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ASH 2018 Benign Heme Updates

ASH 2018 Benign Heme Updates. Penelope Harris MD. Disclosures. Overview. thromboprophylaxis in cancer cassini trial. LBA-1 Rivaroxaban Thromboprophylaxis in High-Risk Ambulatory Cancer Patients Receiving Systemic Therapy: Results of a Randomized Clinical Trial ( CASSINI )

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ASH 2018 Benign Heme Updates

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  1. ASH 2018Benign Heme Updates Penelope Harris MD

  2. Disclosures

  3. Overview

  4. thromboprophylaxis in cancercassini trial • 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 • Randomized 1:1 to Rivaroxaban 10 mg daily vs placebo • Endpoints VTE, Death, Bleeding Alok A Kharana, et al.

  5. Khorana risk score ≥2 identifies patients at high risk of VTE Rivaroxaban10 mg significantly decreased VTE and VTE-related death during tx >1/3 events were after drug dc Major bleeding low Alok A Khorana, et al.

  6. 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, et al.

  7. 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

  8. 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, Kenya and Uganda, 2014-2016 • 600 children aged 1-10 at 15-20 mg/kg/day for 6 mos f/b dose escalation Leon Tshilolo MD PhD, et al. Guardian.ng.news/

  9. 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  1.1/100 pt years on tx Leon Tshilolo MD PhD, et al.

  10. Gene therapy to inhibit BCL11a in sickle cell Manipulating RNA to target and inhibit BCL11A induces HbF in transduced HSCs www.slideshare.net www.broadinstitute.org Erika B Esrick MD, et al.

  11. Inhibiting Bcl11a in Sickle cell Epizyme Inc. • Abstract 1023 Flipping the Switch: Initial Results of Genetic Targeting of the Fetal to Adult Globin Switch in Sickle Cell Patients • 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 conditioning Erica B Esrick MD, et al.

  12. Luspatercept in Beta thalassemia

  13. LUSPATERCEPT in Beta thalassemia Lovinglabscience.wordpress.com Piga A, et al. Blood. 2015;126:Abstract 752. • 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 • 336 pts randomized 2:1luspatercept 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) ptachieved >33% reduction over any 12 wks vs 29.5% (33) placebo (p <0.0001) Maria Domenica Cappellini MD, et al.

  14. Hemophilia

  15. Hemophilia A • Factor VIII deficiency • Factor treatment requires frequent IVs • Or use of bypassing agents Hemophilia Awareness Foundation Emicizumab Prophylaxis for Patients with Hemophilia A with Inhibitors. MaHTAS Medical Development Division Ministry of Health, Malaysia 2018

  16. 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 N Engl J Med 2016;374:2044-53. Victor Jimenez-Yuste, et al.

  17. Congenital Anemias

  18. Fanconi anemia DNA repair disorder Pancytopenia Predisposed to malignancy Short stature Microcephaly Developmental delay Café-au-lait spots Abnormal thumbs From Nathan DC, Orkin SH, Ginsburg D, et al, editors: Nathan and Oski’s hematology of infancy and childhood, ed 6, vol I, Philadelphia, 2003, WB Saunders, p 285.

  19. 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 • Low toxicity treatment for bone marrow failure Cell Stem Cell. Volume 11, Issue 1, 6 July 2012, Pages 36-49. Juan A Bueren, et al.

  20. 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 America;23(2):261-282. April 2009.

  21. Diamond-blackfan Anemia • Abstract 753 Small Molecule Screens Identify CDK8-Inhibitors 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 rps19-deficient 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 Haematologica November 2008 93: 1601-1604 Jun Chen MD PhD, et al.

  22. Dyskeratosis congenita • Impaired telomere maintenance (TERC) • Predispose BM failure, MDS, AML • ½ 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 2003, Pages 217-225.

  23. Dyskeratosis congenitapapd5 inhibitor leads to telomere elongation Nagpal, Neha PhD, et al.

  24. 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 US Natl Library of Med. Genetics Home Reference. Dyskeratosis Congenita. Nagpal, Neha PhD, et al.

  25. PNH/Aplastic Anemia/ITP

  26. 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 naïve to complement inhibitor therapy American Journal of Blood Research 5(1):1-9 · July 2015 Lee JW, et al. EHA Learning Center, Jun 17, 2018;LB2603.

  27. Ravulizumab in pnh JumPic.com 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 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, Hb stabilization and if transfusion free, C5 levels Austin G Kulasekararaj MBBS, MD, MRCP, FRCPath

  28. Ravulizumab in Pnh ALXN1210 PNH Naïve Phase 3 Study Results John Orloff, M.D. Head of R&D Austin G Kulasekararaj MBBS, MD, MRCP, FRCPath

  29. Ravulizumab in PNH • Better C5 inhibition with ravulizumab correlates with less breakthrough hemolysis JumPic.com Abstract 626 Regis Peffault De Latour, et al.

  30. Eltrombopag in moderate AA https://step2.medbullets.com/heme/120232/aplastic-anemia • Abstract 538. Eltrombopag for Moderate Aplastic Anemia and UnilineageCytopenias: Dosing, Long-Term Follow-up, Clonal Evolution and Somatic Mutation Profililng. • Eltrombopag is FDA approved for SAA • Eltrombopag in moderate AA or hypo-productive uni-lineage cytopenias • Phase II, 25-300 mg daily, 34 pts 2012-2017 • Assessed hematologic response 16-20 weeks • Responding pts continue Eltrombopag Xing Fan MD, et al. Drug Design, Development and Therapy. 13 September 2016 Volume 2016:10 Pages 2833—2843.

  31. Eltrombopag in moderate aa • Eltrombopag at escalating doses was well-tolerated and 50% had clinically-meaningful 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, et al.

  32. 2nd line Eltrombopag discontinuation in itp • Abstract 1135 Eltrombopag As Second Line Therapy in Adult Patients with Primary Immune 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 dx’d or persistent ITP • 55 adults, plt <30, not responsive or in relapse after 1st line tx • 50 mg/day (titrated prn) x24 weeks  tapered and dc (weeks 25-32)  observed til week 52 • Primary endpoint CR (>100) or R (>30) Elisa Lucchini MD, et al. Drug Design, Development and Therapy. 13 Sept 2016;2016:10;2833—2843.

  33. 2nd line Eltrombopag discontinuation in itp Suggestive eltrombopag given earlier in disease may be more effective, and one may consider tx dc after 6 mos if plt 30+ (many pts hadn’t completed observation) @PlateletBioGen Elisa Lucchini MD, et al.

  34. Iron

  35. Thrombocythemia 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. 73:3;108-118.

  36. 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 in KO recipients Similar skewing towards Mk in Human MEP Juliana Xavier-Ferrucio PhD, et al. https://veteriankey.com/hematopoiesis/

  37. Thrombocythemia in iron deficiency • Low iron affects MEP 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 al. Cell Reports;25(8):2083-2093e4. 20 Nov 2018.

  38. 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 inhibitonincreased erythroid proliferation in DBA PAPD5 inhibitor  telomere elongation in DC Ravulizumab can be given q8 wks in PNH Eltrombopagwas effective in moderate Aplastic Anemia Consider eltrombopag2nd line in ITP w/ discontinuation Thrombocythemia in IDA due to Megakaryocytic bias MEPs www.medicalnewstoday.com

  39. New ash vte guidelines • Prophylaxis for Medical Patients • Diagnosis • Anticoagulation Therapy • HIT • Pregnancy • Pediatric • COMING SOON • Prophylaxis in Surgical Patients • Treatment • Cancer • Thrombophilia

  40. Thank you!

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