Long-Term Dosing of AMG 531 in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura: 2-Year Update.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 568-568 ◽  
Author(s):  
James B. Bussel ◽  
D.J. Kuter ◽  
J.Th.M de Wolf ◽  
T.H. Guthrie ◽  
A. Newland ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Neutralizing Antibodies ◽  
Drug Exposure ◽  
Therapeutic Option ◽  
Platelet Response ◽  
Initial Report ◽  
Chronic Itp ◽  
Long Term Treatment

Abstract AMG 531, a novel thrombopoiesis-stimulating peptibody, increases platelet production by stimulating the TPO receptor. This study is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, SC administration of AMG 531 in patients with chronic ITP who completed a previous AMG 531 study. Patients previously treated with AMG 531 received the same starting dose as the final dose given in the previous study; placebo-treated patients began the extension at 1μg/kg. Doses could be adjusted based on platelet response. As of an April 2007 analysis, 137 patients were enrolled and 136 had received AMG 531. The longest treatment duration was 122 weeks; 22 patients were followed for 96 weeks or longer. At baseline, 91 women and 46 men had a mean age of 53±15(SD) years and a median (range) platelet count of 18(1–50)x109/L; 82 patients (60%) had undergone splenectomy. The most frequently reported adverse events (AEs) were headache (overall incidence 31%), contusion (27%), fatigue (24%), diarrhea (24%), epistaxis (23%), nasopharyngitis (21%), and arthralgia (20%). Exposure-adjusted analysis showed no trend for AEs to increase in frequency with increased drug exposure (table). Eleven patients had serious AEs judged by investigators as treatment-related including 3 withdrawn from study (vaginal hemorrhage, increased reticulin in the bone marrow reported as myelofibrosis, and initial report of multiple myeloma later reclassified as monoclonal gammopathy of undetermined significance - 1 report each) and 8 who continued on-study (bone marrow disorder/reticulin fibrosis - 3, unacceptably high platelet count - 2, thrombosis - 2, and cerebral thrombosis/papilloedema/temporary blindness - 1). One patient developed neutralizing antibodies to AMG 531 (absent on retesting 4 months after drug cessation), with no clinical sequelae and no cross-reactive antibodies to TPO. Overall, 112 patients (82%) achieved a platelet response (≥50x109/L and doubling of baseline). From week 4 onward, weekly incidence of platelet response ranged from 52–73% (figure). Median number of weeks to first response was 2 (median dose 3μg/kg). Of 30 patients with baseline use of concurrent ITP therapies, 13 were able to discontinue them and 6 additional patients had a >25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for long-term treatment of chronic ITP. The safety profile has been acceptable, and most patients have been able to maintain a platelet response and discontinue or reduce concurrent ITP therapies. Exposure-Adjusted incidence of AEs with Overall Incidence ≥ 20% Platelet Response (≥ 50x109/L and Doubling of Baseline) by Study Week Platelet Response (≥ 50x109/L and Doubling of Baseline) by Study Week

Long-Term Dosing of AMG 531 Is Effective and Well Tolerated in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 220-220 ◽  
Author(s):  
James B. Bussel ◽  
David J. Kuter ◽  
James N. George ◽  
Louis M. Aledort ◽  
Alan E. Lichtin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Neutralizing Antibodies ◽  
Therapeutic Option ◽  
Platelet Response ◽  
Open Label ◽  
Baseline Platelet Count ◽  
First Response ◽  
The Mean

