Development and Validation of a Model to Predict Response to Romiplostim in Patients with Lower-Risk Myelodysplastic Syndromes (MDS).

Abstract Abstract 2801 Background: Recommendations for use of erythropoiesis-stimulating agents (ESAs) in anemic patients with MDS are based on baseline endogenous erythropoietin levels and red blood cell transfusion requirements, factors which predict the likelihood of a response to ESA treatment. These recommendations for ESA use have been incorporated into quality-of-care treatment guidelines for MDS. We examined whether baseline endogenous thrombopoietin (TPO) levels and platelet transfusion requirements likewise predict response of thrombocytopenic MDS patients to treatment with romiplostim, a TPO receptor agonist. Patients and Methods: In a placebo(PBO)-controlled trial of romiplostim (randomized 2:1) in 250 thrombocytopenic [median (Q1, Q3) baseline platelet count 19.3 (12.5, 30.3) × 109/L] IPSS low/int-1 MDS patients, study drug was discontinued early due to data monitoring committee concerns that the potential small benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML and that the transient increases in blast cell counts may put patients at risk for diagnosis of and treatment for AML. Hematologic improvement of platelets (HI-P, per IWG 2006) is defined as 8 consecutive weeks of an absolute platelet increase of 30×109/L (for patients with baseline platelet counts >20×109/L) or an increase from <20×109/L to >20×109/L and by at least 100% (for patients with baseline platelet counts <20×109/L). In this trial of romiplostim in MDS, HI-P rates were higher with romiplostim than PBO (36.5% vs. 3.6%, odds ratio 15.6, p<0.001) as were median platelet counts from Week 4 on (p<0.001). Data from this trial were used to examine the relationship between baseline TPO levels and platelet transfusion needs and outcomes. TPO levels (in pg/mL) were assessed by ELISA at baseline, weeks 14, 28, 42, and at the end of treatment. In this study, platelet response is defined as meeting the same criteria as HI-P, but for 1 week as opposed to for 8 consecutive weeks. As with the ESA model (Hellstrom-Lindberg BJH 1997), a TPO model was developed from log-likelihood ratios and logistic coefficients, with scaling of the log-likelihood ratios to obtain predictive scores. The TPO model was then validated using data from a previous phase 1/2 study of romiplostim in lower-risk thrombocytopenic MDS patients (Sekeres Cancer 2010, Kantarjian J Clin Onc 2009). Variables analyzed in formulating the model included baseline platelet count, number of platelet units transfused in the past year, and baseline endogenous TPO levels. Results: For romiplostim-treated patients (N = 167), the median age was 71 years, the most common WHO subgroups were RCMD (68.3%), RAEB-1 (14.4%), and MDS-U (9.6%), and IPSS scores were 0 (24.0%), 0.5 (51.5%), 1 (20.4%), 1.5 (0.6%), and missing (3.6%). Median (Q1, Q3) baseline TPO levels were 212 (84, 2290) pg/mL. Among romiplostim-treated patients, patients with an HI-P (vs. those not having an HI-P) had lower median baseline TPO levels (172 vs. 236 pg/mL, p = 0.3589) and lower mean baseline TPO levels (854 vs. 1,210, p = 0.0497), and were less likely to have had ≥6 platelet units transfused in the past year (p = 0.0027). For those with a platelet response during ≥50% of study weeks, median baseline TPO levels were lower (138 vs. 1,034 pg/mL, p = 0.0215) as were mean baseline TPO levels (695 vs. 1,390, p = 0.001) and the likelihood of having had ≥6 platelet units transfused in the past year (p = 0.0037). A model for predicting response to romiplostim (i.e., platelet response for ≥50% of weeks) in patients with lower-risk MDS was developed (Figure, top panel). Of note, history of prior platelet transfusion (<6 vs. ≥6 units in the past year) was a better predictor of platelet response than baseline platelet counts. The model was then validated in a second independent romiplostim monotherapy study in MDS, showing a similar pattern of response rates associated with baseline TPO levels and the presence of past platelet transfusions (Figure, bottom panel). Conclusions: For thrombocytopenic patients with lower-risk MDS, lower baseline TPO levels (<500 pg/mL) and limited platelet transfusion history (<6 units in the past year) predict a greater likelihood that a patient will have a platelet response when treated with romiplostim. Disclosures: Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: The use of romiplostim in MDS was examined in this abstract. Giagounidis:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kantarjian:Amgen: Research Funding. Mufti:Celgene: Consultancy, Research Funding. Fenaux:Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Jia:Amgen: Employment, Equity Ownership. Yang:Amgen: Employment, Equity Ownership. Platzbecker:Novartis: Consultancy; Celgene: Consultancy; GlaxoSmithKline: Consultancy; Amgen: Consultancy.

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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 ◽

10.1182/blood.v118.21.3279.3279 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3279-3279 ◽

Cited By ~ 6

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.

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

Blood ◽

10.1182/blood-2018-99-109763 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2428-2428 ◽

Cited By ~ 1

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.

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Biomarkers of Response to Romiplostim in Patients with Lower-Risk Myelodysplastic Syndrome (MDS) and Thrombocytopenia - Results of the Europe Trial By the Emsco Network

Blood ◽

10.1182/blood-2019-129047 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2998-2998

Author(s):

Uwe Platzbecker ◽

Anne Sophie Kubasch ◽

Aristoteles Giagounidis ◽

Georgia Metzgeroth ◽

Anna Jonasova ◽

...

