Supportive care measures for bispecific T-cell engager therapies in haematological malignancies.

PURPOSE OF REVIEW: Bispecific T-cell engager (TCE) therapies are revolutionising the treatment of several haematological malignancies, including B-cell acute lymphoblastic leukaemia, various subtypes of B-cell non-Hodgkin lymphoma, and multiple myeloma. Due to their unique mode of action in activating endogenous T cells, they are associated with several important early side effects, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. In addition, TCEs can cause target-specific toxicities and carry a significant risk of infection. RECENT FINDINGS: Currently, supportive care measures for TCEs have largely been inferred from other T-cell therapies, such as CAR-T (chimeric antigen receptor) therapy. Further research into TCE-specific supportive care measures is needed to improve the tolerability of these therapies for patients. A key question moving forward is understanding how to predict and minimise early toxicity (cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome). Associated infection risk is a significant cause of patient morbidity, therefore a better understanding of how to optimise TCE-dosing and prophylactic measures, such as intravenous immunoglobulin and antimicrobials, will be crucial to achieving an improved balance of toxicity and efficacy. Enabling early outpatient delivery of these therapies to select patients at lower risk of toxicity may also help to improve patient experience and quality of life. SUMMARY: Here we review up-to-date guidance and literature on existing supportive care measures for bispecific TCE therapy-related toxicities. We highlight both unique and serious side effects of TCE therapies that require improved management strategies to enable more patients to benefit from these efficacious drugs.

Trends in telemedicine visits among pediatric asthma patients during COVID-19.

Background: Environmental and social factors, including lack of access to asthma care, contribute to persistent inequities in asthma outcomes among children from historically marginalized ethnoracial groups. Telemedicine, which expanded rapidly during the coronavirus disease 2019 (COVID-19) pandemic, may be an approach to augment access to pediatric asthma care. Objectives: We sought to describe characteristics of pediatric (0-17 years) telemedicine users with asthma and characterize use trends throughout the COVID-19 pandemic. Methods: We conducted a retrospective analysis using electronic health record data of pediatric patients with asthma seen at University of California, Los Angeles, Medical Center between March 2019 to March 2022 describing telemedicine user characteristics, trends of asthma-related telemedicine use, and associations between user characteristics and having a telemedicine visit. Results: Among 6,777 patients with asthma, the percentage of asthma-related telemedicine visits peaked early in the pandemic, comprising 74.3% of visits, before decreasing to 13.6% in 2022. Compared to White patients, Black patients had lower odds of an asthma telemedicine visit (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.26, 0.94). Those with public insurance (OR, 1.7; 95% CI, 1.19, 2.43), severe persistent asthma (OR, 3.03; 95% CI, 1.70, 5.42), or comorbidities (OR, 1.59; 95% CI, 1.08, 2.33) had higher odds. Time to first emergency department visit and hospitalization comparing those with at least one telemedicine visit to those with none were similar. Conclusions: More pediatric asthma patients are using telemedicine since the COVID-19 pandemic, particularly those with medical complexity and comorbidities, and outcomes appear similar. However, Black patients at our institution have lower odds of using telemedicine.

Longitudinal dynamics and clinically available predictors of poor response to COVID-19 vaccination in multiple myeloma.

Not available.

Non-HLA Antibodies to G Protein-coupled Receptors in Pediatric Kidney Transplant Recipients: Short- and Long-term Clinical Outcomes.