Abstract AMG 531 is a novel platelet-stimulating peptibody that targets the TPO receptor, resulting in increased production of platelets. This ongoing, open-label study assessed the safety and efficacy of long-term AMG 531 dosing in ITP patients. Eligible patients have completed a previous AMG 531 study in ITP, are ≥18 years of age, have a baseline platelet count ≤50 x 109/L, with no recent significant change in medical history. The AMG 531 starting dose is 1μg/kg by SC injection with dose adjustment to an original maximum of 30μg/kg, since reduced to 15μg/kg. Patients are treated weekly unless the platelet count is >400x109/L. Concurrent corticosteroids can be tapered when the platelet count is ≥50x109/L. Preliminary data are available for 26 patients treated for up to 24 weeks: 17 women and 9 men; mean age, 48.4±11.6 (SD) years; mean baseline platelet count, 18.5±12.3 (SD) x109/L. Twenty-one patients (80.8%) had undergone a splenectomy before study entry; 6 (23.1%) were receiving concurrent corticosteroids for ITP. Twenty-one of 26 patients (80.8%) had a protocol-defined platelet response to AMG 531 (doubling of the baseline platelet count and ≥50x109/L). The mean AMG 531 dose at the first response was 3.7±2.7 (SD) μg/kg (at median 5 weeks); the mean dose at week 24 was 7.2±4.2 (SD) μg/kg. Twelve of 26 patients (46.2%) had a durable platelet response (doubling of the baseline count and ≥50x109/L at 6 or more of weeks 17–24). Twenty patients (76.9%) had a platelet count ≥100x109/L at least once; 7 (26.9%) had a platelet count ≥400x109/L. Of 6 patients on concurrent corticosteroids, 3 discontinued treatment and 2 had a ≥25% dose reduction. At least 1 serious adverse event was reported in 4 patients: anal fistula (unrelated to treatment), adverse drug reaction (unrelated), multiple sclerosis relapse (unrelated), bone pain (related), and diffuse reticulin formation in the bone marrow reported as myelofibrosis (related). Reticulin formation is hypothesized as due to excessive accumulation of megakaryocytes in the bone marrow. AMG 531 was discontinued, and a bone marrow 3 months later showed improvement. One patient experienced adverse events (musculoskeletal pain and headache) resulting in withdrawal from the study. No neutralizing antibodies have been detected to date. In summary, repeated exposure to AMG 531 has been generally well tolerated in this ongoing study. A total 80.8% of patients achieved a platelet response, defined as doubling of the baseline count and ≥50x109/L. Individualized weekly doses of AMG 531 may provide a therapeutic option in ITP, potentially enabling patients to taper off long-term corticosteroid therapy.

Long-Term Dosing of AMG 531 in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura: 48-Week Update.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 476-476 ◽  
Author(s):  
David Kuter ◽  
James Bussel ◽  
James George ◽  
Louis Aledort ◽  
Alan Lichtin ◽  
...  
Keyword(s):  
Platelet Count ◽  
Neutralizing Antibodies ◽  
Sinus Thrombosis ◽  
Therapeutic Option ◽  
Subcutaneous Administration ◽  
Transverse Sinus ◽  
Platelet Response ◽  
Open Label ◽  
The Mean

Abstract AMG 531 is a novel thrombopoiesis-stimulating peptibody that increases platelet production by targeting the TPO receptor. The study described here is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, subcutaneous administration of AMG 531 in ITP patients who have completed a previous AMG 531 study. Patients previously treated with AMG 531 receive the same starting dose as the final dose given in the previous study; placebo-treated patients begin the extension with a 1 μg/kg dose. Doses may be skipped, decreased, maintained, or increased based on platelet response. Patients who achieve a stable dose for at least 3 weeks (later amended to 4 weeks) may be allowed to self-administer the drug. A total of 104 patients have been enrolled; the longest AMG 531 treatment duration is 96 weeks. This planned interim analysis includes 36 patients (safety subset) whose previous study was a phase 2 trial. Data for patients previously enrolled in a phase 3 trial are still blinded. The 25 women and 11 men have a mean age of 50±13 (SD) years; 30 (83%) have had a splenectomy. Twelve patients entered the study using concurrent corticosteroids, which were tapered when the platelet count was >50x109/L. Adverse event (AE) profiles were similar for the intervals of weeks 1–24 vs 25–48 and beyond. The most frequent were headache (incidence of 2.0 per 100 weeks of subject exposure for weeks 1–24 vs 1.7 for weeks 25–48), upper respiratory infection (1.3 vs 0.8), and fatigue (0.9 vs 1.0). Four patients had serious treatment-related AEs: vaginal hemorrhage/anemia (withdrawn from treatment), diffuse reticulin formation in the bone marrow (withdrawn), bone pain (continues on treatment), and transverse sinus thrombosis with papilledema and temporary decrease in visual acuity (64-year-old patient with diabetes mellitus and a platelet count of 293x109/L at the time of the AE; this patient continues on treatment). No neutralizing antibodies have been detected to date. The efficacy subset consists of 27 patients who completed week 48 or beyond. Both the mean platelet count and the mean dose of AMG 531 have remained stable between weeks 24–48. The mean platelet count was 100x109/L ± 4.4 (SE) during weeks 1–24 and 131x109/L ± 5.3 (SE) during weeks 25–48. Eleven patients (41%) have had at least one platelet count >450x109/L, excluding counts associated with ITP rescue medication. Six of 12 patients were able to discontinue concurrent corticosteroids, and 2 had a >25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for ITP. Most patients have been able to maintain a safe platelet count and to decrease or discontinue concurrent corticosteroid therapy.

