Initial Infusions Research Articles

Immune checkpoint inhibitor infusion times and clinical outcomes in patients with melanoma.

Circadian rhythms impact immune function; a previous study demonstrated that immunotherapy treatment times taking place later in the day correlated with poorer outcomes in patients with melanoma. However, this finding has not been replicated, and other infusion timing schemas are unexplored. The objective of this retrospective, cohort study was to determine if the time of immunotherapy infusion affects outcomes. Five hundred and sixteen participants age ≥18 years diagnosed with cutaneous, acral, mucosal, or unknown primary melanoma treated with >1 infusion of nivolumab, pembrolizumab, or combination ipilimumab/PD-1 inhibitors were included. Response rate, toxicity rate, overall survival (OS), and progression-free survival (PFS) were determined based on infusion timing. Patients with ≥1 late infusion (after 4pm) among their first 4 infusions had slightly poorer objective response rate compared with only pre-4pm infusions (39.7% vs 44.5%), but no significant associations with late infusions and PFS and OS (P = .23, .93, respectively). Multivariable analyses showed no statistically significant association with outcomes for patients with any post-4pm infusion among the first 4; median infusion time was also not associated with outcomes. However, considering all infusion times, we found inferior PFS (median 10.6 vs 38.9 months, P < .0001), and numerically inferior OS (median 54.6 vs 81.2 months, P = .19) in patients with ≥20% late infusions. Multivariable models had similarly inferior response and PFS for patients with ≥20% late infusions, and later median infusion times were associated with inferior response, PFS, and OS. Late immunotherapy infusion times were associated with inferior outcomes when considering all infusions, but not when considering initial (first 4) infusions.

Tebentafusp Induces a T-Cell–Driven Rash in Melanocyte-Bearing Skin as an Adverse Event Consistent with the Mechanism of Action

Tebentafusp is a gp100xCD3 bispecific ImmTAC designed to redirect polyclonal T cells against cells presenting the melanocyte lineage specific antigen gp100 on HLA-A*02:01. Skin-related adverse events, predominantly rash, are frequent and occur within a few hours after initial infusions, yet the mechanisms are unknown. Here we analysed clinical data from the randomised phase 3 trial (NCT03070392) of tebentafusp (n=252) versus investigator's choice (n=126). Translational analyses were performed on paired on-treatment skin samples from 19 patients collected in the phase 1 trial (NCT01211262). Our analyses showed that rash is a clinical manifestation of tebentafusp-induced recruitment of T cells to cutaneous melanocytes. Development of rash depended on baseline expression levels of gp100 and other melanin pathway genes in the skin. On treatment, melanocyte number was reduced and expression of melanocytic genes decreased, while gene expression related to immunity and cytokine signalling increased. When adjusted for baseline prognostic features, patients with rash within the first week of tebentafusp treatment had the same overall survival compared to patients without a rash in the phase 3 randomized trial IMCgp100-202 (HR 0.84; 95% CI 0.53-1.32). In summary, skin rash is an off-tumour, on-target effect of tebentafusp against gp100+ melanocytes, in line with the mechanism of action.

484 - Phase 2 trial in progress - lirentelimab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments

Abstract Background Atopic dermatitis (AD) is a chronic pruritic inflammatory dermatitis that affects approximately 16.5 million (7.3%) adults in the US, of which around 6.6 million (40%) have moderate-to-severe disease. The current standard of care includes topical treatments supplemented with corticosteroids with and without immunosuppressants. Patients with AD inadequately controlled by topical treatments and immunosuppressants are often treated with biologics and/or JAK inhibitors. Some patients do not have an adequate clinical response or are unable to tolerate these treatments prompting the need for novel therapies. Study Rationale Mast cells (MCs) and eosinophils (eos) are implicated in the pathogenesis of AD. Sialic acid-binding Ig-like lectin (Siglec)-8 is expressed selectively on MCs and eos; engagement with an antibody results in broad inhibition of MC activation and eos depletion. Lirentelimab (AK002) is a humanized, nonfucosylated IgG1 monoclonal antibody that binds specifically to Siglec-8. Preclinical data demonstrates that lirentelimab can broadly inhibit multiple modes of mast cell stimulation that drive AD pathogenesis. Lirentelimab, administered every 4 weeks as an infusion (IV), has been tested in over 600 healthy volunteers and patients with inflammatory and allergic diseases; in those with concomitant AD, improvements in AD were observed. Overall, lirentelimab IV has been well-tolerated; the most common AE being infusion related reactions (IRRs) typically associated with the initial infusions. In a phase 1 study, a subcutaneous (SC) formulation of lirentelimab was well-tolerated with no IRRs. The results of these studies provide a strong rationale for conducting this phase 2 proof-of-concept, randomized, double-blind, placebo-controlled study of lirentelimab SC in adults with moderate–severe atopic dermatitis inadequately controlled by topical treatments (NCT05155085, “ATLAS”). Key Inclusion/Criteria Adults (18-80 years) are eligible for screening if they have had chronic AD presented for ≥3 years with moderate-to-severe symptoms defined as: Eczema Area and Severity Index (EASI) score ≥16, involvement of ≥10% of the Body Surface Area (BSA), and Investigator Global Assessment (IGA) score ≥3, documented recent history of inadequate response to treatment with medications such as topical corticosteroids, calcineurin inhibitors, JAK inhibitors, or PDE4 inhibitors (crisaborole), and biologic-naïve or biologic-exposed (secondary loss of response, intolerance, or lack of access). The complete list of inclusion/exclusion criteria will be presented. Study Design 130 patients will be randomized 1:1 to receive either 7 SC injections of 300mg lirentelimab or placebo every two weeks and then followed for 12 weeks after the last dose. The primary endpoint is the proportion of patients who achieve EASI-75 at week 14 (2 weeks after last dose) compared with baseline. All patients who receive study medication will be included in the safety analysis. Secondary endpoints include percent change in EASI at week 14 from baseline and proportion of patients with IGA of 0 or 1 and a 2-point improvement at week 14 compared to baseline. Patients who complete the study (day 99 visit of double-blind period) will be given the option to enroll in an open-label extension (OLE) for 7 doses of 300mg lirentelimab SC for 12 weeks. Qualified participants will receive medication, lab tests and medical care related to the study at no cost. Study Sites This study is currently enrolling in the USA and Germany. Please visit clinicaltrials.gov (NCT05155085) or email atlas.info@allakos.com to learn more about this study.

