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 Also leading to withdrawal were consent withdrawn (romiplostim 13%, PBO 15%), adverse events (AE) (12%, 5%), and alternative therapy (7%, 11%).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.

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.

Romiplostim in Thrombocytopenic Patients with Low- or Int-1- Risk MDS Results in Reduced Bleeding without Impacting Leukemic Progression: Final Follow-up Results from a Randomized, Double-Blind, Placebo-Controlled Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2000-2000
Author(s):  
Hagop Kantarjian ◽  
Pierre Fenaux ◽  
Mikkael A. Sekeres ◽  
Jeffrey Szer ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Study Drug ◽  
Controlled Study ◽  
Bleeding Events ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: Thrombocytopenia occurs in ~50% of patients with low/int-1 risk myelodysplastic syndrome (MDS) and is associated with reduced survival. In a placebo (PBO)-controlled study, 250 patients with MDS were randomized 2:1 to receive weekly romiplostim or PBO. In the original June 2011 analysis, romiplostim reduced clinically significant bleeding events [hazard ratio (HR) romiplostim vs PBO 0.83, 95% CI: 0.66−1.05, P = 0.13] and platelet transfusions (relative risk 0.77, 95% CI: 0.66−0.88, P<0.001) and increased IWG hematologic improvement platelets (HI-P) incidence (odds ratio 15.6, 95% CI: 4.7−51.8, P<0.001). Peripheral blast count increases >10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.6%) and resolved after discontinuation in most cases. In February 2011, the DMC recommended that treatment with study drug be discontinued as the potential 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 might put patients at risk for diagnosis of and treatment for AML. Patients were moved into long-term follow-up (LTFU). Previously reported (Giagounidis et al, Cancer 2014) 58-week incidence of AML was 6.0% (N = 10) for romiplostim and 4.9% for PBO (N = 4); HR 1.20 (95% CI: 0.38−3.84). This report provides final 5-year LTFU data. Methods: Eligible patients were receiving only supportive care and had IPSS low/int-1 risk MDS and platelets 1) ≤20 × 109/L or 2) ≤50 × 109/L with a history of bleeding. Disease progression to AML was defined as 1) ≥20% blasts in bone marrow or peripheral blood after 4 weeks following discontinuation of romiplostim; 2) pathology consistent with leukemia; or 3) antileukemic treatment. Results are presented by treatment group. Results: At baseline, median (Q1, Q3) age was 70 (61, 77) years, the majority (59%) of patients were male; 27.6% were IPSS low risk and 72.4% were int-1 risk. WHO classifications were RCMD: 67.6%, RAEB-1: 13.2%, MDS-U: 11.2%, RA: 4.4%, RCMD-RS: 2.4%, RARS: 0.8%, and RAEB-2: 0.4%. Of 250 patients in the study, 210 entered LTFU and 66 completed the 5 years of LTFU; median (Q1, Q3) follow-up was 27.5 (10.8, 58.7) months. Reasons for discontinuation (death, lost to follow-up, and consent withdrawal) during LTFU were similar in both groups. During the active study period and LTFU, death was reported in 93 (55.7%) patients in the romiplostim group and 45 (54.2%) patients in the PBO group (HR romiplostim vs PBO 1.03, 95% CI: 0.72−1.47) (Figure); mortality rates were greater in those with IPSS int-1 vs low risk for both groups (Table). AML was reported in 20 (11.9%) patients in the romiplostim group and 9 (11.0%) patients in the PBO group (HR 1.06, 95% CI: 0.48−2.33). The proportions of patients who either died or developed AML were 56.9% (N = 95) in the romiplostim group and 55.4% (N = 46) in the PBO group (HR for AML-free survival 1.04, 95% CI: 0.73−1.48) (Figure). Nearly half (N = 14, 48%) of the 29 AML cases occurred in patients who were RAEB-1 at screening (none RAEB-2), and 6 cases were diagnosed because of anti-AML treatment use alone (Table). In LTFU, patient-reported use of MDS therapy (eg, azacitidine or cyclosporine) was 42.8% (N = 59, 95% CI: 34.4%−51.5%) in the romiplostim group and 31.4% (N = 22, 95% CI: 20.9%−43.6%) in the PBO group. AML therapy (eg, chemotherapy) was used in 14 (10.2%) patients in the romiplostim group and 7 (10.0%) patients in the PBO group. Conclusions: Following the decision in 2011 to stop study drug secondary to increased AML rates at that time and transient blasts increases, final 5-year LTFU HRs (romiplostim vs placebo) for death or progression to AML, respectively, are 1.03 (95% CI: 0.72−1.47) and 1.06 (95% CI: 0.48−2.33). In conclusion, romiplostim reduced bleeding events and platelet transfusions, with no increase in AML incidence or impact on survival. Disclosures Kantarjian: Amgen Inc.: Research Funding. Fenaux:Amgen Inc.: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Australia: Consultancy, Honoraria; Amgen Inc.: 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; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Platzbecker:Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kuendgen:Celgene: Research Funding. Gaidano:Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wiktor-Jedrzejczak:Angelini: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy, Research Funding; BMS: Research Funding; Sandoz: Consultancy; Amgen Inc.: Research Funding. Carpenter:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership. Giagounidis:Amgen Inc.: Consultancy, Honoraria.

