Impact of Platelet Transfusion on Pulmonary Function of Hematology Oncology Patients: The Piper Study

Abstract Background. Platelet transfusion is a critical therapy for hematology-oncology patients at risk of transfusion-transmitted infection (TTI) and pulmonary injury. Amotosalen-UVA pathogen reduction (PR) treatment of apheresis platelet components (PC) in plasma or additive solution (INTERCEPT Blood System for Platelets, Cerus, Concord, CA) is FDA approved to reduce risk of TTI and transfusion associated graft vs. host disease (TA-GVHD). PRPC meet the FDA bacteria risk reduction guidance, and approximately 50% of U.S. PC are PRPC. Amotosalen-UVA PR replaces bacteria screening, gamma irradiation, and CMV serology. PR is performed within 24 hours of collection enabling early release of PRPC with 5-day storage. We tested the hypothesis that PRPC were not inferior to conventional PC(CPC) for the incidence of pulmonary injury. Methods. An open-label sequential cohort study in platelet transfusion dependent hematology-oncology patients was conducted under routine practice conditions in 15 clinical centers. Each site enrolled a CPC cohort followed by a PRPC cohort using 4 primary therapy strata matched ± 10%: chemotherapy without hematopoietic cell transplant (HCT), HCT with myeloablation, HCT with non-myeloablative conditioning, and HCT with reduced intensity conditioning (RIC). Patients were supported with the assigned PC type for up to 21 days with 7 days of surveillance after the last PC exposure. Patients participated in only one cohort. The primary endpoint was treatment emergent assisted mechanical ventilation (TEAMV) by intubation or tight mask with positive end expiration pressure (5cm H 2O) after initiation of study PC. All endpoint patients were adjudicated by a blinded pulmonary expert panel (PEP) for diagnosis of acute respiratory distress syndrome (ARDS) by the Berlin Criteria. Secondary endpoints included: time to initiation of TEAMV, clinically significant pulmonary adverse events (CSPAE, CTCAE ≥ Grade 2), transfusion reactions, and mortality. The incidence of TEAMV by non-inferiority (margin = 2.3%), and secondary endpoints were analyzed by modified intention to treat (mITT) and per protocol (PP). Sensitivity analyses with propensity score matching for key variables were conducted for the primary endpoint. The associations between PC and categorical variables were tested by stratified Cochran-Mantel-Haenszel and continuous variables by ANOVA for two-sided significance p = 0.05. results. A total of 2291 pediatric and adult patients (1068 PRPC and 1223 CPC) were enrolled in the respective cohorts with transfusion of 5,277 PRPC and 5,491 CPC. PC assignment compliance and study completion were > 94%. For the mITT data set, the cumulative incidence of TEAMV was lower for the PRPC cohort (log rank p = 0.039) than the CPC cohort (2.9% versus 4.6%, HR = 0.633: 95% CI 0.408-0.982). PRPC by mITT were non-inferior to CPC for the incidence of TEAMV due to all indications, and for TEAMV with pulmonary dysfunction (PD) by PEP (Table). PP analyses were consistent with mITT. Relative risk (RR) of TEAMV showed significantly (p<0.05) decreased RR of PRPC respectively for baseline covariates: age < 65 (0.53), male (0.54), non-white (0.32), chemotherapy (0.40), prior pulmonary disease (0.55), and prior cardiac disease (0.58). Least squares (LS) mean days to initiation of TEAMV for patients with PD were longer for PRPC recipients. PEP adjudicated incidence of ARDS was not significantly different between cohorts (Table). Total and serious CSPAE were not different between the cohorts. There were no significant differences between cohorts in Respiratory, Thoracic, and Mediastinal Disorders, the most frequent system organ class event. Mortality was not different between cohorts. Multivariate analysis (mITT) for the probability of CSPAE or transfusion associated cardiac overload (TACO) showed PC type had no effect. The odds ratio (OR) of CSPAE or TACO during PC support was significantly increased (p< 0.05) in both cohorts for history of cardiac disease (1.35), history of pulmonary disease (2.57), diagnosis of Myelodysplasia (1.88), and diagnosis of Myelodysplasia/Myeloproliferative disease (2.27). There was a significant treatment interaction (p= 0.043) between PC type and acute myelogenous leukemia (AML), increased OR = 1.49 for CPC versus PRPC. Conclusions. PRPC did not potentiate pulmonary injury during PC support; and their use may decrease TEAMV risk with benefit of reduced TTI risk. Figure 1 Figure 1. Disclosures Wheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Nooka: Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Adaptive technologies: Consultancy; GlaxoSmithKline: Consultancy, Other: Travel expenses; Karyopharm Therapeutics: Consultancy. Uhl: UpToDate: Patents & Royalties; Abbott: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau. Spinella: Secure Transfusion Services: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cerus Corporation: Consultancy, Research Funding. Liu: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Benjamin: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Corash: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company.

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Thrombosis and Risk of Mortality in Newly Diagnosed High-Risk Polycythemia Vera: An Analysis of the Medicare Claims Database in the United States

Blood ◽

10.1182/blood-2020-141370 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Naveen Pemmaraju ◽

Aaron T. Gerds ◽

Shreekant Parasuraman ◽

Jingbo Yu ◽

Anne Shah ◽

...

Keyword(s):

