Real-World Clinical Outcomes of Patients with Myelofibrosis Treated with Ruxolitinib: Evidence from a Multinational Medical Record Review

Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by cytopenia, splenomegaly, and debilitating constitutional symptoms, such as fatigue, night sweats, weight loss, bone pain, and pruritus. Prior to the approval of the selective Janus kinase-2 (JAK2) inhibitor fedratinib for adults with Intermediate (Int)-2 or High-risk MF in 2019, ruxolitinib (RUX) was the only FDA-approved JAK inhibitor and considered standard of care; treatment (tx) options after RUX were limited. Furthermore, although about 60% of pts carry JAK2 mutations, not all patients respond to RUX. The aim of this study was to describe real-world tx patterns and determine unmet need in pts with MF treated with RUX. Methods: We report interim data collected from the UK and USA as part of a global retrospective medical chart review of adult pts with Int-1, Int-2, or High-risk MF who started RUX tx between Jan 2012 and Dec 2016 in the USA, UK, Germany, Spain, Canada, and France, Pts were required to have discontinued RUX prior to data abstraction (Apr-May 2020). Prior tx was allowed, except for allogeneic hematopoietic cell transplantation or JAK2 inhibitor trial participation. Study measures included pt and tx characteristics at RUX initiation, tx patterns, dose modifications (DMs), and clinical outcomes. The rate of DMs (decrease or increase) during the first 6 months of tx was assessed. Recommended dose (REC) as per US FDA label of RUX was determined via baseline platelet count; atypical dose (ATY) was defined as non-REC RUX. The Kaplan-Meier method was used to estimate median overall survival (OS) from start of RUX tx. Descriptive statistics are used in this report. Results: A total of 183 pts (USA: 105, UK: 78) were included in the analysis. Mean age at diagnosis was 63 years, 69% were male, and 82% were White. Most pts had primary MF (84%), Int-2-risk disease (51%), and JAK2 V617F driver mutation (67%). RUX was first-line MF tx in 100 pts (55%). Of 140 pts with baseline platelet counts, 46% started on REC RUX, and 54% started ATY RUX. Of pts who initiated ATY RUX, those with platelet count below 200 ×109/L were more likely to receive a higher dose; those with a platelet count above 200 ×109/L, were more likely to receive a lower dose. The median time from diagnosis to RUX initiation overall was 1.3 months (mos); this was shorter in pts initiated on REC RUX and longer in pts initiated on ATY RUX (Table). The median duration of tx (DoT) was higher for pts who initiated ATY RUX vs REC RUX (Table). Among pts who had a dose change (n = 61), change in platelet/neutrophil count (43%), and inadequate response (33%) were the main reasons for the first dose change; dose changes due to toxicity were more common with ATY RUX (33%) vs REC RUX (5%). Eighty-six pts (47%) had clinician-defined inadequate response or progressed on RUX. Pts starting ATY RUX (63% vs 39% for REC RUX) or having a DM within 6 mos of initiation (59% vs 49% for no DM) had a higher proportion of progressive disease (PD). Of those with inadequate response/PD, 69% discontinued RUX and 22% continued RUX due to lack of other effective tx. Twenty-eight percent of pts that started REC RUX discontinued RUX due to experiencing no additional clinical benefit after initial improvement; for pts who started ATY RUX, progression due to anemia (33%) was the main reason for discontinuation. In pts who did not discontinue RUX immediately after inadequate response/PD, median time to RUX discontinuation from inadequate response/PD was higher in pts who received ATY RUX vs REC RUX (6.1 vs 1.9 mos). Of 164 evaluable pts, 32 (20%) received post-RUX tx, most commonly hydroxyurea (28%) or lenalidomide (27%, USA only). Median OS since RUX initiation was 44.2 mos. OS was shorter in pts who started ATY vs REC RUX (40.9 vs 43.1 mos) and those who had a DM vs no DM within 6 mos (38.6 vs 43.0). The most common causes of death were PD (34%) and progression to AML (19%) - pts who received DMs within the first 6 mos were more likely to die from progression to AML (27%) vs those with no DMs (19%). Conclusions: In this population of adults with MF, we provide observational data that indicates DMs, including starting ATY RUX at higher or lower than REC doses, may be associated with poorer survival outcomes and higher rates of discontinuation due to PD. Relatively few pts received subsequent tx after discontinuing RUX, underscoring a significant unmet need for newer and more effective tx for MF. Disclosures Passamonti: Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support; BMS: Speakers Bureau. Heidel:Novartis: Consultancy, Honoraria, Research Funding. Parikh:RTI Health Solutions: Other: I am a full-time employee of RTI Health Solutions, which received research funding from BMS to perform this study. RTI Health Solutions is a unit of Research Triangle Institute, an independent, nonprofit, research organization that does work for govern. Tang:BMS: Current Employment, Current equity holder in publicly-traded company. Lahue:BMS: Consultancy; Alkemi LLC: Current Employment. Nadal:BMS: Current Employment. Davis:RTI Health Solutions: Other: I am a full-time employee of RTI Health Solutions, which received research funding from BMS to perform this study. RTI Health Solutions is a unit of Research Triangle Institute, an independent, nonprofit, research organization that does work for govern; BMS, Astra Zeneca, Vertex, Novartis, Esai, United Therapeutics, Pfizer: Research Funding. Ajmera:RTI Health Solutions: Current Employment. Kee:Bristol Myers Squibb: Current Employment. Abraham:BMS: Current Employment, Current equity holder in publicly-traded company.

Download Full-text

Six Month Treatment of Low Dose Eltrombopag Is Efficacious in Japanese Patients with Refractory Chronic Immune Thrombocytopenic Purpura (ITP).

Blood ◽

10.1182/blood.v114.22.1324.1324 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1324-1324 ◽

Cited By ~ 2

Author(s):

Yoshiaki Tomiyama ◽

Yoshitaka Miyakawa ◽

Shinichiro Okamoto ◽

Shinya Katsutani ◽

Akiro Kimura ◽

...

