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Research
Preliminary Communication
Association of Nonmyeloablative Hematopoietic Stem Cell
Transplantation With Neurological Disability in Patients With
Relapsing-Remitting Multiple Sclerosis
Richard K. Burt, MD; Roumen Balabanov, MD; Xiaoqiang Han, MD; Basil Sharrack, MD; Amy Morgan, NP; Kathleeen Quigley, RN;
Kim Yaung, RN; Irene B. Helenowski, PhD; Borko Jovanovic, PhD; Dzemila Spahovic, MD; Indira Arnautovic, MD; Daniel C. Lee, MD;
Brandon C. Benefield, MS; Stephen Futterer, MD; Maria Carolina Oliveira, MD; Joachim Burman, MD
Editorial page 251
IMPORTANCE No current therapy for relapsing-remitting multiple sclerosis (MS) results in
significant reversal of disability.
Author Audio Interview at
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OBJECTIVE To determine the association of nonmyeloablative hematopoietic stem cell
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transplantation with neurological disability and other clinical outcomes in patients with MS.
DESIGN, SETTING, AND PARTICIPANTS Case series of patients with relapsing-remitting MS
(n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85
women) treated at a single US institution between 2003 and 2014 and followed up for 5
years. Final follow-up was completed in June 2014.
INTERVENTIONS Treatment with cyclophosphamide and alemtuzumab (22 patients) or
cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated
peripheral blood stem cells.
MAIN OUTCOMES AND MEASURES Primary end point was reversal or progression of disability
measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater
(score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale
(NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite
(MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on
brain magnetic resonance imaging scan.
RESULTS Outcome analysis was available for 145 patients with a median follow-up of 2 years
and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant
median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR,
1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant
improvement in disability (decrease in EDSS score of ⱖ1.0) in 41 patients (50%; 95% CI, 39%
to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year
relapse-free survival was 80% and progression-free survival was 87%. The NRS scores
improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78)
at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The
median MSFC scores were 0.38 (IQR, −0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to
0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI,
43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years
posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a
pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45
cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128).
CONCLUSIONS AND RELEVANCE Among patients with relapsing-remitting MS,
nonmyeloablative hematopoietic stem cell transplantation was associated with improvement
in neurological disability and other clinical outcomes. These preliminary findings from this
uncontrolled study require confirmation in randomized trials.
JAMA. 2015;313(3):275-284. doi:10.1001/jama.2014.17986
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Richard K.
Burt, MD, Division of
Immunotherapy, Department of
Medicine, Northwestern University
Feinberg School of Medicine,
446 E Ontario, Chicago, IL 60611
(rburt@northwestern.edu).
(Reprinted) 275
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Research Preliminary Communication
Hematopoietic Stem Cell Transplantation for Multiple Sclerosis
M
ultiple sclerosis (MS) is thought to be an immunemediated disorder of the central nervous system that
in most patients begins as an inflammatory relapsingremitting disease.1 Despite standard therapies, the majority of
patients eventually enter a secondary-progressive phase for
which no therapy has demonstrated efficacy. Fifty percent of
patients are unable to continue employment by 10 years from
diagnosis, require assistance to ambulate by 15 years, or are unable to walk by 25 years.2 Despite an annual cost of approximately US $47 000 per patient3,4 to treat MS, no therapy approved by the US Food and Drug Administration (FDA) has been
demonstrated to significantly reverse neurological disability
or improve quality of life.5-11
Autologous hematopoietic stem cell transplantation
(HSCT) is a form of immune suppression but unlike standard
immune-based drugs, it is designed to reset rather than suppress the immune system.12-14 In a previous study, a nonmyeloablative regimen for patients with relapsing-remitting MS
was associated with improvement in neurological disability and
quality of life in 21 patients.15 This report includes all patients
from a single institution treated with a nonmyeloablative regimen with at least 6 months of follow-up, including the 21 patients previously reported.15
Methods
Patients
All patients who underwent HSCT for MS at Northwestern University (Chicago, Illinois) between July 2003 and February 2014
are included in this report. All patients signed informed consent and were treated and followed up identically per a study
protocol approved by the Northwestern University institutional review board. Similar institutional review board approval was obtained for the reporting of patients treated off
the study protocol. Race/ethnicity was recorded by the transplant team during the initial history and physical of each patient.
