Thursday, October 08, 2009

Who needs a transplant?

I think another article about bone marrow transplants is due. A paper has appeared in Blood detailing the European experience in CLL, so it is timely to review this and to reacquaint readers with the issues.

First off, we don’t call it ‘bone marrow transplantation’ anymore, because we quite often take the graft from the blood. We tend to talk about stem cell transplants, though this is confusing now that infusions of embryonic stem cells are being used for some neurological diseases. The authors entitle their paper “Allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: ready for prime time?”

Note the ‘allogeneic’. 25 years ago when I started in transplantation, we used to think that autografting; taking the donated marrow from the patient him (or her) self; would avoid the nasty complications of rejection and graft-versus-host disease. However, nobody is cured by an autograft. Tom McCune, who for a long time was thought to be the one patient to be cured in this way, has relapsed. I had a patient who went 13 years after an autograft and died of something else without relapsing, but I suspect he would have relapsed over time if he hadn’t got lung cancer.

So, let’s be clear, the purpose of allografting is to cure. How does it cure? Well, it’s not by allowing us to give more chemotherapy and then rescuing the damaged marrow with a graft. We used to think that was what we were doing, and the superiority over autografting was because the autograft would always be contaminated by residual disease; hence the fashion for laundering the marrow with monoclonal antibodies. However, allografts are also superior to transplants from identical twins whose marrow was completely clean.

No, it turns out that the efficiency of an allograft depends on its ability to mount an immune attack on the leukemia – the so-called ‘graft-versus-leukemia’ effect. This being so there was no longer any need to give the whopping doses of chemotherapy or radiotherapy, just enough immunosuppression was needed to ensure the graft would take. These days most transplants use ‘reduced intensity conditioning’ and because of this we can do them in increasingly older people. I used to joke that my ambition was to get so old that nobody would think of doing a transplant on me. I have a way to go as they are done routinely up to the age of 70 and exceptionally in people who are older. This is good news for patients with CLL since the median age of presentation is 72, and though some patients present at an earlier age (my youngest is 21) and older patients can often be managed to the end of their natural lifespan with palliative chemotherapy, nearly 50% of patients fall within the age when a transplant is feasible.

So who should have a transplant? I guess the answer is that bit is a judgement issue, since there are no randomized clinical trials to give us an answer. Even reduced intensity conditioning allografts are hazardous. So like matrimony, transplantation is not to be enterprized, nor taken in hand, unadvisedly, lightly, or wantonly, to satisfy man’s carnal lusts or appetites, like brute beasts that have no understanding; but reverently, discreetly, advisedly, soberly and in the fear of God, duly considering the causes for which transplants were ordained.

Transplantation should be reserved for patients with poor-risk disease, among them, those who are fludarabine refractory. The outlook for these patients is dismal. Before the availability of monoclonal antibodies, the overall response rate for the first salvage therapy after relapse from a fludarabine-induced remission was only 22% with a median overall survival (OS) of 10-12 months, and even though alemtuzumab is licensed for fludarabine-refractory patients, the response rate is only 33% and the median OS is only 16 months. FCR will produce a higher response rate in fludarabine refractory patients (58%), but the length of remission is probably not very long. I say probably because the paper does not tell us, though the more intense regimen of OFAR gives an overall survival of less than a year in this situation.

Define ‘fludarabine refractory’. This means that there was no PR or CR following treatment with standard doses of fludarabine or that if there was a response, progression occurred within 6 months of stopping treatment.

The major reason for failing to respond adequately to fludarabine is loss of p53 activity. p53 is a protein discovered more than a quarter of a century ago by Richard Lane at Dundee in Scotland. It is called the ‘guardian of the genome’. Its function is to detect damage to DNA and assess whether the damage is reparable. If it is, then damage repair is initiated, if it is not, then p53 starts up a program that results in cell death. Most anti-cancer drugs (including fludarabine, chlorambucil and bendamustine) use p53 induced apoptosis (programmed cell death) to kill tumor cells. We can detect that p53 has gone missing with FISH, since the p53 gene resides on the short arm of chromosome 17. The technical term for those who have lost it is del 17p.

Don’t we have two chromosome 17s? Isn’t the gene for p53 on the other chromosome 17 sufficient? In some cases it may be. We have certainly seen some del 17p patients who have a benign disease; these usually have mutated IGHV genes and do not require treatment according to the IWCLL guidelines. However, whenever a patient with del 17p requires treatment according to the IWCLL guidelines, the other chromosome 17 carries a p53 gene that codes for a disabled p53 molecule. Such patients are refractory to fludarabine and almost always refractory to FCR.

In clinical trials around 5-7% of patients presenting for treatment for the first time have del 17p, but in trials of patients presenting for salvage treatment following relapse, the incidence of del 17p is about 30%.

So who needs a transplant? Anyone aged 70 or under without significant co-morbidities who needs treatment and had del 17p or who is refractory to fludarabine.


Burke said...

Doc, I have a question or two, if you don't mind.

If a person is successful with frontline FCR and later relapses after a lengthy period and if tests after relapse show no del 17p, would he be wise to go straight into a transplant? Or should he continue chemo until he is seen to be fludarabine refractory? If he waits until he is refractory, isn't he greatly decreasing his chances of having a successful transplant? (Chaya Venkat's "Catch 22" issue)

And something I've wondered about a long time: If conventional chemo can destroy marrow to the point that the patient will have marrow failure (as I understand it sometimes does), how does a patient ever have a successful transplant where the chemo conditioning is far more intensive?

Terry Hamblin said...

I think current teaching would be to try a second line treatment after a lengthy FCR remission.

A transplant will reseed a marrow with haematopoietic stem cells so that a normal blood count will result.

Burke said...

"A transplant will reseed a marrow with haematopoietic stem cells so that a normal blood count will result."

What prevents this from happening after conventional therapy as it does following a transplant? Don't some stem cells survive the therapy or all they all destroyed? If so, how do such patients ever recover?

Terry Hamblin said...

There are usually some surviving stem cells, depending on how severe teh chemotherapy. We used to use high dose melphalan to treat myeloma in the days before autografts. The bonde marrow would be destroyed, but it would start to grow back again after 6 weeks.