Received Rituximab Infusions Research Articles

Rituximab Monotherapy Is Effective as First-Line Treatment for Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in CVID Patients

Granulomatous lymphocytic interstitial lung disease (GLILD) represents a fatal immune dysregulatory complication in common variable immunodeficiency (CVID). Evidence-based diagnostic guidelines are lacking, and GLILD treatment consists in immunosuppressive drugs; nonetheless, therapeutical strategies are heterogeneous and essentially based on experts’ opinions and data from small case series or case reports.We aimed to evaluate the efficacy and safety of first-line Rituximab monotherapy for CVID-related GLILD, by assessing symptoms and quality of life alterations, immunological parameters, pulmonary function tests, and lung computed tomography.All six GLILD patients received Rituximab infusions as a first-line treatment. Rituximab was administered at 375 mg/m2 monthly for six infusions followed by maintenance every 3 months; none of the patients experienced severe adverse events. Symptom burden and quality of life significantly improved in treated patients compared to a control group of CVID patients without GLILD. Rituximab treatment indirectly caused a trend toward reduced T-cell activation and exhaustion markers sCD25 and sTIM-3. Lung function improved in treated patients, with statistically significant increases in TLC and DLCO. Lung CT scan findings expressed by means of Baumann scoring system displayed a reduction in the entire cohort.In conclusion, first-line monotherapy with Rituximab displayed high efficacy in disease remission in all treated patients, with improvement of symptoms and amelioration of quality of life, as well as restoration of PFTs and lung CT scan findings.

Hypogammaglobulinemia and Infections in Patients With Multiple Sclerosis Treated With Rituximab.

Background and ObjectivesTo determine the frequency of hypogammaglobulinemia and infections in patients with multiple sclerosis (PwMS) receiving rituximab (RTX).MethodsThis prospective observational study included all consecutive PwMS receiving RTX at the university hospital of Marseille, France, between 2015 and 2020. Patient visits occurred at least every 6 months.ResultsWe included 188 patients (151 with relapsing-remitting MS; the mean age was 43.4 years [SD 12.9], median disease duration 10 years [range 0–36], median Expanded Disability Status Scale 5 [range 0–8], median follow-up 3.5 years [range 1–5.8], and median number of RTX infusions 5 [range 1–9]). Overall, 317 symptomatic infections and 13 severe infections occurred in 133 of 188 (70.7%) and 11 of 188 (5.9%) patients, respectively. After 4 years, 24.4% of patients (95% CI 18.0–33.1) were free of any infection and 92.0% (95% CI 87.1–97.1) had not experienced a severe infection. At RTX onset, the immunoglobulin G (IgG) level was abnormal in 32 of 188 (17%) patients. After RTX, IgG level was <7, <6, <4 and <2 g/L for 83 (44%), 44 (23.4%), 8 (4.2%) and 1 (0.53%) patients, respectively. The risk of infection was associated with reduced IgG levels (multivariate Cox proportional hazards hazard ratio [HR] = 0.86, 95% CI 0.75–0.98, p = 0.03). The risk of reduced IgG level <6 g/L increased with age (HR = 1.36, 95% CI 1.05–1.75, p = 0.01).DiscussionIn PwMS receiving RTX, reduced IgG level was frequent and interacted with the risk of infection.

К ПРОБЛЕМЕ СВЯЗИ ИММУНОТЕРАПИИ У ПАЦИЕНТОВ, СТРАДАЮЩИХ РЕЦИДИВИРУЮЩИМ РАССЕЯННЫМ СКЛЕРОЗОМ, С РИСКОМ ТЯЖЕЛОГО ТЕЧЕНИЯ COVID-19

