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Autologous Hematopoietic Stem CellTransplantation in the Treatmentof Multiple Sclerosis

Carolina A. Rush,1 Harold L. Atkins,2 and Mark S. Freedman1

1Department of Medicine-Neurosciences, Ottawa Hospital Research Institute, University of Ottawa, Ottawa,Ontario K1H 8L6, Canada

2Department of Medicine-Hematology, Ottawa Hospital Research Institute, University of Ottawa, Ottawa,Ontario K1H 8L6, Canada

Correspondence: [email protected]

Multiple sclerosis (MS) is an autoimmune disorder that typically affects young peopleduring their most productive years, causing irreversible damage and accumulation of dis-ability. Treatments over time have had modest effects at completely controlling or suppress-ing disease activity, but are generally aimed at controlling early dominating inflammationthat, over time, accumulates damage and leads to progressive disability. Some unfortunatepatients are destined to deteriorate despite even newer and more effective agents becauseof the inability of these drugs to fully curb the inflammatory component of the disease.These patients require something more that might be capable of halting the disease process.Using high-intensity myeloablative chemotherapeutic agents, it is now possible tocompletely remove the peripheral immune system and replace it anew from autologousbone marrow–derived hematopoietic stem cells, purged of disease-causing MS cells. Thisprocedure, referred to as hematopoietic stem cell transplantation (HSCT), produces anew immune system that appears tolerant and no longer attacks the central nervoussystem (CNS).

Multiple sclerosis (MS) is the most commonneurological autoimmune condition cur-

rently treated with hematopoietic stem celltransplantation (HSCT). The first experiencetreating MS, as the primary indication for usingHSCT, dates back to the early 1990s (Fassas et al.1997), yet it continues to spark interest aroundthe world with increasingly more internationaltransplantation groups getting involved. The

body of evidence available on the effects ofHSCT in MS stems from different sources. Ex-perimental animal studies showed clinical re-mission after ablative treatment and stem celltransplants (van Gelder and van Bekkum 1993,1996), and anecdotal reports of patients withMSundergoing allogeneic HSCT for a concomitantmalignancy (McAllister et al. 1997; Mandalfinoet al. 2000; La Nasa et al. 2004) suggested the

Editors: Howard L. Weiner and Vijay K. KuchrooAdditional Perspectives on Multiple Sclerosis available at www.perspectivesinmedicine.org

Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reservedAdvanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a029082

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effectiveness of immunoablation in the controlof MS. Allogeneic stem cell transplantation ismore complex, requiring donor stem cells, and,thus, the procedure is fraught with higher ratesof morbidity and mortality, including graft–ver-sus–host disease (GVHD)—an event that doesnot occur when autologous stem cell sources areused—and risks of opportunistic infectionsfrom immunosuppressants used to preventGVHD. Thus, autologous bone marrow graftsare currently the preferred regimen for HSCTin MS for a number of reasons: there is no riskof GVHD and the risk of infection is lower asthere is no ongoing post-HSCT immune sup-pression. Long-term data from small trials andlarge international registries support the role forautologous HSCT in MS. The European BoneMarrow Transplant Registry (EBMTR) and theConsortium for International Bone MarrowTransplant Research (CIBMTR) have docu-mented more than 1200 patients undergoingtransplantation over the last 20 years.

HSCT IN MS: OLDER TRIALS AND MODERNEXPERIENCE

Initially, HSCT was chosen for patients withmore severe forms of MS, mainly including pa-tients who had long-standing disease and werealready severely disabled. In retrospect, it is hardto see where the benefit might lie, given that thetarget of such treatment is ongoing inflamma-tion, which was likely long over before thesepatients were treated. The studies were small-phase I/II single-center or multicenter studiesthat at least helped to establish the safety of thetechnique. The characteristics of patients treatedin those early trials were significantly differentthan those currently considered for HSCT. Themajority of the early patients had advanced dis-ease with high Expanded Disability Status Scale(EDSS) scores (sometimes as high as 9), andmost had primary or secondary progressive dis-ease with only a small fraction of relapsing re-mitting patients (Atkins 2010; Radaelli et al.2014; Currò and Mancardi 2016). Historically,at that point in time, there were a limited num-ber of disease-modifying drugs available or onlylow-level immunosuppression was available, so

patients were offered HSCT as a last-resort in-tervention or through compassionate access.

Contemporary studies of HSCT in MS havehelped to validate HSCT in MS as a legitimatetherapeutic option. Recently, multiple prospec-tive clinical trials and long-term follow-up stud-ies highlighting favorable outcomes of HSCTwith increasinglyacceptablemorbidityandmor-tality have been published. A meta-analysis per-formed by Sormani et al. (2017) summarized theevidence of HSCT inMS from studies publishedbetween 1995 and 2016. Data from 764 patientsreported theassociationof lowerdiseaseprogres-sion rate and treatment-relatedmortality (TRM)in patients with relapsing remitting MS (RRMS)versus secondary progressive MS (SPMS). Moredisabled patients had higher TRM. An interest-ing finding was the analysis of NEDA (no evi-dence of disease activity) reported in a group ofpatients. Despite different investigators usingvariable terms in the trials (event-free survival[EFS] or disease activity-free survival [DFS]),the premise is similar to NEDA. The proportionof patients who achieved NEDA at 5-year post-HSCTwas 67%, which is higher than in any clin-ical trial of disease-modifying treatment (DMT)for MS to date (Sormani et al. 2016).

