Chimeric anti-CD20 Antibody Research Articles

Ocrelizumab: a step forward in the evolution of B-cell therapy

Recent advances in our understanding of B-cell dysregulation and its important link to autoimmunity have brought about a radical change in the management of autoimmune diseases. Over the past few years, encouraging data from several clinical trials of rituximab, a chimeric anti-CD20 antibody, have led to its approval for use in rheumatoid arthritis (RA). These data, regarding clinical efficacy, safety, improved patient-reported outcomes and cost-effectiveness with the use of rituximab in patients with RA, have led to the exploration of other agents targeting B-cell functions. Ocrelizumab, a novel humanized anti-CD20 antibody, has shown clinical efficacy and safety in a recently reported trial in patients with RA. Future clinical trials will help evaluate further the role of ocrelizumab in RA and its potential use in other autoimmune diseases. This review describes current understanding of B-cell therapy, the role of rituximab in the treatment of RA and the evolving role of ocrelizumab as a B-cell-targeted therapy.

A new approach for pharmacokinetics of single-dose cetuximab in rhesus monkeys by surface plasmon resonance biosensor

A novel assay method has been developed and validated, using surface plasmon resonance (SPR), for quantitation of cetuximab (C225) in monkey serum. By injecting non-labeled antibody samples onto a biosensor surface on which epidermal growth factor receptor (EGFR) was immobilized, the concentration of C225 can be accurately measured. This assay has a range of reliable response from 0.05 to 50 μg/ml C225 in monkey serum, which was well fitted with a sigmoidal model. The immobilized EGFR was found to be stable for at least 100 regeneration cycles at room temperature. Intra- and inter-assay CVs ranged from 3.20% to 8.89% and from 5.93% to 11.11%, accuracy from 92% to 107.52% and from 90% to 106.88%, respectively. Matrices such as 50% human serum, 50% Sprague Dawley rat serum, chimeric recombinant anti-CD20 monoclonal antibody, human γ-globulin and chimeric recombinant her2 antibody did not interfere with C225 analysis on the sensor surface. This is the first report on the quantitation of C225 in monkey serum by an optical biosensor technology. This method was used to characterize the pharmacokinetics of C225 in rhesus monkeys. After a single-dose of intravenous infusion administration of 7.5, 24 and 75 μg/kg, average C max ranged from 168 ± 28 to 1624 ± 113 μg/ml, and AUC 0–∞ ranged from 15,739 ± 1059 to 295,017 ± 44,533 μg h/ml. C225 elimination followed a bi-exponential profile with t 1/2 ranging from 2.7 ± 0.7 to 6.7 ± 0.1 h. It was non-linear serum pharmacokinetics of C225 across the investigated dosage range in monkeys (7.5–75 mg/kg).

Anti-CD20 en oncohématologie

Twelve years ago, rituximab, a chimeric monoclonal anti-CD20 antibody, became available for the treatment of relapsing follicular lymphoma. It has resulted in an improvement of approximately 20% in survival for nearly all B cell lymphomas. In follicular lymphoma, rituximab combined with chemotherapy is indicated as first-line treatment when treatment is necessary. It is also an interesting option, alone or in combination with chemotherapy for the treatment of relapses, after verifying the persistence of CD20 expression on the surface of malignant cells. As a maintenance treatment after chemotherapy with or without rituximab, it improves relapse-free survival and overall survival. The standard treatment for high-grade diffuse lymphoma, regardless of age and regardless of predicted severity, is now the combination of CHOP chemotherapy and rituximab. The combination of fludarabine, cyclophosphamide, and rituximab is currently the reference treatment for chronic lymphoid leukemia as first-line treatment for patients with few comorbidities and for those with relapses. The role of this antibody in the treatment of more serious forms of lymphoma is under evaluation. The administration of rituximab, alone or in combination, in the treatment of low-grade non-follicular lymphoma must be decided as a function of existing protocols in multidisciplinary consultations. New-generation anti-CD20 antibodies, designed to improve still further the already remarkable efficacy/toxicity ratio, are now taking the road that rituximab opened.

