scholarly journals Early Initiation of Defibrotide in Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Following Hematopoietic Stem Cell Transplantation Improves Day +100 Survival

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4311-4311 ◽  
Author(s):  
Paul G. Richardson ◽  
Angela R. Smith ◽  
Brandon M. Triplett ◽  
Nancy A. Kernan ◽  
Stephan A. Grupp ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Treatment Initiation ◽  
Survival Rates ◽  
Occlusive Disease ◽  
Sinusoidal Obstruction Syndrome ◽  
Employment Equity ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Equity Ownership

Abstract Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT). Severe VOD/SOS (ie, with multi-organ dysfunction [MOD]) may be associated with >80% mortality. Defibrotide is approved for treatment of severe VOD/SOS in the EU. In the US, defibrotide is available through an ongoing, expanded-access study. The optimal time to initiate VOD/SOS treatment with defibrotide is of interest. Methods In the expanded-access study, patients were eligible in the original protocol if they had VOD/SOS and renal/pulmonary MOD by Baltimore criteria post-HSCT or by biopsy. The protocol was amended to include (1) post-chemotherapy patients, (2) patients without MOD, and (3) VOD/SOS per modified Seattle criteria. Defibrotide 25 mg/kg/day was given in 4 divided doses for a recommended ≥21 days. Here, Day +100 survival in patients with HSCT was examined post hoc based on time from VOD/SOS diagnosis (with or without MOD as relevant to study entry criterion) to initiation of defibrotide. Two analyses were conducted: (1) survival rate analyzed by treatment initiation for the entire population before or after each of the following days: 1, 2, 3, 4, 7, and 14, using Fisher's exact test; (2) survival rate for only those patients with treatment initiated on a particular day: 0, 1, 2, 3, 4, 5, 6, 7, 8-14, and ≥15, with a Cochran-Armitage test for trend across days. Results Among HSCT patients enrolled through 2013 who received ≥1 dose of defibrotide, treatment date was available for 573 patients. Of these, 351 also had MOD. Defibrotide was started on the day of diagnosis in >30% of patients; >90% of patients started defibrotide before day 7 post-diagnosis. In the population-wide analysis of treatment initiation before or after days 1, 2, 3, 4, 7, and 14, earlier initiation of defibrotide was associated with higher survival rates (Table), and was statistically significant for all cut-points considered except 14 days, with only 2.8% of patients beginning treatment post-day 14. Survival differences between earlier vs. later initiation ranged from 8.8% to 22.1% overall (MOD: 12.8% to 25.6%; Table) for the cut-points considered. In the analysis of relationship between Day +100 survival and treatment initiation day, survival rates were generally higher if treatment was initiated earlier. This was demonstrated by a statistically significant trend over time for better outcomes with earlier initiation (Figure). Similar results for both analyses were obtained for all patients with VOD/SOS and for the subgroup of patients with MOD. Conclusions Data indicate decreased Day +100 survival associated with longer treatment delays, confirmed by the Cochran Armitage trend test (P<0.001). Thus, defibrotide treatment should be initiated as soon as possible after VOD/SOS diagnosis. Table. Day +100 Survival by Defibrotide Initiation Day n (%) HSCT VOD/SOS (N=573) HSCT VOD/SOS with MOD (n=351) Initiation Period Alive Dead Unknown Alive Dead Unknown ≤1 Day 183 (53.5) 142 (41.5) 17 (5.0) 103 (50.2) 93 (45.4) 9 (4.4) >1 Day 105 (45.5) 116 (50.2) 10 (4.3) 56 (38.4) 85 (58.2) 5 (3.4) Difference (95% CI)a 8.8% (0.2%, 17.3%) 12.8% (2.0%, 23.4%) P valueb 0.045 0.021 ≤2 Days 235 (55.7) 166 (39.3) 21 (5.0) 132 (52.2) 111 (43.9) 10 (4.0) >2 Days 53 (35.1) 92 (60.9) 6 (4.0) 27 (27.6) 67 (68.4) 4 (4.1) Difference (95% CI)a 22.1% (12.6%, 31.2%) 25.6% (13.8%, 36.9%) P valueb <.001 <.001 ≤3 Days 251 (53.5) 193 (41.2) 25 (5.3) 138 (49.5) 129 (46.2) 12 (4.3) >3 Days 37 (35.6) 65 (62.5) 2 (1.9) 21 (29.2) 49 (68.1) 2 (2.8) Difference (95% CI)a 20.3% (9.6%, 30.8%) 21.7% (8.6%, 34.5%) P valueb <.001 0.001 ≤4 Day 263 (52.6) 212 (42.4) 25 (5.0) 146 (48.7) 142 (47.3) 12 (4.0) >4 Day 25 (34.2) 46 (63.0) 2 (2.7) 13 (25.5) 36 (70.6) 2 (3.9) Difference (95% CI)a 20.2% (7.7%, 32.4%) 24.2% (9.1%, 38.9%) P valueb 0.002 0.002 ≤7 Days 275 (51.6) 232 (43.5) 26 (4.9) 152 (47.4) 156 (48.6) 13 (4.0) >7 Days 13 (32.5) 26 (65.0) 1 (2.5) 7 (23.3) 22 (73.3) 1 (3.3) Difference (95% CI)a 20.9% (4.5%, 37.1%) 25.2% (6.1%, 43.8%) P valueb 0.013 0.011 ≤14 Days 282 (50.6) 249 (44.7) 26 (4.7) 156 (45.9) 171 (50.3) 13 (3.8) >14 Days 6 (37.5) 9 (56.3) 1 (6.3) 3 (27.3) 7 (63.6) 1 (9.1) Difference (95% CI)a 13.1% (-12.9%, 39.5%) 17.7% (-14.6%, 51.5%) P valueb 0.433 0.344 aAlive and Dead. 95% CI calculated using exact method. bFisher's exact test, Alive and Dead. Support: Jazz Pharmaceuticals. Disclosures Richardson: Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Kernan:Gentium S.p.A.: Research Funding. Grupp:Novartis: Consultancy, Research Funding. Antin:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Miloslavsky:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees.

