments. RITUXIMAB Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, is the first therapeutic monoclonal antibody available for the treatment of NHL, and has already been widely incorporated into clinical use. The CD20 antigen (also the target for the investigational radioimmunoconjugates tositumomab and ibritumomab) is an excellent target because it is widely expressed on B lymphocytes and does not shed, modulate, or internalize. After binding to the CD20 antigen, the Fc portion of the rituximab antibody binds to Fc receptors on effector cells (e.g., cytotoxic T cells, natural killer cells) and triggers a lytic reaction leading to cell death. The antibody also leads to activation of the complement cascade, resulting in cell lysis. In addition to these mechanisms, which apply to other monoclonal antibodies, targeting the CD20 receptor probably adds a third mechanism of cell death. Although the normal function of this antigen is not completely understood, it is probably involved in regulation of calcium channel activity in the cell membrane. Binding with the anti-cd20 antibody leads to high intracellular calcium levels, which keeps the cell in the G 1 phase, and results in maturation arrest and apoptosis. This third mechanism of action probably best explains the synergism seen with anti-cd20 antibody and chemotherapeutic agents. Initial clinical trials with rituximab evaluated its efficacy in patients with refractory low-grade B-cell lymphoma, and the large majority of clinical use of rituximab remains in this group of patients. However, rituximab has several other potential roles in the treatment of low-grade lymphomas, including first-line therapy and concurrent administration with chemotherapy. Since the CD20 antigen is expressed by most B-cell lymphomas, rituximab has potential utility in several additional diseases including large-cell lymphoma,

3 Hainsworth 378 mantle cell lymphoma, MALToma, chronic lymphocytic leukemia (CLL), and Waldenstrom s macroglobulinemia. INDOLENT LYMPHOMA Single-Agent Rituximab in Refractory Disease Initial phase I and II trials with rituximab targeted patients with refractory low-grade lymphoma [3-5]. Phase II trials used a dose of 375 mg/m 2 administered weekly for four consecutive weeks; however, the length of treatment was empiric, and a maximum-tolerated dose of rituximab has not been identified. In the pivotal phase II trial, rituximab produced a 48% overall response rate (6% complete responses) in a group of 166 patients, with a median response duration of 12 months [5]. In this trial, patients had already received a median of three previous chemotherapy regimens. Patients with follicular center cell lymphoma had a substantially higher response rate (60%) than did patients with small lymphocytic (CLLtype) lymphoma (13%). Treatment-related toxicity was generally mild and occurred most often with the first infusion of rituximab. Infusion-related side effects included fever, chills, myalgias, and more rarely, hypotension, cardiac arrhythmias, and anaphylaxis. In spite of the well-documented depletion of mature B lymphocytes following treatment with rituximab, bacterial and opportunistic infections have not been common problems following therapy. The high response rate as well as the 12-month duration of response defined rituximab as one of the most active single agents in the treatment of indolent lymphoma and led to rapid Food and Drug Administration (FDA) approval. On this basis, rituximab should be considered an integral part of treatment for patients with refractory indolent follicular center cell lymphoma. Tumor Lysis Syndrome With increased clinical experience, a unique and uncommon tumor lysis syndrome has been recognized with rituximab and is outlined in Table 2 [6]. Patients at risk for this syndrome have a high number of circulating malignant lymphocytes. Symptoms occur precipitously during the first rituximab infusion, and include severe infusion-related reactions (rigors, fever, bronchospasm, hypoxemia), thrombocytopenia, rapidly decreasing circulating lymphocyte count, and mild electrolyte evidence of tumor lysis. With the appropriate supportive management, the syndrome is completely reversible. Although incompletely defined, this syndrome is probably produced by rituximab-induced lymphocyte agglutination in the lungs, liver, and spleen. Initial rapid cytokine release is followed by a more gradual destruction of lymphocytes by immune effector cells, producing the mild laboratory lysis abnormalities [6]. Some of these patients