Graft versus Leukemia

First, how do bone marrow transplants (BMTs) work? Most chemotherapeutic agents (i.e. drugs used to treat cancer) act by targeting rapidly dividing cells. They have various mechanisms like interfering with DNA replication, cross-linking DNA strands and disrupting mitosis, but all interfere with cells duplicating themselves. Radiation works in a similar way. Since cancer cells are, by definition, growing out of control they help kill off cancers. But the side effects of chemo and radiation are damage to other rapidly dividing cells in the body, including the hair (cosmetic problem only), the mucosa of the GI tract (nausea, vomiting, mucositis), and cells of the bone marrow. The last is the real limiting toxicity because destroying white blood cells leaves the recipient open to infection (which is why fever and neutropenia has led to so many people getting cancer).

The initial idea behind bone marrow transplants was that by reinfusing someone else’s bone marrow after higher doses of chemo and radiation. By increasing the intensity of treatment you increased the chance of cure. Of course, there are some problems with bone marrow transplants. The recipients immune system can reject the graft, basically fighting it off, like we all do to the few maternal cells that made their way into our circulation in utero or the white cells that come along in a transufion of red blood cells. That this ever happens, even after huge doses of chemo and total body irradiation is incredible to me and it can even happened weeks to months after transplant. The other problem, graft versus host disease (GVHD) is basically the converse. The transplanted white cells (from the donor) recognize recipient cells as foreign and attack them.

At first GVHD was a major problem and a variety of approaches were developed to prevent and treat it (purging of mature T cells from the donor marrow, immunosuppression, etc.). But then something interesting emerged. Patients with GVHD had a higher chance of cure of their cancer (early bone marrow transplants were mostly for leukemia). A number of lines of evidence now show that in addition to replacing the recipients immune system which has been destroyed the infused cells also kill of the cancer. So the best result after a BMT is probably to have a little bit of GVHD: it isn’t too troublesome (patients can die from GVHD) but it helps cure the cancer)

Oncologists are now trying to take advantage of this graft versus tumor effect and expanding it from blood cancers to solid tumors (that primarily arise from internal organs). In general, bone marrow transplants haven’t been very effective for solid tumors, perhaps because higher doses of chemo and radiation aren’t as effective to them. An initial problem with BMTs for solid tumors is that, for reasons that aren’t completely clear, large tumors are strongly immunosuppressive. But there is starting to be evidence that by first reducing the size of the tumor (and thereby its immunosuppressive effect) the graft versus tumor effect may cure (or at least stop/slow the growth) some solid tumors.

In the July 23rd Lancet (yes, I’m behind on my reading again, summer and vacations make it tough to keep up; in my defense I read this a while ago and am just getting around to blogging about it) is an interesting commentary about this and a trial showing some efficacy in patients with metastatic breast cancer.

Remarkably, three patients had delayed graft-versus-tumour effects occurring in association with acute graft-versus-host disease (GVHD) resulting in complete tumour regression, and remain in remission 3·6, 4·2, and 5·9 years after transplantation

Unfortunately there was substantial morbidity among participants.

NOTE: The Lancet makes it impossible to link directly even to abstracts, which require registration to view.

UPDATE: Sorry not to give full references, commentary is Childs Lancet 05 366:273, study itself is Carella Lancet 05 366:318.