Early-Onset Osteopenia and Osteoporosis in Patients with Pyruvate Kinase Deficiency

Background: Hereditary pyruvate kinase (PK) deficiency results in lifelong hemolytic anemia and several significant comorbidities, the epidemiology of which are not well characterized. Among these is reduced bone mineral density (BMD), which can result in premature osteopenia, osteoporosis, and fractures. To better characterize the bone density abnormalities in patients with PK deficiency, this study evaluated pooled pre-treatment baseline data from 3 clinical trials involving patients with PK deficiency investigating mitapivat, an allosteric activator of PK: DRIVE-PK (NCT02476916), ACTIVATE (NCT03548220), and ACTIVATE-T (NCT03559699). This is the first large PK deficiency cohort in which dual-energy x-ray absorptiometry (DXA) scores were systematically and consistently assessed. Methods: DRIVE-PK is a completed phase 2, global, randomized, open-label study. ACTIVATE is an ongoing phase 3, global, randomized, double-blind, placebo-controlled study. ACTIVATE-T is an ongoing phase 3, global, open-label, single-arm study. In all 3 studies, patients ≥ 18 years of age with a confirmed diagnosis of PK deficiency were eligible to participate. Patients were eligible to participate in DRIVE-PK and in ACTIVATE if they were not regularly transfused (DRIVE-PK: ≤ 3 units of red blood cells in the prior 12 months; no transfusions in the prior 4 months; ACTIVATE: ≤ 4 transfusion episodes in the previous year; no transfusions in the prior 3 months) and in ACTIVATE-T if they were regularly transfused (≥ 6 transfusion episodes in the previous year). BMD was measured using DXA scans at baseline; scans were obtained locally for all 3 studies. Scans were interpreted locally for DRIVE-PK and centrally for ACTIVATE and ACTIVATE-T. Osteopenia and osteoporosis were identified on DXA scanning according to standard definitions, and the prevalence of each was compared to the prevalence ascertained via medical history. Results: Full demographics and characteristics of patients at baseline are shown in the Table. Of 159 patients evaluated (DRIVE-PK, n = 52; ACTIVATE, n = 80; ACTIVATE-T, n = 27), the median age was 34 years (range, 18-78) and the majority were female (n = 88; 55.3%). Of 155 patients who had baseline T-scores for total femur, spine, and femoral neck, 38 (24.5%) had a T-score of ≥ -1.0 at all locations, indicating normal BMD; 91 (58.7%) had a T-score of < -1.0 to > -2.5 at 1 or more locations, indicating osteopenia; and 26 (16.8%) had a T-score of ≤ -2.5 at 1 or more locations, indicating osteoporosis. The proportion of patients in each T-score range for each of the 3 locations is shown in the Figure. In contrast to the DXA scan findings, only 28 (17.6%) patients had a known medical history of osteopenia and 23 (14.5%) had a known medical history of osteoporosis. Taking together DXA scan results and medical history for all 159 patients, 85 patients (53.5%) had osteopenia and 33 patients (20.8%) had osteoporosis. The median age for patients with either osteopenia or osteoporosis (n = 118) was 36 years (range, 18-78). Of these, 20 patients (16.9%) were regularly transfused and 98 patients (83.1%) were not regularly transfused. Conclusions: In this large cohort, universal DXA scanning revealed that over three-quarters of adults with PK deficiency had osteopenia or osteoporosis, irrespective of transfusion requirements. Given the young median age of the cohort (34 years), these findings have considerable significance and implications for the screening and care of patients with PK deficiency throughout their adult lives. Early monitoring of these patients with DXA scans in order to ensure a prompt diagnosis of bone density abnormalities and indicated treatment may be warranted. Disclosures Al-Samkari: Argenx: Consultancy; Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Rigel: Consultancy; Amgen: Research Funding. Grace:Novartis: Research Funding; Agios: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Glenthoej:Novartis: 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; Bluebird: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexicon: Research Funding; Novo Nordisk: Honoraria. Barcellini:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: invited speaker , Research Funding; Novartis: Honoraria, Other: invited speaker , Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Kuo:Bluebird Bio: Consultancy; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy; Celgene: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding. Layton:Cerus: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morado:Sanofi Genzyme: Honoraria, Other: Grants. Viprakasit:BMS, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios Pharmaceuticals, Ionis Pharmaceuticals, La Jolla Pharmaceuticals, Protagonist Therapeutics, Vifor Pharma: Consultancy, Research Funding. Dong:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Tai:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Hawkins:Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; Infinity Pharmaceuticals: Current equity holder in publicly-traded company; Jazz Pharmaceuticals: Current equity holder in publicly-traded company. Gheuens:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Bowden:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Porter:Silence Therapeutics: Honoraria; La Jolla Pharmaceuticals: Honoraria; Vifor Pharmaceuticals: Honoraria; Protagonist Therapeutics: Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria; BMS: Consultancy, Honoraria. van Beers:Novartis: Research Funding; Pfizer: Research Funding; RR mechatronics: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Osteoarticular Pain after Discontinuation of Tyrosine Kinase Inhibitors (TKI): A French Cohort

Blood ◽

10.1182/blood.v126.23.137.137 ◽

2015 ◽

Vol 126 (23) ◽

pp. 137-137 ◽

Cited By ~ 9

Author(s):

Marc G Berger ◽

Bruno Pereira ◽

Charlotte Oris ◽

Sandrine Saugues ◽

Pascale Cony-Makhoul ◽

...

Keyword(s):

