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Introduction: STAT1 gain-of-function (GOF) disease is associated with chronic mucocutaneous candidiasis (CMC) and a broad spectrum of infectious, inflammatory, and vascular manifestations. The Janus Kinase inhibitor ruxolitinib has been used successfully for CMC and autoimmune phenomena. We describe a case of warm autoimmune hemolytic anemia (WAIHA) in a patient with STAT1 GOF disease after initiating ruxolitinib. Case report: A 36-year-old man with STAT1 c.850G>A (p.Glu284Lys) mutation presented with CMC as well as recurrent viral and bacterial infections, lymphadenopathy, enteritis, nodular regenerative hyperplasia (NRH) and splenomegaly. Immune workup confirmed a combined immunodeficiency with hypogammaglobulinemia and T-cell lymphopenia. Ruxolitinib was initiated at 5 mg twice daily (due to pre-existing thrombocytopenia) with up titration over 3 months to 20 mg twice daily. He improved with weight gain, increased energy, resolution of chronic anemia, and improved lymphadenopathy and splenomegaly on imaging. Serum CXCL9 only minimally decreased from 4660 pg/ml to 3990 pg/ml. Soon after reaching ruxolitinib 20 mg twice daily, he developed JC viremia, prompting dose reduction to 15 mg BID. Within two weeks, he developed a non-COVID upper respiratory tract infection followed by fatigue, shortness of breath with ambulation, and dark urine. Emergency evaluation revealed warm antibody positive hemolytic anemia with a hemoglobin of 5 g/dL, and worsened thrombocytopenia. He was treated with blood transfusions, pulse steroids, and high-dose IVIG with stabilization but continued hemolysis. Due to the JC viremia, there was concern to give rituximab with increased PML risk. Bone marrow showed trilineage hematopoiesis, a mild increase in megakaryocytes and RBC precursors, and a loss of B-cell progenitors with retention of mature B cells. His B and T lymphocyte numbers had increased since prior to ruxolitinib, with a predominance of Tfh1-cells (58.7% of total Tfh-cells). He was started on sirolimus with a slow taper of prednisone with continued stable hemoglobin and platelets, and resolution of hemolysis after 3 months. Conclusion(s): To our knowledge, this is the first case of a STAT1 GOF patient developing WAIHA while receiving ruxolitinib therapy. Treatment choices were complicated by the risks of PML. Sirolimus combined with ruxolitinib allowed wean of corticosteroid and subsequent resolution of hemolysis.Copyright © 2023 Elsevier Inc.
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Background/Aims Advances in rational drug design and recent clinical trials are leading to emergence of a range of novel therapies for SLE and therapeutic options in clinical practice are expected to broaden rapidly. The optimal real-world place of emerging and established agents will be guided by understanding their differential efficacy on specific SLE manifestations as well as efficacy for more resistant disease. Anifrolumab, a type-I interferon receptor blocking monoclonal antibody, showed efficacy in SLE in phase III trials with a notable effect on mucocutaneous disease although specific lesion subtypes and chroncicity were not explored. Severe refractory mucocutaneous SLE such as scarring discoid lesions are an important and common clinical challenge in current practice. We therefore prospectively evaluated the real-world efficacy and quality of life impact of anifolumab for active mucocutaneous SLE, recalcitrant to multiple biologic and immunosuppressant therapies. Methods Seven patients commenced anifrolumab (300mg by monthly iv infusion) following application to the manufacturer's early access programme (NCT 04750057). Prior biologic therapies were discontinued at least 5 half-lives in advance. Mucocutaneous disease activity was captured by Cutaneous Lupus Disease Area and Severity Index (CLASI) activity score and medical photography. Patient reported health-related quality of life comprising the Dermatology Life Quality Index (DLQI);Lupus-QoL and EQ5D-5L were evaluated at baseline, three and six months. Results Seven female patients with active mucocutaneous SLE (Discoid LE n=5, chilblain LE n=1, subacute cutaneous LE n=1) and median disease duration of 17 years were evaluated. Median baseline CLASI activity score was 17 (range 10-26;higher scores indicating severe disease). Median number of previously failed therapies was 7 and included rituximab in 6/7, belimumab in 2/7 and thalidomide in 4/7. Rapid resolution of scale and erythema in DLE was established within 1 month of anifrolumab treatment. Improvements to chilblain lupus were evident by three months. CLASI activity score was improved >=75% in all patients at 3 months. Clinical responses were associated with significant improvements in DLQI (p<0.001) and EQ5D-VAS (p=0.002) by three months. Lupus-QoL trended toward improvement across all domains but most strongly for fatigue (p=0.01) and pain (p=0.002) by 6 months. One patient discontinued treatment after 4 months due to polydermatomal shingles complicated by sensorineural hearing loss. Infection coincided with background prednisolone dose >15mg daily, recent COVID-19 infection and new on-treatment hypogammaglobulinaemia (IgG <5g/L). Prolonged aciclovir treatment was required for lesion resolution. Conclusion We report rapid real-world efficacy and quality of life impact of anifrolumab on highly refractory mucocutaneous SLE, which exceeded that anticipated from existing clinical trial data. Findings suggest a unique role for emerging interferon targeting therapies in management of mucocutaneous SLE but emphasize need for enhanced VZV precautions among higher risk patients.