365 Phase 2 trial in progress—lirentelimab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments

Abstract Atopic dermatitis (AD) is a chronic pruritic inflammatory dermatitis that affects approximately 16.5 million (7.3%) adults in the USA, of which around 6.6 million (40%) have moderate-to-severe disease. The current standard of care includes topical treatments supplemented with corticosteroids with and without immunosuppressants. Patients with AD inadequately controlled by topical treatments and immunosuppressants are often treated with biologics and/or JAK inhibitors. Some patients do not have an adequate clinical response or are unable to tolerate these treatments prompting the need for novel therapies. Mast cells (MCs) and eosinophils (eos) are implicated in the pathogenesis of AD. Sialic acid-binding Ig-like lectin (Siglec)-8 is expressed selectively on MCs and eos; engagement with an antibody results in broad inhibition of MC activation and eos depletion. Lirentelimab (AK002) is a humanized, nonfucosylated IgG1 monoclonal antibody that binds specifically to Siglec-8. Preclinical data demonstrate that lirentelimab can broadly inhibit multiple modes of MC stimulation that drive AD pathogenesis. Lirentelimab, administered every 4 weeks as an infusion (IV), has been tested in over 600 healthy volunteers and patients with inflammatory and allergic diseases; in those with concomitant AD, improvements in AD were observed. Overall, lirentelimab IV has been well-tolerated; the most common AE being infusion related reactions (IRRs) typically associated with the initial infusions. In a phase 1 study, a subcutaneous (SC) formulation of lirentelimab was well-tolerated with no IRRs. The results of these studies provide a strong rationale for conducting this phase 2 proof-of-concept, randomized, double-blind, placebo-controlled study of lirentelimab SC in adults with moderate-to-severe AD inadequately controlled by topical treatments (NCT05155085, ‘ATLAS’). Adults (18–80 years) are eligible for screening if they have had chronic AD presented for ≥3 years with moderate-to-severe symptoms defined as: Eczema Area and Severity Index (EASI) score ≥16, involvement of ≥10% of the Body Surface Area and Investigator Global Assessment (IGA) score ≥3, documented recent history of inadequate response to treatment with medications such as topical corticosteroids, calcineurin inhibitors, JAK inhibitors or PDE4 inhibitors (crisaborole), and biologic-naïve or biologic-exposed (secondary loss of response, intolerance or lack of access). The complete list of inclusion/exclusion criteria will be presented. One hundred and thirty patients will be randomized 1 : 1 to receive either seven SC injections of 300-mg lirentelimab or placebo every 2 weeks and then followed for 12 weeks after the last dose. The primary endpoint is the proportion of patients who achieve EASI-75 at week 14 (2 weeks after last dose) compared with baseline. All patients who receive study medication will be included in the safety analysis. Secondary endpoints include percent change in EASI at week 14 from baseline and proportion of patients with IGA of 0 or 1 and a 2-point improvement at week 14 compared with baseline. Patients who complete the study (Day 99 visit of double-blind period) will be given the option to enroll in an open-label extension for seven doses of 300-mg lirentelimab SC for 12 weeks. Qualified participants will receive medication, lab tests and medical care related to the study at no cost. This study is currently enrolling in the USA and Germany. Please visit clinicaltrials.gov (NCT05155085) or email atlas.info@allakos.com to learn more about this study.

