Uitspraken

De octrooifamilie en verleningsgeschiedenis

EXAMPLE 3

Phase I/II Study of RITUXAN® in CLL

[0033] RITUXAN® is a monoclonal antibody targeting CD20 that has significant activity in the treatment of low-grade lymphoma (LGL). When given at a dosage of 375 mg/m2 weekly/four response rate in relapsed patients (PTS) was 43% (McClaughlin et al, KOO, Vol. 14, 1998). Patients with small lymphocytic lymphoma had lower response rates (13%) than patients with other subtypes of LGL and lower serum levels of RITUXAN®. Reduced response seen in SLL could be related to lower density of CD20 antigen and/or higher circulating B-cell counts. Both factors would be expected to impact (negatively) on response seen in CLL. In an attempt to maximize activities in CLL we are conducting a Phase I/II study. All patients receive a first dose of 375 mg/m2 to m2 minimize infusion-relapsed side effects.

[0034] Subsequent weekly dosages (3) remain the same but are given at an increased dose level. Sixteen patients have been treated at dosages of 500-1500 mg/m2. Medium age was 66 years (range, 25-78). Eighty-one percent had end-stage III-IV disease. Medium white blood cell count was 40 x 109/L (range, 4-200), Hgb 11.6 g/dl (range, 7.7-14.7), platelets 75 x 109/L (range, 16-160), median β2 immunoglobulin was 4.5 mg/L (range, 3.1-9.2). Median numbers of prior therapies was 2.5 (range 1-9). Sixty percent of patients were refractory to treatment. Two patients developed severe hypertension with the first dose (375 mgm2); another one received further therapy. Toxicity at subsequent escalated dosages has been mild although no patient at the 1500 mg/m3 [bedoeld wordt: 1500 mg/m2 huidoppervlak, rb] dose level has been fully evaluated. Eight patients have completed therapy (4 at 500 mg/m2, 3 at 650 mg/m2, 1 at 825 mg/m2). One patient treated at 560 mg/m2 achieved full remission. One patient has progressive lymphocytosis on treatment and all other patients had reduction in peripheral blood lymphocytosis but less effect on lymph nodes. Dose escalation studies are ongoing.

De stand van de techniek 2

Background. Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are considered different tissue expressions of the same disease process, although they are clinically separable nosologic entities. A systematic comparison of the membrane phenotypes in the two entities needs to be investigated.

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Methods. Cell suspensions from peripheral blood of 184 patients with CLL, bone marrow from 23 patients with CLL, and lymph nodes from 86 patients with SLL were analyzed to compare the membrane phenotypes.

Results. There were no significant differences between the three groups in the mean percentages of cells expressing surface immunoglobulin (SIg), CD5, CD19, CD20, CD2 or in the frequency of cases with weak SIg.

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Conclusions. The similarity of membrane phenotypes between CLL and SLL provided evidence that the two are different tissue expressions of the same disease.

IMMUNOLOGIC FINDINGS

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Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia appears to be the leukemic equivalent of SLL because the immunophenotype of the two is similar. (…)

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COMMENTARY

Malignant disorders of small lymphocytes, despite their morphologic and immunologic similarity, differ clinically and hematologically; therefore they require separate classification and clinical consideration. This is particularly significant because some of the modern lymphoma classifications fail to recognize them as separate entities (particularly the category of SLL). The simple fact, for example, that a patient with the lymph node

histology of SLL and blood lymphocytosis has CLL and not SLL is overlooked. As a result of this approach, in a

recent report of 268 cases of SLL, more than 30% of the patients had absolute blood lymphocytosis (the higher

number of white blood cells in this report was 232.7 X 109/1), and therefore they were cases of CLL. Another

significant implication of making no distinction between SLL and CLL is the fact that, if CLL cases are classified as SLL on the basis of lymph node histology alone, automatically all are going to be considered as stage IV according to the Ann Arbor staging system, because in CLL the bone marrow is always involved. Small lymphocytic lymphoma and CLL, however, have other significant differences that make their distinction necessary. SLL involves the bone marrow occasionally, and its pattern of positivity is nodular, whereas in CLL the bone marrow is always involved and four patterns have been demonstrated; SLL is rarely complicated by bone marrow failure or autoimmune cytopenias and hypogammaglobulinemia, findings that are frequent in CLL.