Efficacy and Safety of Romiplostim in Patients with Low or Intermediate-Risk Myelodysplastic Syndrome (MDS) Receiving Decitabine.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1769-1769 ◽  
Author(s):  
Peter L Greenberg ◽  
Guillermo Garcia-Manero ◽  
Michael R Moore ◽  
Lloyd E. Damon ◽  
Gail J. Roboz ◽  
...  
Keyword(s):  
Placebo Group ◽  
Research Funding ◽  
Hypomethylating Agents ◽  
Bleeding Events ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Equity Ownership ◽  
Clinically Significant ◽  
Platelet Transfusions

Abstract Abstract 1769 Poster Board I-795 Introduction MDS patients receiving hypomethylating agents commonly develop clinically significant thrombocytopenia, for which platelet transfusions are often the only treatment. Romiplostim is a peptibody protein that increases platelet production by a mechanism similar to thrombopoietin. This report describes a phase 2, multicenter, randomized, double-blind, placebo-controlled study of romiplostim in combination with hypomethylating agents in patients with MDS. Results from patients receiving azacitidine have previously been reported (Kantarjian et al, ASH 2008, #224); we report results from the combination of romiplostim with decitabine. Methods Eligible patients had low, intermediate-1, or intermediate-2 risk MDS per IPSS. Patients were randomized (1:1) to receive placebo or 750μg romiplostim by weekly subcutaneous injection and were stratified by baseline platelet count (≥ or &lt;50×109/L). Patients received decitabine according to the FDA-approved dose and schedule, or using a modified dosing regimen (20 mg/m2 IV over 1 hour for 5 days every 4 weeks). The primary endpoint was the incidence of clinically significant thrombocytopenic events, defined as platelet counts &lt;50×109/L starting at week 3 of treatment, or receipt of platelet transfusions at any time during the treatment period. Other endpoints included the safety of romiplostim in combination with decitabine and the incidence of platelet transfusions, bleeding events, and platelet nadir during decitabine treatment cycles. Results from 4 decitabine treatment cycles are presented. Results Twenty-nine patients were randomized and treated. Nine of 14 (64%) placebo-treated and 10/15 (67%) romiplostim-treated patients completed 4 cycles of decitabine. Baseline characteristics were generally well balanced between the 2 groups, except that more patients in the placebo group had an IPSS score &gt;1 (8/14, 57%) than those in the romiplostim group (5/15, 33%). The primary endpoint was reached in 11/14 (79%) placebo patients and 12/15 (80%) romiplostim patients: After the first cycle, median platelet counts at the beginning of each decitabine cycle were lower in placebo-treated than in romiplostim-treated patients (Table). Platelet transfusions were administered to 57% of placebo patients and 47% of romiplostim patients. The overall incidence of bleeding events was higher in the placebo group (43%) than the romiplostim group (27%). An MDS treatment response (complete or partial response) was achieved by 5/14 (36%) placebo patients and 7/15 (47%) romiplostim patients. All patients experienced at least 1 adverse event. Serious adverse events occurred in 57% of placebo- and 53% of romiplostim-treated patients. One patient in the romiplostim group experienced a treatment-related serious adverse event (pulmonary artery thrombosis leading to study withdrawal). Bone marrow blasts were increased in 2 patients, both from the placebo group. Disease progression to AML (23% bone marrow blasts and 21% peripheral blasts) occurred in one patient from each treatment group. Four patients died: 2 in the placebo group (neutropenic sepsis and intracranial hemorrhage) and 2 in the romiplostim group (sepsis and acute cholecystitis). None of the deaths were considered investigational product-related. Conclusions Romiplostim in combination with decitabine appeared to be well tolerated in lower-risk MDS patients. A clinical benefit of adding romiplostim to decitabine treatment was indicated by numerically increased platelet counts at the beginning of each treatment cycle, decreased platelet transfusion rates and decreased bleeding events in romiplostim-treated patients compared with the placebo group. Conclusions are limited by the small sample size of this exploratory phase 2 study, and further investigation of the safety and efficacy of romiplostim in treatment-related thrombocytopenia in MDS is warranted. Disclosures Greenberg: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding. Off Label Use: Use of romiplostim, a thrombopoietin mimetic, to treat Thrombocytopenia in MDS. Damon:Celgene: Speakers Bureau; Genentech: Equity Ownership; Eisai: Speakers Bureau. Wei:Amgen Inc.: Employment, Equity Ownership. Kantarjian:Amgen Inc.: Research Funding. Franklin:Amgen Inc.: Employment, Equity Ownership.