BACKGROUND: Angiotensin II type 1 receptor antibodies (AT1R-Abs) and endothelin-type A receptor antibodies (ETAR-Abs) are G protein-coupled receptor activating autoantibodies associated with antibody-mediated rejection, vascular pathology, increased cytokines, allograft dysfunction, and allograft loss in pediatric kidney transplant recipients in the first 2 y posttransplantation. The impact of AT1R-Ab and ETAR-Ab positivity on longer-term 5-y transplant outcomes is unknown. METHODS: One hundred pediatric kidney transplant recipients were tested for ETAR-Ab and AT1R-Ab on serially collected blood samples in the first 2 y posttransplant. Biopsies were collected per protocol and 6, 12, and 24 mo posttransplant and at any time during the 5-y follow-up period for clinical indication. Clinical outcomes, including renal dysfunction, rejection, HLA donor-specific antibodies, and allograft loss, were assessed through 5 y posttransplantation. RESULTS: AT1R-Ab or ETAR-Ab were positive in 59% of patients. AT1R-Ab or ETAR-Ab positivity was associated with greater declines in estimated glomerular filtration rate, and de novo AT1R-Ab or ETAR-Ab was associated with allograft loss in the first 2 y posttransplant. There was no association between antibody positivity and rejection, antibody-mediated rejection, or allograft loss in the first 5 y posttransplant. In a model controlled for age, sex, immunosuppression, and HLA mismatch, AT1R-Ab or ETAR-Ab positivity was significantly associated with the development of HLA donor-specific antibodies at 5 y posttransplant (odds ratio 2.87, P = 0.034). CONCLUSIONS: Our findings suggest temporally distinct clinical complications associated with AT1R-Ab or ETAR-Ab positivity in pediatric patients; these injury patterns are of significant interest for developing effective treatment strategies.

Cellular mechanisms associated with sub-optimal immune responses to SARS-CoV-2 bivalent booster vaccination in patients with Multiple Myeloma.

BACKGROUND: The real-world impact of bivalent vaccines for wild type (WA.1) and Omicron variant (BA.5) is largely unknown in immunocompromised patients with Multiple Myeloma (MM). We characterize the humoral and cellular immune responses in patients with MM before and after receiving the bivalent booster, including neutralizing assays to identify patterns associated with continuing vulnerability to current variants (XBB1.16, EG5) in the current post-pandemic era. METHODS: We studied the humoral and cellular immune responses before and after bivalent booster immunization in 48 MM patients. Spike binding IgG antibody levels were measured by SARS-CoV-2 spike binding ELISA and neutralization capacity was assessed by a SARS-CoV-2 multi-cycle microneutralization assays to assess inhibition of live virus. We measured spike specific T-cell function using the QuantiFERON SARS-CoV-2 (Qiagen) assay as well as flow-cytometry based T-cell. In a subset of 38 patients, high-dimensional flow cytometry was performed to identify immune cell subsets associated with lack of humoral antibodies. FINDINGS: We find that bivalent vaccination provides significant boost in protection to the omicron variant in our MM patients, in a treatment specific manner. MM patients remain vulnerable to newer variants with mutations in the spike portion. Anti-CD38 and anti-BCMA therapies affect the immune machinery needed to produce antibodies. INTERPRETATION: Our study highlights varying immune responses observed in MM patients after receiving bivalent COVID-19 vaccination. Specifically, a subgroup of MM patients undergoing anti-CD38 and anti-BCMA therapy experience impairment in immune cells such DCs, B cells, NK cells and TFH cells, leading to an inability to generate adequate humoral and cellular responses to vaccination. FUNDING: National Cancer Institute (National Institutes of Health), National Institute of Allergy and Infectious Diseases (National Institutes of Health), NCI Serological Sciences Network for COVID-19 (SeroNet) and The Icahn School of Medicine at Mount Sinai.

Sex differences in acute ischemic stroke presentation are a matter of infarct location.