Efficacy of new biologics on bone destruction in rheumatoid arthritis

Rheumatoid arthritis (RA) is a representative bone disease. TNF-alpha plays a pivotal role in the pathological processes of RA, leading to cartilage and bone destruction. Although biologics targeting TNF have brought about a marked reduction of progression of bone destruction, the rate of remission induction is about 30% and the rest of the patients require alternative biologics such as B cell targeting (chimeric anti-CD20 antibody : rituximab) or T cell targeting (CTLA [cytotoxic T-lymphocyte antigen]-4-Igfusion protein : abatacept) therapies. To date, the efficacy of these new biologics on the disease activity and bone destruction was confirmed by randomized control trials. Then abatacept and rituximab were recommended for the treatment of the patients who do not respond adequately to TNF inhibitors.

Accelerated Allogeneic Haemopoietic Engraftment after Preceding Rituximab-Therapy

The chimeric monoclonal anti-CD20 antibody rituximab and the graft-versus-leukaemia/lymphoma effect after allogeneic stem cell transplantation have improved therapy of lymphatic malignancies during the last decade. In addition, successful therapy of chronic graft-versus-host disease after stem cell transplantation with rituximab has been published. Other investigators correlated prolonged neutropenia after autologous stem cell transplantation with prior rituximab- therapy. To address the question, if rituximab pre-treatment prior to transplantation diminishes the graft versus lymphoma effect afterwards and can prolong engraftment of allogeneic haemopoiesis, we retrospectively analysed data from 34 patients al- lografted for lymphoid malignancies. 19 patients had received at least one course of rituximab prior to allogeneic stem cell transplantation and 15 did not. Both groups matched very good. Patients with rituximab pre-treatment engrafted with 1 leukocyte/nl significantly faster than patients without prior rituxi- mab therapy (12 days (median, range 1-32) vs. 18 days (median, range 12-31), p<0,005). Engraftment of platelets (PLT) occurred as well faster after rituximab pre-treatment. The differences were significant for all three steps (20PLT/nl: 11,5 days (median, range 1-28) vs. 27 days (median, range 11-54) p<0,001; 50PLT/nl: 16,5 days (median, range 11-37) vs. 42 days (median, range 22-70) p<0,001; 100PLT/nl: 22,5 days (median, range 13-52) vs. 60 days (median, range 25-117) p<0,005). The mechanism leading to faster engraftment remains unclear so far. Preceding therapy with rituximab had no influence on event-free survival, overall survival, or manifestation freedom from graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Patients with GVHD had a significantly better overall survival (p=0,0001) comparing to patients without. In conclusion, this investigation gives no hint for a suppression of GvH and GvL effects by rituximab administration prior to allogeneic stem cell transplantation. In addition, in contrast to results published for autologous stem cell transplantation, no detrimental effects on establishment of graft haemopoiesis after allogeneic stem cell transplantation by preceding ri- tuximab therapy were found.

Class-switched B cells display response to therapeutic B-cell depletion in rheumatoid arthritis

