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HALT-MS Phase II Clinical Trial of High Dose Immunosuppressive Therapy and AutoLogous Hematopoietic Stem Cell Transplantation for Active Relapsing-Remitting.

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Presentation on theme: "HALT-MS Phase II Clinical Trial of High Dose Immunosuppressive Therapy and AutoLogous Hematopoietic Stem Cell Transplantation for Active Relapsing-Remitting."— Presentation transcript:

1 HALT-MS Phase II Clinical Trial of High Dose Immunosuppressive Therapy and AutoLogous Hematopoietic Stem Cell Transplantation for Active Relapsing-Remitting MS George J. Hutton, MD

2 Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis Aggressive therapeutic approach performed in several hundred (mostly progressive) MS patients worldwide. Aggressive therapeutic approach performed in several hundred (mostly progressive) MS patients worldwide. Goal is to “reset” a patient’s immune system. 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 is the progenitor of RBC, platelets, neutrophils, T lymphocytes, B lymphocytes, monocytes, and macrophages.

3 HSC Transplantation in MS The problem: The problem: Currently available MS treatments are unable to offer a sustained remission in most MS patients. 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. The immune attack is long lasting and the treatments have failed to eliminate the “memory” of the myelin attack.

4 HSC Transplantation in MS Hypothesis: 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. 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.

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6 HSC Transplantation in MS Prior studies have demonstrated Prior studies have demonstrated Large decreases in number of enhancing lesions Large decreases in number of enhancing lesions Persistence of oligoclonal bands Persistence of oligoclonal bands Better outcomes for patients with baseline EDSS<6.0 Better outcomes for patients with baseline EDSS<6.0 Probability of confirmed progression-free survival at 2-3 years is 50-85% Probability of confirmed progression-free survival at 2-3 years is 50-85% Reviewed in: Mancardi, Saccardi, Lancet Neurology, 2008

7 Lessons Learned Mobilization with G-CSF alone may lead to MS exacerbation Mobilization with G-CSF alone may lead to MS exacerbation use Prednisone or CTX use Prednisone or CTX Engraftment syndrome is common and may lead to neurological worsening Engraftment syndrome is common and may lead to neurological worsening Prednisone post-HSCT Prednisone post-HSCT TBI-based regimens have unclear risk-benefit ratio TBI-based regimens have unclear risk-benefit ratio BEAM regimen BEAM regimen CD34 selection: Removing potentially autoreactive disease-causing lymphocytes from the infused graft may decrease risk of disease reactivation CD34 selection: Removing potentially autoreactive disease-causing lymphocytes from the infused graft may decrease risk of disease reactivation

8 HALT-MS: Objectives To determine the five-year durability of disease stabilization in MS subjects after HDIT and autologous HSCT 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 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 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

9 HALT-MS: Endpoints Primary endpoint is the time to treatment failure during the 5 years after transplant Primary endpoint is the time to treatment failure during the 5 years after transplant Death due to any cause Death due to any cause Change in pre-transplant EDSS of >0.5 as compared to baseline (confirmed at 3 months) 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) Presence of at least 2 independent new MRI lesions (GD+ and/or new T2-W) Clinical relapse (after day 56) Clinical relapse (after day 56)

10 Reconstitution/mechanistic studies Immunophenotyping of PBMC for major cell subsets Immunophenotyping of PBMC for major cell subsets T cell repertoire analysis T cell repertoire analysis Thymic function and output Thymic function and output Gene expression profiles in PBMC Gene expression profiles in PBMC Intracellular signaling in PBMC Intracellular signaling in PBMC EBV serology and viral load EBV serology and viral load T cell response to myelin antigens T cell response to myelin antigens B cell/antibody to myelin antigens B cell/antibody to myelin antigens CSF studies: OCB, mechanistic studies CSF studies: OCB, mechanistic studies

11 HALT-MS Eligibility Age Age RRMS or PRMS RRMS or PRMS Poor response to standard DMT with residual disability Poor response to standard DMT with residual disability MS duration < 15 years MS duration < 15 years EDSS (inclusive) EDSS (inclusive) 2 or more relapses within last 18 months with EDSS increase ≥0.5 sustained for ≥4 weeks 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 1 relapse within last 18 months with EDSS increase ≥1.5 for ≥4 weeks AND new Gd+/T2 MRI lesions separated from clinical relapse

12 BEAM: BCNU, etoposide, ARA-C (cytarabine), melphalan

13 Participants n=10(6 female, 4 male) Age32.5 years(median, range 26-46) Baseline EDSS4.5(median, range ) Disease duration3 years(median, range 1-11) Follow-up12.2 months(median, range 0-27) CD34+ cells/kg4.1x10 6 (median, purity 93.4%) Engraftment11 days post AHSCT (median, range 11-13) Subjects

14 Enhancing MRI Lesions Screening n=10 Baseline n=10 2 n=9 6 n=7 12 n=5 13 n=5 months AHSCT # gd+ MRI lesions

15 Relapses months prior AHSCT n=10 FU 0-12 n=9 FU 6-12 n= n=5 >24 months n=1 On DMT No relapses No DMT

16 median months12 months n=7n=5 improvement worsening EDSS Change from Baseline

17 Engraftment syndrome n=1 Pseudo-Relapsen=1 Pseudo-GVHDn=1 Gallbladder obstructionn=1 Rehospitalization for leukopenia/fatiguen=1 Rehospitalization for IV line infectionn=1 MRSA Infectionn=1 Late leukopenian=1 Post-HSCT Complications

18 Results Follow-up of up to 27 months (median 12 months) Follow-up of up to 27 months (median 12 months) No relapses since HSCT No relapses since HSCT 1 patient with worsened EDSS, others improved (up to 2.5 EDSS points) 1 patient with worsened EDSS, others improved (up to 2.5 EDSS points) No new Gd+ lesions No new Gd+ lesions No patients have required DMT No patients have required DMT Observed AEs were transient and mild. Observed AEs were transient and mild.

19 Conclusions HDIT and autologous HSCT can be performed safely in patients with treatment-refractory MS. HDIT and autologous HSCT can be performed safely in patients with treatment-refractory MS. Initial results are encouraging. Initial results are encouraging. HALT-MS is ongoing and open to enrollment. HALT-MS is ongoing and open to enrollment. Prospective trial with planned 5 year follow-up after last transplanted subject. Prospective trial with planned 5 year follow-up after last transplanted subject.

20 ClinicalTrials.gov Identifier: NCT ClinicalTrials.gov Identifier: NCT

21 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 Texas MD Anderson Cancer Center ●George J. Hutton, MD Baylor College of Medicine Ohio State University ● Michael K. Racke, MD ● Steven M. Devine, MD ●Linda Griffith, MD, PhD Medical Officer DAIT, NIAID, NIH ●Peter H. Sayre, MD, PhD Immune Tolerance Network San 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, PhD Imperial College, London, UK ●Douglas L. Arnold, MD, FRCP(C) NeuroRx Research, Montreal ●Roland Martin, MD University Medical Center Eppendorf Hamburg, Germany ●Harry McFarland, MD NINDS/NIH, Bethesda IND Sponsor: Division of Allergy, Immunology and Transplantation (DAIT) National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health (NIH)


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