Keyword(s):

Adverse Events ◽

Myelodysplastic Syndrome ◽

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Platelet Transfusion ◽

Weekly Dose ◽

Advisory Committees ◽

The Impact ◽

Spearman Test

Introduction: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and peripheral cytopenia. In about half of patients with lower-risk (LR) MDS, thrombocytopenia is present at the time of diagnosis and associated with shortened survival and an increased risk of progression to acute myeloid leukemia (AML). The thrombopoietin receptor agonist (TPO-RA) romiplostim has shown safety and marked efficacy in a still poorly-defined subset of LR-MDS patients with thrombocytopenia. Methods: The EUROPE multicenter phase 2 trial within the EMSCO network investigated the impact of biomarkers like endogenous thrombopoietin (TPO) level and platelet transfusion events (PTE) on the efficacy of romiplostim (750µg SC qw) treatment in patients with LR-MDS (IPSS low/int-1). Patients were eligible if baseline bone marrow blast count was <5% as assessed by central morphology and platelet counts were ≤30 Gpt/L or ≤50 Gpt/L in case of bleeding history. According to a previously published model of response to TPO-RA (Sekeres at al. BJH 2014), patients were assigned into 3 different cohorts at the time of screening based on their previous PTE as well as centrally assessed TPO serum levels (cohort A: TPO<500 ng/l, PTE<6 units/past year; cohort B: TPO<500 ng/l, PTE≥6 units or TPO≥500 ng/l, PTE<6 units, cohort C: TPO≥500 ng/l, PTE≥6 units). Primary endpoint of the study was the rate of hematologic improvement of platelets (HI-P) according to IWG 2006 criteria after 16 weeks of romiplostim treatment. We here present the analysis for the first 16 weeks of romiplostim treatment. Results: From 2015 to 2018, a total of 68 patients were included in 20 trial sites in Germany, France and Czech Republic. Patients displayed a median age of 74 years and a median platelet count of 25 G/L (range 1-50 G/L) and were stratified into cohort A (n=47), B (n=17) or C (n=4), respectively. All patients received at least one cycle of romiplostim with a median weekly dose of 750μg and a median of 15 cycles of romiplostim until week 16. Reasons for premature study discontinuation before week 16 were investigator/patient decision (n=8), adverse events (n=5), disease progression (n=4) or death (n=1). There were 9 reported severe treatment-related adverse events in seven patients including pulmonary embolism (n=1), subacute stroke (n=1), mucocutaneous hemorrhage (n=1), asthenia (n=1), suspicion of anti-romiplostim antibodies (n=1), progression to AML (n=1) and varicella zoster infection (n=1). Two patients had transient increases in peripheral blasts to more than 10% and 1 patient progressed to AML after 1 month of treatment. HI-P was observed in 26 of 68 (38%) patients, while response was ongoing in 24 of them beyond week 16. Moreover, rate of HI-P lasting for at least 8 weeks was notably higher in cohort A (45%, n=21/47) compared to patients in cohort B and C (24%, n=5/21) (p=0.11). Median peak increase of PLT count in responding patients was 199 G/L in cohort A and 83 G/L in cohort B (p=0.25) and was observed in median after 7 weeks (range 3-16). In addition, responses occurred also in 2 patients in the neutrophil (HI-N) and in 7 patients in the erythroid (HI-E) lineage according to IWG 2006 criteria (Table 1). Explorative analysis showed a correlation between pretreatment platelet transfusion requirement and endogenous TPO-levels (spearman-test, p=0.034). Median pretreatment endogenous TPO-level was lower in responders compared to non-responders (82 vs. 103 pg/ml, p=0.15). Higher response rates occurred in patients with lower TPO-levels (<500 ng/l) and lower pre-treatment transfusion needs (PTE<6 units/past year), but both variables were not significantly associated with response to romiplostim (univariable logistic regression, p= 0.13 and p=0.53, respectively). Evaluation of the mutational profile in a subgroup of 49 patients demonstrated that 67% of responders exhibited spliceosome mutations including SRSF2, SF3B1, U2AF1 and ZRSR2 compared to 35% in non-responders (p=0.06) (Table 1). Conclusion: This prospective study confirms that romiplostim treatment is highly effective in a subgroup of LR-MDS patients, but neither baseline platelet transfusion requirements nor baseline TPO levels were significantly associated with clinical response to romiplostim. Further translational analyses are ongoing to elucidate potential biomarkers of response. Disclosures Platzbecker: Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Götze:AbbVie: Membership on an entity's Board of Directors or advisory committees. Cony-Makhoul:Pfizer: Consultancy; Novartis: Consultancy; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Park:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thiede:Daiichi Sankyo: Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; AgenDix GmbH: Employment, Equity Ownership; Diaceutics: Membership on an entity's Board of Directors or advisory committees. Ades:Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. OffLabel Disclosure: Romiplostim is formally not licensed for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS).

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An Interim Analysis Of a Phase 2, Single-Arm Study Of Platelet Responses and Remission Rates In Patients With Immune Thrombocytopenia (ITP) Receiving Romiplostim

Blood ◽

10.1182/blood.v122.21.1074.1074 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1074-1074 ◽

Cited By ~ 1

Author(s):

Roberto Stasi ◽

Adrian Newland ◽

Bertrand Godeau ◽

Victor Priego ◽

Jean-Francois Viallard ◽

...

Keyword(s):

