Rituximab-treated Group Research Articles

Rituximab-to-vaccine interval on SARS-CoV-2 immunogenicity in children: The potential role of prior natural infection.

Treatment with anti-CD20 antibodies (rituximab) is used in both adults and children to treat various autoimmune and oncological diseases. Rituximab depletes B CD20+ cells and, thereby, antibody response to vaccines. This study aimed to examine the antibody response to mRNA-based COVID-19 vaccines in children aged 5-18 years undergoing rituximab treatment compared to healthy matched children. Between 31 January and 18 July 2022, we conducted a prospective observational study at the Geneva University Hospitals, enrolling children aged 5-18 years under rituximab treatment who had received two mRNA-based SARS-CoV-2 vaccine doses. Controls were healthy volunteers with no significant medical conditions. Exclusion criteria included a recent SARS-CoV-2 infection. Blood samples were collected at day 60 (±30) and day 270 (±90) after the second vaccination. The rituximab-treated group exhibited significantly lower levels of antibodies specific to the anti-receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein than healthy controls at 60 (±30) days after the second vaccine dose (geometric mean concentration: 868.3 IU/mL in patients and 11,393 IU/mL in controls; p = .008). However, patients with a rituximab-to-vaccine interval shorter than 6 months and with evidence of a past infection (based on positive anti-N antibody levels) had a high level of anti-RBD antibodies. A past infection with SARS-CoV-2 may induce anti-RBD-specific memory B cells that can be re-activated by SARS-CoV-2 vaccination, even after rituximab-induced B-cell depletion. This suggests that it is possible to vaccinate earlier than 6 months after rituximab to develop a good antibody response, especially in the case of past SARS-CoV-2 infection.

Accelerated Allograft Vasculopathy With Rituximab After Cardiac Transplantation

BackgroundThe CTOT-11 (Prevention of Cardiac Allograft Vasculopathy Using Rituximab Therapy in Cardiac Transplantation [Clinical Trials in Organ Transplantation-11]) study was a randomized, placebo-controlled, multicenter, double-blinded clinical trial in nonsensitized primary heart transplant (HTX) recipients. ObjectivesThe study sought to determine whether B cell depletion therapy would attenuate the development of cardiac allograft vasculopathy. MethodsA total of 163 HTX recipients were randomized to rituximab 1,000 mg intravenous or placebo on days 0 and 12 post-transplant. Primary outcome was change in percent atheroma volume (PAV) from baseline to 1 year measured by intravascular ultrasound. Secondary outcomes included treated episodes of acute rejection, de novo anti-HLA antibodies (including donor-specific antibodies), and phenotypic differentiation of B cells. ResultsThere were no significant differences at study entry between the rituximab and placebo groups. Paired intravascular ultrasound measures were available at baseline and 1 year in 86 subjects (49 rituximab, 37 placebo). The mean ± SD change in PAV at 12 months was +6.8 ± 8.2% rituximab versus +1.9 ± 4.4% placebo (p = 0.0019). Mortality at 12 months was 3.4% rituximab versus 6.8% placebo (p = 0.47); there were no retransplants or post-transplant lymphoproliferative disorder. The rate of treated rejection was 24.7% rituximab versus 32.4% placebo (p = 0.28). Rituximab therapy effectively eliminated CD20+/CD19+ B cells followed by a gradual expansion of a CD19– cell population in the rituximab-treated group. ConclusionsA marked, unexpected increase in coronary artery PAV with rituximab was observed during the first year in HTX recipients. One-year mortality was not impacted; however, longer-term follow-up and mechanistic explanations are required. (Prevention of Cardiac Allograft Vasculopathy Using Rituximab [Rituxan] Therapy in Cardiac Transplantation; NCT01278745)

Association of Rituximab Treatment With Disability Progression Among Patients With Secondary Progressive Multiple Sclerosis

