Upper Limit Of Normal Research Articles

Categorization of Hematological Responses to Oral Iptacopan Monotherapy in Anti-C5-Treated Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) and Persistent Anemia in the Phase III APPLY-PNH Trial and Complement Inhibitor-Naïve Patients in the Phase III APPOINT-PNH Trial

Background: PNH is an ultrarare disease characterized by complement-mediated hemolysis and consequent anemia. Iptacopan is the first oral, selective complement inhibitor that targets factor B to inhibit the alternative pathway proximally in the complement system. Iptacopan monotherapy led to normal/near normal hemoglobin (Hb) values and transfusion avoidance in the majority of complement inhibitor-naïve patients and anti-C5-treated patients with persistent anemia in the Phase III APPOINT-PNH (NCT04820530) and APPLY-PNH (NCT04558918) trials, respectively, with iptacopan achieving its primary endpoints and demonstrating superiority to anti-C5 treatment in APPLY-PNH. Aim: To apply hematological response categories, adapted from Risitano et al. in Front Immunol 2019, to the data from APPLY-PNH (baseline and Week 24 data) and APPOINT-PNH (Week 24 data). Methods: APPLY-PNH enrolled adult PNH patients with a mean Hb level <10 g/dL who had been receiving eculizumab or ravulizumab for ≥6 months. Patients were randomized 8:5 to receive iptacopan monotherapy 200 mg twice daily or to continue their anti-C5 regimen for 24 weeks. APPOINT-PNH enrolled complement inhibitor-naïve adult PNH patients, with a mean Hb level <10 g/dL and lactate dehydrogenase (LDH) >1.5 × upper limit of normal (ULN); patients received iptacopan monotherapy 200 mg twice daily. Using central laboratory data, hematological responses were categorized primarily based on Hb levels (at baseline and between Days 126 and 168) and the need for packed red blood cell transfusions (in the 6 months prior to baseline and between Days 14 and 168). LDH levels and absolute reticulocyte counts were ancillary indicators to discriminate between complete and major responses. In the original definition of the response categories, absolute reticulocyte count was used to rule out patients with bone marrow failure; however, for this analysis, as patients with laboratory evidence of bone marrow failure were excluded from APPLY-PNH and APPOINT-PNH, absolute reticulocyte count was not used to define the suboptimal categories (ie good, partial, minor and no response categories). Week 24 categories were defined as follows: complete response - median Hb ≥12 g/dL, no transfusions, and both median LDH ≤1.5 × ULN and median absolute reticulocyte count ≤150,000/µL between Days 1 and 168; major response - median Hb ≥12 g/dL, no transfusions, and either LDH >1.5 × ULN or absolute reticulocyte count >150,000/µL between Days 1 and 168; good response - median Hb ≥10 and <12 g/dL and no transfusions; partial response - median Hb ≥8 and <10 g/dL and ≤2 transfusions; minor response - median Hb <8 g/dL and ≤2 transfusions; or median Hb <10 g/dL and 3-6 transfusions; or median Hb <10 g/dL and a reduction in transfusions by ≥50% between Days 14 and 168 compared with the number of transfusions received in the 6 months prior to baseline; no response - median Hb <10 g/dL and >6 transfusions. Results: Sixty-two patients received iptacopan and 35 patients received anti-C5 treatment in the APPLY-PNH trial; 40 patients received iptacopan in the APPOINT-PNH trial. There were no baseline differences between patients in the iptacopan arm and patients in the anti-C5 arm of the APPLY-PNH trial, with most patients having a partial hematological response to complement inhibitor treatment at baseline (62.9% [39/62] of patients in the iptacopan arm and 62.9% [22/35] in the anti-C5 arm; Figure 1). At Week 24, most iptacopan-treated patients in the APPLY-PNH trial achieved a complete response (71% [44/62] of patients versus 0% in the anti-C5 arm; Figure 1). Most patients in the APPOINT-PNH trial also achieved a complete response to iptacopan (62.5% [25/40] of patients; Figure 2). As expected, at Week 24, none of the patients in the anti-C5 arm of APPLY-PNH achieved complete or major hematological responses, with most continuing to maintain a partial hematological response (54.3% [19/35] of patients). Conclusions: This post hoc analysis of the APPLY-PNH and APPOINT-PNH trial data demonstrates that the majority of patients achieved complete or major hematological responses during treatment with iptacopan monotherapy, highlighting the ability of both complement inhibitor-naïve patients and anti-C5-treated patients with persistent anemia to achieve transfusion avoidance and improvement of Hb to normal/near normal levels with iptacopan.

An Externally Controlled Trial to Indirectly Compare Tazemetostat Plus Lenalidomide and Rituximab Versus Lenalidomide and Rituximab after at Least One Prior Systemic Therapy in Patients with Refractory and Relapsed Follicular Lymphoma

BACKGROUND: Follicular lymphoma (FL) is an indolent, incurable lymphoma with a heterogeneous clinical course characterized by multiple relapses. Recent data indicate a potential synergism between tazemetostat and lenalidomide and an additive effect with rituximab, offering a clinical rationale for this as a combination strategy (Batlevi, Blood 2022). SYMPHONY-1 Phase 1b, Stage 1 (EZH-302; NCT04224493) is an open-label, single-arm, safety run-in trial to evaluate the safety and tolerability of tazemetostat combined with lenalidomide plus rituximab (R2). This study indirectly compares the efficacy results of the SYMPHONY-1 Phase 1b single arm trial with an external control arm (ECA) derived from the Flatiron Health Research Database (FHRD), consisting of real-world FL patients treated with R2 after receiving ≥1 prior systemic therapy. METHODS: This study utilized individual patient data from SYMPHONY-1 based on a data cutoff date of July 10, 2023, and the FHRD, a large database of electronic health records from oncology practices in the United States, including data through December 31, 2022. The treatment arm consisted of patients enrolled in the safety run-in portion of SYMPHONY-1 treated with a combination of tazemetostat plus R2, followed from enrollment to the data cutoff date. The ECA was constructed by applying eligibility criteria adapted from SYMPHONY-1 to real-world patients from the FHRD treated with R2 in second line (2L); patients were followed from the start date of the earliest eligible line of therapy (LOT) to the end of the patient's record. The primary endpoint was objective response rate (ORR), defined as the proportion of patients who achieved a complete or partial response. In SYMPHONY-1, ORR was assessed by an independent review committee according to the 2014 Lugano Classification. In the ECA, real-world ORR (rwORR) was determined by the treating clinician's interpretation of change in disease burden. The analysis set included patients from the treatment arm with ≥1 evaluable response assessment and patients from the ECA with ≥1 radiographic assessment documented in the FHRD. The statistical analysis used propensity score weighting (PSW) to adjust the distribution of seven prespecified baseline patient characteristics of the ECA to align with the treatment arm. These characteristics were age, Eastern Cooperative Oncology Group Performance Status, disease grade at diagnosis, progression of disease within 24 months (POD24) from diagnosis, lactate dehydrogenase (LDH) > upper limit of normal (ULN), size of the largest node, and Follicular Lymphoma International Prognostic Index (FLIPI) risk group. An impute-then-exclude multiple imputation strategy was used to handle missing data for variables required in the eligibility criteria and PSW. The primary endpoint was indirectly compared by estimating the difference between the ORR of the treatment arm and rwORR of the balanced ECA on each imputed dataset, and the associated standard errors were approximated using bootstrapping. Rubin's rules were applied to combine the results into a single estimate with a 95% confidence interval and corresponding two-sided p-value. RESULTS: The primary analysis compared 42 patients in the treatment arm from SYMPHONY-1 and a median of 36 patients (range: 34 to 38) in the ECA among 815 total patients in the FHRD across ten imputed datasets. The unweighted analysis found an ORR of 95.2% in the treatment arm and 75.7% in the ECA, resulting in a difference of 19.6% (95% confidence interval [CI]: 3.6-35.5) (Table 2). After PSW, the distribution of baseline characteristics for the ECA was comparable with the treatment arm (all standardized mean differences < 0.16), and the median effective sample size was reduced to 12.7 (range: 4.9 to 19.1) (Table 1). ORR was 95.2% in the treatment arm and 77.9% in the ECA, resulting in a difference of 17.3% (95% CI: -17.5-52.1; two-sided P = 0.16) (Table 2). CONCLUSIONS: This ECA study found that patients treated with tazemetostat combined with R2 were estimated to have a higher ORR than those treated with R2, though inference is limited due to small sample sizes. These findings help contextualize the SYMPHONY-1 Phase 1b single-arm trial results and combination potential of tazemetostat plus R2. There is a randomized Phase 3 confirmatory trial underway to confirm the clinical benefit of tazemetostat plus R2 (SYMPHONY-1 Stage 2, NCT04224493).