Outcomes Following Lenalidomide for Relapsed/Refractory Mantle Cell Lymphoma Patients at Risk of Bleeding Events Because of Multiple Comorbidities or Treatment: A Post-Hoc Subgroup Analysis of the SPRINT (MCL-002) Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2978-2978
Author(s):  
Marek Trneny ◽  
Thierry Lamy ◽  
Jan Walewski ◽  
David Belada ◽  
Jiri Mayer ◽  
...  
Keyword(s):  
At Risk ◽  
Board Of Directors ◽  
Subgroup Analysis ◽  
Research Funding ◽  
Treatment Options ◽  
Bleeding Risk ◽  
Bleeding Events ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) have limited treatment options, especially those receiving multiple prior therapies. Patients with MCL are mostly an elderly population with various comorbidities who receive multiple medications that may lead to an increased risk of toxicity from underlying disease, as well as drug interactions. These multiple, concomitant conditions introduce complexity into the evaluation of the risk-benefit ratio of available therapies. In the relapsed setting, there is increasing use of new treatment options, such as lenalidomide, which is an immunomodulatory agent with direct and immune-mediated mechanisms of action. Lenalidomide has shown efficacy and a tolerable safety profile in multiple studies of R/R MCL, including the randomized MCL-002 (SPRINT) study comparing lenalidomide vs. investigator's choice (IC) of monotherapy. The objective of this post hoc subgroup analysis from the MCL-002 study was to examine the effect and safety of lenalidomide in patients who are at risk of bleeding events because of multiple comorbidities or treatments (i.e., polymedication) denoted as LEN-CM compared with those not at risk (LEN), LEN-CM being a population with a limited choice of treatment options. Methods: The multicenter MCL-002 study randomized patients 2:1 to lenalidomide vs. single-agent IC of monotherapy (rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine; NCT00875667). Patients had 1-3 relapses or had failed prior therapy, and were ineligible for intensified chemotherapy or stem cell transplantation. Oral lenalidomide was initiated at 25 mg/day on days 1-21 of 28-day cycles until disease progression or as tolerated. Progression-free survival (PFS) was the primary endpoint (per modified 1999 IWG criteria); secondary endpoints included response rates, duration of response (DOR), overall survival (OS), and safety. The current analyses were based on investigator's assessment. Specific patient groups with or without increased bleeding risk due to comorbidities and/or treatment were identified for the subgroup analysis based on pre-existing characteristics at study initiation. Patients in the LEN-CM group included those with hemorrhages (or predispositions to such), concomitant anticoagulant therapy with vitamin K antagonists or nonsteroidal anti-inflammatory drugs, and/or current or preexisting atrial fibrillation requiring anticoagulants. Results: Of 170 patients originally randomized to lenalidomide treatment, there were 60 (35%) LEN-CM vs. 110 (65%) LEN patients included in this subanalysis. At baseline, patients in both groups generally had a similar baseline patient profile and prior treatment history, although there were some differences between groups: more patients in the LEN-CM group (vs. LEN) were >=65 years of age (78% vs. 62%) and had more high-risk MIPI score at baseline (47% vs. 29%), whereas fewer had positive bone marrow (7% vs. 15%), high tumor burden (37% vs. 54%), or bulky disease (15% vs. 25%). Median PFS by investigator assessment was 10.7 months (95% CI, 4.3-14.0) for LEN-CM and 7.0 months (95% CI, 5.3-14.6) for LEN (Table 1). Overall response rates (ORR) in the LEN-CM vs. LEN patients were 29/60 (48%) and 49/110 (45%) with complete response (CR)/CR unconfirmed (CRu) rates of 6/60 (10%) and 13/110 (12%), respectively. Median DOR and OS were also similar in both groups of lenalidomide-treated patients. The safety profiles were similar for these subgroups, with similar rates of AEs leading to discontinuations and dose reductions/interruptions. Most common any grade treatment-emergent AEs (>=20%) for LEN-CM vs. LEN groups respectively were 48% vs. 52% neutropenia, 33% vs. 38% thrombocytopenia, 32% vs. 27% anemia, 25% vs. 19% fatigue, 23% vs. 22% diarrhea, and 5% vs. 23% pyrexia. Conclusions: For patients with R/R MCL, there is a high, unmet medical need for effectivetherapy with acceptable toxicity. Overall, the LEN-CM and LEN subgroups showed similar efficacy and safety outcomes. Results from this subgroup analysis of the MCL-002 study show that lenalidomide leads to clinically meaningful PFS and other efficacy outcomes irrespective of the presence or absence of bleeding risk due to comorbidities and/or treatment. Disclosures Walewski: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Novartis: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Belada:Seattle Genetics: Research Funding. Radford:Novartis: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; GSK: Equity Ownership; Astra-Zeneca: Equity Ownership; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jurczak:Morphosys: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Celtron: Research Funding; Bayer: Research Funding; Takeda: Research Funding; Servier: Research Funding; Teva: Research Funding; Roche: Research Funding, Speakers Bureau; Sandoz-Novartis: Speakers Bureau. Morschhauser:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Kaplanov:State Budgetary Healthcare Institution "Volgograd Regional Clinical Oncology Dispensary #1: Employment. Thyss:Takeda: Research Funding; Millennium: Research Funding. Kuzmin:Republican Clinical Oncology Dispensary: Employment. Stelitano:Azienda Ospedaliera: Employment. Marks:Pfizer: Honoraria. Trümper:Roche: Research Funding; Mundipharma: Research Funding; Hexal: Membership on an entity's Board of Directors or advisory committees. Biyukov:Celgene: Employment, Equity Ownership. Barnett:Celgene Corporation: Employment, Equity Ownership. Casadebaig Bravo:Celgene: Employment, Equity Ownership. Arcaini:Sandoz: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding.