IntroductionReconstitution of peripheral blood (PB) B cells after therapeutic depletion with the chimeric anti-CD20 antibody rituximab (RTX) mimics lymphatic ontogeny. In this situation, the repletion kinetics and migratory properties of distinct developmental B-cell stages and their correlation to disease activity might facilitate our understanding of innate and adaptive B-cell functions in rheumatoid arthritis (RA).MethodsThirty-five 'RTX-naïve' RA patients with active arthritis were treated after failure of tumour necrosis factor blockade in an open-label study with two infusions of 1,000 mg RTX. Prednisone dose was tapered according to clinical improvement from a median of 10 mg at baseline to 5 mg at 9 and 12 months. Conventional disease-modifying antirheumatic drugs were kept stable. Subsets of CD19+ B cells were assessed by flow cytometry according to their IgD and CD27 surface expression. Their absolute number and relative frequency in PB were followed every 3 months and were determined in parallel in synovial tissue (n = 3) or synovial fluid (n = 3) in the case of florid arthritis.ResultsSix of 35 patients fulfilled the European League Against Rheumatism criteria for moderate clinical response, and 19 others for good clinical response. All PB B-cell fractions decreased significantly in number (P < 0.001) after the first infusion. Disease activity developed independently of the total B-cell number. B-cell repopulation was dominated in quantity by CD27-IgD+ 'naïve' B cells. The low number of CD27+IgD- class-switched memory B cells (MemB) in the blood, together with sustained reduction of rheumatoid factor serum concentrations, correlated with good clinical response. Class-switched MemB were found accumulated in flaring joints.ConclusionsThe present data support the hypothesis that control of adaptive immune processes involving germinal centre-derived, antigen, and T-cell-dependently matured B cells is essential for successful RTX treatment.

Serious Pulmonary Toxicity with SGN-30 and Gemcitabine, Vinorelbine, and Liposomal Doxorubicin in Patients with Relapsed/Refractory Hodgkin Lymphoma (HL): Cancer and Leukemia Group B (CALGB) 50502

Background: SGN-30 is a chimeric anti-CD30 antibody that is well-tolerated but has modest single agent activity in classical HL. Synergistic cytotoxicity is observed in vitro when SGN-30 is combined with gemcitabine. In CALGB 59804, a phase II study of gemcitabine, vinorelbine, and liposomal doxorubicin (GVD), 70% of patients (pts) with HL responded (Bartlett, et al. Ann Onc 18:1071–1079, 2007). Based on these results and the potential synergy between gemcitabine and SGN-30, the CALGB conducted a doubleblind randomized, phase II trial of SGN-30/placebo + GVD to determine overall response rate (ORR) and event-free survival (EFS).Methods: 30 pts with CD30-positive classical HL relapsed/refractory after „□ 1 therapy were treated with GVD + 12 mg/kg SGN-30 or placebo. Pts were permitted to come off study after „□ 2 cycles for stem cell transplant (SCT). To assess the safety of the combination, 16 pts in part 1 of the trial received open label SGN-30 + GVD, without unexpected grade 3–4 toxicity during cycle 1. In part 2, 14 pts were randomized to SGN-30 + GVD (n=7) or placebo + GVD (n=7). After 2 pts developed late pulmonary events in part 1, part 2 was amended to stop the trial if the risk of grade 2–5 pulmonary events with SGN-30 + GVD compared to placebo + GVD exceeded 20%.Results: In 30 pts, median age was 35 years (range, 19–78 years), median prior therapies 2 (range 1–4), 11 pts had undergone a previous autologous SCT, 12 pts had received radiation, and 12 pts were refractory to their last regimen. After a median of 3 cycles of therapy, ORR was 63% (32% complete response (CR)) in 30 pts, 65% (35% CR) in 23 pts receiving SGN-30 + GVD, and 58% (29% CR) in 7 pts receiving placebo + GVD. Median EFS was 9 months (7.8 months for those pts with prior SCT and not yet reached for pts without prior SCT), with no statistically significant differences in EFS with the addition of SGN-30. Grade 2–5 pneumonitis occurred in 5 pts, all receiving SGN-30 + GVD, leading to closure of the trial. In part 1, 1 pt (prior ABVD, ICE) developed grade 4 pneumonitis after 3 cycles with fevers, hypoxia, and ground glass infiltrates requiring mechanical ventilation. A 2nd pt (prior ABVD, spine XRT) died from pneumonitis after 2 cycles despite intubation, antibiotics, and steroids. In part 2, 2 pts (prior ABVD and prior ABVD, ICE, SCT, mediastinal XRT) developed grade 3 pneumonitis after 4 and 2 cycles, respectively, that improved with steroids, and 1 pt (prior ABVD) developed grade 5 pneumonitis after 5 cycles. Autopsy in this pt demonstrated mild interstitial fibrosis and Pseudomonas and Enterococcal lobar pneumonia without evidence of HL. In the 4 other pts, bronchoalveolar lavage (n=4) and transbronchial lung biopsy (n=2) demonstrated no evidence of infection or progressive HL. In univariate analysis, age, gender, number of prior therapies, time from last treatment, prior autologous SCT, prior XRT, use of GCSF, and the number of GVD cycles were not significantly associated with the development of grade 2–5 pneumonitis (p-values=0.34–1.00).Conclusion: With grade 2–5 pneumonitis in 5/23 pts receiving SGN-30 + GVD, no events in the placebo arm (n=7), and historical results from CALGB 59804 demonstrating a 2% incidence of pulmonary events with GVD, the data from CALGB 50502 suggest that SGN-30 cannot safely be administered concurrently with GVD. Compared with historical GVD outcomes, the addition of SGN-30 to GVD does not appear to improve ORR or EFS.

