Pharmacokinetics of a Recombinant Von Willebrand Factor in Patients with Severe Von Willebrand Disease

Abstract Introduction Recombinant von Willebrand factor (rVWF, vonicog alfa, BAX 111), which is manufactured using a plasma-free method (Turecek et al Semin Thromb Hemost 2010), may provide an important alternative replacement therapy for VWD subjects. In contrast to plasma-derived (pd) VWF concentrates, BAX 111 contains a high ratio of high molecular weight (HMW) and ultralarge VWF multimers (ULM), which improve platelet and collagen binding and enhance FVIII stabilization (Kragh et al Thromb Res 2014), and may therefore be associated with better hemostatic outcomes and simplify bleeding management in VWF patients for a variety of clinical conditions. As BAX 111 is a pure VWF product, it is also not restricted to co-administration with coagulation factor VIII (FVIII). The pharmacokinetic profile of BAX 111 has been evaluated in two prospective trials (phase 1 and phase 3) in adults with severe VWD. Methods The pharmacokinetic profile of BAX 111 (with vs. without rFVIII; and BAX 111:rFVIII compared with a pdVWF:pdFVIII) in subjects with VWD, evaluated in a non-bleeding state, was determined in two clinical trials by assessment of ristocetin co-factor activity (VWF:RCo), VWF antigen (VWF: Ag); collagen-binding activity (VWF:CB), FVIII activity, and VWF multimer activity. Lower doses were examined in the first-in-human phase 1 dose-finding study, and the expected therapeutic doses (as recommended for licensed pdVWF-containing concentrates) of 50 IU VWF:RCo/kg and 80 IU VWF:RCo/kg (for major bleeding episodes) were selected for further evaluation in phase 3. PK assessments were also repeated after 6 months with the 80 IU VWF:RCo/kg dose. Results The PK profile of BAX 111 has been evaluated in a total of 56 unique subjects with severe VWD. A rapid increase in VWF:RCo was observed after a single infusion of BAX 111. There was no apparent dose-dependency at a wide range of dose levels (20 IU, 50 IU and 80 IU VWF:RCo/kg) and BAX 111 PK was not affected by administration together with rFVIII in the crossover study with the 50 IU VWF:Co/kg dose (Figure 1). A tendency toward a longer mean terminal half-life (T1/2) of VWF:RCo for BAX 111:rFVIII as compared with a pdVWF:pdFVIII was observed in the phase 1 study (23.6 h for 20 IU BAX 111:rFVIII, 19.3h for 50 IU BAX 111:rFVIII) and the mean T1/2 at 50 IU VWF:RCo/kg in the phase 3 study (19.6 h for BAX 111:rFVIII and 21.9 h for BAX 111) is also considerably longer than that of pdVWF products (Batlle et al Blood Coagul Fibrinolysis 2009). PK parameters were similar for the first (19.1 h) and second (21.2 h) assessment in the repeated PK study at 80 IU VWF:RCo/kg. VWF:CB parameters were comparable to VWF:RCo across dose levels in the phase 1 study (15.7 h for 20 IU BAX 111:rFVIII, 24.4h for 50 IU BAX 111:rFVIII) and phase 3 study (19.3h for BAX 111:rFVIII and 18.3h for BAX 111 at 50 IU; 18.8h for 80 IU in the first assessment and 20.9h 80 IU in the second assessment). ULMs were detected after 15 minutes post-infusion of BAX 111 (earliest time point measured), followed by a substantial decline due to rapid degradation by endogenous ADAMTS13 between 12 and 24 hours. A substantial increase in FVIII activity was observed after infusion with BAX 111 and BAX 111:rFVIII, followed by a secondary rise in FVIII activity after 12 hours due to the stabilization of endogenous FVIII, which was more pronounced for BAX 111:rFVIII than for pdVWF:pdFVIII (geometric mean ratio for AUC0-inf = 1.36 [90% Clopper-Pearson confidence interval: 0.93; 1.99]), and similar for BAX 111 alone as compared with BAX 111:rFVIII, confirming the ability of BAX 111 to stabilize endogenous FVIII:C. Conclusion BAX 111 has an enhanced PK profile compared to plasma-derived concentrates and there is no apparent dose dependency over a wide dose range (20 IU, 50 IU, 80 IU VWF:RCo/kg). The ULM present in BAX 111 may be more effective in stabilizing endogenous FVIII, and therefore BAX 111 may have the potential for less-frequent administration compared with plasma-derived VWF concentrates, and for FVIII-independent dosing after the initial infusion or in non-emergency bleeds. Disclosures Ragni: Biogen: Research Funding; Biomarin: Research Funding; Genentech Roche: Research Funding; Vascular Medicine Institute: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; SPARK: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Dimension: Research Funding; CSL Behring: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castaman:Bayer, Baxalta, CSL Behring, Kedrion, Novo Nordisk, and Pfizer: Membership on an entity's Board of Directors or advisory committees. Gill:Bayer: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees. Kouides:CSL Behring: Membership on an entity's Board of Directors or advisory committees. Chapman:Baxalta: Employment. Sytkowski:Baxalta: Employment. Obermann-Slupetzky:Baxalta: Employment. Presch:Baxalta: Employment. Fritsch:Baxalta: Employment. Ewenstein:Baxalta: Employment.