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multi-Organ Dysfunction: Final Results from a Pivotal, Historically Controlled, Phase 3 Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 737-737
Author(s):  
Paul G. Richardson ◽  
Marcie Riches ◽  
Nancy A. Kernan ◽  
Joel A. Brochstein ◽  
Shin Mineishi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Study Drug ◽  
Final Analysis ◽  
Occlusive Disease ◽  
Sinusoidal Obstruction Syndrome ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership

Introduction Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), is a rare and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Severe cases, historically defined by multi-organ dysfunction (MOD), may be associated with mortality rates of >80%. There is no FDA-approved treatment for VOD/SOS. Defibrotide (DF) has a proposed mechanism of action that includes stabilization of endothelial cells and restoration of thrombo-fibrinolytic balance. Earlier analyses of a pivotal phase 3 trial of DF in VOD/SOS plus MOD (Richardson et al. Blood. 2009;114:Abstract 654) underpinned approval of DF in the EU to treat severe hepatic VOD/SOS after HSCT. Additional data were obtained at the request of US health authorities. Here we present the final analysis: day +100 survival (primary endpoint) and complete response (CR; secondary). Methods This was a multicenter, open-label, phase 3 historical control (HC) study assessing DF. Eligible patients met Baltimore VOD/SOS criteria (total bilirubin ≥2.0 mg/dL with ≥2 of: hepatomegaly, ascites, or 5% weight gain) by day +21 post-HSCT, plus MOD (renal [trebling of creatinine levels, reduced creatinine clearance, or dialysis] and/or pulmonary [oxygen saturation ≤90%, need for oxygen supplementation/ventilator dependence]) by day +28 post-HSCT. Exclusion criteria included severe graft-versus-host disease (GvHD) of liver or gut, clinically significant bleeding, or need for ≥2 pressors. HC patients were reviewed for inclusion/exclusion criteria in a sequential review of medical charts starting 6 months prior to use of DF at each site; a blinded medical review committee made the final determination of HCs unequivocally meeting criteria for VOD/SOS with MOD. DF dose was 25 mg/kg/d in 4 divided 2-hour IV infusions q6h; recommended treatment duration was ≥21 days. Primary endpoint was day +100 survival. CR by day +100 was a secondary endpoint. Treatment difference in survival and CR rates and their 95% confidence intervals were estimated using propensity-stratified and weighted (Koch-adjusted) estimates of differences in proportions that account for baseline prognostic factors of survival (ie, ventilator and/or dialysis dependency at entry, age ≤/>16 years, transplant type, and prior HSCT). Analyses included patients treated with DF and HCs. Results There were 102 patients in the DF group and 32 cases selected as HCs. Baseline characteristics were similar in the DF and HC groups: mean age (26 and 25 years; 43% and 44% ≤16 years), allogeneic graft (88% and 84%), prior HSCT (13% and 9%), ventilator- and/or dialysis-dependent at study entry (33% and 22%), myeloablative conditioning (87% and 94%), and the most common underlying diseases (acute leukemias: 45% and 47%), respectively. In the DF-treated group, common GvHD medications included tacrolimus (49%), methotrexate (41%), and cyclosporine (38%); in the HC group, common medications were cyclosporine (72%) and methotrexate (63%). Survival at day +100 in the DF and HC groups was 38% and 25%, respectively. The propensity-stratified difference in survival was 23.0% (95.1% CI, 5.2-40.8, P = .0109). Respective observed CR rates by day +100 were 25.5% and 12.5%, and the propensity-stratified difference in CR was 19.0% (95.1% CI, 3.5-34.6, P = .0160). Comparing the earlier EU and final analyses, the survival rates at day +100 in each group did not vary; however, the propensity adjusted final analysis provided a different level of statistical significance. Day +100 CR rates in the original analysis were slightly lower in both arms at 24% and 9% due to increased data capture to investigate CR; the P value was essentially unchanged. For the DF group, 45% had an adverse event (AE) at least possibly related to study drug, and 21% had a serious AE at least possibly related to study drug. In this very sick population, percentages of patients with ≥1 AE leading to death were similar between DF and HC patients (64% and 69%), as were hemorrhagic AEs (64%, 75%) and hypotension (39%, 50%). Conclusions Based on observed study data and using a propensity-adjusted rate difference estimator, patients treated with DF had a 23% reduction in risk of death by day +100 and 19% improvement in CR rate. Overall incidence of hemorrhage and fatal AEs were similar between groups with AEs consistent with those expected in this critically ill population. Support: Jazz Pharmaceuticals. Disclosures Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Marizomib, pmalidomide, and low dose dexamethasone in RR MM. Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States. . Kernan:Gentium S.p.A.: Research Funding. Grupp:Novartis: Consultancy, Research Funding. Guinan:Gentium SpA/Jazz Pharmaceuticals: Other: My institution received fees for research.. Martin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium SpA/Jazz Pharmaceuticals: Research Funding. Steinbach:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Krishnan:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy; Janssen: Consultancy; Onyx: Speakers Bureau; Jazz: Consultancy; Millenium: Speakers Bureau. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding. Rodriguez:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Doyle:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. D'Agostino:Gentium SpA/Jazz Pharmaceuticals: Consultancy. Massaro:Gentium SpA/Jazz Pharmaceuticals: Consultancy. Miloslavsky:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Iacobelli:Gentium SpA: Employment. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Gentium SpA: Other: Personal fees during conduct of the study.. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Defibrotide for the Treatment of Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with/without Multi-Organ Dysfunction Following Chemotherapy: Results from an Ongoing Expanded Access Program