Clinical Trials ◽

Tyrosine Kinase ◽

Medical History ◽

Board Of Directors ◽

Tyrosine Kinase Inhibitors ◽

Research Funding ◽

Kinase Inhibitors ◽

Duration Of Treatment ◽

Advisory Committees ◽

History Of

Abstract Context: The Tyrosine Kinase Inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) increasing dramatically the survival of CML patients and leading to a residual disease with a sustained and deep molecular response. In this subset of very good responder patients, the attempts of stopping treatment in different clinical trials were successfully achieved without relapse. The Swedish team in the EURO-SKI protocol already reported cases of musculoskeletal pain occurring after cessation of TKI (Richter et al., JCO, 2014). Since several clinical trials regarding TKI discontinuation have been also run in France, we decided to retrospectively collect data using the pharmacovigilance system of the different Trials collected prospectively. Method: 428 patients from STIM2 (n=204) and EURO-SKI (n=224) trials were systematically analyzed from the case report from each trial. For the EURO-SKI only French patients were included. Statistical analysis was performed using Stata 13 software (StataCorp LP, College Station, TX, US). Comparisons between the independent groups were realized using the Chi-squared or Fisher's exact tests for categorical variables, and using Student t-test or Mann-Whitney test for quantitative. Multivariate analyses were performed to take into account adjustment on covariates fixed according to univariate results and clinically relevance. Results: Among the 428 patients the main characteristics were as follow i,e; 208 (48.6%) men and 220 (51.4%) women, with a median age of 77.5 years (24-93). Sokal scores (n=449) were low in 187 (41.6%) patients, intermediate in 188 (41.9%) patients and high in 74 (16.5%) patients. A withdrawal TKI syndrome (WS) was reported for 102 (23.8%) patients (100 after imatinib and 2 after nilotinib). 2). The WS consists in bone and articular pains and arthritis and affects the upper limbs, shoulders and cervical rachis, with a grade 1 or 2 in most patients and grade 3 in 22% of patients . The prevalence of WS depends on the trials, 34.8% in EURO-SKI group and 13.8% in STIM2 group (p<0.001). The WS was treated by non-steroidal anti-inflammatory drugs, corticosteroids or by local infiltration. The median duration of WS was 7 months (range: 3-30 months, 24 exploitable cases). We did not observe any difference between WS group and the group without painful syndrome in terms of sex ratio (p=0.92), age (p=0.33), sokal score (p=0.15), BCR-ABL transcript (p=0.42) or duration of CML (p=0.24). However the median duration of TKI therapy appeared longer in this subgroup (median: 88.8 months vs 79.8 months (p=0.02). There was no biological inflammatory syndrome and the results of medical imaging were inconclusive. However, a medical history of osteoarticular pains or disease appeared as predisposing to withdrawal syndrome (22.9% in WS group vs 9.8% in control group; p=0.002). Finally the two factors, duration of treatment and medical history were confirmed using multivariate analysis (RR=1.73 and 1.76 respectively). Among 19 exploitable cases suffering CML relapse and requiring further TKI treatment, pain disappeared in 7 patients (37%) within a median period of 3.5 weeks. Conclusion: About 23% of patients who stopped TKIs experienced a TKI WS and all TKI seems to be concerned. The predisposing factors were a medical history of osteoarticular pain or disease, and the duration of treatment. So patients and physicians should be aware and recommendations should be proposed for patients who have treated longtime with a history of arthritis. Disclosures Legros: Novartis: Research Funding, Speakers Bureau; ARIAD: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rousselot:Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Rea:Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Mahon:Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy.

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FLT3 and LSD1 Inhibitor Combinations Synergistically Repress Growth of FLT3-Mutant Acute Myeloid Leukemia Via Blockage of MYC Function

Blood ◽

10.1182/blood-2020-143029 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-32

Author(s):

Daniel J. Coleman ◽

Brittany M. Smith ◽

Cody Coblentz ◽

Rowan L. Callahan ◽

Jake VanCampen ◽

...

Keyword(s):

Transcription Factor ◽

Board Of Directors ◽

Transcriptional Activation ◽

Myeloid Leukemia ◽

Research Funding ◽

Target Genes ◽

Publicly Traded ◽

Private Company ◽

Advisory Committees ◽

Flt3 Inhibitor

Internal Tandem Duplication mutations of Fms Related Receptor Tyrosine Kinase 3 (FLT3), known as FLT3-ITD mutations, are associated with poor prognosis in Acute Myeloid Leukemia (AML). The clinical efficacy of inhibiting FLT3 in AML is limited by the rapid development of drug resistance and relapse, underscoring a need for more potent and durable treatment strategies. The early persistence of leukemic blasts during FLT3 inhibition is a key driver of resistance. We find that in combination, inhibitors of Lysine Specific Demethylase 1 (LSD1) potentiate the activity of FLT3 inhibitors, driving synergistic cell death. This novel therapeutic approach has the potential to drive deeper therapeutic responses in FLT3-Mutant AML, delaying or preventing the development of resistance. LSD1 is a dynamic DNA-associated protein that functions as a chromatin modifier and transcription factor. LSD1 removes methylation on both lysine 4 of histone H3 (H3K4), associated with transcriptional activation, and lysine 9 (H3K9), associated with transcriptional repression. Additionally, LSD1 has been reported to function as a transcription factor independent of its catalytic demethylase function. LSD1 inhibition reduces cell proliferation in several cancer types. In AML specifically, inhibition of LSD1 has been reported to activate enhancers associated with genes that promote differentiation. We hypothesized that combining LSD1 inhibition with FLT3 inhibition in FLT3-ITD AML would result in synergistic effects on cell viability through reactivating differentiation pathways and more strongly blocking proliferation. In this study, we aimed to examine the efficacy, transcriptional effects, and changes in chromatin dynamics when combining LSD1 inhibition with FLT3 inhibition in a FLT3-ITD mutant cell line and patient samples. We used matrix combination screening to determine that combining the FLT3 inhibitor Quizartinib with LSD1 inhibitors (GSK-2879552 or ORY-1001) synergistically represses cell viability in the FLT3-ITD mutant MOLM-13 cell line and in multiple primary AML samples. RNA-seq followed by Gene Set Enrichment Analysis revealed that combining LSD1 and FLT3 inhibition synergistically represses target genes of the oncogenic transcription factor MYC. This finding was corroborated through high-throughput genome-wide profiling of histone marks, using the recently developed technique Cleavage Under Targets and Tagmentation (CUT&Tag). Specifically, we discovered several promoter regions in which acetylation of lysine 27 of Histone H3 (H3K27Ac), associated with transcriptional activation, was repressed by combining LSD1 and FLT3 inhibition. The genes associated with these regions were strongly enriched for known MYC target genes. Through additional genomic profiling methods including ChIP-seq and ATAC-seq, we have established potential roles for several DNA-binding transcription factors including CEBPA, RUNX1, STAT5, and LSD1 itself, that may mediate repression of MYC function resulting from combining LSD1 and FLT3 inhibition. Together, our work establishes LSD1 and FLT3 inhibitor combinations as a promising treatment strategy in FLT3-ITD AML. Importantly, this study identifies combined FLT3 and LSD1 inhibition as an effective strategy to indirectly target MYC function, as MYC is often referred to as an "undruggable" target. Furthermore, it has the potential to drive deeper molecular responses in FLT3-mutant AML, decreasing the likelihood of treatment resistance. Disclosures Druker: Bristol-Myers Squibb: Research Funding; Blueprint Medicines: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millipore (formerly Upstate Biotechnology): Patents & Royalties; Pfizer: Research Funding; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Patient True Talks: Consultancy; Oregon Health & Science University: Patents & Royalties; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; MolecularMD (acquired by ICON): Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Henry Stewart Talks: Patents & Royalties; Iterion Therapeutics (formerly Beta Cat Pharmaceuticals): Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics Inc. (formerly Lorus): Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Merck & Co: Patents & Royalties; GRAIL: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Membership on an entity's Board of Directors or advisory committees; McGraw Hill: Patents & Royalties; Leukemia & Lymphoma Society: Research Funding; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Dana-Farber Cancer Institute: Patents & Royalties; EnLiven: Consultancy, Research Funding. Maxson:Gilead Sciences: Research Funding; Ionis Pharmaceuticals: Other: Joint oversight committee for a collaboration between OHSU and Ionis Pharmaceuticals.