Muraro et al. (2017) assessed long-term dataof HSCT recipients between 1995 and 2006 andrecently reported that transplant-related factorsare associated with better outcomes. Relapsingsubtypes of MS, younger age at time of trans-plant, lower pretransplant disability scores, andfailure of no more than two DMTs were linkedwith better prognosis and overall survival.

The Swedish cohort included very active pa-tients with a mean annualized rate of 4.8 ob-served in the RRMS subgroup in the pretrans-plant year and reported NEDA values of 78% at2 years and 68% at 5 years. The Halt MS trialdocumented a NEDA or EFS of 69.2% at 5 years.

Data from prospective single-arm trials aswell as the ASTIMS (Autologous HematopoieticStem Cell Transplantation trial in MS) supportthe positive results of HSCT outcomes despitemarked differences in inclusion criteria, studydesign, conditioning and mobilization regi-mens, and follow-up procedures (Table 1) (Lon-doño and Mora 2016).

C.A. Rush et al.

2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a029082

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Table 1. Contemporary trials of HSCT in multiple sclerosis (MS)

References

Mancardi et al.2015

Nash et al.2017

Burt et al.2015

Shevchenko et al.2015

Atkins et al.2016

Type of trial Phase II,multicenter/randomized(HSCT vs.Mx) (Italy–Spain)

Phase II,multicenter/prospective,open-label,single-arm(United States)

Open-label,single center(United States)

Phase II, singlecenter (RussianFederation)

Phase II, singlearm(Canada)

Number ofpatients

21 (9 HSCT arm,12 Mx arm)

24 145 95 24

MS type RRMS: 33%SPMS: 67%

RRMS: 100% RRMS: 81.4%SPMS: 18.6%

RRMS: 44%SPMS: 37%PPMS: 19%

RRMS: 50%SPMS: 50%

Mean age (range)in years

35.5 (19–46) 38 (27–53) 36 (18–60) 35 (18–55) 34 (24–45)

Median EDSS(range)

6 (5.5–6.5) 4.5 (3.0–5.5) 4.0 (3.0–5.5) 3.5 (1.5–8) 5.0 (3.0–6.0)

Median diseaseduration(range) inyears

10.2 (2–23) <15 years4.9 (0.6–12)

5 (0.75–22) 5 (0.5–24) 5.8 (1.3–11.2)

Inflammation inbaseline MRI

100% of patients 42% of patients 57.9% of patients 40% of patients 87.5% ofpatients

Conditioningregimen

Mitoxantroneversusintermediate-intensityBEAM+ ATG

Intermediate-intensityBEAM +ATG

Low-intensity Cywithalemtuzumabor ATG

Low-intensitymodifiedBEAM

High-intensity(busulphan,Cy, andATG)

Treatment-relatedmortality

0% 0% 0% 0% 4.2%

Outcomemeasures

Reduction of T2lesions of 79%and 100%resolution ofenhancinglesions inHSCT arm

Reduction inARR: 0.6 forMx and 0.19for HSCT—p:0.026, nodifference indisabilityprogression

EFS: 69.2%RFS: 86.9%MFS: 86.3%PFS: 91.3%

EFS/DFS: 68%diseaseactivity-freesurvivalRFS: 80%PFS: 87%

Reversal orprogression indisability(measured bychange inEDSS score of1.0 or greater)

EFS: 80% DFS/EFS:69.3%RFS: 100%MFS: 100%

Follow-up 4 years 5 years 5 years 5.1 years 6.7 yearsEvidence of

improvementNot assessed Yes Yes Yes Yes

Continued

Stem Cell Treatment of MS

Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a029082 3

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PATIENT SELECTION

Patient selection for higher efficacy MS treat-ments is crucial, but this becomes more criticalwhen considering the option of HSCT. Patientsdeemed to be good candidates for HSCT need toundergo a much stricter selection process. Someimportant patient characteristics that need to beaddressed are age, duration of disease, MS type,comorbidities, pregnancy desire, prior failure ofDMT, personal preference, risk tolerance, geo-graphical parameters, access to other treat-ments, and funding options, among others. Giv-en that the target of HSCT is the relentlessinflammatory disease that typically is unable tobe controlled using current DMT, eligible pa-tients should have readily demonstrable evi-dence of ongoing inflammation. These wouldinclude frequent clinical relapses and radiolog-

ical confirmation of new or enlarging T2 lesionsor enhancing lesions. Typical patients will stillhave some evidence of relapsing disease, al-though highly inflammatory early primary pro-gressive disease may be considered as well. Usu-ally longer disease duration is directly related toa higher chance of having accrued more disabil-ity as the natural history of the disease shiftsfrom a mainly inflammatory to a more degen-erative process; so, ideally, patients should beconsidered if they have only had no more than5–10 years of disease.