Association of circadian timing of initial infusions of immune checkpoint inhibitors with survival in advanced melanoma.

Aims: Chronomodulation of immune checkpoint inhibitors (ICIs) is not well understood. The authors evaluated the circadian timing of initial ICI infusions. Patients & methods: A retrospective cohort study of patients with advanced melanoma (n=121) was conducted. Results: Exclusive afternoon timing of the first four infusions was associated with worse overall survival (5.5 vs 24.9months; p<0.001) and progression-free survival (3.3 vs 7.6months; p=0.009) on Kaplan-Meier curves. In multivariable Cox analysis, the rate of overall survival was lower in patients who received all first four ICI infusions in the afternoon versus patients who received ≥1 of the first four infusions in the morning (hazard ratio: 2.4; p=0.004). Conclusion: Deliberate morning scheduling for the first several ICI treatments may improve patient-centered outcomes.

286 Phase 2 proof-of-concept trial in progress—lirentelimab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments

Abstract Atopic dermatitis (AD) is a chronic pruritic inflammatory dermatitis that affects approximately 16.5 million (7.3%) adults in the US, of which around 6.6 million (40%) have moderate-to-severe disease. The current standard of care includes topical treatments supplemented with corticosteroids with and without immunosuppressants. Patients with AD inadequately controlled by topical treatments and immunosuppressants are often treated with biologics and/or JAK inhibitors. Some patients do not have an adequate clinical response or are unable to tolerate these treatments prompting the need for novel therapies. Mast cells (MCs) and eosinophils (eos) are implicated in the pathogenesis of AD. Sialic acid-binding Ig-like lectin (Siglec)-8 is expressed selectively on MCs and eos; engagement with an antibody results in broad inhibition of MC activation and eos depletion. Lirentelimab (AK002) is a humanized, nonfucosylated IgG1 monoclonal antibody that binds specifically to Siglec-8. Preclinical data demonstrates that lirentelimab can broadly inhibit multiple modes of mast cell stimulation that drive AD pathogenesis. Lirentelimab, administered every 4 weeks as an infusion (IV), has been tested in over 600 healthy volunteers and patients with inflammatory and allergic diseases; in those with concomitant AD, improvements in AD were observed. Overall, lirentelimab IV has been well-tolerated; the most common AE being infusion-related reactions (IRRs) typically associated with the initial infusions. In a phase 1 study, a subcutaneous (SC) formulation of lirentelimab was well-tolerated with no IRRs. The results of these studies provide a strong rationale for conducting this phase 2 proof-of-concept, randomized, double-blind, placebo-controlled study of lirentelimab SC in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments (NCT05155085, ‘ATLAS’). Adults (18–80 years) are eligible for screening if they have had chronic AD presented for ≥ 3 years with moderate-to-severe symptoms defined as Eczema Area and Severity Index (EASI) score ≥ 16, involvement of ≥ 10% of the Body Surface Area (BSA) and Investigator Global Assessment (IGA) score ≥ 3, documented recent history of inadequate response to treatment with medications such as topical corticosteroids, calcineurin inhibitors, JAK inhibitors, or PDE4 inhibitors (crisaborole) and biologic-naïve or biologic-exposed (secondary loss of response, intolerance or lack of access). The complete list of inclusion/exclusion criteria will be presented. 130 patients will be randomized 1 : 1 to receive either seven SC injections of 300 mg lirentelimab or a placebo every 2 weeks and then followed for 12 weeks after the last dose. The primary endpoint is the proportion of patients who achieve EASI-75 at week 14 (2 weeks after the last dose) compared with baseline. All patients who receive study medication will be included in the safety analysis. Secondary endpoints include a percent change in EASI at week 14 from baseline and a proportion of patients with IGA of 0 or 1 and a 2-point improvement at week 14 compared to baseline. Patients who complete the study (day 99 visit of double-blind period) will be given the option to enroll in an open-label extension (OLE) for seven doses of 300 mg lirentelimab SC for 12 weeks. Qualified participants will receive medication, lab tests and medical care related to the study at no cost. This study is currently enrolling in the USA and Germany. Please visit clinicaltrials.gov (NCT05155085) or email atlas.info@allakos.com to learn more about this study.

Early efficacy and safety of obinutuzumab with chemotherapy in previously untreated patients with follicular lymphoma: A real-world retrospective report of the Polish Lymphoma Research Group.

