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

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.

Download Full-text

Long-Term Use of Open-Label Romiplostim in Children with Chronic/Refractory Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v120.21.621.621 ◽

2012 ◽

Vol 120 (21) ◽

pp. 621-621

Author(s):

James B Bussel ◽

George R. Buchanan ◽

David J. Gnarra ◽

Richard H. Ho ◽

Kun Nie ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Extension Study ◽

Open Label ◽

Advisory Committees ◽

Bone Marrow Biopsies ◽

Platelet Counts ◽

Open Label Extension

Abstract Abstract 621 Background: Treatment options for children with chronic/refractory ITP are not well characterized. In a phase 1/2 16-week randomized double-blind placebo-controlled study of 22 patients (romiplostim n = 17, placebo n = 5), the thrombopoietin (TPO) receptor agonist romiplostim was well tolerated and 15 of 17 romiplostim-treated patients achieved platelet counts ≥50×109/L (Bussel et al, Blood 2011). Twenty-one of 22 patients from this phase 1/2 study subsequently entered an open-label extension study; 1/21 patients discontinued the extension study before receiving romiplostim. For the 20 patients who received romiplostim in the first extension study, the mean duration of treatment was 1.6 years (range, 0.1 to 2.1 years); all 20 achieved platelet counts >50×109/L (Nugent et al, 2011 ASPHO abstracts). Of the 17 patients who completed this extension study, 12 rolled over into a second open-label extension study for up to 2.5 years of further romiplostim treatment. Results from those 12 patients are described here. Objective: To investigate the safety and efficacy of long-term use of romiplostim in pediatric ITP. Methods: During the second extension study, patients received weekly subcutaneous injections of romiplostim with the initial dose being the same as the last dose in the prior study. Dose adjustment was allowed to maintain platelet counts in the target range of 50–200×109/L. The maximum allowed romiplostim dose was 10 μg/kg. The primary endpoint of this study was incidence of adverse events; platelet response was a secondary endpoint. The protocol did not require bone marrow biopsies to be conducted at pre-defined intervals, but any bone marrow biopsies performed as clinically indicated were to be analyzed. As deemed appropriate by investigators, patients or their caregivers had the option to administer romiplostim at home during this study; those patients who administered romiplostim at home used diary cards to record dosing date, time, volume administered, and any dosing errors. Patients who turned 18 years of age during this study were permitted to remain on study. Results: Baseline demographics for this second extension study included a median age of 12 years (range 3, 16 years), 67% male, and 33% with a prior splenectomy. Median romiplostim treatment duration in this second extension study was 118.9 weeks (range 100.1, 125.9 weeks); median average weekly romiplostim dose was 5.2 μg/kg (range 1, 10 μg/kg). Of the 3 patients who discontinued the study, 2 withdrew consent and 1 was noncompliant; no patients withdrew due to safety issues and 9 continued on study. Median platelet counts for all 12 patients were above 50×109/L throughout, and were in the target range of 50–200×109/L for all visits but Weeks 3 and 76 (Figure). Interestingly, the median dose decreased over time from a median (Q1, Q3) of 8.0 (5.5, 9.0) μg/kg at Week 1 to 1.0 (0.0, 6.0) μg/kg at Week 116 (last timepoint for which data are available) (Figure). Two patients received rescue medications (defined as medications used for platelet counts <10×109/L, bleeding/wet purpura, or investigator decision); one patient received platelet transfusions and another prednisone. Four patients (33.3%) had serious adverse events (asthma, epistaxis, hemangioma, hypotension, pyrexia, thrombocytopenia, and transfusion reaction) and one had a life-threatening adverse event (thrombocytopenia). None of the adverse events were deemed treatment-related by the investigators. There were no fatal adverse events. Eight patients had bleeding adverse events; one of which (gingival bleeding) was deemed treatment-related. These bleeding adverse events included epistaxis (4 patients), petechiae (3 patients), gingival bleeding (2 patients), and (in 1 patient each) bleeding from the anus, injection site, lip, and mouth; 1 patient also had unspecified bleeding. No bone marrow biopsies were reported to have been performed. Conclusion: In this open-label extension study, romiplostim increased platelet counts in pediatric patients with chronic ITP without significant toxicity. Thus, romiplostim has been well tolerated and shown to be of clinical benefit to pediatric patients with refractory severe chronic ITP. As this study is ongoing, future results will provide additional data regarding even longer-term use of TPO receptor agonists in this patient population. Disclosures: Bussel: Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy; Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: The use of romiplostim in pediatric patients was examined in this study. Nie:Amgen: Employment, Equity Ownership. Eisen:Amgen: Employment, Equity Ownership.

