Fhbb.ae

Autologous stem cell transplantation for progressive multiple sclerosis: Update of the European
Group for Blood and Marrow Transplantation autoimmune diseases working party database
R Saccardi, T Kozak, C Bocelli-Tyndall, A Fassas, A Kazis, E Havrdova, E Carreras, A Saiz, B Löwenberg, P AW te Boekhorst, F Gualandi, H Openshaw, G Longo, F Pagliai, L Massacesi, E Deconink, J Ouyang, F JZ Nagore, J Besalduch, I A Lisukov, A Bonini, E Merelli, S Slavin, A Gratwohl, J Passweg, A Tyndall, A J Steck, M Andolina, M Capobianco, J LD Martin, A Lugaresi, G Meucci, R A Sáez, R E Clark, M N Fernandez, L Fouillard, B Herstenstein, V Koza, E Cocco, H Baurmann, G L Mancardi and Autoimmune Diseases Working Party of EBMT The online version of this article can be found at: http://msj.sagepub.com/cgi/content/abstract/12/6/814 can be found at:
Multiple Sclerosis
Additional services and information for
Citations (this article cites 29 articles hosted on the
SAGE Journals Online and HighWire Press platforms): 2006 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
Autologous stem cell transplantation for progressivemultiple sclerosis: Update of the European Group forBlood and Marrow Transplantation autoimmunediseases working party database R Saccardi1, T Kozak2, C Bocelli-Tyndall3, A Fassas4, A Kazis5, E Havrdova6, E Carreras7,A Saiz8, B Lo ¨wenberg9, PAW te Boekhorst9, F Gualandi10, H Openshaw11, G Longo1, F Pagliai1, L Massacesi12, E Deconink13, J Ouyang14, FJZ Nagore15, J Besalduch16,IA Lisukov17, A Bonini18, E Merelli19, S Slavin20, A Gratwohl21, J Passweg21, A Tyndall3,AJ Steck22, M Andolina23, M Capobianco24, JLD Martin25, A Lugaresi26, G Meucci27,RA Sa´ez28, RE Clark29, MN Fernandez30, L Fouillard31, B Herstenstein32, V Koza33,E Cocco34, H Baurmann35 and GL Mancardi36on behalf of the Autoimmune DiseasesWorking Party of EBMT 1 BMT Unit Department of Hematology, Ospedale di Careggi, Florence, Italy 2 Department of Clinical Hematology, Third Medical School, Charles University, Prague 10, Czech Republic 3 Department of Rheumatology, University Hospital, Basel, Switzerland 4 Hematology Department/BMT Unit, George Papanicolaou General Hospital, Thessaloniki, Greece 5 Department of Neurology, George Papanicolaou General Hospital, Thessaloniki, Greece 6 Department of Neurology, First Medical School, Charles University, Prague 2, Czech Republic 7 Department of Hematology, Hospital Clinic, Institute of Hematology and Oncology, Barcelona, Spain 8 Laboratory of Experimental Neurology and Immunology, Hospital Clinic, Barcelona, Spain 9 Erasmus University Medical Center, Rotterdam, The Netherlands 10 Department of Hematology, San Martino Hospital, Genova, Italy 11 City of Hope National Medical Center, Duarte, CA, USA 12 Department of Neurology, Ospedale di Careggi, Florence, Italy 13 Service d’He´matologie, Hopital Jean Minjoz, Besanc¸on, France 14 Department of Hematology, Drum Tower Hospital, Nanjing, PR China 15 Hospital Vall d’Hebron, Barcelona, Spain 16 Hematology Service, Hospital Universitari Son Dureta, Palma de Mallorca, Spain 17 Institute of Clinical Immunology, Novosibirsk, Russia 18 Hematology Unit, Azienda Ospedaliera ASMN, Reggio Emilia, Italy 19 Clinica Neurologica, Azienda Ospedaliera Policlinico, Modena, Italy 20 Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel 21 Department of Hematology, University Hospital, Basel, Switzerland 22 Department of Neurology, University Hospital, Basel, Switzerland 23 Istituto per l’Infanzia Burlo Garofolo, Trieste, Italy 24 Ospedale di San Luigi Gonzaga, Orbassano, Torino, Italy 25 Seccio´n de Trasplante de Medula Osea, Hospital Gregorio Maran˜o´n, Madrid, Spain 26 Universita` Gabriele d’Annunzio, Chieti, Italy 27 Department of Neuroscience, University Hospital of Pisa, Neurology Clinic, Pisa, Italy 28 Department of Hematology, Hospital de la Princesa, Madrid, Spain 29 Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK 30 Clinica Puerta de Hierro, Servicio de Hematologia y Hemoterapia, Madrid, Spain 31 Department of Hematology, Hopital Saint Antoine, Paris, France 32 Department of Hematology/Oncology, Hannover Medical University, Hannover, Germany 33 Department of Hematology/Oncology, Charles University Hospital, Pilsen, Czech Republic 34 ‘R Binaghi Hospital’, Centro Sclerosi Multipla, Cagliari, Italy 35 Neurologie und Klinische Neurophysiologie, Wiesbaden, Germany 36 Department of Neuroscience, Ophthalmology and Genetics, San Martino Hospital, University of Genova, Genova,Italy 2006 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