The first-line obinutuzumab-based immunochemotherapy improves the outcome of patients with follicular lymphoma (FL) compared with rituximab-based regimens. However, infusion-related reactions occur in almost half of patients during the 1st obinutuzumab administration. The study aimed to evaluate the early effectiveness and safety of obinutuzumab-based induction regimens in a real-world setting. Outcomes of patients diagnosed with FL and treated with obinutuzumab between January 2020 and September 2021 were analyzed. The study group included 143 treatment-naïve patients with FL. The median age was 52 years (range: 28-89 years); 45.1% of patients had a high-risk disease as assessed using the Follicular Lymphoma International Prognostic Index (FLIPI). Induction chemotherapy included: O-CVP (obinutuzumab, cyclophosphamide, vincristine, prednisolone) in 49.0% of patients, O-CHOP (O-CVP plus doxorubicin) in 28.7% and O-BENDA (obinutuzumab, bendamustine) in 22.4%. Complete response (CR) and partial response (PR) rates were 69.9% and 26.5%, respectively. There was no difference in response rates between different regimens (p = 0.309). Maintenance was started in 115 patients (85.2%). In the 1st cycle, obinutuzumab was administered as a single 1000-milligram infusion in 47.9% of patients, whereas in 52.1%, initial infusions were split over 2 days (100 mg/900 mg). Infusion-related reactions were reported only during the 1st administration of obinutuzumab in 9.1% of patients, with a similar incidence in those receiving the total dose on a single day or split over 2 days (p = 0.458). The most common adverse events were hematological. Five patients died from coronavirus disease 2019 (COVID-19). The early responses to induction regimens and adverse events profile were similar for every type of induction treatment. The infusion-related reactions were rare and limited to the 1st dose of obinutuzumab.

Abstract 11067: Off-Heparin Implantation of Leadless Pacemaker, a Single Center Study

Introduction: Leadless pacing(LP) technology has been expanding in recent practice as an alternative to traditional pacing This technology is associated with reduce complications such as infection, dislodgment, and hardware burden. There has been recent reports on effusions with its implantation .Historically the manufacturer has recommend bolus of heparin or infusions We present the results and operative outcomes of patients who received a LP without initial heparinization or infusion from 2016 to 2021 at a single center. Objective We sought to describe the outcomes of LP implantation without the need of heparin administration. Methods: We report the clinical outcomes and operative findings of 200 patients who underwent LP implantation without initial heparin loading or infusions . An aggressive flushing strategy of the sheaths before and during the procedures was performed Data recorded include indication, ejection fraction (EF) R waves, capture thresholds, ventricular ectopy on deployment,recaptures, procedure times, and complications. Patients on chronic anticoagulation were excluded Results: A total of 200 patients were included , average age was 77 years and 20 (10%) had a reduced EF (&lt;40%) pre-procedure. The most common indications included complete AV block (97, 48.5%) and atrial fibrillation with slow ventricular response (76, 38%). All patients (100%) had successful establishment of ventricular pacing with no short-term complications postoperatively. Average R waves after deployment were 9.7 with average capture thresholds of 0.84 @ 0.24 Ventricular ectopy was seen for 134 (67%) of patients upon deployment with 62 (31%) patients requiring recaptures, and 29 (14.5%) requiring more than one recapture. There was no evidence of thrombus in the sheaths or implanting instruments . There were no embolic or thrombotic complications. Conclusions: LP implantation is highly effective and efficacious in establishing single-chamber ventricular pacing for a variety of conduction pathologies with minimal complications postoperatively. It appears that an aggressive flushing strategy of the implanting equipment &amp; sheaths is safe &amp; effective without the need of heparinization. Further studies will be require to validate this strategy

P063: Trial in Progress: Individualized Immunotherapy in Early-Stage Unfavorable Hodgkin Lymphoma - The Investigator-Initiated Phase II GHSG INDIE Trial

Figure 1: INDIE Trial Flowchart (Main Cohort age 18–60 years, N=100) Background: Immune-checkpoint blockade targeting the programmed cell death protein 1 (PD1) axis continue to reshape the therapeutic landscape of classical Hodgkin lymphoma (HL). The randomized phase II GHSG NIVAHL trial investigated nivolumab-based 1st-line treatment of early-stage unfavorable HL, either fully concomitant (4x nivo-AVD) or sequential (4x nivolumab, 2x nivo-AVD, 2x AVD) each followed by 30Gy involved-site radiotherapy (IS-RT; Bröckelmann PJ et al. JAMA Oncol 2020). The most recent update continued to show feasibility, a favorable safety profile and outstanding efficacy with 2-year progression-free (PFS) and overall survival (OS) of 99% and 100%, respectively (Bröckelmann PJ et al. ASH 2020). The upcoming GHSG phase II INDIE trial will investigate an individualized immunotherapy with the anti-PD1 antibody tislelizumab in this setting. Trial design: INDIE is an investigator-sponsored open-label phase II trial conducted at 35 GHSG trial sites in Germany. Patients with newly diagnosed early-stage unfavorable HL by GHSG criteria will receive two initial infusions of tislelizumab (200mg Q3W) followed by an FDG-PET/CT based restaging. Patients in complete metabolic remission will continue treatment with four additional tislelizumab infusions (300mg Q4W). Patients with residual metabolic activity will receive concomitant treatment with four cycles of AVD at standard dose and tislelizumab (300mg Q4W, tis-AVD). In the main cohort of N=100 patients aged 18–60 years, consolidative 30Gy IS-RT will only be applied in case of PET-positive residues (Figure 1). In an exploratory of N=20 patients >60 years of age, 30Gy IS-RT will be applied irrespective of remission status at end of systemic treatment. Primary endpoint is the 1-year PFS with 1- and 3-year OS, 3-year PFS, feasibility and safety, patient-reported outcomes and correlative studies being secondary endpoints. The trial is registered at clinicaltrials.gov (NCT04837859) and financially supported by BeiGene. Outlook: INDIE is the first trial to investigate an individualized immunotherapy in treatment naïve early-stage unfavorable HL, potentially omitting both chemo- and radiotherapy in optimally responding patients. Together with extensive correlative studies on longitudinal tumor biopsies, blood and stool samples, this trial will generate critical insights into response-adapted 1st-line HL immunotherapy.

