ASH 2018 Benign Heme Updates

ASH 2018 Benign Heme Updates

ASH 2018 BENIGN HEME UPDATES Penelope Harris MD DISCLOSURES No financial disclosures Will discuss off label use of drugs THROMBOSI S DOAC

SICKLE CELL THALASSEMI AS HEMOPHILIA OVERVIEW CONGENITAL ANEMIAS ACQUIRED CYTOPENIAS IRON

LBA-1 Rivaroxaban Thromboprophylaxis in High-Risk Ambulatory Cancer Patients Receiving Systemic Therapy: Results of a Randomized Clinical Trial (CASSINI) Double-blind, randomized, placebo-controlled, multicenter THROMBOPROPHYLAXIS IN CANCER CASSINI TRIAL Randomized 1:1 to Rivaroxaban 10 mg daily vs placebo

Endpoints VTE, Death, Bleeding Alok A Kharana, et al. Khorana risk score 2 identifies patients at high risk of VTE Rivaroxaban10 mg significantly decreased VTE and VTErelated death

during tx >1/3 events were after drug dc Major bleeding Alok A Khorana, et al. LBA-5 PERIOPERATIVE ANTICOAGULANT USE FOR SURGERY EVALUATION (PAUSE) STUDY: A PERIOPERATIVE MANAGEMENT

PLAN FOR PATIENTS WITH ATRIAL FIBRILLATION WHO ARE RECEIVING A DIRECT ORAL ANTICOAGULANT James Douketis MD, PERIOPERATIVE DOAC MANAGEMENT IN A FIB Low rates of perioperative MB (<2%) Low rates of perioperative ATE (<1%) High proportion of patients (>90% overall;

98.8% at high bleeding risk) had minimal or no residual DOAC level at the time of the surgery/procedure James Douketis MD, et al REACH TRIAL IN SICKLE CELL Abstract 3 Realizing Effectiveness across Continents with Hydroxyurea (REACH): A Prospective Multi-National Trial of Hydroxyurea for Sickle Cell Anemia in Sub-Saharan Africa HU is safe and effective Most studies have been in the US or Europe

Children in low-resource settings are affected by malnutrition, malaria, other infections Angola, Congo, KenyaLeon and Uganda, Tshilolo MD PhD, Guardian.ng.ne REACH TRIAL IN SICKLE CELL Excellent adherence, ~85% MTD

Increases in Hb, fetal Hb Decreases in wbc, ANC, retic VOC, ACS, transfusions dec ~50% Rate and severity of malaria 47.8/100 pt years 22.3 events/100 pt years Deaths dec 3.6/100 pt years Leon Tshilolo MD PhD, 1.1/100 pt years on et al.tx GENE THERAPY TO INHIBIT BCL11A IN SICKLE CELL

www.slideshar e.net www.broadinstitute .org Manipulating RNA to target and inhibit BCL11A induces HbF in transduced HSCs Erika B Esrick MD, et INHIBITING

BCL11A IN SICKLE CELL Abstract 1023 Flipping the Switch: Initial Results of Genetic Targeting of the Fetal to Adult Globin Switch in Sickle Cell Patients Epizyme Inc. Pilot study of shRNAmir LVV targeting BCL11A in stem cells 3 Adults with severe SCD Auto CD34+ cells transduced

>95% transduced erythroid colonies HbF 50-95% 1 pt received cells post Bu Erica B Esrick MD, et a Inherited hemoglobinopathy Luspatercept firstin-class erythroid maturation agent Erythroid maturation defect ineffective erythropoiesis, impaired RBC

maturation Binds to TGF superfamily ligands reduce aberrant Smad2/3 signaling and enhance late stage erythropoiesis LUSPATERCEPT IN BETA THALASSEMIA LUSPATERCEPT IN BETA THALASSEMIA Lovinglabscience.wordpre

ss.com Abstract 163 The Believe Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept in Adult Beta-Thalassemia Patients Who Require Regular Red Blood Cell (RBC) Transfusions Piga A, et al. Blood. 2015;126:Abstract 752. 336 pts randomized 2:1 luspatercept or placebo SQ, q3 wks, titrated dose (transfusions, chelation) Primary endpoint >33% reduction in

transfusions weeks 13-24 (after 12 week baseline) 21% (48) pts achieved primary endpoint 70% (158) pt achieved >33% reduction over any 12 wks vs 29.5% (33) placebo (p <0.0001) Maria Domenica Cappellini HEMOPHILIA HEMOPHILIA A Factor VIII deficiency Factor treatment requires frequent IVs Or use of bypassing agents Emicizumab Prophylaxis for Patients with Hemophilia A with

Hemophilia Awareness HEMOPHILIA A Abstract 1187 Preference for Emicizumab over Prior Factor Treatments: Results from the HAVEN 3 and HAVEN 4 studies 2 phase III studies demonstrated efficacy and safety of SQ emicizumab Administered q1-2 weeks without inhibitors (HAVEN 3) Q4 weeks with inhibitors (HAVEN 4) Patient preference surveys 92%-100% patients preferred emicizumab

