scholarly journals Narratives of Patients with Fatal Outcomes During the Phase 2 TITAN and Phase 3 HERCULES Studies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4908-4908 ◽  
Author(s):  
Spero Cataland ◽  
Marie Scully ◽  
Flora Peyvandi ◽  
Paul Knoebl ◽  
Johanna A. Kremer Hovinga ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Fatal Outcome ◽  
Study Drug ◽  
Adamts13 Activity ◽  
Advisory Committees ◽  
Baseline Platelet Count ◽  
Disease Characteristics ◽  
Patient Narratives

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening thrombotic microangiopathy, with an untreated mortality rate of >90%. Prompt treatment with therapeutic plasma exchange (TPE) and immunosuppression improves outcomes in patients with aTTP, but 10-20% of patients still die acutely from this disease. The aim of this analysis was to describe in more detail the characteristics and disease courses of the patients who died during the caplacizumab clinical development program. Methods: Patient narratives on all deaths occurring during the phase 2 TITAN and phase 3 HERCULES studies were extracted. Results: In the overall study periods, a total of 6 patients died, 2 patients enrolled in TITAN (Patients 1 and 2) and 4 patients enrolled in HERCULES (Patients 3-6). Five patients received placebo, while 1 (Patient 6) received caplacizumab. Demographics and baseline disease characteristics are summarized in Table 1. The patient narratives are provided below. Patient 1 (placebo) was a 57-year-old male, with a recurrent episode of aTTP. Baseline platelet count was 25 x109/L and ADAMTS13 activity <10%. The patient was treated with daily TPE and cyclosporine. Because of lack of response to TPE, treatment was intensified (increased plasma volume exchanged, and rituximab and cyclophosphamide initiated). Still, the patient's clinical condition declined with rising lactate dehydrogenase (LDH) values and persistent thrombocytopenia, with a fatal outcome on Day 23. Patient 2 (placebo) was a 49-year-old female, with an initial presumed aTTP episode. Baseline platelet count was 7 x109/L and baseline ADAMTS13 activity was 75%. The patient did not respond to therapy (TPE and corticosteroids), with platelet counts remaining below 35 x109/L over the whole period. On Day 10 of the study, the patient experienced a cerebral hemorrhage, for which study drug treatment was permanently discontinued. The patient was intubated and died the next day of cerebral hemorrhage. Patient 3 (placebo) was a 62-year-old female with an initial aTTP episode. Baseline platelet count was 18 x109/L and ADAMTS13 activity <10%. The patient was treated initially with daily TPE and corticosteroids. On Day 2 the patient suffered from a massive ischemic stroke with hemorrhagic transformation; TPE was interrupted for 2 days and restarted thereafter. The platelet count improved to 104 x109/L, but fell to 44 x109/L on Day 6. Rituximab was added on Day 8, however, the patient died on Day 14 from the consequences of the stroke. Patient 4 (placebo) was a 72-year-old female with an initial aTTP episode. Baseline platelet count was 21 x109/L and baseline ADAMTS13 activity was <10%. Despite an initial (partial) platelet count response, the disease worsened with coma starting on study Day 6 and severe septic shock 2 days later. The patient died on Day 8 due to these events. Patient 5 (placebo) was a 30-year-old female enrolled with her third aTTP episode. Baseline platelet count was 21 x109/L and ADAMTS13 activity <10%. The patient did not respond to therapy (TPE, corticosteroids, rituximab), with platelet count remaining below 30 x109/L over the whole period. Respiratory failure was reported on study Day 8, likely due to alveolar hemorrhage, with fatal outcome the same day; an autopsy was not performed. Patient 6 (caplacizumab) was a 77-year-old female with her initial aTTP episode. Baseline platelet count was 38 x109/L and ADAMTS13 activity <10%, and was treated with TPE, corticosteroids and caplacizumab. Following daily TPE (for 36 days without tapering), the patient completed 30 days' treatment with caplacizumab, maintaining normal platelet counts during that period. ADAMTS13 activity at the end of study drug treatment was 62%. On follow-up Day 5, the patient was hospitalized with severe cerebral ischemia leading to death 3 days later; the event was considered not related to the study drug. Conclusion: Although the use of TPE and immunosuppression reduces mortality in patients with aTTP, the disease is still associated with a substantial risk of mortality. The fact that all 5 immediate deaths occurred in the placebo arm suggests that the use of caplacizumab has the potential to reduce acute mortality in patients with aTTP. Table 1. Baseline demographics and disease characteristics. Table 1 Disclosures Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Scully:Alexion: Consultancy; Ablynx/Sanofi: Consultancy; Novartis: Consultancy; Shire/Takeda: Consultancy; Shire: Research Funding. Peyvandi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria; Kedrion: Honoraria; Alnylam: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding. Knoebl:Roche: Consultancy; Shire/Takeda: Consultancy; Novo-Nordisk: Consultancy, Research Funding; CSL-Behring: Consultancy; Ablynx/Sanofi: Consultancy. Kremer Hovinga:Ablynx/Sanofi: Consultancy, Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Shire: Consultancy, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology), Research Funding; CSL-Behring: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Roche: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Siemens: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology). Coppo:Ablynx/Sanofi: Consultancy; Alexion: Consultancy; Shire: Consultancy. Metjian:Genentech: Consultancy, Research Funding; AblynxNV/Sanofi: Consultancy, Research Funding. De La Rubia:Takeda: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy. Pavenski:Ablynx: Honoraria, Research Funding; Bioverativ: Research Funding; Shire: Honoraria; Octapharma: Research Funding; Alexion: Honoraria, Research Funding. De Winter:Ablynx, a Sanofi company: Employment. Callewaert:Sanofi (formerly employed by Ablynx, a Sanofi company): Employment.

scholarly journals Results of the Randomized, Double-Blind, Placebo-Controlled, Phase 3 Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. LBA-1-LBA-1 ◽  
Author(s):  
Marie Scully ◽  
Spero R Cataland ◽  
Flora Peyvandi ◽  
Paul Coppo ◽  
Paul Knöbl ◽  
...  
Keyword(s):  
Platelet Count ◽  
Drug Treatment ◽  
Board Of Directors ◽  
Treatment Period ◽  
Research Funding ◽  
Thromboembolic Event ◽  
Study Drug ◽  
Adamts13 Activity ◽  
Advisory Committees

