Introduction
Hematopoietic stem cell transplantation has been used with increasing frequency over
the
last 16 years, albeit still experimentally. Data is available from the International
Bone Marrow Transplant Registry (IBMTR) totaling more than 300 transplant recipients
by
2008(1). In 2009, a Consensus
Meeting was held to review available evidence on the subject of autoimmune
diseases(2). The procedure has
improved and the incidence of complications and mortality decreased over time. There
are
still many points of discussion, some of which should be clarified by ongoing randomized
studies.
This consensus paper aims to gather data available in the international literature
and
to compare it to the Brazilian experience in order to establish evidence-based
recommendations for the application of hematopoietic stem cell transplantation (HSCT)
in
the treatments of systemic and multiple sclerosis in Brazil.
Systemic sclerosis
Systemic sclerosis is an autoimmune disease in which the skin and, in most cases,
internal organs are involved. The clinical evolution usually begins from vascular
hyperreactivity and endothelial changes associated with inflammatory phenomena that
result in progressive tissue damage, leading to fibrosis. The etiology is still unknown,
but it certainly comes from the interaction between genetic predisposition and
environmental stimuli that cause an immune imbalance and tissue lesions. Cardiopulmonary
involvement is common and affects up to 80% of patients(1). The response to conventional
immunosuppression is
usually poor and the mortality rate among patients with diffuse cutaneous and/or
visceral involvement ranges from 30 to 50% in 5 years(1,3). The most
frequent causes of death are cardiac involvement and, secondly, pulmonary involvement.
A
recently published meta-analysis showed that the mortality rate has not decreased
in
recent years despite the introduction of new therapeutic options(4).
Conventional treatments
Systemic sclerosis is a challenge to the available conventional therapies.
Corticosteroids and immunosuppressants commonly used and successful in the treatment
of rheumatic diseases have little influence on the course of systemic sclerosis. More
recently, antifibrotic drugs such as penicillamine, and endothelin receptor
antagonists, including bosentan, have also been prescribed but with limited
responses. Other drugs, such as mycophenolate mofetil, imatinib and dasatinib have
also been used, but with no conclusive results(5).
Randomized studies conducted in recent years have shown conflicting results. In 1996,
van der Hoogen et al. published a study comparing methotrexate with placebo in the
treatment of early stage systemic sclerosis(6). There was significant cutaneous improvement
in the group
treated with low dose methotrexate (15 mg/week), but the follow-up time was short
(between 24 and 48 weeks) and only 11/29 (38%) of the patients had the diffuse type
of disease. Besides, there were more patients with the limited disease in the placebo
group than in the group treated with methotrexate (12 versus six, respectively). A
later, double blind, randomized study, evaluated 71 patients with the early form of
systemic sclerosis, with a follow-up time of one year. In this study, unlike the
previous one, there were no differences between the groups, suggesting a lack of
efficacy of methotrexate to treat systemic sclerosis(7).
In 2002, an English study evaluated 14 patients with interstitial lung involvement
by
systemic sclerosis, who underwent monthly pulses of cyclophosphamide and
methylprednisolone(8).
High-resolution computed tomography (CT) scans and evaluations of the diffusion of
carbon monoxide (CO) showed improvement in pulmonary symptoms after six months of
pulses, a response that remained after six months of observation, once the pulses
were suspended. However, at a mean period of 26 months, 67% of patients again
presented progression of the pulmonary involvement. In 2006, a multicenter,
prospective, double-blind study, also from England, evaluated 45 patients with
pulmonary involvement, divided into two groups. The first group received low-dose
corticosteroids plus six monthly pulses of cyclophosphamide followed by oral
azathioprine for maintenance, and the second group received placebo. Patients were
followed for around 12 months, but there were no differences between
groups(9). In the same year,
a U.S. group evaluated 145 patients with pulmonary involvement in a randomized,
double-blind and prospective study. There was a slight, but significant improvement
of pulmonary function, skin thickening and increase in quality of life of patients
treated with oral cyclophosphamide for one year(10,11).
In recent years, tyrosine kinase inhibitors, particularly imatinib mesylate, have
been experimentally applied in systemic sclerosis, but with no conclusive results.
A
North American phase I/IIA study showed only a tendency of the drug to promote
increased forced vital capacity of the lung and improvements in the Rodnan
score(12). The results were
hampered by poor compliance of the patients to the high doses of medication
prescribed. Similarly, a study published in 2011, with a small number of patients,
was interrupted early due to poor tolerance to the drug. Efficacy of treatment was
not, therefore, observed(13). More
recently, a Chinese case series described cutaneous improvement and stabilization
of
pulmonary involvement in patients treated with low doses of imatinib(14). Furthermore,
a review gathered data
from 108 patients previously reported in small clinical studies, concluding that,
in
selected cases, imatinib mesylate may be beneficial(15). Further investigations are
needed.
