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HALT-MSPhase II Clinical Trial of High Dose
Immunosuppressive Therapy and AutoLogous Hematopoietic Stem Cell Transplantation for
Active Relapsing-Remitting MS
George J. Hutton, MD
Autologous Hematopoietic Stem Cell Transplantation in Multiple
Sclerosis Aggressive therapeutic approach
performed in several hundred (mostly progressive) MS patients worldwide.
Goal is to “reset” a patient’s immune system.
HSC is the progenitor of RBC, platelets, neutrophils, T lymphocytes, B lymphocytes, monocytes, and macrophages.
HSC Transplantation in MS
The problem: Currently available MS treatments are
unable to offer a sustained remission in most MS patients.
The immune attack is long lasting and the treatments have failed to eliminate the “memory” of the myelin attack.
HSC Transplantation in MS
Hypothesis: Destroy or maximally suppress the
immune compartment with high dose chemotherapy and/or radiotherapy and then infuse hematopoietic stem cells to allow maturation of new lymphocyte progenitors in an environment with no or minimal memory T cell influence.
Muraro, J Exp Med, 2005.
HSC Transplantation in MS
Prior studies have demonstrated Large decreases in number of enhancing
lesions Persistence of oligoclonal bands Better outcomes for patients with
baseline EDSS<6.0 Probability of confirmed progression-free
survival at 2-3 years is 50-85%
Reviewed in: Mancardi, Saccardi, Lancet Neurology, 2008
Lessons Learned
Mobilization with G-CSF alone may lead to MS exacerbation use Prednisone or CTX
Engraftment syndrome is common and may lead to neurological worsening Prednisone post-HSCT
TBI-based regimens have unclear risk-benefit ratio BEAM regimen
CD34 selection: Removing potentially autoreactive disease-causing lymphocytes from the infused graft may decrease risk of disease reactivation
HALT-MS: Objectives
To determine the five-year durability of disease stabilization in MS subjects after HDIT and autologous HSCT
To evaluate the safety and efficacy of the procedure
To evaluate myelin content and axonal integrity using MRI approaches in MS subjects undergoing the procedure. Immune reconstitution and mechanisms of disease following autologous HCT for MS will also be explored through a number of specific endpoints
HALT-MS: Endpoints
Primary endpoint is the time to treatment failure during the 5 years after transplant Death due to any cause Change in pre-transplant EDSS of >0.5
as compared to baseline (confirmed at 3 months)
Presence of at least 2 independent new MRI lesions (GD+ and/or new T2-W)
Clinical relapse (after day 56)
Reconstitution/mechanistic studies
Immunophenotyping of PBMC for major cell subsets
T cell repertoire analysis Thymic function and output Gene expression profiles in PBMC Intracellular signaling in PBMC EBV serology and viral load T cell response to myelin antigens B cell/antibody to myelin antigens CSF studies: OCB, mechanistic studies
HALT-MS Eligibility
Age 18-60 RRMS or PRMS Poor response to standard DMT with residual
disability MS duration < 15 years EDSS 3.0-5.5 (inclusive) 2 or more relapses within last 18 months with
EDSS increase ≥0.5 sustained for ≥4 weeksOR
1 relapse within last 18 months with EDSS increase ≥1.5 for ≥4 weeks AND new Gd+/T2 MRI lesions separated from clinical relapse
BEAM: BCNU, etoposide, ARA-C (cytarabine), melphalan
Participants n=10 (6 female, 4 male)
Age 32.5 years (median, range 26-46)
Baseline EDSS 4.5 (median, range 3.0-5.0)
Disease duration 3 years (median, range 1-11)
Follow-up 12.2 months (median, range 0-27)
CD34+ cells/kg 4.1x106 (median, purity 93.4%)
Engraftment 11 days post AHSCT (median, range 11-13)
Subjects
Enhancing MRI Lesions
37 38
0 0 0 00
20
40
Screening
n=10
Baseline
n=10
2
n=9
6
n=7
12
n=5
13
n=5
monthsAH
SC
T
# g
d+
MR
I le
sions
Relapses
0
5
10
15
20
1-12 monthsprior AHSCT
n=10
FU 0-12
n=9
FU 6-12
n=7
12-24
n=5
>24 months
n=1
On DMT
No relapsesNo DMT
median 0 median 0
1
0
-1
-2
6 months 12 monthsn=7 n=5
imp
rovem
en
tw
ors
en
ing
-2.5 -2.5
1.0
EDSS Change from Baseline
Engraftment syndrome n=1
Pseudo-Relapse n=1
Pseudo-GVHD n=1
Gallbladder obstruction n=1
Rehospitalization for leukopenia/fatigue n=1
Rehospitalization for IV line infection n=1
MRSA Infection n=1
Late leukopenia n=1
Post-HSCT Complications
Results
Follow-up of up to 27 months (median 12 months) No relapses since HSCT 1 patient with worsened EDSS, others
improved (up to 2.5 EDSS points) No new Gd+ lesions No patients have required DMT Observed AEs were transient and mild.
Conclusions
HDIT and autologous HSCT can be performed safely in patients with treatment-refractory MS.
Initial results are encouraging. HALT-MS is ongoing and open to
enrollment. Prospective trial with planned 5 year
follow-up after last transplanted subject.
www.halt-ms.org www.halt-ms.com ClinicalTrials.gov Identifier:
NCT00288626
HALT-MS Team
University of Washington●Richard A. Nash, MD
Fred Hutchinson Cancer Research Center●James D. Bowen, MD
MS Center at Evergreen ●George H. Kraft, MD●Annette Wundes, MD
Houston, TX● Uday Popat, MD
University of TexasMD Anderson Cancer Center
●George J. Hutton, MDBaylor College of Medicine
Ohio State University● Michael K. Racke, MD● Steven M. Devine, MD
●Linda Griffith, MD, PhDMedical OfficerDAIT, NIAID, NIH
●Peter H. Sayre, MD, PhDImmune Tolerance NetworkSan Francisco
Consultants
University of Texas Southwestern●Elliott Frohman, MD, PhD●Olaf Stuve, MD, PhD
City of Hope●Harry Openshaw, MD●Stephen J. Forman, MD
●Paolo Muraro, MD, PhDImperial College, London, UK
●Douglas L. Arnold, MD, FRCP(C)NeuroRx Research, Montreal
●Roland Martin, MDUniversity Medical Center EppendorfHamburg, Germany
●Harry McFarland, MDNINDS/NIH, Bethesda
IND Sponsor: Division of Allergy, Immunology and Transplantation (DAIT) National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health (NIH)