Local Institutional Review Board Research Articles

Design and implementation of community consultation for research conducted under exception from informed consent regulations for the PreVent and the PreVent 2 trials: Changes over time and during the COVID-19 pandemic.

Emergency clinical research has played an important role in improving outcomes for acutely ill patients. This is due in part to regulatory measures that allow Exception From Informed Consent (EFIC) trials. The Food and Drug Administration (FDA) requires sponsor-investigators to engage in community consultation and public disclosure activities prior to initiating an Exception From Informed Consent trial. Various approaches to community consultation and public disclosure have been described and adapted to local contexts and Institutional Review Board (IRB) interpretations. The COVID-19 pandemic has precluded the ability to engage local communities through direct, in-person public venues, requiring research teams to find alternative ways to inform communities about emergency research. The PreVent and PreVent 2 studies were two Exception From Informed Consent trials of emergency endotracheal intubation, conducted in one geographic location for the PreVent Study and in two geographic locations for the PreVent 2 Study. During the period of the two studies, there was a substantial shift in the methodological approach spanning across the periods before and after the pandemic from telephone, to in-person, to virtual settings. During the 10 years of implementation of Exception From Informed Consent activities for the two PreVent trials, there was overall favorable public support for the concept of Exception From Informed Consent trials and for the importance of emergency clinical research. Community concerns were few and also did not differ much by method of contact. Attendance was higher with the implementation of virtual technology to reach members of the community, and overall feedback was more positive compared with telephone contacts or in-person events. However, the proportion of survey responses received after completion of the remote, live event was substantially lower, with a greater proportion of respondents having higher education levels. This suggests less active engagement after completion of the synchronous activity and potentially higher selection bias among respondents. Importantly, we found that engagement with local community leaders was a key component to develop appropriate plans to connect with the public. The PreVent experience illustrated operational advantages and disadvantages to community consultation conducted primarily by telephone, in-person events, or online activities. Approaches to enhance community acceptance included partnering with community leaders to optimize the communication strategies and trust building with the involvement of Institutional Review Board representatives during community meetings. Researchers might need to pivot from in-person planning to virtual techniques while maintaining the ability to engage with the public with two-way communication approaches. Due to less active engagement, and potential for selection bias in the responders, further research is needed to address the costs and benefits of virtual community consultation and public disclosure activities compared to in-person events.

Robotic-assisted plate fixation of the anterior acetabulum - clinical description of a new technique

IntroductionWe present a detailed procedure for the robotic-assisted plate osteosynthesis of an anterior acetabular fracture. The purpose of this work was to describe a robotic-assisted minimally invasive technique as a possible method for reducing complications, pain, and hospitalization. Another goal was to present technical recommendations and to assess potential pitfalls and problems of the new surgical approach.MethodsSurgery was performed in an interdisciplinary setting by an experienced orthopedic surgeon and a urologist. The DaVinci System with standard instruments was used. Reduction was achieved through indirect traction of a pin that was introduced into the femoral neck and direct manipulation via the plate. The plate position and fixation were achieved through 7 additional minimally invasive incisions.ResultsThe technique has multiple advantages, such as no detachment of the rectus abdominal muscle, a small skin incision, and minimal blood loss. Furthermore, this approach might lower the incidence of hernia formation, infection, and postoperative pain.DiscussionWe see the presented technique as a demanding yet progressive and innovative surgical method for treating acetabular fractures with indications for anterior plate fixation.Trial registrationThe study was approved by the local institutional review board (Nr. 248/18).

Fetal aortic valvuloplasty for critical aortic stenosis: single‐center retrospective study focusing on postnatal outcome

ABSTRACTObjectiveWe aimed to report our experience on fetal aortic valvuloplasty (FAV) for critical aortic stenosis (AS) focusing on the postnatal evolution of the patients.MethodsThis retrospective study was approved by our local Institutional Review Board (n°2002‐0128143827). All fetuses with critical AS who underwent FAV in a single center between 01/2011 and 06/2022 were included. FAV were performed under ultrasound guidance. Technical success was based upon balloon inflation across the aortic valve and improvement of the anterograde aortic flow across the aortic valve. At birth, biventricular circulation (BVC) strategy was decided assuming the left ventricle (LV) systolic and diastolic functions would ensure the systemic circulation.ResultsSixty‐three FAV were performed on 58 fetuses at 24.6[21.4‐32.4] weeks of gestation. The procedure was successful in 52/58(89.6%) fetuses. There were 11/58(19%) in utero demises and 9/58(15.5%) terminations of pregnancy. There were no liveborn patients after the unsuccessful procedures. 38/58(65.5%) infants were delivered at a median gestational age of 38.1[29‐40.6] weeks and 21/38(55.3%) of them required prostaglandin. 28/38(73.7%) [28/58(48.3%)] children entered the BVC path at birth. Among them, 20 required an aortic valvuloplasty at birth (11 percutaneous, 9 surgical) and 8 did not require any treatment at birth but of those, 5/8 underwent a surgical valvuloplasty between day 26 and day 1200 of life. 11/28(39.3%) infants with BVC at birth required a second intervention and four of them required a third intervention. Two infants who entered the BVC at birth underwent a conversion to UVC. None of the surviving children with BVC developed pulmonary hypertension. The global survival rate in case of BVC was 22/28(78.6%) at 23.3[8‐112] months of life. 10 patients had UVC at birth. Among them, 6 received comfort care from birth and only 4 underwent surgery. 3/10 patients were still alive at the latest assessment (48[22‐102] months).ConclusionFAV for critical aortic stenosis led to anterograde aortic flow in 89.6% of the fetuses, with BVC being achieved in 48.3% (73.7% of the live born). Among patients with BVC at birth, the rate of reintervention is high but long‐term survival is satisfactory.This article is protected by copyright. All rights reserved.