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C3 Inhibition with Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria: Results from the Paddock and Palomino Trials

Blood ◽

10.1182/blood-2020-134436 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-4

Author(s):

Raymond S Wong ◽

Kalina Ignatova ◽

Humphrey Pullon ◽

Jameela Sathar ◽

Pimjai Niparuck ◽

...

Keyword(s):

Aplastic Anemia ◽

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Normal Range ◽

Open Label ◽

Private Company ◽

Advisory Committees ◽

Regional Office ◽

Lower Limit Of Normal

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal hematopoietic stem cell disorder characterized by chronic complement-mediated intravascular and extravascular hemolysis (IVH and EVH), and thrombosis. C5 inhibitors reduce IVH by inhibiting membrane attack complex formation and are the current standard of treatment for PNH. EVH persists in the presence of C5 inhibition. Pegcetacoplan is a C3 inhibitor targeted to control both IVH and EVH. The PADDOCK and PALOMINO studies assessed the safety and preliminary efficacy of pegcetacoplan in complement inhibitor-naïve patients. METHODS PADDOCK was a phase 1b, open-label, pilot study (NCT02588833) with 2 cohorts. Subjects in cohort 1 received pegcetacoplan at a suboptimal dose of 180 mg/day for 28 days; subjects in cohort 2 received pegcetacoplan 270 mg/day for up to 1 year. Subjects could participate in both cohorts. PALOMINO was a phase 2a, open-label, single-cohort study (NCT03593200) in which subjects received pegcetacoplan 270 mg/day for up to 1 year. Both studies enrolled subjects ≥18 years old diagnosed with PNH and no prior treatment with eculizumab. Primary efficacy endpoints in both studies were change from baseline in lactate dehydrogenase (LDH), haptoglobin, and hemoglobin. Secondary efficacy endpoints included change from baseline in reticulocyte count, total bilirubin, and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. The number of packed red blood cell transfusions was also recorded. Primary safety endpoints were the incidence and severity of treatment emergent adverse events (TEAEs). RESULTS Three subjects were enrolled in PADDOCK cohort 1 and 20 in cohort 2; 1 subject was enrolled in both cohorts. PALOMINO enrolled 4 subjects. PADDOCK cohort 2 and PALOMINO efficacy data are shown in the Table. At baseline, mean LDH levels were >8× upper limit of normal in both studies. At day 365, mean LDH had decreased to <2× upper limit of normal in PADDOCK and was within the normal range in PALOMINO. At baseline, mean hemoglobin levels were below the lower limit of normal in both studies. At day 365, mean hemoglobin levels had increased to within the normal range in both studies. In PALOMINO, 3 subjects achieved hemoglobin levels above the lower limit of normal at day 365, and 1 subject had a hemoglobin level of 10.14 g/dL. An increase from baseline in mean FACIT-Fatigue scores of 7.1 and 6.5 at day 365 was observed in PADDOCK and PALOMINO, respectively. In PADDOCK and PALOMINO, mean reticulocyte count decreased from 194.9 × 109 cells/L and 238.3 × 109 cells/L at baseline, respectively, to 96.4 × 109 cells/L and 94.0 × 109 cells/L at day 365. Total bilirubin levels also decreased from 42.6 µmol/L and 30.85 µmol/L at baseline to 13.9 µmol/L and 9.33 µmol/L at day 365 in PADDOCK and PALOMINO, respectively. In PADDOCK cohort 2, 18/20 subjects received ≥1 transfusion in the 12 months prior to screening, and 13/20 subjects did not require a transfusion during the study. In PALOMINO, all subjects received ≥1 transfusion in the 12 months prior to screening, and none required a transfusion during the study. Overall, 143 TEAEs were reported in 19/22 subjects (86.4%) in PADDOCK cohorts 1 and 2, of which 35 were either possibly or probably related to pegcetacoplan. Thirteen serious adverse events (SAEs) were reported in PADDOCK. Three SAEs (aplastic anemia, abdominal neoplasm, and hypersensitivity) led to pegcetacoplan discontinuation in 3 subjects. Two of these SAEs (aplastic anemia and abdominal neoplasm) resulted in study discontinuation. The aplastic anemia SAE was fatal and considered not related to pegcetacoplan. In PALOMINO, 60 TEAEs were reported in 3 (75.0%) subjects, of which 52 were possibly treatment-related. One SAE (rib fracture) was reported and was considered not related to pegcetacoplan. In PALOMINO, no TEAEs led to death, pegcetacoplan discontinuation, or study discontinuation. CONCLUSIONS In PADDOCK and PALOMINO, pegcetacoplan improved hematological parameters by controlling both IVH and EVH in patients with PNH. Improvements in clinical parameters were also observed. Pegcetacoplan was shown to have an acceptable safety profile and was generally well tolerated in both studies. PADDOCK and PALOMINO demonstrate the therapeutic potential of pegcetacoplan in the treatment of PNH and support further evaluation in the ongoing phase 3 PRINCE trial (NCT04085601) in complement inhibitor-naïve patients. Disclosures Wong: Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis: Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sathar:Novo Nordisk: Honoraria; Bayer: Honoraria; Roche: Honoraria. Tse:MSD: Research Funding; Janssen: Research Funding. Roman:Alexion: Speakers Bureau; Novartis: Speakers Bureau. Amine:Acibadem City Clinic Tokuda Hospital: Current Employment. Tan:Apellis: Consultancy, Patents & Royalties. Di Casoli:Apellis: Current Employment, Current equity holder in private company. Deschatelets:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Francois:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Grossi:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Bogdanovic:Takeda (regional office in Serbia, only local activities in Serbia): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer (regional office in Serbia, only local activities in Serbia): Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Investigator fee in clinical trial; Novartis Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

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Health-Related Quality of Life Outcomes for Patients with Transfusion-Dependent Beta-Thalassemia Treated with Luspatercept in the Believe Trial

Blood ◽

10.1182/blood-2020-136312 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Maria Domenica Cappellini ◽

Ali T. Taher ◽

Antonio Piga ◽

Farrukh Shah ◽

Ersi Voskaridou ◽

...

Keyword(s):