Furthermore SLL, lymph node lymphocytes express the adhesion molecule LFA-1 (CD11a/CD 18), which is absent from the lymph nodes or blood lymphocytes of CLL, although both SLL and CLL share a large number

of common antigens, including CD5. These observations support the notion that CLL is primarily a disease

of the bone marrow and SLL a disease of the lymph nodes.

The B-cell antigen CD20 is expressed on normal B cells and by nearly all B-cell lymphomas. This nonmodulating antigen provides an excellent target for antibody-directed therapies. A chimeric anti-CD20 antibody (IDEC-C2B8), consisting of human IgG1-k constant regions and variable regions from the murine monoclonal anti-CD20 antibody IDEC-2B8, has been produced for clinical trials. It lyses CD20+ cells in vitro

via complement and antibody-dependent cell-mediated lysis. Preclinical studies have shown that the chimeric antibody selectively depletes B cells in blood and lymph nodes in macaque monkeys. In this phase I clinical trial, 15 patients (3 per dose level) with relapsed low-grade B-cell lymphoma were treated with a single dose (10, 50, 100, 250, or 500 mg/m2) of antibody administered intravenously. Treatment-related symptoms correlated with the number of circulating CD20 cells and grade II events consisted of fever (5 patients), nausea (2), rigor (2), orthostatic hypotension (2), bronchospasm (1), and thrombocytopenia (1). No significant toxicities were observed during the 3 months of follow-up. Serum C3, IgG, and IgM levels, neutrophils, and T cells were largely

unchanged. At the three higher dose levels, pharmacokinetics of the free antibody showed a serum half-life of 4.4 days (range, 1.6 to 10.5). Levels greater than 10 µg/mL persisted in 6 of 9 patients for more than 14 days. No quantifiable immune responses to the infused antibody have been detected. CD20+ B cells were rapidly and specifically depleted in the peripheral blood at 24 to 72 hours and remained depleted for at least 2 to 3 months in most patients. Two-week postinfusion tumor biopsies showed the chimeric antibody bound to tumor cells and a decrease in the percentage of B cells. Tumor regressions occurred in 6 of 15 patients (2 partial and 4 minor responses). The results of this single-dose trial have been used to design a multiple-dose phase I/II study.

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In contrast, the antigen CD20, a 32-kD nonglycosylated phosphoprotein present on the surface of nearly all B cells provides a more universal target for immunotherapy. CD20 is expressed on the surface of normal B cells from the time of cytoplasmic µH chain expression throughout differentiation until the antibody-secreting plasma cell stage. Importantly, it is not expressed on early pre-B cells, stem cells, or antigen-presenting dendritic reticulum cells. More than 90% of B-cell NHLs express this surface protein. It is also expressed at a lower density on B-cell chronic lymphocytic leukemia. Although the function of this molecule is not completely defined, it may aggregate and function as a calcium channel. Antibodies binding to surface CD20 can induce a transmembrane signal that can cause a variety of effects from cell activation to blocking cell cycle progression and differentiation.

The CD20 protein has multiple trans-membrane domains and does not modulate from the cell surface in response to antibody binding and thus provides an ideal target for immunotherapeutic strategies not depending on internalization for their antitumor effect.

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DISCUSSION

In this phase 1 clinical trial, patients with relapsed NHL received a single infusion of chimeric anti-CD20 MoAb IDEC-C2B8 in doses ranging from 10 to 500 mg/m2. All patients received the planned dose and no dose-limiting toxicities were identified. Symptoms were mild to moderate and easy manageable and more commonly observed in the three patients with high numbers of CD20 antigen-bearing B cells (normal or malignant) present in the peripheral blood, suggesting that the destruction or removal of these cells during the early portions of the antibody infusion may contribute to the adverse events observed.

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Treatment caused a selective elimination of the peripheral CD20-expressing B cells in all but 1 patient receiving doses of 100 mg/m2 or greater. (…)
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The mechanism of the antibody-induced antitumor effect is not clear. Serum complement levels (C3) were slightly changed in only 2 patients during therapy. The chimeric antibody is capable of lysing target tumor cell lines in vitro by complement and antibody-dependent cell-mediated lysis. (…)

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Based on these observations of safety and tumor responses to a single infusion of this chimeric anti-CD20 MoAb, a phase I/II trial using four weekly doses of antibody in patients with relapsed B-cell NHL has been initiated.