A Randomized, Double-Blind, Placebo-Controlled Phase 1/2 Study to Determine the Safety and Efficacy of Romiplostim in Children with Chronic Immune (Idiopathic) Thrombocytopenic Purpura (ITP).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 680-680 ◽  
Author(s):  
George R. Buchanan ◽  
Lisa Bomgaars ◽  
James B. Bussel ◽  
Diane J. Nugent ◽  
David J. Gnarra ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Treatment Period ◽  
Research Funding ◽  
Bleeding Events ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Equity Ownership

Abstract Abstract 680 Introduction: ITP is an autoimmune disorder characterized by thrombocytopenia due to accelerated destruction as well as suboptimal platelet production. Childhood ITP is most commonly an acute illness; however, chronic ITP (duration > 6 months) develops in 20%–30% of ITP cases. Romiplostim, a peptibody protein designed to increase platelet production, is approved for treating chronic ITP in adults. The objective of this study was to evaluate the safety and efficacy of romiplostim in the treatment of thrombocytopenia in children with chronic ITP. Patients and Methods: ITP patients aged 12 months to <18 years with persistent severe thrombocytopenia for at least six months before enrollment (mean of 2 platelet counts ≥ 30 × 109/L at baseline) were included in this study. Patients were randomized (3:1) to receive romiplostim or placebo and stratified by age: 12 months - <3 years (N=4), 3 - <12 years (N=8), and 12 - <18 years (N=8). Treatment for a 12 week period was followed by a 4 week pharmacokinetic (PK) assessment period for responding patients (those who achieved a platelet count of >20 × 109/L above baseline for 2 consecutive weeks without rescue therapy at any point during the treatment period). Treatment was initiated at 1 μg/kg once weekly by subcutaneous injection. The dose was adjusted in 2 μg/kg increments every two weeks, to a maximum dose of 10 μg/kg/week based on weekly platelet counts. The incidence of adverse events (AEs) during the 12-week treatment period and the number of patients achieving platelet counts >50 × 109/L for 2 consecutive weeks during the treatment period, or achieving an increase in platelet count >20 × 109/L above baseline for 2 consecutive weeks during the treatment period was recorded. Results: A total of 22 (romiplostim, 17; placebo, 5) patients were randomized; 16 (73%) were boys and 6 (27%) were girls. Eight patients had undergone splenectomy. The mean age was 9.5 (SD: 5.1) years, with 4 subjects aged 12 months - <3 years, 10 aged 3 - <12 years, and 8 aged 12 - <18 years. The median baseline platelet count was 13 × 109/L (range 2 to 29 × 109/L) and the median duration of ITP was 2.4 years (range 0.6 to 14 years). All patients completed the study. Sixteen of 17 patients in the romiplostim arm (94%) and 5/5 in the placebo arm (100%) had at least 1 AE during the treatment period. The most common AEs were (romiplostim, placebo, respectively) headache (35%, 40%), epistaxis (35%, 20%), cough (12%, 40%), and vomiting (12%, 40%). Serious AEs were experienced by 1 patient in the romiplostim arm (moderate influenza and sepsis) and none in the placebo arm. AEs considered to be treatment related were reported for 3 (18%) and 1 (20%) subjects in the romiplostim and placebo arms, respectively; none of the treatment-related AEs were serious or of ≥3 grade severity. No patients died during the study and none tested positive for neutralizing antibodies to romiplostim or thrombopoietin. The same group of patients in the romiplostim-treated arm (15/17, 88.2%, 95% CI: 63.6%, 98.5%) achieved both efficacy endpoints during the treatment period. The median platelet count in the romiplostim-treated arm after 6 weeks of treatment was ≥50 × 109/L. The median weekly platelet count in the placebo arm remained stable at approximately 10 × 109/L. None of the placebo-treated patients achieved either platelet count endpoint. Rescue medication was administered to 2/17 (12%) of romiplostim- and 2/5 (40%) of placebo-treated patients during the 12 week treatment period. Twelve (71%) and 2 (40%) subjects in the romiplostim and placebo arms, respectively, experienced bleeding events. The majority of bleeding events (15/17) in the romiplostim arm occurred in the first 6 weeks of treatment. Most bleeding events (14/17) in the romiplostim arm and all bleeding events in the placebo arm occurred when the platelet count was < 30 × 109/L. A total of 14 patients treated with romiplostim entered the PK assessment period. The romiplostim serum concentration results were not different among the 3 age cohorts. The mean weekly dose of romiplostim in the treatment period was 3.4 (SD: 1.6) μg/kg. Conclusion: Treatment with romiplostim appeared to be well tolerated in pediatric ITP patients, with no new safety concerns observed in this study as compared to adults with chronic ITP. Romiplostim was effective in treating thrombocytopenia in children with chronic ITP. Disclosures: Buchanan: Amgen Inc.: Research Funding. Off Label Use: Use of romiplostim, a thrombopoietin mimetic, in treatment of thrombocytopenia in pediatric ITP patients. . Bomgaars:Novartis: Research Funding. Bussel:Eisai, Inc: Research Funding; Sysmex: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; Scienta: Speakers Bureau. Nie:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

