Rationale and Design of an Observational Multicenter Study to Evaluate the Use and Effectiveness of Avatrombopag in Adult Patients with Immune Thrombocytopenia: The Adopt Study

Abstract Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts caused by a combination of both impaired platelet production and increased peripheral platelet destruction. Current first-line ITP treatments include glucocorticoids and intravenous immunoglobulin (IVIG). However, these drugs have variable and transient efficacy, significant toxicities, and relapse is common upon discontinuation. Subsequent treatment options include the thrombopoietin receptor agonists (TPO-RAs). Avatrombopag (AVA) is an orally administered small molecule TPO-RA. It binds to the human TPO receptor (c-Mpl) at a site that is different from the endogenous TPO binding, stimulating signal transduction and mimicking the biological effects of endogenous TPO. In phase 2 and 3 studies in patients with ITP, AVA was administered to 128 patients for a median duration of 7 months (maximum duration >2 years; Birhiray R, et al. EHA 2020). In a phase 3 trial (NCT01438840), the primary efficacy endpoint of cumulative number of weeks with platelet count ≥50×10 9/L during 6 months of treatment in the absence of rescue therapy was statistically significant favoring AVA over placebo. The most common treatment-emergent adverse events (AEs) in these phase 2 and 3 trials were headache, fatigue, and contusion. AVA has no significant hepatotoxicity and is administered with food without restrictions on meal composition. AVA is approved by FDA and EMA for the treatment of primary chronic ITP in adult patients who are refractory to other treatments (e.g. corticosteroids, IVIG). However, there is a need to provide data to treaters and the ITP community on the real-world usage and effectiveness of AVA (including patients previously treated with TPO-RAs). Described here is the rationale and design of the ADOPT study (NCT04943042), evaluating the use and effectiveness of AVA in adult patients with ITP in routine clinical practice in Europe. Study design and methods: This is a multicenter, observational, phase 4 study, with the primary objective to describe the real-world effectiveness of AVA treatment over a prospective period of 12 months in adult patients with ITP. Prospective data will be collected at routine clinical visits. In addition, retrospective data will be collected from patients' medical records for up to 12 months prior to AVA treatment start. Eligible patients must be ≥18 years, have provided informed consent, have an established and well documented ITP diagnosis, and are treated with or initiating treatment with AVA for ITP at enrollment. Decision to initiate treatment shall be made by the treating physician, independently from the decision to include the patient in the study. Exclusion criteria include enrollment in other clinical interventional study or intake of an investigational medicinal product ≤3 months prior to inclusion, and secondary ITP. The primary endpoint is cumulative number of weeks with a platelet count ≥30×10 9/L during AVA treatment. Platelet counts during rescue medication use and within 4 weeks after stopping a rescue medication or following splenectomy are considered non-response and thus not included in the primary endpoint cumulative number. Secondary endpoints supporting the primary objective include cumulative number of weeks with a platelet count ≥50×10 9/L, patients (n [%]) with a platelet count ≥30×10 9/L and ≥50×10 9/L for at least 8 consecutive weeks, patients (n [%]) experiencing WHO bleeding grade ≥2, patients (n [%]) requiring rescue medication, and time from AVA treatment start to platelet count ≥30×10 9/L and ≥50×10 9/L. Additional secondary endpoints are AVA dose and dosing frequency, reason for ITP treatment discontinuation or change from one ITP treatment to another (prior to and during the study), use of concomitant ITP medications, physician satisfaction with outcome of AVA treatment (5-point scale), physician assessment of clinical change of AVA treatment (Clinical Global Impression of Change scale), healthcare resource use, as well as a number of patient reported outcomes (Table 1). Secondary safety endpoints include serious AEs, AEs of special interest (thromboembolic events, significant bleeding) and AEs leading to AVA discontinuation. Data will be summarized using descriptive statistics. Study status: The study is planned to start 2021 and aims to enroll 150 patients. Figure 1 Figure 1. Disclosures McDonald: Grifols: Research Funding; Bayer, Sobi, Novartis, Amgen, argenx: Honoraria. Matzdorff: Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Current holder of individual stocks in a privately-held company. Mellbring: Sobi: Current Employment. Nazir: Sobi: Current Employment. Lindqvist: Sobi: Current Employment. Santagostino: Sobi: Current Employment.

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

Blood ◽

10.1182/blood.v114.22.891.891 ◽

2009 ◽

Vol 114 (22) ◽

pp. 891-891 ◽

Cited By ~ 1

Author(s):

Ilene Ceil Weitz ◽

Miguel A Sanz ◽

David H. Henry ◽

Martin Schipperus ◽

Bertrand Godeau ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Rescue Medication ◽

Bleeding Event ◽

Bleeding Events ◽

Phase 3 ◽

Advisory Committees ◽

Platelet Counts ◽

Chronic Itp

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

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Association between Megakaryocyte Abnormalities on Bone Marrow Smear and Response to Thrombopoietin Receptor Agonists in Adult Patients with Primary Immune Thrombocytopenia

Blood ◽

10.1182/blood-2021-151435 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3160-3160

Author(s):

Ondine Walter ◽

Agnès Ribes ◽

Johanne Germain ◽

Jean-Baptiste Rieu ◽

Thibault Comont ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Adult Patients ◽