Download Full-text

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.

Download Full-text

Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Download Full-text

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.

Download Full-text

Sustained Improvement in Health-Related Quality of Life in Patients with Hemophilia A with or without Inhibitors Treated with Fitusiran Prophylaxis

Blood ◽

10.1182/blood-2021-147286 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3197-3197

Author(s):

Viridiana Cano ◽

José Bartelt-Hofer ◽

Wenruo Hu ◽

Shauna R. Andersson ◽

Pronabesh Dasmahapatra ◽

...

Keyword(s):

Quality Of Life ◽

Board Of Directors ◽

Phase 1 ◽

Publicly Traded ◽

Open Label ◽

Advisory Committees ◽

Open Label Extension ◽

Related Quality

Abstract BACKGROUND Fitusiran is an investigational, subcutaneous (SC), prophylactically administered small interfering RNA (siRNA) therapeutic. It targets antithrombin and restores thrombin generation sufficient to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors. Long-term exposure to fitusiran is being studied in a Phase 1/2, 6-year open-label extension study (NCT02554773) in patients with hemophilia (PwH) A or B with or without inhibitors. Improvement in the health-related quality of life (HRQoL) as measured by Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) total score, and specifically in the physical health domain was previously reported by von Mackensen et al. for PwHA with inhibitors (NCT02554773, N=17, von Mackensen et al. Blood 2020;136(1):23-24). This analysis aimed to present HRQoL changes from baseline to last available measure (LAM), as measured by the Haem-A-QoL total score and domains (filtered by actual treatment exposure following 2 voluntary dosing holds) in PwHA, with or without inhibitors, who continued into the Phase 2 open-label extension study. METHODS Participants who completed the Phase 1 study (NCT02035605) were eligible to participate in Phase 2 long-term exposure study (NCT02554773). All participants received fixed monthly doses of 50 mg (N=9) or 80 mg (N=18) of fitusiran. HRQoL data were collected in 3-month lapse periods. Mean changes from baseline to LAM were calculated for the Haem-A-QoL (total score and domains). RESULTS As of February 2021, 26 severe and 1 moderate PwHA (13 with, 14 without inhibitors) with mean baseline age (SD) 37.3 (9.7) were treated for up to mean (SD) 33.32 (17.06) months. For the total Haem-A-QoL score and each of 10 domains, mean improvements from baseline to LAM (lower scores denoting better HRQoL) were consistently observed in PwHA (except for the sport & leisure domain that was higher in the non-inhibitor group). Mean estimated reductions (SD) in the Haem-A-QoL total score were -8.33 (13.84) and -9.16 (14.55) while that in the physical health domain score were -13.21 (25.07) and -7.14 (22.80), for PwHA with and without inhibitors respectively (Table 1). When comparing Haem-A-QoL domains in inhibitor to non-inhibitor participants, results suggest a modest favorable trend for non-inhibitor patients (greater reductions in 4 vs 6 domains, respectively). CONCLUSIONS Mean improvements in the Haem-A-QoL total scores and 9 out of 10 domains suggest sustained HRQoL improvements in PwHA. Small sample size and outlying results might limit the interpretation. Further research in HRQoL for fitusiran will include a larger population on the new 50 mg every other month dose regimen, and notably Phase III results from NCT03549871 (open-label study in patients switching to fitusiran from previous prophylaxis or bypassing agents) and NCT03754790 (open-label, long-term safety and efficacy study of fitusiran) in various subpopulations. Figure 1 Figure 1. Disclosures Cano: Sanofi Genzyme: Current Employment, Current equity holder in publicly-traded company; Takeda: Ended employment in the past 24 months. Bartelt-Hofer: Sanofi: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Hu: Sanofi: Current Employment. Andersson: Sanofi: Current Employment, Current equity holder in publicly-traded company; WEST advisory committee member: Membership on an entity's Board of Directors or advisory committees. Dasmahapatra: Sanofi: Current Employment, Current equity holder in publicly-traded company. Von Mackensen: Biomarin: Speakers Bureau; Novo Nordisk: Consultancy; Sanofi: Consultancy; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; University Medical Centre Hamburg-Eppendorf: Current Employment; CSL Behring: Speakers Bureau; Chugai/Roche: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Phase 3, Placebo-Controlled, ASPIRE Study (TRC114968) of Eltrombopag (EPAG) Treatment of Thrombocytopenia (TCP) in Advanced Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML): Assessment of Clinical Benefit, Safety, and Tolerability

