UNRELATED DONOR TRANSPLANTATION FOR SICKLE CELL DISEASE AN UPDATE

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1 UNRELATED DONOR TRANSPLANTATION FOR SICKLE CELL DISEASE AN UPDATE Naynesh Kamani, M.D. Children s National Medical Center GW University School of Medicine Washington, DC

2 SCD scope of problem in USA Commonest inherited disorder in AA; median life expectancy 40 s; with current SOC, ~ 5-8% die before age 18 years In USA, about K individuals with SCD and ~4000 babies born annually with Hgb SS disease; exact prevalence unknown Wide range of clinical severity; 5-25% have severe phenotype Target organs for vasculopathy and severe disease include the CNS, lung, kidney, etc. Patients with severe symptoms or high risk for early mortality gain the most benefit from successful allo-transplantation Miller ST et al, NEJM 342:83, 2000 Platt O, et al NEJM 330:1639, 1994 Castro & Gladwin, Hematol/Onc Clin NA 19:881, 2005

3 SCD Worldwide 1-2 million children affected world wide with origins from Africa, Middle East, India Mortality >80% by age 18 in Africa Miller ST et al, NEJM 342:83, 2000 Platt O, et al NEJM 330:1639, 1994 Castro & Gladwin, Hematol/Onc Clin NA 19:881, 2005

4 Percent BMT for SCD (N=59) P610 Nov Median follow-up 6.5 years (range: ) 93% 85% Event = death, graft rejection, or disease recurrence. 9% Time (years) after BMT

5 Percent Sibling Donor Cord Blood Transplant for SCA/Thalassemia (N=53) Feb Survival 92% Event-free Survival 87% (Event = death, graft rejection, or disease recurrence.) Median follow-up: 3.5 yrs (range ) Cumulative Incidence of graft rejection/recurrence: 7% Time (years) after UCBT

6 MSD BMT in SCD world experience USA Belgium France France Walters et al Vermylen et al Bernaudin et al Bernaudin et al # Patients Median age 9.4 y(3.3-14) 7.5 y(0.9-23) 8.3 y(3.2-20) 9.3 y(3.2-22) Graft rejection % Overall survival % Event-free survival %

7 Long-term benefits Stabilization of CNS lesions Improvement of TCD findings Stabilization of pulmonary function Normal growth after BMT Freedom from recurrent VOC/ACS Normalization of splenic function Risk of sterility still a major concern

8 Summary Myeloablative HLA identical sib HCTs have excellent outcomes with long-term cure Risk of rejection ~5 10%; stable mixed chimerism results in freedom from SCD Morbidity of URD HCT is a barrier to extending curative therapy to more patients Outcomes after URD HCT unknown Strategy that reduces toxicity of URD BMT and risk of GVHD will result in acceptability of this approach for eligible patients with SCD

9 Newer approaches for BMT in SCD Problem Small risk of early death and overall toxicity of the procedure Possible solution Reduce morbidity and mortality by using RIC and accepting mixed donor chimerism as outcome Safer approach but rejection of marrow likely

10 Newer approaches for BMT in SCD Problem Inability to find a matched sibling donor for majority of patients (for 80-85% of patients) Possible solution Use unrelated donor marrow and other sources of stem cells

11 Unrelated Donor Hematopoietic Cell Transplantation for children with severe SCD using a reduced intensity regimen SCURT (BMT-CTN 0601)

12 BMT-CTN children with severe SCD (Hgb SS or Hgb S- thal) 1 o end-points: EFS at 1 yr after URD HCT (death, disease recurrence or graft rejection) 2 o end-points: Effect on clinical/lab manifestations of SCD Incidence of HCT-related outcomes: OS, count recovery, agvhd, cgvhd, VOD, IPS, infection, donor chimerism, health related QOL etc

13 Eligibility criteria 3 19 yr old with Hgb SS or S-β o thal > ONE of the following: Stroke or neurologic deficit lasting > 24 hrs + infarct on cerebral MRI TCD velocity > 200 cm/sec by non-imaging technique (or TCD measurement of >185 cm/sec by imaging technique) measured at least twice one month or more apart > 2 episodes of ACS in past 2 yrs > 3 VOC/yr in past 2 yrs URD: 8/8 allele matched URD bone marrow OR > 5/6 UCB unit

14 Preparative regimen Alemtuzumab 10/15/20 mg Days -21 to -19 Fludarabine 30 mg/m 2 Days -8 to -4 Melphalan 140 mg/m 2 Day -3 Stem cell infusion Day 0 G-CSF 5 mcg/kg/day Day +7 until ANC>500 Hgb S < 45% within 7 days prior to Alemtuzumab Shenoy et al: BMT 2005; 35:345; Kamani et al: BBMT Feb 16. [Epub ahead of print]