The Presence of Bulky Disease and/or Very High LDH Defines a High-Risk Subset of IPI 1-2 for Eligibility in Clinical Trials of Newly Diagnosed Aggressive B-Cell Lymphoma

Background: The goal of clinical trial eligibility criteria is to identify a population of patients that have high risk disease or have unmet needs with standard of care therapy. Frontline trials of diffuse large B-cell lymphoma (DLBCL) include patients with International Prognostic Index (IPI) scores of 3-5 as a way to identify a high risk population. Trials typically include patients with IPI score=2, and sometimes IPI score=1, to expand the eligible patient population. However, broader patient populations must be balanced by the potential inclusion of low-risk patients with excellent outcomes to standard of care therapy, leading to potentially underpowered trials. IPI is a sum of dichotomous variables which makes implementation easy but can result in heterogeneity in outcomes within IPI scores. This heterogeneity may be caused by unequal prognostic information across IPI variables, loss of information within IPI variables due to the use of cutoffs, as well as information captured by variables that are not included in the IPI. In prior modeling of outcomes in DLBCL (Maurer et al, AJH 2016), we identified that: i) LDH has a strong prognostic ability beyond the upper limit of normal (ULN) and ii) bulky disease is an independent variable for prognosis. Here we evaluate if the presence of either of these two variables, easily captured at diagnosis within the current standard clinical work-up, can identify a high-risk subset of patients within the population of those with IPI scores of 1-2. Methods: Patients with newly diagnosed lymphoma were enrolled within 6 months of diagnosis in the LEO Cohort at 8 academic medical centers from 2015-2020 and prospectively followed. Inclusion criteria for this analysis was aggressive B-cell lymphoma typically included in frontline trials (e.g. DLBCL, high grade B-cell lymphoma, FL3B), IPI 1-5, frontline therapy with rituximab and anthracycline-based chemotherapy, stage II-IV disease and ages 18-80 years. Event-free survival (EFS) was defined as the time from diagnosis until progression, initiation of 2 nd line therapy, or death due to any cause; EFS was evaluated at 24 months (EFS24). Very high LDH was defined as LDH>1.3xULN based on prior modeling (Maurer et al, AJH 2016) and bulky disease was defined as maximum tumor diameter (MTD) of 7cm or greater. IPI 1 and 2 were first evaluated separately and then combined due to similar outcomes in patients with very high LDH and/or bulky disease. High risk IPI1-2 was defined as the presence of either bulky disease and/or very high LDH within an IPI score of 1-2. Confirmation was performed in a similar cohort of patients enrolled in the Iowa/Mayo SPORE Molecular Epidemiology Resource (MER) from 2002-2015; bulky disease was defined using a 10cm cutoff per availability in MER data collection forms. Results: 1560 patients from LEO were analyzed; median age was 64 years (IQR: 54-71), 42% were female and 83% had stage III/IV disease; subtype was DLBCL, NOS in 1335 (86%). IPI was 1-2 in 766 patients, 3 in 496 patients and 4-5 in 298 patients ( table). 391 (51%) with IPI1-2 had either bulky disease and/or very high LDH (high risk IPI1-2) and 375 had low-risk IPI1-2. EFS24 in high risk IPI1-2 (71.6%, 95% CI: 67.2-76.3) was significantly inferior to IPI1-2 without bulky disease or very high LDH (85.2, 95% CI: 81.7-88.9 logrank p=0.0035, figure) and similar to patients with IPI3 (70.7%, 95% CI: 66.8-74.9). Consistent results were observed in 1014 patients analyzed in the MER using a higher cutoff for bulky disease (10cm) due to data availability ( table). Patients with high risk IPI1-2 had significantly shorter diagnosis to treatment interval (DTI) in both the LEO (per-week OR=0.83, 95% CI: 0.77-0.88) and MER (per-week OR=0.77, 95% CI: 0.68-0.87) cohorts compared to low risk IPI1-2, both p<0.0001). In sensitivity analysis, LEO results were similar when performed in the subset of patients with DLBCL, NOS. Conclusion: The presence of either bulky disease and/or very high LDH at presentation identifies a high-risk subset of patients with IPI 1-2 that have similar outcomes to patients with IPI 3 disease. These simple criteria can be easily implemented within existing clinical trial diagnostic work-ups. Future trial designs in frontline aggressive B-cell lymphoma should include patients with IPI 3-5 and patients with IPI 1-2 with either bulky disease and/or very high LDH to better define a high-risk population of patients for clinical trial eligibility.

Development of a Novel Prognostic Score in Patients with Waldenström Macroglobulinemia Prospectively Enrolled in the Observational NF10 Study of Fondazione Italiana Linfomi

Background. IPSSWM and revised-IPSSWM are the two currently prognostic scores used for survival prediction in symptomatic Waldenström Macroglobulinemia (WM) patients in need of treatment. In addition to age and serum beta-2 microglobulin levels, which are present in both scores, the IPSSWM includes anemia, thrombocytopenia and the concentration of the serum monoclonal component (MC), while revised-IPSSWM includes LDH and serum albumin levels. Both IPSSWM and revised-IPSSWM have been developed in retrospective series and apply only to symptomatic WM patients. Aim. To analyze WM patients prospectively enrolled in the NF10 observational study since 2010 with the aim to define a prognostic score applicable to all WM patients at diagnosis, either symptomatic or asymptomatic. Methods. The progression-free survival (PFS) and overall survival (OS) rate was estimated and plotted using the Kaplan-Meier method, with 95% confidence interval (95% CI), and the effect of covariables on PFS was estimated by means of the Cox proportional hazard (PH) regression. The association with PFS was expressed as hazard ratio (HR) with 95% CI, either in univariable or multivariable regression. All statistical tests were two-sided. The proportionality of risk of the multivariable Cox PH model was checked graphically by means of the scaled Schoenfeld residuals, and the model performance was analyzed using the likelihood displacement method. Starting from a model with 10 variables selected on the basis of clinical and statistical considerations, the final model was selected on considering the Akaike (AIC) and likelihood ratio test. The cut-offs were selected after modelling the covariate with restricted cubic spline in Cox regression. The final model was internally validated using bootstrap techniques to evaluate the discriminant power (C-index), slope shrinkage to check for overfitting, and calibration (comparison between predicted and actual survival). Results. We identified 303 eligible patients from the NF10 study, of whom 185 (60%) needed treatment immediately after diagnosis (42%) or later (18%). These were main patients characteristics: 59% were male, 46% were aged >70 years, 8% had constitutional symptoms, 55% had Hb <12 g/dL, 54% had an absolute lymphocyte count ≥2x10 9/L, 9% had platelets <100x10 9/L, 37% had a serum MC >2 g/dL, 21% had albumin <3.5 g/dL, 23% had LDH > upper limit of normal (ULN), 32% had beta-2 microglobulin >1.5xULN. With a median follow-up of 51 months, 5-year PFS for the entire cohort was 67% (95%CI 60-73%). In univariate analysis, age >70 years (P=0.043), constitutional symptoms (P=0.009), nodal sites (P=0.002), Hb <12 g/dL (P<0.001), absolute lymphocyte count ≥2x10 9/L (P=0.033), serum MC >2 g/dL (P=0.003), high beta-2 microglobulin (P<0.001) and LDH (P=0.001), albumin <3.5 g/dL (P<0.001), C-reactive protein >4 mg/dL (P=0.008) were associated with shorter PFS. In multivariate analysis, age, anemia, hypoalbuminemia and high LDH retained prognostic value and thus entered the final model. Patients were classified into 3 risk groups: low (0-1 factors, 62% of patients), intermediate (2 factors, 24%) or high (3-4 factors, 15%), with a 5-year PFS of 80% (95%CI 70-87%), 49% (95%CI 32-64%) and 25% (95%CI 11-42%), respectively, with C-Harrell=0.744 and robust internal validation and calibration. OS was respectively 96% (95%CI 90-98%), 77% (95%CI 62-87%) and 43% (95%CI 25-60%) for the low, intermediate and high risk group (Figure 1). Conclusions. We developed a prognostic model based on 4 parameters easily attainable in clinical practice, able to predict PFS and OS at diagnosis. This is the first prognostic score for WM developed in a prospective study and applicable to patients presenting either with symptomatic or asymptomatic disease. This prognostic model identifies a subset of high-risk patients with a dismal outcome and a median OS <5 years. External validation in independent cohorts is needed.