Platelet Count ◽

Adverse Events ◽

Board Of Directors ◽

Treatment Period ◽

Research Funding ◽

Alternative Therapy ◽

Platelet Response ◽

Advisory Committees ◽

Serious Adverse Events ◽

Platelet Counts

Abstract Background We describe here platelet response and remission observed with romiplostim treatment in patients with ITP. Methods Patients with an ITP diagnosis for less than 6 months who received first-line therapies only (ie, corticosteroids, IVIG, anti-D) received QW romiplostim for up to 12 months in the treatment period (Fig 1). The primary objective was to describe the number of months with a platelet response during the 12-month treatment period; secondary objectives included incidence of ITP remission and splenectomy. The romiplostim dose was increased QW by 1 μg/kg from 1 μg/kg up to 10 μg/kg to reach a platelet count of ≥50x109/L, adjusting to maintain a platelet count of 50-200x109/L. Patients who maintained platelet counts ≥50x109/L on romiplostim only entered a dose-tapering period in which the romiplostim dose was decreased by 1 μg/kg Q2W as long as platelet counts remained ≥50x109/L. Starting when the dose tapered to 0 during either the 12-month treatment period or at the end of the dose-tapering period, patients were followed to determine whether they had ITP remission (24 weeks platelet counts ≥50x109/L without any treatment for ITP, including romiplostim). At the end of 12 months, patients who 1) had platelet counts ≤20x109/L for <4 consecutive weeks, 2) had platelet counts of 20-50x109/L, and/or 3) were receiving treatment for ITP besides romiplostim had the option to enter a stabilization period (≤8 weeks) while the investigator determined suitable post-study therapy. Patients with platelet counts ≤20x109/L for ≥4 consecutive weeks on the highest romiplostim dose were discontinued from the study for non-response. Interim data up to March 2013 are reported here. Results Of the patient population (N = 71), 59.2% were women, median (Q1, Q3) age was 37 (28, 56) years, median (Q1, Q3) time since ITP diagnosis was 2.2 (0.9, 4.4) months, and median (Q1, Q3) platelet count at screening was 20 (12, 25) x109/L. Past treatments included steroids (96%), IVIG (42%), and anti-D (1%). Prior to the study, platelet transfusions were received by 9% of patients. 30 patients (42%) completed treatment, 31 (44%) are continuing treatment, and 10 (14%) discontinued romiplostim (due to consent withdrawn n = 2, adverse event n = 3, requirement for alternative therapy n = 3, lost to follow-up n = 1, death n = 1). Patients had a median (Q1, Q3) of 51 (34, 52) weeks of treatment with a median (Q1, Q3) average QW dose of 2.1 (1, 3.8) μg/kg. 66 (93%) patients had a peak platelet count ≥50x109/L. The median (Q1, Q3) time with a platelet response was 9 (6, 12) months; the median (95% CI) time to platelet response was 2.1 (1.1, 3.1) weeks; platelet counts are in Fig 2. Of 38 evaluable patients (ie, known remission status), 11 (29%, 95% CI 15% to 46%) had ITP remission. One patient had a splenectomy and 6 had treatment failure (defined as platelet count ≤20x109/L for 4 consecutive weeks at 10 μg/kg QW, requirement of alternative therapy, or death). Of the 71 patients receiving romiplostim, 9 patients had serious adverse events (2 treatment-related: 1 case each of gastritis and increased transaminases). There were also 3 adverse events leading to discontinuation of romiplostim (non-Hodgkin's lymphoma, leukocytosis, and the aforementioned increased transaminases, these last 2 treatment-related). Other serious adverse events, also occurring in 1 patient each, included atrial fibrillation, dapsone syndrome, fecaloma, the aforementioned non-Hodgkin's lymphoma, pleuritic pain, and tendon rupture. There were no fatalities reported as adverse events; the death leading to discontinuation was due to cerebral hemorrhage which began before the patient received romiplostim. The most common adverse events were headache (17%), arthralgia (13%), and nasopharyngitis (10%). The most common hemorrhage adverse events were hematoma (7%), petechiae (7%), and epistaxis (7%). No bone marrow findings were reported. Conclusions In this trial, patients with an ITP diagnosis for less than 6 months treated with romiplostim had a high response rate (over 90%), with platelet responses occurring quickly (median time to response of 2 weeks) and median number of months with a platelet response of 9 months. To date, 29% of evaluable patients have shown remission (24 weeks of platelet counts ≥50x109/L without any ITP treatment). There were no new safety signals. Updated data from this ongoing study will be presented in the future. Disclosures: Stasi: Amgen: Honoraria, Speakers Bureau; GSK: Honoraria, Speakers Bureau; Genzyme: Honoraria, Speakers Bureau; Suppremol: Consultancy. Newland:Geron: Consultancy; Amgen: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Research Funding. Godeau:Amgen: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Roche: Consultancy, Research Funding; GSK: Consultancy; LFB: Consultancy. Jia:Amgen: Employment, Equity Ownership. Lopez:Amgen: Employment, Equity Ownership.

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Efficacy of Eltrombopag in Adult East Asian and Non-East Asian Patients with Chronic Immune Thrombocytopenia (cITP): Results from the Extend Study

Blood ◽

10.1182/blood.v128.22.4930.4930 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4930-4930 ◽

Cited By ~ 3

Author(s):