The choice of younger patients, earlier intheir course of disease with less disability alongwith actively inflammatory disease has resultedin better outcomes with HSCT than had beenseen in the earlier studies. In fact, there has evenbeen evidence of recovery, remarkable at times,with improvement of some acquired disabilities.

Table 1. Continued

References

Mancardi et al.2015

Nash et al.2017

Burt et al.2015

Shevchenko et al.2015

Atkins et al.2016

EDSSimprovement?

EDSS scoreimprovement(decrease bymore than or= 0.5) in62.5% ofpatients

64% of RRMShad decreasein EDSS scoreof more thanor = 1.0 points(4 years)—52% at 5 years(NS)

47% EDSSimprovementof at least 0.5points

70% ofpatients hadstable EDSSwith 35% ofpatientswithsustainedEDSSimprove-ment

Other scores/scalesimprovement?

Trend inMSFC (MSfunctionalcompositescore),improvementat 3 years butnot sustainedat 5 years

Nine-hole pegtest, timed25-ft walk, andMFSC showedimprovement

Quality of life(QoL) (SF-36)parametersshowedimprovement

Brain atrophysloweddown tonormalaging rate

Some trials report event-free survival (EFS), which is comparable but not identical to no evidence of disease activity (NEDA).Others use disease activity-free survival (DFS), which is a composite of relapse-free survival (RFS),magnetic resonance imaging(MRI), activity-free survival (MFS), and progression-free survival (PFS).

HSCT, Hematopoietic stem cell transplantation; Mx, mitoxantrone; RRMS, relapsing remitting MS; SPMS, secondaryprogressive MS; PPMS, primary progressive MS; Cy, cyclophosphamide; ARR, annualized relapse rate; EDSS, ExpandedDisability Status Scale; NS, not significant; SF-36, 36-item short form health survey.

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Despite this, it would seem rather futile to useHSCT in an older, more advanced patient withlittle to no demonstrable inflammation in thehope of reversing the disease process. This isbecause we believe that the recovery is causedby freeing up diseased tissue from the ongoinginflammation that may have been impeding anormal recovery process. Long-standing, fixed,noninflammatory lesions would not be expectedto recover with a potent anti-inflammatory ther-apy. We do, however, reserve the possibility thatthe cells used to reestablish a normal immunesystem might be capable of more in terms ofsome neuroregenerative effects, although thishas been difficult to establish in human studies.

It can be difficult to determine which pa-tients may be the best candidates for HSCT,but most would be considered to have someform of aggressive MS (AMS). These patientstypically have poor prognostic factors (Table2), and face unrelenting disease activity and pro-gression. Common features of this subgroup ofpatients are the early accrual of disability asso-

ciated with frequent and severe relapses (oftenwith partial recovery) and very active magneticresonance imaging (MRI) scans, both T2 andenhancing lesions in follow-up scans. Earliertrials included patients with high EDSS scores.Most likely, an EDSS of 6.0 or higher harbingersunfavorable outcomes. Hence, we propose a lessstringent definition for AMS suggesting anEDSS of 4.0 to try to capture “salvageable pa-tients” with repair and recovery potential (Rushet al. 2015).

The EBMTRworking group has suggested intheir guidelines to include (Saccardi et al. 2012):

• RRMS patients who show high clinical andMRI inflammatory activity with rapid deteri-oration despite use of one or more conven-tional treatment;

• SPMS patients or transitional MS with evi-dence of inflammatory activity manifestedby relapses and MRI lesion evolution on sub-sequent scans, and increased in disability inthe previous yearwith EDSS upper limit of 6.5;

Table 2. Prognostic factors for aggressive multiple sclerosis

Demographicfactors

MaleOlder age >40 yearsAfrican-AmericanAfrican–Latin-American

Relapsecharacteristics

Relapseseverity

Moderate/severe (≥1-point change on EDSS or ≥2-point change on anyindividual KFS, or ≥1-point change on any two KFS)Steroid requirementHospitalization

Type of relapse MultifocalPartial or incomplete recoveryAffecting motor cerebellar sphincteric or cognitive functions

Relapsefrequency

Frequent relapses in the first 2–5 yearsShort interattack interval

Disease course Rapid accrual of disability—EDSS of 3.0/4.0 within 5 years with superimposed relapsesMRI features At onset

High T2 lesion burdenMore than two gadolinium-enhancing lesionsPresence of T1 lesions (black holes)Early discernible atrophyInfratentorial vs. supratentorial lesions

Follow-up MRI while on treatmentPresence of new T2 lesionsMore than one gadolinium-enhancing lesion

Table from data in Rush et al. 2015; modified, with permission, from the authors.EDSS, Expanded Disability Status Scale; KFS, Kurtzke Functional System; MRI, magnetic resonance imaging.



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• Patients with malignant (Marburg) formsusually have severe disability scores becauseof the aggressive and rapid course. The upperlimit of 6.5 is not applicable and would censorsome eligible candidates.