Successful Treatment of Chronic Antibody-Mediated Rejection With IVIG and Rituximab in Pediatric Renal Transplant Recipients

Chronic antibody-mediated rejection (CAMR) of renal allografts has recently been recognized as a defined nosologic entity. The outcome of CAMR is poor; there is no established treatment protocol for this condition. We therefore initiated a pilot study on treatment of CAMR with an antihumoral regimen consisting of high-dose intravenous immunoglobulin (IVIG) and the chimeric anti-CD20 antibody rituximab. Six pediatric renal transplant recipients with CAMR received four weekly doses of IVIG (1 g/kg body weight per dose), followed by a single dose of rituximab (375 mg/m2 body surface area) 1 week after the last IVIG infusion. Renal allograft biopsies were evaluated using the Banff '05 classification. Human leukocyte antigen-specific antibodies were detected by panel-reactive lymphocytotoxicity and solid phase ELISA assays. Median glomerular filtration rate during 6 months before intervention dropped by 25 (range, 11-26) mL/min/1.73 m2 (P<0.05) and increased in response to antihumoral therapy by 21 (-14 to +30) 6 months (P<0.05) and by 19 (-14 to +23) mL/min/1.73 m2 12 months (P=0.063) after start of treatment. Glomerular filtration rate improved or stabilized in 4 patients; the two nonresponders had the highest degree of transplant glomerulopathy, the highest degree of C4d deposition in peritubular capillaries and pronounced interstitial inflammation. The treatment regimen was well tolerated. This pilot study demonstrates that CAMR in pediatric renal transplant recipients can be treated successfully and safely with a combination of IVIG and rituximab. This observation should encourage more extensive studies to evaluate this new treatment strategy.

Rituximab in the treatment of non-Hodgkin's lymphoma.

Besides traditional cytostatic drugs the introduction of monoclonal antibodies has substantially influenced current treatment concepts of non-Hodgkin's lymphoma (NHL). Rituximab, a monoclonal anti-CD20 chimeric antibody, now has been widely evaluated in the various B-cell lymphatic neoplasms. Large phase III studies helped to prove the value of this drug in follicular lymphoma as part of induction or relapse treatment as well as maintenance treatment. The addition of rituximab to the well established CHOP regimens has increased achievable cure rates in diffuse large cell lymphoma, and this combination is now accepted worldwide as standard of care. Although conflicting results are available, rituximab is widely used for the treatment of mantle cell lymphoma. For the less frequent lymphoma entities phase 2 studies show a considerable efficiency for most of these B-NHL variants. Current research focuses on combined chemoimmunotherapy approaches, optimization of dosing regimens, and combination with novel agents.

