Imetelstat Treatment Leads To Durable Transfusion .
Imetelstat Treatment Leads to Durable TransfusionIndependence in RBC Transfusion-Dependent,Non-Del(5q) Lower Risk MDS Relapsed/Refractoryto Erythropoiesis-Stimulating Agent Who AreLenalidomide and HMA NaiveDavid P. Steensma, MD1, Uwe Platzbecker, MD2, Koen Van Eygen, MD3, Azra Raza, MD4, Valeria Santini, MD5,Ulrich Germing, MD, PhD6, Patricia Font, MD7, Irina Samarina, MD8, Maria Díez-Campelo, MD, PhD9,Sylvain Thepot, MD10, Edo Vellenga, MD11, Mrinal M. Patnaik, MD, MBBS12, Jun Ho Jang, MD, PhD13,Jacqueline Bussolari, PhD14, Laurie Sherman, BSN14, Libo Sun, PhD14, Helen Varsos, MS, RPh14,Esther Rose, MD14 and Pierre Fenaux, MD, PhD151Dana-FarberCancer Institute (US), 2University Hospital Carl Gustav Carus, Dresden (DE), 3Algemeen Ziekenhuis Groeninge, Kortrijk (BE),4Columbia University Medical Center (US), 5MDS Unit, AOU Careggi-University of Florence (IT), 6Heinrich-Heine-Universität, Düsseldorf (DE),7Hospital General Universitario Gregorio Marañon, Madrid (ES), 8Emergency Hospital of Dzerzhinsk, Nizhny Novgorod (RU),9The University Hospital of Salamanca (ES), 10CHU Angers (FR), 11University Medical Center Groningen (NE), 12Mayo Clinic, Rochester (US),13Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (KO), 14Janssen Research & Development, LLC (US),15Hôpital Saint-Louis, Université Paris (FR)Abstract #463Funded by Janssen Research & Development and Geron CorporationSteensma et al. ASH 2018 Oral Presentation
Background: Myelodysplastic Syndromes (MDS) and Imetelstat Patients with TD LR-MDS that has relapsed or is refractory to ESA therapy havelimited treatment options Higher telomerase activity, expression of hTERT and shorter telomeres predict forshorter overall survival in lower risk MDS Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomerelengths and active telomerase and has clinical activity in myeloid malignancies1-3o FDA granted Fast-Track designation for LR-MDS (Oct 2017) IMerge is an ongoing global phase 2/3 study of imetelstat in RBC TD patients withLR-MDS (IPSS Low or Int-1)4ESA, erythropoiesis-stimulating agent; hTERT, human telomerase reverse transcriptase;IPSS, International Prognostic Scoring System; Int-1, Intermediate-1;LR, lower risk; RBC, red blood cell; TD, transfusion dependent.Steensma et al. ASH 2018 Oral Presentation1.2.3.4.Baerlocher GM, et al. N Engl J Med 2015;373:920-928Tefferi A, et al. N Engl J Med 2015;373:908-919Tefferi A, et al. Blood Cancer J 2016;6:e405Fenaux P, et al. HemaSphere 2018;2(S1):S1557[oral presentation]2
Background: IMerge/NCT02598661 (Part 1) Study Design1Patients with MDS IPSS Low or Int-1 Relapsed / refractory to ESA or ineligible forESA Transfusion dependent ( 4u RBC/8 weeks) ANC 1.5 x 109/L Platelets 75 x 109/Lsingle armopen label1o Endpoint: 8-Week RBC TI2o Endpoints: 24-Week RBC TI / Time to TI / TI duration /TR (HI-E: Transfusion Reduction by 4 RBC units over 8 weeks) /MDS response per IWG / Overall survival / Incidence of AML / SafetyExploratory: telomerase activity / hTERT / telomere length /genetic mutationsImetelstat Treatment7.5 mg/kg IV q4w(2-hr infusion)Pre-medication: diphenhydramine,hydrocortisone 100-200 mg (or equivalent)Supportive care: RBC transfusions, myeloidgrowth factors per local guidelinesAML, acute myeloid leukemia; ANC, absolute neutrophil count;1. Fenaux P, et al. HemaSphere 2018;2(S1):S1557 [oral presentation]HI-E, hematologic improvement-erythroid; IWG, International Working Group;TI, transfusion independence; TR, transfusion reduction.3Steensma et al. ASH 2018 Oral Presentation
Background: Key Efficacy and Safety Outcomesfrom IMerge (Part 1)1All Treated(N 32)Lenalidomide and HMA naïveand Non-del (5q)(n 13)Rate of 8-week TI, n (%)11 (34)7 (54)Rate of 24-week TI, n (%)5 (16)4 (31)Rate of transfusion reduction (HI-E), n (%)19 (59)9 (69)23 (72)7 (54)Grade 3 / 48 (25) / 13 (41)2 (15) / 5 (38)Thrombocytopenia18 (56)8 (62)Grade 3 / 410 (31) / 8 (25)5 (38) / 3 (23)ParametersMost common adverse events, n (%)NeutropeniaMost grade 3 cytopenias were reversible in 4 weeksHI-E, hematologic improvement-erythroid; HMA, hypomethylating agents;TI, transfusion independence.1FenauxSteensma et al. ASH 2018 Oral PresentationP, et al. HemaSphere 2018;2(S1):S1557 [oral presentation]4
