scholarly journals Rituximab Yielded a Significantly Longer Response Compared to Placebo in Steroid Free Population - a Post Hoc Analysis of the Ritp Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2358-2358
Author(s):  
Waleed Ghanima ◽  
Marc Michel ◽  
Abderrahim Khelif ◽  
Bernadette Darne ◽  
Pal André Holme
Keyword(s):  
Platelet Count ◽  
Treatment Failure ◽  
Research Funding ◽  
Post Hoc Analysis ◽  
Risk Of Bleeding ◽  
Adequate Response ◽  
Duration Of Response ◽  
Bleeding Episodes ◽  
Time To Relapse ◽  
Post Hoc

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by immune mediated platelet destruction causing thrombocytopenia and increase risk of bleeding. Treatment is indicated in patients who present with bleeding or are at risk of bleeding. Corticosteroids (CS) are the main first-line treatment in adult patients, but since not all patients achieve adequate response to CS, most patients require a second line therapy. Rituximab is one of the most widely used second line therapies; its advantages include the ability to induce relatively long lasting remissions after 2-4 infusions and its favorable safety profile. The RITP study was a randomized placebo-controlled trial in which ITP patients who failed to achieve adequate response to CS were randomized to receive rituximab or placebo. The study outcomes were treatment failure (splenectomy or meeting criteria for splenectomy), response rates and duration of response during an 18-month follow-up period. Apart from a longer duration of response in the rituximab arm, the study showed no significant differences in the other outcomes (Ghanima et al. Lancet 2015; 385: 1653-61). The use of stable dose of CS was allowed during the study. This report represents a post-hoc analysis of the RITP trail, restricting the population to those who did not receive any CS during the study, until relapse or treatment failure in the two arms. By this we aimed to eliminate the possible interference resulting from concomitant use of CS on the effect and safety of rituximab and placebo. For effect, we estimated the duration of response, splenectomy rates, platelet counts, and time to bleeding and for safety we estimated time to infection episodes in both arms. We included patients who did not receive CS before treatment failure or relapse or until the end the of the study, if none of the endpoints was achieved. The duration of response was estimated from time of achieving response to relapse (platelet count <30x109/L). Kaplan Meier plots were constructed to depict time to relapse, bleeding and infections using log-rank test to determine statistical significance between the two study groups. Of the 109 included patients, 45 (41%) patients did not receive CS in the two arms. Of these 45 patients, 27 achieved a response during the study; 14 in the rituximab arm and 13 in the placebo arm. Median duration of response was significantly longer in the rituximab arm (median 308 days; IQR: 168- not reached) vs placebo (41 days; IQR: 36-42) arm (p=0.0019), figure 1. Splenectomy rates did not differ between the two arms; 4 in the rituximab arm vs 3 in the placebo. A trend towards lower bleeding episodes was observed in the rituximab arm (p=0.12), figure 2. Mean platelet count was higher during the study in the rituximab arm compared to placebo as shown in figure 3. There was no difference in time to infection in both arms. One of the limitations of the RITP study was that CSs (prednisolone) were allowed in an unstandardized fashion. Thus, use of corticosteroids could have reduced the difference in effect between the two treatment arms masking some of the benefit of rituximab. Interestingly, no difference was found in the rate of response in the 2 arms; however, almost all those who were classified as responders in the placebo arm, relapsed within the first few weeks, whereas a much longer time to relapse was observed after rituximab. The unexpectedly high response rates in the placebo arm may be explained by the use of pre-medications, with CS received prior to infusion. Although the duration of response was also significantly longer in the original study, a greater difference was observed when restricting the population to those who did not use CS. Nevertheless, splenectomy rates were similar. In conclusion, rituximab yielded significantly longer duration of response and although response to rituximab was transient, half of the patients, displayed a treatment free response of more than 10 months, as well as it resulted in higher platelet count and less bleeding episodes without causing more infections. Disclosures Ghanima: Amgen: Consultancy, Honoraria; Pfizer/BMS: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bayer: Honoraria, Research Funding. Michel:Novartis: Consultancy; Amgen: Consultancy; Rigel: Consultancy. OffLabel Disclosure: Rituximab for ITP

scholarly journals Thromboprophylaxis for Patients with Newly Diagnosed Vs. Recurrent Cancers: A Post-Hoc Analysis of the Avert Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3660-3660
Author(s):  
Marina Atalla ◽  
James Zhang ◽  
Ranjeeta Mallick ◽  
Philip S. Wells ◽  
Marc Carrier
Keyword(s):  
Major Bleeding ◽  
Research Funding ◽  
Bleeding Complications ◽  
Primary Efficacy ◽  
Newly Diagnosed ◽  
Recurrent Cancer ◽  
Post Hoc Analysis ◽  
Increased Risk ◽  
Bleeding Episodes ◽  
Post Hoc