Immunomodulatory drugs are important to control disease activity in relapsing-remitting multiple sclerosis (MS). Anti-CD 20-therapy is one of such medications. In Sweden, extensive off label prescription of rituximab (RTX) in MS has been documented; it is presently prescribed for more than half of all treated MS patients. The rationale for the increasing prescription of RTX was previous data from phase II and observational studies supporting high efficacy and safety, in addi- tion to the financial aspect. We report national data on usage of disease modifying therapies in MS patients and risk of se- vere COVID-19 in association with RTX exposure within this group. The Swedish National MS Registry (SMSreg) aims to cover all patients with MS in the country, (n=approximately 18,000). After COVID-19 pandemic started in Sweden, a new section was established in it to register clinical and demo- graphic parameters in COVID-19-infected patients. Data presented in the current report were obtained from the SMSreg. A total of 85 out of approximately 6,000 RTX-treated Swedish MS patients had been hospitalized with COVID-19 (as re- ported from the SMSreg, June 16, 2021) and adjusted analyses showed a 2–3 fold increase in a risk (OR = 2.89; p = 0.001) of hospitalization for anti-CD20 treated patients. A change of praxis was introduced in Sweden in spring 2020, resulting in a ma- jority of patients receiving RTX infusions with extended intervals in order to reduce the risk of severe COVID-19 infection. Current Swedish registry data suggest that exposure to RTX in MS may affect the clinical outcome of COVID-19 infec- tion. These observations have rapidly impacted use of immunomodulatory drugs in Swedish MS patients.

THE RISK OF COVID-19 SEVERITY IN PATIENTS WITH MS APPEARS TO BE ASSOCIATED WITH IMMUNOTHERAPY

Immunomodulatory drugs are important to control disease activity in relapsing-remitting multiple sclerosis (MS). Anti-CD 20-therapy is one of such medications. In Sweden, extensive off label prescription of rituximab (RTX) in MS has been documented; it is presently prescribed for more than half of all treated MS patients. The rationale for the increasing prescription of RTX was previous data from phase II and observational studies supporting high efficacy and safety, in addi- tion to the financial aspect. We report national data on usage of disease modifying therapies in MS patients and risk of se- vere COVID-19 in association with RTX exposure within this group. The Swedish National MS Registry (SMSreg) aims to cover all patients with MS in the country, (n=approximately 18,000). After COVID-19 pandemic started in Sweden, a new section was established in it to register clinical and demo- graphic parameters in COVID-19-infected patients. Data presented in the current report were obtained from the SMSreg. A total of 85 out of approximately 6,000 RTX-treated Swedish MS patients had been hospitalized with COVID-19 (as re- ported from the SMSreg, June 16, 2021) and adjusted analyses showed a 2–3 fold increase in a risk (OR = 2.89; p = 0.001) of hospitalization for anti-CD20 treated patients. A change of praxis was introduced in Sweden in spring 2020, resulting in a ma- jority of patients receiving RTX infusions with extended intervals in order to reduce the risk of severe COVID-19 infection. Current Swedish registry data suggest that exposure to RTX in MS may affect the clinical outcome of COVID-19 infec- tion. These observations have rapidly impacted use of immunomodulatory drugs in Swedish MS patients.

Rituximab-associated hypogammaglobulinemia in autoimmune rheumatic diseases: a single-center retrospective cohort study.

B-cell targeted therapies, such as rituximab (RTX), are used widely in autoimmune rheumatic diseases (AIRD). RTX can cause hypogammaglobulinemia and predispose patients to infections. Herein, we asked whether the underlying diagnosis influences the risk for hypogammaglobulinemia in patients treated with RTX. All patients who received RTX infusions and carried a diagnosis of rheumatoid arthritis (RA), ANCA-associated vasculitis (AAV), or connective tissue disease (CTD) were included in this single-center retrospective cohort study. We used STATA® for analysis: Chi-square test was used for comparing categorical variables. Based on distribution, continuous variables were compared using the t test/ANOVA or the Wilcoxon/Kruskal–Wallis tests. Of the 163 patients who received RTX for an AIRD, 60 with pre- and post- RTX immunoglobulins were analyzed. A higher incidence of post-treatment hypogammaglobulinemia was seen in AAV (45%) compared to RA (22%) and CTD (9.1%) groups (p = 0.03). Glucocorticoid exposure of 10 mg or more was identified as a significant risk factor for hypogammaglobulinemia. Finally, we observed a higher number of clinically significant infections per person in the AAV group than in the RA and CTD groups. We observed an increased incidence of hypogammaglobulinemia in the RTX-treated AAV group, with almost half of patients developing post-RTX hypogammaglobulinemia. The rate of infections per person was highest in the AAV group. Screening immunoglobulins were not consistently measured pre- and post-RTX. Results highlight a need for increased awareness of the role of immunoglobulin measurement before maintenance doses of RTX, especially in patients with AAV and steroid exposure.

Adverse electrocardiographic effects of rituximab infusion in pemphigus patients.