Quality Of Life ◽

Board Of Directors ◽

Research Funding ◽

Publicly Traded ◽

Advisory Committees ◽

Meaningful Improvement ◽

Sf 36 ◽

La Jolla ◽

Domain Scores

Introduction: Patients (pts) with transfusion-dependent (TD) β-thalassemia may require long-term red blood cell transfusions (RBCT) that can lead to iron overload and associated complications, which impact negatively on health-related quality of life (HRQoL). Administration of RBCT provides transient relief from anemia-related symptoms associated with β-thalassemia; reduction of RBCT may increase anemia-related symptoms and thereby worsen HRQoL. The phase 3 BELIEVE study (NCT02604433) showed that the first-in-class erythroid maturation agent luspatercept provided clinically meaningful reduction in RBCT burden, but the impact of luspatercept on HRQoL is not well understood. This analysis assessed the effect of luspatercept plus best supportive care (BSC, including RBCT, iron chelation therapy) vs placebo (PBO) plus BSC on HRQoL in pts with TD β-thalassemia. Methods: Pts received luspatercept (starting dose 1.0 mg/kg with titration up to 1.25 mg/kg every 3 weeks) or PBO, subcutaneously for ≥ 48 weeks plus BSC. HRQoL was assessed using the generic 36-item Short Form Health Survey (SF-36) and the thalassemia-specific Transfusion-dependent Quality of Life questionnaire (TranQol), at screening (≤ 4 weeks prior to first study dose) and every 12 weeks up to 48 weeks of treatment. The HRQoL evaluable population included all pts who completed the HRQoL assessment at screening and ≥ 1 post-screening assessment visit. The TranQol and SF-36 were considered complete if ≥ 75% and ≥ 50% of items, respectively, were answered at a given time point. The primary analysis assessed changes from baseline between groups up to Week 48. The primary domains of interest were: TranQol total score and Physical Health (PH); and the SF-36 Physical Component Summary (PCS), Physical Functioning (PF), and General Health (GH). Other domains were considered exploratory domains. Changes from baseline were compared using ANCOVA models adjusting for baseline domain scores and geographic region. In exploratory analyses, the proportion of pts achieving a clinically meaningful improvement in domain scores were compared between pts on luspatercept achieving a clinical response (≥ 50% reduction in RBCT burden over 12 weeks; ≥ 33% reduction in RBCT burden over 12 weeks; transfusion independence [TI] any 8 weeks; or TI any 12 weeks), and PBO. Results: 336 pts were randomized to treatment; 224 to luspatercept and 112 to PBO. The HRQoL evaluable population was 212 (94.6%) in the luspatercept arm and 104 (92.9%) in the PBO arm. HRQoL questionnaire compliance rates among pts still on treatment were > 87.5% for both questionnaires at Week 48. Baseline HRQoL scores were similar to the US general population for most SF-36 domains, although GH, Role-Emotional, and Role-Physical domain scores were impaired in the BELIEVE population. Mean scores on all primary and exploratory domains were stable over time in both treatment groups and did not differ between treatment groups at Week 24 and 48. When considering responders to luspatercept, pts receiving luspatercept and achieving a ≥ 50% reduction in RBCT burden over 12 weeks were significantly more likely than pts receiving PBO to have a clinically meaningful improvement in PCS (31.1% vs 16.5%; P = 0.024), and PF (30.0% vs 13.2%; P = 0.007) at Week 48 (Table). Statistically significant differences between luspatercept and PBO were also seen among pts achieving TI for any 8 or any 12 weeks for some SF-36 domains, but no statistical difference was seen in pts achieving a ≥ 33% reduction in RBCT burden for either SF-36 or TranQol domains although the proportion of pts with improved scores was higher with luspatercept, especially at Week 48. Conclusions: Overall, the addition of luspatercept to BSC reduced transfusion burden while sustaining TranQol and SF-36 HRQoL scores over time through Week 48 compared with those receiving PBO. Pts with TD β-thalassemia responding to luspatercept were more likely to achieve clinically meaningful improvements in HRQoL compared with PBO. Disclosures Cappellini: Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics, Novartis, Vifor Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Taher:Silence Therapeutics: Consultancy; Vifor Pharma: Consultancy, Research Funding; Ionis Pharmaceuticals: Consultancy; BMS: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding. Piga:BMS: Research Funding; Novartis: Research Funding. Shah:Novartis, BMS: Consultancy, Honoraria, Speakers Bureau; Bluebird Bio: Consultancy, Honoraria; IQVIA: Consultancy, Membership on an entity's Board of Directors or advisory committees. Voskaridou:ADDMEDICA Company: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ACCELERON Company: Consultancy, Research Funding; PROTAGONIST Company: Research Funding; GENESIS Company: Consultancy, Research Funding; NOVARTIS Company: Research Funding. Viprakasit:Agios Pharmaceuticals, Ionis Pharmaceuticals, La Jolla Pharmaceuticals, Protagonist Therapeutics, Vifor Pharma: Consultancy, Research Funding; BMS, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Porter:Silence Therapeutics: Honoraria; La Jolla Pharmaceuticals: Honoraria; Vifor Pharmaceuticals: Honoraria; Protagonist Therapeutics: Honoraria; BMS: Consultancy, Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria. Hermine:AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; BMS, Alexion, Novartis, Inatherys: Research Funding. Neufeld:Takeda: Consultancy; Octapharma: Consultancy; Novo Nordsik: Consultancy; genetech: Consultancy; Bayer: Other: DSMB; Imara Pharma: Other: DSMB service; ApoPharma/Chiezi: Other: DSMB service; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Acceleron Pharma: Consultancy, Other: DSMB. Thompson:BMS: Consultancy, Research Funding; Baxalta: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CRISPR/Vertex: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Biomarin: Research Funding. Tang:BMS: Current Employment, Current equity holder in publicly-traded company. Yu:Evidera: Current Employment. Guo:BMS: Consultancy. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Miteva:BMS: Current Employment. Zinger:Celgene, a Bristol Myers Squibb company: Current Employment. Backstrom:Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company. Oliva:Abbvie: Consultancy; Amgen: Consultancy; Novartis: Consultancy; BMS: Consultancy, Honoraria, Patents & Royalties, Speakers Bureau; Alexion: Consultancy; Apellis: Consultancy.

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A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2021-147335 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3675-3675

Author(s):