IDEC-C2B8 is a chimeric monoclonal antibody (MoAb) directed against the B·cell-specific antigen CD20 expressed on non·Hodgkin's lymphomas (NHL). The MoAb mediates complement and antibody-dependent cell-mediated cytotoxicity and has direct antiproliferative effects against malignant B-cell lines in vitro. Phase I trials of single doses up to 500 mg/m2 and 4 weakly doses of 375 mg/m2 showed clinical responses with no dose-limiting toxicity. We conducted a phase II, multicenter study evaluating four weekly infusions of 375 mg/m2 IDEC·C2B8 in patients with relapsed low·grade or follicular NHL (Working Formulation groups A-D). Patients

were monitored for adverse events, antibody pharmacokinetics, and clinical response. Thirty-seven patients with a median age of 58 years (range, 29 to 81 years) were treated. All patients had relapsed after chemotherapy (median of 2 prior regimens) and 54% had failed aggressive chemotherapy. Infusional side effects (grade 1-2) consisting of mild fever, chills, respiratory symptoms, and occasionally hypotension were observed mostly with the initial antibody infusion and were rare with subsequent doses. Peripheral blood B-cell depletion occurred rapidly, with recovery beginning 6 months posttreatment. There were no significant changes in mean lgG levels and infections were not increased over what would be expected in this population. Clinical remissions were observed in 17 patients (3 complete remissions and 14 partial remissions), yielding an intent to treat response rate of 46%. The onset of these tumor responses was as soon as 1 month posttreatment and reached a maximum

by 4 months posttreatment. In the 17 responders, the median time to progression was 10.2 months (5 patients exceeding 20 months). Likelihood of tumor response was associated with a follicular histology, with the ability to sustain a high serum level of antibody after the first infusion, and with a longer duration of remission to prior chemotherapy. One patient developed a detectable but not quantifiable immune response to the antibody that had no clinical significance. IDEC·C2B8 in a dose of 375 mg/m2 weekly for 4 weeks has antitumor activity in patients with relapsed low-grade or follicular NHL. Results with this brief, outpatient treatment compare favorably with results with standard chemotherapy, and IDEC·C2B8 has a better safety profile. Further studies evaluating IDEC-C2B8 in other types of lymphoma either alone or combined with chemotherapy are warranted.

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IDEC-C2B8 is a chimeric anti-CD20 MoAb containing human IgGl and k constant regions with murine variable regions. It binds the CD20 antigen with high affinity (5x10-9 mol/L). Because of the human constant Ig regions, the chimeric antibody efficiently kills CD20 cells in virtro by augmented complement-mediated lysis and participates in antibody-dependent cell-mediated cytotoxicity (ADCC) using human complement and immune effector cells. In some NHL cell lines, the binding of the antibody inhibits proliferation and directly induces apoptosis. In patients with lymphoma, the administration of single doses up to 500 mg/m2 was not associated with any dose limiting toxicity. Rapid binding to and depletion of CD20+ normal B cells and tumor cells in the peripheral blood and bone marrow was observed, and tumor cells in lymph node biopsies obtained 2 weeks after antibody therapy showed that the chimeric MoAb bound to CD20 antigen sites. The treatment was well tolerated, causing only minimal infusion-related symptoms. (…)

Summary In this report we present a patient with B-cell chronic lymphocytic leukemia who developed an acute tumor lysis syndrome after administration of the human anti-CD20 antibody IDEC-C2B8 (RITUXIMAB) in standard dose of 375 mg/m2. IDEC-C2B8 has been demonstrated to have only mild and tolerable side effects in patients with follicular lymphoma. In these trials patients with lymphocytosis >5000/l were excluded. Physicians must be aware of this hitherto unreported phenomenon in patients with high CD20-positive blood counts.

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Introduction

Clinical trials with the chimeric human monoclonal anti-CD20 antibody IDEC-C2B8 (rituximab) demonstrated remission rates up to 50% in relapsed low-grade follicular non-Hodgkin's lymphoma. Efficacy and safety in the treatment of chronic lymphocytic leukemia (CLL) and other blood-born tumors has not been investigated yet. Here we report on a 26-year-old woman with B-CLL who experienced a rapid reduction of circulating malignant cells accompanied by severe side effects after her first rituximab infusion.