Abstract Introduction: Acquired or immune-mediated thrombotic thrombocytopenic purpura (aTTP) is a life-threatening thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia. Inhibitory autoantibodies cause a severe deficiency of the von Willebrand factor (vWF) cleaving enzyme ADAMTS13, leading to intravascular vWF-platelet aggregation and microvascular thrombosis. The mainstays of treatment are plasma exchange (PE) and immunosuppression. Caplacizumab, a bivalent Nanobody, targets the A1 domain of vWF, inhibiting the interaction between ultra-large vWF and platelets. Methods: Patients with an acute episode of aTTP who had received one PE treatment were randomized 1:1 to placebo or 10 mg caplacizumab, in addition to daily PE and corticosteroids. A single IV dose of study drug was given before the first on-study PE and a SC dose was given daily during the PE period and 30 days thereafter. If at the end of this period there was evidence of ongoing disease, such as suppressed ADAMTS13 activity, investigators were encouraged to extend the blinded treatment for a maximum of 4 weeks together with optimization of immunosuppression. All patients entered a 28-day treatment-free follow up period after the last dose of study drug (Figure 1). Primary endpoint was time to platelet count response, defined as platelet count ≥ 150×109/L with stop of daily PE within 5 days. There were 4 key secondary endpoints, hierarchically ranked. The 1st was a composite of aTTP-related death, aTTP recurrence, or major thromboembolic event during the study drug treatment period. A blinded, independent committee adjudicated aTTP-related deaths and major thromboembolic events. The 2nd looked at recurrences during the entire study period, including the follow up period. The 3d evaluated refractoriness to therapy, defined as absence of platelet count doubling after 4 days of treatment and LDH still above normal. The 4th was the time to normalization of 3 organ damage markers: LDH, cardiac troponin I and serum creatinine. Results: 145 patients were randomized, 73 to placebo and 72 to caplacizumab. Demographics and baseline disease characteristics were balanced between groups, except for a higher proportion of initial episodes in the caplacizumab arm. Compared to patients treated with placebo, those on caplacizumab were &gt;50% more likely to achieve a platelet response at any given time point (platelet count normalization rate 1.55, 95% CI 1.10 - 2.20, p &lt;0.01). During the study drug treatment period, treatment with caplacizumab resulted in a 74% reduction in TTP-related death, recurrence of TTP, or a major thromboembolic event (p &lt;0.0001, Table 1). During the overall study period, 28 patients in the placebo group experienced a recurrence versus 9 patients in the caplacizumab group, a 67% reduction (p &lt;0.001, Table 2). In all 6 caplacizumab-treated patients with a relapse during the follow up period, ADAMTS13 activity was still &lt;10% at stop of study drug, reflecting ongoing disease. No caplacizumab-treated patients were refractory to therapy, while 3 patients on placebo were (p =0.057). Treatment with caplacizumab was associated with a trend toward faster normalization of the 3 organ damage markers. Safety is summarized in Table 3. In the caplacizumab group, the most common study drug-related TEAEs were epistaxis, gingival bleeding, and bruising. During the study drug treatment period, 3 patients on placebo died. One death occurred during the follow up period in a caplacizumab-treated patient and was assessed by the investigator as not related to study drug. Conclusions: Results of the Phase 3 HERCULES study confirm that treatment with caplacizumab reduces the time to platelet count response, resulting in faster resolution of aTTP. Treatment with caplacizumab also resulted in a highly clinically meaningful reduction in aTTP-related death, recurrence of aTTP, or a major thromboembolic event during study drug treatment. The relapses after stop of study drug in patients with ADAMTS13 activity &lt;10% suggest that treatment should be continued until complete resolution of the underlying disease. Caplacizumab has a favorable safety profile, with mucocutaneous bleeding the most frequently reported AE. Caplacizumab, through rapid blocking of vWF-mediated platelet aggregation, represents a novel treatment option for patients with aTTP. (clinicaltrials.gov: NCT02553317) Disclosures Scully: Ablynx: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Novartis: Honoraria; Alexion: Honoraria. Cataland:Ablynx NV: Membership on an entity's Board of Directors or advisory committees. Peyvandi:Ablynx, Roche: Membership on an entity's Board of Directors or advisory committees; Ablynx, Bayer, Grifols, Novo Nordisk, Sobi: Speakers Bureau;Freeline, Kedrion, LFB, Octapharma: Consultancy. Coppo:Ablynx: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Knöbl:Novo Nordisk: Consultancy, Research Funding; Shire: Consultancy, Research Funding. Kremer Hovinga:Baxalta/Shire: Other: unrestricted grant hereditary TTP registry; Ablynx NV: Membership on an entity's Board of Directors or advisory committees. Metjian:Ablynx NV, Shire, Omeros: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Other: Honoraria; Celgene: Other: Honoraria; Janssen: Other: Honoraria. Pavenski:Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria; Ablynx: Other: participation in industry sponsored RCT; CSL Behring: Research Funding. Callewaert:Ablynx NV: Employment. Biswas:Ablynx NV: Employment. De Winter:Ablynx NV: Employment. Zeldin:Ablynx NV: Employment.

scholarly journals Safety and Efficacy of Romiplostim in over 200 Children with Immune Thrombocytopenia (ITP): Results of an Integrated Database of 5 Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2428-2428 ◽  
Author(s):  
Michael D. Tarantino ◽  
Jenny M. Despotovic ◽  
John Roy ◽  
John Grainger ◽  
Nichola Cooper ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Platelet Response ◽  
Open Label ◽  
Advisory Committees ◽  
Baseline Platelet Count ◽  
Platelet Counts