Raymond SM Wong ◽

James B Bussel ◽

Mansoor N. Saleh ◽

Abderrahim Khelif ◽

Balkis Meddeb ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

East Asian ◽

Platelet Response ◽

Advisory Committees ◽

Asian Origin ◽

Platelet Counts ◽

Asian Patients ◽

Starting Dose ◽

East Asian Patients

Abstract Introduction: Eltrombopag is an oral thrombopoietin receptor agonist, approved for the treatment of patients with cITP (persisting >12 months) aged ≥1 year, who are refractory to other treatments (eg corticosteroids, immunoglobulins). Pharmacokinetic studies of eltrombopag have demonstrated that patients of East Asian origin (eg Japanese, Chinese, Taiwanese and Korean) experience increased plasma exposure to eltrombopag compared to non-East Asian patients (predominantly Caucasian). As such, the recommended starting dose is 25 mg/day for East Asian patients, compared with 50 mg/day in non-East Asians. In the EXTEND (Eltrombopag eXTENded Dosing) study, all patients, irrespective of ancestry, received 50 mg/day starting dose that was subsequently adjusted to the platelet response. Unpublished anecdotal reports of platelet responses in East Asian patients from EXTEND describe lower doses of eltrombopag. Here, we examine the responses to eltrombopag in East Asian and non-East Asian patients who completed the EXTEND study. Methods : Adult patients (≥18 years old) diagnosed with cITP who had completed a previous ITP study of eltrombopag were enrolled in EXTEND. All patients received eltrombopag starting at 50 mg/day, titrated to 25-75 mg/day or less often as required, based on individual platelet count responses (range ≥50-200x109/L). Maintenance dosing continued after minimization of concomitant ITP medication and optimization of eltrombopag dosing. Patients who received 2 years of treatment and transitioned off due to commercial availability of eltrombopag were considered to have completed the study. Patients could remain on study beyond 2 years until eltrombopag became commercially available. Here we describe the efficacy and durability of response in East Asian and non-East Asian patients. Analyses were conducted using the safety population, defined as all patients who had taken at least one dose of the study medication. Results: Of 302 patients enrolled and exposed to treatment (median duration 2.4 years [range, 2 days to 8.8 years]), 41 (14%) were of East Asian origin. Mean average eltrombopag dose in East Asian and non-East Asian patients was 48.9 (range 4.2-74.9) mg/day and 50.4 (range 1.0-74.6) mg/day, respectively. Maintenance of platelet counts ≥30×109/L for at least 25 weeks was seen in 25/35 (71%) East Asian and 158/222 (71%) non-East Asian patients. In total, 13/35 (37%) East Asian patients and 120/222 (54%) non-East Asian patients maintained continuous platelet counts ≥50×109/L for at least 25 weeks, without rescue therapy (Figure). At the start of response, mean daily dose in East Asian and non-East Asian patients was 45.2 and 45.4 mg/day, respectively. The number of patients receiving dose adjustments according to platelet response was similar in East Asian and non-East Asian patients (Table). Conclusions: Treatment with eltrombopag in East Asian and non-East Asian patients resulted in sustained platelet responses ≥30×109/L for at least 25 weeks in a similar proportion of patients. However, a higher proportion of non-East Asian patients achieved continuous platelet counts ≥50×109/L. Direct comparisons should be interpreted with caution because: a) of limited patient numbers in the East Asian group; b) the possible selection bias of patients entering the EXTEND study following completion of earlier eltrombopag studies, eg, primarily responders; and c) the absence of PK data from these patient groups. All patients received similar doses of eltrombopag irrespective of racial background, and dose modifications according to platelet responses were similar. Further investigations are ongoing to determine whether there were any differences in terms of safety and tolerability outcomes in East Asian and non-East Asian patients. Disclosures Wong: Bayer, Biogen-Idec, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, and Roche: Research Funding; Biogen-Idec and Novartis: Membership on an entity's Board of Directors or advisory committees; Bayer, Biogen-Idec and Novartis: Consultancy. Bussel:Amgen, Novartis & GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingleheim, Prophylix Pharma, Protalex, Rigel Pharmaceuticals: Research Funding; Momenta Pharmaceuticals, Novartis, Prophylix Pharma, Protalex, Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; UptoDate: Patents & Royalties; Physicians Education Resource: Speakers Bureau. Saleh:GSK: Consultancy, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Quebe-Fehling:Novartis: Employment.

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Incidence and Predictors of Hepatic Veno-Occlusive Disease after Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-113130 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3376-3376

Author(s):

Clinton Lewis ◽

Haesook T. Kim ◽

Corey S. Cutler ◽

John Koreth ◽

Sarah Nikiforow ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Platelet Transfusion ◽

Kidney Injury ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Transfusion Requirements ◽

Reduced Intensity

Abstract Introduction: Hepatic veno-occlusive disease (VOD)/Sinusoidal Obstruction Syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT) that is triggered, at least in part, by conditioning regimen-induced sinusoidal endothelial cell injury. VOD is thus commonly, but not exclusively, associated with myeloablative conditioning (MAC). The incidence of VOD in reduced intensity conditioning (RIC) HSCT was ≈2% in a single center series (Carreras et al. BBMT 2011), and risk factors for VOD in RIC HSCT remain poorly defined. Methods: We performed a retrospective review to confirm all cases of VOD among patients undergoing RIC HSCT at the Dana-Farber Cancer Institute/Brigham and Women's Cancer Center between January 2007 and June 2017. Diagnosis of VOD was based on modified Seattle or Baltimore criteria and/or liver biopsy or RUQ ultrasound in conjunction with fluid retention/ascites and hepatomegaly/RUQ pain. Diagnosis dates for all VOD cases were confirmed and clinico-laboratory values collected in the 10 days preceding the diagnosis. The same data were collected for a randomly selected control non-VOD RIC cohort, calculated from the median day of VOD onset derived from the cases. Acute kidney injury was defined as an absolute increase in creatine by 0.3 mg/dL or a relative increase of > 50% within a 48-hour period. Increased platelet transfusion requirement was defined as requiring a platelet transfusion on 2 consecutive days in the 7 days prior to VOD diagnosis, excluding transfusions for procedures. Incidence of VOD at D50 was calculated using a competing risk framework. Cox regression was used to identify significant features for predicting VOD. Survival was compared to a concurrent cohort of 76 patients with VOD after MAC HSCT recently published from our center (Roeker et al. BBMT 2018). Results: A total of 1492 patients underwent RIC HSCT, of whom 1070 (67.8%) received sirolimus (Sir) with tacrolimus (Tac) as part of the GVHD prophylaxis, and 1217 (82%) received intravenous busulfan(Bu) 3.2 or 6.4mg/kg with fludarabine(Flu) as conditioning. Twenty-six developed VOD (median day of diagnosis = d+26, range 5-48 days), for a cumulative incidence of 1.6% (95%CI 1.1%-2.4%). The median bilirubin at diagnosis was 1.1 mg/dL(range 0.6-5.2). Only 5 (19.2%) patients had a bilirubin of ≥2.0 mg/dL on the date of VOD diagnosis, although total bilirubin peaked at ≥ 2 mg/dL in 17 of 26 (65.4%). VOD was mild/moderate in 16 and severe in 10 patients. Sixteen had received ursodiol as VOD prophylaxis. Defibrotide was used as treatment in 17 cases. The 2-year overall survival (OS) was 54% from VOD onset. VOD was associated with increased risk for NRM (HR 4.02, 95% CI 2.1-7.7, p<0.0001), but not OS (HR 1.53, 95% CI 0.9-2.6, p= 0.11), PFS (HR 1.42, 95% CI 0.9-2.4, p= 0.17) or relapse (HR 0.68, 95% CI 0.3-1.5, p= 0.35). Compared to patients who developed VOD after MAC, OS at 2 years after VOD was better in RIC patients (54% vs. 28%, p=0.04). Use of ursodiol was not associated with any reduction in VOD incidence. In the multivariable model, the only significant risk factor for VOD was use of Sir with Tac for GVHD prophylaxis (HR 3.2, 95% CI 1.26-12.17). Among RIC Bu/Flu patients who received Tac/Sir based GVHD prophylaxis, 18/877 (2.1%) developed VOD, compared to 1/351 (0.28%) in RIC Bu/Flu patients without Sir, p <0.01. To assess clinico-laboratory predictors of VOD patients in the 10 days prior to VOD diagnosis, we compared the 26 VOD cases to 65 randomly selected control RIC patients. The groups were well matched with regards to baseline characteristics. In the 10 days prior to VOD diagnosis (or D+26 for controls), VOD patients were significantly more likely to develop acute kidney injury, peak creatinine >1, increasing platelet transfusion requirements, and increasing Tac and Sir trough levels (Table 1, Fig 1). Conclusions: The incidence of VOD in this large modern cohort of 1492 RIC HSCT patients was 1.6%, and was associated with the use of Sir with Tac. Onset of VOD in RIC patients was delayed (median D+26 vs. D+14) and 2 yr-OS is superior compared to MAC patients. Only 19% of the RIC VOD cases met the bilirubin threshold for Baltimore and Seattle criteria at diagnosis, suggesting that the rise in bilirubin is a later event in these RIC VOD cases, whereas increasing platelet transfusion requirements, sudden rise in Tac and Sir levels, elevated serum creatinine and acute renal injury appear to be early clinical predictors. Disclosures Nikiforow: Kite Pharma: Consultancy. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Ho:Jazz Pharmaceuticals: Consultancy.

