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Rituximab Anti-CD20 Monoclonal Antibody Therapy in Non-Hodgkin’s Lymphoma: Safety and Efficacy of Re-Treatment

From the Stanford University, Stanford; IDEC Pharmaceuticals Corp, San Diego, CA; University of Texas M.D. Anderson Cancer Center, Houston, TX; Roswell Park Cancer Center, Buffalo, NY; University of Iowa, Iowa City, IA; and Fred Hutchinson Cancer Research Center, Seattle, WA.

Address reprint requests to Thomas Davis, MD, EPN715, 6130 Executive Blvd, Rockville, MD 20852; email davist{at}ctep.nci.nih.gov

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: This phase II trial investigated the safety and efficacy of re-treatment with rituximab, a chimeric anti-CD20 monoclonal antibody, in patients with low-grade or follicular non-Hodgkin’s lymphoma who relapsed after a response to rituximab therapy.

PATIENTS AND METHODS: Fifty-eight patients were enrolled onto this study, and two were re-treated within the study. Patients received an intravenous infusion of 375 mg/m² of rituximab weekly for 4 weeks. All patients had at least two prior therapies and had received at least one prior course of rituximab, with a median interval of 14.5 months between rituximab courses.

RESULTS: Most adverse experiences (AEs) were transient grade 1 or 2 events occurring during the treatment period. Clinically significant myelosuppression was not observed; hematologic toxicity was generally mild and reversible. No patient developed human antichimeric antibodies after treatment. The type, frequency, and severity of AEs in this study were not apparently different from those reported in the phase III trial of rituximab. The overall response rate in 57 assessable patients was 40% (11% complete response and 30% partial responses). Median time to progression (TTP) in responders and median duration of response (DR) have not been reached, but Kaplan-Meier estimated medians are 17.8 months (range, 5.4+ to 26.6 months) and 16.3 months (range, 3.7+ to 25.1 months), respectively. These estimated medians are longer than the medians achieved in the patients’ prior course of rituximab (TTP and DR of 12.4 and 9.8 months, respectively, P > .1) and in a previously reported phase III trial (TTP in responders and DR of 13.2 and 11.6 months, respectively). Responses are ongoing in seven of 23 responders.

CONCLUSION: In this re-treatment population, safety and efficacy were not apparently different from those after initial rituximab exposure.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE EFFICACY AND safety of rituximab (Rituxan, MabThera, IDEC-C2B8; IDEC Pharmaceuticals Corp, San Diego, CA), both as a single agent and in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), interferon, or radioimmunotherapy, have been demonstrated in patients with relapsed or refractory, low-grade, or follicular non-Hodgkin’s lymphoma (NHL) in several clinical trials.^1-9 Rituximab is a highly specific mouse/human chimeric antibody engineered by grafting the variable regions targeting the CD20 antigen from a murine antibody (2B8) onto human constant regions. Rituximab binds complement and induces antibody-dependent cellular cytotoxicity.^10,11 It also inhibits cell proliferation and directly induces apoptosis.¹²

Certain characteristics make the CD20 antigen an appealing target for monoclonal antibody therapy; it is present on the surface of mature B cells¹³ and has been noted in approximately 93% of patients with B-cell lymphoma,¹⁴ but is not present on precursors to B cells, plasma cells, or other nonlymphoid normal tissues.^13,14 Additionally, it does not circulate in the plasma as free protein that could competitively inhibit antibody binding to lymphoma cells^13,15; does not shed from the surface of CD20+ cells after antibody binding^16,17; and does not seem to be internalized or, subsequently, downregulated on antibody binding.¹⁶ The CD20 antigen arises during the pre–B-cell stage of B-cell differentiation¹⁸; thus, after anti-CD20–induced depletion, a normal B-cell population can be reconstituted from the stem cells and pre- (or pro-) B-cells.

The efficacy and safety of rituximab single-agent therapy have been reported in patients with low-grade or follicular NHL in four phase I/II studies.^1-4 In a phase III study,⁵ adverse events (AEs) associated with treatment were primarily grade 1 or grade 2, infusion-related, and included transient fever, chills, nausea, and headache. Only one patient (< 1%) developed human antichimeric antibodies (HACA). The overall response rate (ORR) was 48% for the intent-to-treat population and 50% for the assessable population, with a median time to progression (TTP) and duration of response (DR) in assessable responders of 13.2 and 11.6 months, respectively.¹⁹ Additionally, treatment with the combination of rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP),^6,7 rituximab and IDEC-Y2B8,⁹ and rituximab and interferon⁸ have been investigated, as well as trials of rituximab in patients with intermediate- and high-grade lymphoma.^20,21

