Hematopoietic Stem Cell Transplantation for Sickle Cell Disease

Disclosures: None

Shalini Shenoy, MD Professor of Pediatrics

Director, Stem Cell Transplant Program

Why discuss HSCT in a treatable disorder?

Quinn et al. Blood 2010 Platt et al. NEJM 1994 Fitzhugh et al. Am J Hematol 2010

2007

1975

Mean age at death: 33.4 for males and 36.9 for females (reviewed in 2013)

Lanzkron et al. Pub Health Rep April 2013

The reason ….

It is not fun to live with SCD • Stroke, cerebral vasculopathy – moyamoya disease,

high TCD, poor performance score (20% recur with overt stroke; 28% with silent strokes;

30% have a third stroke) • Recurrent acute chest syndrome • Chronic pain and narcotic dependence • Osteonecrosis; avascular necrosis; nephropathy;

retinopathy • Red cell allo-immunization • Prolonged hospitalization

Scothorn J et al. Pediatr 2002; Hulbert M et al. Blood 2011

Transplant is curative (CNS, lung, spleen, kidney)

Can we fulfill this wish list?

• Low TRM, low organ toxicity, High DFS • Low or NO GVHD (especially chronic) • Minimal toxicities and late side effects • Fertility preservation • Early immune reconstitution • Low graft rejection • QOL, QOL, QOL

Eapen et al Lancet 2007

Outcomes based on donor selection of unrelated product

6/6 matched UCB

5/6 matched UCB

Cord/BM Match Rates

Provided by NMDP, 2011. Used with permission.

*Less than 14% of SCD patients have matched sibling donors!

Ruggeri et al BBMT 2011 Locatelli et al Blood 2013

URD UCBT - Graft rejection and mortality are the problem

Variables we have to work with

Immunosuppresssion

MMUD-GVHD MUD-GVHD Sib-GVHD

Stem cell source

Intensity of Conditioning

Focus: Reducing toxicity of conditioning in UCBT

• Hypogonadism (60%), ovarian failure (71%), sterility

• Neurocognitive – 20% with memory problems, 32% with neuro events, 25% seizures, 10% cognitive impairment

• Height impaired in pubertal recipient

Myeloablative transplants for SCD

Walters BBMT 2010; Fitzhugh Blood 2008; Eggleston Br J Haematol 2007

“Perhaps less is better” – the case for reducing intensity of conditioning – alemtuzumab, fludarabine & melphalan

Rationale • Early host immune suppression (day -21) • Some continued T cell depletion due to long

half-life of alemtuzumab - ?GVHD benefit • Early immune reconstitution • Offset risk for PTLD (T and B cell depletion) • Early infection risk • Potentially lower incidence of irreversible

organ damage and late effects

Food for thought (for a prospective transplant consideration with RIC )

• The transplanter’s ability to accept a change of paradigm from myeloablative conditioning where most children will recover from early toxicities

• All RICs not equal; one failure is not applicable to all • Acceptance of “stable long-term mixed chimerism”

for non-malignant disorders • A change of definition of “acceptable” – in some

situations, graft rejection is perhaps more acceptable than major transplant related toxicities

• A second transplant is feasible following RIT

Based on multi-center experience with SCD HSCT

• # transplanted: 32 • Follow up: 3m - 8 yrs • Age: 2-18 yrs • TRM: 5% • Graft Rejection: 8% • Gr 2-4 aGVHD: 22% Gr 3-4 aGVHD: 7% • cGVHD: 15%

Cord arm closed on the BMT CTN SCURT trial for increased rejection

Kamani N et al. BBMT 2012

The SCURT Trial Reduced intensity trial of unrelated donor transplantation for

severe SCD

Bednarski J et al…Tandem 2013

Late Effects - > 2 years post

Madden L, et al……2013

Fertility

The Intensified RIT approach The URTH trial (Unrelated RIT for thalassemia)

Prednisone – d 28

Calcineurin inhibitor – d 100

A F

M

T MTX

TT HU

Extended to: -mismatched marrow -cord blood

Enhancing outcomes

• Size of cord product: > 4 x 10E7 TNC/Kg • Renal function, HYPERTENSION, fluid

balance • Seizure prophylaxis • Maintain platelet counts – risk of ICH • Weekly infection surveillance – CMV,

adeno, RSV, paraflu, flu - All • Bacterial and fungal infection prophylaxis • Anti-HLA antibodies; non-inherited maternal

ags; cord product CFUs

Early experience

• Enrolling on phase I design • Eligible: 5-6/6 matched cords with target

cell dose • 13 transplants • 1 rejection • 1 death – GVHD • All non-malignant disorders

Additional avenues of research

• Mesenchymal stem cell infusion with UCB • Ex-vivo expansion of cord products using

proliferative signaling molecules • Haplo-identical cell infusion with cord

blood transplant following RIC • “Reduced toxicity” transplants • Notch-mediated expansion of cord

progenitors for myeloid reconstitution

Cellular anti-viral therapy

• Dual antigen specific third party T cells – anti EBV, CMV, adenovirus ( over 2 weeks)

• No GVHD risk • Developed from peripheral blood

mononuclear cells

Hanley PJ et al. Cytotherapy 2011

Bolanos-Meade et al. Blood 2012

Haploidentical transplants for SCD

14 patients; graft rejection 43%; NO deaths

Cairo et al. NYMC: Haploidentical transplant for severe SCD using CD34 enriched familial product

Freed/Cairo et al. BMT 2012

Summary • Transplantation for SCD is evolving and

improving • New frontiers in conditioning, optimizing

stem cell source, supportive care, and GVHD therapy is helping the field advance

• Our definitions of success must now be based not just on OS/DFS but on short and long term toxicities and QOL

• The ONLY way of moving the field forward is developing, cooperating with and participating in formal trials designed to improve and track outcomes

Acknowledgement • M. Pulsipher – Utah • K. Schultz – Vancouver • D. Wall; K. Chan – San Antonio • M. Nieder; G.Hale – Tampa • M. Andreansky – Miami • S. Chaudhry – Chicago • M. Bhatia – New York • R. Adams – Phoenix • J. Brochstein – New York • N. Bunin – Philadelphia • L. Yu – New Orleans • A. Gilman – Charlotte • K. Kasow – Chapel Hill • D. Jacobsohn – Washington DC • P. Haut – Indianapolis • J. Dalal – Kansas City • J. Fort – Miami • E. Anderson – San Diego

• BMT Team – St. Louis Children’s

Hospital, Washington University

• DSMB for the various trials • BMT CTN, CIBMTR, SCD CRN,

PBMTC, TCRN

• Participating patients and their families