FDA-approved Therapy Research Articles

Racial or ethnic differences on treatment adherence and persistence among patients with inflammatory bowel diseases initiated with biologic therapies

BackgroundInflammatory bowel disease (IBD) is a chronic disease with the potential for significant morbidity in case of suboptimal treatment (e.g. low treatment adherence). In spite of immense research in IBD, literature on association of IBD with race/ethnicity is fragmented. In this study, we aimed to evaluate the association between race/ethnicity and treatment adherence and persistence among patients with Crohn’s disease (CD) or ulcerative colitis (UC) initiated with biologic therapies.MethodsThis observational, retrospective study utilized the Optum Clinformatics (Optum) Extended Data Mart Socioeconomic Status (SES) database. Adult patients with ≥ 2 medical claims for CD or UC diagnosis, ≥ 1 medical or pharmacy claim for corresponding FDA-approved biologic therapy, and a ≥ 12-month pre-index (index date: date of the first biologic medical/pharmacy claim) continuous health plan enrollment were included. Treatment adherence was measured as the proportion of days covered of ≥ 80% and treatment persistence by the number of days from the index date to the biologics discontinuation date. Switching among biologics was allowed for both treatment adherence and treatment persistence. Multivariable regression analyses were performed to evaluate the association between race/ethnicity and treatment adherence/persistence.ResultsAmong patients with CD (N = 1430) and UC (N = 1059) included, majority were White (CD: 80.3%, UC: 78.3%), followed by African Americans (AA; CD: 10.5%, UC: 9.7%). Among patients with CD, AA were significantly less likely to adhere to biologics (adjusted OR [95%CI]: 0.61 [0.38; 0.99]) and more likely to discontinue biologics earlier (adjusted HR [95%CI]: 1.52 [1.16; 2.0]) during the follow-up period compared to Whites, after adjusting for other patient sociodemographic and clinical characteristics. Among patients with UC, no significant differences in the treatment adherence/persistence were observed between different races/ethnicities.ConclusionsPatients with CD were found to display racial differences in the treatment adherence and persistence of biologics, with significantly lower adherence and earlier discontinuation in AA compared to Whites. Such differences were not observed in patients with UC. Future studies are warranted to understand the possible reasons for racial differences, particularly in patients with CD.

High fat diet exacerbates long-term metabolic, neuropathological, and behavioral derangements in an experimental mouse model of traumatic brain injury

AimsTraumatic brain injury (TBI) constitutes a serious public health concern. Although TBI targets the brain, it can exert several systemic effects which can worsen the complications observed in TBI subjects. Currently, there is no FDA-approved therapy available for its treatment. Thus, there has been an increasing need to understand other factors that could modulate TBI outcomes. Among the factors involved are diet and lifestyle. High-fat diets (HFD), rich in saturated fat, have been associated with adverse effects on brain health. Main methodsTo study this phenomenon, an experimental mouse model of open head injury, induced by the controlled cortical impact was used along with high-fat feeding to evaluate the impact of HFD on brain injury outcomes. Mice were fed HFD for a period of two months where several neurological, behavioral, and molecular outcomes were assessed to investigate the impact on chronic consequences of the injury 30 days post-TBI. Key findingsTwo months of HFD feeding, together with TBI, led to a notable metabolic, neurological, and behavioral impairment. HFD was associated with increased blood glucose and fat-to-lean ratio. Spatial learning and memory, as well as motor coordination, were all significantly impaired. Notably, HFD aggravated neuroinflammation, oxidative stress, and neurodegeneration. Also, cell proliferation post-TBI was repressed by HFD, which was accompanied by an increased lesion volume. SignificanceOur research indicated that chronic HFD feeding can worsen functional outcomes, predispose to neurodegeneration, and decrease brain recovery post-TBI. This sheds light on the clinical impact of HFD on TBI pathophysiology and rehabilitation as well.

Current Therapeutic Options and Potential of Mesenchymal Stem Cell Therapy for Alcoholic Liver Disease

Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The therapeutic efficiency of current therapies for ALD is limited, and there is no FDA-approved therapy for ALD at present. Various strategies targeting pathogenic events in the progression of ALD are being investigated in preclinical and clinical trials. Recently, mesenchymal stem cells (MSCs) have emerged as a promising candidate for ALD treatment and have been tested in several clinical trials. MSC-released factors have captured attention, as they have the same therapeutic function as MSCs. Herein, we focus on current therapeutic options, recently proposed strategies, and their limitations in ALD treatment. Also, we review the therapeutic effects of MSCs and those of MSC-related secretory factors on ALD. Although accumulating evidence suggests the therapeutic potential of MSCs and related factors in ALD, the mechanisms underlying their actions in ALD have not been well studied. Further investigations of the detailed mechanisms underlying the therapeutic role of MSCs in ALD are required to expand MSC therapies to clinical applications. This review provides information on current or possible treatments for ALD and contributes to our understanding of the development of effective and safe treatments for ALD.

Targets for chimeric antigen receptor T-cell therapy of acute myeloid leukemia.

Acute Myeloid Leukemia (AML) is an aggressive myeloid malignancy associated with high mortality rates (less than 30% 5-year survival). Despite advances in our understanding of the molecular mechanisms underpinning leukemogenesis, standard-of-care therapeutic approaches have not changed over the last couple of decades. Chimeric Antigen Receptor (CAR) T-cell therapy targeting CD19 has shown remarkable clinical outcomes for patients with acute lymphoblastic leukemia (ALL) and is now an FDA-approved therapy. Targeting of myeloid malignancies that are CD19-negative with this promising technology remains challenging largely due to lack of alternate target antigens, complex clonal heterogeneity, and the increased recognition of an immunosuppressive bone marrow. We carefully reviewed a comprehensive list of AML targets currently being used in both proof-of-concept pre-clinical and experimental clinical settings. We analyzed the expression profile of these molecules in leukemic as well normal tissues using reliable protein databases and data reported in the literature and we provide an updated overview of the current clinical trials with CAR T-cells in AML. Our study represents a state-of-art review of the field and serves as a potential guide for selecting known AML-associated targets for adoptive cellular therapies.