Second Line ◽

Bone Marrow Smear ◽

Advisory Committees ◽

Thrombopoietin Receptor

Abstract Introduction: Immune thrombocytopenia (ITP) is an autoimmune disease due to peripheral destruction but also impaired central production of platelets. Autoimmune reaction directed against megakaryocytes (MKs) has been described, and may explain morphological abnormalities of MKs observed in some patients with primary ITP. Thrombopoietin receptor agonists (TPO-RAs) are indicated as second-line treatments for ITP, but no predictive factors of response used in clinical routine practice has been demonstrated. The utility of systematic bone marrow smears (BMS) at ITP diagnosis is discussed. Howerer, it is usually recommended before second-line treatments. Two studies have suggested an association between MK abnormalities and response to corticosteroids in primary ITP, but none have investigated this association for TPO-RAs. This study aimed to investigate the association between MK abnormalities and response to TPO-RAs in adult patients with primary ITP. Methods: The source of population was the CARMEN registry. The CARMEN (Cytopénies Auto-immunes: Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ≥18 years) with incident ITP in routine visit or hospital stay. ITP was defined by international definition (platelet count <100 x 10 9/L and exclusion of other causes of thrombocytopenia). The study population consisted in all patients included in the CARMEN registry between June 2013 and March 2018 with primary ITP, treated by TPO-RA and with a BMS before initiating TPO-RA. We excluded the patients with a number of MKs <10 MK on the BMS. Morphological abnormalities were established based on literature and defined by consensus among 3 expert cytologists (AR, JBR and VDM). All MKs present on each smear were analyzed. MKs were categorized by the presence of dysplasia (monolobed MK and/or separated nuclei and/or microMKs), and according to their stage of maturation (basophilic, granular and thrombocytogenic). All patients' medical charts were reviewed by two experts in ITP (OW and GM) to determine the response to TPO-RAs. Response was defined by a platelet count between 30 and 100 G/L with at least a doubling of basal platelet count according to the international definition. In case of subsequent exposure to both TPORAs in a single patient, response was defined by response to at least one TPO-RA in the main analysis. We performed a subgroup analysis by TPORAs. Results: During the study period, 451 patients with incident ITP were included in CARMEN-registry. Among them, 105 had been treated by TPO-RAs, including 65 with BMS before the exposure to TPORA. We then excluded 20 patients with secondary ITP and 7 with less than 10 MKs on the BMS. We finally included 38 patients in the analysis. Median age at diagnosis was 71 years (interquartile range - IQR: 31 - 94) and 34.2% were women. Thirty-three patients were treated with eltrombopag, 17 with romiplostim including 13 who were exposed to both TPORAs. Thirty-four (89.4%) achieved response. The median number of MKs analyzed per patient was 137 (IQR: 50 - 265). All results are presented in Table 1. In the main analysis, there was no significant difference in the median percentage of dysplastic MKs in responders (4.0%, 95% confidence interval - CI: 2.3 - 6.4) and non-responders (4.5%, 95% CI: 0.7 - 7.1). There was a trend for a higher proportion of granular MKs (4.5%, 95% CI: 3 - 6) and basophilic MKs (30.1%, 95% CI: 21.9 - 39.1) in non-responders comparing to responders (granular: 2.0%, 95% CI: 0 - 4.1; basophilic: 21.3%, 95% CI: 11.4 - 40.7). Results were similar in the subgroup of patients treated with eltrombopag (data not shown; the low number of patients treated with romiplostim precluded any analysis). Conclusion: In this study, neither MK abnormalities nor the pattern of MK maturation stages were significantly associated with response to TPO-RAs. These results do not support a systematic bone marrow smear in patients with primary ITP to look for morphological predictive factors of response to TPO-RA. Figure 1 Figure 1. Disclosures Comont: AstraZeneca: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Moulis: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees.

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Hepatobiliary and Thromboembolic Events during Long-Term E.X.T.E.N.Ded Treatment with Eltrombopag in Adult Patients with Chronic Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v128.22.1368.1368 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1368-1368

Author(s):

Mansoor N. Saleh ◽

James B Bussel ◽

Raymond SM Wong ◽

Balkis Meddeb ◽

Abdulgabar Salama ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Adult Patients ◽