Background: The risk of venous thromboembolism (VTE) is increased in cancer patients, which can result in significant increases in mortality, morbidity and healthcare expenditures. The recent AVERT trial (N Engl J Med 2019 Feb 21;380(8):711-719), showed that prophylactic apixaban lowered the rate of VTE when compared to placebo in cancer patients starting chemotherapy. However, the risk-benefit ratio of primary thromboprophylaxis in patients initiating chemotherapy for recurrent disease compared to those with newly diagnosed patients who are chemotherapy naïve is unknown. Methods: This is a post-hoc analysis of the AVERT trial. The AVERT trial assessed apixaban therapy vs. placebo for prophylaxis among patients with cancer who were intermediate-to-high risk for VTE (Khorana score ≥2; the Khorana score is ranged from 0 to 6 with higher scores reflecting an increased risk of VTE) and were initiating chemotherapy. It was a randomized, placebo-controlled, double-blind clinical trial. The primary efficacy outcome was VTE and the main safety outcomes were major bleeding episodes. Secondary outcome measures included clinically relevant non-major bleeding (CRNMB). The severity of major bleeding was stratified from category 1 to 4, with category 4 being the most severe type. We performed time-to-event analysis on the primary efficacy and main safety end-points in patients with recurrent and new diagnosed cancers. The hazard ratio (HR) for the outcomes were estimated using a Cox regression model controlling for age, gender, and center. Results: A total of 574 patients were randomized in the AVERT trial. 563 were included in the modified intention-to-treat analysis. 237 and 232 patients with newly diagnosed cancer were allocated to the apixaban and placebo groups, respectively. Similarly, 51 and 43 patients with recurrent cancer were allocated to the apixaban and placebo groups, respectively. Baseline demographics and clinical characteristics are depicted in Table 1A and Table 1B. In patients with newly diagnosed cancers, the use of apixaban was associated with a significantly lower risk of VTE (HR: 0.45; 95% CI: 0.27-0.76; p = 0.002) and a higher rate of major bleeding complications (HR: 2.10; 95% CI: 1.09-4.08; p = 0.028) but not of CRNMB (HR: 1.06; 95% CI: 0.61-1.82) (Table 2A). A majority of the major bleeding complications were of category 2. In patients with recurrent cancer, apixaban was associated with a significant lower rate of VTE (HR: 0.26; 95% CI: 0.13-0.53; p &lt; 0.001) without an associated significant increased risk of major bleeding complication (HR: 1.82; 95% CI: 0.36-9.15; p = 0.466) but with a significant increase rate of CRNMB (HR: 2.78; 95% CI: 0.58-1.34; p = 0.006) (Table 2B). Major bleeding episodes were split evenly between severity category 1 and 2. Conclusion: The risk-benefit ratio of primary thromboprophylaxis with apixaban might differ between patients with recurrent or newly diagnosed cancers. Apixaban was associated with a lower rate of VTE compared to placebo in both groups. Patients with recurrent cancer initiating chemotherapy may potentially have a more favorable risk benefit profile, as shown through the HR and the prevalence of major bleeding episodes. However, more trials are required to confirm these findings to help tailor thromboprophylaxis in this patient population. (AVERT ClinicalTrials.gov number, NCT02048865.) Disclosures Wells: BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Honoraria. Carrier:Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Servier: Honoraria; Bayer: Honoraria; Pfizer: Honoraria, Research Funding. OffLabel Disclosure: Apixaban can be used as postoperative prophylaxis of DVT/PE and for treatment of DVT/PE. This study will show whether the prophylactic effects of apixaban will be more effective when used with patients with recurrent cancer or patients with newly diagnosed cancer.