Lower frequency, ease of administration, reduced concern for bleeding (lower bleeding rates), improved QOL Victor Jimenez-Yuste, et al. N Engl J Med 2016;374:204453. CONGENITAL ANEMIAS FANCONI ANEMIA DNA repair disorder Pancytopenia Predisposed to malignancy

Short stature Microcephaly Developmental delay Caf-au-lait spots Abnormal thumbs From Nathan DC, Orkin SH, Ginsburg D, et al, editors: Nathan and Oskis hematology of infancy and childhood, ed 6, vol I, Philadelp FANCONI ANEMIA Abstract 1022 Advances in the Gene Therapy of Patients with Fanconi Anemia Gene therapy trial initiated in 2016 6 patients, at least 12 months follow-up Fresh and cryopreserved CD34+ cells Mobilized with G-CSF and plerixafor Marked in vivo expansion of gene corrected

cells Increased resistance to MMC and stability to DEB Corrected cells increase, Defective cells decrease Juan A Bueren, et Low toxicity treatment for bone marrow failure al. Cell Stem Cell. Volume 11, Issue 1, 6 July 2012, Pages 36-49. DIAMOND-BLACKFAN ANEMIA

Congenital hypoplastic anemia Infancy Ribosome dysfunction Congenital anomalies Predisposition to malignancy Treated with steroids RBC dependent, iron overload Allogeneic transplant Jeffrey M Lipton MD PhD, Stephen Ellis PhD. Hematology/Oncology Clinics of North DIAMOND-BLACKFAN ANEMIA

Abstract 753 Small Molecule Screens Identify CDK8Inhibitors As Candidate Diamond-Blackfan Anemia Drug Small molecule screen of mouse fetal liver cells (c-KIT+) w/ induced DBA phenotype Molecules that increased proliferation of the rps19deficient erythroid progenitors Appeared that CDK8-inhibitors rescue proliferation and erythroid maturation Erythroid cultures of DBA and healthy controls CDK8-inhibitors increased erythroid proliferation 5-10x DBA Bone marrow failure and anemia is partially rescued in mice Reduced expression of the p53-target genes and increased expression MYC-target genes Lack of adverse effects in vivo warrants further development of SEL120-34A as a tx for DBA

Jun Chen MD PhD, et Haematologica November 2008 93: 1601-1604 DYSKERATOSIS CONGENITA Impaired telomere maintenance (TERC) Predispose BM failure, MDS, AML patients with BM failure by 40 Abnormal skin pigmentation Dystrophic nails Oral leukoplakia Developmental delay Pulmonary fibrosis Dokal, Inderjeet and Vulliamy, Tom. Blood, Reviews. Volume 17 Issue 4, December

DYSKERATOSIS CONGENITA PAPD5 INHIBITOR LEADS TO TELOMERE ELONGATION Nagpal, Neha PhD, DYSKERATOSIS CONGENITA Abstract 647 Therapuetic Targeting of Telomere Diseases Via Novel Small Molecule Modulators of Non-Coding RNA Biogenesis DC caused by PARN mutations Interfering w/ PAPD5 restores telomere length

BCH001 inhibited rPAPD5 telomere elongation Normalized over weeks and reversed with drug removal Affected primary fibroblasts, transformed cell lines, normal iPSCs and iPSCs from DC TERC RNA and telomere length can be controlled in human cells by modulation of the PARN/PAPD5 post-transcriptional regulatory axis Nagpal, Neha PhD, et US Natl Library of Med. Genetics Home Reference. Dyskeratosis Congenita. PNH/APLASTIC

ANEMIA/ITP RAVULIZUMAB IN PNH PNH terminal complement mediated intravascular hemolysis, thrombosis and bone marrow failure Eculizumab, humanized mAb binds C5 (blocking C5b-9), q2 weeks Hb stabilization and reduction of transfusions Ravulizumab, innovative C5 inhibitor, high C5 affinitiy, half life 4x that of Eculizumab, administered q8 weeks Ravulizumab has been shown to be non-inferior to eculizumab q2 weeks in PNH patients nave to

complement inhibitor therapy Lee JW, et al. EHA Learning Center, Jun 17, 2018;LB2603. American Journal of Blood Research 5(1):1-9 July 2015 RAVULIZUMAB IN PNH Abstract 625 Results from a Phase 3, Multicenter, Non-Inferiority Study of Ravulizumab (ALXN1210) Versus Eculizumab in Adult Patients with PNH Currently Treated with Eculizumab JumPic.com Prove non-inferiority for switching Phase 3, open label, multicenter trial PNH patients on eculizumab x6 months with LDH <1.5x ULN

197 patients,1:1 continue eculizumab 900 mg q2 week or switch to ravulizumab (D1, 15, then q8wk, weight based through Day 183) Measured hemolysis (change in LDH from baseline) primarily As well as breakthrough hemorrhage, QOL, stabilization and AustinHb G Kulasekararaj MBBS, MD,ifMRCP, transfusion free, C5 levels FRCPath RAVULIZUMAB IN PNH ALXN1210 PNH Nave Phase 3 Study Results John Orloff, M.D.