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3121-3121
Author(s):  
Nancy A. Kernan ◽  
Paul G. Richardson ◽  
Angela R. Smith ◽  
Brandon M. Triplett ◽  
Stephan A. Grupp ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
The United States ◽  
Occlusive Disease ◽  
Sinusoidal Obstruction Syndrome ◽  
Employment Equity ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
Equity Ownership ◽  
Chemotherapy Patients

Abstract Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning regimens for hematopoietic stem cell transplant (HSCT). Although VOD/SOS usually is thought of as a complication of HSCT, there is also a known risk in patients following chemotherapy in a non-HSCT setting. Severe hepatic VOD/SOS (ie, with multi-organ dysfunction [MOD]), may be associated with >80% mortality. Endothelial cell (EC) damage is a critical factor in the pathophysiology of VOD/SOS. Preclinical data suggest that defibrotide stabilizes ECs with direct, as well as EC-mediated, restoration of the thrombo-fibrinolytic balance. Defibrotide is approved for treatment of severe hepatic VOD/SOS in adult and pediatric patients in the European Union. In the United States, defibrotide is available as an investigational drug through an ongoing expanded-access protocol for treatment of hepatic VOD/SOS. Methods In the original protocol, patients were eligible if they had hepatic VOD/SOS by Baltimore criteria post-HSCT and MOD, defined by renal (tripling of creatinine levels or reduced creatinine clearance with or without dialysis) and/or pulmonary (need for oxygen supplementation with or without assisted ventilation) dysfunction. Symptoms of VOD/SOS were not considered adverse events (AEs) unless the event was considered serious. The protocol was later amended to include (1) post-chemotherapy patients with hepatic VOD/SOS; (2) patients with hepatic VOD/SOS without MOD, and (3) VOD/SOS per modified Seattle criteria. Enrolled patients received defibrotide 25 mg/kg/d in 4 divided doses for a recommended ≥21 days. Here, we describe efficacy and safety results with defibrotide for the subset of patients that developed VOD/SOS post-chemotherapy. Results Out of 642 patients who developed VOD/SOS and received ≥1 dose of defibrotide, 69 patients received chemotherapy without HSCT; 52% (n=36) had MOD, and 48% (n=33) did not. Median age was 8 years (range, <1 month-58.0 years), and 55 patients (80%) were ≤16 years (39 patients were children aged 2-11); 54% of patients were male. The most common primary diseases were acute lymphocytic leukemia (44%) and acute myelogenous leukemia (10%). Chemotherapeutic agents received by more than 30% of patients were vincristine, cyclophosphamide, cytarabine, doxorubicin, methotrexate and PEG-L-asparaginase. Antibody-drug conjugates linked to ozogamicin that are associated with development of VOD/SOS (gemtuzumab and inotuzumab) were received by 3 and 1 patient, respectively. The Kaplan-Meier estimated day +100 survival rate was 77.4% (95% confidence interval, 65.4%-85.7%). For patients with MOD and without MOD, the Kaplan-Meier estimated day +100 survival rates were 74.3% (56.4%-85.7%) and 80.9% (62.3%-90.9%), respectively. Overall, ≥1 AE was reported in 44 chemotherapy patients (63.8%). Of these, 14 (20.3%) had AEs assessed by the investigator as possibly, probably, or definitely related to defibrotide. Treatment-related AEs occurring in ≥2 patients were hypotension (4.3%), nausea (2.9%), vomiting (2.9%), and epistaxis (2.9%). Hemorrhagic AEs of any severity occurring in ≥2 patients were pulmonary (7.2%), epistaxis (5.8%), and gastric (2.9%). Serious AEs were reported in 26 patients (37.7%), most commonly multi-organ failure (7.2%), hypoxia (5.8%), and pulmonary hemorrhage (5.8%). AEs led to discontinuation in 4 patients (gastric, gastrointestinal and mouth hemorrhages, epistaxis, and hypotension). No treatment-related deaths were reported. Conclusions Day+100 survival of 77.4% in patients developing VOD/SOS following a variety of chemotherapy regimens without HSCT (80% of which were pediatric, primarily children) is a clinically encouraging finding. Defibrotide treatment in this group of 69 patients developing VOD/SOS post-chemotherapy was generally well-tolerated, with only 5.8% of patients discontinuing due to an AE and no treatment-related fatalities. Enrollment to the study continues. Support: Jazz Pharmaceuticals. Disclosures Kernan: Gentium S.p.A.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Richardson:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis: Consultancy, Research Funding. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Hematopoietic Stem Cells Develop in the Absence of Endothelial Cadherin 5 Expression