can successfully receive rituximab on the day following the initial reaction, particularly if the circulating lymphocyte count has been lowered. Table 2 summarizes this syndrome and its suggested management. Rituximab Retreatment Patients who respond to an initial four-week course of rituximab can frequently benefit by retreatment with rituximab at the time of progression. In a group of 39 patients with refractory lymphoma who responded initially, the response rate to a repeat four-week course of rituximab was 40% [7]. In addition, the median duration of second response was 16 months, slightly longer than the first response to rituximab. Although loss of the CD20 antigen has been documented in some lymphomas becoming resistant to rituximab, most lymphomas remain CD20 + [8]. The mechanism of rituximab resistance in these patients is unclear. Since repeated courses of rituximab are well tolerated and not associated with any cumulative toxicities, retreatment until the time of resistance seems a reasonable strategy in patients who continue to respond. Extended Courses of Rituximab The standard four-week course of rituximab was empirically derived, and several investigators have used longer courses, usually eight weeks. Several observations have suggested that longer courses may benefit some patients. First, the 40% response rate in retreated patients suggests that these patients retain sensitivity to rituximab, and therefore remission Table 2. Rituximab-associated acute tumor lysis syndrome Risk factors High circulating lymphocyte count Large tumor burden Onset First rituximab dose, usually during first 30 min Symptoms Severe rigors, fever Bronchospasm, hypoxemia Thrombocytopenia Mild lysis-related laboratory abnormalities (hyperuricemia, hypercalcemia, elevated LDH) Treatment Immediate discontinuation of rituximab infusion Supportive care (oxygen, i.v. fluids) Meperidine mg i.v. for rigors Restart rituximab infusion at 25 cc/h if symptoms resolve rapidly (otherwise, administer the remainder of the rituximab dose on the following day).

4 379 Monoclonal Antibodies for NHL may be prolonged by a longer initial course. Second, serum rituximab levels increase with consecutive weekly doses, and are higher in patients who have a response when compared to nonresponders. Patients with large tumor bulk or large numbers of circulating malignant lymphocytes usually achieve lower serum rituximab levels with a standard four-week schedule [9]. In these patients, more prolonged courses may be necessary to deal with increased tumor bulk. In a group of 37 patients with refractory low-grade lymphoma who received rituximab 375 mg/m 2 for eight consecutive weeks, the overall response rate was 60% (14% CR), and the median response duration was more than 13 months [10]. These results are suggestive, but not definitely superior to other phase II trials using a four-week schedule. Additional information regarding the treatment of poor prognosis subsets (i.e., large tumor bulk, high circulating lymphocyte count) with an extended course of rituximab will soon be available. First-Line Therapy A retrospective analysis of the rituximab pivotal trial suggested higher response rates in patients who had received fewer previous chemotherapy regimens. Overall response rate in patients treated with only one previous chemotherapy regimen was 57%, versus 38% in patients who had received three or more regimens [5]. Preliminary information is now available regarding the results of first-line treatment with rituximab in patients with low-grade NHL. We treated a group of 41 patients with stage II-IV, previously untreated low-grade lymphoma with a standard four-week schedule of rituximab [11]. Following initial treatment, patients with objective response or stable disease received four-week maintenance courses of rituximab at six-month intervals. When patients were evaluated two weeks after completing the first course of rituximab, the response rate was 54%; an additional 36% of patients had stable disease. With additional follow-up and scheduled retreatment with rituximab, the overall response rate subsequently improved to 72%, with 18% CR. At the time of our preliminary report, the median duration of response has not been reached; progression-free survival at one year was 77%. Similar results were reported by Solal-Celigny et al. in a group of 50 patients with follicular NHL and low tumor burden (tumor masses <7 cm, no B symptoms, normal lactic dehydrogenase [LDH] level, no organ compression) [12]. In this group, 