Although not recognized by the European Society of Rheumatology (EULAR) as a
therapeutic approach to systemic sclerosis, extracorporeal photopheresis (ECP) has
been applied in some centers as a treatment for the cutaneous forms of systemic
sclerosis(6,9,16-19). Case reports show stabilization or
even improvement in patients with milder and initial forms of the skin disease, but
a
randomized trial comparing ECP sessions with placebo failed to show a significant
difference between groups(20).
However, as there was a trend to better results in the ECP group, new studies with
a
larger number of patients investigating this will probably be started soon.
Additionally, none of the studies demonstrated improvement or stabilization of the
visceral involvement of the disease.
Finally, biologic products have been applied to the treatment of systemic sclerosis.
Studies with infliximab and etanercept, both inhibitors of the tumor necrosis factor
(TNF) pathway, suggest improvement of joint inflammation and quality of life. Other
agents, such as rituximab, antithymocyte globulin, and others, failed to demonstrate
significant results(21).
Autologous hematopoietic stem cell transplantation: international experience
Much of the information on HSCT for systemic sclerosis comes from multicenter,
non-randomized, North American and European studies, which have been published since
2001. The European record of transplants reported in 2004 experience with 57 patients
receiving HSCT(21). Of these, 50 had
the diffuse cutaneous form of the disease and 40 had some type of pulmonary involvement,
such as interstitial lung disease or pulmonary hypertension. There was a wide variety
of
schemes used, but the predominant conditioning regimen was high-dose cyclophosphamide
with or without antithymocyte globulin (ATG). Approximately 60 to 70% of the patients
had a significant and lasting improvement of the skin, and the pulmonary involvement
stabilized. Five (8.6%) patients died from causes associated with transplantation
and
eight (14%) due to disease progression in an average follow up of 22 months. About
35%
of patients showed disease progression on average 10 months post-transplant. When
the
data were compared with those of the first publication of the same group, in 2001,
improved survival and decreased transplant-related mortality (TRM) were seen(21,22).
In 2007 a US multicenter group, led by Dr. Nash, published a series of 34 cases of
patients with diffuse cutaneous involvement, who underwent conditioning with total
body
irradiation (TBI), cyclophosphamide and ATG(17). This myeloablative regimen has brought
some criticism from
other transplant groups, who advocate less toxic regimens(23). Significant skin improvement
and stabilization of
pulmonary, kidney and heart function were observed. Unprecedentedly in this study,
the
improvement of skin involvement was confirmed by comparative skin biopsies performed
before and six months after transplantation. There were 12 deaths during the study,
eight related to transplantation and four due to disease progression. The
progression-free survival and overall survival were estimated at 64%.
The transplant center at Northwestern University, in Chicago, presented a small case
series published in 2007(24). Their
results are of great relevance due to the experience of Dr. Burt with HSCT for
autoimmune diseases, especially for the low rate of deaths related to the procedure.
Ten
cases with the diffuse type of the disease were described, impairment of at least
one
organ (lungs, heart or gastrointestinal tract). The patients underwent non-myeloablative
conditioning with cyclophosphamide (120 mg/kg) and rabbit ATG (7.5 mg/kg) followed
by
the infusion of unselected in vitro autologous cells. All patients had
gastrointestinal involvement and interstitial lung disease, but none had pulmonary
hypertension or significant renal changes. All patients had initial skin improvement
but
two had progression of the disease after transplantation. Moreover, all patients had
their lung, heart and kidney function stabilized. There was only one death, unrelated
to
the transplant. Overall survival was 90% and progression-free survival was 70%.
The longest follow-up period in studies was reported in 2008 by the consortium of
one
French and two Dutch centers(25). In
that study, 26 patients underwent autologous transplantation, all conditioned with
200
mg/kg of cyclophosphamide and rescued with cells previously selected for
CD34+ concentration. Twelve patients had diffuse cutaneous involvement and
14 visceral involvement, particularly of the lungs. In an average follow up of 5.3
years, 81% of patients showed clinical improvement with transplantation. There was
also
significant improvement of skin condition in 94% of patients and stabilization of
pulmonary, renal and cardiac functions. The estimated overall survival (calculated
by
the Kaplan-Meier method) was 96.2% at five years and 86.8% in seven years. Six (28%)
patients had disease reactivation after transplantation, requiring additional
immunosuppressive treatment. Of these, only one developed disease progression.