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1165-1165
Author(s):  
Heidi Anderson ◽  
Taylor Patch ◽  
Pavan Reddy ◽  
Elliott Hagedorn ◽  
Owen J. Tamplin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Hematopoietic Stem Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemogenic Endothelium ◽  
Employment Equity ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Equity Ownership

Abstract Rare endothelial cells in the aorta-gonad-mesonephros (AGM) transition into hematopoietic stem cells (HSCs) during embryonic development. Lineage tracing experiments indicate that HSCs emerge from Cadherin 5 (Cdh5, VE-cadherin)+ endothelial precursors, and isolated populations of Cdh5+ cells from mouse embryos and embryonic stem (ES) cells can be differentiated into hematopoietic cells. Cdh5 has also been widely implicated as a marker of AGM-derived hemogenic endothelial cells. Since Cdh5-/- mice embryos die before the first HSCs emerge, it is unknown if Cdh5 has a direct role in HSC emergence. Our previous genetic screen yielded malbec (mlbbw306), a zebrafish mutant for cdh5, with normal embryonic and definitive blood. Utilizing time-lapse imaging, parabiotic surgical pairing of zebrafish embryos, and blastula transplantation assays, we show that HSCs emerge, migrate, engraft, and differentiate in the absence of cdh5 expression. By tracing Cdh5-/- GFP+/+ cells inchimeric mice, we demonstrated that Cdh5-/- GFP+/+ HSCs emerging from E10.5 and E11.5 AGM or derived from E13.5 fetal liver not only differentiate into hematopoietic colonies but also engraft and reconstitute multi-lineage adult blood. These data establish that Cdh5, a marker of hemogenic endothelium in the AGM, is dispensable for the transition of hemogenic endothelium to HSCs. Disclosures Bauer: Biogen: Research Funding; Editas Medicine: Consultancy. Zon:FATE Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Scholar Rock: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder. Orkin:Editas Medicine: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding; Pfizer: Research Funding; Sangamo Biosciences: Consultancy.

scholarly journals Real-World Risk Assessment and Treatment of Patients with Myelofibrosis at Community Oncology Practices in the United States