Phase Iii ◽

First Year ◽

Thromboembolic Events ◽

Advisory Committees ◽

Platelet Counts

Abstract Introduction: ITP, characterized by a reduction in platelets leading to thrombocytopenia, which persists for >12 months is considered chronic (cITP). Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of patients with cITP aged ≥1 year refractory to other treatments (eg corticosteroids, immunoglobulins). The recently completed Phase III EXTEND (Eltrombopag eXTENded Dosing) study was a global, open-label, extension study of patients with cITP, who received eltrombopag or placebo in prior eltrombopag clinical studies. The primary objective of EXTEND was to describe the long-term safety and tolerability of eltrombopag treatment in these patients. Here, we examine the occurrence of hepatobiliary and thromboembolic events (TEEs) as adverse events (AEs) of special interest in this study. Methods :Adult patients (≥18 years old) diagnosed with cITP according to ASH/BCSH guidelines were enrolled and received eltrombopag starting at 50 mg/day. Dose was titrated to 25-75 mg per day or less often as required, based on individual platelet count responses (targeted range ≥50-200x109/L). Patients who received 2 years of treatment and transitioned off eltrombopag due to commercial availability of eltrombopag were considered to have completed the study, whether or not they continued treatment with eltrombopag. The primary endpoint included detection and documentation of investigator-reported AEs, which included hepatobiliary AEs and TEEs. Analyses were conducted using the safety population, defined as all subjects who entered the study and had taken at least one dose of the study medication. Results:302 patients were enrolled and received at least one dose of eltrombopag: 67% were female; 38% splenectomized; 49% aged 18-49 years. Median duration of exposure was 2.4 years (range, 2 days to 8.8 years) and mean average daily dose was 50.2 (range, 1-75) mg/day. Overall, 259/302 (86%) achieved platelet counts of ≥50×109/L at least once during the study and 126/248 (51%) patients maintained continuous platelet counts ≥50×109/L for at least 31 weeks. Incidence of bleeding symptoms (WHO grades 1-4) generally decreased over time in patients with available data, from 57% (n=171/302) at baseline to 16% at 1 year (n=13/80), and 21% (12/58) at 2 years. 45 (15%) patients experienced at least one hepatobiliary AE, with the highest incidence within the first year of treatment (Figure A). AEs of increased ALT or AST led to the discontinuation of five and three patients, respectively and four patients discontinued due to an AE of increased blood bilirubin. Nine patients experienced ALT and/or AST >3 x upper limit of normal (ULN) and total bilirubin >1.5xULN. 19 (6.3%) patients experienced a total of 23 TEEs. Most events occurred in the first year (Figure B), and none after year 4. TEEs included deep vein thrombosis (n=6), cerebral infarction (stroke) [n=3], myocardial infarction (n=4), transient ischemic attack (n=2), others (n=8, 1 occurrence of each). A clear association with elevated platelet counts was not observed. Platelets >200x109/L at the time of the TEE were recorded in 8/19 patients; 6/19 experienced the TEE at or shortly after achieving their maximum platelet count. In total, 10 patients discontinued because of TEEs. Conclusions: Long-term treatment with eltrombopag in patients with cITP led to sustained platelet increases and reduced bleeding symptoms. The highest incidences of hepatobiliary AEs and TEEs occurred during the first year of treatment, though several events were recorded after 3 years of therapy. Long-term eltrombopag therapy was well-tolerated with a positive benefit-risk relationship in adults with cITP, with decreasing events after the first year of treatment. Disclosures Saleh: GSK: Consultancy, Research Funding, Speakers Bureau. 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. Wong:Bayer, Biogen-Idec and Novartis: Consultancy; 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. El-Ali:Novartis: Employment. Quebe-Fehling:Novartis: Employment.

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A Phase 1/2 Study to Evaluate the Safety and Efficacy of Ponatinib with Chemotherapy in Pediatric Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood-2020-134724 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 47-47

Author(s):

Yousif Matloub ◽

Lia Gore ◽

Mignon L. Loh ◽

Chin-Hon Pui ◽

Michael J. Hanley ◽

...

Keyword(s):

Board Of Directors ◽

Pediatric Patients ◽

Phase 1 ◽

The United States ◽

Advisory Board ◽

Marketing Approval ◽

Phase 2 ◽

Advisory Committees ◽

Free Survival ◽

Secondary Endpoints

Introduction: Ph+ ALL accounts for 3-5% of pediatric ALL and is associated with improved outcomes when tyrosine kinase inhibitors (TKIs) are added to chemotherapy, with 5-year event-free survival (EFS) and overall survival (OS) of 58-60% and 70-86%, respectively. Ponatinib is a potent third-generation TKI pan-BCR-ABL1 inhibitor that is active against BCR-ABL1 and all identified single resistance mutations, including the gatekeeper alteration, T315I, which confers resistance to other TKIs. Ponatinib has marketing approval in more than 50 countries, which includes the United States and European Union, for adults with chronic-/accelerated-/blast-phase chronic myeloid leukemia or Ph+ ALL that are resistant/intolerant to other TKIs or are T315I+. Ponatinib may also overcome drug resistance in pediatric patients with relapsed or resistant Ph+ ALL. This study will assess the pharmacokinetics, safety, and efficacy of ponatinib in pediatric patients. Methods: This Phase 1/2, single-arm, open-label, multicenter study (NCT04501614) will enroll approximately 18 patients in Phase 1 and 68 patients in Phase 2, including those enrolled in Phase 1 at the recommended Phase 2 dose (RP2D). Patients (aged ≥1 year to ≤21 years) with Ph+ ALL, Ph+ mixed phenotype acute leukemia, or Ph-like ALL (US only) with ABL class lesions will be enrolled. Enrolled patients must have either relapsed or are resistant or intolerant to ≥1 prior therapy with a BCR-ABL1-targeted TKI or have a BCR-ABL1 T315I mutation. Patients >16 years must have a Karnofsky performance status ≥50%; patients ≤16 years must have a Lansky Play Scale ≥50%. During Phase 1, prior to availability of an age-appropriate formulation (AAF), patients must weigh ≥30 kg and be able to swallow tablets. The Phase 1 study will establish the RP2D of ponatinib in combination with the chemotherapy backbone using the adult tablet formulation in patients able to swallow tablets. Patients will receive fixed doses of ponatinib based on body weight ranges. The initially selected doses are expected to achieve systemic exposures that approximately match adult exposures after a 30-mg dose. Dose selection for the AAF will be in a separate cohort and informed by the results of a relative bioavailability study in healthy adult volunteers. A rolling 6 design will be used for both cohorts; additional cohorts may be enrolled at lower or higher doses based on the emerging data. In both Phase 1 and Phase 2, patients will receive two 35-day blocks of therapy (reinduction and consolidation). Each block includes 29 days of study treatment consisting of daily ponatinib and a modified United Kingdom ALL R3 chemotherapy backbone regimen, followed by a rest period of at least 6 days with daily ponatinib only. Disease assessment will occur at the end of each block. Patients will undergo an end-of-treatment visit 25 to 30 days after the last dose of study treatment in the consolidation block, or earlier if the patient is proceeding to alternate therapy or optional ponatinib continuation therapy. For the Phase 1 study, the primary endpoint is the RP2D of ponatinib (tablet and AAF) in combination with chemotherapy. Secondary endpoints are complete response (CR) rate at the end of the reinduction block and characterization of BCR-ABL1 domain mutations prior to and following ponatinib treatment. For the Phase 2 study, the primary endpoint is the CR rate at the end of the reinduction block. Secondary endpoints will be summarized descriptively, and include the proportion of patients in continued CR or who achieve CR at the end of consolidation, the proportion with minimal residual disease-negative status <0.01% at the end of each block, and the proportion who relapsed or progressed, and time-to-event estimates including EFS, progression-free survival, and OS. The study will include approximately 70 study sites in approximately 16 countries. Disclosures Matloub: Takeda: Current Employment. Gore:Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. Pui:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Hanley:Takeda: Current Employment. Lu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Leonard:Takeda: Current Employment. Granier:Incyte: Current Employment. Silverman:Servier: Other: advisory board; Syndax: Other: advisory board; Takeda: Other: advisory board. OffLabel Disclosure: Ponatinib has marketing approval in the United States and European Union for adult patients with chronic-/accelerated-/blast-phase chronic myeloid leukemia or Ph+ ALL that are resistant/intolerant to other TKIs or are T315I+. This trials-in-progress abstract describes a study in pediatric patients.