Long-Term Treatment with Romiplostim in Patients with Chronic Immune Thrombocytopenic Purpura (ITP): 3-Year Update from An Open-Label Extension Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 402-402 ◽  
Author(s):  
David J Kuter ◽  
James B Bussel ◽  
Adrian Newland ◽  
Joost TM de Wolf ◽  
Troy Guthrie ◽  
...  
Keyword(s):  
Platelet Count ◽  
Term Treatment ◽  
Duration Of Treatment ◽  
Open Label ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Long Term Treatment ◽  
Open Label Extension ◽  
Grade 3

Abstract Chronic ITP is characterized by increased platelet destruction and suboptimal platelet production. Romiplostim is an investigational Fc-peptide fusion protein (peptibody) being studied for its ability to increase platelet counts in patients with chronic ITP. We report data from an open-label extension study of romiplostim in adult patients with chronic ITP. Collection of safety and efficacy data from long-term treatment of these patients is ongoing. Eligible patients had completed a prior romiplostim study and had platelet counts □50×109/L. Romiplostim was administered subcutaneously once weekly with dose adjustments to maintain a platelet count of 50–250×109/L. As of July 13 2007, 142 patients had been treated with romiplostim. Their median time since diagnosis was 6.4 years (range 0.6–46.4 years). Most were female (67%) and had previously undergone a splenectomy (60%). The median baseline platelet count was 17×109/L (range 1–50×109/L). The median duration of treatment was 65 weeks (range 1–156 weeks). Twenty-nine (20%) patients discontinued the study, 10 (7%) due to adverse events (AEs) [2 each of bone marrow reticulin and thrombosis; 1 each of bleeding, pain, cardiac arrest, pneumonia, hepatic and renal failure, and monoclonal gammopathy of undetermined significance]. Different measures of platelet count response were analyzed; any platelet counts within 8 weeks of receiving rescue medications were excluded from these analyses. Platelet counts were increased from baseline by ≥20×109/L more than 80% of the time in 54% of patients and more than 50% of the time in 73% of patients. Platelet counts remained above 20×109/L more than 90% of the time in 67% of patients and more than 50% of the time in 94% of patients. A platelet count >50×109/L and double baseline was achieved by 30% (42/138) of patients after the first dose, by 51% (71/138) of patients after the third dose, and by 87% (124/142) of patients overall. The durability of platelet count increases was analyzed: platelet counts >50×109/L were sustained for ≥10, ≥25, and ≥52 consecutive weeks in 78% (102/131), 54% (66/122), and 35% (29/84) of patients, respectively. The patient incidence of bleeding events both of any severity and of clinical significance (≥Grade 3) declined over time (Table). AEs were reported in 95% of patients, with most mild to moderate in severity. The most common were headache (37%); nasopharyngitis (32%); and contusion, fatigue and epistaxis (each 30%). AE frequency did not increase with time on study (Table). Bone marrow reticulin was present or increased in 8 patients with no evidence of progression to collagen fibrosis or chronic idiopathic myelofibrosis. Thrombotic events were reported in 7 (5%) patients; 6 had pre-existing risk factors for thrombosis. In conclusion, romiplostim increased platelet counts in most patients for most of the time, and clinically relevant bleeding was reduced over time. Romiplostim was well-tolerated and AEs did not increase with longer duration of treatment. Table. Summary of patient incidence of AEs by study period <24 wks (N=142) n (%) 24 to <48 wks (N=126) n (%) 48 to <72 wks (N=97) n (%) 72 to <96 wks (N=65) n (%) 96 to <120 wks (N=29) n (%) 120 to <144 wks (N=25) n (%) AEs 129 (91) 110 (87) 64 (66) 36 (55) 23 (79) 21 (84) Serious AEs 25 (18) 13 (10) 7 (7) 4 (6) 4 (14) 1 (4) Treatment-related AEs 48 (34) 14 (11) 12 (12) 7 (11) 4 (14) 3 (12) Treatment-related serious AEs 6 (4) 3 (2) 1 (1) 2 (3) 1 (3) 1 (4) Study withdrawals due to AEs 4 (3) 5 (4) 0 (0) 0 (0) 0 (0) 1 (4) Bleeding any grade 60 (42) 37 (29) 22 (23) 13 (20) 11 (38) 8 (32) Bleeding ≥ Grade 2 (moderate) 25 (18) 12 (10) 8 (8) 4 (6) 3 (10) 2 (8) Bleeding ≥ Grade 3 difference in thisresponsebetween refractory (severe) 9 (6) 1 (1) 1 (1) 1 (2) 0 (0) 0 (0)