David M Ross ◽

Alejandro Arbelaez ◽

Lynette C.Y. Chee ◽

Chun Yew Fong ◽

Devendra Hiwase ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Phase 2 ◽

Publicly Traded ◽

Open Label ◽

Advisory Committees ◽

Maximum Increase ◽

Phase 2 Study ◽

Dose Levels

Abstract Background: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis leading to cytopenias, including anemia and thrombocytopenia. KER-050, a modified activin receptor type IIA inhibitor, is designed to target transforming growth factor-β ligands, including activin A. In preclinical studies, KER-050 promoted the maturation of progenitors across the full spectrum of erythropoiesis and thrombopoiesis and elicited bone anabolic effects. In a Phase 1 study in healthy participants, KER-050 treatment resulted in robust and sustained increases in reticulocytes (RETs), hemoglobin (HGB), and platelets. Increases in the bone formation marker bone specific alkaline phosphatase were also observed. Here we report results of an ongoing Phase 2 study to evaluate whether KER-050 provides therapeutic benefit in MDS patients with anemia. Aims: Evaluate safety, tolerability, pharmacodynamics and efficacy of ascending doses of KER-050 in participants with MDS in an open-label, 2-part Phase 2 study. Methods: IPSS-R very low-to-intermediate risk MDS patients (both RS+ and non-RS) with anemia (HGB <10g/dL or requiring RBC transfusions) are enrolled. In Part 1, ascending dose cohorts receive KER-050 subcutaneously every 4 weeks for 4 doses starting at 0.75mg/kg until a recommended Part 2 dose is determined. Part 2 dose expansion will begin following Part 1, with treatment extended to 2 years. Safety endpoints include incidence of adverse events (AEs); erythroid efficacy endpoints (≥8 weeks duration) include rates of transfusion independence (TI) in transfused participants, reduction in RBC transfusions by ≥4 units or ≥50% reduction in high transfusion burden participants (HTB) and HGB increase ≥1.5g/dL in non-transfused (NT) and low transfusion burden (LTB) participants. Results are reported for efficacy-evaluable participants in cohorts 1 and 2 of Part 1 dose escalation, defined as having ≥8 weeks of HGB and transfusion data. Results: At data cut-off (July 10, 2021) with median follow-up of 140 days (range 1 to 169 days), 17 participants had received ≥1 dose of KER-050 across 3 dose levels: 0.75 mg/kg, 1.5 mg/kg and 2.5 mg/kg. Baseline characteristics are described in Table 1. No related serious AEs, dose-limiting toxicities, or dose modifications were reported. One participant developed grade 2 maculopapular rash after the first dose which was considered treatment related, resolved and did not recur with subsequent doses. No other related AEs were reported. Two discontinued study drug prior to end of treatment: 1 due to participant decision, 1 due to death unrelated to study drug. None developed high risk MDS or AML. In 10 efficacy-evaluable participants, overall erythroid response rate was 60% (n=6/10). 33% (n=1/3) NT participants had a HGB increase of ≥1.5g/dL sustained ≥ 8 weeks. 5 of 7 transfused participants (71%) (n=1/2 LTB and n=4/5 HTB; n=2/3 non-RS and n=3/4 RS+) had erythroid responses sustained ≥8 weeks (range 8-20 weeks, ongoing) and 57% (n=4/7) achieved TI (Figure 1, Panel A). Maximum increase from baseline in RETs observed in transfused responders (TR) (n=5) was 24.6 x10 9/L (mean), range 10.5- 41.6 x10 9/L from day 1-29 with increases in RETs seen after each dose (Panel B). Maximum reduction in serum ferritin in TR was 40.4% (mean), range 10-66%, and maximum increase in soluble transferrin receptor (sTfR) was 52.8% (mean), range 29.8-116.4%. Increases in platelets were observed in TR (Panel C). Mean baseline platelet count for TR was 234 x10 9/L (range 104-401 x10 9/L), and maximum increase from baseline was 130 x10 9/L (mean), range 32-235 x10 9/L. No participants required dose reduction due to thrombocytosis. Summary: Erythroid responses have been observed in RS+ and non-RS MDS patients including reduction in transfusion burden at the initial dose levels. Observed increases in RETs and sTfR and observed decreases in ferritin suggest that KER-050 treatment is potentially associated with increased erythropoiesis. Increases in platelets have been observed in TR. These data support the potential of KER-050 as a treatment for multilineage cytopenias in MDS by potentially targeting multiple stages of hematopoiesis. As of data cut-off, KER-050 has been well tolerated. Dose escalation is ongoing in this Phase 2 study of anemic patients with MDS; data from planned cohorts from Part 1 will be presented. Part 2 dose expansion phase is expected to initiate prior to the meeting. Figure 1 Figure 1. Disclosures Ross: Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Keros Therapeutics: Consultancy, Honoraria. Arbelaez: Amgen: Other: Travel, Accommodations, Expenses. Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fong: AbbVie: Consultancy; Amgen: Consultancy; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Phizer: Consultancy; Novotech: Honoraria; Specialised Therapeutics: Honoraria. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Wight: Jannsen: Honoraria, Other: Travel subsidies; Abbvie: Honoraria, Other: Travel subsidies. Rovaldi: Keros Therapeutics: Current equity holder in publicly-traded company. Furutani: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gaggi: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Jiang: Keros Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Natarajan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ordonez: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

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LSD1 Inhibitor CPI-482 Shows Efficacy and Prolongs Survival in Mouse Models of AML and Post-MPN AML in the Context of Constitutive JAK-STAT Pathway Activation

Blood ◽

10.1182/blood-2020-140186 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 50-51

Author(s):

Raajit K. Rampal ◽

John P. McGrath ◽

Aishwarya Krishnan ◽

Bing Li ◽

Wenbin Xiao ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Cell Lines ◽

Research Funding ◽

Myelogenous Leukemia ◽

Publicly Traded ◽

Private Company ◽

Advisory Committees ◽

Pathway Activation ◽

Stat Pathway

Several novel mechanism-based therapeutic modalities are currently being clinically investigated for the treatment of patients with acute myelogenous leukemia (AML), including agents that exploit genomic vulnerabilities, attenuate leukemia stem cell populations and/or or synergize with anti-leukemic cytotoxic/epigenetic therapies. Lysine-specific demethylase 1 (LSD1) is an enzyme that functions in transcriptional repression by catalyzing the removal of histone H3 lysine 4 methylation, a histone modification associated with transcriptionally competent gene enhancers and transcriptional start sites. Small molecule mediated inhibition of LSD1 alters the chromatin state and the transcriptional output of LSD1 target genes. Transcriptional 'reprogramming' by LSD1 inhibitors either causes a direct impact on cell fate and/or renders malignant cells more susceptible to the treatment with other cancer therapeutic agents. LSD1 inhibitors have shown encouraging phenotypic effects in myelogenous leukemia (AML) models but the key molecular determinants governing LSD1 inhibitor sensitivity remain to be further investigated. Here, we explored the in vitro sensitivity of 350 cancer cell lines to our LSD1 inhibitor CPI-482 to identify potential hyper-responder cell contexts. Four AML cell lines showed high sensitivity with low nanomolar concentration GI50s, each of which contained either a JAK2V617F mutation or a genetic aberration that resulted in JAK-STAT pathway activation. Oral administration of LSD1 inhibitor CPI-482 on a once daily or a once weekly dosing schedule resulted in significant tumor growth inhibition in SET-2 and HEL 92.1.7 JAK2 mutant AML xenograft mouse models. Given the unmet need and poor prognosis in post-MPN secondary AML (sAML) we then explored CPI-482 in a tertiary transplant post-MPN AML retroviral transduction murine model (Jak2V617F retrovirus transduced intoTp53 null bone marrow). Jak2V617F/Tp53 null spleen cells were transplanted into lethally irradiated recipient mice along with wild-type donor support whole bone marrow cells. Mice were randomized to treatment with vehicle, Ruxolitinib (60mg/kg twice daily) or CPI-482 (60mg/kg weekly). Once-weekly treatment with CPI-482 significantly improved survival compared to vehicle (p<0.001) or ruxolitinib (p<0.043) (Figure 1A). Spleen weights were significantly reduced by CPI-482 compared to ruxolitinib (p<0.05;Figure 2B). The white blood cell count was unchanged in mice treated with CPI-482 but increased in both vehicle and ruxolitinib treated mice. Evaluation at the time of terminal take-down of mice demonstrated a significant increase in the proportion of lineage positive cells in both the bone marrow and spleen (compared to vehicle, p<0.05) consistent with restoration of normal hematopoiesis (Figure 1D). Histopathologic evaluation of the spleen demonstrated marked reduction in infiltration by blast cells, restoration of lymphoid follicles, emergence of megakaryocytes (Figure 1E), and modest reductions in reticulin fibrosis in CPI-482 treated mice, which was not observed in ruxolitinib treated mice. Mice tolerated treatment with CPI-482 well, with no changes in weights of treated mice (Figure 1F). Treatment of the JAK2V617F mutant AML cell lines SET-2 and HEL with CPI-482 resulted in specific transcriptional effects, including increased expression of the myeloid differentiation markers LY96 and CD86 and inflammatory response genes. CPI-482 also resulted in upregulation of genes that are repressed by the HOXA9 oncogene in other leukemia contexts. The induction of specific CPI-482 mediated gene expression and phenotypic changes was recapitulated by knockdown of the transcription factor GFI1B, suggesting that, consistent with prior findings in other leukemia contexts, LSD1 functionally cooperates with GFI1B in JAK2V617F mutant AML cells. These data provide support for a potential therapeutic impact of the LSD1 inhibitor CPI-482 in AML and sAML in the context of the JAK2V617F mutation, and thus extend the previous findings that LSD1 inhibitors may have utility in JAK2V617F mutated malignant proliferative neoplasms. Given the pressing need for new therapies for sAML which evolves from a pre-existing MPN, we believe these data form the rationale for a mechanism based clinical trial in this adverse risk myeloid malignancy. Figure Disclosures Rampal: Pharmaessentia: Consultancy; Galecto: Consultancy; Abbvie: Consultancy; Stemline: Consultancy, Research Funding; Constellation: Research Funding; Incyte: Consultancy, Research Funding; Celgene: Consultancy; Promedior: Consultancy; CTI Biopharma: Consultancy; Jazz Pharmaceuticals: Consultancy; Blueprint: Consultancy. McGrath:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Xiao:Stemline Therapeutics: Research Funding. Nikom:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Wang:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Levine:Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Lilly: Consultancy, Honoraria; Janssen: Consultancy; Astellas: Consultancy; Morphosys: Consultancy; Novartis: Consultancy; Amgen: Honoraria; Gilead: Honoraria; Prelude Therapeutics: Research Funding; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Trojer:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