71% achieved objective responses, with no serious toxicity. In addition, 17 of 30 patients (57%) with initial bcl-2 rearrangements detected by polymerase chain reaction (PCR) analysis had clearing of this abnormality following rituximab therapy [13]. Follow-up data have not yet been reported. Further follow-up is necessary to interpret the results of these trials and compare the results of first-line treatment with rituximab to the therapeutic outcome using standard chemotherapeutic approaches. However, the response rate and duration to first-line rituximab therapy appear superior to single-agent therapy with standard chemotherapeutic agents, with a shorter, less toxic treatment course. In addition, the response rate to rituximab may be higher when the drug is used earlier in therapy. At present, the use of rituximab as first- or second-line therapy is probably the optimal treatment for elderly or medically compromised patients. Firstline treatment with rituximab may also provide a reasonable alternative to observation alone in patients who are uncomfortable with this strategy. Treatment of Small Lymphocytic (CLL-type) Lymphoma The efficacy of rituximab in the treatment of patients with small lymphocytic lymphoma differs from its efficacy in follicular lymphoma. In the pivotal trial, only 4 of 30 patients (13%) with refractory small lymphocytic subtype had objective response to treatment [5]. Although the reason for this difference is not definitively explained, most patients with small lymphocytic lymphoma (and with classic CLL) express lower density CD20 antigen on their malignant lymphocytes, possibly decreasing rituximab efficacy [14]. Several strategies are currently being investigated in this group of patients, including increased frequency of rituximab dosing and the use of higher doses. In a phase I/II trial at M.D. Anderson, weekly rituximab doses were escalated to 2,250 mg/m 2 in patients with previously treated CLL. The response rate in this patient group was 40% [15]. An alternate strategy has been a thrice-weekly dosing schedule; preliminary results indicate good patient tolerance and a response rate of approximately 50% [16]. Since both of these approaches involve considerable expense, routine use should await additional information regarding response duration and efficacy compared to standard approaches. Limited data also suggest that first-line treatment with rituximab may yield higher response rates in patients with small lymphocytic lymphoma, when compared to previously reported response rates in refractory patients. In our first-line trial, 14 of 22 patients (64%) with this subtype responded, compared to a 58% response rate in patients with follicular lymphoma [17]. In a follow-up trial, we are evaluating the effects of first-line rituximab (standard dose/schedule + maintenance courses at six-month intervals) in patients with classic CLL or small lymphocytic lymphoma, and correlating the density of CD20 antigen expression with response to therapy. Concurrent Rituximab and Chemotherapy A large number of ongoing trials are evaluating the feasibility and efficacy of administering rituximab concurrently with various combination chemotherapy regimens. This concept is appealing not only because of the unique mechanism

5 Hainsworth 380 Table 3. Rituximab + CHOP for patients with indolent NHL summary of treatment results [19] Treatment schedule: Week R R CHOP CHOP R CHOP CHOP R CHOP CHOP R R Doses: Rituximab (R) 375 mg/m 2 i.v. (doses 2, 3, and 4 given two days prior to CHOP) Cyclophosphamide (C) 750 mg/m 2 i.v. D1 Doxorubicin (H) 50 mg/m 2 i.v. D1 Vincristine (O) 1.4 mg/m 2 i.v. D1 Prednisone (P) 100 mg/m 2 PO D of 40 patients (95%) had objective response, with 55% CR rate Median time-to-progression > 40 months Toxicity similar to CHOP alone of action of rituximab, but also based on preclinical data demonstrating that lymphoma cell lines are sensitized to cytotoxic drugs following exposure to rituximab [18]. Initial clinical trials have focused on the concurrent use of rituximab with CHOP chemotherapy. Concomitant administration of rituximab with the CHOP regimen has been feasible in all trials, with no unexpected or synergistic toxicities observed [19, 20]. In most trials to date, rituximab has been empirically administered two days prior to CHOP chemotherapy, based on preclinical observations of rituximab-induced sensitization to chemotherapy. Although no randomized trials comparing concurrent rituximab/chemotherapy regimens with standard chemotherapy have