Autologous stem cell transplantation for progressive multiple sclerosis Over the last decade, hematopoietic stem cells transplantation (HSCT) has been increasingly used inthe treatment of severe progressive autoimmune diseases. We report a retrospective survey of 183multiple sclerosis (MS) patients, recorded in the database of the European Blood and MarrowTransplantation Group (EBMT). Transplant data were available from 178 patients who received anautologous graft. Overall, transplant related mortality (TRM) was 5.3% and was restricted to theperiod 1995 Á 2000, with no further TRM reported since then. Busulphan-based regimens weresignificantly associated with TRM. Clinical status at the time of transplant and transplant techniquesshowed some correlations with toxicity. No toxic deaths were reported among the 53 patientstreated with the BEAM (carmustine, etoposide, cytosine-arabinoside, melphalan)/antithymocyteglobulin (ATG) regimen without graft manipulation, irrespective of their clinical condition at the timeof the transplant. Improvement or stabilization of neurological conditions occurred in 63% ofpatients at a median follow-up of 41.7 months, and was not associated with the intensity of theconditioning regimen. In this large series, HSCT was shown as a promising procedure to slow downprogression in a subset of patients affected by severe, progressive MS; the safety and feasibility of theprocedure can be significantly improved by appropriate patient selection and choice of transplantregimen. Multiple Sclerosis 2006; 12: 814 Á 823. http://msj.sagepub.com CD34 positive cells selection or T-cell depletion.
An in vivo depletion of autoreactive T cells, which In the last decade, intense immunosuppression could either have been reintroduced with the graft followed by autologous transplantation of hemato- or which escaped the conditioning regimen, is poietic stem cells (AHSCT) has been proposed as a usually carried out by either animal-derived anti- possible strategy for the treatment of severe auto- thymocyte antiserum (ATG) or monoclonal anti- immune disorders (ADs) [1 Á 4], including multiple sclerosis (MS). The graft is made up of hematopoie- The rationale for AHSCT derives from the possi- tic stem cells (HSCs), which are usually collected bility of eradicating self-reactive immune cells by from peripheral blood (PB). Under physiological intensive immunosuppression, followed by full conditions, HSCs are mostly located in the bone immune reconstitution on the engraftment of the marrow (BM), but can be mobilized into the PB by autologous HSCs. Beyond its immunosuppressive the administration of a non-myeloablative che- potential, AHSCT may also be beneficial for the motherapy, followed by haematopoietic growth possible ‘resetting’ of the immune system due to a factors, such as granulocytic colony stimulating de novo regeneration of the T-cell compartment, factor (G-CSF). The most common mobilization with an extensive renewal of clonal specificities regimen in ADs is cyclophosphamide (CY), ranging after therapy, thereby becoming tolerant against between 1.5 and 4 g/m2, followed by G-CSF [5].
self-antigens [6], possibly for an extended period of G-CSF alone can also be used as a unique mobiliz- time. This has never been shown previously with ing agent. In an autologous setting, PB-HSCs are purely immunosuppressive treatments. Tolerance- preferred to BM-HSCs because the shorter engraft- inducing mechanisms of action of HSCT in ADs ment of PB-HSCT results in a safer procedure. After the harvest of HSCs, the patient is treated with a In MS, currently available therapies, such as conditioning or preparatory regimen, consisting of interferons and glatiramer acetate, are of limited high doses of immunosuppressive drugs, which efficacy and many cases continue to deteriorate.
may also include total body irradiation (TBI), Mitoxantrone, the only approved immunosuppres- followed by the reinfusion of HSCs. The graft may sive treatment for MS, is now used when first line be depleted of autoreactive cells by different meth- immunomodulating therapy fails, but because of ods of ex vivo manipulation (graft purging), ie, its cumulative cardiotoxicity, the total dosage of Author for correspondence: Ricardo Saccardi, BMT Unit, SOD Ematologia, Policlinico di Careggi, 50134-Firenze, Italy.
E-mail: [email protected] 10 February 2006; accepted 30 May 2006 2006 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
100 Á 120 mg/m2 cannot be exceeded and, there- fore, its use has to be limited [8 Á 10].
