Pharmacokinetic study of patients with follicular or mantle cell lymphoma treated with rituximab as ‘in vivo purge’ and consolidative immunotherapy following autologous stem cell transplantation

J. Mangel1, R. Buckstein1, K. Imrie1, D. Spaner1, E. Franssen1, P. Pavlin1, A. Boudreau1, N. Pennell1, D. Combs2 and N. L. Berinstein1,+

1 The Advanced Therapeutics Program, Toronto Sunnybrook Regional Cancer Centre, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada; 2 Genentech, San Francisco, CA, USA

Received 4 October 2002; revised 16 December 2002; accepted 17 January 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Little is known about the pharmacokinetics of rituximab in an autologous stem cell transplant (ASCT) setting.

Patients and methods:

We evaluated serum rituximab levels in 26 patients with follicular or mantle cell lymphoma treated with a combination of ASCT and immunotherapy. Patients received nine infusions of rituximab (375 mg/m2): one dose as an ‘in vivo purge’ prior to stem cell collection, and two 4-week cycles at 8 and 24 weeks following ASCT. Pre- and post-infusion serum rituximab levels were measured during the purging dose, with doses 1 and 4 of both sets of maintenance rituximab cycles, and 12 weeks and 24 weeks following treatment.

Results:

Rituximab levels were detectable after the first infusion, and peaked at a mean concentration of 463.8 µg/ml after the final dose. Levels remained detectable 24 weeks after completion of treatment. There was a trend toward higher rituximab levels in patients with follicular lymphoma. Serum concentrations achieved during the maintenance cycles were similar to levels observed in patients with measurable lymphoma treated during ‘the pivotal trial’. No correlation was observed between serum rituximab levels achieved in the minimal disease state and the risk of later clinical relapse, nor with the ability to achieve a molecular remission following ASCT.

Conclusions:

The finding that patients treated in minimal disease states and at the time of active disease both achieve similar final serum rituximab concentrations after four infusions suggests that the pharmacokinetics are complex, and may not necessarily correlate with disease burden. The precise factors influencing rituximab clearance in patients with lymphoma are unresolved, and this remains an area of active research.

Key words: autologous stem cell transplantation, pharmacokinetics, rituximab


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, USA, and Genentech, Inc., San Francisco, CA, USA) is a chimeric IgG kappa monoclonal antibody that recognizes the CD20 antigen expressed on normal B cells and most malignant B-cell lymphomas [1]. It is therapeutically active when used for the treatment of indolent and aggressive lymphoproliferative diseases, both as a single agent [210] and in combination with cytotoxic chemotherapy [1113]. Rituximab can safely be used for ‘in vivo purging’ during autologous peripheral blood stem cell collection without compromising stem cell yields or delaying time to engraftment post-transplant [1418]. It has also been used as consolidative therapy following autologous stem cell transplantation (ASCT) in an attempt to decrease the risk of lymphoma relapse [19, 20].

The standard dose of rituximab used for the treatment of patients with non-Hodgkin’s lymphoma (NHL) is 375 mg/m2 weekly for 4 weeks. Several studies have analyzed the pharmacokinetics (PK) of rituximab in patients receiving four or eight doses of the antibody for the treatment of active relapsed or refractory NHL [3, 4, 2125].