yet been completed, data from phase II trials are encouraging. The trial with the longest follow-up was reported by Czuczman et al., and evaluated concurrent CHOP chemotherapy and rituximab in patients with low-grade B-cell lymphoma [19]. The treatment schedule and results of this trial are summarized in Table 3. Two doses of weekly rituximab were given prior to the administration of chemotherapy, and then rituximab was continued intermittently throughout the six courses of CHOP. Forty patients (78% previously untreated) entered this trial, and 55% achieved a complete response following therapy. Median duration of response has not been reached at 40 months, and follow-up is ongoing. In this trial, limited information was available regarding conversion of bcl-2 rearrangements; seven of eight patients who achieved a clinical CR also had clearing of the bcl-2 rearrangement by PCR analysis. Therefore, the long remission duration and observation of molecular CR (rarely seen with CHOP chemotherapy alone) are encouraging for the increased efficacy of this novel combination therapy. Ongoing randomized, phase III trials are comparing standard chemotherapy (CHOP or CVP) to chemotherapy + rituximab in patients with previously untreated indolent NHL. In addition, phase II trials are evaluating concurrent treatment with rituximab and several other commonly used chemotherapy regimens, including CVP, chlorambucil, fludarabine, and fludarabine-based combinations [21, 22]. Summary and Current Recommendations in Indolent Lymphoma Rituximab is now well established as one of the most active single agents in the treatment of indolent NHL. It can be administered to most patients with minimal toxicity, and the short duration of therapy is also very attractive. All patients with indolent lymphoma who require treatment should therefore receive a trial of rituximab at some point during their clinical course. The response rate to singleagent rituximab is somewhat higher when the drug is administered to patients with less previous treatment. Therefore, use of this drug as second- or third-line therapy is preferable to use as salvage therapy for patients who are highly refractory to chemotherapy. In addition, a substantial percentage of patients who benefit from their first rituximab treatment (i.e., objective response or stable disease for >9 months) will have repeat responses to retreatment with another four-week course. This treatment strategy can result in control of disease for long periods, with mild acute toxicity and no cumulative effects on bone marrow function. For some patients, first-line therapy with rituximab may be the best clinical management. Patients who are symptomatic and very elderly, or have other severe medical problems, will probably tolerate rituximab better than other chemotherapeutic options. In addition, patients who are asymptomatic but strongly desire therapy rather than observation may also be good candidates for initial rituximab therapy, which will often allow postponement of exposure to chemotherapy and its acute and chronic side effects. Further follow-up of first-line rituximab clinical trials is necessary before this approach can be

6 381 Monoclonal Antibodies for NHL definitively recommended for all patients. Similarly, the role of concurrent rituximab plus combination chemotherapy requires further evaluation, and a definitive answer awaits the completion of randomized trials. However, based on initial observations of high complete response rates and long response durations, this combination approach seems reasonable in patients with high-risk situations, who require initial treatment with combination chemotherapy rather than with sequential single agents. INTERMEDIATE GRADE B-CELL LYMPHOMA Large-cell lymphomas of B-cell derivation also express the CD20 surface antigen, and have been shown to respond to treatment with rituximab. In a phase II trial of 54 patients, most of whom had relapsed or progressed after one previous chemotherapy regimen, Coiffier et al. achieved a 32% overall response rate with single-agent rituximab [23]. The median duration of response was eight months. Phase II trials with concurrent rituximab and CHOP chemotherapy have also been completed. Vose et al. reported a 97% overall response rate, with 73% complete response following treatment with CHOP plus rituximab; long-term follow-up from that trial is not yet available [20]. Randomized phase III trials comparing standard CHOP chemotherapy to combined CHOP plus rituximab are in progress. MANTLE