Keyword(s):

Platelet Count ◽

Initial Dose ◽

Research Funding ◽

Japanese Patients ◽

Target Range ◽

Advisory Committees ◽

Platelet Counts ◽

Caucasian Patients ◽

The Individual ◽

To Receive

Abstract Abstract 1324 Poster Board I-346 INTRODUCTION Eltrombopag (PROMACTA®, GlaxoSmithKline) is the first non peptide, oral thrombopoietin receptor agonist which promotes the differentiation and proliferation of megakaryocytes and increases platelet counts. This study is a randomized study comprising a double-blind (DB), placebo (PBO)-controlled phase, followed by an open-label (OL) phase in previously treated Japanese patients with chronic ITP and platelet counts <30Gi/L. Since eltrombopag exposure has been reported to be 70% higher in East Asian patients with ITP as compared to Caucasian patients and given the chronic nature of the disease state, the lower initial dose of 12.5mg/day was used in this study. METHODS In the DB phase, patients were randomized into one of two treatment groups to receive either an initial dose of 12.5mg of eltrombopag or matching PBO once daily. A dose increase was allowed at Day 22 based on individual platelet count. For each patient, primary data up to Week 6 were frozen and the treatment assignment was unblinded at Week 7 before entering into the OL phase. The primary endpoint of the DB phase was to compare the proportion of patients achieving a platelet count of ≥50Gi/L and ≤400Gi/L after 6 weeks of eltrombopag or PBO. All patients completing the DB phase progressed to the OL phase. In the OL phase, patients who had received eltrombopag during the DB phase continued to receive eltrombopag for up to 26 weeks with dosage (12.5, 25 or 50mg/day) based on the individual platelet count. Patients who had received PBO during the DB phase initiated treatment with 12.5mg of eltrombopag and received eltrombopag for 26 weeks with dosage (12.5, 25 or 50mg/day) based on the individual platelet count. The primary efficacy endpoint of the long-term OL phase was to assess the ability of eltrombopag to elevate and maintain platelet counts in a target range (50-400Gi/L) during 6 months of treatment. Bleeding symptoms were also assessed subjectively and objectively at each visit. Blood samples were collected to describe the PK profile of eltrombopag. RESULTS Of 23 patients randomized, 16 had undergone splenectomy, 17 had received H. pylori eradication and 19 were receiving concomitant ITP medication at baseline. DB Phase: 23 patients were randomized to receive 6 weeks of once daily eltrombopag (n=15) or matching PBO (n=8). By Week 3, 5 of 15 (33.3%) patients receiving 12.5mg eltrombopag achieved platelet counts >50Gi/L. Three of the responders had platelet counts ≥100Gi/L at Week 3. At the end of the Week 6, 9 of the 15 patients (60.0%) receiving eltrombopag were responders (platelet count 50-400Gi/L). Three of these patients were receiving 12.5mg and the remaining 6 were receiving 25mg. All PBO patients failed to achieve a response at any point during the 6 weeks. Long-term OL Phase: During the first 3 weeks when all patients received 12.5mg of eltrombopag, 21.7% of patients achieved a platelet response of ≥50Gi/L. From Day 22 onwards a greater proportion of patients (47.8-69.6%) achieved platelet counts within the target range of 50-400Gi/L. Over the initial 3 week period a gradual rise in median platelet counts was observed and a marked increase in the median platelet count was observed from Day 22. From Day 36 until Week 26 the median platelet count was consistently within the target range of 50-400Gi/L. Eltrombopag therapy was associated with a consistent reduction in the proportion of patients with bleeding. 36.8% (7/19) had a reduction in concomitant ITP medication (corticosteroids) during the 6 months. Adverse events (AE) were reported in 22 out of 23 patients throughout the study. Nasopharyngitis was the most common AE (43%). One patient receiving eltrombopag developed a serious AE (transient ischemic attack of mild severity, considered related to study medication by the investigator) on day 10 and was withdrawn from the study. The AEs were mostly mild to moderate. There was a linear relationship between eltrombopag dose and exposure. CONCLUSION Six month treatment of low dose eltrombopag with an initial dose of 12.5mg up to a maximum dose of 50mg increased platelet counts and reduced bleeding and the use of concomitant ITP medication in Japanese patients with refractory ITP. The higher eltrombopag exposure in Japanese patients than in Caucasian patients may explain the equivalent efficacy at lower dosages of eltrombopag. Eltrombopag was well-tolerated and is an important new treatment option for patients with chronic ITP. Disclosures Miyakawa: GlaxoSmithKline: Consultancy; Nissan Chemical Industries: Research Funding; Shionogi: Honoraria; Ono Pharmaceutical: Honoraria. Ikeda:Daiichi-Sankyo: Research Funding; Tanabe-Mitsubishi: Research Funding; Chugai: Research Funding; Bayer: Research Funding; Daiichi-Sankyo: Honoraria; Bayer: Honoraria; Sanofi-Aventis: Honoraria; Takeda: Honoraria; GlaxoSmithKline: Honoraria; Kaken: Honoraria; Sumitomo: Honoraria; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Boehringer: Membership on an entity's Board of Directors or advisory committees. Koh:GlaxoSmithKline: Employment. Katsura:GlaxoSmithKline: Employment. Kanakura:GlaxoSmithKline: Consultancy; Kyowa Hakko Kirin: Research Funding; GlaxoSmithKline: Research Funding.

Download Full-text

O23 Ixekizumab (IXE) vs. adalimumab (ADA) for the treatment of PSA: 52-week efficacy and safety outcomes

Rheumatology ◽

10.1093/rheumatology/keaa110.022 ◽

2020 ◽

Vol 59 (Supplement_2) ◽

Author(s):

Christopher J Edwards ◽

Andrew J Bradley ◽

Mani H Nassab ◽

Burkhard Möller ◽

Klaus P Machold ◽

...

Keyword(s):

