Curing Sickle Cell Disease: Bone Marrow Transplant, The Clinical - PowerPoint PPT Presentation

Curing Sickle Cell Disease: Bone Marrow Transplant, The Clinical Perspective Courtney D. Fitzhugh, M.D. Investigator Lasker Clinical Research Scholar Laboratory of Early Sickle Mortality Prevention

Sickle Cell Disease Has an Immense Global Burden and can be Cured with HSCT • Globally, more than 300,000 babies are born with SCD each year 1 • SCD is caused by a point mutation which leads to red blood cell sickling, vaso-occlusion, organ damage, and early mortality • Because SCD affects the red blood cell, it is perfect for hematopoietic stem cell-based therapy 1. Piel FB et al. NEJM, 2017. 376(16): 1561-1573.

Bone Marrow Transplants Replace the Seeds of the Blood Sickling Red blood cells Lymphocytes Platelets Granulocytes Bone marrow stem cells produce all types of blood cells for the life of a patient. Progenitors Bone marrow hematopoietic *Sickle mutation John Tisdale, MD “stem cells”

Stem Cell Transplantation Offers a Cure for Sickle Cell Disease • With a traditional transplant, stem cells from a healthy PATIENT donor are given to the patient • Donors are most commonly Graft Rejection HLA-matched siblings • Myeloablative (full) conditioning completely replaces the patient’s bone Graft versus Host marrow with that of their Disease DONOR donor

Myeloablative HLA-Matched Sibling Transplant has a High Success Rate • 1000 patients transplanted • At 5 years after the transplant • 93% alive • 91% free of sickle cell disease • 15% graft versus host disease • For children younger than 16 years • 95% alive • 93% free of sickle cell disease Gluckman E et al. Blood, 2017. 129(11): 1548-1556.

Mixed Chimerism is Sufficient to Reverse SCD PATIENT DONOR

Non-myeloablative HLA-Matched Sibling Peripheral Blood Stem Cell Transplant for SCD Sirolimus (target 10-15 ng/dL) Hsieh MM, Kang E, Fitzhugh CD, et al. NEJM, 2009. 361(24): 2309-2317.

Transplant Outcome • 55 patients transplanted • Median age 29 years, range 10-65 years • Median follow-up 6.4 years (range 0.5-14.4 years) • 93% alive • 87% free of sickle cell disease • No graft versus host disease • 8 patients have had 13 healthy babies post-transplant Matthew Hsieh John Tisdale

Our Results Were Duplicated at Other Institutions • 12 of 13 adults at University of Illinois, Chicago free of SCD (=92% free of SCD) 1 • No graft versus host disease • 31 of 34 patients >14 years in Saudi Arabia free of SCD (=91% free of SCD) 2 • No graft versus host disease • 16 of 16 children down to 3 years of age in Alberta, Canada free of SCD (=100% free of SCD) 3 • No graft versus host disease • Multi- center study is being initiated in children at Children’s National Medical Center 1. Saraf SL et al. Biology of Blood and Marrow Transplantation, 2015. 22(3): 441-448. 2. Alzahrani M et al. American Society of Hematology Annual Meeting, 2018. 3. Guilcher G et al. Biol Blood Marrow Transplant, 2019.

Why aren’t More Patients with Sickle Cell Disease Transplanted?

Vast Majority of Patients do not have an HLA-Matched Sibling 287 patients had HLA typing 36% with an HLA matched 102 patients had sibling donor 6/6 HLA-match siblings 18 patients had insufficient information to determine 12 patients did not meet disease severity eligibility 19 patients excluded for major ABO mismatch or other In 2 patients, their donors antibodies to donor red cells declined to donate 13 patients receiving 2 patients died prior to optimizing medical transplantation therapy patients 36 patients underwent transplant

Pediatric Related Umbilical Cord Transplants for SCD Number of Alive without Acute GvHD Chronic GvHD HLA match patients (age Death (cause) Reference SCD (Gr 2-4) (extensive) range) Brichard, 6/6 1 (5) 1 0 0 0 1996 Miniero, 6/6 3 (3-11) 2 0 0 0 1998 Gore, 2000 6/6 1 (9) 1 0 0 0 6/6 42 pts, 1 (intractable Walters, 8 (NR) 6 NR NR 2005 4/6 4 pts* seizures) Matthes- 6/6 1 (11.1) 1 0 0 0 Martin, 2013 11% (Gr 3 (2 hemorrhage, Locatelli, 6/6 30 (2-20) * 27 0 2013 2-3)* 1 organ failure)* Mostly 6/6 44 38 (86%) 11% 0 9% (of total) Total *Includes patients with sickle cell disease and thalassemia

Pediatric Unrelated Umbilical Cord Transplants for SCD Number of Alive without Acute GvHD Chronic GvHD Reference HLA match patients (age Death (cause) SCD (Gr 2-4) (extensive) range) 5/6 2 pts, 1 1 (multi-organ Adamkie- 7 (3.4-16.8) 3 4 wicz, 2007 4/6 5 pts failure) 6/6 (2) Ruggeri, 5/6 (4) 16 (6) 8 23% 16% 1 acute GvHD 2011 4/6 (10) 6/6 (1) 1 (respiratory Kamani, 8 (7.4-16.2) 3 2 (Gr 2) 1 (extensive) 2012 5/6 (7) failure) Radhak- rishnan, NR 8 (1-10) 4 4 0 3 (infection) 2013 Khar- 4/6 2 (8) 0 0 0 0 banda 2014 18 33% 11% 15% Mostly 41 Total mismatched (44%) (of total) (of total) (of total) • More recent study more encouraging: 9 children transplanted, 100% alive, 78% free of SCD, 10-20% GVHD 1 Abraham A el al. Biol Blood Marrow Transplant, 2017. 23: 1580-1596.