In an early study of anti-idiotype therapy in patients with NHL,²² 46% (five of 11) of patients developed an immune response to murine immunoglobulins (HAMA). None of these patients experienced or continued a clinical response after antimouse antibodies were detected. Pharmacokinetic data confirmed that anti-idiotype antibody levels decreased concomitant with an increase in HAMA levels. Subsequent studies of murine antibodies in patients with different types of hematologic malignancies also showed that responses were limited by HAMA.^23,24 Relative to murine antibodies, mouse/human chimeric antibodies have the clinical advantages of extended half-lives in humans, enhanced interaction with human effector cells,^10,11,16 and reduced immunogenicity,^23-25 which may allow for repeated courses of therapy. This phase II study of the chimeric antibody rituximab was designed to investigate the safety and efficacy of rituximab in the re-treatment of relapsed patients who had responded previously to rituximab therapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
Patients at least 18 years of age with histologically confirmed, relapsed low-grade or follicular B-cell NHL (International Working Formulation [IWF] types A to D; defined in Table 1) were enrolled provided they had responded previously to rituximab therapy, had a prestudy performance status of 0, 1, or 2, according to the World Health Organization scale, were not pregnant or lactating, were following accepted birth control methods, and had a life expectancy of 4 months. Within 2 weeks before receiving the first infusion, patients were required to have a hemoglobin level 8.0 g/dL, absolute granulocyte count 1,500/µL, platelet count 75,000/µL, serum creatinine 2.0 mg/dL, total bilirubin 2.0 mg/dL, and alkaline phosphatase and AST two times normal. For patients with IWF type A lymphoma, lymphocyte counts had to be 5,000/µL. Patients with an active opportunistic infection, a serious nonmalignant disease, or recent major surgery were not eligible for enrollment. Concurrent corticosteroid use was not allowed. The study was approved by the institutional Review board at each study site, and written informed consent was obtained from all patients.

Monitoring
Laboratory testing included hematology and serum chemistry assays, immunoglobulin levels, and urinalysis. Evaluations for disease assessment included physical examination (baseline, weeks 4 and 8, and every 3 months through 2 years, then every 6 months), chest x-ray (baseline), bone marrow biopsy (baseline and at confirmation of complete response, if positive at baseline), and computed tomography (CT) or magnetic resonance imaging (week 4, then 1 month after treatment, every 3 months through 2 years, then every 6 months). An evaluation including a CT or magnetic resonance image was performed 28 days after the onset of response.

Serum samples were collected and assayed for the presence of HACA,^2,3 using a sandwich enzyme-linked immunosorbent assay. Samples were added to microtiter plates coated with rituximab, and bound antichimeric antibody was detected using labeled rituximab. Serum chimeric antibody levels were determined. Serum samples were added to microtiter plates coated with polyclonal goat anti–IDEC-2B8 antibody. Bound rituximab was detected using labeled goat antihuman immunoglobulin G and compared with a standard curve.

End Points and Response Criteria
To investigate the efficacy of re-treatment with rituximab, ORR (complete response [CR] plus partial response [PR]), DR, and TTP in responders were determined. TTP in responders, rather than in all patients, is presented to provide comparability with published data from other rituximab trials, including the phase III pivotal trial. Patients were assessable for efficacy if they completed four full infusions of rituximab, satisfied all prestudy entry criteria, and met criteria for evaluation of response. Response categories consisted of CR, PR, stable disease (SD), and progressive disease (PD).^26-28 CR required all lymph nodes visible on CT scans of neck, chest, abdomen, and pelvis to be less than 1 cm x 1 cm in size; any node that was palpable on physical examination (and considered to be involved in lymphoma) must have been no longer palpable or negative on biopsy or fine-needle aspirate; bone marrow must have been histologically negative for lymphoma; and the liver and spleen (if abnormal at baseline) must have returned to normal size. PR was defined as 50% or greater decrease from baseline in the sum of the products of the greatest perpendicular diameters of all the measured lesions (SPD) and no simultaneous increase in size of any other lesion or no new lesions. SD referred to patients who did not exhibit at least a 50% decrease or increase in SPD, and PD was considered as any single observation of a 50% increase in SPD from nadir or the appearance of a new lesion. Response classifications of PR and CR were confirmed by reassessment 28 days after the determination of response. Toxicity was evaluated using the National Cancer Institute’s common toxicity criteria (February 1988 guidelines).²⁹