Clinical Breakthrough Hemolysis (BTH) during Monotherapy with the Oral Factor B Inhibitor Iptacopan Is Generally Not Severe and Managed without Treatment Discontinuation: 48-Week Data from the Phase III Apply-PNH and Appoint-PNH Trials in Paroxysmal Nocturnal Hemoglobinuria (PNH)

Background: In PNH, BTH is characterized by the re-emergence of intravascular hemolysis (IVH) despite ongoing complement inhibition and is recognized by the reappearance of IVH/PNH signs/symptoms, coupled with a marked increase in lactate dehydrogenase (LDH) and sharp decrease in hemoglobin (Hb). Iptacopan is the first oral proximal complement inhibitor targeting factor B in the alternative pathway and has shown efficacy and safety in complement inhibitor-naïve PNH patients (pts; APPOINT-PNH; NCT04820530) and pts with persistent anemia despite anti-C5 treatment (APPLY-PNH; NCT04558918). In the APPLY-PNH 24-week (wk) analysis, iptacopan monotherapy showed superiority in the adjusted annualized rate of clinical BTH vs C5 inhibitors. Aim: We report the proportion of pts with clinical BTH, exposure-adjusted occurrence rates and BTH characteristics during iptacopan monotherapy in the Phase III APPLY-PNH and APPOINT-PNH trials (study completion [48-wk data]: 6 March and 18 April 2023, respectively). Methods: The prespecified protocol criteria for clinical BTH were LDH >1.5 × upper limit of normal (ULN) and increased vs the last 2 assessments, plus a ≥2 g/dL Hb decrease (vs the last assessment or within 15 days) or significant PNH signs/symptoms. All BTH was classed as an adverse event and evaluated for severity (investigator assessment) and seriousness (per protocol). In APPLY-PNH, adults who had received anti-C5 therapy for ≥6 months and had mean Hb <10 g/dL were randomized to receive oral iptacopan 200 mg twice daily or continue their anti-C5 regimen for 24 wks (randomized treatment period [RTP]). In APPOINT-PNH, adult complement inhibitor-naïve pts with mean Hb <10 g/dL and mean LDH >1.5 × ULN received iptacopan 200 mg twice daily for 24 wks. Both trials then had extension periods in which all pts could receive iptacopan monotherapy for another 24 wks. Results: In APPLY-PNH, 61/62 pts in the iptacopan arm continued iptacopan in the extension period and 34/35 in the anti-C5 arm switched to iptacopan. All 40 pts in APPOINT-PNH entered the extension period. When these 48-wk trials completed, 136 pts had received iptacopan with varying exposure (total exposure ~111 pt-years), of whom 9 had clinical BTH (10 events, Table). Two pts were in APPOINT-PNH (2/40, 2 events) and 7 in APPLY-PNH (7/96, 8 events). Of the iptacopan-treated pts in APPLY-PNH, 2 had BTH in the RTP; 1 of these pts plus 5 others had BTH in the extension period (including 1 who switched from anti-C5 to iptacopan at Wk 24). The exposure-adjusted occurrence rate of clinical BTH on iptacopan was 11.0 events per 100 pt-years in APPLY-PNH (95% confidence interval [CI] 5.2‒23.3) and 5.2 events per 100 pt-years in APPOINT-PNH (95% CI 1.3‒20.5). In the 24-wk APPLY-PNH RTP, 6/35 pts in the anti-C5 arm had clinical BTH (11 events); the exposure-adjusted occurrence rate was 66.9 events per 100 pt-years (95% CI 25.0‒178.9), which is >6 times higher than the rates on iptacopan. Of the 10 clinical BTH events reported on iptacopan, all were mild or moderate except 1 severe (and serious) event despite large PNH RBC clone sizes of >90% reported before 5/8 events with available clone size data. The impact of BTH on Hb was generally transient (Figure). Potential complement-amplifying conditions (CACs) were identified for 8 clinical BTH events during iptacopan treatment; the severe event was associated with COVID-19 and the temporal appearance of cold agglutinins. No pts discontinued iptacopan because of clinical BTH. RBC transfusions were the most common intervention; 1 pt received a 900 mg dose of eculizumab. In the anti-C5 arm in the APPLY-PNH RTP, 1/11 BTH events was severe and 2/11 were associated with potential CACs. Conclusions: In Phase III trials, 136 PNH pts received iptacopan monotherapy and few pts had clinical BTH, with severity being comparable to that with anti-C5 despite PNH RBC clone sizes >90%. Most clinical BTH events on iptacopan were associated with potential CACs; BTH was manageable with no intervention or RBC transfusion and without iptacopan discontinuation. The exposure-adjusted occurrence rates support our prior finding of a significantly lower adjusted annualized rate of clinical BTH with iptacopan vs anti-C5. BTH must be monitored with any complement inhibitor, but these data show that BTH was infrequent on iptacopan and support the positive safety profile of proximal complement inhibition with oral iptacopan monotherapy in hemolytic PNH.

Chemotherapy-Free Combination of Blinatumomab and Ponatinib in Adults with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Updates from a Phase II Trial

Background Blinatumomab and ponatinib demonstrated efficacy in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). A chemotherapy-free regimen combining both drugs in the frontline setting may mitigate the risk of toxicities and the need for hematopoietic stem cell transplantation (HSCT). Methods In this phase II trial, patients ≥18 years of age with newly diagnosed Ph-positive ALL were eligible. They were required to have a performance status of ≤2, total bilirubin ≤2x the upper limit of normal (ULN), and ALT/AST ≤3x the ULN. Patients with uncontrolled cardiovascular disease or clinically significant central nervous system (CNS) comorbidities (except for CNS leukemia) were excluded. Patients received up to 5 cycles of blinatumomab in combination with ponatinib, followed by ponatinib maintenance for ≥5 years. Ponatinib 30mg daily was given during Cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. Patients also received 12 doses of prophylactic intrathecal (IT) chemotherapy with alternating cytarabine and methotrexate. The primary endpoint was the CMR rate. Secondary endpoints included response rates, safety measures, event-free survival (EFS), and overall survival (OS). Results Between June 2018 and May 2023, 62 pts with newly diagnosed Ph-positive ALL were treated. Baseline characteristics are shown in Table 1. Twenty-two patients were in complete remission (CR) at the start of therapy. Among 40 patients evaluable for hematologic response, 39 (98%) achieved CR/CRi; 1 patient had early death. Among 55 patients evaluable for molecular response, 37 (67%) achieved CMR after 1 cycle, and 46 (84%) achieved CMR at any time. Forty-seven patients were evaluated for measurable residual disease (MRD) by next-generation sequencing at a sensitivity level of 10 -6, of whom 43 (91%) were found to have negative MRD. Five of these patients with undetectable MRD by NGS had low-level BCR:ABL1 transcripts detected by PCR at the same time (ranging from 0.01% to 1.23% IS). Four of them had p190 transcript and one had p210. The median follow-up was 17 months (range, 2-61 months). Six patients (10%) relapsed after a median of 21 months of remission (range, 8-24 months): two relapsed in the bone marrow (one with acquired E225V mutation), one had an extramedullary-only relapse (Ph-negative and MYC-rearranged relapse), and three had a CNS-only relapse (after 20, 22, and 23 months). Four patients died (one from intracranial hemorrhage, one from post-procedural hemorrhage, one from brain aneurysm, and one following CNS relapse with intracranial edema and septic shock). One leukemia-related death occurred on study; the estimated 2-year EFS and OS rates were 77% and 89%, respectively (Figure 1). Only one patient underwent HSCT in first CR due to persistently low-level BCR:ABL1 positivity. Among the 52 patients in ongoing remission without HSCT, the median duration of response was 16 months (range, 2-61). Most adverse events were grade 1-2 and were consistent with the known toxicity profile of the two agents. Ponatinib was discontinued in two patients due to possibly related adverse events (cerebrovascular accident and coronary artery stenosis in one patient each). Conclusions The chemotherapy-free combination of blinatumomab and ponatinib is safe and effective in newly diagnosed Ph-positive ALL, with high rates of MRD negativity. Encouraging duration of remission and OS has been observed without the need for HSCT.