Pemphigus encompasses a group of chronic autoimmune blistering diseases of the skin and/or mucosa. Rituximab (RTX) has shown promising efficacy for the treatment of pemphigus in the past decade. Considering potential cardiac side effects, this study was conducted to assess the effects of RTX on electrocardiogram (ECG) parameters in pemphigus patients. This observational cross-sectional study was conducted in 80 consecutive patients with pemphigus who were eligible for RTX infusion. The patients' heart rhythm was monitored before, during and after RTX infusion and ECG parameters were compared before and after the infusion. Eighty patients were included in the study. The median age of the patients was 42 years. The mean and maximum heart rate (HR) increased significantly after RTX infusion compared with pre-infusion mean and maximum HR. The mean corrected QT (QTc) interval, premature atrial contraction (PAC), and premature ventricular contraction (PVC) counts increased significantly after RTX infusion (P value: 0.009, 0.004 and 0.007 respectively). According to the results of this study, RTX has potential arrhythmogenic side effects including increased mean and maximum HR, QTc interval, PAC and PVC count. However, these findings are minor and should not prevent eligible patients from receiving RTX infusion.

Inflammatory choroidal neovascularization associated with immunoglobulin G4-related disease: a case report

BackgroundImmunoglobulin G4-related disease is a recently recognized condition with pathologic features that are consistent across a wide range of organ systems. Orbital manifestations of this disease entity typically involve the lacrimal gland and lacrimal duct, extraocular muscles, orbital soft tissue, and sclera. Here, the authors report the first known case of inflammatory choroidal neovascular membrane associated with immunoglobulin G4-related disease and offer suggestions for clinical management of this enigmatic condition.Case presentationA 38-year-old Caucasian man with a history of recurrent tonsillitis presented with blurry vision in his left eye of 1-week duration and was diagnosed as having inflammatory choroidal neovascular membrane. An infectious workup was negative, but his serum immunoglobulin G4 level was elevated at 248 mg/dL (reference 4–86), and a subsequent tonsillectomy for a repeat episode of tonsillitis revealed increased immunoglobulin G4 staining on histopathology, thus confirming the diagnosis of immunoglobulin G4-related disease. The inflammatory choroidal neovascular membrane was treated with intravitreal bevacizumab injections and orally administered prednisone resulting in improved visual acuity and choroidal neovascular membrane regression. He later received rituximab infusions for immunoglobulin G4-related disease.ConclusionsWe report a case of choroidal neovascularization associated with immunoglobulin G4-related disease, a chronic inflammatory condition whose ophthalmic manifestations typically include dacryoadenitis, orbital myositis, or scleritis. This is the first reported instance of inflammatory choroidal neovascular membrane associated with immunoglobulin G4-related disease. Early detection of this disease is important to avoid organ damage and potential complications, so clinicians should maintain an index of suspicion for this condition when inflammatory choroidal neovascular membrane is observed.

Activation of natural killer cells by rituximab in granulomatosis with polyangiitis

ObjectiveIn the last few years, anti-CD20 antibody rituximab profoundly changed the therapeutic landscape of granulomatosis with polyangiitis (GPA). Here, we investigated whether natural killer (NK) cells may play a role in rituximab’s mechanism of action in GPA.MethodsB cell depletion, NK cell degranulation, and the expression of CD69 and CD16 on NK cells were measured in a series of in vitro experiments using peripheral blood mononuclear cells (PBMCs). In vivo activation of NK cells was investigated in patients receiving rituximab infusions. Cells were analyzed by seven-color flow cytometry.ResultsNK cells from GPA patients were activated by immobilized rituximab. Also soluble rituximab activated NK cells, provided that B cells were present. NK cells degranulated and expressed the activation marker CD69 while CD16 expression was decreased. This activation of NK cells by soluble rituximab was accompanied by a reduction of B cells. The next-generation anti-CD20 antibody obinutuzumab showed stronger effects compared to rituximab on both the reduction of B cells and the activation of NK cells. Finally, we found that rituximab led to the activation of NK cells in vivo, provided that B cells were not depleted due to prior rituximab infusions.ConclusionB cell-bound rituximab activates NK cells in GPA. While NK cells therefore participate in rituximab’s mechanism of action in humans, their potential may be more efficiently exploited, e.g., by Fc engineering of therapeutic antibodies.