scholarly journals Long Term Discontinuation of Eltrombopag after Remission in Primary Immune Thrombocytopenia: 8-Year Follow-up Data from 15 Spanish Centers

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2352-2352
Author(s):  
Tomas Jose Gonzalez-Lopez ◽  
Fernando Fernandez-Fuertes ◽  
Maria Cristina Pascual Izquierdo ◽  
Isabel Caparros ◽  
Silvia Bernat ◽  
...  
Keyword(s):  
Platelet Count ◽  
Median Time ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Previous Treatment ◽  
Complete Response ◽  
Platelet Response ◽  
Platelet Counts

Background: Successful discontinuation of eltrombopag in certain immune thrombocytopenia (ITP) patients after complete response has already been demonstrated. However, the frequency of this phenomenon and type of candidate patients are still matter of discussion. Moreover, possibility of long term discontinuation responses is not clearly established. Methods: Here we retrospectively evaluated our whole cohort of 508 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry with a focus on the patients who achieved a durable (at least six months) platelet response after stopping eltrombopag. Successful discontinuation of eltrombopag (SDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 6 months in absence of eltrombopag or any rescue therapies administered. Long term discontinuation of eltrombopag (LTDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 36 months in the absence of eltrombopag or any rescue therapies administered. The study was approved by the Hospital Universitario de Burgos Ethics Committee and fulfilled Helsinki declaration standards. Results: While 37.4% of our patients relapsed of ITP with subsequent platelet count drop sometime during first six months of discontinuation of eltrombopag, a total of 74 patients (14.6%) were able to achieve SDOE. The median age of SDOE patients was 62 [range, 47-79] years. There were 47 women and 27 men. According to the standard definition, patients were allocated to newly diagnosed (n=17), persistent (n=15) and chronic (n=42) ITP groups. The median time from diagnosis to eltrombopag initiation was 31 [range, 4-104] months. The median number of previous therapies was 2 [range, 1-2], including splenectomy (14%), rituximab (18%) and romiplostim (12%). As expected, all patients but 1 achieved a complete response (platelet count ≥100 x 109/L) prior to eltrombopag discontinuation The median duration of eltrombopag treatment was 7 [range, 2-19] months. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=43), platelet count >400x109/L (n=16), aspartate aminotransferase elevation (n=5), diarrhea (n=4), thrombosis (n=3), patient's request (n=2) and other reasons (n=1). Analysis of these SDOE discontinued patients show that with a median follow-up of 55 [range, 29-79] months, 38 patients (51.3%) maintained treatment-free response 36 months after stopping eltrombopag with no need of additional ITP therapies (median time of eltrombopag discontinuation was 70 [range, 50-77] months).This condition is what we define now as LTDOE. Nevertheless, 36 patients relapsed beyond 6 months but before 36 months of eltrombopag discontinuation (median time of eltrombopag discontinuation was 10 [range,7 -22] months). Characteristics of LTDOE population were a median time since ITP diagnosis of 32 [range, 5-88] months with 15/38 patients having ITP <1 year. 9 patients (24%) were male and their median age was 50 [range, 37-64] years. They had received a median of only two previous treatment lines [range: 1-2 lines]. The median platelet count before starting eltrombopag was 19 x 109/L [range, 8-40]. Meanwhile, platelet count before eltrombopag stop was 218 x 109/L [range, 123-356]. The main characteristics (age, gender, duration of ITP, prior ITP lines, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 38 patients with LTDOE were compared with those of the SDOE cohort who did not achieve a LTDOE. Unfortunately, no predictive factors of LTDOE could be identified. Conclusion: Durable platelet response following eltrombopag cessation may be observed in only 15% of primary ITP patients treated with this drug. On the contrary, half of patients who achieve a sustained response after eltrombopag withdrawal will get a long term discontinuation. However, we are lacking predictor factors for successful and long-term discontinuation of eltrombopag in primary ITP. Disclosures Gonzalez-Lopez: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy. Sánchez-González:Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Jarque:Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