Leukemia Inhibitory Factor, Tissue Factor, Thrombomodulin, P-Selectine, D-Dimer, Thrombin Generation and Procoagulant Phospholipid Dependent Clotting Time Are Predictive for in Vitro Fertilization Outcome. the Prospective Roadmap-IVF Study

Background The link between blood hypercoagulability, endothelial cell activation and infertility or in vitro fertilization (IVF) failure is a puzzling issue. Activation of platelets, endothelial cells and blood coagulation, proinflammatory and angiogenetic potential play important role in implantation and early embryonic development. Biomarkers of cellular hypercoagulability are associated with high risk of IVF failure. Soluble Leukemia Inhibitory Factor (LIF), an interleukin 6 class cytokine expressed in the trophectoderm of the developing embryo is an important regulator in the establishment of pregnancy. Endoglin (Eng), a co-receptor for TGF-β1 and TGF-β3 is implicated in vascular complications of pregnancy and particularly in preeclampsia. Aim: The prospective longitudinal monocentric observational cohort study ROADMAP-IVF, evaluated the synergistic prognostic value of LIF and Eng with the biomarkers of cellular hypercoagulability in predicting the endometrial receptivity of fresh IVF cycles. Materials and Methods. The ROADMAP-IVF enrolled 40 women eligible for IVF with normal blood count, PT, aPTT, Fg, renal and liver function. The control group (CG) consisted of 30 healthy women with history of uncomplicated pregnancies. Exclusion criteria: Use of anticoagulant or antiplatelet agents during the last 30 days before inclusion. Known cardiovascular disease, active cancer. Active corticosteroid treatment. Primary end-point: Echographically documented pregnancy at 7 weeks from implantation. Blood was collected on day 2 (D2) from the natural cycle and 6 days after hormone treatment initiation corresponding to D8 of the cycle. Procoagulant phospholipid-dependent clotting time (PPL-ct), tissue factor (TF), thrombomodulin (TM), von Willebrand factor (vWF) and D-Dimers (DDi) were measured with assays from Diagnostica Stago (Asnieres, France). P- and E-Selectin, LIF and Eng were measured with ELISA. Thrombin generation (TG) with the TF 5 pM PPP-Reagent ® was assessed on Calibrated Automated Thrombogram (Stago, France). The cut-off values for studied biomarkers have been selected on the basis of ROC analysis. Univariate and multivariate logistic regression analysis examined the associations between the biomarkers and the study outcome. Results: 40 women were enrolled in the study. In 11 women pregnancy was confirmed with ultrasound and in 23 women no pregnancy was echographically documented. Age was not significantly different between the IVF (41 ys; range 22 - 48 ys) and the control group (40 ys; range 20 - 46 ys). At D2 and D8 the DDi and LIF were significantly higher in IVFG as compared to the CG. At D2 most of the patients had PPL-ct, DDi and MRI of TG higher than the upper normal limit (UNL). At D8 only TF was significantly increased as compared to the CG. Analytical data are presented in Table 1. Age did not correlate with the levels of the studied biomarkers. Significant correlations (p<0.05) were found between DDi and ETP (r=0.35); TM, TF and P-Selectin (r=0.4) at D2; TF, LIF and Eng (r=0.5) at D2 and D8; P-Selectin and PPL-ct (r=-0.4) at D2; P-Selectin and TM (r=0.4), E-Selectin (r=0.5), LIF (0.4) at D2; E-Selectin and P-Selectin (r=0.5), TF (r=0.3), and LIF (r=0.4) at D2. The ROC analysis showed that IVF failure was associate with DDi increase at D2 (AUC = 0.64); P-Selectin increase at D2(AUC = 0.57) and D8 (AUC = 0.61); TM increase at D8 (AUC = 0.61); TF increase at D8 (AUC = 0.57); LIF increase at D8 (AUC = 0.59); ETP increase at D2 (AUC = 0.67) and D8 (AUC = 0.67); Peak increase at D2 (AUC = 0.64) and D8 (AUC = 0.61). Prolongation of PPL-ct on D8 was predictive for positive pregnancy outcome(AUC 0.64). Conclusion The ROADMAP-IVF study showed that at least one out of four women eligible for IVF present biological evidence of activation of platelets, endothelial cells, blood coagulation or LIF upregulation. Hormone treatment administration does not significantly alter the proinflammatory or the hypercoagulable state. Among the studied biomarkers the levels of LIF, DDi, P-Selectine, TM and TF as well as the status of thrombin generation and PPL-ct showed a significant predictive value for the IVF outcome, particularly when measured at 6 days after hormone treatment administration. These findings will lead to the elaboration of an risk assessment model for IVF failure combining the selected biomarkers of hypercoagulability with LIF.

A Novel Model Combining Circulating Absolute Monocyte Counts and a Four-Gene Monocyte Signature in Leukapheresis Identifies Lymphoma Patients at Very High Risk of Progression after Tisagenlecleucel or Axicabtagene Ciloleucel Therapy

Introduction CD19-directed chimeric antigen receptor (CAR) T can induce durable remissions in a fraction of relapsed/refractory large B-cell lymphomas (R/R LBCL), but 60% of patients (pts) still relapse. Biological mechanisms explaining lack of responses are emerging but they are largely unsuccessful in predicting disease response at the patient level. Aim To address the potential role of lymphocyte features before CAR T manufacturing, we performed transcriptomic and functional evaluations of leukapheresis products (LK) in 95 R/R LBCL pts enrolled in a prospective observational study, to identify correlates of response and survival to tisagenlecleucel (Tisa-cel) and axicabtagene ciloleucel (Axi-cel). Methods RNA of sorted CD3+ cells from LK was digitally quantified using the nCounter CAR T Characterization Panel (NanoString). Flow cytometry (FCM) was used for CAR T enumeration and monocyte analysis. Disease response at day 90 was assessed by computed tomography (CT) and positron emission tomography-CT (PET/CT) according to Lugano criteria. Statistical analyses were performed by GraphPad Prism v.9.00 and R v.4.1.2. Results We identified a 4-gene transcriptional signature (including MS4A4A, CD86, CD163 and SIGLEC5) able to divide LBCL pts into two groups, [namely Expressors (EXP) and poor-Expressors (poor-EXP)], characterized by significantly different survival probabilities. EXP have shorter PFS (P<0.0001: median PFS for EXP was 61 days and not reached for poor-EXP) (Fig. 1) and are less likely to respond (P<0.01). As the identified genes are highly expressed in monocytes but not in T cells, we sought to define whether monocytes contained in LK have a role in determining post CAR T outcome. In line with the fact that EXP had higher frequencies of monocytes in LK by FCM, we confirmed elevated absolute monocyte counts (AMC) both in LK (P<0.01) and in peripheral blood (PB) (P<0.05) of EXP. We then checked if monocyte levels could influence response and survival. When compared to responders, non-responders (NR) had higher LK AMC (P<0.01), higher percentages of monocytes (P<0.01) but also decreased percentages of lymphocytes (P<0.001), a parameter that was also associated with reduced PFS [HR: 0.97 (CI 0.96 - 0.99) P=0.01]. Consistent with the fact that circulating monocytes significantly correlated with those in LK (r= 0.6621, P<0.0001), NR also had significantly higher AMC (P<0.001) and AMC levels in PB negatively correlated with PFS [HR: 1.8 (CI 1.2 - 2.9) P=0.01]. Additionally, pts with serum C-reactive protein (CRP) and ferritin levels higher than the upper normal limit, displayed significantly higher AMC (P<0.001 for CRP; P<0.05 for ferritin). Accordingly, univariate analysis indicated that high ferritin, CRP and LDH levels at the time of LK were associated with the lack of response, but only high serum ferritin levels correlated with shorter PFS [HR: 2.86 (CI 1.25-6.55) P=0.013]. We next investigated if the combination of the monocyte signature and high ferritin levels and/or high circulating monocytes could better identify a group of pts at high risk of progression, compared to the expression of the 4 genes alone. Remarkably, albeit high ferritin levels and monocyte counts are overall associated with significantly reduced survival, the shortest PFS was achieved in EXP with monocyte counts above the median (P=0.0234: median PFS for EXP with high monocytes was 32.5 days and for EXP with low monocytes 209 days) (Fig. 2), thus supporting the hypothesis that CAR T treatment outcome is influenced by the presence of elevated levels of monocytes expressing the 4 genes. Concatenated monocyte FCM data from 30 pts analyzed with FlowSOM, followed by a consensus clustering algorithm combined with t-SNE (t-stochastic neighbor embedding), indicated that EXP had higher frequencies of CD14hi monocytes co-expressing MS4A4A, CD86, CD163 and SIGLEC5 at the protein level than poor-EXP (P<0.05), and accordingly, the presence of this population was also associated with lack of response (P<0.05). Conclusions Our data suggest that the poor outcome of some LBCL pts receiving CAR T is due to the presence of high monocytes levels expressing a four-gene signature in an inflammatory microenvironment. Additionally, the pre-manufacturing combined analysis of the gene signature and of PB AMC, could be used to plan trials evaluating CAR T cells versus other newly approved therapies such as bispecific antibodies.