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Weekly Carfilzomib with Dexamethasone for Patients with Relapsed or Refractory Multiple Myeloma: Updated Results from the Phase 1/2 Study Champion-1 (NCT01677858)

Blood ◽

10.1182/blood.v126.23.373.373 ◽

2015 ◽

Vol 126 (23) ◽

pp. 373-373 ◽

Cited By ~ 2

Author(s):

James Berenson ◽

Alan Cartmell ◽

Roger Lyons ◽

Wael Harb ◽

Dimitrios Tzachanis ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

The United States ◽

Primary Objective ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction: Carfilzomib is an irreversible proteasome inhibitor that is approved as a single agent in the United States and other countries for the treatment of relapsed and refractory multiple myeloma (MM); carfilzomib in combination with lenalidomide (LEN) and dexamethasone is also approved in the United States for the treatment of relapsed MM. The approved dose and schedule of carfilzomib is a twice-weekly, 10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (starting dose: 20 mg/m2 [days 1 and 2 of cycle 1]; escalated to a target dose of 27 mg/m2 thereafter). Here we present updated results from the multicenter, phase 1/2 study CHAMPION-1 (NCT01677858), which evaluated the safety and efficacy of once-weekly carfilzomib with dexamethasone (Kd) in patients with relapsed or refractory MM. Methods: Patients with relapsed or refractory MM (1-3 prior lines of therapy) were eligible. Patients received carfilzomib as a 30-min IV infusion on days 1, 8, and 15 of 28-day cycles. The phase 1 portion of the study utilized a standard 3+3 dose-escalation scheme. All patients received carfilzomib at 20 mg/m2 on day 1 of cycle 1; patients received 45, 56, 70, or 88 mg/m2 beginning on day 8 of cycle 1 in successive dose-level cohorts until the maximum tolerated dose (MTD) was reached. All patients received dexamethasone 40 mg (IV or oral administration) on days 1, 8, 15, and 22 of cycles 1-8; dexamethasone was omitted on day 22 in cycles ≥ 9. In the phase 2 portion, patients received carfilzomib at the MTD (carfilzomib dose of 20 mg/m2 on cycle 1, day 1; escalating to the MTD for subsequent doses) and dexamethasone at the same dose and schedule. Kd was administered until unacceptable toxicity or disease progression. The primary objective of the phase 1 portion was to determine the MTD of carfilzomib in the Kd regimen; the primary objective of the phase 2 portion was to determine the overall response rate (ORR [≥partial response]). Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Results: A total of 27 patients were enrolled in phase 1; the MTD of carfilzomib was determined to be 70 mg/m2. Results are presented for all patients treated with Kd at the carfilzomib MTD in both the phase 1b (n=15) and phase 2 (n=89) portions of the study. Among these 104 patients, median patient age was 68.5 years (range, 41-88). Patients received a median of 1 prior line of therapy (range, 1-3); 83% of patients had received prior bortezomib (BTZ), 49% of patients were BTZ-refractory, 27% were LEN-refractory, and 16% were refractory to both BTZ and LEN. Median carfilzomib treatment duration was 7.7 months (range, 0.03-24.2). The ORR was 77% (95% confidence interval [CI]: 68%-85%); the clinical benefit rate (≥minimal response) was 84% (95% CI: 75%-90%). Kaplan-Meier median progression-free survival was 12.6 months (95% CI: 9.0-not estimable). Twelve patients (12%) discontinued treatment due to an adverse event. The most common adverse events of any grade and of grade ≥3 are shown in the Table. Five patients died on study: 1 patient each had cause of death reported as disease progression, acute respiratory distress syndrome, acute respiratory failure, acute kidney injury, and cardiopulmonary arrest. The mean area under the curve and maximum concentration following a 70-mg/m2 carfilzomib dose was 1050 ng×h/mL and 2510 ng/mL, respectively. At 1 hour post dosing of carfilzomib 70 mg/m2, the activity of the predominant chymotrypsin-like proteasome catalytic subunit in peripheral blood mononuclear cells (ie, low molecular mass polypeptide 7) was strongly inhibited (97% inhibition as determined by an enzyme-linked immunosorbent assay [ProCISE]; 93% inhibition as determined by a fluorogenic substrate assay). Conclusions: CHAMPION-1 is the first clinical study to evaluate carfilzomib on a weekly dosing schedule. Once-weekly carfilzomib (70 mg/m2) with dexamethasone demonstrated acceptable safety and tolerability with promising efficacy for patients with relapsed or refractory MM. The dose and schedule of carfilzomib used in the CHAMPION-1 study (20/70 mg/m2) is currently being compared with the regulatory-approved carfilzomib dose and schedule (20/27 mg/m2 administered twice-weekly) in the ongoing, phase 3, superiority study ARROW (NCT02412878). Disclosures Lyons: Amgen: Consultancy, Honoraria; Insyte: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Harb:Onyx Pharmaceuticals: Consultancy. Boccia:Incyte Corporation: Honoraria. Moss:Onyx: Honoraria, Research Funding. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schupp:Amgen: Employment, Equity Ownership. Dixon:Onyx/Amgen: Employment, Equity Ownership. Ou:Onyx/Amgen: Employment, Equity Ownership. Anderl:Onyx/Amgen: Employment, Equity Ownership. Berdeja:Abbvie: Research Funding; BMS: Research Funding; Acetylon: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Onyx: Research Funding; Janssen: Research Funding; Novartis: Research Funding; MEI: Research Funding; Array: Research Funding; Curis: Research Funding.