Case report

In October 1997, a 26-year-old female patient with progressive low-grade B-cell lymphoma was admitted to our hospital. She had been heavily pretreated including 12 cycles of intensive chemotherapy and high dose chemotherapy with peripheral stem cell support. She had enlarged cervical and abdominal lymph nodes, hepatosplenomegaly and bone marrow infiltration. A leukocytosis of 111.9 x 109/L with 97% small malignant lymphocytes was noticeable, phenotypically resembling B-cell chronic lymphocytic leukemia (CD5+, CDl0-,

CD19+, CD23+, CD25+). The CD20 surface marker was expressed on 100% of these cells. As a result of clinical reevaluation, a treatment with the anti-CD20 antibody rituximab was initiated.

After prophylactic hydration, as well as administration of 1000 mg acetaminophen and 300 mg allopurinol, treatment was begun with a predose of 50 mg antibody. The patient complained about moderate scratching sensations in her throat, chills, and a moderate rise in body temperature 90 min after this test infusion. Following pethidine, she recovered quickly, and the remaining 550 mg of the planned dose (375 mg/m2) was given over

four and one-half hours. Shortly after the infusion was completed, chills occurred again and fever up to 39.7C developed. The pulse increased to 124/min. The patient complained about nausea and vomiting. A blood count revealed a sharp decline in leukocytes from 111.9 x 109/L to 24.0 x 109/L and a drop in platelets from 137.0 x 109/L to 35.0 x 109/L. The plasma prothrombin time fell from 92% to 65%, and serum LDH activity rose from 464 U/L to 793 U/L.

During the following 24 hours, the clinical condition and laboratory parameters of the patient further deteriorated (see Figure), resembling an acute tumor lysis syndrome with disseminated intravascular coagulation. Serum LDH rose to >2000 U/L; plasma prothrombin time and platelets continued to drop to 47% and 23 x 109/L, respectively. The plasma D-dimers rose from 4.8 mg/L to 42.2 mg/L; serum transaminase activities were moderately increased (Figure). Importantly, complement factors were undetectable 7 hours after the beginning of the infusion. The patient was intensively treated with forced diuresis including furosemide, bicarbonate, calcium, potassium, platelet transfusion as well as ondansetron. As a result, the clinical performance status gradually improved from day two onwards, and laboratory parameters began to normalize. Three further infusions of rituximab were administered in full dose on days 8, 15, and 22 without clinical problems. The patient's leukocyte count subsequently normalized (8.8 x 109/L) for 3 weeks whereafter she showed signs of progressive disease, requiring salvage chemotherapy.

Discussion

Fast but transient clearance of circulating lymphoma cells without major side effects using a monoclonal antibody was reported by Nadler et al. in a patient with diffuse, poorly differentiated lymphocytic lymphoma

(DPDL) and a WBC of 110.000 x 109/L. In patients with chronic lymphocytic leukemia, elimination of malignant cells from the blood stream has been observed using another human monoclonal antibody, Campath-

1H (anti-CD52). The effector mechanisms of Campath-1H include complement-mediated lysis and cellular

cytotoxicity and are very similar to those employed by rituximab. Since complement factors dropped to

undetectable levels in our patient within seven hours, it might be speculated that the complement-mediated cell

lysis played a decisive role in triggering the acute tumor lysis observed.

Although the major non-hematological side effects such as nausea, fever, rigor or hypotension are similar for rituximab and Campath-1H, none of 29 CLL patients treated with Campath-1H showed signs of rapid tumor lysis. One possible explanation is the different schedule used: Campath-1H was administered three times weekly at initial doses of 3 or 10 mg which were escalated to 30 mg. The recommended standard dose of 375 mg/m2 for rituximab was established in patients with follicular lymphoma and lymphocyte counts of less than 5.0 x 109/L. Thus, this dose might be too high for the treatment of patients with substantial peripheral tumor load. Alternatively, high peripheral tumor cell counts must be reduced using cytostatic drugs prior to

administration of rituximab.

Recently, we have treated six additional B-CLL patients and one patient with a leukemic mantle cell lymphoma

with rituximab. The clinical side effects were minor in three patients with lymphocyte counts of 0.2 x 109/L, 6.6 x 109/L, and 9.4 x 109/L, respectively. Signs of acute tumor lysis and NCI grade III and IV toxicities occurred in patients with marked lymphocytosis who had 30.7 x 109/L, 60.8 x 109/L, 69.8 x 109/L, 108.5 x 109/L, and 294.3 x 109/L lymphocytes, respectively.

