Usability and Performance Testing of Pointcheck™: A Noninvasive Neutropenia Screening Device for Chemotherapy Outpatients

Abstract Introduction Every year, approximately 110,000 cancer patients treated with cytotoxic chemotherapy in the US endure at least one episode of febrile neutropenia (FN). Each FN episode will require an approximate 8-9-day admission costing $25,000 and may have associated mortality rates as high as 7% . Timely detection and awareness of severe neutropenia (i.e., Absolute Neutrophil Count (ANC) <500/µL) is key to managing FN. The current gold standard relies on blood draws and analysis is hence limited to the clinical setting. We have developed PointCheck™, a noninvasive, portable technology (Fig. 1-A) that can automatically monitor for severe neutropenia and enables prompt detection in the home- as described in Bourquard et al (2018) and Pablo-Trinidad et al (2019). Methods We conducted a multicenter study to evaluate the usability and diagnostic performance of PointCheck™ in a cohort of 26 participants. The primary study objectives were to assess device usability when operated by first-time users and to meet a priori specified diagnostic performance goals in achieving 92% sensitivity (true positive rate) and 80% specificity (true negative rate). Study coordinators read a short script providing the participants with information about how to use the device. In addition, participants watched a 1-minute tutorial video, were provided with a one-page user guide before attempting to take a measurement on their own following the on-screen Graphical User Interface instructions (Fig. 1-B). They did so autonomously to simulate home usage. Usability data was collected using a combination of methods, including the think-aloud technique, a short-answer qualitative questionnaire, and a standardized quantitative System Usability Survey (SUS)- a usability evaluation method widely used in UI/UX design comprising 10 questions. Participants were also given the opportunity to document their thoughts, feelings, and experience using the device in the form of an e-questionnaire containing 4 questions about their perceptions. Design and functionality issues were primarily identified by the research staff through observation of participants and documentation of missed or incorrectly completed steps. Participants also had their blood drawn for a comparison with their complete blood count (CBC) to assess diagnostic performance. PointCheck™ measurement results were compared with clinical standard CBC tests and assessed for accuracy in classifying subjects as severely neutropenic (<500/µL, grade IV neutropenia) or non-severely neutropenic (≥500/µL). Results Usability and diagnostic performance data was gathered from untrained cancer patients and healthy volunteers. We included patients with lymphoma and myeloma, among other tumor types, who visited either Boston Medical Center (BMC) and Hospital Universitario 12 de Octubre (H12O) for routine chemotherapy administration. The healthy volunteers were recruited at the Massachusetts Institute of Technology Clinical Research Center (MITCRC). The PointCheck™ device detected severe neutropenia with 92% sensitivity and 83% specificity in 24 subjects (Fig. 1-C). Two out of 26 subjects were flagged and excluded by the device Quality Control system. With respect to usability, we found that 80.8% of participants scored above 80.8 on the SUS scale across all sites, with a mean SUS score of 89.1 across all sites (Fig. 1-D). The most common user errors seen were incorrect placement of the finger, hand, and arm. Discussion We have shown that PointCheck™, a novel technology for non-invasive, home-based neutropenia detection, is accurate and easy to use by first-time users in a simulated home environment with a mean SUS score of 89.1, indicating above average perception of user experience and falling within the top 10% of systems as evaluated by the SUS scale. The technology accurately detects severe neutropenia in the cohort of patients presented here, which included liquid tumors, other cancer conditions, and healthy volunteers. These preliminary results show that PointCheck™ is a promising technology to aid in the detection of severe neutropenia in the home setting. These results need to be confirmed in a larger patient cohort with a final device design. Figure 1 Figure 1. Disclosures Lamaj: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Pablo-Trinidad: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Butterworth: Leuko Labs, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bell: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Benasutti: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Verdone: Leuko Labs, Inc.: Current Employment, Current holder of stock options in a privately-held company. Bourquard: Leuko Labs, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Patents & Royalties. Sanchez-Ferro: Leuko Labs, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Patents & Royalties. Castro-Gonzalez: Leuko Labs, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. Sloan: Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Stemline: Honoraria.

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Bleeding Complications in Patients with Cancer and COVID 19- Analysis from the COVID 19and Cancer Consortium (CCC19) Registry

Blood ◽

10.1182/blood-2021-154314 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4997-4997

Author(s):

Surbhi Shah ◽

Shuchi Gulati ◽

Ang Li ◽

Julie Fu ◽

Vaibhav Kumar ◽

...

Keyword(s):

Mechanical Ventilation ◽

Board Of Directors ◽

Stock Options ◽

Research Funding ◽

Tumor Board ◽

Bleeding Complications ◽

Advisory Committees ◽

Icu Admission ◽

Patients With Cancer ◽

Privately Held

Abstract Background : Patients (pts) with COVID-19 are reported to have increased risk of venous thromboembolism yet bleeding has been an under recognized complication. Rates of bleeding remain unexamined in all patients especially in pts with cancer and COVID-19. Aim: To estimate the incidence of bleeding complication in patients with cancer and COVID 19 Methods: The CCC19 international registry (NCT04354701) aims to investigate complications of COVID-19 in pts with cancer. Our aim was to investigate the frequency of bleeding in hospitalized adult pts with cancer andCOVID-19, enrolled between March 16, 2020 and Feb 8, 2021. The incidence of bleeding complications was captured as defined by CCC19 and included both major and non major bleeding . Associated baseline clinic-pathologic prognostic factors and outcomes such as need for mechanical ventilation, intensive care unit (ICU) admission and mortality rates were assessed Results :3849 pts met analysis inclusion criteria. Bleeding was reported in 276 (7%) pts with median age of 70years; incidence was 6.6 % in females and 7.6 % in males, 6.5% in non-Hispanic white pts, 8.2 % in non-Hispanic Black pts, and 7.8 % in Hispanic pts. 74% had solid cancer and 29% had hematologic malignancies, 33% had received anti-cancer therapy in preceding 30 days, and 8% had surgery within 4weeks. In pts taking antiplatelet or anticoagulant medications at baseline, 7.2% developed bleeding. Need for mechanical ventilation, ICU admission, 30-day mortality, and total mortality were significantly higher in those with bleeding complications compared to those without, p<0.05 Conclusion : We describe the incidence of bleeding in a large cohort of pts with cancer and COVID-19. Bleeding events were observed in those with adverse outcomes including mechanical ventilation, ICU admission, and high mortality; the overall mortality of 43% in patients with bleeding complications is especially notable. This important complication may reflect underlying COVID-19 pathophysiology as well as iatrogenic causes. Figure 1 Figure 1. Disclosures Kumar: Diagnostica Stago: Honoraria. Zon: AMAGMA AND RLZ: Consultancy, Current holder of individual stocks in a privately-held company. Byeff: Pfizer, BMS, Takeda,Teva, Merck, United health: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Nagaraj: Novartis: Research Funding. Hwang: astrazaneca,Merck,bayer, Genentech: Consultancy, Research Funding. McKay: Myovant: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calithera: Membership on an entity's Board of Directors or advisory committees; Tempus: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tempus: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dendreon: Consultancy; Caris: Other: Serves as a molecular tumor board ; Vividion: Consultancy; Sorrento Therapeutics: Consultancy; Bayer: Research Funding. Warner: Westat, Hemonc.org: Consultancy, Current holder of stock options in a privately-held company. Connors: Pfizer: Honoraria; CSL Behring: Research Funding; Alnylam: Consultancy; Bristol-Myers Squibb: Honoraria; takeda: Honoraria; Abbott: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Obinutuzumab Short Duration Infusion Is Preferred By Healthcare Providers and Has Minimal Impact on Patient-Reported Symptoms Among Patients with Untreated, Advanced Follicular Lymphoma