SAT0247 Safety of RAPID Rituximab Infusion in Rheumatoid Arthritis in A Single Community Practice

BackgroundRituximab, a chimeric monoclonal anti-CD20 antibody, is approved to be infused over 4hours and 15minutes, due to the potential for infusion reactions. The risk of infusion reactions has been shown...

Rituximab Therapy for Refractory Orbital Inflammation

Orbital inflammation is a potentially blinding and disfiguring disease process that is often treated with systemic corticosteroids and immunosuppression; better treatments are needed. To determine whether rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20, is effective in the treatment of refractory orbital inflammation. A dose-ranging, randomized, double-masked phase 1/2 clinical trial was conducted at a tertiary referral ophthalmology clinic. Ten individuals with orbital inflammation refractory to systemic corticosteroids and at least 1 other immunosuppressive agent were enrolled from January 2007 to March 2010. Rituximab infusions were administered on study days 1 and 15 at doses of either 500 mg or 1000 mg. Initial responders with recurrent inflammation after week 24 were permitted reinfusion with an additional cycle of 2 open-label 1000-mg rituximab infusions. The primary outcomes were reduction of inflammation measured with a validated orbital disease grading scale and corticosteroid dose reduction by at least 50%. The secondary outcomes were visual acuity, reduction in pain, and participant- and physician-reported global health assessment. Of 10 enrolled patients, 7 demonstrated improvement on the orbital disease grading scale at the 24-week end point with rituximab therapy. Of these 7 individuals, 4 were receiving corticosteroids at study inception and all achieved successful dose reduction. For the secondary outcome measures in the 10 participants, 7 patients and 8 patients improved in self-rated and physician global health scores, respectively, and 7 patients had reduction in pain by 25% or more at 24 weeks. Four patients who were positive responders at the week 24 end point experienced breakthrough inflammation after week 24 and received reinfusions between 24 and 48 weeks. Vision remained stable in all participants. Three of 10 patients had short-term objective or subjective worsening 2 to 8 weeks after receiving rituximab infusions, which was averted in subsequent patients with oral corticosteroids administered during the infusion and did not affect the eventual positive treatment outcome. No significant differences with regard to efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms. Rituximab was safe and effective in 7 of 10 patients with noninfectious orbital disease, although 4 required reinfusion with rituximab to maintain control of orbital inflammation. Substantial toxicity was not noted. Rituximab should be considered in the treatment of refractory orbital inflammation. clinicaltrials.gov Identifier: NCT00415506.

Impact of rituximab on height and weight in children with refractory steroid-dependent nephrotic syndrome

Children with steroid-dependent nephrotic syndrome (SDNS) often suffer from serious adverse events, including growth retardation and obesity. Rituximab (RTX) is a promising therapeutic option to overcome steroid dependency. We have examined the impact of RTX on growth and obesity in children with SDNS. Thirteen pediatric patients with SDNS who were refractory despite treatment with multiple immunosuppressive agents received RTX infusions. Mean follow-up was 2.3 years from the first administration of RTX. Improvement in the height and obesity indexes from prior to the initial RTX infusion through to the last visit was assessed. After RTX, the number of relapses [2.8 (before RTX) vs. 0.8/year (after RTX); p = 0.0008] and the prednisolone dose (287.9 vs. 70.7 mg/kg/year, respectively; p = 0.0002) were significantly decreased. Marked improvement in the height standard deviation score (SDS) was achieved by ten of the 13 patients (77 %) [n = 13; -1.6 (before RTX) vs. -0.8 SDS (after RTX); p = 0.03]. Notably, the height SDS of seven of the eight patients whose height was less than average at the first RTX improved from -2.6 to -1.4 SDS with RTX therapy. At the same time, the obesity index of 12 of the 13 patients (92 %) significantly improved (n = 13; 16.9 vs. 3.1 %; p = 0.004). Therapy with RTX may contribute to an improvement in the growth and obesity indexes in some patients suffering from severe side effects of steroids.