The recent publication from a German group brought the results of 26 patients submitted
to autologous HSCT, who had been conditioned with cyclophosphamide and ATG and received
infusions of selected CD34+ cells(26). A significant improvement in skin and lung
function was seen in
78.3% of patients during six months of follow up. Three patients died between
mobilization and conditioning, two due to progression to severe disease and one for
treatment-related toxicity. During the 4.4 years of follow-up, seven patients relapsed.
The progression-free survival was 74%. Four patients died during follow-up with the
most
frequent causes being cardiac and pulmonary complications of systemic sclerosis.
Although autologous HSCT has consolidated as an alternative therapy for the treatment
of
systemic sclerosis, high rates of disease progression stimulate the search for more
aggressive treatment regimens. In Seattle, two patients with severe lung disease
received myeloablative allogeneic HSCT. Both presented clinical responses, but one
of
them evolved with fatal sepsis due to Pseudomonas, 18 months after
transplantation(27). In Chicago,
one patient received allogeneic non-myeloablative HSCT with a progressive improvement
of
skin disease, complete donor chimerism and without graft versus host disease (GVHD)
or
infectious complications(28). The same
occurred in Houston, Texas(27). In
Japan, the case of a female patient with interstitial lung disease who underwent
non-myeloablative allogeneic transplantation, together with TBI and fludarabine, was
recently reported. One year after transplantation, she developed membranous
glomerulonephritis due to GVHD which remitted with corticosteroids. The skin score
improved dramatically and lung function remained stable for four years after the
procedure(29). Overall,
individual reports of allogeneic transplants have described encouraging results, but
they are still insufficient to prove safety and superiority to autologous
transplants.
Three randomized studies were designed, with similar inclusion criteria and control
groups treated with cyclophosphamide to comparatively assess the effects of autologous
transplantation for systemic sclerosis. The ASTIS (European Multicenter Autologous
Stem
Cell Transplantation International Scleroderma) study(30), with a non-myeloablative
conditioning regimen
(cyclophosphamide and rabbit ATG), selected CD34+ cells positively, while the
US study (ASSIST)(28) infused not
selected cells. In the third research, the multicenter North American Scleroderma:
Cyclophosphamide or Transplantation (SCOT) study, cyclophosphamide pulses were compared
to myeloablative autologous transplantation performed with TBI plus 120 mg/kg of
cyclophosphamide and horse ATG(3).
The ASSIST study was the first to publish results. Held at Northwestern University,
Chicago, this phase II study compared patients receiving cyclophosphamide (1
g/m2 intravenous monthly for six months) with transplant performed with
cyclophosphamide (200 mg/kg) and rabbit ATG (6.5 mg/kg) without selection of the infused
CD34+ cells. From 2006 to 2009, 19 patients were screened, and of these,
ten were randomized to undergo transplant. All ten patients had improved Rodnan scores
and forced vital capacity scores within 12 months of follow up. Of the nine patients
receiving monthly cyclophosphamide, eight evolved with disease progression, and seven
were transplanted. Improvements in Rodnan score and forced vital capacity persisted
in a
two-year post-transplant follow-up of 11 patients(31).
For the ASTIS study, patient recruitment was closed in 2009 and the results of the
156
patients included will be released in the coming months. These studies bring answers
regarding the real efficacy and safety of autologous HSCT in the treatment of systemic
sclerosis.
Experience with HSCT for systemic sclerosis since 1996, when it was first used, has
shown some difficulties in the management of the disease during the procedure. Among
autoimmune diseases, systemic sclerosis has the highest rates of TRM most likely due
to
visceral involvement and the poor clinical condition of these patients, including
malnutrition, skin ulcers and prior chronic use of immunosuppressive drugs.
Cardiopulmonary involvement, which is often subclinical and not evidenced by
echocardiography, is worrisome, because it contributes to the poor outcome of
transplantation. Currently, there is great concern in selecting appropriate patients
to
be transplanted, and detecting subtle cardiac dysfunction, which may worsen during
and
after the procedure.
Non-myeloablative conditioning regimens show remission rates similar to myeloablative
regimens, but with lower TRM. In the multicenter, North American study, all patients
received myeloablative conditioning with TBI and horse ATG(17). This regimen was criticized
by Dr. Burt, who, in his
experience, considered the non-myeloablative regimen equally effective and less toxic,
taking into account the cardiac lability of these patients(23). In the European multicenter
group study, there was
greater variation between conditioning regimens, but among the 57 patients included
in
the study, at least 47 were conditioned with high-dose cyclophosphamide
(non-myeloablative), with or without ATG. The three studies showed similar results
as to
the control of the disease, but the study with the myeloablative regimen showed a
TRM of
23.4%, while with the non-myeloablative regimens the TRM was 8.6% (European Group),
and
zero (Chicago Group).