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1765-1765
Author(s):  
Srdan Verstovsek ◽  
Jingbo Yu ◽  
Jonathan K. Kish ◽  
Dilan Chamikara Paranagama ◽  
Jill Kaufman ◽  
...  
Keyword(s):  
Risk Assessment ◽  
High Risk ◽  
Risk Stratification ◽  
Board Of Directors ◽  
Research Funding ◽  
Treatment Initiation ◽  
Risk Classification ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by marrow fibrosis, extramedullary hematopoiesis, and leukoerythroblastosis. Clinical manifestations include severe anemia, splenomegaly, and symptoms. Median survival in patients with primary MF ranges from 2 to 11 years, depending on risk categorization. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines recommend the International Prognostic Scoring System (IPSS) for risk stratification at diagnosis; other systems including the Dynamic IPSS (DIPSS) and the DIPSS-Plus are also cited in the Guidelines. Treatment recommendations are risk-adapted in the NCCN Guidelines. The objective of this study is to describe how patients are risk stratified at diagnosis by community hematologists/oncologists and the impact that risk stratification has on the initiation of MF-directed treatments. Methods Medical chart reviews were conducted at community hematology/oncology practices in the OPEN network. Adult patients diagnosed with primary MF, post-PV MF, or post-ET MF between 1/2012 and 12/2016 and receiving care for at least 6 months were included. Data were collected with an electronic case report form (eCRF) with questions on clinical characteristics (symptoms, Hgb, WBC, blast %, and PLT) and risk assessment method used at diagnosis (IPSS, DIPSS, or DIPSS-Plus), treatments, and outcomes. A data-derived IPSS risk score was calculated for each patient. To assess the accuracy of the assigned risk, a data-derived risk score, corresponding to the system used by the provider, was also calculated. Patients were classified as treated at diagnosis if they received MF-directed therapy (hydroxyurea, interferon, ruxolitinib, or clinical trial) or allogeneic hematopoietic cell transplant (HCT) within 120 days of diagnosis. The methods and rates of risk stratification, accuracy of the provider-assigned risk versus data-derived risk, and treatment administered were reported. Results A total of 338 patients with MF from 28 community hematology/oncology practices were included. Mean (SD) age at diagnosis was 65.3 (11.8) years, 51.8% were male, and 68.3% had primary MF. JAK2, MPL, and CALR mutations were tested in 86.1%, 70.1%, and 60.9% of patients at diagnosis, of these, 71.1%, 23.2%, and 14.6% were positive, respectively; 18.4% (38/206) were triple negative. Median follow-up from diagnosis was 27.5 months (IQR, 18.5-42.6). Approximately 32% of patients did not have a risk classification in their medical records at diagnosis. A scoring system was used for risk assignment in 45.3% of patients; DIPSS (23.0%) and IPSS (21.3%) were most commonly used. Of all 338 patients, the corresponding data-derived risk classifications were: 5.6% low, 20.1% int-1, 18.3% int-2, and 55.9% high risk. Among those patients who were not assigned risk by their treating physicians (n=108), most had int-1 (28.7%), int-2 (17.6%), or high risk (43.5%) disease based on the data-derived IPSS risk classification. Of those who received a risk classification from their treating physician, 47.4% (n=109) received an inaccurate risk classification; among these patients, the risk was under-estimated for most (82.6%) (Table 1). Overall, 55.8% of patients (63.2% low-risk, 55.9% int-1, 52.5% int-2, 56.1% high-risk) received MF-directed pharmacological treatment or HCT within 4 months of diagnosis. Among all patients receiving MF-directed treatment, the mean time from diagnosis to treatment initiation was 5.3 months (SD=1.8), and the most common first pharmacological treatments were ruxolitinib (49.8%) and hydroxyurea (46.7%). Splenomegaly (81.3%), symptoms (72.6%), and anemia (65.6%) were top cited indications for treatment initiation. The treatment initiation rate was higher among those patients correctly risk classified compared to those incorrectly classified (64.2% versus 49.5%, p=0.032). Conclusions Nearly one-third of patients with MF did not receive a risk classification at diagnosis. When risk was assigned, almost half were incorrectly classified. Just over half of patients received treatment within four months of diagnosis. Patients who were correctly risk classified at diagnosis were more likely to start treatment promptly upon diagnosis versus those incorrectly risk classified, which may be attributable to the under-estimation of risk. Disclosures Verstovsek: Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees. Yu:Incyte Corporation: Employment, Equity Ownership. Kish:Cardinal Health: Employment. Paranagama:Incyte: Employment, Equity Ownership. Kaufman:Cardinal Health: Employment. Chung:Cardinal Health: Employment. Grunwald:Genentech: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medtronic: Equity Ownership; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding. Colucci:Incyte: Employment, Equity Ownership. Mesa:UT Health San Antonio - Mays Cancer Center: Employment; NS Pharma: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Novartis: Consultancy; Pfizer: Research Funding.

Treatment with the Thrombopoietin (TPO)-Receptor Agonist Romiplostim in Thrombocytopenic Patients (Pts) with Low or Intermediate-1 (int-1) Risk Myelodysplastic Syndrome (MDS): Follow-up AML and Survival Results of a Randomized, Double-Blind, Placebo (PBO)-Controlled Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 421-421 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Ghulam J. Mufti ◽  
Pierre Fenaux ◽  
Mikkael A. Sekeres ◽  
Jeffrey Szer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Survival Rates ◽  
Study Drug ◽  
Employment Equity ◽  
Advisory Committees ◽  
Free Survival ◽  
Equity Ownership