In recent years, a number of studies have ad- dressed the feasibility, toxicity, impact on MS progression and MRI findings of AHSCT, utilizingdifferent mobilization and conditioning regimens [11 Á 18]. Data published so far show that AHSCT is a promising approach to MS cases which fail the first line disease modifying drugs (DMDs) and continue to rapidly worsen. However, such an intensive therapy carries morbidity and mortality risks that can only be justified by disease severity Party (ADWP) of the EBMT set the guidelines for Disease duration indicates the interval between the reported the application of AHSCT to ADs in phase I-2 date of diagnosis and HSCT. Patients are considered evaluable clinical studies and advised that all cases treated for neurological outcome when the follow-up is greater than should be registered in the EBMT database [19]. The six months and adequate feedback was obtained from the aim was to discourage the proliferation of protocols resulting in anecdotal and uninterpretable results.
The first retrospective report on 85 MS cases Disability was severe, with a median EDSS before registered in the EBMT database was published by mobilization of 6.5 (range: 3.5 Á 9). In 151 of 183 Fassas et al . in 2002 [20]. At that time, this retro- patients, data on previous treatments were available spective study showed that the mortality of the (Table 2): 27 cases had been treated with glucocor- procedure was 7.4%, while 74% of treated cases did tico-steroids only; 88 received, in addition to not progress over the three years following HSCT.
steroids, DMDs such as interferons, glatiramer The EBMT has also promoted a prospective trial, acetate, and immunosuppressive drugs, such as named ASTIMS (Autologous Stem Cell Transplanta- azathioprine, methotrexate, CY, mitoxantrone, cla- tion in Multiple Sclerosis), which compares AHSCT dibrine and others. Thirty-six cases were treated with mitoxantrone (www.astims.org). The ASTIMS with DMDs, only 21 of which being IFNs.
After the mobilization procedure, five patients In this study, we report an updated, retrospec- did not undergo AHSCT. In this retrospective tive, analysis carried out on the total number of MS analysis, we also evaluated, as a separate cohort, cases now registered in the EBMT database, mainly patients fulfilling the inclusion criteria used in focusing on transplantation safety and the evalua- the ASTIMS trial (ie, age 5/50 years, documented tion of disease progression by the Kurtzke Expanded worsening of EDSS in the last year, failure of conventional therapies, EDSS 3.5 Á 6.5 at the timeof AHSCT, and secondary progressive (SP) or relap-sing-remitting (RR) form of MS), and these cases arereferred to as ‘ASTIMS eligible’ cases.
From June 1995, data on 183 patients with pro- A total of 169 evaluable patients underwent a gressive MS, enrolled for the AHSCT procedure, mobilization procedure. Mobilization regimens have been reported to the EBMT ADWP registryfrom 45 centers in Europe, Russia, China and the US. In order to collect essential information ontreatment schedule, toxicity and the clinical out- come of the treatment, a data collection form was created and sent to all the centers. Data on transplant characteristics and toxicity were ob- tained for all cases, whilst information on the neurological outcome was available in 145 cases.
Disease modifying drugs (DMDs) are considered azathioprine, Due to a lack of standardized procedures and cyclophosphamide, glatiramer acetate, interferons, mitoxan- missing data, MRI information was not collected.
trone, intravenous immunoglobulins, methotrexate, cladribrine Patient characteristics are shown in Table 1.
2006 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
Autologous stem cell transplantation for progressive multiple sclerosis consisted of CY with G-CSF in the majority of score at baseline was /5 and by ]/1 EDSS points if patients (131/169; 78%); the CY dose varied from EDSS score at baseline was 5/5. Progression was 1.5 to 4 g/m2, with the most common dose of defined as an increase of ]/1 EDSS points if EDSS 4 g/m2 given in 58 cases. The dose of G-CSF varied score at baseline was 5/5, and by 0.5 EDSS points if between 5 and 12 mg/kg per day. The other EDSS score at baseline was /5, confirmed at the mobilization regimens used were G-CSF only subsequent evaluation. The time of the first in- (n 0/19), CY with GM-CSF (n 0/6) or alone (n 0/3), crease of EDSS was taken as the time of disease and other chemotherapeutic agents with G-CSF progression. The primary endpoint was the assess- (n 0/2). In nine cases, data on mobilization regi- ment of the safety of the procedure. Any adverse mens were not available. Patients receiving a bone event related to the procedure was registered; such marrow transplant (n 0/14) were mostly not mobi- events were considered early or late when they lized. The grafts were manipulated to remove occurred before or after 100 days from transplanta- immune cells in 97/178 transplanted cases (54%), tion, respectively. Death was related to transplant in 77 of the cases, by positive selection of CD34'/ procedure if it occurred within 100 days from cells; other purging methods were T cell-depletion transplant. If death occurred after this point, then by either negative immunomagnetic selection or by the physician had to report in the collection form Campath-1H incubation; several grafts were purged whether it could be related in any way to the by incubation with cytostatic drugs.
procedure, to the progression of disease or another A total of 178 patients underwent AHSCT. The unrelated event. Confirmed progression-free survi- most common conditioning regimen was BEAM val (PFS) was the secondary endpoint of this study, (carmustine, etoposide, cytosine-arabinoside, mel- consisting of the probability of being alive without phalan), with or without antithymocyte globulin clinical progression when compared to baseline.