Drug Pricing of Domestic Anti-PD-L1 Antibody Adebrelimab: Cost-Effectiveness Analysis of the First-Line ES-SCLC Treatment in China.

The market price of adebrelimab, the first Chinese-developed anti-PD-L1 antibody used as a first-line treatment for extensive stage-small-cell lung cancer (ES-SCLC), has garnered significant public attention. This study sought to investigate the affordable price of adebrelimab for Chinese patients with untreated ES-SCLC through a cost-effectiveness analysis. We conducted a cost-effectiveness analysis using a Markov model, incorporating a what-if scenario of adding adebrelimab to first-line etoposide/platinum (EP) chemotherapy is cost-effective for ES-SCLC patients from the perspective of the Chinese healthcare system. The model included three mutually exclusive health states, with transition probabilities derived from the CAPSTONE-1 trial. Health state utilities and costs were acquired from a myriad of authoritative sources. We compared the incremental cost-effectiveness ratios (ICERs) for adebrelimab plus EP chemotherapy (AEP) versus EP with a willingness-to-pay threshold of $37,654 per quality-adjusted life-years (QALYs) to estimate the affordable price ceiling of the upcoming adebrelimab. For the entire ES-SCLC population, the estimated price ceiling of adebrelimab/mg was $0.542 (95% CI, $0.542-$0.552). Subgroup analyses found that the highest price ceiling of adebrelimab/mg was observed in ES-SCLC patients with lactate dehydrogenase concentration ≤ upper normal limit [$0.824 (95% CI, $0.815-$0.830)]; and the lowest was found in ES-SCLC patients with liver metastasis [$0.252 (95% CI, $0.250- $0.256)]. Sensitivity analysis revealed a heightened probability of cost-effectiveness for the first-line AEP as the price of adebrelimab decreased, encompassing both the entire ES-SCLC population and its subgroups. The affordable price range for adebrelimab/mg Chinese patients with untreated ES-SCLC was estimated to be between $0.252 and $0.824, with variations observed across different subgroups. In the context of universal healthcare coverage, our study provides valuable evidence to inform the implementation of a value-based pricing strategy for cancer treatment.

Association between matrix metalloprotease-3 levels andradiographic progression inpatients with rheumatoid arthritis: A post hoc analysis from a Japanese Phase 3 clinical trial ofpeficitinib (RAJ4).

The current study assesses the utility of matrix metalloprotease-3 (MMP-3) as a biomarker for joint damage in patients with rheumatoid arthritis receiving peficitinib. Rheumatoid arthritis patients with inadequate response to methotrexate were randomised to peficitinib 100 mg, peficitinib 150 mg, or placebo, combined with methotrexate, for 52 weeks; patients receiving placebo switched to peficitinib 100/150 mg at Week (W)12/28. This post hoc analysis investigated association between MMP-3 above/below upper limit of normal (ULN) at W12/28 and radiographic progression [modified total Sharp score (mTSS), joint space narrowing score, or erosion score >0.5] at W52 or swollen joint count 66 at W28, stratified by baseline glucocorticoid use and renal function. MMP-3 levels decreased in both peficitinib-treated groups but more slowly in patients with baseline glucocorticoids and those with radiographic progression at W52. There was no clear correlation between MMP-3 change from baseline (CFB) at W12, CFB in mTSS, joint space narrowing score, or erosion score at W52, or CFB in swollen joint count 66 at W28. More patients with MMP-3 ≤ULN versus >ULN at W12 had radiographic non-progression at W52. MMP-3 normalisation at W12 was significantly associated with mTSS non-progression at W52. Normalisation of MMP-3 at W12 may be a predictor for subsequent non-progression of joint damage at W52.

Elevated serum transaminases in patients with acute coronary syndromes: Do we need a revision of exclusion criteria for clinical trials?

Elevations of hepatic transaminase (serum alanine transaminase [ALT] and serum aspartate aminotransferase [AST]) levels in patients with acute coronary syndrome (ACS), although transient, may result in exclusions from clinical efficacy trials due to suspected liver disease. The aim of this study was to evaluate the concentrations of serum transaminases in ACS and relate these to currently accepted AST/ALT exclusion criteria from clinical trials. One hundred consecutive patients with ACS were prospectively examined. Blood samples for AST, ALT, total bilirubin and troponin I concentration were obtained at the time of admission and after 6, 12 and 24 hours. Eighty percent of patients had elevated AST, and 47% ALT; 43% of patients characterized AST concentration > 3 × upper limit of normal (ULN) in at least one measurement, while 8% of patients presented ALT concentration > 3 × ULN. AST presented higher concentrations when compared to ALT, resulting in a high De-Ritis ratio at every time point. No significant or high correlations were found between the concentrations of serum transaminases, De-Ritis ratio and troponin I. Two different cut-off values of troponin I were adopted to define the amount of infarcted myocardium that distinguished 28-31% of individuals with "large infarction". Among these patients, approximately 93% presented AST concentrations > 3 × ULN. Hepatic transaminases are often elevated in ACS, with the majority of patients with more extensive myocardial injury presenting high concentrations of AST. In the setting of ACS, current transaminase thresholds for liver dysfunction used in clinical trials may lead to excessive and inadequate exclusions of patients with larger infarcts from such trials.

Preferable effects of pemafibrate on liver function and fibrosis in subjects with type 2 diabetes complicated with liver damage

BackgroundPemafibrate has been reported to ameliorate lipid profiles and liver dysfunction. However, which patients derive benefit from the hepatoprotective effects of pemafibrate is unclear.MethodsWe conducted a sub-analysis of the PARM-T2D study where subjects with type 2 diabetes complicated by hypertriglyceridemia were prospectively treated with pemafibrate or conventional therapies for 52 weeks. From the original cohort, subjects who had metabolic-associated fatty liver disease without changing their treatment regimens for comorbidities were analyzed. Eligible subjects (n = 293) (average age 61.2 ± 11.7 years, 37.5% female) treated with pemafibrate (pemafibrate, n = 152) or controls who did not change their treatment regimens (controls, n = 141) were divided into three groups based on their alanine aminotransferase (ALT) levels: ALT ≤ upper normal limit (UNL) (pemafibrate, n = 65; controls, n = 50), UNL < ALT ≤ 2×UNL (pemafibrate, n = 58; controls, n = 54), and 2×UNL < ALT (pemafibrate, n = 29; controls, n = 27).ResultsPemafibrate treatment significantly ameliorated ALT levels (from 29 to 22 U/L, p < 0.001 by Wilcoxon’s signed-rank test) in the total cohort and subjects with high ALT levels (2×ULN < ALT), and improved liver fibrosis as assessed by the Fibrosis-4 index (mean change − 0.05 (95% confidence interval: −0.22 to − 0.02), p < 0.05 versus baseline by the Mann-Whitney U-test and p < 0.05 versus the ALT ≤ UNL group by the Kruskal–Wallis test followed by Dunn’s post-hoc analysis).ConclusionsThe hepatoprotective effects of pemafibrate were dominant in subjects with type 2 diabetes complicated with liver dysfunction.Trial registrationThis study was registered with the University Hospital Medical Information Network Center Clinical Trials Registry (UMIN000037385).