510 Addressing the Regulatory Needs and Challenges of Academic Researchers by Creating a One-Stop Shop Web Portal

OBJECTIVES/GOALS: To identify challenges faced by academic researchers in accessing online regulatory information and/or tools to advance their research work to develop a free, publicly accessible, interactive web portal that provides regulatory support. METHODS/STUDY POPULATION: The Regulatory Knowledge and Support core of the Southern California Clinical and Translational Science Institute interviewed five local research professionals. These interviews guided the development of a Qualtrics survey, consisting of multiple responses and open-ended questions, submitted to our local institutional review board (IRB). After receiving IRB approval, the survey was disseminated via email, newsletters, flyers, and presentations targeting researchers at academic institutions and members of clinical and translational science hubs. Survey data will be used to identify the challenges academic researchers face in finding regulatory resources and to compile the types of regulatory information or tools they would find helpful for their research. RESULTS/ANTICIPATED RESULTS: According to the interviews, researchers with extensive involvement in clinical trials found regulatory resources easily accessible compared to those with less experience. Additionally, they all stated having a colleague or regulatory specialist whom they can consult about regulatory requirements. Insights from these initial interviews confirmed the need to obtain a comprehensive view across research professionals. Anticipated results will show the challenges in accessibility, source, and type of regulatory resources researchers typically encounter. It is also anticipated that researchers will share what kinds of resources they would find most useful for their work. Ultimately, the information and tools identified as essential by survey takers will be collected and incorporated into the web portal. DISCUSSION/SIGNIFICANCE: Academic researchers find navigating through regulatory hurdles persistently challenging when translating their work from bench to clinic, especially since academia is typically resource-constrained. Findings from this study will allow the creation of a web portal for researchers that is broadly accessible and meets their regulatory needs.

220 The Unheard Voices of Clinical Trials: Fostering Inclusivity for People Experiencing Homelessness in Clinical Trials

OBJECTIVES/GOALS: Investigate the perspectives of people experiencing homelessness (PEH) on clinical trials to uncover knowledge gaps and attitudes. This study aims to offer insights for clinical researchers to enhance engagement with this marginalized group, ushering in a more inclusive clinical trial process. METHODS/STUDY POPULATION: A 14-question survey was developed in collaboration with the Street Medicine Team at the University of Southern California and other stakeholders of PEH research. Initial questions assess knowledge of clinical trials, followed by questions gauging sentiments on clinical trial participation, and final questions on the significance, benefits, and risks of clinical trials. Upon approval by the local Institutional Review Board, the survey will be administered in an interview format. Study participants will be from locations within the area of operations of the USC Street Medicine team–in and around Hollywood, South Los Angeles, and/or the Los Angeles Council District 1. RESULTS/ANTICIPATED RESULTS: We anticipate that the results of this study will offer valuable insights into the perspectives of PEH regarding clinical trials. Results will also provide varying levels of knowledge and understanding among PEH about clinical trials, along with their past experiences in clinical trial participation, and willingness for future involvement in such trials. Further, the results will reveal whether respondents feel they are being properly represented in clinical research projects that could impact themselves and their community. This project can also enhance our understanding of the expectations and concerns of PEH regarding their potential participation in clinical trials. DISCUSSION/SIGNIFICANCE: The outcomes of this research project have the potential to lay the groundwork for enhancing the involvement of PEH in translational science research, encompassing aspects from study design to participation. This improvement could benefit not only participants but also various stakeholders involved.

Rapid Review of Therapy Protocols for Public Health Emergencies.

How research during a public health emergency is conducted is recognized as essential to the public health response to that emergency. Such research needs to undergo substantive and meaningful ethical review in a timely manner. Rapid ethical review may be accomplished through a number of mechanisms, including use of local rapid-response institutional review boards (IRBs). We describe use of such a model in the setting of the 2014 Ebola virus disease epidemic and the Rapid-Response IRB's subsequent transition to a multisite single IRB model during the current Covid-19 pandemic. The rapid-response review model is characterized by a small IRB with extensive use of alternate members with specific expertise and by close collaboration with the investigator in an iterative process.