(ATG). Conditioning regimens are summarized inTable 3. ATG was utilized in 132 (74%) patients. In62 (35%) cases, a particularly intensive immuno- suppressive regimen was used with the associationof ATG and in vitro manipulation (double purging).
SPSS ver. 12 (SPSS Inc. Chicago, IL, US) was utilized Hematologic engraftment was defined as a poly- for all statistical analyses. Categorical data were compared using Fisher exact test and continuous variables were compared with Student’s t -test.
Regarding TRM, variables associated with outcome in univariate analysis at P B/0.20 were further testedin a multivariate binary logistic analysis with Outcomes are reported based on the last follow-up stepwise forward (or backward) selection.
of each patient. Neurological assessment consisted Nonetheless, the limited number of outcomes of measuring changes in the EDSS score for a (n 0/9), in comparison with the amount of variables minimum of six months of follow-up compared to which would be logical to consider, weakens the baseline. The EDSS score was evaluated before statistical power of our multivariable analysis. The mobilization (baseline) and six months after end points of survival analysis were either death or AHSCT, then every year until the last follow-up of progression, respectively. Time variable was the each patient. Clinical improvement, confirmed at interval between transplantation and either the the subsequent evaluation, was defined as a de- event or the last examination, when no event crease in the EDSS score of at least 0.5 points if the occurred. The Kaplan Á Meier method was used tocompute the time to event curves and to estimate median values. Log rank test was used to comparecurves in univariate models, significant variables were those included in Cox proportional hazard BEAM0/BCNU (carmustine)0/300 mg/m2; ARAC (cytosine ara-binoside)0/200 mg/m2 per day; VP (etoposide) 0/200 mg/m2 Mobilization data were available from 160 patients.
per day; M (Melphalan) 0/140 mg/m2. ATG, anti-thymocyte Mobilization failure was registered in three patients, globulin; Bus, busulphan; Cy, cyclophosfamide; Mel, mel- who were successfully re-mobilized with G-CSF, G-CSF and CY and CY plus vepeside, respectively.
2006 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
Of 125 patients, evaluable for adverse events 25(20%) patients were reported to have a mild toxicityduring mobilization, mostly related to the immu-nosuppression. Six patients were reported to havetransient neurological events.
Five patients were mobilized only; the remaining178 received a transplantation of PB-HSCs (163),BM-HSCs (14) or both (1). Such a distributionreflects the current trend to use PB-HSCs in anautologous setting. All 178 patients did engraft.
Early non-neurological toxicity was reported in 80/144 (56%) evaluable patients, mostly associatedwith the immunosuppression and as expected forautologous HSCT in other settings. This early Overall survival curve. Kaplan Á Meier curve of the toxicity is detailed in Table 4. Neurological toxicity cumulative overall survival. The thick marks representcensored events. The analysis was performed on the 178 was reported in 26/149 (17%) evaluable patients; it patients who underwent the transplant.
occurred within 60 days from the transplant andwas reported as transient. Late toxicity occurred in9/160 evaluable patients (6%): mean time of onset patients, six died from progression of MS (4.7%). In from AHSCT was 20 months, ranging between four these cases, the treating physician communicated and 41. Three out of nine were Varicella Zoster that the neurological condition of the patients Virus (VZV) infections; five patients (3.4%) showednon-neurological new ADs, such as autoimmune continued to deteriorate in spite of the therapy, and that the patients died after a period of 15 Á 42 months due to the progression of the disease. Nine out of 169 evaluable patients died for reasons con-nected with the transplantation procedure, resulting in an overall 5.3% TRM (Table 5). All the deaths wererecorded before the end of 2000, whilst no toxic Kaplan Á Meier analysis showed an overall survival of deaths were reported among the 62 evaluable pa- 91.2% at eight years (Figure 1). Out of 169 evaluable tients transplanted after this date.
Inclusion criteria for the ASTIMS trial were chosen according to a consensus amongst variousexperienced specialists. In particular, an age of 5/50 years, documented worsening of at least 1 point at EDSS in the last year, failure of conventional therapies, EDSS 5/6.5 and SP or RR form of MS, were the most relevant criteria in terms of clinical feasibility. We then, retrospectively, evaluated the population of 169 MS transplanted cases with and without the inclusion criteria for ASTIMS. TRM, among the 87 patients who did not fulfil ASTIMS inclusion criteria, was 6.9% compared to 3.6% in the patients who did fulfil the criteria. Moreover, if we consider the 53 patients who received the conditioning regimen used in the ASTIMS trial (BEAM followed by ATG without manipulation of the graft), no TRM was reported, irrespective oftheir clinical condition at the time of the trans- Non-neurological toxicity recorded within 100 days from HSCT.