Patients who were treated according to the study protocol underwent transplant and met all the following criteria:
(1) had relapsing-remitting MS defined as acute relapses followed by partial or complete recovery and stable clinical
manifestations between relapses, (2) fulfilled revised
McDonald Diagnostic Criteria for MS,16 (3) treatment was
unsuccessful with at least 1 FDA-approved drug, (4) had an
Extended Disability Status Scale (EDSS) score from 2.0 to
6.0, (5) were aged 18 to 55 years, and (6) during the preceding year, had either at least 2 relapses treated with a corticosteroid or 1 relapse treated with a corticosteroid and additional gadolinium-enhanced lesions on magnetic resonance
imaging (MRI) scan at a separate time.
In addition, there were also patients treated off the study
protocol on a compassionate basis for secondary-progressive
MS, which was defined as a gradual progression of disability
with or without superimposed relapses, or received HSCT for
other reasons, including (1) brainstem, visual, or cognitive
impairment with high risk of further paraplegic, quadriplegic, visional, or cognitive impairment, (2) EDSS score greater
276
than 6.0, (3) treatment was unsuccessful with currently available FDA-approved drugs, (4) coexisting autoimmune or neurological disease, (5) allergy to gadolinium, (6) older than 55
years, and (7) tumefactive MS (tumor-like MRI appearance).
Most immune-modulation or suppression medications
were stopped at the time of mobilization (collection of stem
cells), except for natalizumab and fingolimod, which were discontinued 6 and 3 months, respectively, before transplant. After HSCT, patients did not receive immune-based therapies until clinical relapse or when new lesions were detected on an
MRI scan.
Stem Cell Collection and Transplant Regimen
Peripheral blood stem cells were collected 10 days after
patients received 2 g/m 2 of cyclophosphamide (administered intravenously) and 5 to 10 μg/kg of filgrastim (administered subcutaneously) daily beginning 5 days after receiving cyclophosphamide. The conditioning (immunoablative)
regimen consisted of 50 mg/kg/d of cyclophosphamide (administered intravenously) 5 to 2 days before stem cell infusion (day 0) plus either 20 mg of alemtuzumab given 2 days
before stem cell infusion (22 patients) or 0.5 mg/kg of thymoglobulin (administered intravenously) 5 days before stem
cell infusion, 1.0 mg/kg 4 days before, and 1.5 mg/kg on 3
days, 2 days, and 1 day before stem cell infusion (129
patients).
In addition, 1000 mg of methylprednisolone was infused
30 minutes prior to each antithymocyte globulin infusion. On
the day of stem cell infusion, oral prednisone was initiated with
a dose of 60 mg/d given for 3 days, 40 mg/d for 2 days, 20 mg/d
for 2 days, and 10 mg/d for 2 days. If fever developed, 250 mg
of methylprednisolone was administered intravenously.
Supportive Care Guidelines
Blood products were irradiated and leukocytes were depleted. Filgrastim (5-10 μg/kg/d) was started on day 5 and continued until engraftment. Hyperhydration (150 mL/h of normal saline), diuretics, and intravenous mesna were continued
until 24 hours after the last dose of cyclophosphamide. A Foley
catheter was placed in patients with a history of urinary retention. Intravenous cefepime or piperacillin-tazobactam was
started on the day of stem cell infusion and intravenous vancomycin was added for a febrile episode.
Oral daily acyclovir was started at hospital admission and
continued for 1 year, oral fluconazole was started 2 days after
HSCT and continued for 6 months, and oral trimethoprimsulfamethoxazole (3 times/wk) was started after platelet engraftment and continued for 6 months. Cytomegalovirus was
monitored for 90 days and treated preemptively by switching
from acyclovir to oral valganciclovir (900 mg twice/d) until a
negative result was reached on quantitative polymerase chain
reaction.
