Variability in Response to Rituximab in Autoimmune Diseases
Variability in Response to Rituximab in Autoimmune Diseases
Rituximab (IDEC-C2ref-8) is a chimeric IgG1κ (variable CDR regions [mouse] and Fc constant portion [human]) monoclonal antibody (mAb) directed against CD20. It was first developed by IDEC Pharmaceuticals Corporation. CD20 was chosen as a therapeutic target because it was thought to: be exclusively expressed on B cells; not modulate or shed; and be expressed by more than 90% of B-cell malignancies such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). The mechanisms of action of rituximab have been extensively studied in the context of B-cell malignancies. The knowledge thus gained is being exploited for the development of better therapies to improve patient outcomes.
In the initial Phase I, single dose-ranging (10, 50, 100, 250 and 500 mg/m) study of rituximab in NHL, peripheral blood B cells were specifically depleted and remained depleted for 1 to more than 3 months. Serum rituximab levels were variable and the serum half-life was 4.4 days for patients treated with doses of 100 mg/m or higher. Tumor tissue examination 2 weeks after treatment showed rituximab bound to tumor cells in several of the cases, which suggests that not all rituximab-coated cells are deleted. Modest tumor responses were seen in seven of the nine patients treated with doses equal to or greater than 100 mg/m. Subsequently, the therapeutic regimen of 4 weekly infusions of 375 mg/m was chosen following a Phase I, multiple-dose (125, 250 or 375 mg/m each) study and first used in a Phase II study of rituximab, in 37 patients with NHL, who had relapsed despite aggressive chemotherapy. Rituximab was licensed for use in refractory NHL, following the pivotal study by McLaughlin and colleagues demonstrating that at least half patients with refractory low-grade or follicular lymphoma (FL) responded to rituximab monotherapy. In this Phase II/III study of NHL, 166 patients with refractory NHL were treated with rituximab. The response rate was 48% after a median follow-up duration of 11.8 months. Responding patients were noted to have follicular histology, higher serum rituximab levels, and also lower tumor burdens. Fifteen of the 16 patients who did not deplete peripheral blood B cells to undetectable levels did not respond to treatment. Only one patient developed human antichimeric antibodies (HACA). Response rate in FL increased to 60% using, instead of four, eight consecutive weekly infusions of 375 mg/m of rituximab. Igarashi et al. reported that extranodal disease was also associated with poor response in FL.
Association of response with follicular histology was also described in another small early study where all seven responding patients had FL while the nonresponders included two with diffuse large-cell lymphoma (DLCL) and one with mantle cell lymphoma (MCL). Interestingly, serum rituximab levels increased incrementally with repeated infusions and were detectable in most patients at 3 months. Serum half-life of rituximab was estimated at 18 ± 15 (mean ± SD) days. Lower response rates in DLCL and MCL were also reported in another Phase II study of 54 patients with DLCL or MCL, which yielded response rates of 37 and 33%, respectively. The features that were more commonly noted in nonresponders were chemotherapy-refractory disease, MCL histology and tumor size > 5cm in diameter. Response rates in small lymphocytic lymphoma (SLL)/CLL were also much lower. A study of 33 patients with SLL/CLL treated with variable doses of rituximab (100 mg × 1, 250 mg/m, weekly infusions of 375 mg/m for 4 weeks) showed that the overall response rate was 45% with only 3% achieving complete response. O'Brien and colleagues reported that clinical response in CLL may be improved using a higher dose of rituximab. In this study involving 40 patients with CLL, a dose-escalation regimen with a starting dose of 375 mg/m and subsequently the dose was escalated from 500 to 2250 mg/m. Interestingly, a dose-dependent clinical response was noted with 22, 43 and 75% for dosing regimens 500–825, 1000–1500 and 2250 mg/m, respectively. Further the duration of response was shorter than that seen for NHL. Interestingly, even in patients with same histology, CLL, genomic microarray either alone or in combination with laboratory parameters such as IgVH mutation has been shown to accurately distinguish responders from nonresponders to rituximab.
Other studies explored the use of rituximab in combination with chemotherapy. In NHL, the response rates were impressive at 89–95% overall response rate and 56% complete response when rituximab was used in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) chemotherapy. Furthermore, the responses were sustained at long term with median follow-up period of 63 months achieving a 5-year progression-free survival of 82%. The efficacy of a combination chemoimmunotherapy, rituximab-CHOP, for NHL was also confirmed in larger studies. In NHL, serum rituximab levels correlated with female gender (higher), tumor burden (bone marrow infiltration) and clinical response. Pfreundschuh and colleagues have conducted a randomized trial comparing rituximab-CHOP versus CHOP in 824 patients with a follow-up duration of 6 years showing better overall survival in the group receiving rituximab at 74% when compared with 56% for the group without rituximab. Griffin et al. have published an excellent critical overview of the use of rituximab in NHL in RCT settings.
Thus, taken together, it appears that the clinical response to rituximab in B-cell malignancies was influenced by: the histological type, extra-nodal disease and the tumor burden; rituximab dose used; persistent high serum levels of rituximab; better response to prior chemotherapy; and rituximab used in combination with chemotherapy. However, the mechanisms underlying variability between individuals in clinical response within each disease category and factors influencing serum rituximab levels remained elusive. Therefore, several groups focused on understanding the mechanisms of action of rituximab (see secion 'So, what factors determine resistance to depletion with rituximab?').
What Can We Learn From the Experience of Using Rituximab for B-Cell Malignancies?