Therapeutic options for patients with secondary progressive multiple sclerosis (SPMS) are limited. To analyze disability progression in patients with SPMS treated with rituximab compared with matched control patients never treated with rituximab. This retrospective cohort study analyzed data obtained from patients with SPMS at 3 multiple sclerosis centers located in Basel and Lugano, Switzerland, and Amsterdam, the Netherlands, from 2004 to 2017. Patients were included for analysis if they had received a diagnosis of SPMS, were treated (57 eligible; 54 included) or never treated (504 eligible; 59 included) with rituximab, and had at least 1 follow-up visit. The variables used for propensity score matching were sex, age, Expanded Disability Status Scale (EDSS) score, and disease duration. Follow-up duration was up to 10 years, with a mean (SD) of 3.5 (2.6) years for rituximab-treated patients and 5.4 (2.4) years for controls in the total cohort and a mean (SD) of 3.5 (2.7) years for rituximab-treated patients and 4.8 (2.2) years for controls in the matched cohort. Comparing EDSS score progression in patients with SPMS (treated with rituximab vs not treated with rituximab) using propensity score matching. The primary end point was progression of EDSS score after baseline, and the secondary end point was time to confirmed disability progression. After 1:1 propensity score matching, 44 matched pairs (88 patients) were included in the analysis. At baseline, patients treated with rituximab had a mean (SD) age of 49.7 (10.0) years, mean (SD) disease duration of 18.2 (9.4) years, and mean (SD) EDSS score of 5.9 (1.4), and 26 (59%) were women, whereas controls had a mean (SD) age of 51.3 (7.4) years, mean (SD) disease duration of 19.4 (8.7) years, and mean (SD) EDSS score of 5.70 (1.29), and 27 (61%) were women. In the covariate-adjusted analysis of the matched set, patients with SPMS who were treated with rituximab had a significantly lower EDSS score during a mean (SD) follow-up of 3.5 (2.7) years (mean difference, -0.52; 95% CI, -0.79 to -0.26; P < .001). Time to confirmed disability progression was significantly delayed in the rituximab-treated group (hazard ratio, 0.49; 95% CI, 0.26-0.93; P = .03). In this study, patients with SPMS treated with rituximab had a significantly lower EDSS score for up to 10 years of follow-up and a significantly delayed confirmed progression compared with matched controls, suggesting that B-cell depletion by rituximab may be therapeutically beneficial in these patients. A prospective randomized clinical trial with a better level of evidence is needed to confirm the efficacy of rituximab in such patients.

Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study

ObjectivesWe explored the effects of B-cell directed therapy in subjects at risk of developing autoantibodypositive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and explored biomarkers predictive of arthritis...

Infectious Complications in Kidney-Transplant Recipients Desensitized with Rituximab and Intravenous Immunoglobulin

Rituximab and intravenous Ig (IVIG) are commonly used for desensitization of HLA and blood group-incompatible (ABOi) transplants. However, serious infections have been noted in association with rituximab administration. In this study, we retrospectively compared infectious outcomes in those who received rituximab plus IVIG for HLA or ABOi transplants (RIT group) with a group of nonsensitized, ABO-compatible transplant recipients (non-RIT group). Patients undergoing kidney transplantation at Cedars-Sinai Medical Center were included in the analysis. A total of 361 patients were identified. All received antimicrobial prophylaxis and viral surveillance. The primary outcome was infection. Overall patient survival was 97 and 96%, and graft survival was 91 and 89% in the RIT and non-RIT groups, respectively, after an average follow-up of 18 months. There were equal rates of bacterial (34.7% versus 39.1%), viral (21.8% versus 25.1%), fungal (5.9% versus 5.2%), and serious infections (22.9% versus 25.5%) in the RIT and non-RIT groups respectively. Urinary tract infection was the most common infection, accounting for 50% of all bacterial infections. Cytomegalovirus viremia was nonsignificantly more common in the nonrituximab-treated group (15.2% versus 10%), whereas BK viremia was marginally more frequent in the rituximab-treated group (10.6% versus 5.8%). There were no graft losses caused by BK-associated nephropathy. There were two deaths in each group related to infection (1%). Rituximab does not increase infection risk when used with intravenous Ig for desensitization.

Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab

For patients with rheumatoid arthritis (RA), yearly influenza vaccination is recommended. However, its efficacy in patients treated with rituximab is unknown. The objectives of this study were to investigate the efficacy of influenza vaccination in RA patients treated with rituximab and to investigate the duration of the possible suppression of the humoral immune response following rituximab treatment. We also undertook to assess the safety of influenza vaccination and the effects of previous influenza vaccination. Trivalent influenza subunit vaccine was administered to 23 RA patients who had received rituximab (4-8 weeks after rituximab for 11 patients [the early rituximab subgroup] and 6-10 months after rituximab for 12 patients [the late rituximab subgroup]), 20 RA patients receiving methotrexate (MTX), and 29 healthy controls. Levels of antibodies against the 3 vaccine strains were measured before and 28 days after vaccination using hemagglutination inhibition assay. The Disease Activity Score in 28 joints (DAS28) was used to assess RA activity. Following vaccination, geometric mean titers (GMTs) of antiinfluenza antibodies significantly increased for all influenza strains in the MTX-treated group and in healthy controls, but for no strains in the rituximab-treated group. However, in the late rituximab subgroup, a rise in GMT for the A/H3N2 and A/H1N1 strains was demonstrated, in the absence of a repopulation of CD19+ cells at the time of vaccination. Seroconversion and seroprotection occurred less often in the rituximab-treated group than in the MTX-treated group for the A/H3N2 and A/H1N1 strains, while seroprotection occurred less often in the rituximab-treated group than in the healthy controls for the A/H1N1 strain. Compared with unvaccinated patients in the rituximab-treated group, previously vaccinated patients in the rituximab-treated group had higher pre- and postvaccination GMTs for the A/H1N1 strain. The DAS28 did not change after vaccination. Rituximab reduces humoral responses following influenza vaccination in RA patients, with a modestly restored response 6-10 months after rituximab administration. Previous influenza vaccination in rituximab-treated patients increases pre- and postvaccination titers. RA activity was not influenced.

SAR650984: A Potent Anti-CD38 Therapeutic Antibody with Three Mechanisms of Action (Apoptosis, ADCC, CDC) for Hematological Malignancies

CD38 is a promising target for antibody therapeutics for the treatment of various hematological malignancies, including multiple myeloma as well as non-Hodgkin's lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, and chronic myeloid leukemia. CD38 is a type II transmembrane glycoprotein with ectozyme activity that has been implicated in Ca2+ mobilization. CD38 expression correlates with the poor disease prognosis in some hematological malignancies.It has been proposed that rituximab, a well-established anti-CD20 antibody for the treatment of non-Hodgkin's lymphoma, works by several mechanisms, including antibodydependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. A panel of murine anti-CD38 antibodies was first screened for their ability to induce apoptosis, as measured by Annexin V staining, in various lymphoma, leukemia, and multiple myeloma cell lines. Chimeric human IgG1 versions of the selected murine antibodies with potent apopototic activity were then produced and screened for ADCC and CDC activities. Among the screened antibodies, a chimeric version of SAR650984, a humanized anti-CD38 antibody, had the best overall activities. SAR650984 induced potent apoptosis in Daudi, Raji, Ramos, and SU-DHL-8 lymphoma cells, as well as MOLP-8 multiple myeloma (MM) cells and DND-41 acute T lymphocytic leukemia (T-ALL) cells, which like most, if not, all MM and T-ALL cells, express CD38, but not CD20. SAR650984 also induced potent ADCC and CDC in these tumor cells. When the activities of SAR650984 and rituximab were directly compared in Daudi and Raji lymphoma cells that express similar levels of CD38 and CD20, SAR650984 had similar ADCC and CDC activities as rituximab, and, in addition, SAR650984 induced a greater percentage of lymphoma cells to undergo apoptosis than did rituximab.SAR650984 and rituximab showed similar efficacy in a SCID disseminated survival model with Daudi lymphoma cells. Groups of 10 mice were intravenously injected with 5 × 106 Daudi cells on day 0 and then treated with 40 mg/kg SAR650984, 40 mg/kg rituximab, or PBS control on days 7, 11, 14, 18, 21 and 25. The median survival (range) was 28 days (26–30 days) for the PBS-treated group, 47 days (40–51 days) for the SAR650984-treated group and 42.5 days (40–51 days) for the rituximab-treated group. SAR650984 also showed strong anti-tumor activity in a subcutaneous xenograft SCID model with CD38+ CD20− NCI-H929 multiple myeloma cells. Groups of 10 mice were subcutaneously injected with 106 NCI-H929 cells on day 0, and then treated with 40 mg/kg SAR650984, 40 mg/kg rituximab (non-binding IgG1 control), or PBS control twice weekly for three weeks starting on day 6 when the tumors were palpable. A mean tumor volume of 1000 mm3 was reached by PBS-treated group on day 89 and rituximab-treated group on day 84 (70–80% tumor take rate for NCI-H929). SAR650984 treatment completely prevented the tumor growth in all 10 mice (tumor free at the end of study on day 128).In summary, the humanized anti-CD38 antibody, SAR650984, has potent ADCC, CDC, and apoptotic activities in vitro and anti-tumor activity in vivo. SAR650984 is a promising therapeutic antibody candidate for various hematological malignancies, especially in diseases such as multiple myeloma, where rituximab is inactive.

