Rituximab Combination Therapy Research Articles

B-lymphocytes as Targets for Therapy in Chronic Cold Agglutinin Disease

Primary chronic cold agglutinin disease (CAD) is an autoimmune hemolytic anemia induced by cold reactive autoantibodies (cold agglutinins) against erythrocyte surface antigens. Corticosteroids or alkylating agents have been used in the treatment of CAD, but the results have been disappointing. The cold agglutinins in CAD patients are monoclonal immunoglobulins, usually of the IgMkappa type encoded by the V(H)4-34 gene segment. Flowcytometric assessment of lymphocytes from bone marrow aspirates and immunohistochemical assessment of biopsy samples have revealed a monoclonal CD20(+) kappa(+) B lymphocyte population in 90% of the patients. These pathogenetic features have provided a basis for novel therapies in primary CAD. Infusions of rituximab, a chimeric human-murine anti-CD20 antibody known to be effective in B-cell lymphoma, produced partial response rates of approximately 50% and occasional complete responses. Median response duration, however, was only 11 months. Complement C3 and C4 depletion in many CAD patients, as well as Fc-gamma-RIIIa receptor polymorphism, have been proposed as explanations for the inconstant efficacy of rituximab therapy. In order to increase response rates and response duration, we are undertaking a phase 2 study of rituximab and fludarabine combination therapy. The preliminary results are encouraging, but further studies are required in order to allow firm conclusions.

Use of Rituximab in Patients with Follicular Lymphoma

Advanced stage symptomatic follicular non-Hodgkin's lymphoma (NHL) is rarely, if ever, curable with conventional chemotherapy. Patients classically experience a pattern of remission and relapse, eventually dying of their disease. Data from a number of large-scale randomised phase III trials, both as first-line therapy and in relapsed/refractory patients, comparing rituximab plus chemotherapy with chemotherapy alone indicate that the addition of rituximab to a number of different chemotherapy regimens increases response rates and progression-free survival (PFS), without significantly increasing toxicity. Moreover, in four trials, three in first-line and one in relapsed disease, a significant overall survival benefit has been observed for rituximab combination therapy. These data indicate that patients with follicular NHL who require therapy should now receive rituximab plus chemotherapy as first-line treatment. Additionally, a strong case remains for offering rituximab-based therapy to patients with relapsed disease who have not previously received it, and in those who have previously responded well to this agent. Rituximab maintenance therapy has also been shown to significantly prolong PFS after rituximab in combination with chemotherapy in patients with relapsed disease and in newly diagnosed patients who have not received rituximab during induction, and the benefit of maintenance after immunochemotherapy in relapsed patients may yet be mirrored by ongoing studies in the first-line setting. This overview considers the most recently published clinical trials of rituximab and their potential effect on clinical practice in the treatment of follicular NHL.

A Phase 2 Study of Rituximab in Combination with Recombinant Interleukin-2 for Rituximab-Refractory Indolent Non-Hodgkin's Lymphoma

The incidence of non-Hodgkin's lymphoma (NHL), the fifth most common malignancy in the United States, has increased over 70% in the last 30 years. Fifty percent to 75% of patients with low-grade or follicular NHL respond to rituximab therapy. However, responses are generally of limited duration, and complete responses are rare. Preclinical work suggests that human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) enhances rituximab efficacy. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of action of rituximab. rIL-2 induces expansion and activation of Fc receptor (FcR)-bearing cells, thereby enhancing ADCC. Therefore, a large, multicenter phase 2 trial to assess the effects of rIL-2 on rituximab therapy in patients with rituxumab-refractory low-grade NHL was conducted. The combination of rituximab and rIL-2 was studied in 57 patients with rituximab-refractory low-grade NHL (i.e., patients must have received a single-agent course of rituximab and showed no tumor response, or had a response lasting <6 months). I.V. rituximab was given at 375 mg/m(2) (weeks 1-4). S.C. rIL-2 was given thrice a week at 14 MIU (weeks 2-5) and at 10 MIU (weeks 6-9). Rituximab plus rIL-2 combination therapy was safe and generally well tolerated, but responses were low. Fifty-seven patients were enrolled with 54 evaluable for response; however, only five responses (one complete and four partial) were observed. Correlative data indicate that rIL-2 expanded FcR-bearing cells and enhanced ADCC. However, other factors, such as FcgammaR polymorphisms in patients refractory to single-agent rituxumab and heterogeneous tumor biology, may have influenced the lack of clinical efficacy seen with this combination therapy. rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL.

Mobilization of Peripheral Blood Stem Cells with Rituximab Plus ESHAP Combination Regimen in B-Cell NHL - Preliminary Results.