Abstract Background: Romiplostim is approved globally for use in adults with ITP and in the EU for children with ITP. More comprehensive data are needed on the use of romiplostim in children with ITP. Objective: To examine the safety and efficacy of romiplostim in trials in children with ITP. Methods: Data were combined from 5 romiplostim trials in children with ITP, both placebo-controlled (a phase 1/2 and a phase 3 trial) and open-label (a 3-year trial and 2 extension trials); trial data have been reported previously (Bussel Blood 2011, Bussel PBC 2014, Tarantino Lancet 2016, Tarantino ASH 2017, Grainger ASH 2017). Platelet counts in the 4 weeks after use of rescue medication were excluded from analyses. Descriptive statistics were used. Number (n), mean, standard deviation (SD), median, quartile range (Q1, Q3), minimum (min), and maximum (max) for continuous variables, and number and percentage for categorical variables were provided. Results: Patients (N=286, 24 initially placebo and 262 initially romiplostim) had median (Q1, Q3) age of 10 (6, 13) years, ITP duration of 1.9 (1, 4) years, and baseline platelet count of 14 (8, 23)×109/L. Previously, 88% had received corticosteroids, 87% IVIg, and 21% rituximab; 23% had received >3 prior treatments and 7% had prior splenectomy. Of the 282 patients exposed to romiplostim (20 initially received placebo), the median (min, max) duration of treatment was 65 (8, 471) weeks, with a median (min, max) average weekly dose of 6.6 (0.1, 9.7) μg/kg; total exposure was 468 patient-years. The most common reasons for discontinuing the parent study for romiplostim-treated patients were per protocol (19%; eg, sponsor decision, death, lost to follow-up), consent withdrawn (3%), noncompliance (1%), and administrative decision (1%). Of romiplostim-treated patients, 24% had serious adverse events (SAEs), most commonly epistaxis, low platelet counts, and headache (Table). There were 7 cases of postbaseline neutralizing antibody against romiplostim: 2 transient and 5 persistent. There were no neutralizing antibodies against endogenous TPO. For patients undergoing bone marrow biopsies in the 3-year open-label trial, there were no findings of collagen or bone marrow abnormalities (Year 1 n=27, Year 2 n=5, vs. baseline) (Grainger et al, ASH 2017). One patient had an increase in modified Bauermeister bone marrow grade from 0 to 2 (fine reticulin fiber network) with no associated AEs (the only AEs were a cold and injection site pain); per protocol, there was no follow-up biopsy. Once at a steady dose of 10 μg/kg, most (11/16) of this patient's platelet counts were ≥30×109/L. Investigators reported thrombocytosis AEs; 1 patient had a platelet count of 1462×109/L at Week 14 for 1 week and another had elevated platelet counts 10 times between Weeks 20-172 (max of 872×109/L); there were no associated thrombotic events. Median platelet counts rose quickly and were over 50×109/L from Week 12 on (Figure). Platelet response rates also rose quickly. Overall, 89% of romiplostim-treated patients (vs 8% of placebo) had a platelet response (platelet counts ≥50×109/L; Figure). For romiplostim-treated patients, the first platelet responses occurred after a median of 6 weeks. The median % (Q1, Q3) of months responding was 76% (25%, 93%) and # of months responding was 11 (3, 20); from time of first monthly response, the median (Q1, Q3) % of months responding was 92% (75%, 100%) and # of months responding was 14 (7, 23). Nineteen romiplostim-treated patients discontinued all ITP therapies including romiplostim for ≥6 months while maintaining platelet counts ≥50×109/L (here defined as remission). These treatment-free periods lasted a median (Q1, Q3) of 12 (8, 14) months; no placebo patients remained free of treatment. There were no clear differences between those who did and did not enter remission (ie, age, sex, race, past treatment, ITP duration, baseline platelet count). Bleeding was reported for most (68%) patients: mostly grade 1/2, with 10% having grade 3 bleeding (most commonly epistaxis in 13 patients) and 2 patients having grade 4 bleeding (both reported as "ITP"). Conclusions: In this comprehensive database of romiplostim ITP trials in 286 children with 468 patient-years of romiplostim exposure, romiplostim was well tolerated. With romiplostim, the vast majority (89%) of patients had a platelet response, with some children able to discontinue all ITP treatments for ≥6 months. Disclosures Tarantino: Health Resources and Services Administration: Research Funding; Centers for Disease Control and Prevention: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Other: Reviews grants; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Grifols: Research Funding, Speakers Bureau. Despotovic:AmGen: Research Funding; Sanofi: Consultancy; Novartis: Research Funding. Grainger:Biotest: Consultancy; Ono Pharmaceuticals: Consultancy; Amgen: Consultancy, Honoraria, Other: Educational grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cooper:Amgen, Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership.

A Randomized, Double-Blind, Placebo-Controlled Phase II Trial on the Efficacy, Safety and Tolerability of E5501 (AKR501) In Subjects with Chronic Immune Thrombocytopenia (ITP)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 71-71 ◽  
Author(s):  
James B. Bussel ◽  
Jenny Zhang ◽  
Shande Tang ◽  
Joe McIntosh ◽  
David J. Kuter
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Responder Rate ◽  
Dependent Manner ◽  
Advisory Committees ◽  
Double Blind ◽  
Baseline Platelet Count ◽  
Platelet Counts ◽  
Dose Dependent

Abstract Abstract 71 Chronic immune thrombocytopenia (ITP) is a condition of low platelet counts due to increased autoimmune-mediated platelet destruction and suboptimal platelet production. Thrombopoietin (TPO) receptor agonists are a novel class of agents which increase platelet counts by mimicking the principal physiologic regulator of platelet production, TPO. TPO agonists have demonstrated efficacy in randomized controlled trials in patients with ITP who are refractory to 1st and 2nd line agents. E5501 (previously AKR501) is a novel, orally-active, once-a-day TPO agonist which increased platelet counts in healthy volunteers. Here, we report data from a Phase II, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, parallel group 4-week study (501-CL-003) of E5501 in subjects with ITP whose disease was refractory to, or had relapsed after, at least one prior ITP therapy. Subjects were enrolled if they had a baseline platelet count of <30 x109/L, or if they had a baseline platelet count of <50 x109/L and were on stable corticosteroid therapy. Sixty-four subjects were randomized to E5501 (2.5, 5, 10 or 20 mg) or placebo in a 3:3:3:3:1 randomization ratio, respectively. E5501 or placebo was administered orally, once daily for 28 days. Response to E5501 was based on weekly platelet counts. The primary endpoint was responder rate at Day 28. Responders were defined as subjects whose platelet count was ≥50 x109/L and had risen by a minimum of 20 x109/L above baseline. Responder rate increased in subjects receiving E5501 in a dose-dependent manner (Table 1). At Day 28, the responder rate in the E5501 20 mg group was 80% (12 of 15 subjects) vs 0% in the placebo group (p=0.0036). The responder rate was also significantly higher with E5501 20 mg than with E5501 2.5 mg (80% vs 13.3%; p=0.0007). In non-splenectomized subjects, the responder rate at Day 28 was 51.2% in the combined E5501 group and 88.9% in the E5501 20 mg group, compared with 44.4% and 66.7% respectively in splenectomized subjects. Median platelet counts at Day 28, and change in platelet counts above baseline, increased in subjects receiving E5501 in a dose-dependent manner (Table 2). The majority (57.6%) of subjects responded to a dose of ≥5 mg E5501 by Day 7. Subjects treated with E5501 20 mg achieved a 93.3% response rate on Day 7. None of the 5 placebo-treated subjects responded at any time during the study. E5501 was well tolerated, with a similar proportion of subjects showing treatment-emergent adverse events (TEAEs) across all dose groups. Most TEAEs were mild, transient, and resolved completely. TEAEs occurring in ≥10% of E5501-treated subjects were fatigue (20.3%), headache (20.3%) and epistaxis (15.3%). There were no clinically relevant changes in vital signs or physical examination findings. Three subjects (2 in the 2.5 mg and 1 in the 10 mg E5501 group) reported serious TEAEs. Of the two subjects in the 2.5 mg E5501 group, one reported thrombocytopenia and one reported a GI bleed; both had platelet counts <10 x109/L. The one subject in the 10 mg E5501 group, a 72-year-old Hispanic male with a significant history of cardiovascular disease (including myocardial infarction [MI], coronary artery vein bypass graft, 3 prior transient ischemic attacks [TIAs], chronic obstructive pulmonary disease, hypertension, systolic ejection murmur, angioplasty, stent placement, hyperlipidemia, and small vessel disease), had TIA and MI on Day 20 and a retinal artery occlusion 14 days after E5501 was discontinued. At the time of the events his platelet counts were 40–47 x109/L. Three other E5501-treated subjects (6.8% in total) experienced TEAEs leading to study drug withdrawal: 1 receiving 5 mg E5501 had Grade 2 musculoskeletal chest pain; 2 receiving 20 mg E5501 had excessively increased platelet counts with no clinical sequellae. In conclusion, E5501 was effective in increasing platelet counts in subjects with ITP. At 20 mg E5501, 80% of patients had responded at Day 28, with a median platelet count of 95 x109/L, and >90% of patients had responded by Day 7. E5501 was generally well tolerated and had a favorable safety profile. These data support continued development of E5501 as a potentially effective treatment with an acceptable safety profile in non-splenectomized and splenectomized patients with ITP. Disclosures: Bussel: Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy. Zhang:Eisai: Employment. Tang:Eisai: Employment. McIntosh:Eisai: Employment. Kuter:Amgen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; ONO: Consultancy; Shionogi: Consultancy, Research Funding; Pfizer: Consultancy; Protalix: Consultancy, Research Funding; Risk Managment Foundation: Consultancy.