Severe Psoriasis ◽

Tender Joint Count ◽

Stock Ownership ◽

Physician Global Assessment ◽

Inadequate Response ◽

Full Time ◽

Research Support ◽

Open Label ◽

Tender Joint ◽

Full Time Employee

Abstract Background With multiple biologic disease-modifying anti-rheumatic drugs (bDMARDs) available, comparisons are important for treatment decisions. At week 24 of the SPIRIT H2H study in patients with active PSA, IXE showed superiority to ADA for the simultaneous achievement of ACR50 and PASI100. Here we report the 52-week efficacy outcomes including individual ACR components and in subgroups +/- concomitant methotrexate (MTX). Methods SPIRIT H2H (NCT03151551) was a 52-week, multicentre, open-label, blinded-assessor study of bDMARD naïve patients with active PSA (defined as swollen joint count ≥3/68, and tender joint count ≥3/66), with a body surface area (BSA) ≥3% and inadequate response to conventional synthetic (cs)-DMARDs. Patients were randomised 1:1 to IXE or ADA stratified by concomitant csDMARD use and the presence of moderate-to-severe psoriasis (defined as Psoriasis Area and Severity Index [PASI] ≥12 combined with a static Physician Global Assessment ≥3 and BSA ≥10%). Patients received approved label dosing of assigned treatment dependent on presence/absence of moderate-to-severe psoriasis. Primary outcome was achievement of simultaneous ACR50 + PASI100; secondary outcomes were achievement of PASI100, ACR20/50/70 and changes in individual ACR component scores. Data were analysed using logistic regression with non-responder imputation for missing data. Results Baseline characteristics were balanced across treatment groups. At week 52, a significantly larger percentage of IXE- vs. ADA-treated patients achieved simultaneous ACR50 + PASI100 and PASI100, consistent with 24-week results (table). IXE performed at least as well as ADA at week 52 for all other outcomes (table). With/without MTX, IXE efficacy was consistent at week 52 across ACR20/50/70 with a significantly greater achievement of simultaneous ACR50 + PASI100 and ACR70 (table). IXE- versus ADA-treatment resulted in comparable changes from baseline for each individual ACR component at week 52. Safety was consistent with previous reports. Conclusion In patients with PSA, treatment with IXE versus ADA resulted in a significantly greater achievement of simultaneous skin and joint improvement at week 52, consistent with week 24 results. At week 52 consistent efficacy was shown for IXE when used with/without MTX. Disclosures C.J. Edwards: Consultancies; Celltrion, Abbvie, Samsung. Honoraria; Abbvie, BMS, Biogen, Chugai, Fresenius, Gilead, Janssen, Lilly, Pfizer, Roche, Samsung, UCB. Member of speakers’ bureau; Abbvie, BMS, Biogen, Chugai, Fresenius, Gilead, Janssen, Lilly, Pfizer, Roche, Samsung, UCB. Grants/research support; Pfizer, Biogen, Abbvie. A.J. Bradley: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. M.H. Nassab: Other; Full time employee of Eli Lilly. B. Möller: None. K.P. Machold: Honoraria; Arsanis, Astro, Baxter, BMS, Celgene, Eli-Lilly, MSD, Pfizer, Roche, Novartis, Sandoz. Member of speakers’ bureau; MSD, Pfizer, BMS, Janssen-Cilag, Sandoz, Novartis, Eli-Lilly. Grants/research support; AbbVie, BMS, Eli-Lilly, Novartis, MSD, Pfizer, Sanofi-Aventis, UCB. C. Sapin: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. R. Ranza: Consultancies; Abbvie, Novartis, Lilly, Pfizer, Janssen. Member of speakers’ bureau; Abbvie, Novartis, Lilly, Pfizer, Janssen. Grants/research support; Abbvie, Novartis, Pfizer, Janssen. S.L. Leage: Other; Full time employee of Eli Lilly.

Download Full-text

P204 Effect of baricitinib on functional impairment in RA patients with moderate disease activity and an inadequate response to conventional DMARDs

Rheumatology ◽

10.1093/rheumatology/keaa111.199 ◽

2020 ◽

Vol 59 (Supplement_2) ◽

Author(s):

Bruce Kirkham ◽

Elena Nikiphorou ◽

Pedro López-Romero ◽

Ilias Kouris ◽

Thorsten Holzkaemper ◽

...

Keyword(s):

Disease Activity ◽

Physical Function ◽

Stock Ownership ◽

Inadequate Response ◽

Full Time ◽

Research Support ◽

Moderate Disease ◽

Conventional Dmards ◽

Full Time Employee ◽

Moderate Disease Activity

Abstract Background In RA, disease activity correlates with physical function and there is a link between joint damage and functional disability. In many countries, RA patients with inadequate response (IR) to MTX or other conventional DMARDs (cDMARDs) are not eligible for potentially more effective treatments, such as biologic or targeted synthetic DMARDs (tsDMARDs), unless they have high disease activity (HDA). Thus, managing RA patients with persistent moderate disease activity (MDA) despite cDMARD treatment poses a problem. Baricitinib (BARI) is a tsDMARD approved for the treatment of moderate to severe RA in adults. This post-hoc analysis assessed if RA patients with MDA benefit from improved physical function with BARI treatment to the same extent as patients with HDA. Methods Patients analysed were from the modified intention-to-treat populations in the BARI phase 3 studies RA-BEAM (MTX-IR) and RA-BUILD (cDMARD-IR) with moderate to severe disability (HAQ-Disability Index [HAQ-DI] score ≥1), MDA (Simplified Disease Activity Index [SDAI] score 11.1-26.0) or HDA (SDAI score>26.0) and non-missing SDAI data at baseline. All patients fulfilled ACR criteria for RA. Patients from RA-BEAM received BARI 4 mg + MTX once daily (n = 396), adalimumab 40 mg every 2 weeks + MTX (n = 270) or placebo (PBO) + MTX (n = 390); patients from RA-BUILD received BARI 4 mg (n = 189) or 2 mg (n = 186) or PBO (n = 185). Multivariable linear regression (MLR) models were used to estimate mean HAQ-DI scores at baseline and week 24 (W24) for the treatment arms stratified by baseline disease activity (MDA or HDA SDAI). Age, RA duration, BMI, high-sensitivity CRP, baseline SDAI disease activity (MDA/HDA), treatment and treatment-by-baseline SDAI interaction were included as covariates. The MLR model for HAQ-DI at (W24) was further adjusted by baseline HAQ-DI. Results In patients from RA-BEAM with MDA at baseline, the mean adjusted HAQ-DI score at W24 was greater in PBO (1.314) than in BARI 4 mg (0.843) patients (Δ = 0.472; p = 0.001). A similar pattern of improved physical function with BARI was seen in RA-BUILD, but the adjusted mean difference in HAQ-DI score between PBO (1.376) and BARI 4 mg (1.113) was not statistically significant (Δ = 0.263; p = 0.109). In patients with HDA at baseline, the W24 mean adjusted HAQ-DI score was 0.443 points greater (p < 0.001) with PBO (1.387) than with BARI 4 mg (0.944) in RA-BEAM, and 0.257 points greater (p < 0.001) in RA-BUILD. Conclusion MTX-IR and/or cDMARD-IR RA patients with MDA and moderate to severe disability at baseline treated with BARI showed a similar pattern of improvement in physical function vs. PBO-treated patients to that seen in patients with HDA, supporting early use of BARI in MDA patients. As for those with HDA, patients with persistent MDA despite MTX and/or other cDMARD treatment could benefit from access to biologic and tsDMARDs to prevent disability progression. Disclosures B. Kirkham: Consultancies; AbbVie, Eli Lilly, Gilead, Janssen, Novartis, Pfizer. Grants/research support; Eli Lilly, Novartis. E. Nikiphorou: Honoraria; Pfizer, Sanofi, Gilead, Celltrion, Eli Lilly. P. López-Romero: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. I. Kouris: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. T. Holzkaemper: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. L. Zaremba-Pechmann: Other; contractor for Eli Lilly and Company. I. de la Torre: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. P.C. Taylor: Consultancies; AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly, Pfizer, Roche, Sanofi, Nordic Pharma, Fresenius, UCB. Grants/research support; Celgene, Galapagos, Janssen, Eli Lilly.