Objectives: The mobilization chemotherapy should be directed toward the dual objectives of good antilymphoma activity and adequate PBSC mobilization. Previously, we reported the ESHAP plus G-CSF is an effective mobilization regimen in patients with relapsed and high risk NHL. The purpose of this study is to assess the efficacy and feasibility of autologous stem cell collection after mobilization with Rituximab plus ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) combination therapy in B-cell Non-Hodgkin's lymphoma.Patients and Methods: CD20 + B-cell NHL patients with either high risk, relapsed or refractory patients were eligible for the study. The regimen consisted of: Rituximab 375mg/m2 given on day 1, standard ESHAP therapy (etoposide 40mg/m2 IV/2hr day 2–5, methylprednisolone 500mg/m2 days 2–6, cytarabine 2g/m2 IV/3hr on day 5 and cisplatin 25mg/m2 CIV days 2–5).In all patients, the collection of PBSC was performed during recovery after giving G-CSF (10μ/kg/day) started on day 7. The first harvest was started only if the peripheral blood hematopoietic progenitor cell (HPC) count exceeded 5/μl.Results: Fifty-five mobilization procedures performed on 20 patients with a median of three apheresis (range 2–5) per patient. Median age was 37 years (range 15–65). At the time of PBSC mobilization, Seventeen patients were considered to be responsive (CR, PR and sensitive relapse). Aphereses were started on day 16 (range 13–18). The number of total MNCs (×106/kg) collected was 5.4 (range, 1.4–14.5) and the number of CD34+cells (× 106/kg) was 10.6 (range, 4.9–52.6). The median days of G-CSF usage was 11(range 9–15). Most non-hematologic adverse events were mild and reversible. Nineteen patients (95%) were achieved optimal response, which was defined as ≥ 5 × 106 CD34 cells/kg. In all, sixteen of the patients underwent high-dose chemotherapy. The median time to ANC ≥ 0.5 × 109/L was 10 days (range, 8–17). The median days to platelets ≥ 20 × 109/L was 12 (range, 7–27).Conclusion: Addition of Rituximab to ESHAP chemotherpy does not show any adverse effect in autologous stem cell mobilization and collection. R-ESHAP regimen is effective as a combined mobilization and second-line regimen for patients with pretreated B-cell lymphoma. [Display omitted]

In lupus nephritis, the benefit of rituximab monotherapy, as opposed to rituximab plus cyclophosphamide combination therapy, remains uncertain: Comment on the article by Sfikakis et al

In lupus nephritis, the benefit of rituximab monotherapy, as opposed to rituximab plus cyclophosphamide combination therapy, remains uncertain: Comment on the article by Sfikakis et al

IL-21 Improves Rituximab-Mediated B Cell Depletion.

IL-21 is a cytokine produced by activated CD4+ T cells that augments the growth, survival, and function of NK, T and phagocytic cells. IL-21 also plays an important role in regulating B cell proliferation and differentiation. In a previous study of cynomolgus monkeys treated with recombinant human IL-21, we demonstrated increased numbers of NK cells and phagocytic cells expressing Fcγ RI and III, enhancement of ex vivo antibody dependent cellular cytotoxicity (ADCC) activity, altered lymphocyte trafficking, and improved B cell depletion with subclinical doses of rituximab. The current study aimed to extend these findings to a clinically relevant rituximab dose regimen, and to evaluate the safety and tolerability of IL-21 administration in this setting. Three groups of cynomolgus monkeys (n=8) were treated by IV injection once weekly for four weeks with rituximab (10 mg/kg), concurrently with vehicle or IL-21 (0.3 or 1.5 mg/kg). Standard toxicology data were collected. The number and activation state of peripheral blood leukocyte subsets were determined by flow cytometry. Effects on B cells within spleen and lymph nodes were evaluated by immunohistochemistry. Co-administration of rituximab and IL-21 was well tolerated at both dose levels of IL-21 tested. The primary toxicological responses to the combination treatment were moderate anemia and thrombocytopenia, which were IL-21 dose dependent and similar in magnitude to those observed in previous IL-21 toxicology studies. In animals treated with rituximab alone, circulating B cells were depleted to a nadir 0.3–3 % of baseline on Day 11 of the study (Figure 1). In contrast, significantly lower B cell nadirs were observed following the first treatment with rituximab and IL-21 combination therapy (p< 0.01, ANOVA). In animals receiving the 1.5 mg/kg dose of IL-21, circulating B cells were depleted to a nadir 0 −1 % of baseline on Day 4, followed by partial recovery and further depletion to 0.3 – 2% of baseline on Day 11. More importantly, B cell recovery was significantly delayed in the group treated with rituximab and 1.5 mg/kg IL-21, compared to rituximab treatment alone (p< 0.05, ANOVA/PLSD). Thirty days following the fourth and final treatment, B cell numbers had recovered to only 6% of baseline, compared to 22% in the rituximab monotherapy treated group. Additionally, coadministration of IL-21 with rituximab increased circulating activated monocytes, granulocytes and NK cells compared with rituximab monotherapy. In conclusion, addition of IL-21 to a standard weekly, 4-dose regimen of IV rituximab was well-tolerated in cynomolgus monkeys and resulted in more complete, rapid and durable depletion of circulating CD20-expressing target cells. As depletion of B cells in this model serves as a surrogate for clearance of CD20-expressing malignant cells, these data support the evaluation of IL-21 and rituximab combination therapy in patients with advanced CD20 positive malignancies. [Display omitted]

Investigation of FcγR Polymorphisms and Response to IL-2 (Proleukin®) and Rituximab Treatment in Rituximab-Resistant NHL Patients: Importance of the F/F Polymorphism at Position 158 of the Fcγ.