Most patients in HSCT trials have failedmultiple agents, translating into longer diseaseduration and higher disability scores. Higherdisability scores before HSCT and longer timesat higher EDSS levels have been associated withpoorer outcomes and,more importantly, a high-er risk of morbidity and mortality, as shown insome of the earlier studies. This does not neces-sarily apply to previously described malignantMS patients who, despite rapidly reaching highdisability scores, can still show remarkable re-covery (Mancardi et al. 2005; Kimiskidis et al.2008; Fagius et al. 2009). There are no reports oftreatment-naïve patients undergoing HSCTwho are deemed AMS from the outset, warrant-ing some form of “induction” treatment. How-ever, we believe that HSCT plays a role in thosepatients, as we have experienced very encourag-ing outcomes in five patients with no previousMS-specific treatments

Previous issues with poor compliance toDMTs, symptomatic medications, and follow-up recommendations should raise early red flagsin the selection process. It is not infrequent thatwe see patients that, over time, have refused tostart DMT because of fear of minor inconve-nience or side effects or exaggerated concernsof potential toxicities and request HSCT as a“quick fix.” This view has been fueled by sensa-tionalism and, more importantly, untrue claimsof “stem cell therapies”without lymphocyte-de-pleting conditioning regimens in the last 5 years.

The changes in outcomes from earlier trialscompared with more recent studies have shownthat a better selection of patients can make a bigdifference, not only in terms of efficacy, but alsoby reducing morbidity and mortality. The ratio-nale for such selectivityofMSpatients comparedwith patients with hematological malignanciesderives from the perception that HSCT is anextreme treatment for a chronic, nonfatal condi-tion. There are still important ethical qualmswithin the medical community and skepticism

regarding HSCT in the treatment of MS as thisparadigm shift is still very provocative.

MS TREATMENT-SPECIFIC ISSUESTO CONSIDER BEFORE HSCT

Patients with MS who are selected for HSCTrequire close monitoring in the preparatoryphases of pre-HSCT to prevent systemic orMS-related issues (treatment and prevention ofrelapses and management and optimization offunctional deficits and comorbid conditions).We believe it is best to quiet down disease activ-ity to allow patients to recover before undergo-ing stem cell mobilization. The process of induc-tion with chemotherapeutic agents has beenused (mostly cyclophosphamide [Cy], mitoxan-trone [Mx], and cladribine [Cd]) and is variablein duration, ranging from 3 to 9 months.

The correct sequencing of therapies is theholy grail of current MS treatment. Previoususe of immunosuppressants and unknownlong-term safety data of newer agents expose pa-tients to novel side effects and increased long-term toxicity. Most patients would have failedmultiple agents, be they second- or third-lineagents or even chemotherapeutic agents usedoff-label. The compounded toxic effects andthe order in which different agents are used inMS will allow or preclude the use of newer andmore potent interventions, including HSCT.

Whereas the previous use of some agents(platform therapies, teriflunomide and dime-thylfumarate [DMF]) does not pose a clinicalchallenge to transition to HSCT, some willdefinitely be problematic and need extra sur-veillance. Interferons can cause mild bonemarrow suppression and should be stoppedabout a month before stem cell mobilization.Blood counts should return to normal beforestarting the mobilization chemotherapy. Thereis no data showing teriflunomide effects onbone marrow stores but it would be advisableto discontinue it a month before stem cell mo-bilization.

Mitoxantrone can potentially cause myelo-dysplasia or leukemia. We recommend that amarrowaspiration andbiopsy formorphologicaland cytogenetic examination be performed dur-

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ing thepretransplant evaluation for patientswhohave received previous anthracycline. Prolongedsuppression of B cells seen with rituximab andocrelizumab may prevent reconstitution of B-cell population after HSCT, magnifying the riskof severe infections because of the time it takesfor T cells to reconstitute (individual would beleft without T-cell and B-cell responses).

Fingolimod and natalizumab (Nz) with-drawal need to be anticipated and risk-mitiga-tion strategies put in place to avoid disease re-bound, like bridging therapy with of Cy, Mx, orparenteral Cd. The oral formulation of Cd willlikely be approved and available in most coun-tries in the imminent future.

It is advisable to rule out silent or incipientprogressive multifocal leukoencephalopathy(PML) induced by the prior agent, Nz, fingoli-mod, or DMF, by performing high-sensitivityJohn Cunningham (JC) virus polymerase chainreaction (PCR) tests on the cerebrospinal fluid(CSF) before starting chemotherapeutic agentsor embarking on HSCT.

TREATMENT SELECTION

The number of approved therapies for the treat-ment of MS continues to expand, promisinghigher efficacy and better clinical outcomes.The ultimate goal of these interventions shouldbe to approachNEDA; however, in clinical prac-tice, NEDA status is not sustained over time(Rotstein et al. 2015) and less than 50% attainit within 2 years (Sormani et al. 2016).