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A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v128.22.1068.1068 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1068-1068 ◽

Cited By ~ 1

Author(s):

Anna B. Halpern ◽

Megan Othus ◽

Emily M Huebner ◽

Kaysey F. Orlowski ◽

Bart L. Scott ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Research Funding ◽

Phase 1 ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

Dose Levels

Abstract Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

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Phase 1 Study Update of the Novel Pan-Pim Kinase Inhibitor LGH447 in Patients with Relapsed/ Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.301.301 ◽

2014 ◽

Vol 124 (21) ◽

pp. 301-301 ◽

Cited By ~ 20

Author(s):

Marc S Raab ◽

Enrique M Ocio ◽

Sheeba K. Thomas ◽

Andreas Günther ◽

Yeow-Tee Goh ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Kinase Inhibitor ◽

Phase 1 ◽

Single Agent ◽

Hematologic Malignancies ◽

Advisory Committees ◽

Once Daily ◽

Grade 3 ◽

Dose Levels

Abstract Background: LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM (Provirus Integration site for Moloney leukemia) kinase gene family encodes 3 serine/threonine protein kinases that have roles in cell cycle progression and survival. In human disease, elevated levels of Pim1 and Pim2 are associated with hematologic malignancies, with MM showing the highest level of Pim2 expression. In preclinical studies, a majority of MM cell lines proved sensitive in vitro to LGH447-mediated Pim inhibition, exhibiting a dose-dependent decrease in cell proliferation. LGH447 demonstrated significant tumor growth inhibition in xenograft mouse models of MM as compared with control animals, supporting the clinical development of LGH447 in MM patients. Methods: Patients with relapsed/refractory MM for whom no effective treatment options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses of single-agent LGH447 were administered orally on a continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of LGH447 administered as a single agent, orally, once daily. Secondary objectives included assessing the safety, tolerability, preliminary anti-myeloma activity, and pharmacokinetics of LGH447. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Efficacy assessments were made by investigators according to International Myeloma Working Group (IMWG) uniform response criteria with modifications. Results:At the data cutoff, 54 patients have been treated at the following doses: 70 mg (n = 5), 150 mg (n = 6), 200 mg (n = 6), 250 mg (n = 7), 300 mg (n = 4), 350 mg (n=10), 500 mg (n=10), 700 mg (n=6), with the MTD determined to be 500 mg once daily. Median age was 65 years (range, 41-87 years). Most patients (92.6%) presented with baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated with a median of 4 prior lines of therapy (range, 1-16). 81.5% had received prior proteasome inhibitor therapy, 83.3% had received prior immunomodulatory therapy (70.4% lenalidomide and 48.1% thalidomide), 68.5% were treated with both proteasome inhibitor and immunomodulatory therapies, and 87.0% had received prior stem cell transplant. Seventeen patients are ongoing at doses between 250-700 mg, with a median duration of exposure of 10.6 weeks (range, 0.1-56.1 weeks), and 37 patients discontinued (disease progression [n = 29], AEs [n = 4], withdrawal of consent [n = 4]). There were 8 DLTs, consisting of four grade 3/4 thrombocytopenia (1 each at 200, 250, 350, 500 mg dose levels), two grade 3 fatigue (1 each at 500 and 700 mg dose levels), one grade 3 hypophosphatemia (300 mg), and one episode of vaso-vagal syncope (700 mg). This last event was the only reported unexpected serious AE that was suspected to be due to LGH447 treatment. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were thrombocytopenia (18.5%), anemia (18.5%), neutropenia (13%), and fatigue (11.1%). No deaths have occurred on study. Forty-eight individuals (70-500 mg) were evaluable for disease response assessments. Evidence of single agent activity was noted at doses ≥ 150 mg, including 1 VGPR at 200 mg (exposure duration > 55 weeks) and 4 PRs noted at doses ranging from 150-500 mg (respective exposure durations of 32, 29, 24, and 21 weeks). Five additional patients achieved MR, resulting in a clinical benefit rate (≥ MR) of 20.8%, and 23 patients were noted to have SD, resulting in a remarkable disease control rate (≥ SD) of 68.8%. In addition, of those patients with SD, 8 had exposure durations for > 20 weeks. Conclusions:In heavily treated patients with relapsed/refractory MM, LGH447 was generally well tolerated and exhibited evidence of durable single-agent efficacy in multiple patients, with the best response being a VGPR. These findings validate Pim kinase inhibition as a promising therapeutic rationale in MM patients and support further clinical development in patients. Disclosures Ocio: Novartis: Honoraria. Thomas:Novartis: Research Funding; Celgene: Consultancy, Research Funding; Millennium: Research Funding; Idera Pharmaceuticals: Research Funding; Immunomedics: Research Funding. Günther:Novartis: Consultancy, Research Funding. Goh:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Lebovic:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millennium: Consultancy. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Song:Novartis: Employment. Xiang:Novartis: Employment. Patel:Novartis: Employment. Vanasse:Novartis: Employment, Equity Ownership. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Research Funding; Array: Research Funding; Cephalon: Research Funding.

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Prolonged Circulation of Ultra-Large Von Willebrand Factor and a Reduction in ADAMTS13 Activity Promotes Microvascular Disease Following Traumatic Injury

Blood ◽

10.1182/blood-2019-124531 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 444-444 ◽

Cited By ~ 1

Author(s):

William E Plautz ◽

Mitchell Dyer ◽

Margaret V. Ragni ◽

Shannon Haldeman ◽

Wyeth E Alexander ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Traumatic Injury ◽