scholarly journals Pooled Analyses of Total Symptom Score (TSS) Responses in Patients with Myelofibrosis (MF) Treated with Pacritinib (PAC) Vs Best Available Therapy (BAT) in Phase 3 Studies (PERSIST-1, PERSIST-2)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4281-4281
Author(s):  
Ruben A. Mesa ◽  
Francisco Cervantes ◽  
Claire N. Harrison ◽  
Adam J. Mead ◽  
Alessandro M. Vannucchi ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Pooled Analysis ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Baseline Platelet Count ◽  
State Response ◽  
Equity Ownership

Abstract Background : MF is a hematologic malignancy characterized by splenomegaly and debilitating systemic symptoms. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) questionnaire was developed for patient self-report of MF symptoms (Emanuel 2012). Although there have been several versions of this questionnaire, they have demonstrated consistent reliability, cross-sectional validity, and high level of comparability for both TSS and individual symptoms (Dueck 2017). The JAK2/FLT3 inhibitor PAC has demonstrated durable spleen volume reduction and symptom control in patients with MF irrespective of baseline platelet count in 2 phase 3 trials vs BAT (Mesa 2017, Mascarenhas 2018). Since changes in study design and external factors limited the ability to assess TSS in PERSIST-1 and PERSIST-2, respectively, a pooled analysis of all available TSS data from both phase 3 trials was undertaken to further evaluate TSS response. Methods : PERSIST-1 was a phase 3 study of PAC 400 mg QD vs BAT (excluding ruxolitinib) in patients with MF (excluding those with prior ruxolitinib treatment); PERSIST-2 was a phase 3 study of PAC 400 mg QD or 200 mg BID vs BAT (including ruxolitinib) in patients with MF and baseline thrombocytopenia (platelet count ≤100x109/L); 48% of patients in PERSIST-2 had prior ruxolitinib and 44% of patients randomized to BAT received ruxolitinib treatment during the study. In PERSIST-1, 2 versions of the questionnaire were administered; MPN-SAF TSS in the first 179 patients and MPN-SAF TSS 2.0 in the subsequent 148 patients. In PERSIST-2, all 311 patients used the MPN-SAF TSS 2.0 questionnaire. In both trials, the efficacy endpoint associated with TSS was defined as the proportion of patients achieving ≥50% reduction in TSS from baseline to Week 24 based on MPN-SAF TSS 2.0. In the post-hoc analyses of PAC vs BAT herein, data were presented based on the pooled MPN-SAF TSS 2.0 responses, as well as the pooled MPN-SAF TSS and MPN-SAF TSS 2.0 (6 symptoms in common) responses from PERSIST-1 and PERSIST-2. A multivariate stepwise analysis was also performed using potential prognostic factors for MF as predictors of TSS response. These analyses were performed in the intent-to-treat efficacy populations in both studies: all patients randomized in PERSIST-1 and all patients with randomization date allowing for Week 24 data in PERSIST-2. Results : Data from 548 patients (n = 369 PAC, n = 179 BAT) were analyzed, with 179 patients administered the MPN-SAF TSS and 369 administered the MPN-SAF TSS 2.0. Baseline patient and disease characteristics were balanced for PAC and BAT groups, with a higher rate of primary MF in the PAC group (66% vs 57%). Median TSS scores at baseline were 19.5 (range, 0.3-57.3) and 19.6 (range, 1.6-55.9) in PAC and BAT groups, respectively. Results of the pooled analysis demonstrate significantly higher rates of ≥50% reduction in TSS from baseline to Week 24 with PAC vs BAT for MPN-SAF TSS 2.0 (P=0.0241) and the pooled versions of the questionnaire (MPN-SAF TSS or TSS 2.0; P<0.0001; Table). In multivariate logistic regression analyses of treatment group and baseline potential prognostic variables, only treatment group (PAC vs BAT) and MF type (secondary vs primary) were significant predictors of TSS response for MPN-SAF TSS 2.0 and for the pooled versions of the questionnaire (Table 1). Study (PERSIST-1 vs PERSIST-2) did not significantly impact TSS response (P=0.2243), supporting the validity of data pooling. Reduction in symptoms with PAC were rapid, occurring as early as Week 4 (Figure). Patients in the PAC group achieved a steady state response rate of ≈35% around Week 20, while steady state response rate in the BAT group was ≈15% around Week 12. Additionally, larger absolute reductions and percent reductions in TSS at Week 24 were correlated with improvement as measured by Patient Global Impression of Change and change in EQ-5D-5L (Table 2). Conclusions : The integrated results from the phase 3 PERSIST-1 and PERSIST-2 trials demonstrate significant improvement in the rate of TSS response with PAC vs BAT. Overall, phase 3 data demonstrate that PAC was significantly more effective than BAT for the reduction spleen volume and symptom burden in patients with MF irrespective of baseline platelet count or prior treatment with JAK2 inhibitors. Disclosures Mesa: Pfizer: Research Funding; Novartis: Consultancy; Incyte Corporation: Research Funding; Promedior: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; CTI Biopharma: Research Funding; Genentech: Research Funding. Cervantes:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hospital Clinic Barcelona: Employment. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Gilead: Honoraria, Speakers Bureau. Mead:Bristol-Myers Squibb: Consultancy; Celgene: Research Funding; ARIAD: Consultancy; Cell Therapeutics: Consultancy; Elstar: Research Funding; Evotek: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Wang:CTI BioPharma: Employment, Equity Ownership. Granston:CTI BioPharma: Employment, Equity Ownership. Mascarenhas:Merck: Research Funding; Novartis: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Promedior: Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Safety and Efficacy of PRTX-100, a Highly Purified Form of Staphylococcal Protein A, in Patients with Immune Thrombocytopenia (ITP)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4929-4929 ◽  
Author(s):  
James B. Bussel ◽  
David J Kuter ◽  
Sylvain Audia ◽  
Richard J. Francovitch ◽  
Marc Michel
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Protein A ◽  
Staphylococcal Protein A ◽  
Platelet Response ◽  
Advisory Committees ◽  
Baseline Platelet Count ◽  
Grade 3