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Immature Platelet Fraction Does Not Correlate with Treatment Response in Immune Thrombocytopenia

Blood ◽

10.1182/blood-2021-151681 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1024-1024

Author(s):

Emily M. Harris ◽

Michele P. Lambert ◽

Jenny M. Despotovic ◽

Susan E Kirk ◽

Abinaya Arulselvan ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Response To Treatment ◽

Platelet Response ◽

Advisory Committees ◽

Platelet Counts ◽

Thrombopoietin Receptor ◽

Immature Platelet Fraction ◽

Pre Treatment

Abstract Background: As the treatment options for immune thrombocytopenia (ITP) continue to expand, the choice of which treatment to give to an individual patient has become increasingly complex. Therefore, a laboratory marker to help guide treatment selection would be clinically useful. The immature platelet fraction (IPF), measured clinically by automated Sysmex hematologic analyzers, correlates with bone marrow thrombopoietic activity and may correlate with disease activity in patients with ITP. Objective: To investigate the relationship between pre-treatment immature platelet fraction (IPF) and treatment response among pediatric patients with ITP. Methods: This is an observational cohort study of 148 patients with ITP who received ITP-directed treatment as monotherapy at 3 tertiary academic children's hospitals. Eligibility included a clinical diagnosis of ITP, ITP-directed surgical or pharmacologic treatment given as monotherapy, and available pre-treatment IPF values. The Sysmex XN-series measures IPF by adopted fluorescence flow cytometry using a semiconductor dioxide laser to measure platelets stained with oxazine fluorescent dyes. Demographic and clinical characteristics, laboratory studies, and treatments were collected. Response to treatment was defined as a platelet count ≥30 x 10 9/L and at least 2-fold increase from the baseline platelet count within 3 weeks of first dose of IVIG, Rh(D) immune globulin, or corticosteroid or within 3 months of all other therapies. For second-line treatments, platelet counts within 1 month after a rescue therapy were excluded. Regression analysis was utilized to estimate association between variables; estimated coefficients and p values are reported. Results: The cohort included 148 patients, 52% (n=77) of whom were female. Median age of diagnosis was 8 years (IQR: 3-13). Twenty percent (n=29) of treated patients had secondary ITP including 9 (6%) with Evans syndrome. Median platelet count at time of diagnosis was 5 x 10 9/L, and median IPF at diagnosis was 16.7% (IQR: 7.7-25.8). Median pre-treatment platelet count was 17 x 10 9/L with a median pre-treatment IPF of 16.6% (IQR: 10.0-25.7). There was a significant association between pre-treatment platelet count and pre-treatment IPF (coefficient -0.176, p = 0.003). Increased variation in IPF was seen at lower platelet counts compared to higher platelet counts (p=0.014, Figure 1a). IPF at diagnosis and pre-treatment IPF were not correlated with platelet response to treatment overall (p=0.28 for pre-treatment IPF, p=0.31 for IPF at diagnosis). IPF prior to treatment did not correlate with platelet response to individual medications: IVIG (coefficient 0.001, p=0.78, n=64), corticosteroids (coefficient 0.007, p=0.28, n=43), Rituximab (coefficient -0.01, p=0.52, n=10), and thrombopoietin receptor agonists (coefficient 0.0006, p=0.93, n=26, Figure 1b). Similarly, IPF at diagnosis of ITP did not correlate with platelet response to individual medications. Conclusions: Pre-treatment platelet count and IPF are inversely correlated in children with ITP, although there is significant variability in IPF at low platelet counts. The IPF at ITP diagnosis and prior to treatment does not correlate with platelet response to the most common ITP-directed treatments in children. A normal or elevated IPF should not impact decision-making about initiation of any specific ITP-directed treatments, including thrombopoietin receptor agonists or immunosuppressive therapy, in children with ITP. Figure 1 Figure 1. Disclosures Lambert: Principia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy; Sysmex: Research Funding; Astra Zeneca: Research Funding; Dova: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PDSA: Research Funding; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; ClinGen, ISTH, ASH, GW University: Honoraria; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Despotovic: Apellis: Consultancy; UpToDate: Patents & Royalties: Royalties; Novartis: Consultancy, Research Funding; Agios: Consultancy. Kirk: Biomarin: Honoraria. Grace: Agios: Research Funding; Novartis: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Principia: Membership on an entity's Board of Directors or advisory committees.