Effect of Adding Rituximab to Three Cycles of CHOP Plus Invoved-Field Radiotherapy for Limited-Stage Aggressive Diffuse B-Cell Lymphoma (SWOG-0014).

The 5-year survival rate of patients with limited disease (LD) and aggressive histologies of non-Hodgkin lymphoma (NHL) who have at least one adverse risk factor is about 70% after treatment with three cycles of CHOP followed by involved-field radiotherapy (CHOP(3) plus RT). We tested the effect of adding four infusions of rituximab to CHOP(3) plus RT in 62 evaluable patients. Patients had an aggressive histology of diffuse B-cell NHL (diffuse large cell or Burkitt's-like) and had LD. LD is defined as stage I with at least one adverse risk factor (age > 60 years, elevated serum LDH, or a performance status of 2) OR non-bulky stage II disease. Adverse risk factors are defined using a stage-modified IPI system and include: non-bulky stage II, age >60 years, elevated serum LDH and a performance status of 2. Patients with bulky stage II disease were excluded as their prognosis is similar to advanced disease, and patients with stage I disease and no risk factors were excluded as their prognosis exceeds 90% survival at 10 years with CHOP(3) plus RT. Rituximab was infused at 375 mg/m2 on days −7, 1, 22, and 43, and CHOP was given at standard doses on days 3, 24, and 45 (CHOP(3) plus R plus RT). Involved-field RT was given as previously described (N Engl J Med 1998; 339:21–26). With a median follow-up of 2.4 years, the progression-free survival (PFS) and overall survival (OS) measured at 2 years was 94% and 95%, respectively. In order to estimate whether the addition of rituximab adds benefit to CHOP(3) plus RT, and therefore, would be worth testing in a comparative trial, we identified 68 patients from SWOG study 8736 treated with CHOP(3) plus RT using the same criteria to include LD and aggressive diffuse B-cell histologies. These previously reported patients treated with CHOP(3) plus RT (ref above) have a median follow-up of 12.0 years. The PFS and OS for this group measured at 2 years was 85% and 93%, respectively. Four patients have relapsed in the rituximab-treated group and 10 patients had relapsed in the CHOP(3) plus RT alone treated group within the first 2 years. Three patients have died in the rituximab- treated group and five patients had died on the CHOP(3) plus RT alone treated group within the first 2 years (see Table). Short-term toxicity appeared similar. We conclude that the addition of rituximab to standard treatment with CHOP(3) plus RT results in outcome which compares favorably to our historical experience and merits further study.Effect of Rituximab in Treating Limited DiseaseMEASUREMENTCHOP(3) + R + RT (0014)CHOP(3) + RT (8736)No. patients62682-year PFS94%85%2-year OS95%93%No. relapses 2 yrs410No. deaths 2 yrs35Results of SWOG study 0014 compared to SWOG study 8736