Among myeloablative conditioning regimens, HSCT for autoimmune diseases mostly employs
high-dose cyclophosphamide. The vast experience with the drug has overcome the learning
curve, which contributes to the reduction of complications related to the transplant.
Cyclophosphamide, however, is known to be toxic for the heart and it can generate
dose-dependent myocardial hemorrhage and edema which manifest by acute, severe,
potentially fatal heart failure(16).
Patients with cardiac involvement should therefore be assessed individually for drug
substitution or suspension of transplantation. Melphalan and fludarabine-containing
regimens may also be associated with cardiac toxicity, although there are no
descriptions of such toxic events in transplantation for autoimmune diseases(32).
Komatsuda et al. described HSCT
applied to a patient with cardiac involvement using thiotepa and cyclophosphamide
in
small doses (100 mg/kg) as a conditioning regimen. There was no toxicity during
transplantation and the patient was in disease remission(33).
In systemic sclerosis, there may be involvement of the electrical impulse conduction
system of cardiac contractility, besides pulmonary hypertension and, less commonly,
coronary disease(16,34). Conventional cardiac tests used in the pre-transplant
evaluation, such as an electrocardiogram or echocardiogram may fail to detect myocardial
involvement, especially diastolic dysfunction. Recently, some publications have
addressed the issue by proposing algorithms for pre-transplant evaluation in order
to
detect patients at high risk(16,35). In 2007 Miniati et al. proposed a
sequence of steps to be followed in the investigation of cardiac dysfunction in patients
with systemic sclerosis(16). The first
step would be a careful clinical cardiac evaluation, followed by electrocardiography
(ECG) and chest radiography. Then, echocardiogram, serum atrial natriuretic peptide
dosage and the troponin curve would be used to assess myocardial involvement and Holter
monitoring to evaluate conduction disturbances. In case of abnormalities found in
the
previous steps, stress ventriculography and even cardiac catheterization should follow,
the latter if ischemic areas are detected. Burt et al. also suggest detailed cardiac
evaluations, including invasive and costly tests, such as right heart catheterization
and magnetic resonance imaging (MRI)(36).
Many centers select the cells infused into the patient by removing T cells and
concentrating CD34+ cells. Not all researchers, however, agree with this
procedure(37,38). In addition to increasing the cost of transplant, the
selection reduces the number of stem cells available for infusion and predisposes
the
material to potential contamination by handling(18,39). The benefits,
moreover, are questionable. Snowden et al. found that patients with rheumatoid arthritis
undergoing transplant with or without T-cell depletion had the same remission
rate(37,38). Other centers, including Chicago, do not use the
depletion of T cells in their most recent protocols(5,24). This issue is not yet
clarified and a randomized study, selecting CD34+ or not, is being planned in
Europe.
HSCT for systemic sclerosis has shown great impact on the skin of patients with
significant reduction of skin fibrosis, which is associated with recovery of joint
range
of motion, decreased incidence of extremity ulcers and improvement in quality of
life(17,21,24,25). Additionally, patients with diffuse
skin disease, even if isolated, without visceral involvement, have poor long-term
survival, thus justifying the risks of transplantation(40).
Deficiencies in the perfusion of extremities and digital ulcers are frequent and
debilitating manifestations in patients with systemic sclerosis. Miniati et al. describe
recovery of impaired nail bed capillaries, showing angiogenesis and revascularization
of
ischemic areas in six patients after transplant(41). The angiogenic effect of stem
cells was also demonstrated by
Nevskaya et al. in 2009, in a study of local injections of cells from marrow or
peripheral blood in the palms and calves of patients with severe impairment of
circulation and ulcers of the extremities(42). The patients had significant improvement
in irrigation of treated
limbs and healing of much of the ischemic ulcers.