Case Report: Case report: An unusual presentation of granulomatosis with polyangiitis

Aim: We are reporting a case of an unusual presentation of granulomatosis with polyangiitis (GPA) with liver involvement. Case presentation: A 45-year-old male patient presented with erythematous plaques on the face and bilateral nasal obstruction. On physical examination, the patient had a ring-shaped squamous plaque on the face. The laboratory findings revealed an accelerated erythrocyte sedimentation rate at 100 mm/h, an elevated C-reactive protein at 66 mg/L, hyper gamma globulinemia 16 g/L and an elevated alkaline phosphatase (twice the upper normal limit). The craniofacial and thoracoabdominal computed tomography (CT) -scans showed ethmoid and maxillary sinusitis, low facial bone density, multiple mediastinal and hilar lymphadenopathy, diffuse small pulmonary nodules, and hepatomegaly. A cutaneous lesion biopsy, the nasal mucosa, and the liver showed a chronic inflammatory granulomatosis process with necrosis. Serum anti-neutrophil cytoplasmic antibody (ANCA) against PR3 was positive. The clinical, biological, radiological, and histological findings substantiated the diagnosis of GPA. The patient received systemic steroids combined with cyclophosphamide pulses on days 1, 14 and 28 and then he was lost to follow-up. Two-years later, he presented with a cardiac failure and skin ulcer in the right lower limb. A nasal endoscopic exam showed nasal septum cartilage perforation with resorption of the middle and inferior nasal concha. Two weeks later, he developed a diffuse alveolar hemorrhage and was therefore transferred to the intensive care unit but died of respiratory failure 3 days later. Conclusion: Clinicians should be aware of GPA atypical clinical manifestations.

Third-Generation Thyrotropin Receptor Antibody (TRAb) assay for predicting neonatal thyroid dysfunction in pregnant women with Graves' disease.

The aim is to validate the third generation Thyrotropin receptor antibody (TRAb) assay for predicting neonatal thyroid dysfunction and adverse pregnancy outcomes in pregnant women with Graves' disease. This prospective cohort study was conducted in TRAb positive pregnant women with Graves' disease and their off springs. The primary outcome was to assess different forms of neonatal thyroid dysfunction in relation to maternal and neonatal TRAb levels. The secondary outcome was to predict adverse pregnancy outcomes by using maternal TRAb levels. Serum T3, FT4, TSH, TRAb levels were measured using electrochemiluminescence immunoassay. 51 pregnant women were included. Five women had adverse pregnancy outcomes, TRAb levels of > 19.06 IU/L (10.9 times the upper limit of normal (ULN)) predicted adverse pregnancy outcomes with 100% sensitivity and 93.5% specificity. Among the 46 successful live births, 13 (28.3%) had neonatal thyroid dysfunction. Out of 13 neonates, 7 (32%) had neonatal thyrotoxicosis, 4 (18%) had primary hypothyroidism, and 2 (9%) had central hypothyroidism. Third trimester maternal TRAb levels of > 7.99 IU/L (4.6 times the ULN)and day three neonatal TRAb levels of > 5.03 IU/L (2.9 times the ULN), predicted the neonatal thyrotoxicosis with 100% sensitivity and 97.4% specificity. Very high maternal third generation TRAb levels strongly predicted the adverse pregnancy outcomes and neonatal thyroid dysfunction in pregnant women with Graves' disease. Neonatal thyroid function test along with the TRAb levels strongly correlated with different forms of neonatal thyroid dysfunction and is very useful in avoiding inadvertent treatment to neonates.

THU038 Osilodrostat Dosing In Cushing’s Disease: A Pooled Analysis Of The LINC Program

Abstract Disclosure: J. Newell-Price: Consulting Fee; Self; HRA Pharmaceuticals, Diurnal, Novartis Pharmaceuticals, Recordati Rare Diseases, Crinetics. Grant Recipient; Self; Crinetics, Diurnal, HRA Pharmaceuticals, Novartis Pharmaceuticals, Recordati Rare Diseases. R. Pivonello: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Pfizer, Inc., Bresmed Health Solutions, Damor farmaceutici, S&amp;R Farmaceutici SpA, Organon Italia Srl, Siunergos Pharma, Biohealth Italia Srl. Grant Recipient; Self; Novartis Pharmaceuticals, Recordati, Xeris Pharmaceuticals (Strongbridge), Corcept Therapeutics, Takeda, Neurocrine Biosciences, Camurus AB, Pfizer, Inc., Merk Serono, Ibsa. A. Lacroix: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Ipsen, Novo Nordisk. Grant Recipient; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Ipsen, Novo Nordisk. B.M. Biller: Consulting Fee; Self; HRA Pharmaceuticals, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Research Investigator; Self; served on the LINC 3 steering committee. R. Feelders: Consulting Fee; Self; HRA Pharmaceuticals, Recordati. Grant Recipient; Self; Corcept Therapeutics. M. Gadelha: Advisory Board Member; Self; Novo Nordisk, Recordati, Crinetics Pharmaceuticals. Speaker; Self; Recordati, Ipsen, Crinetics, Novo Nordisk. J. Bertherat: Consulting Fee; Self; Atterocor, Shire, HRA Pharmaceuticals, Novartis Pharmaceuticals, Corcept Therapeutics, Recordati. Grant Recipient; Self; Novartis Pharmaceuticals, Pfizer, Inc., HRA Pharmaceuticals. Z. Belaya: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. M. Fleseriu: Consulting Fee; Self; HRA Pharmaceuticals, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Research Investigator; Self; served on the LINC 3 steering committee. Introduction: Phase II (LINC 2, NCT01331239) and Phase III (LINC 3, NCT02180217; LINC 4, NCT02697734) studies showed that osilodrostat, a potent oral 11β-hydroxylase inhibitor, was an effective long-term therapy for Cushing’s disease (CD) patients (pts). Objective: This pooled analysis of the LINC program examined how dosing, including dose uptitration and adjustments during long-term maintenance, can provide rapid, sustained mUFC control, minimize AEs and improve treatment outcomes. Methods: Individual pt data from LINC 2, LINC 3 and LINC 4 were pooled and analyzed. Given differences in study designs across trials, placebo treatment periods were excluded. Pts with mUFC &amp;gt;1.5 times the upper limit of normal (ULN) (LINC 2 and LINC 3) or mUFC &amp;gt;1.3 x ULN (LINC 4) were enrolled. In LINC 2, pts started open-label osilodrostat 2 mg twice daily (bid), with dose increases every 2 weeks (W) if mUFC &amp;gt;ULN. In LINC 3, pts started open-label osilodrostat 2 mg bid, with dose increases every 2W until W12 if mUFC &amp;gt;ULN, then every 4W after W12. In LINC 4, pts were randomized to osilodrostat 2 mg bid or placebo for the first 12W. Dose was increased every 3W until W12 if mUFC &amp;gt;ULN and every 3W after W12. Maximum dose was 30 mg bid in all studies (reduced from 50 mg bid in LINC 2 core phase). Dose adjustments were permitted during the extensions based on efficacy and tolerability. Results: This analysis included 229 pts. Median (min-max) osilodrostat exposure was 100.1 weeks (1–351). Median (min–max) daily osilodrostat dose was 6.8 mg/day (1–47); dose needed to achieve mUFC control varied widely between pts. Median time to first mUFC control was 35 days (D; 95% confidence interval [CI] 34–41) in all pts; according to baseline (BL) mUFC severity: mUFC &amp;lt;2 x ULN, 28D (95% CI 17–34); mUFC 2–5 x ULN, 40D (95% CI 34–42); mUFC &amp;gt;5 x ULN, 52D (95% CI 41–56). Median time to first AE of special interest (AESI) was 12W (95% CI 10–15); AESIs occurred at different osilodrostat doses. AEs related to hypocortisolism (BL to W12, 23%; W12–48, 24%; W48–72, 8%; W72 onwards, 20%) and accumulation of adrenal hormone precursors (BL to W12, 36%; W12–48, 37%; W48–72, 14%; W72 onwards, 18%) were less frequent during long-term maintenance than dose titration. AESIs were mostly manageable with dose interruption and/or additional therapy; few patients discontinued treatment as a result (hypocortisolism-related AEs, n=8; adrenal hormone precursor accumulation-related AEs, n=3). Conclusions: Osilodrostat led to sustained mUFC control in all 3 studies; time to control was shorter in pts with lower BL mUFC values. Median daily osilodrostat dose was low but varied widely. Dose titration regimens differed for each study, but AESIs were less frequent during long-term treatment than dose uptitration and were manageable in most pts without stopping treatment. Personalized therapy during dose titration and lifelong monitoring are needed to optimize clinical outcomes in CD pts. Presentation: Thursday, June 15, 2023

