anti-CD20 Monoclonal Antibody Therapy Research Articles

Prolonged viral pneumonia and high mortality in COVID-19 patients on anti-CD20 monoclonal antibody therapy

PurposeIn clinical practice, we observed an apparent overrepresentation of COVID-19 patients on anti-CD20 monoclonal antibody therapy. The aim of this study was to characterize the clinical picture of COVID-19 in these patients.MethodsAll adult patients from Turku University Hospital, Turku, Finland, with COVID-19 diagnosis and/or positive SARS-CoV-2 PCR test result up to March 2023, and with anti-CD20 therapy within 12 months before COVID-19 were included. Data was retrospectively obtained from electronic patient records.ResultsNinety-eight patients were identified. 44/93 patients (47.3%) were hospitalized due to COVID-19. Patients with demyelinating disorder (n = 20) were youngest (median age 36.5 years, interquartile range 33–45 years), had less comorbidities, and were least likely to be hospitalized (2/20; 10.0%) or die (n = 0). COVID-19 mortality was 13.3% in the whole group, with age and male sex as independent risk factors. Persistent symptoms were documented in 33/94 patients (35.1%) alive by day 30, in 21/89 patients (23.6%) after 60 days, and in 15/85 after 90 days (17.6%), mostly in patients with haematological malignancy or connective tissue disease. Prolonged symptoms after 60 days predisposed to persistent radiological findings (odds ratio 64.0; 95% confidence interval 6.3–711; p < 0.0001) and persistently positive PCR (odds ratio 45.5, 95% confidence interval 4.0–535; p < 0.0001). Several patients displayed rapid response to late antiviral therapy.ConclusionAnti-CD20 monoclonal antibody therapy is associated with high COVID-19 mortality and with a phenotype consistent with prolonged viral pneumonia. Our study provides rationale for retesting of immunocompromised patients with prolonged COVID-19 symptoms and considering antiviral therapy.

Real-World Response Rates across Lines of Therapy Among Patients with Relapsed/Refractory Follicular Lymphoma

Background: Follicular lymphoma (FL) is the most common indolent subtype of non-Hodgkin lymphoma. Despite the generally indolent nature of the condition, there are subgroups of FL patients who may not have an indolent experience, with their disease not responding to multiple lines of therapy. Thus, optimization of novel therapy could improve patient outcomes. This analysis examined treatment patterns, overall response rates (ORR), and complete response (CR) rates by line of therapy (LOT) in relapsed/refractory (R/R) FL in third-line or later (3L+) therapy. Methods: This retrospective observational study was conducted using the COTA database, comprising electronic health records (EHR) from academic (50%) and community (50%) practices in the US. Adults with a confirmed diagnosis of FL, with 3L+ therapy initiation in 2010 or later, at least 3 months of follow-up, and any response assessment after 3L initiation were included. LOTs eligible for inclusion met the following conditions: treatment with an anti-CD20, alkylating agent, or lenalidomide, and no investigational drug in the selected LOT. In addition, patients with only 3L had that line selected; patients with more than 1 eligible LOT had only 1 LOT randomly selected for the analysis. Outcomes were assessed by FL International Prognostic Index (FLIPI), double refractory (DR) status, and type of therapy. DR status was defined as being refractory (disease progression or initiation of a new LOT in &amp;lt;6 months) to an anti-CD20 monoclonal antibody therapy and an alkylating agent. Chemoimmunotherapy (CIT) regimens included obinutuzumab/rituximab + bendamustine (OB/BR), rituximab/obinutuzumab+cyclophosphamide, doxorubicin, vincristine, and prednisolone (R/O+CHOP), R/O+CVP, R/O+other alkylating agent, and R/O+fludarabine and cyclophosphamide (FC). Novel therapies included lenalidomide + rituximab (R 2), phosphatidylinositol-3-kinase (PI3K) inhibitors, and chimeric antigen receptor T-cell therapy (CAR T). The proportion of patients with CR (as retrieved from clinician documentation in EHR) as the physician-reported response within each LOT was calculated. ORR was calculated as the proportion of patients with a CR or PR. Response rates were reported by LOT (3L, 4L, 5L+) and stratified by patient age (&amp;lt;65 vs ≥65 years), FLIPI score (low/intermediate vs high), and DR (not DR vs DR). Results: Overall, 240 patients with R/R 3L+ FL were included: 3L (n=140), 4L (n=55), and 5L+ (n=45). At 3L initiation, median age was 66 years and most patients were male (58.8%), White (89.6%), and had FL grade 1/2 (72.5%); 47.9% of patients were DR, 22.9% had novel therapy use, and 51.3% had CIT use. A total of 152 patients had FLIPI scores available, 38.2% of whom had high-risk scores at 3L initiation. Among all R/R 3L+ FL patients, ORR was 67.9%, with CR in 30.4% ( Figure 1). Response rates decreased across LOTs for both ORR (3L: 72.9%; 4L: 65.5%; 5L+: 55.6%) and CR (3L: 35.0%; 4L: 30.9%; 5L+: 15.6%) ( Figure 2). ORR was higher among all R/R 3L+ FL patients &amp;lt;65 years vs ≥65 years (75.5% vs 62.3%), as was CR rate (36.3% vs 26.1%). Among the subset of R/R 3L+ FL patients with a FLIPI score, those with low/intermediate risk vs high risk had a greater ORR (78.7% vs 58.6%) and CR rate (36.2% vs 20.7%). ORR was also higher for R/R 3L+ patients without DR status vs with DR status (73.0% vs 63.2%), as was CR rate (37.4% vs 24.0%). Patients receiving novel therapy 3L+ had an ORR of 70.9% and a CR rate of 27.3%. Among R/R 3L+ FL patients, more LOTs of CIT were associated with decreased response rates; patients with CIT in 1 LOT vs CIT in &amp;gt;2 LOTs had greater ORR (76.4% vs 69.2%) and CR rate (37.4% vs 26.9%). Conclusions: This analysis provides granular details on patients with R/R FL with poor prognosis. Patients with FL who progress to later LOTs have worsening response rates. This analysis included more patients with later LOTs than previously published reports, providing additional insight into response rates as treatment progresses. Lower response rates were observed among patients ≥65 years, those with a high-risk FLIPI score, and those with DR status. The high utilization of CIT in later LOTs, despite suboptimal response rates, especially among subgroups of patients with FL who may not have indolent experience of the disease, underlines the need for efficacious alternative therapies in patients with R/R 3L+ FL.