CELL LYMPHOMA Mantle cell lymphoma, comprising approximately 5% of B-cell lymphomas, has emerged as a distinct clinical entity with relatively poor prognosis. Although incurable with standard chemotherapy, survival is substantially worse than the other indolent lymphoma histologies, usually measuring between three and five years [24, 25]. Most mantle cell lymphomas express CD20 antigen, and phase II studies have documented the activity of rituximab in both previously treated and untreated patients with this disorder [26, 27]. Response rates to single-agent rituximab have ranged from 22% to 37%, with response durations of approximately eight months. Rituximab is therefore a reasonable choice for patients with refractory mantle cell lymphoma. Preliminary results of a phase II trial using concurrent rituximab plus CHOP chemotherapy in patients with newly diagnosed mantle cell lymphoma have recently been reported [28]. The initial response rate was high (48% complete responses), and 11 of 23 patients with bcl-1 rearrangements at the start of treatment had clearing of this abnormality. However, many patients (including some with molecular complete responses) have already relapsed, with median progression-free survival of 16 months. The benefit of using rituimab in addition to CHOP as initial treatment for mantle cell lymphoma is therefore not clear at this time. WALDENSTROM S MACROGLOBULINEMIA Waldenstrom s macroglobulinemia, a rare indolent lymphoma subtype, often causes clinical symptoms related to production of monoclonal IgM. Most of these lymphomas are strongly CD20 +, and high response rates to rituximab have been reported, even in refractory patients [29, 30]. In a recent report, 25 of 28 patients (89%) had >25% decreases in IgM levels, and most patients had improvements in anemia and thrombocytopenia [30]. Mean time to treatment failure was seven months (range 3-20+). Rituximab is therefore one of the most active single agents in this rare lymphoma subtype and provides an additional treatment option. INVESTIGATIONAL MONOCLONAL ANTIBODIES AND RADIOIMMUNOCONJUGATES FOR THE TREATMENT OF NHL A large number of novel monoclonal antibodies, targeting a variety of surface antigens, are currently in development for the treatment of NHL. Several of these will likely receive FDA approval during the next 12 months and are briefly reviewed. Tositumomab ( 131 I-anti-CD20; Bexxar) Tositumomab is a murine IgG2a antibody conjugated with I 131 as a radiation source. Although this radioimmunoconjugate targets CD20, the same antigen as rituximab, the I 131 provides an additional mechanism of cytotoxicity. Initial studies with this antibody involved administration of myeloablative doses, followed by hematopoietic support [31]. More recently, a method of giving bone marrow-sparing doses of tositumomab has been developed, and the standard treatment regimen is diagrammed in Table 4. Early Table I-tositumomab treatment schema Day 0 Begin Lugol s solution or oral potassium iodide solution Day 1 Dosimetric dose 450 mg unlabeled anti-b1 antibody, followed by 5 mici 131 I-tositumomab Measurement of whole body counts and calculation of therapeutic dose Day 7 Therapeutic dose 450 mg unlabeled anti-b1 antibody, followed by calculated therapeutic-dose 131 I-tositumomab Days 8-21 Continue Lugol s solution or oral potassium iodide solution

7 Hainsworth 382 phase II trials containing small numbers of patients documented high overall response rates, with complete response rates of >40% following a single dose of tositumomab [32, 33]. In a subsequent multicenter phase II trial containing 47 patients with refractory indolent NHL, the overall response rate remained high (57%), with 32% complete response [34]. In a recent report, first-line treatment with tositumomab in 76 patients with indolent lymphoma resulted in overall response rates of 97%, with 63% complete response [35]. Actuarial three-year progression-free survival was 68%. The most common toxicity with tositumomab has been hematologic with 11% of previously treated patients developing grade IV thrombocytopenia and/or neutropenia. Only 5% of previously untreated patients had grade 4 neutropenia. Onset of myelosuppression is usually delayed, with a nadir at days. Patients with more than 25% of bone marrow involvement with lymphoma have been routinely excluded from trials of tositumomab. The potential of this murine antibody to elicit human antimouse antibody (HAMA) responses, which could interfere with subsequent antibody therapy, is of some concern. Forty-nine of 76 previously untreated patients (65%) developed HAMA after a single dose of tositumomab [35]. Similarly, bone marrow tolerance of other chemotherapy in combination with or following tositumomab has not been completely evaluated. The comparative efficacy of this agent versus rituximab is also unknown. 