Laparoscopic Multibipolar Radiofrequency Myolysis for Symptomatic Myomas in 10 Steps

ObjectiveTo describe a minimal invasive 10-step technique of laparoscopic multibipolar radiofrequency myolysis for symptomatic myomas. DesignA step-by-step video demonstration of the technique SettingA woman with symptomatic FIGO 5 myoma of 60 mm of diameter, confirmed by magnetic resonance imaging. The patient included in this video gave consent for publication of the video and posting of the video online including social media, the journal website, scientific literature websites (such as PubMed, ScienceDirect, Scopus, etc.) and other applicable sites. InterventionsApproximately 30% of women of child-bearing age with myomas will present with symptoms (1) that include chronic pelvic pain, abnormal uterine bleeding or infertility (2-3). Data regarding fertility preservation and obstetrical outcomes suggest that radiofrequency myoma ablation may offer an alternative to existing treatments for women who desire future fertility (4). The local institutional review board stated that approval was not required because the video describes a technique and not a clinical case. In our center, all radiofrequency indications are discussed during a monthly multidisciplinary myomas meeting.This video presents the procedure divided into the following 10 steps: planning of the surgery; materials; installation; laparoscopic exploration; transvaginal ultrasound examination; visual and transvaginal ultrasound guided transparietal puncture of the myoma; control of the applicators’ position; radiofrequency myolysis; end of myolysis, applicators removal; final check and additional procedures. ConclusionRadiofrequency myolysis is a simple and reproductible procedure that can be offered as an alternative to myomectomy (5). This video presents 10 steps to make the procedure easier to adopt and to reduce its learning curve.

Effectiveness and safety of edaravone dexborneol in acute ischemic stroke (EXPAND): Study protocol for a prospective, multicenter, real-world cohort study

Background: Edaravone dexborneol has been confirmed as a novel neuroprotective agent by acting on multiple active targets of antioxidation and anti-inflammation. Objectives: This study aims to evaluate the effectiveness and safety of edaravone dexborneol in patients with acute ischemic stroke (AIS) within 14 days of symptom onset in real-world clinical practice. Methods: This prospective, multicenter, 2-arm, parallel, real-world cohort study will involve 72 stroke centers in China and plans to recruit 4750 exposed/unexposed patients with a 2:1 ratio to gather additional safety information on edaravone dexborneol. Patients eligible of the Effectiveness and Safety of Edaravone Dexborneol in Acute Ischemic Stroke (EXPAND) are diagnosed with AIS within 14 days of symptom onset. The eligible patients who receive edaravone dexborneol will be assigned to the exposed group, while those without using edaravone dexborneol will be assigned to the unexposed group. All participants will be followed up for 90 days. The primary outcome is a favorable functional outcome as defined by a modified Rankin Scale (mRS) score 0–1 at 90 days. Primary efficacy in the 2 groups will be compared using multivariable logistic regression. Results: EXPAND is the first real-world study to elucidate the efficacy and safety of edaravone dexbornel in AIS, which has the potential to extend the therapeutic time window of neuroprotective treatment and propose a multiple-target approach for AIS. Conclusions: The protocol was approved by the Ethics Committee at all participating sites [the reference number of central ethic committee: (2022)090] and by the local Institutional Review Board of each participating center. The findings of the study will be published in peer-reviewed scientific journals and presented at national and international conferences. This cohort study only collects real-world patient data during the diagnosis and treatment process. The refusal of a patient to participate or the decision to withdraw from the study will not interfere with the clinical decision-making. Thus, no additional risk will be imposed. Trial registration number: NCT05644223.

Association of Functional Status and Symptom Severity Among Patients Who Received Palliative Care Consultations.

Background: The relationship between functional status and the severity of different symptoms in patients with serious illnesses has not been explored in detail. Methods: We retrospectively evaluated registry data of hospitalized patients who received inpatient palliative care consults at the Mount Sinai Health System between January 01, 2020, and December 31, 2022. The registry was approved by the local institutional review board. During the initial consult, palliative care clinicians administered the Australia-modified Karnofsky Performance Status (KPS) and the Edmonton Symptom Assessment System (ESAS). We extracted these measures and other variables of interest from electronic health records and billing data, and assessed the association of functional status and symptom severity for different symptoms using ordinal logistic regression models. Results: The study included 9800 patients who received a palliative care consult. When modeling the association of functional status and the severity of different symptoms, two distinct groups of symptoms emerged: Nausea, physical discomfort, anxiety, depression, and constipation were more prevalent and severe among patients with higher functional status. Conversely, drowsiness, inactivity, dyspnea, anorexia, and agitation were more prevalent and severe among patients with lower functional status. These findings remained statistically significant after adjusting for possible confounders. Conclusion: Among patients who received inpatient palliative care consults, lower functional status was associated with a higher symptom burden. Furthermore, symptom profiles differed between patients with reduced functional status and those with preserved functional status.

Disparities in Demographics in Hip Arthroplasty Between U.S. Active Duty Military and the ACS-NSQIP Clinical Registry.