High Risk ◽

Median Time ◽

Research Funding ◽

Index Date ◽

Newly Diagnosed ◽

Publicly Traded ◽

Risk Of Mortality ◽

Increased Risk ◽

History Of

Background Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with an increased risk of thrombotic events (TEs), a major cause of morbidity and mortality. Patients aged ≥60 years and/or with a history of thrombosis are considered to have high-risk PV. There is limited contemporary, real-world evidence exploring the effect of TEs on mortality in patients with PV. The aim of this analysis was to compare the risk of mortality in patients newly diagnosed with high-risk PV who experienced a TE vs those who did not experience a TE. Study Design and Methods All data from the Medicare Fee-for-Service (FFS) claims database (Parts A/B/D) from January 2010-December 2017 were used to identify patients with a PV diagnosis (all high risk based on cohort being ≥65 years of age) with ≥1 inpatient or ≥2 outpatient claims. The index date was the date of the first qualifying PV claim. Patients with a PV diagnosis or use of cytoreductive therapy within 12 months before the index date (pre-index period) were excluded; ≥12-months continuous medical and pharmacy enrollment pre-index dates was required. The study sample was categorized into TE and non-TE groups based on the occurrence of any of the following events during follow-up: deep vein thrombosis, pulmonary embolism, ischemic stroke, acute myocardial infarction, transient ischemic attack, peripheral arterial thrombosis, or superficial thrombophlebitis. TEs were evaluated from the index date to the end of follow-up. Cox regression analyses with time-varying effects were used to assess mortality risk among patients with PV, with post-index TE as a time-dependent variable, stratified by pre-index TE, and adjusting for patient demographic characteristics and comorbid conditions. Results A total of 56,176 Medicare FFS beneficiaries with PV diagnoses met inclusion criteria. The median age was 73 years, 51.9% were men, and 90.7% were white; 10,110 patients (18.0%) had a history of TE before diagnosis (ie, pre-index). In the follow-up period, 20,105 patients (35.8%) had a TE and 36,071 patients (64.2%) did not have a TE. In the comparison between the TE vs non-TE groups, the median (range) age (75.0 [65-104] vs 73.0 [65-106] years, respectively), mean (SD) Charlson comorbidity index score (3.1 [2.6] vs 2.2 [2.3]), and percentage of patients with a history of cardiovascular events (34.1% vs 23.8%), bleeding (13.3% vs 10.4%), or anemia (28.6% vs 23.4%) were higher (Table 1). Among all patients with PV, the median time from diagnosis to first post-index TE was 7.5 months. Among those with pre-index TE (n=10,093), median time from index to first post-index TE was 0.6 months, whereas patients without pre-index TE (n=46,083) had a median time to first post-index TE of 14.2 months. Among all patients with TE during follow-up, the most common TEs were ischemic stroke (47.5%), transient ischemic attack (30.9%), and acute myocardial infarction (30.5%). The risk of mortality was increased for patients who experienced a TE compared with those who did not (hazard ratio [HR; 95% CI], 9.3 [8.4-10.2]; P<0.0001). For patients who experienced a pre-index TE, the risk of mortality was increased for patients who experienced a subsequent TE during follow-up compared with patients who did not (HR [95% CI], 6.7 [5.8-7.8]; P<0.0001). Likewise, for patients who did not experience a pre-index TE, the risk of mortality was increased for patients who experienced a TE during follow-up compared with patients who did not (HR [95% CI], 13.1 [11.4-15.0]; P<0.0001). Conclusions In this real-world study, approximately one-third of patients with newly diagnosed high-risk PV experienced a TE during follow-up and had a 9-fold increased risk of mortality vs those who did not experience a TE. TE risk mitigation remains an important management goal in patients with PV, particularly in those with prior TE. Disclosures Pemmaraju: Samus Therapeutics: Research Funding; Celgene: Honoraria; SagerStrong Foundation: Other: Grant Support; Affymetrix: Other: Grant Support, Research Funding; MustangBio: Honoraria; Blueprint Medicines: Honoraria; LFB Biotechnologies: Honoraria; Plexxikon: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Daiichi Sankyo: Research Funding; Incyte Corporation: Honoraria; Roche Diagnostics: Honoraria; Cellectis: Research Funding; DAVA Oncology: Honoraria. Gerds:Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Imago Biosciences: Research Funding; Pfizer: Research Funding; CTI Biopharma: Consultancy, Research Funding; Roche/Genentech: Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding. Parasuraman:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Yu:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Shah:Avalere Health: Current Employment. Xi:Incyte Corporation: Other: Avalere Health is a paid consultant of Incyte Corporation; Avalere Health: Current Employment. Kumar:Avalere Health: Current Employment; Incyte Corporation: Other: Avalere Health is a paid consultant of Incyte Corporation. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; Sierra Oncology: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding.

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Effect of denosumab on bone mineral density (BMD) in women with breast cancer (BC) and men with prostate cancer (PC) undergoing hormone ablation therapy

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.9520 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 9520-9520

Author(s):

M. R. Smith ◽

G. Ellis ◽

F. Saad ◽

T. Tammela ◽

H. Bone ◽

...

Keyword(s):

Bone Resorption ◽

Primary Endpoint ◽

Human Monoclonal Antibody ◽

Mineral Density ◽

Ablation Therapy ◽

Skeletal Site ◽

Hormone Ablation ◽

History Of ◽

Secondary Endpoints ◽

Vitamin D Supplements

9520 Background: Hormone ablation therapies, including adjuvant aromatase inhibitor (AI) therapy and androgen deprivation therapy (ADT), improve recurrence-free survival in patients (pts) with BC and PC, respectively. However, these treatments increase bone resorption, leading to bone loss and fractures. RANKL is a key mediator of osteoclast-mediated bone resorption. In this 24 month (mo) comparison, we investigated the effects of denosumab, a fully human monoclonal antibody against RANKL, on preserving BMD across both populations. Methods: Two trials were conducted: a 24-mo BC study and a 36-mo PC study. Postmenopausal women with low BMD receiving AI therapy for nonmetastatic BC and men receiving ADT for nonmetastatic PC (with low BMD or history of osteoporotic fracture if < 70 yrs) were randomized to receive placebo or denosumab 60mg subcutaneously every 6 mos. All pts in both studies were prescribed calcium and vitamin D supplements. The primary endpoint was % change from baseline in lumbar spine (LS) BMD at 12 mos for the BC study and at 24 mos for the PC study. Herein, we present changes in BMD at 24 mos at LS, total hip (TH), and 1/3 radius from both studies. Power calculations were based on enrollment of at least 208 patients in the BC study (for primary endpoint only) and 1226 in the PC study (for primary and key secondary endpoints). The actual numbers randomized were 252 and 1468, respectively. Results: Denosumab increased BMD of the LS, TH, and 1/3 radius compared with placebo at 24 mos in both pt populations ( Table ). In both studies, differences between denosumab and placebo at each skeletal site were consistent, and the effects of denosumab were statistically significantly different from placebo as early as 1 month at the LS in both studies. The overall safety profile was similar to placebo in each study. Conclusions: Denosumab consistently increased BMD at all 3 skeletal sites compared with placebo in both women with BC undergoing AI therapy and in men with PC undergoing ADT. [Table: see text] [Table: see text]

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Short Course of Bendamustine and Rituximab Followed by 90Y-Ibritumomab Tiuxetan in Patients with Chemotherapy-Naïve Follicular Lymphoma: Early Results of “Fol-Brite”

Blood ◽

10.1182/blood.v120.21.3657.3657 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3657-3657

Author(s):

Frederick Lansigan ◽

Eric Winer ◽

Sara R Metzler ◽

Lynn Shaw ◽

Peggy Alton ◽

...

Keyword(s):

