Mult Scler. 2017 Nov 1:1352458517742532. doi: 10.1177/1352458517742532. [Epub ahead of print]
Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis.
In the majority of relapsing multiple sclerosis patients, the disease can be quite easily controlled by already available, approved therapies. There are, however, some aggressive cases who continue to have clinical and magnetic resonance imaging (MRI) activity in spite of the treatment. These are the cases who may now receive benefit from intense immunosuppression followed by autologous haematopoietic stem cell transplantation (aHSCT). In this review, we describe the method and the rationale of aHSCT, the more recently published studies that demonstrate its efficacy in selected multiple sclerosis cases, the problems related to safety and the transplant-related mortality risk of the procedure. A description of the ideal patient who can take advantage of aHSCT is outlined and, finally, the ongoing studies which are near to completion or are close to starting are briefly reported.
Some might say that HSCT (haematopoietic stem cell transplantation) is the final frontier in MS? Like the voyages of the Starship Enterprise, the saying “to boldly go where no man has gone before” has been debated for the best part of a century over its correctness and conformity to current standards, likewise HSCT practices the world over have been heavily scrutinised on an off for the better half of two decades on wording alone. You might say that a comparison between the Starship Enterprise and HSCT is nonsensical – maybe; but the correct selection of words can make a world of difference.
I allude to these considerations below…
‘High-dose’ vs. ‘Low-dose’ conditioning regimens
The authors have provided a link to the European Blood and Marrow Transplantation society (EBMT, www.ebmt.org) where you can find detailed descriptions of the different conditioning regimens.
High-dose i.e. myeloablative regimens are expected to ablate marrow haematopoiesis (the process of formation of blood cellular components), thereby preventing haematological recovery. In contrast, low-dose i.e. nonmyeloablative regimens, although causing minimal depletion in immune cells, do not require stem cell support.
The best conditioning regimen is debatable, but not surprisingly the high-dose regimen has the most likelihood of eliminating autoreactive T cell clones from your marrow, but safety is a big concern. Low-dose regimens, on the other hand, are almost immunoablative and maybe more appropriate in the autoimmune setting rather than in the cancer setting. With low-dose regimens, 25% experience relapses after the procedure (Burt RK, Lancet Neurol 2009; 8:244-253) and MRI activity is not completely eradicated (Curro’D, Mult Scler 2015; 21: 1423-1430).
RRMS vs. progressive disease i.e. if the disease is still in the inflammatory stage.
Relapsing-remitting, as opposed to progressive forms of MS greatly influence progression free survival outcomes with HSCT. HSCT has been particularly successful in severe cases of relapsing MS where it is able to completely eradicate Gd-enhancement on MRI (cutting out relapses), often leading to dramatic clinical improvement (Mancardi GL, Mult Scler 1005; 11: 367-371) – with as much as 1 EDSS (MS disability rating scale) point; a feet rarely observed in progressive MS. Leading us to conclude that HSCT efficacy is closely linked to its capacity to suppress inflammatory activity.
The authors point out that in their cohort, NEDA (no evidence of disease activity) status at 5 years was observed in 72% RRMS vs. 55% SPMS cases. This is not to say that targeting inflammation in progressive MS is a waste of time, experience with targeted B cell therapies have clearly highlighted that this is feasible in practice, and should also be considered for HSCT. A note of caution, however, registry data collected by EBMT clearly point out that a progressive disease course and a higher EDSS score at entry were associated with increased transplant related mortality.
In summary, more and more transplants are being performed for MS around the world than ever before. Currently, we lack convincing data on the conditioning regimen that best balances efficacy and safety. Patient selection is key (see Table below) and HSCT should be considered as an early option in aggressive cases of inflammatory MS, rather than as salvage therapy in later disease.