Abstract Abstract 421 Background: There are few therapies for thrombocytopenia in MDS, which is found in ∼50% of pts with low/int-1 MDS and is associated with shortened survival. In a June 2011 analysis of a 58-wk study (2:1 romiplostim:PBO), romiplostim reduced clinically significant bleeding events (HR 0.83, 95% CI: 0.66, 1.05, P = 0.13) and platelet transfusions (RR 0.77, 95% CI: 0.66, 0.88), and increased HI-P rates (OR 15.6, 95% CI: 4.7, 51.8). Increases in peripheral blast counts to >10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.6%), and in most cases resolved after discontinuation. Through 58 wk, acute myeloid leukemia (AML) was diagnosed in 10 romiplostim pts (6.0%) and 2 PBO pts (2.4%) (HR 2.51, 95% CI: 0.55, 11.47); the differences for romiplostim vs. PBO 58-wk overall survival (OS) and AML-free survival were not statistically significant. This report updates the previous results, with a particular emphasis on AML incidence. Methods: Eligible pts had IPSS low/int-1 MDS and were receiving supportive care, with platelets 1) ≤20×109/L or 2) ≤ 50×109/L with a history of bleeding. AML progression was defined as: 1) ≥20% blasts in the bone marrow or peripheral blood after 4 wk off romiplostim, 2) pathology consistent with leukemia (eg, chloroma or leukemia cutis), or 3) anti-leukemic treatment initiation. Due to data monitoring committee concerns that the potential small benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML and that transient increases in blast cell counts may put pts at risk for diagnosis of and treatment for AML, study drug was stopped in February 2011. Pts were then moved into the long-term follow-up (LTFU) portion of the study. At the time of the 2011 analysis, not all pts had been on study 58 wk, thus the 58-wk data have been updated with LTFU data. Results: Results are presented by randomization group, although study drug was stopped in February 2011. Of 250 pts in the study (randomized 2:1 romiplostim:PBO), 224 entered LTFU, and 134 remained on study as of July 2012; the median (Q1, Q3) follow-up was 17.8 (10.8, 25.1) months. Through 58 wk, the proportions of deaths were romiplostim: 18.0% (30 pts), PBO: 20.5% (17 pts), for an OS HR of 0.86 (95% CI: 0.48, 1.56). Since June 2011, 2 additional AML cases were reported in the PBO arm which occurred within the 58-wk study period, but were not recorded in time for the primary analysis in 2011. Updated 58-wk AML rates were romiplostim: 6.0% (10 pts), PBO: 4.9% (4 pts), for an HR of 1.20 (95% CI: 0.38, 3.84). The resulting AML-free survival rates were romiplostim: 19.8% (33 pts), PBO: 22.9% (19 pts), for an HR of 0.86 (95% CI: 0.49, 1.51). For data to date (beyond 58 wk), proportions of deaths were romiplostim: 38.3% (64 pts), PBO: 37.3% (31 pts), for an OS HR of 1.09 (95% CI: 0.71, 1.68). AML rates were romiplostim: 8.9% (15 pts), PBO: 8.5% (7 pts), for an HR of 1.15 (95% CI: 0.47, 2.85). The resulting AML-free survival rates were romiplostim: 39.5% (66 pts), PBO: 38.6% (32 pts), for an HR of 1.11 (95% CI: 0.72, 1.70) (Figure). Twelve of the 22 AML cases occurred in pts who were RAEB-1 and 5 cases were diagnosed by anti-AML treatment alone (Table). In LTFU, pt-reported rates of MDS therapy use (e.g., azacitidine, cyclosporine, and romiplostim) were romiplostim: 31.1%, PBO: 23.2%. Reported rates of AML therapy use (e.g., azacitidine and chemotherapy) were romiplostim: 6.0%, PBO: 7.2%. A retrospective review of all available bone marrow aspirates and biopsies, including samples from pts diagnosed as having progressed to AML, was conducted by an independent hematopathologist; analyses are ongoing. Conclusion: Following the 2011 decision to stop study drug, study results have been updated with more time on study. Specifically, with the additional AML cases in the PBO arm during the 58-wk study period and data from the LTFU period, the HRs for progression to AML were 1.20 and 1.15, respectively, in contrast with the finding of a year ago (HR of 2.51 for 58-wk). As LTFU continues, additional data will be evaluated. Safety concerns regarding risk of disease progression to AML are still being investigated. Disclosures: Kantarjian: Amgen: Research Funding. Off Label Use: The use of romiplostim in MDS was examined in this trial. Mufti:Celgene: Consultancy, Research Funding. Fenaux:GlaxoSmithKline: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sekeres:Celgene: 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. Platzbecker:Amgen: Consultancy; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Novartis: Consultancy. Kuendgen:Celgene: Honoraria. Gaidano:Amgen: Honoraria. Wiktor-Jedrzejczak:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy; Janssen-Cilag: Consultancy; Celgene: Speakers Bureau; Genzyme: Speakers Bureau; Genopharm: Speakers Bureau. Bennett:Onconova: Consultancy; Amgen: Consultancy; GlaxoSmithKline: Consultancy; Ambit: Consultancy; Pfizer: Consultancy; Celgene: Consultancy. Meibohm:Merck: Employment, Equity Ownership; Amgen: Consultancy; Ockham: Employment. Yang:Amgen: Employment, Equity Ownership. Giagounidis:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Incidence and Survival Impact of Self-Reported Symptom and Psychological Distress Among Patients with Multiple Myeloma

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 679-679
Author(s):  
Joshua R Richter ◽  
Noa Biran ◽  
Dhakshila Paramanathan ◽  
Srikesh Arunajadai ◽  
Victoria DeVincenzo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Disease ◽  
Board Of Directors ◽  
Research Funding ◽  
Performance Status ◽  
Survival Rates ◽  
Employment Equity ◽  
Advisory Committees ◽  
Distress Score ◽  
Equity Ownership