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An Adaptive, Randomized, Placebo-Controlled, Double-Blind, Multi-Center Study of Oral FT-4202, a Pyruvate Kinase Activator in Patients with Sickle Cell Disease (PRAISE)

Blood ◽

10.1182/blood-2020-134266 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 19-20

Author(s):

Kenneth W. Wood ◽

James Geib ◽

Eric Wu ◽

Jason Berlin ◽

Irena Webster ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Response Rate ◽

Oxygen Affinity ◽

Phase 2 ◽

Advisory Committees ◽

Double Blind ◽

Secondary Endpoints ◽

2,3 Dpg

The hallmark of sickle cell disease (SCD) is hemoglobin S (HbS) polymerization upon deoxygenation, resulting in red blood cell (RBC) sickling, oxidative damage, membrane damage, hemolysis, chronic anemia, cell adhesion, vaso-occlusion and inflammation. Exacerbating the pathogenesis of SCD, the HbS RBC has increased (↑) levels of 2,3-diphosphoglycerate (2,3-DPG), resulting in reduced (↓) Hb oxygen affinity (↑ P50), and ↓ ATP, essential for RBC homeostasis. FT-4202 is a potent, selective, and orally bioavailable allosteric activator of erythrocyte pyruvate kinase (PKR) that increases PKR activity, resulting in ↓ 2,3-DPG levels and ↑ ATP levels in RBCs. Preliminary data from the ongoing phase 1 study [NCT03815695] in healthy volunteers and patients with SCD indicate that FT-4202 is well tolerated, has no effect on steroidogenesis, and exhibits linear and time-independent pharmacokinetics (PK) and associated pharmacodynamic (PD) responses (↓ 2,3-DPG and ↑ ATP). Furthermore, in patients with SCD, a single dose of FT-4202 demonstrated favorable biologic effects, including increased Hb oxygen affinity (↓ P50), decreased point of sickling (PoS), improved RBC deformability, and improved RBC membrane function, indicative of overall improved RBC health (Estepp, J. EP1531; EHA 2020). Accordingly, we designed a phase 2/3, randomized, double-blind, placebo-controlled global study (PRAISE) to investigate the safety and efficacy of FT-4202 in patients with SCD. The PRAISE study will enroll up to 344 adult and adolescent patients with SCD, including 60 to 90 patients in the Dose Determination (DD) Group and ~ 274 patients in the Efficacy Continuation (EC) Group (see Figure). Key inclusion criteria: SCD (all genotypes), at least 2 vaso-occlusive crises (VOCs) in the past 12 mos, baseline Hb ≥ 5.5 and ≤ 10 g/dL, stable hydroxyurea (HU) therapy for the previous 90 days (if applicable). Key exclusion criteria: More than 10 VOCs in the past 12 mos, hospitalization for sickle cell crisis or other vaso-occlusive event within 14 days of consent, routine RBC transfusions, significant hepatic or renal dysfunction, history of unstable or deteriorating cardiac or pulmonary disease, or overt stroke within 2 yrs. Endpoints: The co-primary endpoints are (1) Hb response rate at Week 24 (increase of > 1 g/dL from baseline) and (2) annualized VOC rate during the blinded treatment period based on adjudicated VOC review. Secondary endpoints include measures of hemolysis, time to first VOC, and the PROMIS fatigue scale. Safety endpoints include the incidence of AEs, concomitant medications, vital signs, ECGs, clinical laboratory measurements, and physical examination. Design: The study design is a group-sequential, adaptive, phase 2/3 study (see Figure). Patients will be stratified by age, number of VOCs (2-3 vs. 4-10) in the preceding 12 mos, and prior/concomitant HU use in the preceding 12 mos. The phase 2 DD portion will assess 2 active doses and placebo with patients randomized 1:1:1. The dose will be chosen at the first interim analysis (IA1) based on safety and Hb response rate at Week 12 of the first 60 DD patients. A futility analysis will also be conducted on Hb response at that point. After dose selection, patients will be randomized 1:1 into the phase 3 EC portion to assess FT-4202 efficacy. Once 110 patients from phase 2 or 3 who have been randomized to the selected dose or placebo have completed 24 weeks of follow-up or have dropped out, a second interim analysis (IA2) will be performed to assess both efficacy and futility. IA2 will assess the co-primary endpoint of Hb response rate at Week 24 (p<0.001). The final analysis after 52 weeks of blinded treatment will test the VOC endpoint, the Hb response rate, and all secondary endpoints. Key secondary endpoints will be tested at IA2 and all will be tested at the final analysis, when there will be adequate power. Treatment: Patients will be randomized to receive FT-4202 or placebo. In the DD phase, two doses will be evaluated, and in the EC phase, the selected dose of FT-4202 from the DD phase will be evaluated in comparison to placebo. Patients in DD on the unselected dose will remain on treatment at that dose level for 52 weeks. Following completion of 52 weeks of double-blind treatment, patients may enter a 52-week open-label extension period to receive FT-4202 at the selected dose. Status: Study initiation is planned for late 2020; status will be updated at presentation. Figure Disclosures Wood: Forma Therapeutics, Inc.: Current Employment. Geib:Forma Therapeutics, Inc.: Current Employment. Wu:Forma Therapeutics, Inc.: Current Employment. Berlin:Forma Therapeutics, Inc.: Current Employment. Webster:Forma Therapeutics, Inc.: Current Employment. Ataga:Shire/Takeda: Research Funding; Editas Medicine: Honoraria; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Modus Therapeutics: Honoraria; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Consultancy; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Howard:Agios, Forma Therapeutics, Inc., Global Blood Therapeutics, Imara, Inc., Novo Nordisk, Novartis: Membership on an entity's Board of Directors or advisory committees; Imara, Inc., Novartis, Resonance Health: Honoraria. Estepp:ASH, NHLBI: Research Funding; Daiichi Sankyo, Esperion, Global Blood Therapeutics: Consultancy; Global Blood Therapeutics, Forma Therapeutics, Pfizer, Eli Lilly and Co: Research Funding. Telen:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics Inc.: Consultancy; Forma Therapeutics: Research Funding. Brevard:Forma Therapeutics, Inc.: Current Employment.

