Haploidentical BMT with Post Transplant Cyclophosphamide “The Great Equalizer” Heather Symons, MD, MHS Clinical Director, Pediatric Blood and Marrow Transplantation Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland, USA hsymons2@jhmi.edu

Conflict of interest statement Jazz – Speaker’s Bureau Novartis – Clinical trial participation BMS – Clinical trial participation

HaploBMT with PTCy has what it takes! ✓ Safe Efficacious Simple/Transportable Inexpensive Track record of success National/International Reputation Used for a wide variety of diseases ✓ ✓ ✓ ✓ ✓ ✓

Single Institution Success

National Success in Hematologic Malignancies National, multi-center trials with successful outcomes Outcomes of Haplo= HLA-matched graft sources

Haplos with PTCy have caught up to HLA-matched 3 year progression free survival, stratified by disease risk index Matched Haplo Disease Stage/ Risk 1997* (matched sib) 2015† (sib + MUD) 2015‡ Early/Low Risk 66 25 63 Intermediate 44 31 20 39 Advanced/High Risk 12 15 22 *R Szydlo et al. J Clin Oncol 15: 1767-1777, 1997 †Personal communication with P. Armand (n=614) ‡S McCurdy et al. Blood 125:3024-31, 2015

Haploidentical Transplantation Using Post-Transplantation Cyclophosphamide Compared With 10/10 Allele-Matched Unrelated and HLA-Identical Sibling Donors Transplantation Bashey A, et al. BBMT 2016: 22: 125-133

RIC Haplo-BMT vs Matched URD HCT for lymphoma Kanate AS, et al RIC Haplo-BMT vs Matched URD HCT for lymphoma Kanate AS, et al. Blood 2016; 127:938-947

Parallel Phase 2 Trials Using Partially HLA-MM Related Bone Marrow or Unrelated dUCB Grafts Brunstein CG, Fuchs EJ, Carther SL, et al. Blood 2011; 118: 282-288 CTN Study: 2 Parallel Multicenter Phase 2 Studies 56% AML (cord), 44% AML (haplo) RIC Regimen of FLU/CY/ Low dose TBI for both groups Early TRM higher with UCBT (24% vs 7%) but relapse rate lower (31% vs 45%) UCBT 1 year OS 54%, PFS 46% Haplo-BMT 1 year OS 62%, PFS 48% Haplo aGVHD Gr 3-4 = 0%

Pediatric Specific Data N Engraftment aGVHD II-IV aGVHD III-IV Mod-severe cGVHD TRM Relapse (3y) EFS (3y) OS Hopkins (NMA)1 40 91% 33% 5% 7% 13% 52% 46% 32% (MA)2 29 96% 18% 4% 12% 10% 25% 55% 72% AIEOP-GITMO3 33 97% 22% 3% 9% 24% 61% (1y) 72% (1y) PBMTC 0% 1 Klein et al, BBMT, 2017 2 Symons et al, BBMT, 2016 3 Berger et al, BBMT , 2016

HaploBMT success in nonmalignant disorders

Haplo-BMT with PTCY for non-malignant disorders Disease N Engraftment GVHD Death Sickle Cell and thal (ATG, Flu, Cy, 400cGy TBI, sirolimus)1 17 94% 2 (Gr 2) 1 (Gr 3) 1 mod CGVHD Thalassemia2 31 1 Aplastic Anemia3 16 100% 2 (Gr 1-2 skin) 0% Immunodeficiencies/ BMF4 11 90% 2 (Gr 1) 1 (Gr 2) 1 cGVHD 1 Jones, et al, ASH abstract 2017 2 Anurathapan et al, Bone Marrow Transplant (2016) 3 DeZern et al, BBMT, 2017 4 Klein et al, BBMT, 2016

Bonus Points No PTLD with antibody-therapy free platforms1 No increase in donor derived malignancies2 # of HLA mismatches does not matter3 Can use second degree haplo relatives4 Can d/c CNI at Day 60 safely5 DLI feasible and potentially beneficial6 Low rate of infections and rapid immune reconstitution as c/w T cell depleted haplos7,8,9 1 Kanakry et al, BBMT, 2013 2 Majzner et al, BBMT, 2017 3 McCurdy et al, Blood Adv, 2018 4 Elmariah et al, BBMT, 2018 7Ciurea et al, BBMT, 2012 5 Kasamon et al, BBMT , 2018 8Luznik et al, Blood, 2001 6 Zeiden et al, BBMT, 2014 9Crochiollo et al, Trnsp Infec Dis, 2015

HaploBMT with PTCY is the platform for new national haplo initiatives

BMT CTN 1502: Aplastic Anemia Haploidentical Cohort Flu Flu Flu Flu Flu GVHD Prophylaxis: Tacrolimus, MMF, & Post-HSCT Cy Cy Cy ATG ATG ATG TBI Cy Cy -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 Flu = Fludarabine 30 mg/m2 IV daily Cy = Cyclophosphamide 14.5 mg/kg IV daily TBI = 200 cGy Cy = Cyclophosphamide 50 mg/kg IV daily ATG = Thymoglobulin 0.5 mg/kg (day-9) & 2 mg/kg (day -8,-7)

Reduced Intensity Conditioning before HLA-Haploidentical Bone Marrow Transplantation in Patients with Symptomatic Sickle Cell Disease BMT CTN protocol development Michael R. DeBaun MD MPH Adetola Kassim, MD Mark Walters, MD Robert Brodsky, MD

HaploBMT with PTCy Summary PTCY is the dominant method of GVHD prophylaxis in the haplo setting 15 years of experience Safe and efficacious for malignant and non-malignant disorders All conditioning intensities possible- myeloablative, RIC or non-myelo Low rates of acute and chronic GVHD and non-relapse mortality Relapse on par with other graft sources when DRI is factored in Efficacious for malignant and non-malignant disorders Haplo plus PTCy outcomes are = cord blood or HLA-matched BMT Low cost, easily transportable, simple, no extra training required New national initiatives to treat sickle cell disease and aplastic anemia using haploBMT with PTCy

“In character, in manner, in style, in all things, the supreme excellence is simplicity” Henry Wadsworth Longfellow PTCy Day + 3, +4 60-72 hours from the start of graft infusion Ideally avoid other immunosupressive agents before this time a/b depletion CliniMACS® TCRαβ-Biotin system, Three IDE exemption cross references: BB MF 12011, SN 073 (Clinimacs® CD19 reagent system), BB MF 12251, NS 054 (Clinimacs® depletion tubing set), and BB MF 15678, SN 012, Clinimacs® TCR α/β reagent system) Long instruction booklets that requires a cell processing lab with skilled personnel and equipment

Haplo with PTCy: may not be the most sophisticated or attractive approach but it’s a clear winner