Microvascular Disease ◽

Severe Trauma ◽

Trauma Patients ◽

Adamts13 Activity ◽

Advisory Committees ◽

Von Willebrand ◽

Willebrand Factor

Introduction: Increases in plasma von Willebrand Factor (vWF) levels, accompanied by decreases in its respective metalloprotease, ADAMTS13, have been demonstrated in diseases of microvascular injury. We hypothesized that following severe trauma, a burst of ultra-large vWF (UL-vWF) is released into the bloodstream by damaged endothelium, resulting in increased thrombogenicity due to circulating vWF multimers. We further hypothesized that traumatic injury would lead to a deficit of ADAMTS13, promoting the accumulation of UL-vWF forms and, ultimately, the increased risk of microvascular disease, such as acute kidney injury (AKI). Methods: A cohort of 37 severely injured trauma patients was analyzed for antigen levels of plasma vWF and ADAMTS13 at 0- and 24-hours after admission. Circulating vWF multimeric composition from both time points was determined by vertical agarose gel electrophoresis. Multivariate analyses were performed with data abstracted from the electronic medical records to identify further dependences. A similar analysis was also performed on plasma from a cohort of 8 patients with trauma induced AKI at 0-, 24-, and 72-hours after admission; these patients were well matched against trauma patients without AKI. Finally, we utilized a murine model of polytrauma and hemorrhage, in conjunction with qRT-PCR of ADAMTS13 in total liver RNA, to specifically address how the expression of ADAMTS13 is altered by the systemic effects of traumatic injury. Results: Circulating vWF levels were increased in severe trauma patients when compared to healthy controls at presentation (189% (110-263) vs. 95% (74-120)) and persisted through 24-hours (213% (146-257) vs. 132% (57-160)). Ultra-large vWF forms were elevated at both 0- and 24-hours when compared to pooled normal plasma ((10.0% (8.9-14.3) and 11.3% (9.1-21.2), respectively, vs 0.6%). The largest vWF forms within trauma patient plasma circulated at 33±4 dimers vs 18±1 dimer in length within pooled normal plasma. Severe trauma patient ADAMTS13 activity was decreased at 0-hours (66% (47-86) vs. 100% (98-100)) and at 24-hours (72.5% (56-87.3) vs 103% (103-103)) when compared to healthy patients. Furthermore, the proportion of circulating low molecular weight multimeric (LMWM) vWF to total circulating vWF forms was directly dependent upon ADAMTS13 activity at 24-hours (Decreased ADAMTS13 Activity: 20.4% (15.0-22.7) LMWM vWF vs Normal Activity: 25.8% (22.7-35.2) LMWM vWF). Strikingly, ADAMTS13 activity independently predicted the development of coagulopathy, correlating with presentation INR (ρ =-0.63), activated clotting time of thromboelastography (TEG) (ρ=-0.36), and TEG maximum amplitude (ρ=0.36). ADAMTS13 activity also closely correlated with injury severity (ISS) (ρ=-0.34) and blood product transfusion (ρ =-.45). The cohort of 8 trauma patients who went on to develop AKI showed a 1.54-fold (1.02-2.05) increase in plasma vWF antigen levels between 0 and 72 hours, while those who did not develop AKI showed no change in vWF levels over this time period. Furthermore, those who developed AKI demonstrated a smaller proportion of LMWM vWF in plasma than those who did not (25.4% (23.4-28.0) vs 31.2% (27.2-35.6)), suggesting the increased thrombogenicity of their circulating vWF forms. Finally, qRT-PCR of total liver RNA in 6 mice demonstrated a 2-fold decrease in ADAMTS13 RNA expression levels between the times immediately before and 24-hours after trauma. Altogether, these data indicate that both circulating ADAMTS13 and its production are deficient in the days following severe injury. Conclusions: Severe traumatic injury alters the circulating composition of ADAMTS13 and its target, vWF, shifting their equilibrium to one that promotes thrombosis. Not only is the concentration of circulating ADAMTS13 decreased following traumatic injury, but hepatic expression of the enzyme is lacking as well. In the immediate moments following injury, these mechanisms contribute to life-saving hemostasis; however, as these changes extend into the following days, the early hemostatic benefit quickly shifts to burden that may exacerbate microvascular disease. Disclosures Ragni: Bioverativ/Sanofi: Consultancy, Research Funding; Sangamo: Research Funding; Shire/Takeda: Consultancy, Other: Study drug; Alnylam/Sanofi: Consultancy, Research Funding; Bayer: Consultancy; Spark Therapeutics: Consultancy, Research Funding; ICER: Consultancy; OPKO: Research Funding; Biomarin: Consultancy, Research Funding. Rollins-Raval:Bayer, Inc: Membership on an entity's Board of Directors or advisory committees. Raval:Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer, Inc: Research Funding. Neal:Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees.

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A Systematic Review and a Survey Both Reveal Wide Heterogeneity across Trials and Investigators on Time-to-Event Endpoints Definitions in Marginal Zone Lymphoma

Blood ◽

10.1182/blood-2021-150603 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4502-4502

Author(s):