Rituximab as rescue therapy in anti-neutrophil cytoplasmic antibody-associated vasculitis: a single-centre experience with 15 patients

B-cell depletion with rituximab, a chimeric anti-CD20 antibody, is a novel treatment for refractory and relapsing ANCA-associated small-vessel vasculitis. Data are limited and most reports describe single patients or small numbers of patients followed prospectively. We report a single-centre experience with 15 patients who received rituximab for refractory or relapsing ANCA-associated vasculitis. All patients had been treated with corticosteroids and cyclophosphamide and a variety of other second-line immunosuppressive agents. None of the patients had evidence of infection and received four infusions of 375 mg/m(2) of rituximab. Disease activity was assessed in accordance with the Birmingham Vasculitis Activity Score (BVAS). BVAS, C-reactive protein and ANCA titres were recorded at baseline and during follow-up. B-cell depletion was achieved in all patients. Partial or complete remission was seen in 14 of 15 patients with a significant decline in BVAS compared to baseline (P < 0.007). One patient with granulomatous ANCA-associated vasculitis did not respond to rituximab. There were no side effects during rituximab infusion. Transient leucopenia was observed in two patients. One patient with bronchial stenosis died of pneumonia 5.5 months after the initiation of rituximab treatment. One initially anti-HBc-positive/HBsAg-negative patient experienced a reactivation of hepatitis B, developed end-stage renal failure and died after refusal of dialysis. We report the largest case series of rituximab use for ANCA-associated vasculitis so far. Our data support that the drug is capable of inducing partial or complete remission in refractory or relapsing patients. Leucopenia and infectious complications remain a matter of concern.

Acquired Factor XIII Deficiency Secondary to an Inhibitor: Effect of Factor XIII Replacement and Rituximab Therapy

Factor XIII (FXIII) is the last enzyme in the clotting cascade. Its main function is to convert the loose fibrin polymer into a firm, cross-linked structure. FXIII inhibitor is a rare condition, in which three different types of inhibitors have been described usually due to IgG antibodies. We describe two male patients with acquired FXIII deficiency (age; 73 and 69 years), who had a history of significant bleeding. Functional assay using the acetic acid/urea clot solubility test showed residual FXIII levels between 1–2%. Molecular studies by PCR and DNA sequencing excluded an inherited FXIII deficiency. In addition, we demonstrated an inhibitor pattern for FXIII by in vitro mixing studies with both purified FXIII (Fibrogammin, Aventis Behring) and cryoprecipitates as sources of FXIII. Transglutaminase assay of FXIII (Dade Behring) was normal for both patients, consistent with a type III FXIII inhibitor, which believed to be directed against the activated FXIII-fibrin complex. Both patients showed transient correction of clot solubility to normal after infusion of high doses of Fibrogammin. In view of previous reports describing FXIII inhibitors of the IgG class, we attempted a novel treatment with rituximab (chimeric monoclonal anti-CD20 antibody, Roche) to interfere with production of the inhibitor. However, neither patient showed correction of FXIII activity as measured by clot solubility tests during and up to 2 weeks after therapy. Preliminary results suggest that high dose Fibrogammin is required to correct FXIII deficiency due to an acquired type III inhibitor. The role of rituximab or other immunosuppressive therapy requires further investigation.

In vivo treatment with a monoclonal chimeric anti-CD4 antibody results in prolonged depletion of circulating CD4+ cells in chimpanzees.

Chimeric M-T412 (cM-T412), an anti-CD4 antibody, was tolerated in chimpanzees at a dosage of 5 mg/kg per day for up to 7 consecutive days, or 5 mg/kg per dose, twice weekly for 4 weeks. All cM-T412-treated chimpanzees showed a prolonged CD4-cell depression. Weak chimpanzee antibody responses to chimeric M-T412 were observed. One of the chimpanzees on the biweekly dosage regimen exhibited a hypersensitivity reaction immediately after receiving its seventh dose. Following supportive treatment, the animal recovered and remained asymptomatic during the non-treatment observation period. The hypersensitivity reaction was not an unexpected response considering the animal received repeated intermittent i.v. administration of a foreign protein. This animal also showed a chimpanzee antibody response to chimeric M-T412 after the seventh dose. Chimeric M-T412 also induced an anti-cM-T412 response in some of the other animals. The level of this response was lower than the anti-mouse responses observed in animals treated with murine anti-CD4. Moreover, the anti-cM-T412 response was mainly directed to idiotypic determinants. The decrease in CD4+ cells observed for all chimeric M-T412-treated chimpanzees is an expected effect of the anti-CD4 antibody. The duration of this CD4+ cell decrease is, however, much longer than observed for other CD4-specific MoAbs described. No selective loss of either memory or naive CD4+ cells was observed after either the single, 7-day or twice-weekly treatments. The CD4+ cell depression was reversible, although individual variation in time to recovery was observed. Therefore, cM-T412 could be a good candidate for clinical use in autoimmune conditions.