Anti-CD20 monoclonal antibody therapy in postpartum women with neurological conditions.

Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti-CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease-modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti-CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. Fifty-seven cis-women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post-infusion. Breastmilk was collected pre-infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients' questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. The median average concentration of mAb in breastmilk was low (OCR: 0.08 μg/mL, range 0.05-0.4; RTX: 0.03 μg/mL, range 0.005-0.3). Concentration peaked 1-7 days post-infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was <1% (OCR: 0.1%, range 0.07-0.7; RTX: 0.04%, range 0.005-0.3). Forty-three participants continued to breastfeed post-infusion. At 8-12 months, the proportion of infants' growth between the 3rd and 97th World Health Organization percentiles did not differ for breastfed (36/40) and non-breastfed (14/16, p > 0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non-breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. These confirm minimal transfer of mAb into breastmilk. Anti-CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well-tolerated for both mother and infant.

Pharmacogenomic Analyses Implicate B Cell Developmental Status and MKL1 as Determinants of Sensitivity toward Anti-CD20 Monoclonal Antibody Therapy.

Monoclonal antibody (mAb) therapy directed against CD20 is an important tool in the treatment of B cell disorders. However, variable patient response and acquired resistance remain important clinical challenges. To identify genetic factors that may influence sensitivity to treatment, the cytotoxic activity of three CD20 mAbs: rituximab; ofatumumab; and obinutuzumab, were screened in high-throughput assays using 680 ethnically diverse lymphoblastoid cell lines (LCLs) followed by a pharmacogenomic assessment. GWAS analysis identified several novel gene candidates. The most significant SNP, rs58600101, in the gene MKL1 displayed ethnic stratification, with the variant being significantly more prevalent in the African cohort and resulting in reduced transcript levels as measured by qPCR. Functional validation of MKL1 by shRNA-mediated knockdown of MKL1 resulted in a more resistant phenotype. Gene expression analysis identified the developmentally associated TGFB1I1 as the most significant gene associated with sensitivity. qPCR among a panel of sensitive and resistant LCLs revealed immunoglobulin class-switching as well as differences in the expression of B cell activation markers. Flow cytometry showed heterogeneity within some cell lines relative to surface Ig isotype with a shift to more IgG+ cells among the resistant lines. Pretreatment with prednisolone could partly reverse the resistant phenotype. Results suggest that the efficacy of anti-CD20 mAb therapy may be influenced by B cell developmental status as well as polymorphism in the MKL1 gene. A clinical benefit may be achieved by pretreatment with corticosteroids such as prednisolone followed by mAb therapy.

Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

There have been significant advances in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) over the past two decades. However, the intention of treatment remains control of the disease and delay of progression rather than a cure which remains largely elusive. Considering that CLL is mostly seen in older patients, there are multiple factors that play a role in the selection of CLL beyond the frontline treatment. Here, we review the concept of relapsed CLL, factors that predispose to relapse, and therapeutic options available to this patient population. We also review investigational therapies and provide a framework for selection of therapies in this setting. Targeted therapies with continuous BTK inhibitors (BTKi) or fixed duration venetoclax plus anti-CD20 monoclonal antibody therapy have established superiority over chemoimmunotherapy in relapsed CLL and have become the preferred standard of care treatment. The second-generation more selective BTK inhibitors (acalabrutinib and zanubrutinib) have shown improved safety profile compared to ibrutinib. However, resistance to the covalent BTK inhibitors may emerge and is commonly associated with mutations in BTK or other downstream enzymes. The novel non-covalent BTK inhibitors such as pirtobrutinib (Loxo-305) and nemtabrutinib (ARQ 531) are showing promising activities for relapsed CLL refractory to prior covalent BTKi. Other novel therapies such as chimeric antigen receptor (CAR) T cell therapy have also shown significant activities for relapsed and refractory CLL. Measurable residual disease (MRD) assessment has a growing importance in venetoclax-based limited-duration therapy and there is mounting evidence that MRD negativity improves outcomes. However, it remains to be seen if this will become an established clinically significant endpoint. Further, the optimal sequence of various treatment options remains to be determined. Patients with relapsed CLL now have more options for the treatment of the disease. The choice of therapy is best individualized especially in the absence of direct comparisons of targeted therapies, and the coming years will bring more data on the best sequence of use of the therapeutic agents.

COVID-19 infection in patients on anti-CD20 monoclonal antibodies: Changes in clinical outcomes and management over time.

e19542 Background: As the COVID-19 pandemic progressed, survival of patients in the general population with COVID-19 improved over time. It is less clear based on current data whether patients on anti-CD20 therapy experienced similar improvement in outcomes over time. Methods: We performed a retrospective study of all patients aged ≥ 18 years diagnosed with COVID-19 while receiving anti-CD20 therapy for hematologic malignancy and/or rheumatologic indications at our center from January 2020-January 2022. Our primary endpoint was median overall survival (OS) and clinical outcomes stratified by date of diagnosis (“early cohort” = 03/01/20 to 12/31/20, “later cohort” = 01/01/21 to 10/15/21, and “latest cohort” = 10/16/21 to 01/16/22”). Secondary endpoints were to describe changes in the management of patients receiving anti-CD20 agents as the pandemic progressed and to assess independent predictors of OS in this population. Results: The median OS of 186 patients in the entire group was 13 months and the case fatality rate (CFR) was 23%. The CFR of admitted patients was 84%, whereas it was 16% for those who were not admitted. To examine trends over time, we compared 71 patients in the early cohort to 69 in the later cohort, and 42 patients in the latest cohort. The median OS of patients in the early cohort was 18 months (0.1-27) compared to 9 months (0-22) in the later cohort, and 8 months (0-20) in the latest cohort (P = 0.1884). The proportion of patients who received steroids was relatively consistent as the pandemic progressed with 45% in the early vs. 41% in the latest cohort. Fewer patients received remdesivir (31% for early cohort vs 21% for latest cohort) and convalescent plasma (13% for early cohort vs 2% for latest cohort) over time. The only baseline or treatment characteristics associated with adverse outcomes were receipt of steroids and anticoagulation, both of which were associated with an increased risk of death ((HR = 5.5, p = 0.002) and (HR = 2, p = 0.043 respectively)). Conclusions: Patients receiving monoclonal anti-CD20 antibody therapy had worse clinical outcomes than previously reported outcomes for the general population. OS did not significantly improve as the pandemic progressed; the phase of the pandemic with the shortest median OS was from 01/01/21 to 10/15/21 during the Delta SARS-COV-2 wave. Our data demonstrates an increased risk of death in patients on monoclonal anti-CD20 who experienced a COVID-19 infection and were treated with steroids, consistent with other reports.