Despite the current use of potent agents,many patients still experience breakthrough ac-tivity, ultimately requiring the use of immuno-suppressants in a desperate bid to control thedisease. The use of chemotherapeutic agents inthe past has taught us a valuable lesson, tradingshort-lasting efficacy for lifelong cumulativetoxicity. People also resort to these treatmentsbecause of limited availability or reimbursementof DMT.

The advances in stem cell technology andexperience with HSCT allows for use of evenhigher intensity chemotherapy capable ofcompletely eliminating an incumbent hemato-poietic and immune system, but would also re-

sult in long-lasting or permanent severe pancy-topenia that would ultimately predispose tofatal complications. It is not possible to survivewithout a functioning hematopoietic/immunesystem, but the advent of hematopoietic stemcell transplantation that can fully regenerateboth systems makes the delivery of these high-dose chemotherapy regimens feasible. The re-sulting immune system seems more toleranttoward the central nervous system (CNS) (bynot attacking it anymore). Earlier trials ofHSCT in MS included multiple transplantationprotocols that were center specific and used var-iable mobilization and conditioning regimens.Outcome measures and long-term follow-upare only reported for a small proportion ofpatients. Additionally, the HSCT process wasled by hematologists, experts in transplantation,without input from neurologists. Throughout theyears, the care of these patients has evolved intoa collaborative effort, with scientists around theworld striving for evidence-based confirmationof the role and benefit of HSCT in MS treatment.

Another factor in selecting HSCT as a legit-imate intervention in MS patients is the favor-able outcome and decrease in TRM observedover time. Older trials reported HSCTmortalityas high as 20% (Openshaw et al. 2000a). How-ever, reassuringly, in the procedures performedafter 2001, there is a reported decrease inTRM risk of 1.3% (Mancardi and Saccardi2008). Newer trials of RRMS (HALT MS)documented no treatment-related death. Addi-tionally, trials using reduced intensity regimenshave shown lower mortality rates but also re-duced long-term success in preventing newdisease activity. Published data from the Swedishtrial and Northwestern University cohortshave also reported no HSCT-related casualties.It is tempting to suggest that high-intensity reg-imens would trade slightly higher toxicity forbetter long-term efficacy versus low-intensityprotocols.

HEMATOLOGICAL-SPECIFIC ISSUESIN HSCT FOR MS

The HSCT process inMS is similar to the HSCTprocedure used for malignant disorders. Fortu-



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nately, MS patients who undergo HSCT are usu-ally younger and have less comorbid conditionsthan patients who have malignant disorders re-ceiving transplantation, translating into a lesscomplicated posttransplant course.

Stem Cell Mobilization

Hematopoietic stem cells (HSCs) can be har-vested from bone marrow through multiple as-pirations from the iliac crests under general an-esthesia or by apheresis from peripheral bloodafter mobilization into the circulation. Hemato-poietic stem and progenitor cellsmobilized fromthe peripheral blood is themost common sourceused for patients undergoing HSCT for MS asthese collections yield higher numbers of pro-genitor cells and result in more rapid engraft-ment reducing the risk of neutropenic infec-tions. Stem cell mobilization is accomplishedthrough the administration of a cytokine, oftengranulocyte colony-stimulating factor (G-CSF)in combination with Cy or steroids. G-CSF canactivate the immune system and flares of MSactivity have been reported following its use(Openshaw et al. 2000b). The use of cyclo-phosphamide or steroids prevents potentialworsening of MS activity induced by the G-CSF. Additionally, the Cy used during stemcell mobilization resulting in more efficient mo-bilization will lead to a lower burden of lympho-cytes in the graft product and, to some degree,induce disease activity control. Following mobi-lization into the circulation, the peripheralblood hematopoietic cells are collected by leu-kapheresis. In our program, this is almost en-tirely performed using venipuncture. Occasion-al patients with poor venous access may requirea central venous catheter. The HSC graft can bemanipulated and/or cryopreserved and storeduntil the patient is ready for HSC infusion(Mancardi and Saccardi 2008).

Ex vivo graft manipulation can reduce theburden of immune cells, including autoreactivelymphocytes in the graft. Although technologyexists to selectively remove T lymphocyte pop-ulations, it is infrequently used. Rather, whenselective depletion of immune cells is per-formed, all immune cells are removed from the

graft product using positive selection of hema-topoietic stem and precursor cells bearing theselectively expressed CD34+ surface antigen. Se-lection is performed using clinical scale devicesbased on immunomagnetic separation in whichthe cells in the HSC graft are incubated with anantibody to CD34 covalently bound to a para-magnetic bead. The cell suspension is passedthrough a column in a magnetic field. TheCD34 expressing cells are retained and the othercells (including lymphocytes and monocytes)are washed away. The magnetic field is releasedallowing collection of purified CD34+ bearingHSC. This procedure is performed in accreditedstem cell laboratory facilities associated withstem cell transplant programs.

Conditioning Regimen

The ultimate objective of the conditioning reg-imen is to systematically deplete autoreactiveimmune cells from the bone marrow, peripheralblood, lymphoid tissue, and the CNS to stopongoing disease activity. A handful of differentchemotherapeutic conditioning regimens havebeen used to deplete immunologic memorydriving the MS disease activity. The regimenused tends to vary regionally.