Abstract Background: ITP is a rare autoimmune hematologic disorder characterized by isolated thrombocytopenia caused by antibody-dependent platelet destruction and impaired platelet production. Several therapeutic options (eg glucocorticoids, intravenous immunoglobulin and thrombopoietin receptor agonists) are available to treat patients with ITP, although inadequate efficacy, side effects and/or cost can make them undesirable. PRTX-100 is a highly purified form of Staphylococcal protein A (SpA), which binds to human B-lymphocytes and monocytes, and modulates immune processes. Preclinical data indicate that PRTX-100 may have the potential to treat ITP by reducing immune-mediated destruction of platelets. Here we present safety/efficacy data from the scheduled analysis for dose escalation from the initial dose cohorts of patients with ITP enrolled in two Phase 1/2 open-label studies, PRTX-100-202 and PRTX-100-203. Methods: Adult patients with persistent/chronic ITP and either a platelet count <30,000/µL (if not receiving any ITP therapy) or a platelet count of <50,000/µL (if receiving a constant dose of permitted ITP treatment) were eligible for inclusion. Study 202 requires prior treatment with a thrombopoietin receptor agonist (TPO-RA) plus one additional standard ITP treatment, while Study 203 only requires prior treatment with one standard ITP treatment. In both studies, PRTX-100 was administered via a 30-min infusion (60 min if total dose >500 µg) on Days 1, 8, 15 and 22 in a standard 3 + 3 dose-escalation design. Starting dose was 1 µg/kg (Study 202) or 3 µg/kg (Study 203) with subsequent dose increases planned up to a maximum of 24 µg/kg. Platelet counts were monitored on Days 1, 3, 8, 15, 22, 29, 36, 43, 50, 78 and 106. Safety analyses included consideration of adverse events (AEs), serious AEs, infusion reactions, clinical laboratory tests, vital signs, physical findings and electrocardiograms. The key efficacy endpoint was platelet response defined as: a platelet count ≥30,000/µL and at least a doubling of baseline platelet count in patients with a baseline platelet count <30,000/µL; or, in patients receiving permitted treatments for ITP with a baseline platelet count ≥30,000/µL and <50,000/µL, an increase in platelet count to ≥50,000/µL and at least a doubling of baseline platelet count or an increase to >100,000/µL. Results:Data are available from 6 patients (Study 202 n=3; Study 203 n=3) enrolled in the lowest-dose cohorts of the PRTX-100 ITP studies. There were 3 women and 3 men who were all Caucasian and ranged in age from 49 to 78 years; four patients had a splenectomy. Concomitant ITP medications were prednisone (n=4), dapsone (n=1), and TPO-RAs (n=2). Two patients in Study 202 received four doses of PRTX-100 (1 µg/kg); three patients in Study 203 received four doses of PRTX-100 (3 µg/kg). One patient receiving a dose of 1 µg/kg (Study 202) experienced a grade 3 vasculitis allergic reaction and discontinued from the study after 2 doses. This patient had a history of milder allergic reactions to other therapies. No additional serious or grade >3 AEs or immediately reportable events have been reported for any patient. Three grade 3 laboratory abnormalities have been reported: one patient (1 µg/kg; Study 202) experienced decreased hemoglobin and hyperkalemia, and one patient (1 µg/kg; Study 202) experienced high white blood cell count. One grade 1 infusion reaction occurred (itching rash at the infusion site in one patient receiving 3 µg/kg [Study 203]). No other infusion reactions were reported. Baseline platelet counts ranged from 6,000 - 30,000/µL. One patient in Study 203 (3 µg/kg) had a platelet response with a peak platelet count of 105,000/µL following the initiation of treatment. Platelet count elevation was observed as early as Day 3 and remained elevated for 2-3 weeks following the initiation of treatment (Figure 1). Conclusions:Data from initial cohorts in two dose escalation trials of patients treated with PRTX-100 at a dose of 1 µg/kg or 3 µg/kg have demonstrated an acceptable safety profile to support continued enrollment into higher-dose cohorts in both trials. A platelet response was observed in one patient treated at the lowest dose in one of the trials. Enrollment into higher-dose cohorts is ongoing and updated data from patients treated in those cohorts will be included in any presentation. Figure 1 Figure 1. Disclosures Bussel: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees; Immunomedics: Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; UpToDate: Patents & Royalties; Sysmex: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; BiologicTx: Research Funding. Kuter:Syntimmune: Consultancy; MedImmune: Consultancy; Eisai: Consultancy; Genzyme: Consultancy; 3SBios: Consultancy; Shire: Consultancy; Amgen: Consultancy, Paid expert testimony; Pfizer: Consultancy; Shionogi: Consultancy; ONO: Consultancy; GlaxoSmithKline: Consultancy; Bristol-Myers Squibb: Research Funding; Protalex: Research Funding; CRICO: Other: Paid expert testimony; Rigel: Consultancy, Research Funding. Francovitch:Protalex, Inc.: Employment. Michel:Amgen: Honoraria; Novartis: Honoraria.

