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Therapeutic uses of MAbs directed against CD20
Cytotherapy (2000) Vol. 2, No. 6, 455–462
M Ab Therapy: the use of Anti-CD20 Abs
Therapeutic uses of MAbs directed against CD20 JM Vose University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE, USA Background
Discussion
There are two main classes of Abs directed against the CD20 Ag that have been developed for therapeutic intent: unconjugated and radiolabeled Abs.
Both of these classes of agents have shown promise in clinical trials both alone and in conjunction with conventional chemotherapy or highdose chemotherapy and transplantation. Ongoing research with these agents will provide further evidence of the place in clinical practice for these agents.
The clinical results available from the large clinical trials utilizing both the unconjugated and radiolabelled Abs are summarized in this article.
Rituximab for indolent NHL The two main classes of Abs directed against CD20 that have been developed for therapeutic intent are unconjugated or radiolabeled Abs. The unconjugated MAb that has been the most extensively studied and used clinically is the chimeric anti-CD20 MAb, rituximab (IDEC Pharmaceuticals, San Diego, CA and Genetech, Inc., South San Francisco, CA). This Ab consists of the murine variable regions from the parent 2B8 murine anti-CD20, grafted onto a human IgG1 constant region [1]. The CD20 Ag is an excellent target for immunotherapy since it is found only on mature B cells and not on precursor B cells, which would lead to long-term depletion, and the Ag is not shed, internalized, or modulated to any great extent once Ag–Ab binding has occurred [2]. Apoptosis also appears to be triggered by this Ag–Ab binding motif [3]. The initial Phase I studies of the rituximab anti-CD20 Ab used a bolus of the Ab that was repeated weekly in patients with relapsed CD20 NHL [4]. Multiple Phase II studies enrolled many patients with relapsed indolent CD20 NHL. The patients received a dose of 375 mg/m2 of rituximab weekly for 4 weeks. The pivotal trial showed a 6% complete response (CR) rate and a 42% partial response (PR) rate, for an overall response rate of 48% in this patient population with relapsed indolent NHL [5].
Key Words
monoclonal antibodies, rituximab, Bexxar, Zevalin
The patients had received a median of two prior chemotherapy regimens before being treated with the rituximab. Patients who were tested before and after therapy with rituximab could clear a detectable bcl-2 rearrangement [PCR for the t(14;18)] in the blood and BM compartments; however, some of these patients still had lymph nodes that were detectable [6]. The median time to progression for the responders in the pivotal trial was 13 months (Figure 1). Relapses with a CD20 negative lymResponders (n 75) Evaluable patients (n 151) 100 % Progression free
Methods
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8 10 12 14 16 18 20 22 Months to progression
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Figure 1. Time to treatment failure in the pivotal trial evaluating rituximab for the therapy of relapsed indolent lymphoma [5].
Correspondence to: Julie M. Vose, Professor of Medicine, University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198-7680, USA © 2000 ISHAGE
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phoma have now been reported to occur, although they represent a minority of the relapse cases [7]. Following concerns about penetration of the Ab in large masses, a separate study was performed in patients with bulky disease. In this trial, patients with masses > 10 cm with relapsed or refractory indolent NHL received rituximab for four doses, as per previous trials. The overall response rate in this population was 43%, with a median time to progression of 8 months [8]. More recently, studies of rituximab in previously untreated patients have been evaluated. Gutheil et al. [9] reported on 20 patients with previously untreated indolent lymphoma who received rituximab in a Phase II trial. An overall response rate of 50% was seen in these patients; the follow-up is too short to have yet obtained the median time to relapse. In addition to the single agent use of rituximab for indolent lymphoma, it has been combined with conventional chemotherapy. This combination therapy is based on the in vitro study that demonstrated synergism with the anti-CD20 Ab and chemotherapy in sensitizing previously chemotherapy-resistant cell lines [10]. The first combination study was reported by Czuczman et al. [11], in which 38 patients with indolent lymphoma were treated (31 previously untreated) with rituximab and CHOP chemotherapy (cyclophosphamide, adriamycin, vincristine, and prednisone). The response rate was 100%, including a 66% complete response rate. With no comparison other than a historical one, it is difficult to know if an improvement in the event-free survival will be shown over CHOP alone. A prospective randomized trial is needed. Other combination trials are also currently ongoing with combinations such as Fludara (Berlex, Richmond, CA), CVP (cyclophosphamide, vincristine and prednisone), or FND [fludara (Berlex, Richmond, CA) mitoxantrone (Immunex, Seattle, WA) and dexamethasone].
Rituximab for aggressive NHL With respect to aggressive NHL, only a few trials have been published. Coiffier et al. [12], evaluated 54 patients with relapsed diffuse large-cell or mantle-cell lymphoma who received rituximab for 8 weekly doses. A total of five complete responses and 12 partial responses were observed for an overall response rate of 31%. Another study by Foran et al. [13] evaluated 120 evaluable patients with newly-diagnosed or recurrent mantle-cell lym-
phoma, immunocytoma, and small lymphocytic lymphoma, who received rituximab for 4 weekly infusions. The overall response rate in these patients was 30% (36 out of 120 patients). Ten patients, all with mantle-cell lymphoma achieved a CR with the therapy. With respect to combination therapy for aggressive NHL, the most mature study is a Phase II trial, in which 33 patients with newly-diagnosed diffuse large B-cell NHL received rituximab at 375 mg/m2 on Day 1 of each cycle, followed by CHOP on Day 3 of each cycle. The CR rate in this trial was 61%, with a PR rate of 35%, for an overall response rate of 97% [14]. All patients were able to receive all the cycles of therapy and had a 27% neutropenia rate; < 1% of cycles had thrombocytopenia. With a minimum follow-up of 24 months, 29/33 patients (88%) are alive and free of disease following this therapy. From this encouraging study, a large international Phase III trial is currently underway in this patient population, which randomizes patients to CHOP alone or CHOP rituximab. The combination of CHOP rituximab has also been evaluated in patients with newly-diagnosed mantlecell lymphoma. A report from Dana Farber Cancer Institute evaluated 40 patients who received this regimen [15]. The CR rate was 33%, CR(u) rate was 15% and the PR rate was 49%, for an overall response rate of 98% [15]. The median progression-free survival was 16 months, which was not different from similar historical control patients receiving CHOP alone. Although 11/23 patients with detectable bcl-1 rearrangements became PCR-negative, it did not correlate with the overall response to therapy.