Blood ◽

10.1182/blood.v126.23.1661.1661 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1661-1661 ◽

Cited By ~ 1

Author(s):

Moshe Mittelman ◽

Uwe Platzbecker ◽

Boris V Afanasyev ◽

Sebastian Grosicki ◽

Raymond SM Wong ◽

...

Keyword(s):

Platelet Count ◽

Adverse Events ◽

Research Funding ◽

Open Label ◽

Employment Equity ◽

Advisory Committees ◽

Once Daily ◽

Thrombopoietin Receptor ◽

Open Label Extension ◽

Equity Ownership

Abstract Introduction: Thrombocytopenia (TCP) is a serious and life-threatening complication of advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Eltrombopag (EPAG), an oral thrombopoietin-receptor agonist, is approved for treatment of chronic immune thrombocytopenic purpura and severe aplastic anemia. Preclinical studies showed that EPAG has potential antileukemic effects. A phase 1 study in advanced MDS/AML demonstrated an acceptable safety profile at doses up to 300 mg, with no worsening of leukemia, and it also showed a trend towards efficacy. Eltrombopag as monotherapy in MDS/AML has not been studied in a randomized fashion. Methods: In Study TRC114968 (ASPIRE), after 8 weeks of open-label, dose-defining EPAG treatment (Study Part 1), patients with highly advanced MDS or AML were randomized 2:1 to EPAG 100-300 mg or placebo (PBO) once daily for 12 weeks (Part 2), then entered a 6-month, open-label extension (Part 3). Patients were stratified by baseline platelet count (<10 Gi/L vs ≥10 Gi/L), and by MDS vs AML. Eligibility included 10-50% baseline bone marrow blasts and a baseline platelet count of <25 Gi/L. The primary endpoint was improvement in the clinically relevant thrombocytopenic event (CRTE) rate during the 12-week double-blind period. CRTE was a composite of a platelet transfusion requirement, significant bleeding event, or platelet count <10 Gi/L. Part 1 results have been presented previously. Blinded results for patients randomized in Part 2 of the study are presented below. Analyses of results by treatment arm, including those for the primary endpoint of CRTE, are ongoing and will be presented at the meeting. Results: A total of 145 patients were enrolled and randomized. According to WHO criteria, 72 (50%) had MDS and 73 (50%) had AML. See Table 1 for baseline characteristics. The majority of patients (n=91, 63%) were escalated to 300 mg (150 mg for East Asians) once daily. 70 patients (48%) completed the randomized portion of the study, and 58 (40%) entered the open-label extension. Patient disposition is described in Table 2. Out of the 144 treated patients, 97 patients (67%) have died (67 patients in Part 2 and 30 patients in Part 3). The main reasons for withdrawal from the study were adverse events (49 patients, 34%) and progressive disease (39 patients, 27%). The most common adverse events in Part 2 were petechiae, epistaxis, fatigue, pyrexia, and diarrhea. The main serious adverse events in Part 2 were pneumonia, sepsis, and febrile neutropenia. Liver test abnormality occurred in 1 (<1%). The median number of platelet transfusions for both groups was 10. Conclusions: This is the first study to evaluate EPAG as monotherapy in a randomized fashion in patients with advanced MDS or AML and severe thrombocytopenia. Overall safety was as expected for this patient population with no unexpected adverse events. This study provides evidence for the safety of EPAG in this mostly heavily pretreated patient population. An Independent Response Committee (IRC) is currently assessing responses and disease progression centrally by arm, and final data will be presented at the meeting. Funding: This study was sponsored by GlaxoSmithKline; eltrombopag is an asset of Novartis AG as of March 2, 2015. Disclosures Mittelman: Celgene: Research Funding, Speakers Bureau; GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding, Speakers Bureau; Novartis Pharmaceuticals Corporation: Research Funding; Roche: Research Funding; Amgen: Research Funding. Off Label Use: Eltrombopag is a once daily oral thrombopoietin receptor agonist approved for treatment of chronic ITP, hepatitis C associated thrombocytopenia, severe aplastic anemia, and pediatric cITP. Data will be presented on use in myeloid malignancies for which eltrombopag is not approved.. Platzbecker:Novartis: Honoraria; Celgene: Honoraria; Amgen, Inc.: Honoraria; GlaxoSmithKline: Honoraria, Research Funding. Wong:Johnson & Johnson: Research Funding; Bristol-Myers Squibb: Research Funding; Merck Sharp & Dohme: Research Funding; Biogen-Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding; GlaxoSmithKline: Research Funding. Anagnostopoulos:GlaxoSmithKline: Research Funding. Nagler:Novaratis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Mannino:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership; GlaxoSmithKline: Employment, Equity Ownership. Stone:Novartis Pharmaceuticals Corporation: Employment; GlaxoSmithKline: Employment, Equity Ownership. Chan:Novartis Pharmaceuticals Corporation: Employment; GlaxoSmithKline: Employment, Equity Ownership. Mostafa Kamel:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership; GlaxoSmithKline: Employment, Equity Ownership. Selleslag:Amgen: Consultancy, Honoraria, Speakers Bureau.