We have combined ASCT and immunotherapy with rituximab in a phase II clinical trial for patients with relapsed follicular lymphoma (FL) or newly diagnosed mantle cell lymphoma (MCL). In this trial, rituximab has been given both as an ‘in vivo purge’ during stem cell mobilization and as post-transplant immunotherapy to eliminate minimal residual disease. In order to investigate the pharmacokinetics of rituximab when used in a transplant setting, pre- and post-infusion serum rituximab levels were obtained at the time of the purging dose, and before and after doses 1 and 4 of both sets of maintenance rituximab cycles. Samples were also drawn at the time of apheresis, and at 3 and 6 months following the second set of infusions. We present the results of the PK analyses performed in 26 patients treated on this trial.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Phase II trial
This was a prospective, non-randomized phase II clinical trial to assess the role of high-dose therapy (HDT) and ASCT in combination with rituximab immunotherapy in patients with one to three relapses of FL or newly diagnosed MCL. Patients with MCL received initial de-bulking chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Patients with FL received either CHOP or DHAP (dexamethasone, cytarabine, cisplatin) depending upon their previous anthracycline exposure. Stem cell collection took place once patients achieved <15% bone marrow (BM) involvement by lymphoma. Patients were mobilized with 5 days of granulocyte colony-stimulating factor 10 µg/kg/day, with a single infusion of rituximab 375 mg/m2 used as an ‘in vivo purge’ 5 days prior to stem cell collection. Patients who achieved at least a 75% reduction in tumor bulk proceeded to HDT with CBV (cyclophosphamide, carmustine, etoposide) and ASCT. Post-transplant consolidative immunotherapy consisted of rituximab 375 mg/m2, administered as two 4-week courses at 8 and 24 weeks following ASCT (set 1 = weeks 8, 9, 10, 11; set 2 = weeks 24, 25, 26, 27). Patients therefore received a total of nine 375 mg/m2 infusions of rituximab (see Figure 1).



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Figure 1. Study timeline. R, rituximab infusion.

 
Morphologically positive baseline samples of lymph node, BM or peripheral blood (PB) were assessed by PCR for the presence of bcl-1, bcl-2 or patient-specific V(D)J rearrangements in all patients. Serial molecular monitoring for minimal residual disease was performed on all follow-up BM and PB samples (pre-apheresis, pretransplant and post-transplant at 12 week intervals) in the patients in whom a molecular marker was identified. The stem cell graft was similarly evaluated for the presence of occult disease.

Pharmacokinetic measurements
Serum samples for rituximab concentrations were obtained at 13 time points during the nine infusions. Levels were measured before and immediately after dose 1 (the purging dose), dose 2 (set 1 infusion 1, at week 8), dose 5 (set 1 infusion 4, at week 11), dose 6 (set 2 infusion 1, at week 24) and dose 9 (set 2 infusion 4, at week 27). Samples were also drawn at the time of apheresis, and at 3 and 6 months following initiation of the second set of infusions (9 and 12 months post-ASCT, respectively). Serum samples were kept frozen at –70°C until analysis.

Serum levels of rituximab were quantified at IDEC Pharmaceuticals (San Diego, CA, USA) and at Genentech, Inc. (South San Francisco, CA, USA) by enzyme-linked immunosorbent assay (ELISA). Microwell plates were coated with a purified goat anti-CD20 (2B8) idiotype polyclonal antiserum. Serial dilutions of patient serum were added to the wells and a goat anti-human IgG conjugated to horseradish peroxidase was used for detection. The plates were developed using the substrate 2,2-azino-bis(3-ethylbenzthiazoline sulfonic acid) (ABTS) and quantitated using absorbence spectophotometry with a known standard curve of rituximab. This assay was validated to quantify >=0.5 µg/ml of rituximab in serum.

Statistical considerations
Means, medians and standard deviations were calculated using Microsoft Excel for Windows 97 version 4.0 software package. Student’s t-test was used to compare the mean rituximab concentrations observed in patients with different histologies (FL and MCL) at the various time points, and similarly to compare levels in patients according to their current remission status.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Thirty-four patients (22 FL, 12 MCL) were transplanted and completed all planned maintenance rituximab infusions. Pharmacokinetic data is available on 26 patients, 20 with FL and six with MCL.

Two hundred and seven serum rituximab levels were measured in 26 patients over 13 different time points. Although an attempt was made to collect serum samples from all patients at all designated time-points, one or more data-points were missed in a number of patients. Table 1 displays the number of samples drawn at each time point, and the mean concentrations obtained for each measurement.