Rituximab combined with high-dose therapy and autologous stem-cell transplantation Rituximab has been demonstrated to have the effect of ‘clearing’ bcl-2 positive cells from the blood and BM, it has therefore been tested recently in the transplant setting as an additive therapy. A few preliminary studies have now been presented in abstract form. A study from Salles et al. [16], evaluated 26 patients treated with rituximab prior to hematopoietic stem-cell harvest. The patients had follicular lymphoma (n = 17), mantle-cell lymphoma (n = 4), marginal zone and small lymphocytic lymphoma (n = 5). The patients received four doses of rituximab at 375 mg/m2. Mobilization was attempted with high-dose cyclophosphamide, etoposide and G-CSF at 4 weeks after
Therapeutic uses of MAbs directed against CD20
the rituximab. Three of the patients failed to mobilize and the rest were transplanted. For those patients with adequate follow-up, 10/11 patients were alive in CR. The PCR analysis in the stem-cell product demonstrated PCR negativity in 6/7 follicular lymphoma patients, while two mantle-cell lymphoma patients and one small lymphocytic lymphoma patient had residual PCR-positive cells. Another trial by Flinn et al. [17], evaluated 40 patients with follicular (n = 19), mantle-cell lymphoma (n = 9), small lymphocytic, marginal zone, or lymphoplasmacytic (n = 12) who were receiving autologous transplantation. The patients received rituximab 375 mg/m2 on Day 1 of mobilization, followed by cyclophosphamide and G-CSF or GM-CSF. The last 15 patients were also CD34 selected. Preliminary results demonstrated that seven of the patients with unmanipulated grafts had a PCR-positive product, however, none of the CD34 selected grafts had a PCR-positive product. The final results from both of these trials are pending. At the University of Nebraska Medical Center, recently we completed a 30 patient trial of rituxamab with the BEAM (BCNU, Etoposide, Ara-C, and Melphalan) transplant regimen. In this study design, the patients received one dose of rituximab prior to the BEAM regimen initiation, at Day 30 and Day 60 post-transplant. The patients in this trial were follicular or mantle-cell lymphoma patients and chemotherapy sensitive. With very early follow-up, 29/30 patients are alive following the transplant — with a CR rate of 88%. There was no additional toxicity of adding the rituximab in this manner and engraftment was identical to patients receiving BEAM alone. Our newest study uses the principals outlined above to take advantage of the rituximab premobilization to clear the blood. Rituximab is given during the regimen to sensitize the lymphoma cells and another four doses are given at 6 months post-transplant when the B cells are starting to recover (Figure 2). Quantitative bcl2 determination will be performed on these patients.
Expanding therapeutic areas for rituximab CLL, Waldenstrom’s macroglobulinemia and hairy cell leukemias More mature lymphocytes, such as those in CLL and the differentiated plasma-cell of multiple myeloma, in general have a lower density of CD20 Ag on the surface, compared with lymphocytes of other types of NHL. Rituxamab has, as a result, been less well-studied in these
Rituximab PSC harvest
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Rituximab BEAM
Day-7
Day Rituximab Rituximab 0
Day 30 6 months posttransplant
Figure 2. Schema for rituximab + BEAM (BCNU, Etoposide, Ara-C, and Melphalan) followed by autologous stem cell transplantation for NHL. malignancies. A Phase I/II study by Byrd et al. [18] evaluated CLL patients with a three times per week dosing schedule of rituximab. Twenty-seven patients were treated during the study. Of the 18 patients evaluable for response, there was a 50% response rate, with most being partial responses. Rituximab has also been combined with other agents for CLL therapy. A study by Keating et al. [19] evaluated 30 patients with previously untreated CLL who received rituximab 375 mg/m2 or 500 mg/m2 on Day 1 given with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 given on Days 2–4 of each cycle. Patients demonstrated a more significant fall in the lymphocyte count as compared with patients who received fludarabine or the combination of fludarabine and cyclophosphamide. It is felt that either combination therapy or augmentation of the CD20 Ag may be extremely important in lymphoma subtypes that are CD20 dim. Waldenstrom’s macroglobulinemia (WM) has also recently been treated with rituximab. In an abstract by Treon et al. [20], 31 patients with WM were treated with single agent rituximab. For the 28 evaluable patients, 28% demonstrated a > 50% reduction in the IgM following the rituximab. Prior to the therapy, 25% of patients required transfusions, compared with only 4% following therapy. Eight patients with refractory or relapsed hairy-cell leukemia were treated with rituximab in a study by MD Anderson; the overall response rate in the five evaluable patients was 80% [21]. Clearly, many B-cell lymphoproliferative disorders may demonstrate an improvement with rituximab therapy either alone, or in combination therapy.
Post-transplant lymphoproliferative disorders (PTLD) PTLD is a serious complication of patients who have received solid organ transplants or BMT. It is believed to
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result from the rapid proliferation of Epstein–Barr (EBV)transformed B cells in the setting of T-cell deficiency that occurs in immunosuppressed patients. The first line of therapy for PTLD is typically a reduction of the immunosuppression. However, this does not work in all patients and further therapy is often necessary. There have now been several pilot studies evaluating the use of rituximab for the therapy of PTLD. In an abstract by Milpied et al. [22] 32 patients with PTLD were enrolled in a study of rituximab at 375 mg/m2 for 4 weekly doses. Twenty-six of these patients were solid organ transplant patients and six were BM transplant patients. The overall response rate was 69%, with 63% of patients having CR and 6% PR. The median time to response was 54 days (range, 11–148 days). Of the responding patients, 59% were still in remission at a median follow-up of 10 months. Several other small studies of the use of rituximab for the treatment of PTLD have now been published in abstract form [23,24]. Since many of these patients are quite ill when the PTLD is diagnosed, a therapeutic intervention with a less toxic agent is ideal in this clinical situation.