Efficacy and Safety of Nilotinib in Elderly Patients with Imatinib-Resistant or -;Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A Sub-Analysis of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3286-3286 ◽  
Author(s):  
Philipp D. le Coutre ◽  
Anna Turkina ◽  
Dong-Wook Kim ◽  
Bernadeta Ceglarek ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Study Drug ◽  
Cytogenetic Response ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Abstract 3286 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods: The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results: Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (<60: 51.1 months; =60: 69.3; =70: 66.6) and higher proportions with CML duration >5 years (<60: 43%; =60: 56%; =70: 52%). Besides imatinib, prior CML treatments received by elderly pts included dasatinib (=60: 20%; =70: 19%), cytarabine (=60: 23%; =70: 19%), busulfan (=60: 10%; =70: 7%), and interferons (=60: 50%; =70: 42%). Elderly pts were previously treated with imatinib for longer median durations (<60: 27.4 months; =60: 32.7; =70: 29.9), with higher proportions treated for >5 years (<60: 12%; =60: 19%; =70: 18%). The proportion of imatinib-intolerant to resistant elderly pts was about 1:1, which was higher than the proportion among <60 pts at about 0.6:1, such that relatively few elderly pts had prior highest imatinib dose >800 mg (<60: 34%; =60: 26%; =70: 21%). While response rates to prior imatinib were similar, among pts who required therapy after failing imatinib, elderly pts had lower cytogenetic response rates (<60: 22%; =60: 17%; =70: 19%) to prior dasatinib. During ENACT, less than 50% of elderly pts experienced nilotinib dose interruptions (=60: 46%; =70: 41%) and reductions (=60: 7%; =70: 6%) lasting >5 days, which was consistent with the overall ENACT dataset. The median duration of dose interruptions and reductions was 15 (=70: also 15) and 41 (=70: 32) days, respectively. The main reason for dose interruptions and reductions was adverse events (AEs). The median duration of nilotinib exposure was 227 days (=70: 219) and the median dose intensity was 749 mg/day (=70: 775). Efficacy was similar among elderly pts, with 39% (=70: 35%) of pts achieving complete hematologic response (CHR), 41% (=70: 39%) achieving major cytogenetic response (MCyR) and 31% (=70: 33%) achieving complete cytogenetic response (CCyR). MCyR rate was also similar among elderly hematologic responders (=60: 64%; =70: 65%). Among elderly pts requiring nilotinib therapy after both imatinib and dasatinib, and therefore have more resistant CML, CHR rate was 39% (=70: 32%), MCyR rate was 28% (=70: 29%) and CCyR rate was 20% (=70: 16%). Safety was likewise similar among elderly pts, with grade 3/4 study drug-related AEs occurring in 56% of pts (=70: 53%). The most frequent of these AEs were thrombocytopenia (=60: 24%; =70: 21%) and neutropenia (=60: 14%; =70: 11%). The most common method of managing these AEs was brief dose interruptions and/or reductions [thrombocytopenia (=60:86/108 pts; =70: 30/35), neutropenia (=60: 42/62 pts; =70: 9/18)]. Among elderly pts with prior dasatinib, 53% (=70: 58%) experienced grade 3/4 study drug-related AEs, while 7 out of 8 pts with pleural effusion on dasatinib no longer had it on nilotinib. Conclusions: In ENACT, pts aged =60 years at study initiation appear to have longer durations of CML, be more heavily pre-treated and more intolerant to imatinib than the younger cohort. Nonetheless, nilotinib induced comparable clinical responses in CML-CP pts regardless of age. Importantly, the safety profile of nilotinib is maintained in elderly pts. Disclosures: le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

Plerixafor (Mozobil ®)Plus G-CSF Is Effective in Mobilizing Hematopoietic Stem Cells in Patients with Concurrent Thrombocytopenia Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3229-3229 ◽  
Author(s):  
Ivana N Micallef ◽  
Eric Jacobsen ◽  
Paul Shaughnessy ◽  
Sachin Marulkar ◽  
Purvi Mody ◽  
...  
Keyword(s):  
Stem Cell ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Platelet Counts ◽  
Cd34 Cells ◽  
Low Platelet Count ◽  
Equity Ownership

Abstract Abstract 3229 Poster Board III-166 Introduction Low platelet count prior to mobilization is a significant predictive factor for mobilization failure in patients with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) undergoing autologous hematopoietic stem cell (HSC) transplantation (auto-HSCT; Hosing C, et al, Am J Hematol. 2009). The purpose of this study is to assess the efficacy of HSC mobilization with plerixafor plus G-CSF in patients with concomitant thrombocytopenia undergoing auto-HSCT. Methods Patients who had failed successful HSC collection with any mobilization regimen were remobilized with plerixafor plus G-CSF as part of a compassionate use program (CUP). Mobilization failure was defined as the inability to collect 2 ×106 CD34+ cells/kg or inability to achieve a peripheral blood count of ≥10 CD34+ cells/μl without having undergone apheresis. As part of the CUP, G-CSF (10μg/kg) was administered subcutaneously (SC) every morning for 4 days. Plerixafor (0.24 mg/kg SC) was administered in the evening on Day 4, approximately 11 hours prior to the initiation of apheresis the following day. On Day 5, G-CSF was administered and apheresis was initiated. Plerixafor, G-CSF and apheresis were repeated daily until patients collected the minimum of 2 × 106 CD34+ cells/kg for auto-HSCT. Patients in the CUP with available data on pre-mobilization platelet counts were included in this analysis. While patients with a platelet count <85 × 109/L were excluded from the CUP, some patients received waivers and were included in this analysis. Efficacy of remobilization with plerixafor + G-CSF was evaluated in patients with platelet counts ≤ 100 × 109/L or ≤ 150 × 109/L. Results Of the 833 patients in the plerixafor CUP database, pre-mobilization platelet counts were available for 219 patients (NHL=115, MM=66, HD=20 and other=18.). Of these, 92 patients (NHL=49, MM=25, HD=8 and other=10) had pre-mobilization platelet counts ≤ 150 × 109/L; the median platelet count was 115 × 109/L (range, 50-150). The median age was 60 years (range 20-76) and 60.4% of the patients were male. Fifty-nine patients (64.1%) collected ≥2 × 109 CD34+ cells/kg and 13 patients (14.1%) achieved ≥5 × 106 CD34+ cells/kg. The median CD34+ cell yield was 2.56 × 106 CD34+ cells/kg. The proportion of patients proceeding to transplant was 68.5%. The median time to neutrophil and platelet engraftment was 12 days and 22 days, respectively. Similar results were obtained when efficacy of plerixafor + G-CSF was evaluated in 29 patients with platelet counts ≤ 100 × 109/L (NHL=12, MM=10, HD=3 and other=4). The median platelet count in these patients was 83 × 109/L (range, 50-100). The median age was 59 years (range 23-73) and 60.4% of the patients were male. The minimal and optimal cell dose was achieved in 19(65.5%) and 3(10.3%) patients, respectively. The median CD34+ cell yield was 2.92 × 106 CD34+ cells/kg. The proportion of patients proceeding to transplant was 62.1%. The median time to neutrophil and platelet engraftment was 12 days and 23 days, respectively. Conclusions For patients mobilized with G-CSF alone or chemotherapy ±G-CSF, a low platelet count prior to mobilization is a significant predictor of mobilization failure. These data demonstrate that in patients with thrombocytopenia who have failed prior mobilization attempts, remobilization with plerixafor plus G-CSF allows ∼65% of the patients to collect the minimal cell dose to proceed to transplantation. Thus, in patients predicted or proven to be poor mobilizers, addition of plerixafor may increase stem cell yields. Future studies should investigate the efficacy of plerixafor + G-CSF in front line mobilization in patients with low platelet counts prior to mobilization. Disclosures Micallef: Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jacobsen:Genzyme Corporation: Research Funding. Shaughnessy:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Mody:Genzyme Corporation: Employment, Equity Ownership. van Rhee:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Evaluation of Bleeding-Related Episodes in Patients with Chronic Immune Thrombocytopenia (ITP) Treated with Romiplostim in Two Phase 3 Placebo-Controlled Clinical Trials.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 891-891 ◽  
Author(s):  
Ilene Ceil Weitz ◽  
Miguel A Sanz ◽  
David H. Henry ◽  
Martin Schipperus ◽  
Bertrand Godeau ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Rescue Medication ◽  
Bleeding Event ◽  
Bleeding Events ◽  
Phase 3 ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Chronic Itp