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Background: Patients with systemic lupus erythematosus (SLE) are at an increased risk of infection relative to the general population. We aimed to describe the frequency and risk factors for serious infections in patients with moderate-to-severe SLE treated with rituximab, belimumab, and standard of care therapies in a large national observational cohort. Method(s): The British Isles Lupus Assessment Group Biologics Register (BILAG-BR) is a UK-based prospective register of patients with SLE. Patients were recruited by their treating physician as part of their scheduled care from 64 centres across the UK by use of a standardised case report form. Inclusion criteria for the BILAG-BR included age older than 5 years, ability to provide informed consent, a diagnosis of SLE, and starting a new biological therapy within the last 12 months or a new standard of care drug within the last month. The primary outcome for this study was the rate of serious infections within the first 12 months of therapy. Serious infections were defined as those requiring intravenous antibiotic treatment, hospital admission, or resulting in morbidity or death. Infection and mortality data were collected from study centres and further mortality data were collected from the UK Office for National Statistics. The relationship between serious infection and drug type was analysed using a multiple-failure Cox proportional hazards model. Finding(s): Between July 1, 2010, and Feb 23, 2021, 1383 individuals were recruited to the BILAG-BR. 335 patients were excluded from this analysis. The remaining 1048 participants contributed 1002.7 person-years of follow-up and included 746 (71%) participants on rituximab, 119 (11%) participants on belimumab, and 183 (17%) participants on standard of care. The median age of the cohort was 39 years (IQR 30-50), 942 (90%) of 1048 patients were women and 106 (10%) were men. Of the patients with available ethnicity data, 514 (56%) of 911 were White, 169 (19%) were Asian, 161 (18%) were Black, and 67 (7%) were of multiple-mixed or other ethnic backgrounds. 118 serious infections occurred in 76 individuals during the 12-month study period, which included 92 serious infections in 58 individuals on rituximab, eight serious infections in five individuals receiving belimumab, and 18 serious infections in 13 individuals on standard of care. The overall crude incidence rate of serious infection was 117.7 (95% CI 98.3-141.0) per 1000 person-years. Compared with standard of care, the serious infection risk was similar in the rituximab (adjusted hazard ratio [HR] 1.68 [0.60-4.68]) and belimumab groups (1.01 [0.21-4.80]). Across the whole cohort in multivariate analysis, serious infection risk was associated with prednisolone dose (>10 mg;2.38 [95%CI 1.47-3.84]), hypogammaglobulinaemia (<6 g/L;2.16 [1.38-3.37]), and multimorbidity (1.45 [1.17-1.80]). Additional concomitant immunosuppressive use appeared to be associated with a reduced risk (0.60 [0.41-0.90]). We found no significant safety signals regarding atypical infections. Six infection-related deaths occurred at a median of 121 days (IQR 60-151) days from cohort entry. Interpretation(s): In patients with moderate-to-severe SLE, rituximab, belimumab, and standard immunosuppressive therapy have similar serious infection risks. Key risk factors for serious infections included multimorbidity, hypogammaglobulinaemia, and increased glucocorticoid doses. When considering the risk of serious infection, we propose that immunosupppressives, rituximab, and belimumab should be prioritised as mainstay therapies to optimise SLE management and support proactive minimisation of glucocorticoid use. Funding(s): None.Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
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Background. Rituximab (RTX) is a chimeric monoclonal antibody that binds the CD20 molecule on the surface of B cells and leads to B cell depletion. RTX is recommended by the European League Against Rheumatism (EULAR) as off-label in patients affected by idiopathic inflammatory myopathies (IIM). The real-world experience has shown that hypogammaglobulinemia occurring early after anti-CD20 treatment can be multifactorial (active disease, effect of other drugs) and usually transient, with a minimal increase in the risk of infections. The present study aimed to analyse the differences in the rate of RTX-associated hypogammaglobulinemia in a cohort of IIM patients in clinical practice, as well as the onset of major infections and its correlation with hypogammaglobulinemia. Methods. Patients followed at Rheumatology Unit of Siena University Hospital from January 2020 to September 2021 were retrospectively enrolled. Inclusion criteria were as follows: fulfilment of disease-specific classification criteria 2017 EULAR criteria and /or Peter and Bohan criteria for dermatomyositis (DM) and polymyositis (PM), positivity of anti-synthetase antibody and typical clinical features for anti-synthetase syndrome (ASS) and the measurement of serum Ig levels at the time of RTX administration (maximum 2 weeks before) (T0) and 6 (T1) to 12 (T2) months later, consistently with previous studies. Ig serum levels, measured by standard nephelometry (normal ranges: IgG 700-1600 mg/dL, IgM 40-240 mg/dL, IgA 70-400 mg/dL) were assessed as part of routine clinical care. Hypogammaglobulinemia was defined as moderate (serum IgG <600 mg/dL) and severe (IgG <400 mg/dL), as previously reported. Results. Seven patients (mean+/-SD, 57.3+/-19.7 years;7 female) were enrolled. Three of them had diagnosis of DM, three ASS and one PM. Two patients showed MDA5-positivity, two JO1-positivity, one TIF1-gamma-positivity, one PL7-positivity and the other one PM/Scl-positivity. All patients had at least two organs involved, and 4 out of 7 (57%) suffered from interstitial lung disease. Before starting RTX treatment, three and four patients underwent at least one and two synthetic immunosuppressants. All patients underwent low dosage of corticosteroids, and four patients underwent concomitant synthetic immunosuppressants (2 hydroxychloroquine and 2 MTX). IgG concentrations were statically lower at T2 compared to those at baseline (p=0.0391). None of them showed severe hypogammaglobulinemia. Similarly, IgM concentration significantly decreased at T2 compared to those at baseline (p=0.0078). Two patients showed major infections and two patients had paucisymptomatic COVID-19 (one of them had twice). Corticosteroids dosages were inversely correlated with IgG T2 concentrations (p=0.040, r=-0.919). Conclusion. Hypogammaglobulinemia following RTX is uncommon in IIM and is more likely in patients with high glucocorticoids, immunosuppressants and CYC exposure. IgG monitoring at least 6 months after RTX treatment may be useful in stratifying patients to identify those who require closer monitoring. These results shine a spotlight for increased awareness of the role of immunoglobulin measurement before maintenance doses of RTX.