Linfoma cutáneo de células B del centro folicular tratado con rituximab intralesional

Cutaneous follicular center B-cell lymphomas are indolent tumors characterized by the presence of neoplastic follicular center cells. They contain a mixture of centrocytes with a variable number of centroblasts. The tumor is usually treated by surgery or radiotherapy, although other treatments may be used such as interferon-α, chemotherapy, and biological agents (rituximab). Rituximab is a chimeric monoclonal anti-CD20 antibody that can be administered intravenously or intralesionally.We report the case of a 41-year-old man who consulted for violaceous nodular lesions in the left scapular region and who was diagnosed with cutaneous follicular center B-cell lymphoma after biopsy, laboratory tests, thoracic-abdominal-pelvic computed tomography, abdominal ultrasound, and bone marrow biopsy. It was decided to treat him with 30 mg of intralesional rituximab administered for 1 week (3 times) every month for 4 months. Complete response was obtained. We also review the published cases of cutaneous B-cell lymphoma treated with intralesional rituximab.

Consolidation radioimmunotherapy of follicular lymphoma: a step towards cure?

Radioimmunotherapy (RIT) of non-Hodgkin’s lymphoma was pioneered at the end of the 1980s [1, 2]. This clinical indication was chosen because of the availability of appropriate antibodies and of the relative radiosensitivity of lymphoma cells: Even moderate absorbed doses were expected to translate into some tumor response. In the meantime, rituximab, a naked chimeric anti-CD20 antibody, became a real clinical and commercial success and is now part of the standard treatment of CD20 positivediffuse large B cells and follicular non-Hodgkin’s lymphoma. However, it is clear that rituximab administered in combination with chemotherapy is not a curative treatment of follicular lymphoma. Thus, radiolabelled anti-CD20 antibodies have been introduced with the aim of improving the efficacy of naked antibodies. Multiple clinical studies were performed first with tositumomab/iodine-131 tositumomab (Bexxar; GlaxoSmithKline, Philadelphia, PA, USA) then with rituximab/yttrium-90 ibritumomab tiuxetan (Zevalin; Biogen Idec, Cambridge, MA, USA), which demonstrated both their safety and efficacy with overall response rates between 50% and 80% and complete response (CR) rates between 20% and 40% in patients with relapsed, refractory or transformed follicular nonHodgkin’s lymphoma. Subsequently, both products have been approved in the US (tositumomab/iodine-131 tositumomab and rituximab/yttrium-90 ibritumomab tiuxetan) and one in Europe (rituximab/yttrium-90 ibritumomab tiuxetan). In the absence of randomised trials, it is difficult to compare the safety and efficacy of both products. Nevertheless, it appears from the literature that they are roughly comparable in terms of response rates and progression-free survival (PFS) even if tositumomab/ iodine-131 tositumomab using a patient-specific dosing regimen seems to induce less bone marrow toxicity than rituximab/yttrium-90 ibritumomab tiuxetan using weightbased dosing regimen [3]. However, from the time of approval, their routine use has not been very successful, with sales showing a much slower progression than expected. Several reasons to this limited commercial performance have been put forward. First, RIT needs a close coordination between haematologists and nuclear medicine physicians. Some referring physicians or haematologists have certainly considered that such coordination was too difficult and RIT too cumbersome even if it is quite simple in a routine practice in most institutions [4]. A stronger reason of the limited success was probably the nonsignificant difference of time to progression (TTP) between patients treated with RIT and those treated with rituximab, making haematologists rather disappointed [5]. In routine clinical practice, both radiopharmaceuticals have been mainly used as a last-line, salvage treatment in patients who had often high tumor burden and had been heavily pretreated, whereas clinical trials had clearly shown that TTP was significantly longer when RIT was used at an earlier stage, after only one prior therapy [6]. There is a relative consensus to consider that the best indication of RIT is the treatment of residual disease characterised by small-sized or microscopic tumors, which are still rather well vascularised and consequently accessible to circulating radiolabelled antibodies. Moreover, the small size of the tumors fits well with the short path length of electrons emitted by iodine-131 (<2 mm) and by yttrium-90 (<5 mm). This favourable situation of residual disease prompted investigators to use RIT as a consolidation Eur J Nucl Med Mol Imaging (2008) 35:1236–1239 DOI 10.1007/s00259-008-0727-z