scholarly journals Peak Thrombin and D-Dimer Levels in Subjects with Severe Hemophilia Receiving Acute Treatment for Bleeding Episodes Experienced during Prophylactic Marstacimab Treatment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Satyaprakash Nayak ◽  
Sangeeta Raje ◽  
John Teeter ◽  
Lutz Harnisch ◽  
Steven Arkin
Keyword(s):  
Bleeding Episode ◽  
Phase 2 ◽  
Bleeding Events ◽  
Post Hoc Analysis ◽  
On Demand ◽  
Increased Risk ◽  
Phase 2 Study ◽  
Bleeding Episodes ◽  
Post Hoc ◽  
D Dimer

Introduction: Marstacimab is a fully humanized monoclonal immunoglobulin G1 that targets the shared K2 domains of tissue factor pathway inhibitor (TFPI)α and (TFPI)β and is currently in phase 3 development. The intended indication is routine prophylaxis treatment to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B (with or without inhibitors). Factor replacement or bypass treatment for bleeding events may lead to increased levels of peak thrombin and D-dimer associated with an increased risk of thrombosis . In this post hoc analysis of data from a phase 2 study in patients with hemophilia with and without bleeding episodes, receiving prophylactic marstacimab treatment, peak thrombin and D-dimer levels were investigated to assess the changes in these biomarker levels observed after bleeding episodes. Methods: Individual subject data from the phase 2 study (clinicaltrials.gov identifier: NCT02974855)were used for this analysis. Biomarker data for healthy volunteers who received single doses of marstacimab in a phase 1 dose escalation study (clinicaltrials.gov identifier: NCT02531815) were used as control data, as these subjects represent an intact and uncompromised coagulation system. Study subjects in the phase 2 study received subcutaneous (SC) marstacimab at doses of (1) 150 mg once weekly (QW), with a loading dose of 300 mg, (2) 300 mg QW, and (3) 450 mg QW. All subjects with bleeding episodes were identified, along with on-demand treatment administered for each bleeding episode. Treatments permitted for bleeding episodes included activated coagulation factor VIIa, factor VIII, or factor IX; use of activated prothrombin complex concentrate was prohibited. D-dimer and peak thrombin data collected within 3 days after each bleeding episode were used for this analysis. Time profiles of peak thrombin and D-dimer levels were analyzed to assess the effect of bleed treatment. Biomarker profiles were compared between subjects with and without bleeding episodes, as well as with the data from healthy volunteers (n=41). Results: A total of 15 bleeding episodes were reported in 8 of 26 subjects during the study (excluding screening and follow-up). No subject participating in the study showed any relevant increases in D-dimer levels after receiving on-demand treatment for a bleeding episode while receiving regular prophylaxis with marstacimab, compared with levels seen in subjects who did not experience a bleeding episode. Based on the peak thrombin data (see Figure), 150 nM was observed as the upper limit for 18 of 26 subjects who did not experience any bleeding episodes, which was approximately 50% of the 300 nM observed in healthy volunteer controls treated with 450 mg intravenous marstacimab. Transient increases in peak thrombin of &gt;150 nM were observed at several time points in 3 of 8 subjects who experienced bleeding episodes. The highest peak thrombin level reported was approximately 211 nM in one subject receiving marstacimab 300 mg SC QW and factor VIII concentrate on demand during the study. Conclusions: No transient increases in D-dimer could be attributed to the administration of bleeding episode treatment. The transient increases in peak thrombin levels following on-demand treatment for bleeding episodes did not exceed peak thrombin levels seen in subjects without bleeding events or the levels seen in healthy volunteer controls receiving single doses of marstacimab. Based on peak thrombin and D-dimer levels observed in this post hoc analysis, there does not appear to be any indication of an increased risk of thrombosis post administration of acute on-demand bleeding episode treatment while on prophylactic marstacimab therapy at the doses studied. Disclosures Nayak: Pfizer Inc.: Current Employment, Other. Raje:Pfizer Inc.: Current Employment, Other. Teeter:Pfizer Inc.: Current Employment. Harnisch:Pfizer Inc.: Current Employment, Other. Arkin:Pfizer: Current Employment, Current equity holder in publicly-traded company, Other: own stock/options in the company.