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Safety and Preliminary Clinical Activity of REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Antibody, in Patients with B-NHL Previously Treated with CD20-Directed Antibody Therapy

Safety and Preliminary Clinical Activity of REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Antibody, in Patients with B-NHL Previously Treated with CD20-Directed Antibody Therapy

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Shorter infusion time of ocrelizumab: Results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis

Background: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5–6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocrelizumab infusions was investigated using results from ENSEMBLE PLUS.Methods: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early-stage relapsing-remitting MS received ocrelizumab 600 mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, ocrelizumab 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration); the durations of the initial infusions (2×300 mg, 14 days apart) were unaffected. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first Randomized Dose.Results: From November 1, 2018, to December 13, 2019, 745 patients were randomized 1:1 to the conventional or shorter infusion group. At the first Randomized Dose, 99/373 patients (26.5%) in the conventional and 107/372 patients (28.8%) in the shorter infusion group experienced IRRs. The majority of IRRs were mild or moderate; >99% of all IRRs resolved without sequelae in both groups (conventional infusion group, 99/99; shorter infusion group, 106/107). No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuations occurred. During the first Randomized Dose, 22/373 (5.9%) and 39/372 (10.5%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. Adverse events were consistent with the known safety profile of ocrelizumab.Conclusion: The rates and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shortening the infusion time to 2 hours reduces the total site stay time (including mandatory pre-medication/infusion/observation) from 5.5–6 hours to 4 hours, and may reduce patient and site staff burden. A short video summarizing the key results is provided in supplemental material.

An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study.

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare multisystem vascular disorder that causes chronic gastrointestinal bleeding, epistaxis, and severe anemia. Bevacizumab, an anti-vascular endothelial growth factor antibody, may be effective to treat bleeding in HHT. This international, multicenter, retrospective study evaluated the use of systemic bevacizumab to treat HHTassociated bleeding and anemia at 12 HHT treatment centers. Hemoglobin, Epistaxis Severity Score (ESS), red cell units transfused, and intravenous iron infusions before and after treatment were evaluated using paired means testing and mixed-effects linear models. Bevacizumab was given to 238 HHT patients for a median of 12 (range, 1-96) months. Compared with pretreatment, bevacizumab increased mean hemoglobin by 3.2 g/dL (95% confidence interval: 2.9-3.5 g/dL); i.e., from a mean hemoglobin of 8.6 (8.5-8.8) g/dL to 11.8 (11.5-12.1) g/dL; P<0.0001) and decreased the ESS by 3.4 (3.2-3.7) points (mean ESS 6.8 [6.6-7.1] versus 3.4 [3.2-3.7]; P<0.0001) during the first year of treatment. Compared with 6 months before treatment, the number of red blood cell units transfused decreased by 82% (median of 6.0 [interquartile range, 0.0-13.0] units versus 0 [0.0-1.0] units; P<0.0001) and iron infusions decreased by 70% (median of 6.0 [1.0-18.0] infusions versus 1.0 [0.0-4.0] infusions, P<0.0001) during the first 6 months of bevacizumab treatment. Outcomes were similar regardless of the underlying pathogenic mutation. Following initial induction infusions, continuous/scheduled bevacizumab maintenance achieved higher hemoglobin and lower ESS than intermittent/as-needed maintenance but with more drug exposure. Bevacizumab was well tolerated: hypertension, fatigue, and proteinuria were the most common adverse events. Venous thromboembolism occurred in 2% of patients. In conclusion, systemic bevacizumab was safe and effective for managing chronic bleeding and anemia in HHT.

Intravenous bisphosphonate therapy in children with spinal muscular atrophy.