Radioimmunotherapy (RIT) is ideal treatment for NHL since the CD20 Ab has shown therapeutic efficacy as a solo agent and because NHL is very radiosensitive. The major anti-lymphoma effect of RIT is mediated by the 131I or the 90Y that is conjugated to the Ab directed against CD20. Both radioconjugates emit β particles. This energy causes lethal DNA damage in the cell that is targeted and to nearby cells that do not necessarily express the target Ag (bystander effect). 90Y emits a particle that has a higher energy, with a longer path length compared with 131I; this allows for a deeper tissue penetration. However, 131I emits γ emissions, which allows for imaging of the patient with localization of the radioimmunoconjugate. There are two anti-CD20 radioimmunoconjugates currently being evaluated for NHL therapy.
Immune-mediated thrombocytopenia
131I
There have also been a few reports of rituximab being used for diseases caused by autoimmune B-cell dysregulation. An example of this is a case report by Rathanatharathorn et al. [25] in which a patient with severe autoimmune thrombocytopenia from chronic GvHD was treated with rituximab. The patient had previously been refractory to i.v. immunoglobulin, steroids, anti-D, vincristine and cyclophosphamide. The patient’s platelet count had a gradual increase starting after the second dose of rituximab and has continued to stay normal at least 200 days following the therapy, despite decreases in the other immunosuppressive agents. The evaluation of rituximab for other autoimmune disorders that are B-cell mediated, such as idiopathic thrombocytopenia purpura (ITP), is also proceeding.
The radioimmunoconjugate that has been most extensively studied is Bexxar. This Ab is an IgG2a murine Ab (Coulter Pharmaceuticals, South San Francisco, CA). With RIT administration, a dosimetric dose is administered with an unlabeled Ab, given prior to the trace 131I-labeled (5 mCi) dose administered to the patient. Over the next week, three whole-body gamma-camera images are taken of the patient, to calculate their exact elimination of the radioactivity in preparation for individualized dose administration. One week after the dosimetric dose is given, the therapeutic dose is administered. Once again, an unlabeled Ab predose is given, followed by the 131I anti-CD20, calculated to administer 75 cGy total body dose (65 cGy for patients with a platelet count 100 000–150 000/µL) (Figure 3). In the initial Phase I/II trial at the University of Michigan, 57 patients with indolent, transformed, or de novo aggressive lymphoma were treated in this manner with Bexxar. Twenty patients had CR and 22 patients demonstrated PR with this one-time therapy [26]. Further long-term follow-up on these patients demonstrated a CR duration median of 20 months, with seven patients remaining in CR for 3–5.7 years (Figure 4)[27].
Up-regulation of the CD20 Ag Some of the subtypes of NHL, such as CLL/SL, have a decreased CD20 Ag density and do not seem to respond as well to rituximab. It is postulated that modulation of the CD20 Ag density might improve this response. Venugopal et al. [25] evaluated several different cytokines and their ability to up-regulate CD20 Ag density. It
appeared that TNF-α, IL-4 and GM-CSF were the three cytokines that up-regulated CD20 the most. In ongoing trials, GM-CSF is being utilized for patients with CD20 dim lymphomas, to try to improve the density prior to rituximab administration.
Radioimmunotherapy
anti-CD20 (Tositumomab, Bexxar)
Therapeutic uses of MAbs directed against CD20
Treatment regimen
SSKI or Lugol’s solution Day-1 given daily through 14 days post-therapeutic dose
Day-0
Dosimetric dose [450 mg Anti-B1 Antibody, 5 mCi 131 I Anti-B1 Antibody (35 mg)]
Day-7
Whole body counts
Therapeutic dose [450 mg Anti-B1 Antibody, dose of 131 I Anti-B1 Antibody to deliver 75 cGy TBD (35 mg)]
Figure 3. Schema for the administration of (Tositumomab).
131I
anti-CD20
Overall survival Progression-free survival
Proportion in category
100 90 80 70 60 50 40 30 20 10 0 0
20 40 60 80 Time from treatment (months)
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Figure 4. Overall and progression-free survival of 59 patients with relapsed or refractory B-cell lymphoma who received dosimetric and/or therapeutic doses of 131I-tositumomab [27]. This original study led to a Phase II dosimetry validation study, in which 45 patients with indolent or transformed lymphoma were treated with 75 cGy total body dose of 131I anti-CD20, as described. In this trial, the overall response rate was 57% and was similar in patients with indolent lymphoma (57%) or transformed lymphoma (60%). The CR rate was 32%, with a median duration of 20 months. The principal toxicity was hematologic, with 11% of patients having a platelet nadir of < 10 000 cells/µL and 4% of the patients having an absolute neutrophil count of < 100µL [28]. The pivotal trial was performed in 60 patients at several centers throughout the USA and in two sites in the UK. The patients in this trial had received a median of
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four prior regimens (range 2–13) and had a median age of 60 years. The overall response to the Bexxar was 65%, compared with 28% for the patients’ last prior chemotherapy (p < 0.001), and the CR rate was 17% for the Ab compared with 3% for the last chemotherapy (p = 0.011) [29]. Similar mild hematologic toxicities were seen in this trial as in the Phase II trial. Kaminski et al. [30] have also evaluated Bexxar in the previously untreated follicular-lymphoma patient population. They evaluated 76 patients given 75cGy total body dose of Bexxar, as previously outlined. The overall response rate was 97%, with 48 (63%) of patients achieving CR with this therapy. The 3 year progression-free survival was 68%. Of the 34 patients who were PCR in the blood or BM prior to therapy, 79% were PCR– after Bcell recovery. There was mild hematologic toxicity, with the median absolute neutrophil nadir being 1300 cell/µL, hemoglobin 12.2 g/dL and platelets 83 000 cell/µL. Bexxar has also been evaluated at much higher doses in the setting of autologous stem-cell transplantation. The Phase I/II study conduced by Press et al. [31] achieved doselimiting toxicity at 27 cGy dose to the healthy organs. In this study, patients only went on to the therapy dose if they had a favorable biodistribution of the tracer dose. Tumor bulk and splenomegaly presented problems with biodistribution in some patients. In a follow-up of the original study, Lui et al. [32] found 45% of the patients progression-free and 60% alive at several years post-therapy. More recently, Press et al. [33] have reported on the preliminary results of a Phase I/II study combining highdose 131I anti CD20, with high-dose cyclophosphamide and etoposide, followed by autologous hematopoietic stem-cell transplantation. This study was an attempt to substitute the radioimmunoconjugate for TBI in the NHL transplant regimen. Thirty-eight patients with relapsed NHL were treated. After a median follow-up of 18 months, 78% of the patients are progression-free. However, with the addition of standard high-dose chemotherapy, transplant complications, such as mucositis and opportunistic infections, became more of a problem. A Phase III trial, comparing this regimen with the standard cyclophosphamide, etoposide and TBI regimen, will be initiated after the Phase II study is complete. Another method of using radioimmunoconjugate therapy with a standard transplant regimen involves combining the lower dose of Bexxar (75cGy total body dose), which can be administered on an outpatient basis,