Blood ◽

10.1182/blood-2021-147911 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1345-1345

Author(s):

Peter Trask ◽

Jaisson Bortolini ◽

Shinya Rai ◽

Antonio Salar ◽

Miguel Canales ◽

...

Keyword(s):

Follicular Lymphoma ◽

Board Of Directors ◽

Stock Options ◽

Advisory Committees ◽

Bulky Disease ◽

Time Savings ◽

Low Levels ◽

Grade 3 ◽

Privately Held

Abstract Background: Patients with follicular lymphoma (FL) who are on initial treatment, report low levels of symptoms and a higher quality of life index in contrast to patients who have relapsed (Pettengell et al. Ann Oncol 2008). In the immunochemotherapy era, effective and safe treatments should create minimal treatment-related symptoms, regardless of the underlying patient characteristics. In the GALLIUM study (NCT01332968), patients treated with obinutuzumab (G)-chemotherapy followed by G maintenance reported low levels of symptoms (Davies et al. Ann Hematol 2020). Short duration infusions (SDI) of treatments for patients with untreated, advanced FL may yield substantial time savings for patients, and free up healthcare resources. The GAZELLE study (NCT03817853) is a prospective open label, multicenter, single arm, Phase IV study, which evaluated the safety of G administered as a 90-minute (min) SDI infusion from Cycle 2 (C2) onwards in patients with previously untreated advanced FL. G SDI appears to be safe, with no Grade 3 infusion-related reactions (IRRs) reported in C2, and only one Grade 3 IRR reported in subsequent cycles (Canales et al. ASCO 2021). In this analysis, we report symptom levels and provider preference during G SDI administration. Methods: During the first cycle, patients received the first three infusions of G (1000mg) administered at the standard infusion rate on Days 1, 8, and 15. Patients who did not experience any Grade ≥3 IRRs during the first cycle received G as a SDI from C2 onwards. The M.D. Anderson Symptom Inventory (MDASI: range 0 [not present) to 10 [worst]) was used to assess the severity of disease/treatment-related symptoms, and how symptoms interfere with aspects of the patient's daily living. It was completed on Day 1 of C1-6, at the end of induction, during maintenance, at the end of maintenance, and at the end of the study. Additional MDASI analyses were conducted based on patient risk groups (bulky disease, Ann Arbor staging, Eastern Cooperative Oncology Group performance score, B-symptoms, Follicular Lymphoma International Prognostic Index). At any time point after C4 Day 1, study investigators (physicians and nurses) completed an evaluation composed of questions addressing their site's experience with regards to time saved, convenience and infusion preference after administration of SDI and standard infusion of G, across all patients enrolled in the study. Results: 110/113 patients received at least one SDI of G, as per protocol. Median age was 62 years, (range: 28-86 years) and 62% of patients had stage IV FL, 51% presented with B-symptoms at baseline, 45% with bulky disease and 45% were classified as high-risk FLIPI. Median baseline MDASI severity and interference scores were 0 or 1 for most symptoms. Interference scores did not meaningfully change over the course of treatment. Median MDASI scores (baseline or change over treatment), also did not differ by risk subgroups. Over 60% of providers reported that SDI of G would save at least 2 hours in infusion time per visit, with >65% saying it was much more convenient versus regular infusion. SDI was preferred by >95% of providers for reasons attributed to time savings and patient comfort. Conclusions: Untreated, advanced FL patients had no or mild symptom severity and interference at baseline regardless of risk group. These low levels were maintained during G SDI administration. Additionally, SDI administration was preferred by providers for the time it saved, convenience, and comfort for patients, suggesting that G SDI administration can be a beneficial treatment option for untreated, advanced FL patients by minimizing patient treatment burden with no impact on health-related quality of life. Disclosures Trask: Genentech: Current Employment; Genentech/Roche: Current equity holder in publicly-traded company. Bortolini: Novartis: Speakers Bureau. Rai: Janssen Pharmaceutical: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau. Salar: Abbvie: Research Funding; Beigene: Consultancy; BMS/Celgene: Consultancy, Speakers Bureau; EusaPharma: Consultancy; Janssen: Consultancy, Speakers Bureau; Hospital del Mar: Current Employment. Canales: Eusa Pharma: Consultancy, Honoraria; iQone: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Incyte: Consultancy; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Sandoz: Honoraria, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau. Klingbiel: F.Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Parreira: Hoffmann la Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Ended employment in the past 24 months, Honoraria. Deraet: Hoffmann La Roche: Current Employment, Current holder of individual stocks in a privately-held company. Vorozheikina: IQVIA: Current Employment. Hübel: Celgene: Consultancy; Servier: Consultancy, Speakers Bureau; EUSA: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Buchholz: Scripps Health Care System: Current Employment; Roche (Navify software): Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nucleix LLC: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Ultimate Opinions in Medicine LLC: Honoraria; Empyrean medical systems: Membership on an entity's Board of Directors or advisory committees; Mirada: Membership on an entity's Board of Directors or advisory committees.

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SLN124, a GalNAc Conjugated 19-Mer Double-Stranded SiRNA Reduces Iron and Increases Hepcidin Levels of Healthy Volunteers in a Phase 1 Clinical Study

Blood ◽

10.1182/blood-2021-147852 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2009-2009

Author(s):

John B. Porter ◽

Alison Scrimgeour ◽

Alberto Martinez ◽

Leo James ◽

Manuela Aleku ◽

...