First dose infusion reaction during anti-CD20 monoclonal antibody therapy in chronic lymphocytic leukemia associates with high IP-10 levels amid cytokine release syndrome

Abstract Intravenous (IV) anti-CD20 monoclonal antibody (mAb) therapy for chronic lymphocytic leukemia (CLL) patients often produces a first dose infusion reaction (FDIR) within the first 2 h that requires careful monitoring to avoid serious complications and fatalities. To better understand FDIR, we studied blood samples collected from 37 treatment-naïve CLL patients in our clinical trial NCT03788291 undergoing IV treatment with 50 mg of anti-CD20 mAb (rituximab). We analyzed four time points: baseline (prior to infusion), 1 h later (during infusion), at the end of infusion (~2.5 h) and at 48 h. Infusion reactions (CTCAE (v5) grade ≥2 events) were managed by interrupting the infusion and with symptomatic treatment. 24 (65%) patients had a FDIR and all patients completed the infusion. Patient and CLL characteristics including measures of disease severity (Rai stage, IGHV mutation status, cytogenetic defects) did not correlate with FDIR. High levels of CLL cells and/or CD20 and their subsequent depletion resulting in decreased serum mAb and/or complement are thought to be risks for FDIR. However, measurements of these parameters did not correlate. Induction of cytokine release syndrome (CRS) may correlate with FDIR. However, CRS was observed in all samples after mAb infusion. The only significant associations with FDIR were higher levels of IP-10, IL-6, and IL-8, with IP-10 most significant. Anti-CD20 mAb activated cytotoxic effector cells, such as tissue-resident macrophages that ingest CLL cells via antibody-dependent cellular phagocytosis (ADCP), may be responsible for these events leading to FDIR. A mouse model of anti-CD20 mAb FDIR and in vitro ADCP cell systems will be useful to further understand the biology of FDIR. Supported by funding from Acerta/AstraZeneca, the Cadregari Foundation, a generous donation by Elizabeth Aaron, and the NIH NCI grant number R21CA267040.

Flashback Foreword: Chimeric Anti-CD20 Monoclonal Antibody Therapy

Flashback Foreword: Chimeric Anti-CD20 Monoclonal Antibody Therapy

Rituximab Induces an Inflammatory Cytokine Response with Increased IP-10 (CXCR10) in Patients with Infusion Reactions

Most patients initiating anti-CD20 monoclonal antibody (mAb) therapy for CLL have a disruptive infusion reaction that can cause serious complications and be fatal. A better understanding of the risk factors and etiology of infusion reactions is required to improve preventative measures and management. We report a study to test the hypothesis that IV rituximab induces an inflammatory cytokines response with differences in individual cytokine concentrations correlating with infusion reactions. We designed a clinical trial (NCT03788291) for initial treatment of patients with progressive CLL that provided clinical data and blood specimens from 37 patients treated with 50 mg of IV rituximab infused at 25 mg/h. Blood specimens were collected immediately prior to initiation of rituximab (baseline), one hour later (1h), at the end of the infusion (post-infusion) and at 48 h after initiation of therapy (48h). Infusion reactions (CTCAE grade ≥2 events) were managed by interrupting the infusion and initiating symptomatic treatment. We measured circulating CLL cell counts and CD20 levels, and serum rituximab concentration, complement levels, and cytokine concentrations of IFN-γ, IL-10, IL-18, IL-2, IL-4, IL-6, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, and TNF-α using standard methods. Twenty-four (65%) patients had 25 infusion reactions (all CTCAE grade 2) at a median of 78 minutes (range 35-128) after initiation of rituximab therapy (median dose 32 mg, range 15-50). All patients completed the 50 mg rituximab infusion (median time 150 minutes, range 119-195). Patient and CLL characteristics including baseline CLL cell counts did not predict the risk of infusion reactions. Median CLL counts at 1h decreased to 14.7% of baseline with no further changes post-infusion and no significant difference between patients with or without infusion reactions (60x109/L vs. 45x109/L, p=0.61). Median CLL cell membrane CD20 levels (x103 molecules/cell) decreased from 4.77 at baseline to 3.10 at 1h (p=0.002) and 1.59 post-infusion (p<0.0001 vs. baseline and 1h) with no significant differences between patients with or without an infusion reaction. The median estimated number of circulating CLL cell membrane CD20 molecules (x1012 molecules/L) decreased from 325.8 at baseline to 34.1 at 1h (p<0.0001) and 14.5 post-infusion (p<0.0001 vs. baseline, p<0.03 vs. 1h) with no significant differences between patients with or without an infusion reaction. There was no correlation between risk of infusion reaction and serum levels of rituximab or serum complement. Thirty-five (95%) patients had a ≥4 fold increase in serum concentration of ≥1 cytokine with resolution of the cytokine response at 48h. All patients with an infusion reaction had significantly higher median post-infusion serum concentrations of IP-10, IL-6 and IL-8. All 17 patients with IP-10 serum concentrations above the limit of detection (40,000 pg/ml) post-infusion had an infusion reaction, and all 24 patients with an infusion reaction had a ≥4 fold increase in serum IP-10 concentrations. Of 13 patients without an infusion reaction, the highest measured serum IP-10 concentration was 22,013 pg/ml and only 3 (23%) had ≥4 fold increases in serum IP-10 concentrations. Slow infusion of a reduced dose of rituximab induced a cytokine response in 95% of patients and therapy disrupting infusion reactions occurred at a comparable rate (65%) to standard rituximab therapy. Infusion reactions were associated with increased levels of IP-10, IL-6 and IL-8. IP-10 levels were increased by ≥4 fold in all patients with an infusion reaction compared to 23% without an infusion reaction. These data suggest that rituximab infusion reactions are caused by inflammatory cytokines produced by cytotoxic effector cells activated by rituximab independent of the pre-treatment amount of circulating CLL cells or CD20 levels, or efficacy of rituximab in reducing the circulating CLL cell count. Infusion reactions occurred after at least 35 minutes of therapy concurrent with a rapid decrease in circulating CLL cells. This observation suggests that cytokine release could be a result of activation of effector cells responsible for CLL cell elimination. Our data provides novel insights into the potential mechanism of infusion reactions and could form the basis of further research to determine methods to control this clinically important and therapy limiting complication.