Cutaneous Follicular Center B-Cell Lymphoma Treated With Intralesional Rituximab

Cutaneous follicular center B-cell lymphomas are indolent tumors characterized by the presence of neoplastic follicular center cells. They contain a mixture of centrocytes with a variable number of centroblasts. The tumor is usually treated by surgery or radiotherapy, although other treatments may be used such as interferon-α, chemotherapy, and biological agents (rituximab). Rituximab is a chimeric monoclonal anti-CD20 antibody that can be administered intravenously or intralesionally. We report the case of a 41-year-old man who consulted for violaceous nodular lesions in the left scapular region and who was diagnosed with cutaneous follicular center B-cell lymphoma after biopsy, laboratory tests, thoracic-abdominal-pelvic computed tomography, abdominal ultrasound, and bone marrow biopsy. It was decided to treat him with 30 mg of intralesional rituximab administered for 1 week (3 times) every month for 4 months. Complete response was obtained. We also review the published cases of cutaneous B-cell lymphoma treated with intralesional rituximab.

Rituximab for the treatment of autoimmune cytopenias

B- or T-lymphocyte-mediated autoimmune disorders may lead to clinical disease characterized by low blood cell counts. The term autoimmune cytopenias has been collectively applied to this heterogeneous group of disorders. After the introduction of the humanized, chimeric monoclonal anti-CD20 antibody

Efficacy and Safety of Rituximab in Post Transplant Lymphoproliferative Disorders (PTLD): Pooled Analysis and Review of Literature.

PTLD are heterogeneous monoclonal or polyclonal neoplasm usually of B-cell origin with a variable incidence in allogenic bone marrow and solid organ transplant recipients. Due to immunosuppresion in transplant patients, PTLD follows an aggressive course with enhanced treatment-associated toxicity, leading to a overall poor clinical outcome and mortality. Rituximab is a chimeric monoclonal anti-CD20 antibody with known activity in B-cell PTLD and minimal toxicity. A few anecdotal uncontrolled studies and case reports have evaluated the use of rituximab-based therapy for PTLD. In order to define the efficacy and safety of rituximab single agent in the treatment of patients with PTLD we conducted a review of the current available literature and performed a pooled-analysis. We conducted a MEDLINE literature search using Pub med, Ovid software for the key words rituximab, anti-CD20 antibody, PTLD, hematopoetic stem cell transplant (HSCT), solid organ transplant (SOT) and lymphoproliferative disorders on all available published literature analyzed to date (January 1998 to June 30, 2007). Studies involving children (<18 years), individual case reports with less than 5 patients, patients who were treated with chemo-immunotherapy combination were excluded and our search was limited to those PTLD patients treated with rituximab single agent after failure to respond to withdrawal of immunosuppressants. References of each article were also reviewed for additional literature. Studies were also analyzed for duration of PTLD from time of transplantation, rituximab toxicity, and characteristics of responders. A total of 164 peer-reviewed publications were identified after the electronic search using the above keywords. After excluding patients based on above criteria, the pooled-analysis consisted of 308 patients described in 17 reports. Diagnosis of PTLD cases was based on histological examination and World Health Organization classification. Among the 17 reports, 3 studies included HSCT patients with n=24; the rest consisted of SOT patients. The mean age of the patients was 57; PTLD classified as late onset (>1 year) in most patients (∼70%). Rituximab was used as first line therapy after failure of immunosuppression withdrawal, and patients were initially treated with four weekly doses of rituximab at 375mg/m2. Rituximab was continued as maintenance therapy in responding patients in few studies. The complete response rate (International Workshop Criteria) was 58% (29%–78%), among SOT patients and 70% (66%–83%) among HSCT patients. Side effects were minimal and no treatment related deaths were attributed to rituximab. Long term follow up from 2 prospective studies demonstrate a durable remission in 30%–37% SOT patients at 5 years. Limited evidence exists for optimal treatment approach in PTLD. Clinical heterogeneity among small number of patients diagnosed makes it difficult to conduct randomized prospective studies in this disorder. Our study is the first pooled analysis evaluating the role of rituximab in PTLD. Minimal toxicity with good efficacy favors rituximab's use among patients with less aggressive PTLD who fail or unable to tolerate withdrawal of immunosuppression.

