A CML therapy that emerged in the 1980s was stem-cell transplantation (SCT) (Thomas and colleagues. Ann Intern Med 1986;104:155-163). The idea was that leukemia originated in the bone marrow, so destroying the bone marrow and replacing it with new cells might cure the disease that was harboured there. “Conditioning regimens”, such as chemotherapies and radiation, were used to knock out the bone marrow in a process known as myeloablation. Then the marrow was replaced with blood-forming (or “hematopoietic”) stem cells, which would be able to produce new blood cells, such as red blood cells, white blood cells and platelets. The source of the new stem cells could be the person him/herself (called autologous), or a donor with a different genetic makeup (called allogeneic; ‘allo” meaning ‘other’).
Autologous transplants offered certain advantages. The most obvious was that receiving your own cells eliminated the need to find a donor. An immune mismatch can cause the host’s immune system to attack or “reject” the graft. However, it was the reverse situation that created problems in CML. Since the host’s immune system had been knocked out with the conditioning regimen, the donor marrow – which contains immune cells from the donor’s immune system – could attack the transplant recipient. This is called graft-versus-host disease. In GVHD, donor immune cells don’t recognize the immune profile of the host’s cells, so they initiate an immune attack on key tissues, such as the skin, gastrointestinal tract and liver (Vogelsang and colleagues. Annu Rev Med 2003;54:29-52). This can have fatal consequences.
The main culprit in GVHD is a type of immune cell called the T cell. These cells recognize foreign proteins (called antigens) when other types of immune cells “present” the antigen for their inspection: if the T cells don’t recognize the “ID badge”, they initiate an immune reaction. A key player in how antigens are presented is the MHC molecule (for major histocompatibility complex), also known as HLA (for human leukocyte antigen). An immune reaction is less likely if HLA is similar between host and donor; HLA matching (or “tissue typing”) needs to be done. An HLA match is more likely with someone who is genetically similar to you, such as a sibling. But for most people, an HLA-identical donor isn’t available, a situation that is becoming increasingly common as families have fewer children.
The initial results with autologous transplantation were somewhat disappointing. The duration of leukemia remission was only 4-6 months, which suggested that transplanted marrow harboured leukemia cells and were re-establishing the disease (Santos GW. Yale J Biol Med 1982;55:477-485). A second consideration was that autologous transplants rebuilt the same immune system that you had before – and that system hadn’t been entirely reliable in the first place in controlling leukemia – so it might not be fully effective after the transplant. Thirdly, there was the observation that a donor’s immune system might provide an added boost to your body’s ability to fight CML, which we’ll look at in more detail later on.
The ideal situation was to receive a transplant from an identical twin (called a syngeneic transplant), but obviously this wasn’t possible for most people. That left allogeneic transplants from an HLA-matched donor. Indeed, by the 1990s, the most common reason for performing an allogeneic transplant worldwide was to treat CML (Gratwohl and colleagues. Blood 2002;100:2374-2386).
Transplanting donor stem cells was associated with three main challenges. A compatible donor couldn’t be found in a majority of cases, so this form of treatment wasn’t available to everyone. Secondly, knocking out the immune system could result in potentially fatal bacterial, viral and fungal infections. Thirdly, there was the very real danger of GVHD.
Transplantation was the only treatment that could actually cure CML, but it was a high-risk solution. Throughout the 1990s, different transplantation techniques and drug regimens were tried, which substantially lowered the risk of dying from complications such as GVHD. By 2003, the proportion of people surviving three years was as high as 86%, and a good proportion were disease-free (Radich and colleagues. Blood 2003;102:31-35).
Progress had been slow – and by the early 2000s other events had overtaken transplantation. The development of Gleevec, the first of the tyrosine kinase inhibitors (TKIs), provided a good, lower-risk alternative to transplantation. TKIs might not cure CML, but they could suppress the disease so well that most people with CML could live a normal lifespan.
However, for all their benefits, TKIs haven’t been the ideal solution. Not everyone responds to these medications or can tolerate them, and they are less effective in people with progressive disease, such as accelerated-phase or blast-crisis CML. So transplantation continues to have a role. GVHD remains a concern – but it has also led to some surprising ideas about how CML is cured and how treatments can target the disease in the future.
We’ll look at the role of stem-cell transplants in the TKI era in Part 2 of this article.
We’ll look at this in more detail in Part 3.