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Introduction Disruption to clinical services, triggered by the COVID-19 pandemic, led to extended intervals between ocrelizumab treatments for some patients. Objectives To assess the rates of developing low immunoglobulin levels and timing of CD19+ B-cell count repopulation in a real-world clinical population. To assess for evidence of clinical or radiological MS disease activity with extended interval dosing of ocrelizumab. Methods We audited 712 patients given ocrelizumab by our seven clinical services. All monitoring of immunoglobulin levels and CD19+ cell counts were recorded. Disease activity was defined as on treatment clinical relapse, radiological activity, and EDSS progression. Results Low immunoglobulin levels developed in 102 patients, the odds ratio for developing hypogam- maglobulinaemia comparing extended to standard interval dosing was 0.42 (CI 0.22-0.81). Disease activity included 20 participants with clinical relapses and 72 with new MRI lesions. There was no evidence of excess clinical or radiological disease activity on switching to extended interval dosing. 38 had EDSS progression, giving an odds ratio comparing extended to standard interval dosing of 0.77 (CI 0.38-1.56). Conclusions This real-world data of extended interval dosing of ocrelizumab indicates lower rates of hypogammaglobulinaemia and no detrimental effect on short-term treatment efficacy.
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Purpose: Primary focal segmental glomerulosclerosis (FSGS) recurs after kidney transplantation (KT) in 30-50% of recipients with a median time of 1.5 months post- KT. Recurrence is associated with early graft loss in 60% of cases. The aim of this study is to assess the efficacy of pre-emptive therapeutic plasma exchange (TPE) and rituximab for the prevention of FSGS recurrence post-KT. Method(s): This single-center, retrospective study included patients receiving KT for primary FSGS between May 2016 and August 2021. Living-donor KT recipients received three sessions of TPE prior to scheduled transplant. Recipients of both living and deceased donor KT received 3 postoperative sessions of TPE followed by one dose of 375 mg/m2 rituximab with or without intravenous immune globulin (IVIG) 0.5 g/kg. Recipients underwent protocol biopsy at one month to screen for FSGS recurrence. The primary endpoint was a composite for disease recurrence including proteinuria (>=1 g/day) or/and biopsy-proven FSGS within one month. Result(s): 54 patients received KT for FSGS during the study period using the TPE/ rituximab protocol. 5 patients (9%) experienced FSGS recurrence within one month of transplant. A total of 10 patients (19%) were found to have disease recurrence within a year, with median (IQR) time to recurrence of 37 days (27-66). White race and history of hypertension were independent risk factors for recurrence, whereas African American race and diabetes were associated with a reduced risk of recurrence. 31 patients (57%) also received IVIG prior to discharge due to concerns for hypogammaglobulinemia. There were 18 documented infections in 13 patients (24%) within 3 months of transplant. Patients who received IVIG had significantly fewer cases of infection (3 cases: 1 viral and 2 COVID-19) compared to patients who did not receive IVIG (15 cases: 4 bacterial, 9 viral, 1 fungal, and 1 COVID-19), p<0.001. At one year, 9 patients (19%) had biopsy-proven rejection (5 acute cellular rejection, 1 antibody-mediated rejection, and 3 mixed rejection). There were no instances of graft loss or mortality observed at one year. Conclusion(s): The utilization of plasma exchange and rituximab may prevent early disease recurrence of FSGS without significant rates of infection, graft loss, or mortality.
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Background: Hematopoietic stem cell transplant recipients (HSCTs) may experience the diminished immunogenicity to COVID- 19 vaccines. Aim: To summarize current evidence on COVID-19 vaccine responses and risk factors for their attenuation in HSCTs. Methods: A literature was systematically searched and reviewed from the existence of databases through June 22, 2022. Descriptive statistics and random-effects model were used for a meta-analysis. Results: From 46 studies, representing 4446 HSCTs, the weighted mean (95% confidence interval [CI]) of positive antispike seroconversion after COVID-19 vaccines was 40% (30%-51%), 80% (77%- 83%), and 80% (69%-88%) for 1, 2, and 3 doses, respectively. The cellular immune response was 58% (40%-75%) after 2 doses. Notably, the risk factors (pooled odds ratio [95% CI]) for poor antibody response after 2 vaccine doses comprised recent rituximab exposure (0.10 [0.02-0.57]), haploidentical allografts (0.49 [0.28-0.87]), post-HSCT duration less than 24 months (0.22 [0.07-0.71]), lymphopenia (0.27 [0.16-0.45]), hypogammaglobulinemia (0.32 [0.22-0.47]), concomitant chemotherapy (0.48 [0.29-0.78]), immunosuppressants (0.22 [0.14-0.34]) and corticosteroids (0.29 [0.16-0.53]). Ongoing immunosuppressants (0.06 [0.00-0.81]) also increased risk of poor cellular immunogenicity. Conclusion: In HSCTs, humoral and cellular immunogenicity to 2-3 doses of COVID-19 vaccines are attenuated by several risk factors. Further efforts on COVID-19 prevention including neutralizing monoclonal antibody uses are needed for this vulnerable population.
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Background: Although patients with lymphoma appear to be particularly vulnerable to SARS-CoV-2, clinical evolution of COVID-19 in lymphoma has been under-represented. Purpose: To investigate the outcome of SARS-CoV-2 in patients with lymphoma and the risk factors for COVID-19 pneumonia. Methods: Among adult patients with lymphoma at Yeouido St. Mary's hospital, we retrospectively reviewed the medical records with diagnosis of SARS-CoV-2 from January 2020 to April 2022. Results: A total of 117 patients (64 males) with median age of 53 years were identified. Sixty-eight were in complete remission when diagnosed of SARS-CoV-2. Sixty-one had more than one comorbidity and 29 had hypogammaglobulinemia. Thirty-four never had been vaccinated for SARS-CoV-2. During median follow-up of 61 days, COVID-19 pneumonia developed in 37 (31.6%) and 31 had persistent pulmonary conditions even after one month. Overall mortality was 6.0% (7 of 117), of which 4 were infection related. Multivariable analysis demonstrated that rituximab maintenance theraphy in follicular lymphoma (adj. OR of 3.67, 95% CI, 1.3-10.39, p = 0.01) was significant risk factor for COVID-19 pneumonia. Hypogammaglobulinemia (adj. OR of 2.27, 95% CI, 0.82-6.25, p = 0.08) and never vaccinated (adj. OR of 2.26, 95% CI, 0.85-6.01, p = 0.08) were not. Conclusions: In patients with lymphoma, SARS-CoV-2 causes pneumonia more frequently and most of them progress to COVID- 19 pneumonia. More aggressive vaccination and intervention for patients with lymphoma who have impaired humoral response related to rituximab maintenance, are needed.