Non-Myelofibrosis Chronic Myeloproliferative Neoplasm Patients Show Better Seroconversion Rates after SARS-CoV-2 Vaccination Compared to Other Hematologic Diseases: A Multicentric Prospective Study of KroHem.

Disease- and treatment-mediated immunodeficiency might render SARS-CoV-2 vaccines less effective in patients with hematologic diseases. We performed a prospective non-interventional study to evaluate humoral response after one and two doses of mRNA-1273, BNT162b2, or ChAdOx1 nCoV-19 vaccine in 118 patients with different malignant or non-malignant hematologic diseases from three Croatian treatment centers. An electrochemiluminescent assay was used to measure total anti-SARS-CoV-2 S-RBD antibody titers. After one vaccine dose, 20/66 (33%) achieved seropositivity with a median antibody titer of 6.1 U/mL. The response rate (58/90, 64.4%) and median antibody titer (&gt;250 U/mL) were higher after two doses. Seropositivity varied with diagnosis (overall p &lt; 0.001), with the lowest rates in lymphoma (34.6%) and chronic lymphocytic leukemia (52.5%). The overall response rate in chronic myeloproliferative neoplasms (CMPN) was 81.3% but reached 100% in chronic myeloid leukemia and other non-myelofibrosis CMPN. At univariable analysis, age &gt; 67 years, non-Hodgkin's lymphoma, active treatment, and anti-CD20 monoclonal antibody therapy increased the likelihood of no vaccine response, while hematopoietic stem cell recipients were more likely to respond. Age and anti-CD20 monoclonal antibody therapy remained associated with no response in a multivariable model. Patients with the hematologic disease have attenuated responses to SARS-CoV-2 vaccines, and significant variations in different disease subgroups warrant an individualized approach.

Simulated treatment comparison of efficacy outcomes for ofatumumab in ASCLEPIOS I/II versus ocrelizumab in OPERA I/II for the treatment of patients with relapsing multiple sclerosis

BackgroundOfatumumab is a subcutaneously administered anti-CD20 monoclonal antibody (MoAb) therapy that has been evaluated in two identically designed randomized controlled trials (RCTs), ASCLEPIOS I (NCT02792218) and ASCLEPIOS II (NCT02792231), in patients with relapsing multiple sclerosis (RMS). Ocrelizumab is another anti-CD20 MoAb therapy, administered intravenously, that has been evaluated in two identically designed RCTs, OPERA I (NCT01247324) and OPERA II (NCT01412333) in RMS. Given the absence of published RCTs with head-to-head comparisons between these MoAbs, this study assessed the indirect comparative efficacy of ofatumumab and ocrelizumab. MethodsGiven the availability of individual patient data for ASCLEPIOS I/II and summary-level data for OPERA I/II, simulated treatment comparisons were used to assess the comparative efficacy of ofatumumab versus ocrelizumab while adjusting for differences in baseline characteristics between trials. Comparative efficacy was estimated for the proportion of patients with 3- and 6-month confirmed disability progression (CDP) and for annualized relapse rate (ARR). Exploratory analyses were conducted for the outcome of no evidence of disease activity based on three parameters (NEDA-3) and magnetic resonance imaging (MRI) outcomes (proportion of patients with gadolinium-enhancing T1 lesions and brain volume change). ResultsAlthough comparative results were not significant for 3-month CDP (hazard ratio [HR]: 0.90 [95% confidence interval [CI]: 0.57−1.42]) or 6-month CDP (HR: 0.84 [95% CI: 0.47−1.49]), ofatumumab showed a significant improvement in ARR (rate ratio: 0.60 [95% CI: 0.43−0.84]) compared with ocrelizumab. Significantly favorable results were also associated with ofatumumab for NEDA-3 and MRI outcomes. ConclusionOfatumumab was associated with more favorable efficacy results compared with ocrelizumab for clinical, NEDA-3, and MRI outcomes.

Applicability of probabilistic graphical models for early detection of SARS-CoV-2 reactive antibodies after SARS-CoV-2 vaccination in hematological patients.