Abstract Abstract 891 Background: Chronic Immune thrombocytopenia (ITP) is characterized by low platelet counts and increased risk of bleeding. Rescue medications used to treat or prevent bleeding produce transient increases in platelet counts but may be associated with additional toxicities and costs. Romiplostim, approved for the treatment of adult chronic ITP, is a TPO mimetic peptibody protein that increases platelet production. Previously published data from phase 3 romiplostim trials showed that despite the increased use of rescue medication in the placebo arm, patient (pt) incidence of bleeding was reduced in the romiplostim arm vs placebo arm: 15% vs 34% (p = 0.02) for bleeding of grade ≥2 severity and 7% vs 12% (p=0.36) for grade ≥3 severity. Objective: To evaluate the effects of romiplostim treatment on bleeding outcomes in the phase 3 placebo controlled studies in chronic ITP pts with and without previous splenectomy. Bleeding events were captured as adverse events making it difficult to identify a single event reported multiple times versus persistent or recurrent bleeding. Further, we have developed a composite endpoint, termed bleeding-related episodes (BREs), which combines bleeding events and rescue medication administration to account for use of rescue medications to prevent bleeding. Methods: Adults with chronic ITP and a mean baseline platelet count <30 × 109/L were eligible. The previously published studies were conducted separately in splenectomized and nonsplenectomized populations. Pts were randomized (2:1) to receive romiplostim or placebo by subcutaneous injection once weekly for 24 weeks, with dose adjustments to maintain platelet counts between 50-200 × 109/L. Rescue medications were permitted to treat or prevent bleeding and included immunoglobulins, platelet transfusions, corticosteroids, or an increase in dose or frequency of a concurrent ITP medication. A BRE was defined as an actual bleeding event and/or the use of rescue medication. To collapse related events into episodes, events (bleeding events and/or the use of rescue medication) that occurred concurrently or within 3 days of each other were considered a single BRE. Bleeding events beginning 7 or more days after the start of the initial bleeding event were considered a new BRE. To account for differences in time spent on-study, rates of BRE per 100 pt-weeks were calculated. Results: A total of 125 pts (41 placebo, 84 romiplostim) were enrolled in the two studies. Baseline characteristics were well-balanced between the placebo and romiplostim-treated groups. During the treatment period, the rate of BREs was lower in the romiplostim group than in the placebo group, and results were consistent between splenectomized and nonsplenectomized pts (Table). Across both studies, the rate of BREs was reduced by 55% in pts receiving romiplostim compared to those receiving placebo (95% CI, 41% to 65%). BREs were more frequent at platelet counts <50 × 109/L (Table). BREs associated with hospitalizations were less common among romiplostim- than placebo-treated pts, and occurred at platelet counts <50 × 109/L in 10 of 11 cases. Corticosteroids (58 romiplostim, 38 placebo) and immunoglobulins (30 romiplostim, 73 placebo), were the most commonly used rescue medications and the rate of BREs including immunoglobulins was reduced by 88% in pts receiving romiplostim compared to placebo. Conclusions: In adults with chronic ITP, romiplostim was associated with a significant reduction in BREs compared to placebo. There was a marked reduction in BREs requiring immunoglobulins in the romiplostim arm compared to the placebo arm. Results were comparable in splenectomized and nonsplenectomized populations. The platelet count for a BRE starting ≥1 day after a platelet count measurement was calculated from the 2 proximal weekly measurements. Disclosures: Weitz: Amgen Inc.: Speakers Bureau. Sanz:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Henry:Amgen Inc.: Research Funding, Speakers Bureau; Orthobiotech: Research Funding, Speakers Bureau; Watson Pharma: Research Funding, Speakers Bureau. Schipperus:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Godeau:Amgen Inc.: Consultancy, Research Funding; Laboratoire Français de Fractionnement et de Biotechnologies (LFB): Consultancy; Roche: Research Funding. Gleeson:Amgen Inc.: Consultancy, Research Funding. Danese:Amgen Inc.: Consultancy, Research Funding. Deuson:Amgen Inc.: Employment, Equity Ownership.

The Population-Based ‘real world’ of Low Risk Myelodysplastic Syndromes; Second Interim Analysis of the European LeukemiaNet MDS Registry at 800 Registered New Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1867-1867
Author(s):  
David Bowen ◽  
Alex Smith ◽  
Jackie Droste ◽  
Pierre Fenaux ◽  
Argyris Symeonidis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Creatinine Clearance ◽  
Board Of Directors ◽  
Neutrophil Count ◽  
Real World ◽  
Research Funding ◽  
Population Based ◽  
Low Risk ◽  
Advisory Committees