It has been split into events related to the immunosuppression Finally, a correlation analysis between TRM and and to others. The last column reports the percentage of the twogroups relative to the total number of reported events. VOD, items likely to be related to it was carried out: either veno-occlusive disease; TTP, thrombotic thrombocytopenic busulphan or TBI including regimens, graft manip- purpura; CMV, cytomegalovirus; HSV, herpes simplex-virus.
ulation and the association of combined in vivo 2006 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
Autologous stem cell transplantation for progressive multiple sclerosis Descriptive report of deaths referred by the consulting specialists to the HSCT and statistical analysis of same (see Table 6). Statisticalmethodology is reported in the text. Abbreviations are reported in Table 3 legend.
and in vitro purging (double purging), age, MS show any advantages in this series of patients. The subgroup, EDSS at the time of the transplant, MS subgroup has been previously addressed as a disease duration more or less then 5 years before major prognostic factor, with primary progressive the HSCT were evaluated both in uni- and multi- (PP) forms more prone to progression [20]. In our variate analysis. Results are reported in Table 6.
analysis, only 19/142 (13%) evaluable patients were Regimens including busulphan exerted a negative considered to have a PP form; no differences in the impact both in univariate (P 0/0.001) and multi- two groups were found, possibly due to the numer- variate analysis (P 0/0.001), respectively. It was noted that six of nine TRM events were associated Overall, the EDSS at follow up (median: 41.7 with infections, and in five a double purging was months) decreased or remained stable in 63% of performed (Table 5). However, this item did not cases, whilst in 37% of patients it worsened.
result significantly associated with TRM either in Interestingly, we evaluated, as a separate cohort, univariate (P 0/0.077) or multivariate analysis (P 0/ the patients treated with the ASTIMS protocol (ie, 0.2). There was also a trend between age and TRM, BEAM followed by ATG without manipulation of which did not reach statistical significance. The low the graft) and 75% of cases remained stable number of events might account for the low compared with 25% that worsened with time. If one considers only the ‘ASTIMS eligible’ casestreated with the ASTIMS protocol, the percentageof stable or improved patients remain almost the same (71 versus 29%). If ‘ASTIMS eligible’ cases aretreated with a more intense regimen (double Neurological follow-up was available in 145 pa- purging, in vitro and in vivo ), this more aggressive tients, but in two patients, the period of follow-up treatment does not, apparently, add any advantage (62% better or stable versus 38% of worsened /6 months, and thus were not considered.
Manipulation of the graft (ex vivo purging) did not Age and interval prior to HSCT considered separately showed some impact on disease progres-sion, although not statistically significant. We arbitrarily compared the cumulative PFS of patients B/40 years and transplanted within five years from diagnosis versus older patients transplanted after five years (Figure 2). The difference between the two groups resulted statistically significant (P 0/ 0.01) and was independent, in multivariate analy- sis, from other relevant variables (MS subtype, conditioning intensity, double purging, EDSS at HSCT). While EDSS before and after AHSCT was available in 145 cases, the trend was also investi- Descriptive report of deaths referred by the consulting specia- gated, looking at the EDSS one year before trans- lists to the HSCT (Table 5) and statistical analysis of same plantation compared with the years after. Data (Table 6). Statistical methodology is reported in the text.
concerning this issue were available in 63 patients Abbreviations are reported in Table 3 legend.
and showed a rapid worsening in the year before 2006 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
obtaining an intense immunosuppression, followedby marrow rescue by means of infusion of AHSCs, anumber of severe MS cases have been treated withAHSCT in Europe, the US, Russia and China. Theresults of single center studies [12,13,21 Á 23], andcountry multi-center co-ordinated studies [16,18],have since been published. From these studies, itappears that AHSCT is a promising therapeuticstrategy in severe, rapidly worsening, MS cases,unresponsive to conventional therapies. AHSCThas an effect on inflammatory activity detected byMRI, with complete abrogation of gadolinium-enhancing areas [15,17]. It also has an impact onthe clinical evolution of the disease, with a clini-cally relevant reduction of the frequency of relapses[22], and slowing down the progression of the Progression-free survival according to the interval disease, demonstrated in almost 70% of severe MS prior to HSCT and age. Cumulative progression-free survival cases [18,20,24], at least in the first three years of plotted according to both the interval between diagnosis follow-up. However, the treatment is associated and HSCT and to the age of the patient at the time of HSCT.