Safety of Surgery After Rituximab Therapy in 133 Patients With Rheumatoid Arthritis: Data From the AutoImmunity and Rituximab Registry

We used data from the AutoImmunity and Rituximab (AIR) registry to investigate the safety of surgery for patients with rheumatoid arthritis receiving rituximab (RTX) in routine care. Data for patients included in the AIR registry and undergoing surgery during the year following an infusion of RTX were reviewed to describe the frequency of postsurgical complications, compare patients with and without complications, and identify factors associated with complications. We examined data for 133 patients with a known date of surgery and at least 1 followup visit, corresponding to 140 procedures, including 94 orthopedic surgeries (67%) and 23 abdominal surgeries (16.5%). The median delay between surgery and the last RTX infusion was 6.4 months (interquartile range 4.3– 8.7 months), without any difference between patients with and without complications. Nine patients (6.7%) experienced 12 complications (8.5%), including 8 surgical site infections (5.7%) and 1 death due to septic shock. Postoperative complications occurred after 4.3% of abdominal surgeries (1 of 23) and 7.4% of orthopedic surgeries (7 of 95). On univariate analysis, spine surgery was associated with postoperative complications (P = 0.048). In common practice, the risk of complications may be more important in case of spine surgery, but does not seem to be linked to the time between the last RTX infusion and surgery.

Neuromyelitis optica in patients with coexisting human immunodeficiency virus infections

Two patients with known human immunodeficiency virus (HIV) infections and receiving antiretroviral treatment developed neuromyelitis optica (Devic’s disease). One patient tested positive for serum aquaporin-4 immunoglobulin G antibodies. Both patients were treated with high dose pulsed intravenous methylprednisolone followed by standard sessions of plasma exchange both at the onset attack and during disease relapses. For maintenance therapy, one patient received rituximab infusions and the second patient received mycophenolate mofetil orally. Despite treatment, both patients are currently wheelchair-bound due to severe paraparesis. Neuromyelitis optica can occur in the course of HIV infection and poses an ongoing therapeutic challenge.

Bewertung einer Infusionbehandlung der rheumatoiden Arthritis durch Patienten und Rheumatologen

The various biologic agents currently available for the treatment of RA can be administered subcutaneously (s.c.) or via intravenous (i.v.) infusion with variable intervals depending on the drug. This investigation aims to identify the preferences and concerns of affected patients and their physicians. We conducted a survey of 102 patients with RA currently receiving Rituximab (RTX) therapy. They were asked about different aspects of their current and previous RA therapy, including overall satisfaction, tolerability, mode of drug administration, as well as duration and intervals. In addition, 17 rheumatologists were asked about different aspects of s.c. or i.v. drug administration, their preference and the suspected preference of their patients. The mean age of our patients was 59 ± 11.2 years. Patients had failed ≥2 DMARD therapies and ≥ 1 biologic treatment. The impact of RTX infusions on planning different activities including job, hobbies or travelling was considered as low or very low in 76% of the respondents. Interestingly, 63.4% of patients would prefer an infusion every 6-9 months as RA therapy, whereas 21.5% would prefer tablets only; 12.9% of our patient cohort would prefer s.c. injections every second week, and only 2% would prefer an infusion every month. In all, 92% of patients questioned would choose RTX therapy again. In contrast, 88% of rheumatologists preferred s.c. injection and even 94% of them assumed that their patients would do so as well if they had the choice. The suggested reasons included greater flexibility, convenience and independence during s.c. therapy. Contrary to the assumption of rheumatologists, we have demonstrated a preference among RTX patients for i.v. drug administration every 6-9 months over other methods of administration.

Incidence of Infusion-Associated Reactions with Rituximab for Treating Multiple Sclerosis

Rituximab is a monoclonal antibody approved for treating CD20-positive B-cell non-Hodgkin's lymphoma and rheumatoid arthritis but is used off-label for treating many autoimmune disorders, including multiple sclerosis (MS). Similarly to other monoclonal antibodies, the incidence of infusion-related reactions to rituximab is high. Reactions to monoclonal antibodies, including rituximab, vary widely in type and severity, but may include mild pruritis and rash to more severe complications such as Stevens-Johnson syndrome and anaphylactic reactions. To assess the incidence of infusion-associated reactions in our MS patients receiving rituximab infusions and compare it to previous trials investigating rituximab for treating MS. From 1 to 30 November 2009, we retrospectively reviewed medical charts from Partners Multiple Sclerosis Centre, Brookline, MA, USA, of patients being treated with rituximab for MS between 20 November 2007 and 24 November 2009 for evidence of infusion-associated reactions and further classified reactions on a grading scale. During the period studied, 70 patients were infused with rituximab. Infusion-associated events occurred in 25.7% of our patients. Reactions were mild to moderate and most commonly occurred during the first infusion. Most patients were able to complete the infusion after appropriate treatment of the reaction was administered, and most patients went on to receive subsequent doses without any further reactions. The occurrence of infusion-associated reactions to rituximab in patients with MS is fairly common. However, premedication that includes corticosteroids may reduce the incidence of reactions dramatically. Should they occur, proper treatment of reactions with histamine H(1) or H(2) receptor antagonists and infusion rate reduction is an effective management strategy in this situation.