INTRODUCTION: Recognition of stroke by Emergency Medical Services (EMS) is critical to initiate rapid emergency department treatment. Most prehospital stroke screening tools rely heavily on presentation with the classic symptoms of facial droop, speech changes, unilateral weakness. However, women may be less likely to present with classic symptoms and may also have different distributions of stroke by anatomical location. This study seeks to determine the association between biological sex, presentation with classic symptoms, and the location of the infarcted tissue. METHODS: This is a retrospective cohort study. Data from electronic health records were extracted for patients with acute ischemic stroke who presented via EMS to a single Comprehensive Stroke Center between January 1, 2018 and December 31, 2020. We used descriptive statistics characterize the cohort. Multivariable logistic regression identified factors associated with classic symptom presentation (facial droop, speech changes, and/or unilateral weakness). Biological sex, location of the infarct, stroke etiology, age and the interaction between sex and infarct location were assessed as covariates. RESULTS: There were 364 (58.6%) males and 257 (41.1%) females with an acute ischemic stroke included in this study. EMS documented one or more classic symptoms in 125 (72.3%) males and 161 (67.9%) females. There were no baseline differences in infarct location or presentation with classic symptoms as documented by EMS comparing males and females. Multivariate logistic regression found no association between biological sex and presentation with classic symptoms (Odds Ratio 1.08; 95% CI 0.58 to 1.55) after controlling for age, stroke location, etiology of stroke or the interaction between sex and infarct location. Presence of an anterior circulation infarct compared to posterior circulation infarct was positively associated with a classic presentation to EMS (Odds Ratio 3.41; 95% CI 2.15 to 5.41). CONCLUSIONS: This study found no difference in the frequency of patient presentation with classic stroke symptoms based on biological sex alone, nor a significant different in distribution of infarcts between males and females. Infarct location (i.e., involving the anterior circulation) was associated with a classic presentation. This suggests that the likelihood of presenting with classic stroke symptoms is not influenced by sex, but rather the location of the infarct.

IGF2BP3 as a Prognostic Biomarker in Well-Differentiated/Dedifferentiated Liposarcoma.

BACKGROUND: Although IGF2BP3 has been implicated in tumorigenesis and poor outcomes in multiple cancers, its role in soft-tissue sarcoma (STS) remains unknown. Preliminary data have suggested an association with IGF2BP3 expression among patients with well-differentiated/dedifferentiated liposarcoma (WD/DD LPS), a disease where molecular risk stratification is lacking. METHODS: We examined the survival associations of IGF2BP3 via univariate and multivariate Cox regression in three unique datasets: (1) the Cancer Genome Atlas (TCGA), (2) an in-house gene microarray, and (3) an in-house tissue microarray (TMA). A fourth dataset, representing an independent in-house TMA, was used for validation. RESULTS: Within the TCGA dataset, IGF2BP3 expression was a poor prognostic factor uniquely in DD LPS (OS 1.6 vs. 5.0 years, p = 0.009). Within the microarray dataset, IGF2BP3 expression in WD/DD LPS was associated with worse survival (OS 7.7 vs. 21.5 years, p = 0.02). IGF2BP3 protein expression also portended worse survival in WD/DD LPS (OS 3.7 vs. 13.8 years, p < 0.001), which was confirmed in our validation cohort (OS 2.7 vs. 14.9 years, p < 0.001). In the multivariate model, IGF2BP3 was an independent risk factor for OS, (HR 2.55, p = 0.034). CONCLUSION: IGF2BP3 is highly expressed in a subset of WD/DD LPS. Across independent datasets, IGF2BP3 is also a biomarker of disease progression and worse survival.

Angiotensin II type 1 receptor antibodies and native kidney function in pediatric liver and intestinal transplant recipients.