with known toxicity, infections and side effects The dotted line represents the 32 patients B/40 years of age,who were transplanted within five years from diagnosis. The are common and, of major concern, there is an solid line represents the 40 patients transplanted after such associated TRM. On the other hand, transplant- interval, and who were /40 years of age. The Kaplan Á related toxicity is usually limited to the peri- Meier method was used to plot the curves. The thick marks transplant period in the vast majority of cases, represent censored events. Statistical comparison of the twogroups was significant (P 0/0.01).
and the patients may thereafter experience a pro-longed period of neurological stability, free of transplantation and a substantial stabilization of treatment. Moreover, the toxicity can be controlled EDSS progression in the subsequent time period by a better selection of patients and also by the experience of the transplant center [25]. An ap-proach to the use of allogeneic HSCT for MS iscurrently under investigation [26]. In 2002, the ADWP of EBMT published a retrospective analysisof the first 85 cases treated in Europe with AHSCT Since 1997, when Fassas et al . reported, for the first [20], showing that nearly 74% of MS-treated cases time, the use of therapeutic regimens aimed at did not progress after three years, with a TRM of7.4%. This mortality risk was considered high by many in the neurological community, even forrapidly worsening MS cases, who are at high riskof becoming wheelchair bound or bed-ridden in a short period of time. A significant reduction in theTRM, as well as the demonstration of durableclinical benefit, are considered important by neu- rologists for further consideration of AHSCT as apossible therapeutic option in severe MS cases.
Transplant-related adverse events can be reduced by avoiding high intensity regimens, with theirconcomitant organ toxicity and profound, sus- tained immunosuppression. Selection of patientsmight also have an impact on both safety andclinical outcome, as more advanced patients and patients without signs of inflammation at MRI, are A major aim of this work was to retrospectively EDSS score before and after HSCT (n 0/63). Box- evaluate these variables, specifically in MS patients.
plot graphs of EDSS score one year before and at different Despite the limitations of a retrospective analysis, time points after the transplant. Each box shows the median, such as, eg, missing data in some cases or lacking of quartiles, and extreme values within each time point. Thetwo lines below the graph represent the number of cases information on the presence of relapses before and and the months from the HSCT, respectively.
after therapy, the present study has had the unique 2006 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
Autologous stem cell transplantation for progressive multiple sclerosis opportunity of examining the largest series of MS obtained by currently available immunosuppressive cases treated with AHSCT reported so far, with the aim of supplying evidence to provide an equipoise AHSCT was not associated with important neu- rological complications related to the procedure, In this study, we confirmed that a more aggres- despite the frequent occurrence of transient wor- sive conditioning regimen, including busulphan, sening during the neutropenic phase of the post- is statistically associated with a higher risk of mor- conditioning period, when fever occurred in most tality in the single, as well as the multivariate, analysis. In addition, an intense immunosuppres- Data on neurological outcome confirm the re- sion achieved through the association of graft sults of phase 1 Á 2 studies, with a consistent manipulation and in vivo T-cell depletion was number of patients showing an arrest of disability associated with a higher risk of TRM, although progression. When we examined all the evaluable not statistically significant either in univariate patients (143 cases with a median follow-up of 41.7 (P 0/0.077) or in multivariate (P 0/0.2) analysis. Of months), the disease remained stable or improved great relevance is that the procedure utilized in the in 63% of cases and worsened in 37%.
ASTIMS trial (BEAM followed by ATG, without any In principle, the inflammatory component of in vitro purging) was not associated with mortality: MS is the major target of such an intensive 53 MS cases have been treated with this regimen immunosuppressive treatment, considering also without any toxic deaths. These findings also previously published data on the effect of AHSCT confirm in MS a relationship between intensity of on MRI gadolinium-enhancing areas on cases conditioning and TRM, as well as in other Ads [27].
registered in the present EBMT database, which While less intense, immunosuppressive-only regi- demonstrate a complete suppression of the enhan- mens are possible, many such strategies over the cing activity [15,17]. Taking into account that past 30 years have failed to induce durable long- inflammation is mostly active in the initial phase term remission once the immunosuppression is of the disease, early treatment should be more withdrawn. The recent work of Muraro et al . [6], effective. In this series, we showed that younger suggests, for the first time, that an intense auto- patients, transplanted within five years from diag- logous HSCT (CY, ATG and TBI) regimen could nosis, show a significantly better progression-free induce durable long-term remission. The results survival, thus confirming the previous assumption presented here suggest that this may also be and indicating that AHSCT could be considered if, possible with a moderate regimen (and therefore after the failure of conventional treatments, the less toxic, such as BEAM/ATG), with a durable patients continue to progress rapidly. Progression benefit seen in some patients up to nine years in MS is most likely linked to inflammation in the early stages of disease, but can subsequently Although there was a trend for an increased risk proceed independently due to degenerative me- of mortality in more disabled patients, this item was not shown as statistically significant. However, The place of autologous HSCT in the treatment in immobilized patients, the risk of infection is of severe, treatment refractory MS needs to be intuitively higher and, therefore, we strongly re- established with prospective, randomized con- commend that only ambulatory cases, ie, with an trolled trials, which are proceeding or in the EDSS not higher than 6.5, should undergo this procedure. A possible exception to this statementare MS cases with a rapidly worsening clinicalcourse, unresponsive to traditional therapies, or who have acquired a severe loss of strength in thelower limbs in a few months [28].