Follicular Lymphoma ◽

Primary Endpoint ◽

Research Funding ◽

Complete Response ◽

Ibritumomab Tiuxetan ◽

Stage Design ◽

Short Course ◽

Secondary Endpoints ◽

Grade 3 ◽

To Receive

Abstract Abstract 3657 Background: Bendamustine and rituximab is proving to be a superior first-line option in the treatment of follicular lymphoma. 90Y-ibritumomab tiuxetan is an effective consolidation strategy after chemotherapy induction in patients with follicular lymphoma, but has never been sequentially combined with bendamustine. In this prospective, single-arm, open-label, multicenter phase II trial (Fol-BRITE), we aim to assess the response rate and safety of a short induction course of bendamustine and rituximab (B-R) for 4 cycles followed by consolidation with 90Y-ibritumumab tiuxetan (90Y-IT) for chemotherapy-naïve patients with follicular lymphoma. Methods: Subjects greater than the age of 18 with chemotherapy-naïve follicular lymphoma (grade 1–2 and 3a) requiring treatment are eligible for this study. Treatment consists of an initial dose of rituximab 375mg/m2, and then one week later, bendamustine 90mg/m2 on days 1 and 2, and rituximab 375mg/m2 on day 1 of a 28-day cycle. B-R is given for a total of 4 cycles. Patients are eligible for consolidation with 90Y-IT if they obtain at least a partial response (PR) after induction, with a platelet count over 150,000/mm3, and granulocyte counts 1,500/mm3 and a bone marrow infiltration of <25%. The primary endpoint of this study is the determination of the complete response (CR) rate after sequential therapy with B-R followed by 90Y-IT. Secondary endpoints are overall response (OR=CR+PR) rate after a short course of B-R (4 cycles) and conversion rate from PR after B-R to CR after 90Y-IT. Secondary endpoints also include progression-free survival and safety. An optimal Simon two-stage design is incorporated to allow an early futility look for complete responses. Results: Nineteen patients have started treatment in this study to date, 13 have completed B-R and 7 have received 90Y-IT. Response rates after 4 cycles of B-R: Thirteen patients have completed 4 cycles of B-R and 13 are evaluable for response. Seven of 13 evaluable patients have had a CR (53.8%) and 5 of 13 patients have had a PR (38.5%) after 4 cycles of B-R for an OR rate of 92.3%. Response rates after B-R followed by 90Y-IT: Seven of 13 B-R-treated patients have received 90Y-IT and are evaluable for the primary endpoint of complete response. Of the 13 B-R treated patients, one patient in CR was unable to receive 90Y-IT due to thrombocytopenia, and one other patient was not eligible to receive 90Y-IT due to achievement of stable disease only. Six of the 7 evaluable patients are in CR (85.7%) and one patient remains in a PR (14.3%) after consolidation with 90Y-IT. Of the 3 subjects who attained a PR after B-R, 2 (66.7%) converted to a CR after 90Y-IT, with one late conversion 16 months after 90Y-IT. Hematologic toxicities after B-R included grade 4 neutropenia (1), grade 3–4 lymphopenia (3), and no grade 3–4 thrombocytopenia, out of 13 patients evaluable. Hematologic toxicities after 90Y-IT were acceptable, including grade 3–4 neutropenia (6), grade 3–4 lymphopenia (5), and grade 3–4 thrombocytopenia (4), out of 7 patients evaluable for toxicity. There have been no incidences of neutropenic fever. All patients have recovered their blood counts 7 to 12 weeks after Y90-IT. One out of 19 patients treated in this study has developed chronic myelogenous leukemia, occurring 11 months after treatment with Y90-IT. Conclusions: In this early pre-planned analysis of the first-stage of an optimal Simon two-stage design, we report this combination of therapy is both effective and safe. The CR rate of patients completing all study therapy is 85.7%, and well exceeds the limits required to continue this trial with an accrual goal of 39 subjects. Sequential treatment with B-R followed by Y90-IT is a promising option for the treatment of follicular lymphoma. Disclosures: Lansigan: Spectrum Pharmaceuticals: Advisory Board Other, Research Funding; Teva: Research Funding. Beaven:Celgene: Research Funding.

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Oral Rilzabrutinib, a Bruton Tyrosine Kinase Inhibitor, Showed Clinically Active and Durable Platelet Responses and Was Well-Tolerated in Patients with Heavily Pretreated Immune Thrombocytopenia

Blood ◽

10.1182/blood-2020-134932 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-14

Author(s):

David J. Kuter ◽

Merlin Efraim ◽

Jiri Mayer ◽

Vickie McDonald ◽

Robert J. Bird ◽

...

Keyword(s):

Tyrosine Kinase ◽

Median Duration ◽

Primary Endpoint ◽

Clinical Studies ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Publicly Traded ◽

Platelet Counts ◽

Bruton Tyrosine Kinase ◽

Heavily Pretreated

Introduction: Rilzabrutinib is an oral, reversible, covalent inhibitor of Bruton tyrosine kinase (BTK) that targets underlying disease mechanisms of platelet destruction without inhibiting platelet aggregation (common with ibrutinib). The mechanisms of BTK inhibition provide a new approach for treating patients with immune thrombocytopenia (ITP). Completion of dose-escalation study phase determined that the minimally-effective dose was rilzabrutinib 400 mg given twice daily (BID; Kuter. ASH 2019). Methods: This open-label phase I/II study evaluated rilzabrutinib in adults with relapsed ITP who had at least two platelet counts <30×109/L in the 14 days prior to the first dose of rilzabrutinib, and included patients who had inadequate response to prior corticosteroids (CS)/thrombopoietin receptor agonists (TPO-RA) but were allowed to continue receiving stable doses of these medications. The primary endpoint was ≥2 consecutive platelet counts of ≥50×109/L and an increase of ≥20×109/L from baseline without requiring rescue medication. Subgroup analyses included assessing the impact of select prior therapies on reaching the primary endpoint, as well as the ability of rilzabrutinib to maintain durable responses and safety in the long-term extension (LTE) period. Results: As of May 5, 2020, 32 patients initiated treatment with rilzabrutinib 400 mg BID. The median baseline age was 50 years (range, 21-74) and 97% were classified as having primary ITP. Patients had a median baseline platelet count of 13×109/L, had ITP for a median duration of 7.3 y (range, 0.4-52.5), and were heavily pretreated with a median of 6 prior therapies (range, 1-53; 28% prior splenectomy). Median duration of rilzabrutinib 400 mg BID treatment was 18.0 wk (range, 1.4-24.6). Overall, 14/32 patients (44%) achieved the primary endpoint, and responders maintained platelet counts ≥50×109/L for a median of 71% (range, 33%-100%) of weekly counts. Primary endpoint responses were achieved despite prior splenectomy or lack of response to prior ITP therapies (Table). Independent of the primary response, 67% of all patients were able to achieve clinically meaningful benefit of platelet counts ≥30×109/L. Nine patients continued rilzabrutinib 400 mg BID into the LTE period for an additional median of 20 wk (range, 4-36) of treatment. Four of these LTE patients were on rilzabrutinib monotherapy and 5 on rilzabrutinib with concomitant ITP therapy (n=3 corticosteroids, n=2 romiplostim). Baseline characteristics for the 9 LTE patients were a median duration of ITP of 2.6 y (1.2-14.3) and a median of 5 prior therapies (range, 1-8; 1 patient had a prior splenectomy). Platelet counts of ≥50×109/L in the LTE period were maintained for a median of 100% (range, 36%-100%) of weekly counts (Figure). Treatment-related, treatment-emergent adverse events (TEAEs) were all grade 1/2 in patients initiating rilzabrutinib 400 mg BID; 1 patient each experienced grade 1 diarrhea and grade 1 hypophosphatemia in the LTE period. Conclusions: Oral rilzabrutinib treatment achieved clinically significant platelet responses (≥50×109/L) in patients with heavily pretreated ITP irrespective of splenectomy or lack of response to prior ITP therapy, and maintained responses for the majority of time. In addition, most patients (67%) achieved a clinically meaningful response (platelet counts ≥30×109/L). In patients treated beyond 6 months in the LTE, responses remained consistently reliable (median 100% of weeks). Rilzabrutinib was well tolerated with only grade 1/2 treatment-related TEAEs overall, with only 2 related grade 1 events observed in the LTE period. Continued study is warranted to further demonstrate the magnitude and durability of rilzabrutinib's clinical benefit. Disclosures Kuter: Zafgen: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; Protalix Biotherapeutics: Consultancy; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Protalex: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Kezar Life Sciences, Inc: Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Immunovant: Other: Travel Expenses, Research Funding; Principia: Consultancy, Research Funding; Momenta: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria. Efraim:UMHAT"ST.MARINA": Consultancy, Current Employment, Current equity holder in private company. Mayer:AbbVie: Research Funding; Principia Biopharma: Research Funding. McDonald:Bayer: Consultancy, Honoraria; Rigel: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Consultancy, Honoraria, Other: Travel Expenses. Bird:Sanofi: Consultancy, Other: (pls note personal honoraria declined for ad board); Principia Biopharma: Other: investigator in clinical studies; Amgen: Consultancy, Other: (pls note personal honoraria declined for all), Speakers Bureau; Novartis: Consultancy, Other: (pls note personal honoraria declined for all), Speakers Bureau; Rigel: Other: investigator in clinical studies; CSL-Behring: Other: investigator in clinical studies; Bristol-Myers Squibb Company: Other: investigator in clinical studies; Ablynx: Other: investigator in clinical studies. Regenbogen:Roche: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company. Garg:Takeda: Consultancy. Kaplan:Celgene: Honoraria; Novartis: Honoraria. Bandman:Principia Biopharma: Current Employment. Burns:Principia Biopharma: Current Employment. Neale:Principia Biopharma: Current Employment. Thomas:Principia Biopharma: Current Employment, Current equity holder in publicly-traded company. Cooper:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Principia: Consultancy, Honoraria. OffLabel Disclosure: Rilzabrutinib is an investigational therapy being evaluated in a clinical study for the treatment of patients with immune thrombocytopenia.