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Large Population Dataset Linkage to Understand Evolving Practice in Red Cell and Platelet Transfusion and Clinical Outcomes in Patients with Myelodysplastic Syndromes (MDS): A 15-Year Study

Blood ◽

10.1182/blood-2021-147132 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3255-3255

Author(s):

Allison Mo ◽

Jake Shortt ◽

Erica M. Wood ◽

Zoe K McQuilten

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Platelet Transfusion ◽

Hospital Admissions ◽

Advisory Committees ◽

Disease Modifying Therapies ◽

Transfusion Requirements ◽

Rbc Transfusion ◽

Over Time ◽

Platelet Transfusions

Abstract Aim: Transfusions are frequently administered for anemia and thrombocytopenia in MDS. However, evidence to guide transfusion remains sparse, along with data about real-world MDS transfusion practices, transfusion-related outcomes and changes over time with increasing access to disease-modifying therapies. In Australia, from 2011, 5-azacitidine was funded through the Pharmaceutical Benefit Scheme (PBS) for patients with IPSS classification intermediate-2 or high-risk MDS, or Chronic Myelomonocytic Leukemia-2 (CMML-2). Australian Patient Blood Management (PBM) guidelines were also first published in 2011. We aimed to characterise red blood cell (RBC) and platelet transfusion practices, and transfusion-related outcomes of MDS and CMML patients over a 15 year period, and explore whether access to disease-modifying therapies or the introduction of PBM guidelines impacted on transfusion requirements. Methods: Retrospective longitudinal cohort study including all patients with MDS/CMML admitted to hospitals in Victoria, Australia's second most populous state, from 2002-2017. Data linkage from the Victorian Admissions Episode Dataset (VAED) (contains data from all public and private hospital admissions in Victoria, including all transfusion episodes), the Victorian Cancer Registry and the Victorian Death Index was performed. We analysed transfusion episodes and outcome events (cardiac ischemia/failure, transfusion reactions, bleeding). Results: 6771 patients with a diagnosis of MDS/CMML reported to the Cancer Registry were included (5970 MDS; 801 CMML). The cohort was elderly (>50% aged 70y and over) and predominantly male (male 61%; female 39%). The majority of patients had a low number of comorbidities (Charlson Comorbidity Score: 60% low (0-2); 32% moderate (3-5); 8% high (≥6)). Of the 179 patients on 5-azacitidine, 38 (21.2%) commenced prior to 2011 and 141 (78.8%) from 2011 onwards. Patients on 5-azacitidine were more likely to be RBC transfusion dependent (TD) (defined as 2 or more RBC transfusions within 16 weeks) (77.7.1% vs 49.9%, p<0.001) and receive platelet transfusions (54.2% vs 28.6%, p<0.001). During the study period, the patients had a total of 142,765 hospital admissions. 66,068 (46.3%) admissions involved RBC transfusion, with median 3 admissions (IQR 1-10) per patient and median 14 days (IQR 14-33) between transfusions. 3433 (50.7%) of patients were RBC transfusion-dependent (TD). Comparing pre-and post-2011, the proportion of admissions involving RBC transfusion, median number of RBC transfusion admissions per patient, and rates of RBC-TD decreased (table 1). Cardiac events were common, and more frequent in RBC-TD patients (acute cardiac ischemia 14.6% vs 10.3%, p<0.001; acute cardiac failure 27.3% vs 14.1%,p<0.001). 10,049 (7.0%) admissions involved platelet transfusion. Platelet transfusion admissions increased over time (table 1). Median time between platelet transfusions was 7 days (IQR 4-16). 2436 patients (36.0%) experienced bleeding, including 51.3% of platelet-transfused patients. The commonest bleeding site was gastrointestinal (n=1388, 20.5%). Intracranial bleeding occurred in 175 patients (2.6%). 300 patients (4.4%) died from bleeding complications, with higher bleeding-related mortality in platelet-transfused patients (7.0% vs 3.4%, p<0.001) and RBC-TD patients (5.2% vs 4.0%, p=0.001). Conclusion: This study highlights the high transfusion burden in MDS patients, and related adverse cardiac and bleeding outcomes and mortality. RBC transfusion requirements reduced over time but platelet transfusions increased. This may be related to changing availability or use of MDS therapies, or clinical transfusion decision-making practices, or both - although national PBM guidelines do not specify a particular hemoglobin threshold for chronically transfused MDS patients, clinicians may be extrapolating from recommendations for restrictive transfusion thresholds in other settings (e.g. critical care, perioperative transfusion). These data will help design future MDS transfusion trials, which should include quality-of-life and health economics outcomes, given the burden of transfusion on these elderly patients. Figure 1 Figure 1. Disclosures Shortt: Amgen: Research Funding; Astex: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Wood: Amgen, Celgene, Gilead, Janssen, Novartis, Sanofi, Takeda: Research Funding; Abbvie, Amgen, Antengene, Bristol-Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi, and Takeda.: Other: The Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) has received funding from Abbvie, Amgen, Antengene, Bristol-Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi, and Takeda. .