Rituximab may form a complex with iGmκ mixed cryoglobulin and induce severe systemic reactions in patients with hepatitis C virus–induced vasculitis

To report on 6 cases of hepatitis C virus (HCV)-induced mixed cryoglobulinemia (MC) vasculitis in patients who developed severe systemic reactions after rituximab infusion, and to report the results of the in vitro analysis of the underlying immunologic mechanisms. Twenty-two HCV-infected patients with MC vasculitis received rituximab infusions (a low-dose protocol cycle with 375 mg/m2/week for 4 consecutive weeks in 18 patients and a high-dose protocol cycle with 1,000 mg on days 1 and 15 in 4 patients). Systemic drug reactions following rituximab infusion were recorded and analyzed clinically and immunochemically. Six of 22 patients (27.3%) experienced systemic drug reactions after rituximab infusion. Four patients developed a severe flare of MC vasculitis 1 or 2 days after rituximab infusion. Two patients developed serum sickness syndrome 7 and 9 days after the first 1,000 mg rituximab infusion. Compared with patients without drug reactions, those with drug reactions had higher mixed cryoglobulin levels (mean+/-SD 1.4+/-0.82 gm/liter versus 0.71+/-0.77 gm/liter; P=0.0475) and lower C4 levels (mean+/-SD 0.02+/-0.006 gm/liter versus 0.07+/-0.07 gm/liter; P=0.02), and more of them received 1,000 mg high-dose rituximab protocol (50% versus 6.25%; P=0.046). In vitro immunochemical assays showed that rituximab formed a complex with the cryoprecipitating IgMkappa that had rheumatoid factor (RF) activity. Moreover, the in vitro addition of rituximab to serum containing an RF-positive IgMkappa type II mixed cryoglobulin was associated with visibly accelerated cryoprecipitation. In HCV-associated MC vasculitis, rituximab may form a complex with RF-positive IgMkappa, leading to accelerated cryoprecipitation and to severe systemic reactions. Rituximab should be administered with caution in MC vasculitis, with use of the 375 mg protocol and plasma exchanges prior to rituximab infusion in patients with high baseline levels of mixed cryoglobulin.

Rituximab Infusion Two Months after HCT Decreases Alloreactive B Cell Responses While Recipient Plasma Cells Persist.