FDA Approved Treatments for Neuromyelitis Optica Spectrum Disorder in Clinical Practice: A Survey of Academic Neuroimmunologists

Objective To assess utilization and barriers to use of three recently FDA-approved treatments for neuromyelitis optica spectrum disorder (NMOSD) by academic neuroimmunologists. Background Since 2019, eculizumab, inebilizumab, and satralizumab have received FDA approval for the treatment of aquaporin-4 IgG positive (AQP4+) NMOSD after showing efficacy in reducing attack frequency. However, little is known regarding the adoption of these therapies into practice or barriers to their use. We conducted a survey of academic neuroimmunologists to identify current treatment practices. Design/Methods An electronic survey study was conducted of US neuroimmunologists. Recipients were identified on department websites of university-associated hospitals with affiliated neurology residencies. The survey was administered via email, and included questions regarding clinical background, patient cohort, treatment use in different scenarios, and barriers. The authors were blinded to the identity of respondents. Results 383 neuroimmunologists from 105 institutions were identified, of whom 33 from 18 states completed the survey. Nearly all (88%) reported treating patients with the newly FDA-approved therapies (NFTs). None reported discomfort discussing any NFT with their patients. Respondents reported uncommonly switching clinically stable patients to NFTs (69% never switch, 22% switch 1-25% of the time). For newly diagnosed AQP4+ NMOSD patients, NFT initiation rates varied (16% initiate none, 42% 1-25% of the time, 6.5% 25-50%, 19% 50-75%, 16% 75-100%). For patients with a relapse, responses were dichotomized regarding switching to NFTs - respondents either switch 75-100% of their patients (60%) or none or 1-25% (16%, 24% respectively). Nearly half (16/33) of respondents reported being unable to start NFTs, with insurance/cost issues being the most cited barrier. Conclusions Among academic neuroimmunologists, FDA-approved therapies for AQP4+ NMOSD are being utilized for newly diagnosed patients and those with disease recurrence, although individual practice patterns vary. The main perceived barriers to NFT use are insurance/cost-related issues.

Abstract B018: Novel therapeutics for targeting the aberrant nuclear export machinery in colorectal cancer

Abstract XPO1 is a nuclear export receptor responsible for exporting many key proteins critical for cell survival from the nucleus to the cytoplasm. Recently, we identified a highly statistically significant hotspot mutation in XPO1 R749Q occurring in patients with colorectal cancer. Out of 96 patients identified to have XPO1 R749Q mutations, 27 (28%) were in colorectal cancer (CRC). 95% of XPO1 R749Q mutant CRC were tumor mutation burden-high (TMB-H; >10 mut/Mb) and 0 were mis-match repair deficient (dMMR)/micro satellite instability-high (MSI-H). Co-mutation analysis showed that 95% of XPO1 R749Q CRC were POLE mutated, which was significantly enriched over XPO1 WT tumors. To investigate whether XPO1 R749Q might play a role in CRC biology, we have generated two different isogenic colorectal cancer cell lines bearing the XPO1 R749Q mutation (HCT116 and LS174T) using CRISPR-CAS9 to better understand the role of this aberrant XPO1 mutation on nuclear export and tumorigenesis. Immunofluorescence (IF) and Stochastic Optical Reconstruction Microscopy (STORM) super-resolution experiments showed that R749Q mutant cells had significantly increased localization of XPO1 in the cytoplasm of the XPO1 R749Q mutant cells when compared to wildtype (XPO1 WT) cells, particularly at the edge of the nuclear pores of the XPO1 R749Q mutant cells suggesting increased nuclear export. Mass spectrometry analysis of nuclear and cytoplasmic fractionated proteins confirmed that XPO1 R749Q mutant cells had increased export of proteins from the nucleus compared to XPO1 WT cells. Structural modeling using published structures of XPO1 bound to Ran-GTP predicted that XPO1 R749Q mutation increased affinity of the regulatory H9-loop of XPO1 to Ran, thus favoring increased shuttling and retention in the cytoplasmic compartment. Therefore, we hypothesize that XPO1 R749Q may represent a novel mechanism of nuclear export alteration involved with kinetic tuning of global transport. Despite the increased nuclear export function, XPO1 R749Q cells did not show a proliferative advantage. We thus set out to test whether XPO1 R749Q might be enriched in cancer as an adaptive response to chemotherapy treatment. Using a chemical compound library of >200 FDA-approved cancer therapies we observed a strong therapeutic resistance of XPO1 R749Q cells relative to XPO1 WT cells, specifically to chemotherapies used in the treatment of colon cancer, such as irinotecan. However, these cells remained sensitive to treatment with the XPO1 inhibitor selinexor. Mice xenografted with XPO1 R749Q mutant HCT116 cells showed moderate tumor response to selinexor or irinotecan monotherapies but prolonged tumor responses to combination therapy. Recent clinical data has shown POLE mutations to be a biomarker for response to PD-1 immune checkpoint blockade, especially in CRC. Since our genetic data identify POLE mutations commonly co-occurring with XPO1 R749Q in colon cancer, we are planning to test the combination of PD-1 inhibitors and selinexor to target both these mutations, as well as CRC tumors without these mutations. Citation Format: Tulasigeri M. Totiger, Sana Chaudhry, Skye Montoya, Monika Chojnacka, Gabriel Gaidosh, Jumana Afaghani, Maurizio Affer, Jenna Zabroski, Jacob Jahn, Vindhya Nawaratne, Ryan Notti, Ramiro Verdun, Daniel Bilbao, Josean Rodriguez, Justin Taylor. Novel therapeutics for targeting the aberrant nuclear export machinery in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B018.