scholarly journals Hematologic Responses in Patients with Aplastic Anemia Treated with Deferasirox: A Post-Hoc Analysis From the EPIC Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1344-1344
Author(s):  
Jong Wook Lee ◽  
Sung-Soo Yoon ◽  
Zhi Xiang Shen ◽  
Arnold Ganser ◽  
Hui-Chi Hsu ◽  
...  
Keyword(s):  
Partial Response ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Research Funding ◽  
Severe Disease ◽  
Complete Response ◽  
Post Hoc Analysis ◽  
Hematologic Response ◽  
Transfusion Independence ◽  
Post Hoc

Abstract Abstract 1344 Background: Although reports are emerging of hematologic responses associated with iron chelation therapy in patients with myelodysplastic syndromes (MDS, eg, Gattermann et al. Blood 2010;116(21):abst 2912), there are limited studies in aplastic anemia (AA) patients. The EPIC study enrolled 116 transfusion-dependent AA patients with iron overload (Cappellini et al. Haematologica 2010; Lee et al. Blood 2010); deferasirox treatment resulted in a decrease in iron overload assessed by serum ferritin. As iron overload has a suppressive effect on erythroid progenitors (Hartmann et al. Blood 2008;112(11):abst 2694), it is of interest to evaluate hematologic responses with the iron chelator deferasirox in AA patients from the EPIC trial. Methods: Full study design and inclusion/exclusion criteria for EPIC have been described (Cappellini et al. Haematologica 2010). Deferasirox dose was initiated at 20 mg/kg/day with adjustments of 5–10 mg/kg/day up to 40 mg/kg/day based on serum ferritin trends and safety assessments. For this post-hoc analysis of hematologic response and the classification of patients, UK treatment guideline criteria for AA diagnosis (2 or 3 of the following: hemoglobin [Hb] <100 g/L, platelets <50 ×109/L, neutrophils <1.5 × 109/L) and hematologic response were used (Marsh et al. Br J Haematol 2009). Bone marrow data and reticulocyte counts were not recorded in EPIC, hence patients were classified as “severe” AA based on fulfillment of platelet and neutrophil criteria. For patients with severe AA, hematologic response was defined as: no response=still severe; partial response=transfusion independent, no longer meeting criteria for severe disease; complete response=normal Hb for age and neutrophil count >1.5 × 109/L and platelet count >150 × 109/L. For patients with “non-severe” AA, hematologic response was defined as: no response=worse or not meeting criteria for partial or complete response; partial response=transfusion independence (if previously dependent), or doubling or normalization of at least one cell line, or increased Hb >3 g/dL if initially <6 g/dL, or increased neutrophils >0.5 × 109/L if initially <0.5 × 109/L, or increased platelets >20 × 109/L if initially <20 × 109/L; complete response=same criteria as severe disease. All responses were confirmed with a second measure 28 days after the first assessment. Transfusion independence was defined as at least 1 8-week period without transfusion. Serum ferritin changes from baseline to end of study (EOS) were assessed for hematologic responders and non-responders. Results: Of 116 iron-overloaded AA patients, 72 (62%) had evaluable hematologic parameters (according to UK criteria) at baseline and EOS; 9 (12.5%) and 63 (87.5%) were considered severe AA and non-severe AA, respectively. Thirty-five (48.6%) patients had a partial hematologic response; 33/63 [52.4%] with non-severe AA and 2/9 [22.2%] with severe AA. Forty-eight (67%) patients received at least one concomitant immunosuppressive treatment (IST); partial hematologic response was observed in 19/48 (39.6%) of these patients. As IST can influence hematologic response, analyses were focused on patients receiving deferasirox without IST. Twenty-four patients received deferasirox without concomitant IST; partial hematologic response was observed in 16/24 [66.7%] patients, all of whom became transfusion-independent, with 2 patients having an additional platelet response and 1 patient having an additional platelet and Hb response (Table). Median time to response was 42 days. For patients without concomitant IST, overall median change in serum ferritin from baseline to EOS was greater in partial hematologic responders (–2295 ng/mL, range –15,704 to 489 [n=16]) compared with non-responders (–815 ng/mL, range –8506 to 3671 [n=8]; P=0.22). Conclusions: Similar to MDS patients, alongside a reduction in iron overload, deferasirox may improve hematologic parameters in AA patients. Sixty-seven percent (16/24) of patients receiving deferasirox without concomitant IST had a partial hematologic response and became transfusion-independent. Changes in serum ferritin were more pronounced in partial hematologic responders compared with non-responders, suggesting that decrease in iron load could play a role in inducing a hematologic response. Further analyses are required to elucidate mechanisms of hematologic improvement with deferasirox. Disclosures: Lee: Novartis: Honoraria; Alexion: Honoraria. Yoon:NK Bio: Consultancy; Celgene: Consultancy. Ganser:Novartis: Honoraria, Research Funding. El-Ali:Novartis: Employment. Habr:Novartis: Employment. Roubert:Novartis: Employment. Porter, MD on behalf of the EPIC study investigators:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Categorized Hematologic Response to Pegcetacoplan Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from a Phase 3 Randomized Trial (PEGASUS)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Antonio Risitano ◽  
Ilene C. Weitz ◽  
Carlos M. de Castro ◽  
Jean-Jacques Kiladjian ◽  
Morag Griffin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Response To Treatment ◽  
Publicly Traded ◽  
Phase 3 ◽  
Advisory Committees ◽  
Post Hoc Analysis ◽  
Hematologic Response ◽  
Post Hoc

