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Background Janus kinase inhibitors are actively investigated for treating various hematological, rheumatological, gastrointestinal and dermatological indications. Thus, we have initiated a living systematic review to define the toxicity profile of JAKi agents. Here, we report an up-to-date assessment of toxicity profile of JAKi in patients with myelofibrosis. Methods MEDLINE, EMBASE and CENTRAL were systematically searched from each database's inception through June 13, 2023, to identify phase I/II/III clinical trials assessing JAKi in myelofibrosis reporting adverse events. The main outcomes of interest included incidence rates of all-cause and treatment-related grade ≥ 3, grade 5 and all-grade AEs of interest (infections, hematological, gastrointestinal, and cardiovascular adverse events). Incidence rates (incidence per 100-person-years) for AEs of interest were calculated at the level of each trial. A random-effects meta-analysis was conducted to pool the incidence rates of AEs using an inverse-variance approach. Results The literature search identified 2044 studies from which 28 clinical trials (33 references) met the inclusion criteria - 4 (14%) trials were phase I, 4 (14%) trials were phase I/II, 13 (46%) trials were phase II, and 7 (25%) trials were phase III. A total of 4505 participants received JAKi and were eligible for analysis. All-cause and treatment-related hematological toxicities were reported in 28 (100%) and 18 (64%) trials, all-cause and treatment-related gastrointestinal toxicities were reported in 28 (100%) and 18 (64%) trials, all-cause and treatment-related cardiovascular toxicities were reported in 20 (71%) and 12 (43%) trials whereas all-cause and treatment-related infections were reported in 26 (93%) and 14 (50%) trials, respectively. The incidence rate per 100-person years for all-cause and treatment related adverse events of interest are summarized in Table 1a and 1b respectively. For treatment-related AEs, the incidence of grade ≥ 3 diarrhea with JAKi is 8.50 (95% CI: 5.34-13.53) events per 100-person years. The incidence of treatment-related grade ≥ 3 anemia and thrombocytopenia is 39.40 (95% CI: 25.57-60.71) and 29.25 (95% CI: 20.12-42.51) events per 100-person years respectively. The incidence of treatment-related grade 5 diarrhea with JAKi is 2.15 (95% CI: 1.07-4.29) events per 100-person years whereas the incidence of treatment-related grade 5 anemia and thrombocytopenia is 2.03 (95% CI: 1.04-3.97) and 2.01 (95% CI: 1.02-3.93) events per 100-person years respectively. For all-cause AEs, the incidence of grade ≥ 3 nausea, vomiting and diarrhea with JAKi is 1.72 (95% CI: 0.97-3.05), 3.56 (95% CI: 1.92-6.61) and 5.29 (95% CI: 3.48-8.04) events per 100-person years respectively. The incidence of all-cause grade ≥ 3 infections with JAKi is 4.38 (95% CI: 1.95-9.83) events per 100-person years whereas the incidence of all-cause grade ≥ 3 respiratory tract infections with JAKi is 4.21 (95% CI: 2.41-7.36) events per 100-person years. The incidence of all-cause grade ≥ 3 anemia, neutrophil decrease and thrombocytopenia is 46.83 (95% CI: 32.68-67.11), 29.11 (95% CI: 14.86-57.02) and 34.39 (95% CI: 23.82-49.64) events per 100-person years respectively. Moreover, the incidence of all-cause grade 5 nausea, vomiting and diarrhea with JAKi is 1.25 (95% CI: 0.72-2.18), 2.01 (95% CI: 1.08-3.74) and 1.60 (95% CI: 0.94-2.72) events per 100-person years respectively. In addition, the incidence of all-cause grade 5 infections and infestations is 3.71 (95% CI: 1.96-7.04) events per 100-person years with the incidence of grade 5 respiratory tract infections being 1.66 (95%CI: 0.89-3.10) events per 100-person years. Furthermore, the incidence of all-cause grade 5 anemia, neutrophil decrease and thrombocytopenia is 2.10 (95% CI: 1.26-3.52), 3.00 (95% CI: 1.25-7.21) and 1.95 (95% CI: 1.15-3.33) events per 100-person years respectively. Conclusions This report of living systematic review provides the best current evidence on toxicity profile of JAKi in patients with myelofibrosis. Current evidence suggests an overall higher incidence of all grade and grade ≥ 3 treatment related gastrointestinal adverse events in patients receiving JAKi. This living review will be updated as soon as new data becomes available.