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Table 1. Pharmacokinetic results
 
As expected, at all time points, the post-infusion level was higher than the pre-infusion level. Prior to the single purging dose of rituximab, levels were undetectable in the serum, and rose to a mean of 196.3 µg/ml immediately post-infusion. At the time of apheresis 5 days later, moderate levels of antibody remained detectable in the serum (mean 55.2 µg/ml). A median of 20.1 weeks elapsed between the purging dose and the onset of post-transplant immunotherapy. By this time, only traces of the first infusion remained, and the mean serum concentration at the onset of maintenance rituximab was 3.7 µg/ml (range 0–16.2 µg/ml). During the first set of maintenance infusions (set 1), the mean concentration following infusion 1 was 215 µg/ml, and this increased almost two-fold to a mean of 424.2 µg/ml immediately post-infusion 4. Levels were still detectable 13 weeks later, at the time of initiating set 2 (mean 47.3 µg/ml), and reached their peak mean concentration of 463.8 µg/ml (±109.4) by the end of the fourth and final dose. There was a continued decline in levels during the post-treatment follow-up time points, but low levels of rituximab could still be detected in most patients at the 9 and 12 month follow-ups, ~3 and 6 months after completion of treatment. Figure 2 displays the mean levels for the entire patient group at the 13 different time points.



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Figure 2. Rituximab serum profile from 26 lymphoma patients. Serum rituximab concentrations are given as mean ± standard deviation.

 
In Table 2, serum rituximab levels are presented according to histological subtype of NHL. Aside from at the 12 month follow-up, mean antibody levels were consistently lower at all time points in patients with MCL compared with patients with FL. However, using Student’s t-test, these differences were not statistically significant at any of the time points.


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Table 2. Serum rituximab levels versus histological type
 
Serum levels in this study were compared to the levels observed in 147 patients with recurrent NHL who were treated with 4 weekly doses of rituximab 375 mg/m2 in the pivotal trial [21]. Our patients received two full courses of rituximab at 8 and 24 weeks post-ASCT, at the identical dose and schedule used in the pivotal trial. Figure 3 depicts the median serum concentrations immediately before and after infusions 1 and 4 for sets 1 and 2 of the current study, and for patients treated in the pivotal trial. The graph shows that the levels achieved during sets 1 and 2 were quite similar, and that they both closely paralleled the levels seen in patients with active lymphoma treated in the pivotal trial [21]. The baseline median serum level was ~45 µg/ml higher in the group about to begin set 2, reflecting antibody that persisted in the serum 13 weeks after completing the first set of infusions. This small difference probably accounted for the slightly higher median concentrations observed post-infusion 1 and pre-infusion 4 for set 2 in comparison to the other two groups; however, by the end of the fourth infusion, final levels were virtually indistinguishable in all three groups.



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Figure 3. Comparison of median serum concentrations of rituximab for similar dosing regimens.

 
Of the 26 patients in this study, two died within 1 year of transplant while still in remission. Sixteen patients remain alive and in remission (four MCL, 12 FL), and eight have suffered a relapse (one MCL, seven FL). The median follow-up duration of the latter two groups is comparable. The patients in ongoing remission achieved similar median peak rituximab concentrations post-infusion 4 of set 2 as the patients who later relapsed (440.5 versus 522 µg/ml, respectively). Antibody concentrations measured 3 and 6 months after completion of therapy were also quite similar in the two groups (68.1 versus 93.4 µg/ml at 3 months, and 8.8 versus 25.6 µg/ml at 6 months). Using Student’s t-test, no statistically significant differences were observed at any of the 13 time points (see Table 3). The likelihood of developing recurrent lymphoma could not be predicted based on the antibody levels achieved post-transplant.


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Table 3. Median serum rituximab levels according to relapse status
 
A molecular marker enabling serial PCR analysis was available in 15 of 26 study patients (see Figure 4). When serum rituximab levels were compared between the patients in molecular remission versus those who had a relapse at the molecular level, no statistically significant differences were observed between the groups (data not shown).



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Figure 4. Molecular monitoring of minimal residual disease in 15 study patients (12 follicular lymphoma, three mantle cell lymphoma). Patients were followed by PCR for the bcl-2 rearrangement (n = 11), for the bcl-1 rearrangement (n = 1) or for a patient-specific V(D)J rearrangement (n = 3).

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Rituximab is a monoclonal antibody with clinical activity in indolent and aggressive NHL [210]. PK data have been reported in a number of studies evaluating rituximab use in patients with relapsed lymphoma [24, 2125]. Serum rituximab levels have been shown to be proportional to the antibody dose infused [4], and higher, more sustained serum levels are achieved after multiple doses compared with after single doses [2, 3].