When treating patients with CLL and marked lymphocytosis with the monoclonal antibody rituximab, physicians need to be aware of the risk of hitherto unreported acute tumor lysis and intravascular coagulation.

Purpose : The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively mediates host effector functions and is itself less immunogenic than are murine antibodies.

Patients and Methods : This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8.

Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC·

C2B8 375 mg/m2 intravenously weekly for four doses.

Results : From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a

median follow-up duration of 11.8 months, the projected median time to progression for responders is

months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and

were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred

during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of

patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one

patient.

Conclusion : The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration

according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.

Approximately 80% of malignant lymphomas are of B-cell origin. Virtually all patients with low grade or follicular histology will eventually relapse after treatment with currently available standard therapies, as will many with more aggressive histologic categories. Those who relapse need alternative therapeutic approaches.

The cell-surface antigen CD20 is expressed on more than 90% of B-cell lymphomas and chronic lymphocytic leukemias, and on 50% of pre-B-cell acute lymphoblastic leukemia. It is expressed on normal B cells from the pre-B-cell stage to the activated B-cell stage, but is not expressed on stem cells, plasma cells, or cells of other lineages. It is a transmembrane protein that appears to act as a calcium channel and to play an important role in cell-cycle progression and differentiation. Monoclonal antibodies that target the CD20 antigen have been developed, both for diagnostic and therapeutic purposes. The CD20 antigen is appealing for targeted therapy, because it does not shed, modulate, or internalize.

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The chimeric human-mouse anti-CD20 monoclonal antibody, Rituximab (IDEC-C2B8; IDEC Pharmaceuticals Corp, San Diego, CA), is a human immunoglobulin (Ig) G1 kappa antibody, with mouse variable regions isolated from a murine anti-CD20 monoclonal antibody, IDEC-2B8. A single-dose phase I trial demonstrated both biologic efficacy in terms of transient B-cell depletion and a good safety profile. [voetnoot 18: 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 84:2457-2466, 1994] Subsequently, a multiple-dose schedule was shown to be feasible and to achieve a 50% response rate in a cohort of 34 patients with relapsed low grade lymphoma. [voetnoot 19: Maloney DG, Grillo-Lopez AJ, White CA, et al: IDEC-C2B8 (Rituximab) anti-CD20 antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma, Blood 90:2188-2195, 1997]

The current report summarizes results of a multiinstitutional trial of a four-dose course of therapy with this chimeric anti-CD20 monoclonal antibody.

PATIENTS AND METHODS

Eligibility

Adult patients with relapsed low grade or follicular B-cell lymphoma, histologically confirmed and positive for CD20, were eligible. Patients with chronic lymphocytic leukemia (lymphocytes >5x109/L) were excluded. Patients had to have either not responded to primary therapy or relapsed (…), have progressive measurable disease, and sign an institutional review board-approved informed consent. (…)

Therapy

The antibody dose was 375 mg/m2, administered intravenously once weekly for a total of four infusions (days 1, 8, 15, and 22) on an outpatient basis. (…)

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RESULTS

Patient Features

The 166 patients were enrolled at 31 centers in the United States and Canada between April 1995 and March 1996. The median age was 58 years (range, 22 to 79). There were 105 men and 61 women. There were 33 with small lymphocytic lymphoma (SL), 67 with follicular small cleaved, 53 with follicular mixed, three with other low grade lymphoma variants, and 10 with follicular large cell. The median time since diagnosis was 4.1 years (range, 0.5 to 25).

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Response

The overall response rate for the intent-to-treat group of all 166 patients was 48%, of which 6% were CRs and the remainder PRs.

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DISCUSSION

The response rate was 50% with this outpatient four-dose course of therapy with IDEC-C2B8 for patients with relapsed low grade or follicular lymphoma. Most of the responses were partial (6% complete), which is typical of single-agent therapy in the setting of relapsed lymphoma. These results are comparable to some of the most encouraging recent chemotherapy results for relapsed indolent lymphoma, such as with fludarabine or 2-chlorodeoxyadenosine.