Matched Unrelated Donor Transplants for SCD Number of Alive without Acute GvHD Chronic GvHD Reference Death (cause) patients (age) SCD (Gr 2-4) (extensive) Strocchio, 6 (27-48) 5 0 0 0 2015 6 (GVHD) Shenoy, 29 (6-19) 20 8 11 1 (following 2016 2 nd transplant) 2 Marzollo, 2 (6.5-10.5) 2 0 0 2017 Gr 2 Gillman, 2 (5-13) 2 0 0 0 2017 1 Krishna- 5 3 1 1 (GVHD) murti, 2019 Gr 3 25% 27% 18% Total 44 29 (73%) (of total) (of total) (of total)

Matched Unrelated Donor Transplant for Adolescents and Young Adults with SCD Results of all 22 patients • 22 patients median age 22 years • 17 HLA-matched sibling • 5 MUD • MUD results • 4 of 5 alive • 3 of 5 free of SCD • 4 th SCD-free after 2 nd transplant • 1 patient developed grade 3 acute GVHD and 1 severe chronic GVHD Krishnamurti L et al. American J Hematology, 2019.

BMT CTN #1503 • Phase 2 multi-center study comparing 2-year overall survival in young adults with severe SCD who receive transplant compared to standard of care • Age 15-40 years • Donors: • HLA-matched sibling • Matched unrelated donor

Haploidentical PBSC Transplantation for Adults with Severe Sickle Cell Disease • Haploidentical donors – Most accessible – Large cell doses feasible – Repeat collections feasible • Immunologic barrier greater – Higher degree of immunosuppression

Post-Transplant Cyclophosphamide in the Haploidentical Setting for Patients with Severe Hemoglobinopathies • 17 patients received BMT, 14 haploidentical donors, 3 HLA-matched sib donors • Median age 30 (15-46 years) • 100% alive • 50% free of SCD • No graft versus host disease • 75% engrafted patients off of immunosuppressive therapy Balanos-Meade J et al. Blood, 2012. 120(22): 4285-4291 .

Nonmyeloablative Haploidentical PBSC Transplantation for Adults with Severe Congenital Anemias Fitzhugh CD et al. Blood Advances, 2017. 1(11): 652-661.

Nonmyeloablative Haploidentical PBSC Transplantation for Adults with Severe Congenital Anemias • N = 23 • Age range: Median 36, range 20-56 years old • Follow-up: 5.9 years (range 3.4-8.6 years) • Except where indicated, the remainder have HbSS 7 6 Number of individuals 1 b -thal 5 1 Hb S b 0 4 1 b -thal 1 HbSC 3 2 1 0 18-20 21-25 26-30 31-35 36-40 41-45 >45 Age range

Haplo Patients with Severe Organ Damage Tolerate Conditioning N (%) Hepatic 20 (87) Iron overload 18 (78) Cirrhosis 2 (9) Recurrent ACS and/or VOC 19 (83) Neurologic 8 (35) Stroke 6 (26) Moyamoya syndrome 4 (17) TIA 1 (4) Cardiac 7 (30) Systolic dysfunction 5 (22) Diastolic dysfunction 3 (13) Renal 6 (26) ESRD on PD 3 (13) ESRD on HD 1 (4) CRI with baseline Cr 2.5-5.0 mg/dL 2 (9) Pulmonary hypertension 5 (22) Autoimmune 2 (9) Multiple sclerosis 1 (4) Rheumatoid arthritis 1 (4)

Engraftment and Success Rates Improve with PT-Cy Cumulative Engraftment Cytoxan Graft Versus Cohort Rate (Before Day Free of SCD Dose Host Disease +100) (mg/kg) 1 0 1/3 (33%) 0/3 (0%) 0 1 Grade I 2 50 5/8 (63%) 2/8 (25%) Acute 1 Grade I Acute 3 100 10/12 (83%) 6/12 (50%) 1 Mild Chronic • No mortality before day 100 • 5 patients who rejected their grafts died 6 months and 3, 5, 7 and 8 years post- transplant, mostly from SCD-related complications (78% free of SCD) Fitzhugh CD et al. Blood Advances, 2017. 1(11): 652-661.

Additional Up Front Conditioning and T cell Depletion has Improved the Outcome for Haploidentical HSCT

Modified Hopkins Regimen for Patients with SCD Undergoing Haploidentical Transplant • 8 patients • Age 20-38 years TBI 300 cGy PBSCT infusion Saraf SL et al. Biol Blood Marrow Transplant, 2018. 24: 1754-1770.

Improved Results with 300cGy TBI and Peripheral Blood Stem Cells • W ith a median follow-up of 17 months: • 7 patients are alive (88%) • 6 patients are free of SCD (75%) • 2 patients developed >2 acute GVHD, 1 chronic GVHD Saraf SL et al. Biol Blood Marrow Transplant, 2018. 24: 1754-1770.

Another Modified Hopkins Regimen for Patients with SCD Undergoing Haploidentical Transplant • 17 (12 patients with SCD, 5 patients with b -Thal) • Age 6-31 years MMF 15mg/kg po tid TBI 400 cGy Sirolimus rabbit ATG Bolanos-Meade J et al. Lancet Haematology, 2019.