Autologous hematopoietic stem cell transplantation: national experience
In Brazil, the first autologous HSCT for systemic sclerosis was performed in 1999
at the
Pontifícia Universidade Católica do Rio Grande do Sul (PUC-RS) in Porto
Alegre, in a patient with cutaneous, pulmonary and digestive tract involvement, who
received low dose conditioning (1.5 g/m2 of cyclophosphamide and 105
mg/m2 of fludarabine) followed by infusion of 2 x 106 of
autologous hematopoietic stem cells (HSC) per kg. There was a transient improvement
of
the intestinal problem, but three months after transplantation, he presented a
hypertensive crisis and intestinal relapse, when once more the immunosuppressive regimen
was administered (three and five months post-transplant). However, one year after
transplantation, there was a bowel obstruction, probably due to recurrence of the
underlying disease, aspiration pneumonia and death(43).
In an International Workshop held in Ribeirão Preto in October 2000, attended by
transplant specialists from Europe, the United States and the main groups in Brazil,
together with specialists in autoimmune diseases, it was decided to start a nationwide
cooperative pilot project (phases I/II) of HSCT for autoimmune diseases coordinated
by
the Center for Cellular Therapy, Blood Center of Ribeirão Preto and the Bone
Marrow Transplant (BMT) Unit of the Hospital das Clínicas, FMRPUSP. The
transplants were started in June 2001, primarily in severe forms of systemic lupus
erythematosus (SLE), systemic sclerosis and multiple sclerosis refractory to
conventional therapy, using autologous unmanipulated HSC with in vivo
depletion of T cells and ATG(2) .
Until May 2012, 36 patients with systemic sclerosis were included in the Brazilian
protocol, 32 from the University Hospital of the Universidade de São Paulo (USP)
in Ribeirão Preto and four from other services. Three were not transplanted: one
patient died before transplantation due to disease reactivation and post-mobilization
infectious complications and two had great improvement of the skin after mobilization
with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) and opted
not to
pursue the conditioning and transplantation. Of the 33 transplants performed, all
patients had diffuse cutaneous involvement. Twenty-three also had pulmonary interstitial
type involvement and pulmonary hypertension. In 22 patients, esophageal involvement
by
systemic sclerosis was identified, and in four, cardiac involvement. The mean time
with
the disease prior to the HSCT was 2.8 years. There was one death due to sepsis 23
days
after transplantation. All other patients presented with large initial improvement
in
skin elasticity and posterior stabilization, but three of them again presented worsening
of the skin after transplant. The others kept the skin elasticity and stabilization
of
pulmonary involvement with a median follow-up time of 27 months (range: 2-90 months).
Of
the three patients who presented recurrence, the first has digital involvement even
with
prescribed bosentan. The second has progress of the skin and pulmonary involvement,
even
on receiving monthly pulses of cyclophosphamide; this patient began to take mofetil
mycophenolate. While the third, also with progression of the skin condition, is taking
methotrexate with partial response.
Systemic sclerosis: conclusions
The international publications reveal that autologous HSCT has been consolidated as
an
alternative therapy for systemic sclerosis. The results, especially regarding the
control of pulmonary involvement, are encouraging, since it attains responses so far
not
obtained with other treatments. Additionally, the mortality and frequency of adverse
events related to the procedure have been decreasing as the experience and the number
of
transplanted patients grow. It is believed that this is due to more careful selection
of
patients with the exclusion of those with serious comorbidities and organ dysfunctions
secondary to the disease. Patients with severe cardiac dysfunctions, especially
diastolic dysfunction detected by echocardiography or ventriculography, as well as
those
with severe gastrointestinal involvement, manifested by alternating periods of
constipation and explosive diarrhea due to bacterial proliferation should be excluded.
In Brazil, the results, although more recent, are similar to those of the international
literature; the doubts and disagreements regarding the procedure are also similar.
Additionally, during the Second Consensus Meeting in Bone Marrow Transplantation held
in
2012, there was an agreement in the assembly that Brazilian transplant centers treating
patients with systemic sclerosis should have the support of a rheumatologist with
experience in the management of such patients who is able to evaluate and judge the
severity of disease manifestations that would contraindicate transplantation.
Based on available published evidence, which consist of case studies and in one
randomized trial, we conclude that, for the treatment of systemic sclerosis, autologous
transplants are classified as level A-II recommendation. The other ongoing randomized
studies (ASTIS and SCOT) should reinforce the recommendation of autologous HSCT. The
recommendation is still level B-II for allogeneic transplants. Table 1 summarizes
the recommendations.