Keyword(s):

Board Of Directors ◽

Stock Options ◽

Serum Iron ◽

Phase 1 ◽

Transferrin Saturation ◽

Beta Thalassemia ◽

Advisory Committees ◽

Treatment Groups ◽

The Mean ◽

Privately Held

Abstract Background Hepcidin, a peptide hormone consisting of 25-amino-acids, is the central regulator of systemic iron homeostasis. It is synthesized predominantly in hepatocytes, and dysregulation of its production leads to a variety of disorders of iron metabolism, including iron overload as well as congenital or acquired iron-loading anaemias. These conditions are a major source of morbidity and mortality. SLN124 increases hepatic hepcidin synthesis and hence plasma hepcidin by silencing its repressor, TMPRSS6. SLN124 has been shown to lower serum iron levels for at least 6 weeks after single administration in mice and has also been shown to increase haemoglobin in a mouse model of beta-thalassemia. Here we report results from a randomised, double-blind, placebo-controlled phase 1, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneously (sc) administered SLN124 in healthy volunteers. Objectives The primary objective was to evaluate the safety and tolerability of single ascending doses of SLN124 in healthy subjects. In addition, PK parameters of SLN124 and PD biomarkers of iron metabolism were evaluated. Methods Each subject received a single dose of SLN124 or placebo given by sc injection into their abdomen. Dose levels of 1 mg/kg, 3 mg/kg and 4.5 mg/kg were evaluated. At each dose level, 6 subjects received SLN124 and 2 received matching placebo. Results Three cohorts of 8 subjects (6:2) were included in the study. The mean age of subjects was 31.3 years (SD 7.8) and 71% were male. There were no serious adverse events or severe treatment emergent adverse events (TEAEs) or TEAEs leading to withdrawal. The majority of TEAEs were mild, including transient mild injection site reactions, which resolved without intervention. No dose limiting toxicities were observed. Plasma hepcidin levels at baseline were (mean ± SD) 2.3±1.1, 2.5±1.8 and 2.7±2.0 nM in the three treatment groups, respectively. After a single administration of 1, 3 or 4.5 mg/kg of SLN124, levels were increased by 3.1±2.7, 5.8±2.6 and 7.8±2.9 nM on day 29 and by 2.6±2.6, 2.8±1.4 and 3.5±1.8 nM day 57 post dosing, respectively. Serum iron was reduced by mean (±SD) 32% (26), 40% (14) ,46% (21) on day 8 and by 42% (20), 48% (14) and 47% (26) on day 29 for single doses of 1, 3 and 4.5 mg/kg, respectively. Average percentage changes in all three treatment groups were also still reduced from baseline at day 57. The mean (±SD) percent transferrin saturation (TSAT) was reduced from baseline levels in all single dose administration groups with maximum decreases observed at day 29 but reductions still observed at day 57. (Table 1). The observed PK is consistent with the PK model based on preclinical data. Thus, whereas the effects of SLN124 on plasma hepcidin show clear increments across the dose range tested, the effect on lowering serum iron and transferrin saturation shows something of a plateau effect at the highest dose. In future studies in patients with raised baseline transferrin saturations, it will be of note to determine whether transferrin saturation continues to decrease at the highest SLN124 doses. Conclusion/summary In summary, SLN124, a GalNAc conjugated siRNA targeting TMPRSS6, effectively reduces serum iron levels and has the potential as a therapeutic for patients with alpha and beta-thalassemia, myelodysplastic syndromes, hereditary hemochromatosis and other related disorders. The effect on hepcidin levels at the end of study, day 57, suggest a prolonged duration of action. The encouraging efficacy signal on serum iron and transferrin saturation and the expected benign safety profile of SLN124 supports further development. The GEMINI II trial (NCT04718844) is currently recruiting and wil l evaluate single and multiple doses of SLN124 in patients withthalassemia and myelodysplastic syndromes. Figure 1 Figure 1. Disclosures Porter: bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla Pharmaceuticals: Honoraria; Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees. Scrimgeour: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Martinez: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. James: Silence Therapeutics: Consultancy. Aleku: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Wilson: Silence Therapeutics: Consultancy. Muckenthaler: Silence Therapeutics: Research Funding. Schaeper: Silence Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Campion: Silence Therapeutics: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company.

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Clofarabine-Based Chemotherapy for KMT2Ar Infantile Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2021-148936 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3406-3406

Author(s):

Tanja Andrea Gruber ◽

Deqing Pei ◽

John Kim Choi ◽

Cheng Cheng ◽

Elaine Coustan-Smith ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Stock Options ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