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Trial in Progress: The Phase III, Randomized, Open-Label, Multicenter COMMODORE 2 Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Adult and Adolescent Patients with Paroxysmal Nocturnal Hemoglobinuria Not Previously Treated with Complement Inhibitors

Blood ◽

10.1182/blood-2020-136647 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-34

Author(s):

Austin Kulasekararaj ◽

Guangsheng He ◽

Talha Munir ◽

Jeffrey Pu ◽

Antonio Risitano ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Medical Writing ◽

Third Party ◽

Phase Iii ◽

Publicly Traded ◽

Open Label ◽

Advisory Committees ◽

Complement Inhibitors ◽

Previously Treated

Background Crovalimab is a novel anti-human complement component 5 (C5) antibody engineered to significantly extend half-life and enable subcutaneous (SC) administration once every 4 weeks in C5-mediated diseases. Based on the promising results of the Phase I/II COMPOSER trial (NCT03157635; Röth et al. Blood. 2020), crovalimab is currently under investigation as a potential therapy for paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disorder characterized by hemolytic anemia and thrombosis. Eculizumab and ravulizumab are C5 inhibitors currently approved for the treatment of patients with PNH, yet treatment limitations include breakthrough hemolysis due to unsustained C5 inhibition, lack of efficacy in patients with C5 mutational variants, and the treatment burden of regular intravenous (IV) infusions. Study Design and Methods The Phase III, randomized, open-label, active-controlled, multicenter COMMODORE 2 study (NCT04434092) is evaluating the efficacy and safety of crovalimab compared with eculizumab in patients aged ≥ 12 years with PNH not previously treated with complement inhibitors. Patients are randomized 2:1 to receive crovalimab or eculizumab (Figure 1). Two hundred patients in the crovalimab arm will receive a loading series of crovalimab (IV dose on Day 1, followed by weekly SC doses for 4 weeks starting on Day 2). This is followed by SC maintenance dosing every 4 weeks starting at Week 5. Patients in the eculizumab arm receive a weekly IV loading dose of eculizumab for the first 4 weeks, followed by IV maintenance dosing starting at Week 5 and then once every 2 weeks for 24 weeks. After 24 weeks of treatment, patients can continue crovalimab or switch from eculizumab to crovalimab if their physician determines this is in their best interest. The primary efficacy objective of COMMODORE 2 is to evaluate the noninferiority of crovalimab compared with eculizumab based on the co-primary endpoints of (1) the proportion of patients who achieve transfusion avoidance and (2) the proportion of patients with hemolysis control. Secondary efficacy objectives are to evaluate the noninferiority of crovalimab compared with eculizumab in regard to the (1) proportion of patients who experience breakthrough hemolysis, (2) proportion of patients who achieve stabilization of hemoglobin, and (3) mean change in fatigue, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. The safety objective is to evaluate the safety and tolerability of crovalimab compared with eculizumab based on the incidence and severity of adverse events, including infections (meningococcal meningitis and other infections), injection-site reactions, infusion-related reactions, hypersensitivity, and adverse events leading to study drug discontinuation. Pharmacokinetic, immunogenicity, biomarker, and health status utility objectives will also be assessed. Disclosures Kulasekararaj: Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. He:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; LongBio Pharma: Consultancy, Research Funding. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Pu:SUNY Upstate Medical University: Current Employment; Pennsylvania State University: Patents & Royalties; F. Hoffmann-La Roche Ltd: Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; RA pharma: Research Funding. Röth:Roche: Consultancy, Honoraria, Research Funding; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria. Sima:F. Hoffmann-La Roche Ltd/Genentech: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Appius:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sreckovic:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Vignal:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Nishimura:Alexion: Honoraria, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

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Genomic and Transcriptomic Characterization of IgM Multiple Myeloma Identifies a Pre-Germinal Center Plasma Cell Disorder with Immature B-Cell Transcription-Factor Signature

Blood ◽

10.1182/blood-2020-138951 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Abdul Hamid Bazarbachi ◽

Herve Avet-Loiseau ◽

Zachary R Hunter ◽

Raphael Szalat ◽

Anil Aktas-Samur ◽

...