Table 1
Summary of the consensus on hematopoietic stem cell transplantation for the
treatment of autoimmune diseases
Procedure
Systemic sclerosis
Multiple sclerosis
A-II recommendation
B-II recommendation
Autologous transplant
• excluding patients with severe comorbidities and organ
dysfunctions secondary to the disease
• recommended for patients unresponsive to conventional therapy with
EDSS between 3.0 and 6.0
• severe cardiac dysfunction, especially diastolic
dysfunction detected by echocardiography or ventriculography
• recommended for patients with the malignant form of MS with
disability
• recommended for patients in the secondary progressive
phase or in the progressive phase with evident inflammatory activity
• severe gastrointestinal involvement, manifested by alternating
periods of constipation and explosive diarrhea due to bacterial
proliferation
Allogeneic transplant
B-II recommendation
Not recommended
Multiple sclerosis
Multiple sclerosis (MS) is a chronic inflammatory disease that causes destruction
of
central nervous system (CNS) myelin, with varying degrees of axonal damage. It mainly
affects young adults (the symptoms appear around 30 years old), and is twice as common
in women as in men. Mortality in patients with MS is not very different from that
found
in the normal population, but the progression of neurological deficits occurs in all
patients with the disease. It is estimated that 20 years after disease onset,
approximately 60% of patients are unable to walk(44,45).
MS leads to incapacitation through impairment of sensory, motor, autonomic and
neurocognitive functions. Clinical manifestations are nonspecific and include visual
loss, extraocular movement disorders, paresthesis, sensory loss, weakness, dysarthria,
spasticity, ataxia and bladder dysfunction. The majority of patients present with
alternating clinical outbreaks and remissions. Outbreaks are considered as neurological
dysfunction symptoms found in anamnesis data over 24 hours, in the absence of fever
or
infections and with impairment of at least two long fiber systems (white
matter)(46). The most used
disability scale in neurological diagnosis is the Expanded Disability Status Scale
(EDSS) described by Kurtzke(47).
The etiology of multiple sclerosis is not fully understood; it is believed that the
disease is triggered by environmental factors in genetically susceptible individuals.
It
is considered an autoimmune disease because some studies have suggested an auto
reactivity role of T lymphocytes that enter the CNS through smaller veins, triggering
an
immunological cascade, which induces and sustains other immune and inflammatory events
causing typical changes in the white mass. The histopathological picture of MS is
characterized by the presence of demyelinating plates normally located around the
ventricles, optic nerves and brain. In outbreaks, perivascular infiltrates of
lymphocytes are observed in the plaques(48).
Multiple sclerosis is present in three main types with different clinical approaches.
The relapsing-remitting type is characterized by episodic outbreaks followed by partial
or complete recovery of the dysfunction, interspersed with periods of remission of
at
least three days. After an average period of 10 years, outbreaks become less frequent,
with less evident recovery, more sequelae and gradual worsening of neurological
symptoms, characterizing the secondary progressive form. The primary progressive form
is
characterized by continuous functional decline since the onset of the disease. A
"malignant" form of MS has also been recognized: these are serious cases,
progressing quickly to a severe form of neurological disability or even death in a
short
period of time. The secondary progressive form, as mentioned above, starts with the
relapsing-remitting form, which, at some point, starts a continuous neurological
deterioration with or without overlapping outbreaks(49).
Conventional treatment
The introduction of immunomodulatory therapy in MS since 1993 has changed the disease
scenario. The first-line treatments of MS are immunomodulators such as glatiramer
acetate(50) and interferon-beta
(IFN-β)(51) which delay
the progression of disability, acting in the long term. Therapy with high doses of
corticosteroids is used for acute relapses (attacks). After this, immunosuppressants
(cyclosporine, cyclophosphamide, azathioprine, mitoxantrone etc.) can be used. Recently,
the emergence of an oral medication, sphingosine 1 phosphate receptor agonist, has
been
considered more effective than IFN-β and glatiramer acetate(52) and is also approved
as first-line
therapy. Second line treatments are mitoxantrone(53) and the monoclonal natalizumab(54).
Both first- and second-line treatments aim to treat
the early stage of inflammation and modify disease evolution, but virtually none stop
the development of long-term disabilities. In addition, administration of these agents
may be complicated by adverse events that are infrequent, but can be severe, such
as
progressive multifocal leukoencephalopathy with natalizumab, severe infections and
other
effects with the sphingosine 1 phosphate receptor agonist, and cardiomyopathy and
secondary leukemia with mitoxantrone(55). Overall, a subset of unresponsive patients
was observed in
clinical studies with older and newer therapies. Treatment alternatives are especially
needed for this group of patients, i.e., those who have failed multiple treatments
and
evolve with progressive clinical disability.