Prior studies of antibody response after full SARS-CoV-2 vaccination in hematological patients have confirmed lower antibody levels compared to the general population. Serological response in hematological patients varies widely according to the disease type and its status, and the treatment given and its timing with respect to vaccination. Through probabilistic machine learning graphical models, we estimated the conditional probabilities of having detectable anti-SARS-CoV-2 antibodies at 3-6 weeks after SARS-CoV-2 vaccination in a large cohort of patients with several hematological diseases (n= 1166). Most patients received mRNA-based vaccines (97%), mainly Moderna® mRNA-1273 (74%) followed by Pfizer-BioNTech® BNT162b2 (23%). The overall antibody detection rate at 3 to 6 weeks after full vaccination for the entire cohort was 79%. Variables such as type of disease, timing of anti-CD20 monoclonal antibody therapy, age, corticosteroids therapy, vaccine type, disease status, or prior infection with SARS-CoV-2 are among the most relevant conditions influencing SARS-CoV-2-IgG-reactive antibody detection. A lower probability of having detectable antibodies was observed in patients with B-cell non-Hodgkin's lymphoma treated with anti-CD20 monoclonal antibodies within 6 months before vaccination (29.32%), whereas the highest probability was observed in younger patients with chronic myeloproliferative neoplasms (99.53%). The Moderna® mRNA-1273 compound provided higher probabilities of antibody detection in all scenarios. This study depicts conditional probabilities of having detectable antibodies in the whole cohort and in specific scenarios such as B cell NHL, CLL, MM, and cMPN that may impact humoral responses. These results could be useful to focus on additional preventive and/or monitoring interventions in these highly immunosuppressed hematological patients.

COVID-19 Vaccine Effectiveness in Oncology Patients.

Oncology patients are at greater risk of morbidity and mortality from coronavirus disease 2019 (COVID-19) infection than the general population. Patients with malignancies were prioritized in vaccine distribution to confer protection to a vulnerable population. However, immunocompromised patients were not included in the initial COVID-19 vaccine trials. Will patients with cancer mount an adequate serologic response to vaccination to be protected from COVID-19 infection? Overall, oncology patients had diminished antibody response to the COVID-19 vaccines compared with healthy patients. The patients with the lowest seroconversion rates were those who received anti-CD20 monoclonal antibody therapy, Bruton tyrosine kinase inhibitor therapy, stem cell transplantation, and chimeric antigen receptor T-cell therapy. Although the response may not be robust, expert organizations strongly recommend that oncology patients should pursue COVID-19 vaccination and booster to ensure some degree of protection from infection. Immunocompromised patients should continue to practice mask wearing, social distancing, and proper hand hygiene to minimize the risk of contracting COVID-19.

Delayed B cell repopulation after rituximab treatment in multiple sclerosis patients with expanded adaptive natural killer cells.

Background and purposeThe aim was to evaluate whether adaptive NKG2C+ natural killer (NK) cells, characterized by enhanced antibody‐dependent cell cytotoxicity (ADCC), may influence time to B cell repopulation after rituximab treatment in multiple sclerosis (MS) patients.MethodsThis was a prospective observational study of MS patients treated with rituximab monitoring peripheral B cells for repeated doses. B cell repopulation was defined as CD19+ cells above 2% of total lymphocytes, classifying cases according to the median time of B cell repopulation as early or late (≤9 months, >9 months, respectively). Basal NK cell immunophenotype and in vitro ADCC responses induced by rituximab were assessed by flow cytometry.ResultsB cell repopulation in 38 patients (24 relapsing–remitting MS [RRMS]; 14 progressive MS) was classified as early (≤9 months, n = 19) or late (>9 months, n = 19). RRMS patients with late B cell repopulation had higher proportions of NKG2C+ NK cells compared to those with early repopulation (24.7% ± 16.2% vs. 11.3% ± 10.4%, p < 0.05), and a direct correlation between time to B cell repopulation and percentage of NKG2C+ NK cells (R 0.45, p < 0.05) was observed. RRMS cases with late repopulation compared with early repopulation had a higher secretion of tumor necrosis factor α and interferon γ by NK cells after rituximab‐dependent NK cell activation. The NK cell immunophenotype appeared unrelated to B cell repopulation in progressive MS patients.ConclusionsAdaptive NKG2C+ NK cells in RRMS may be associated with delayed B cell repopulation after rituximab, a finding probably related to enhanced depletion of B cells exerted by NK‐cell‐mediated ADCC, pointing to the use of personalized regimens with anti‐CD20 monoclonal antibody therapy in some patients.

Convalescent plasma improves overall survival in patients with B-cell lymphoid malignancy and COVID-19: a longitudinal cohort and propensity score analysis.

Patients with hematological malignancy and COVID-19 display a high mortality rate. In such patients, immunosuppression due to underlying disease and previous specific treatments impair humoral response, limiting viral clearance. Thus, COVID-19 convalescent plasma (CCP) therapy appears as a promising approach through the transfer of neutralizing antibodies specific to SARS-CoV-2. We report the effect of CCP in a cohort of 112 patients with hematological malignancy and COVID-19 and a propensity score analysis on subgroups of patients with B-cell lymphoid disease treated (n = 81) or not (n = 120) with CCP between May 1, 2020 and April 1, 2021. The overall survival of the whole cohort was 65% (95% CI = 56–74.9) and 77.5% (95% CI = 68.5–87.7) for patients with B-cell neoplasm. Prior anti-CD20 monoclonal antibody therapy was associated with better overall survival, whereas age, high blood pressure, and COVID-19 severity were associated with a poor outcome. After an inverse probability of treatment weighting approach, we observed in anti-CD20–exposed patients with B-cell lymphoid disease a decreased mortality of 63% (95% CI = 31–80) in the CCP-treated group compared to the CCP-untreated subgroup, confirmed in the other sensitivity analyses. Convalescent plasma may be beneficial in COVID-19 patients with B-cell neoplasm who are unable to mount a humoral immune response.