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Background: Patients (pts) with cancer have increased mortality from COVID-19 and their vaccination is crucial to prevent severe infection. We aimed to identify demographic and laboratory determinants of humoral immune responses to COVID-19 vaccination in pts with cancer and investigate differences in responses based on the vaccine platform. Methods: We searched for records in PubMed, Embase, and CENTRAL up to 28/09/21, as well as conference proceedings from ASCO and ESMO 2021. We included studies of pts ≥16 yr with a cancer diagnosis, who were vaccinated against SARS-CoV-2. Studies were excluded if ≥10% of the participants had other causes of immunosuppression or baseline anti- SARS-CoV-2 spike protein antibodies (Ab)/previous COVID-19 (PROSPERO ID: CRD42021282338). For this subgroup analysis of studies that reported a proportion of pts with cancer and positive Ab titers at any timepoint following complete vaccination, a random-effects model was used to estimate the humoral response rate (HRR) with 95% confidence intervals (CI). Results: We included 64 records, reporting data from 10,511 cancer pts. The HRR in the overall population and by subgroup are shown in Table. Elder patients with hematologic cancers (59%, CI 47-70%,N= 667) and patients with lymphopenia (50%, CI 25-75%, N = 111) or hypogammaglobulinemia (36%, CI 19-57%, N=226) were the subgroups with lower HRR. Male (77%, CI 69-84%, N = 2,659) and Asian (84%, CI 54-96%, N = 37) pts showed a trend to lower HRR when compared with females and other races, respectively. Pts vaccinated with mRNA vaccine platforms (79%, CI 74-83%, N = 9,404) had numerically higher HRR than those receiving the adenovirus vaccines (28%, CI 19-40%, N = 74). Conclusions: This study highlights demographic and laboratory determinants of weaker immune responses to SARS-CoV-2 vaccination, permitting better identification of more vulnerable pts. Despite the small number of pts included receiving adenovirus vaccines, these data also suggest prioritizing mRNA platform vaccination in pts with cancer.
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Background: Vaccination against SARS-CoV-2 has shown efficacy and safety in patients with chronic infammatory rheumatic disease, similar to the general population. However, in patients treated with rituximab (RTX) it is known that usually have a lower vaccination response rate (1-2), and recent studies suggest that it also happens with the new SARS-CoV 2 vaccine (3), which entails an increased risk of hospitalization and mortality in this specifc group of patients. Objectives: To describe humoral immune response to SARS-CoV-2 vaccine in rituximab-treated patients after one and six months from the vaccination, and study if there is any other factor associated with a lower response rate. Methods: Prospective analysis of a cohort of patients treated with RTX who received the SARS-CoV-2 vaccine between the months of April and October 2021. Demographic and medical data were collected through electronic medical records. Blood tests and serologies with levels of antibodies against SARS-CoV-2 were performed one and six months after having received the vaccine against SARS-CoV-2. The administration of a booster dose of the vaccine was recorded. A descriptive and statistical analysis of the data was carried out using the SPSS program. Results: From a cohort of 41 patients, of whom 81,4% were women with a mean age of 56 (13,4 SD) years, vaccine response rate was only 36,7% after a 6-month follow-up. The 88,4% of them received a booster dose of the vaccine, but this failed to produce a vaccine response in any of the patients who had not developed it with the previous ones. One patient became infected after receiving one dose of the vaccine and failed to develop a serological response either. Hypogammaglobulinemia was associated with a statistically signifcant lower probability of vaccine response (p=0,04). A trend of lower vaccination response rate was observed in patients who had received the last cycle of RTX in the 6 months prior to vaccination (p=0,058). In addition, the antibody levels developed one month after vaccination were statistically signifcantly correlated with the time between the last RTX cycle and vaccination (p=0,014) and also with CD19 B cells levels prior to vaccination (p<0,001);however, there was no correlation with the antibody levels detected at the 6-months serology. No statistically signifcant differences were found in relation to the number of previous cycles of RTX, concomitant treatment with synthetic disease-modifying drugs (DMARDs) or corticosteroids. Conclusion: In our sample, after a 6-month follow-up only 36,9% achieved a vaccine response against SARS-CoV-2, which did not improve despite the administration of a booster dose. Hypogammaglobulinemia, the time between the last RTX cycle and vaccination (at least 6 months), and previous CD19 B cells levels signifcantly influenced in the development of a humoral response to the vaccine.