Safety and Efficacy of Extended Treatment with Eltrombopag in Adults with Chronic Immune Thrombocytopenia (ITP) From June 2006 to February 2011,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3296-3296 ◽  
Author(s):  
Mansoor N Saleh ◽  
Gregory Cheng ◽  
James B Bussel ◽  
Paul Burgess ◽  
Lisa Marcello ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Equity Ownership ◽  
Clinically Significant

Abstract Abstract 3296 Background: Eltrombopag is an oral, nonpeptide thrombopoietin receptor agonist approved for treatment of chronic immune thrombocytopenia (ITP). In 6-week, and 6-month, placebo-controlled trials, eltrombopag safely increased platelets and reduced bleeding in patients (pts) with previously treated chronic ITP. EXTEND is an ongoing, open-label extension study of the safety and efficacy of long-term treatment with eltrombopag in chronic ITP pts. Methods: Pts had received eltrombopag or placebo in one of the following studies: TRA100773A or B (6-weeks), RAISE (6-months), or REPEAT (intermittent treatment). The EXTEND study was designed to: 1) identify an individual dose that increases platelets to ≥100,000/μL to support reduction of concomitant ITP medications, 2) identify a minimal dose of eltrombopag and concomitant ITP medication to maintain platelets ≥50,000/μL, and 3) evaluate long-term safety and efficacy. Pts completed the study if they completed ≥2 years of therapy and transitioned off study due to commercial availability of eltrombopag. Results: Of 301 pts enrolled, 21% (63) completed the study, 48% (143) withdrew, and 32% (95) remain on study. The most common reasons for withdrawal were adverse events (AEs, 14%), pt decision (13%), and lack of efficacy (11%). At baseline, platelet counts were ≤15,000/μL, >15,000-<30,000/μL, 30,000–50,000/μL, and >50,000/μL in 43%, 27%, 17%, and 13% of pts, respectively; 38% were splenectomized, 34% were receiving concomitant ITP medication, and 53% had received ≥3 previous ITP therapies. As of this report, 252, 215, 176, and 84 pts had been treated for ≥6 months, 1 year, 2 years, and 3 years, respectively. Twenty-three pts (8%) were treated for ≥4 years. Median duration of exposure was 121 weeks (range, 0.3–237 weeks). Overall, 88% (264/301) of pts achieved a platelet count ≥50,000/μL at least once. The proportion of pts achieving on-treatment platelets ≥50,000/μL was similar regardless of the following baseline characteristics: splenectomy vs no splenectomy (85% vs 89%); use vs no use of ITP medication (89% vs 87%); and platelet counts (<30,000/μL, 84%; 30,000–50,000/μL, 98%; >50,000/μL, 95%). Median platelet counts increased to ≥50,000/μL by week 2 and remained consistently ≥50,000/μL through week 208. The incidence of any bleeding symptoms (WHO grades 1–4) decreased from 56% at baseline to 16%, 19%, and 9% at weeks 52, 104, and 156, respectively. Clinically significant bleeding (WHO grades 2–4) decreased from 16% at baseline to 3%, 5%, and 0% at weeks 52, 104, and 156, respectively. AEs and serious AEs (SAEs) occurred in 89% (269) and 29% (86) of pts, respectively. The most frequent AEs were headache (27%), nasopharyngitis (24%), and upper respiratory tract infection (21%). Forty pts (13%) had AEs leading to withdrawal; 28 (9%) had SAEs leading to withdrawal. Twenty-five thromboembolic events (TEEs) have been reported in 19 pts (6%); the incidence rate is 3.02/100 pt years (95% CI [1.82–4.71]). Observed TEEs were deep vein thrombosis (10), central nervous system ischemic events (7), myocardial infarction (5), and pulmonary embolism (3). No association has been observed with elevated platelet counts, as only 3/19 pts experienced the TEE at or closest to their maximum platelet count achieved on study. Hepatobiliary laboratory abnormalities (HBLAs) meeting drug-induced liver injury screening criteria (Center for Drug Evaluation and Research 2009 [FDA]) were reported in 34 pts (11%). None were associated with signs of liver impairment, and most (n=30) resolved either while on treatment or after discontinuation. Eight pts were withdrawn as a result of their HBLA. Two pts were diagnosed with lymphoma and none with leukemia during the 622 pt years of eltrombopag exposure during EXTEND. An independent central review of bone marrow biopsies from >100 pts treated with eltrombopag for 1–4 years, including 39 pts who had ≥2 biopsies during the study, revealed no clinically significant increase in reticulin deposition. Conclusions: Eltrombopag was effective in increasing and maintaining platelet counts ≥50,000/μL and reducing bleeding symptoms. Eltrombopag was well-tolerated during treatment of pts with chronic ITP with exposures up to 4.5 years. No new safety signals have been observed in this long-term study. Additional long-term safety data continue to be assessed, especially in terms of bone marrow reticulin, HBLAs, and TEEs. Disclosures: Saleh: GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau. Cheng:GlaxoSmithKline: Speakers Bureau. Bussel:Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding. Burgess:GlaxoSmithKline: Employment, Equity Ownership. Marcello:GlaxoSmithKline: Employment. Bailey:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership.