Download Full-text

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.

Download Full-text

Long-Term Durability, Safety and Efficacy of Fitusiran Prophylaxis in People with Hemophilia a or B, with or without Inhibitors - Results from the Phase II Study

Blood ◽

10.1182/blood-2020-136501 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-4

Author(s):

Steven W. Pipe ◽

John Pasi ◽

Toshko Lissitchkov ◽

Margaret V. Ragni ◽

Claude Négrier ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Principal Investigator ◽

Open Label ◽

Advisory Committees ◽

Advisory Boards ◽

Scientific Advisory ◽

Open Label Extension

Introduction: Hemophilia is a bleeding disorder characterized by ineffective clot formation due to insufficient thrombin generation. The burden of disease for individuals with hemophilia is high, and less invasive treatment approaches are needed (Machin and Ragni. J Blood Med. 2018). Fitusiran is a once a month subcutaneously administered investigational RNA interference therapeutic targeting antithrombin as a means to improve thrombin generation and promote hemostasis in people with hemophilia A or B, with or without inhibitors. A completed Phase I study demonstrated that monthly subcutaneous administration of fitusiran was generally well tolerated and lowered antithrombin in a dose-dependent manner, resulting in increased thrombin generation and decreased bleeding frequency (Pasi et al. New Engl J Med. 2017). The aim of this abstract is to describe long-term durability, safety and efficacy of monthly fitusiran treatment for patients with hemophilia A or B, with or without inhibitors, in the Phase II open-label extension study. Methods: The fitusiran Phase I study (NCT02035605) followed by the Phase II open-label extension study (NCT02554773) included male patients, >18 years of age, with moderate or severe hemophilia A and B, with or without inhibitors. Patients received monthly fixed doses of fitusiran 50 mg or 80 mg subcutaneously. Exploratory post-hoc analysis of bleed events was used to calculate median annualized bleed rate in patients with hemophilia A and B, with or without inhibitors. Results: Thirty-four patients (hemophilia A, n=27 [13 with inhibitors and 14 without inhibitors]; hemophilia B, n=7 [2 with inhibitors and 5 without inhibitors) were enrolled in the Phase 2 open-label extension study, and were treated for up to 4.7 years with a median exposure of approximately 2.6 years (as of March 10, 2020). Once-monthly subcutaneous dosing of fitusiran prophylaxis lowered antithrombin (a reduction of between 85% to 72% from baseline) across patients over a sustained period of time. An exploratory analysis of bleeding events showed an overall median annualized bleed rate of 0.84 during the observation period (see figure). Breakthrough bleeds were managed successfully in accordance with the revised bleed management guidelines for reduced doses of bypassing agents and replacement factors. As of March 10, 2020, fitusiran was generally well tolerated and no anti-drug antibody formation was detected. Conclusions: Monthly fitusiran prophylaxis provided sustained antithrombin lowering in people with hemophilia A and B, with or without inhibitors, resulting in a low annualized bleeding rate over a median of 2.6 years in an open-label extension study. Disclosures