90 Y Ibritumomab Tiuxetan (IDEC-Y2B8; Zevalin) IDEC-Y2B8 is a murine monoclonal antibody that targets the CD20 surface antigen and is attached to yttrium-90 as a radiation source. Compared to I 131, yttrium-90 has a shorter half-life that can be used more easily in the outpatient setting. In addition, the radiation penetration is greater than with I 131 (5-10 mm versus 1 mm), providing theoretic advantages in the treatment of bulky lymphomas. Initial phase II trials with this agent targeted patients with refractory indolent lymphoma, and results are similar to those obtained with tositumomab (60%-70% overall response rate; 25%-30% complete response rate) [36]. Preliminary results from a prospective randomized trial comparing treatment with IDEC-Y2B8 versus rituximab in patients with relapsed or refractory low-grade follicular lymphomas are now available [37]. The initial response rates in the 143 patients randomized were 80% for IDEC-Y2B8 versus 44% for rituximab. The response rate to IDEC-Y2B8 was similar for chemotherapy-sensitive versus refractory patients (81% versus 77%); however, rituximab response rates were lower in chemotherapy-refractory patients versus the chemotherapysensitive subgroup (32% versus 59%). Time to progression and survival data have not yet been published. Toxicity observed with IDEC-Y2B8 is similar to that recorded with tositumomab, and its potential for combination with chemotherapy has not yet been investigated. Campath-1H Campath-1H is a humanized anti-cd52 monoclonal antibody that binds to the cell membrane in more than 95% of all normal human circulating lymphocytes, as well as to most B- cell and T-cell lymphomas [38]. Phase II trials with this agent have been completed in patients with refractory CLL and lowgrade B-cell lymphomas [39-41]. In a recently reported multicenter phase II trial, 92 patients with CLL refractory to fludarabine received Campath-1H antibody (30 mg 3 weekly by 2-h i.v. infusion) [41]. Responses occurred in 33% of patients (2% complete response); with short follow-up, median time-to-progression was projected to be >9 months. Blood and marrow involvement responded better than bulky tumor involving lymph nodes or spleen. Campath-1H has shown less activity in patients with previously treated indolent lymphomas. In a multicenter study, 6 of 50 patients (14%) with indolent B-cell lymphoma achieved partial remission [42]. Four of eight patients with mycosis fungoides responded. As in CLL, activity seemed greater in the blood and bone marrow than in nodal disease. Toxicity with Campath-1H is more pronounced than with rituximab or the radioimmunoconjugates. Grade IV neutropenia and/or thrombocytopenia occurred in approximately 25% of patients, and all patients had long-lasting lymphopenia. Acute infusion-related side effects were seen in most patients, but were severe in a minority. Opportunistic infections (herpes simplex reactivation, oral candidiasis, Pneumocystis carinii pneumonia), probably related in part to the long-lasting lymphopenia produced by Campath-1H, have been reported in a small percentage of patients in all studies. SUMMARY AND CONCLUSIONS The use of monoclonal antibodies as targeted therapy in the treatment of lymphoid malignancies has now become a clinical reality, and will result in major therapeutic improvements during the next 10 years. Table 5 summarizes the clinical and pharmacologic aspects of the four monoclonal antibodies that are currently available, or will be available in the near future. Already, rituximab has become an integral component of the treatment of indolent lymphomas based on its high level of activity, favorable toxicity profile, and convenient schedule of administration. In the near future, the indications for this drug will expand as its optimum use is defined in indolent lymphoma (e.g., previously untreated patients, chemotherapy/rituximab combination) as well as in other CD20-expressing lymphoid neoplasms. Several additional active agents will be clinically available shortly; their optimum use will also require further exploration in well-designed clinical trials. ACKNOWLEDGMENT Grant support for clinical research provided by Genentech, Idec, and SmithKline Beecham.