The most comprehensive PK assessment of rituximab was performed in 147 patients with relapsed or refractory indolent NHL treated with 4 weekly infusions of rituximab at 375 mg/m2 in the pivotal trial [5, 21]. Rituximab levels were shown to increase throughout the course of treatment, reaching mean concentrations of 206 and 465 µg/ml after the first and fourth infusions, respectively. Levels remained detectable in the serum for up to 3–6 months following completion of treatment. The estimated half-life of rituximab increased from 76.3 h after the first infusion to 205.8 h after the fourth infusion, with a concomitant marked decrease in the antibody clearance. One proposed mechanism for the finding of prolongation of half-life with subsequent infusions was the clearance of normal and malignant circulating B cells from the peripheral blood, and saturation of CD20 binding sites after the first infusion [21]. Similar findings were reported by other groups evaluating rituximab at the same dose and schedule [3, 22, 23, 25]. In a study in which rituximab was administered to patients at 375 mg/m2 weekly for 8 weeks, the median post-infusion serum levels peaked higher than in studies using only four doses, but appeared to plateau after the sixth infusion (range 518–558 µg/ml) [24]. A statistically significant correlation was found between the serum rituximab concentration and clinical response in a number of studies, with higher mean serum antibody levels observed in responders than in non-responders [3, 21, 24, 25]. In the pivotal trial, serum rituximab levels also correlated inversely with both the degree of tumor bulk and the number of circulating B cells at baseline [21].

The PK of rituximab when administered in a stem cell transplant setting has not been previously studied. This setting is different from the previously published PK assessments, because patients are in minimal disease states post-HDT ASCT, and do not have measurable amounts of lymphoma. In addition, no previous study has measured rituximab levels while the antibody was being used for the purpose of ‘in vivo purging’.

Maloney et al. [2] have previously reported that antibody levels >10 µg/ml persisted for >14 days in the serum of six of nine lymphoma patients receiving a single dose of rituximab (100, 250 or 500 mg/m2). In our patients, immediately following administration of the purging dose of rituximab, mean serum levels reached 196.3 µg/ml (range 139.2–352.7 µg/ml), and were 55.2 µg/ml (range 1.4–112.1 µg/ml) 5 days later at the time of apheresis. When administered as a single dose in this way, these findings suggest that levels of rituximab adequate to bind circulating lymphoma cells were present in the serum in the days prior to stem cell collection.

Low levels of rituximab may have been present throughout the period of HDT and ASCT in a proportion of patients, and thus would have been available to potentially synergize with the cytotoxic drugs used in the HDT [13, 26]. Eight weeks after ASCT, at the time of initiating the first set of consolidative rituximab infusions, eight of the 16 patients in whom pre-infusion levels were available had antibody concentrations measuring >=1 µg/ml (range 1–16.2 µg/ml). In these eight patients, a median of only 16.1 weeks (range 11.5–21 weeks) had elapsed between the rituximab purging dose and the onset of post-transplant immunotherapy. In contrast, levels were undetectable in six of seven patients, in whom >22 weeks passed between these two time points. Since the time between the HDT and post-transplant immunotherapy was fairly constant (8 weeks), the likelihood of having persistent levels of rituximab in circulation at the time of HDT was mainly dependent on the duration of time elapsing between the purging dose and the administration of HDT. If it is believed that the potential for synergy might be important, future trials should be designed with the purging and apheresis scheduled as close as possible to transplant, in order to ensure that significant levels of rituximab would be present in the serum during the HDT.

Two full courses of rituximab at the standard dose and schedule were administered at 8 and 24 weeks post-transplant. Antibody levels fluctuated from patient to patient, but some definite patterns emerged. Serum rituximab concentrations were detectable after the first infusion, generally doubling by the end of each of the two treatment sets. There was a small amount of detectable antibody that persisted in the serum 13 weeks after completing the first set of infusions, at the time of beginning set 2. Again, only low levels of rituximab were detected in most patients ~3 months after completion of treatment. Interestingly, detectable levels were found at 6 months post-treatment.

