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Just stumbled on this. Go figure, I missed my own study update. The results are pretty powerful so far, but there have been a few "failures" as defined by the study. And a number of 2-year updates (from those transplanted in the spring of 2010 like myself) were not included. Bottom line: 22 of 24 patients have had zero disease progression (and are on no medication), a success rate of over 90%. Let's hope that continues. - Dave
Treatment of Severe Relapsing-Remitting Multiple Sclerosis with High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation: Early Results of the HALT MS Clinical Trial (Immune Tolerance Network: ITN033AI)
Program: Oral and Poster Abstracts
Session: 731. Clinical Allogeneic and Autologous Transplantation - Results: Poster II
Sunday, December 11, 2011, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)
Richard A. Nash, MD1, George J Hutton, MD2*, Michael K Racke, MD3*, Uday R Popat, MD4, Steven M. Devine, MD5, Linda M. Griffith, MD, PhD6, Paolo A Muraro, MD7*, Harry Openshaw, MD8*, Peter H. Sayre, MD, PhD9, Olaf Stuve, MD10*, Douglas L Arnold, MD11*, Lisa Wruck, PhD12*, Annette Wundes, MD13*, George H Kraft, MD14* and James D Bowen, MD15*
1Clinical Research Division, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA
2Neurology, Baylor College of Medicine, Houston, TX
3Neurology, Ohio State University, Columbus, OH
4Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
5The Ohio State University Comprehensive Cancer Center, Columbus, OH
6Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infection Diseases, National Institutes of Health, Bethesda, MD
7Division of Neuroscience and Mental Health, Imperial College
8Department of Neurology, City of Hope
9Immune Tolerance Network
10Neurology, University of Texas Southwestern Medical School, Dallas
11Neurology, McGill University
12Rho Inc., Chapel Hill, NC
13Neurology, University of Washington
14Rehabilitation Medicine, Unniversity of Washington
15Neurology, Swedish Hospital Medical Center
Multiple sclerosis (MS) is an autoimmune disease which in most patients presents as defined relapses followed by remissions (relapsing-remitting (RR)). Over time the clinical course evolves to a gradual but irreversible loss of neurological function to which a neurodegenerative process likely contributes. Previous studies of high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT) were done in patients with advanced progressive MS and many patients continued to lose neurological function. To investigate the potential benefit of HDIT/HCT to halt the evolution of MS and prevent the development of the neurodegenerative processes, HDIT/HCT was studied in RRMS.
A phase II clinical trial of HDIT (BCNU, etoposide, ara-C and melphalan (BEAM) and antithymocyte globulin (ATG)) and autologous HCT was conducted in patients with highly active RRMS who had failed conventional therapy to determine if sustained remissions could be induced. Eligibility criteria required Expanded Disability Status Scale (EDSS) 3.0 (moderate disability, fully ambulatory) -5.5 (severe disability, ambulatory only 100 meters without aids) and ≥2 relapses on MS treatment with EDSS worsening over the previous 18 months. Hematopoietic progenitor cells were mobilized with G-CSF and a 10-day course of prednisone. The graft was CD34-selected (Baxter, Isolex). The primary endpoint was treatment-failure defined as a composite endpoint of 1) mortality 2) relapse 3) new lesions on MRI or 4) progression in disability ≥1.0 EDSS point. Adverse events (AE) were recorded according to NCI-CTCAE v3.0. Twenty-five patients at a median age of 38(27-53) years had autologous hematopoietic stem cells collected. There were 7 Grade 3 non-hematopoietic AEs during mobilization; mostly line-associated thromboses and infections. There was 1 Grade 4 AE with pretransplant withdrawal from study; a pulmonary embolus associated with heparin-induced thrombocytopenia and pre-existing arteriovenous malformation in the brain. During mobilization, a MS flare occurred in one patient who was non-compliant with the prednisone prophylaxis. Twenty-four patients proceeded to transplant. Median follow-up is 80(52-232) weeks. Patients were infused with a median of 4.58(2.95-9.73) x 106 CD34+ cells/kg. Neutrophil recovery occurred at a median of +11(9-15) days. In the 1st year after transplant, there were 17 Grade 3 and 4 Grade 4 non-hematopoietic, non-GI AEs. The Grade 4 AEs were suicide attempt (recorded as 2 separate events), hypokalemia and increase in ALT. At baseline (n=24), one (n=23) and two (n=8) years after HDIT/HCT, the mean EDSS (SD) was 4.42(+/-0.637), 3.78(+/-0.951) and 4.13(+/-0.916) respectively. There was only one case with gadolinium-enhancing lesions after 6 months (at Year 3) (Table 1). T2 lesion volume decreased and T1 lesion volume increased from baseline to Month 12. Despite the decrease in T2 lesion volume, there was early posttransplant loss in brain volume. Four patients failed by the composite endpoint (relapses at +22 and +96 weeks; new MRI brain lesions at +197 weeks and progression of disability/death at +82/138 weeks). Event-free survival at 1 and 2 years was 95.8(90% CI:73.9, 99.4)% and 76.7(90% CI:41.1, 92.4)% respectively. 22/24 patients were without progression of disability at last follow-up.
High-dose immunochemotherapy was well-tolerated with few serious early complications. Early control of highly active RRMS was obtained post transplant but has not been complete in all patients. Patient follow-up is planned for 5 years to determine durability of responses.