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The toxicity of the current program was notably mild, particularly with respect to myelosuppressive toxicities that are typical of standard chemotherapy or RIT. Adverse events occurred mainly with the first infusion, in a constellation that typically included modest (grade 1 or 2) and brief (minutes to hours) fever, chills, and aches. By the second and subsequent infusions, the majority of patients experienced no further infusion-related toxicities. (…)

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The high response rate with this antibody was encouraging, including its efficacy in patients with adverse prognostic features (…) and in patients who often tolerate standard therapies poorly (…). Observations in patient subsets with low response rates were also informative. A rapid clearance of the antibody, which may be related, in part, to high tumor burden (“antigen sink”), correlated with a lower response rate. Conceivably, higher doses or more protracted dosing schedules might overcome this problem. The lower response rate with SL lymphoma, compared with follicular lymphoma, may relate to the lower density of CD20 antigen expression on SL cells. However, patients with SL in this trial also typically had higher circulating B-cell counts and consequently a more rapid clearance of the agent than other patients, so the lower response rate in SL lymphoma may also be related to their lower measurable antibody levels.

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Many additional issues about this agent remain to be explored. (…) On the basis of the 50% response rate in this trial, using this well-tolerated, outpatient treatment schedule that is completed in 22 days, further trials with this agent are warranted.

Summary

Background: Monoclonal antibodies are being utilized for treatment of patients with low-grade non-Hodgkin's lymphoma as well as other cancers. Results from phase I and II clinical studies has shown that the chimeric monoclonal antibody Rituximab has minimal toxicity and significant therapeutic activity in low grade non-Hodgkin's lymphoma.

Patients and methods: We have recently reported on a multi-centre pivotal phase III clinical trial involving 166 patients with recurrent low-grade lymphoma who were treated with four infusions of Rituximab. Eighty patients (48%) achieved objective responses including 10 patients (6%) with complete responses. Overall, 126 patients (76%) had a 20% reduction in overall tumor size. The median response duration and time to progression are 11.6 and 13.2 months, respectively. The infusional and long term toxicities were limited.

Results: In this report we describe the pharmacokinetic data obtained on these patients. Measurable concentrations of Rituximab were detected in all patients after the first infusion and increased throughout the treatment course. The half-life of the monoclonal antibody increased from 76.3 hours after the first infusion to 205.8 hours after the fourth infusion and was concomitant with a four-fold decrease in the antibody clearance. At three months and six months post-treatment, the median Rituximab serum levels were 20.3 µg/ml (range 0.0 to

µg/ml in 104 patients) and 1.3 µg/ml (range 0.0-28.7 µg/ml in 13 patients), respectively. A statistically significant correlation was found between the median antibody concentration and response for multiple time points during the treatment and followup. The mean serum antibody concentration was also inversely correlated with measurements of tumor bulk and with the number of circulating B cells at baseline.

Conclusions: We conclude that Rituximab is therapeutically effective against B-cell lymphoma. Pharmacokinetic data suggests that certain subsets of patients may possibly benefit from increased dosing and studies to address this are currently underway.

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Discussion

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The level of Rituximab used in this study (375 mg/m2) was chosen based upon these previous studies because it was a safe, non toxic dose with demonstrable therapeutic activity. However extrapolation of these results suggest that higher doses of Rituximab may result in even higher serum levels of Rituximab and possibly greater therapeutic activity in certain patient subsets.

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The association of high serum antibody concentration and response and the association of high serum antibody concentration with lower tumor bulk suggest that higher doses (or more doses) of Rituximab may be necessary to induce responses in some subsets of patients such as those with bulky disease.

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Future studies will address whether anti-tumor activity can be enhanced even further by administration of larger total doses of Rituximab.

In conclusion, the results of this study indicate that rituximab therapy has significant anti-lymphoma activity in DLCL and MCL patients without the toxicity commonly observed with combination chemotherapy regimens. There was no marked differences in efficacy between the two dosing regimens, but the safety profile of the higher dose (500 mg/m2) was less favorable as compared with the standard dose regimen (375 mg/m2). This regimen should be evaluated in combination with standard chemotherapy in patients with aggressive B-cell lymphoma.

De kort geding procedure

- althans voor recht te verklaren dat Biogen niet gerechtigd is tot handhaving van het Nederlandse deel van EP 313 jegens Celltrion.

Zoals hiervoor sub 1.2. is overwogen, is deze wijziging van eis ter zitting geweigerd.