Download Full-text

Ruxolitinib Efficacy By Hematocrit Control in Patients with Polycythemia Vera: An Analysis of the RESPONSE Trial

Blood ◽

10.1182/blood.v124.21.3201.3201 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3201-3201

Author(s):

Srdan Verstovsek ◽

Jean-Jacques Kiladjian ◽

Ruben Mesa ◽

Mark M Jones ◽

Shui He ◽

...

Keyword(s):

Polycythemia Vera ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Jak2 Inhibitor ◽

Equity Ownership ◽

To Receive ◽

Response Trial

Abstract Background: Polycythemia vera (PV) is characterized by erythrocytosis and overactive JAK/STAT activity. The RESPONSE trial compared ruxolitinib (RUX), a JAK1/JAK2 inhibitor, with best available therapy (BAT) in patients (pts) with PV intolerant of or resistant to hydroxyurea according to modified European LeukemiaNet criteria. RUX was superior to BAT in achieving the primary endpoint (21% vs 1%; P<0.0001), and 60% of pts randomized to RUX achieved protocol-defined hematocrit (HCT) control through Wk 32 vs 20% of pts randomized to BAT (J Clin Oncol32:5s, 2014; suppl, abstract 7026). However, the actual phlebotomy rate between Wks 8−32 was only 20% in pts randomized to RUX compared with 62% in pts randomized to BAT, and 85% of pts in the RUX arm continued to receive treatment at the median 81-wk follow-up, suggesting most pts derived some benefit from RUX. Therefore, an analysis was conducted to evaluate the clinical efficacy of RUX in pts who did and did not achieve protocol-defined HCT control. Methods: Phlebotomy-dependent PV pts with splenomegaly, aged ≥18 years, and resistant to or intolerant of HU were enrolled. Pts were required to have HCT between 40%−45% 14 days prior to randomization; those who did not could enter a phlebotomy control period to achieve a HCT in this range within 14 days of randomization. Eligible pts were randomized 1:1 to RUX or BAT. BAT pts could cross over to receive RUX from Wk 32 if they had not met the primary endpoint, or after Wk 32 due to protocol-defined disease progression. The primary composite endpoint comprised HCT control and a ≥35% reduction from baseline in spleen volume (SV) at Wk 32. HCT control was defined as lack of phlebotomy eligibility between Wks 8−32 with no more than 1 phlebotomy eligibility between randomization and Wk 8. Phlebotomy eligibility was based on protocol-defined HCT values (regardless of receipt of phlebotomy), and pts with missing data or assessments outside of protocol-defined time windows were considered non-responders. In pts who were HCT control non-responders (HCT-N) as defined by protocol, time to second phlebotomy eligibility was evaluated. For this analysis, pts without phlebotomy eligibility were excluded and phlebotomies in the first 8 wks were not considered. Patient-reported outcomes were evaluated in both HCT control responders (HCT-R) and HCT-N, including the 14-item modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the Patient Global Impression of Change (PGIC). Results: Of 222 randomized pts (RUX, n=110; BAT, n=112), most were male (RUX, 60%; BAT, 71%) and the median age (range) was similar between treatment arms (RUX, 62.0 [34.0–90.0]; BAT, 60.0 [33.0–84.0]). Although pts had a HCT between 40% and 45% within 14 days prior to randomization (with or without phlebotomy), 24% of pts had a HCT >45% on Day 1 (similar between treatment arms) illustrating that many pts have poor HCT control over short intervals of observation. RUX treatment resulted in long-term benefits on HCT levels, even in pts who did not achieve protocol-defined HCT control through Wk 32. Among the RUX HCT-R group, the probability of maintaining HCT response was 97% at 48 wks and 87% at 80 wks. Most BAT pts crossed over to receive RUX immediately after the Wk 32 visit (84% between Wks 32 and 48). In the RUX HCT-N pts, the median time to subsequent phlebotomy eligibility was 52 wks, compared with 21 wks for BAT HCT-N pts (Figure). Compared with the entire BAT group, more RUX-R and RUX-N pts had a ≥50% improvement in the MPN-SAF total symptom score at Wk 32 (RUX-N, 38%; RUX-R, 40%; BAT, 4%). Median changes from baseline at Wk 32 in key symptoms such as tiredness (RUX-N; −50%; RUX-R, −49%; BAT, −4%), itching (RUX-N, −88%; RUX-R, −97%; BAT, −2%), and night sweats (RUX-N, −100%; RUX-R, −97%; BAT, 4%) were also greater among RUX-R and RUX-N pts than BAT pts. RUX-N and RUX-R pts were also more likely to consider their symptoms to be “much improved” or “very much improved” on the PGIC compared with BAT pts (RUX-N, 57%; RUX-R, 74%; BAT, 13%). Conclusion: Among pts receiving RUX who did not achieve protocol-defined HCT control, the median time to subsequent phlebotomy eligibility was 1 year. In contrast, pts on BAT had a median time to subsequent phlebotomy eligibility of 21 wks. Furthermore, pts in the RUX arm achieved meaningful improvements in PV-related symptoms, regardless of meeting the endpoint of HCT control, while pts treated with BAT showed worsening or no improvement. Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Kiladjian:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Trial in Progress: Phase Ib/II Study of Bcl-2/Bcl-Xl Inhibitor Pelcitoclax (APG-1252) in Patients with Myelofibrosis (MF) That Progressed after Initial Therapy

Blood ◽

10.1182/blood-2020-137260 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Naveen Pemmaraju ◽

Boyd Mudenda ◽

Cunlin Wang ◽

Jiao JI ◽

Ming Lu ◽

...