Figure 3 depicts the median serum concentrations of rituximab obtained immediately pre- and post-infusions 1 and 4 of sets 1 and 2 in our study patients, as well as the levels achieved at the same time points during rituximab administration in the pivotal trial. It is interesting that the rituximab levels measured before and after infusions 1 and 4 of set 1 so closely parallel the levels achieved during the pivotal trial. At the time that our patients received their first course of post-transplant immunotherapy, they were all in clinical remission with little to no measurable disease burden [22 in complete remission/complete remission (unconfirmed), four in partial remission]. In contrast, the patients treated in the pivotal trial had recurrent low grade NHL with active, measurable disease. Prior studies have demonstrated an inverse correlation between serum rituximab concentration and the degree of tumor bulk, suggesting that the amount of accessible lymphoma may be an important influence on serum antibody levels [21, 25]. One might therefore expect that patients treated post-transplant while in a state of minimal disease would achieve higher peak levels than those being treated for active disease. The finding that peak levels reached after the fourth infusion were quite similar in the two groups suggests that the PK of a monoclonal antibody such as rituximab are complex, and are determined by multiple factors. One other small study evaluated PKs in patients treated at a time of low disease burden [27]. Seven patients with FL receiving rituximab as consolidation after CHOP chemotherapy achieved median concentrations that were similar to those observed in patients in the pivotal trial. This supports the observation that tumor bulk alone is not the only factor influencing serum antibody levels [27]. The precise factors influencing the clearance of rituximab in patients with lymphoma remain unresolved.

The PKs of monoclonal antibodies are related to a number of factors, including the dose administered, the frequency of administration, the antibody’s inherent stability, and both the specific and non-specific clearance of the antibody. The rituximab dose and dosing schedule were identical in the two patient populations we compared. The specific clearance, whereby rituximab is taken up by binding to CD20+ cells, certainly has the potential to be affected by the degree of tumor bulk present. However, the non-specific clearance of antibody, for example via Fc receptors, is unlikely to be affected by tumor bulk. Our results suggest that non-specific mechanisms may play a greater role in determining serum rituximab levels than the specific factors. FcRn receptors found in endothelial cells have been shown to play an important role in the regulation of serum IgG levels [28]. A recent study demonstrated an association between the genotype of the IgG1 Fc receptor Fc{gamma}RIIIa and the therapeutic response to rituximab, whereby patients with the homozygous 158-V polymorphism had superior clinical and molecular response rates to the antibody [29]. This was attributed to favorable binding of rituximab to these Fc{gamma}RIIIa receptors on natural killer cells and macrophages, leading to enhanced antibody-dependent cellular cytotoxicity (ADCC) of lymphoma cells. Although this reflects the role of Fc{gamma}RIIIa-mediated ADCC in the anti-tumor effects of rituximab, not on its PKs, perhaps this or other Fc receptor polymorphisms might in fact play a role in regulating the non-specific clearance of rituximab.

We were unable to assess whether serum rituximab concentrations correlated with clinical response to the antibody in our patients, as they were all in remission at the time they received their post-transplant immunotherapy. However when we compared the rituximab levels of the eight patients who later relapsed to the levels of the 16 patients who still remain in remission, there was no clear correlation between the levels and the durability of responses. The likelihood of developing recurrent lymphoma could not be predicted by the antibody levels achieved in the minimal disease state. Similarily, we also looked at molecular responses in the 15 of 26 study patients in whom PCR information was available (five relapsers, 10 non-relapsers), attempting to relate this surrogate marker to serum levels of rituximab. There was very strong correlation between our clinical results and our molecular results: all five relapsing patients with known molecular results had reconverted to PCR positivity prior to relapse, and all 10 non-relapsers were PCR negative at their last follow-up. No difference in the serum rituximab levels was observed between the patients in molecular remission and those who had a relapse at the molecular level.