Background: Antibody-dependent cellular cytotoxicty (ADCC) is an important mechanism of rituximab activity. Genetic polymorphisms in FcγRIIIa have been reported to influence response to rituximab in follicular non-Hodgkin's lymphoma (NHL) patients, and the F/F polymorphism at position 158 has been associated with decreased response (Cartron, et al. Blood 2004). IL-2 induces expansion and activation of FcR bearing cells, enhancing ADCC (Gluck, et al. Clin Cancer Res 2004).Methods: The combination therapy of IL-2 and rituximab (IL-2+R) was evaluated in low grade NHL patients who were rituximab-resistant by standard criteria. Rituximab was administered weeks (wks) 1–4 at 375 mg/m2 IV; IL-2 was administered SC 3 times/wk at 14 MIU wks 2–5 and at 10 MIU wks 6–9.Results: 57 patients (pts) were enrolled. Twenty-nine pts are evaluable with at least week 8 response data, all of whom have been genotyped. Best response to date: 4 responders (1 CR, 3 PR), 22 patients with stable disease (SD), and 3 pts have progressed (PD) on therapy. Follow-up is on-going. FcγRIIIa polymorphism analysis at position 158 from 36 pts typed to date shows a frequency of 53% F/F, 36% V/F, and 11% V/V as compared to 35%F/F, 45%V/F and 20% V/V in previously untreated pts (Cartron et al, 2004). To date, the data has shown a higher response rate for the F/F pts (4/17; 24%) than the overall population (4/29; 14%). Best response to date for 17 F/F pts: 4 responders and 13 SD; for the 9 V/F pts: 0 responders, 7 SD, and 2 PD; for the 3 V/V pts: 0 responders, 2 SD, and 1PD. In addition, 9 pts had responses lasting = 4 months with 6/9 being F/F and 3/9 being V/F. Patients will be followed periodically up to 2 years or until disease progression. The regimen was well tolerated and the majority of adverse events (AEs) were CTC grade 0, 1, or 2 (flu like symptoms, injection site reactions and rash). No grade 3 or 4 AEs occurred in 10% or more of pts.Conclusions: These data support an association of the genetic polymorphism of FcγRIIIa 158F/F with prior failure to respond to rituximab. Immunotherapy with IL-2+R may achieve a critical threshold to drive ADCC more effectively in patients carrying the low affinity F/F IgG FcR polymorphism, restoring their response to monoclonal antibody therapy. All pts with this F/F polymorphism either responded to therapy or achieved SD as their best response to date. This outpatient regimen was generally well tolerated. The role of the FcγRIIIa F/F polymorphism is currently being evaluated in a prospective randomized trial comparing rituximab to rituximab + IL-2 in patients with follicular lymphoma.

A Pilot Trial of Rituximab and Alemtuzumab Combination Therapy in Patients with Relapsed and/or Refractory Chronic Lymphocytic Leukemia (CLL)

The treatment of patients with chronic lymphocytic leukemia (CLL) who fail purine analogues is sub optimal. CLL lymphocytes express two antigens, namely CD 20 and CD 52, for which monoclonal antibodies are readily available. Rituximab is a chimeric monoclonal antibody targeted against CD 20, which has some activity in refractory CLL, with primary effect on nodal disease. Alemtuzumab is a humanized anti-CD 52 antibody that is approved for the treatment of CLL in patients who fail alkylating agents and purine analogues. Alemtuzumab has better activity in the peripheral blood and the bone marrow compared to nodal disease. We investigated whether combining both antibodies is safe in refractory CLL. Both antibodies were given to a total of 12 patients divided into 3 cohorts with escalating alemtuzumab doses (3 mg, 10 mg, and 30 mg). The combination was proven to be safe, not toxic, feasible, and active. One patient attained PR by NCI criteria while all other patients had stable disease lasting a median of 101.5 days. All patients normalized their peripheral lymphocytosis within a median of 23.5 days. No treatment-related mortality was identified. No CMV reactivation occurred. Additional studies are needed to investigate the clinical significance of such a combination in this patient population, and whether this combination can be administered safely with systemic chemotherapy. These studies are currently underway.

Belimumab and Rituximab Combination Therapy for the Treatment of Diffuse Cutaneous Systemic Sclerosis

Belimumab and Rituximab Combination Therapy for the Treatment of Diffuse Cutaneous Systemic Sclerosis