8 383 Monoclonal Antibodies for NHL Table 5. Comparison of clinical and pharmacologic aspects of monoclonal antibodies for lymphoid malignancies Rituximab 131 I - Tositumomab 90 Y - Ibritumomab (Rituxan) (Bexxar) (Zevalin) Campath -1H Target antigen CD20 CD20 CD20 CD52 Mechanism of action ADCC, CDC, ADCC, CDC, ADCC, CDC, ADCC, CDC apoptosis apoptosis, apoptosis, radiation radiation Schedule of administration 375 mg/m 2 i.v. Single i.v. dose Single i.v. dose i.v. three times weekly 4 weekly Toxicity Infusion-related Infusion-related, Infusion-related, Infusion-related, (mild) myelosuppression, myelosuppression, myelosuppression, HAMA-reactions HAMA-reactions opportunistic infections Response rate (CR 45%-50% 50%-70% 50%-70% 14% rate), refractory (5%-10%) (25%-35%) (25%-35%) indolent NHL Other B-cell neoplasms Large-cell lymphoma Transformed low- Large-cell lymphoma CLL (33% with documented activity Mantle cell lymphoma grade lymphoma response rate) Waldenstrom s ADCC = antibody dependent cellular cytotoxicity; CDC = complement dependent cytotoxicity REFERENCES 1 Multani PS, Grossbard ML. Monoclonal antibody-based therapies for hematologic malignancies. J Clin Oncol 1998;16: Miller RA, Maloney DG, Warnke R et al. Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. N Engl J Med 1982;306: Maloney DG, Grillo-Lopez AJ, Bodkin DJ et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-hodgkin s lymphoma. J Clin Oncol 1997;15: Maloney DG, Grillo-Lopez AJ, White CA et al. IDEC-C2B8 Rituximab anti-cd-20 monoclonal antibody therapy in patients with relapsed low-grade non-hodgkin s lymphoma. Blood 1997;90: McLaughlin P, Grillo-Lopez JA, White CA et al. IDEC- C2B8 Rituximab chimeric anti-cd20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16: Byrd JC, Waselenko JK, Maneatis TJ et al. Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol 1999;17: Davis TA, Grillo-Lopez AJ, White CA et al. Rituximab anti-cd20 monoclonal antibody therapy in non-hodgkin s lymphoma: safety and efficacy of re-treatment. J Clin Oncol 2000;18: Davis TA, Czerwinski DK, Levy R. Therapy of B-cell lymphoma with anti-cd20 antibodies can result in the loss of CD20 antigen expression. Clin Cancer Res 1999;5: Berinstein NL, Grillo-Lopez AJ, White CA et al. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-hodgkin s lymphoma. Ann Oncol 1998;9: Piro LD, White CA, Grillo-Lopez AJ et al. Extended Rituximab (anti-cd20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-hodgkin s lymphoma. Ann Oncol 1999;10: Hainsworth JD, Burris HA III, Morrissey LH et al. Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-hodgkin lymphoma. Blood 2000;95: Solal-Celigny P, Brousse N, Eftekhari P et al. Rituximab as first-line treatment of follicular lymphoma patients with low tumor burden. Preliminary results of a phase II trial. Ann Oncol 1999;10(suppl 3):130a. 13 Salles G, Colombat P, Soubeyran P et al. Early molecular responses in newly diagnosed follicular lymphoma patients with Rituximab as first-line treatment. The 7th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 2-5, Almasri NM, Duque RE, Iturraspe J et al. Reduced expression of CD20 antigen as a characteristic marker for chronic lymphocytic leukemia. Am J Hematol 1992;40: O Brien SM, Thomas DA, Freireich EJ et al. Rituxan has significant activity in patients with CLL. Blood 1999;94(suppl 1):603a. 16 Murphy TJ, Ling G, Flynn IW et al. Infusion-related events following rituximab therapy in chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL): association with inflammatory cytokines. Blood 1999;94(suppl 1):312a.