Increased Comorbidities and Hospitalizations Associated with Idiopathic Multicentric Castleman Disease

Background: Castleman disease (CD) describes a group of disorders that share characteristic lymph node histopathology with heterogeneous symptoms. Unicentric Castleman disease (UCD) involves a single region of enlarged lymph nodes, localized symptoms, and is typically curable with excision. In contrast, multicentric Castleman disease (MCD) involves multiple regions of enlarged lymph nodes, systemic inflammation, cytopenias, and life-threatening multiorgan dysfunction. MCD can be associated with human herpesvirus-8 infection or is idiopathic (iMCD). Presentation is heterogeneous, and multiple clinical phenotypes exist, including iMCD patients who meet criteria for the most severe form of the disease, the TAFRO subtype (thrombocytopenia, anasarca, fevers, reticulin fibrosis, organomegaly). Furthermore, iMCD is difficult to diagnose. Though there is an FDA-approved therapy (siltuximab) for iMCD, major unmet need exists as many patients do not receive this treatment and a subset of patients do not respond to siltuximab. To elucidate the burden of iMCD, we interrogated hospitalization and comorbidity data from patients with iMCD and UCD, as well as from a comparator group of patients who demonstrated iMCD-like features determined to result from a reactive process ('Other'). Methods: The ACCELERATE Natural History registry was leveraged to identify a cohort of 193 patients with a pathology report suggestive of CD. All patients were reviewed by a panel of expert CD physicians to confirm or reject a CD diagnosis. Following review, 85 patients were categorized as having iMCD - including 49 (58%) iMCD-TAFRO, 65 were UCD, and 43 patients were consistent with an inflammatory or reactive processes not reflective of iMCD (Other). Results: The mean (SD) age of patients was 39 (16) with a range of 1-75. Prior to diagnosis, the top 10 comorbidities found among both iMCD and UCD patients included common chronic diseases observed in the general US population, such as diabetes, hypertension, GERD, obesity, asthma, anxiety, and depression. Among UCD patients, the top common comorbidities remained unchanged after diagnosis. Among iMCD patients, however, a number of other comorbidities emerged as top-most common, such as acute renal failure (20%), pneumonia (11%), sepsis (8%), chronic kidney disease (8%), thrombotic microangiopathy (7%), acute cholecystitis (7%), and diverticulitis (6%). We also found that the iMCD patients spent a significantly longer time hospitalized in the 1st year following diagnosis (mean 34.3 days) compared to UCD (mean 14 days) (p<0.05), but there was no significant difference from patients with an Other diagnosis (22 days). We saw a similar trend in days hospitalized per year since diagnosis, with iMCD patients hospitalized for a significantly greater time than UCD (24.2 vs. 10.5 average days hospitalized per year of diagnosis, p<0.001). There was no difference with the Other group (16.2 days). iMCD patients also spent an average of 12.1 days hospitalized before the first iMCD-treating drug and 44.7 days after the administration of the first iMCD-treating drug. Further, a large proportion of iMCD patients required supportive interventions, such as dialysis (23.6%, n=20) and mechanical ventilation (16.5%, n=14). This compares to 7% (n=3) of Other patients and no UCD patients who required dialysis and 9.3% (n=4) of Other patients and 4.6% (n=3) UCD patients who required mechanical ventilation. Discussion: Overall, these data demonstrate that iMCD patients face a significant disease burden, even years after a diagnosis is rendered and treatment is initiated. While siltuximab can effectively control symptoms in a subset of iMCD patients, not all patients receive siltuximab and not all patients treated respond to siltuximab. We found that patients require hospitalization and costly intervention such as dialysis and mechanical ventilation for extended periods of time. These findings have real implications for patient healthcare costs and hospital systems. iMCD patients demonstrate relatively common comorbidities prior to diagnosis and subsequently develop life-threatening conditions such as acute kidney failure and sepsis following diagnosis. These data highlight the importance of continuing research into iMCD etiology, subgroups, treatments, and outcomes, to control the burden of disease and improve outcomes and prognosis for this severely ill group of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trial in Progress: Acalabrutinib Maintenance Following Cellular Therapy for Large B-Cell Lymphoma Patients at High Risk for Relapse