Head of R&D Austin G Kulasekararaj MBBS, MD, MRCP, RAVULIZUMAB IN PNH Better C5 inhibition with ravulizumab correlates with less breakthrough hemolysis JumPic.co m Abstract 626 Regis Peffault De Latour, ELTROMBOPAG IN MODERATE AA

Abstract 538. Eltrombopag for Moderate Aplastic Anemia and Unilineage Cytopenias: Dosing, Long-Term Follow-up, Clonal Evolution and Somatic Mutation Profililng. https://step2.medbullets.com/heme/120232/ aplastic-anemia Eltrombopag is FDA approved for SAA Eltrombopag in moderate AA or hypoproductive uni-lineage cytopenias Phase II, 25-300 mg daily, 34 pts 20122017 Assessed hematologic response 16-20 Xing Fan

MD, et al. Drug Design, Development and Therapy. 13 September 2016 Volume 2016:10 ELTROMBOPA G IN MODERATE AA Eltrombopag at escalating doses was well-tolerated and 50% had clinicallymeaningful responses, including those not previously treated w/ IST. Responses were durable, robust

(though frequently needing re-tx), and clonal evolution was rare. Xing Fan MD, 2ND LINE ELTROMBOPAG DISCONTINUATI Abstract 1135 Eltrombopag As Second Line ON INPatients ITPwith Primary Immune Therapy in Adult Thrombocytopenia (ITP) in Attempt to Achieve

Long-Term Remission, Preliminary Analysis of a Phase II, Multicenter, Prospective Study by Gimema Group (the ESTIT Study) TPO-R agonists eltrombopag and romiplostim both effective for R/R ITP Study of eltrombopag 2nd line in newly dxd or persistent ITP 55 adults, plt <30, not responsive or in relapse after 1st line tx Elisa Lucchini MD, Drug Design, Development and Therapy. 13 Sept 2016;2016:10;28332843. 2ND LINE ELTROMBOPAG

DISCONTINUATION IN ITP @PlateletBio Gen Suggestive eltrombopag given earlier in disease may be more effective, and one may consider tx dc after 6 mos if plt 30+ (many pts hadnt completed observation) Elisa Lucchini MD, et IRON THROMBOCYTH EMIA IN IRON DEFICIENCY Abstract 2 Low Iron Promotes

Megakaryocytic Commitment of Megakaryocytic-Erythroid Progenitors in Human and Mice Mechanism of thrombocythemia? Tmprss6 KO mice genetic model of IDA Tmprss6 is expressed in the liver, but not hematopoietic cells, required Fe uptake KO mice have higher platelet counts (915,000) Juliana Xavier-Ferrucio PhD, et al. Neth J of Med. Mar 2015.

THROMBOCYTHEMIA IN IRON DEFICIENCY MEprogenitors were similar KO mice showed bias towards CFU Mk Suggesting low iron reprograms cells Transplanted WT or KO BM into mice Mk-bias was evident in Tmprss6 -/- recipients Transferrin receptor 1 (CD71) is higher in cell lines Juliana Xavier-Ferrucio

PhD, in https://veteriankey.com/hematopoiesis/ et al. THROMBOCY THEMIA IN IRON Low iron affects MEP DEFICIENCY metabolism Leading to lower ERK phosphorylation, slower proliferation and increased Mk commitment Form of adaptive protection?

To reduce rbc production and Fe utilization Could be exploited to increase plt counts for transfusion ex vivo? Juliana Xavier-Ferrucio PhD, et Cell Reports;25(8):2083-2093e4. 20 Nov 2 SUMMARY Thromboprophylaxis in cancer? PAUSE guidelines to hold DOACs perioperatively BCL11A inhibitor, effective autologous gene therapy in SCD Luspatercept reduced RBC transfusions in Beta Thalassemias

Emicizumab bispecific mAb used in Hemophilia A patients Gene therapy shown promise in Fanconi Anemia CDK8 inhibiton increased erythroid proliferation in DBA PAPD5 inhibitor telomere elongation in DC Ravulizumab can be given q8 wks in PNH Eltrombopag was effective in moderate Aplastic Anemia Consider eltrombopag 2nd line in ITP w/ discontinuation Thrombocythemia in IDA due to Megakaryocytic bias MEPs www.medicalnewstoda NEW ASH VTE GUIDELINES Prophylaxis for Medical

Patients COMING SOON Diagnosis Prophylaxis in Surgical Patients Anticoagulation Therapy Treatment HIT Cancer

Pregnancy Thrombophilia Pediatric THANK YOU!

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