Keyword(s):

Multiple Myeloma ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Switch Region ◽

Publicly Traded ◽

Private Company ◽

Advisory Committees ◽

Transcript Levels ◽

Unique Signature

Multiple myeloma (MM) is a proliferation of terminally differentiated plasma cells (PC) producing monoclonal immunoglobulins (Ig), most commonly IgG and IgA (50% and 25% respectively), and less frequently, light-chain only disease, non-secretory, and IgD. IgM-MM is a rare entity (<0.5%), and its differentiation from common IgM producing PC disorders like Waldenström's macroglobulinemia (WM) is essential considering their distinct treatments and prognoses. Recent advancements in molecular techniques have shed light on the genomic characteristics and unique alterations in MM and WM, however, comprehensive profiling is still lacking for IgM-MM. We performed deep whole-genome sequencing on five IgM samples as well as 211 MM and 34 WM samples, and transcriptome sequencing on the IgM samples as well as 30 MM, 35 WM, and 3 PC. All IgM-MM samples harbored t(11;14) which combines super enhancers in Ig genes with CCND1. All translocations involved VHDHJH regions (Figure 1A) at the immunoglobulin heavy chain (IGH) locus, compared to IgG/IgA MM samples that had predominantly switch-region translocations (Figure 1B/C). Switch-region translocations are generated through class-switch recombination (CSR) in mature B-cells in germinal centers (GC), and VHDHJH translocations occur during recombination at the early pro-B-cell stage in the bone marrow (BM). While IgG/IgA-MM displayed evidence of CSR with deletions between IGHM switch-region and IGHG/IGHA switch regions, IgM-MM had no such events. IgM-MM therefore appears to undergo malignant transformation prior to late-stage B-cell maturation, after which CSR is unlikely, which is supported by a lack of progression of IgM-monoclonal gammopathy of undetermined significance (MGUS) to non-IgM-MM. IgM-MM also displayed similar copy number variation (CNV) patterns and driver mutations compared to non-IgM-MM suggesting similar progression events. Unsupervised hierarchical clustering using differentially expressed genes between non-IgM-MM and WM separated the IgM-MM samples within non-IgM-MM. This indicates a closer molecular homology to MM compared to WM with a unique signature for this group not accounted for by the t(11;14) translocation. Running the same analysis using only B-cell specific transcription factors (TFs) yielded similar results, with separation of WM and MM and preferential clustering of IgM-MM within the latter while also exhibiting a unique signature (Figure 1D). Some noteworthy examples were the upregulation of PBX3, PAX5, BCL11A, and ATF2, and the downregulation of PRDM1 and BCL3 compared to non-IgM-MM. The loss of PAX5 and upregulation of PRDM1 in B-cells has been implicated in promoting commitment to PC differentiation, while BCL11A was found essential for early B-cell progenitor development through the GC but extinguished in terminally differentiated PC. It appears that IgM-MM has therefore a more immature phenotype compared with non-IgM-MM, which further supports the previously discussed findings of its pre-GC origin and lack of terminal development. Three clinically relevant targets were noted to be upregulated in IgM-MM, Bruton's tyrosine kinase (BTK), CD20 and BCL-2. BTK was significantly higher in IgM-MM compared to non-IgM-MM (log2fold=1.3; FDR<10-3) with no difference between IgM-MM and WM (log2fold =-0.4; FDR>0.2). This could elucidate a more prominent role for BTK-inhibition in the IgM-MM subgroup. Furthermore, as documented in t(11;14)-MM, IgM-MM had elevated transcript levels of CD20 with possible targeting using anti-CD20 antibodies. Finally, elevated levels of BCL-2 in both IgM and non-IgM-t(11;14)-MM were observed, an established target for both single-agent and combination therapy. Interestingly, although not significant, IgM-MM had lower transcript levels of BCL-XL and MCL-1 compared to non-IgM-t(11;14)-MM, believed to be a predictor of higher sensitivity to venetoclax, and therefore an important guide for treatment choice. Clinical data however is lacking, and further investigations are needed to fully understand the potential role of these drugs in treating IgM-MM. In summary we describe a unique genomic and transcriptomic profile of IgM-MM, compared to both non-IgM-MM and WM, that describes its cellular origin and provides the rationale for potential therapeutic intervention. Disclosures Fulciniti: NIH: Research Funding. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: 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; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.. Parmigiani:Phaeno Biotehnologies: Current equity holder in publicly-traded company; CRA Health: Current equity holder in publicly-traded company; Foundation Medicine Institute: Consultancy; Delphi Diagnostics: Consultancy; BayesMendel Laboratory: Other: Co-lead. Treon:Bristol-Meyer-Squibb: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding. Mohty:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Munshi:Takeda: Consultancy; BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; C4: Current equity holder in private company; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; AbbVie: Consultancy.

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Patterns of Venetoclax Sensitivity in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2020-137674 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 12-14

Author(s):

James T Dibb ◽

Nicola Long ◽

Christopher A. Eide ◽

Stephen E Kurtz ◽

Cristina E. Tognon ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Ex Vivo ◽

Single Agent ◽

Drug Combinations ◽

Lymphocytic Leukemia ◽

Publicly Traded ◽

Private Company ◽

Advisory Committees

Patterns of Venetoclax Sensitivity in Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is predominantly a disease of older adults. The 5-year overall survival is 70-91%, depending on Rai/Binet stage at diagnosis (80% overall), and although a subset of CLL takes a very indolent course, it can be aggressive as well. Disease course and responsiveness to therapeutic agents may be predictable, to some degree, based on specific genetic lesions or other patient population characteristics. Monotherapies targeting specific cell pathways are rapidly increasing in prevalence. Ibrutinib (Bruton tyrosine kinase inhibitor) has shown promise as a single agent as well as in combination with other agents. In particular, ibrutinib has shown efficacy in combination with venetoclax (inhibitor of cell death suppressor BCL2). This combination appears to be particularly potent in patients with a del(11q) karyotype. Cytogenetic information is used already in several other leukemias to inform prognosis and treatment. Although CLL is a disease of monoclonal proliferation, precise definition of the diseased clone will allow for more individualized treatment. Stratification of drug sensitivity based on genetic and cytogenetic features will directly affect patient outcomes in CLL. Primary patient mononuclear cells (from either peripheral blood or bone marrow) were plated ex vivo with a panel of 49 drug combinations and the 16 respective single agents (SA) in 384-well plates using 10,000 cells/well. Drugs were tested in 7-point concentration series; wells with drug combinations were added at fixed molar ratios. Cell viability was assessed after a 72 hour culture period. In this assay, primary cells maintain viability but do not proliferate. In CLL, the most frequent mutations were: del(17p); del(11q); del(13q14); trisomy 12; complex karyotype (at least three chromosomal aberrations). Selected analysis of these data from 157 unique patients were performed by isolating the most potent inhibitors (defined by lowest median AUC) either as a single agent or in combination with known treatments. These were evaluated with nonparametric tests (Kruskal-Wallace, Mann-Whitney, Spearman rank coefficient) on the statistical software Prism. By subdividing the data by available genetic and cytogenetic information, patterns that have not been previously described in the literature emerged. In the cohort of patients with any karyotypic abnormality (not complex karyotype), SA venetoclax and the combination of venetoclax-ibrutinib (VEN/IBRUT) were equivalently effective with no significant difference in efficacy observed between SA venetoclax and the combination. As previously described, del(11q) independently predicts increased efficacy of SA venetoclax and VEN/IBRUT, and this efficacy was validated by ex vivo potency here as well. However, we show that male gender is an independent predictor of potency in both SA venetoclax and VEN/IBRUT as well. Interestingly, doramapimod (an inhibitor of p38 MAP kinase) was not particularly potent as a SA, however, the combination of venetoclax-doramapimod (VEN/DORA) proved to be the most potent of all combinations tested, more potent than even VEN/IBRUT. This effect could not be replicated in any subgroup, as VEN/DORA samples for the entire cohort were relatively limited (n=31). Although this analysis has inherent limitations, including underpowered data to analyze in less frequent cytogenetic events (e.g. del(6q)), we did find significant patterns of potency. These may or may not translate to clinical efficacy in CLL and do not address any potential toxicity. However, these data suggest future directions for more targeted research on these drugs and drug combinations. Disclosures Tyner: Petra:Research Funding;Janssen:Research Funding;Seattle Genetics:Research Funding;Incyte:Research Funding;Genentech:Research Funding;Constellation:Research Funding;AstraZeneca:Research Funding;Aptose:Research Funding;Gilead:Research Funding;Takeda:Research Funding;Syros:Research Funding;Agios:Research Funding;Array:Research Funding.Druker:EnLiven:Consultancy, Research Funding;Gilead Sciences:Consultancy, Membership on an entity's Board of Directors or advisory committees;Cepheid:Consultancy, Membership on an entity's Board of Directors or advisory committees;Dana-Farber Cancer Institute:Patents & Royalties;Bristol-Myers Squibb:Research Funding;Blueprint Medicines:Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees;Aptose Therapeutics Inc. (formerly Lorus):Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;ARIAD:Research Funding;Third Coast Therapeutics:Membership on an entity's Board of Directors or advisory committees;The RUNX1 Research Program:Membership on an entity's Board of Directors or advisory committees;Pfizer:Research Funding;Patient True Talks:Consultancy;Oregon Health & Science University:Patents & Royalties;Novartis Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding;MolecularMD (acquired by ICON):Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;Millipore (formerly Upstate Biotechnology):Patents & Royalties;VB Therapeutics:Membership on an entity's Board of Directors or advisory committees;Vivid Biosciences:Membership on an entity's Board of Directors or advisory committees;ALLCRON:Consultancy, Membership on an entity's Board of Directors or advisory committees;Amgen:Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;Aileron Therapeutics:Membership on an entity's Board of Directors or advisory committees;Merck & Co:Patents & Royalties;McGraw Hill:Patents & Royalties;GRAIL:Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees;Henry Stewart Talks:Patents & Royalties;Iterion Therapeutics (formerly Beta Cat Pharmaceuticals):Membership on an entity's Board of Directors or advisory committees;Leukemia & Lymphoma Society:Research Funding.