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with a standard chemotherapy-only transplant regimen. An ongoing trial at the University of Nebraska Medical Center combines Bexxar at 75cGy total body dose with the BEAM regimen (BCNU, Etoposide, Ara-C, and Melphalan), followed by autologous stem-cell transplantation. No results are yet available. 90Y
anti-CD20 (Y2B8)(ibritumomab tiuxetan, Zevalin)
Another radioimmunoconjugate that has undergone much clinical evaluation is 90Y-2B8 (IDEC, San Diego, CA). This compound is composed of a murine immunoglobulin G1 kappa MAb ibrutumomab (IDEC2B8); the linker chelator tiuxetan (isothiocyanateobenzyl MX-DTPA); and the radioisotope 90Y that is securely chelated via the linker. This Ab was initially used with an indium-labeled tracer dose for dosimetry, since Ytrrium does not emit γ emissions and cannot be imaged. Results from the Phase I/II trials showed the MTD to be 0.4 mCi/kg in most patients and 0.3 mCi/kg in patients with mild thrombocytopenia. The overall response rate was 67% (26% CR and 41% PR) in all histologies at all doses and 82% overall response rate in the patients with indolent lymphoma [34]. Ten percent of the patients developed a platelet count < 10 000/µL and 28% of the patients developed an ANC < 500/µL. Zevalin has also been considered for patients who have failed rituximab therapy. Twenty-nine patients with follicular NHL who were refractory to rituximab were treated with Zevalin. The median age of the patients was 54 years and 80% of the patients had bulky disease with > 5 cm lymph nodes. Of the 28 evaluable patients, 13 achieved a PR, giving an overall response rate of 46% [35]. Hematologic toxicity was transient and reversible. Grade IV neutropenia and thrombocytopenia occurred in 28% and 14% of patients, respectively. The median ANC nadir was 800/µL, with a median recovery of 9 days. The median platelet nadir was 34 000/µL, with a median recovery in 14 days. The interim results of a Phase III randomized trial, comparing rituximab with Zevalin was reported by Witzig et al. [36]. The first 90 patients treated to assess the interim analysis demonstrated an overall response rate of 80% for the Zevalin-treated patients, and 44% for the rituximab-treated patients (p < 0.001). The interim analysis was positive and the final results await completion of the full 143-patient analysis of the trial.
Conclusions Immunotherapy against the CD20 Ag has been developed to a great extent over the past few years. The future of MAb therapy will depend on our ability to successfully integrate these therapies with standard- or high-dose chemotherapy and stem-cell transplantation. Additionally, alternative agents with other radioimmunoconjugates, toxins, or chemotherapy labels may be developed in the future to augment our current results.
References 1
Reff ME, Carner K, Chambers KS et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994;83:435–1433. 2 Anderson KD, Bates MP, Slaughenhoupt BL et al. Expression of human B-cell associated antigens on leukemias and lymphoma: a model of human B cell differentiation. Blood 1984;63:1424–33. 3 Maloney DG, Smith B, Appelbaum FR. The anti-tumor effect of monoclonal anti-CD20 antibody (mAb) therapy includes direct anti-proliferative activity and induction of apoptosis in CD20 positive non-Hodgkin’s lymphoma (NHL) cell lines. Blood 1996;84:2535a. 4 Maloney DG, Grillo-Lopez AJ, Bodkin KJ et al. IDECC2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin Oncol 1997;15:3266–74. 5 McLaughlin P, Grillo-Lopez AJ, White CA et al. IDECC2B8 (Rituximab) anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of the patients respond to a four-dose treatment program. J Clin Oncol 1998;16:2825–33. 6 Czuczman M, Grillo-Lopez AJ, McLaughlin P et al. IDECC2B8 clears bcl-2 t(8;14) in patients with relapsed low-grade or follicular lymphoma. Proc Am Assoc Cancer Res 1997; 38:565a. 7 Davis TA, Czerwinski DK, Levy R et al. Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression. Clin Cancer Res 1999;5: 611–15. 8 Davis TA, White CA, Grillo-Lopez AJ et al. Single-agent monoclonal antibody efficacy in bulky non-Hodgkin’s lymphoma: results of a phase II trial of Rituximab. J Clin Oncol 1999;17:1851–7. 9 Gutheil JC, Finucane, Rodriguez R et al. Phase II study of Rituximab (Rituximab) in patients with previously untreated low-grade or follicular non-Hodgkin’s lymphoma. Proc Am Soc Clin Oncol 2000;19:79a. 10 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;12:177–86. 11 Czuczman M, Grillo-Lopez AJ, White CA et al. Treatment of patients with low-grade B-cell lymphoma with the com-
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bination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999;17:268–76. Coiffier B, Haioun C, Ketterer N et al. Rituximab (AntiCD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter Phase II study. Blood 1998;92:1927–32. Foran JM, Rohatiner AZS, 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;18:317–24. Vose JM, Link BK, Grossbard ML et al. Phase II study of Rituximab in combination with CHOP chemotherapy in patients with previously untreated intermediate- or highgrade non-Hodgkin’s lymphoma (NHL). Blood 1999;94:388a. Howard O et al. Rituximab/CHOP induction therapy in newly diagnosed patients with mantle cell lymphoma. Blood 1999;94:2804a. Salles G, Moullet I, Charlot C et al. In vivo purging with Rituximab before autologous peripheral blood progenitor cell (PBPC) transplantation in lymphoma patients (pts). Blood 1999;94:619a. Flinn IW, O’Konnell P, Noga SJ et al. In vivo purging with Rituximab during stem cell transplantation for indolent lymphoma. Blood 1999;94:2833a. Byrd JC, Grever MR, Davis B et al. Phase I/II study of thrice weekly rituximab in chronic lymphocytic leukemia (CLL/SL): A feasible and active regimen. Blood 1999;94:3114a. Keating MJ, O’Brien S, Cortes J et al. Fludarabine and cyclophosphamide combined with Rituximab (FCR) is a potent cytoreductive regimen as initial therapy of chronic lymphocytic leukemia. Proc Am Soc Clin Oncol 2000;19:21a. Treon SP, Agus DB, Link B et al. Rituximab is an active agent in Waldenstrom’s macroglobulinemia. Proc Am Soc Clin Oncol 2000;19:13a. Thomas DA, O’Brien S, Cortes J et al. Pilot study of Rituximab in refractory or relapsed hairy cell leukemia (HCL). Blood 1999;94:3116a. Milpied N, Vasseur B, Antoine C et al. Chimeric anti-CD20 monoclonal antibody (rituximab) in B post-transplant lymphoproliferative disorders (PTLD): a retrospective analysis on 32 patients. Blood 1999;94:631a. Grillo-Lopez AJ, Lynch J, Coiffier B et al. Rituximab therapy of lymphoproliferative disorders in immunosuppressed patients. Ann Oncol 1999;10:662a. Cook RC, Connors J, Gascoyne RD et al. Treatment of post-transplant lymphoproliferative disease with rituximab monoclonal antibody after lung transplantation. Lancet 1999;354:1698–9.