BACKGROUND: Angiotensin II type-1 receptor antibody (AT1R-Ab) has been associated with vascular injury and kidney dysfunction in pediatric kidney transplant recipients. The role of AT1R-Ab in the development of chronic kidney disease in pediatric liver and intestinal transplant recipients has not been explored. METHODS: Twenty-five pediatric intestinal transplant recipients and 79 pediatric liver transplant recipients had AT1R-Ab levels measured at varying time points in the post-transplant period. Estimated glomerular filtration rate (eGFR) was determined using creatinine based CKiD U25 equation and measured at time of AT1R-Ab measurement, at 1 year post-AT1R-Ab measurement, at 5 years post-AT1R-Ab measurement, and at the most recent routine clinic visit. The prevalence of hypertension and antihypertensive medication use were also evaluated. RESULTS: Younger age at time of AT1R-Ab measurement was associated with AT1R-Ab positivity in liver transplant recipients. There was no association between AT1R-Ab status and change in eGFR, prevalence of hypertension, or use of antihypertensive medications at the described time points. CONCLUSIONS: AT1R-Ab positivity was not associated with a decline in eGFR or hypertension in pediatric liver and intestinal transplant recipients. Further studies are needed using other markers of kidney function, such as cystatin C, to validate this finding. A higher resolution version of the Graphical abstract is available as Supplementary information.

A call for better validation of opioid overdose risk algorithms.

Clinical decision support (CDS) systems powered by predictive models have the potential to improve the accuracy and efficiency of clinical decision-making. However, without sufficient validation, these systems have the potential to mislead clinicians and harm patients. This is especially true for CDS systems used by opioid prescribers and dispensers, where a flawed prediction can directly harm patients. To prevent these harms, regulators and researchers have proposed guidance for validating predictive models and CDS systems. However, this guidance is not universally followed and is not required by law. We call on CDS developers, deployers, and users to hold these systems to higher standards of clinical and technical validation. We provide a case study on two CDS systems deployed on a national scale in the United States for predicting a patient's risk of adverse opioid-related events: the Stratification Tool for Opioid Risk Mitigation (STORM), used by the Veterans Health Administration, and NarxCare, a commercial system.

Does "Low-Grade" Dedifferentiated Liposarcoma Exist? The Role of Mitotic Index in Separating Dedifferentiated Liposarcoma From Cellular Well-differentiated Liposarcoma.

BACKGROUND: Subjective, varying criteria identify "low-grade" dedifferentiation in well-differentiated/dedifferentiated liposarcoma (WD/DDLPS). The value of mitotic rate (MR) in defining DDLPS is not confirmed. We studied all patients with the resection of their primary or first recurrence retroperitoneal WD/DDLPS at our institution to determine the value of MR in diagnosing DDLPS and if MR associates with patient survival. DESIGN: Ninety-eight patients with retroperitoneal WD/DDLPS operated at our institution from January 1, 1989 to December 31, 2013 were included. Cases were defined as acellular (AC) WDLPS, LS0-4 (tumors with non-lipogenic areas and MR 0-4/10HPFs) or LS5+(non-lipogenic areas, MR≥5/10 HPFs) and graded using the French system. Kaplan-Meier survival estimates with log-rank test and multivariate Cox (mCox) analyses were performed. RESULTS: Follow-up was available on all patients (median 9.3 y, range 0.02-23.16 y). Kaplan-Meier demonstrated a significant ( P =0.004) difference in disease-specific survival (DSS) among the 3 groups. mCox demonstrated no difference in DSS between the AC and LS0-4 groups (HR 1.51; 95% CI 0.57-3.99, P =0.412) but significantly lower DSS in the LS5+group compared with the AC group (HR 2.68; 95% CI 1.07-6.71, P =0.035). The difference in DSS was not significant between grade 2 and 3 tumors ( P =0.094). DSS between MR 5-19/10 HPFs and MR20+/10 HPFs subgroups was significant ( P =0.007) but by mCox did not reach significance (HR 2.47; 95% CI 0.96-6.35, P =0.060). CONCLUSION: This study confirms that MR distinguishes DDLPS from WDLPS with non-lipogenic areas, also known as cellular WDLPS. For consistency in diagnosis and research, only WD/DDLPS with≥5 mitoses/10 HPFs should be considered DDLPS.

Envarsus XR® pharmacokinetics in adolescents post-kidney transplantation - A pilot study.