9 Hainsworth Hainsworth JD, Burris HA III, Morrissey LH et al. Rituximab as initial therapy for patients with low-grade non-hodgkin s lymphoma. Proc Am Soc Clin Oncol 2000;19:46a. 18 Demidem A, Lam T, Alas S et al. Chimeric anti-cd20 (IDEC- C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother Radiopharm 1997;12: Czuczman MS, Grillo-Lopez AJ, White CA et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-cd20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999;17: Vose JM, Link BK, Grossbard ML. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated intermediate or high-grade non-hodgkin s lymphoma. Ann Oncol 1999;10(suppl 3):195a. 21 Czuczman MS, Jonas C, Stephan M et al. Pilot study of Rituxan in combination with fludarabine chemotherapy in patients with low-grade or follicular non-hodgkin s lymphoma. Proc Am Soc Clin Oncol 1999;18:17a. 22 Garcia-Conde J, Conde E, Sierra J et al. Rituximab (IDEC- C2B8) and CVP chemotherapy in follicular or low-grade B-cell lymphoma after relapse: results after 6 months of follow-up. Proc Am Soc Clin Oncol 2000;109:26a. 23 Coiffier B, Haioun C, Ketterer N et al. Rituximab (anti-cd20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 1998;92: Armitage JO, Weisenberger DD. New approach to classifying non-hodgkin s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin s Lymphoma Classification Project. J Clin Oncol 1998;16: A clinical evaluation of the International Lymphoma Study Group classification of non-hodgkin s lymphoma. The Non- Hodgkin s Lymphoma Classification Project. Blood 1997;89: Foran JM, Rohatiner AZ, Cunningham D et al. European phase II study of rituximab (chimeric anti-cd20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol 2000;18: Ghielmini M, Schmitz SF, Burki K et al. The effect of Rituximab on patients with follicular and mantle-cell lymphoma. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 2000;11(suppl 1): Howard OM, Gribben JG, Neuberg D et al. Rituximab/CHOP induction therapy in newly diagnosed patients with mantle cell lymphoma. Blood 1999;94(suppl 1):631a. 29 Weber DM, Gavino M, Huh Y et al. Phenotype and clinical evidence supports rituximab for Waldenstrom s macroglobulinemia. Blood 1999;94(suppl 1):125a. 30 Treon SP, Agus DB, Link B et al. Rituximab is an active agent in Waldenstrom s macroglobulinemia. Proc Am Soc Clin Oncol 2000;19:6a. 31 Press OW, Eary JF, Appelbaum FR et al. Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support. N Engl J Med 1993;329: Kaminski MS, Zasadny KR, Francis IR et al. Radioimmunotherapy of B-cell lymphoma with [ 131 I] anti-b1 (anti-cd20) antibody. N Engl J Med 1993;329: Kaminski MS, Zasadny KR, Francis IR et al. Iodine-131-anti- B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol 1996;14: Vose JM, Wahl RL, Saleh M et al. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-hodgkin s lymphoma. J Clin Oncol 2000;18: Kaminski MS, Estes J, Tuck M et al. Iodine I-131 tositumomab therapy for previously untreated follicular lymphoma. Proc Am Soc Clin Oncol 2000;19:5a. 36 Witzig TE, White CA, Wiseman GA et al. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20 + B-cell non-hodgkin s lymphoma. J Clin Oncol 1999;17: Witzig TE, Leigh BR, Gordon LI et al. Interim results from a prospective randomized controlled trial comparing Zevalin radioimmunotherapy to rituximab immunotherapy for B-cell non-hodgkin s lymphoma: resistance to prior chemotherapy vs response rate. Proc Am Soc Clin Oncol 2000;19:29a. 38 Salisbury JR, Rapson NT, Codd JD et al. Immunohistochemical analysis of CDw52 antigen expression in non-hodgkin s lymphomas. J Clin Pathol 1994;47: Osterborg A, Dyer MJ, Bunjes D et al. Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European Study Group of CAMPATH- 1H Treatment in Chronic Lymphocytic Leukemia. J Clin Oncol 1997;15: Kennedy B, Rawstron AC, Evans P et al. Campath-1H therapy in 29 patients with refractory CLL: True complete remission is an attainable goal. Blood 1999;94(suppl 1):603a. 41 Keating MJ, Byrd JC, Rai KR et al. Multicenter study of Campath-1H in patients with chronic lymphocytic leukemia refractory to fludarabine. Blood 1999;94(suppl 1):705a. 42 Lundin J, Osterborg A, Brittinger G et al. CAMPATH-1H monoclonal antibody in therapy for previously treated lowgrade non-hodgkin s lymphomas: a phase II multicenter study. European Study Group of CAMPATH-1H Treatment in Low-Grade Non-Hodgkin s Lymphoma. J Clin Oncol 1998;16: