Initial Regimen Research Articles

Venous Thromboembolism Risk in Cancer Patients Receiving First-Line Immune Checkpoint Inhibitor Vs. Chemotherapy

Introduction: Whether immune checkpoint inhibitors (ICIs) are associated with an increased risk of venous thromboembolism (VTE) compared to traditional chemotherapy (chemo) is unclear (PMID: 34572833). While retrospective cohort studies reported higher than expected rate of VTE among patients receiving ICI, these patients were often sicker and having received multiple prior lines of therapy. In recent years, ICIs have been used increasingly in the front line setting for several cancers. In the current study, we assessed the incidence of VTE associated with first-line ICIs vs. chemo among comparable cancer patients. Methods: We performed a retrospective cohort study using the national Veterans Affairs (VA) healthcare system. Patients with de novo incident cancer diagnosis 2016-2020 were identified from the VA Cancer Registry and linked to the VA Corporate Data Warehouse. Patients were excluded if they had benign histology, were not primary VA user, or did not receive systemic therapy. For the primary analysis (chemo vs. ICI +/- chemo), we restricted the population to patients with stage III-IV cancers of lung, skin (melanoma), kidney, bladder, liver (hepatocellular carcinoma), and head/neck who received first-line ICI or first-line chemo within first year of diagnosis (Figure 1). For the secondary analysis (chemo vs. ICI vs. ICI/chemo), we further restricted the population to those with lung cancers as concurrent first-line ICI/chemo administration was only observed in this cohort. Incident VTE and PE/LE-DVT were defined using our computable phenotype algorithm (PMID: 35647478). When tested against the gold standard of chart abstractor review in a random sampling of 400 patients, the algorithm had a positive predictive value of 90% and weighted sensitivity of 82%. The following covariates were extracted at the time of first-line ICI or chemo (index date): age, sex, race, diagnosis year, VA frailty index (proxy for performance status), history of VTE, recent prolonged hospitalization last 3 months, cancer type, cancer stage, time delay between diagnosis and treatment, and other Khorana Score components (body mass index, hemoglobin, white blood cell count, platelet count). To address confounding, we used inverse probability weighting (IPW) with overlap weights by fitting a propensity score (PS) logit model from these baseline covariates (2 groups for primary analysis, 3 groups for secondary analysis). Average potential outcome (APO) for VTE and PE/LE-DVT were estimated at 6-months. Weighted relative risk (RR) with bootstrapped 95% confidence interval (CI) were calculated using weighted logistic regression. IPW analyses were performed using the PSweight package in R. Results: From 2016-2020, 45,253 veterans with new cancer diagnosis requiring systemic therapy met the inclusion criteria of whom 6,068 (13.4%) received ICI with a median continuous follow-up of 334 days. However, only 4,615 (10.2%) received ICI within first year of diagnosis, 2,109 (4.7%) received ICI as the initial regimen, and 1,660 (3.7%) received it for FDA-approved cancers (vs. 6,489 comparable chemo patients) (Figure 1). Despite initial cohort matching, the groups remained imbalanced with standardized mean difference (SMD) >0.1 in age, diagnosis year, cancer type, cancer stage, and time to therapy. After IPW, all covariates were balanced with SMD <0.1. In the primary analysis (Table 1), VTE occurred in 5.55% of chemo group vs. 6.10% of ICI group at 6 months. The weighted RR was 1.10 (95% CI 0.83-1.46) for ICI (+/- chemo) vs. chemo (no ICI). In the secondary analysis restricted only to lung cancers, VTE occurred in 5.83% of chemo group vs. 6.13% of ICI group (no chemo) vs. 8.13% of ICI group (+ chemo) at 6 months. The weighted RR was 1.05 (95% 0.62-1.68) for ICI (no chemo) vs. chemo (no ICI). The weighted RR was 1.39 (95% 0.93-2.07) for ICI (+ chemo) vs. chemo (no ICI). The PE/LE-DVT outcome followed a similar trend. Conclusions: In this PS-weighted analysis of 8,149 patients, we found that first-line ICI and chemo had a similar rates of VTE. Larger studies are needed for the subgroup of lung cancer patients where combination ICI/chemo regimen had a non-significant 39% increase in VTE rate compared to either chemo or ICI alone. Previous retrospective studies likely reported inflated rate of VTE in ICI due to indication bias. Nonetheless, patients receiving ICI had a similar rate of VTE and should be risk stratified as those receiving chemo. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Eptacog Beta (rFVIIa) Has a Low Incidence of Spontaneous Rebleeding through 24 and 48 Hours in Adult and Adolescent Patients with Hemophilia A or B with Inhibitors

Introduction Bypassing agents (BPAs [ie, recombinant FVIIa (rFVIIa) or activated prothrombin complex concentrate]) are the primary treatment option to control breakthrough bleeding episodes (BEs) in persons with hemophilia A or B with inhibitors (PwHABI). BPAs can have variable efficacy that may lead to rebleeding following initial successful hemostasis; this can result in additional product usage for rebleed treatment or prevention, delayed recovery, and possible re-hospitalization or prolonged hospitalization. Eptacog beta (SEVENFACT®; HEMA Biologics and LFB) is a human rFVIIa that is approved for use in the US for the treatment and control of BEs in PwHABI (aged ≥12 years). In the PERSEPT 1 trial (PwHABI aged ≥12 years), 2 dosing regimens were investigated for the treatment of mild/moderate BEs: the 225µg/kg initial dose regimen (IDR) and the 75µg/kg IDR (Fig 1). Efficacy at 12h was 91% (225µg/kg IDR) and 82% (75µg/kg IDR); efficacy at 24h was 99.5% (225µg/kg IDR) and 96.7% (75µg/kg IDR). The median number of doses to treat a mild/moderate BE were 1 (225µg/kg IDR) and 2 (75µg/kg IDR). No thrombotic events were observed. Aims The aim of this analysis is to examine the incidence of rebleeding in PwHABI ≥12 years when using eptacog beta to treat mild/moderate BEs. Methods PERSEPT 1 (NCT02020369) was a prospective, randomized, crossover trial that investigated eptacog beta (225µg/kg and 75µg/kg IDRs). Informed consent/assent was obtained. Subjects with hemophilia A or B with inhibitors (who were not using prophylaxis) received an initial dose of eptacog beta (225µg/kg or 75µg/kg) for BE treatment followed by 75µg/kg doses at predefined intervals determined by clinical response (Fig. 1). Treatment success for mild/moderate BEs was defined as a patient-reported hemostasis evaluation of excellent or good (using a predefined 4-point scale) with no use of additional eptacog beta, alternative hemostatic agents or blood products, and no increase in pain following the first excellent or good assessment. Rebleeding through the first 24h was reported by the subject and defined as a BE in the same anatomical location after an initial excellent/good assessment. Rebleeding through 48h was an exploratory analysis of all BE data on a subject-by-subject basis: if subsequent bleeds occurred in the same anatomical location, and the initial doses of eptacog beta for each BE were administered within 48h of each other, then the latter BE was considered a rebleed. Results Twenty-seven subjects (aged 12-54) enrolled in PERSEPT 1; 465 mild/moderate bleeds were reported. Subjects used the same IDR to treat both the initial BE and the rebleed. All rebleeds were reported as mild/moderate. During the first 24h of BE treatment a single rebleed was reported (1/465; 0.2% incidence; Table 1). During the first 48h following initial treatment of a BE, this intention-to-treat analysis identified 19 rebleeds at the same anatomical location (incidence of 4.1%) in 11 subjects; the incidence by IDR is shown in Table 1. The majority (91%) of rebleeds through 48h treated with the 225µg/kg IDR were controlled with a single 225µg/kg dose (1 rebleed required an additional 75 µg/kg dose); 50% (4/8) of those treated with the 75µg/kg IDR required a single 75µg/kg dose to achieve bleed control (the remainder required 2 or 3 75µg/kg doses). All rebleeds achieved hemostasis by 12h and none required a hospital/HTC visit. A second analysis that excluded 2 rebleeds in 1 subject who was removed from the trial due to lack of treatment adherence and 1 rebleed in a 2nd subject that was a result of traumatic reinjury, resulted in a 3.4% incidence of rebleeding during the first 48h (Table 1). Conclusion Eptacog beta has a low incidence of rebleeding through 24h (0.2%) and 48h (4.1%) as observed in PERSEPT 1; in the few cases where rebleeding did occur, the majority of rebleeds required a single dose of only eptacog beta to achieve hemostasis and none required a hospital/HTC visit. In hemophilia without inhibitors, it is typical to be able to administer a minimal number of FVIII/FIX doses to control a BE and have a low risk of rebleeding; the data reported in PERSEPT 1 suggest a similar outcome for the control of mild/moderate BEs in inhibitor patients with eptacog beta. These new data may permit providers to make informed treatment decisions for inhibitor patients to reduce or avoid the possibility of rebleeding without the need for additional doses and their associated cost. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Odronextamab in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): Results from a Prespecified Analysis of the Pivotal Phase II Study ELM-2

Background Odronextamab is a hinge-stabilized, human IgG4-based CD20×CD3 bispecific antibody (Ab) that binds CD20 on B cells and CD3 on T cells, triggering T-cell-mediated cytotoxicity of malignant B cells. In ELM-1 (Ph1, NCT02290951), odronextamab demonstrated encouraging activity in pts with DLBCL receiving ≥2 prior lines of therapy (LOT). DLBCL pts treated with odronextamab at doses ≥80 mg had an ORR of 53% and a CR rate of 53%. Responses were durable with 88% probability of an ongoing response at 12 mos (Bannerji R. et al. Lancet Haematol. 2022). The R2PD for R/R DLBCL was determined as 160 mg weekly. Here, we present for the first time, results from a prespecified analysis of the 160 mg DLBCL cohort from the pivotal ELM-2 study (Ph2, NCT03888105), which incorporated an optimized step-up regimen designed to maintain efficacy while minimizing acute toxicity including cytokine release syndrome (CRS). Methods ELM-2 is a global, multicenter study enrolling pts at 91 sites in 13 countries. Adult pts with DLBCL who had relapsed or were refractory to ≥2 prior LOT including an anti-CD20 Ab and an alkylator were enrolled. IV odronextamab was administered in 21-day cycles with steroid prophylaxis and weekly step-up dosing during Cycle (C) 1 to mitigate risk of acute toxicity. The initial step-up regimen was 1 mg split over C1 Day (D) 1 and C1D2, and 20 mg split over C1D8 and C1D9, followed by the 160 mg full dose on C1D15 (1/20 regimen). The 1/20 regimen was revised during the study to further mitigate CRS risk by adding an intermediary step-up dose. The modified regimen consisted of 0.7 mg split over C1D1 (0.2 mg) and C1D2 (0.5 mg), 4 mg split over C1D8 and C1D9, and 20 mg split over C1D15 and C1D16, followed by the 160 mg full dose on C2D1 (0.7/4/20 regimen). 160 mg weekly continued until the end of C4. After C4, maintenance treatment was 320 mg odronextamab every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was ORR assessed by independent central review (ICR) according to Lugano 2014 criteria. CRS was assessed using 2019 ASTCT criteria. Results As of April 20, 2022, 121 pts with DLBCL were evaluable for safety; 90 for efficacy. Median age 67 y (range 24-88), 60% male, 80% Ann Arbor stage III-IV, 58% IPI score ≥3, median prior LOT 2 (range 2-8), and 56% were primary refractory. 65% were double refractory to anti-CD20 Ab and alkylator in any LOT. Median duration of study follow-up was 17.1 mos. ORR and CR rate by ICR were 53% (48/90) and 37% (33/90), respectively, and were consistent across high-risk subgroups and in the subgroup treated with the 0.7/4/20 step-up regimen. CRs were durable; median duration of CR was not reached (95% CI: 10.2 mos-not estimable) and the probability of an ongoing CR at 9 mos was 73%. TEAEs occurred in 117 (97%) pts, considered treatment related in 102 (84%). In the overall safety-evaluable population, the most common TEAEs (>30% all grades) were CRS (53%), pyrexia (41%), and anemia (34%). Following implementation of the 0.7/4/20 step-up regimen in C1, no Grade ≥3 CRS events were observed. Only Grades 1 and 2 CRS were observed in 35% and 13% of DLBCL pts, respectively. All CRS events resolved with supportive measures; 20% of pts received tocilizumab and none required vasopressors or mechanical ventilation for CRS management. ICANS was reported in only 2 pts (4%) following revisions to step-up dosing, and both were low grade; ICANS occurred in 6% of pts with the 1/20 regimen. Treatment-related Grade 5 AEs occurred in 2 pts (2%), and treatment-related AEs led to odronextamab discontinuation in 8 pts (7%). Conclusions In the first results from a pivotal Ph 2 trial, odronextamab demonstrated clinically meaningful efficacy, durable CRs, and manageable safety with only low grade ICANS reported with the 0.7/4/20 regimen. The results of this study confirm the preliminary odronextamab activity observed in ELM-1, and collectively show odronextamab efficacy both before and after CAR T therapy in hard-to-treat, highly aggressive R/R DLBCL, while at the same time demonstrating a manageable safety profile. The 0.7/4/20 odronextamab step-up dose regimen for C1 mitigates the risk of high-grade CRS, which has been observed consistently with other bispecifics and CAR T therapies and may present an important future option for the management of pts with R/R DLBCL. Updated safety and efficacy data will be presented.

Safety, Tolerability, Pharmacokinetics (PK) and Preliminary Antitumor Activity of the Cyclin-Dependent Kinase-9 (CDK9) Inhibitor AZD4573 in Relapsed/Refractory Hematological Malignancies: A Phase 1 First-in-Human Study

Introduction: CDK9, a serine/threonine kinase, regulates transcription elongation by phosphorylating RNA polymerase II at serine 2 (pSer2). Transient inhibition of CDK9 modulates expression of genes with short-lived transcripts and labile proteins, providing a potential therapeutic opportunity in tumors dependent upon oncogenes fitting these criteria. AZD4573 is a highly potent and selective CDK9 inhibitor that rapidly and preferentially decreases BCL2 family anti-apoptotic proteins MCL-1, BFL-1 as well as the oncogene MYC, inducing apoptosis in a broad range of human hematological malignant cell lines. AZD4573 monotherapy has shown antitumor effects associated with transient CDK9 inhibition in leukemia and lymphoma preclinical models. This multicenter, nonrandomized, open-label, phase 1 study (NCT03263637) was conducted to assess safety, tolerability, PK, pharmacodynamics (PD) and preliminary antitumor activity of AZD4573 in patients (pts) with relapsed or refractory hematological malignancies. Methods: The study comprised two parallel dose-escalation arms using a 3+3 design. Arm A included pts with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, or multiple myeloma. Arm B included pts with acute myeloid/lymphocytic leukemia, chronic myelomonocytic/lymphocytic leukemia, or hairy cell leukemia. Pts must have received at least 2 prior lines of therapy for the current histology. In each arm, pts received AZD4573 IV on an 8-week cycle using an intra-patient ramp up starting at 6 mg and increasing in 3 mg increments to a target dose of 18 mg (cohort 1) or 12 mg (cohort 2). The initial dosing regimen was 2 days on/12 days off but was changed to once weekly (QW) in cohort 1. Pts in Cohort 3 received AZD4573 9 mg QW on a 4-week cycle including intra-patient ramp up (3 mg, 6 mg, 9 mg). The primary objectives were to assess safety and to determine the biologically effective dose/maximum tolerated dose (MTD). Adverse events (AE) were assessed using CTCAE v4.03. Secondary/exploratory endpoints included PK, PD, and antitumor efficacy. Results: Overall, 44 pts were treated and evaluated for safety and efficacy: 22 each in Arms A and B. Median age was 69.0 years (range, 26.0 - 84.0), 65.9% were male, and median number of prior lines of therapy was 3 (range, 1-11). At data cutoff (Sept 30, 2021), all pts had discontinued treatment, mainly due to disease progression (47.7%) or AEs (22.7%). All pts had treatment-emergent adverse events (TEAEs) which were serious in 88.6%. The most common TEAEs were diarrhea (59.1%), pyrexia (52.3%) and nausea (50.0%). The most common TEAE that led to discontinuation was pneumonia (4.5%). Treatment-related AEs (TRAEs) occurred in 93.2% of pts and were serious in 59.1%, but none led to death. The most common TRAEs were diarrhea (50%), nausea (47.7%) and tumor lysis syndrome (TLS, 40.9%: laboratory TLS, 38.6%; clinical TLS, 6.8%) (Table 1). Elevated liver enzymes were transient and resolved spontaneously. These increases were assumed to be mainly due to down-modulation of hepatic transporter proteins and reduced enzyme clearance rather than direct hepatocellular cytotoxicity (based on clinical, in-vitro and in-silico assessments). Regarding MTD, the 18 mg dose was not tolerated in either arm (clinical TLS and acute kidney injury in Arm A; hypotension and liver injury in Arm B). AZD4573 12 mg was tolerated in Arm A, but not tolerated in Arm B due to clinical TLS (n=2). The recommended Phase 2 dose (RP2D) was 12 mg QW in Arm A and 9 mg QW in Arm B. AZD4573 showed dose-proportional increases in AUC and Cmax, with moderate PK variability (~30-60% CV), and a t1/2 of ~5 hrs. Furthermore, AZD4573 led to dose-dependent reduction in pSer2 (>75%) and MCL-1 (>70%) in peripheral blood as evidence of target engagement and mechanism of action. Median duration of exposure was 10.1 wks in Arm A (range, 1.0-130.1) and 5.2 wks in Arm B (range, 1.0-35.7). In Arm A, there was 1 complete and 1 partial response in 17 DLBCL pts. Median overall survival was not reached in Arm A and was 8.8 months in Arm B, with 7 (31.8%) deaths in each. Conclusion: AZD4573 had manageable safety and a PK profile suitable for QW dosing in a broad range of hematologic malignancies including lymphoma and leukemia. The reduction in pSer2 and MCL-1 supports the RP2D of 12 mg for lymphoma and 9 mg for leukemia. A combination study of AZD4573 and acalabrutinib (NCT04630756) is ongoing to further examine the DLBCL response signal seen in this study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Eptacog Beta Efficacy in Treating Mild or Moderate Bleeds in Target Joints of Individuals with Hemophilia A or B and Inhibitors in PERSEPT 1

Introduction Recurrent bleeding in the same joint of a patient with hemophilia can lead to painful and chronic inflammation of the synovium, joint swelling, reduced range of motion, and in the long term joint arthropathy and irreversible joint damage. Early bleed resolution in the susceptible joint (known as a target joint) is thought to be crucial for preventing joint arthropathy and other incapacitating sequelae, and thus ultimately preserving joint function and health in persons with hemophilia. Eptacog beta was FDA-approved in 2020 as a recombinant activated human factor VII for the treatment and control of bleeding episodes (BEs) in persons with hemophilia A or B and inhibitors (PwHABI) ages 12 years and older using two initial dose regimens (IDRs) of 75 or 225 µg/kg eptacog beta that were shown to be safe and efficacious. The pivotal phase 3 trial (PERSEPT 1; NCT02020369) included 27 PwHABI ages 12 to 54 years who treated 465 mild or moderate BEs, with treatment success proportions at 12 hours post-initial infusion of 82% and 91% for 75 and 225 µg/kg IDRs, respectively. Objective To evaluate eptacog beta efficacy when treating target and non-target joint BEs in PwHABI from PERSEPT 1, at 12 and 24 hours post-initial dose of eptacog beta. Methods PERSEPT 1 was a global, multicenter, open-label, prospective phase 3 trial using a crossover design (Wang et al., Haemophilia 23, pp. 832-43 [2017]). PwHABI who were not using prophylaxis were randomized to either the 75 or the 225 µg/kg IDR to treat BEs, and were crossed over to the alternate IDR every 3 months. Subjects in the 75 µg/kg IDR treated BEs with initial doses of 75 µg/kg eptacog beta followed by 75 µg/kg q3h as needed. Subjects in the 225 µg/kg IDR treated BEs with an initial 225 µg/kg eptacog beta dose, followed after 9 hours by 75 µg/kg q3h as needed. Mild or moderate BE treatment success at a given timepoint was defined as obtaining a hemostasis evaluation of "excellent" or "good" on a 4-point scale ("excellent" or "good" indicating hemostatic efficacy; "moderate" or "none" indicating lack of efficacy) with no additional eptacog beta being infused, no alternative hemostatic agents or blood products being used, and no increase in pain following the first "excellent" or "good" assessment. A target joint was defined in this trial as a joint in which recurrent bleeding had occurred on 4 or more occasions during the previous 6 months, or a joint in which 20 lifetime BEs had occurred. Results Twenty-seven PwHABI treated 396 mild or moderate joint BEs in PERSEPT 1; 17 of these subjects had been previously diagnosed with target joints. Of the 396 mild or moderate joint BEs treated, 135 were target joint bleeds (in 15 subjects) and 261 were non-target joint bleeds (in 25 subjects). At 12 hours post-initial infusion, target joint treatment success proportions and 95% confidence intervals (CIs) were 82% (95% CI: [63%, 100%]) and 93% (95% CI: 82%, 100%]) in the 75 and 225 µg/kg IDRs, respectively (Figure 1). Corresponding success proportions and CIs for non-target joint bleeds were 86% (95% CI: [75%, 97%]) and 95% (95% CI: [90%, 100%]), respectively. The increase in treatment success proportion observed at 12 hours with the 225 µg/kg IDR over the 75 µg/kg IDR was statistically significant for both target joint and non-target joint groups (p < 0.05). For both IDRs, the difference in treatment success proportions between target and non-target joint BEs was not statistically significant. Nearly all target (97-100%) and non-target joint bleeds (96-100%) were successfully treated at 24 hours post-initial eptacog beta infusion in each IDR (Figure 1). Conclusions The increase in both target and non-target joint bleed treatment success seen at 12 hours for the 225 µg/kg IDR over the 75 µg/kg IDR was statistically significant, and is consistent with a dose-dependent thrombin burst driving effective clot formation at the site of injury. While the 75 µg/kg IDR may be appropriate for certain patients, the 225 µg/kg IDR shows improved treatment success at 12 hours and may be the preferred choice in most circumstances. With the high efficacy seen at 24 hours, eptacog beta offers an important treatment option for treating both target and non-target joint BEs in PwHABI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Combination Therapy with Ruxolitinib and Interferon in Newly Diagnosed Patients with Polycythemia Vera

Background: In the COMBI-I trial, we have shown that the combination treatment of Interferon-alpha-2a (IFN) and ruxolitinib is safe and efficacious in patients with polycythemia vera (PV) and myelofibrosis, who were mostly intolerant or refractory to IFN monotherapy. Interferon-alpha2 (IFN) has been used successfully for decades in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. However, 20-30% of patients are intolerant or show limited response to IFN treatment. Ruxolitinib is an anti-inflammatory agent and is used as first-line treatment in patients with myelofibrosis as well as second-line treatment in patients with PV. Combination therapy with the two agents may be more efficacious than monotherapy. Several reports suggest that after achieving a deep hematological and molecular response, treatment pause for several months to years is safe after IFN treatment. Therefore, an initial high-intensity regimen may help to control the disease allowing for treatment pause or low-dose IFN monotherapy. Herein, we report preliminary safety and efficacy data from the COMBI-II trial in patients with newly diagnosed PV. Aims: To evaluate the safety and efficacy of combination therapy with IFN and ruxolitinib in newly diagnosed patients with PV. Methods: A preplanned interim analysis after at least one year of treatment. Twenty-five patients with newly diagnosed PV were included. They were pretreated according to normal clinical standard with phlebotomies and, if high risk, hydroxyurea before inclusion and initiation of combination treatment. Hydroxyurea was withheld 1 week before initiation of treatment. Patients with severe kidney-, liver-, or heart disease were excluded. Initial therapy was IFN (Pegasys®) 45 μg sc/week and ruxolitinib (Jakavi®) 10 mg BID. The study duration was planned to be two years. Safety was assessed by registering all adverse events graded according to the CTCAE V 5.0. Efficacy was evaluated using the 2013 ELN and IWG-MRT response criteria. The JAK2V617F allele burden was measured using high-sensitivity real-time qPCR on whole blood with a lower detection limit of below 0.1%. Histological response, QoL data, and bone marrow MRI results will be presented in the final report. Results: Twenty-five patients with PV were included in 2019-2021. They had a median age of 70 years; 14 were females and 11 were males. Of the 25 patients, 19 patients were high-risk and 6 were low-risk; 5 patients had previous thrombosis. The median time from accepted referral to initiation of treatment was 67 days. The median follow-up time was 21 months. At time of data evaluation, 13 patients had completed 24 months, while 24 patients had completed 12 months of treatment. One patient was withdrawn from the study early due to the development of myelofibrosis 10 months after beginning treatment. One patient was diagnosed with follicular lymphoma 9 months after initiation of treatment. One patient had an acute myocardial infarction. No other thromboembolic events occurred. No grade 3-4 infections were observed. At follow-up, 19 patients were still receiving combination therapy. One patient was receiving concomitant hydroxyurea; 1 ruxolitinib monotherapy; 1 IFN monotherapy; 1 combination of hydroxyurea and IFN; and 1 hydroxyurea monotherapy. Grade 1-2 anemia was frequent and managed with dose reductions. The median doses of ruxolitinib and IFN at follow-up were 5 mg BID and 45 μg sc/2.week, respectively. High rates of complete hematological response were observed after 1 month of treatment (Figure 1). Three patients required phlebotomy after the first 2 weeks of treatment. The JAK2V617F allele burden was significantly reduced 3 months after the start of treatment, and continued to decline from a median of 47% (95%CI 35-59) at baseline to 6% (95%CI 3-12) after 24 months (figure 2);4 patients had a JAK2V617F allele burden < 1%, and 7 patients had a JAK2V617F allele burden below 5% at the latest measurement. No significant difference in JAK2V617F allele burden was observed between referral and initiation of the combination treatment. Conclusion: Combination therapy with IFN and ruxolitinib is relatively well tolerated and is highly efficacious in newly diagnosed PV patients with frequent normalization of cell counts and a marked reduction of the JAK2V617F allele burden. This therapy could lead to a subsequent long-term approach with low-dose interferon or treatment pauses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Odronextamab in Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) Grade 1-3a: Results from a Prespecified Analysis of the Pivotal Phase II Study ELM-2

Background Odronextamab is a hinge-stabilized, human IgG4-based CD20×CD3 bispecific antibody that binds CD20 on B cells and CD3 on T cells, triggering T-cell-mediated cytotoxicity of malignant B cells. In ELM-1 (Ph1, NCT02290951), pts with FL Grade 1-3a receiving ≥2 prior lines of therapy and treated with odronextamab doses of ≥5 mg, had an ORR of 91% and CR rate of 72%. Responses were durable with a 4-y PFS rate of 54% (Bannerji R, et al. Lancet Haematol. 2022). The RP2D dose in R/R FL pts was determined as 80 mg weekly. Here, we present for the first time, results from a prespecified analysis of the FL Grade 1-3a cohort from the pivotal ELM-2 study (Ph2, NCT03888105), which incorporated an optimized step-up regimen designed to maintain efficacy while minimizing acute toxicity including cytokine release syndrome (CRS). Methods ELM-2 is a global, multicenter study enrolling pts at 91 sites in 13 countries. Adult pts with FL Grade 1-3a who had relapsed or were refractory to ≥2 prior lines of therapy including an anti-CD20 antibody and alkylator were enrolled. IV odronextamab was administered in 21-day cycles with steroid prophylaxis and weekly step-up dosing during Cycle (C) 1 to mitigate risk of acute toxicity. The initial step-up regimen consisted of 1 mg split over C1 Day (D) 1 and C1D2, and 20 mg split over C1D8 and C1D9, followed by the 80 mg full dose on C1D15 (1/20 regimen). The 1/20 regimen was revised during the study to further mitigate CRS risk by adding an intermediary step-up dose. The modified regimen consisted of 0.7 mg split over C1D1 (0.2 mg) and C1D2 (0.5 mg), 4 mg split over C1D8 and C1D9, and 20 mg split over C1D15 and C1D16, followed by the 80 mg full dose on C2D1 (0.7/4/20 regimen). 80 mg weekly continued until the end of C4. After C4, maintenance treatment with 160 mg odronextamab occurred every 2 wks until disease progression or unacceptable toxicity. The primary endpoint was ORR assessed by independent central review (ICR) according to Lugano 2014 criteria. CRS was assessed using 2019 ASTCT criteria. Results As of April 20, 2022, 96 pts were evaluable for safety; 85 for efficacy. Median age 59 y (range 22-84), 52% male, 58% FLIPI 3-5, 15.6% had bulky disease, and median prior lines of therapy were 3 (range 2-13). 74% were refractory to their last therapy, 79% refractory to prior anti-CD20 therapy, and 48% had progression of disease within 2 y (POD24). Median duration of study follow-up was 17.3 mos. ORR and CR rate by ICR were 81% (69/85) and 75% (64/85), respectively. ORR and CR rate were consistent across high-risk subgroups, including pts aged ≥65 y, POD24, FLIPI 3-5, and pts refractory to their last line of therapy; ORR and CR rate were also consistent for the subgroup of pts treated with the 0.7/4/20 step-up regimen. Responses were durable with both a median duration of response and a median duration of CR of 18.2 mos. Median PFS was 20.2 mos (95% CI 14.8-not estimable [NE]) and median OS was not reached (95% CI 23.0 mos-NE). TEAEs occurred in 95 (99%) pts, considered treatment related in 86 (90%). In the overall safety evaluable population, the most common TEAEs (>30% all grades) were CRS (51%), pyrexia (32%), anemia (31%), and infusion-related reaction (31%). Following implementation of the 0.7/4/20 step-up regimen in C1, no Grade ≥2 CRS was observed; only Grade 1 CRS was reported in 39% of pts. All CRS events resolved and only 1 pt received tocilizumab for CRS management. No ICANS was reported in the 0.7/4/20 regimen compared with 3% in the 1/20 regimen. COVID-19 was reported (n=13,14%), including Grade ≥3 (n=5, 5%). Treatment-related Grade 5 AEs were reported for 2 pts; treatment-related AEs led to discontinuation in 6 pts. Conclusions Consistent with the ELM-1 Ph1 study, the ELM-2 pivotal Ph2 study of odronextamab demonstrated compelling efficacy in pts with FL Grade 1-3a receiving ≥2 prior lines of therapy, with 75% of pts achieving CR by ICR and an acceptable safety profile. Durability of responses and favorable survival outcomes are clinically important in the context of heavily pretreated, highly R/R FL, where prognosis is typically poor. The 0.7/4/20 step-up regimen compares favorably to other CD20×CD3 bispecifics, with no Grade 2 or higher CRS reported. Odronextamab may represent an important treatment option for R/R FL, providing a more accessible option with favorable benefit/risk compared with existing therapies including CAR T cell therapy. Updated safety and efficacy data will be presented.

Real-World Treatment Patterns and Outcomes of Daratumumab Retreatment in Multiple Myeloma in the United States

Background: Daratumumab (Dara) combination therapy is approved in transplant ineligible newly diagnosed multiple myeloma (MM), and ongoing trials evaluating Dara in transplant eligible newly diagnosed MM may result in increased first-line (1L) use. Because Dara combinations are also approved in relapsed/refractory MM, patients may receive Dara retreatment in subsequent lines of therapy (LOTs); however, data regarding optimal sequencing and benefit of Dara retreatment are lacking. Here, we present a real-world evaluation of treatment patterns and effectiveness of retreatment with Dara-based regimens. Methods: This retrospective observational study utilized deidentified electronic health records data from the Concert AI Patient360 database, representing primarily United States community-based oncology centers. The analysis included adult patients who met the following inclusion criteria: diagnosed with MM on or after January 1, 2011 through December 31, 2021, received ≥1 LOT postdiagnosis, had no prior stem cell transplantation, and had no other primary cancer diagnosis at baseline. Within this population, patients who received treatment with Dara (1L and beyond) and subsequent retreatment with Dara (second line [2L] and beyond) were identified. 1L was defined as all MM medications used within 35 days of MM-related medication initiation. Advancement of LOT was based on regimen change and documented progression events or stem cell transplant. The primary objective was to determine the proportion of MM patients initially treated and retreated with Dara-based regimens overall and by LOT. Key secondary objectives were to determine duration of treatment (DOT) and time to next treatment (TTNT) using the Kaplan-Meier method. A maximum follow-up date was determined for each patient using activity dates from multiple data files to identify the last active date of any medical encounter. Patients without subsequent LOT or death dates were censored at the maximum follow-up. Data were reported for the overall group and by the LOT in which initial Dara treatment was received. Results: Among 2367 patients with MM who met the inclusion criteria, 713 (30%) were treated with a Dara-based regimen, of which 97 (4%) were retreated with Dara and included in the analysis. Among the 97 patients analyzed, 21 (22%) started initial Dara treatment in 1L, 38 (39%) in 2L, 23 (24%) in third line (3L), and 15 (15%) in fourth or later line (4L+). Median age at diagnosis was 61-68.5 years across these groups, and 35%-50% of patients were male. Most patients had a baseline ECOG performance status of 1-2 (61%-65% for 1L, 2L, and 3L) with the exception of 4L+ (33%), and stage 2 (20%-42%) or 3 (27%-48%) disease at diagnosis. Patients were mostly treated at community (67%-81%) vs academic centers (19%-33%). Initial treatment regimens were Dara + immunomodulatory drug (IMiD) ± proteasome inhibitor (PI) (67%), Dara + PI (21%), or Dara monotherapy (12%). Dara retreatment occurred in the LOT subsequent to the initial Dara treatment episode for 90%-100% of patients; the most common retreatment regimen was Dara + IMiD (43%), followed by Dara + IMiD + PI (33%) and Dara + PI (15%). The Table shows clinical outcomes for initial Dara treatment and retreatment episodes in the same set of patients, with data by LOT indicating the line in which initial Dara treatment was received. Among 95 Dara retreated patients who had a maximum follow-up date, median DOT was 254 days and 196 days for initial Dara treatment and retreatment episodes, respectively. Median DOT by LOT for initial Dara treatment episodes ranged from 173 days (4L+ initiation) to 288 days (1L initiation). Median DOT by LOT for Dara retreatment episodes ranged from 149 days (4L+ initiation) to 304 days (1L initiation). Median TTNT was 308 days and 457 days for initial Dara treatment and retreatment episodes, respectively. Median TTNT by LOT for initial Dara treatment episodes ranged from 286 days (4L+ initiation) to 434 days (1L initiation). Median TTNT by LOT for Dara retreatment episodes ranged from 256 days (3L initiation) to not yet reached (1L initiation). Conclusion: This analysis of real-world data from adult patients diagnosed with MM showed that DOT and TTNT for Dara retreatment episodes were reasonably long and aligned with clinical expectations for subsequent therapy, suggesting that patients continue to receive meaningful clinical benefit with Dara retreatment despite prior exposure. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interim Subgroup Analysis of the Effectiveness and Safety of Damoctocog Alfa Pegol Prophylaxis in Previously Treated Patients with Hemophilia A Treated Every 5 or Every 7 Days: Results from the Real-World Observational HEM-POWR Study

Background: Extended half-life (EHL) FVIII products have been developed to reduce the burden of frequent intravenous infusions for people with hemophilia A (HA). Damoctocog alfa pegol is an EHL PEGylated B-domain-deleted recombinant FVIII concentrate approved for use in previously treated patients (PTPs) aged ≥12 years with HA. The recommended initial prophylactic dosing regimen in the USA is twice weekly, which may be adjusted to every 5 days (E5D) and can then be individually tailored to less or more frequent dosing based on bleeding episodes (FDA 2018). The safety and efficacy of extended dosing intervals were demonstrated in the pivotal PROTECT VIII studies (Reding et al, Haemophilia 2021). Real-world safety and effectiveness of damoctocog alfa pegol administered with any dosing regimen has been reported in the previously presented interim analyses of the HEM-POWR study (Reding et al., ISTH 2021, 2022). However, separate analyses of E5D or every-7-day (E7D) prophylaxis regimens in the real-world have not yet been reported. Objective: Post hoc analysis to explore the safety and effectiveness of extended dosing with damoctocog alfa pegol in PTPs receiving prophylactic treatment in the ongoing real-world HEM-POWR study. Methods: HEM-POWR (NCT03932201) is a prospective, multinational, observational open-label Phase IV cohort study of damoctocog alfa pegol in PTPs with mild, moderate, and severe HA. Patients in this subgroup analysis received prophylactic damoctocog alfa pegol E5D or E7D. The primary endpoint was annualized bleeding rate (ABR), and secondary endpoints included measures of joint health and safety. Safety analyses were primarily performed on treatment-emergent adverse events (TEAEs) in the safety analysis set population. Effectiveness analyses were primarily performed on the full analysis set (FAS). Data were captured from patient diaries and physician records, and ethical approval was obtained for all sites. Results: At data cut-off (31 August 2021), a total of 162 patients were enrolled in the study. In this subgroup analysis, 21 patients in the FAS received prophylactic treatment E5D (n=14) or E7D (n=7). The majority of patients had severe HA (n=12/14, 85.7% E5D; n=5/7, 71.4% E7D). Prior to initial visit, all patients received FVIII replacement therapy; some of these patients received prior damoctocog alfa pegol prophylactic treatment (n=7/14, 50.0% E5D; n=5/7, 71.4% E7D). The proportion of patients with no affected joints increased over time in both E5D and E7D subgroups (Figure 1). In the E5D subgroup at follow-up 1 (n=10), 40.0% of patients had no affected joints. In the E7D subgroup, all patients reported no affected joints at the first follow-up (n=5). Median (mean, SD) total ABR was 0.0 (1.0, 1.6) for the E5D subgroup and 0.0 (0.8, 1.5) for the E7D subgroup. The median (mean, SD) difference in ABR between observation period and prior to initiation of damoctocog alfa pegol in the E5D and E7D subgroups is reported in Table 1. No development of FVIII inhibitors, TEAEs, or deaths were reported. Conclusions: Damoctocog alfa pegol continues to show a favorable effectiveness and safety profile in PTPs with mild, moderate, or severe hemophilia in a real-world clinical setting with extended prophylactic dosing intervals. Improvements in joint health and ABR were demonstrated with both E5D and E7D prophylaxis regimens. The option of extended dosing intervals allows for further PK-guided treatment individualization for selected patients, based on bleeding phenotype and lifestyle, without compromising treatment efficacy. References Bayer. Damoctocog alfa pegol (Jivi®). Prescribing Information. Last updated August 2018. Available at: https://www.fda.gov. Accessed: July 2022. Reding MT, Pabinger I, Holme PA, et al. Haemophilia. 2021;27:e347-e356. Reding M, Alvarez Román M, Sanabria M, et al. [abstract presented at ISTH 2021]. Res Pract Thromb Haemost. 2021;5(Suppl 2). Reding M, Alvarez Román M, Sanabria M, et al. [abstract presented at ISTH 2022]. https://abstracts.isth.org/abstract/annualised-bleeding-rate-and-joint-health-second-interim-analysis-of-the-real-world-hem-powr-study-evaluating-the-effectiveness-of-damoctocog-alfa-pegol-in-patients-with-haemophilia-a/. Accessed July 19, 2022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 11659: Comparing Rates of Acute Myocardial Infarction Between Cancer Therapies in Patients With Non-Small Cell Lung Cancer

Introduction: The prevalence of cardiovascular disease (CVD) has increased in patients with cancer, contributing significantly to mortality among cancer survivors. Cardiotoxicity of anti-cancer drugs may play a role in the development of CVD among cancer survivors, including incidence of acute myocardial infarction (AMI). We analyzed AMI rates in patients with non-small cell lung cancer (NSCLC) treated with one of four cancer regimens. Methods: We used national data from the Veterans Affairs (VA) Corporate Data Warehouse and VA Cancer Registry. We identified 9,619 veterans diagnosed with NSCLC during 2015-2019 who initiated one of four oncological therapies: chemotherapy, immune checkpoint inhibitors (ICI) with chemotherapy, ICI monotherapy, or tyrosine kinase inhibitors monotherapy (TKI). Patients were categorized according to the first therapy received. We identified subsequent hospitalizations for AMI within two years of initiating the oncological treatment. We estimated AMI rates per 100 patient-years and risk adjusted relative hazard ratio (HR) of AMI by treatment type using Cox Regression Model to adjust for age, AMI history, comorbidities, malignancy stage, and histology. Results: Among 9,618 veterans identified, 5,510 (57.3%) initiated treatment with chemotherapy, 2,820 (29.3%) ICI with chemotherapy, 829 (8.6%) with ICI monotherapy, and 459 (4.8%) with TKI. Over a follow-up period of 2 years, 158 (1.6%) patients experienced an AMI and 5,917 (61.5%) died. The incidence of AMI per 100 patient-years (95% CI) was as follows; chemotherapy 0.86 (0.70-1.06), ICI with chemotherapy 0.77 (0.58-1.03), ICI monotherapy 0.91 (0.52-1.60), and TKI 0.43 (0.16-1.15). When compared to chemotherapy alone, adjusted HR (95% CI) for ICI with chemotherapy, ICI monotherapy, and TKI were 1.09 (0.91-1.31), 1.02 (0.75-1.38), and 1.50 (0.94-2.37), respectively. When compared to TKI or ICI with chemotherapy, the ICI monotherapy cohort did not have a statistically significant adjusted HR for AMI risk. Conclusion: Among Veterans with NSCLC, the incidence of AMI was low and there was no difference in risk between the initial oncological regimens. The high competing risk of mortality in our cohort may also have contributed to the lack of between-group differences.

Moving beyond chemotherapy in the management of follicular lymphoma

Follicular lymphoma (FL) is the most common indolent lymphoma. It is estimated that approximately 2,000 Canadians are newly diagnosed with FL each year; however, this is an underestimation of the disease burden due to the indolent nature of FL. Indeed, the life expectancy for most patients can be measured in decades, with slow but constant improvement in survival estimates having been achieved over time.&#x0D; Traditionally, FL has been considered a chemo-sensitive disease and, for the last 15 years, antibodies targeting the CD20 surface epitope on B cells have become a compelling adjunct to induce long-lasting remission in the frontline setting. Outcomes are favourable for most patients; a long-term follow-up from the seminal PRIMA trial showed that the median progression-free survival (PFS) was 10.5 years in patients treated with immunochemotherapy as part of an initial induction regimen followed by rituximab maintenance, as compared with just over 4 years in the control arm (initial induction regimen followed by observation). In terms of chemotherapy backbone, bendamustine has established itself as the preferred standard in Canada and induces durable response in the majority of patients.&#x0D; This article will focus on patients with high-tumour burden disease in need of treatment, as opposed to patients with limited-stage disease who may benefit from localized radiation or patients with advanced-stage with low-tumour burden disease who may benefit from observation or single agent rituximab.

ODP171 Choosing GLP-1RA Over Insulin for Patients with Type 2 Diabetes and Severe Hyperglycemia

Abstract Introduction Although insulin remains the recommended treatment in type 2 diabetes for hyperglycemia with catabolic symptoms, it is also the generally recommended treatment for persistent hyperglycemia or hemoglobin A1c (HbA1c) values above 10% 1 . Recent data has suggested that glucagon like peptide 1 receptor agonists (GLP-1RAs) are also powerful at glucose lowering while additionally offering extra-glycemic benefits such as weight loss with minimal risk of hypoglycemia. Unfortunately, data on initial use of GLP-1RA is limited in patients with very high hemoglobin A1cs. Our objective was to evaluate outcomes in patients with type 2 diabetes and a baseline HbA1c of 10% or greater treated with GLP-1RAs instead of insulin. Methods This study is a small retrospective case series of insulin-naïve patients with uncontrolled type 2 diabetes who were prescribed an injectable GLP-1RA. Patients included had a baseline hemoglobin A1c ≥ 10% without signs of catabolism (weight loss, ketosis, significant polyuria), a minimum of one follow-up visit after initiating GLP-1RA, and at least one HbA1c measurement within six months of initiating treatment. Patients were excluded if they had previously been on insulin or a GLP-1RA in the past 1 year. The primary endpoint was change in HbA1c after 3-6 months of GLP-1 RA use. Results Of the patients initially screened, 7 patients fulfilled criteria and were included in the final analysis. The age range was 45-73 with 4 female patients and 3 male patients. The number of years patients had been diagnosed with type 2 diabetes ranged from 0 to 13 with 1 patient having newly diagnosed diabetes not previously on medications. Of the 6 patients who were on medical treatment at baseline, 3 patients were on monotherapy with either metformin or a sulfonylurea and 3 patients were on 2-4 oral hypoglycemic agents. Patients were continued on their initial medication regimen with the exception of DPP-4 inhibitors which were stopped at the time of GLP-1RA initiation. Mean baseline HbA1c prior to initiation of GLP-1RA was 11.9%. Following 3-6 months of GLP-1RA use, mean HbA1c significantly improved to 7.5% (p value= 0. 0005). All patients showed improvement of HbA1c in response to GLP-1RA initiation (mean HbA1c reduction = 4.4, minimum = 1.9, maximum = 7.5). All patients remained on GLP-1RA without significant side effects. Conclusion In this limited case series of patients with HbA1c ≥ 10%, GLP-1RAs were well tolerated and resulted in significant improvement in HbA1c. Our results suggest that GLP-1RAs should be considered as an alternative treatment option to insulin in non-catabolic patients with very high hemoglobin A1cs.

ODP604 | LBSUN287 Ketosis-prone Type 2 Diabetes (Flatbush Diabetes) In Remission: Report Of Two Cases

Abstract Diabetic ketoacidosis (DKA) is a triad of uncontrolled hyperglycemia, metabolic acidosis, and increased total body ketone concentration1. Diabetic ketoacidosis (DKA) is a well-known manifestation of Type 1 diabetes2; however, there has been an increase in the incidence of DKA as the first presentation in Type 2 diabetes. This subtype of diabetes is typically seen in non-Caucasian middle-aged obese males due to non-autoimmune disruption of glucose metabolism, which requires an initial intensive insulin regimen. After initial insulin treatment for several weeks to several months, a significant percentage of people can become insulin independent with an oral hypoglycemic agent(OHA) and /or just lifestyle modification, and in remission for many years3. This hybrid form of diabetes sharing the characteristics of T1DM and T2DM is called "Flatbush diabetes", also known as "ketosis-prone T2DM4 5. This article aims to emphasize the importance of early recognition of this heterogeneous syndrome through the two representative case reports of Ketosis-prone T2DM. Case presentation We describe two cases of African American men (elderly and young adult) with no past medical histories, who presented to the Emergency Department with a few days history of polyphagia, polydipsia, polyuria and fatigue. New onset of Type 2 diabetes and unprovoked DKA were diagnosed. Both of them received standard treatment with intravenous fluid and insulin drip, recovered uneventfully and discharged with insulin. Both of them followed up closely in our endocrinology clinic, their GAD antibodies were 0. 00(n&amp;lt;=0. 02nmol/L), Islet cell antibody&amp;lt;1: 4(n&amp;lt;1: 4) and C-peptide were 2.6ng/mL and 6ng/mL(1.1-4.4ng/mL) respectively. Their insulin was gradually withdrawn with the addition of an oral hypoglycemic agent. Both the patients are currently insulin independent for more than 15 months. Conclusion This is an important clinical entity to recognize ketosis-prone T2DM as insulin independence positively impacts quality of life and decreases economic burden on the health care system. For patients with suspected ketosis-prone T2DM, B-cell autoantibodies and C-peptide level should be obtained 1-3 weeks at the first outpatient visit, as it can predict patients’ prognosis. These patients should also be referred to an endocrinologist and need careful follow-up. Among all ketosis-prone T2DM patients, those with preserved B-cell function are more likely to be insulin independent and go into remission phase. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Long-term efficacy of low-dose rituximab treatment in patients with primary membranous nephropathy

Objective: To explore the long-term efficacy of low-dose rituximab (RTX) treatment in patients with primary membranous nephropathy (PMN). Methods: Patients with biopsy-proven PMN who received low-dose RTX as initial or second-line regimen from August 2018 to May 2020 in the Department of Nephrology, Tianjin Medical University General Hospital were respectively enrolled. The clinical parameters of patients were urinary protein>3.5 g/24 h, serum albumin<30 g/L and estimated glomerular filtration rate (eGFR)>20 ml·min-1·(1.73 m2)-1. The treatment response of patients with PMN was observed during follow-up, and the remission rate of patients with urinary protein<8 g/24 h or ≥8 g/24 h, anti-PLA2R antibody<150 RU/ml or ≥150 RU/ml, eGFR≥ 60 ml·min-1·(1.73 m2)-1 or<60 ml·min-1·(1.73 m2)-1 were analyzed, respectively. Results: A total of 40 patients were enrolled, including 26 males and 14 females, aged (53±15) years. There were 14 patients received RTX as initial treatment and 26 patients as second-line therapy. The total median dose of RTX in the first course was 800 (425, 1 075) mg. The overall remission rate at the 1st, 3rd, 6th, 12th and 24th months were 12.5% (5/40), 17.5% (7/40), 47.5% (19/40), 57.5% (23/40), 60% (24/40), respectively. The median overall response time was 6.0 (3.0, 7.5) months. Two cases relapsed. Patients with remission (n=24) had a higher level of baseline eGFR [(93.9±28.0) vs (62.4±28.1) ml·min-1·(1.73 m2)-1, P=0.001), and a lower level of both urinary protein [5.9 (5.0, 6.5) vs 11.7 (8.6, 15.5) g/24 h, P<0.001] and anti-PLA2R antibody level [73 (29, 132) vs 453 (182, 950) RU/ml, P=0.004] than those without remission (n=16) 24 month after treatment. There was no statistically significant difference in the remission rate between initial and second-line treatment (P=0.101). Moreover, patients had a higher remission rate in urinary protein<8 g/24 h group (21/26 vs 3/14, P<0.001), anti-PLA2R antibody<150 RU/ml group (16/19 vs 5/16, P=0.002) and eGFR ≥ 60 ml·min-1·(1.73 m2)-1 group (22/29 vs 2/11, P=0.003). Conclusions: Low-dose RTX treatment in PMN is effective during long-term follow-up, and has a lower recurrence rate. The results also suggest that it is more suitable for patients with baseline urinary protein<8 g/24 h, anti-PLA2R antibody<150 RU/ml and eGFR≥ 60 ml·min-1·(1.73 m2)-1.

TO CHALLENGE OR AVOID? POSSIBLE ASPIRIN ALLERGY IN PATIENTS WITH CHRONIC IDIOPATHIC URTICARIA AND ANGIOEDEMA

<h3>Introduction</h3> Aspirin remains an important component of dual antiplatelet therapy following percutaneous coronary intervention (PCI). Despite studies showing safety in discontinuing aspirin post PCI through use of P2Y12 inhibitor therapy plus anticoagulation, no large, randomized trials evaluate an initial aspirin-free regimen post PCI without systemic anticoagulation. Aspirin intolerances occur in 20% of patients, with only 2% being true allergies. Most aspirin intolerances are linked to asthma, rhinitis, and chronic idiopathic urticaria (CIU). Differentiating this population is important for optimizing care. <h3>Case Description</h3> C.P. is a 54-year-old male with CIU referred for evaluation of aspirin allergy prior to coronary angiography with possible PCI. In 2001, C.P. developed right periorbital edema an hour after his third dose of daily aspirin therapy. Antihistamines reduced the swelling within hours, however due to reaction, his physician recommended discontinuing aspirin. He noted taking aspirin as a child and ibuprofen as an adult without incident. An in-clinic open oral drug challenge to aspirin was conducted. The patient was given 1/10^th of the full dose, followed by the remaining dose then monitored for 1 hour. The patient was diagnosed with NSAID exacerbated CIU and discharged with aspirin and antihistamines for control. <h3>Discussion</h3> Without clear guidelines for managing NSAID induced CIU, many physicians recommend avoidance, resulting in suboptimal care. 20-40% of CIU patients have flares triggered by NSAIDs, and many are misdiagnosed with an aspirin allergy. Our case demonstrates that through careful history and oral challenge, aspirin exacerbated CIU can be effectively managed without forgoing quality care.

PSAT002 Unilateral Adrenalectomy as a Treatment Option in Patient with Cyclical Cushing's Syndrome

Abstract Background Patients with Cyclical Cushing`s Syndrome (CSS) are at risk for a lengthy timeline of living with the untreated disease. Continual increased amounts of cortisol can lead to increased morbidity and mortality in these patients and finding effective treatments is of the utmost importance. Here we present a treatment course of the patient with CCS who eventually underwent unilateral adrenalectomy, resulting in marked improvements in excessive cortisol- mediated metabolic derangements. Clinical Case In 2014, a 51-yo female with hypertension (HTN), hyperlipidemia (HLD), and type 2 diabetes (T2D) presented to VA endocrinology clinic for the evaluation of incidentally found bilateral adrenal nodules. Based on the extensive biochemical evaluation, the patient was diagnosed with ACTH-dependent Cushing's disease (CD). In the setting of newly diagnosed CD and complex metabolic co-morbidities, in 09/2016 she underwent pituitary resection. However, she remained hypercortisolemic and in 12/2016 she had a second hypophysectomy. Despite surgical efforts, hypercortisolemia persisted. Neuroendocrine imaging studies and chest computed tomography excluded non-pituitary etiology of CD. She was subsequently started on ketoconazole but it was stopped due to side effects. Other CD-directed agents were not approved, so we continued routine management of T2D, HTN, and HLD. In 2018, the patient developed acute coronary syndrome and received percutaneous intervention despite therapy with statin and ezetimibe. Further, since her second hypophysectomy she required sequential addition of hypoglycemic agents and by the end of 2020, exenatide weekly, empagliflozin, and pioglitazone were added to her escalating basal-bolus insulin therapy due to persistent A1C elevation &amp;gt;10%. Continuous evaluation of her hypercortisolemia post-hypophysectomy suggested presence of CCS. To alleviate the metabolic burden of hypercortisolemia, the patient was offered unilateral adrenalectomy which she underwent in 03/2021. Within 6 months after the surgery, she has had unintentional 22-lb weight loss and we stopped both of her anti-HTN medications, discontinued weekly exenatide, and gradually de-escalated her initial daily insulin regimen of approximately 1.0 u/kg to an only basal insulin at 0.15 u/kg dose achieving A1C of 6.5%. There was no biochemical evidence of adrenal insufficiency since adrenalectomy was performed. Conclusion The patient with initial diagnosis of CD, which we later proved being CCS, underwent a unilateral adrenalectomy with the goal of reduction of cortisol burden. This decision was taken with the consideration that this would likely not be curative but intended to improve the course of her metabolic conditions. The 6-month observation following adrenalectomy has proven that we were able to in large extend achieve our goals. Therefore, this treatment approach should be considered for patients with CSS or CD. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Probability of successful inhaled corticosteroids cessation in preschool wheezers: a predictive score.

Predictors of less successful ICS cessation were the following: perinatal oxygen use, allergic rhinitis, blood eosinophil count > 500 cell/mm3, and previous ICS use > 6months. A simple predictive score developed in this study may help general practitioners to be more confident in making a decision regarding the discontinuation of ICS after initial therapeutic trials. • Early allergic sensitization is associated with reduced chances of inhaled corticosteroid cessation at school age. • Prolonged ICS is associated with the emergence of adverse effect and discontinuing too early can result in recurrence symptoms. • Requirement of oxygen support within 7 days after birth in term neonate is a postnatal factor associated with less successful ICS cessation. • We propose a simple predictive tool with easily available clinical parameters (perinatal oxygen use, allergic rhinitis, blood eosinophil count, parental asthma history, and duration of previous ICS use) to determine the timing of inhalational corticosteroid cessation in preschool wheezers.

Metagenomic next-generation sequencing for the diagnosis of fever of unknown origin in pediatric patients with hematological malignancy

Background and aimsThe aim of this study was to evaluate the performance of metagenomic next-generation sequencing (mNGS) in identifying microbiological etiologies in pediatric patients with hematological malignancies undergoing fever of unknown origin (FUO). MethodsA total of 147 children with hematological malignancy suffering febrile diseases without definite microbiological etiologies under conventional tests were enrolled. The clinical record, serum inflammatory biomarkers and mNGS results were analyzed. ResultsAt least one microorganism was identified by mNGS in 112 of 147 patients (76.2 %). Two or more types of organisms were detected simultaneously in 35.7 % (40/112) of samples. Of the 112 cases with positive mNGS results, the reported microorganisms were considered as etiologies of fever in 50 (44.6 %) cases. The initial antimicrobial regimens were adjusted according to the mNGS results in 48 cases, with 41 patients’ febrile diseases resolved. Totally, 27.9 % (41/147) of patients benefit from mNGS. High IL-6 (>390 pg/mL) level was associated with bacterial infection and could help to interpret the results of mNGS. ConclusionmNGS is a novel approach to determine the microbiological etiology of FUO in hematological malignancy patients, which benefits about a quarter of all patients tested. Integration of IL-6 can improve the diagnostic precision of bacterial infection.

Macitentan for pulmonary arterial hypertension related to repaired congenital heart disease: real-world UK experience

Abstract Introduction Patients with pulmonary arterial hypertension (PAH) following congenital heart disease (CHD) repair are an emerging population at increased risk of complications. Small numbers of such patients have been included in studies evaluating the efficacy of macitentan, but since obtaining a license for use in this population, limited real-world data have been published. Purpose To describe the safety and efficacy of macitentan therapy in a population of adults with repaired PAH-CHD. Methods We conducted a retrospective observational study of patients with repaired PAH-CHD newly started on macitentan in 2 UK specialist centres between 2014 and 2020. Clinical variables, including WHO functional class (FC), 6-minute walk (6MW) or incremental shuttle walk (ISW) distance, and EMPHASIS-10 score were recorded prior to and after initiation of macitentan therapy. Results Overall, 49 patients were included, 63.3% female, median age 40.8 [26.7–53.7] years at initiation of macitentan therapy. Macitentan was started as part of the initial PAH therapeutic regimen in 18 (36.7%) and was an add-on to existing therapy in 31 (63.3%) patients, of whom over a third (35.5%) were switched from another endothelin receptor antagonist. At the time of therapy initiation, most patients (68.4%) were in WHO functional class (FC) III, while 26.3% were in FC II and 5.3% in FC I. Baseline 6-minute walk distance (n=31, 72.1%) was 355.0 [263.5–461.2] m and incremental shuttle walk distance (n=12, 27.9%) was 220.0 [175.0–302.5] m. EMPHASIS-10 score (n=39) was 24 [10–36]. After 12.7 [9.8–16.1] months of macitentan therapy, objective exercise capacity improved by 11.8 [−4.3–36.9]% (p=0.01). Health-related quality of life improved by at least 5 points in 41.9% of patients, but there was no significant change in quality of life score in the overall group (0.0 [−20.3–18.1]% change, p=0.78). Macitentan therapy was stopped in 4 (8.2%) patients due to an adverse event or patient choice, and 5 (10.2%) due to clinical worsening or absence of clinical improvement. At 1 year following macitentan initiation, 6 (12.2%) patients had been further escalated to triple therapy and 5 (10.2%) had died. Conclusions Patients with repaired PAH-CHD treated with macitentan in the UK are a highly symptomatic group with limited exercise tolerance. Macitentan was well-tolerated overall and led to a significant improvement in objective exercise capacity. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship.

INITIAL TREATMENT STRATEGY IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION USING TWO LARGE US ADMINISTRATIVE CLAIMS DATABASES

INITIAL TREATMENT STRATEGY IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION USING TWO LARGE US ADMINISTRATIVE CLAIMS DATABASES