Given the fact that earlier published studies have observed a correlation between serum rituximab concentration and clinical response [3, 21, 24, 25], our findings are somewhat surprising. It may be that lower levels of rituximab are sufficient to saturate the fewer lymphoma cells present in the minimal residual state, so that variations in serum rituximab levels may not be as important in determining response duration in this setting. Alternately, the HDT ASCT component of our treatment may have exerted a much greater influence on the duration of response in these patients than the post-transplant rituximab. In patients with follicular lymphoma, the median duration of response after HDT ASCT is ~3–4 years, whereas it is only 1 year after single-agent rituximab. The therapeutic effect induced by the HDT ASCT may have overshadowed any additional benefit derived from the rituximab. The difference in patient population evaluated may have affected our results; the current study included patients with both FL and MCL, whereas the prior studies, which found a correlation between levels and response, did not include patients with MCL [3, 21, 24, 25]. Nevertheless, when we tested only the subgroup of patients with FL (seven relapsers, 12 non-relapsers), we still failed to find a correlation between PKs and outcome (data not shown). It is also possible that patient numbers were simply too small to detect any differences.

Patients with different lymphoma histologies may require different rituximab doses or dosing schedules in order to achieve optimal results. In a number of studies, it was observed that patients with International Working Formulation (IWF) class A achieved lower serum rituximab levels than patients with IWF types B, C or D [21, 24, 25]. These patients also had significantly lower response rates than those with the other lymphoma subtypes [5, 21]. Since the standard once weekly schedule of rituximab 375 mg/m2 appears to be suboptimal in patients with small lymphocytic lymphoma or chronic lymphocytic leukemia (SLL/CLL) [9], investigators have proposed using higher doses or more frequent antibody dosing in this patient subset [30, 31]. Using a three times a week administration schedule, patients with SLL/CLL were actually able to achieve higher response rates and a more favorable PK profile [31].

We observed a trend toward higher mean serum rituximab levels in patients with FL compared with those with MCL. This difference failed to reach statistical significance; however, only a small number of patients were evaluated. It is not clear why MCL patients might achieve lower antibody levels, but one could postulate that perhaps they have a more active non-specific clearance accounting for the lower levels of rituximab attained. Patients with MCL are also known to respond less well to standard single-agent rituximab than patients with FL [710]. One might hypothesize that this is related to the lower serum levels of rituximab attained in these patients, which is a feature known to be associated with lower response rates [3, 21, 24, 25].

This study is the first to provide information on the PK of rituximab in a stem cell transplant setting. We found that patients treated in a minimal disease state achieve serum rituximab concentrations that are quite similar to the levels observed in patients with measurable disease. This suggests that the PKs of rituximab are complex and are influenced by multiple factors. The same doses of rituximab will result in similar serum levels in patients at times of low disease burden, such as the post-transplant period, and in patients with higher active disease burden. The trend toward lower serum rituximab levels in patients with MCL is a novel observation that warrants further study.


    Acknowledgements
 
The authors would like to acknowledge Genentech, Inc. and IDEC Pharmaceuticals for their support with this trial.


    Footnotes
 
+ Correspondence to: Dr N. L. Berinstein, Toronto Sunnybrook Regional Cancer Centre, Sunnybrook and Women’s College Health Sciences Centre, 2075 Bayview Avenue, Toronto, Canada M4N 3M5. Tel: +1-416-480-4928; Fax: +1-416-217-1338; E-mail: neil.berinstein{at}tsrcc.on.ca Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 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: 435–445.[Abstract/Free Full Text]

2. Maloney DG, Liles TM, Czerwinski DK et al. Phase I clinical trial using escalating single dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC C2B8) in patients with recurrent B-cell lymphoma. Blood 1994; 84: 2457–2466.[Abstract/Free Full Text]

3. Maloney D, Grillo-Lopez AJ, Link BK et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 1997; 90: 2188–2195.[Abstract/Free Full Text]

4. 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: 3266–3274.[Abstract]

5. McLaughlin P, Grillo-Lopez AJ, Link BK et al. 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: 2825–2833.[Abstract]

6. Coiffier B, Haioun C, Ketterer N et al. Rituximab for the treatment of relapsing refractory aggressive lymphoma: a multicenter phase II study. Blood 1998; 92: 1927–1932.[Abstract/Free Full Text]

7. 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: 317–324.[Abstract/Free Full Text]

8. Ghielmini M, Hsu Schmitz SF, Burki K et al. The effect of rituximab on patients with follicular and mantle-cell lymphoma. Ann Oncol 2000; 11 (Suppl 1): S123–S126.