Effect of Lenalidomide (LEN) Exposure on AML-Free Survival and Overall Survival in LEN-Treated Patients (Pts) with IPSS Low- or Intermediate-1-Risk Myelodysplastic Syndromes (MDS) with Del(5q)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2870-2870 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Arlene S. Swern ◽  
Alan F. List ◽  
Pierre Fenaux ◽  
Mary M. Sugrue
Keyword(s):  
Board Of Directors ◽  
Dose Reduction ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Free Survival ◽  
Treatment Groups ◽  
Equity Ownership ◽  
Dose Modifications ◽  
Dose Reductions

Abstract Introduction: The efficacy and safety of LEN in red blood cell (RBC) transfusion-dependent pts with International Prognostic Scoring System (IPSS)-defined Low- or Intermediate-1-risk MDS and del(5q) was assessed in 2 large pivotal trials; protocol-defined dose modifications due to adverse events were required in the majority of LEN-treated pts (MDS-003 [List A, et al. N Engl J Med. 2006;355:1456-65] and MDS-004 [Fenaux P, et al. Blood. 2011;118:3765-76]). Previously we have shown that achievement of cytogenetic response (CyR) with LEN is associated with LEN dose and with achieving RBC transfusion-independence and improved acute myeloid leukemia (AML)-free survival. The current analysis evaluates the impact of actual LEN exposure, including induction-type dosing in Cycle 1 and subsequent dose reductions for LEN-associated cytopenias, and CyR on AML-free survival and overall survival (OS) in lower-risk MDS pts with del(5q) treated in the MDS-003 and MDS-004 studies. Methods: This analysis includes pooled data from pts who were treated with LEN in MDS-003 and MDS-004. Pts received LEN at one of the following starting doses and schedules: 5 mg/day, days 1-28 (MDS-004); 10 mg/day, days 1-21 (MDS-003 and MDS-004); or 10 mg/day, days 1-28 (MDS-003); all given in 28-day cycles. LEN dose reductions related to adverse events (NCI CTCAE v3.0) of grade ≥ 3 (MDS-003) or grade 4 thrombocytopenia or neutropenia (MDS-004) were predefined in the study protocols. Full dose modification guidelines for MDS-004 have been published previously (Fenaux P, et al. Blood. 2011;118:3765-76). Dose interruptions were not considered. AML-free survival and OS were estimated by the Kaplan-Meier method with differences evaluated by the log-rank test. Univariate and multivariable Cox proportional hazards models were used to identify predictive factors for AML-free survival and OS. CyR and LEN dose reduction were analyzed as time-varying covariates. Results: Among the 286 LEN-treated pts from MDS-003 and MDS-004, median total doses in Cycle 1 were 245, 210, 280, and 140 mg in the 10 mg (MDS-003: 10 mg × 28 days), 10 mg (MDS-003: 10 mg × 21 days), 10 mg (MDS-004: 10 mg × 21 days), and 5 mg (MDS-004: 5 mg × 28 days) treatment groups, respectively. Median total times on LEN were 364, 385, 510, and 273 days, respectively, and median times to first dose reduction were 53, 63, 54, and 63 days across the treatment groups, respectively. AML-free survival and OS were significantly longer in pts who received > 210 mg versus ≤ 210 mg in Cycle 1 of therapy (log-rank P = 0.0005 and P = 0.0002, respectively). In multivariable analyses, higher total LEN dose in Cycle 1, analyzed as a continuous variable, was significantly associated with improved AML-free survival (hazard ratio [HR] 0.97; P = 0.033) and OS (HR 0.97; P = 0.036) (Table). Sensitivity analyses showed total dose in Cycles 1-3 to be significant, but total dose in Cycle 1 was a better predictor. In the same model, the occurrence of LEN dose reduction was significantly associated with improved AML-free survival (HR 0.54; P < 0.001) and OS (HR 0.56; P = 0.001) (Table) and was strongly associated with longer duration on study (P < 0.001). Conclusions: In this pooled analysis of LEN-treated pts with MDS and del(5q) from the pivotal MDS-003 and MDS-004 trials, the total cumulative LEN dose actually received in Cycle 1 was a significant predictor of AML-free survival and OS; this is likely mediated through clone suppression, evidenced by the association with CyR. Long-term outcomes were significantly improved in LEN-treated pts who had received early cumulative exposure using 10 mg daily and longer duration through dose modifications. These findings support the use of LEN 10 mg as the recommended induction starting dose, and the importance of dose reductions as required to maximize treatment duration and optimize response and survival outcomes in these pts with lower-risk MDS with del(5q). Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. List:Celgene Corporation: Honoraria, Research Funding. Fenaux:Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Sugrue:Celgene Corporation: Employment, Equity Ownership.