Keyword(s):

Bone Marrow ◽

Clinical Benefit ◽

Research Funding ◽

Publicly Traded ◽

Bone Marrow Fibrosis ◽

Dual Inhibitor ◽

Jak2 Inhibitor ◽

Grant Support ◽

Marrow Fibrosis ◽

Jak2 Inhibitors

Background: Pelcitoclax (APG-1252), a novel dual inhibitor of Bcl-2/Bcl-xL, is active as monotherapy in patients with advanced solid tumors and well tolerated up to 240 mg twice weekly (NCT03387332). Preclinical data suggest that cells with Janus-associated kinase-2 (JAK2) mutations, including those associated with bone marrow fibrosis, are dependent on Bcl-2/Bcl-xL for survival and that addition of BH3 mimetics targeting Bcl-2/Bcl-xL induces apoptosis. Furthermore, in JAK2‒mutated cell models, apoptotic synergy is demonstrated when a JAK2 inhibitor and Bcl-2/Bcl-xL inhibitor are combined, as inhibition of Bcl-xL overcomes resistance to JAK2 inhibitors. Taken together, APG-1252 could overcome resistance to JAK2 inhibitors, and the combination could augment clinical benefit in patients with suboptimal responses to JAK2 inhibitor‒based therapy. Study Objectives: The primary objective of this open-label trial is to evaluate the safety and efficacy of APG-1252, as monotherapy and when combined with ruxolitinib, in adults with histologically or cytologically confirmed MF who require therapy and are ineligible for JAK2 inhibitors (and can receive single-agent APG-1252) or have had inadequate responses to ruxolitinib-based therapy (and can receive this treatment plus APG-1252). Secondary objectives include APG-1252 pharmacokinetics, time to response, and duration of response. Exploratory objectives include changes in cytogenetics and molecular mutations, bone marrow fibrosis, and cytokines on treatment. Study Design: The study is divided into Part 1 (APG-1252 monotherapy) and Part 2 (APG-1252 plus ruxolitinib). For Part 1, the key inclusion criterion is ineligibility for JAK2 inhibitors and for Part 2, inadequate responses to prior ruxolitinib-based therapy. A standard 3+3 dose-escalation design is being implemented to determine the maximum tolerated dose (MTD) of APG-1252 monotherapy in Part 1 and APG-1252 combined with ruxolitinib in Part 2. APG-1252 will initially be administered at 160 mg intravenously by 30-minute injection once weekly in a 28-day cycle. The dose can be escalated to a maximum of 240 mg or reduced to a minimum of 80 mg, depending on tolerability. Part 2 will begin once the MTD and recommended phase 2 dose (RP2D) of APG-1252 monotherapy have been determined. In Part 2, ruxolitinib will be administered orally twice daily per the package insert. After the MTD for APG-1252 monotherapy has been determined, no additional patients will be enrolled in Part 1; however, up to 15 to 30 additional patients can be enrolled in Part 2, to further evaluate the safety and anticancer activity of the combination at MTD or RP2D. Patients will continue treatment until disease progression or unacceptable toxicity. Clinical responses are being assessed every 12 weeks according to criteria from the International Working Group‒Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet panels, while optimal clinical benefit will be evaluated at 24 weeks. Enrollment will be from September 2020 and preliminary results estimated in October 2022. For further information, contact: [email protected]. Registration: ClinicalTrials.gov Identifier NCT04354727. Disclosures Pemmaraju: Pacylex Pharmaceuticals: Consultancy; Roche Diagnostics: Honoraria; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; DAVA Oncology: Honoraria; Blueprint Medicines: Honoraria; Novartis: Honoraria, Research Funding; Incyte Corporation: Honoraria; SagerStrong Foundation: Other: Grant Support. Mudenda:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Wang:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. JI:Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Lu:Ascentage Pharma Group: Current Employment, Current equity holder in publicly-traded company. Fu:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Liang:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. McClain:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Sheladia:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; PharmaEssentia: Research Funding; ItalPharma: Research Funding; AstraZeneca: Research Funding; Protagonist Therapeutics: Research Funding; Promedior: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; Genentech: Research Funding; CTI Biopharma Corp: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Gilead: Research Funding. Yang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests. Zhai:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests.

Download Full-text

A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients with Polycythemia Vera

Blood ◽

10.1182/blood-2021-149219 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1504-1504

Author(s):

Srdan Verstovsek ◽

Andrew T. Kuykendall ◽

Ronald Hoffman ◽

Yelena Ginzburg ◽

Naveen Pemmaraju ◽

...

Keyword(s):

Iron Deficiency ◽

Polycythemia Vera ◽

Board Of Directors ◽

Research Funding ◽

Data Safety Monitoring Board ◽

Publicly Traded ◽

Phase 3 ◽

Eligibility Criteria ◽

Advisory Committees ◽

To Receive

Abstract Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) alone or in combination with either hydroxyurea (HU), ruxolitinib (RUX) or interferon (IFN) to maintain hematocrit (HCT) levels below 45% as per NCCN guidelines. Since patients are seen periodically, PV patients may spend significant time with HCT levels above 45%, thereby increasing their risk of thrombosis [Marchioli NEJM 2013]. PV is associated with systemic symptoms with fatigue. These fatigue-related symptoms are found to be the most prevalent and severe as reported in an international survey among PV patients [Scherber Cancer 2016]. Symptomatic iron deficiency represents an unaddressed clinical challenge to PV patients as most PV patients have iron deficiency at diagnosis due to increased iron utilization [Ginzburg Leukemia 2018]. The iron deficiency worsens after repeated TP. We have demonstrated in a phase 2 study that rusfertide (PTG-300) has a good tolerability profile and achieves HCT control in PV patients with improvement in iron deficiency. Methods. This is a Phase 3, multicenter, global, randomized trial that compares the efficacy and safety of rusfertide compared to placebo when added on to current therapy for PV (Figure 1). The study population is PV subjects who require frequent phlebotomies to control their hematocrit with or without concurrent therapy. This is a three-part study in subjects with polycythemia vera: - Part 1a: randomized, double-blind, placebo-controlled, add-on parallel-group period for 32 weeks. Subjects will be stratified by their ongoing PV treatment and randomized 1:1 to rusfertide or placebo added-on to their ongoing PV treatment. - Part 1b: open-label treatment phase during which all subjects who complete Part 1a successfully will receive rusfertide for 20 weeks (Week 32 through Week 52). - Part 2: Long term extension (LTE) phase during which all subjects who complete Part 1b will continue to receive rusfertide for 32 weeks (Week 52 to Week 84). Inclusion Criteria: Approximately 250 subjects will be randomized. Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and frequent phlebotomies with or without concurrent cytoreductive therapy to maintain HCT below 45% in the 6 months prior to enrollment in Part 1. Eligible subjects will continue to receive their therapy at screening for PV (phlebotomy alone (TP) or cytoreductive therapy + TP) and must have a hematocrit <45% at Week 0 prior to randomization. Subjects who meet the eligibility criteria will be stratified by ongoing PV therapy (TP only, TP+hydroxyurea, TP+ruxolitinib, TP+interferon, TP+other) and randomized 1:1 to treatment with rusfertide or placebo added on to the subject's ongoing PV therapy at Week 0. The "add on" design allows subjects to receive standard cytoreductive therapy to control WBC and/or platelets and to receive rusfertide/placebo. The dose of cytoreductive therapy in Part 1a and Part 1b may be decreased for safety but may not be increased for efficacy including control of hematocrit, elevated platelets and/or WBC. Primary endpoint: Proportion of subjects achieving a response starting at Week 20 through Week 32 (inclusive) who receive rusfertide compared to placebo. A response is defined as absence of phlebotomy eligibility defined as either: 1. a confirmed hematocrit ≥45% and that is at least 3% higher than the baseline hematocrit (value immediately prior to randomization at Week 0); confirmation required within 1 to 7 days, or 2. a hematocrit ≥48%. Key words: Hepcidin, Hematocrit, Rusfertide, PTG-300, Polycythemia Vera, PV, Therapeutic Phlebotomy Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; Ital Pharma: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Kuykendall: Pharmaessentia: Honoraria; Protagonist: Consultancy, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria; Abbvie: Honoraria; Incyte: Consultancy; Blueprint: Honoraria. Hoffman: AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding; Novartis: Other: Data Safety Monitoring Board, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Kartos Therapeutics, Inc.: Research Funding. Pemmaraju: Incyte: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; Sager Strong Foundation: Other; Aptitude Health: Consultancy; Affymetrix: Consultancy, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Valone: Protagonist Therapeutics: Consultancy, Current equity holder in publicly-traded company. Modi: Protagonist Therapeutics: Current Employment. Khanna: Protagonist: Current Employment, Current equity holder in publicly-traded company. O'Connor: Protagonist Therapeutics: Current Employment. Gupta: Protagonist Therapeutics: Current Employment. Kiladjian: Taiho Oncology, Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Comparing Eras: Assessing Treatment Trends before and after Ruxolitinib Approval