Hemagophagocytic Lymphohistiocytosis Associated with Recurrent Babesiosis with Lyme Disease Co-Infection in an Immunocompromised Host on Anti-CD20 Monoclonal Antibody Therapy: A Case Report

Hemagophagocytic Lymphohistiocytosis Associated with Recurrent Babesiosis with Lyme Disease Co-Infection in an Immunocompromised Host on Anti-CD20 Monoclonal Antibody Therapy: A Case Report

Antibody and T-Cell Responses to Covid-19 mRNA Vaccines in Patients with B-Cell Lymphomas and Chronic Lymphocytic Leukemia (CLL)

Introduction: While the approval of three commercial vaccines for the SARS-CoV-2 virus has provided upwards of 95% protection against the coronavirus for healthy subjects, the efficacy among patients with hematologic malignancies remains unknown. Immune dysfunction and impaired humoral responses to other vaccines are well documented in patients with CLL and B-cell lymphomas. Furthermore, they suffer increased risk of morbidity and mortality with Covid-19 infections compared to healthy controls. As such, the immune response elicited by the available Covid-19 vaccines in these patients is of utmost importance to investigate.Methods: We performed a prospective exploratory analysis in CLL and B-cell lymphoma patients to evaluate humoral and T-cell responses to the commercially available mRNA Covid-19 vaccines. The objective was to obtain samples at baseline and 2-3 weeks post-vaccination, although some samples were obtained outside of this timeframe. IgG to the SARS-CoV-2 spike receptor-binding domain (RBD) was quantified using the ImmunoCAP platform (Thermo Fisher); results were compared to data from 167 subjects in a healthy vaccine cohort at the University of Virginia. T-cell responses to spike protein of SARS-CoV-2 were measured in 3 NHL patients and 3 matched healthy controls at 2-3 weeks post-2nd vaccine dose, by T cell receptor dependent activation-induced marker (AIM) assay using pooled peptides spanning spike protein.Results: Among 18 patients currently evaluable, median age is 67 y and 72% are male. Diagnoses include CLL (5), marginal zone lymphoma (MZL; 4), diffuse large B-cell lymphoma (3), follicular lymphoma (1), mantle cell lymphoma (MCL;4), and Waldenstrom's macroglobulinemia (1). All patients except 1 MZL patient are currently receiving or have received systemic treatment for their hematologic malignancy. Treatments include immunochemotherapy in 5 patients, Bruton's tyrosine kinase inhibitors (BTKi) with or without anti-CD20 monoclonal antibody therapy in 5, single agent anti-CD20 monoclonal antibody in 4, and other targeted therapy in 4 patients including venetoclax, lenalidomide, and bortezomib. Two patients had received prior autologous stem cell transplantation, 1 patient allogeneic transplantation, and 1 patient chimeric antigen receptor T-cell therapy. Among patients on therapy (n=10), median time from start of current treatment to Covid-19 vaccine was 136 days (range 13 - 829d). In patients who had completed therapy (n=8), median time from end of last treatment to vaccine was 153 days (range 37 - 355d). Seven patients had a blood sample drawn between 1 week and 1 month post-second mRNA vaccine dose.IgG antibody levels to spike RBD were markedly lower in NHL/CLL patients compared to those observed in the control cohort (median 2.1 µg/mL [IQR 0.23-7.6 µg/mL] versus 60.3 µg/mL [IQR 42.5-87.0 µg/mL], Mann-Whitney P<0.001, Figure 1). Of the 16 samples that were obtained post-vaccine dose 2, nine had IgG levels less than 2 µg/mL (manufacturer lower threshold of detection), whereas only 5 of 252 samples from the control cohort were less than this level (Chi-square P<0.001, RR =39.6 (95%CI 15.1-100)). Antibody responses were independent of type of therapy (Figure 2).The percentage of total lymphocytes and T cells was generally reduced in NHL patients versus controls; however, CD4+ T cells responding to spike protein were readily detected, despite the absence of antibody responses in 2 of these patients, both of whom had MCL. Curiously, 2 patients (1 MZL with and 1 MCL patient without antibodies) displayed a higher percentage of activated CD4+ T cells compared to controls, and CD8+ T cells also responded in each of these patients. T-cell responses were specific for spike protein as evidenced by no response to peptides of whole nucleoprotein.Conclusions: Compared to a reference cohort, patients with B-cell malignancies, both treatment-naïve and on treatment, have impaired antibody response to the commercially available mRNA Covid-19 vaccines. Despite this, virus-responsive T-cells can be readily detected, even in the absence of antibodies. Further research is needed to determine whether antibody levels can be used as a biomarker for vaccine efficacy, whether the presence of virus-specific T-cells confers protection in the absence of antibodies, and to determine the effect of booster doses of vaccine on immune response. [Display omitted] DisclosuresWilson: Thermo-Fisher Phadia: Research Funding. Woodfolk: Regeneron: Other: Salary Support, Research Funding; NIH/NIAID: Other: Salary support, Research Funding; University of Virginia: Other: Salary Support; Regeneron: Other: research sponsor and salary support; FDA: Membership on an entity's Board of Directors or advisory committees; Clinical and Experimental Allergy: Other: Editorial Board. Portell: Abbvie: Research Funding; Aptitude Health: Honoraria; Merck: Honoraria, Research Funding; Xencor: Research Funding; Pharmacyclics: Honoraria; BeiGene: Honoraria, Research Funding; Targeted Oncology: Honoraria; Morphosys: Honoraria; SeaGen: Research Funding; TG Therapeutics: Honoraria, Research Funding; Acerta/AstraZeneca: Research Funding; Kite: Honoraria, Research Funding; Genentech: Research Funding; VelosBio: Research Funding. Williams: Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding.

Production of Anti-Spike Antibodies in Response to COVID Vaccine in Lymphoma Patients