Statistical Methods
DR and TTP in responders were measured from the first infusion and the first observation of response, respectively, until progression. The Kaplan-Meier product-limit method was used to analyze the TTP in responders; curves were generated using PROC LIFETEST (SAS Institute, Cary, NC).³⁰ Clinical AE data were assigned preferred terms using Coding Symbols For Thesaurus of Adverse Reaction Terms (COSTART),³¹ and the frequency, incidence, severity, and relationship to treatment were reported. Any AE reported as probably or possibly related or of unknown relationship to the study treatment was considered a related AE. If the same AE was reported on consecutive days, then the specific number of times that the event occurred was recorded as a single event. The most severe grading among the individual events was used to characterize this unified event. AEs were further classified as having occurred during the treatment period (time interval between first rituximab infusion and 30 days after the fourth infusion) or follow up ( 31 days after the fourth infusion).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Fifty-eight patients were enrolled onto this study, and two patients were re-treated within the study. Thus, there are 60 patient numbers. Patient characteristics included the following: 95% were white, 97% had low-grade (IWF: A, B, or C) and 3% follicular intermediate-grade (IWF: D) histologies, and 77% had stage III/IV disease at initial diagnosis. Patients were a median of 4.7 years from diagnosis, and the median age was 56 years (range, 31 to 81 years). All patients had at least two prior therapies (median, four therapies; range, two to 11 therapies) and had received and responded to at least one prior course of rituximab therapy; five patients had received two prior courses of rituximab. The median interval between rituximab courses was 14.5 months (range, 3.8 to 35.6 months). Three patients had radiotherapy between the current and immediately prior rituximab treatments; rituximab was the prior therapy for all other patients. Demographic and prior treatment data are listed in Tables 1, 2, and 3.

Clinical AEs
Most clinical AEs (92% of events) were mild to moderate (grade 1 or 2) and self limiting. The majority of patients experienced AEs during the first infusion, and both incidence and frequency declined with subsequent infusions. Approximately half of all events were considered to be related (probably or possibly related, or of unknown relationship) to the study treatment. Of grade 3 or 4 events, 69% were considered unrelated to the treatment. The most common related events observed during the treatment period (22 days of treatment plus 30 days of follow-up) included transient fever (30% of patients), chills (23%), asthenia (23%), and pruritus (20%). Infusion-related events (related events reported on an infusion day) included episodes of fever, chills, pain, and throat irritation that were grade 1 or 2, usually continued for less than 1 week, and resolved without treatment or without interrupting the infusion. Infections were generally mild to moderate and only two patients with infection required hospitalization. Two additional patients were hospitalized; one with ovarian cancer and one with phlebitis and facial edema. No patient deaths were attributable to the study treatment. Significant myelosuppression was not observed; hematologic toxicity was generally mild and reversible.

One patient developed grade 3 neutropenia approximately 1 month after his fourth infusion on this protocol. The neutropenia resolved with granulocyte colony-stimulating factor (G-CSF) therapy. This patient had also developed similar neutropenia approximately 1 month after completion of his initial rituximab therapy. A marrow sample taken during the nadir showed only regenerating myeloid elements with no malignant involvement, and with a thorough work up, no other infectious or toxic cause for his marrow suppression was found. Again, the neutropenia responded to G-CSF treatment.

Hematology and Chemistry Laboratory Effects
Five patients had grade 3 or 4 levels of one or more hematologic parameter; no patient experienced a clinically significant decline in platelets (< 50,000/µL). During the treatment period, hemoglobin levels declined to less than 8g/dL and absolute neutrophil count declined to less than 1,000/µL in one patient each; WBC was less than 2000/µL in two patients. During the 1-year follow up, absolute neutrophil count declined to less than 1,000/µL in two patients. Levels of these hematologic parameters recovered within 2 weeks in three patients and by 4 months in one patient; levels in one patient had not recovered by database closure. No hepatic or renal toxicity was noted. No patient developed HACA. Mean serum immunoglobulin levels did not decrease below the normal range.

Response to Treatment
Two patients were not assessable for efficacy; one was ineligible because the single baseline lesion (< 1 x 1 cm) was less than the protocol-required minimum size, and one did not receive all four scheduled infusions. The latter patient was re-treated within the protocol and, thus, received two patient numbers but received only one of the four scheduled infusions of each course.

In the 57 assessable patients, the ORR was 40% (23 of 57 patients) with six CRs and 17 PRs, as listed in Table 4. The ORR was 38% in the 60 intent-to-treat patients, with six CRs and 17 PRs. The median time to response was 49 days. The median DR and TTP in responders have not been reached; Kaplan-Meier median estimates are 17.8 months for DR (range, 5.4+ to 26.6 months) and 16.3 months for TTP (range, 3.7+ to 25.1 months). These data are listed in Table 5, and a Kaplan-Meier curve of TTP is presented in Fig 1.