Conditioning regimens can be categorizedas high- and low-intensity protocols based onthe degree of myelotoxicity and side effectsthey provoke. Greater immunodepletion resultsas the intensity of the conditioning regimen in-creases. Although there have not been directcomparisons of these differentHSCT condition-ing regimens on MS outcomes, looking acrossthe breadth of studies, it appears that higherintensity regimens may result in more durabledisease control but certainly result in greatermorbidity, including higher risk of infectionsand systemic toxicity, in particular affectingthe gastrointestinal tract. There is no consensusas to which regimen is superior because of thelack of randomized trials and the very heteroge-neous nature of cohort studies, including differ-ences in trial design, outcome measures, patientselection, and length of follow-up.

Historically, conditioning regimens includ-ed chemotherapy with total body irradiation

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(TBI). These very high-intensity regimens havefallen out of use because of less optimal out-comes, higher risk of progression, and less re-covery of disabilities after HSCT (Atkins 2010).

Somewhat less-intense regimens includecombination chemotherapy with BCNU, etopo-side, cytosine arabinoside (Ara-C) melphalan,and antithymocyte globulin (BEAM +ATG) orbusulphan (Bu) in combination with high dosesof Cy and ATG (BuCyATG). Busulphan-basedregimens may have an advantage over BEAMbecause of the better penetration of the blood–brain barrier, allowing for targeting of the CNSimmune system and better disease control.Whereas the initial transplants used very highdoses of busulphan, doses have been somewhatreduced and the morbidity of BuCyATG is sim-ilar to BEAM-ATG. Almost all regimens includeantithymocyte globulin as a way of achieving invivo depletion of T cells. Because of the longhalf-life of these antibodies, it also partiallywill eliminate lymphocytes contaminating theHSC graft product. BEAM has been one of themost frequently used protocols for HSCT inMS,although a more recent survey of HSCT activityshows increasing use of a low-intensity regime,Cy in combination rabbit antithymocyte globu-lin (Fig. 1).

Stem Cell Infusion, Engraftment,and Recovery

In the postconditioning phase, patients experi-ence the expected side effects of the chemother-apeutic agents, different degrees of cytopenia,febrile neutropenia with increased risk of infec-tions, variable multiple organ toxicity, and gas-trointestinal and hepatic complications. Com-prehensive supportive care is critical throughthis period. The stem cell infusion denotes day0 of the new immune system and is a relativelysimple process that is performed at the bedsidewith minimal toxicity. Engraftment ensuesthereafter between 10 days to 2 weeks and isthe process in which grafted cells settle in thebone marrow and start producing replacementblood cells. Full immune reconstitution and pa-tient systemic and neurological convalescencemay take 12 months or longer.

SPECIFIC ISSUES IN YOUNG PATIENTSUNDERGOING HSCT

There are many common but complex aspectsencountered by young patients post cancer andHSCT treatment. The AYA (adolescent andyoung adults) group is a vulnerable populationthat faces unique challenges when dealing withcancer treatment between the ages of 15 and 39.Unfortunately, there is a known gap of knowl-edge in the oncological literature addressingthose different domains (Cooke et al. 2011; Bel-lizzi et al. 2012; Kent et al. 2012; Ramphal et al.2016). Specifically, there is no data on these is-sues for MS patients owing to the small numberof MS patients treated with HSCT around theworld. Hopefully, awareness and more patient-centered research will guide and direct priori-tized strategies to manage this population.Most issues can be extrapolated from cancer reg-istries and guidelines of these topics for youngadults (Hayes-Lattin 2015). It is important toconsider them in MS patients after HSCT.

Financial Concerns

Financial issues are among the most pressingconcerns in the AYA population. They are intri-cately related to interrupted studies or disruptedcareers stemming from acquired disabilities,time to recover from treatment, and residualdeficits they may encounter.

Young adults aremore likely to be uninsuredor to have very limited health insurance becausethey may be in a transitional state between theirparents’ insurance and their own. Part-time em-ployment, sometimes the only realistic goal forpatients with disabilities, does not provide ap-propriate health insurance or suitable accom-modations.

These patients are also more likely to facefinancial burden from student loans, consumerdebt, and mortgage payments, and risk higherrates of bankruptcy and dependence on welfareassistance.

Missed education or training leads to lack ofemployment opportunities, lower income, andperpetuates precarious financial matters with adetrimental effect on stress and coping skills.



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Fertility

Fertility is an important aspect of someone’s life.Obviously, patients of reproductive age who areselected to undergo HSCT should have specificeducation sessions and informed consent aboutthe risk of infertility. Rates of azoospermia andovarian failure after high doses of conditioningregimens are as high as 90% and 99%, respec-tively. Regimens with Cy and ATGmay not nec-essarily cause permanent reproductive issues,but more intensive regimens are likely to resultin permanent infertility. Younger age may beassociated with lower risk of infertility.