Abstract Background: Advances in the management of multiple myeloma (MM) have significantly extended survival and dramatically reduced painful skeletal-related events for most patients. As MM is evolving to a chronic disease increased attention towards symptom and psychological impact is required. We sought to determine the incidence of self-reported pain, depression, financial and family burden, and impairment of performance status in a cohort of patients with MM receiving outpatient therapy at a tertiary cancer center and to determine the correlation of total distress with survival. Methods: The Living with Cancer (LWC) patient reported outcome (PRO) instrument is a statistically validated tool (ASCO Palliative Care Symposium 2016) that evaluates distress from the point of view of the advanced cancer patient. The 7-item 5-level Likert survey measures 4 personhood domains (performance status, pain, burden [financial and family], depression). The questions are also weighted by the patient with regards to importance, yielding a total score range 0-112. In a pilot study of advanced cancer patients a score of &gt;28 was associated with an increased likelihood of physicians' (blinded) opinion regarding need for end-of-life care discussions (J Palliative Med 2016). For individual survey items, a self-reported rating of 2-4 was considered to indicate patient concern. Results: 239 patients with MM completed the LWC PRO between Sept 2015 and Oct 2016. Patients were 57% male with a median age 67 years. 48% of patients were concerned that they could not do the things they wanted to do, with 33% reporting decreased performance status. Financial toxicity concerns were self-reported by 44%, with family burdens noted in 24%. Although depression was reported by only 15%, 41% reported lack of pleasure. Pain was self-reported as a concern by 36%. With a median follow up of 316 days since LWC completion, 13% of patients had died. A high total distress score (&gt;28) was noted in 57 (24%) and associated with a decreased survival rate compared to the 182 (76%) patients with a low total distress score (p&lt;0.05). The 6 month survival rates from the completion of the LWC survey for patients with high/low distress scores were 86% and 96% respectively, and 12 month survival rates were 76% and 87% respectively. Conclusions: Despite dramatic improvements in survival among patients with MM, symptom, financial, and psychosocial concerns continue to plague patients. As a chronic disease, additional attention to addressing these issues is required. Figure 1 Figure 1. Disclosures Richter: BMS: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Biran: Celgene, Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau. Paramanathan: COTA: Employment. Arunajadai: COTA: Employment. DeVincenzo: COTA: Employment. Pe Benito: COTA: Employment. Gruman: COTA: Employment. Kaur: COTA: Employment. Hervey: COTA: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Schultz: COTA: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Paddock: COTA: Employment, Equity Ownership. Pecora: Caladrius Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Siegel: Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Goldberg: Ariad: Speakers Bureau; Pfizer: Honoraria; COTA: Employment, Equity Ownership; Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Speakers Bureau.

Treatment with the Thrombopoietin (TPO)-Receptor Agonist Romiplostim in Thrombocytopenic Patients (Pts) with Low or Intermediate-1 (Int-1) Risk Myelodysplastic Syndrome (MDS): Results of a Randomized, Double-Blind, Placebo(PBO)-Controlled Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 117-117 ◽  
Author(s):  
Aristoteles Giagounidis ◽  
Ghulam J. Mufti ◽  
Hagop M. Kantarjian ◽  
Pierre Fenaux ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Supportive Care ◽  
Board Of Directors ◽  
Research Funding ◽  
Survival Rates ◽  
Bleeding Events ◽  
Employment Equity ◽  
Advisory Committees ◽  
Free Survival ◽  
Equity Ownership ◽  
Clinically Significant