Patient demographics, such as sex and age, are known risk factors for undergoing revision following primary total hip arthroplasty (THA). The military population is unique because of the increased rates of primary and secondary osteoarthritis of the hip. Treatment options are limited for returning patients to their line of duty; however, THA has been shown to be an effective option. The primary purpose of this study was to evaluate and contrast the demographic differences of patients undergoing primary THA between the U.S. active duty military population and the general population. The secondary goal was to identify the proportion of primary THA performed at the MTF within the military health system (MHS). This was an exempt study determined by the local institutional review board. A retrospective analysis of the MHS Data Repository (MDR) and the National Surgical Quality Improvement Program (NSQIP) was performed. The databases were used to identify the patients who underwent THA from January 1, 2015 to December 31, 2020. The MDR was used to identify demographics such as sex, age, setting of surgery, geographic location, previous military deployments, history of deployment-related injuries, branch of service, and rank. The NSQIP database was queried for sex and age. The median age of the population was compared using the Mann-Whitney U test and gender was compared using the Chi-square test. The MDR was used to evaluate 2,734 patients, whereas the NSQIP database was used to evaluate 223,832 patients. In the military population, patients who underwent THA were 87.7% male with an average age of 45 years, whereas in the general population as measured via the NSQIP database, 45.2% patients were male with an average age of 66.0 years. Comparing the two groups, we demonstrated that the military patients were significantly more likely to be younger (P < .001) and males (P < .001). Only 29.6% of primary THAs were performed within the MTF. Patients in the MHS are undergoing THA at a younger age and are more likely to be male compared to the general population. A significant portion of primary THAs in the MHS are also being performed at civilian institutions. These demographics may result in increased risk of revision; however, long-term studies are warranted to evaluate survivorship in this unique population.

IRB challenges in multisite studies: A case report and commentary from the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA)

A shift from single to multi-site health studies enabled a range of research benefits including faster recruitment of larger and more diverse samples; increased statistical power, greater rigour, generalisability, and external reliability; and increased likelihood of impacting policy and clinical practice. However, ethical review of multi-site studies by Institutional Review Boards (IRBs) raises specific challenges compared with single site studies, with requirements to apply to multiple local IRBs increasing the burden on research, possibly endangering the integrity of the research process or inhibiting development of multi-site studies. The option of a single centralised IRB may offer a clearer, more consistent and efficient review process. This study presents a case report and commentary from 15 years engaging with IRBs in multiple sites in Ireland by the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA). It examines the ethics review process for IDS-TILDA through its first four waves. While the majority of 48 IRBs granted ethical approval within 13 weeks, six IRBs took 21–47 weeks to approve, leading to delays in data collection of up to 11 months. Despite additional review time, no changes were required to the study protocol. Therefore, a critical impact of the process was the delay in starting data collection within a small number of organisations, and reduced involvement in the study for one organisation. The ethical review process with multiple IRBs increased the degree of complexity of the process, with added bureaucracy and far greater communication required across 48 IRBs, substantially adding to the resource commitment for the review process. The relatively quick approval from the majority of IRBs was partially a result of the longitudinal study building relationships with organisations throughout multiple waves. That other health studies may not accrue this benefit supports calls for a single IRB system for multi-site health studies.

Protocol for an evaluation of the initiation of an integrated longitudinal outpatient care model for severe chronic non-communicable diseases (PEN-Plus) at secondary care facilities (district hospitals) in 10 lower-income countries

IntroductionThe Package of Essential Noncommunicable Disease Interventions—Plus (PEN-Plus) is a strategy decentralising care for severe non-communicable diseases (NCDs) including type 1 diabetes, rheumatic heart disease and sickle cell disease, to...

Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) – protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids

IntroductionUterine fibroids affect 30%–77% of reproductive-age women and are a significant cause of infertility. Surgical myomectomies can restore fertility, but they often have limited and temporary benefits, with postoperative complications...

Understanding evidence ecosystems: What influences the production, translation, and use of modeled evidence in Burkina Faso, Nigeria, India, and Kenya?

Background This study sought to document and understand facilitators and barriers to producing, translating, and using modeled evidence in decision-making in Burkina Faso, Nigeria, India, and Kenya. We explored researcher-decision-maker engagement mechanisms as key facilitators of evidence use, with a focus on knowledge brokers and boundary organizations. Methods The study used mixed methods drawing on analysis from key informant interviews and surveys, complemented by a rapid desk review to map modeling activities and actors. The survey was conducted online while the qualitative research entailed in-depth interviews with modelers, knowledge brokers, and decision-makers working in a representative variety of health fields, organizations, and levels of government. This study was approved by Health Media Lab IRB (Institutional Review Board) in the United States and a local IRB in each study country and conducted between September 2021 and June 2022. Results Informants interviewed for this study described a range of factors that facilitate and inhibit the use of modeled evidence in public health decision-making at the individual, organizational, and environmental levels. Key themes included the capacity to produce, translate, and use modeled evidence; the timing and relevance of modeling outputs; the existence of communications channels between modelers and decision-makers; the strength of underlying data systems; the role of sustained funding; and the impact of global crises. Conclusion This study highlights the importance of taking an ecosystem approach to supporting modeling activities, considering individual, organizational, and environmental factors and how different actors and interact to inform the production, translation, and use of modeled evidence. Structured interaction that promotes dialogue, debate, and joint sense making between the producers and users of evidence is critical to informing and influencing the use of evidence in decision-making.