9. Nguyen DT, Amess JA, Doughty H et al. IDEC-C2B8 anti-CD20 (rituximab) immunotherapy in patients with low-grade non-Hodgkin’s lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients. Eur J Haematol 1999; 62: 76–82.[ISI][Medline]

10. Foran JM, Cunningham D, Coiffier B et al. Treatment of mantle-cell lymphoma with rituximab (chimeric monoclonal anti-CD20 antibody): analysis of factors associated with response. Ann Oncol 2000; 11 (Suppl 1): S117–S121.

11. 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: 268–276.[Abstract/Free Full Text]

12. Emmanouilides C, Teletar M, Rosen P et al. Excellent tolerance of rituximab when given after mitoxantrone–cyclophosphamide: an effective and safe combination for indolent NHL. Blood 1999; 94: 92a (Abstr 402).

13. Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med 2001; 346: 235–242.[CrossRef][ISI]

14. Buckstein R, Imrie K, Spaner D et al. Stem cell function and engraftment is not affected by ‘in vivo purging’ with rituximab for autologous stem cell treatment for patients with low-grade non-Hodgkin’s lymphoma. Semin Oncol 1999; 26: 115–122.[ISI][Medline]

15. Magni M, Di Nicola M, Devizzi L et al. Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion. Blood 2000; 96: 864–869.[Abstract/Free Full Text]

16. Emmanouilides C, Bosserman L, Grody W. Mobilization of peripheral stem cells in patients with indolent lymphoma using a combination of MINE with rituximab. Blood 1999; 94: 351b (Abstr 4798).

17. Flinn IW, O’Donnell P, Noga SJ et al. In vivo purging with rituximab during stem cell transplantation for indolent lymphoma. Blood 1999; 94: 638a (Abstr 2833).[ISI]

18. Voso MT, Pantel G, Weis M et al. In vivo depletion of B cells using a combination of high-dose cytosine arabinoside/mitoxantrone and rituximab for autografting in patients with non-Hodgkin’s lymphoma. Br J Haematol 2000; 109: 729–735.[CrossRef][ISI][Medline]

19. Brugger W, Hirsch J, Repp R et al. Treatment of follicular and mantle cell non-Hodgkin’s lymphoma with anti-CD20 antibody rituximab after high-dose chemotherapy with autologous CD34+ enriched peripheral blood stem cell transplantation. Blood 2000; 96: 482a (Abstr 2075).

20. Horwitz SM, Negrin RS, Stockerl-Goldstein E et al. Phase II trial of rituximab as adjuvant therapy to high dose chemotherapy and peripheral blood stem cell transplantation for relapsed and refractory aggressive non-Hodgkin’s lymphomas. Blood 2001; 98: 862a (Abstr 3578).

21. 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: 995–1001.[Abstract]

22. 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: 3135–3143.[Abstract/Free Full Text]

23. Tobinai K, Kobayashi Y, Narabayashi M et al. Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma. Ann Oncol 1998; 9: 527–534.[Abstract]

24. 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: 655–661.[Abstract]

25. 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: 1851–1857.[Abstract/Free Full Text]

26. Demiden 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: 177–186.[ISI][Medline]

27. Iacona I, Lazzarino M, Antonietta M et al. Rituximab (IDEC-C2B8): validation of a sensitive enzyme-linked immunoassay applied to a clinical pharmacokinetic study. Ther Drug Monit 2000; 22: 295–301.[CrossRef][ISI][Medline]

28. Ghetie V, Ward ES. Multiple roles for the major histocompatibility complex class I-related receptor FcRN. Annu Rev Immunol 2000; 18: 739–766.[CrossRef][ISI][Medline]

29. Carton G, Dacheux L, Salles G et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor Fc{gamma}RIIIa gene. Blood 2002; 99: 754–758.[Abstract/Free Full Text]

30. O’Brien SM, Kantarjian H, Thomas DA et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001; 19: 2165–2170.[Abstract/Free Full Text]

31. Byrd JC, Murphy T, Howard RS et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 2001; 19: 2152–2164.