Abstract Abstract 117 Background: There are few therapies for thrombocytopenia in MDS, which is found in ∼50% of pts with low/int-1 MDS and is associated with shortened survival. Methods: IPSS low/int-1 MDS pts receiving supportive care, with platelets 1) ≤20×109/L or 2) ≤ 50×109/L with a history of bleeding, were randomized 2:1 to 750 μg romiplostim:PBO for 26 wk with MDS supportive care, and a 4-wk washout followed by bone marrow (BM) biopsy. Pts continued as randomized, with any MDS therapy, for 24 wk with another 4-wk washout followed by a BM biopsy. The 1° endpoint was the number of clinically significant bleeding events (CSBE, grade ≥2 per modified WHO scale); other endpoints included protocol-defined platelet transfusion events (PTE), platelet response per IWG 2006 (HI-P), survival, and safety, including progression to AML, defined conservatively as: 1) ≥20% blasts in the BM or peripheral blood after 4 wk off romiplostim, or 2) pathology consistent with leukemia (eg, chloroma or leukemia cutis), or 3) anti-leukemic treatment initiation. Results: Of 250 pts enrolled (romiplostim 167, PBO 83): 59% were male, median (Q1, Q3) age was 70 (61, 77) year, WHO classes RCMD (68%), RAEB-1 (13%), MDS-U (11%), RA (4.4%), RCMD-RS (2.4%), RARS (0.8%), RAEB-2 (1%), IPSS status low (25%), int-1 (71%), int-2 (0.4%), and IPSS cytogenetics good (78%), intermediate (18%), poor (1.6%). There were more pts who were RAEB-1 (14% vs 11%) and RAEB-2 (1% vs 0%) and fewer who were MDS-U (10% vs 15%) with romiplostim (all NS). Due to DMC concerns regarding the potential for transient increases in blast cell counts and the risk for progression to or treatment for AML, study drug was discontinued in Feb 2011, affecting 28% of pts. Also leading to withdrawal were consent withdrawn (romiplostim 13%, PBO 15%), adverse events (AE) (12%, 5%), and alternative therapy (7%, 11%). The mean number of CSBE/pt was romiplostim 1.47, PBO 1.94 (HR 0.83, 95% CI: 0.66, 1.05, p = 0.13); rates were romiplostim 18.6%, PBO 26.5%. The overall number of bleeding events was reduced with romiplostim (RR 0.92, 95% CI: 0.86, 0.99, p = 0.026). PTE rates/100 pt-year were romiplostim 748.9, PBO 1013.5 (RR 0.77, 95% CI: 0.66, 0.88, p<0.001). HI-P rates were romiplostim 36.5% (61 pts), PBO 3.6% (3 pts) (OR 15.6, 95% CI: 4.7, 51.8, p<0.001). From wk 4 on, median platelets with romiplostim were consistently higher than with PBO (p<0.001). The overall 1-year K-M survival was romiplostim 80%, PBO 78% (HR 1.03, 95% CI: 0.54, 1.95) (Figure 1), with 28 deaths (17%), none (0%) hemorrhagic and 5 (3%) from AML and MDS disease progression, with romiplostim and 14 deaths (17%), including 4 (4.8%) hemorrhagic and 3 (3.6%) from AML and MDS disease progression, with PBO. Median time on romiplostim was 21.5 wk (range: 1, 50). SAE rates were romiplostim 40%, PBO 27%; those frequent (≥5%) SAE occurring ≥2x more with romiplostim were pneumonia, pyrexia, thrombocytopenia, and atrial fibrillation; those occurring ≥2x more with PBO were diarrhea, dyspnea, and cerebral hemorrhage. Peripheral blast increases are described below (Table). AML rates through 58 wk were romiplostim 6.0%, PBO 2.4% (HR 2.51, 95% CI: 0.55, 11.47). Of the 13 AML cases, 9 (69%) were in pts who were initially RAEB-1 and 4 (31%) were diagnosed by anti-leukemic therapy initiation, which could include hypomethylating agents. Of pts who were RAEB-1 at baseline, 2/9 (22%) PBO pts developed AML vs 7/24 (29%) of romiplostim pts. AML-free survival rates were similar (HR 1.13, 95% CI: 0.60, 2.13). Conclusion: Romiplostim treatment in low/int-1 MDS pts resulted in a 15-fold increase in achieving HI-P. Although there were more platelet transfusions with PBO (p <0.001), there still was a trend for more clinically significant bleeding events with PBO (p = 0.13) than romiplostim. The AE profile of romiplostim was generally comparable with PBO, with no hemorrhagic deaths with romiplostim. Increases in peripheral blasts >10% occurred more frequently with romiplostim but generally resolved after romiplostim discontinuation. AML was defined conservatively; cases are pending central pathology review. AML occurred primarily in pts who were initially RAEB-1 and in more pts with romiplostim. Overall and AML-free survival rates were similar. Disclosures: Giagounidis: Amgen: Consultancy; GlaxoSmithKline: Consultancy. Off Label Use: This trial examined the use of romiplostim, which is indicated for use in ITP, in MDS. Mufti:Celgene: Consultancy, Research Funding. Kantarjian:Amgen: Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Amgen: Honoraria; Roche: Research Funding; Janssen Cilag: Research Funding. Sekeres:Celgene Corp: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kuendgen:Celgene: Honoraria. Platzbecker:Amgen: Honoraria; GSK: Honoraria. Gaidano:Amgen: Honoraria. Jedrzejczak:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hu:Amgen: Employment, Equity Ownership. Yang:Amgen: Employment, Equity Ownership. Jun:Amgen: Employment, Equity Ownership.

scholarly journals Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1961-1961
Author(s):  
John F. DiPersio ◽  
Jonathan Hoggatt ◽  
Steven Devine ◽  
Lukasz Biernat ◽  
Haley Howell ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Board Of Directors ◽  
Preliminary Data ◽  
Research Funding ◽  
Fold Change ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

scholarly journals Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3129-3129
Author(s):  
Hans C. Lee ◽  
Sikander Ailawadhi ◽  
Cristina Gasparetto ◽  
Sundar Jagannath ◽  
Robert M. Rifkin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Causes Of Death ◽  
Age Groups ◽  
Treatment Patterns ◽  
Age Group ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

scholarly journals Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4739-4739
Author(s):  
Pieter Sonneveld ◽  
Maria-Victoria Mateos ◽  
Adrián Alegre ◽  
Thierry Facon ◽  
Cyrille Hulin ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Indirect Comparison ◽  
Employment Equity ◽  
Advisory Committees ◽  
Post Transplant ◽  
Post Induction ◽  
Adjusted Indirect Comparison ◽  
Equity Ownership

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. 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; Sanofi: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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