Childhood All ◽

Risk Patients ◽

Severe Infections ◽

Privately Held

Abstract Rearrangements in KMT2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis, with an event-free-survival (EFS) of 33.6-36.9%. In the context of the remarkable improvements in the treatment of childhood ALL, the dismal outcome of infantile KMT2Ar ALL and the lack of any significant progress for more than two decades are striking . The St. Jude Total Therapy 16 study (the most recently reported study of a program for childhood ALL that begun in 1962) yielded a 5-year EFS of 88.2% overall. Total 16 enrolled all subtypes of newly diagnosed pediatric ALL patients including infants, with intensity of treatment adapted to presenting clinical and genomic features, and early treatment response as determined by minimal/measurable residual disease (MRD). KMT2Ar infants were treated on an intensified high-risk arm and received clofarabine in combination with cyclophosphamide and etoposide (CCE) at two points during treatment: Induction days 22-25 and Reinduction I. Infants who lacked KMT2Ar and KMT2Ar patients who were one year of age or older received the same risk-directed treatment plan given to all other patients enrolled on study. A total of 28 patients with KMT2Ar were enrolled on Total 16; the 19 patients > 1 year of age received standard-risk therapy, and the 9 patients < 1 year of age received high-risk therapy on the infant arm with CCE. The probabilities of 5-year EFS and overall survival in KMT2Ar patients > 1 year of age and those < 1 year of age were 73.3% vs. 44.4% (p=0.071) and 84.2% vs. 55.6% (p=0.060), respectively. Six of the nine infants were MRD-positive on Induction day 15 prior to CCE (MRD-positive range, 0.012% to 13.7%; median, 2.13%) with MRD negative status (<0.01%) achieved post CCE in six of the eight patients with data (MRD was 0.011% and 0.07% in the remaining two patients). The trend towards superior outcomes in older KMT2Ar patients was not due to a lower incidence of relapse, as the 5-year cumulative incidence of relapse was 26.7% in patients > 1 year of age and 12.5% for those < 1 year of age (p=0.454). Five infants remain alive (four in CR1, one in CR2), while four expired in CR1. Three deaths were secondary to infection, including a multi-drug resistant soft tissue bacterial infection during Induction days 1-21, a respiratory syncytial virus pneumonia during Reinduction II, and a chronic parainfluenza 3 infection during Continuation weeks 70-101 that led to chronic pneumonitis and interstitial fibrosis. The fourth patient developed grade 5 pulmonary hypertension following induction, a complication potentially compounded by their presenting WBC count of 905 x 10 9/L and pulmonary leukostasis. A comparison of 3-year cumulative risk of selected major toxic effects of treatment revealed that high-risk infants had a lower incidence of asparaginase allergic reactions, osteonecrosis, hyperglycemia, and pancreatitis; in contrast, the incidence of fever and neutropenia, hepatic toxicity and seizures, was similar in high-risk patients regardless of age. Infants had a higher risk of thrombosis (46.7% vs. 23.1%, p<0.001) and of severe infection (70% vs. 19.7%, p<0.001). To further study the contribution of clofarabine to severe infections, we looked at the incidence in high-risk patients > 1 year of age that received one or more clofarabine-containing Reintensification chemotherapy cycles prior to hematopoietic stem cell transplant in first remission (CR1). This revealed a higher frequency of infections in infants, suggesting a greater susceptibility to this complication independent from clofarabine exposure (mean number of episodes, 2.39 vs. 1, p<0.001, Poisson regression modeling). In conclusion, treatment of infants with KMT2Ar ALL with chemotherapy including high-intensity clofarabine leads to a lower cumulative incidence of relapse but a higher risk of treatment-related mortality. Severe infections were a major cause of morbidity and mortality. Disclosures Gruber: Kura Oncology: Consultancy. Coustan-Smith: Juno Therapeutics: Patents & Royalties; Nkarta Therapeutics: Current holder of individual stocks in a privately-held company; Medisix Therapeutics: Current holder of individual stocks in a privately-held company. Campana: Nkarta Therapeutics: Current holder of stock options in a privately-held company; Medisix Therapeutics: Current holder of stock options in a privately-held company; Juno: Other: patent licensing payments; Juno Therapeutics (a Bristol-Myers Squibb company),: Other: patents on methods for minimal residual disease detection.. Evans: St. Jude Children's Research Hospital, Emeritus Member (began Jan 2021): Ended employment in the past 24 months; BioSkryb, Inc.: Membership on an entity's Board of Directors or advisory committees; Princess Máxima Center for Pediatric Oncology, Scientific Advisory Board, Chair: Membership on an entity's Board of Directors or advisory committees. Pui: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Data Monitoring Committee.

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Outcomes for Myelofibrosis Patients Following Myeloablative Allogeneic Stem Cell Transplantation Using the Orca-T Graft from HLA-Matched Related and Unrelated Donors

Blood ◽

10.1182/blood-2021-150521 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1819-1819

Author(s):

Arpita Gandhi ◽

Anna Moroz ◽

Lori Muffly ◽

Parveen Shiraz ◽

Levanto Schachter ◽

...

Keyword(s):

Board Of Directors ◽

Stock Options ◽

Research Funding ◽

Immune Reconstitution ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Donor Chimerism ◽

Marrow Fibrosis ◽

Privately Held

Abstract Background: Allogeneic stem cell transplantation (allo SCT) is the only potentially curative therapy for patients with intermediate-2 and high-risk myelofibrosis (MF). Allo SCT for MF has historically been challenging as many patients are transplanted with active or advanced disease and immune reconstitution in MF patients is often hindered by inflammation and bone marrow fibrosis. When compared to non-SCT therapies, MF patients who receive allo SCT achieve long-term survival benefits. However, it comes with an upfront cost of an increased risk of non-relapse mortality in the first year after allo SCT (Gowin K et al, Blood Av 2020). Therefore, there is an unmet need to improve on the early outcomes of transplantation for MF. Methods: We reviewed MF patients who underwent myeloablative allo SCT with Orca-T derived from HLA matched donors on NCT01660607 and NCT04013685. Orca-T is an investigational cellular product comprising stem and immune cells that leverages highly purified donor regulatory T cells to control alloreactive immune responses. Single agent GVHD prophylaxis was administered as tacrolimus or sirolimus. Results: We present outcomes for 7 MF patients with DIPSS risk of int-1 (n=1), int-2 or higher risk MF (n=6) treated with the Orca-T graft and compared this to 6 MF patients who underwent standard of care (SOC) allo SCT at Stanford, between 2017 - 2021 (Table 1). All patients were high or very high-risk based on MIPSS70 plus score v, 2.0. All patients had 10/10 HLA-matched donors, except 1 of 7 Orca-T patients who had 9/10 HLA-matched donor. All but 1 patient in both, Orca-T and SOC, recipients had prior Jakafi exposure. All Orca-T recipients had splenomegaly with spleen size of 16.3 - 23 cm. Engraftment occurred at median of D+13 (range 10-29) and 6 of 7 patients had 100% CD3 donor chimerism at D+100. 1 patient was 90% CD3 donor chimerism at D+100 but achieved 100% CD3 donor chimerism at D+180. All patients had significant marrow fibrosis, MF grade 2 or 3, before allo SCT. Regression of marrow fibrosis to MF grade 0 or 1 was noted by D+ 100 in 7 of 7 Orca-T recipients but only in 1 of 6 SOC patients. Orca-T recipients did not have grade 2-4 acute GVHD and 1 of 7 recipients had extensive chronic GVHD. Tacrolimus was tapered off in 3 of 7 patients at D+180. SOC recipients had 2 of 6 recipients with grade 2-4 acute GVHD, 3 of 6 recipients with extensive chronic GVHD and only 1 recipient was taken off tacrolimus at D+180. There were no deaths in Orca-T recipients and 2 deaths in SOC recipients before D+180, cause of death was acute GVHD and relapse. Finally, when compared to standard allo SCT, Orca-T recipients may have a reduced frequency and severity of infections without significant consequences while the SOC patients had severe and often multiple infections. Conclusion: Our data indicates that Orca-T graft was well tolerated and potentially efficacious in MF patients undergoing allo SCT. We observed early regression of marrow fibrosis at D+100 in all Orca-T recipients. This limited data suggests that Orca-T may afford an early resolution of an inflammatory microenvironment that allows for robust immune reconstitution and potentially lower incidence of serious infections. Orca-T is under continued investigation to reduce early non-relapse mortality for MF. Figure 1 Figure 1. Disclosures Gandhi: CareDx Inc: Honoraria; Gamida Cell: Consultancy, Membership on an entity's Board of Directors or advisory committees. Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding. Shiraz: Kite Pharma-Gilead: Research Funding. Fernhoff: Orca Bio: Current Employment. McClellan: Orca Bio: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Gotlib: Allakos: Consultancy; Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Meyer: Triursus Therapeutics: Current holder of stock options in a privately-held company; GigaImmune: Current holder of stock options in a privately-held company; Orca Biosystems: Research Funding; Indee, Jura: Consultancy.