INTRODUCTION: Envarsus XR® (LCPT), a once daily dosage formulation of tacrolimus, is an FDA-approved medication in adult renal transplant recipients (RTRs). There are limited data on its pharmacokinetics (PK) in adolescent RTRs. We report here the PK profile of LCPT in adolescent RTRs. METHODS: The dose of LCPT was determined using a dose conversion ratio targeting 0.7 relative to the total daily immediate-release tacrolimus (IR-Tac) dose. On day 7 after converting to LCPT, patients had an abbreviated PK assessment with sampling at: 0 h (pre-dose), 8-, and 12-h post-dose. The PK data analysis was performed using Bayesian estimators. Our results were compared to those of published adult PK data for LCPT and pediatric PK data for IR-Tac and extended release tacrolimus (ER-Tac) formulation (Advagraf). RESULTS: PK data from three adolescent patients on LCPT were evaluated. The mean (±SD) area under the time-concentration curve (AUC) was 240 (±20.22) h*ng/mL. The mean Tmax was 9.01 ± 2.12 h, and the % fluctuation was 77.71 ± 3.96%. The AUC, Tmax , and % fluctuation were similar to reported results in adult patients taking LCPT. The AUC was higher and the Tmax was longer than what has been reported in pediatric patients taking IR-Tac and ER-Tac. In addition, the LCPT group showed a lower % fluctuation than patients receiving ER-Tac. CONCLUSION: The PK evaluation of LCPT in adolescent RTRs showed similar results to adults. Adolescents taking LCPT had a higher AUC, a more attenuated Tmax , and a lower fluctuation than that seen with ER-Tac in pediatrics.

Orthodontic treatment protocols in patients with alveolar clefting: a survey of ACPA-approved cleft teams in the United States.

OBJECTIVES: To describe pre- and post-alveolar bone graft (ABG) practice protocols of orthodontists associated with American Cleft Palate-Craniofacial Association-approved cleft and cleft/craniofacial teams. MATERIALS AND METHODS: Electronic survey responses from team orthodontists were evaluated regarding pre-ABG orthodontic treatment type(s), timing of post-ABG imaging and post-ABG orthodontic treatment, and craniofacial orthodontic fellowship training status of the team orthodontists. A P value of <.05 was considered significant. RESULTS: Of 31 responding orthodontists, 54.8% had fellowship training and 45.2% did not. Pre-ABG orthodontic preparation ranged from solely maxillary expansion for alveolar segment alignment (35.5%) to a combination of maxillary expansion for both alveolar segment alignment and posterior crossbite correction, anterior tooth alignment, and anterior crossbite correction (19.4%). Most captured post-ABG radiographs prior to orthodontic tooth movement (90.3%). Orthodontists began treatment at least 6 months (35.5%), 2-4 months (32.3%), or 4-6 months (29%) post-ABG. No significant differences were found when comparing fellowship subgroups. In addition, 47.1% of fellowship-trained orthodontists deferred post-ABG orthodontic treatment to at least 6 months post-operatively, vs 21.4% of non-fellowship trained orthodontists (P = .14). CONCLUSIONS: A large variation in approaches is evident in pre-ABG orthodontic treatment types and timing of post-ABG treatment. Post-operative imaging is pursued by most orthodontists to assess graft status prior to initiating orthodontic treatment. Additional clinical research is needed to support providers in their decision-making with regard to evidence-based approaches.

Monoclonal gammopathy of increasing significance: time to screen?