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25 Venugopal P, Sivaraman S, Huang X et al. Cytokine induced upregulation of CD20 antigen expression in chronic lymphocytic leukemia cells by in vitro exposure to cytokines. Blood 1998;92:247a. 26 Kaminski MS, Zasadny KR, Francis IR et al. Iodine-131 antiB1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol 1996;14:1974–81. 27 Kaminski MS, Estes J, Zasadny KR et al. Radioimmunotherapy with iodine 131-I tositumomab for relapsed or refractory B-cell non-Hodgkin’s lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood 2000;96: 1259–66. 28 Vose JM, Wahl RI, Saleh M et al. Multicenter phase II study of iodine 131 Tositumomab for chemotherapy refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphoma. J Clin Oncol 2000;18:1316–23. 29 Kaminski MS, Zelenetz AD, Press O et al. Multicenter, phase III study of iodine-131 Tositumomab (Anti-B1 antibody) for chemotherapy-refractory low-grade or transformed low-grade non-Hodgkin’s lymphoma (NHL). Blood 1998; 92:1296a. 30 Kaminski MS, Estes J, Tuck M et al. Iodine 131 Tositumomab therapy for previously untreated follicular lymphoma. Proc Am Soc Clin Oncol 2000;19:11a. 31 Press O, Eary JF, Appelbaum FR et al. Phase II trial of 131Iodine (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B-cell lymphomas. Lancet 1995;346:336–40. 32 Lui S, Eary J, Martin P et al. Follow-up of relapsed B-cell lymphoma patients treated with Iodine-131 labeled antiCD20 (B1) antibody and autologous stem cell rescue. J Clin Oncol 1998;16:3270–8. 33 Press O, Eary J, Liu S et al. A phase I/II trial of high-dose iodine-131 anti-B1 (anti-CD20) monoclonal antibody, etoposide, cyclophosphamide, and autologous stem-cell transplantation for patients with relapsed B-cell lymphomas. Proc Am Soc Clin Oncol 1998;17:9a. 34 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;17:3793–803. 35 Gordon LI, White CA, Witzig TE et al. Zevalin (IDECY2B8) radioimmunotherapy of Rituximab refractory follicular non-Hodgkin’s lymphoma (NHL): interim results. Blood 1999;94:396a. 36 Witzig TE, White CA, Gordon LI et al. Prospective randomized controlled study of Zevalin (IDEC-Y2B8) radioimmunotherapy compared to Rituximab immunotherapy for B-cell NHL: report of interim results. Blood 1999;94:2805a.
M Ab Therapy: the use of Anti-CD20 Abs
Therapeutic uses of MAbs directed against CD20 JM Vose University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE, USA Background
Discussion
There are two main classes of Abs directed against the CD20 Ag that have been developed for therapeutic intent: unconjugated and radiolabeled Abs.
Both of these classes of agents have shown promise in clinical trials both alone and in conjunction with conventional chemotherapy or highdose chemotherapy and transplantation. Ongoing research with these agents will provide further evidence of the place in clinical practice for these agents.
The clinical results available from the large clinical trials utilizing both the unconjugated and radiolabelled Abs are summarized in this article.
Rituximab for indolent NHL The two main classes of Abs directed against CD20 that have been developed for therapeutic intent are unconjugated or radiolabeled Abs. The unconjugated MAb that has been the most extensively studied and used clinically is the chimeric anti-CD20 MAb, rituximab (IDEC Pharmaceuticals, San Diego, CA and Genetech, Inc., South San Francisco, CA). This Ab consists of the murine variable regions from the parent 2B8 murine anti-CD20, grafted onto a human IgG1 constant region [1]. The CD20 Ag is an excellent target for immunotherapy since it is found only on mature B cells and not on precursor B cells, which would lead to long-term depletion, and the Ag is not shed, internalized, or modulated to any great extent once Ag–Ab binding has occurred [2]. Apoptosis also appears to be triggered by this Ag–Ab binding motif [3]. The initial Phase I studies of the rituximab anti-CD20 Ab used a bolus of the Ab that was repeated weekly in patients with relapsed CD20 NHL [4]. Multiple Phase II studies enrolled many patients with relapsed indolent CD20 NHL. The patients received a dose of 375 mg/m2 of rituximab weekly for 4 weeks. The pivotal trial showed a 6% complete response (CR) rate and a 42% partial response (PR) rate, for an overall response rate of 48% in this patient population with relapsed indolent NHL [5].
Key Words
monoclonal antibodies, rituximab, Bexxar, Zevalin
The patients had received a median of two prior chemotherapy regimens before being treated with the rituximab. Patients who were tested before and after therapy with rituximab could clear a detectable bcl-2 rearrangement [PCR for the t(14;18)] in the blood and BM compartments; however, some of these patients still had lymph nodes that were detectable [6]. The median time to progression for the responders in the pivotal trial was 13 months (Figure 1). Relapses with a CD20 negative lymResponders (n 75) Evaluable patients (n 151) 100 % Progression free
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Figure 1. Time to treatment failure in the pivotal trial evaluating rituximab for the therapy of relapsed indolent lymphoma [5].