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Molecular Biomarker Testing and Targeted Therapy Patterns in Patients with Acute Myelogenous Leukemia (AML) in Community Health Systems in the United States: A Real-World Data Analysis

Blood ◽

10.1182/blood-2021-148634 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4443-4443

Author(s):

Francesca Coutinho ◽

Zartash Gul ◽

Anna B. Berry ◽

Michael A. Thompson ◽

Christopher Allen Willner ◽

...

Keyword(s):

Targeted Therapy ◽

Board Of Directors ◽

Real World ◽

Stock Options ◽

Research Funding ◽

Molecular Testing ◽

Molecular Biomarker ◽

Advisory Committees ◽

Biomarker Testing ◽

Privately Held

Abstract Background and Objective: Molecular testing and treatment patterns for patients (pts) diagnosed with acute myelogenous leukemia (AML) have evolved over recent years. Next-generation sequencing (NGS) technologies allow for detection of somatic gene alterations that have prognostic and/or predictive/therapeutic significance. To describe the real-world testing patterns and clinical management of patients with AML, NGS testing, other molecular testing, mutations detected, and targeted treatment administration were analyzed in 2 large community health systems in the US. Methods: Pts >18 years, diagnosed with AML from January 1, 2015 to December 31, 2020, were identified in the Syapse Learning Health Network, a real-world database with clinical and genomic data from integrated community delivery networks. Study end date was March 31, 2021, allowing for a minimum follow up of 3 months from diagnosis. Pts with less than 2 clinical encounters were excluded. Electronic health records were reviewed retrospectively to analyze molecular biomarker testing patterns, actionable and prognostic biomarkers detected as defined by NCCN guidelines version 3, 2021, and targeted treatments administered. This study received Institutional Review Board (IRB) exemption. Results: The study included 685 pts with median age at AML diagnosis of 70 and median follow up of 5.4 months. 55% were male, 73% were non-Hispanic white, 10% were non-Hispanic black, 31% had ECOG performance status (PS) 0 or 1 and 16% had ECOG PS > 2 at diagnosis, and 69% had de novo AML. Pts with secondary AML consisted of pts evolving from prior myelodysplasia, myeloproliferative disorder, or aplastic anemia, or therapy related AML. 4% had favorable cytogenetic prognosis, 33% intermediate, and 30% adverse, with the remaining 33% unknown. 541 (79%) pts received either NGS or other molecular biomarker tests. 375 (55%) pts received NGS with or without other molecular biomarker tests and 166 (24%) pts received other molecular biomarker tests only [e.g. Sanger Sequencing, RT-PCR (reverse transcription polymerase chain reaction), PCR]. Pts who did not receive molecular biomarker testing (n=144) were older with median age of 78 and median follow-up of 2 months. There was no statistically significant difference in molecular biomarker testing received between non-Hispanic white and non-Hispanic black population (p=0.275) in the study. There was a statistically significant difference in molecular biomarker testing received between de novo (84% tested) and secondary (67% tested) AML (p=<0.001). NGS tested pts had a median time of 0 days from initial diagnosis to specimen drawn and 13 days from specimen drawn to report generation. 80% of pts first received NGS testing in the upfront diagnostic setting, 15% in the relapse or post diagnostic window (>30 days after diagnosis), with 5% missing relevant dates. 294 (78%) pts had NGS performed on bone marrow aspirate. NGS testing rates rose from 9% of pts diagnosed with AML in 2015, to 77% of pts in 2020. Among pts who received molecular testing (n=541), the proportions of pts tested for specific prognostic and actionable biomarkers by year of diagnosis are found in figures 1 and 2. 204 (38%) pts who received molecular testing had an actionable biomarker detected and of those 204 pts, 70 (34%) received at least one targeted therapy. The proportion of pts with one or more actionable mutations (FLT3, IDH1, IDH2) who receive targeted therapy is presented in table 1 below. Conclusions: Real-world data provide insights into molecular testing and targeted therapy patterns in routine clinical practice. In this study, testing uptake has increased over time with most pts diagnosed in 2020 receiving testing for FLT3-TKD, FLT3-ITD, IDH1, IDH2 and NPM1. Testing uptake did not differ by race. Among pts with a documented actionable alteration, one third received a targeted therapy. These findings show progress in testing for pts with targetable biomarkers in AML in the community setting, although further increases in testing and faster results could provide additional clinical benefit. Future directions for this work include analyzing patient outcomes. Figure 1 Figure 1. Disclosures Coutinho: Syapse: Ended employment in the past 24 months. Berry: Syapse: Current Employment, Current holder of stock options in a privately-held company. Thompson: Doximity: Current equity holder in publicly-traded company; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS (Celgene): Membership on an entity's Board of Directors or advisory committees, Research Funding; Syapse Precision Medicine Council: Membership on an entity's Board of Directors or advisory committees; Lilly: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Elsevier ClincalPath (VIA Oncology): Membership on an entity's Board of Directors or advisory committees; Strata Oncology Advisory Board: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate - Plasma Cell Dyscrasia: Patents & Royalties; TG Theerapeutics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; LynxBio: Research Funding; Amgen: Research Funding; Epizyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Denovo: Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Hoosier Research Network: Research Funding. McCracken: Syapse: Current Employment, Current holder of stock options in a privately-held company. Geverd: Syapse: Current Employment, Current holder of stock options in a privately-held company. Law: Syapse: Current Employment, Current holder of stock options in a privately-held company. Wolf: Syapse: Current Employment, Current holder of stock options in a privately-held company. Brown: Syapse: Current Employment, Current holder of stock options in a privately-held company; GenomiCare Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Sygnomics: Current holder of individual stocks in a privately-held company. Kuriakose: Alexion: Speakers Bureau; Celgene, Takeda, Pfizer, Kedrion, Apellis, Sanofi-Genzyme, Chiesi, TG Therapeutics, CSL Behring, CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Via industry sponsored institutional clinical trials.: Research Funding.