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.

scholarly journals Association of Bleeding Severity with Mortality with in-Hospital and Extended Thromboprophylaxis in the Medically Ill in the Magellan Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2441-2441
Author(s):  
Alex C. Spyropoulos ◽  
Gary E. Raskob ◽  
Alexander T Cohen ◽  
Walter Ageno ◽  
Jeffrey I. Weitz ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Major Bleeding ◽  
Research Funding ◽  
Bleeding Events ◽  
Employment Equity ◽  
Advisory Committees ◽  
Increased Risk ◽  
Bayer Healthcare ◽  
Equity Ownership

Background: Venous thromboembolism (VTE) is common after hospitalization in acutely ill medical patients, yet extended thromboprophylaxis has not been widely implemented due to concerns about bleeding. The MAGELLAN study (NCT00571649) evaluated whether rivaroxaban (10 mg QD for 35±4 days) compared with enoxaparin (40 mg QD for 10±4 days) followed by placebo could prevent asymptomatic deep vein thrombosis, symptomatic VTE, and VTE-related death. Through Day 35, rivaroxaban was superior to enoxaparin/placebo in the modified intent-to-treat population (4.4% vs 5.7%, RR 0.77, 95%CI, 0.62 to 0.96, p=0.02), but there was an increase in clinically relevant bleeding, the composite of major and non-major clinically relevant (NMCR) bleeding (4.1% vs 1,7%, RR 2.5, 95%CI 1.85-3.25, p<0.001). Although major bleeding has been associated with increased mortality, the relationship between NMCR bleeding and all-cause mortality (ACM) is not established. We hypothesized that subjects in the MAGELLAN trial with major bleeding but not those with NMCR bleeding, would be at an increased risk of ACM irrespective of treatment group. Methods: We evaluated all bleeding events in subjects taking at least one dose of study drug from randomization until 2 days after the last dose (safety population) and their association with ACM through the Day 90 visit in 3 mutually exclusive groups: (1) subjects with no major or NMCR bleeding; (2) subjects whose first event was NMCR bleeding; and (3) subjects whose first event was major bleeding. Subjects only developing minimal or trivial bleeding were grouped with those who had no clinically relevant bleeding. Using a Cox proportional hazards model that included the bleeding group variable and baseline covariates significantly associated with ACM at p<0.05 (age, BMI, history of cancer, history of anemia, inflammatory disease, acute ischemic stroke, and acute respiratory insufficiency), we compared the risk of ACM in subjects with and without bleeding events. Results: The incidence of ACM for subjects who had NMCR bleeding was numerically higher but not significantly increased compared with subjects with no bleeding (20/176, 11.4% vs 468/7763, 6.0%, HR 1.41 95%CI 0.88, 2.25, p=0.151), while subjects with major bleeding were at a significantly increased risk of death (28/59, 47.5% vs 468/7763, 6.0%, HR 7.74 95%CI 5.16, 11.59, p<0.0001). Results of landmark analyses from the first bleeding event or end of treatment + 2 days to ACM for the three groups are displayed (Figure). Limitations: This analysis was post hoc and may have been underpowered to detect differences in ACM associated with NMCR bleeding. Conclusion: Major bleeding was associated with a significantly increased risk of ACM but NMCR bleeding was not. This suggests that a modest increase in NMCR bleeding associated with extended thromboprophylaxis with rivaroxaban may be acceptable to prevent VTE. Strategies to better select patients at lower risk of bleeding may improve the benefit risk profile of extended thromboprophylaxis with rivaroxaban. Disclosures Spyropoulos: Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Portola: Consultancy; Bayer Healthcare: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; Janssen R&D, LLC: Consultancy. Raskob:Janssen R&D, LLC: Consultancy, Honoraria; Novartis: Consultancy; Tetherex: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Anthos: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy, Honoraria; Portola: Consultancy; Bayer Healthcare: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Eli Lilly: Consultancy. Cohen:Boston Scientific: Consultancy; CSL Behring: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Consultancy, Speakers Bureau; GLG: Consultancy; AbbVie: Consultancy; ACI Clinical: Consultancy; Aspen: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Guidepoint Global: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy; Medscape: Consultancy, Speakers Bureau; McKinsey: Consultancy; Navigant: Consultancy; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Temasek Capital: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism. Ageno:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Other: conference and travel support; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research support,travel support ; BMS Pfizer: Other: travel support; Aspen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Portola: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: travel support. Weitz:Janssen R&D, LLC: Consultancy; Bayer Healthcare: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Portola: Consultancy, Honoraria. Spiro:Bayer U.S. LLC: Employment, Equity Ownership. Lu:Janssen R&D, LLC: Employment, Equity Ownership. Lipardi:Janssen Research and Develompent: Employment, Equity Ownership. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership. OffLabel Disclosure: Rivaroxaban is a Factor Xa inhibitor. It is currently under review by FDA for approval as thromboprophylaxis in acutely ill medical patients at risk for venous thromboembolism.