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Rituximab Plus Lenalidomide Versus Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. First Analysis of Survival Endpoints of the Randomized Phase-2 Trial SAKK 35/10

Blood ◽

10.1182/blood.v128.22.1099.1099 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1099-1099 ◽

Cited By ~ 6

Author(s):

Eva Kimby ◽

Stephanie Rondeau ◽

Anna Vanazzi ◽

Bjorn Ostenstad ◽

Ulrich J.M. Mey ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Stage Iv ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Trial ◽

Secondary Endpoints ◽

Lymphoma Therapy ◽

Randomized Phase 2

Abstract Background: The randomized phase-2 trial SAKK 35/10 was conducted by the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) to compare the activity of single-agent rituximab versus rituximab plus lenalidomide in the first-line treatment of symptomatic follicular lymphoma (FL). The results of primary endpoint (complete remission [CR/CRu] at week 23) assessment were previously reported, showing that addition of lenalidomide to rituximab results in a significantly higher CR/CRu rate at the expected cost of increased but manageable toxicity (Kimby et al. Blood 2014.124 (21):799; Zucca et al. Hematol Oncol 2015. 33(s1): 105). Here we report the first analysis of secondary endpoints, progression-free survival (PFS), time to next anti-lymphoma treatment (TTNT), CR duration, as well as CR/CRu rate at 30 months (CR30). Methods: 154 patients (pts) with grade 1 to 3a FL, untreated and in need of systemic therapy, were randomized to receive either rituximab (375mg/m2 at week 1, 2, 3, 4, 12, 13, 14 and 15) or rituximab (same schedule) plus lenalidomide (15 mg daily, from 14 days before the first until 14 days after the last rituximab administration). The sample size was calculated to allow the detection of a 20% increase of the CR/Cru rate with 90% power and type I error 0.10; a one-sided Z-test for proportions was used to compare the two arms. Treatment was discontinued in pts who did not achieve at least a 25% reduction in the sum of products of tumor diameters at week 10. Primary and secondary endpoints were defined according to the NCI international standardized criteria (Cheson et al 1999). Results: 77 pts (median age 63 years, 52% with stage IV and 47% with poor-risk FLIPI score) were allocated in the single-agent rituximab arm and 77 (median age 61 years, 48% with stage IV and 47% with poor-risk FLIPI score) in the combination arm. A higher CR/CRu rate in the combination arm was documented both by the investigator assessment (36% vs 25%) and by the independent response reviewers of CT scans (61% vs. 36%). Adverse events of grade ≥3 were more common (56% vs 22% of pts) in the combination arm, including neutropenia (23% vs 7%). At a median follow up of 3.1 years, a longer CR duration was seen for the pts in the combination arm (median not reached vs 2.3 years) as well as a longer PFS (median not reached vs. 2.3 years), these differences were not statistically significant. The CR30, recently identified as a reliable surrogate of PFS (Sargent et al. Hematol Oncol 2015. 33(s1): 166), was significantly improved by the addition of lenalidomide to rituximab (42% vs 19%, p=0.001). Moreover, TTNT was significantly longer with the combination (median not reached vs 2.1 years, p=0.02) [Figure1]. Overall survival rates at 3 years were 93% and 92%, respectively. Conclusions: The SAKK 35/10 randomized trial confirmed that lenalidomide plus rituximab is an active and feasible initial treatment for FL pts in need of therapy. Addition of lenalidomide significantly increased the CR/CRu rate at week 23 (primary endpoint) and was maintained throughout 30 months. Although the trial was not powered to detect survival differences (secondary endpoints), a significantly better TTNT and a trend towards prolonged PFS and CR duration was seen in the combination arm. The excellent overall survival in both arms suggests that chemotherapy-free strategies should be further explored. Figure 1. Time to next anti-lymphoma therapy by treatment arm Figure 1. Time to next anti-lymphoma therapy by treatment arm Disclosures Kimby: Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lecture at educational session; Celgene: Other: Honoraria for lecture. educational meeting; Pfizer: Other: Research grant; Roche: Other: Honoraria for lecture in educational meetings; Gilead: Honoraria, Other: honoraria for educational lecture in meeting sponsored by Gilead. Mey:roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Wahlin:Roche: Consultancy. Hernberg:Roche: Consultancy, Honoraria. de Nully Brown:Roche: Research Funding. Ferreri:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zander:Bristol Myers, Celgene, Amgen, Mundipharma, Janssen-Cilag, Takeda Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Reduced Intensity Conditioned Sibling Transplantation Versus No Transplant in Intermediate or High Risk Acute Myeloid Leukemia: A Prospective Multi-Center Study in Patients 50-70 Years in First Complete Remission and with at Least One Potential Sibling Donor (ClinTrialGov 00342316)