Correspondence to: Julie M. Vose, Professor of Medicine, University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198-7680, USA © 2000 ISHAGE
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phoma have now been reported to occur, although they represent a minority of the relapse cases [7]. Following concerns about penetration of the Ab in large masses, a separate study was performed in patients with bulky disease. In this trial, patients with masses > 10 cm with relapsed or refractory indolent NHL received rituximab for four doses, as per previous trials. The overall response rate in this population was 43%, with a median time to progression of 8 months [8]. More recently, studies of rituximab in previously untreated patients have been evaluated. Gutheil et al. [9] reported on 20 patients with previously untreated indolent lymphoma who received rituximab in a Phase II trial. An overall response rate of 50% was seen in these patients; the follow-up is too short to have yet obtained the median time to relapse. In addition to the single agent use of rituximab for indolent lymphoma, it has been combined with conventional chemotherapy. This combination therapy is based on the in vitro study that demonstrated synergism with the anti-CD20 Ab and chemotherapy in sensitizing previously chemotherapy-resistant cell lines [10]. The first combination study was reported by Czuczman et al. [11], in which 38 patients with indolent lymphoma were treated (31 previously untreated) with rituximab and CHOP chemotherapy (cyclophosphamide, adriamycin, vincristine, and prednisone). The response rate was 100%, including a 66% complete response rate. With no comparison other than a historical one, it is difficult to know if an improvement in the event-free survival will be shown over CHOP alone. A prospective randomized trial is needed. Other combination trials are also currently ongoing with combinations such as Fludara (Berlex, Richmond, CA), CVP (cyclophosphamide, vincristine and prednisone), or FND [fludara (Berlex, Richmond, CA) mitoxantrone (Immunex, Seattle, WA) and dexamethasone].
Rituximab for aggressive NHL With respect to aggressive NHL, only a few trials have been published. Coiffier et al. [12], evaluated 54 patients with relapsed diffuse large-cell or mantle-cell lymphoma who received rituximab for 8 weekly doses. A total of five complete responses and 12 partial responses were observed for an overall response rate of 31%. Another study by Foran et al. [13] evaluated 120 evaluable patients with newly-diagnosed or recurrent mantle-cell lym-
phoma, immunocytoma, and small lymphocytic lymphoma, who received rituximab for 4 weekly infusions. The overall response rate in these patients was 30% (36 out of 120 patients). Ten patients, all with mantle-cell lymphoma achieved a CR with the therapy. With respect to combination therapy for aggressive NHL, the most mature study is a Phase II trial, in which 33 patients with newly-diagnosed diffuse large B-cell NHL received rituximab at 375 mg/m2 on Day 1 of each cycle, followed by CHOP on Day 3 of each cycle. The CR rate in this trial was 61%, with a PR rate of 35%, for an overall response rate of 97% [14]. All patients were able to receive all the cycles of therapy and had a 27% neutropenia rate; < 1% of cycles had thrombocytopenia. With a minimum follow-up of 24 months, 29/33 patients (88%) are alive and free of disease following this therapy. From this encouraging study, a large international Phase III trial is currently underway in this patient population, which randomizes patients to CHOP alone or CHOP rituximab. The combination of CHOP rituximab has also been evaluated in patients with newly-diagnosed mantlecell lymphoma. A report from Dana Farber Cancer Institute evaluated 40 patients who received this regimen [15]. The CR rate was 33%, CR(u) rate was 15% and the PR rate was 49%, for an overall response rate of 98% [15]. The median progression-free survival was 16 months, which was not different from similar historical control patients receiving CHOP alone. Although 11/23 patients with detectable bcl-1 rearrangements became PCR-negative, it did not correlate with the overall response to therapy.
Rituximab combined with high-dose therapy and autologous stem-cell transplantation Rituximab has been demonstrated to have the effect of ‘clearing’ bcl-2 positive cells from the blood and BM, it has therefore been tested recently in the transplant setting as an additive therapy. A few preliminary studies have now been presented in abstract form. A study from Salles et al. [16], evaluated 26 patients treated with rituximab prior to hematopoietic stem-cell harvest. The patients had follicular lymphoma (n = 17), mantle-cell lymphoma (n = 4), marginal zone and small lymphocytic lymphoma (n = 5). The patients received four doses of rituximab at 375 mg/m2. Mobilization was attempted with high-dose cyclophosphamide, etoposide and G-CSF at 4 weeks after
Therapeutic uses of MAbs directed against CD20
the rituximab. Three of the patients failed to mobilize and the rest were transplanted. For those patients with adequate follow-up, 10/11 patients were alive in CR. The PCR analysis in the stem-cell product demonstrated PCR negativity in 6/7 follicular lymphoma patients, while two mantle-cell lymphoma patients and one small lymphocytic lymphoma patient had residual PCR-positive cells. Another trial by Flinn et al. [17], evaluated 40 patients with follicular (n = 19), mantle-cell lymphoma (n = 9), small lymphocytic, marginal zone, or lymphoplasmacytic (n = 12) who were receiving autologous transplantation. The patients received rituximab 375 mg/m2 on Day 1 of mobilization, followed by cyclophosphamide and G-CSF or GM-CSF. The last 15 patients were also CD34 selected. Preliminary results demonstrated that seven of the patients with unmanipulated grafts had a PCR-positive product, however, none of the CD34 selected grafts had a PCR-positive product. The final results from both of these trials are pending. At the University of Nebraska Medical Center, recently we completed a 30 patient trial of rituxamab with the BEAM (BCNU, Etoposide, Ara-C, and Melphalan) transplant regimen. In this study design, the patients received one dose of rituximab prior to the BEAM regimen initiation, at Day 30 and Day 60 post-transplant. The patients in this trial were follicular or mantle-cell lymphoma patients and chemotherapy sensitive. With very early follow-up, 29/30 patients are alive following the transplant — with a CR rate of 88%. There was no additional toxicity of adding the rituximab in this manner and engraftment was identical to patients receiving BEAM alone. Our newest study uses the principals outlined above to take advantage of the rituximab premobilization to clear the blood. Rituximab is given during the regimen to sensitize the lymphoma cells and another four doses are given at 6 months post-transplant when the B cells are starting to recover (Figure 2). Quantitative bcl2 determination will be performed on these patients.
