1. Outcome of STRIDE Pilot Study and Study Design of BMT CTN 1503

2. STRIDE Pilot study of HCT for Young Adults with SCD: Introduction
EFS is ~90-95% after HLA-ID sibling HCT in pediatricSCD
Toxicity observed after HCT in adults with SCD in early trials limited its therapeutic application
HLA-ID sib HCT in adults with SCD using non-myeloablative conditioning effective, but alternate donor HCT will require higher intensity prep (Hsieh et al 2014)
Bu+Flu+ATG conditioning effective in URD HCT for Thalassemia, AML
Is HCT with Bu+Flu+ATG in adults with SCD safe and effective?

3. STRIDE Pilot Study Design
Pilot Study of HCT for Adults with SCD
Test safety and efficacy of conditioning regimen and plan larger multicenter dual arm trial to compare HCT and regular care
Objective
Determine if HCT in patients aged years with severe SCD will result in 1-year disease-free survival ≥75%
Primary endpoint: 1 year event free survival
Events : Graft failure, Disease Recurrence, Death
Secondary endpoints
Donor Chimerism, Transplant related toxicities
SCD related complications
NHLBI 1R34-HL

4. Inclusion Criteria
SCD (any genotype), Ages years with 8/8 HLA-allele matched sib/unrelated donor
Severe disease defined as having 1 or more of the following:
Clinically significant neuro event or deficit lasting > 24 hrs
≥ 2 episodes ACS in last 2-yrs despite supportive care
≥ 3 severe VOCs/yr in last 2-yrs despite supportive care
≥ 8 RBC transfusion/year
TRJ velocity ≥ 2.7 m/sec

5. Conditioning Regimen BMT Flu 35mg/m2/day Bu 3.2/kg/day
rATG total 6 mg/kg
Methotrexate
Tacro or CsA

6. Patient Characteristics and Study Timeline
Gender
Female 13, Male 9
Median Age ( Range) in years
22( 18-36)
Indication for HCT n
VOC 17
Chronic transfusion 6
TRJ velocity>2.7 5
Single indication 11
more than 1 indication
Donor Type
Sibling 17, unrelated 5
Participating Institutions
Children’s Healthcare of Atlanta, GA
Children’s Hospital of Oakland, CA Children’s Hosp Pittsburgh, PA
Children’s National Medical Center
City of Hope, CA
Duke University Medical Center
Emory University, Atlanta, GA
Virginia Commonwealth Univ
Study Timeline
4 patients transplanted
6 months
observation
1 year follow up
18 patients transplanted
Jul ‘12-Apr ‘13
May ‘13-Oct’13
Nov ‘13-Jul ‘15
Jul ‘15-Jul ‘16

7. Survival and HCT Outcomes in 22 Patients
OS and EFS (median follow up 13.6 months): %
N(%)
Grade II-IV AGVHD: 4(18)
Moderate CGVHD: 3(13)
Severe CGVHD: (4)
Deaths:
PRES/intracranial bleed( 1), GVHD(1)
Bacteremia:
Viral reactivation:
Overall Survival
Time (mos after BMT)

8. High RBC Chimerism Despite Partial Lymphoid Chimerism
Mean Percentage Donor Chimerism
d d d d+360
Median Percentage Donor Chimerism ( Range)
D +28
D +100
D+180
D+365
RBC
100
(89-100)
n=22
(24-100)
n=20
(93-100)
n-14 91
(79-100)
n=11
Lymphoid Chimerism
55.5
(12-100)
n=21
80.5
(10-100)
88.5
(11-100)
n-16
81.5
n=13

9. High RBC Chimerism Despite Partial Lymphoid Chimerism
RBC chimerism assayed by pyrosequencing of the sickle cell mutation
Quantifies relative levels of normal and sickle beta globin mRNA
Mixed lymphoid chimerism despite myeloablative therapy
? Impact of rATG
Lymphoid chimerism increases over time
RBC chimerism remains high despite low lymphoid chimerism
Hb Electrophoresis demonstrates complete donor erythropoiesis in all patients.

10. Conclusions Future Directions
Bu/Flu/ATG conditioning is safe in eligible young adults with SCD
No graft rejection and low rates of GVHD
We observed 90% EFS after HLA-matched HCT
No pain or SCD related events after 180 days
Future Directions
Conduct a larger trial of HCT with donor and no donors cohorts and compare survival
Impact of donor erythropoiesis on SCD phenotype

11. Hematopoietic Cell Transplantation for Young Adults with Severe Sickle Cell Disease
BMT CTN 1503
Drs. Krishnamurti, Walters, Sullivan, Neuberg, Mendizabal and Eapen for the Protocol Team

12. Specific Aims – BMT CTN 1503 Specific Aim 1
Determine the tolerability and efficacy of HCT in adolescents and young adults with severe SCD
The difference in 2 year overall survival between HCT recipients and those receiving standard of care should not exceed 15% (i.e., the donor vs. no-donor arms of the proposed trial)
Specific Aim 2
Measure the benefit of donor hematopoiesis on sickle-related events, organ function (pulmonary, renal), health related quality of life and pain assessments (via e-diary)