Côme Bommier ◽

Emanuele Zucca ◽

Catherine Thieblemont ◽

Jérôme Lambert

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Marginal Zone ◽

Phase 1 ◽

Marginal Zone Lymphoma ◽

Time To Event ◽

Phase 3 ◽

Advisory Committees ◽

Free Survival ◽

Secondary Endpoints

Abstract Background: Marginal zone lymphoma (MZL) is an indolent and heterogeneous B-cell lymphoma. Because of its very indolent course, many time-to-endpoints are used across MZL trials without clear consensus on their definitions. Our aim was to carry out a description of the endpoints used in trials involving MZL patients and to point out the different definitions of time-to-event (TTE) endpoints, both in the literature and among the MZL experts. Methods: We searched over the last 35 years via PubMed, The Cochrane Library, clinicaltrials.gov and clinicaltrialsregister.eu for published and registered clinical trials using the keyword "marginal zone lymphoma". We excluded studies focusing on pediatric populations, cutaneous MZL and on use of allogenic stem cell transplant. Endpoints were reviewed and definitions were analyzed. Afterwards, an online questionnaire was sent to a panel of leading international experts involved in the conduct of lymphoma clinical trials. Experts were selected for their commitment in published phase 2/phase 3 indolent lymphoma trials or for their membership in international lymphoma study groups (International Extranodal Lymphoma Study Group, Lymphoma Research Foundation). The questionnaire proposed 12 criteria to define Progression-free survival (PFS), Event-free survival (EFS), Time to failure (TTF), and Time to next treatment (TTNT). Results: 1192 references were identified by the initial screening. Among the 309 included references (111 published, 198 registered), 213 (69%) were phase 2, 65 (21%) phase 1/2 and 31 (10%) phase 3 trials. The majority of them were open-label (n=295, 95%) non-randomized (n=256, 83%) trials, included all subtypes of MZLs (n=239, 77%), and also non-MZL patients (n=232, 75%). Among phase 1/2 and 2 trials, Overall/complete response rate (ORR/CRR) was the most used primary endpoint (n=196, 70.5%), followed by PFS (n=28, 10.1%); in phase 3 trials PFS was the most used primary endpoint (n=18, 58.1%; ORR/CRR n=6, 19.4%, p<0.001). Overall, the most frequent secondary endpoints were overall survival (OS, n=153, 50%), PFS (n=142, 46%) and ORR/CRR (n=116, 38%). Distribution of endpoints was similar when considering trials with only MZL patients. Time-to-event endpoints definitions were inconsistent across published trials, with up to 9 different definitions of EFS and TTF, and 4 different definitions of Duration of response. A total of 60 MZL experts from 16 different countries (Europe 66%, Northern America 26%, Asia 4%, Oceania 2%, Southern America 2%) took the questionnaire. Forty-nine (82%) of them were clinicians hematologists, and the other were oncologists, radiologists, nuclear medicine physicians, or radiotherapists. Eighty percent and 75% of them had already been primary investigator or coinvestigator in a prospective clinical trial including either MZL-only patients or MZL patients merged with other lymphoma patients, respectively. Among the experts' answers, a total of 23 different definitions of PFS were retrieved, 44 of EFS, 38 of TTF and TTNT. The main divergences concerned the consideration as event of: the add-on of a new therapy and the non-lymphoma related death for PFS; the treatment discontinuation due to adverse events and the add-on of a new therapy for EFS and TTF; the progression of the disease for TTNT. Conclusion: Trials involving MZL patients showed marked heterogeneity both in the choice and definitions of primary and secondary endpoints, thus hampering comparability between trials. This heterogeneity was confirmed through a survey among leading international MZL experts. If PFS and TTNT definitions have been well established by the Food Drug Administration and the European Medicines Agency, a consensus shall be pursued on EFS and TTF definitions within the MZL community. Disclosures Zucca: AstraZeneca: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: 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, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biomedicine: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Gilead, Kite: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Support. Thieblemont: Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses .

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Treatment of Haemophilia a (HA) Patients with Inhibitors: Immune Tolerance Induction with a Single Factor VIII/Von Willebrand Factor Concentrate in an Observational Immune Tolerance Induction Study (ObsITI)

Blood ◽

10.1182/blood-2018-99-114408 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2482-2482

Author(s):

C. Escuriola Ettingshausen ◽

Erik Berntorp ◽

Yesim Dargaud ◽

Zeynep Gutowski ◽

Claude Negrier ◽

...

Keyword(s):

Board Of Directors ◽

Von Willebrand Factor ◽

Immune Tolerance ◽

Research Funding ◽

Tolerance Induction ◽

Advisory Committees ◽

Immune Tolerance Induction ◽

Inhibitor Titre ◽

Von Willebrand ◽

Willebrand Factor

Abstract Introduction and objectives: Development of neutralising inhibitors against factor VIII (FVIII) is one of the most serious and costly complications in the treatment of HA. An ongoing international, open-label, uncontrolled, multicentre observational study, ObsITI (ClinicalTrials.gov. NCT 02207894) started in 2005 to assess immune tolerance induction (ITI), the standard of care in patients with inhibitors. The study evaluates patient- and therapy-related variables on ITI course, outcome and morbidity in HA patients with inhibitors. ObsITI satellite studies additionally look at other factors related to tolerisation. Methods and Materials: As of February 2018, 193 patients from 20 countries undergoing ITI have been recruited in ObsITI. 152 patients completed the study and 41 are ongoing. A subgroup of more than 80 prospective patients were treated exclusively during the complete ITI course with a single plasma-derived (pd) FVIII concentrate that contains von Willebrand factor (VWF) in a VWF/FVIII ratio of 0.4 (Octapharma AG). According to the recommended Bonn protocol, low responders at ITI start received 50-100 IU FVIII kg-1 daily, or every other day; high responders received 100 IU FVIII kg-1 every 12 hours. Results: In this ongoing study, the majority of patients treated with the pdFVIII/VWF product achieved a negative inhibitor titre. ITI outcome was significantly correlated with the bleeding rate during ITI, the peak titre during ITI, the inhibitor titre at start of ITI >10 BU, and the number of poor prognosis factors. Conclusion: Treatment with this particular pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in HA patients with inhibitors and corroborates previously published success rates (77.1% complete/partial success in 48 inhibitor patients undergoing ITI with the same product). Disclosures Escuriola Ettingshausen: SOBI: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria; Roche: Honoraria; Grifols: Honoraria; Pfizer: Honoraria; LFB: Honoraria. Berntorp:Octapharma: Consultancy; CSL Behring: Consultancy; Shire: Consultancy, Other: honoraria for lecturing . Negrier:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Research Funding. Pavlova:Novo Nordisk: Honoraria; Octapharma: Honoraria. Oldenburg:Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Obtaining a Von Willebrand Evaluation at Time of Acute Heavy Menstrual Bleeding Presentation Leads to Overestimation of Von Willebrand Levels

Blood ◽

10.1182/blood-2019-127258 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 627-627

Author(s):