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A Novel Methodology for Building Longitudinal, Patient-Centric Real World Datasets in Hemophilia A

Blood ◽

10.1182/blood-2021-146160 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 594-594

Author(s):

Mark W Skinner ◽

Gillian Hanson ◽

Tao Xu ◽

Richard Ofori-Asenso ◽

Richard H. Ko ◽

...

Keyword(s):

Board Of Directors ◽

Real World ◽

Stock Options ◽

Research Funding ◽

Hemophilia A ◽

Advisory Board ◽

Real World Data ◽

Advisory Committees ◽

Patient Reported ◽

Privately Held

Abstract Background: There are limited real-world data (RWD) available on the unmet needs of people with mild or moderate hemophilia A (PwHA). This population accounts for 40-52% of all PwHA, including nearly all women with hemophilia A (HA), and is under-represented in scientific literature (Michele, et al. Haemophilia 2014; Benson, et al. Blood Transfus 2018; Peyvandi, et al. Haemophilia 2019). Available claims data from payer databases are confined to billing codes, and lack key information on outcomes and disease characterization (e.g. severity, treatment response.) (Tyree, et al. Am J Med Qual 2006). Registry datasets can require resource-intensive data entry and potentially miss key information about care received at outside facilities, at home, or after patients switch providers (Gliklich, et al. Registries for Evaluating Patient Outcomes: A User's Guide. 2014). To address these data gaps, we developed a novel, patient-centered approach to create a longitudinal healthcare database from individuals with mild and moderate HA in the United States. This study assessed the feasibility of this approach, which integrates medical record data collected during routine clinical care along with patient-reported outcomes (PROs) to provide needed insights into this under-represented population. Methods: Recruitment began in June 2020 via a broad strategy of social media outreach, healthcare provider partnerships, and patient advocacy groups. Eligibility was confined to mild or moderate PwHA, confirmed via physician report within provider notes in combination with baseline factor VIII levels (>5-50% mild, 1-5% moderate.) This study received research ethics board approval and abides by the guiding principles of the Declaration of Helsinki. PwHA enrolled via an online record management platform, PicnicHealth. After signing authorization forms for collection of their electronic health records (EHR) and informed consent to share their de-identified data for research, participants were prompted to enter information on their care providers. Records were gathered from all providers, across any facility, retrospectively as records were available. (Figure 1) All records obtained were made available to the participants via a medical timeline. Records were translated to text via optical character recognition with human review. Data elements from structured text as well as disease-specific elements from narrative text were captured using natural language processing and supervised machine learning. All elements, including visit metadata, conditions, measurements, drugs, and procedures were mapped to standardized medical ontologies and reviewed by a team of nurses. (Table 1) Quality control was assessed via inter-abstractor agreement on outputs with physician review. Patient-reported bleed, treatment, and pain data were collected via online questionnaire for a subset of PwHA, with participants prompted to enter data every 2 weeks. Abstracted EHR data was linked to PRO responses in a de-identified dataset. Cohort and abstraction characteristics were summarized descriptively. Results: From June 1, 2020 to June 30, 2021, 104 PwHA met eligibility criteria for enrollment (65 [62.5%] mild; 39 [37.5%] moderate). Participants saw providers across 34 states in the US, 22.1% (23/104) were female, and 20.6% (14/68) of those with known race/ethnicity status were from minority groups. Records were gathered from a median of six care sites and 16 providers per participant. A median of 50 (IQR [21-93]) clinical documents from 11 years were processed for each PwHA. (Table 2) Inter-abstractor agreement to assess abstraction quality averaged 95.9% for condition, 99.5% for drug name, and 95.4% for drug start date. As of June 2021, the average PRO response rate was 90.3% (150/166 of all requests) and continues prospectively. Conclusions: The patient-centric data collection methods implemented in this study provide a novel approach to build longitudinal real-world data sets. Technology-enabled data abstraction showed consistent high quality when processing the heterogeneous clinical records across disparate providers and care sites, and direct engagement with patients complements potential gaps in the clinical record. Additionally, this approach provides needed data on groups under-represented in RWD and traditional PwHA cohorts, including those with mild and moderate disease and women with HA. Figure 1 Figure 1. Disclosures Skinner: ICER: Membership on an entity's Board of Directors or advisory committees; Spark (DMC): Honoraria; Sanofi: Honoraria; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Honoraria; Pfizer (DMC): Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; uniQure: Research Funding; Takeda: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Freeline: Research Funding; BioMarin: Honoraria, Research Funding; IPA Ltd.: Current holder of individual stocks in a privately-held company; National Hemophilia Foundation: Consultancy; Institute for Policy Advancement Ltd: Current Employment; WFH USA: Membership on an entity's Board of Directors or advisory committees; BCBS MAP: Membership on an entity's Board of Directors or advisory committees. Hanson: PicnicHealth: Current Employment, Current holder of stock options in a privately-held company. Xu: F. Hoffmann-La Roche AG: Current Employment. Ofori-Asenso: F. Hoffmann-La Roche Ltd: Current Employment. Ko: Genentech, Inc.: Current Employment; Genentech, Inc.-Roche: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Cibelli: PicnicHealth: Current Employment. Nissen: Novartis: Consultancy; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. Witkop: Roche Advisory Panel: Consultancy; National Hemophilia Foundation: Current Employment. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Shapiro: Novartis: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Octapharma: Research Funding; Pfizer: Research Funding; OPKO: Research Funding; Prometric BioTherapeutics: Research Funding; Sangamo: Other: Advisory board fees, Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Takeda: Research Funding; Kedrion Biopharma: Research Funding; Glover Blood Therapeutics: Research Funding; Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; BioMarin: Research Funding; Agios: Research Funding.

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Diversity of Intratumoral Regulatory T Cells in Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2021-152801 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3519-3519

Author(s):

Ivana Spasevska ◽

Ankush Sharma ◽

Chloe B. Steen ◽

Sarah Josefsson ◽

Yngvild Nuvin Blaker ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Stock Options ◽