Fortunately, assistive reproductive tech-niques (ARTs) have evolved dramatically overthe last decade. In males, the process is straight-forward and requires sperm cryopreservation.Rarely, invasive techniques of sperm retrievalare needed. In women in particular, the processis more complex because hormonal manipu-lation needs to be planned within a certaintime frame with the use of different protocolsof gonadotropin-releasing hormone (GnRH).An honest discussion regarding fertility preser-vation options, views on fertility-enhancingtechniques if needed, and alternate parenting(including adoption, surrogacy, and egg dona-tion) need to be had as part of the HSCT selec-tion and screening procedures. Extensive litera-ture from younger patients undergoing cancertreatment for other types of cancer confirms thisas an important issue for young patients.

Changes in Roles

A chronic illness like MS and especially severeforms of the disease receiving HSCT will pre-cipitate shifts in roles and responsibilities forthe patient and their family. This would createchanges in family dynamics and the inevitableoccurrence of conflict. Parenting and caring foryoung children could be stressful under normalcircumstances, but for patients going throughHSCT it is particularly challenging because ofthe possible need for relocation to a differentcity away from family, isolation during trans-plant, and ongoing symptoms of fatigue andmalaise in the recovery phase. Returning to for-

mer roles is also an ongoing concern and acause for anxiety and feeling of lack of indepen-dence for most patients. Going “back to nor-mal” is the ultimate goal but there is no settime frame for it, varying greatly from patientto patient. Role realignment needs to be dis-cussed early on and negotiated with an openand flexible mind to balance the demands ofcare with other roles such as parent, spouse,sibling, friend, or employee.

SPECIFIC ISSUES IN MS PATIENTSUNDERGOING HSCT

MS patients who undergo HSCT will encounterparticular concerns. One challenge that is spe-cific to MS patients is the functional deficits anddisability impairments that are inherent in MSand put them at higher risk of developing par-ticular issues during and after transplantation(Atkins and Freedman 2013).

Triggering of Pseudorelapses

Fever and infections can easily exacerbate symp-toms and trigger pseudorelapses. These usuallyare transient and typical of the fluctuating symp-tomatology that patients may have experiencedin the past from previous MS attacks and canhappen any time during the transplant process.They include worsening spasticity or weakness,increased sensory complaints, exacerbation ofneuropathic pain, recurrence of paroxysmalsymptoms like Lhermitte’s and Uhthoff’s phe-nomena, thoracicMS hug, and others. The treat-ment of these symptoms is supportive andshould focus on patient reassurance, hydration,analgesia, sleeping aids, and spiritual or psycho-logical support. Thorough neurological exami-nation and frequent assessment during HSCTand in the recovery phase are crucial to differ-entiate these manifestations of pseudoattacksfrom true MS relapses, because unnecessarytreatment with steroids may contribute to adeeper degree of immunosuppression, increas-ing the chance of infection and heightened pa-tient anxiety.



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Infections

MS patients are more predisposed to have uri-nary tract infections owing to the high preva-lence of neurogenic bladder symptoms and thefrequent use of in-dwelling catheters to mini-mize cyclophosphamide-related hemorrhagiccystitis. By the same token, the risk of developinghemorrhagic cystitis is higher in these patientsowing to altered bladder function. Viral infec-tion, in particular reactivation of certain herpesviruses, including varicella zoster virus, humanherpes virus, cytomegalovirus, and Epstein–Barr virus, is not uncommon and the latter hasalso been linked with some lymphoproliferativedisorders reported in patients treated with ATGor CD34+ grafts.

Secondary Autoimmune Disorders

Secondary autoimmune diseases (SADs) havebeen reported after HSCT in autoimmune dis-eases in∼9%of the studied population (Daikeleret al. 2011). Most were autoimmune thyroiditiswithmore severe disorders like autoimmune cy-topenias occurring less frequently. Burman et al.(2014) reported 8.3% of the Swedish patientsdeveloped SAD, whereas Atkins et al. (2016) de-scribed an incidence of 26%. Loh et al. (2007)described two cases of idiopathic thrombocyto-penic purpura among 41 MS patients (4.8%).Transplant protocols using alemtuzumab reporthigher autoimmunity than if ATG is used.

Worsening of Physical Deficits

MS patients who undergo HSCT are frequentlyindividuals who have had severe relapses withincomplete recovery and experience moderatedegrees of residual physical and mobility defi-cits. They are at higher risk of worsening disabil-ity because of significant deconditioning andmyopathic manifestations, chemotherapy-in-duced cachexia, and drug neurotoxicity. Somepatients who are moderately disabled may be-come further debilitated and require inpatientstay in rehabilitation units to recover the previ-ous baseline of functioning.

Experience from early trials when severelydisabled patients were transplanted attest to this

observation. Physical and occupational thera-pies need to be instituted in the screening phaseand maintained during the inpatient periodalong with dynamic reassessment throughoutthe recovery process.

Cognitve Issues and Fatigue

Fatigue is a very common manifestation in therecovery phase posttransplant and can take sev-eralmonths to improve. InMS patients in whomfatigue is a prevalent symptom, the effects can bemagnified and more disabling than physicalcomplaints. It is multifactorial and related tothe disease itself, the effects of the conditioningregimen, and other drugs used for symptomcontrol during the posttransplant recovery.