Children with SMA are at high risk for fragility fractures and low BMD. IV BP have been used for treatment of disuse osteoporosis in pediatrics. However, safety and efficacy of IV BP in the SMA population has not been reported. Retrospective chart review of IV BP for treatment of disuse osteoporosis and low BMD in children with SMA at a tertiary pediatric center from 2010 to 2018 RESULTS: Eight patients (50% female; 75% SMA type 1; median age at first infusion 6.7 years) receiving a total of 39 infusions (54% pamidronate, 46% zoledronic acid) were included in this report. Acute phase reactions occurred following 38% and 3% of initial and subsequent infusions, respectively. BMD trended toward improvement at 1 year post-treatment. Among six patients who had > 2 years of follow-up, fracture rate decreased from 1.4 to 0.1 fracture/year. An atypical femur fracture was observed in one patient. These findings suggest that in children with SMA, IV BP therapy appears to be safe with minimal acute side effects and effective to reduce fracture rate. Caution is still needed given the occurrence of an atypical femur fracture in SMA population.

SAT-LB052 Intravenous Bisphosphonate Therapy in Children with Spinal Muscular Atrophy

Introduction: Children with Spinal Muscular Atrophy (SMA) are at high risk for poor bone health with 50% of the most severely affected patients reporting at least one fragility fracture prior to age 10 years. Intravenous bisphosphonate (IV BP) has been used for treatment of disuse osteoporosis, primarily in children with cerebral palsy or muscular dystrophy. Our group has previously demonstrated that children with secondary osteoporosis are at increased risk for developing acute adverse events following IV BP but the safety and efficacy of IV BP in SMA population have not been studied. Objective: To evaluate safety profile and the efficacy of IV BP for treatment of concerns for osteoporosis in children with SMA. Methods: We retrospectively reviewed IV BP use in children with SMA at a tertiary pediatric center from 2010 to 2018. Demographic data, fractures history, laboratory indices, and bone mineral density (BMD) by DXA were obtained from electronic medical record and are presented in this case series. Results: Eight children (50% female; 75% SMA type I, 25% SMA type II) were included in this study. The median age of first IV BP infusion was 6.7 years (range 2.3 - 19.0 years). Six had long bone fractures (total of 15) prior to IV BP treatment; two of these fractures were healing fractures discovered 1 month after IV BP started. Two patients were treated based on declining BMD. Patients received a total of 39 infusions (54% pamidronate, 46% zoledronic acid). All received their first IV BP in an inpatient setting due to need for monitoring of respiratory support (BiPAP). Acute phase reactions occurred following 38% (3/8) and 3% (1/31) of initial and subsequent infusions, respectively. All were considered mild and no adverse respiratory events were noted. Hypocalcemia was observed following 5% of infusions (2/37). Hypophosphatemia was common (73%, 27/37) but rarely required intravenous replacement. There was no significant change in BMD at 1 year pre- and post-IV BP treatment among four who had DXA scans for comparison. In 32.7 patient years of follow up, two patients (25%) had total of 3 subsequent fractures, including an occurrence of atypical femur fracture which was observed in one patient 3 years after initiation of IV BP. Conclusion: Although the acute adverse events from IV BP therapy were generally mild, caution needs to be taken given the occurrence of an atypical femur fracture in this population. More follow up is needed to determine the efficacy of therapy in maintaining BMD and preventing further fracture in patients with disuse osteoporosis secondary to SMA. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Cost and Value Analysis of Standard Versus Rapid Daratumumab Infusion in Multiple Myeloma

▪Introduction: There is growing interest regarding cost and affordability of cancer care, particularly in the area of pharmaco-economics. Multiple myeloma has emerged as a model for discussion given the advances in diagnosis, treatments, and subsequent improvement in patient survival. Unfortunately the cost of myeloma therapy has also increased with the advent of novel therapies. Patients are commonly treated with multi-drug combinations that are well tolerated and significantly improve symptoms and outcome, allowing them to return to pre-disease activities. Therefore it is important to consider cost and value when developing new therapeutic strategies. Approval of Daratumumab (DARA) revolutionized the care of myeloma but long infusion times are costly and cumbersome to patients. After initial infusions are administered without infusion reactions DARA is normally infused over 3.5 hours. A recent study showed that a 90-minute infusion is feasible and well-tolerated in patients who have received two prior doses of DARA at standard infusion rates (Barr H et al. Blood 2017). We sought to evaluate the cost and value benefit to patients and payers since implementing this practice change throughout our institution.Methods: We performed a retrospective chart review of patients who received standard DARA versus rapid infusion DARA between February to June 2018 at our institution. The utilization of rapid DARA infusion was implemented on April 24, 2018, so patients who received DARA prior to that date were categorized as pre-rapid DARA and those who received DARA after were considered post-rapid DARA. Pharmacy and billing data was reviewed for these patients and infusions.Results: A total of 181 patients received DARA infusions over the four month time period. 48% of patients (n=86) were treated during the standard pre-rapid DARA timeframe and 52% (n=95) were treated with rapid DARA infusions once eligible. 246 total infusions were administered at standard dosing and 305 infusions were administered as rapid infusions. An average of 2 hours infusion time was saved with each rapid DARA infusion resulting in 610 hours saved over the two months since initiating the rapid treatment protocol. Based on our financial data, we predict that will translate to approximately $7000 savings for the first 6 cycles of treatment if patients are started on rapid infusion DARA with their third treatment dose.Conclusion: There have been dramatic improvements in quality of life and survival of myeloma patients with the introduction of novel therapies. This requires clinicians to adjust their framework of care to account for cost, quality, and value as it applies to patients, providers, and payers. Our analysis shows that with two hours less infusion time both direct and indirect costs savings are achieved. This decrease in cost means less charges to the patient and payer. Therefore overall cost of DARA treatment is reduced. The savings to the patient and payer will quickly add up as patients continue on treatment until disease progression or inability to tolerate further treatment. This helps to decrease the burden of financial toxicity with prolonged treatment. It also improves opportunity cost of the patient and caregiver. With our two month data, we anticipate approximately 3500 hours of infusion time saved over twelve months. In centers with high chair utilization this can improve efficiency. Ongoing efforts should be made to provide value to patients, payers, and providers. DisclosuresNo relevant conflicts of interest to declare.