Pipe: Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees; Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding. Pasi:Catalyst Biosciences: Consultancy, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Biotest: Consultancy, Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Alnylam (Sanofi): Other: Personal fees and nonfinancial support ; Octapharma: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia , Speakers Bureau; Pfizer: Other; Novo Nordisk: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia ; Roche: Honoraria, Other; Sobi: Consultancy, Honoraria, Other; Tremeau: Research Funding; Sigilon: Research Funding; ApcinteX: Consultancy, Other: Personal fees ; uniQure: Other: Grants and nonfinancial support , Research Funding; BioMarin: Consultancy, Honoraria, Other: Grants, personal fees, and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Sanofi: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia, Research Funding; Takeda: Consultancy, Honoraria, Other: Personal fees; honoraria as member of scientific advisory boards and symposia . Lissitchkov:CSL Behring: Other: Principal investigator of clinical trials ; Bayer: Other: Principal investigator of clinical trials ; Novo Nordisk: Other: Principal investigator of clinical trials ; Octapharma: Other: Principal investigator of clinical trials ; Sanofi: Other: Principal investigator of clinical trials ; Roche: Membership on an entity's Board of Directors or advisory committees, Other: lecturer; Shire: Other: lecturer; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: lecturer; Catalyst Biosciences: Other: Principal investigator of clinical trials . Ragni:Alnylam Pharmaceuticals Inc., Baxalta/Takeda, BioMarin, Bioverativ, and Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sangamo: Consultancy, Research Funding; Takeda: Research Funding; Bioverativ: Consultancy, Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding; Alnylam/Sanofi, ATHN, BioMarin, Bioverativ, Sangamo, Spark: Research Funding; Alnylam/Sanofi, BioMarin, Bioverativ, Spark: Consultancy; American Thrombosis Hemostasis Network: Other: Committee work; Baxalta/Takeda, CSL Behring, Genentech, a member of the Roche Group, OPKO Biologics, and Vascular Medicine Institute: Research Funding. Négrier:CSL, F. Hoffmann-La Roche Ltd, Sobi: Other: Travel support; CSL Behring, Octapharma, Shire/Takeda, Sobi: Research Funding; Bayer, Biomarin, CSL Behring, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Shire/Takeda, Sobi, Spark: Consultancy. Yu:Sanofi: Other: was an employee and stockholder of Sanofi, at the time of study; Albireo Pharmaceuticals, Inc: Current Employment. Poloskey:Sanofi: Current Employment. Mei:Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson:Sanofi: Current Employment, Current equity holder in publicly-traded company.

Download Full-text

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.

Download Full-text

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

Blood ◽

10.1182/blood-2021-150932 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4924-4924

Author(s):

Ganimete Lamaj ◽

Alberto Pablo-Trinidad ◽

Ian Butterworth ◽

Nolan Bell ◽

Ryan Benasutti ◽

...

Keyword(s):

Healthy Volunteers ◽

Board Of Directors ◽

Cancer Patients ◽

Stock Options ◽

Diagnostic Performance ◽

Severe Neutropenia ◽

Primary Study ◽

Advisory Committees ◽

First Time ◽

Privately Held

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.

Download Full-text