All the co-authors actively reported specific data for When the mortality was plotted against the year this analysis. We would like to acknowledge the of treatment, it appeared that in the last three years following centers who entered their data in the (2001 Á 2003) no deaths occurred among the 63 EBMT Database: University Hospital Complex, transplanted patients, compared to 1997 Á 2000, Brest, France; Institut Jules Bordet, Experimental when nine of 121 patients died for reasons related Hematology, Brussels Bordet, Belgium; Department to the procedure. It might be speculated that, as of Hematology, ULB Á Hopital Erasme, Brussels, well as in other hematological disorders, a better patient selection and transplant experience has led to such a finding. This ‘learning curve’ shows that, Germany; Milan HSR, Istituto Scientifico HS Raf- in selected MS cases, the de novo mortality risk faele, Hematology and BMT, Milan, Italy; Depart- ment of Hematology and Oncology, University cedure acceptable due to benefits that cannot be Regensburg, Regensburg, Germany; Department of 2006 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
Hematology and BMT, Rambam Medical Center, 11. Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Haifa, Israel; Department of Hematology, Univer- Sakellari I, Kimiskidis V et al . Peripheral blood stemcell transplantation in the treatment of progressive sity Hospital Gasthuisberg, Leuven, Belgium; De- multiple sclerosis: first results of a pilot study. Bone Marrow Transplant 1997; 20: 631 Á 38.
University of Medical Science, Poznan, Poland; 12. Burt RK, Traynor AE, Cohen B, Karlin KH, Davis Department of Hematology and BMT, Ospedale S.
FA, Stefoski D et al . T cell-depleted autologous hema- Camillo-Forlanini, Rome, Italy; Universita topoietic stem cell transplantation for multiple sclerosis:report on the first three patients. Bone Marrow Transplant pienza’, Dip. Biotecnologie Cellulari ed Ematologia, Rome, Italy; Department of Hematology, Universita 13. Kozak T, Havrdova E, Pit’ha J, Gregora E, Pytlik Tor Vergata, St. Eugenio Hospital, Rome, Italy; R, Maaloufova J et al . High-dose immunosuppressive Department of BMT, SPb State I. Pavlov Medical therapy with PBPC support in the treatment of poor riskmultiple sclerosis. Bone Marrow Transplant 2000; 25: University, Centre of Hematology, St. Petersburg, Russia; Hospital Clı´nico Universitario, Servicio de 14. Openshaw H, Lund BT, Kashyap A, Atkinson R, Hematologia y Oncologia, Valencia, Spain.
Sniecinski I, Weiner LP et al . Peripheral blood stemcell transplantation in multiple sclerosis with busulfanand cyclophosphamide conditioning: report of toxicityand immunological monitoring. Biol Blood Marrow Trans- 15. Mancardi GL, Saccardi R, Filippi M, Gualandi 1. Hough RE, Snowden JA, Wulffraat NM. Haemo- F, Murialdo A, Inglese M et al . Autologous he- poietic stem cell transplantation in autoimmune dis- matopoietic stem cell transplantation suppresses Gd- eases: a European perspective. Br J Haematol 2005; 128: enhanced MRI activity in MS. Neurology 2001; 57: 2. Marmont AM. Stem cell transplantation for severe 16. Nash RA, Bowen JD, McSweeney PA, Pavletic SZ, autoimmune disorders, with special reference to rheu- Maravilla KR, Park MS et al . High-dose immunosup- matic diseases. J Rheumatol Suppl 1997; 48: 13 Á 18.