Primary chronic cold agglutinin disease: An update on pathogenesis, clinical features and therapy

Chronic cold agglutinin disease (CAD) is a subgroup of autoimmune hemolytic anemia. Primary CAD has traditionally been defined by the absence of any underlying or associated disease. The results of therapy with corticosteroids, alkylating agents and interferon-α have been poor. Cold reactive immunoglobulins against erythrocyte surface antigens are essential to pathogenesis of CAD. These cold agglutinins are monoclonal, usually IgMκ autoantibodies with heavy chain variable regions encoded by the VH4-34 gene segment. By flowcytometric and immunohistochemical assessments, a monoclonal CD20+κ+B-lymphocyte population has been demonstrated in the bone marrow of 90% of the patients, and lymphoplasmacytic lymphoma is a frequent finding. Novel attempts at treatment for primary CAD have mostly been directed against the clonal B-lymphocytes. Phase 2 studies have shown that therapy with the chimeric anti-CD20 antibody rituximab produced partial response rates of more than 50% and occasional complete responses. Median response duration, however, was only 11 months. In this review, we discuss the clinical and pathogenetic features of primary CAD, emphasizing the more recent data on its close association with clonal lymphoproliferative bone marrow disorders and implications for therapy. We also review the management and outline some perspectives on new therapy modalities.

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.

Treatment of Severe Pemphigus With Rituximab

Treatment of pemphigus vulgaris can be challenging. Systemic steroids associated with other immunosuppressant agents are the mainstay of therapy and have dramatically reduced morbidity and mortality from pemphigus vulgaris. In some patients, however, these agents are not able to control the disease or have severe adverse effects. Rituximab (MabThera; Roche, Basel, Switzerland), a chimeric monoclonal anti-CD20 antibody, induces depletion of B cells in vivo and has shown efficacy in patients with refractory antibody-mediated autoimmune disorders. We report 10 cases of pemphigus vulgaris and 2 cases of pemphigus foliaceous treated with rituximab--to our knowledge the largest series of patients so far--and review the existing literature on the topic. The 12 patients were selected for treatment with the anti-CD20 antibody. Rituximab was administered intravenously at a dosage of 375 mg/m(2) once weekly for 4 weeks. The treatment was well tolerated, and all 12 patients showed a good clinical response during an 18-month follow-up period, along with a consensual decline of the serum antidesmoglein titers. No infectious complications were observed. Rituximab is able to induce a prolonged clinical remission in patients with both pemphigus vulgaris and pemphigus foliaceous after a single course of 4 treatments. The preliminary experiences worldwide make rituximab a promising therapeutic option for patients with autoimmune diseases. The high costs and the limited knowledge of long-term adverse effects, however, limit its use to selected patients with treatment-resistant or life-threatening disease.