Megan C. Brown ◽

Michael H. White ◽

Robert F. Sidonio

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Heavy Menstrual Bleeding ◽

Menstrual Bleeding ◽

Quality Improvement Initiative ◽

Advisory Committees ◽

Von Willebrand ◽

Willebrand Factor

Background: Acute heavy menstrual bleeding (HMB) is common for adolescent females, with about a quarter of menstruating females seeking care for HMB over a 3-year time period (O'Brien et al, Blood 2018). Inherited bleeding disorders are common in this adolescent population, identified in 24.6% referred for hematologic evaluation (Zia et al, Blood 2016). The timing and contents of the hemostatic workup for acute HMB in adolescents is extrapolated from adults, although the causes of acute HMB varies significantly between adult women and adolescents. A consensus statement by the American College of Obstetrics and Gynecology recommends obtaining a variety of hemostatic tests including CBC, von Willebrand studies, factor VIII, prothrombin time, partial thromboplastin time, fibrinogen, and thyroid stimulating hormone at the time of presentation (Committee Opinion 557, ACOG 2011). Factor VIII and Von Willebrand studies are known to be increased in the setting of physiologic stress and supplemental estrogen use, questioning their diagnostic accuracy in the setting of acute bleeding. Repeat testing is often required for diagnosis of von Willebrand disease A von Willebrand factor antigen (VWF:Ag) or von Willebrand factor ristocetin cofactor level over 100IU/dL has been shown to have a negative predictive value (NPV) of 95%.(Doshi et al, ASH 2018). Methods: As part of a quality improvement initiative to improve the evaluation and management of adolescents with HMB at Children's Healthcare of Atlanta (CHOA), we instituted an acute HMB protocol for emergency department (ED) and inpatient use. This protocol was implemented at all CHOA emergency departments in metropolitan Atlanta. Subjects were included if they presented with acute HMB as determined by an adapted Philip Menorrhagia Screening Tool. Subjects with a previously diagnosed bleeding disorder, ITP, active rheumatologic disease, cancer, or anticoagulant use were excluded. Descriptive statistics were used to summarize demographics and clinical characteristics. Patients with a positive Philip screen underwent a uniform bleeding inventory and a standardized set of laboratory tests based on the adult consensus statement. Inpatient and outpatient treatments were standardized by hemoglobin level and symptomology. Follow up with hematology and gynecology was encouraged for all. Data was extracted using various heavy menstrual bleeding ICD-10 codes from January 1, 2017 to December 31, 2018. Individuals with von Willebrand studies at baseline and follow up were identified. T-tests and Wilcoxon rank sum tests were utilized to compare VWF:Ag, VWF:RCo and Factor VIII as baseline and follow up. Results: Over a 2-year period, 232 adolescent girls were seen in CHOA EDs for acute HMB with 88 (37.9%) requiring admission and 6 (2.6%) requiring intensive care. The population was primarily African American (63%) with a median age at presentation of 14.8 years (IQR 13.1-16.7). The majority of adolescents had the core hemostatic labs drawn (55.6%) as described per protocol. Thirty-six individuals had baseline and follow up VWD studies. Those with repeat VWD studies were younger (median 13.2 years vs 15.0 years), more commonly white (44.4% vs 21.2%), were more likely to have been admitted (83.3% vs 29.6%) and more likely to have had a hematology follow up appointment (63.4% vs 7.8%). Mean and median VWF:Ag, VWF:RCo and Factor VIII were significantly higher at presentation with HMB than at follow up. Of those with a baseline VWF:Ag and/or VWF:RCo >100, there was a 96.4% NPV for the diagnosis of VWD. For individuals whose initial VWF:Ag and VCWF:RCo were both >100, there was 100% NPV. Conclusions: Among the adolescents cared for at our institution with acute HMB who had confirmatory VWD testing, initial VWF:Ag and VWF:RCo >100 ruled out VWD based on repeat testing. However, poor adherence with hematology or gynecology follow-up may give false reassurance against a diagnosis of VWD. Further improvements of our quality improvement initiative will include a limited hemostatic workup at presentation with a focus on improved adherence to follow up and subsequent hemostatic evaluation. Disclosures White: National Hemophilia Foundation: Other: Shire Clinical Fellowship Program. Sidonio:Kedrion: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees.

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Phase 1/2 Clinical Trial of HQK-1001, An Oral Fetal Hemoglobin Stimulant, In Sickle Cell Anemia

Blood ◽

10.1182/blood.v116.21.943.943 ◽

2010 ◽

Vol 116 (21) ◽

pp. 943-943 ◽

Cited By ~ 1

Author(s):

Abdullah Kutlar ◽

Kenneth I. Ataga ◽

Marvin Reid ◽

Loray A Blair-Britt ◽

Elliott Vichinsky ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Phase 1 ◽

Fetal Hemoglobin ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Dose Levels ◽

Peak Increase

Abstract Abstract 943 Definitive therapies to reduce the underlying pathology in sickle cell syndromes are still needed, particularly non-cytotoxic therapeutics which could be used either alone or in combination with hydroxyurea. Increased fetal hemoglobin (HbF) levels correlate with reduction in organ damage and improved patient survival. An oral, promoter-targeted fetal globin gene stimulant, HQK-1001, which also prolongs erythroid survival and proliferation, has demonstrated favorable pharmacokinetic (PK) and safety profiles in normal volunteers in a Phase 1 clinical trial. Accordingly, a randomized, blinded dose-ranging Phase 1/2 trial was performed in 24 adult patients with sickle cell disease (including HbSS or S/ß thalassemia). The study therapeutic was administered once daily for two 6-week cycles of daily therapy with a 2 week treatment break between the two cycles. Three dose levels (10, 20, 30 mg/kg/dose) were studied sequentially, with 4 placebo treated subjects. 21 patients were evaluable. Five patients received active drug at the lower two dose levels; 7 patients received active study drug at the 30 mg/kg dose level. HQK-1001 was well-tolerated with no significant drug-related adverse events. Increases in HbF levels were observed at all dose levels with the highest effects observed at 30 mg/kg, where 5 of 7 treated patients responded with a mean peak increase of 2.6% HbF (absolute 0.2 g/dl, p=0.04) above baseline. HbF increased both in patients who did, and who did not, take concomitant hydroxyurea. A mean peak increase in total hemoglobin of 1.3 g/dL (range 0.9 to 2.4) above baseline was also observed in these HQK-1001-treated patients. F-reticulocytes and F-cells increased by 20–33% and 6–18%, respectively, in the 5 responders at the 30 mg/kg dose level. LDH declined in 4 of 5 responding subjects receiving 30 mg/kg doses. Fetal globin mRNA increased by 4- to 9-fold over baseline throughout the study period in treated patients and was still increasing at the end of the dosing period, implying that HbF expression had not yet peaked. Other fetal globin inducing agents, such as hydroxyurea require 6–9 months of treatment for optimal effects on HbF to be achieved. Therefore, the findings of HbF induction and rises in total Hgb in 70% of subjects with short treatment duration in the current study indicate that longer trials of HQK-1001 are warranted to evaluate potential therapeutic effects on HbF expression and anemia more definitively in sickle cell disease. Disclosures: Kutlar: HemaQuest Pharmaceuticals, Inc: Research Funding. Vichinsky:HemaQuest Pharmaceuticals, Inc: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Neumayr:Novartis : Honoraria, one time honoraium 10/09; NIH: Research Funding. Labotka:HemaQuest Pharmaceuticals, Inc: Research Funding. Keefer:HemaQuest Pharmaceuticals, Inc: Research Funding. Shen:HemaQuest Pharmaceuticals, Inc: Research Funding. Boosalis:HemaQuest Pharmaceuticals, Inc: Equity Ownership, Research Funding. Thomson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Bobbitt:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Patents & Royalties. Wallis:HemaQuest Pharmaceuticals: Consultancy, Equity Ownership. Johnson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Berenson:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Perrine:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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The Relationship between Baseline Biomarkers and Efficacy of Isatuximab in Combination with Pomalidomide and Dexamethasone in RRMM: Insights from Phase 1 and Phase 3 Studies