Final Results from an International, Multi-Center, Single-Arm Study Evaluating the Safety and Efficacy of Romiplostim in Adults with Primary Immune Thrombocytopenia (ITP),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3279-3279 ◽  
Author(s):  
Ann Janssens ◽  
Michael D. Tarantino ◽  
Robert Bird ◽  
Maria Gabriella Mazzucconi ◽  
Ralph Vincent V. Boccia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Platelet Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Production ◽  
Platelet Counts ◽  
Equity Ownership

Abstract Abstract 3279 Background: ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Romiplostim stimulates platelet production via the TPO-receptor, and is recommended for second- and third-line treatment of chronic ITP in adults. We report final data from a large prospective study of romiplostim in adults with ITP of varying duration and severity. Methods: Eligibility criteria were broad: patients ≥18 years of age, who had received prior ITP therapies (final protocol amendment: ≥1, previous amendments: ≥3), with low platelet counts (final amendment: ≤ 30 × 109/L, previous amendments: ≤ 10, ≤ 20 × 109/L) or experiencing uncontrolled bleeding. The only excluded comorbidities were: hematological malignancy, myeloproliferative neoplasms, MDS and bone marrow stem cell disorder. Romiplostim was initiated at 1 (final amendment) or 3 (previous amendments) μg/kg/week, with dose adjustments allowed to maintain platelet counts ≥50 × 109/L. Patients could continue on study until they had access to commercially available romiplostim. Rescue medications were allowed at any time; concurrent ITP therapies could be reduced when platelet counts were > 50 × 109/L. Primary endpoint was incidence of adverse events (AEs) and antibody formation. Secondary endpoint was platelet response, defined as either (1) doubling of baseline count and ≥ 50 × 109/L or (2) ≥20 × 109/L increase from baseline. Results: A total of 407 patients received romiplostim, 60% of whom were female. Median (Q1, Q3) time since ITP diagnosis was 4.25 (1.20, 11.40) years (maximum 57.1 years), with 51% of patients splenectomised and 39% receiving baseline concurrent ITP therapies. Seventy-one percent of patients completed the study, with requirement for alternative therapy and withdrawn consent the most common reasons for discontinuation (5% each). Median (Q1, Q3) on-study treatment duration was 44.29 (20.43, 65.86) weeks (maximum 201 weeks), with a total of 20,201 subject-weeks on study. Incidence and type of AEs were consistent with previous studies. The most common serious treatment-related AEs were cerebrovascular accident, headache, bone marrow reticulin fibrosis (with no evidence of positive trichrome staining for collagen and no evidence suggesting primary idiopathic myelofibrosis), nausea, deep vein thrombosis, hemorrhage and pulmonary embolism, with each reported in 2 of 407 (0.5%) patients. All other serious treatment-related AEs were each reported in one patient. Eighteen patients died; 3 deaths (hemolysis, intestinal ischaema, aplastic anemia) were considered treatment-related. No neutralizing antibodies to romiplostim or TPO were reported. Approximately 90% of patients achieved each of the platelet response definitions, regardless of splenectomy status. Overall, median (Q1, Q3) time to response was 2 (1, 4) weeks for response definition 1, and 1 (1, 3) week for response definition 2. Median (Q1, Q3) baseline platelet count was 14 (8, 21) × 109/L. After 1 week of treatment median (Q1, Q3) platelet count had increased to 42 (18, 101) × 109/L. From week 8 onwards, and excluding counts within 8 weeks of rescue medication use, median platelet counts were consistently above 100 × 109/L (range 101.0–269.5 × 109/L). Median (Q1, Q3) average weekly romiplostim dose was 3.62 (1.99, 6.08) μg/kg. Summary/conclusions: This is the largest prospective study in adult ITP reported to date. The data reported here are similar to those reported for previous romiplostim studies, with romiplostim able to safely induce a rapid platelet response in adult ITP patients with low platelet counts or bleeding symptoms. Romiplostim is an important, well-tolerated, treatment option for adult ITP patients, which significantly increases and maintains platelet counts. Adverse Event Subject Incidence Platelet Response Disclosures: Janssens: Amgen: Consultancy; Roche: Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Tarantino:Cangene corporation: Research Funding; Baxter: Research Funding; Talecris: Honoraria, Speakers Bureau; Up-to-date: Patents & Royalties; The Bleeding and Clotting Disorders Institute: Board Member. Bird:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Boccia:Amgen: Equity Ownership, Honoraria, Speakers Bureau. Lopez-Fernandez:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kozak:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Steurer:Amgen: Honoraria. Dillingham:Amgen Limited: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