View larger version (14K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curve of TTP in 23 patients responding to re-treatment with rituximab (dotted lines indicate 95% confidence intervals, and C indicates a censored value).

Tumor size was reduced substantially in most patients. The average decrease in lesion size was 86% in patients achieving a PR and 32% in patients with SD. Tumor size was reduced by at least 20% in 73% of patients (44 of 60). Thirty percent of patients (18 of 60) reported B symptoms or other disease-related signs and symptoms at baseline, and symptoms resolved completely or were relieved transiently in 16 (89%) of 18 patients. Eight of these 16 patients responded to rituximab therapy; the two patients with continuing B symptoms did not respond to rituximab.

Response to Current and Prior Rituximab Treatment
All patients had responded to at least one prior course of rituximab. Different schedules and doses were used in the previous single-agent or combination trials (Table 2).

The Kaplan-Meier estimated median DR and TTP in responders to the current therapy (17.8 and 16.3 months, respectively) were longer but not significantly different from those achieved after the prior course of rituximab (12.4 and 9.8 months, respectively; P = .224 and .164, respectively) based on Kaplan-Meier analyses.³⁰ When the data were analyzed using the Wilcoxon test, TTP in responders was significantly longer in the current versus the previous courses (P = .036). The Wilcoxon test emphasizes the early portion of the Kaplan-Meier curve. Kaplan-Meier estimates were determined using SAS/GRAPH Software (SAS/STAT User’s Guide, Version 6; SAS Institute, Cary, NC, 1990).

Although it is difficult to compare results across studies because of heterogeneity of the patient population, the same inclusion/exclusion criteria were used in the re-treatment trial and the phase III trial; thus, the patient populations were similar between studies. Again, the estimated median DR and TTP in responders in the re-treatment trial were longer but not significantly different from those achieved in the previously reported rituximab phase III trial (13.2 and 11.6 months, respectively; P = .913 and 0.773, respectively)⁵ (Table 6 and Fig 2).

View larger version (26K): [in this window] [in a new window]   Fig 2. DR and TTP (with upper 95% confidence interval stems) in the current (Kaplan-Meier estimates) and previous course of rituximab in patients responding to rituximab therapy.

Rituximab Serum Levels
Antibody concentration increased after each infusion, with a median of 254 µg/mL, 326 µg/mL, 414 µg/mL, and 450 µg/mL after the first, second, third, and fourth infusions, respectively. Median values declined to 290 µg/mL by 1 week after treatment and to 31 µg/mL by 3 months after treatment.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The efficacy and safety of rituximab single-agent therapy have been demonstrated in patients with relapsed or refractory, low-grade or follicular NHL.^1-3,5 Results from the phase III trial of rituximab revealed an ORR of 50%; a median TTP in responders and DR of 13.2 and 11.6 months, respectively; and a mild to moderate side-effect profile. On the basis of these results, rituximab has become widely used in patients with B-cell malignancies. There has been no evidence of significant immune suppression after primary therapy with rituximab, further supporting the value of this treatment as a single-agent therapy. Because less than 1% of patients developed an immune response to rituximab after treatment in the phase III trial, it is reasonable to consider recurrent courses of therapy that will have the additional benefit of delaying chemotherapy and potentially further prolonging overall survival. In the current study, the safety and efficacy of re-treatment with rituximab in NHL patients who had responded previously to rituximab therapy were evaluated.^39,40

In general, rituximab therapy was well tolerated in this re-treatment population. Most AEs were transient grade 1 or 2 events occurring during the treatment period. No patient deaths were attributable to the study treatment. Infections were generally mild to moderate, and only two patients with infection required hospitalization. Mean serum immunoglobulin levels remained within the normal range, and significant myelosuppression was not observed; hematologic toxicity was generally mild and reversible.

One patient provided an interesting insight into the neutropenia that is reported rarely after rituximab therapy. The patient developed severe neutropenia 1 month after each of two courses of rituximab therapy. The neutropenia resolved rapidly after G-CSF therapy, and no etiology could be found. There is no known connection between B cells and myeloid maturation, yet it is possible that there is some interdependency that is manifested in only a small population of patients undergoing rituximab therapy. Further research on this connection may lead to the development of novel growth factors.