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Background: Rituximab (RTX) achieved high remission-induction and sustained maintenance rates for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) [1], [2]. However, RTX is an expensive medication, which may potentially lead to serious side effects. Defning the best dose regimen for maintenance in AAV is still an unmet need. Objectives: The aim of the present study is to compare the effects of ultra-low dose RTX (500 mg or 1000 mg once per year) to standard low dose RTX (500 or 1000 mg twice per year) as remission-maintenance therapy in AAV patients. Methods: We included consecutive AAV patients (classifed as GPA and MPA [3]) referring to four different Rheumatology centers in Italy. We assessed all AAV patients who successfully achieved disease remission (BVASv3=0) with conventional RTX or cyclophosphamide regimens and have been subsequently treated with RTX for maintenance of remission. All included patients received at least three maintenance infusions with either 1000 mg or 500 mg, twice per year (standard low dose) or once per year (ultra-low dose). After a period of 18 months, we assessed the remission rate, damage (VDI), glucocorticoids intake, ANCA status, B-cells depletion and serum IgG levels. Results: From January 2011 to December 2021, 83 AAV patients (mean age 51±16, 49.4% female, 95.2% ANCA positive, 65.8% anti PR3, 34.2% anti MPO), 61 classifed as GPA and 22 MPA, achieved complete disease remission with conventional RTX induction regimen. After 7 [6-9] months, 29.9% patients started maintenance treatment with ultra-low dose RTX (once per year), while 70.1% patients with standard low dose (twice per year), for 18 months. No signifcant differences at baseline were noted between patients receiving ultra-low dose when compared to those treated with conventional low-dose. At the end of observation period, a disease fare was observed in 22.7% of the low-dose group, and 21.2% in those treated with the standard dose (p=0.881). Relapse-free survival was comparable between the two group (log-rank p=0.818, Figure 1). When comparing AAV patients treated with ultra-low dose regimen to those treated with low-dose, no differences were noted in negative ANCA rate (72.2% vs 67.1%, p=0.262), ANCA titer (0 [0-7.8] vs 0 [0-50] UI/mL, p=0.232), B-cells depletion rate (70.6% vs 75%, p=0.725), mean serum IgG (811 [146-922] vs 680 [429-861] mg/dL, p=0.367), mean daily glucocorticoid dosage (2.5 [0-5] vs 3.75 [0-5] mg/d, p=0.647), VDI (4 [1-5] vs 2 [1-4], p=0.098), hypogammaglobulinaemia rate (31.8% vs 36.5%, p=0.697) and deaths (4.5% vs 5.8%, p=0.831). Although not signifcant, patients treated with ultra-low dose had lower severe infection rate (10.5% vs 26.8%, p=0.154). Notably, in the all cohort 5 deaths were related to COVID19 pneumonia. Conclusion: Reduced exposure to RTX was not associated with an impaired efficacy of maintenance therapy in patients with AAV. Remission maintenance with ultra-low dose RTX is a safe and more cost-effective option.
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Background: Patients with systemic autoimmune diseases (SADs) are often treated with drugs that interfere with the immune system and previous data showed a reduced seroconversion rate after anti-SARS-CoV2 vaccine in these subjects compared to healthy controls1. Administration of a booster dose of the vaccine could be particularly important in these patients, but data available to date are still scarce. Objectives: To evaluate the antibody response to the booster dose of mRNA SARS-CoV2 vaccine in patients with SADs and to compare it to the response after completion of the frst vaccination course. Secondly, to fnd possible correlations between a low antibody titre and patients' clinical features, with special regard to ongoing immunosuppressive therapies. Methods: Consecutive patients with an established diagnosis of SADs undergoing SARS-CoV2 vaccine were prospectively enrolled from January 2021;among them, we selected the patients who received the third vaccination dose between September and December 2021. Demographic and clinical data were collected at enrolment (sex, age, diagnosis, disease duration, ongoing therapies, previous SARS-CoV2 infection, presence of hypogammaglobulinemia);the last three elements were reassessed at each follow-up visit. Blood samples were collected 4 weeks both after the second (W4a) and the third (W4b) dose of the vaccine;a minority of patients was also tested 12 weeks after the second dose (W12). IgG antibodies to SARS-CoV2 receptor-binding domain (RBD) and neutralizing antibodies inhibiting the interaction between RBD and angiotensin converting enzyme 2 were evaluated. IgG anti-RBD were detected by solid phase assay on plates coated with recombinant RBD, while neutralising antibodies by using the kit SPIA (Spike Protein Inhibition Assay). Cut-off values were defned as the 97.5th percentile of a pre-vaccine healthy population. Statistical analysis was performed using IBM SPSS Statistics 20 and GraphPad Prism statistical packages. P values <0.05 were considered signifcant. Results: Forty-five patients (95.6% female;mean age ±SD 55.6±14.1 years;mean disease duration 12.9±10.6 years) were enrolled. Diagnosis was in most cases connective tissue disease (31/45, 68.9%), followed by infammatory arthritis (11/45, 24.4%) and systemic vasculitis (3/45, 6.7%). Two patients (4.4%) had a previous SARS-CoV2 infection and three had hypogammaglobulinemia (6.7%). At the time of the second dose, 18/45 patients were treated with glucocorticoids (GCs) [mean daily 6-methylprednisolone (6MP) dose 3.9 mg (min. 2, max. 14)], 17/45 with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and 12/45 with biologic DMARDs (bDMARDs). At the third dose administration, 19/45 patients were treated with GCs [mean daily 6MP dose 4.1 mg (min. 1.5, max. 10)], 18/45 with csDMARDs and 13/45 with bDMARDs. Anti-RBD IgG were positive in 42/45 patients (93.3%) at W4a, in 16/18 (88.9%) at W12 and in 42/45 (93.3%) at W4b. Neutralizing antibodies were present in 38/45 patients (84.4%) at W4a, in 14/18 (77.8%) at W12 and in 42/45 (93.3%) at W4b. Both anti-RBD IgG titers and neutralizing antibody titers signifcantly increased after the third dose if compared to W4a (p<0.0001 both) (Figure 1). Interestingly, of the 7 patients who had not developed an adequate neutralizing antibody response after the frst vaccination course, 5 mounted an adequate titer after the booster. Two non-responder patients were both on combination therapy (one with low dose of GCs plus mycophenolate mofetil, the other with methotrexate and infiximab). Conclusion: Our data suggest that in patients with SADs there is a decline in the antibody titers developed after COVID-19 vaccination, however the booster dose is effective in restoring an adequate antibody titre. These data consolidate the importance of a booster dose of COVID-19 vaccination in patients with SADs to aid in the generation of an immune response.