BackgroundPatients with hematologic malignancies have poor outcomes from COVID infection with associated mortality of up to 30-40%. Studies have shown that these patients are less likely to mount an antibody response after COVID infection 1. The Pfizer-BioNTech and Moderna COVID mRNA vaccines have been shown to be 94% effective in preventing severe disease in the general population. There is limited data on the efficacy of these vaccines in lymphoma patients, and to suggest the optimal timing of vaccination to elicit immunity in patients receiving immunochemotherapy.MethodsThis is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/2020 and 04/2021. The primary endpoint was a positive anti-COVID spike protein antibody titer following 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Additional outcomes of interest included key variables, such as lymphoma subtype and treatment with anti-CD20 monoclonal antibodies. Subgroups were compared using Fisher's exact test, and unadjusted and adjusted logistic regression models were used for univariate (UVA) and multivariate (MVA) analyses.ResultsOne-hundred thirty-seven patients were identified with baseline characteristics as shown in Table 1. Overall, the study population was older at a median age of 69 (IQR 59-78) years old, 52% of patients were male, and 72% of patients were white. The most frequent comorbidities were cardiovascular disease (39%) and former smoking history (34%), and 45 (33%) patients were obese (BMI >= 30).Testing for anti-COVID spike protein antibodies occurred at a median 48 (IQR 25-62) days [range 6-120] after second vaccination. Lymphoma subtypes in our cohort were: indolent lymphomas (35%), CLL/SLL (20%), 27 (20%) patients with Burkitt's, DLBCL, PMBCL combined, and 25 (18%) patients with Hodgkin's and T-cell lymphomas (HL/TCL) combined. Majority of patients received COVID mRNA vaccines, and we were able to confirm the specific type in 71 (52%) patients. Only 1 person received the COVID adenovirus vaccine.Ninety-two patients (67.2%) developed anti-COVID spike protein antibodies after receiving a COVID vaccine. Of 27 patients who received an anti-CD20 monoclonal antibody-containing regimen in the last 12 months prior to vaccination, 14 (52%) patients produced antibodies. This rate was numerically lower than 72% (26/36) of those who developed antibodies and received an anti-CD20 antibody greater than 12 months prior to vaccination.There were differences observed in the ability to produce serology towards the COVID vaccine amongst lymphoma subtypes. Of 28 patients with CLL, 12 (43%) produced antibodies. There were 6 CLL patients receiving anticancer treatment at the time of vaccination, of which 2 patients produced antibodies. CLL/SLL patients were less likely to mount an antibody response to the COVID vaccine when compared to those with other types of lymphoma, and this difference was significant on UVA (OR 0.270, 95% CI 0.112-0.648), p=0.003) and MVA (OR 0.259, 95% CI 0.104-0.643, p=0.004). For patients with HL/TCL, 22 of 25 (88%) patients produced antibodies. Among the 3 HL/TCL patients that did not produce antibodies, 1 patient had HIV/AIDS post-transplant, 1 had relapsed AITL, and 1 received rituximab. All HL/TCL patients who received anticancer treatment in the last 6 months (10 of 10) produced antibodies at a median titer of 120 AU/mL (reference >=15 AU/mL), with 4 patients having a robust response of antibody titers >400 AU/mL. On statistical analysis, HL/TCL patients were more likely to elicit an antibody response to the COVID vaccine when compared to those with other types of lymphoma, and this response was significant on UVA (OR 4.084, 95% CI 1.149-14.515, p=0.03) and MVA (OR 4.442, 95% CI 1.219-16.191, p=0.024).ConclusionLymphoma patients are capable of mounting a humoral response to the COVID mRNA vaccines. CLL/SLL appears predictive of a negative antibody response to the COVID vaccine, while HL/TCL histologies appeared to correlate to a positive antibody response, even with treatment within 6 months of vaccination. Our study suggests anti-CD20 monoclonal antibody therapy in the last 12 months may affect the ability to produce serology towards a COVID vaccine. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population.1. Passamonti et al, Br J Haematol 2021 [Display omitted] DisclosuresLeslie: Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy. Goy: Acerta: Consultancy, Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Hoffman la Roche: Research Funding; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Rosewell Park: Consultancy; LLC(Targeted Oncology): Consultancy; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Michael J Hennessey Associates INC: Consultancy; Hoffman la Roche: Consultancy; Xcenda: Consultancy; Medscape: Consultancy; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; MorphoSys: Honoraria, Other; Novartis: Consultancy, Honoraria; OncLive Peer Exchange: Honoraria; Xcenda: Consultancy, Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity/Verastem: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Phamacyclics: Research Funding; Constellation: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator.

Immune Reconstitution following High-Dose Chemotherapy and Autologous Stem Cell Transplantation with or without Pembrolizumab Maintenance Therapy in Patients with Lymphoma

Autologous stem cell transplantation (ASCT) is a standard of care for patients with chemosensitive, relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and diffuse large B cell lymphoma (DLBCL). Whereas the clinical benefit of ASCT has traditionally been attributed solely to cytoreduction from intensive chemotherapy, ASCT has important immunogenic effects that may contribute to its antitumor efficacy and could provide a favorable immune environment for post-ASCT immune-based maintenance treatments. We previously reported clinical results of a phase II trial (ClinicalTrials.gov identifier NCT02362997) testing 8 doses of pembrolizumab maintenance therapy after ASCT for patients with R/R cHL or DLBCL. To clarify the impact of pembrolizumab on immune reconstitution, we compared the kinetics of peripheral blood immune cell recovery after ASCT for trial patients receiving pembrolizumab maintenance to those of a contemporaneous control cohort of similar patients undergoing ASCT without pembrolizumab maintenance. This study was conducted to characterize the impact of post-ASCT pembrolizumab maintenance therapy on immune reconstitution for patients with R/R DLBCL and cHL and to identify candidate biomarkers of efficacy and immune-related adverse events (irAEs). Peripheral blood (PB) mononuclear cell samples were prospectively collected at 1 to 18 months after ASCT and analyzed by flow cytometry using a panel of fluorophore-conjugated monoclonal antibodies to identify B cells, natural killer (NK) cells, and various dendritic cell (DC) and T cell subsets. A median of 5 (range, 1 to 8) post-ASCT PB samples were collected from 144 patients (59 in the pembrolizumab group and 85 in the control group). Clinical characteristics of the 2 cohorts were similar. Compared with cHL patients, DLBCL patients (all of whom received anti-CD20 monoclonal antibody therapy before ASCT) had delayed CD19+ cell reconstitution that persisted for at least 18 months after ASCT. No other differences in immune reconstitution based on lymphoma subtype were observed. Post-ASCT pembrolizumab maintenance therapy was associated with an elevation in circulating DCs (driven by higher levels of plasmacytoid and immature DCs) that persisted for the duration of pembrolizumab treatment, along with a significant reduction in PD-1+ T cells that persisted for 6 to 12 months after completion of pembrolizumab therapy. Despite the key role of T cells in mediating the effects of PD-1 blockade, pembrolizumab maintenance did not affect recovery of any T cell subsets. In an exploratory analysis, a higher baseline CD4+ terminal effector memory cell count (defined as CD3+CD4+CD45RA+CD62L-) was associated with inferior progression-free survival (PFS), but only among patients who received pembrolizumab maintenance (P=.003). As continuous variables, lower absolute levels of NK cells (P=.009), PD-1+ CD4+ T cells (P=.005), and PD-1+ CD8+ T cells (P=.005) before pembrolizumab initiation were each associated with a higher risk of grade 2+ irAEs. Our findings indicate that post-ACST pembrolizumab maintenance therapy is associated with a persistent elevation of circulating DCs, but its impact on the reconstitution of other immune cells in peripheral blood appears limited. Our study suggests that early features of post-ASCT immune reconstitution could be associated with PFS and the risk of irAE and warrant additional investigation. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