B cells and their effector molecules, antibodies, are implicated in pathophysiology of the chronic graft-vs-host disease (cGVHD) and rituximab is effective cGVHD therapy. Here we investigate B cell reconstitution in bone marrow aspirates collected from 14 mantle cell lymphoma and 22 chronic lymphocytic leukemia patients receiving rituximab infusion 375mg/m2 weekly x 4 beginning 56 days after allogeneic hematopoietic cell transplantation (HCT) following total lymphoid irradiation 80cGy x10 daily fractions and anti-thymoglobulin (1.5 mg/Kg/day x 5). Primary GVHD prophylaxis was mycophenolic acid and cyclosporine tapered off by 6 months. We hypothesized rituximab would deplete alloreactive na•ve and memory B cells and result in less chronic GVHD. Here we present multi-parameter B cell FACS analysis characterizing extent of B cell depletion and developmental stage analysis and subsequent reconstitution kinetics. We collected bone marrow aspirates prior to rituximab, and then days 90, 180, and 365 following HCT.Peripheral B cells were detected in 17 of 34 HCT patients prior to rituximab infusion day 56. Following rituximab, peripheral blood CD19+ B cells were detected in 4 by one year, 18 by 1.5 years, and 9 by 2 years post HCT.Multi-parameter (12 colors-14 parameters) FACS analysis of bone marrow B cells using 2 different cocktails on the same bone marrow cells distinguished: common lymphoid progenitor (CD34+CD117+CD7+), Pro B cells (CD34+CD20−CD10−), pre B cells (CD34−CD20−, CD10+), immature B cell (CD20−CD38−IgM+ IgD low/neg), mature (CD20+CD38+IgD+, IgM+) B cells, and CD38+ CD138+ plasma cells.Despite only modest reconstitution of PERIPHERAL B cells 2 months after HCT (17/32), bone marrow B cells expressing CD19 were present in 9 out of 9 patients at 56 days post HCT and were depleted to less than 0.05% of total lymphocytes after 4 rituximab infusions when measured 90 days post-HCT (below table). Following rituximab, CD19+ B cells were first detected in the bone marrow 180 days after HCT. The mature CD19+ B cells accounted for 2–5% by 365 days post HCT.While rituximab depleted mature B cells, plasma cells remained unchanged. Furthermore, CD138+CD38+ plasma cells were FACS sorted shown by STR DNA polymorphism testing to be recipient derived (n=5).Consistent with observed stable plasma cell frequency, total plasma IgG showed no significant change. Inherited polymorphisms in IgG heavy chain constant regions can be recognized by allotype-specific monoclonal antibodies and thereby distinguish donor and recipient antibodies. Such allotype detection of antimicrobial IgG confirmed stable anti-VZV and EBV as well as recipient origin of these plasma IgG up to 2 years post HCT.In support of our hypothesis, alloreactive IgG responses against 5 minor histocompability antigens (mHA) encoded on Y chromosome (DBY, UTY, ZFY, RPS4Y, and EIF1AY) were decreased in TLI/ATG/rituximab treated patients. None of the 11 male patients with female donors treated with rituximab developed antibodies against H-Y proteins while 12 out of 24 (50%) F̂M undergoing TLI/ATG without rituximab developed allo-antibodies against H-Y proteins (p=0.09).In summary, multi-parameter (12 colors-14 parameters) immunophenotyping of bone marrow shows rituximab treatment two months after allo-HCT causes delayed donor derived B cell reconstitution, persistent antimicrobial IgG from persistent recipient plasma cells, and undetectable allogeneic H-Y antibodies.Summary table.Days after HCTLYMPHOID PROGENITORS CD34+ CD117+ CD7+PRO B CELLS CD34+ CD20− CD10−PRE B CELLS CD34+ CD20− CD10−MATURE B CELLS CD20+ Ig D+ Ig M+PLASMA CELLS CD38+ CD138+TOTAL IgG μg/dl(pre)56 pre = ritux n = 920–25%2–6%0.1–4%0.2–1%0.7–1%655 81%90 n = 2520–40%2–9%0.5–2%ND**0.5–3%910 101%180 n = 2813–20%5–12%0–0.7%ND**0.5–2%507 60%365 n = 163–8%2–10%0–0.5%1–5%0.5–3.7%642 78%

A Placebo-Controlled Phase III Trial of Patient-Specific Immunotherapy with Mitumprotimut-T (ID-KLH) and GM-CSF Following Rituximab in Patients with CD20+ Follicular Lymphoma