Blood ◽

10.1182/blood-2019-128071 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3179-3179

Author(s):

Paul G. Richardson ◽

Joseph Mikhael ◽

Thierry Facon ◽

William I. Bensinger ◽

Sandrine Macé ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Nk Cell ◽

Phase 1 ◽

Phase 3 ◽

Advisory Committees ◽

Blood Samples ◽

Bone Marrow Plasma

Background: Anti-CD38 monoclonal antibody therapy has become an integral component of treatment for relapsed/refractory multiple myeloma (RRMM) but not all patients respond. Identification of predictive biomarkers could help clinicians identify the best treatment course for a patient. We present baseline biomarker analyses on samples from a Phase 1 (Study 1; NCT02283775) and Phase 3 (Study 2; NCT02990338 [ICARIA-MM]) clinical study that evaluated the addition of isatuximab (Isa), an anti-CD38 monoclonal antibody, to pomalidomide and dexamethasone (Pd) for the treatment of RRMM. CD38 receptor density (RD), FCGR3A (Fc immunoglobulin receptor) genotype, and bone marrow or peripheral blood immunophenotyping were evaluated as potential predictive biomarkers for a response to the Isa-Pd regimen. Methods: Both studies enrolled similar patient populations with RRMM who had received ≥2 prior lines of therapy including lenalidomide and a proteasome inhibitor. Baseline blood samples were taken prior to first treatment in both studies; in addition, a bone marrow sample was taken during screening in Study 1. In Study 1, bone marrow plasma cells were analyzed for CD38 RD. Immune cell populations (CD19+ B-cell, CD3+ T-cell, CD4+ T-cell, regulatory T-cells (Tregs) and natural killer (NK) cells [CD56+ bright CD16+ low subset and CD56+ dim CD16+ bright subset]) were characterized using blood samples and bone marrow aspirates. Blood samples from both studies were analyzed for FCGR3A genotyping (V158 and F158 high- and low-affinity alleles). Biomarker results were correlated with response, defined as at least partial response according to IMWG criteria. Results: Study 1 enrolled and treated 45 patients with Isa-Pd. Study 2 randomized 154 patients to Isa-Pd and 153 patients to Pd. Baseline patient demographics were similar for both studies and the median number of prior lines of therapy was 3 (range: 1-10) for Study 1 and 3 (2-11) for Study 2. The overall response rates (ORR) with Isa-Pd were 62.2% (28/45) in Study 1 and 60.4% (93/154) in Study 2. In Study 1, the median CD38 RD, for 31 patients with evaluable results, was 108,172 receptors/cancer cell (range: 12,950-337,335). In patients responding to Isa-Pd (n=21), the median CD38 RD value was 120,931 (48,770-337,335) receptors/cancer cell; in patients not responding to Isa-Pd (n=10), the median CD38 RD value was 85,370 (range 12,950-309,003) receptors/cancer cell. Univariate analysis in Study 1 showed no association between CD38 RD and ORR (p=0.2870). Across five Phase 1/2 clinical studies with Isa, 4/198 patients (2.0%) had a CD38 RD level below 48770, the lowest value in a responder patient. FCGR3A genotyping results were available for both studies. Across both studies, the distribution of the F158V single nucleotide polymorphism of FCGR3A gene was 42% for F/F, 42% for F/V and 16% for V/V. In both studies, responses were observed for all 3 genotypes (Table 1). In Study 1, the observed ORRs with the Isa-Pd regimen for the 3 genotypes ranged from 50.0% to 80.0%, whereas in the larger Phase 3 Study 2, the ORR was more similar across genotypes (range 56.9% to 65.5%). Median progression-free survival (PFS) ranged from 8.97 months to 14.78 months and Isa-Pd showed a PFS benefit vs Pd for all 3 genotypes (Table 1). In Study 1, 42 patients had at least one baseline peripheral blood immune biomarker value; of these, 17 patients were non-responders and 25 patients were responders. In addition, 41 patients had at least one baseline bone marrow immune biomarker measurement (16 were non-responders and 25 were responders). No significant difference was observed between responders and non-responders for the tested immune biomarkers in bone marrow during screening. P-values were 0.2817 (CD19+ B-cell), 0.6446 (CD3+ T-cell), 0.7780 (CD4+ T-cell), 0.1620 (Tregs), 0.9591 (NK cell), 0.8275 (CD56+ bright/CD16+ low NK cell), and 0.7389 (CD56+ dim/CD16+ bright NK cell). Similarly, there was no significant difference between responders and non-responders for the immune biomarkers in baseline blood samples. Conclusion: Biomarker analyses on samples from patients treated with Isa-Pd did not find a significant association between tumor response and baseline bone marrow plasma cell CD38 RD, FCGR3A genotype, or immunophenotypes in bone marrow plasma cells or peripheral blood. These results suggest there is no benefit in prescreening patients for these parameters before treatment with Isa-Pd. Disclosures Richardson: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bensinger:Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant; Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau. Macé:Sanofi: Employment. Chiron:Sanofi: Employment. van de Velde:Sanofi: Employment. Campana:Sanofi: Employment. Liu:Sanofi: Employment. OffLabel Disclosure: Isatuximab is an investigational agent and has not been approved by the US Food and Drug Administration or any other regulatory agency worldwide for the uses under investigation.