Effectiveness of transcranial direct current stimulation (tDCS) as adjunctive treatment for chronic headache in adults with clinically stable systemic lupus erythematosus (SHADE): a randomised double-blind multiarm sham controlled clinical trial

BackgroundChronic headache is a ‘silent’ neuropsychiatric systemic lupus erythematosus symptom with heterogeneous prevalence, potentially reaching 54.4%. It may reduce quality of life by increasing the likelihood of depression and sleep...

Real-World Multicenter Study of PD-1 Blockade in HIV-Associated Hodgkin Lymphoma across the United States

Background: Despite a 5 to 20-fold higher risk of Hodgkin lymphoma (HL) in people with HIV (PWH) than the general population, PWH were excluded from clinical trials that led to the approval of anti-PD-1 agents (PD-1) in HL. PD-1 have overall response rates (ORR) of 65-70% in the general population and are used in all lines of HL therapy. Several prospective and retrospective studies have shown PD-1 are safe in PWH, but they remain underutilized in HIV-associated HL (HIV-HL) where data are limited. Methods: Patients (pts) with HIV-HL were identified from the retrospective, international database, “Cancer Therapy using Checkpoint inhibitors in PWH-International (CATCH-IT)” consortium, that is maintained at the Dana-Farber Cancer Institute (DFCI) and approved by DFCI and local institutional review boards. Pts who received either nivolumab or pembrolizumab, alone or in combination with other agents were included. Records were reviewed for demographics, HL and HIV characteristics, and treatment data. Safety was evaluated by the occurrence of immune-related adverse events (irAEs) per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response to treatment was evaluated using descriptive statistics, and immune reconstitution was measured by changes in CD4 + T cell counts (CD4) from prior to end of PD-1 therapy via paired t-tests. ORR was defined as the proportion of pts with partial or complete response (PR/CR) per the 2014 Lugano classification for HL. Duration of response (DOR) was defined as the time from the date of the first CR or PR to the date of progressive disease (PD) or death. Progression-free survival (PFS) was defined as the time from PD-1 initiation to disease progression, death, or censored on the date of the last follow-up. Overall survival (OS) was defined as the time from PD-1 initiation to death or censored at the last follow-up. DOR, PFS, and OS were evaluated by Kaplan-Meier methodology. Results: We identified 23 pts with HIV-HL from 12 institutions in the United States: 20 cisgender men, 3 cisgender women; 10 Black,10 White, and 10 Hispanic; median age 48 years [interquartile range (IQR): 36-58]. At HL diagnosis, 19 (83%) pts had advanced stage disease, and in 20 pts where EBV status of the tumor was known, all were positive. Nine (39%) pts had primary refractory disease. The median number of prior systemic therapies was 2 (IQR: 1-3). One pt had PD-1 as 1 st-line therapy, 6 had PD-1 as 2 nd-line therapy, and 16 had PD-1 as ≥3 rd-line therapy. Fourteen (61%) pts received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as 1 st-line therapy. Two pts had prior autologous stem cell transplant (ASCT). At the time of PD-1 initiation, 22 pts (96%) had advanced stage disease, 17 (46%) had extranodal disease, and the median ECOG performance status was 1 (IQR: 0-2). Seventeen (74%) pts received PD-1 monotherapy, 5 (22%) received nivolumab + brentuximab vedotin, and 1 received nivolumab + ifosfamide, carboplatin, and etoposide. Four pts had uncontrolled HIV at the time of PD-1 initiation (HIV viral load range=10,000-2,000,000 copies/mL). All pts received antiretroviral therapy during treatment. Median baseline CD4 was 155 cells/µL (IQR: 66-297) and CD8 was 429 cells/µL (IQR: 158-716). Median CD4 and CD8 increased to 310 and 653 cells/µL at the end of PD-1 treatment (P=0.0084, P=0.32). The median number of PD-1 cycles was 6 (IQR: 4-21). Three (13%) pts had irAEs (all grade 3): hypothyroidism, autoimmune pancreatitis, and pneumonitis. None required PD-1 discontinuation. The ORR was 83% in the overall cohort. Sixteen pts (70%) had CR, 3 (13%) PR, and 4 (17%) PD as best response. Among the 19 pts with CR or PR, the median DOR was 19.7 months; 8 had PD after initial response and 11 had ongoing CR at data cut-off. Ten pts received consolidation with ASCT after PD-1, 6 of whom had received PD-1 at ≥3 rd line treatment. All pts who received ASCT had ongoing CR at data cut-off. Median PFS was 21.2 months in the overall cohort. Among pts with CD4 &amp;lt;200 and &amp;gt;200 cells/µL, PFS was not statistically different (17.3 vs 29 months; P=0.95). At data cut-off, 17 pts (74%) were alive and 6 (26%) had died due to HIV-HL. Median OS was 23.6 months in the overall cohort. Conclusion: In HIV-HL, PD-1 blockade was safe, had a high ORR and CR rate, and allowed for immune reconstitution in pts across a wide range of CD4 counts and HIV viral loads. These data add to the evidence that anti-PD-1 agents are effective in PWH and should be used in HIV-HL.