Monoclonal gammopathy (MG) is a frequently detected clonal B-cell or plasma-cell disorder. Importantly, every multiple myeloma (MM) case is preceded by MG. Although clinical algorithms now allow earlier treatment of patients with biomarkers of malignancy before MM-induced tissue damage (CRAB) occurs, most patients are still diagnosed late. It is important to revisit how MG should be managed in clinical practice and whether screening is required. As the prevalence of MG and other medical co-morbidities both rise with increasing age, the degree of contribution of MG to disease states other than malignant progression is often unclear. This can lead to monitoring lapses and under recognition of the organ dysfunction that can occur with monoclonal gammopathy of clinical significance (MGCS). Therefore, models of progression to MM and/or MGCS require further refinement. While MG is currently detected incidentally, a case for screening has been made with ongoing studies in this area. Screening has the potential benefit of earlier detection and prevention of both MGCS and delayed MM presentations, but important drawbacks include the psychosocial impact on individuals and resource burden on healthcare services. MG terminology should transition alongside our increasing understanding of the condition and genomic characterization that have already begun to revise the MG nomenclature. The biology of MG has been poorly understood and is often inferred from the biology of MM, which is unhelpful. We review the literature and case for MG screening in this paper. In particular, we highlight areas that require focus to establish screening for MG.

Diagnostic Protocols for Alveolar Clefting and Barriers to Acquiring Imaging: A Survey of ACPA-Approved Cleft Teams in the United States.

OBJECTIVE: To report current diagnostic protocols, practices, and barriers related to imaging of alveolar clefting among American Cleft Palate-Craniofacial Association (ACPA)-approved cleft/craniofacial teams. METHODS: An electronic survey was sent to 162 ACPA-approved teams in the United States. Key items were team location, venue of orthodontic treatment, imaging modality(s) and access, barriers to imaging, billing, imaging protocols including team members involved in decisions pre- and post-alveolar bone grafting (ABG), and craniofacial fellowship status of team orthodontist(s). RESULTS: A total of 66 responses were received (40.7%). Responding teams were university-based (47%), hospital-based (42.4%), and independent clinics (10.6%). Orthodontic treatment for most patients was in private practice (53%). On-site 2-dimensional (2D) and 3-dimensional (3D) dental imaging capabilities were reported by 42% of teams; 29% have no on-site imaging. One or more barrier(s) to acquiring imaging were reported by 67%, with insurance challenges reported by 47%. Most teams bill medical payors for cleft-related dental imaging (58%). Pre- and post-ABG imaging was most frequently 3D (35% and 36%, respectively). Surgeons and orthodontists commonly evaluate ABG timing and outcome together (53%-65%). Periapical radiographs were included significantly more often in cleft imaging protocols by orthodontists with versus without fellowship training (P = .011, P = .04). CONCLUSIONS: Barriers to acquiring imaging are frequent. 3D is the most common imaging pre- and post-ABG. Our study endorses multi-level advocacy for improved medical insurance coverage of diagnostic cleft-related dental imaging to decrease barriers to providing timely care.

Tumor and microenvironmental mechanisms of resistance to immunomodulatory drugs in multiple myeloma.

Resistance to immunomodulatory drugs (IMiDs®) is a major cause of treatment failure, disease relapse and ultimately poorer outcomes in multiple myeloma (MM). In order to optimally deploy IMiDs and their newer derivates CRBN E3 ligase modulators (CELMoDs®) into future myeloma therapeutic regimens, it is imperative to understand the mechanisms behind the inevitable emergence of IMiD resistance. IMiDs bind and modulate Cereblon (CRBN), the substrate receptor of the CUL4CRBN E3 ubiquitin ligase, to target novel substrate proteins for ubiquitination and degradation. Most important of these are IKZF1 and IKZF3, key MM survival transcription factors which sustain the expression of myeloma oncogenes IRF4 and MYC. IMiDs directly target MM cell proliferation, but also stimulate T/NK cell activation by their CRBN-mediated effects, and therefore enhance anti-MM immunity. Thus, their benefits in myeloma are directed against tumor and immune microenvironment - and in considering the mechanisms by which IMiD resistance emerges, both these effects must be appraised. CRBN-dependent mechanisms of IMiD resistance, including CRBN genetic aberrations, CRBN protein loss and CRBN-substrate binding defects, are beginning to be understood. However, only a proportion of IMiD-resistant cases are related to CRBN and therefore additional mechanisms, which are currently less well described, need to be sought. These include resistance within the immune microenvironment. Here we review the existing evidence on both tumor and immune microenvironment mechanisms of resistance to IMiDs, pose important questions for future study, and consider how knowledge regarding resistance mechanism may be utilized to guide treatment decision making in the clinic.