MS cognitive symptoms andmanifestations,premorbid to HSCT, will most likely worsen inthe posttransplant phase, gradually plateau, andthen in many circumstances show improve-ment. “Chemo brain” or “chemo fog” are oftenterms used to describe cancer treatment–relatedcognitive impairment. For most patients, its ef-fects are short-lived but for some can be perma-nent. It is very difficult to discern whether thecognitive deficit and complaints are either relat-ed toMS, the treatment, or both. Baseline neuro-cognitive assessment is crucial in MS patientsand will be invaluable in the long-term follow-up of transplanted individuals.

Sexual Dysfunction

Sexual dysfunction is common in MS patients,with prevalence as high as 90% (Kessler et al.2009) and is directly related to quality of life,depression, and relationships with partners (Fo-ley et al. 2013; Schairer et al. 2014). Most MSpatients undergoing HSCT are young (<45 yearsold) and experience longer life expectancy sur-vival than patients with malignant disorders,hence requiring special attention. Sexuality dif-ficulties inHSCT survivors are also frequent andsome investigators report that 50% of male and80% of female patients disclose sexual dysfunc-tion posttransplant. The etiology is multifacto-rial and is caused by hypogonadism secondaryto endocrinopathy, psychological factors related

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to depression, anxiety or self-esteem issues, orsituational associated with role changes and fi-nancial concerns. The presence of systemicsymptoms and medication side effects alsoplay an important role. In women, in particular,the advent of early menopause is the major con-tributor to sexual dysfunction as it triggers amultitude of physical and emotional symptoms.Prompt referral to a women’s health specialtyclinic is recommended within the first 9 monthspost-HSCT to address common symptoms ex-perienced by female patients tominimize fatigueand to improve quality of life, including sleep,mood, libido, and activity levels. Early hormonereplacement in early menopause is indicatedto prevent cardiovascular complications andosteoporosis.

Fertility Issues in MS

As MS affects patients at their most fertile age,and women twice as much as men, fertility-re-lated issues need to be appropriately addressed.The discussion should ideally take place whenyoung women are first diagnosed to estimatepregnancy desire and family planning timeframe. These patients can also face fertility dif-ficulties related to prior DMTs.

Different protocols of ART have been usedin patients with MS. GnRH agonists or antago-nists are used to down-regulate the hypothalam-ic–pituitary gland axis and to control luteinizinghormone (LH) surge and ovulation. These fre-quently need to be timed and synchronized overseveral menstrual cycles (Hellwig et al. 2017).However, in the context of HSCT in MS, manyof these patients do not have much time to con-template these options because of the aggressivenature of their disease. Additionally, there is ev-idence that both GnRH protocols cause exacer-bation of disease activity, both clinically and ra-diologically, triggering relapses and new lesions(Correale et al. 2012; Michel et al. 2012; Hellwigand Correale 2013).

Employment Issues and Vocational Training

Patients with severe MS have resigned them-selves to be unemployed or are afraid of taking

new challenges. Many are out of the workforcefor a long time or have decided against under-taking postsecondary education or skills train-ing because of MS symptoms.

Improvement in disability and quality-of-life scores seen in many transplanted patientshas been very reassuring. Atkins et al. (2016)reported that 37% of patients were able to returnto school or resume employment after HSCT.

Formal vocational counseling and rehabili-tation are extremely important and frequentlyneglected in this special population of patients.They should be proactively offered once patientshave recovered and stabilized both systemicallyand neurologically. School and work integrationassistance strategies are crucial and have shownto be empowering to patients after HSCT andcancer treatment and have given them a renewedsense of purpose.

CONCLUDING REMARKS

Development of a phase III, prospective con-trolled multicenter trial comparing autologousHSCT with conventional high-potency DMTwith planned long-term follow-up of patientsis needed to assess the ultimate efficacy and safe-ty of HSCT. The role of HSCT in changing thenatural history of MS is promising as observedin progression-free survival curves but system-atic and critical analysis is warranted. Further-more, it will hopefully address questions aboutrepair mechanisms and which patients mayhave the best potential for improvement.

The selection of centers with expertise inboth hematology and stem cell transplantationand MS “know-how” is critical, because thesepatients have particular characteristics that sep-arate them from the regular typical patients re-ceiving treatment for their MS. This cannot beemphasized enough in an era of increasing un-regulated centers promising stem cell treatmentsto treat multiple neurological and systemic dis-eases without the required infrastructure, exper-tise, and scientific support needed to performsuch a complex intervention. Patients are con-tinuously bombarded with offers of offshore lo-cations to receive HSCT and stem cell therapy,overestimating the benefits of the procedure and



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many times promising a guaranteed outcome,failing to disclose morbidity and mortality.

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published online April 2, 2018Cold Spring Harb Perspect Med Carolina A. Rush, Harold L. Atkins and Mark S. Freedman of Multiple SclerosisAutologous Hematopoietic Stem Cell Transplantation in the Treatment

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http://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see

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