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Von Willebrand Factor to Prevent Postpartum Hemorrhage

Blood ◽

10.1182/blood.v128.22.1400.1400 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1400-1400 ◽

Cited By ~ 1

Author(s):

Nicoletta Machin ◽

Margaret V. Ragni ◽

Andra H. James ◽

Craig D. Seaman ◽

Lynn M. Malec ◽

...

Keyword(s):

Blood Loss ◽

Board Of Directors ◽

Research Funding ◽

Structured Interviews ◽

First Line ◽

Vascular Medicine ◽

Advisory Committees ◽

Thrombosis Risk ◽

Von Willebrand ◽

Willebrand Factor

Abstract Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is characterized by deficient and/or defective von Willebrand factor (VWF) which results in spontaneous and traumatic mucosal bleeding. In women with VWD, pregnancy is associated with excess blood loss and poor quality of life. Recently, a prospective cohort study by James et al Haemophilia 2015, determined that even when treatment is given, women with VWD had lower VWF levels, greater blood loss at delivery, and lower hematocrit than controls without VWD. The reason for this finding remains unknown. Current VWF dosing is weight-based, but does not account for the ~1.4-1.5-fold increase in blood volume during pregnancy. To address this, we conducted a feasibility study for a prospective, randomized phase III trial comparing weight-based, 50 IU/kg, with volume-based, 80 IU/kg, VWF to prevent postpartum hemorrhage (PREVENT PPH Trial). Methods: To establish trial feasibility: 1) we compared pre-pregnancy and 8th-month VWF levels in women with VWD with and without PPH (≥500 cc blood loss in the 1st 24 hours) following vaginal delivery; 2) we evaluated VWF dosing in women with PPH in the James study; 3) we assessed thrombosis risk and VWF concentrate dose by literature review; 4) we surveyed current practice regarding VWF concentrate use at delivery by U.S. hemophilia treatment center (HTC) MDs; and 5) we conducted structured interviews of MDs and VWD patients to determine trial acceptability. Analysis was by Student's t-test for continuous data, and Fisher's exact test for discrete data. Results:In the Retrospective VWD-PPH Study of 16 women with VWD (14 type 1; 2 type 2) undergoing vaginal delivery, PPH was associated with higher pre-delivery weight, pre: 88.1 vs. 67.6 kg; 8thmonth: 99.9 vs. 75.0 kg; and delivery: 104.0 vs. 78.6 kg, all p<0.005; and a family bleeding history, 75.0% vs. 12.5%, p=0.041. Women with PPH had lower pre-pregnancy VWF:RCo, 0.34 IU/ml vs. 0.48 IU/ml, non-significant, p=0.067; similar 8th month VWF:RCo, 1.31 IU/ml vs. 1.45 IU/ml, p=0.484, and were more likely to be treated with VWF, 75.0% vs. 37.5%, p=0.315. Pre-pregnancy bleeding score (BS) correlated directly with EBL (blood loss) at delivery, r=0.663, p=0.005. VWF Dosing Data from James co-authors indicated a mean VWF dose of 46 IU/kg (median 50 IU/kg), range 28-83 IU/kg, at delivery, followed by 3.8 days (median 3 days), range 2-19 days, postpartum treatment. The Literature Review identified 13 publications between 1992-2015 reporting pharmacokinetic, safety, and/or efficacy studies in a total of 570 patients (none pregnant) at VWF doses 10-222 IU/kg. Thrombosis rate was low, 0.4%, including 2 of 353 (0.6%) receiving plasma-derived (pd) VWF and none of 95 (0%) receiving recombinant (r) VWF: these two patients included one with injection-site phlebitis and one with a remote postoperative VTE, each receiving VWF≤100 IU/kg. An HTC Survey distributed to 70 MDs, 19 (27.1%) of whom responded, 16/18 (88.9%) reported VWF was first-line therapy at delivery, mean dose 50 IU/kg; DDAVP was the most common second-line therapy in 7/17 (41.2%), and anti-fibrinolytic therapy was third-line, 8/10 (80.0%). All 19 indicated interest and willingness to participate in a trial comparing weight-based, 50 IU/kg, vs. 1.6-fold higher volume-based, 80 IU/kg, VWF at delivery. In Structured Interviews of 18 MDs and 18 VWD patients, the trial was acceptable to MDs if staff costs are covered, if the drug is safe re thrombosis, if there are sufficient patients, and if there is obstetrician collaboration to facilitate in-hospital dosing and blood draws. The trial was also acceptable to VWD patients if the drug is safe for mother and child, if childcare and travel costs are covered, and if visits are minimized in the postpartum period. Conclusions: The findings of this feasibility study indicate that pre-pregnancy VWF:RCo may be a better predictor of PPH than 8thmonth VWF:RCo. High pre-delivery weight which is associated with high blood volume may increase PPH, possibly through dilution of VWF levels. A VWF dose of ~50 IU/kg, which is the first line of therapy at delivery and the current standard of practice, may not prevent PPH. Thrombosis risk with VWF in published studies is low even at doses >80 IU/kg. Drug safety, local obstetric collaboration, and coverage of staff, travel, and childcare costs are critical issues to address in trial design. Disclosures Ragni: SPARK: Research Funding; Genentech: Research Funding; Tacere Benitec: Consultancy; Vascular Medicine Institute: Research Funding; OPKO: Research Funding; Novo Nordisk: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Baxalta: Research Funding; Biogen: Consultancy, Research Funding; Biomarin: Consultancy; Shire: Consultancy; CSL Behring: Research Funding. James:Intramural University of Ghana Research Fund: Research Funding; Vanderbilt University Medical Center Gift Funds: Research Funding. Malec:Biogen: Consultancy; Vascular Medicine Institute: Research Funding; Biogen: Research Funding; Baxalta: Research Funding. Kessler:Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Genentech: Consultancy, Research Funding; Biogen: Consultancy; Bayer: Consultancy, Research Funding; Pfizer: Consultancy; Baxalta: Consultancy, Research Funding; LFB: Other: Member of DSMB. Kouides:CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy. Neff:Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: DSMB Chair for research study; ABIM: Other: Hematology Exam committee; CSL Behring: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Philipp:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: Data Safety Monitoring Board. Brooks:Gilead Sciences: Research Funding.