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Efficacy and Safety of Pegcetacoplan Treatment in Complement-Inhibitor Naïve Patients with Paroxysmal Nocturnal Hemoglobinuria: Results from the Phase 3 Prince Study

Blood ◽

10.1182/blood-2021-147493 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 606-606

Author(s):

Raymond S Wong ◽

Juan Ramon Navarro ◽

Narcisa Sonia Comia ◽

Yeow Tee Goh ◽

Henry Idrobo ◽

...

Keyword(s):

Research Funding ◽

Complement Inhibitor ◽

Publicly Traded ◽

Open Label ◽

Phase 3 ◽

Complement Inhibitors ◽

Primary Endpoints ◽

Secondary Endpoints ◽

Peg Treatment ◽

Inhibitor Treatment

Abstract Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening disease characterized by hemolysis and thrombosis. Many patients with PNH use C5-inhibitors (i.e., eculizumab/ravulizumab) to control their symptoms. Although C5-inhibition prevents intravascular hemolysis (IVH), it fails to prevent extravascular hemolysis (EVH). Because of persistent EVH, up to 72% of eculizumab-treated patients remain anemic, and up to 36% require at least one transfusion per year. Pegcetacoplan (PEG), a C3-inhibitor recently approved by the US FDA to treat adults with PNH, controls IVH and prevents EVH. Studies of PEG treatment in patients with PNH that remained anemic despite eculizumab treatment demonstrated that PEG was superior to eculizumab in achieving improvements in hemoglobin (Hb) levels (Hillmen P, et al., N Engl J Med, 2021 384 (11):1028-1037). Additionally, two early phase open-label trials demonstrated the efficacy of PEG in complement-inhibitor naïve patients with PNH (Wong RS, et al., Blood, 2020 136 [Supplement 1]). Aims: To present results from the Phase 3 PRINCE study (NCT04085601), a multicenter, randomized, open-label, controlled study evaluating the efficacy and safety of PEG compared to standard of care (SOC; excluding complement-inhibitors) in complement-inhibitor naïve patients with PNH. Methods: Fifty-three adult (≥18 years old), complement-inhibitor naïve (no complement-inhibitor treatment [i.e., eculizumab/ravulizumab] within 3 months prior to screening) patients with PNH and Hb levels below the lower limits of normal (males: ≤13.6 g/dL; females: ≤12.0 g/dL), and lactate dehydrogenase (LDH) levels ≥1.5 times the upper limit of normal (1.5x ULN; ≥339 U/L) were enrolled. Patients were randomized 2:1 to receive PEG (1080 mg subcutaneously twice weekly [n=35]) or SOC (excluding complement-inhibitors eculizumab/ravulizumab [n=18]) through Week 26. Patients on SOC had the option to switch to the PEG group if their Hb decreased by ≥2 g/dL from baseline. Co-primary endpoints were Hb stabilization (avoidance of a >1 g/dL decrease in Hb levels in the absence of transfusions) and change from baseline (CFB) in LDH level from baseline to Week 26. Secondary endpoints included CFB in Hb levels, transfusion avoidance (defined as the proportion of subjects who did not require a transfusion through Week 26), and the incidence of adverse events (AEs). Statistical analyses were performed using the Cochran-Mantel-Haenszel test and ANCOVA model. Results: PEG was superior to SOC in both co-primary endpoints. Hb stabilization was achieved by 85.7% (n=30) of PEG-treated patients and 0.0% of SOC patients through Week 26 (p<0.0001). PEG-treated patients demonstrated superior reductions in mean LDH levels from baseline to Week 26 compared to SOC patients (least-squares mean CFB: PEG, -1870.5 U/L; SOC, -400.1 U/L; p<0.0001), and mean LDH levels in PEG-treated patients at Week 26 (mean level: 204.6 U/L) were below the ULN for LDH (226.0 U/L). PEG was also superior to SOC in the secondary endpoints: mean CFB in Hb levels (least-squares mean CFB: PEG, 2.9 g/dL; SOC, 0.3 g/dL; p=0.0019; Week 26 mean Hb: PEG, 12.8 g/dL; SOC, 9.8 g/dL) (Figure) and transfusion avoidance (PEG, 91.4%, n=32; SOC, 5.6%, n=1; p<0.0001). Serious AEs were reported by 8.7% (n=4) of PEG-treated patients and 16.7% (n=3) of SOC patients through Week 26. Two deaths (PEG, 2.9%, n=1, septic shock related to medullary aplasia; SOC, 5.6%, n=1, respiratory failure), both deemed unrelated to treatment, occurred. No events of meningitis or thrombosis were reported in either group. The most common AEs reported during the study were injection site reaction (PEG, 30.4%, n=14; SOC, 0.0%), hypokalemia (PEG, 13.0%, n=6; SOC, 11.1%, n=2), and fever (PEG, 8.7%, n=4; SOC, 0.0%). There were no AEs leading to discontinuation of PEG. Conclusions: Patients with PNH that were naïve to complement-inhibitor treatment demonstrated meaningful hematological and clinical improvements following 26 weeks of PEG treatment. The safety profile of PEG was similar to previous study results and represent a favorable risk-benefit profile. These results provide evidence for the safety and efficacy of PEG treatment in complement-inhibitor naïve patients with PNH. Figure 1 Figure 1. Disclosures Wong: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis Pharmaceuticals: Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau. Al-Adhami: Apellis Pharmaceuticals: Current Employment. Ajayi: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Alvarenga: Apellis Pharmaceuticals: Consultancy. Deschatelets: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Francois: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Grossi: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

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Thiotepa-Fludarabine-Treosulfan (TFT) Conditioning for 2nd Allogeneic Peripheral Blood Hematopoietic Cell Transplantation (HCT) from a Second Unrelated Donor in Patients with Acute Myeloid Leukemia (AML) Relapsed after Prior Allogeneic HCT: A Prospective Multicenter Phase II Trial

Blood ◽

10.1182/blood-2018-99-118999 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 210-210

Author(s):

Jürgen Finke ◽

Claudia Schmoor ◽

Matthias Stelljes ◽

Andreas Burchert ◽

Peter Dreger ◽

...