Abstract Purpose: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3β (GSK-3β) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied. Patients and Methods: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy. Results: Patients received monotherapy (n = 67) or combination therapy (n = 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n = 62) and part 2 combination (n = 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2–2.6] and 6.9 (95% CI, 5.7–8.4) months, respectively. Conclusions: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.

Novel targeted therapies (small molecule inhibitors, antibody–drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton’s tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

AbstractBackgroundThe prevalence of acute coronary syndrome (ACS) among young adults (premature ACS) has dramatically increased in recent years, especially in developing countries. Yet, the data on these patients' attributed risk factors and outcomes are inconsistent. In this study, we aimed to investigate these data in a cohort of premature ACS cases who underwent percutaneous coronary intervention (PCI) compared to older patients.HypothesisWe hypothesize that premature ACS patients undergoing PCI will exhibit different risk factor profiles and outcomes compared to non‐premature patients. specifically, we anticipate that premature patients do not necessarily have better outcomes than non‐premature.MethodsOverall, 3142 and 10 399 patients were included in premature and non‐premature groups, respectively. Patients' pre‐operative, post‐operative, and follow‐up data were retrieved retrospectively from the Tehran Heart Center PCI databank.ResultsThe mean age of premature and non‐premature cohorts was 48.39 and 67 years, respectively. Patients were predominantly male in both groups. Family history of coronary artery disease (CAD), dyslipidemia, smoking, and opium addiction were more prevalent among the younger cohort. After adjustment, in‐hospital mortality in younger patients was considerably higher, with all‐cause mortality and major cardiovascular and cerebrovascular events (MACCE) exhibiting no noticeable difference among the two groups.ConclusionsRisk factor profile is different in young patients, and traditional cardiovascular risk factors, such as hypertension and diabetes mellitus, are more prevalent among older adults. Younger age is not equivalent to a better prognosis; hence, similar or even more caution should be taken into consideration regarding secondary prevention for these patients.

ImportanceLip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.ObjectiveTo analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence ReviewThe incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.FindingsIn 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and RelevanceIn this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

Abstract In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.

Background: Despite major scientific advances in contemporary resuscitation, survival outcome in both in-hospital and out-of-hospital cardiac arrest (CA) patients remain dismal. Objective: How do individuals’ demographic and socioeconomic status, insurance status, and hospital characteristics play a role in survival following CA in patients living with human immunodeficiency virus (PLWH)? Methods: Using the ICD10 codes B20-B24 for HIV and ICD10 code I46 for CA, we queried the national inpatient sample from 2016 to 2019 to identify admission cases of PLWH with CA. Weighted data was analyzed using logistic regression model. Results: Out of 475,910 admissions for PLWH from 2016 to 2019, 4,650 cases had CA. Of these, 3,065 patients died during the course of hospitalization (65.9%). Although mortality rate decreased for both genders over time, the decline was steeper for females (72% in 2016 to 62% in 2019) compared to the males (68% in 2016 to 64% in 2019). Female gender was however associated with an increased odds of death compared to male (OR: 1.2, 95%CI: 1-1.3, p=0.03). Asian or Pacific Islanders were associated with a lower odds ratio for mortality (OR: 0.6, 95%CI: 0.3-1, p=0.04). Additionally, beneficiaries of all the insurance types had higher odds of mortality compared to Medicare beneficiaries (OR between 1.8 and 3). The odds of death decreased with increasing household income (OR between 0.7 and 0.9). Patients admitted to the hospitals of West South Central (OR:1.6) and Pacific Regions (OR:1.7) had a higher mortality rate as had those residing in areas with less than 250,000 populaces (OR: 1.7). Conclusion: Despite declining trend in mortality from CA among hospitalized PLWH, more than 60% of the cases die during their hospital stay. Female gender, lower household income, non-Medicare beneficiaries, and being a resident of smaller size population areas were associated with higher mortality among PLWH hospitalized with CA.