Expanding therapeutic areas for rituximab CLL, Waldenstrom’s macroglobulinemia and hairy cell leukemias More mature lymphocytes, such as those in CLL and the differentiated plasma-cell of multiple myeloma, in general have a lower density of CD20 Ag on the surface, compared with lymphocytes of other types of NHL. Rituxamab has, as a result, been less well-studied in these
Rituximab PSC harvest
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Rituximab BEAM
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Figure 2. Schema for rituximab + BEAM (BCNU, Etoposide, Ara-C, and Melphalan) followed by autologous stem cell transplantation for NHL. malignancies. A Phase I/II study by Byrd et al. [18] evaluated CLL patients with a three times per week dosing schedule of rituximab. Twenty-seven patients were treated during the study. Of the 18 patients evaluable for response, there was a 50% response rate, with most being partial responses. Rituximab has also been combined with other agents for CLL therapy. A study by Keating et al. [19] evaluated 30 patients with previously untreated CLL who received rituximab 375 mg/m2 or 500 mg/m2 on Day 1 given with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 given on Days 2–4 of each cycle. Patients demonstrated a more significant fall in the lymphocyte count as compared with patients who received fludarabine or the combination of fludarabine and cyclophosphamide. It is felt that either combination therapy or augmentation of the CD20 Ag may be extremely important in lymphoma subtypes that are CD20 dim. Waldenstrom’s macroglobulinemia (WM) has also recently been treated with rituximab. In an abstract by Treon et al. [20], 31 patients with WM were treated with single agent rituximab. For the 28 evaluable patients, 28% demonstrated a > 50% reduction in the IgM following the rituximab. Prior to the therapy, 25% of patients required transfusions, compared with only 4% following therapy. Eight patients with refractory or relapsed hairy-cell leukemia were treated with rituximab in a study by MD Anderson; the overall response rate in the five evaluable patients was 80% [21]. Clearly, many B-cell lymphoproliferative disorders may demonstrate an improvement with rituximab therapy either alone, or in combination therapy.
Post-transplant lymphoproliferative disorders (PTLD) PTLD is a serious complication of patients who have received solid organ transplants or BMT. It is believed to
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result from the rapid proliferation of Epstein–Barr (EBV)transformed B cells in the setting of T-cell deficiency that occurs in immunosuppressed patients. The first line of therapy for PTLD is typically a reduction of the immunosuppression. However, this does not work in all patients and further therapy is often necessary. There have now been several pilot studies evaluating the use of rituximab for the therapy of PTLD. In an abstract by Milpied et al. [22] 32 patients with PTLD were enrolled in a study of rituximab at 375 mg/m2 for 4 weekly doses. Twenty-six of these patients were solid organ transplant patients and six were BM transplant patients. The overall response rate was 69%, with 63% of patients having CR and 6% PR. The median time to response was 54 days (range, 11–148 days). Of the responding patients, 59% were still in remission at a median follow-up of 10 months. Several other small studies of the use of rituximab for the treatment of PTLD have now been published in abstract form [23,24]. Since many of these patients are quite ill when the PTLD is diagnosed, a therapeutic intervention with a less toxic agent is ideal in this clinical situation.
Radioimmunotherapy (RIT) is ideal treatment for NHL since the CD20 Ab has shown therapeutic efficacy as a solo agent and because NHL is very radiosensitive. The major anti-lymphoma effect of RIT is mediated by the 131I or the 90Y that is conjugated to the Ab directed against CD20. Both radioconjugates emit β particles. This energy causes lethal DNA damage in the cell that is targeted and to nearby cells that do not necessarily express the target Ag (bystander effect). 90Y emits a particle that has a higher energy, with a longer path length compared with 131I; this allows for a deeper tissue penetration. However, 131I emits γ emissions, which allows for imaging of the patient with localization of the radioimmunoconjugate. There are two anti-CD20 radioimmunoconjugates currently being evaluated for NHL therapy.
Immune-mediated thrombocytopenia
131I
There have also been a few reports of rituximab being used for diseases caused by autoimmune B-cell dysregulation. An example of this is a case report by Rathanatharathorn et al. [25] in which a patient with severe autoimmune thrombocytopenia from chronic GvHD was treated with rituximab. The patient had previously been refractory to i.v. immunoglobulin, steroids, anti-D, vincristine and cyclophosphamide. The patient’s platelet count had a gradual increase starting after the second dose of rituximab and has continued to stay normal at least 200 days following the therapy, despite decreases in the other immunosuppressive agents. The evaluation of rituximab for other autoimmune disorders that are B-cell mediated, such as idiopathic thrombocytopenia purpura (ITP), is also proceeding.
The radioimmunoconjugate that has been most extensively studied is Bexxar. This Ab is an IgG2a murine Ab (Coulter Pharmaceuticals, South San Francisco, CA). With RIT administration, a dosimetric dose is administered with an unlabeled Ab, given prior to the trace 131I-labeled (5 mCi) dose administered to the patient. Over the next week, three whole-body gamma-camera images are taken of the patient, to calculate their exact elimination of the radioactivity in preparation for individualized dose administration. One week after the dosimetric dose is given, the therapeutic dose is administered. Once again, an unlabeled Ab predose is given, followed by the 131I anti-CD20, calculated to administer 75 cGy total body dose (65 cGy for patients with a platelet count 100 000–150 000/µL) (Figure 3). In the initial Phase I/II trial at the University of Michigan, 57 patients with indolent, transformed, or de novo aggressive lymphoma were treated in this manner with Bexxar. Twenty patients had CR and 22 patients demonstrated PR with this one-time therapy [26]. Further long-term follow-up on these patients demonstrated a CR duration median of 20 months, with seven patients remaining in CR for 3–5.7 years (Figure 4)[27].
