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

Unrelated CBT in hemoglobinopathies

Ruggeri A et al: Biol Blood Marrow Transplant 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)

Acknowledgements

Shalini Shenoy, MD

Mark Walters, MD

BMT-CTN 0601 study committee members

BMT Clinical Trials Network (NHLBI/NIH)

National Marrow Donor Program