A case report of long-term complete remission following cessation of romiplostim dosing in a previously severe ITP patient.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17001-e17001
Author(s):  
Allison Ashley Baxley ◽  
James N George ◽  
Deirdra Terrell ◽  
Meredith Moorman ◽  
Jennifer L. Holter
Keyword(s):  
Clinical Trial ◽  
Platelet Count ◽  
Case Report ◽  
Bleeding Complications ◽  
Drug Discontinuation ◽  
High Dose ◽  
Platelet Response ◽  
Open Label ◽  
Platelet Production

e17001 Background: Primary Immune thrombocytopenia(ITP) is a chronic autoimmune disorder characterized by low platelet counts and bleeding complications. Platelet destruction together with insufficient platelet production occur through an antibody-mediated process and early treatment options revolve around targeting antibodies and immunologic pathways. Such therapies may not produce long-term responses and may be accompanied by considerable adverse effects which can lead to complications and/or drug discontinuation. Romiplostim is a thrombopoietic agent that stimulates platelet production and offers an alternative method for treatment of patients with ITP. In clinical trials, patients have achieved durable platelet count responses without clinically important side effects. Methods: We report the case of a 44 year-old female with refractory ITP who has achieved successful remission following treatment with romiplostim. Results: As previously described in Haematologica (2008;93:1445) this patient presented with purpura, menorrhagia, and a platelet count of 7,000. Throughout 2005 she had only transient responses to high dose dexamethasone, intravenous immunoglobulin, rituximab, and splenectomy. She was placed on romiplostim in August 2005 as part of a clinical trial and received a dose of 7 mcg/kg/week for approximately 50 weeks. She was able to tolerate dose reductions and by May 2007 her dose had been de-escalated to 3 mcg/kg/week, which she continued through 2009 as part of an open-label continuation study. In January 2010, after completion of the clinical trial, she began receiving romiplostim by prescription. She was able to gradually tolerate extended dosing intervals due to sustained platelet response. Her last dose was administered on October 27, 2010 and she has maintained a platelet count above 197,000 without further therapy. Conclusions: This case represents, to our knowledge, one of the longest maintained durable responses to romiplostim therapy. Romiplostim provides an alternative approach of treatment for ITP, and as evidenced by this case report, in some patients it may also lead to disease remission and eliminate the need for further treatment.

scholarly journals Bone marrow stem and progenitor cell contribution to neovasculogenesis is dependent on model system with SDF-1 as a permissive trigger