15 Reducing the Intensity of Conditioning (The SCURT Trial) A F M T MTX -22 to to -3 Prednisone d 28 Calcineurin inhibitor d 100 A-Alemtuzumab; F-Fludarabine; M-Melphalan; T-Transplant; MTX-Methotrexate Shenoy et al: BMT 2005; 35:345; Kamani et al: BBMT Feb 16. [Epub ahead of print]

16 GVHD prophylaxis Regimen 1(BMT): Tacrolimus/cyclosporine + MTX + Prednisone Regimen 2 (UCBT): Tacrolimus/cyclosporine + MMF

17 Additional study measures Health related QOL assessment at pre- BMT, days 100, +6, +12, +24 mos Cerebral MRI/MRA, Neurocognitive assessment and pitted red blood cell count pre-bmt and +2 yrs Hgb electrophoresis at pre-bmt, days 100, +6, +12, +24 mos

18 SCURT Trial Initiated in July 2008 Study now activated at 18 centers 25 subjects enrolled, 24 have undergone BMT 8: unrelated cord blood; arm closed in Jan : unrelated marrow; accruing pts

19 SCURT Trial Stopping rules Day 100 mortality: > 15% Day 100 graft rejection rate: > 20% Day 100 gr III/IV agvhd: > 15%

20 SCURT Trial Cord blood cohort 8 children: y (median 13.7 y); 6 females, 2 males VOC -3; ACS 3; Stroke 2; Median cell dose: Pre-cryo TNC 6.4 x 10 7 /kg ( ) Post-thaw CD34+: 1.5 x 10 5 /kg ( ) CB Match status: 6/6: 1; 5/6: 7

21 SCURT Trial Cord blood cohort Hematopoietic recovery ANC > 500: median 22 days (all by d +33) Plts > 50K: 5/8 by day 100 agvhd: 2 pts (gr II); cgvhd: 1 Donor cell engraftment: 3/8; 5 pts had GR w/autologous recovery; 2/2 with both C allele matched engrafted; 5/6 with >1 mm rejected; Of 6 pts tested, none had anti-hla DSA Death: one at +14 mos from cgvhd All engrafted pts had 100% donor cell chimerism CB arm of trial STOPPED due to high rejection rates

22 UCBT in SCD retrospective CIBMTR/Eurocord/NYBC analysis 16 patients with SCD 7/16 graft rejections (4/7 following a myeloablative regimen) 94% OS; 50% DFS Patients who received > 5 x 10 7 TNC/kg had a better 2 yr DFS ( 45% vs 13%) Ruggeri A: BBMT 2011; 17:1375

23 Unrelated CBT in hemoglobinopathies Ruggeri A et al: Biol Blood Marrow Transplant 2011; 17:1375

24 Limited institution trial (8 centers) of Campath/Flu/Mel regimen for SCD Ages: y; follow-up: y(med 2 y) MSD cohort 20 pts (19 BM, 1 CB) 2 graft rejection (1 BM/1 CB); 2/18: mixed chimerism agvhd: 2 gr I-II; 1 gr III cgvhd: 3 (1 limited; 2 extensive) Unrelated donor cohort 5 pts (4 BM, 1 CB); 1 pt died 11+ mo cerebral thrombosis 1 graft rejection (BM); 1 gr IV agvhd; 2 cgvhd

25 Graft Rejection after unrelated donor transplantation Significantly more rejection with use of unrelated CB than with marrow/pbsc Factors that contribute to rejection Cell dose (5-10 fold less cells in CB unit) Degree of mismatch between donor/recipient Pre-existing antibodies due to allo-immunization Preparative chemotherapy regimen Other factors: e.g. NIMA mismatch;?abo mismatch Marrow + CB when using sibling CB Not feasible when using unrelated CB

26 Unrelated (alternative) donor HCT for SCD Next steps Improve results of CBT by: Changes in conditioning regimen? Double cord transplants Better selection of CB units (higher cell dose, absence of anti-donor HLA Ab, better HLA-C match,?nima match) Expanded CB units; co-transplanting with accessory cells Consider using 7/8 unrelated marrow donors Await results of haploidentical HCT NIH study ongoing (Mel/TBI/sirolimus, high CD34+) JHU study ongoing (Flu/CY/TBI with post-hct CY)

27 Acknowledgements Shalini Shenoy, MD Mark Walters, MD BMT-CTN 0601 study committee members BMT Clinical Trials Network (NHLBI/NIH) National Marrow Donor Program