Keyword(s):

Primary Endpoint ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Allogeneic Hct ◽

Gvhd Prophylaxis ◽

Secondary Endpoints ◽

Full Analysis

Abstract Introduction: Relapse of AML after allogeneic HCT has a dismal prognosis. Long-term survival after 2nd allogeneic HCT has been described in selected patients. Here we tested a specific protocol with a fixed drug combination for myeloablative conditioning and GvHD prophylaxis for 2nd allogeneic HCT from a different unrelated donor. (EudraCT no.: 2012-005414-18, German Clinical Trials Registry no.: DRKS00005126) Methods : Aim of the trial was to show efficacy and safety of a 2nd alloHCT from an unrelated donor after a uniform conditioning with Treosulfan 3x12gm/m2, Fludarabin 3x30mg/m2, and Thiotepa 3x 5mg/kg (TFT), and GvHD prophylaxis with cyclosporine A (CyA) /Mycophenolate and ATG-F (Neovii) 3x10mg/kg. Eligible were adult patients with AML, ECOG ≤ 2, with sensitive or refractory hematologic relapse (≥ 20% blasts) > 6 months after a prior allogeneic HCT , including secondary (s) and/ or tAML. CR prior 2nd HCT was no prerequisite. The primary endpoint of the study was disease-free survival (DFS) defined as being alive and free of disease at 1 year post 2nd HCT. Secondary endpoints were relapse, relapse mortality (RM), NRM, overall survival (OS), acute GvHD, chronic GvHD, engraftment, and adverse events. According to the Fleming one-stage design, 50 evaluable patients had to be included. If 16 or more patients were alive and free of disease at 1 year post 2nd SCT, the regimen could be considered as successful for evaluation in further trials. With this decision rule, it can be shown at one-sided α=0.1 that the probability of DFS at 1 year post 2nd HCT is higher than 23% with a power of 90%, when it is at least 40%. This is a first analysis of the study covering the first year after 2nd HCT of each patient. The analysis is based on the full analysis set, which includes all patients, for whom the conditioning regimen TFT and the GvHD prophylaxis regimen CyA, MPA/MMF, ATG-F has started, and for whom allogeneic HCT from an unrelated donor has been performed. Results: Fifty-two patients were registered for the study from 25th March 2014 up to 10th March 2017 from 9 German centres. The full analysis set includes 50 patients (median age 53.5 years). ECOG was median 1. Donors for 1st allo HCT had been related (n=11 (22.0%)) or unrelated (n=39 (78.0%)) (n=48 PBSCT, n=2 bone marrow). Conditioning for 1st HCT was myeloablative in 23 (46.0%) patients. After 1st HCT, the rate of acute GvHD I-IV was 34.0%, and of chronic GvHD was 40.0%. Median time from 1st HCT to relapse was 17.2 months and from relapse after 1st HCT to 2nd HCT 2.5 months. Thirty-six (72%) patients had received induction chemotherapy for relapse prior to 2nd HCT, 11 (22.0%) patients had received azacytidine or decitabine, and 11 (22.0%) had received donor lymphocyte infusions (DLI). Remission status prior to 2nd HCT was complete remission in 16 (32.0%) patients, chemo-refractory relapse in 33 (66.0%), one patient was in partial remission. With regard to the primary endpoint, 23 (46%, 95%-CI (31.8-60.7%) of the patients were alive and free of relapse at 1 year after 2nd SCT. With regard to the secondary endpoints at 1 year, the cumulative incidence of relapse (95%-CI) was 26 (17-42)%, 9/50 patients (18 (10-33)%) died after relapse of AML, NRM was 14/50 patients (28 (18-44)%, cause: infection n=6, infection after aGvHD n=6, PTLD n=2), OS was 54 (39-66)%. Four patients are alive after relapse. aGvHD rate was 54 (42-70)%, aGvHD III-IV 26 (16-42)%, cGvHD 26 (16-42)%, extensive cGvHD 20 (12-35)%, engraftment rate with ANC > 1.0 x 103/µl was 92 (85-100)%, with platelets > 20 x 103/µl was 80 (70-92)%, and with platelets > 100 x 103/µl was 66 (54-81)%. After 1 year, 4 patients had received DLI for prophylaxis, and 5 patients for mixed chimerism as per protocol. Conclusion: Second alloHCT with an ablative double alkylator containing conditioning regimen with Thiotepa, Fludarabine, and Treosulfan is feasible and can result in sustained disease control in patients with AML relapse after a first alloHCT, and therefore seems to be a valid option in this otherwise detrimental setting. Disclosures Finke: Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; Novartis: Honoraria; Amgen: Honoraria; JAZZ: Honoraria. Burchert:Novartis: Research Funding; Bayer: Research Funding; AOP Orphan: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Schub:Affimed: Research Funding. Kobbe:Celgene: Honoraria, Other: Travel Support, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

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Long-Term Cardiac, Vascular, and Hypertension Safety of Bosutinib (BOS) Versus Imatinib (IMA) for Newly Diagnosed Chronic Myeloid Leukemia (CML): Results from the Bfore Trial

Blood ◽

10.1182/blood-2020-134912 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-35

Author(s):

Jorge E. Cortes ◽

Philipp D le Coutre ◽

Carlo Gambacorti-Passerini ◽

Henrik Hjorth-Hansen ◽

Pia Raanani ◽

...