Multicenter Retrospective Analysis of Eosinophilic Myeloid Neoplasms

Background. Some patients who present with clinical features consistent with idiopathic hypereosinophilic syndrome (HES; absolute eosinophil count (AEC) ≥1.5 x 10 9/L with related end organ damage) are ultimately diagnosed with a myeloid neoplasm. Although FIP1L1::PDGFRA is the most common molecular abnormality in this setting, many other fusion genes, point mutations and cytogenetic abnormalities have been implicated in driving primary (neoplastic) eosinophilia. Given the poor prognosis of these disorders in the absence of treatment and the availability of targeted therapies for many of the driver mutations, it is becoming increasingly important to rapidly identify the underlying genetic alteration. In this regard, the expense and variable sensitivity of molecular diagnostic tests remains problematic. Although clinical features have been reported to distinguish between PDGFRA-associated myeloid neoplasms and D816V KIT-positive systemic mastocytosis with hypereosinophilia, little is known about the clinical phenotypes of other subsets of patients. This multicenter retrospective study aimed to assemble a large cohort of patients with HES secondary to a myeloid neoplasm to explore the utility of clinical and laboratory features in predicting the underlying molecular abnormality. Methods. Retrospective, de-identified data from 16 centers were collected via an online Research Electronic Data Capture repository. Patients and associated data were obtained from in-house research databases and/or electronic medical record searches at each site. Clinical and laboratory data were entered in accordance with local Institutional Review Boards. Inclusion criteria were peripheral blood hypereosinophilia (AEC &amp;gt;1.5 x 10 9/L) on at least two occasions and one of the following: ≥1 confirmed genetic abnormality recurrently associated with primary myeloid neoplasms, other evidence of clonal eosinophilia, or increased blasts (≥2% in the blood or &amp;gt;5% but &amp;lt;20% in the marrow). Patients with acute myeloid leukemia were excluded. Results. A total of 277 patients followed between 1990 and 2022 were included in the analysis. Median length of follow up was 31 months (range &amp;lt;1-356), and 217/277 (78%) were alive at last follow up. The most common genetic abnormality was FIP1L1::PDGFRA (n=131) followed by D816V KIT mutations (n=39) and alterations involving JAK2 (n=22) (Figure 1). Five patients had genetic abnormalities involving two distinct genes recurrently associated with eosinophilic myeloid neoplasms. The overall median age at diagnosis was 55 years (range 12-89) and 79% of the patients were male. When patients with abnormalities involving PDGFRA and PDGFRB were excluded from the analysis, the male predominance was significantly lower at 62% (p&amp;lt;0.001, Fisher's exact test as compared to the data set as a whole). The overall pattern of organ system involvement was similar irrespective of the underlying genetic abnormality with a few notable exceptions. Cardiac involvement was most common in patients with FIP1L1:: PDGFRA, abnormalities involving JAK2 or without pathologic alterations identified (reported in 22%, 32% and 30%, respectively); whereas skin and gastrointestinal involvement, lymphadenopathy and splenomegaly were most frequent in patients with KIT D816V. Laboratory abnormalities also differed between groups. Whereas anemia was the most common blood abnormality (reported in &amp;gt;50% of patients), erythrocytosis was noted primarily in patients with abnormalities involving JAK2. In contrast, circulating blasts were identified in 70% of patient with BCR::ABL1 and 29% of patients with chromosomal abnormalities or KIT D816V, but in &amp;lt;15% of patients in any of the other groups. Whereas peak AEC alone did not discriminate between the different patient groups, the AEC/tryptase ratio was increased in patients with PDGFRA-associated myeloid neoplasms, molecular abnormalities involving JAK2, or chromosomal abnormalities as compared to those with KIT mutations (Figure 2). Conclusions. Despite the limitations of retrospective data analysis, the data from this large multicenter cohort of patients with HES due to a chronic myeloid neoplasm suggest that routine demographic, clinical and laboratory features vary depending on the underlying molecular abnormality. This approach could ultimately help guide empiric therapy when molecular studies are negative or unavailable.