IMerge: Patients and Treatment Exposure An additional 25 lenalidomide and HMA naïve patients without del(5q) wereenrolled Here we report updated results for 38 patientsMedian Follow-upInitial 13 lenalidomide and HMA naïvepatients without del(5q)29.1 mo25 patients meeting the same criteria8.7 mo Clinical Cutoff: 26-Oct-2018 Median number of treatment cycles: 8.0 (range: 1‒34) cycleso Mean dose intensity was 6.9 mg/kg/cycleSteensma et al. ASH 2018 Oral Presentation5
IMerge: Baseline CharacteristicsParametersN 38Median age (range), years71.5 (46-83)Male, n (%)25 (66)ECOG PS 0-1, n (%)34 (89)IPSS risk, n (%)LowIntermediate-124 (63)14 (37)Baseline median (range) RBC transfusion burden, units/8 weeks8 (4–14)WHO 2001 category, n (%)RARS or RCMD-RSAll others27 (71)11 (29)Prior ESA use, n (%)34 (89)sEPO 500 mU/mL, n (%)12a (32)aOfthe 37 patients with sEPO levels reported.Steensma et al. ASH 2018 Oral Presentation6
IMerge: Longest Transfusion-Free IntervalLongest Transfusion Free Interval (Weeks)1501251007550Treatment Group: Imetelstat (N 38)ParametersN 38Rate of 8-week TI, n (%)14 (37)Rate of 24-week TI, n (%)10 (26)Median time to onset of TI (range), weeks8.1 (0.1-33.1)Median duration of TI (range), weeksNE (17.0-NE)Among the patients achieving durable TI, all showed a Hb rise of 3.0 g/dL compared to baseline during the transfusion-free interval252480Patients24-week TI8-week TIHI-E (TR)No responseHb, hemoglobin; HI-E, hematologic improvement-erythroid; TI, transfusion independence; TR, transfusion reduction.Steensma et al. ASH 2018 Oral Presentation7
IMerge: Hemoglobin and Imetelstat DosingAmong Patients with Durable TIHgb(g/L)Hemoglobin Levels 98387919599103 107 111 599103 107 111 rior RBC TransfusionBurden (units/8 weeks)0500-225811 14 17 20 23 26 29 32 35 38 41 44 47 50 53 56 59 62 65 68 71Steensma et al. ASH 2018 Oral Presentation8
IMerge: Absolute Change in Transfusion Amountin the Best 8-Week Interval4Treatment Group: Imetelstat (N 38)Absolute Change in Transfusion Amountin the Best 8-week interval20-2-4-6-8-10ParametersN 38Rate of transfusion reduction (HI-E), n (%)Mean relative reduction of RBC transfusionburden from baseline, %27 (71)-68-12Patients24-week TI8-week TIHI-E (TR)No responseHI-E, hematologic improvement-erythroid; RBC, red blood cell; TI, transfusion independence; TR, transfusion reduction.Steensma et al. ASH 2018 Oral Presentation9
IMerge: Key Efficacy OutcomesParametersN 38Rate of 8-week TI, n (%)14 (37)Rate of 24-week TI, n (%)10 (26)Median time to onset of TI (range), weeks8.1 (0.1-33.1)Median duration of TI (range), weeksNE (17.0-NE)Rate of transfusion reduction (HI-E), n (%)27 (71)Mean relative reduction of RBC transfusionburden from baseline, %-68CR marrow CR PR (per IWG), n (%)8 (21)CR, complete remission; HI-E, hematologic improvement-erythroid; IWG, International Working Group; NE, not estimable; PR, partialremission; RBC, red blood cell; TI, transfusion independence.Steensma et al. ASH 2018 Oral Presentation10
IMerge: Efficacy Results in EPO and RS Subgroups8-week TI rate37%RARS/RCMD-RS (n 27)36%Other (n 11)40%EPO 500 mU/mL (n 25)33%EPO 500 mU/mL (n 12)010203040% of PatientsSimilar efficacy was observed across these subgroupsEPO, erythropoietin; RARS, refractory anemia with ringed sideroblasts; RCMD-RS, refractory cytopenia with multilineage dysplasia and ringed sideroblasts;RS, ring sideroblast; TI, transfusion independence.Steensma et al. ASH 2018 Oral Presentation11