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Bone Pain As a Presenting Symptom in Patients with Newly Diagnosed Multiple Myeloma in the Primary Care Setting: A Population-Based Cohort Study

Blood ◽

10.1182/blood-2020-138819 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-18

Author(s):

Anouchka Seesaghur ◽

Natalia Petruski-Ivleva ◽

Victoria Banks ◽

Jocelyn Ruoyi Wang ◽

Pattra Mattox ◽

...

Keyword(s):

Primary Care ◽

Renal Impairment ◽

Board Of Directors ◽

Clinical Features ◽

Research Funding ◽

Bone Pain ◽

Care Setting ◽

Publicly Traded ◽

Private Company ◽

Advisory Committees

Background: Diagnosing multiple myeloma (MM) is challenging, because MM can present with a myriad of non-specific signs and symptoms, such as bone pain, fatigue, fractures, infection, within an elderly patient population (median age of MM diagnosis is 70 years). Patients with MM therefore experience significant delays in diagnosis, resulting in increased morbidity and reduced survival. In the primary care setting, the presence of bone pain in combination with laboratory abnormalities, such as hypercalcaemia or unexplained renal impairment, have a critical diagnostic role in MM. However, the occurrence of these clinical features prior to MM diagnosis within a population-based incident cohort of patients with MM has not been previously well described. Aims: To describe the frequency and timing of the initial clinical features among patients with newly diagnosed MM (NDMM) in the UK primary care setting. Methods: We used Clinical Practice Research Datalink (CPRD), an electronic health records database, derived from routinely collected general practitioner (GP) data across the UK primary care, containing approximately 17.1 million patients at the time of analysis. We identified patients with NDMM (2006-2016), aged ≥18 years with no history of solid tumors, and ≥2 years of GP registration prior to MM diagnosis. Baseline clinical characteristics were assessed during the 2-year period before MM diagnosis. We assessed clinical features, including bone pain, skeletal-related events (SREs) and CRAB criteria (hyperCalcemia, Renal failure, Anemia, Bone lesions) for MM during the 2-year period before MM diagnosis and from the time of symptom presentation or relevant diagnostic CRAB criteria to the diagnosis of MM. Results: We identified 2,646 eligible patients with NDMM with a median [Q1, Q3] age of 70 [61, 77]; 53.3% of patients were male. During the 2-year period prior to MM diagnosis, 47.5% of patients had a record of bone pain, mainly affecting the back or other joints, and 4.8% had a record of SRE. The median time between the first record of bone pain and MM diagnosis was 220 days. Regardless of recorded bone pain, laboratory investigations for hypercalcaemia, renal impairment, and anaemia and were conducted in 36.4%, 74.2%, 65.6% and of patients prior to MM diagnosis, respectively. Approximately 5.5% of patients presented with hypercalcemia, 13.5% with renal impairment and 31.3% with anemia. The median time from the first-recorded hypercalcaemia, renal impairment or anaemia event to MM diagnosis was 23, 58 and 73 days, respectively. An imaging investigation or referral for an imaging investigation was recorded for approximately 60% of patients with bone pain/SRE and 32% without bone pain/SRE. One out of five patients with bone pain/SRE and imaging investigations had a record of magnetic resonance imaging or computed tomography scan (Table 1). Conclusions: Nearly half of patients with newly diagnosed MM presented with a bone pain symptom in primary care, approximately 7 months prior to MM diagnosis. Investigations for hypercalcaemia were not frequent in patients presenting with bone pain, and tests to explore CRAB criteria were underutilized. Underuse of targeted imaging in patients presenting with bone pain was observed. Early recognition and testing for clinical features of MM in primary care may potentially expedite the disease diagnosis and lead to timely medical care. Disclosures Seesaghur: Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company. Petruski-Ivleva:Aetion: Current equity holder in private company, Ended employment in the past 24 months. Banks:Amgen (Europe) GmbH: Ended employment in the past 24 months, Other: Contract worker at Amgen during the conduct of the study. Wang:Aetion: Current Employment, Current equity holder in private company. Mattox:Aetion: Current Employment, Current equity holder in private company. Abbasi:Amgen (Europe) GmbH: Other: Contract worker at Amgen. Maskell:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company. Neasham:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company. Ramasamy:Takeda: Honoraria; Janssen: Honoraria; Janssen: Research Funding; Takeda: Research Funding; Sanofi: Honoraria; Amgen: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria; Oncopeptides: Honoraria; Takeda: Speakers Bureau; Bristol Myers squibb: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Amgen: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees.

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