Blood ◽

10.1182/blood.v128.22.3124.3124 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3124-3124

Author(s):

Andrew Kuykendall ◽

Chetasi Talati ◽

Najla Al Ali ◽

Eric Padron ◽

David Sallman ◽

...

Keyword(s):

Patient Population ◽

Research Funding ◽

First Line ◽

Jak2 Inhibitor ◽

First Line Therapy ◽

Line Therapy ◽

Fda Approval ◽

Before And After ◽

Frontline Therapy ◽

To Receive

Abstract Background: Ruxolitinib is a JAK1/2 inhibitor that gained FDA approval for treatment of intermediate and high-risk myelofibrosis (MF) in 2011. Prior to ruxolitinib, a variety of treatments were used for myelofibrosis, with variable efficacy. Even in the ruxolitinib era, treatment decisions are primarily focused on symptom management, as no treatment, other than allogeneic hematopoietic stem-cell transplant (allo-HSCT) has shown to have a strong disease-modifying effect. Ruxolitinib significantly improves splenomegaly and constitutional symptoms associated with MF. Here, we aim to compare MF treatments before and after ruxolitinib approval to assess treatment patterns and impact on clinical outcomes. We hypothesized that an increased use of ruxolitinib after its FDA-approval would affect those with constitutional symptoms and/or splenomegaly and correlate with decreased use of other treatments aimed at these symptoms. Methods: This was a single institution, retrospective study of all patients with a diagnosis of MF who were seen at our center between 2/2001 and 6/2016. The World Health Organization 2016 definition of primary myelofibrosis (PMF) was used for confirmation of diagnosis. Initial treatment was defined as first treatment after diagnosis of MF. Specific phenotypes were assigned retrospectively based on chart review reflecting the patient's initial complaints which led to diagnosis. Results: We identified 312 eligible patients. This group was divided into two cohorts: those diagnosed prior to the ruxolitinib era (cohort PRE, n = 177) and those diagnosed in the ruxolitinib era (cohort POST, n = 135). Demographics (gender, race, age at diagnosis) and presenting features were comparable between the cohorts. In the PRE cohort, JAK2 inhibitor use occurred in the setting of a clinical trial as well as in patients who were diagnosed prior to ruxolitinib approval, but first received treatment after its approval. In this cohort, 25% of patients received a JAK2 inhibitor, with 36% of these patients receiving it as frontline therapy (see figure 1). This compared to 44% of POST patients who received a JAK-2 inhibitor, with 69% receiving it in the frontline setting. POST patients were, more likely to receive ruxolitinib overall (OR 2.28, p = 0.001) and as first-line therapy (OR 4.49, p < 0.0001). POST patients were less likely to receive an erythropoiesis-stimulating agent (ESA) overall (OR 0.40, p = 0.0003) and as first line therapy (OR 0.51, p = 0.02). Thalidomide was also less commonly used in the POST patients (OR 0.34, P = 0.003). The use of hydroxyurea was similar between cohorts. When stratified based on the presence of constitutional symptoms (CS) and/or splenomegaly (S), patients most commonly received an ESA, JAK-2 inhibitor, or hydroxyurea as frontline therapy (see figure 2). When both CS and S were present, patients more commonly received the latter two options. Patients presenting with CS and S were more likely to receive ruxolitinib as first line therapy in the POST cohort compared to the PRE (OR 5.5, p = 0.0004); however, the use of first line hydroxyurea was not significantly different between the PRE and POST cohorts (p = 0.28). In all, ten separate frontline treatments were used in the symptomatic PRE cohort while only five were utilized in POST patients. In patients presenting without constitutional symptoms or splenomegaly, there was no difference in initial treatment strategy in the PRE and POST cohorts, and ruxolitinib was rarely utilized in this patient population. No difference in overall survival (OS) was noted between the two cohorts. Conclusion:After FDA-approval, ruxolitinib has emerged as the most common first-line treatment option for MF, specifically in patients with constitutional symptoms and splenomegaly, with decreased up-front use of thalidomide, ESAs and hydroxyurea. Patients presenting without constitutional symptoms or splenomegaly were no more likely to received ruxolitinib in the post-approval era, indicating a preference for alternative treatment options in this group. Longer follow up is needed to assess survival impact of frontline ruxolitinib use in our patient population. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte Corporation: Research Funding. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Comparative Effectiveness of Ofatumumab (O) in Combination with Chlorambucil (Chl) Versus Bendamustine (B), and Obinutuzumab (GA101) or Rituximab (R) in Combination with Chlorambucil for Chronic Lymphocytic Leukaemia (CLL)

Blood ◽

10.1182/blood.v124.21.5993.5993 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5993-5993

Author(s):