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4310-4319 ◽  
Author(s):  
Gerard J. Madlambayan ◽  
Jason M. Butler ◽  
Koji Hosaka ◽  
Marda Jorgensen ◽  
Dongtao Fu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Neutralizing Antibodies ◽  
Model Systems ◽  
Experimental Methodology ◽  
Specific Expression ◽  
Hematopoietic Stem ◽  
Lung Carcinoma Cells ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Abstract Adult bone marrow (BM) contributes to neovascularization in some but not all settings, and reasons for these discordant results have remained unexplored. We conducted novel comparative studies in which multiple neovascularization models were established in single mice to reduce variations in experimental methodology. In different combinations, BM contribution was detected in ischemic retinas and, to a lesser extent, Lewis lung carcinoma cells, whereas B16 melanomas showed little to no BM contribution. Using this spectrum of BM contribution, we demonstrate the necessity for site-specific expression of stromal-derived factor-1α (SDF-1α) and its mobilizing effects on BM. Blocking SDF-1α activity with neutralizing antibodies abrogated BM-derived neovascularization in lung cancer and retinopathy. Furthermore, secondary transplantation of single hematopoietic stem cells (HSCs) showed that HSCs are a long-term source of neovasculogenesis and that CD133+CXCR4+ myeloid progenitor cells directly participate in new blood vessel formation in response to SDF-1α. The varied BM contribution seen in different model systems is suggestive of redundant mechanisms governing postnatal neovasculogenesis and provides an explanation for contradictory results observed in the field.

scholarly journals Comparative evaluation of methods testing in vitro sensitivity to azithromycin in multi-drug resistant Pseudomonas aeruginosa isolated from cystic fibrosis patients

2020 ◽  
Author(s):  
Michael Soerensen ◽  
Dennis Nurjadi ◽  
Bakhodur Khakimov ◽  
Sébastien Boutin ◽  
Alexander H. Dalpke ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Therapeutic Option ◽  
Calf Serum ◽  
Multidrug Resistant ◽  
Term Treatment ◽  
In Vitro Sensitivity ◽  
Mueller Hinton ◽  
Long Term Treatment

Abstract Long-term treatment with azithromycin is a therapeutic option in Cystic Fibrosis (CF) patients chronically infected with P. aeruginosa . It was recently shown that azithromycin has direct antimicrobial activity when P. aeruginosa isolates are tested in Roswell Park Memorial Institute medium supplemented with fetal calf serum (RPMI 1640/FCS) by broth microdilution. We now investigated whether (i) azithromycin might also be active against multidrug resistant (MDR) P. aeruginosa isolated from CF patients and (ii) how in vitro sensitivity assays perform in synthetic cystic fibrosis sputum medium (SCFM), a medium that mimics the particular CF airway environment. In 17 (59%) out of 29 MDR P. aeruginosa CF isolates MICs for azithromycin ranged between 0.25 and 8 µg/ml and 12 isolates (41%) showed a MIC ≥512 µg/ml when measured in RPMI/FCS. In contrast, MICs were ≥256 µg/ml for all P. aeruginosa MDR isolates when tested in either SCFM or in conventional cation-adjusted Mueller Hinton Broth. High MIC values observed in CF adapted medium SCFM for both PAO1 and MDR P. aeruginosa CF isolates, as opposed to findings in RPMI, argue against routine azithromycin MIC testing of CF isolates.

scholarly journals Kidney cell lysates contain an activity that stimulates mature erythroid burst-forming-unit (mBFU-E) proliferation

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 1965-1971
Author(s):  
J Royet ◽  
G Mouchiroud ◽  
S Arnaud ◽  
T Oddos ◽  
S Galland ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Kidney Cell ◽  
Neutralizing Antibodies ◽  
Marrow Cell ◽  
Erythroid Differentiation ◽  
Interleukin 4 ◽  
In Vitro Tests ◽  
Cell Extracts

This study reports the detection of an activity that stimulates the development of a subclass of burst-forming unit-erythroid (BFU-E) progenitors giving rise to small bursts in semi-solid cultures established in the presence of saturating concentrations of erythropoietin. These progenitors are considered to be mature BFU-E. The activity is found in extracts from kidney cells and appears to be physiologically regulated as it was respectively enhanced and decreased in kidneys from anemic and polycythemic mice. The disappearance of activity in kidney-cell extracts during long-term polycythemia correlated with an accumulation of mature BFU-E in the spleen and bone marrow of polycythemic mice. Using specific neutralizing antibodies and in vitro tests, we also show that this activity is different from hemopoietins known to share burst promoting activity (Interleukin-3 [IL- 3], granulocyte-macrophage colony-stimulating factor [GM-CSF], Interleukin-4 [IL-4], erythropoietin [EPO], human interleukin for DA cells [HILDA]) and that it can stimulate erythroid differentiation in long term bone marrow cell cultures.