EBV Reactivation Incidence and Severity in Multiple Sclerosis Patients Treated with Autologous Haematopoietic Stem Cell Transplant and Comparing with Aplastic Anaemia Treated with ATG—Single Site Experience

INTRODUCTION: Autologous haematopoietic stem cell transplant(HSCT) with anti-thymocyte globulin (ATG) based conditioning is currently being explored for its efficacy and safety in the treatment of Multiple Sclerosis (MS). Despite increasing experience gained, the procedure still carries significant risk of morbidity. Epstein Barr Virus (EBV) infection and its role in pathogenesis of MS remain undetermined. EBV reactivation and post-transplant lymphoproliferative disorders (PTLD) are well described in allogeneic HSCT and uncommon with auto HSCT for other malignant conditions. Similarly patients with Aplastic anaemia (AA) treated with standard immunosuppressive therapy with ATG/ciclosporin also have increased risk of EBV reactivation but reports of PTLD in this group are very rare. The incidence of clinically significant EBV reactivation in MS patients undergoing HSCT is increasingly recognised. This retrospective study reports rates of EBV reactivation, PTLD incidence and associated clinical sequelae in patients with MS undergoing HSCT as compared with AA patients receiving ATG in our centre.PATIENTS AND METHODS: 36 patients with MS had AHSCT between Feb 2012 and 2017. 35 were conditioned using standard protocol of cyclophosphamide and ATG (2.5mg/kg/day for 3 days), and one with BEAM-ATG. A Comparator group of 40 patients with AA consecutively treated with ATG (40mg/kg/day for 4 days) between Sept 2013 and Nov 2016 was selected. Prior exposure to EBV (EBV IgG) was assessed pre-HSCT. EBV levels monitoring was performed on whole blood samples by quantitative polymerase chain reaction (PCR) as per standard centre protocol. Data was collected retrospectively.RESULTS: All patients had previous EBV exposure. All MS patients with relapsing remitting (n=22) and primary/secondary progressive (n=14) disease were previously treated with median 2 (range, 0-6) disease modifying therapies (DMT) and 23 had at least 1 highly active DMTs. Median age of 43yrs (range, 22-64yrs) versus 52yrs (range, 19-68yrs) in AA group, with 35 patients severe/very severe AA and 5 non-severe treated with ATG. Where follow up data was available there was no difference in EBV reactivation rates (80.6% vs 65% P-0.13). The median time to EBV detection was 28 days (IQ range, 19-41d) vs 11 days (IQ range 5-39 d)with a maximal EBV DNA titre at median of 39 days (IQ range 29.5-49.5d) vs 11.5 days(IQ Range 0-43.5) in MS and AA cohort respectively.Patients were stratified into their maximum level of reactivation based on the amount of EBV copy numbers; 0-100,000 copies, 100,000 - 500,000 copies and >500,000 copies. In MS group (Table 1), 8 patients had symptomatic EBV reactivation; defined as persistent fever, lymphadenopathy and/or B symptoms. 10 (34.5%) MS patients had EBV copies>500,000. 3 of these had findings consistent with PTLD on CT scan, however none had histological diagnosis. 3 other MS patients had worsening neurological symptoms with one presenting as pseudo-relapse. All 6 of these patients were treated with anti-CD20 monoclonal therapy (Rituximab; 375mg/m2 weekly for 4 weeks) with rapid resolution of their symptoms. MS patients were more likely to develop high EBV (>500k) levels (p-0.03) and receiver operating characteristics (ROC) curve analysis (Fig 1) confirmed high EBV levels>500,000 correlate with high sensitivity 85.5%, specificity 82.5% (p-0.004) for clinical events requiring treatment. No significant rituximab related adverse events noted in treated group. As expected, no significant symptomatic EBV and no PTLD events were noted in AA cohort and none required any rituximab therapy for the EBV reactivations.Significantly raised paraproteinaemia was observed in 21 (72.4%) of MS cohort compared to 3 (11.5%) in the AA group (p < 0.01). 3 of the MS cohort experienced paraprotein levels greater than 20 g/L and one (IgG 61.1g/L) developed hyper-viscosity requiring plasma exchange and developed neurological symptoms mimicking a MS relapse.CONCLUSION: EBV reactivation was observed to occur commonly in patients with MS with significant symptoms and risk of neurological sequelae and PTLD events in this group, which is unlike the AA cohort treated with comparable ATG doses. Regular EBV monitoring in first 3 months should be mandated in MS patients undergoing HSCT and we recommend cut-off of 500,000 copy numbers as trigger for consideration of pre-emptive rituximab therapy. [Display omitted] DisclosuresPotter:Jazz: Honoraria; Pfizer: Other: Advisory board. Raj:Celgene: Speakers Bureau; Mallinckrodt: Speakers Bureau; MSD: Speakers Bureau; Bloodwise: Research Funding. Pagliuca:Bluebird: Honoraria; Gilead: Honoraria; Astellas: Consultancy, Speakers Bureau; Pfizer: Honoraria; Merck: Honoraria, Research Funding; Jazz: Honoraria; Basilea: Honoraria.