Sorrel E Wolowacz ◽

Sarah Mitchell ◽

Amin Haiderali

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Research Funding ◽

Indirect Comparison ◽

Disease Stage ◽

Full Time ◽

Study Research ◽

Adjusted Indirect Comparison ◽

Full Time Employee ◽

Evidence Network

Abstract Introduction: A systematic review of clinical trials investigating interventions used for the first-line treatment of patients with CLL who are not eligible for fludarabine-based therapy was undertaken and the feasibility of performing an adjusted indirect comparison (AIC) for OChl versus B, GA101Chl and RChl was explored. Methods: Trials were identified by a systematic review; details of the methodology can be found in abstract B1333 of Hematologica (Woods et al, 2013). The trial designs, patient populations and treatment doses were examined to identify any evident systematic differences among the trials that might be expected to result in heterogeneity. The feasibility of performing an AIC using conventional methods and also alternative methods such as matching-adjusted indirect comparison (MAIC) was evaluated. Results: The trial evidence network is presented in Figure 1. Figure 1. Evidence Network Figure 1. Evidence Network The following trials were examined in detail to assess the feasibility of conducting an AIC with Chl as the common comparator. µ COMPLEMENT-1 comparing OChl with Chl (Hillmen et al., 2013). µ Knauf et al (2009; 2010, 2012) comparing B with Chl µ CLL11 comparing RChl and GA101Chl with Chl (Goede et al., 2014). Differences were found between studies in terms of treatment regimens, study design, subject characteristics and study endpoints. There were substantial differences in the actual median total dose of Chl monotherapy received by each patient, ranging from 728 mg in COMPLEMENT-1 through 522 mg for Knauf et al. to 384 mg in CLL11. Patient inclusion and exclusion criteria differed among trials, including disease stage (no Stage A patients in Knauf et al), absence or presence of criteria for fitness for fludarabine therapy, as determined by age or co-morbidity measurements such as the Cumulative Illness Rating Scale (CIRS) scores. The COMPLEMENT-1 population was older than that studied by Knauf et al. but younger than the population in the CLL11 trial. The majority of patients had ECOG Performance Status (PS) 1 in the COMPLEMENT-1 trial but PS 0 in the Knauf et al., trial. The definitions of response also varied among trials with COMPLEMENT-1 and CLL11 using the 2008 NCI-WG criteria and Knauf et al. using the earlier 1996 criteria. Discussion: Naïve indirect comparisons are subject to a variety of confounding factors which may bias the estimates in an unpredictable direction with uncertain magnitude. There are a large number of differences between the identified trials which make adjustments for heterogeneity difficult. Different Chl monotherapy regimens have shown differing efficacy (Catovsky et al., 2011) and, there is no available evidence which might be used to calculate the magnitude of this effect. Methods such as MAIC and predictive models may overcome some of the heterogeneity between clinical trials and in some cases allow for comparisons of treatments in the absence of a common comparator. Within this set of studies, there was an insufficient set of matching variables to enable for matching and validation of the match with other variables and/or a common comparator arm. Furthermore, although these methods may account for differences in patient characteristics, they cannot adjust for other differences, such as the definition or ascertainment of endpoints. Conclusions: To avoid bias, any indirect comparison of these interventions should adequately account for heterogeneity within the evidence network, with careful consideration of the factors identified in this review. The effectiveness of these interventions in comparison to Chl in routine clinical practice may differ from the efficacy observed in the trials, particularly where the Chl regimen used in routine practice differs from that investigated in the trials. Disclosures Wolowacz: GlaxoSmithKline. Sorrel Wolowacz is a full-time employee of RTI Health Solutions, which received funding from GlaxoSmithKline group of companies to conduct this study: Research Funding. Mitchell:GlaxoSmithKline. Sarah Mitchell is a full-time employee of RTI Health Solutions, which received funding from GlaxoSmithKline group of companies to conduct this study: Research Funding. Haiderali:GSK: Employment.

Download Full-text

Lines of Therapy in Patients with Relapsed or Refractory Large B-Cell Lymphoma and Stem Cell Transplant-Intended Treatment

Blood ◽

10.1182/blood-2020-134808 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 45-46

Author(s):

Julia Thornton Snider ◽

Paul Cheng ◽

Xue Song ◽

Donna McMorrow ◽

David Diakun

Keyword(s):

Research Funding ◽

Index Date ◽

Intensive Therapy ◽

B Cell Lymphoma ◽

Treatment Patterns ◽

Cell Transplant ◽

Front Line ◽

Publicly Traded ◽

Line Of Therapy ◽

To Receive

Introduction: Large B-cell lymphoma (LBCL) is the most common subtype of non-Hodgkin lymphoma. Front line therapy is curative in about 60% of patients; however, about 30% of patients relapse and about 10% are refractory. For patients failing the front line, stem cell transplant (SCT) is currently the only curative option in second line of therapy (LOT2). This study examined real-world treatment patterns with curative intent in patients with relapsed or refractory LBCL to understand the unmet medical need in the United States. Methods: This retrospective study used IBM MarketScan® Commercial and Medicare Supplemental Databases. Patients with ≥2 LBCL diagnoses on different days in 1/1/2012 - 3/31/2019 were identified (index date = date of the earliest LBCL diagnosis). Patients who were ≥18 years of age on the index date, had ≥1 claim for any LBCL treatment on or following the index date, ≥6 months of data prior to (baseline) and ≥12 months of data after (follow up period) the index date, and had no baseline LBCL diagnosis were included. Treatment patterns, including lines of therapy (LOT), treatment regimen, duration of LOT and time from the end of a previous LOT to the subsequent LOT, were examined. All patients were required to receive first LOT (LOT1) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone +/- rituximab), EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride +/- rituximab), or regimens with anthracycline. Of those, patients were further required to receive LOT2 with SCT-intended intensive therapy or platinum-based chemotherapy as recommended by the National Comprehensive Cancer Network (NCCN). Patients were intended for SCT if they received an SCT-intended LOT2 regimen or received SCT regardless of LOT2 regimen. SCT was identified from the LOT2 start date to the end of the study period. All analyses were stratified by whether a patient was intended for SCT and by receipt of SCT. Results: A total of 3,443 patients with LBCL received an eligible front-line therapy (mean age 59.2 years, male 56.9%, length of follow up 2.5 years, National Cancer Institute (NCI) adapted Deyo-Charlson comorbidity index 0.83). Top comorbidities were other malignancy (63.3%), diabetes (23.3%), psychiatric disturbance (13.9%), and chronic pulmonary obstructive disease (13.2%). Among the LBCL patients, 564 (16.4%) received LOT2 with 197 (34.9%) patients SCT-intended and 367 (65.1%) not SCT-intended (Figure 1). SCT-intended patients were significantly younger than SCT-non-intended patients (55.9 vs. 60.9 years, p<0.001), and patients who received SCT were younger than those who did not receive SCT (53.6 vs. 59.7 years, p<0.001). Among the 197 patients intended for SCT, only 55.3% (n=109/197) received NCCN recommended LOT2 for intensive therapy: ICE (ifosfamide, carboplatin, etoposide) +/- rituximab (32.5%) and GemOx (gemcitabine, oxaliplatin) +/- rituximab (19.3%) were the most common regimens. SCT-intended patients initiated LOT2 nearly one year (345 days) after and third line of therapy (LOT3) 501 days after their LBCL index diagnosis (Figure 2). Duration of LOT decreased as patients moved on to later LOTs (LOT1=121 [standard deviation (SD)=69], LOT2=89 [SD=145] and LOT3=46 [SD=23] days). Likewise, the time between 2 consecutive LOTs decreased (194 [SD=258] days between end of LOT1 and start of LOT2, 124 [SD=182] days between end of LOT2 and start of LOT3). Steroids were often prescribed during LOT1 (82.2%) and LOT2 (74.6%) as concomitant therapy. Among the 109 patients receiving SCT-intended regimens, only 34 (31.2%) went on to receive SCT. An additional 88 patients received SCT without being observed to receive an SCT-intended regimen. They might have received therapy in the inpatient setting, which could not be captured in claims data. Among the 82 patients with LOT3, 60.1% received SCT and 9.8% received Chimeric antigen receptor (CAR) T cell therapy. Conclusion: The findings provide insight into real-world treatment patterns in patients with LBCL who received SCT-intended therapy. A small proportion of LBCL patients received NCCN recommended SCT-preparative regimens in LOT2 and only 31% of them received SCT. This highlights the magnitude of unmet need for relapsed or refractory LBCL patients. Future studies should examine the impact of new therapies on the management of LBCL. Disclosures Thornton Snider: Kite, A Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company, Research Funding; Precision Medicine Group: Ended employment in the past 24 months, Research Funding. Cheng:Kite, A Gilead Company: Current Employment, Current equity holder in publicly-traded company. Song:IBM Watson Health: Research Funding. McMorrow:IBM Watson Health: Current Employment. Diakun:IBM Watson Health: Current Employment, Research Funding.