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Background: Bispecific antibodies (bsAb) are a promising class of therapeutics in RRMM. While hypogammaglobinemia (HGG) is anticipated due to plasma cell depletion, there is a lack of information about the degree of secondary immunodeficiency and resultant infectious complications. We investigated the kinetics of HGG in patients with RRMM on bsAb therapy. Methods: We identified and followed 42 patients treated on early clinical trials of bsAb at our institution between 2019 and 2021. Serial immunoglobulin levels and infections were obtained from the start of therapy until last follow up or 3 months after study exit. Results: 49 treatment courses were included from 42 individual patients. All patients were triple class exposed with a median of 5 prior lines of therapy. The median age was 67 (44-85) years, with 49% females. African Americans accounted for 18% of patients. 96% of patients had at least one prior ASCT. 90% of patients received bsAb targeting BCMA including 7 patients who received more than one line of BCMA targeting therapies. At a median follow up 9.5 (0.9-28.6) months, 40.8% of patients remained on bsAb therapy. At the start of therapy, the median IgG, IgA, and IgM levels were 560 (44-9436), 15 (5-3886) and 6 (5-64) mg/dL, respectively and 50% of patients had severe HGG (≤400mg/dl). Serum IgG levels reached a nadir at 3 months while, IgA and IgM at 1 month, from the start of therapy. The median nadir levels of IgG were 159 (40-2996) mg/dL, while it was < 5 mg/dL for both IgA and IgM. IgG levels were below the detectable range (< 40 mg/dl) in 28% of patients at some point during therapy. IgA and IgM were also below the detectable range (< 5 mg/dl) in 50% and 60% of patients, respectively. At last follow-up, the median IgG levels were 444 (40-1860) mg/dL and IgA 5 (5-254) mg/dL and IgM 5 (5-44) mg/dL. Additionally, 38% of patients remained severely hypogammaglobinemic. 57% (24/42) of patients received IVIG supplements in the current series. About 71% of patients had at least one infectious event and the cumulative incidence of infections progressively increased with increasing duration of therapy with risk at 3, 6, 9 12, 15 months being 41%, 57%, 64%, 67% and 70%, respectively. Among these, 54% of infection were bacterial. Viral infection accounted for 41% of infections. A third of patients had new infectious events during the first 90 days following stopping bsAb treatment. 57% (8/14) of patients did not mount a response to the primary COVID19 immunization series. Among the five patients with repeat antibody titers after the booster dose, 50% were still not able to mount an antibody response. Conclusions: bsAb therapy in RRMM can be associated with profound and prolonged HGG. The cumulative risk of infection correlated with the degree of HGG and progressively increases with treatment and persisted months after being off therapy. Additionally, an impaired antibody response to the COVID-19 immunization series was also noted.
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Background: Coronavirus-2 has profound effects on patients (pts) with Multiple myeloma (MM). At the beginning of the pandemic, COVID-19 infection resulted an overall mortality around 54% (cook et al. BMJ 2020). Here, we report an updated morbidity and fatality for MM. Methods: After obtaining IRB approvals from each participating institute, retrospectively, between January 1, 2021 and August 30, 2021, we identified pts with MM and COVID-19 in two myeloma centers (Levine Cancer Institute (LCI) & the University of Kansas medical center (KUMC). Results: We identified 162 MM pts who had COVID- 19 (LCI n=132, UKMC n=30), including 57% males, with median age of 64 years. Current or former smoking reported in 40% of pts. Most pts have associated comorbid conditions: hypertension (45%), hypogammaglobulinemia (32%), CKD (30%), DM (22%), obesity (16.6%), CHF (14%), and CAD (13.5%). Within 3 months prior to infection, treatment included immunomodulatory combinations in 35%, proteasome inhibitors in 28 %, and Daratumumab in 26.5%. Symptoms are summarized in table. 69% had Mild symptoms (no need for hospitalization), 20 % had moderate symptoms (requiring hospitalization), and 9.8% had severe symptoms (ICU level of care). The 18% of pts required oxygen: 6 pts required invasive oxygenation and 3 pts needed vasopressors. The 32% of pts had RRMM, 29.5% on maintenance, and 12% was getting induction. Regarding MM response: >VGPR in 45% and PD in 18%. The 78 pts had ASCT prior to COVID-19 infection: only 3 pts < 1 year and 3 pts < 6 months. MM response or ASCT did not affect hospitalization or mortality.The case fatality rate (CFR) was 6%. In the univariate analysis, CKD, DM, HTN and hepatic dysfunction were associated with an increased risk of hospitalization. However, in multivariate analysis, only CKD, hepatic dysfunction, and Hypogammaglobulinemia significantly increased the risk of admission with only age and lymphopenia were associated with increased COVID-19 related fatatlity. Conclusions: With implementation of center-specific disease control measures and universal screening, pts might have lower case severity and fatality rate than was initially reported.
ABSTRACT
Individuals with impaired ability to mount a humoral immune response, either during natural infection or upon prophylactic vaccination, are at high risk for a severe course of COVID-19. Besides humoral immunity mediated by B cells, T cell immunity is key for the control of viral infections. We developed the peptide-based vaccine candidate CoVac-1, which primarily aims for the induction of SARS-CoV-2-specific T cells. CoVac-1 comprises six promiscuous HLA-DR-binding SARS-CoV-2-derived T cell epitopes from various viral proteins proven (i) to be frequently and HLAindependently recognized by T cells in COVID-19 convalescents, (ii) to be of pathophysiological relevance for T cell immunity to combat COVID-19, and (iii) to mediate long-term immunity after infection (Nelde et al. Nat Immunol 2021, Bilich et al. Sci Transl Med 2021). CoVac-1 vaccine peptides are adjuvanted with the novel toll-like receptor 1/2 agonist XS15 emulsified in Montanide ISA51 VG. In a first-in-human clinical trial in healthy adults (NCT04546841), CoVac-1 showed a favorable safety profile and induced profound and long-lasting T cell immunity after single dose administration in 100% of the study subjects, mediated by multifunctional T-helper 1 CD4+ and CD8+ T cells. CoVac-1-induced T cell responses surpassed those after SARS-CoV-2 infection as well as those after vaccination with approved vaccines and were unaffected by current SARS-CoV-2 variants of concern (Heitmann et al. Nature 2021). Here we present the interim safety and immunogenicity results of our Phase I/II trial evaluating CoVac-1 in patients with congenital or acquired B cell deficiency, mainly comprising leukemia and lymphoma patients (NCT04954469). 64% of study subjects had previously been vaccinated with approved vaccines without developing any humoral immune response. Alike in the healthy adults, CoVac-1 showed a good safety and tolerability profile without relevant systemic adverse events. CoVac-1-specific T cell responses could be documented in 93% of study subjects on day 28 after CoVac-1 application, with earliest responses evidenced at day 14 (71%). Vaccine-induced T cell responses were mediated by multifunctional T-helper 1 CD4+ T cells. Of note, CoVac-1 induced T cell responses in this highly immune compromised study population were similar to those occurring in healthy volunteers after natural infection or induced by approved vaccines. These results identify CoVac-1 as promising vaccine candidate for cancer and other immunocompromised patients with immunoglobulin deficiency. Recruitment of the Phase II part of the trial is ongoing with results expected for March 2022.