Abstract Abstract 1867 Background: The European LeukemiaNet MDS Registry programme is the largest and most comprehensive prospective population-based registry of ‘low-risk’ MDS patients followed from diagnosis. Objective: The primary objective of this study is to describe the demographics and the disease-management of newly diagnosed MDS patients within IPSS low and intermediate-1 categories. Methods: The project recruits patients from 107 sites in 11 countries, ranging from 2–25 sites per country and including a high proportion of non-University centres in small cities. Consecutive eligible adult patients are registered within 3 months of diagnosis. Local diagnosis is accepted and a large dataset is collected including laboratory data, clinical information (including co-morbidity and concomitant medication) plus health utility (EQ-5D). Data are entered via a web portal and are source verified by study monitoring visits to sites. Results: As of July 2010, 828 patients are registered; data are presented for the first 800 patients. Recruitment is highest from France (n=237) then UK (104), Greece (99), Spain (92), and Sweden (73). Median age is 74.2 yrs (range 18.7–95.3) and from the four largest recruiting countries is 74.6–77.1 yrs. Sixty one percent of patients are male. Twenty patients are non-Caucasian (n=763). Body mass index is overweight (WHO definition) in 43.4% pts and obese in 18.3%, comparable to WHO data for the general adult population (http://apps.who.int/bmi/index.jsp). RCMD is the largest WHO subgroup (34%), followed by RARS (19%), RA (18.4%), RAEB-1 (12.5%), del5q (5.4%), MDS-U (3.5%) and RAEB-2 (0.5%). All WHO subgroups have male predominance except del5q with a striking female excess (79%). IPSS score (n=743) is 0 (52.3%), 0.5 (33.2%), and 1 (14.4%). 84.5% patients have IPSS ‘good’ cytogenetics. 19% patients have 0 cytopenias, 53% 1 cytopenia, 20% 2 cytopenias and 8% 3 cytopenias. WPSS category (with transfusion dependence assessed at time of registration, n=727) is Very Low (35.5%), Low (39.5%), Intermediate (21%), High (4%). Bone marrow features: mean no. of dysplastic lineages = 1.9, bone marrow ring sideroblasts percent = 0 (60% pts), <15 (11.5%), ≥15<50 (19.2%), ≥50 (9.6%). Median haemoglobin (Hb) concentration at presentation is 10.1 g/dl; 36% values were < 10 g/dl and 10% < 8 g/dl. Hb decreased with age (categorical variable Hb. <13>11.5, <11.5>10, <10; Χ2 test, P<.0001). Mean neutrophil count was 2.8 × 109/l with 27% values <1.5 × 109/l, 16% < 1 × 109/l, and 5% < 0.5 × 109/l. Median platelet count was 184 × 109/l; 5% patients had values < 50 × 109/l and 3% < 20 × 109/l. Platelet count and neutrophil count did not change with age. Median serum erythropoietin (EPO) concentration (n=418) was 49 IU/l, 81% values were <200 IU/l and 7% > 500 IU/l. Mean creatinine clearance was 71 mls/min with a marked reduction with age (P<.0001). Baseline serum EPO correlated with Hb. (r=.37, P<.0001), creatinine clearance (r=.22, P<.0001) and age (r=.1, P<.0001). The relationship between creatinine clearance, baseline EPO and response to EPO therapy will be explored. Discussion: This registry records data from the ‘real world’, namely what the hematopathologists in 100 sites diagnose locally as low-risk MDS and will as such be managed as MDS. Median age is consistent with other population-based data (US Medicare, Yorkshire Haematological Malignancy Research Network [www.hmrn.org]). In comparison with registries from specialist MDS centres, median age is higher and a lower proportion have del(5q) WHO subtype. Conclusion: The ELN registry clearly maps the diagnosis and management of low-risk MDS in routine clinical practice in hospitals large and small, specialist and non-specialist and is a unique resource. Acknowledgments: The Steering Committee (SC) acknowledges the commitment and enthusiasm from all 107 sites contributing high quality data to the project. The SC is also grateful for the funding commitment of Novartis Oncology Europe through the University of Nijmegen. Disclosures: Bowen: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Honoraria; Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Hellstrom-Lindberg:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Rituximab Plus Three Cycles of Dexamethasone In the Treatment of Immune Thrombocytopenia (ITP): a Pilot Study.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3697-3697
Author(s):  
Rebecca Elstrom ◽  
Soo Y. Lee ◽  
James B. Bussel
Keyword(s):  
Platelet Count ◽  
Pilot Study ◽  
Board Of Directors ◽  
Initial Treatment ◽  
Research Funding ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Almost All

Abstract Abstract 3697 Introduction: Rituximab has been a useful treatment for patients with ITP; many hundreds of patients have been treated. 30–40% of patients will achieve a complete remission (CR: platelet count >150 × 109/l) with initial treatment and, of this group, the CR will last at least a year in almost all patients. However, emerging data suggests that at least 40% of these patients in CR will relapse between 1 and 3 years from initial treatment suggesting that long-term “cures” only occur in 20% of the initial patients. Therefore it would be desirable if CR's could be achieved in more patients and especially if these would be durable in more than 20%. One approach would be to use rituximab maintenance, however it results in suppression of B-cells for more than 2 years. Dexamethasone has also been used to achieve “cure” in ITP especially in adults at or near diagnosis. Cheng's study suggested that approximately 50% of patients would achieve a long-term response with only one 4-day cycle of high dose (40 mg/day) dexamethasone (N Engl J Med, 2003). A follow up study from GIMEMA suggested that 3–4 cycles of dexamethasone would be better than 1 cycle (Blood, 2007). Finally, Zaja's study suggested that rituximab plus one cycle of dexamethasone was superior to dexamethasone alone with a > 50% CR rate at 6 months (Blood, 2010). Therefore, we elected to perform a pilot study to explore the combination of rituximab with three cycles of dexamethasone at 14 day intervals. Methods: Patients with ITP with platelet counts < 30,000 off therapy and in need of treatment were enrolled. The standard dose (4 infusions of 375mg/m2) rituximab was given on days 1, 8, 15 and 22 and dexamethasone 40 mg (adjusted for size) on days 1–4, 15–18, and 29–32. Results: Fourteen patients between the ages of 4 and 53 years with ITP were treated with rituximab and dexamethasone (R&D) (Table 1). All had received previous steroid therapy as well as other treatments. The median platelet count was 40,000 at initiation of rituximab (range 7,000-230,000); several patients with low counts started with dexamethasone prior to initiating Rituximab to sustain their counts during initial treatment. Patients received rituximab weekly for between 2 and 4 doses and dexamethasone for either 2 or 3 courses at intervals between 1 and 8 weeks (median 2 week intervals). A summary of the results is shown in table 2 demonstrating short-lived platelet increases in response to dexamethasone in almost all patients. With short follow up, there were 7 CR's, 3 PR's and 4 NR's. If this was divided by duration of ITP prior to R&D, there were 4 CR's and 1 NR for ≤ 12 months and 3 CR, 3 PR, and 3 NR for > 12 months. More of the children who were treated had chronic disease than did adults explaining their apparently poorer response. Observed toxicities included hyperglycemia, grade 1 and 2 liver function abnormalities, weight gain, and 1 episode of colitis requiring hospitalization. Three patients opted to skip the third cycle of dexamethasone. Conclusion: A regimen of rituximab + 2–3 courses of dexamethasone is active in patients with pretreated ITP with appreciable but usually manageable toxicity. It appears to yield superior results if administered to patients within one year of diagnosis. This combination merits further exploration in a prospective clinical trial. Disclosures: Bussel: Portola: Consultancy; 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; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc.: Membership on an entity's Board of Directors or advisory committees; Cangene: Research Funding; Genzyme: Research Funding.

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