Advisory Committees ◽

Checkpoint Receptors ◽

Unique Signature ◽

Privately Held

Abstract Introduction: Regulatory T cells (Tregs), a highly immunosuppressive subset of CD4 + T cells, represent a key challenge in the tumor microenvironment by limiting potent antitumor immune responses. While high densities of tumor-infiltrating Tregs are associated with poor prognosis in patients with various types of solid cancers, their prognostic impact in B-cell non-Hodgkin lymphoma (NHL) remains unclear. Emerging studies suggest substantial heterogeneity in the phenotype and suppressive capacities of Tregs, emphasizing the importance of understanding Treg diversity and the need for additional markers to identify highly suppressive Tregs. Our in-depth characterization of Tregs in NHL tumors could open new paths for rational drug design, facilitating selective therapeutic manipulation of Tregs to reduce immunosuppression and improve anti-tumor immunity. Methods: Single-cell suspensions from NHL patients (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and healthy donors (tonsils and peripheral blood)) were analyzed by fluorescent flow- and mass cytometry to characterize Tregs, focusing on their expression of co-stimulatory and co-inhibitory checkpoint receptors. The immunosuppressive capacity of Tregs was measured by in vitro co-culture of FACS-sorted subsets of Tregs together with autologous CellTrace Violet-labelled T effector cells as responder cells, using samples from FL and tonsils. Live CD4 + T cells were obtained by FACS sorting from DLBCL (n = 3), FL (n = 3) and healthy donor tonsils (n = 3) and subjected to single-cell RNA sequencing (scRNA-seq), Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) and scTCR-seq by the 10X Genomics platform. The computational framework of CIBERSORTx was used to generate unique signature matrices for the three Treg subsets identified by scRNA-seq, to facilitate validation in separate scRNA-seq cohorts (King, Sci Immunol 2021; Roider, Nat Cell Biol 2020), and to impute frequencies of the Treg subsets in cohorts with bulk RNA-seq data (Chapuy, Nat Med 2018; Schmitz, NEJM 2018; Pastore, Lancet Oncol 2015). Results: Immunophenotyping by mass cytometry revealed a subset of activated Tregs identified by co-expression of TIGIT, CTLA-4, PD-1, ICOS and OX40, and higher expression of FOXP3, CD25 and CD45RO, that was present in DLBCL and tonsils, but lacking in peripheral blood. This was validated by fluorescent flow cytometry, demonstrating significantly higher frequencies of activated Tregs in NHL tumors compared to PBMCs and tonsils from healthy donors. The phenotypic heterogeneity of intratumoral Tregs reflected different suppressive capacities as activated Tregs more potently suppressed the proliferation of autologous effector CD4 + and CD8 + T cells than naïve Tregs. For global transcriptomic profiling of CD4 + T cells from FL, DLBCL and tonsillar samples, we integrating scRNA-seq and CITE-seq data from 17,774 cells, revealing 13 distinct cellular states including three states of Tregs: naïve, activated and non-conventional LAG3 +FOXP3 - Tregs. Activated Tregs had higher expression of checkpoint receptors (TNFRSF4, TNFRSF18, ICOS), phosphatases (DUSP2, DUSP4), NF-κB pathway (NFKBIA, TNFAIP3, NFKBIZ, REL), chemokine receptors (CXCR4) and transcription factors (JUNB, IRF1, STAT3) as compared to naïve Tregs. We next used a computational approach to develop unique signature matrices for each Treg subset. This approach demonstrated strong concordance between CIBERSORTx estimated cell abundances of the three Treg subsets and the ground truth, and was validated in two external scRNA-seq cohorts. The development of unique signature matrices for Treg subsets facilitated imputation of their frequencies in bulk RNA-seq datasets. These analyses revealed that higher frequency of activated Tregs was enriched in the germinal B cell subtype of DLBCL and was associated with adverse outcome in FL. Conclusion: This study demonstrates that Tregs infiltrating NHL tumors are transcriptionally and functionally diverse and include highly immunosuppressive activated Tregs co-expressing several checkpoint receptors, which distinguish them from peripheral blood Tregs. Activated intratumoral Tregs could hamper clinical responses to checkpoint blockade, and identifying and targeting their vulnerabilities has the potential to improve anti-tumor immune responses. Disclosures Holte: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Nordic: Membership on an entity's Board of Directors or advisory committees; Nanovector: Membership on an entity's Board of Directors or advisory committees, Other: lectures honorarias; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Alizadeh: Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Roche: Consultancy, Honoraria; Janssen Oncology: Honoraria; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Bristol Myers Squibb: Research Funding.

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Follow-up of More Than 5 Years in a Cohort of Patients with Hemophilia B Treated with Fidanacogene Elaparvovec Adeno-Associated Virus Gene Therapy

Blood ◽

10.1182/blood-2021-150541 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3975-3975

Author(s):

Ben J. Samelson-Jones ◽

Spencer K. Sullivan ◽

John E.J. Rasko ◽

Adam Giermasz ◽

Lindsey A. George ◽

...

Keyword(s):

