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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
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 70-100K 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
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
Time (years) after BMT
Per
cen
t BMT for SCD (N=59)
93%
85%
9%
Median follow-up – 6.5 years (range: 3.0 –12.4)
P610
Nov. 2005
Event = death, graft rejection, or disease recurrence.
Time (years) after UCBT
Pe
rce
nt
Sibling Donor Cord Blood Transplant for SCA/Thalassemia
(N=53)
Survival 92%
Event-free Survival 87%
Feb. 2010
(Event = death, graft rejection, or disease recurrence.)
Median follow-up: 3.5 yrs (range 0.2 – 7.6)
Cumulative Incidence of graft rejection/recurrence: 7%
MSD BMT in SCD – world experience
USA
1991-1999 Walters et al
Belgium
1986-1997 Vermylen et al
France
1996-2000 Bernaudin et al
France
2001-2004 Bernaudin et al
# Patients 59 50 43 44
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 % 9 10 12 5
Overall
survival % 93 93 86 100
Event-free
survival % 85 82 75 95
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
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
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
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
Unrelated Donor Hematopoietic Cell Transplantation for children with severe SCD using a reduced intensity regimen SCURT (BMT-CTN 0601)
BMT-CTN 0601
45 children with severe SCD (Hgb SS or Hgb
S- thal)
1o end-points: EFS at 1 yr after URD HCT (death, disease
recurrence or graft rejection)
2o 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
Eligibility criteria
3 – 19 yr old with Hgb SS or S-βo 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
Preparative regimen
Alemtuzumab 10/15/20 mg Days -21 to -19
Fludarabine 30 mg/m2 Days -8 to -4
Melphalan 140 mg/m2 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. 2012 Feb 16. [Epub ahead of print]
Reducing the Intensity of Conditioning (The SCURT Trial)
Prednisone – d 28
Calcineurin inhibitor – d 100
A F
M
T MTX
A-Alemtuzumab; F-Fludarabine; M-Melphalan; T-Transplant; MTX-Methotrexate
Shenoy et al: BMT 2005; 35:345; Kamani et al: BBMT. 2012 Feb 16. [Epub ahead of print]
-22 to -19 -8 to -3
GVHD prophylaxis
Regimen 1(BMT):
Tacrolimus/cyclosporine + MTX + Prednisone
Regimen 2 (UCBT):
Tacrolimus/cyclosporine + MMF
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
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 2011
16: unrelated marrow; accruing pts
SCURT Trial
Stopping rules
Day 100 mortality: > 15%
Day 100 graft rejection rate: > 20%
Day 100 gr III/IV aGVHD: > 15%
SCURT Trial – Cord blood cohort
8 children: 7.4-16.2 y (median 13.7 y); 6 females, 2 males
VOC -3; ACS – 3; Stroke – 2;
Median cell dose:
Pre-cryo TNC 6.4 x 107/kg (3.1 – 7.6)
Post-thaw CD34+: 1.5 x 105/kg (0.2 – 2.3)
CB Match status: 6/6: 1; 5/6: 7
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
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 107 TNC/kg had a better 2 yr DFS ( 45% vs 13%)
Ruggeri A: BBMT 2011; 17:1375
Limited institution trial (8 centers) of Campath/Flu/Mel regimen for SCD
Ages:2-18.6 y; follow-up:0.5-8.5 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
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
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)