Throughout the 1990s, stem-cell transplantation provided a possible cure for CML, but its use declined as tyrosine kinase inhibitors (TKIs) became available starting in 2001. Medications were highly effective in controlling CML, could be taken by most people, and were generally not associated with serious complications. These factors were in sharp contrast to stem-cell transplantation, which was limited to the 30% of people with an HLA-matched donor and which had potentially fatal complications, such as graft-versus-host disease (GVHD).
TKIs were a new and improved technology, but that didn’t mean that transplantation no longer had a role and research advances were expanding the pool of potential candidates. Transplants were generally not advised in people older than 60-65 years because of the toxicity of the chemotherapy regimen that was used to eliminate the bone marrow prior to transplantation. However, less toxic regimens were found to be effective and could be used in older individuals. At the same time, improvements in genetic screening enabled doctors to match unrelated donors more closely to transplant recipients, thereby achieving success rates with unrelated donors that were comparable to what had been seen with HLA-matched sibling donors (Ho and colleagues. Biol Blood Marrow Transplant 2011;17:1196-1204). The use of unrelated donors also appeared to offer some advantages, as we’ll see in Part 3.
A new issue, however, was whether people who had taken a TKI were still able to be transplanted. A number of studies examined this and found that prior treatment with a TKI did not adversely impact the success of transplantation; in fact, taking a TKI beforehand reduced the burden of disease (similar to surgical removal of a tumour before chemotherapy) (Piekarska and colleagues. Ann Hematol 2015;94:1891-1897). That meant that people could start treatment while a search for a suitable donor was underway.
So who is a candidate for a stem-cell transplant?
There are three main scenarios in which transplantation is an option for people with chronic-phase CML, according to European LeukemiaNet recommendations: If you’ve haven’t responded well to two prior TKIs (e.g. Gleevec followed by Tasigna or Sprycel); if you haven’t responded to a second-generation TKI (i.e. Tasigna, Sprycel or Bosulif); or if you develop a drug-resistant mutation (e.g. the T315I mutation) (Baccarani and colleagues. Blood 2013;122:872-884). If you have accelerated-phase CML, there are some data to suggest that transplantation is a better option than TKIs (Xu and colleagues. Front Med 2015;9:304-311). The first option is still to take a TKI, with the plan to undergo transplantation if you don’t respond well to the medication. For blast-crisis CML, transplantation is recommended because there’s a low likelihood of success with medications.
How successful is transplantation? A recent Canadian study reported that among people with treatment-resistant or advanced CML, the overall survival was 68% at 8 years post-transplant (Nair and colleagues. Biol Blood Marrow Transplant 2015;21:1437-1444). So these are very good results for people who are very ill.
The initial goal of stem-cell transplantation was to eliminate the bone marrow that was harbouring leukemia, and replace it with transplanted cells obtained either from the person him/herself (autologous), or from someone genetically identical (syngeneic) or similar (allogeneic). Matching was needed to reduce the risk of GVHD, a potentially fatal immune reaction in which the donor graft “rejected” the person receiving the transplant.
But while researchers were investigating stem-cell transplantation, they noticed something very curious. People who developed GVHD were more likely to be cured of their CML (Weiden and colleagues. N Engl J Med 1981;304:1529-1531). GVHD was caused by immune components in the donor marrow, and yet people didn’t do as well when these components were removed before transplantation. These findings revealed an important goal of transplantation, shifted how the procedure was viewed, and opened up a new area of research in CML.
We’ll look at this in more detail in Part 3.