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Beyond the Bethesda Assay- Towards Individualized Interpretation of Inhibitor Patients' FVIII Brand Specific Profiles

Blood ◽

10.1182/blood.v124.21.2841.2841 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2841-2841

Author(s):

Tami Livnat ◽

Amy Dunn ◽

Shirley Azar- Avivi ◽

Courtney Cox ◽

Einat Avishai ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

High Titer ◽

Individual Therapy ◽

Advisory Committees ◽

Fviii Activity ◽

Group A ◽

Inhibitory Antibodies ◽

Bypassing Agents ◽

Von Willebrand

Abstract Background: Patients with hemophilia A (HA) and inhibitory antibodies are typically treated with bypassing agents if the inhibitor titer is >5 Bethesda units (BU). However, some patients with elevated inhibitor titers are treated with FVIII therapy in conjunction with immune tolerance regimens or in combination with bypassing agents. The Bethesda assay detects the inhibitory capacity for FVIII neutralization after 2 hours' incubation of patient's plasma mixed with pooled normal plasma (PNP). Nonetheless the inhibitory titer does not express the kinetic behavior of the inhibitor throughout the 2 hours of incubation. Furthermore, standard plasma derived FVIII is used for the Bethesda assay, whereas many patients are currently treated with recombinant FVIII products. Patients with severe HA who develop inhibitors typically have a polyclonal response. In vitro responses to monoclonal specific anti- epitope antibodies showed that group A anti-A2 antibodies ( high titer, type I antibodies) rapidly and completely inhibit FVIII and are not affected by the presence of Von Willebrand factor (VWF). In contrast, many anti- C1 and C2 antibodies compete with VWF for binding to FVIII. As patients' response to various FVIII sources (eg: with/ without VWF) may be affected by their unique B cell epitope profile, personalized individually tailored FVIII brand specific therapy may be considered. Aims : We aimed to define our inhibitor patients' individual response to various FVIII sources by assessing the kinetics of FVIII inhibition and by patients' FVIII epitope specificity. Methods: Plasma was obtained from HA patients with inhibitors. FVIII neutralization profile was determined against PNP, recombinant full length FVIII (rFVIII= Kogenate- FS, Bayer), plasma derived Von Willebrand containing FVIII (pdFVIII = Optivate, BPL) and correlated to the inhibitory (BU) titer. To test FVIII neutralization profile, patients' platelet poor plasma was either incubated with PNP or spiked with 2U/ml rFVIII/pdFVIII and sequential measurements of residual FVIII activity was recorded over 120 minutes. FVIII activity was measured by one stage aPTT assay. All inhibitor assays were performed on the same sample simultaneously. Results were compared to the standard Bethesda assay. Domain-specific anti-FVIII antibody mapping was carried out by direct ELISA using purified single human domain hybrid FVIII protein. Patient plasma was serially diluted down the ELISA plate. Domain predominance was determined by comparison of resultant ELISA curves. In addition the presence of anti-A2 group A antibodies in the polyclonal patient plasma was assessed by competition ELISA. Results: Our patient cohort was heterogeneous, consisting of patients aged 3-70 years with inhibitor titers of 0.5-131 BU. No obvious correlation was found between kinetic profiles and the inhibitory BU titer. For each patient, variability of inhibitor activity against different FVIII sources was noted. In individual patients, discrepant inhibitory kinetics were identified when commercial FVIII (rFVIII or pd-FVIII) was added, compared to PNP, utilized for standard determination of inhibitory titer in BU/ml. Among patients with similar BU titer, different FVIII neutralization profile was noted. Furthermore, the source of FVIII yielded individual neutralization curves that did not correlate with the common gold standard of inhibitory (BU) titer (Figure). Correlation between patients' epitopes and their neutralization profile was difficult to assess as in most patients no single predominant inhibitory epitope could be defined. However, in patients with C2 predominance antibodies improved neutralization was detected with pd -FVIII as compared to rFVIII source. High titer patient plasmas that contained anti-A2 group A antibodies inhibited FVIII completely at the first time point regardless of the VWF content of the FVIII source. Conclusion: The Bethesda assay neither predicts inhibitory kinetics nor defines patients' response to various FVIII sources. Our combination of assays may identify the best potential FVIII source for treatment of patients with inhibitory antibodies. We suggest that FVIII source dependent neutralization kinetics and epitope mapping may be applied as additional tools for future individual therapy tailoring. Larger sample sizes and repeated samples over time will be required to validate these results. Figure 1 Figure 1. Disclosures Dunn: CSL Behring,: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Pfiser: Membership on an entity's Board of Directors or advisory committees. Meeks:Grifols: Membership on an entity's Board of Directors or advisory committees; Bayer HealthCare: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Baxter: Membership on an entity's Board of Directors or advisory committees. Kenet:BPL: Research Funding; Opko Biologics (Prolor Biotech): Consultancy, Research Funding; Novonordisk: Honoraria; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees; Baxter: Research Funding.

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