Hematopoietic progenitor cell transplantation in multiple sclerosis
Studies published from the 1990s brought animal models and theoretical considerations
of
HSCT in the prevention and treatment of autoimmune diseases(56-59), with
clinical responses in some patients with autoimmune diseases who received
HSCT(56,60,61), suggesting
that high-dose chemotherapy followed by HSCT rescue could "reset" the
immunological changes through the control of autoreactive clones, followed by
immunological tolerance after immune reconstitution. This led to the conclusion that
HSCT may be a viable therapeutic option for MS(62,63).
Since 1996, HSCT has been extensively described around the world as a tool to induce
a
prolonged restoration of self-tolerance in patients(64-67). Since its first use
in the second half of the 90s, more than 700 HSCTs have been performed in patients
with
MS around the world and its use has been frequently revised(59,68-70).
Most patients were treated in small, phase I-II clinical trials(63,71-83) or in multicenter
studies(62,84-87). In
retrospective analyzes of two centers, there was a progression-free survival of more
than five years after transplant(77,85). The neurological outcomes were
considerably more favorable in patients with the relapsing-remitting type and/or those
who showed an inflammatory pattern in MRI during the pre-transplant screening(77).
In fact, reports of excellent results, particularly in the aggressive forms of
MS(86,87) reinforce the effectiveness HSCT in MS patients with prominent
inflammatory activity. The risk of TRM in HSCT was conventionally considered very
high
but has declined since 2001 to 1.3%, according to the European Group for Blood and
Marrow Transplantation (EBMT, www.ebmt.org) analysis(59,88). This probably
resulted from the suspension of the use of the more aggressive conditioning, thus
reducing toxicity. In particular, the use of busulfan was significantly associated
with
greater TRM in a multivariate analysis(76,89). Besides, high doses
of ATG were associated with depletion of T cells ex vivo, and the use
of a more aggressive conditioning regimen resulted in the unexpected occurrence of
posttransplant lymphomas associated with the Epstein-Barr virus (EBV)(90). It is also
worth mentioning the
evolution of the learning curve for each center with decreasing mortality, a fact
also
noted in the review of North American transplants in autoimmune diseases(91).
Most patients worldwide have been conditioned with a carmustine, etoposide, cytarabine,
melphalan regimen (BEAM) and ATG, showing an acceptable toxicity relative to the
effectiveness(89). Conditioning
with cyclophosphamide and ATG was used for autologous transplantations in 21 patients
with the relapsing-remitting form of MS, with low toxicity, although not insignificant.
After a 24-48 months follow-up period, patients had no worsening of the EDSS expanded
scale, and 16 of 21 patients were free of relapses and significant improvements in
EDSS(5). The Brazilian group
also used a reduced-intensity regimen with cyclophosphamide, with no deaths(92).
More experience is needed to evaluate the role of reducedintensity regimens, as well
as
comparative studies with the best standard treatment(93). Some randomized clinical
trials are already ongoing.
In 2004, the EBMT launched a prospective, randomized phase II study, Autologous Stem
Cell Transplantation International Multliple Sclerosis (ASTIMS)(94), comparing HSCT
with mitoxantrone; the
endpoint was the appearance of new lesions on MRI (number of new lesions on T2* in
the
first and second year after randomization). The study was discontinued due to
difficulties including patients, but other phase II, single-arm studies are ongoing
in
the United States(95,96) and Canada(97). Preliminary analyzes of the Canadian study
showed complete
suppression of relapses and new MRI lesions in 23 patients assessed over a mean
follow-up of five years. The US study (HALT-MS), also with preliminary results, showed
that in 25 patients with high inflammatory activity refractory to conventional
treatments, 77% had a progression-free survival at two years post-HSCT, with an endpoint
that included relapses and new lesions on MRI and progression of neurological
disability(98).
Studies published with the highest number of cases were from the European Group, the
EBMT. Initially, the group performed a retrospective study that showed that 74% of
85
patients were free of disease progression for up to three years after transplantation.
In this study, patients with relapsing-remitting and secondary-progressive MS, who
had
inflammatory characteristics, showed progression-free survival of 78% ± 13%,
while for those with the primary-progressive form (more degenerative) the result was
66%
± 23% in three years(85). In
2006 the update of the analysis of 143 cases, with follow-up of 41.7 months, was
published: the disease remained stable or improved in 63% of cases and worsened in
37%(93).
In 2010, EBMT published a review of all cases of autoimmune diseases studied, and
showed
345 treatments in MS with mortality due to the procedure of 2%, three-year survival
of
93%, and absence of disease progression in 55% of cases(88).
More recent data, with almost 500 autologous transplants for MS in Europe, showed
an
overall survival of 92% in five years and progression-free survival of 46%(99). The
main cause of mortality and
morbidity is the recurrence of the autoimmune disease.