Background Large B-cell lymphoma has been shown to be driven by B-cell receptor signaling, which can be disrupted using Bruton tyrosine kinase (BTK) inhibition. Acalabrutinib has been studied in large B-cell lymphoma in combination with intensive therapies with encouraging results (Davies et al., Blood 2020). Preclinical studies have shown BTK inhibition could improve the effectiveness of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy by improving the tumor microenvironment and delaying T-cell exhaustion (Qin et al., J Immunother 2020). BTK inhibition also has the potential to enhance the T-cell directed graft-versus-malignancy effect of allogeneic stem cell transplantation (alloHCT). This trial seeks to develop an effective therapeutic strategy to prevent relapse following cellular therapy in a specific group of large B-cell lymphoma patients that is high risk for relapse. Design This is a single-arm, open-label, multi-center phase Ib/II clinical trial to evaluate the safety and effectiveness of acalabrutinib as maintenance therapy in a subpopulation of patients with large B-cell lymphoma who are at high risk for relapse after cellular therapy. Inclusion criteria includes 1) patients undergoing autologous stem cell transplant (autoHCT) or any FDA-approved CAR T-cell therapy product for high grade B-cell lymphoma, large B-cell lymphoma with a history of secondary central nervous system (CNS) involvement, histologic transformation of indolent lymphoma to large B-cell lymphoma, or large B-cell lymphoma with high-risk international prognostic index score of 4 or 5 and 2) patients undergoing alloHCT for large B-cell lymphoma. The sample size for this study is 24 patients total, including 12-15 patients treated post-CAR T-cell therapy and 12-15 patients treated post-transplant. Patients will be started on maintenance with acalabrutinib on day +90 following alloHCT, day +60 following autoHCT, or between days +28 and +104 following CAR T-cell therapy. This trial will open at University of California Los Angeles and University of California Davis (two constituent sites of the University of California Hematologic Malignancies Consortium). Objectives The primary objective is to determine the safety and tolerability of maintenance acalabrutinib following cellular therapy in patients with large B-cell lymphoma at high risk for relapse. Secondary objectives include to estimate the effectiveness of maintenance acalabrutinib and to estimate the rates of dose reductions, dose pauses, and permanent discontinuations of acalabrutinib that occur post-cellular therapy. Exploratory objectives include to evaluate CAR T-cell persistence with acalabrutinib maintenance, to determine if there are signs of CNS penetration of acalabrutinib, and to evaluate changes before and after initiation of acalabrutinib in intracellular cytokine and phospho-protein profiling of peripheral blood mononuclear cells. Main Outcomes The primary endpoint is tolerability, determined by permanent discontinuation of acalabrutinib within 12 months from cellular therapy due to intolerance, defined as grade >3 non-hematologic toxicity or grade 4 hematologic toxicity considered related to acalabrutinib that occurs for the third time after previously holding and resuming acalabrutinib. Secondary endpoints include PFS and OS following cellular therapy and the incidence of dose changes and stopping of acalabrutinib. Conclusions This trial will use acalabrutinib as maintenance therapy for large B-cell lymphoma patients at high risk for relapse in the hopes of improving outcomes post-cellular therapy. If there is a PFS benefit in all three groups combined (CAR T-cell therapy, alloHCT, autoHCT), there will be rationale to expand each individual group into a separate larger trial. This study is registered with clinicaltrials.gov: NCT05256641. References Davies A, Caddy J, Mercer K, et al. Acalabrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) As First Line Therapy for Patients with Diffuse Large B-Cell Lymphoma (DLBCL): The Accept Phase Ib/II Single Arm Study. Blood. 2020;136(Supplement_1):38-39. Qin JS, Johnstone TG, Baturevych A, et al. Antitumor potency of an anti-CD19 chimeric antigen receptor T-cell therapy, lisocabtagene maraleucel in combination with ibrutinib or acalabrutinib. J Immunother. 2020;43(4):107-120. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patterns of Disease Progression in Patients with Systemic Mastocytosis: A US Population-Level Analysis Using Health Claims-Based Dataset

Background Systemic mastocytosis (SM) is a rare clonal mast cell neoplasm driven by the KIT D816V mutation in ~95% of patients (pts). SM includes AdvSM (aggressive SM, SM with associated hematological neoplasm, and mast cell leukemia) and non-advanced SM (indolent & smoldering SM), which accounts for ~95% of cases. The uncontrolled proliferation and activation of mast cells can cause severe & unpredictable symptoms resulting in debilitation, reduced QOL, and organ infiltration and damage with reduced survival in AdvSM. While WHO criteria differentiate between subtypes of mastocytosis, there remains a lack of understanding of patterns of disease progression between SM subtypes. In this analysis we developed a novel claims-based algorithm to identify SM cases and assess disease progression. Methods Using a large, nationally representative claims database, we identified a cohort of SM pts with observed claims activity in each of the year 2019-2022. We developed a novel claims-based algorithm based on WHO diagnostic criteria (2016), including codes for laboratory tests, procedures, and treatments typically used for management of SM. Pts were included if they fulfilled 1 of the following criteria: had ≥2 diagnoses with an SM-specific ICD-10 code (D47.02, C96.21, C94.3X) at least 30 days apart in any setting of care; bone marrow biopsy followed by 1 SM diagnosis (dx) claim code in any setting of care; or 1 SM dx code in any setting of care & at least 1 prescription claim for an SM-specific treatment (avapritinib, midostaurin, imatinib, cladribine, interferons, brentuximab, omalizumab, montelukast, or cromolyn sodium). Pts were then categorized as either AdvSM, higher symptom ISM (ISM-higher), or lower symptom ISM (ISM-lower) based on additional disease-specific codes (Table 1) accumulated over the pt's total observable claims history, from 2015 to the date of evaluation. For pts who met these criteria, SM subtyping was evaluated as of Dec 31, 2019, Dec 31, 2020, and Dec 31, 2021. Treatment rates of select SM-directed therapies were also evaluated over the 12- month period from Jan-Dec, 2021. Results Of 10,939 pts with SM, 80% (8,707 pts) with claims in each of the years 2019, 2020, 2021 and 2022 were included. The first analysis looked at pts’ disease category as of Dec 2021 and assessed utilization of several SM-directed Rx therapies. This included 1,587 AdvSM, 2,705 ISM-higher, and 4,415 ISM-lower pts. Among pts across all cohorts, the most frequently observed therapies were anti-mediator therapies (AdvSM 20%, ISM-higher 37%, ISM-lower 20%) and cromolyn sodium (AdvSM 10%, ISM-higher 19%, ISM-lower 12%). When evaluating disease category evolution, 11.3% and 18.8% of pts with ISM-low migrated to ISM-higher or AdvSM over a 12-month (Dec 2020 - Dec 2021), or 24-month (Dec 2019 - Dec 2021) interval respectively. Across all ISM types, 2.2% of pts progressed to AdvSM in a 12-month interval, and 3.9% progressed to AdvSM over a 24-month interval. Among those pts who emerged with AdvSM in a 12-month interval ending Dec 2021 (N=392), 33% progressed from ISM-Lower or ISM-higher while 67% appeared as de novo diagnoses. Conclusions This study used a large claims dataset to identify pts with SM, classified them with a novel algorithm, and describe patterns of disease progression over a 12-month or 24-month interval. Of note, while this algorithm has been developed with expert clinical input, inherent limitations of claims and a single ICD-10 code for SM leave some ambiguity around the true clinical dx of these pts. Despite this, these analyses reflect the accumulation of severe symptoms over time by a meaningful subset of pts. Approximately 35% of pts with an SM dx did not have a SM dx 2 years prior, possibly due in part to the recency of the SM ICD-10 codes and also raising concerns regarding timely dx. Further, not all ISM pts demonstrated truly indolent disease behavior, illustrated by the 30% of ISM pts categorized as ISM-high requiring greater use of symptom-directed and disease-specific therapies. Finally, the proportion of AdvSM pts on FDA-approved TKI-directed therapies remain low, highlighting large unmet treatment need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Daratumumab Based Response Adapted Therapy for Older Adults with Newly Diagnosed Multiple Myeloma: Interim Analysis of Phase II Study