Board Of Directors ◽

Stock Options ◽

Research Funding ◽

Phase 1 ◽

Hemophilia B ◽

Advisory Committees ◽

Adeno Associated Virus ◽

Privately Held

Abstract Fifteen patients with moderately severe to severe hemophilia B (factor IX [FIX] activity ≤2%) were treated with fidanacogene elaparvovec at a dose of 5e11 vg/kg as part of a phase 1/2a study. The study was 52 weeks in duration, after which patients were eligible to enroll in the long-term follow-up (LTFU) study of up to 5 years. All 15 patients completed the phase 1/2a study, and 14 patients were subsequently enrolled in the LTFU study. At the time of the data cut (December 2020), 13 patients were enrolled in the LTFU study, with follow-up ranging from >2.5 years to >5 years following vector administration. Over this period of time, fidanacogene elaparvovec remained generally well tolerated. As reported previously, 3 patients were treated with corticosteroids within the first 6 months of the phase 1/2a study. No patients have required treatment or re-treatment with corticosteroids in the LTFU study. There were no serious adverse events (SAEs) in the phase 1/2a study, and 3 patients reported SAEs in the LTFU study, none of which were considered treatment related. No patient developed an inhibitor or had a thrombotic event. No patients have developed hepatic masses or significant elevations in alpha-fetoprotein (AFP). Annual liver ultrasounds revealed only hepatic steatosis in one patient. Mean FIX activity levels by year remain in the mild hemophilia severity range: 22.8%, year 1 (n=15); 25.4%, year 2 (n=14); 22.9%, year 3 (n=14); 24.9%, year 4 (n=9); and 19.8%, year 5 (n=7) when evaluated centrally using the ACTIN/FSL one-stage assay. These levels have been associated with mean annualized bleeding rates ranging from 0-0.9 over the course of follow-up, and no patients have resumed FIX prophylaxis. Four patients have undergone 6 surgical procedures during the LTFU study, 4 elective and 2 emergent. There were no bleeding complications with these procedures, and the 2 emergent procedures (appendectomy and lumbar discectomy) were performed without the need of additional FIX. Overall, this represents the largest cohort of hemophilia B patients with a duration of follow-up up to 5 years following treatment with an adeno-associated virus gene therapy expressing a highly active variant of FIX. Fidanacogene elaparvovec remains generally well tolerated over a period up to 5 years postinfusion. While encouraging, more long-term data in a larger cohort of patients are needed to further characterize the safety and durability of fidanacogene elaparvovec, which is under way in an ongoing phase 3 study. Disclosures Samelson-Jones: Pfizer: Consultancy, Research Funding; Spark: Research Funding. Sullivan: Genentech: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees. Rasko: Imago: Consultancy; Cynata: Honoraria, Speakers Bureau; Gene Technology Technical Advisory Board: Membership on an entity's Board of Directors or advisory committees; NHMRC Mitochondrial Donation Expert Working Committee: Membership on an entity's Board of Directors or advisory committees; Australian Cancer Research: Membership on an entity's Board of Directors or advisory committees; Cure the Future Foundation: Membership on an entity's Board of Directors or advisory committees; FSHD Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Australian Government: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer Inc: Honoraria, Speakers Bureau; Glaxo-Smith-Kline: Honoraria, Speakers Bureau; Spark: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; bluebird bio: Honoraria, Speakers Bureau; Genea: Current equity holder in publicly-traded company; Celgene: Honoraria, Speakers Bureau. Giermasz: BioMarin: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Bayer: Consultancy; ATHN: Consultancy; NovoNordisk: Consultancy; UniQure: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Bioverativ/Sanofi: Consultancy, Research Funding, Speakers Bureau; Sangamo Therapeutics,: Research Funding. George: CSL Behring: Consultancy; Bayer: Consultancy; Avrobio: Other: Data Safety Monitoring Committee . Ducore: Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Speakers Bureau; HEMA Biologics: Consultancy, Honoraria. Teitel: Pfizer: Consultancy, Research Funding; Spark: Research Funding; Bayer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novo Nordisk: Consultancy; Octapharma: Consultancy; CSL Behring: Consultancy. McGuinn: Biogen: Research Funding; Roche/Genentech: Research Funding; Shire/Baxalta: Consultancy, Research Funding; Spark: Research Funding. O'Brien: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Winburn: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Smith: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Chhabra: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Rupon: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

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Pozelimab, a Human Monoclonal Antibody Against Complement Factor C5, Provided Inhibition of Intravascular Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria

Blood ◽

10.1182/blood-2021-146178 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1128-1128

Author(s):

Jun-Ho Jang ◽

Jonathan Weyne ◽

Umesh Chaudhari ◽

Olivier Harari ◽

Jutta Miller ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Stock Options ◽

Complement Factor ◽

Intravascular Hemolysis ◽

Open Label ◽

Advisory Committees ◽

Open Label Extension ◽

Clinically Significant ◽

Privately Held

Abstract INTRODUCTION Paroxysmal Nocturnal hemoglobuinuria (PNH) is a rare, acquired, life-threatening disorder characterised by intravascular hemolysis and increased risk of thrombosis. Current available treatments represent a significant burden to patients and include anti-complement factor 5 (C5) therapies, eculizumab and ravulizumab, both intravenous infusions, or more recently, twice weekly C3 inhibitor, Pegcetacoplan, a subcutaneous (SC) infusion treatment. Pozelimab (REGN3918), a fully human monoclonal immunoglobulin G4 antibody directed against C5, has been shown to bind with high affinity to wild-type and variant (R885H/C) human C5 and block its activity. In a healthy volunteer study (NCT03115996), SC administration of pozelimab was found to be generally well tolerated while providing complete inhibition of ex vivo-assessed hemolytic activity [Weyne J et al. Blood. 2018;S1:1039]. The data suggested that pozelimab may provide control of intravascular hemolysis in patients with active PNH, and thus could provide an important new alternative for patients supporting progression to a first-in-patient study of pozelimab in patients with active PNH. OBJECTIVE To demonstrate a clinically significant reduction in intravascular hemolysis by once-weekly SC administration of pozelimab over 26 weeks of treatment in patients with active PNH. METHODS This is a phase 2, open-label, single-arm, 26-week treatment study in 24 patients with active symptomatic PNH who are naïve to complement inhibitor therapy, or who have received prior treatment with a complement inhibitor but not within 6 months prior to the start of the study (NCT03946748). The treatment regimen consists of pozelimab as a single IV loading dose of 30 mg/kg followed thereafter by weekly SC 800 mg administrations. The effect of pozelimab on intravascular hemolysis (monitored via LDH levels) and transfusion avoidance, as well as safety, is to be assessed from baseline to week 26 (study day 183; only partial data were available for some patients at the time of abstract submission). Pozelimab pharmacodynamics was assessed utilizing a sheep red blood cell (RBC) complement activity assay (CH50) and rabbit RBC complement activity assay (AH50). RESULTS All 24 patients completed the 26-week treatment period with no study drug discontinuation and have been enrolled into an ongoing open-label extension study (NCT04162470). An interim analysis on the first 17 patients was previously reported. All 17 patients had at least 71 days of treatment, with 10 patients receiving treatment for up to 183 days. All enrolled patients had baseline LDH levels ≥2 x upper limit of normal (ULN). Participants were enrolled in two cohorts: Cohort A for dose confirmation and Cohort B for further evaluation of efficacy and safety. Interim Efficacy Analysis As previously reported, treatment with pozelimab led to a rapid and sustained reduction in LDH through study week 26. All 17 patients achieved LDH reduction to below the clinically significant threshold of LDH ≤1.5 x ULN. All but one patient achieved control of intravascular hemolysis (LDH ≤1.5 x ULN) at week 2, and all but one patient achieved normalization of LDH (LDH ≤1.0 x ULN) at week 4. Importantly, one patient who is a carrier of a C5 variant known to be resistant to blockade by eculizumab/ravulizumab demonstrated rapid and sustained normalization of LDH. Interim Safety As previously reported, no serious adverse events or adverse events leading to treatment discontinuation were reported. Common treatment-emergent adverse events included headache (4 patients; 23.5%) and nausea (2 patients; 11.8%). No breakthrough hemolysis events were observed. CONCLUSIONS Pozelimab administered SC once weekly led to the inhibition of intravascular hemolysis in patients with active PNH and was generally well-tolerated. An update to the previously reported interim analysis will be provided. Upon successful completion of the 26-week treatment period, patients are enrolled into an open-label extension study. Disclosures Weyne: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chaudhari: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Harari: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Miller: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Dain: Regeneron Pharmaceuticals, Inc.: Other: Contractor. Meagher: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Rodgers: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Perlee: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Morton: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Weinreich: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Yancopoulos: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Griffin: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioCryst Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Educational grant support.

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