Download Full-text

Pegcetacoplan Is Superior to Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Regardless of Prior Transfusion Requirement

Blood ◽

10.1182/blood-2020-141061 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 32-33

Author(s):

Regis Peffault De Latour ◽

Carlos M. de Castro ◽

Jeffrey Szer ◽

Kensuke Usuki ◽

Peter Hillmen ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Age Group ◽

Publicly Traded ◽

Advisory Committees ◽

Material Support ◽

Group Sex ◽

Support Research

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by chronic complement-mediated intravascular and extravascular hemolysis. In the phase 3 PEGASUS study (NCT03500549), pegcetacoplan, a C3 inhibitor targeting the proximal complement pathway, was superior to eculizumab (ECU) on the primary endpoint of hemoglobin (Hb) change from baseline at week 16, and improved clinical and hematologic parameters. Additional analyses assessed if any groups of patients might experience further benefit from pegcetacoplan. METHODS Patients ≥18 years old with a diagnosis of PNH and persistent anemia (Hb <10.5 g/dL) at baseline, despite treatment with stable doses of ECU for ≥3 months, entered a 4-week run-in period during which all patients continued their current dose of ECU with the addition of twice-weekly pegcetacoplan (1080 mg, self-administered subcutaneously). On study day 1, patients were stratified based on baseline platelet count and prior transfusion requirements, and randomized 1:1 to monotherapy with pegcetacoplan or ECU for 16 weeks. The primary endpoint of change from baseline (before first dose of pegcetacoplan) at week 16 in Hb and key secondary endpoints (change from baseline at week 16 in absolute reticulocyte count [ARC] and lactate dehydrogenase [LDH]) were analyzed using a mixed-effect model for repeated measures by subgroups based on baseline age group, sex, race, number of packed red blood cell transfusions (<4 vs ≥4) within the 12 months prior to day −28, and platelet count at screening (<100,000/mm3 vs ≥100,000/mm3). The key secondary endpoint of transfusion avoidance was analyzed by calculating the number and proportion of patients who were transfusion-free and also analyzed by subgroups. For patients transfused during the randomized control period or who withdrew from the study, the primary and secondary data endpoints up to the transfusion or time of withdrawal were included, but all subsequent values were censored. RESULTS Pegcetacoplan treatment was associated with significantly greater increases in Hb levels than ECU at week 16, regardless of baseline age group, sex, race, prior transfusions, or platelet count (Tables 1-2). At week 16, regardless of baseline platelet count strata, mean Hb significantly increased from baseline in the pegcetacoplan group and decreased in the ECU group. The proportion of transfusion-free patients was similar in the pegcetacoplan group, regardless of age (≤65 years, 87.1%; >65 years, 80%), sex (female, 81.5%; male, 92.9%), race (Asian, 100%; black, 100%; white, 75.0%), transfusion strata (<4 transfusions, 85.0%; ≥4 transfusions, 85.7%), or platelet strata (<100,000/mm3, 83.3%; ≥100,000/mm3, 86.2%). A smaller proportion of patients were transfusion-free with ECU, regardless of age (≤65 years, 18.8%; >65 years, 0%), sex (female, 18.2%; male, 11.8%), race (Asian, 28.6%; black, 0%; white, 16.0%), transfusion strata (<4 transfusions, 31.3%; ≥4 transfusions, 4.3%), or platelet strata (<100,000/mm3, 0%; ≥100,000/mm3, 20.0%). Similar trends for more favorable results with pegcetacoplan versus ECU were seen across the prespecified subgroups for ARC and LDH. CONCLUSIONS In this prespecified stratified analysis of the phase 3 PEGASUS study of patients with PNH and persistent anemia, mean Hb levels increased significantly more, the proportion of transfusion-free patients was significantly higher, ARC change from baseline at week 16 was significantly lower, and LDH decreases were larger with pegcetacoplan versus ECU, regardless of baseline age group, sex, race, prior transfusion numbers, and platelet count. Disclosures Peffault De Latour: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees. de Castro:Alexion: Honoraria, Research Funding; Apellis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Other: Steering committee; Biocryst: Honoraria, Other: Data monitoring committee. Szer:Apellis: Consultancy; Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Usuki:Alexion: Research Funding, Speakers Bureau; Apellis: Research Funding; Chugai: Research Funding; Novartis: Research Funding, Speakers Bureau. Hillmen:Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Acerta: Other: Financial or material support. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees. Hamdani:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ajayi:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Weitz:Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.

Download Full-text