Introduction The combination of daratumumab (DARA), lenalidomide (Len) and dexamethasone (Dex) is an FDA approved therapy for older adults with newly diagnosed multiple myeloma (NDMM) based on the MAIA study. A less intense bortezomib (Bort) lenalidomide dexamethasone combination (VRD lite) is also used. We thought to investigate a personalized daratumumab based response adapted therapy for older adults with NDMM. Methods Patients were required to have NDMM and were age over 65 and not deemed candidates for high dose chemotherapy and autologous stem cell transplant. Eligible patients received subcutaneous DARA and Dex (20 mg PO weekly) for 2 cycles: in the event of partial response or better, patient continued on DARA Dex per usual dose and schedule, in the event of less than a partial response, frailty adjusted dosing of Len or Bort was added to the usual DARA Dex regimen. The choice of Len or Bort was per the treating physician and informed by Ex Vivo drug sensitivity assay. Modified geriatric assessment (including IMWG frailty score, timed up and go) and bone marrow biopsy (for correlatives) were performed at screening as well as on C2D22. Capitalizing on this unique opportunity to examine the tumor and immune response to DARA Dex, additional correlative studies looking at single cell RNAseq and multi-parameter flow cytometry are included. The primary endpoint was best response per IMWG criteria. Secondary endpoints included PFS, ORR after 2 cycles of DARA Dex. Result: Between November 2019 and July 2022 (the data cutoff date), 25 patients were enrolled. The median age was 79 years (range 71-88) and 13 were males (52%). Frailty score per IMWG were 0 (fit), 1 (unfit), 2+(frail) in 16%, 32%, and 52% of patients respectively. Timed up and go was prolonged (>10s) in 7 (35%) patients. High risk FISH (t(4;14) and del17p) was noted in 3 (12%) with an additional 12 patients (48%) with gain 1q/Amp1q. RISS3 was noted in 16% of patients. After 2 cycles of DARA Dex, 23 patients are evaluable for response (2 patients have not yet completed 2 cycles of therapy); 8 patients (35%) had a partial response or better (no patients had progressive disease, 1 patient discontinued therapy after 1 dose of study therapy and a diagnosis of disseminated tuberculosis). Of the 14 patients (61%) with less than a PR, 9 patients had len added and 5 bort added. The overall best response (PR and better) was 95% for this response adapted strategy including CR/sCR, VGPR, PR in 3 (13%), 14 (61%), 5 (21%) respectively. After a median of 14.7 months of follow up on this response adapted therapy, 5 had progressive disease, the estimated PFS at 1 year was 90% (95%CI 65-97.4). Overall, no unexpected toxicity was noted. The most common grade 3+ AE at least possibly related to therapy included neutropenia, anemia, diarrhea, hyperglycemia, agitation and confusion and hypertension each occurring in 4% of patients. The most common possibly related any grade AE occurring in >25% of patients included hyperglycemia 80%, diarrhea 36%, neutropenia 28%, insomnia 28%, fatigue 28% Conclusions: Preliminary results of this DARA based response adapted therapy are encouraging in this mostly frail patient population with a high response rate and low rate of severe AE. Enrollment in this response adapted therapy for older adults with NDMM continues. With longer follow-up, we will integrate correlative studies evaluating the accuracy of ex vivo predictions in response to DARA and combinations in this unique population of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Overcoming Barriers to T Cell Therapy Against AML with Dual Costimulatory Receptors

