High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS)

A 3-year interim report

Richard A. Nash, George J. Hutton, Michael K. Racke, Uday Popat, Steven M. Devine, Linda M. Griffith, Paolo A. Muraro, Harry Openshaw, Peter H. Sayre, Olaf Stüve, Douglas L. Arnold, Meagan E. Spychala, Kaitlyn C. McConville, Kristina M. Harris, Deborah Phippard, George E. Georges, Annette Wundes, George H. Kraft, James D. Bowen

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

IMPORTANCE Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS.OBJECTIVE To evaluate the safety, efficacy, and durability ofMS disease stabilization through 3 years after HDIT/HCT.DESIGN, SETTING, AND PARTICIPANTS Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled.INTERVENTIONS Autologous peripheral blood stem cell grafts were CD34<sup>+</sup> selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT.MAIN OUTCOMES AND MEASURES The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events.RESULTS Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4%(90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9%(90% CI, 73.7%-97.1%) and 86.3%(90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores.CONCLUSIONS AND RELEVANCE At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.

Original languageEnglish (US)
Pages (from-to)159-169
Number of pages11
JournalJAMA Neurology
Volume72
Issue number2
DOIs
StatePublished - Feb 1 2015

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Relapsing-Remitting Multiple Sclerosis
Cell Transplantation
Immunosuppressive Agents
Multiple Sclerosis
Transplants
Nervous System
Therapeutics
Disease-Free Survival
Poisons
Recurrence
Transplantation
Cells
Dose
Therapy
Carmustine
Melphalan
Antilymphocyte Serum
Survival
National Cancer Institute (U.S.)
Cytarabine

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology
  • Medicine(all)

Cite this

High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS) : A 3-year interim report. / Nash, Richard A.; Hutton, George J.; Racke, Michael K.; Popat, Uday; Devine, Steven M.; Griffith, Linda M.; Muraro, Paolo A.; Openshaw, Harry; Sayre, Peter H.; Stüve, Olaf; Arnold, Douglas L.; Spychala, Meagan E.; McConville, Kaitlyn C.; Harris, Kristina M.; Phippard, Deborah; Georges, George E.; Wundes, Annette; Kraft, George H.; Bowen, James D.

In: JAMA Neurology, Vol. 72, No. 2, 01.02.2015, p. 159-169.

Research output: Contribution to journalArticle

Nash, RA, Hutton, GJ, Racke, MK, Popat, U, Devine, SM, Griffith, LM, Muraro, PA, Openshaw, H, Sayre, PH, Stüve, O, Arnold, DL, Spychala, ME, McConville, KC, Harris, KM, Phippard, D, Georges, GE, Wundes, A, Kraft, GH & Bowen, JD 2015, 'High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): A 3-year interim report', JAMA Neurology, vol. 72, no. 2, pp. 159-169. https://doi.org/10.1001/jamaneurol.2014.3780
Nash, Richard A. ; Hutton, George J. ; Racke, Michael K. ; Popat, Uday ; Devine, Steven M. ; Griffith, Linda M. ; Muraro, Paolo A. ; Openshaw, Harry ; Sayre, Peter H. ; Stüve, Olaf ; Arnold, Douglas L. ; Spychala, Meagan E. ; McConville, Kaitlyn C. ; Harris, Kristina M. ; Phippard, Deborah ; Georges, George E. ; Wundes, Annette ; Kraft, George H. ; Bowen, James D. / High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS) : A 3-year interim report. In: JAMA Neurology. 2015 ; Vol. 72, No. 2. pp. 159-169.
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abstract = "IMPORTANCE Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS.OBJECTIVE To evaluate the safety, efficacy, and durability ofMS disease stabilization through 3 years after HDIT/HCT.DESIGN, SETTING, AND PARTICIPANTS Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled.INTERVENTIONS Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT.MAIN OUTCOMES AND MEASURES The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events.RESULTS Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4{\%}(90{\%} CI, 60.1{\%}-89.0{\%}) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9{\%}(90{\%} CI, 73.7{\%}-97.1{\%}) and 86.3{\%}(90{\%} CI, 68.1{\%}-94.5{\%}), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores.CONCLUSIONS AND RELEVANCE At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.",
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T1 - High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS)

T2 - A 3-year interim report

AU - Nash, Richard A.

AU - Hutton, George J.

AU - Racke, Michael K.

AU - Popat, Uday

AU - Devine, Steven M.

AU - Griffith, Linda M.

AU - Muraro, Paolo A.

AU - Openshaw, Harry

AU - Sayre, Peter H.

AU - Stüve, Olaf

AU - Arnold, Douglas L.

AU - Spychala, Meagan E.

AU - McConville, Kaitlyn C.

AU - Harris, Kristina M.

AU - Phippard, Deborah

AU - Georges, George E.

AU - Wundes, Annette

AU - Kraft, George H.

AU - Bowen, James D.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - IMPORTANCE Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS.OBJECTIVE To evaluate the safety, efficacy, and durability ofMS disease stabilization through 3 years after HDIT/HCT.DESIGN, SETTING, AND PARTICIPANTS Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled.INTERVENTIONS Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT.MAIN OUTCOMES AND MEASURES The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events.RESULTS Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4%(90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9%(90% CI, 73.7%-97.1%) and 86.3%(90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores.CONCLUSIONS AND RELEVANCE At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.

AB - IMPORTANCE Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS.OBJECTIVE To evaluate the safety, efficacy, and durability ofMS disease stabilization through 3 years after HDIT/HCT.DESIGN, SETTING, AND PARTICIPANTS Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled.INTERVENTIONS Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT.MAIN OUTCOMES AND MEASURES The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events.RESULTS Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4%(90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9%(90% CI, 73.7%-97.1%) and 86.3%(90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores.CONCLUSIONS AND RELEVANCE At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.

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