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February 09, 2021; 96 (6) Article

Autologous Hematopoietic Stem Cell Transplantation for Stiff-Person Spectrum Disorder

A Clinical Trial

Richard K. Burt, Roumen Balabanov, Xiaoqiang Han, Kathleen Quigley, Indira Arnautovic, Irene Helenowski, John Rose, Teepu Siddique
First published December 14, 2020, DOI: https://doi.org/10.1212/WNL.0000000000011338
Richard K. Burt
From the Division of Immunotherapy (R.K.B., X.H., K.Q., I.A.), Department of Medicine, Department of Neurology (R.B., T.S.), Department of Preventive Medicine (I.H.), and Department of Pathology and Cell and Developmental Biology (T.S.), Northwestern University, Chicago, IL; and Department of Neurology (J.R.), University of Utah, Salt Lake City.
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Roumen Balabanov
From the Division of Immunotherapy (R.K.B., X.H., K.Q., I.A.), Department of Medicine, Department of Neurology (R.B., T.S.), Department of Preventive Medicine (I.H.), and Department of Pathology and Cell and Developmental Biology (T.S.), Northwestern University, Chicago, IL; and Department of Neurology (J.R.), University of Utah, Salt Lake City.
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Xiaoqiang Han
From the Division of Immunotherapy (R.K.B., X.H., K.Q., I.A.), Department of Medicine, Department of Neurology (R.B., T.S.), Department of Preventive Medicine (I.H.), and Department of Pathology and Cell and Developmental Biology (T.S.), Northwestern University, Chicago, IL; and Department of Neurology (J.R.), University of Utah, Salt Lake City.
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Kathleen Quigley
From the Division of Immunotherapy (R.K.B., X.H., K.Q., I.A.), Department of Medicine, Department of Neurology (R.B., T.S.), Department of Preventive Medicine (I.H.), and Department of Pathology and Cell and Developmental Biology (T.S.), Northwestern University, Chicago, IL; and Department of Neurology (J.R.), University of Utah, Salt Lake City.
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Indira Arnautovic
From the Division of Immunotherapy (R.K.B., X.H., K.Q., I.A.), Department of Medicine, Department of Neurology (R.B., T.S.), Department of Preventive Medicine (I.H.), and Department of Pathology and Cell and Developmental Biology (T.S.), Northwestern University, Chicago, IL; and Department of Neurology (J.R.), University of Utah, Salt Lake City.
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Irene Helenowski
From the Division of Immunotherapy (R.K.B., X.H., K.Q., I.A.), Department of Medicine, Department of Neurology (R.B., T.S.), Department of Preventive Medicine (I.H.), and Department of Pathology and Cell and Developmental Biology (T.S.), Northwestern University, Chicago, IL; and Department of Neurology (J.R.), University of Utah, Salt Lake City.
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John Rose
From the Division of Immunotherapy (R.K.B., X.H., K.Q., I.A.), Department of Medicine, Department of Neurology (R.B., T.S.), Department of Preventive Medicine (I.H.), and Department of Pathology and Cell and Developmental Biology (T.S.), Northwestern University, Chicago, IL; and Department of Neurology (J.R.), University of Utah, Salt Lake City.
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Teepu Siddique
From the Division of Immunotherapy (R.K.B., X.H., K.Q., I.A.), Department of Medicine, Department of Neurology (R.B., T.S.), Department of Preventive Medicine (I.H.), and Department of Pathology and Cell and Developmental Biology (T.S.), Northwestern University, Chicago, IL; and Department of Neurology (J.R.), University of Utah, Salt Lake City.
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Autologous Hematopoietic Stem Cell Transplantation for Stiff-Person Spectrum Disorder
A Clinical Trial
Richard K. Burt, Roumen Balabanov, Xiaoqiang Han, Kathleen Quigley, Indira Arnautovic, Irene Helenowski, John Rose, Teepu Siddique
Neurology Feb 2021, 96 (6) e817-e830; DOI: 10.1212/WNL.0000000000011338

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Abstract

Objective To test the hypothesis that autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) is safe and shows efficacy in the treatment of stiff-person spectrum disorder (SPSD).

Methods Twenty-three participants were treated in a prospective open-label cohort study of safety and efficacy. After stem cell mobilization with cyclophosphamide (2 g/m2) and filgrastim (5–10 µg/kg/d), participants were treated with cyclophosphamide (200 mg/kg) divided as 50 mg/kg IV on day −5 to day −2; rabbit anti-thymocyte globulin (thymoglobulin) given intravenously at 0.5 mg/kg on day −5, 1 mg/kg on days −4 and −3, and 1.5 mg/kg on days −2, and −1 (total dose 5.5 mg/kg); and rituximab 500 mg IV on days −6 and +1. Unselected peripheral blood stem cells were infused on day 0. Safety was assessed by survival and National Cancer Institute common toxicity criteria for adverse events during HSCT. Outcome was assessed by ≥50% decrease or discontinuation of antispasmodic drugs and by quality of life instruments.

Results There was no treatment-related mortality. One participant died 1 year after transplantation of disease progression. Of the 74% of participants who responded, 47% have stayed in remission for a mean of 3.5 years; 26% did not respond. Compared to nonresponders, responders were more likely to have pretransplantation intermittent muscle spasms (16 of 17 vs 0 of 6), normal reflexes (12 of 17 vs 0 of 6), and positive CSF anti–glutamic acid decarboxylase serology (12 of 14 vs 2 of 6). Compared to responders, nonresponders were more likely to have lead pipe rigidity (4 of 6 vs 0 of 17) and EMG-documented simultaneous contraction of agonist/antagonist limb muscles (4 of 6 vs 1 of 17). Pre-HSCT use of prescription serotonin selective receptor inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) was more common in those who relapsed or never responded (9 of 12) compared to those responders who never relapsed (0 of 11).

Conclusion In this cohort, HSCT was safe, but the beneficial effect of HSCT was variable and confined predominately to participants with episodic spasms and normal tendon reflexes without simultaneous cocontraction of limb agonist/antagonist muscles who were not taking SSRI or SNRI antidepressants.

Classification of Evidence This study provides Class IV evidence that, for a subset of people with SPSD, autologous nonmyeloablative HSCT improves outcomes.

ClinicalTrials.gov Identifier NCT02282514.

Glossary

CI=
confidence interval;
CPAQ=
Chronic Pain Acceptance Questionnaire;
GAD=
glutamic acid decarboxylase;
HSC=
hematopoietic stem cell;
HSCT=
HSC transplantation;
IVIG=
IV immunoglobulin;
MS=
multiple sclerosis;
MSC=
mesenchymal stem cell;
NSC=
neural stem cell;
PERM=
progressive encephalomyelitis with rigidity and clonus;
SF-36=
Short Form 36;
SNRI=
serotonin and norepinephrine reuptake inhibitor;
SSRI=
serotonin selective receptor inhibitor;
SPS=
stiff-person syndrome;
SPSD=
stiff-person spectrum disorder

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 239

  • Class of Evidence: NPub.org/coe

  • CME Course: NPub.org/cmelist

  • Received February 20, 2020.
  • Accepted in final form September 24, 2020.
  • © 2020 American Academy of Neurology
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