Acute myeloid leukemia (AML) is a rapidly progressing and highly fatal disease, with only 27% of patients surviving 5 years after diagnosis. Adoptive cell therapy (ACT) provides the opportunity to genetically modify T cells to generate a "living drug" that can recognize and destroy tumor, and subsequently generate a memory population to protect against future recurrence. ACT is particularly attractive as a potential AML therapy, as T cells naturally home to the sites of disease, and ACT has proven effective and is now an FDA-approved therapy for other hematological malignancies. However, several obstacles in the AML bone marrow (AML-BM) can impede T cell therapeutic efficacy, including T cell exhaustion, limited metabolic substrates, and lack of costimulation. Additionally, engineering strategies to improve ACT have mainly been T cell-intrinsic, with little or no support of endogenous anticancer immunity. Costimulatory signals transmitted through cell surface receptors can initiate gene expression programs that address multiple issues in the AML-BM by mechanisms such as lowering the threshold of activation, metabolic reprogramming, and reducing exhaustion. In particular, tumor necrosis family receptor (TNFR) members have been targeted in the clinic with drug-based approaches, with the aim of activating antigen presenting cells (APCs), such as dendritic cells (DCs), macrophages, and B cells, both to boost their own antitumor functions and enhance costimulatory signals leading to enhanced antitumor activity of T and NK cells. Dual costimulatory receptors as a new cell engineering platform. We innovate synthetic transmembrane fusion proteins (FPs) that combine a receptor ectodomain with a costimulatory signaling endodomain. We have shown that engineered fusion proteins, such as immunomodulatory fusion proteins (IFPs) that utilize an inhibitory decoy ectodomain, can empower T cells to overcome several hurdles faced in the tumor microenvironment and significantly improve therapeutic efficacy in cancer models. Here we report our next generation of FP, called Dual Costimulatory Receptors (DCRs), that pair a costimulatory ligand ectodomain with a costimulatory endodomain. This approach addresses two critical objectives: to enable engineered T cells to attack cancer more powerfully and durably AND to support the activation of endogenous immune cells in the AML-BM. To build on insights from agonist antibody research, we developed DCRs with TNFR ectodomains and created a flexible platform with a variety of pre-selected costimulatory endodomains. We hypothesized that this approach would result in greater efficacy over traditional T cell engineering strategies that aim only to enhance cell-intrinsic function and tested this using murine and human models of AML. Primary human DCR-engineered T cells exhibited high surface expression of the DCR ectodomain, and increased DCR-T cell activation and ability to lyse tumor in in vitro studies. DCR-T cells co-cultured with immature DCs induced maturation similar to positive control conditions (LPS-maturation), demonstrating cell-extrinsic DCR activity. To determine if promising DCR candidates could enhance in vivo ACT efficacy, AML-bearing B6 mice were treated with1e6 engineered T cells after a single dose of cyclophosphamide (Cy) conditioning therapy, modeling human ACT protocols. Whereas the native full-length costimulatory ligand only modestly improved survival (P=ns), several DCR candidates showed significantly improved therapeutic efficacy (P<0.01-0.05). Here we describe a first-of-kind engineering strategy for the treatment of AML to expand our basic understanding of how different cell-intrinsic and -extrinsic costimulatory signals might achieve enhanced antitumor function and provide a dataset to support clinical translation for AML patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

REAL-WORLD TREATMENT BURDEN ASSOCIATED WITH PARENTERAL ON-DEMAND THERAPIES FOR HEREDITARY ANGIOEDEMA

<h3>Introduction</h3> The objective of the current study is to describe treatment burden associated with FDA-approved on-demand therapies for hereditary angioedema (HAE) attacks using the real-world frequency of administration site reactions reported in the FDA's Adverse Event Reporting System (FAERS). <h3>Method</h3> : We searched FAERS data from 10/01/2009 to 3/31/2021 for human C1-inhibitor (H-C1-INH), ecallantide, icatibant, and recombinant C1-inhibitor (R-C1-INH). The number of administration site adverse drug reactions (ADRs), where the drug was listed as "primary suspect" were recorded for each drug. ADR preferred terms were then grouped into an ADR domain based on semantic and/or clinical similarity. This process resulted in 15 overarching ADR domains. For each ADR domain, the number of reports for each drug were calculated per year from the time of their approval through March 2021. Descriptive results are presented. <h3>Results</h3> The most frequently reported ADR domains included injection site pain, erythema, swelling as well as access site complications or malfunctions. Icatibant had the highest rate of ADRs per year for site pain (16.6), erythema (7.08), and swelling (6.35). Access site complications/malfunctions (7.75) were highest for R-C1-INH. ADR rates per year for H-C1-INH and ecallantide were under 2. <h3>Conclusion</h3> Results generally support those found in clinical trials, particularly for icatibant, for which 97% of patients experience injection-site reactions. ADR rates are not exposure-adjusted and are based on spontaneous reporting. These real-world descriptive results suggest that patients experience significant treatment burden associated with FDA-approved parenteral on-demand therapies for HAE attacks.

Endobariatrics: well past infancy and maturing rapidly.

This review summarizes the key developments with regard to FDA-approved endoscopic bariatric metabolic therapies (EBMTs) in the last 2 years. The prevalence of obesity has increased during the coronavirus disease 2019 (COVID-19) pandemic, and obesity worsens COVID-19 related outcomes. Several studies have confirmed the safety and short-term efficacy of intragastric balloons (IGBs). In the short-term IGBs may improve steatosis and fibrosis in nonalcoholic fatty liver disease and improve quality of life and mental health. Unfortunately weight loss from these temporarily placed devices is not sustained long-term. Endoscopic sleeve gastroplasty (ESG) may be more effective and durable than IGBs, and result in fewer adverse events compared to bariatric surgery. The recently completed MERIT trial may catapult ESG as a first-line EBMT. Aspiration therapy meets safety and effectiveness thresholds for incorporation into routine practice, but overall acceptance has been lower than other FDA-approved EBMTs. The field of endobariatrics is rapidly maturing. Significant knowledge gaps remain with regards to combining EBMTs with pharmacologic therapy to improve durability of weight loss. The rapid expansion in the literature supporting safety and long-term efficacy ESG may prompt revision of existing guidelines.