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BCX9930, a Potent, Selective, Oral Factor D Inhibitor, Demonstrates Proof-of-Concept As Monotherapy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Blood ◽

10.1182/blood-2020-138838 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-15

Author(s):

Austin Kulasekararaj ◽

Jacques Le Roux Malherbe ◽

Andrew McDonald ◽

Melanie Cornpropst ◽

Phil Collis ◽

...

Keyword(s):

South Africa ◽

Board Of Directors ◽

Research Funding ◽

Total Bilirubin ◽

Proof Of Concept ◽

Advisory Committees ◽

Clone Size ◽

The Past ◽

History Of ◽

Pre Treatment

INTRODUCTION: PNH, a rare, chronic, life-threatening disease, is characterized by hemolytic anemia due to uncontrolled activity of the complement alternative pathway (AP), bone marrow failure, and thrombosis. Inhibition of C5 by intravenously administered eculizumab and ravulizumab reduces intravascular hemolysis, but PNH red blood cells (RBCs) become opsonized and susceptible to extravascular hemolysis (Risitano et al, Blood 2009). Only approximately half of PNH patients become transfusion independent with eculizumab treatment (Hillmen et al, NEJM 2006). BCX9930 is a potent, selective, orally administered inhibitor of complement factor D. Inhibition of factor D may prevent both intravascular and extravascular hemolysis in PNH. In healthy subjects, BCX9930 showed linear pharmacokinetics and dose-related AP suppression, and was safe and generally well-tolerated over a wide dose range. Here we describe safety and laboratory data establishing proof-of-concept for BCX9930 monotherapy in PNH patients in Study BCX9930-101 (NCT04330534). METHODS: Ongoing Study BCX9930-101 includes an open-label, dose-ranging evaluation of BCX9930 in PNH subjects who may either be naïve to C5 inhibitors (and receive BCX9930 as monotherapy) or have an incomplete treatment response to eculizumab or ravulizumab (with BCX9930 added to existing treatment). Up to 4 sequential cohorts each use a forced titration design for the first 28 days (Figure 1). Subjects enrolled in South Africa can participate in an individualized 48-week extension if they derive benefit at Day 28. Clinical benefit from BCX9930 is evaluated using laboratory monitoring and symptom assessment. Safety and tolerability are evaluated via clinical and laboratory monitoring, causality of adverse events is assessed by investigators, and the study is overseen by an independent Data Monitoring Committee. Data from Cohort 1 through 28 days is reported; data from the extension and subsequent cohorts will be subsequently summarized as available. RESULTS: To date, four C5 inhibitor naïve PNH subjects in South Africa have enrolled in Cohort 1. These subjects had PNH for a median of 4.5 years; 2 subjects had a history of transfusions in the past year; 1 subject each had a history of aplastic anemia or major thrombosis. Pre-treatment lactate dehydrogenase (LDH), total bilirubin, hemoglobin (Hb), reticulocyte count, and RBC PNH Type III clone size ranged from 3.7-11.1 × ULN, 0.61-3.3 mg/dL, 6.1-11.6 g/dL, 0.13-0.29 × 106/µL, and 41.4%-88.6% respectively. Treatment over 28 days with 50 mg twice daily (BID; Days 1-14) and 100 mg BID (Days 15-28) of BCX9930 produced dose-dependent, clinically meaningful improvements across hemolysis biomarkers (Figure 2). Decreases were observed in LDH (4/4), reticulocytes (4/4), and total bilirubin (2/2 subjects with elevated pre-treatment values). Increases were observed in Hb (3/4) and PNH RBC clone size (4/4). One subject showed an initial response to BCX9930 50 mg BID, followed by worsening indicators of hemolysis temporally associated with an upper respiratory tract infection (URTI; onset on Day 7). With an increase in dose to 100 mg BID and resolution of the URTI, LDH and reticulocytes fell and Hb rose. All four subjects reported one or more PNH-associated symptoms, including hemoglobinuria, jaundice, fatigue, erectile dysfunction, headache and abdominal pain, prior to enrollment. With the exception of one subject with persistent hemoglobinuria, all symptoms resolved by Day 28 on BCX9930. Three subjects experienced moderate headache that resolved in < 3 days after initiating BCX9930. One subject developed a rash during treatment with amoxicillin for an URTI; the rash resolved while continuing BCX9930 dosing. One subject on concomitant chronic corticosteroids and azathioprine had an unrelated fatal serious adverse event of disseminated varicella during the study extension. Based on review of safety data, Cohort 2 opened at doses of 200 mg BID and 400 mg BID and, in the 3 subjects who continued into the extension, the dose was titrated to ≥ 200 mg BID. CONCLUSIONS: Oral BCX9930 elicited rapid changes in laboratory parameters indicative of reduced hemolysis and clinical benefit and was safe and generally well-tolerated over a 28-day dosing interval. These interim results establish proof of concept for monotherapy with BCX9930 in the treatment of C5-inhibitor naïve PNH patients and support evaluation of higher doses. Disclosures Kulasekararaj: Alexion:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Ra Pharma:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;BioCryst Pharmaceuticals, Inc.:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Apellis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Celgene:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau.Malherbe:Key Oncologics:Honoraria, Other: Conference sponsor;Novartis:Other: Conference sponsor;Astellas:Honoraria, Other: Conference sponsor;Takeda:Consultancy;Acino:Honoraria;Shire:Other: Conference sponsor;BioCryst Pharmaceuticals, Inc.:Consultancy;Janssen:Consultancy, Honoraria, Other: Conference sponsor;Roche:Honoraria, Other: Conference sponsor.McDonald:venetoclax advisory board in South Africa (in CLL context):Consultancy;Alberts Cellular Therapy:Current Employment.Cornpropst:BioCryst Pharmaceuticals, Inc.:Current Employment.Collis:BioCryst Pharmaceuticals, Inc.:Current Employment.Davidson:BioCryst Pharmaceuticals, Inc.:Current Employment.Chen:BioCryst Pharmaceuticals, Inc.:Current Employment.Tower:BioCryst Pharmaceuticals, Inc.:Current Employment.Gesty-Palmer:BioCryst Pharmaceuticals, Inc.:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Sheridan:BioCryst Pharmaceuticals, Inc.:Current Employment.Risitano:Alexion:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Alnylam:Research Funding;Novartis:Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Pfizer:Speakers Bureau;Achillion:Membership on an entity's Board of Directors or advisory committees;Apellis:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Biocryst:Membership on an entity's Board of Directors or advisory committees;RA pharma:Research Funding;Amyndas:Consultancy;Samsung:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;Jazz:Speakers Bureau.