Study End Points
The primary end point was disability defined by the EDSS
score (range, 0-10 in 0.5 increments). A decrease of 1.0 or
greater is considered significant improvement and an
increase of 1.0 or greater is considered significant progres-
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Hematopoietic Stem Cell Transplantation for Multiple Sclerosis
sion (eTable in the Supplement).17-19 Other prespecified and
prospectively collected end points included safety, relapsefree survival (no acute relapses), progression-free survival,
disease activity–free survival (no acute relapses, no progression, and no gadolinium-enhanced or new T2 lesions on
MRI scan), Neurologic Rating Scale (NRS) score,20 Multiple
Sclerosis Functional Composite (MSFC) score, Short Form 36
(SF-36) quality-of-life score, new gadolinium-enhanced
lesions on MRI scan, and total T2-weighted lesion volume
on brain MRI scan. The NRS scores range from 0 to 10019; a
decrease of 10 or greater is considered significant progression and an increase of 10 or greater is considered significant improvement (eTable in the Supplement). 19-21 The
MSFC measures leg function with the Timed 25-Foot Walk,
arm coordination with the 9-Hole Peg Test, and cognitive
function with the Paced Auditory Serial Addition Test 3, and
reports an integrated score from individual z scores (eTable
in the Supplement).18 The SF-36 comprises 8 scales of functional health and well-being and perception of change in
health on a scale of 0 to 100 with scores averaged to give a
physical, mental, and total health score.
Magnetic resonance imaging was obtained on a Siemens
1.5-Tesla scanner, which was used both before and after
HSCT. Postcontrast T1-weighted imaging was delayed until 5
minutes after intravenous infusion of gadolinium (single
dose of 0.1 mmol/kg). Patient positioning inside the scanner
was standardized according to the University of Texas,
Houston, MRI Analysis Center imaging acquisition manual.
The T2 lesion volume, which correlates with clinical disease
severity, was determined using the semiautomated contouring technique with Image J software (National Institutes of
Health; http://rsbweb.nih.gov/ij/docs/faqs.html). The same
observer (X.H.) marked all lesions, and an experienced
reader (S.F.) blinded to MRI chronological order randomly
reviewed MRI scans for accuracy.
Outcome parameters (MRI scan results and scores on the
EDSS, NRS, MSFC, and SF-36) were measured at baseline, 6
months, 1 year, and then annually for 5 years. Thyroid function tests were performed if the patient was symptomatic. Between scheduled assessments, patients and their physicians
were instructed to contact the study team to arrange unscheduled visits if any new symptoms were present.
Preliminary Communication Research
Table 1. Baseline Demographics and Multiple Sclerosis (MS) Disease
Characteristics (N=145)a
No. (%) of
Patients
Sex
Men
Women
Race/ethnicity
White
Black
Asian
Hispanic
Type of MS
Relapsing-remitting
Secondary-progressive
Age group, y
18-25
26-35
36-45
46-60
Prior use of FDA-approved immune-modulation or
suppression therapy
Corticosteroids
Glatiramer acetate
Interferon beta-1a (Avenox)
Interferon beta-1b
Interferon beta-1a (Rebif)
Natalizumab
Fingolimod
Cyclophosphamide
Plasmapheresis
Angioplasty stenting for chronic cerebrospinal venous
insufficiency
Otherc
No. of different immune-modulation or suppression
treatments used before HSCT
2-3
4-5
≥6
No. of relapses during year before study
0
1
2
>2
Baseline disability scored
6
No. of gadolinium-enhanced lesions on baseline MRI scan
0
1-2
3-4
>4
Statistical Analysis
Two-tailed paired t tests (Microsoft Excel 2007) were used for
comparison of prespecified primary and secondary outcome
measures before and after HSCT. In post hoc analyses, a repeated-measures, mixed-effects model (SAS version 9.4; SAS
Institute Inc) was used to calculate the least-squares means and
SDs for change in EDSS score, adjusted for disease duration (>10
years or
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