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal, nonmalignant hematologic disease characterized by complement-mediated red blood cell hemolysis. The current standard of care for patients with PNH is C5 inhibition. Anemia persists in up to ~70% of patients receiving eculizumab and is attributed to persistent intravascular hemolysis (IVH) and mostly to C3-mediated extravascular hemolysis (EVH). Pegcetacoplan is a pegylated pentadecapeptide C3 inhibitor targeting proximal complement to control both IVH and EVH. PEGASUS is a phase 3, open-label, active-comparator controlled study of efficacy and safety of pegcetacoplan versus eculizumab. This post hoc analysis of data from PEGASUS categorized the clinical response to pegcetacoplan or ECU in patients with PNH and hemoglobin &lt;10.5 g/dL (despite stable ECU for ≥3 months). METHODS Hematologic response to treatment was categorized (per Risitano AM, et al. Front Immunol. 2019;10:1157) as complete, major, good, partial, minor, or no response, using number of packed red blood cell transfusions required, hemoglobin level, lactate dehydrogenase (LDH) level, and absolute reticulocyte count (ARC). Complete response: no transfusions required, stable hemoglobin in the normal range, and no evidence of hemolysis (ie, LDH ≤1.5× upper limit of normal, ARC ≤150,000/µL). Major response: no transfusion, normal hemoglobin, but with evidence of hemolysis (LDH &gt;1.5× upper limit of normal and/or ARC &gt;150,000/µL). Good response: no transfusion, but with chronic mild anemia or evidence of hemolysis. Partial response: chronic moderate anemia and/or occasional transfusions (&lt;3 units/6 months). Minor response: regular transfusions required (3-6 units/6 months). No response: regular and frequent transfusions required (&gt;6 units/6 months). Nine patients (6 from the pegcetacoplan arm and 3 from the eculizumab arm) did not readily fit within the existing criteria due to the availability of data at week 16. Although these 9 patients were manually categorized identically by the lead and senior author in a blinded, independent manner, they were not included among these data. RESULTS The intention-to-treat population was comprised of 41 patients randomized to pegcetacoplan and 39 patients randomized to eculizumab. Four patients in the pegcetacoplan arm and 1 patient in the eculizumab arm were not evaluable for analysis due to incomplete data at week 16. Altogether, 61.0% of patients (25/41) in the pegcetacoplan arm have achieved at least a good hematological response, in contrast to 5.1% (2/39) of the eculizumab arm. At week 16, the distribution of response categories was as follows (Figure): in the pegcetacoplan arm and eculizumab arm, respectively, complete responses were 36.6% and 0%, good responses were 24.4% and 5.1%, partial responses were 12.2% and 33.3%, minor responses were 2.4% and 23.1%, and no responses were 0% and 28.2%. The addition of the 9 manually categorized patients did not significantly alter the proportions reported here. Among the factors that may contribute to heterogeneity of hematologic response to treatment are impaired bone marrow function, residual IVH, and residual C3-mediated EVH. Bone marrow failure was ruled out, and no difference in LDH was observed, suggesting that the major factor accounting for the difference between the 2 arms was the prevention of C3-mediated EVH (as confirmed by reduction of C3-opsonization of PNH red blood cells). CONCLUSION In PEGASUS, treatment with pegcetacoplan resulted in a greater proportion of patients with better hematological responses compared to eculizumab. These results further support the concept that proximal complement inhibition, by preventing EVH in addition to controlling IVH, leads to clinical and hematological improvement in the treatment of PNH. Disclosures Risitano: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weitz:Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria. de Castro:Novartis: Honoraria, Other: Steering committee; Alexion: Honoraria, Research Funding; Biocryst: Honoraria, Other: Data monitoring committee; Apellis: Consultancy, Honoraria, Research Funding. Kiladjian:AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Griffin:Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Other: Conference Support. Hamdani:Apellis: Current Employment, Current equity holder in publicly-traded company. Ajayi:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.