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To Treat or Not to Treat? Understanding Treatment Patterns in Patients with Lower-Risk Myelofibrosis at the Time of Enrollment in the MOST Study

Blood ◽

10.1182/blood-2020-134958 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 49-51

Author(s):

Rami S. Komrokji ◽

Brady L. Stein ◽

Robyn M. Scherber ◽

Patricia Kalafut ◽

Haobo Ren ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Symptom Burden ◽

Risk Groups ◽

Treatment Patterns ◽

Low Risk ◽

Publicly Traded ◽

Advisory Committees ◽

Therapy Initiation

Background: Myelofibrosis (MF) is a chronic Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) characterized by extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly, constitutional symptoms, and diminished quality of life. Treatment decisions may involve a variety of factors including prognosis and symptomatology. Data regarding real-world disease and demographic factors that contribute to therapy initiation and choice in pts with lower risk MF are limited. This analysis of data from the ongoing Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST; NCT02953704) assessed whether these factors differ for lower risk pts who were treated vs untreated at enrollment. Methods: MOST is a longitudinal, noninterventional, prospective, observational study in pts with MF or essential thrombocythemia enrolled at clinical practices within the US. Pts included in the analysis (≥18 y), had low risk MF by the Dynamic International Prognostic Scoring System (DIPSS; Blood. 2010;115:1703), or intermediate-1 (INT-1) risk by age >65 y alone. Pt data were entered into an electronic case report form during usual-care visits over a planned 36-month observation period. Pt-reported symptom burden was assessed using the MPN-Symptom Assessment Form (MPN-SAF); Total Symptom Score (TSS) was calculated (0 [absent] to 100 [worst imaginable]; J Clin Oncol. 2012;30:4098). Data were analyzed with basic descriptive and inferential statistics. Results: Of 233 pts with MF enrolled at 124 sites between 11/29/2016 and 03/29/2019, 205 were included in this analysis; 28 were excluded for being INT-1 risk for reasons other than age. Of the 205 pts, 85 (41.5%) were low- and 120 (58.5%) were INT-1 risk; 56.5% (48/85) and 59.2% (71/120), respectively, were being treated at enrollment. Pt characteristics are listed in Table 1A. Fewer low- vs INT-1 risk pts were JAK2 V617F or MPL positive, and more were CALR positive. The proportion of pts with palpable splenomegaly was similar for treated low- and INT-1 risk pts. In low risk pts, the proportion of pts with palpable splenomegaly was higher in untreated vs treated pts; whereas, in INT-1 risk pts, the opposite was observed (ie, lower proportion in untreated vs treated pts). Blood counts were generally similar across cohorts, except median leukocytes were lower for low risk treated pts and platelet counts were elevated in low- vs INT-1 risk pts. The proportion of pts with comorbidities was similar across cohorts, except for fewer cardiovascular comorbidities in low- vs INT-1 risk pts. Mean TSS was lower in low- vs INT-1 risk pts, but the proportion of pts with TSS ≥20 was greater in treated vs untreated pts in both low- and INT-1 risk groups. Fatigue was the most severe pt-reported symptom in all cohorts. Differences in mean TSS and individual symptom scores between risk groups were not significant (P > 0.05), except itching was worse among INT-1 risk pts (P=0.03). Physician-reported signs and symptoms were generally more frequent for untreated vs treated pts, irrespective of risk (all P > 0.05). Most low risk (69.4%) and INT-1 risk pts (61.2%) who were currently untreated at enrollment had not received any prior MF-directed treatment (Table 1B); the most common prior treatment among currently untreated pts was hydroxyurea (HU) in both risk groups. Of currently treated pts, HU was the most common MF-directed monotherapy at enrollment in low-risk pts, and ruxolitinib was most common in INT-1 risk pts. No low risk pts and few INT-1 risk pts were currently receiving >1 MF-directed therapy at enrollment. Conclusion: These real-world data from pts with MF enrolled in MOST show that a substantial proportion of both low- and INT-1 risk pts who had received treatment before enrollment were not being treated at the time of enrollment. Although watch-and-wait is a therapeutic option, the finding that many of these lower risk pts had in fact received prior therapies suggests an unmet need for effective and tolerable second-line treatment options. Treated pts had greater pt-reported symptom burden vs untreated pts, which suggests that high symptom burden may contribute to the decision for treatment. Prospective studies are needed to evaluate symptom burden change with therapy initiation. In this regard, future analyses of data from MOST are planned to assess the longitudinal evolution of the clinical characteristics, treatment patterns, and management of pts with MF. Disclosures Komrokji: Geron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Acceleron: Honoraria. Stein:Incyte: Research Funding; Kartos: Other: educational content presented; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmaessentia: Membership on an entity's Board of Directors or advisory committees. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kalafut:Incyte: Current Employment, Current equity holder in publicly-traded company. Ren:Incyte: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; CTI Biopharma Corp: Research Funding; NS Pharma: Research Funding; ItalPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding.

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