pressive therapy and autologous peripheral blood stem 3. Tyndall A, Fassas A, Passweg J, Ruiz de Elvira C, cell transplantation for severe multiple sclerosis. Blood Attal M, Brooks P et al . Autologous haematopoietic stem cell transplants for autoimmune disease Á feasibility 17. Saiz A, Blanco Y, Carreras E, Berenguer J, Rovira and transplant-related mortality. Autoimmune Disease M, Pujol T et al . Clinical and MRI outcome after and Lymphoma Working Parties of the European Group autologous hematopoietic stem cell transplantation in for Blood and Marrow Transplantation, the European League Against Rheumatism and the International Stem 18. Saccardi R, Mancardi GL, Solari A, Bosi A, Bruzzi Cell Project for Autoimmune Disease. Bone Marrow P, Di Bartolomeo P et al . Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: 4. Tyndall A, Saccardi R. Haematopoietic stem cell impact on disease activity and quality of life. Blood transplantation in the treatment of severe autoimmune disease: results from phase I/II studies, prospective ran- 19. Tyndall A, Gratwohl A. Blood and marrow stem cell domized trials and future directions. Clin Exp Immunol transplants in autoimmune disease. A consensus report written on behalf of the European League against Rheu- 5. Burt RK, Fassas A, Snowden J, van Laar JM, Kozak matism (EULAR) and the European Group for Blood and T, Wulffraat NM et al . Collection of hematopoietic Marrow Transplantation (EBMT). Br J Rheumatol 1997; stem cells from patients with autoimmune diseases. Bone Marrow Transplant 2001; 28: 1 Á 12.
20. Fassas A, Passweg JR, Anagnostopoulos A, Kazis A, 6. Muraro PA, Douek DC, Packer A, Chung K, Kozak T, Havrdova E et al . Hematopoietic stem cell Guenaga FJ, Cassiani-Ingoni R et al . Thymic output transplantation for multiple sclerosis. A retrospective generates a new and diverse TCR repertoire after auto- multicenter study. J Neurol 2002; 249: 1088 Á 97.
logous stem cell transplantation in multiple sclerosis 21. Burt RK, Cohen BA, Russell E, Spero K, Joshi A, patients. J Exp Med 2005; 201: 805 Á 16.
Oyama Y et al . Hematopoietic stem cell transplantation 7. Sykes M, Nikolic B. Treatment of severe autoimmune for progressive multiple sclerosis: failure of a total body disease by stem-cell transplantation. Nature 2005; 435: irradiation-based conditioning regimen to prevent dis- ease progression in patients with high disability scores.
8. Edan G, Morrissey S, Le Page E. Rationale for the use of mitoxantrone in multiple sclerosis. J Neurol Sci 2004; 22. Carreras E, Saiz A, Marin P, Martinez C, Rovira M, Villamor N et al . CD34'/ selected autologous peripheral 9. Hartung HP, Gonsette R, Konig N, Kwiecinski H, blood stem cell transplantation for multiple scle- Guseo A, Morrissey SP et al . Mitoxantrone in progres- rosis: report of toxicity and treatment results at one sive multiple sclerosis: a placebo-controlled, double- year of follow-up in 15 patients. Haematologica 2003; 88: blind, randomised, multicentre trial. Lancet 2002; 360: 23. Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, 10. Saccardi R, Tyndall A, Coghlan G, Denton C, Edan Sakellari I, Kimiskidis V et al . Autologous stem cell G, Emdin M et al . Consensus statement concerning transplantation in progressive multiple sclerosis Á an cardiotoxicity occurring during haematopoietic stem cell interim analysis of efficacy. J Clin Immunol 2000; 20: transplantation in the treatment of autoimmune dis- eases, with special reference to systemic sclerosis and 24. Blanco Y, Saiz A, Carreras E, Graus F. Autologous multiple sclerosis. Bone Marrow Transplant 2004; 34: haematopoietic-stem-cell transplantation for multiple sclerosis. Lancet Neurol 2005; 4: 54 Á 63.
2006 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
Autologous stem cell transplantation for progressive multiple sclerosis 25. Frassoni F, Labopin M, Powles R, Mary JY, Arcese W, Bacigalupo A et al . Effect of centre on outcome of Fassas A, van Laar JM, Farge D et al . Autologous bone-marrow transplantation for acute myeloid leukae- hematopoietic stem cell transplantation for autoimmune mia. Acute Leukaemia Working Party of the European diseases. Bone Marrow Transplant 2005; 35: 869 Á 79.
Group for Blood and Marrow Transplantation. Lancet 28. Mancardi GL, Murialdo A, Rossi P, Gualandi F, Martino G, Marmont A et al . Autologous stem 26. Griffith LM, Pavletic SZ, Tyndall A, Bredeson CN, cell transplantation as rescue therapy in malignant Bowen JD, Childs RW et al . Feasibility of allogeneic hematopoietic stem cell transplantation for autoimmune disease: position statement from a national institute of 29. Trapp BD, Peterson J, Ransohoff RM, Rudick R, allergy and infectious diseases and national cancer Mork S, Bo L. Axonal transection in the lesions of institute-sponsored international workshop, Bethesda, multiple sclerosis. N Engl J Med 1998; 338: 278 Á 85.
MD, March 12 and 13, 2005. Biol Blood Marrow Transplant2005; 11: 862 Á 70.
2006 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.

Source: http://www.fhbb.ae/uploads/IT/articoli_staminali/sclerosi-multipla.pdf