13. Eligibility Criteria – BMT CTN 1503
Age 15 – 40 years
CNS event: stroke or deficit lasting >24 hours
≥ 2 episodes of acute chest syndrome (ACS) in preceding 2 years despite adequate supportive care measures
≥ 3 episodes of pain crisis (VOC) in preceding 2 years despite adequate supportive care measures
≥ 8 transfusions per year for ≥ 1 year to prevent SCD-related complications (VOC, ACS, stroke)
Tricuspid valve regurgitant jet (TRJ) ≥ 2.7 m/sec

14. Study Design: Intent-to-Treat Analysis
Consultation with HCT physician
Not Eligible
ERC: Confirm Clinical Eligibility
HLA typing
Re-register in AdvantageEDCSM
for Biologic Assignment
Off study
Donor
No Donor
HCT
Comparison
Cohort
HCT not Performed
Clinically Eligible; Consent
Register in AdvantageEDCSM
vs.
ITT Analysis *

15. Study Design Donor arm (N=60); No donor arm (N=140)
Patients with ERC confirmed eligibility will be HLA typed and donor search initiated
HLA typing with donor search before referral = INELIGIBLE for BMT CTN 1503
Biologic assignment occurs 60 +/- 30 days after re-registration to AdvantageEDC
Start time: Biologic Assignment
Follow up: 3 years from Biologic Assignment (3rd year follow-up by CIBMTR)

16. Donor/Graft Selection – BMT CTN 1503
Bone marrow grafts ONLY
Target TNC 2-4 x 108/kg patient weight
Donors
Sibling: HLA-matched
Unrelated adult donor matched to patient at the allele-level at HLA-A, -B, -C, -DRB1
All donors will be screened for sickle cell / thalassemia – trait acceptable
Screen for donor specific HLA-antibodies

17. Conditioning Regimen – BMT CTN 1503
Day
Regimen -8
IV busulfan 3.2 mg/kg -7
IV busulfan 3.2 mg/kg, fludarabine 35 mg/m2 -6
IV busulfan 3.2 mg/kg, fludarabine 35 mg/m2, thymoglobulin 0.5 mg/kg -5
IV busulfan 3.2 mg/kg, fludarabine 35 mg/m2,
thymoglobulin 1 mg/kg -4
IV fludarabine 35 mg/m2, thymoglobulin 1.5 mg/kg -3 -2
IV thymoglobulin 1.5 mg/kg -1
Rest
Infuse bone marrow graft

18. GVHD prophylaxis – BMT CTN 1503
Day
Regimen -3
tacrolimus through day +180; taper per institutional standards; may use cyclosporine if unable to tolerate tacrolimus
Bone marrow infusion +1
IV methotrexate 15 mg/m2 +3
IV methotrexate 10 mg/m2 +6
IV methotrexate 10 mg/m2
+11

19. Endpoints
Primary endpoint: estimate of overall survival at 2-years after biologic assignment with the goal of establishing that the difference in the proportion surviving is no more than 0.15 lower in the donor arm
Analyze according to assigned treatment groups (ITT)
Secondary endpoints:
Sickle-related events, organ function (pulmonary, renal), 6 MWD test, HRQoL and pain assessments (via e-diary)
Measured at baseline and 2-years at same institution
Exception: HRQoL, pain and 6 MWD test measured at baseline, 1- and 2-years
All participants will be monitored every 3 mos

20. Guidelines for Safety Monitoring
Truncated SPRT for each rule
Consult DSMB if cross upper boundary
100-day overall mortality:
15% vs 30%
1-year overall mortality
Related donors: 15% vs 30%
Unrelated donors: 15% vs 30%
100-day graft rejection
Related donors: 10% vs 20%

21. Study Activation Benchmarks
Protocol review committee – reviewed on 9/22/15 with second review of modified protocol on 12/15/15, approved 12/21/15.
Data Safety Monitoring Board – reviewed on 1/19/16
Second DSMB review on March 23, 2016

22. Accrual Plan – BMT CTN 1503 Funding period: 5 years
Accrue 200 patients over 3 years;
Begin enrollment: 06/2016
End enrollment: 06/2019
Two-years follow-up from biologic assignment
N = 27 centers have received contracts and 12 are fully executed; 13 of 15 awaiting final protocol/IRB approval to execute the contract
N=13 additional sites indicate interest to participate
Contact Lauren Zahra

23. Extended Follow up – BMT CTN 1503
Survival status on all participants will be followed annually through 10 years from biologic assignment
Donor arm: followed through CIBMTR
No donor arm: direct contact with hematologists at participating sites
Those lost to follow up will be tracked annually searching the National Death Index
Planned 10-year OS estimates/comparison incorporated into statistical plan
Appropriate language in ICFs