Spinal analgesia for severe cancer pain: A retrospective analysis of 60 patients

Background and aimsPain is highly prevalent in advanced cancer, and in some patients refractory to conventional opioid treatment. For these patients, invasive methods of pain relief should be considered. Spinal administration of opioids has been shown to be an effective alternative in refractory cancer pain. The aim of this retrospective study was to collect information on the use of spinal analgesia for cancer pain in Helsinki University Hospital. MethodsA retrospective patient chart study of all cancer patients with spinal analgesia, either intrathecal or epidural, in a single academic center during a five year period (n=60). ResultsForty-four patients were treated with intrathecal (IT) and sixteen with epidural (EP) technique. The most common indication for spinal analgesia was pain refractory to systemic analgesics. Good analgesia was achieved in 50% and 70% of the patients in the EP and IT groups, respectively. The median daily systemic opioid doses prior to spinal analgesia were 874.5mg and 730.5mg as oral morphine equivalents in the IT and EP groups, respectively. The systemic opioid could be discontinued or significantly reduced in 83% of the patients. Morphine was used in all IT infusions and most EP infusions, mostly combined with bupivacaine 10mg (IT) or 66mg (EP). The median starting doses of morphine were 3mg/day (IT) and 19mg/day (EP) and were increased during titration 27% to 3.8mg/day (IT) and 91% to 36.2mg/day (EP). Clonidine (median 0.015mg/day IT and 0.15mg/day EP) and/or ketamine were used as adjuvants. The average titration time to stable analgesia was 7–9 days. Numbness in lower limbs was reported by 24% of the IT group. On average, catheters were placed 98 and 61 days before death in IT and EP groups, respectively. No serious complications occurred. Catheter dislocation occurred in 27% of all sixty patients during follow-up. Treatment was discontinued in 10 patients because of catheter dislocation (n=7) or local infection (n=3). Conclusions and implicationsSpinal administration of opioids is a safe and effective method of pain management in patients with severe cancer pain and can greatly reduce the need of systemic opioids. We are implementing closer collaboration with oncologists to provide spinal analgesia to more patients and earlier to reduce suffering. Catheter dislocation led to discontinuation of spinal analgesia in 17% of the patients and we are evaluating new ways to prevent catheter dislocation. The initial median spinal opioid dose was too low in both groups, and we are now using higher initial doses. A common adverse effect was numbness of the lower limbs, regardless of the relatively low doses of spinal bupivacaine. We now use lower doses and introduce the intrathecal catheter higher at L1–2 to reduce motor blockade at the level of conus.As an initial intrathecal infusions we suggest: morphine dose calculated using an oral to intrathecal ratio of 1:100 (unless the patient is elderly or already drowsy), clonidine dose 30μg/day and bupivacaine dose 7.5mg/day.