Blood ◽

10.1182/blood-2018-99-110260 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 205-205

Author(s):

Mats Brune ◽

Thomas L. Kiss ◽

Elisabeth Wallhult ◽

Harald Anderson ◽

Robert Delage ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Groups ◽

Hla Typing ◽

Control Groups ◽

Advisory Committees ◽

Sibling Donor ◽

Secondary Endpoints ◽

And Control ◽

Reduced Intensity

Abstract Background and study design. Reduced intensity conditioning transplantation (RICT) is a commonly applied treatment option for AML patients >50 years of age. Prospective, controlled studies comparing RICT with standard chemotherapy are warranted. In this study, we aimed to prevent selection biases. Thus, patients were included prior to HLA typing of potential sibling donors, and statistical analyses were based on an intention-to-transplant, donor versus no-donor approach. Hence, the analyses also include events occurring during the donor search period and also the transplantation procedures along with post-transplant events. Patients and procedures. Between 2003 and 2016, 163 patients with AML in CR1 were included in Canada (n=69), Sweden (n=63), and Germany/Finland/Norway/New Zealand (n=31). Eighteen patients were excluded due to enrolment after the start of donor typing (n=14), lack of data (n=1), low-risk AML (n=2) or withdrawn consent (n=1). Thus, results from 145 patients with high (n=48) or intermediate (n=97) risk disease were available for analysis. Included patients were a median of 63 (50-70) years old, deemed fit for RICT and had at least one willing and healthy but not yet HLA typed sibling. The ensuing HLA typings thus yielded one RICT group including patients with ≥1 confirmed matched sibling donor (MSD), and one control group with no MSD. Date of inclusion was defined as date of HLA typing of the first potential MSD. The protocol-specified conditioning regimen for RICT was fludarabine (150-180 mg/m2) and busulfan (8 mg/kg orally or 6.4 mg/kg i.v., used in 95% of patients). Immunosuppression was ciclosporin alone (9%), with methotrexate (53%) or with MMF (35%). Peripheral blood stem cells were used in 95% of transplantations. Control patients received consolidation chemotherapy as per local routines. Statistics. Baseline factors were compared between study groups using Fisher´s exact test and rank sum tests. The primary endpoint was overall survival (OS) with secondary endpoints of relapse-free survival (RFS), relapse incidence (RI) and non-relapse mortality (NRM). Kaplan-Meier curves were used to estimate OS and RFS and cumulative incidence functions were used to estimate NRM and RI considering competing risks. The logrank test was employed for group comparisons of event rates with time censored at 5 yrs post inclusion. Results. The median follow-up time of surviving patients was 7.9 (0.24-14) yrs. Age, AML risk group and time from CR to inclusion did not differ between the study groups. Time lag from diagnosis to study inclusion was 65 (32-256) days (Controls) and 64 (29-319) days (RICT), P=0.74, Mann-Whitney test. Time from CR1 to inclusion was 22 (0-218) days (Controls) and 19 (0-131) (RICT). Excluding conditioning, patients in the RICT group received fewer chemotherapy cycles than controls. The time from start of last chemotherapy to transplant was median 63 (36-212) days. The incidence of acute (grade 2-4) and chronic extensive GvHD in transplanted patients was 25% and 39%, respectively. The non-relapse mortality at 3 years post inclusion (Table) was 12% (RICT group) and 4% (Controls). Causes of death was primarily AML, accounting for 73% and 88% of all deaths in the RICT and control groups, respectively. Twenty pts with an identified donor did not reach RICT due to relapse (n=12), co-morbidities (n=5), death (n=2), other (n=1). Total mortality at time of analysis was slightly lower in the RICT group (66% vs 75%). Overall survival (primary endpoint) at 3 years was 45% (CI 33-56) and 48% (36-60), in RICT and control groups, respectively. At 10 years after inclusion, OS in study groups were similar; RICT 27% (CI 15-41), Control 25% (CI 15-36). There were no significant differences between study groups with respect to primary or secondary endpoints (OS: P=0.27, RFS:P=0.98, RI: P=0.50, NRM: P=0.10, logrank tests. Figure). Conclusions. Applying an intention-to-treat analysis we did not demonstrate clinical benefit of sibling donor search and stem cell transplantation after a reduced intensity busulfan/fludarabine based regimen in AML patients ≥50 years in CR1. Early relapse was the main reason for preventing transplants in patients with an identified donor. Support from study groups: Canadian BMT Group, Australasian Leukaemia and Lymphoma Group, Norwegian/Swedish BMT Group, Swedish AML group Disclosures Kiss: Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wallhult:Jazz Pharmaceuticals: Speakers Bureau; Amgen: Speakers Bureau; Daichii-Sankyo: Speakers Bureau. Finke:Riemser: Consultancy, Honoraria, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding. Sabloff:Celgene: Membership on an entity's Board of Directors or advisory committees.