Keyword(s):

Risk Factors ◽

Adverse Events ◽

Research Funding ◽

Study Drug ◽

Newly Diagnosed ◽

Cardiac Events ◽

Publicly Traded ◽

Vascular Events ◽

Serious Adverse Events ◽

History Of

Introduction: Tyrosine kinase inhibitor therapy has been associated with cardiovascular (CV) events. BOS is approved for patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) CML and Ph+ CML resistant/intolerant to prior therapy. We analyzed cardiac, vascular and hypertension treatment-emergent adverse events (TEAEs) in pts with newly diagnosed CP CML receiving BOS or IMA after 5 yrs follow-up in BFORE. Methods: In the open-label, phase 3 BFORE trial (NCT02130557), 536 pts with newly diagnosed CP CML were randomized 1:1 to receive first-line 400 mg once-daily BOS (n=268) or IMA (n=268; 3 untreated). The current analysis included all pts who received ≥1 dose of study drug. TEAEs were monitored from first dose of study drug until 28 d after last dose; monitoring of non-serious adverse events (AE) ended at the start of a new cancer treatment. Prespecified MedDRA terms (cardiac, n=133; vascular, n=502) comprised clusters of investigator-assessed TEAEs (Table). Multivariable proportional subdistribution hazard models predicting time to first TEAE included treatment group; baseline demographic information; history of cardiac events, vascular events, hypertension, diabetes, hyperlipidemia, and tobacco use; as well as hypertension, cardiac (for vascular model) and vascular (for cardiac model) TEAEs. CI excluding 1 was considered predictive of outcome. This analysis was based on 17-Apr-20 last pt last visit (12-Jun-20 database lock), 5 y (240 wks) after last enrolled pt. Results: At study completion, 59.7% of BOS pts and 58.1% of IMA pts were still on treatment. Median duration of treatment was 55 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 393.6 (39-583) vs 400.0 (189-765) mg/d. In the BOS vs IMA arm, 57.8% vs 56.2% of pts had ≥1 CV risk factor at baseline; 20.9% vs 17.7% had ≥3 risk factors, respectively. The most common risk factors were a history of hypertension (BOS, 34.0%; IMA, 30.6%), BMI >30 (BOS, 23.1%; IMA, 21.9%), age ≥65 y (BOS, 19.8%; IMA, 17.4%), and history of hyperlipidemia (BOS, 16.8%; IMA, 18.9%). Rates of cardiac, vascular and hypertension TEAEs; serious adverse events (AEs); AEs leading to treatment withdrawal and drug-related TEAEs (per investigator) were low in both arms (Table). Exposure-adjusted rates of cardiac, vascular and hypertension TEAEs were similar between arms (Table). Risk factors for cardiac TEAEs (HR; 95% CI) were age in years (1.04 [1.02-1.07]), race other than Asian or black compared to white (<0.01 [<0.01-<0.01]), a history of tobacco use (6.94 [1.89-25.40]) and cardiac events (3.59 [1.68-7.65]), hypertension (3.07 [1.20-7.84]) and vascular TEAEs (5.27 [1.53-18.18]). Risk factors for vascular TEAEs (HR [95% CI]) were black race compared to white (<0.01 [<0.01-<0.01]), a history of vascular events (4.65 [1.81-11.97]) and cardiac TEAEs (7.73 [2.31-25.84]). In multivariable analyses, treatment group was not predictive of time to initial cardiac (HR 0.87 [95% CI 0.45-1.70]) or vascular (HR 2.17 [95% CI 0.94-45.04) TEAEs. The most common cardiac, vascular, and hypertension TEAEs, respectively, were sinus bradycardia (2.2%), angina pectoris (3.0%) and hypertension (9.7%) with BOS vs electrocardiogram QT prolongation (3.8%), peripheral coldness (1.1%) and hypertension (10.9%) with IMA. One grade 5 cardiac (acute cardiac failure) and one vascular (myocardial ischemia) TEAE were reported with BOS, and one vascular (cerebrovascular accident) TEAE with IMA; none were considered related to study drug. Successful treatment rechallenge was achieved in the majority of pts with dose interruptions due to cardiac (BOS, 85.7%; IMA, 100%) and vascular (BOS, 100%; IMA, not applicable) TEAEs who were readministered study drug. No pts had dose interruptions due to hypertension TEAEs. Cardiac, vascular and hypertension TEAEs resolved in 57.7%, 75.0% and 35.7% of pts receiving BOS and 65.2%, 66.7% and 48.3% receiving IMA. Conclusions: In this final analysis of BFORE, the incidence of cardiac, vascular, and hypertension TEAEs in pts with newly diagnosed CP CML receiving BOS or IMA was low and was similar between treatment groups. These AEs infrequently led to treatment discontinuation. In addition to continued improved efficacy with BOS vs IMA after 5 yrs follow-up (Brümmendorf et al., ASH 2020), these safety results support the use of first-line BOS as a standard of care in pts with CP CML. Disclosures Cortes: Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Telios: Research Funding; Astellas: Research Funding; Sun Pharma: Research Funding; Merus: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Immunogen: Research Funding. le Coutre:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Hjorth-Hansen:Pfizer: Honoraria, Research Funding; Austrian Orphan Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Garcia-Gutiérrez:Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding. Kota:Ariad: Honoraria; Incyte: Honoraria; Xcenda: Honoraria; Novartis: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical, Company Ltd, Cambridge, MA, USA: Honoraria; Pfizer: Consultancy, Honoraria. Purcell:Pfizer: Current Employment, Current equity holder in publicly-traded company. Viqueira:Pfizer: Current Employment, Current equity holder in publicly-traded company. Leip:Pfizer: Current Employment, Current equity holder in publicly-traded company. Brümmendorf:Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Other: travel, accommodation, expenses, Research Funding.

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Initial Phase 3 Results Of The First (Frontline Investigation Of Lenalidomide + Dexamethasone Versus Standard Thalidomide) Trial (MM-020/IFM 07 01) In Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible For Stem Cell Transplantation (SCT)

Blood ◽

10.1182/blood.v122.21.2.2 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2-2 ◽

Cited By ~ 28

Author(s):

Thierry Facon ◽

Meletios A. Dimopoulos ◽

Angela Dispenzieri ◽

John V. Catalano ◽

Andrew R Belch ◽

...

Keyword(s):