INFANTILE AGGRESSIVE SYSTEMIC MASTOCYTOSIS TREATED WITH ORAL MIDOSTAURIN

<h3>Introduction</h3> Systemic mastocytosis accounts for less than 10% of all pediatric mastocytosis cases. Midostaurin, a cytoreductive multi-kinase inhibitor, is approved for use in adult systemic mastocytosis. There are no FDA-approved cytoreductive therapies for pediatric patients. <h3>Case Description</h3> A 3-month-old male presented with diffuse pruritic patches and hepatosplenomegaly, in the setting of a markedly elevated tryptase of 187 ng/mL (<11.4mg/mL). Bone marrow biopsy showed multifocal mast cell infiltrates with a subset being spindle shaped. Mast cells immunostaining was positive for tryptase, CD117, CD2 and CD30. Skin biopsy revealed superficial dermal mast cell infiltration. Serum KITD816V mutation was positive. There were no cytopenias. The patient was started on a regimen of H1 and H2 antihistamines and oral cromolyn. Three months later, he presented with fever and progressive hepatosplenomegaly. Labs were notable for: increased tryptase (234 ng/mL), anemia (hemoglobin 9.3 g/dL), mild thrombocytopenia (133 k/uL)<i>,</i> elevated prothromobin time (15.9 sec [11.7-14.7 sec]) and low albumin (2.7 g/dL [2.9-5.5g/dL]). Local IRB approval and FDA emergency expanded use was obtained for oral midostaurin 30mg/m² every 12 hours with weekly monitoring of CBC and tryptase. Within 3 weeks of starting, the tryptase declined to 129 ng/mL and the patient had near complete resolution of head and neck lesions with reduction in hepatosplenomegaly. <h3>Discussion</h3> To our knowledge this is the second case of infantile systemic mastocytosis where oral midostaurin rapidly decreased serum tryptase and improved clinical symptoms without notable adverse effects. This treatment will be continued until normalization of serum tryptase unless adverse effects develop.

THE USE OF LANADELUMAB AS TREATMENT IN A PATIENT WITH ACQUIRED ANGIOEDEMA

<h3>Introduction</h3> There are no FDA-approved therapies for acquired angioedema (AAE). In AAE patients whose underlying disease process is not amenable to therapy, options are limited, sometimes requiring off-label use of medications used for hereditary angioedema (HAE). Lanadelumab with rescue use of icatibant has not been officially studied for the management of AAE but has shown efficacy in HAE patients. <h3>Case Description</h3> A 75-year-old male with history of stage 1 colon adenocarcinoma in remission presented with angioedema initially attributed to apixaban used for treatment of post-COVID-19 pulmonary embolus. Despite discontinuing apixaban, he continued to experience monthly episodes of angioedema involving orofacial and gastrointestinal symptoms, requiring 4 hospitalizations and steroid, oral antihistamine, tranexamic acid, and fresh frozen plasma treatments. One episode involved airway compromise requiring emergency icatibant use and transient intubation. Diagnostic results showed low C4, C1 total protein, and C1 inhibitor function, with negative C1 auto-antibody. Subsequent testing revealed monoclonal gammopathy of undetermined significance (MGUS) of low to intermediate risk (IgG kappa subtype); treatment was not recommended given MGUS staging and risk of treatment. He was started on lanadelumab every 2 weeks with continued icatibant for rescue use and has had remission of AAE over the following 3 months. <h3>Discussion</h3> Lanadelumab in combination with rescue icatibant is emerging as an effective regimen to reduce hospitalizations and morbidity in AAE patients, particularly in patients whose underlying etiology of disease is unknown or for which treatment is not indicated. Investigation on a larger scale is warranted to better understand this therapeutic option for patients with AAE.

CHALLENGES IN MANAGING THE LATE ADOLESCENT PATIENT ON PALFORZIA

<h3>Introduction</h3> Palforzia [Peanut Allergen Powder-dnfp] is the only FDA-approved therapy to minimize the potential for life-threatening anaphylactic reactions to peanut in children. Given the inherent risks, the dosing schedule must be followed exactly. <h3>Case Description</h3> L.B. is a 17-year-old male with severe peanut anaphylaxis, tree nut allergy, and asthma. He began Palforzia in November 2021. All required parties completed the Risk Evaluation and Mitigation Strategy program. A detailed binder created by our nursing staff containing dosing procedures and a dose tracker was provided. Phone calls were made 3 days after each Up-dose. Various issues occurred during treatment. He once forgot to eat breakfast before an Up-dose and was given food in our clinic first. In December, he developed anaphylaxis from tree nut ingestion but only informed our office after 2 days. In January, he began having abdominal pain and diarrhea with each Up-dose. With questioning, he reported taking the doses late at night without parental supervision, on an empty stomach, or going to the gym within 3 hours of the dose. We frequently reviewed the proper dosing protocol and cautioned that treatment would stop if he was noncompliant. Famotidine helped the gastrointestinal symptoms. He achieved Maintenance in April but stopped Palforzia by June 2022. <h3>Discussion</h3> We learned that the care of late adolescents on Palforzia poses particular challenges. Open communication and full engagement with the patient and family are critical throughout the process. Going forward, we must respect their lifestyle and growing autonomy so they can safely incorporate Palforzia into their daily routine.

Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial

Bronchopulmonary dysplasia (BPD) is a disease of chronic respiratory insufficiency stemming from premature birth and iatrogenic lung injury leading to alveolar simplification, impaired alveolar-capillary development, interstitial fibrosis, and often pulmonary hypertension. BPD is the most common pulmonary sequela of prematurity and is often fatal; however, there remains no FDA-approved therapies to treat or prevent BPD. Sildenafil is increasingly used off-label in premature infants despite scant safety and efficacy data. Sildenafil reduces lung injury and preserves normal vasculature in preclinical models, and improves outcomes in children with pulmonary hypertension, and thus is a promising candidate for BPD. Following phase I studies, we developed the phase II SIL02 trial to describe the safety, pharmacokinetics and preliminary effectiveness of intravenous and enteral sildenafil in premature infants at risk for BPD. SIL02 is a randomized, double-blind, placebo-controlled, 3-cohort, sequential dose-escalating trial of enteral or intravenous (IV) sildenafil dosed every 8 h for up to 34 days. The target IV doses were 0.125, 0.5 and 1 mg/kg/dose in cohorts 1, 2 and 3, respectively; while the enteral doses will be double the IV doses. Eligible infants must be < 29 weeks' gestation at birth and requiring respiratory support at 7–28 days' postnatal age. Adverse events and preliminary effectiveness will be compared by treatment group. Using the final population PK model, empirical Bayesian estimates will be generated for each patient. Preliminary effectiveness will be measured by the incidence of moderate to severe BPD or death at 36 weeks and change in the BPD risk estimation.

Pathologic Mechanical Signaling Mediated by Rac2 Promotes the Foreign Body Response to Biomedical Implants

PURPOSE: An estimated $170 billion is spent annually on biomedical devices including breast implants, pacemakers, neurostimulators and orthopedic prostheses around the world. However, between 10% and 30% of these devices fail prematurely. In most cases, implant failure occurs due to a phenomenon termed the foreign body response (FBR). FBR begins as a wound healing response to the trauma created from the insertion of a foreign object. A continued presence of the implant exacerbates this response, resulting in the formation of a collagenous fibrous capsule around the implanted object. This process eventually leads to device malfunction as well as distortion of the surrounding tissues. Currently, there are no FDA-approved therapies that effectively prevent debilitating fibrotic capsule formation and the resulting functional complications around biomedical devices. METHODS: We compared human breast implant tissue and a novel murine model of FBR (mechanically stimulating implant or MSI model) to identify the key signaling pathways associated with pathological FBR. Subsequently, we utilized pathway analyses to identify potential molecular targets that are central to the signaling associated with pathological FBR. Finally, we employed small molecule inhibitors of mechanotransduction signaling in our mouse model as a proof of concept for a pharmacological strategy to target FBR and analyzed its effect on FBR capsule formation using immunostaining and histopathology. RESULTS: We first identified that Rac2, a hematopoietic-specific Rho-GTPase, was differentially upregulated in Baker IV compared to Baker I breast implant capsule tissue. Additionally, single cell sequencing of murine capsule tissue from our MSI model of FBR revealed significant differences in the activation of Rac2 and associated inflammatory markers relative to standard murine implants. Finally, we demonstrated that pharmacologically blocking Rac2 signaling in our MSI model significantly reduced the degree of FBR capsule formation as measured by decreased capsule thickness, total collagen deposition, percent mature collagen, and myofibroblast activation. CONCLUSION: Our results highlight the important role of Rac2 as a mediator of pathologic foreign body response in both mice and humans. We demonstrate that pharmacological inhibition of Rac2 may potentially serve as an effective therapy to reduce FBR in patients receiving biomedical implants, thereby increasing patient quality of life and reducing implant failure rates. Further, these findings provide novel insights into the molecular mechanisms underlying fibrotic responses to implanted devices.

New Developing Treatments for Molluscum Contagiosum.

A large variety of treatments for molluscum contagiosum (MC) are available, but none are Food and Drug Administration (FDA) approved and there is no consensus on the optimal approach, mainly owing to a lack of high-level data. Physical modalities are widely used, but require repeated outpatient visits for administration, are painful and difficult to perform in children, and are associated with the possibility of residual scarring and post-inflammatory hypo- or hyperpigmentation. Two experimental topical drugs, a new standardized preparation of topical cantharidin, called VP-102, and a topical nitric oxide (NO)-releasing product containing berdazimer, called SB206, represent promising products that have been designed to overcome the limitations of current treatments. They have recently shown good results in terms of safety and efficacy in large cohorts of patients in phaseIII studies and have the potential to be the first FDA-approved therapies for the treatment of MC.

Therapeutic potential for P2Y2 receptor antagonism.

G protein-coupled receptors are the target of more than 30% of all FDA-approved drug therapies. Though the purinergic P2 receptors have been an attractive target for therapeutic intervention with successes such as the P2Y12 receptor antagonist, clopidogrel, P2Y2 receptor (P2Y2R) antagonism remains relatively unexplored as a therapeutic strategy. Due to a lack of selective antagonists to modify P2Y2R activity, studies using primarily genetic manipulation have revealed roles for P2Y2R in a multitude of diseases. These include inflammatory and autoimmune diseases, fibrotic diseases, renal diseases, cancer, and pathogenic infections. With the advent of AR-C118925, a selective and potent P2Y2R antagonist that became commercially available only a few years ago, new opportunities exist to gain a more robust understanding of P2Y2R function and assess therapeutic effects of P2Y2R antagonism. This review discusses the characteristics of P2Y2R that make it unique among P2 receptors, namely its involvement in five distinct signaling pathways including canonical Gαq protein signaling. We also discuss the effects of other P2Y2R antagonists and the pivotal development of AR-C118925. The remainder of this review concerns the mounting evidence implicating P2Y2Rs in disease pathogenesis, focusing on those studies that have evaluated AR-C118925 in pre-clinical disease models.