Table 1: Brain MRI: Changes in first year after transplant.
https://ash.confex.com/ash/2011/webp...aper38504.html
Treatment of Severe Relapsing-Remitting Multiple Sclerosis with High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation: Early Results of the HALT MS Clinical Trial (Immune Tolerance Network: ITN033AI)
Program: Oral and Poster Abstracts
Session: 731. Clinical Allogeneic and Autologous Transplantation - Results: Poster II
Sunday, December 11, 2011, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)
Richard A. Nash, MD1, George J Hutton, MD2*, Michael K Racke, MD3*, Uday R Popat, MD4, Steven M. Devine, MD5, Linda M. Griffith, MD, PhD6, Paolo A Muraro, MD7*, Harry Openshaw, MD8*, Peter H. Sayre, MD, PhD9, Olaf Stuve, MD10*, Douglas L Arnold, MD11*, Lisa Wruck, PhD12*, Annette Wundes, MD13*, George H Kraft, MD14* and James D Bowen, MD15*
1Clinical Research Division, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA
2Neurology, Baylor College of Medicine, Houston, TX
3Neurology, Ohio State University, Columbus, OH
4Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
5The Ohio State University Comprehensive Cancer Center, Columbus, OH
6Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infection Diseases, National Institutes of Health, Bethesda, MD
7Division of Neuroscience and Mental Health, Imperial College
8Department of Neurology, City of Hope
9Immune Tolerance Network
10Neurology, University of Texas Southwestern Medical School, Dallas
11Neurology, McGill University
12Rho Inc., Chapel Hill, NC
13Neurology, University of Washington
14Rehabilitation Medicine, Unniversity of Washington
15Neurology, Swedish Hospital Medical Center
Multiple sclerosis (MS) is an autoimmune disease which in most patients presents as defined relapses followed by remissions (relapsing-remitting (RR)). Over time the clinical course evolves to a gradual but irreversible loss of neurological function to which a neurodegenerative process likely contributes. Previous studies of high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT) were done in patients with advanced progressive MS and many patients continued to lose neurological function. To investigate the potential benefit of HDIT/HCT to halt the evolution of MS and prevent the development of the neurodegenerative processes, HDIT/HCT was studied in RRMS.
A phase II clinical trial of HDIT (BCNU, etoposide, ara-C and melphalan (BEAM) and antithymocyte globulin (ATG)) and autologous HCT was conducted in patients with highly active RRMS who had failed conventional therapy to determine if sustained remissions could be induced. Eligibility criteria required Expanded Disability Status Scale (EDSS) 3.0 (moderate disability, fully ambulatory) -5.5 (severe disability, ambulatory only 100 meters without aids) and ≥2 relapses on MS treatment with EDSS worsening over the previous 18 months. Hematopoietic progenitor cells were mobilized with G-CSF and a 10-day course of prednisone. The graft was CD34-selected (Baxter, Isolex). The primary endpoint was treatment-failure defined as a composite endpoint of 1) mortality 2) relapse 3) new lesions on MRI or 4) progression in disability ≥1.0 EDSS point. Adverse events (AE) were recorded according to NCI-CTCAE v3.0. Twenty-five patients at a median age of 38(27-53) years had autologous hematopoietic stem cells collected. There were 7 Grade 3 non-hematopoietic AEs during mobilization; mostly line-associated thromboses and infections. There was 1 Grade 4 AE with pretransplant withdrawal from study; a pulmonary embolus associated with heparin-induced thrombocytopenia and pre-existing arteriovenous malformation in the brain. During mobilization, a MS flare occurred in one patient who was non-compliant with the prednisone prophylaxis. Twenty-four patients proceeded to transplant. Median follow-up is 80(52-232) weeks. Patients were infused with a median of 4.58(2.95-9.73) x 106 CD34+ cells/kg. Neutrophil recovery occurred at a median of +11(9-15) days. In the 1st year after transplant, there were 17 Grade 3 and 4 Grade 4 non-hematopoietic, non-GI AEs. The Grade 4 AEs were suicide attempt (recorded as 2 separate events), hypokalemia and increase in ALT. At baseline (n=24), one (n=23) and two (n=8) years after HDIT/HCT, the mean EDSS (SD) was 4.42(+/-0.637), 3.78(+/-0.951) and 4.13(+/-0.916) respectively. There was only one case with gadolinium-enhancing lesions after 6 months (at Year 3) (Table 1). T2 lesion volume decreased and T1 lesion volume increased from baseline to Month 12. Despite the decrease in T2 lesion volume, there was early posttransplant loss in brain volume. Four patients failed by the composite endpoint (relapses at +22 and +96 weeks; new MRI brain lesions at +197 weeks and progression of disability/death at +82/138 weeks). Event-free survival at 1 and 2 years was 95.8(90% CI:73.9, 99.4)% and 76.7(90% CI:41.1, 92.4)% respectively. 22/24 patients were without progression of disability at last follow-up.
High-dose immunochemotherapy was well-tolerated with few serious early complications. Early control of highly active RRMS was obtained post transplant but has not been complete in all patients. Patient follow-up is planned for 5 years to determine durability of responses.
Table 1: Brain MRI: Changes in first year after transplant.
https://ash.confex.com/ash/2011/webp...aper38504.html
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