Up-regulation of the CD20 Ag Some of the subtypes of NHL, such as CLL/SL, have a decreased CD20 Ag density and do not seem to respond as well to rituximab. It is postulated that modulation of the CD20 Ag density might improve this response. Venugopal et al. [25] evaluated several different cytokines and their ability to up-regulate CD20 Ag density. It
appeared that TNF-α, IL-4 and GM-CSF were the three cytokines that up-regulated CD20 the most. In ongoing trials, GM-CSF is being utilized for patients with CD20 dim lymphomas, to try to improve the density prior to rituximab administration.
Radioimmunotherapy
anti-CD20 (Tositumomab, Bexxar)
Therapeutic uses of MAbs directed against CD20
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Figure 3. Schema for the administration of (Tositumomab).
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Figure 4. Overall and progression-free survival of 59 patients with relapsed or refractory B-cell lymphoma who received dosimetric and/or therapeutic doses of 131I-tositumomab [27]. This original study led to a Phase II dosimetry validation study, in which 45 patients with indolent or transformed lymphoma were treated with 75 cGy total body dose of 131I anti-CD20, as described. In this trial, the overall response rate was 57% and was similar in patients with indolent lymphoma (57%) or transformed lymphoma (60%). The CR rate was 32%, with a median duration of 20 months. The principal toxicity was hematologic, with 11% of patients having a platelet nadir of < 10 000 cells/µL and 4% of the patients having an absolute neutrophil count of < 100µL [28]. The pivotal trial was performed in 60 patients at several centers throughout the USA and in two sites in the UK. The patients in this trial had received a median of
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four prior regimens (range 2–13) and had a median age of 60 years. The overall response to the Bexxar was 65%, compared with 28% for the patients’ last prior chemotherapy (p < 0.001), and the CR rate was 17% for the Ab compared with 3% for the last chemotherapy (p = 0.011) [29]. Similar mild hematologic toxicities were seen in this trial as in the Phase II trial. Kaminski et al. [30] have also evaluated Bexxar in the previously untreated follicular-lymphoma patient population. They evaluated 76 patients given 75cGy total body dose of Bexxar, as previously outlined. The overall response rate was 97%, with 48 (63%) of patients achieving CR with this therapy. The 3 year progression-free survival was 68%. Of the 34 patients who were PCR in the blood or BM prior to therapy, 79% were PCR– after Bcell recovery. There was mild hematologic toxicity, with the median absolute neutrophil nadir being 1300 cell/µL, hemoglobin 12.2 g/dL and platelets 83 000 cell/µL. Bexxar has also been evaluated at much higher doses in the setting of autologous stem-cell transplantation. The Phase I/II study conduced by Press et al. [31] achieved doselimiting toxicity at 27 cGy dose to the healthy organs. In this study, patients only went on to the therapy dose if they had a favorable biodistribution of the tracer dose. Tumor bulk and splenomegaly presented problems with biodistribution in some patients. In a follow-up of the original study, Lui et al. [32] found 45% of the patients progression-free and 60% alive at several years post-therapy. More recently, Press et al. [33] have reported on the preliminary results of a Phase I/II study combining highdose 131I anti CD20, with high-dose cyclophosphamide and etoposide, followed by autologous hematopoietic stem-cell transplantation. This study was an attempt to substitute the radioimmunoconjugate for TBI in the NHL transplant regimen. Thirty-eight patients with relapsed NHL were treated. After a median follow-up of 18 months, 78% of the patients are progression-free. However, with the addition of standard high-dose chemotherapy, transplant complications, such as mucositis and opportunistic infections, became more of a problem. A Phase III trial, comparing this regimen with the standard cyclophosphamide, etoposide and TBI regimen, will be initiated after the Phase II study is complete. Another method of using radioimmunoconjugate therapy with a standard transplant regimen involves combining the lower dose of Bexxar (75cGy total body dose), which can be administered on an outpatient basis,
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with a standard chemotherapy-only transplant regimen. An ongoing trial at the University of Nebraska Medical Center combines Bexxar at 75cGy total body dose with the BEAM regimen (BCNU, Etoposide, Ara-C, and Melphalan), followed by autologous stem-cell transplantation. No results are yet available. 90Y
anti-CD20 (Y2B8)(ibritumomab tiuxetan, Zevalin)
Another radioimmunoconjugate that has undergone much clinical evaluation is 90Y-2B8 (IDEC, San Diego, CA). This compound is composed of a murine immunoglobulin G1 kappa MAb ibrutumomab (IDEC2B8); the linker chelator tiuxetan (isothiocyanateobenzyl MX-DTPA); and the radioisotope 90Y that is securely chelated via the linker. This Ab was initially used with an indium-labeled tracer dose for dosimetry, since Ytrrium does not emit γ emissions and cannot be imaged. Results from the Phase I/II trials showed the MTD to be 0.4 mCi/kg in most patients and 0.3 mCi/kg in patients with mild thrombocytopenia. The overall response rate was 67% (26% CR and 41% PR) in all histologies at all doses and 82% overall response rate in the patients with indolent lymphoma [34]. Ten percent of the patients developed a platelet count < 10 000/µL and 28% of the patients developed an ANC < 500/µL. Zevalin has also been considered for patients who have failed rituximab therapy. Twenty-nine patients with follicular NHL who were refractory to rituximab were treated with Zevalin. The median age of the patients was 54 years and 80% of the patients had bulky disease with > 5 cm lymph nodes. Of the 28 evaluable patients, 13 achieved a PR, giving an overall response rate of 46% [35]. Hematologic toxicity was transient and reversible. Grade IV neutropenia and thrombocytopenia occurred in 28% and 14% of patients, respectively. The median ANC nadir was 800/µL, with a median recovery of 9 days. The median platelet nadir was 34 000/µL, with a median recovery in 14 days. The interim results of a Phase III randomized trial, comparing rituximab with Zevalin was reported by Witzig et al. [36]. The first 90 patients treated to assess the interim analysis demonstrated an overall response rate of 80% for the Zevalin-treated patients, and 44% for the rituximab-treated patients (p < 0.001). The interim analysis was positive and the final results await completion of the full 143-patient analysis of the trial.
Conclusions Immunotherapy against the CD20 Ag has been developed to a great extent over the past few years. The future of MAb therapy will depend on our ability to successfully integrate these therapies with standard- or high-dose chemotherapy and stem-cell transplantation. Additionally, alternative agents with other radioimmunoconjugates, toxins, or chemotherapy labels may be developed in the future to augment our current results.
References 1
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