OR14-03 The Thyroid Hormone Receptor Beta Genotype Of The Fetus Influences The Maternal Thyroid Function During Pregnancy

Abstract Disclosure: F. Salas Lucia: None. X. Liao: None. H. Jiang: None. A.M. Dumitrescu: None. S. Refetoff: None. J. Anselmo: None. When women with resistance to thyroid hormone beta (RTHβ) are pregnant, their high serum thyroid hormone (TH) levels are perceived as normal by affected fetuses (AfFe) carrying the same THRB mutation as their mothers. On the contrary, normal fetuses (NlFe) that do not carry the maternal THRB mutation are exposed to supraphysiologic TH levels and have unfavorable outcomes. This shows the impact maternal TH levels have on the fetus. However, whether the fetus might influence the maternal thyroid function remains unknown. To explore this possibility, we studied the maternal thyroid function tests (TFT) TSH, FT3, and FT4 throughout the pregnancies from 8 women harboring the R243Q THRB mutation (AfMo) during a total of 10 pregnancies: 6 carrying AfFe and 4 NlFe fetuses. Cord blood TFT from 3 of the NlFe and 3 AfFe at birth were also obtained. In addition, 8 pregnancies from 7 normal mothers (NlMo) carrying 4 AfFe who inherited the THRB mutation from the father and 4 NlFe were also evaluated for TFT. Cord blood from these pregnancies was not available. Results were compared to those in pregnancies of normal WT women. In all RTHβpregnancies, the maternal TSH values were within the range of pregnancies in WT women (0.35-4.94 mU/L) with an hCG-mediated nadir at the end of the first trimester. Maternal FT4 and FT3 values in RTHβpregnancies were above the upper limit of normal (ULN) of 100, peaking during weeks 5-16 (150±20% and 175±15% ULN, respectively) and progressively decreasing afterward. We found differences in maternal TFTdepending on the THRB genotype of the fetus. From weeks 25-32, the AfMo carrying an AfFe exhibited lower FT4 than when carrying a NlFe (96±2 vs. 108±5.3% ULN; p&amp;lt;0.05). Similarly, from weeks 25-40, the AfMo carrying an AfFe exhibited lower FT3 values than when carrying a NlFe ULN (110±11 vs. 134±13% ULN; p&amp;lt;0.05). While gestational age at delivery was similar in all RTHβ pregnancies, the NlFe had a lower birth body weight than the AfFe (2.3±0.1 vs. 3.1±0.2 kg; p&amp;lt;0.01). Cord blood TSH in NlFe was undetectable (&amp;lt;0.1 mU/L) but was 9.51 mU/L (2.2-10; range in normal neonates) in AfFe, which indicates that the thyroid function in NlFe could be restricted during pregnancy, but not in AfFe. Cord blood FT4 levels were similar in NlFe and AfFe (98.4±16.4 vs. 89.5±9.4% ULN). However, FT3 levels were significantly higher in NlFe than in AfFe (67.7±3.0 vs. 42.0±9.6% ULN; p&amp;lt;0.05) and represented ∼68, and ∼42% of the serum maternal FT3 level at birth, respectively. NlMo carrying either AfFe or NlFe showed similar TSH and FT3 levels during pregnancies. However, from weeks 33 to 40, FT4 levels were lower when carrying an AfFe than when carrying a NlFe (51.8±2.8 vs. 62.5±3.2% ULN; p&amp;lt;0.001). Our findings indicate that maternal thyroid function are influenced by THRB genotype of the fetus. The quantitation of placental and fetal TH transporters, deiodinases, and TH metabolites could provide insights into the mechanisms involved. Presentation: Friday, June 16, 2023

THU070 Randomized, Placebo-controlled Phase 3 Trial Protocol Assessing The Efficacy And Safety Of Octreotide Subcutaneous Depot (CAM2029) In Patients With Acromegaly

Abstract Disclosure: D. Ferone: Advisory Board Member; Self; Recordati, Novartis-AAA, Sandoz, Camurus. Grant Recipient; Self; Bristol-Myers Squibb, Novartis-AAA, Ipsen, Camurus. Research Investigator; Self; Camurus. P. Freda: Research Investigator; Self; Camurus. L. Katznelson: Advisory Board Member; Self; Recordati, Camurus, Amryt. Research Investigator; Self; Camurus. F. Gatto: Research Investigator; Self; Camurus. A. Gilis-Januszewska: Research Investigator; Self; Camurus. M.B. Gordon: Advisory Board Member; Self; Camurus, Crinetics, HRA Pharma, Novo Nordisk, Recordati. Grant Recipient; Self; Amryt, Ascendis, Camurus, Corcept, Crinetics, Ipsen, Novartis Pharmaceuticals, Novo Nordisk, Opko, Pfizer, Inc., Strongbridge. Research Investigator; Self; Camurus. P. Kadioglu: Research Investigator; Self; Camurus. P. Maffei: Research Investigator; Self; Camurus. J.R. Seufert: Research Investigator; Self; Camurus. J. Silverstein: Advisory Board Member; Self; Amryt, Recordati. Research Investigator; Self; Camurus. J.L. Spencer-Segal: Grant Recipient; Self; Camurus. Research Investigator; Self; Camurus. M. Harrie: Employee; Self; Camurus. A. Svedberg: Employee; Self; Camurus. F. Tiberg: Employee; Self; Camurus. Extended-release formulations of the somatostatin analogues (SSAs), octreotide and lanreotide, are first-line medical therapies for patients with acromegaly who have contraindications for, or are not cured by, surgical intervention and/or radiotherapy. Treatment goals, regardless of modality, include biochemical normalization of insulin-like growth factor 1 (IGF-1) and growth hormone (GH), symptom relief, tumor control, and maintenance of pituitary function. From the patient perspective, treatment satisfaction, autonomy, and quality of life may be as important as biochemical control. Constraints of current SSA formulations include incomplete biochemical and symptom control, and a lack of convenient self-administration options. Octreotide subcutaneous (SC) depot (CAM2029) is a novel FluidCrystal® formulation of octreotide designed for easy administration by patients, in a ready-to-use prefilled syringe or injection pen. In previous clinical trials, CAM2029 provided more than five-fold higher bioavailability compared to the currently marketed long-acting octreotide formulation.The efficacy and safety of CAM2029 in acromegaly is being evaluated in a 6-month, randomized, double-blind, placebo-controlled phase 3 trial (NCT04076462). 72 patients were randomized 2:1 to monthly SC doses of CAM2029 20 mg or placebo, with the option for self-administration. Key inclusion criteria included a biochemical and clinical diagnosis of acromegaly due to a pituitary adenoma with persistent or recurrent disease, treatment with a stable dose of octreotide long-acting release or lanreotide Autogel for at least 3 months as monotherapy, and controlled disease with IGF-1 ≤1 x upper limit of normal (ULN). Key exclusion criteria included GH ≥2.5 μg/L at screening, pituitary surgery within 6 months of screening, prior pituitary irradiation, and recent treatment with pasireotide, pegvisomant, or dopamine agonists. The primary endpoint is the proportion of patients with normalized IGF-1 (≤1 x ULN) after 6 months of treatment. Other endpoints include change from baseline of IGF-1, GH and patient-reported outcomes (Treatment Satisfaction Questionnaire for Medication, Self-Injection Assessment Questionnaire, Acromegaly Quality of Life Questionnaire, EQ-5D-5L), safety and tolerability, clinical signs and symptoms of acromegaly, use of rescue medication and octreotide pharmacokinetics. The estimated primary completion date for the trial is May 2023. After completing study treatment, patients may switch to open-label treatment in a phase 3 long-term safety and extension trial of CAM2029 (NCT04125836). Presentation: Thursday, June 15, 2023

THU034 Severe Obesity In Cushing´s Disease In A Tertiary Center: Current Prevalence And Diagnostic Implications

Abstract Disclosure: B.M. Mascarenhas-Nakano: None. S.R. Correa-Silva: None. P.F. Santos-Neto: None. L.C. Portari: None. J. Abucham: None. Introduction: The prevalence of obesity in the general population has increased dramatically and severe obesity (SO) has become more frequent. Weight gain and obesity are common features of endogenous hypercortisolism but prevalence of SO in that condition was reportedly low in the past. Under the current "obesity epidemics", however, the prevalence of SO in patients with hypercortisolism has not been reassessed. Coexistence of both conditions may have diagnostic and therapeutic implications. Aims: To calculate prevalence of SO (BMI≥40kg/m2) in patients recently diagnosed with Cushing’s disease (CD), the most common form of endogenous hypercortisolism, and to describe/compare their characteristics with CD patients without SO. Patients and Methods: We retrospectively evaluated 68 sequential patients (59 F) with surgically proven CD (2000-2020). Disease severity was classified by a clinical score. Urinary free cortisol (UFC) [ratio to upper limit of normality (ULN)], late-night salivary cortisol (LNSC) and 1mg dexamethasone suppression test (DST) were analyzed. Statistics: Student´s, Mann Whitney, Chi-square, Fisher´s, Spearman, and Pearson tests. Results: mean±SD. P&amp;lt;0.05: significant. 0.05&amp;lt;P&amp;lt;0.10: tendency. Results: Prevalence, Age, and BMI. Ten patients (all women) had SO. Prevalence: 15%. Age was not different (37.7±8.6y vs 32.8± 10.9y, P=0.18). BMI: 42.4±2.2 vs 28.9±4.4 (P&amp;lt;0.0001). Duration and Severity. Disease duration was longer (5.3±3.3y vs 2.5±2.5y, P=0.006) and tended to correlate with BMI (r=0.28, P=0.05). Severity tended to be milder (P=0.08). Comorbities. Prevalences of diabetes mellitus and hypertension were not different (0.50&amp;lt;P&amp;lt;0.57). Tumor. Largest tumor diameter was not different (P=0.98). Diagnostic tests. Overall, false-negative rates were higher (P=0.02) for UFC (12%) as compared to LNSC (2.3%) and DST (1.6%), and UFC correlated inversely with BMI (r=-0.30, P=0.016). UFC false-negative results tended to cluster in severe obesity (3/10 vs 5/58, P=0.09). LNSC, cortisol after dexamethasone, and ACTH showed no differences between groups (0.79&amp;lt;P&amp;lt;0.91). White blood cells. The difference between Neutrophil and Lymphocyte counts (Ne-Ly), recently described as a marker of hypercortisolism was elevated in 100% of patients in the SO group and in 85% in the other group. Conclusion: The 15% prevalence of SO found in our series of CD patients is substantial. Overall, patients with CD and SO presented with longer disease duration, clinically less severe disease, and higher false-negative rates in UFC. Conventional screening for hypercortisolism in SO is not considered cost-effective, but patients with SO and unrecognized hypercortisolism have been submitted to bariatric surgery. A simple calculation using WBC, a test usually at hand, may be a valuable and cost-effective pre-screening test. Our data and conclusions await confirmation in larger series. Presentation: Thursday, June 15, 2023

SAT310 Single Institution Retrospective Case Cohort Of Adult Cyanotic Congenital Heart Disease And Associated Pheochromocytoma And Paraganglioma

Abstract Disclosure: R.B. Jones: None. B. Bennett: None. D. Cohen: Consulting Fee; Self; Novartis Pharmaceuticals, Consultant, Medtronic, Consultant, Recor, Consultant. Grant Recipient; Self; Medtronic, Research Support, Recor, Research Support. Other; Self; Metavention, DSMB. Introduction: Improved management for patients with cyanotic congenital heart disease (CCHD) has led to prolonged lifespan and a noticeable increase in patients with CCHD presenting with pheochromocytoma and paraganglioma (PPGL). PPGL susceptibility genes including VHL, SDH(x), FH, EPAS1 have been connected to a common signaling pathway that activates hypoxia-inducible factors (HIF). 4 of 5 patients with CCHD and PPGL were reported to have a somatic gain-of-function mutation in EPAS1 encoding HIF-2α. One hypothesis is that the hypoxic environment positively selects for cells with gain-of-function mutations predisposing patients to develop PPGL even when environment is no longer hypoxic. PPGL was diagnosed 13-53 years after surgical correction of CCHD in these patients. We report a case series on 9 CCHD/PPGL patients treated at our institution. Objective: To describe a cohort of patients with CCHD who developed PPGLs. Methods: A retrospective chart review of patients with CCHD treated for PPGL at our institution was performed describing demographics, CCHD and related treatments, symptoms of PPGL and Hct/SpO2 at diagnosis, tumor size, catecholamine biochemistries, imaging and genetic analysis when available. Results: Four of 9 patients were female. Average age of diagnosis of PPGL was 30.7 years (SD 9.6 years, range 15-47 years). CCHD anomalies included Tetralogy of Fallot (2), hypoplastic right ventricle (2) and hypoplastic left ventricle (2). Most surgeries to correct CCHD were performed within days of life; the latest reported surgical procedure was at age 12, 1 patient had a subsequent heart transplant. Patients experienced hot flashes (5), arrhythmias (4), hypertension (4), abdominal pain and nausea (2), headaches (1) and asymptomatic (1). Hct and SpO2 ranged from 38%-53% and 85%-99% respectively. Three patients had multiple PPGLs; 2 had metastatic or recurrent PPGL. Metanephrines at diagnosis ranged from normal to 23x the upper limit of normal (ULN). Catecholamines ranged from normal to 16x ULN. Location of PPGL included 6 mediastinal and abdominal paraganglioma (PGLs), 5 head and neck PGLs, and 3 pheochromocytomas. Tumor size ranged from 9-65mm at maximum diameter on pathology. 7/9 patients had germline mutation testing; one SDHB mutation, one SDHA mutation of undetermined significance, and one BARD1 mutation were identified. Conclusions: The extended timeframe between onset of cyanosis and development of PPGL supports long term regular monitoring of CCHD patients to detect PPGL. We suggest screening with plasma metaneprines and catecholamines at age 15 and every 3-5 years after.

Prediction of Survival by IL-6 in a Randomized Placebo-Controlled Trial of Anakinra in COVID-19 Cytokine Storm.

(1) Background: Some severe COVID-19 patients develop hyperinflammatory cytokine storm syndrome (CSS). We assessed the efficacy of anakinra added to standard of care (SoC) in hospitalized COVID-19 CSS patients. (2) Methods: In this single-center, randomized, double-blind, placebo-controlled trial (NCT04362111), we recruited adult hospitalized patients with SARS-CoV-2 infection, evidence of pneumonia, new/increasing oxygen requirement, ferritin ≥ 700 ng/mL, and at least three of the following indicators: D-dimer ≥ 500 ng/mL, platelet count < 130,000/mm3, WBC < 3500/mm3 or lymphocyte count < 1000/mm3, AST or ALT > 2X the upper limit of normal (ULN), LDH > 2X ULN, C-reactive protein > 100 mg/L. Patients were randomized (1:1) to SoC plus anakinra (100 mg subcutaneously every 6 h for 10 days) or placebo. All received dexamethasone. The primary outcome was survival and hospital discharge without need for intubation/mechanical ventilation. The data were analyzed according to the modified intention-to-treat approach. (3) Results: Between August 2020 and January 2021, 32 patients were recruited, of which 15 were assigned to the anakinra group, and 17 to the placebo group. Two patients receiving the placebo withdrew within 48 h and were excluded. The mean age was 63 years (SD 10.3), 20 (67%) patients were men, and 20 (67%) were White. At Day 10, one (7%) patient receiving anakinra and two (13%) patients receiving the placebo had died (p = 1.0). At hospital discharge, four (27%) patients receiving anakinra and four (27%) patients receiving the placebo had died. The IL-6 level at enrollment was predictive of death (p < 0.01); anakinra use was associated with decreases in CXCL9 levels. (4) Conclusions: Anakinra added to dexamethasone did not significantly impact the survival of COVID-19 pneumonia patients with CSS. Additional studies are needed to assess patient selection and the efficacy, timing, and duration of anakinra treatment for COVID-19 CSS.