Background: Early studies demonstrated that patients with indolent B-cell lymphomas have the capacity to mount anti-idiotype (Id) B-cell immune responses following active immunization with patient-specific Id proteins. Durable clinical remissions were observed in patients undergoing vaccination in chemotherapy-induced first remissions. This study evaluated the efficacy and safety of active immunotherapy with mitumprotimut-T (Id- KLH, SPECIFID™, Favrille, San Diego, CA) and GM-CSF (sargramostim, LEUKINE®) in patients with CD20+ follicular lymphoma. Mitumprotimut-T is a patient-specific therapeutic vaccine composed of the Id protein produced by proprietary recombinant technology from the malignant lymphoma biopsy specimen and conjugated to KLH, a potent immunogenic protein.Patients and Methods: Patients with treatment-naïve (T-N) or relapsed/refractory (R/R) WHO Grade 1–3 CD20+ follicular lymphoma received rituximab infusions at 375 mg/m2 weekly for 4 weeks, and those achieving a complete response (CR), partial response (PR), or stable disease (SD) at Week 11 were randomized to mitumprotimut-T (1 mg subcutaneously on Day 1) and GM-CSF (250 mcg subcutaneously daily on Days 1–4) or placebo and GM-CSF. Randomization was stratified by prior therapy (T-N vs. R/R) and response to rituximab (CR/PR vs. SD). Patients were immunized monthly × 6, every other month × 6, and then every 3 months until disease progression (PD). The primary efficacy endpoint was time-to-progression (TTP), which was assessed by an independent central radiology review.Results: 349 patients were randomized; their median age was 54 years (range, 21–86 years), 79% were T-N, 85% had an ECOG performance status of 0, and 86% had Stage III-IV disease. Thirty-four randomized patients (10%) did not receive blinded study drug: 28 because mitumprotimut-T could not be produced, 5 due to PD prior to start of blinded study drug, and 1 who withdrew for personal reasons. The mean number of courses was 10.6 (range, 1–21), and was comparable in the 2 groups. After a median follow-up of 40 months, 215 patients (62%) had progressed, 113 who were randomized to mitumprotimut-T and 102 who had received placebo. Median TTP from randomization was 9.0 months for patients randomized to mitumprotimut-T/GM-CSF and 12.6 months for placebo/GM-CSF (hazard ratio = 1.384, p = 0.019). Significantly more patients with high-risk FLIPI and fewer patients with low-risk FLIPI were unexpectedly randomized to mitumprotimut-T (p = 0.0042). After adjusting for FLIPI risk group in a Cox regression model, there was no significant difference in TTP between the two arms in the intent-to-treat population (p = 0.128), in patients with high risk FLIPI (p = 0.891), in patients with intermediate/low risk FLIPI (p = 0.143), in the 315 patients treated with blinded study drug, or in any of the patient subsets based on stratification factors. Comparisons of TTP between the two treatment arms using the investigators assessment of response were consistent with those obtained from central radiology review. There were no significant differences between the two treatment arms in objective responses (CR+PR) to rituximab at Week 11 (57.6%, combined data from both arms) or in objective responses any time on study (64.7%, combined data). Treatment was usually well tolerated, with 76% of adverse events graded as mild or moderate. The most common side effect was local injection site reaction, reported in 94% of patients.Conclusion: This Phase 3 trial showed no improvement in TTP with mitumprotimut-T and GM-CSF following rituximab in CD20+ follicular lymphoma.

Rituximab for treatment-resistant extensive Wegener`s granulomatosis—additive effects of a maintenance treatment with leflunomide

Extensive Wegener's granulomatosis (WG) is treated by glucocorticosteroids (GC) and cyclophosphamide (CYC). In some cases, the disease is refractory to CYC. For those patients the depletion of B-lymphocytes with rituximab is a promising new treatment modality. This is a retrospective study of six patients receiving rituximab (RTX) with 4 x 375 mg/m(2) body surface weekly because of inefficacy of CYC. Proteinase-3-antineutrophil cytoplasmic antibodies (PR3-ANCA) and c-ANCAs were assessed. For clinical follow-up the Birmingham Vasculitis Activity Score for WG (BVAS/WG) was used. In five of the six cases, leflunomide (LEF) was given as maintenance treatment. Mean follow up was 16 months (12-21 months). The median PR3-ANCA titer fell from 36.8 U/ml at baseline to 21.4 U/ml after 3 months, 8.3 after 6 months, and 4.3 at month 12. The median BVAS/WG at baseline was 5 and 0 after 1 month. Two minor relapses could be noticed at month 3. After 6 months, one patient still had a BVAS of 1, all the others had a BVAS of 0. At month 18, a major relapse occurred in one patient, which was successfully retreated with RTX. The RTX infusions were well tolerated. Rituximab is a well-tolerated, very effective medication for patients with Wegener's granulomatosis. Leflunomide maintenance may increase the efficacy of rituximab and prolong the disease-free period.

Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody–associated vasculitis

To assess the clinical effects of rituximab therapy in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The study group comprised 11 patients who had active AAV despite receiving maximally tolerated doses of cyclophosphamide or had contraindications for cyclophosphamide use. All patients had ANCA reactive against proteinase 3. The patients received rituximab infusions and glucocorticoids to induce remission. Three patients also received plasma exchange. No other immunosuppressive agents were used. Glucocorticoids were tapered as soon as control of disease activity was achieved. Disease activity was monitored using the Birmingham Vasculitis Activity Score, modified for Wegener's granulomatosis. Rituximab therapy was well tolerated by all patients, and adverse events were rare. Following the rituximab infusions, circulating B lymphocytes became undetectable, and ANCA titers decreased significantly. Remission was achieved in all patients and was maintained while B lymphocytes were absent. The ability to achieve stable remissions with rituximab in patients with AAV refractory to conventional therapy suggests that B lymphocyte depletion may be a safe, effective, mechanism-based treatment modality for treatment of patients with these conditions.