scholarly journals Onset of efficacy and duration of response of galcanezumab for the prevention of episodic migraine: a post-hoc analysis

2019 ◽  
Vol 90 (8) ◽  
pp. 939-944 ◽  
Author(s):  
Peter J Goadsby ◽  
David W Dodick ◽  
James M Martinez ◽  
Margaret B Ferguson ◽  
Tina M Oakes ◽  
...  
Keyword(s):  
Migraine Headache ◽  
Episodic Migraine ◽  
Preventive Effect ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Post Hoc Analysis ◽  
Duration Of Response ◽  
Registration Number ◽  
Post Hoc ◽  
Sustained Responses

Background and objectiveAs new migraine prevention treatments are developed, the onset of a preventive effect, how long it is maintained and whether patients initially non-responsive develop clinically meaningful responses with continued treatment can be assessed.MethodsAnalyses were conducted post-hoc of a double-blind, placebo-controlled, phase II-a study in patients with episodic migraine receiving galcanezumab 150 mg or placebo biweekly for 12 weeks (Lancet Neurol 13:885, 2014). The number of migraine headache days per week, and onset of efficacy measured as the first week galacanezumab separated from placebo were determined. Patients with ≥50%, ≥75% and 100% reduction in migraine headache days from baseline at months 1, 2 and 3 were calculated and defined as sustained responses. Non-responders (<50% response) at month 1 or 2 who then showed ≥50%, ≥75% and 100% response at later time-points were calculated.ResultsPatients were randomised to galcanezumab (n=107) or placebo (n=110). A significant (p=0.018) change of −0.89±0.11 (galcanezumab) vs −0.53±0.11 (placebo) migraine headache days indicated onset at week 1. Forty-seven per cent of galcanezumab and 25% of placebo patients responding at month 1 maintained response through months 2 and 3. Of non-responders at month 1, 27% on galcanezumab and 20% on placebo responded on months 2 and 3, and 50% of galcanezumab non-responders in months 1 and 2 responded on month 3, vs 24% on placebo.ConclusionsThe onset of efficacy of galcanezumab is within 1 week in a majority of patients, and patients receiving galcanezumab are twice more likely to maintain responses than placebo patients. Early non-responders may respond by month 2 or month 3.Trial registration numberNCT01625988.

scholarly journals Association of High Body Mass Index with Response Outcomes in Patients with CML-CP Treated with Dasatinib Versus Imatinib in the First Line: Exploratory Post Hoc Analysis of the Phase 3 DASISION Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4155-4155
Author(s):  
Massimo Breccia ◽  
Jorge E. Cortes ◽  
Neil P Shah ◽  
Giuseppe Saglio ◽  
Antonio Jiménez-Velasco ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
High Body Mass Index ◽  
Molecular Response ◽  
Phase 3 ◽  
Post Hoc Analysis ◽  
Post Hoc ◽  
High Bmi

