Autologous Hematopoietic Stem Cell Transplantation in Autoimmune Diseases

Claudio Annaloro; Francesco Onida; Giorgio Lambertenghi Deliliers


Expert Rev Hematol. 2009;2(6):699-715. 

In This Article

Multiple Sclerosis

Multiple sclerosis is a disabling neurological illness mostly affecting young people. The hallmarks of the disease are inflammatory white matter lesions characterized by loss of myelin and axonal damage, having typical contrast-enhanced MRI foci as an imaging counterpart. Autoimmunity is commonly held as the initiating pathogenetic event, although advanced disease is likely to progress irrespective of immunosuppressive treatment. Advances in understanding of MS biology have been offered by the similarities to the aforementioned EAE.

In keeping with the above broad concepts, MS shows three main patterns of clinical course: relapsing/remitting, primary progressive and secondary progressive. Primary progressive disease has the worst outcome, both in terms of early disability and short survival; at the same time, this variety is the least responsive to immunosuppression. Standard treatment of MS includes different immunosuppressive agents, either as first- and second-line therapy. Immunomodulating, not immunosuppressive, agents as IFN-β, have lost most of their past interest and are generally employed in relapsing disease. More recently, mitoxantrone has been recognized as a possible effective alternative for patients with progressive disease.[49,86] In 2008, the monoclonal antibody natalizumab has been approved for the treatment of relapsing–remitting MS patients, resistant to immunomodulating therapy, with a host of papers dealing with this issue. Nevertheless, the available data do not allow the question as to whether natalizumab will upset the scenario in the treatment of MS to be addressed. Presently, disease stabilization and progression-free survival seem to be the most realistic objective of natalizumab therapy;[87,88] moreover, papers dealing with natalizumab side effects almost outnumber those dealing with its activity.[89]

Reports dealing with disease history of MS patients are uncommon. It is generally considered that, even in the presence of early disability, MS patients have only a limited loss in life expectancy during the first 10 years of their disease. This was confirmed by a relatively large-scale survey, showing a 5.4% 10-year and a 22% 15-year mortality, even though the confidence interval was rather wide.[90] Nonetheless, the risk of TRM and long-term effects in a disease with a relatively favorable life expectancy has not hindered the efforts of introducing autologous HSCT among the therapeutic options for MS. Actually, among ADs, MS has been for many years the most widely investigated indication to autologous HSCT, with the first reports having been published in 1996. The application of this treatment strategy in MS has been favored by the availability of objective instruments to define disease activity and disease response. In particular, clinical status is commonly assessed by means of the Expanded Disability Status Scale (EDSS) and disease activity is assessed by looking for contrast-enhanced MRI lesions. More recently, brain MRI volume has also been monitored.[91]

As in SS, periodic registry surveys and limited-size homogeneous reports are the mainstay for recognizing the evolving results of autologous HSCT in MS.[66,92–95] Recent worsening of EDSS and the presence of documented contrast-enhanced MRI lesions as a sign of active disease in a pretreated patient are regarded as common indications to autologous HSCT.[96] Concerning disease pattern, secondary progressive is the standard indication, to avoid overtreatment in relapsing/remitting patients or ineffectual treatment in primary relapsing patients; nevertheless, patients with any clinical pattern have been autografted.[92]

The CTX/G-CSF combination was the most widely used mobilization schedule; mobilization with G-CSF only has been linked to MS flare-up.[66,97] Unlike in SS, harvest manipulation by CD34+ selection was performed only in approximately half of the patients. TBI-based conditioning regimens were uncommon, whereas a combination of BCNU, etoposide, Ara-C and melphalan (BEAM) was the reference regimen; ATG was administered to the majority of patients.[92] More recently, non-myeloablative conditioning regimens have been proposed as a possible alternative, but they seem to offer worse results in terms of disease control.[98]

In comparison with SS, a lower TRM has been reported, which generally did not exceed the corresponding figures for autografting in hematological malignancies; moreover, TRM further decreased with time, although the female preponderance in the MS autografted series deserves to be considered.[66,92,94,95] This may reflect the early development of well-accepted inclusion criteria, ruling out rare patients with life-threatening extra-CNS organ dysfunction. Some additional factors may have helped in reducing TRM, as the abandoning of the most aggressive conditioning regimens (TBI- or busulfan-based) – although BEAM is anyway a myeloablative regimen – and the avoidance of the combination of graft manipulation with ATG.[92]

Concerning response, almost all patients exhibited a disappearance of MRI markers of disease activity;[86,91,93,95,96,99] the significance of this finding has been questioned, since patients with no more lesions can have no clinical benefit and post-transplant disease progression may occur without reappearance of new MRI lesions, therefore, underscoring a possible dissociation between inflammation/autoimmunity and, on the other side, CNS damage and clinical deterioration.[86,100–102] Moreover, some degree of irreversible brain damage should be assumed as a result of disease process. Equally intriguing is the issue concerning MRI brain mass evolution. MRI studies have shown that, at least in the first year post-HSCT, brain mass may decrease to a higher extent than in MS patients not undergoing HSCT, thus casting some doubt about its efficacy; these findings are similar to those reported in patients undergoing autologous HSCT for hematological diseases.[103,104] After this time period, rarer long-term observations seem to suggest that autologous HSCT in MS may result in a lessening of brain mass loss in comparison to reference MS patients.[91,105]

On the basis of EDSS, autologous HSCT in MS expected to induce either disease stabilization or improvement in over 60% of patients, irrespective of selection criteria.[10,66,86,95,106] Age is recognized as the main prognostic factor for response; besides, patients with primary progressive disease are more unlikely to achieve a response.[107] Secondary post-transplant progression of disease in responding patients was not an uncommon event, but the median time to progression still awaits to be established and was influenced by selection criteria.[66,95,106,107] Overall, a 10-year overall survival chance of approximately 90% can be expected, but the gain in survival, if any, has still to be elucidated.

As a biological counterpart of its clinical efficacy, autologous HSCT may have the potential of modifying some predictors of MS activity[108] or of modulating myelin-reactive T cells.[42]

The experience in HSCT for MS patients is summarized by the ongoing perspective randomized EBMT Autologous Stem cell Transplantation International Multiple Sclerosis (ASTIMS) trial, comparing autologous HSCT with mitoxantrone, and by local experiences following the same selection and treatment criteria. In order to minimize TRM, patients without severe organ dysfunction are selected, unmanipulated graft is infused, and the relatively less toxic BEAM regimen is administered as conditioning treatment. To improve response rate, patients below 55–60 years of age, with a relapsing–remitting or a relapsing–progressive clinical course, who has failed the conventional immunomodulatory and immunosuppressive drugs, with MRI signs of inflammation, are included.[107] Using similar selection criteria, a TRM nearing zero and a rate of disease stabilization nearing 100% can be expected, with a 5-year progression-free survival exceeding 50%.[94,96]

At first glance, these results seem to be encouraging. Nevertheless, the gain in survival is questionable, especially because patients with worse prognosis are ruled out.[101] Moreover, disease stabilization rather than improvement is the commonly expected response,[86] and time to progression has to be determined precisely, notably in comparison with non-transplanted patients.[96] In summary, autologous HSCT in MS seems a more promising (and time-honored) therapeutic strategy than in SS; nevertheless, much effort is still to be done to make it a clearly cost-effective procedure.[106,109,110]


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.