The experience with all the studies strongly suggests that the effect of HSCT occurs
mainly in patients with inflammatory manifestations of MS. The efficacy and safety
of
transplantation compared to conventional therapies has not been established. In November
2008, a meeting of experts in MS and BMT was held in Minneapolis, under the auspices
of
Center for International Blood and Marrow Transplant Research (CIBMT), the National
Institute of Allergy and Infectious Diseases (NIAID) and EBMT, with the goal of
establishing common criteria for evaluating the effectiveness of HSCT in MS and to
evaluate the possibility of further prospective studies(100). These studies are already
underway.
Brazilian experience
The study by the Brazilian group of transplantation in autoimmune diseases reported
experience with the use of autologous transplantation in MS in 2010(92). The group
studied patients not
responsive to conventional therapy and who had disease progression. Two types of
conditioning were studies: BEAM/ATG and cyclophosphamide/ATG(101). In this protocol,
41 autologous transplants were
performed. The results showed overall event-free survival of 58.54%, and when analyzed
separately, 47% in the BEAM/ATG and 70% in the cyclophosphamide/ATG; no statistically
significant difference was found (p-value = 0288). There were three deaths in the
BEAM
group and none in the cyclophosphamide group.
After this study(98), other patients
underwent HSCT using cyclophosphamide/rabbit ATG for conditioning. By 2010, when the
first consensus(102) was held, a
total of 46 patients had been treated in University Hospital of the Universidade de
São Paulo (USP) in Ribeirão Preto, with similar results in the evolution
and no mortality. The neurological evaluation, with a mean of 26 months (range: 3-52
months) in the 38 patients with a follow-up longer than six months, showed improvement
in 30% of patients, stabilization in 47% and worsening in 23%. In the Hospital Albert
Einstein, a total of 29 HSCTs were performed in MS by 2010, also with no deaths. The
2012 assessment showed a loss of follow up in nine patients. Of those evaluated, there
was worsening of the EDSS over time in approximately 53% and stability or improvement
with stability in 46% of patients. The importance of this work was to demonstrate
that
conditioning with high-dose cyclophosphamide and ATG was safer than the BEAM (carmustine
300 mg/m2 on D-7, etoposide 200 mg/m2, 200 mg/m2 of
Aracytin in D-6 to D-3 and melphalan 140 mg/ m2 on D-2) and ATG regimen in
our experience and population. The BEAM protocol showed a mortality of 15%, which
was
much higher than acceptable for patients with MS. The conditioning regimen
cyclophosphamide/ATG showed zero mortality(92).
Some groups dispute this conclusion, arguing that patients transplanted in Brazil
had
very advanced disease, with approximately 80% of patients having an EDSS greater than
or
equal to 6. Examples of this were the results of the European Group, showing
progression-free survival of 57% for patients with low-intensity conditioning and
46%
and 49% for patients with intermediate to high intensity regimens
respectively(84,88,89,93).
Although the type of conditioning remains controversial, most transplant groups agree
that the manipulation of the graft for in vitro depletion of T cells is
not necessary. The best results in disease remission are achieved in patients with
the
relapsing-remitting form and up to five years of diagnosis, reaching 70% of
progression-free survival in this group(59).
The use of cell therapy (e.g., mesenchymal cells) in MS has been developed in recent
years(103-107) but enough data for recommendation about
effectiveness and safety are not yet available.
Multiple sclerosis: conclusions
The consensus on HSCT in autoimmune diseases provides an indication of HSCT in patients
with progressive MS unresponsive to conventional therapy and EDSS between 3.0 and
6.0.
The forms of the disease that might benefit from transplantation are:
relapsing-remitting, primary or secondary progressive, and the "malignant"
form, provided there is evidence of inflammatory activity at the time of transplant
indication. The patients should be transplanted preferably in centers with experience
in
this procedure. Table 1 summarizes the
recommendations.
Indications: IIB
- Patients in the relapsing-remitting phase with high inflammatory activity
(clinically and by imaging), with progressive worsening despite the use of one
or two lines of treatment;
- Patients with the "malignant" form of MS, who developed severe
disability in the previous year;
- Patients in the secondary progressive phase when they show evident
inflammatory activity (clinical relapse or new lesions or worsening of lesions
in the imaging exam) with a significant and sustained clinical deterioration
over the last year, despite treatment;
- Primary progressive phase (with evidence of inflammatory activity);
- Patients with EDSS 6.0 (patients who have lost the ability to walk, usually
with a score of 6.5, must be excluded) with the exception of the
"malignant" form.