Introduction: Early responses to tyrosine kinase inhibitors (TKIs) are associated with improved long-term outcomes in patients with chronic myeloid leukemia in chronic phase (CML-CP), and guideline recommendations support the achievement of major molecular response (MMR) at 18 months as a therapeutic goal in CML treatment. Dasatinib is a first-line (1L) treatment option for patients with CML-CP, and long-term results from the DASISION study have demonstrated that patients on dasatinib achieved faster, deeper, and more durable molecular responses than patients on imatinib (Cortes J et al. J Clin Oncol 2016). Earlier reports have shown that obesity may increase the risk of developing CML (Strom SS et al. Cancer Epidemiol Biomarkers Prev 2009) and that patients with a high body mass index (BMI; > 25 kg/m2) at diagnosis who receive 1L imatinib have a significantly longer median time to response and a reduced rate of MMR compared with patients with a normal BMI (< 18.5-25 kg/m2; Breccia M et al. Cancer Lett 2013). In this exploratory post hoc analysis of the phase 3 DASISION trial (NCT00481247), we further investigated the association of high BMI with treatment responses with 1L TKIs. Methods: DASISION was a multinational, open-label, phase 3 trial of dasatinib versus imatinib for newly diagnosed CML-CP. Patients were randomized to receive 100 mg dasatinib (n = 259) or 400 mg imatinib (n = 260) once daily. Response outcomes were retrospectively stratified on the basis of two BMI categories: high (≥ 25 kg/m2) and normal (< 25 kg/m2). Median time to response was estimated using Kaplan-Meier analysis; Cox proportional hazard models and log-rank tests were stratified by Hasford scores. Molecular response rates were compared using Cochran-Mantel-Haenszel tests (stratified by Hasford scores). P values are descriptive and unadjusted for multiple comparisons. Results: In total, 109 patients with a high BMI and 147 patients with a normal BMI were treated with dasatinib, and 107 patients with a high BMI and 147 patients with a normal BMI were treated with imatinib. Baseline characteristics were balanced within BMI subgroups and are listed in the table below (Table). Median time to complete cytogenetic response (CCyR) was significantly shorter with dasatinib versus imatinib in patients with a high BMI (3.1 vs 6.1 months; P < 0.0001). MMR was also achieved faster in patients with a high BMI who were treated with dasatinib versus imatinib (median time 9.2 vs 27.6 months; P < 0.0001; Figure). More patients with a high BMI treated with dasatinib achieved MMR compared with those treated with imatinib (79.8% vs 59.8%; P = 0.0004). Likewise, 54.1% of patients with a high BMI achieved MR4.5 with dasatinib, compared with 34.6% with imatinib (P = 0.0013). In the normal BMI group, median time to CCyR (5.6 vs 6.0 months; P = 0.1055) and MMR (18.0 vs 21.5 months; P = 0.4095) was faster for dasatinib versus imatinib, and more patients on dasatinib versus imatinib achieved MMR (73.5% vs 67.3%; P = 0.3335) and MR4.5 (36.7% vs 33.3%; P = 0.6344). Although these results were numerically better with dasatinib, the differences were not statistically different. A graphical exploratory analysis suggested that there was no difference in exposures across BMI subgroups with respect to dasatinib. However, imatinib exposure data were not available to make comparisons across the BMI subgroups. There was no major difference in the previously reported adverse event profiles between treatment groups when assessed based on BMI. Any-cause pleural effusion occurred more frequently with dasatinib (34.3% [high BMI] and 24.5% [normal BMI]) compared with imatinib (0% [high BMI] and 2.0% [normal BMI]). Additional analyses are being planned to address the role of any potential confounders (eg, Hasford risk scores). Conclusions: In this exploratory post hoc analysis, patients with a high BMI treated with dasatinib demonstrated a significantly faster time to response compared with imatinib, with an increased percentage of patients also achieving MMR and MR4.5 at 5 years. However, these differences were not apparent in patients with a normal BMI. Although these findings highlight the potential role of BMI in affecting treatment responses to TKIs, additional validation of these findings is necessary to define the overall impact of BMI as a prognostic factor for patients with CML-CP. Study support: BMS. Writing support: Jane Cheung, Caudex, funded by BMS. Disclosures Breccia: Bristol-Myers Squibb, Celgene, Incyte, Novartis, Pfizer: Honoraria. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy. Shah:Bristol-Myers Squibb: Research Funding. Saglio:Celgene: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy. Le Coutre:Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Brun:Bristol-Myers Squibb: Employment. DeGutis:Bristol-Myers Squibb: Employment, Other: Stock options. Sy:Bristol-Myers Squibb: Employment, Equity Ownership. Jabbour:AbbVie: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding.

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