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Efficacy and Safety of Ravulizumab in Older Patients Aged >65 Years with Paroxysmal Nocturnal Hemoglobinuria in the 301 and 302 Phase 3 Extension Studies

Blood ◽

10.1182/blood-2020-140777 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Regis Peffault De Latour ◽

Jeffrey Szer ◽

Austin Kulasekararaj ◽

Jin Seok Kim ◽

Caroline I. Piatek ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Complement Inhibitor ◽

Efficacy And Safety ◽

Phase 3 ◽

Advisory Committees ◽

Treatment Naïve ◽

Secondary Endpoints

Background: In the two largest phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH), ravulizumab given every 8 weeks was noninferior to eculizumab given every 2 weeks across all efficacy endpoints. Data on efficacy and safety of ravulizumab in patients aged >65 years with PNH are limited. Aims: To compare the efficacy and safety of ravulizumab in patients with PNH aged >65 years with those aged ≤65 years. Methods: The population included patients from two phase 3 studies that assessed ravulizumab vs eculizumab in complement-inhibitor-naïve (301; NCT02946463) and -experienced (302; NCT03056040) adults with PNH. In study 301, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry and had a lactate dehydrogenase (LDH) level ≥1.5x upper limit of normal (ULN; 246U/L). In study 302, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry, were clinically stable on eculizumab having received ≥6 months of treatment and had a LDH level ≤1.5x ULN. Patients were randomized to either ravulizumab or eculizumab for 26 weeks after which all received ravulizumab up to 52 weeks. This prespecified analysis stratified patients by age: ≤65 or >65 years. Primary endpoints included percentage change in LDH from baseline to weeks 26 and 52, percentage of patients achieving LDH-normalization (LDH-N; LDH levels: ≤1x ULN) at weeks 26 and 52 and transfusion avoidance (TA) from baseline to weeks 26 and 52. Breakthrough hemolysis (BTH), hemoglobin (Hgb) stabilization and FACIT-fatigue score were secondary endpoints. Treatment emergent adverse events (TEAEs) were assessed as an indicator of safety. Results: A total of 58 patients aged >65 years and 383 patients aged ≤65 years were included. Disposition and medical history were similar among subgroups at baseline (Table 1). Results for primary and secondary endpoints for the two subgroups were comparable across studies and efficacy was maintained through 52 weeks. A higher proportion of treatment-experienced patients (>65 years) achieved all endpoints vs -naïve patients (Table 2). The percentage change in LDH levels from baseline to 26 and 52 weeks was similar between subgroups in study 301 (-66.5 to -80.0%) whereas in study 302, LDH levels remained stable in all subgroups up to 52 weeks (-3.7 to 22%). The percentage of patients achieving LDH-N in both studies at 26 and 52 weeks differed; 43.8-63.9% of patients aged ≤65 years achieved LDH-N compared with 21.4-77.8% of patients aged >65 years. A higher proportion of older treatment-experienced patients (57.1‒77.8%) achieved LDH-N compared with older treatment-naive patients (21.4‒50.0%) at 26 and 52 weeks. In patients aged ≤65 years in both studies, 63.7‒89.4% achieved TA. In the >65 years subgroup, 14.3‒50.0% of treatment-naive patients achieved TA whereas in study 302, 54.5‒72.7% of patients achieved TA. The number of BTH events was low, with no events reported in older patients to date. Hgb stabilization was consistent in the ≤65 year subgroup between the studies; a higher proportion of older patients in study 302 (45.5‒71.4%) achieved stabilized Hgb compared with older patients in study 301 (14.3‒35.3%). A clinically significant 3-point change was seen in FACIT-fatigue scores (indicating improvements in fatigue), with higher scores observed for ravulizumab in both subgroups (Figure 1). One patient discontinued the extension of study 301 due to lung cancer onset during the 26-week period and died following discontinuation. Headache was the most frequent TEAE. The incidence of TEAEs reported during ravulizumab treatment up to 52 weeks did not increase vs the 26-week period, with few events (Table 3) and no difference between subgroups. Conclusions: We present clinical outcomes in the largest cohort of patients with PNH (>65 years) on ravulizumab in a clinical trial setting to date. Ravulizumab was associated with similar efficacy and safety in both age subgroups and showed consistent and durable efficacy through 52 weeks of treatment. A higher proportion of patients in study 302 achieved all efficacy endpoints than in study 301, which can be due to patients' prior complement inhibitor experience. This observation was more evident in older patients. There were no BTH events in the older patients to date, and the number of infections in both subgroups was low. Ravulizumab was well tolerated in older patients with no additional safety concerns compared to younger patients. Disclosures Peffault De Latour: Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; 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. Szer:Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Piatek:Alexion Pharmaceuticals: Consultancy, Research Funding. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Yu:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Northstar-2: Updated Safety and Efficacy Analysis of Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Non-β0/β0 Genotypes

Blood ◽

10.1182/blood-2019-126046 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3543-3543 ◽

Cited By ~ 1

Author(s):

Alexis A. Thompson ◽

Mark C. Walters ◽

Janet L. Kwiatkowski ◽

Suradej Hongeng ◽

John B. Porter ◽

...

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Adult Patients ◽

Employment Equity ◽

Advisory Committees ◽

Transfusion Independence ◽

Equity Ownership

Background Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes. Methods Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max). Results Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were <12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively. Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of >11 g/dL without transfusions. Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline. Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported. Summary In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of >11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.

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