Renal Function ◽

Adverse Events ◽

Board Of Directors ◽

Primary Endpoint ◽

Research Funding ◽

Phase Iii ◽

Advisory Committees ◽

Secondary Endpoints ◽

Equity Ownership ◽

To Receive

Abstract Background Melphalan, prednisone and thalidomide (MPT) is a standard therapy for NDMM recognized worldwide based on a statistically significant advantage in overall survival (OS) and progression-free survival (PFS) vs. MP (Facon Lancet 2007; Fayers Blood 2011; NCCN 2013). The combination of lenalidomide and low-dose dexamethasone (Rd) increased OS with fewer adverse events (AEs) than treatment with lenalidomide and high-dose dexamethasone in NDMM pts (ECOG E4A03) (Rajkumar Lancet Oncol 2010). The FIRST trial is a multicenter, open-label, phase III trial comparing the efficacy and safety of Rd versus MPT in transplant-ineligible NDMM pts. Methods NDMM pts either ≥ 65 years of age, or not candidates for SCT were randomized to one of three arms: Rd in 28-day cycles until disease progression (Arm A), Rd in 28-day cycles for 72 weeks (18 cycles, Arm B), or MPT in 42-day cycles for 72 weeks (12 cycles, Arm C). Assessments by International Myeloma Working Group criteria were done after each cycle. Pts with renal impairment were enrolled; however, pts on dialysis were excluded. Starting doses of lenalidomide and dexamethasone were adjusted based on renal function and age, respectively. Melphalan starting dose was adjusted based on age, absolute neutrophil count, platelet count, and renal function; and thalidomide was adjusted for age. Dose adjustments were permitted for AEs. All pts were required to receive anti-thrombotic prophylaxis. Stratification factors included age, International Stage System, and country. The primary endpoint was a comparison of PFS in Arm A vs. Arm C. Secondary endpoints included OS, overall response rate (ORR), time to response, duration of response (DOR), safety, and quality of life (QOL). A preplanned additional analysis included time from randomization to second progression event or death (PFS2). The final preplanned analysis of independently adjudicated progressive disease (PD) events in Arm A vs. Arm C conducted after 960 events of death or PD, and an interim of OS in 64% of survival events (574/896 events) are presented in this abstract. Comparisons of PFS and all secondary endpoints, including OS for all three arms, will be presented at the meeting. Results A total of 1,623 pts were randomized 1:1:1 in three arms. As of today, 121 pts continue to receive lenalidomide on study (Arm A). The median age was 73 (40.0–92.0) years; 35% pts were aged ≥ 75 years; and 41% of pts had ISS stage 3 disease. After a median follow-up of 37 months, the trial met its primary endpoint (PFS), demonstrating a 28% reduction in risk of progression or death (HR=0.72; p= 0.00006). The preplanned interim analysis of OS demonstrated a 22% reduction in risk of death in favor of Arm A vs. Arm C (HR=0.78, p=0.01685); however, the pre-specified boundary (p<0.0096) was not crossed. All other secondary endpoints consistently showed improvement in favor of Arm A vs. Arm C; ORR (PR or better) 75% vs. 62% (p < 0.00001), DOR (HR=0.63; p<0.00001), and PFS2 (HR=0.78, p=0.0051). Relevant Grade 3/4 adverse events in Arm A vs. Arm C were neutropenia (28% vs. 45%), thrombocytopenia (8% vs. 11%), febrile neutropenia (1% vs. 3%), infection (29% vs. 17%), neuropathy (5% vs. 15%), and deep-vein thrombosis (5% vs. 3%). The incidence of secondary primary malignancies (SPM) was evaluated. Hematologic malignancies were 0.4% in Arm A vs. 2.2% in Arm C; the overall incidence of solid tumors was identical (2.8%). Conclusion Continuous treatment with the all oral doublet Rd significantly improved the primary endpoint of PFS compared with the standard triplet, MPT. All secondary endpoints support the clinical benefit of continuous Rd treatment. The safety profile of Rd was manageable, with reduced hematologic SPM compared to MPT. Disclosures: Facon: Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Lenalidomide as treatment for NDMM. Dimopoulos:Celgene, Orthobiotech: Honoraria. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding. Catalano:Celgene, Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Hulin:Janssen: Honoraria; Celgene: Honoraria. Cavo:Celgene, Janssen, Millennium, Onyx, Brystol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Pinto:Mundipharma: Consultancy, Honoraria; Roche: Honoraria; Celgene: Consultancy, Honoraria. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Ludwig:Celgene: Honoraria, Research Funding, Speakers Bureau. Bahlis:Celgene: Consultancy, Honoraria. Delforge:Celgene: Honoraria. Chen:Celgene: Consultancy, Research Funding; Lundbeck: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Roche: Honoraria; GlaxoSmithKline: Research Funding. Oriol:Celgen: Consultancy. White:Celgene: Honoraria, Research Funding. Binder:Celgene: Research Funding. Anderson:Acetylon, OncoPep: Equity Ownership; Celgene, Onyx, Sanofi Aventis, Gileod: Consultancy. Moreau:Celgene Corporation: Honoraria, Speakers Bureau. Attal:Janssen: Lectures, Lectures Other, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Lectures Other, Membership on an entity’s Board of Directors or advisory committees. Knight:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment. Van Oostendorp:Celgene: Employment. Jacques:Celgene: Employment. Ervin-Haynes:Celgene: Employment, Patents & Royalties. Benboubker:Celgene: Consultancy.

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Obinutuzumab or Rituximab Plus CHOP in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma: Final Results from an Open-Label, Randomized Phase 3 Study (GOYA)

Blood ◽

10.1182/blood.v128.22.470.470 ◽

2016 ◽

Vol 128 (22) ◽

pp. 470-470 ◽

Cited By ~ 20

Author(s):

Umberto Vitolo ◽

Marek Trněný ◽

David Belada ◽

Angelo M Carella ◽

Neil Chua ◽

...

Keyword(s):

Board Of Directors ◽

Primary Endpoint ◽

Research Funding ◽

B Cell Lymphoma ◽

Open Label ◽

Phase 3 ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Secondary Endpoints ◽