Abstract Introduction We report outcomes for patients in which the IPP became unusable by the patient because of pump difficulties or inadequate fluid volume in the IPP system. Objective We sought to assess outcomes of penile implant single component exchange or fluid instillation in a cohort of patients, challenging the entire device replacement dogma. Methods 17 patients underwent single component exchange by a single surgeon. CT scan was obtained to ensure device integrity, assess for air in the system, and to delineate device details. In cases of pump difficulties, the old pump was removed and replaced with a “classic” Genesis Coloplast pump regardless of initial device brand (“Frankenstein” if brands are mixed). Patients are taught pump rocking techniques and have > 6 months of difficulty before exchange. Patients are warned of auto-inflation as there is no lock out valve in the Genesis pump. For fluid addition to the system, the two old connector collars are separated and sometimes re-used after saline is added to only the cylinders. We never add fluid to the reservoir using a piston syringe for fear of reservoir capsule rupture into adjacent structures. Revisions were copiously irrigated, as of 2022, with Irrisept. Results Pump exchange: 14 patients underwent single component pump exchange secondary to inability for the patient to be able to adequately cycle the device (11 AMS MS, 1 Coloplast Touch). Remarkable differences were noted in pump cycling between office exam (difficult), exam under anesthesia prior to incision (sometimes difficult), and once the pump is removed from its capsule (universally easy). Complications of these 14 patients include 1 fungal infection requiring replacement with a malleable device and one repeat pump exchange (AMS MS - AMS MS - Genesis). Two patients noted non-bothersome minor auto-inflation. The single Coloplast case had a remarkably thickened capsule after a likely low grade infection. All patients can successfully use their devices now. Fluid Addition: Three patients underwent fluid addition to the system. One had a significant proximal aneurysm for which we added 35 ml. A different case had both a pump exchange and 30 ml added to the system as the initial reservoir appeared to have folded cordoning off fluid. The final fluid addition occurred 18 months after initial Coloplast 22+2 cm placement in which the patient very aggressively cycled the device and could not obtain 10/10 erection. 30 ml was added to the system totaling 140 cc. All patients have done well with fluid addition with mean time since surgery of 1 year. Conclusions Pump exchange with genesis pump or simple fluid addition to the system are safe and feasible and successfully restores IPP functionality. The Frankenstein strategy is a viable alternative, although patients must be counseled that auto-inflation may occur. With modern day irrigation techniques and CT confirmation of fluid system integrity, the dogma to replace the entire device may actually carry higher morbidity in some patients. Disclosure No

Abstract Introduction Intralesional Collagenase Clostridium histolyticum (CCH) is approved for men with Peyronie’s Disease (PD). Most studies use curve improvement ≥ 20% to define treatment success. Objective Here, we sought to further characterize objective and subjective treatment outcomes with CCH. Methods We reviewed our prospectively maintained database for all patients who underwent CCH at our institution from 2013 through the present. We specifically identified those who completed four series of CCH (or elected to discontinue prior to completing four series due to satisfactory penile straightening or lack of results) and had available curvature assessment data. Treatment outcomes were broken down by level of curve improvement (0%, 10%, 20%, 30%, and > 40% improvement). Treatment success was also evaluated by improvements in the ability to engage in penetrative sexual intercourse and perceived surgery avoidance. Statistical analyses were performed using JMP Pro 14.1.0 (SAS Institute, Cary, NC). Results 127 patients had complete data available. The mean age was 57 years (SD 8.4). The mean PD duration was 27 months (SD 59). The mean baseline curvature was 66.1O, and the mean post-treatment curvature was 45.1O (p<0001). The mean curvature improvement was 32% (SD 33). 68% of patients achieved a 20% or greater improvement in penile curvature, including 38% who achieved ≥ 40% improvement. 72% (n=48/67) felt that CCH prevented the need for surgery, and 68% reported CCH restored the ability to penetrate. Stretched flaccid penile length (SPL) increased by ≥ 1 cm in 50% of patients who used concurrent penile traction (PTT) and CCH, including 28% of patients who experienced ≥ 2 cm of length gain. In contrast, only 16% of patients who did not perform concurrent PTT had a ≥ 1 cm increase in SPL (p<0.0001). Conclusions CCH may restore the ability to penetrate with intercourse, and most patients feel that CCH prevents the need for surgery. Almost 40% of patients experienced a 40% or greater curvature improvement. However, 13% of patients may go through the entire series with minimal improvement. Concurrent PTT allows for simultaneous penile length gain in some patients. These data are helpful when counseling patients on expected outcomes. Disclosure No

PURPOSE Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS This retrospective study included PWH treated with anti–PD-1- or anti–PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti–PD-1/anti–PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was –0.06 months (95% CI, –5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, –4.02 to 8.48; P = .48) for OS. CONCLUSION Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.