ABSTRACT
Objective: to compare different variables in MS patients with positive versus negative spike protein antibody following SARS-COV-2 vaccination Background: Many MS-related clinical, demographic, and immunological variables can potentially impact vaccine response and those variables have not been fully explored. Design/Methods: patients with MS and related neuroimmunological disorders who requested verification of the immune response to the SARS-COV-2 vaccine were tested for the spike protein antibody between January and September of 2021. We compared patients with positive versus negative spike protein antibody. Results: Forty patients (mean age 53+/-11, 77% females) were included. Twenty-two patients had positive post-vaccination spike protein antibody (55%) and 18 were negative (45%). Negative patients were more likely to have been on B-cell therapy (83% vs 32%, P=.001) while positive patients were more likely to have been on a fumarate (36% vs 5.5%, P=.02). There was no difference between the two groups in the utilization of S1P1 modulators or non-selective immunosuppressants, gender, age, race, disease phenotype, vaccine brand, and lymphocyte counts. Half the positive patients on fumarates had lymphopenia at the time of vaccination but none below 0.8×109 /L. Among patients on B-cell therapy, 32% had a positive humoral response and were more likely to have detectable CD19 cells at the time of vaccination compared to negative patients (P=0.04). There was no difference between the two subgroups in terms of vaccine timing relative to B-cell therapy dose or the presence of hypogammaglobinemia. None of the patients with or without humoral response had post-vaccination COVID19 infection. Conclusions: B-cell therapy is associated with negative humoral responses to SARS-COV-2 vaccines but patients with detectable CD19 counts are more likely to have a positive antibody. The fumarates are associated with positive humoral response even in the presence of mild lymphopenia. Both positive and negative humoral responses were equally seen in S1P1 modulator patients.
ABSTRACT
Introduction: B cell maturation antigen (BCMA) is a novel target for T cell immunotherapy in MM including bispecific antibody (bsAb) and chimeric antigen receptor therapy (CAR-T). BCMA is critical for survival of the long-lived plasma cell, responsible for generation of protective antibodies. Impaired immune reconstitution, cytopenias, B cell aplasia and hypogammaglobinemia can compound preexisting MM-induced immunosuppression. In the case of bsAb, potential redirection/activation of T regulatory cells can create an immunosuppressive milieu. Herein, we describe the clinically relevant infectious complications observed across different BCMA-directed therapies used across multiple clinical trials at our center. Methods: Infections confirmed by microbiologic or histopathologic evidence were captured from the D1 C1 of bsAb and D 1 of lymphodepleting chemotherapy of autologous BCMA CAR-T therapies. The NCI CTCAE v5 was used to describe the site and grade of infections. Hypogammaglobinemia and severe hypogammaglobinemia were defined as ≤700 mg/dl and ≤400 mg /dl, respectively. Standard antimicrobial prophylaxis included herpes zoster prophylaxis for all MM patients with antibacterial (levofloxacin) / antifungal (fluconazole) during periods of neutropenia and IVIG supplementation as per the treating physician's discretion. PCP prophylaxis was prescribed to CAR T recipient per institutional guidelines. Descriptive statistics and comparisons were performed using two-sample t-test for continuous variables and chi-square goodness of fit test for categorical variables. Results: We identified 62 patients who received BCMA-directed bsAb (n=36) or CAR-T (n=26) between 2019-2021(table 1). The median age was 66 (range 48-84) years with % females and 14.8% of patients belonging to Black race. The median time to bsAb and CAR-T use from diagnosis were 6.6 (range 0.83-15.5) and 2.6 (range 0.35-14.4) years, respectively. The median lines of prior therapy were 6 (range 1-11) with BCMA CAR-T recipients receiving fewer prior lines of therapy (4 vs 6, p=<0.001). The baseline lymphocyte count was higher in the CAR-T (14.71 vs 0.84;p=<0.001). Baseline severe hypogammaglobulinemia and lymphopenia were present in 30% and 26.7% of all patients, respectively. Tocilizumab was used in 40.9% (bsAb -30.8% versus CAR-T 55.6%) patients for CRS. IVIG was used in 25% of patients. The median study duration for bsAb was 4 (range 0.03- 24) months across multiple dose levels. Median follow up among CAR-T recipients was 3.9 (range 0.3 - 22.3) months. Among recipients of bsAb, 41.2% of patients experienced at least one episode of infection vs. 23.1% with CAR-T (p=0.141). The cumulative incidence of infection with bsAb and CAR-T were 22 and 8, respectively. The spectrum of infections with bsAb was predominantly bacterial (64.3% While gram negative infection (Escherichia coli and Klebsiella pneumoniae bacteremia, Proteus mirabilus and Psuedomonas aeroginosa urinary tract infections) were seen in 6 patients, skin infection including cellulitis occurred in 4 patients, with 1 case of necrotizing cellulitis. Bacteremia with rare opportunistic pathogens - Rhizobium radiobacter and recurrent Ochrobacterium anthropi were also observed . Viral infections included rhinovirus, cytomegalovirus, and parvovirus B19 reactivation, and COVID-19. About 50% of infections were ≥ grade 3 with 2 grade 5 events (Pseudomonas aeruginosa bacteremia and COVID-19). In the CAR-T group, we observed more viral infections (66.7% vs 35.7%;p=0.028) and fewer bacterial infections (33.3% vs 64.3%;p=0.028) . Common viral infections included rhinovirus, RSV, and herpes simplex virus reactivation. In this group 25% of infections were ≥grade 3. Conclusion: BCMA-targeted therapies seem to be associated with clinically significant bacterial and viral infections. Repetitive dosing with bsAb therapies could be the reason for the propensity to serious bacterial infections compared to CAR-T recipients and may need novel prophylaxis strategies. (Figure Presented).