Daratumumab, Bortezomib and Dexamethasone Versus Bortezomib and Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma Based on Prior Treatment Exposure: Updated Efficacy Analysis of Castor

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3313-3313 ◽  
Author(s):  
Asher A. Chanan-Khan ◽  
Suzanne Lentzsch ◽  
Hang Quach ◽  
Noemi Horvath ◽  
Marcelo Capra ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Employment Equity ◽  
Advisory Committees ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Equity Ownership ◽  
Line Of Therapy

Abstract Introduction: Daratumumab is a human CD38 IgGκ monoclonal antibody that demonstrated significant activity and a manageable safety profile in combination with bortezomib and dexamethasone. In a randomized phase 3 study, daratumumab in combination with bortezomib and dexamethasone (DVd) significantly prolonged progression-free survival (PFS) versus bortezomib and dexamethasone alone (Vd) in a pre-specified interim analysis of patients (pts) with relapsed or refractory multiple myeloma (RRMM; Palumbo A. N Engl J Med 2016; in press). Herein, we examine subgroups from this study to compare the efficacy of DVd vs Vd in bortezomib-naive and bortezomib-experienced pt populations. In addition, the efficacy of DVd vs Vd in pts who were refractory to lenalidomide at last prior line of therapy was also evaluated. Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to 8 cycles (q3w) of Vd (bortezomib: 1.3 mg/m2 SC on Days 1, 4, 8, 11; dexamethasone: 20 mg PO on Days 1, 2, 4, 5, 8, 9, 11, 12) with or without daratumumab (16 mg/kg IV qw in Cycles 1-3, Day 1 of Cycles 4-8, then q4w until progression). Pts who were refractory to bortezomib were not eligible. The primary endpoint was PFS. Bone marrow aspirate samples that had been prepared with Ficoll were evaluated for minimal residual disease (MRD) using three different thresholds (10-4, 10-5, and 10-6) based on the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA, USA). Results: Median follow-up was 7.4 months. Among bortezomib-naive pts (DVd, n=89; Vd, n=83), PFS was significantly improved with DVd vs Vd (median: not reached [NR] vs 7.5 months; HR, 0.25; 95% CI, 0.13-0.47; P&lt;0.0001); estimated 12-month PFS rates were 72% vs 28%, respectively. ORR was 88% with DVd vs 70% with Vd (P=0.0040), with ≥very good partial response (VGPR) rates of 72% vs 42% (P&lt;0.0001), and ≥complete response (CR) rates of 30% vs 20% (P=0.1199), respectively. For pts who previously received a bortezomib-containing regimen (DVd, n=162; Vd, n=164), PFS was also significantly longer with DVd vs Vd (median: 12.3 vs 6.7 months; HR, 0.46; 95% CI, 0.32-0.66; P&lt;0.0001). Estimated 12-month PFS rates were 55% vs 27%, respectively. ORR was significantly higher with DVd vs Vd (80% vs 60%; P=0.0001), along with significantly higher rates of ≥VGPR (52% vs 22%; P&lt;0.0001) and ≥CR (13% vs 3%; P=0.0019). Among pts who were refractory to lenalidomide at the last prior line of therapy (DVd, n=45; Vd, n=60), PFS was significantly longer in DVd vs Vd (median: 10.3 vs 4.4 mo; HR, 0.37; 95% CI, 0.21-0.65; P=0.0004; Figure). Within this subgroup, ORR was significantly higher for DVd vs Vd (81% vs 50%; P=0.0021), and the same trends were observed for rates of ≥VGPR (54% vs 12%; P&lt;0.0001) and ≥CR (20% vs 5%; P=0.0261). Updated efficacy and safety data, including MRD analyses across different sensitivity thresholds (10-4, 10-5, and 10-6), will be presented at the meeting. Conclusions: These analyses confirm that addition of daratumumab to Vd significantly improves outcomes for RRMM pts regardless of prior treatment with bortezomib. Importantly, this treatment benefit of DVd vs Vd was maintained in pts who were refractory to lenalidomide at the last prior line of therapy. These data lend further support to adding daratumumab to a standard-of-care regimen in RRMM. Figure Progression-free Survival in Patients Refractory to Lenalidomide at the Last Prior Line of Therapy Figure. Progression-free Survival in Patients Refractory to Lenalidomide at the Last Prior Line of Therapy Disclosures Lentzsch: BMS: Consultancy; Foundation One: Consultancy; Celgene: Consultancy, Honoraria. Quach:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Ovilla:Janssen: Consultancy. Qi:Janssen: Employment. Deraedt:Janssen: Employment, Equity Ownership. Schecter:Janssen: Employment, Equity Ownership. Amin:Janssen: Employment. Qin:Janssen: Employment. Casneuf:Johnson & Johnson: Equity Ownership; Janssen R&D, Beerse, Belgium: Employment. Chiu:Janssen: Employment. Sasser:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals R&D: Employment. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.

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