Severe Reaction to Rituximab in Children

Background: Rituximab is a chimeric monoclonal antibody used in various pathologies involving CD20-positive cells. While it is usually well tolerated, infusion-related reactions are frequent but usually mild. Severe reactions such as anaphylaxis and serum sickness nevertheless can occur. Rituximab-induced serum sickness (RISS) is a rare delayed hypersensitivity reaction that may be unrecognized, as it can be confused with severe infection or in some circumstances with primary disease flare-up. We aim to extend our knowledge about severe infusion related reactions to rituximab in children, focusing on RISS and anaphylaxis. Objectives: Our study objective was to study severe reactions to rituximab by evaluating all children and adolescents who received rituximab in our center. Methods: Children and adolescents who received rituximab between 2014 and 2021 at CHU Sainte-Justine, a tertiary and leading pediatric center in Quebec, Canada, were included in the study. Data was collected retrospectively from our electronic medical records in CHU Ste-Justine. The diagnostic criteria proposed by the World Allergy Organization in 2020 were used to classify patients in the anaphylaxis subgroup. Patients with RISS were included if they developed fever and at least rash and/or arthralgia, starting 1 to 30 days following rituximab infusion, and if no other confirmed diagnosis explained symptoms. The study was approved by local Institutional Review Board. Results and discussion: 1534 rituximab infusions in 391 patients were analyzed. A severe infusion reaction to rituximab occurred in 14 patients (3.6%); none resulted in death. Rituximab was prescribed for an auto-immune disease in 61% of cases. Seven patients presented with RISS (1.8%); all were treated for an auto-immune disease including 4 for immune thrombocytopenia (ITP). Mean time from rituximab to RISS was 9 days (ranging from 6 to 12 days). All RISS patients but one presented with the classical triad of fever, rash and arthralgia. Increased C-reactive protein or sedimentation rate was documented in all patients, and decreased complement in 83%. Three patients required admission to intensive care unit due to hemodynamic instability. Patients received corticosteroids and/or intravenous immunoglobulins; mean duration of RISS was 4 days (ranging from 3 to 6 days). Rituximab was reinfused after RISS in one patient; she presented an immediate anaphylactoid reaction after which rituximab was permanently discontinued. Patients who received lower doses of rituximab were less likely to present RISS compared to patients who received higher doses (risk ratio 0.14, CI 0.03-0.74, p=0.016). Although few ITP patients developed RISS, RISS was associated with a greater chance of achieving partial or complete ITP remission (risk ratio 3, CI 1.47-6.14, p=0.033). Such possible association was not observed in other diseases. Seven patients developed severe anaphylaxis (1.8%), 3 of them reacted after the first dose (42.8%). Five of them were able to receive further rituximab infusion, using desensitization protocols. Conclusion: RISS is a rare hypersensitivity reaction in children. To this day, our study is the first to report more than 3 patients in a pediatric setting. RISS in children seems to be more frequent when rituximab is administered for an autoimmune condition, especially ITP. Although the classic triad of fever, rash and arthralgia appears more frequent in children than in adults, RISS should be considered in the differential diagnosis of any suggestive symptom developing within 30 days of infusion. Presence of biological inflammation and/or low serum complement can further support the diagnosis. In all patients, evolution was favorable within a few days with steroids. However, in contrast with anaphylaxis, RISS should be considered as a contraindication for further rituximab therapy.

The Impact of Baseline Genetic Profile and Treatment on Hematological Toxicity in CEBPA-Mutated Acute Myeloid Leukemia

Background: CEBPA-mutated acute myeloid leukemia (AML) is a separate entity in the updated WHO and ICC classifications. Previously identified by double mutations, the clinical profile and favorable outcome were correlated with in-frame mutations in bZIP domain. Beyond mutations recurrent in myeloid neoplasms (involving TET2, FLT3, NRAS), CEBPA-mutated AML is enriched in gene mutations (i.e., GATA2, CSF3R, WT1) rarely observed in CEBPA-wild type AML. No conclusive findings have been drawn for the prognostic impact of additional mutations. Of note, somatic GATA2 mutations have been associated with invasive fungal infections in myeloid neoplasms. Although overall correlating with favorable prognosis, an unexpectedly high rate of treatment-related mortality (TRM) in CR has been described in a large multicenter study on intensively treated CEBPA-mutated patients (pts) (Schlenk et al Blood 2013;122(9):1576). Aims: The aim of our study was to correlate baseline and treatment characteristics with the outcome and hematological toxicity in an intensively treated cohort of CEBPA-bZIP mutated AML pts. Methods: Pts entering the study had a diagnosis of CEBPA-bZIP AML confirmed according to 2022 WHO and ICC criteria. Pts were characterized by next-Generation deep amplicon sequencing with Ion Torrent platform (ThermoFisher Scientific) covering a panel of 40 genes. Sequence alignment and filtering were performed by NextGENe version 2.4.2.1 (SoftGenetics). The first two chemotherapy cycles were categorized according to the delivery of an anthracycline (ANTHRAC) and cytarabine (ARA-C) at high dose (HDAC). The study was approved by the local institutional review board. Results: From 2004 to 2023, 49 pts with CEBPA-bZIP mutated AML met the inclusion criteria at project study sites (Firenze, Bergamo). Their features are detailed in Table 1. CR rate was achieved in 45 of 49 pts (91.8%), with a DFS and OS of 74.3% and 82.4% at 5 y, respectively. Based on NGS, at least one additional mutation was identified in 18 (36.7%) pts (NGS+), the majority of them involving GATA2 (n=14, 28.6%). As per treatment, 44 pts received at least two cycles, of which no (n=2, 4.6%), one (n=14, 31.8%), or two (n=28, 63.6%) ANTHRAC-containing cycles. As regarded HDAC, 19 (43.2%), 17 (38.6%) and 8 (18.2%) pts received no, one or two HDAC-containing cycles, respectively. No significant differences emerged for DFS or OS between NGS+ and NGS- groups (P=0.33 and 0.52, respectively). To gain insight into potential causes of toxicity during CR, we focused on hematopoietic recovery after induction and consolidation. NGS+ pts showed slower neutrophil (ANC) recovery (median, 22 days to &amp;gt;500/uL after induction and 25 days after consolidation) compared to NGS- group (19 days, P=0.018; 18 days P=0.058, respectively). Such effect was enhanced by treatment with ANTHRAC-containing cycles: NGS+ pts receiving two cycles required significantly longer time to recover from first consolidation cycle, both for ANC (30 days) and platelet count (34 days) vs 22 (P=0.012) and 27 (P=.010) days, respectively, of other categories (Figure 1). A proportion of 45.5% (5/11) NGS+/ANTHRAC-2 pts could not complete the planned chemotherapy program due to hematological toxicity compared to 19.3% (6/31, P=0.09) in other categories. No significant prolongation of recovery was observed for HDAC. Conclusions: CEBPA-bZIP mutated AML is featured by high response rate and favorable outcome. Delayed hematopoietic recovery was observed in pts bearing additional mutations (especially GATA2) when treated with anthracyclines in first two cycles. Our findings suggest the cumulative dosage of anthracyclines should be limited in CEBPA-mutated/NGS+ patients to spare hematological toxicity on turn impairing the therapeutic plan.