Number of patients with 1 TEAEIMerge: Most Common Treatment-Emergent Adverse Events252021Grade 1-21510 19 patients (50%) had dose reductionsand 26 patients (68%) had cycle delaysGrade 321 Reversible grade 3 LFT elevations wereobserved in 3 (8%) patients on study2325077353254126664o Independent Hepatic Review Committeeconsidered these not drug-related2Most common TEAEsALT, alanine aminotransferase; AST, aspartate aminotransferase; LFT, liver function test; TEAE, treatment-emergent adverse event.Steensma et al. ASH 2018 Oral Presentation12
IMerge: Occurrence/Reversibility of Grade 3/4 CytopeniasAll events,Recovered in 4 weeks,n (%) of patientsn (%) of patients(N 38)with an eventNeutrophils, n (%) 2 patients had febrileneutropenia 12 patients received G-CSF forneutropeniaGrade 310 (26)8 (80)Grade 412 (32)12 (100) 7 patients received platelettransfusionsGrade 314 (37)13 (93)Grade 410 (26)9 (90) 3 patients with Grade 1bleeding eventsPlatelets, n (%)Steensma et al. ASH 2018 Oral Presentation13
IMerge: Change in Mutation Variant Frequency 6 patients had SF3B1 mutations at baseline, with reduction of variant frequency observed inpatients 200088 and 200095, both of whom had durable TI Patient 200088 also had reduction in DNMT3A mutation, and substantial reduction in bonemarrow ringed sideroblasts (75% to 3%)Longest TI Duration(weeks)253.624.14.633.734.9TI, transfusion independence.Steensma et al. ASH 2018 Oral Presentation14
Conclusions: Overall Efficacy and Safety In this cohort of 38 non-del(5q) LR-MDS patients with a high RBCtransfusion burden who were ESA relapsed/refractory and naïve tolenalidomide/HMA, single-agent imetelstat yielded:ooooo8-week TI rate of 37%24-week TI rate of 26%24-week TI responses were accompanied by Hb rise of 3.0 g/dLMedian duration of TI was not reachedHI-E rate of 71% Side effects were limited, mainly cytopenias that were predictable,manageable and reversibleSteensma et al. ASH 2018 Oral Presentation15
Conclusions: Overall Efficacy and Safety (con’t) Similar efficacy was seen in EPO high/low and RS /RS- subgroups,supporting broad clinical activity Reductions in mutation burden and RS noted among respondingpatients, suggesting potential disease modification These results support the planned Phase 3 study, expected to startmid-2019Steensma et al. ASH 2018 Oral Presentation16
AcknowledgementsThe authors thank all the patients for their participation in thisstudy and acknowledge the collaboration and commitmentof all investigators and their staffMazure, DominiekMeers, StefBreems, DimitriGourin, Marie-PierreGyan, EmmanuelLegros, LaurenceThepot, SylvainKim, InhoLee, Je-hwanPristupa, AlexanderSamoilova, OlgaUdovitsa, DmitryKlein, SaskiaLangemeijer, Saskiavan de Loosdrecht, ArjanDe Paz, RaquelEsteve, JordiValcarcel, DavidXicoy, BlancaSteensma et al. ASH 2018 Oral PresentationOliva, EstherBoccia, RalphErba, Harry / DiStasi,AntonioGrunwald, MichaelJacoby, MeganMiller, CaroleSchiller, GarySilverman, LewisStevens, Don17
ASH 2018 Oral Presentation Imetelstat Treatment Leads to Durable Transfusion Independence in RBC Transfusion-Dependent, Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent Who Are Lenalidomide and HMA Naive David P. Steensma, MD1, Uwe Platzbecker, MD2, K
Mascarenhas et al. ASH 2020, Abstract #53. Potential Improvement in OS with Imetelstat Treatment . Mascarenhas et al. Blood 2018;132:68.5. Encouraging Clinical Benefits in TN MF Patients Treated with
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The sequence of treatment processes through which wastewater passes is usually characterized as: 1. Preliminary treatment 2. Primary treatment 3. Secondary treatment 4. Tertiary treatment This discussion is an introduction to advanced treatment methods and processes. Advanced treatment is primarily a tertiary treatment.
The sequence of treatment processes through which wastewater passes is usually characterized as: 1. Preliminary treatment 2. Primary treatment 3. Secondary treatment 4. Tertiary treatment This discussion is an introduction to advanced treatment methods and processes. Advanced treatment is primarily a tertiary treatment.
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