Pharmacovigilance of a Rituximab Biosimilar (Novex) in Argentina

INTRODUCTIONNovex is a rituximab biosimilar approved in Argentina. From January 2015 to June 2016 as part of the Risk Management Plan approved by ANMAT, every treatment detected was recorded and a follow up was implemented in order to obtain safety information.The aim of this communication is to present the information gathered during this pharmacovigilance program.MATERIALS AND METHODSAll treatments with at least 1 follow up point were selected and reviewed.Treatment duration until last follow up checkpoint or date of treatment finalization was recorded.We summarized demographic data (age, gender), indication distribution, treatment exposition (duration expressed in days and number of cycles received), adverse event frequency (cumulative incidence and incidence density) and distribution.RESULTSWe collected 345 treatment notifications with at least 1 follow up point.Gender distribution: 53.2 % of patients were male patients. Age range was 10 to 90 years old, with a mean of 63.9 years.The indications distribution is summarized in table 1. More than 90% of them were hematological.Average treatment duration was of 235 days with a median duration of 210 days (IQR = 152 - 311).Mean number of cycles 5.5; range (1-12).During the reported period a total of 12 Individual Case Safety Reports (ICSR) were received. This represents a cumulative incidence of 3.5 %, an incidence density of 0.015 ICSR notifications per 100 days of treatment and 0.99 per 100 administered cycles.These 12 ICSR totalized 14 different diagnoses. Of them, the most frequent was Acute Infusion Related Reaction (AIRR), as expected.All AE but 1 were classified as serious (SAE) because they had at least 1 manifestation that prolonged hospitalization or endangered life.As expected, the most frequent AE notified was AIRR (5 cases), followed by cardiovascular manifestations (2 arrhythmia, 1 cardiac failure and 1 ischemic stroke), infections (1 pneumonia, 1 progressive multifocal leukoencephalopathy), neurologic (1 paresthesia), cytopenias (1 pancytopenia) and cutaneous (1 bullous dermatitis).Most of the acute manifestations occurred within the 2 initial infusions of Rituximab, as described.CONCLUSIONThe observed AE frequency and distribution was consistent with product specifications.No AE notified were unlisted or were notified with greater frequency than expected.Treatments registry resulted in a suitable way to detect AE that complements spontaneous reporting. [Display omitted] [Display omitted] DisclosuresFernandez:Laboratorio ELEA S.A.C.I.F y A: Employment. Penna:Laboratorio ELEA S.A.C.I.F y A: Employment. Gomez:Laboratorio ELEA S.A.C.I.F y A: Employment.

Acute Psychosis in an Adolescent Treated With Infliximab for Crohn's Disease.

To the Editor: Infliximab is a monoclonal antibody against tumor necrosis factor-α (TNF-α) and has been shown to be 81% more efficacious than placebo in Crohn’s disease patients who have had an inadequate response to conventional therapy.1 While there are case reports of suicide attempts after treatment with infliximab for inflammatory bowel diseases,2,3 and reports of anti–TNF-α treatment leading to psychosis in elderly patients with rheumatologic disorders,4 to our knowledge, this is the first case of a pediatric patient with Crohn’s disease who developed acute psychosis after treatment with infliximab. Case report. A 15-year-old white male high school honors student, with a history of Crohn’s disease since age 12 years and a history of obsessive-compulsive disorder and attention-deficit disorder, received his first 3 infliximab infusions over a 2-month period for treatment of poorly controlled Crohn’s disease. One month after the third infusion, his teacher and parents noticed odd changes in his personality, which included inappropriate verbal outbursts, increased agitation, and defiant behavior over the course of 2 days. He then became verbally threatening and combative with his mother and was brought to the emergency department. In the emergency department, he was seen by psychiatry staff and found to have disorganized thought process with loose associations, echolalia, delusions of thought broadcasting and grandeur, distractibility, and severe psychomotor agitation. He had no history of recreational drug or alcohol use. Extensive workup results were all within normal limits including a head computed tomography scan, brain 3 magnetic resonance imaging, routine electroencephalograph, Lyme Western blot, urinalysis, lumbar puncture, cerebrospinal fluid culture, serum herpes simplex virus polymerase chain reaction, rapid plasma reagin, vitamin B12, folate, thyroid-stimulating hormone, stool culture, stool ova and parasite, and urine toxicology screen. The patient was started on haloperidol, which was titrated to 1 mg twice a day. Although this tempered his agitation and aggression, his psychosis did not completely resolve, and he experienced an acute dystonic reaction that led to the discontinuation of the medication. He was discharged home but came back in a few days for worsening behavior along with agitation and abusive speech. Treatment with olanzapine titrated to 7.5 mg twice a day resulted in resolution of his psychotic symptoms. However, on the fourth day of olanzapine treatment, a fourth infliximab infusion was administered, and shortly after, he suddenly became agitated and combative and appeared to experience visual hallucinations. The infliximab treatment was terminated, and he was discharged home with outpatient follow-up. At present, olanzapine has also been discontinued. He attends weekly group therapy at an outpatient facility and has returned to his normal mental status. Given the timing of his initial presenting symptoms within the 3 months of his initial infliximab infusions and the immediate relapse of psychotic symptoms after his fourth infliximab infusion, we believe that the patient’s psychosis is best explained by a psychotic reaction to infliximab. He was consistently psychotic with no fluctuations of consciousness to suggest coincidental delirium, and no substance-induced cause was identified. It is interesting to note that his psychosis responded better to an atypical neuroleptic compared to a typical one. There is evidence that atypical neuroleptics inhibit activated microglia release of proinflammatory cytokines, especially nitric oxide and TNF-α.5 Anti–TNF-α therapy has numerous well-recognized adverse events, such as infection and malignancy. However, there is very little information in the literature pertaining to psychiatric side effects. We suggest that patients treated with infliximab for Crohn’s disease could experience an acute psychosis. Treatment with an atypical antipsychotic may be considered over the typical antipsychotics. However, more controlled prospective studies are required to confirm our suspicion of causality between infliximab and psychosis to guide treatment.