ABSTRACT
The first cases of Covid-19 were detected in the UK in early March 2020, leading to the first of three national lockdowns on 23 March 2020. CLL patients were asked to isolate at home (to shield) with a consequent interruption in clinical visits and treatment. Clinicians became concerned about the well-being of their patients in these stressful circumstances and needed information to better inform their clinical decisions. This study describes what happened to the emotional and mental well-being of patients during this period, together with those who were admitted to the hospital with Covid, and indicates what changes are recommended as a result. Method: Three charities, Leukemia Care, CLL Support, and UKCLL Forum worked together to produce five surveys plus a continuous 6th survey of UK physicians which identified CLL Covid patients attending hospital. A total of 4630 patient replies were received. Eighty-nine percentage responded to more than one survey: Survey Date Responses 1 27.03.20 844 2 20.04.20 843 3 20.05.20 1076 4 13.11.20 818 5 31.03.21 1049 6 27.03.20-31.03.2127 centers 81 patients, The first three surveys were designed to assess how patients were coping at the start, one month in, and at the end of the first lockdown. The 4th assessed changed attitudes before the 3rd lockdown and the 5th covered Covid infections, vaccination, and attitudes to unlocking. Results: The average respondent age was 64.7 years (52% male, 48% female) with 22.3% living alone and 50.2% with only one other person. 41.7% of responders were retired. Fifty-nine percentage were treatment-naive on watch and wait with 20.6% on active treatment and 19.8% previously treated. Shielding (93.7% of CLL patients) was highly effective in preventing Covid infection with only 4.2% developing Covid infection and 1.1% requiring hospital admission whereas 42.4% of CLL Covid infected patients attending hospital were not shielding. However, shielding had many behavioral, emotional, and mental impacts with ∼15% of patients seeking professional psychological support (Table 1). Although 96% said they understood how to protect themselves only 72.6% planned to shield during the 3rd lockdown (40% upon medical advice, 20% did not receive a government shielding letter). The number requiring practical help, e.g. shopping, dropped to 40.4% by the 3rd lockdown but only 59.7% thought they could emotionally cope (4.6% not coping every day, 35.6% daily variation). Although there was a high level of patient satisfaction (75.2%) with the medical care received throughout the three lockdowns (1) 22.7% had their CLL treatment disrupted or suspended, (2) 47.8% stopped receiving IVIG, and (3) 24.5% felt their CLL progressed during lockdown (only 16.3% of these received treatments) Of those CLL patients admitted to hospital with Covid (Table 2), 53.1% were treatment naïve and 56.4% had hypogammaglobulinemia. The mortality rate was high (42.5%) compared to published hospital data with pre-existing comorbidities being significant (p-0.04). Despite, the vaccination uptake being phenomenally high (99.2%), 48.3% plan to continue shielding and continue extra anti-infective precautions reflecting an exceptionally large and ongoing need for mental and emotional support. Nearly half, (45.7%) of patients feel the government had not managed the pandemic well with 41.6% saying they hadn't adequately protected the vulnerable. Conclusions: The surveys progressively informed clinicians about the mental and physical condition of CLL patients during the three lockdowns and highlighted areas of concern, enabling changes in working practices, including improved remote appointments, (86% satisfaction), and the closer monitoring of anxious patients. (1) Disruption in treatment plans was shown and, where possible, adjustments were made. (satisfaction with care 75.2% during the first lockdown). (2) Patients with cancer were particularly exposed to social isolation and distance-limited medical care. (3) 59.9% of patients had treatment delayed. Future surveys will assess the impact of this. (4 Mortality in hospitalized patients was higher than previously reported. Over 50% of these patients did not shield vs. 93.4% for surveyed patients. In this group, there were limitations in assessing mortality. However, this data clearly shows the benefits of shielding. (5) Fifty-six percent of patients demand a choice in the mode of care they will receive in the future. (6) The surveys demonstrate the value of charities combining their resources for the benefit of patients and set a pattern for future cooperation, particularly in leading on surveys tackling clinical questions.
ABSTRACT
Aim: The novel coronavirus (SARS-CoV-2) is a highly contagious disease with a significant mortality rate. Haematological patients are among those most at risk. We evaluate here the disease course, association between comorbidities and COVID-19 severity and seroconversion potential in 50 positive patients at our clinic. Methods: We performed 1,600 diagnostic PCR nasopharyngeal swabs over a period of 8 months. We introduced a set of preventive measures so as to protect our patients and personnel. In 50 COVID-19 positive patients, we closely evaluated the course of the disease, the impact of underlying risk factors and the principal haematological diagnoses. We also evaluated the potential for seroconversion in 15 COVID-19 positive patients. Results: Strict barrier measures, especially in patients undergoing autologous stem cell transplantation, have been shown as being crucial for reducing the spread of disease.We did not record any disease outbreak and registered only one positive case during the peri-transplant period at our facility. The most common comorbidities were arterial hypertension or other cardiovascular disease, type 2 diabetes and renal impairment. Two-thirds of positive patients were on first line treatment. Hypogammaglobulinemia did not prove to be a risk factor for a severe COVID-19 course and we did not observe it to be an obstacle for seroconversion. Conclusion: Preventive measures are significant for reducing the spread of disease, especially in haematology centres. In our single centre experience, we report a mortality of 14%. Although we report a relatively small cohort and much remains yet to be clarified, our results can even now be implemented in daily practice.