Grade 3

Abstract Background: Rituximab (R) plus CHOP (R-CHOP) is standard-of-care treatment for previously untreated diffuse large B-cell lymphoma (DLBCL). Approximately 35-40% of patients (pts) will relapse following R-CHOP, and outcomes with salvage therapy remain poor. Obinutuzumab (GA101; GAZYVA/GAZYVARO; G) is a glycoengineered, type II anti-CD20 monoclonal antibody with greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than R. In the Phase 2 GATHER study (NCT01414855), G plus CHOP (G-CHOP) demonstrated manageable toxicity and promising efficacy in pts with advanced untreated DLBCL. GOYA (NCT01287741) is an open-label, multicenter, randomized Phase 3 study comparing the efficacy and safety of G-CHOP with R-CHOP in pts with previously untreated DLBCL. GOYA was sponsored by Roche with scientific support from the Fondazione Italiana Linfomi. Methods: Eligible pts were aged ≥18 years and had adequate hematologic function, ≥1 bi-dimensionally measurable lesion, an ECOG performance status (PS) of ≤2 and an International Prognostic Index (IPI) score of ≥2 (high, high-intermediate or low-intermediate risk). Low-risk pts with an IPI score of 1 (but not due to age alone) or with an IPI score of 0 with bulky disease (one lesion ≥7.5cm) were also eligible. Pts were randomized 1:1 to receive 8 (21-day) cycles of G (1000mg i.v. on Days [D] 1, 8, and 15, Cycle [C] 1 and D1, C2-8) or R (375mg/m2 i.v. on D1, C1-8) in combination with 6 or 8 cycles of CHOP (number of cycles preplanned in advance for all pts at each site). Preplanned radiotherapy was allowed for bulky or extranodal disease. The primary endpoint was investigator (INV)-assessed progression-free survival (PFS); for the target hazard ratio (HR) of 0.75, the 3-year PFS was expected to improve from 60% to 68%. Secondary endpoints included: PFS assessed by Independent Review Committee (IRC); overall survival (OS); complete response (CR) and overall response rate (ORR) with or without PET (assessed by INV or IRC according to modified Cheson 2007 criteria); and safety. Results: 1418 pts were randomized to study treatment: 706 to G-CHOP and 712 to R-CHOP. Baseline characteristics were well balanced between the G-CHOP and R-CHOP arms: mean age, 62.0 years in both arms; ECOG PS ≥2, 12% vs. 14%; IPI score ≥3, 47% vs. 43%; Ann Arbor stage III-IV, 76% in both arms. Cell-of-origin distribution, as assessed by gene-expression profiling (NanoString), was similar in both treatment groups (GCB: 58% [271/471] G-CHOP, 58% [269/462] R-CHOP; ABC: 27% [125/471] G-CHOP, 26% [118/462] R-CHOP; Unclassified: 15.9% [75/471] G-CHOP, 16.2% [75/462] R-CHOP). For the primary endpoint of INV-assessed PFS, there was no significant difference between G-CHOP and R-CHOP (3-year PFS, 69% vs. 66%; stratified HR, 0.92; 95% confidence interval [CI], 0.76, 1.12; p=0.3868; Table). Secondary endpoints, including PFS by IRC, OS, and end-of-treatment ORR/CR rate (with and without PET), were consistent with the primary endpoint, with no clinically meaningful differences observed between the treatment arms (Table). In a prespecified subgroup analysis of INV-assessed PFS, a stratified HR of 0.72 (95% CI, 0.50, 1.01) in favor of G-CHOP over R-CHOP was determined for pts with GCB DLBCL (3-year PFS, 79% vs. 70%). No new safety signals were identified. Grade ≥3 adverse events (AEs; 74% vs. 65%) and serious AEs (43% vs. 38%) were more common in the G-CHOP than in the R-CHOP arm. Grade ≥3 AEs of particular interest that were numerically more common with G-CHOP than R-CHOP included neutropenia (57% vs. 48%), infusion-related reactions (45% vs. 32%), infections (54% vs. 44%), and thrombocytopenia (8% vs. 3%). AEs resulting in withdrawal from treatment (12% [84/704] G-CHOP; 9% [60/703] R-CHOP) and AEs with fatal outcome (6% [41/704] G-CHOP; 4% [30/703] R-CHOP) were slightly more common with G-CHOP. The most common AEs leading to death were pneumonia (5 G-CHOP; 6 R-CHOP) and sepsis/septic shock (7 G-CHOP; 3 R-CHOP). Conclusions: The primary endpoint of this study was not met: G-CHOP did not significantly improve INV-assessed PFS compared with R-CHOP in previously untreated pts with DLBCL. No unexpected safety signals were identified. Further investigation of outcomes in subgroups is planned. Disclosures Vitolo: Gilead: Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures. Trněný:Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Celgene: Research Funding. Belada:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Chua:Roche: Consultancy, Research Funding; Gilead: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Lundbeck: Consultancy. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Kim:Celltrion, Inc.: Consultancy, Honoraria. Pinto:Millennium: Research Funding; Takeda: Honoraria; Helssin: Honoraria; Roche: Honoraria; Celgene: Honoraria; Servier: Honoraria; Janssen: Honoraria. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Oestergaard:Roche: Employment. Wenger:Genentech: Employment. Fingerle-Rowson:F. Hoffmann-LaRoche: Employment. Catalani:Roche: Employment. Nielsen:Hoffmann-La Roche: Employment. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria.

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The Impact of Hemoglobin Level on Risk of End-Organ Damage among Patients with Sickle Cell Disease - A Large-Scale, Longitudinal Analysis

Blood ◽

10.1182/blood-2020-140572 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-28 ◽

Cited By ~ 1

Author(s):

William B Ershler ◽

Laura M De Castro ◽

Zahra Pakbaz ◽

Aaron Moynahan ◽

Derek Weycker ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Large Scale ◽

Organ Damage ◽

Cell Disease ◽

Publicly Traded ◽

Advisory Committees ◽

Lower Odds ◽

Patient Demographics ◽

History Of

Background: Sickle cell disease (SCD) is an inherited, chronic, and multifaceted condition. Anemia affects most patients with SCD, and low hemoglobin (Hb) levels have been demonstrated to be correlated with end-organ damage (EOD) such as stroke, chronic kidney disease (CKD), end-stage renal disease (ESRD), and pulmonary hypertension (PH). This study sought to estimate the relationship between Hb and risk of EOD based on large-scale, longitudinal analyses of recent data. Methods: Patients with SCD aged 12 years and older and at least 1 Hb level reported from January 2013 to March 2019 in the large, US-representative, provider-centric Symphony Health claims database were included. For each qualifying patient, Hb values were identified and included as separate observations. Onset of new EOD, including stroke, CKD (including ESRD), and PH were ascertained during the 1-year period after the date of each Hb assessment (index date). History of EOD and other comorbid conditions were identified using claims from the database start date (January 1, 2012) or first activity date, whichever was later, up to the index date, to differentiate from newly diagnosed EOD. Patient demographics and clinical characteristics were summarized descriptively. Bivariate analyses of Hb levels and EOD were assessed using generalized estimating equations (GEE) regression with a logistic link function to account for clustering of observations at the patient level. Multivariable GEE regression was employed to evaluate the independent association between Hb and EOD, adjusting for patient demographics and other SCD complications. Results: A total of 16,754 patients with SCD aged 12 years and older were identified (mean age: 34.7 years, 37.7% male), contributing 41,692 observations of Hb levels (mean [SD], 9.8 [2.0] g/dL). In univariate analyses, higher Hb levels were significantly associated with lower odds of new EOD of any type (Figure). In multivariable analyses, after controlling for age, gender, and history of other SCD complications, patients with Hb b %12 g/dL had significantly lower odds of new EOD versus patients with Hb <7 g/dL (reference group): any of the 3 types of EOD by 63% (P<0.001), CKD by 64% (P<0.001), and PH by 79% (P<0.001). Patients with Hb b %10 g/dL also had significantly lower odds of stroke (by 34% [P=0.026]) versus patients with Hb <7 g/dL (Table). In addition to lower Hb, patients of older age, those who were publicly insured versus commercially insured, and patients with cardiovascular comorbidities (eg, heart failure or myocardial infarction) or other SCD chronic conditions generally had significantly higher odds of new EOD, regardless of type. Previous CKD and stroke were statistically and significantly associated with presence of new EOD of any type and with any of the other 2 types of EOD studied (previous CKD and new PH: P<0.01, new stroke: P<0.05; previous stroke and new CKD: P<0.01, new PH: P<0.05). Conclusions: In this large-scale, longitudinal analysis, a significant reduction in the risk of new EOD was observed among SCD patients with higher Hb levels. History of any EOD significantly correlated with presence of new EOD. New SCD treatments that can increase Hb levels can potentially offer clinical and economic value. Disclosures Ershler: Pharmacosmos Therapeutics Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. De Castro:GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. Pakbaz:Amgen: Membership on an entity's Board of Directors or advisory committees; Dova: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Terumo BCT: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Global Blood Therapeutics: Speakers Bureau. Moynahan:Global Blood Therapeutics: Research Funding; Novartis: Research Funding; Policy Analysis Inc.: Current Employment. Weycker:Policy Analysis Inc.: Current Employment, Current equity holder in publicly-traded company; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Pham:Policy Analysis Inc.: Current Employment; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Delea:Policy Analysis Inc.: Current Employment, Current equity holder in private company; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Agodoa:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cong:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company.

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