Venetoclax induces deep and durable minimal residual disease-negative remission in high-risk TP53 disrupted B prolymphocytic leukaemia.

B-cell prolymphocytic leukaemia (B-PLL) is an aggressive B-cell lymphoproliferative disease with few clinically proven targeted treatments. Due to the rarity of the condition, there is a paucity of clinical trial data and none that involve targeted inhibitors. We present a unique case of relapsed refractory B-PLL treated to a sustained minimal residual disease-negative remission with venetoclax monotherapy, to add to the current evidence base and rationale for future studies using BCL-2 inhibitors in B-PLL.

Impaired humoral and cellular response to primary COVID-19 vaccination in patients less than 2 years after allogeneic bone marrow transplant.

Allogeneic haematopoietic stem cell transplant (HSCT) recipients remain at high risk of adverse outcomes from coronavirus disease 2019 (COVID-19) and emerging variants. The optimal prophylactic vaccine strategy for this cohort is not defined. T cell-mediated immunity is a critical component of graft-versus-tumour effect and in determining vaccine immunogenicity. Using validated anti-spike (S) immunoglobulin G (IgG) and S-specific interferon-gamma enzyme-linked immunospot (IFNγ-ELIspot) assays we analysed response to a two-dose vaccination schedule (either BNT162b2 or ChAdOx1) in 33 HSCT recipients at ≤2 years from transplant, alongside vaccine-matched healthy controls (HCs). After two vaccines, infection-naïve HSCT recipients had a significantly lower rate of seroconversion compared to infection-naïve HCs (25/32 HSCT vs. 39/39 HCs no responders) and had lower S-specific T-cell responses. The HSCT recipients who received BNT162b2 had a higher rate of seroconversion compared to ChAdOx1 (89% vs. 74%) and significantly higher anti-S IgG titres (p = 0.022). S-specific T-cell responses were seen after one vaccine in HCs and HSCT recipients. However, two vaccines enhanced S-specific T-cell responses in HCs but not in the majority of HSCT recipients. These data demonstrate limited immunogenicity of two-dose vaccination strategies in HSCT recipients, bolstering evidence of the need for additional boosters and/or alternative prophylactic measures in this group.

Long term tolerability and clinical outcomes associated with tocilizumab in the treatment of refractory antibody mediated rejection (AMR) in pediatric renal transplant recipients.

BACKGROUND: Treatment options for antibody-mediated rejection (AMR) are limited. Recent studies have shown that inhibition of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling can reduce inflammation and slow AMR progression. METHODS: We report our experience using monthly tocilizumab (anti-IL6R) in 25 pediatric renal transplant recipients with AMR, refractory to IVIg/Rituximab. From January 2013 to June 2019, a median (IQR) of 12 (6.019.0) doses of tocilizumab were given per patient. Serial assessments of renal function, biopsy findings, and HLA DSA (by immunodominant HLA DSA [iDSA] and relative intensity score [RIS]) were performed. RESULTS: Median (IQR) time from transplant to AMR was 41.4 (24.367.7) months, and time from AMR to first tocilizumab was 10.6 (8.317.6) months. At median (IQR) follow up of 15.8 (8.435.7) months post-tocilizumab initiation, renal function was stable except for 1 allograft loss. There was no significant decrease in iDSA or RIS. Follow up biopsies showed reduction in peritubular capillaritis (p = .015) and C4d scoring (p = .009). The most frequent adverse events were cytopenias. CONCLUSIONS: Tocilizumab in pediatric patients with refractory AMR was well tolerated and appeared to stabilize renal function. The utility of tocilizumab in the treatment of AMR in this population should be further explored.