Chronic Myeloid Leukemia Reduces Survival in Elderly Patients (age ≥ 75 years old): An International Multicenter Retrospective Study

Background Tyrosine kinase inhibitors (TKIs) have significantly improved the life expectancy of individuals with chronic myeloid leukemia (CML), bringing it closer to that of the age-matched general population 1. However, clinical trial data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program indicates that only 3.8% of CML patients aged 75 or above participate in trials, despite this age group representing about 30% of CML patients 2. This study aims to assess the outcomes of elderly patients aged 75 years or older diagnosed with CML. Methods We conducted a retrospective study, using electronic medical records of consecutive CML patients aged ≥ 75 years, diagnosed between January 2002 and December 2021 at four hematological centers in Israel and Moffitt Cancer Center in Florida, United States (MCC). One-year and five-year overall survival (OS) rates were calculated for the whole cohort and for octogenarians (above 80 years). In addition, to assess if CML diagnosis affected life expectancy, we estimated the expected OS of the Israeli cohort based on life expectancy data from the central bureau of statistics (CBS). Kaplan-Meier curves were used to compare expected and observed median OS with the Log-rank analysis. Local Institutional Review Boards approved the study. Results A total of 123 patients (78 treated in MCC and 45 in Israel) aged ≥ 75 years were diagnosed with CML, with a median age of 79 (range: 75 - 100) years, and 55 patients (45%) were octogenarians. At the time of CML diagnosis 84% of had comorbidities, including cardiovascular risk factors in 90 patients (73%), while 50 patients (41%) had cardiovascular/cerebrovascular diseases. Most patients (93%) were diagnosed in chronic phase CML and high/intermediate EUTOS-LTS risk score (96%) treated with imatinib in the 1 st line treatment (69%). After a median duration of 15 (range:1-153) months on 1 st line treatment, 71 patients (58%) discontinued therapy primarily due to intolerance (n=51) while other causes included resistance (n=15), noncompliance/insurance issues (n=4) or progression to blast crisis (n=1). The 2 nd -line treatment included mainly 2 nd generation TKIs (n=53, 74%) (dasatinib-26, nilotinib -19 and bosutinib-8), while 9 patients received imatinib, 1 patient received nilotinib and imatinib, 5 patients received hydroxyurea and 3 patients were lost to follow-up. 35 patients (28%) reached 3 rd line of treatment (imatinib- 5, dasatinib- 3, bosutinib-12, nilotinib-5, ponatinib-2, asciminib-1, hydroxyurea -1, loss to follow up- 6) chiefly (28 patients) due to intolerance and others (7 patients) due to resistance. The best response assessed by RQ-PCR showed deep molecular response (DMR) in 50%, major molecular response (MMR) in 16%, and complete cytogenetic response (CCyR) in 11% of patients with a median time to maximal response of 19 (range: 0.5-111) months. Nevertheless, treatment-free remission (TFR) was rare (n=1). During a median follow-up of 45 (0.4-198) months, 55 (45%) patients died, with cardiovascular complications (n=9), disease progression (n=8), infection (n=7), and secondary malignancy (n=4) being the main known causes. The median OS for the whole cohort was 72.4 (53.1-91.7) months. Improved OS was documented in patients with an age adjusted charlson comorbidity index&amp;lt; 5 (vs. ≥5, p=0.007), those who achieved DMR (vs. no DMR, p=0.001) and median time to best response of 0-18 months (vs. ≥18, p=0.004). Moreover, OS was improved in patients who received 2 nd generation TKIs in 1 st line treatment, 91.1 (81.5-131) vs. 57.7 (35.4-79.9) months in those who received imatinib, (p=0.023). Older age did not affect OS; 1 and 5-year OS for the whole cohort was 86% and 29%, respectively, and 84.3% and 19.6% for the octogenarians, respectively (p=0.076). In the Israeli cohort, while the median expected OS was 103.7 (24-164.7) months, the median observed OS was only 54.77 (2.1-195) months (p=0.03). Conclusions Elderly CML patients were often diagnosed in chronic phase with high/intermediate risk scores. The majority received imatinib as 1 st line treatment and achieved CCyR and MMR, with half of patients achieving also DMR. Surprisingly, patients treated with imatinib had worse OS compared to those receiving 2nd generation TKIs as 1st line treatment. Furthermore, the Israeli cohort analysis supports reduced life expectancy in the very elderly patients with CML.