scholarly journals Management of Cytopenias in CTLA4 Haploinsufficiency Using Abatacept and Sirolimus

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2409-2409 ◽  
Author(s):  
Gulbu Uzel ◽  
Djuro Karanovic ◽  
Hua Su ◽  
Amy Rump ◽  
Anahita Agharahimi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Research Funding ◽  
Bone Marrow Failure ◽  
Critical Role ◽  
Lymphocytic Infiltration ◽  
Splenic Sequestration ◽  
Autoimmune Destruction ◽  
Long Term Treatment

Abstract Background: CTLA4 is a homodimeric cell surface inhibitory receptor that plays a critical role in maintaining immune system homeostasis by suppressing T-lymphocyte activation and proliferation. Heterozygous germline, loss-of-function mutations in CTLA4, present with a diverse clinical phenotype of recurrent infections, lymphoproliferation, autoimmunity, and lymphocytic infiltration of target organs. Cytopenias are common in CTLA4 Haploinsufficiency and can be often multifactorial due to autoimmune destruction, splenic sequestration and bone marrow failure.(Kuehn HS …. Uzel G. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.Science. 2014 Sep 26;345(6204):1623-1627. doi: 10.1126/science.1255904.) Patients and Methods: We have identified 95 CTLA4 mutation-positive subjects at the NIH CC, and a subset (n=74, 77%) of them exhibit symptomatic disease affecting brain, lungs, gut, spleen and bone marrow. Mean age for the affected cohort is 25 ± 2.0 years, and average age of onset of cytopenia is 16 years (range 6-43years). Of all patients with confirmed mutations, there are roughly equal numbers of females to males (1.15:1 ratio), but males dominate the affected cohort (69% males vs 31% females). Cytopenias due to autoimmune destruction, splenic sequestration and/or bone marrow failure with polyclonal lymphocytic infiltration are the most frequent initial presentation (59%; n=33): Thrombocytopenia (n=13), anemia (n=4), Evans' syndrome (n=7), and multilineage cytopenia (n=9). Splenomegaly is seen in 60% of the affected cohort. Results: We share our experience with short and long term immunomodulatory therapy in treating autoimmune cytopenias in 22 patients with CTLA4 deficiency,, including our experience with off-label use of the CTLA4 mimetic, abatacept(n=10), given at a dose of 500-750mg X2 as monthly intravenous infusions and sirolimus (n=19) with a target to maintain 24hr trough levels of 10-15ng/dL. The most frequent other concomitant immunomodulatory medication used was rituximab (n=10), azathioprine (n=5), mycophenolate mofetil (n=4), cyclosporine (n=3), hydroxychloroquine (n=1), ruxolitinib (n=1), mercaptopurine (n=1), and cyclophosphamide (n=1). Three patients received romiplostim and/or eltrombopag. All 22 patients received more than one course of pulse dose steroids. We have cumulative retrospective data of 17 patient-years in 10 CTLA4-deficient patients followed at NIH CC on abatacept. All of them showed either complete or partial response in terms stabilization of their cytopenias and/or improvement of their gastrointestinal symptoms and brain lesions. We did not observe any abatacept related adverse events: including infusion reactions, EBV reactivation, or diagnosis of malignancy. One patient died secondary to Klebsiella pneumoniae sepsis 3 months after stopping abatacept. His disease was complicated by large granular lymphocyte leukemia and treatment with alemtuzumab prior to his diagnosis with CTLA4 deficiency and abatacept treatment. Overall, we used mTOR inhibitors in 19 patients for a total of 37 patient years to treatment. Three most common recorded adverse events were: Clostridium difficile colitis (n=9, in 4 patients), lipid abnormalities (n =7, 3 patients required treatment) and bacterial pneumonia (n=6, in 4 patients). Conclusion: As abatacept replaces the missing CTLA4 protein, it should be part of the treatment regimen in patients with CTLA4 haploinsufficiency presenting with cytopenias. Both long term treatment outcomes and schedule of administration are yet to be determined in a larger cohort in the setting of a clinical trial. Disclosures Uzel: Novartis: Research Funding. Rao:novartis: Research Funding.

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