Rituximab (IDEC-C2ref-8) is a chimeric IgG1κ (variable CDR regions [mouse] and Fc constant portion [human]) monoclonal antibody (mAb) directed against CD20. It was first developed by IDEC Pharmaceuticals Corporation. CD20 was chosen as a therapeutic target because it was thought to: be exclusively expressed on B cells; not modulate or shed; and be expressed by more than 90% of B-cell malignancies such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). The mechanisms of action of rituximab have been extensively studied in the context of B-cell malignancies. The knowledge thus gained is being exploited for the development of better therapies to improve patient outcomes.
Clinical Response to Rituximab: The Effect of Disease Heterogeneity, Rituximab Pharmacokinetics & the Host's Immune System
In the initial Phase I, single dose-ranging (10, 50, 100, 250 and 500 mg/m) study of rituximab in NHL, peripheral blood B cells were specifically depleted and remained depleted for 1 to more than 3 months. Serum rituximab levels were variable and the serum half-life was 4.4 days for patients treated with doses of 100 mg/m or higher. Tumor tissue examination 2 weeks after treatment showed rituximab bound to tumor cells in several of the cases, which suggests that not all rituximab-coated cells are deleted. Modest tumor responses were seen in seven of the nine patients treated with doses equal to or greater than 100 mg/m. Subsequently, the therapeutic regimen of 4 weekly infusions of 375 mg/m was chosen following a Phase I, multiple-dose (125, 250 or 375 mg/m each) study and first used in a Phase II study of rituximab, in 37 patients with NHL, who had relapsed despite aggressive chemotherapy. Rituximab was licensed for use in refractory NHL, following the pivotal study by McLaughlin and colleagues demonstrating that at least half patients with refractory low-grade or follicular lymphoma (FL) responded to rituximab monotherapy. In this Phase II/III study of NHL, 166 patients with refractory NHL were treated with rituximab. The response rate was 48% after a median follow-up duration of 11.8 months. Responding patients were noted to have follicular histology, higher serum rituximab levels, and also lower tumor burdens. Fifteen of the 16 patients who did not deplete peripheral blood B cells to undetectable levels did not respond to treatment. Only one patient developed human antichimeric antibodies (HACA). Response rate in FL increased to 60% using, instead of four, eight consecutive weekly infusions of 375 mg/m of rituximab. Igarashi et al. reported that extranodal disease was also associated with poor response in FL.
Association of response with follicular histology was also described in another small early study where all seven responding patients had FL while the nonresponders included two with diffuse large-cell lymphoma (DLCL) and one with mantle cell lymphoma (MCL). Interestingly, serum rituximab levels increased incrementally with repeated infusions and were detectable in most patients at 3 months. Serum half-life of rituximab was estimated at 18 ± 15 (mean ± SD) days. Lower response rates in DLCL and MCL were also reported in another Phase II study of 54 patients with DLCL or MCL, which yielded response rates of 37 and 33%, respectively. The features that were more commonly noted in nonresponders were chemotherapy-refractory disease, MCL histology and tumor size > 5cm in diameter. Response rates in small lymphocytic lymphoma (SLL)/CLL were also much lower. A study of 33 patients with SLL/CLL treated with variable doses of rituximab (100 mg × 1, 250 mg/m, weekly infusions of 375 mg/m for 4 weeks) showed that the overall response rate was 45% with only 3% achieving complete response. O'Brien and colleagues reported that clinical response in CLL may be improved using a higher dose of rituximab. In this study involving 40 patients with CLL, a dose-escalation regimen with a starting dose of 375 mg/m and subsequently the dose was escalated from 500 to 2250 mg/m. Interestingly, a dose-dependent clinical response was noted with 22, 43 and 75% for dosing regimens 500–825, 1000–1500 and 2250 mg/m, respectively. Further the duration of response was shorter than that seen for NHL. Interestingly, even in patients with same histology, CLL, genomic microarray either alone or in combination with laboratory parameters such as IgVH mutation has been shown to accurately distinguish responders from nonresponders to rituximab.
Other studies explored the use of rituximab in combination with chemotherapy. In NHL, the response rates were impressive at 89–95% overall response rate and 56% complete response when rituximab was used in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) chemotherapy. Furthermore, the responses were sustained at long term with median follow-up period of 63 months achieving a 5-year progression-free survival of 82%. The efficacy of a combination chemoimmunotherapy, rituximab-CHOP, for NHL was also confirmed in larger studies. In NHL, serum rituximab levels correlated with female gender (higher), tumor burden (bone marrow infiltration) and clinical response. Pfreundschuh and colleagues have conducted a randomized trial comparing rituximab-CHOP versus CHOP in 824 patients with a follow-up duration of 6 years showing better overall survival in the group receiving rituximab at 74% when compared with 56% for the group without rituximab. Griffin et al. have published an excellent critical overview of the use of rituximab in NHL in RCT settings.
Thus, taken together, it appears that the clinical response to rituximab in B-cell malignancies was influenced by: the histological type, extra-nodal disease and the tumor burden; rituximab dose used; persistent high serum levels of rituximab; better response to prior chemotherapy; and rituximab used in combination with chemotherapy. However, the mechanisms underlying variability between individuals in clinical response within each disease category and factors influencing serum rituximab levels remained elusive. Therefore, several groups focused on understanding the mechanisms of action of rituximab (see secion 'So, what factors determine resistance to depletion with rituximab?').
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