The patient population of the larger phase III rituximab trial was similar to that of the re-treatment study (Table 1), with the exception of histologic type and bone marrow involvement. The percentage of patients with type A histology was 5% in the re-treatment study and 20% in the phase III study, and the percentage of patients with bone marrow involvement was 33% in the re-treatment study and 54% in the phase III study. Abnormal lactate dehydrogenase levels were present in 10% of the re-treatment patients and in 8% of the phase III patients, and 15% of the re-treatment patients and 14% of the phase III patients had prior autologous bone marrow transplant.

Compared with the results from the phase III rituximab trial,⁵ the type, frequency, and severity of AEs were similar. In the phase III trial, 7% of patients experienced grade 3 or 4 AEs during the treatment period and 9% experienced AEs during follow-up versus 8% and 3% of patients, respectively, in the current trial. Mild to moderate fever, chills, nausea, asthenia, and pruritus were among the most common events in both studies. Overall, the side-effect profile of rituximab in this re-treatment trial was similar to that seen in the phase III trial.

Significant clinical activity was demonstrated, with an ORR of 38% in the intent-to-treat population and 40% in assessable patients and with tumor size reduction of at least 20% in 73% of patients. Five patients received their third course of rituximab in this study, and three responded; one patient was not assessable, and one had SD. Importantly, no patient developed HACA after rituximab re-treatment.

Although median values have not been reached, the Kaplan-Meier estimated median TTP in responders of 17.8 months and DR of 16.3 months after re-treatment were longer than those demonstrated in the phase III trial (13.2 and 11.6 months, respectively) and longer than those achieved in these patients’ prior course of rituximab therapy (12.4 and 9.8 months, respectively). Correspondingly, the median interval between rituximab courses was 14.5 months. Although a progressive decline in DR with each successive treatment has been observed with chemotherapy,⁴¹ results from this study suggest that DR may be similar or actually increase after re-treatment with rituximab. Retreatment with rituximab may allow some patients to avoid cytotoxic therapies for years.

In the postmarketing experience of over 30,000 patients treated with commercial rituximab worldwide, to date, two patients have reportedly relapsed with CD20-negative B-cell NHL.^42-44 All patients in this re-treatment study were CD20 positive at enrollment. It is important to note that patients in this clinical trial were observed more closely than patients receiving commercial rituximab; all were observed through relapse and onto re-treatment with rituximab.

Development of resistance is characteristic of B-cell lymphomas after treatment with all other available therapies. However, sufficient information on the mechanism of action of rituximab is not available to allow us to predict the mechanism of resistance to the therapy. Possible mechanisms include reduction of CD20 expression below some critical threshold necessary for cell death, uncoupling of the apoptotic signal that is initiated by rituximab’s binding of the CD20 molecule, or progressive inhibition, by the disease or by antilymphoma therapy, of the immune response that is recruited by bound rituximab, including complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Exciting developments with potential to improve the efficacy of rituximab include preliminary evidence that the CD20 antigen can be upregulated by certain cytokines and the possibility of enhancing effector function, such as natural killer cells, with interleukins, G-CSF, or other biologic agents.^45-48

Results of this study show that patients can be treated safely and effectively with multiple courses of rituximab without induction of HACA and without the cumulative myelosuppression common after multiple courses of chemotherapy or radiotherapy. A full course of rituximab therapy (375 mg/m² intravenous infusion once weekly for four times) is complete in 22 days and, in this re-treatment population, produced DRs exceeding 25 months in some cases. Median TTP in responders and DR have not been reached; Kaplan-Meier estimated medians are 17.8 and 16.3 months, respectively. In this re-treatment population, toxicity and response duration were not apparently different from those after initial rituximab exposure.

	ACKNOWLEDGMENTS

 
Supported by clinical grants from the National Institutes of Health and IDEC Pharmaceuticals Corporation.

We thank the clinical research efforts of Drs Vinay Jain, Louis Fehrenbacher, John Bennett, Leo Gordon, Russell Schilder, Stanley Frankel, Lawrence Piro, Nalini Janakiraman, Vincent Caggiano, Mansoor Saleh, Isabelle Bence-Bruckler, Jonathan Kolitz, William Velasquez, Anthony Ho, Robert Dillman, Neil Berinstein, Michael Williams, and Lee Schwartzberg; and IDEC staff members Chet Varns, Baha Alkuzweny, Sue Dowden, Brian Dallaire, and Carol Gardner.

	NOTES

 
T.A.D. was a Lymphoma Research Foundation Fellow and, subsequently, a Clinical Associate Physician with the General Clinical Research Centers. R.L. is an American Cancer Society Clinical Research Professor.

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Submitted September 2, 1999; accepted May 1, 2000.

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