Transplants

I promised that I'd say something about cord blood transplants when I returned from the ASBMT meeting at Keystone.

First, I am not an expert in this field. There are several websites that will give you a good idea about this subject. I recommend _www.cordbloodforum.org_ (http://m1e.net/c?38028146-Rq/w3pwEbVDZI@844914-BK5qDL/BNsuHY) and also Chaya's CLLTopics website.

Here is my understanding of what we need to know. One of the problems with bone marrow allografts in CLL is the high treatment related mortality. Before reduced intensity conditioning came along the death rate associated with transplants in CLL was 40%. Acute graft versus host disease was a major problem.

One of the advantages of stem cells from cord blood is that do not so readily induce severe acute graft versus host disease. This is true even if the graft is not perfectly matched.

But there are too few stem cells to engraft an adult, especially if the graft is not a perfect match. To get round this the concept of a double cord transplant was devised. Cells from two cords are transplanted, and although only one will eventually grow out and repopulate the marrow, the other serves as short term support during the early risky period.

Transplants from child to parent or parent to child usually involve 3 out of 6 mismatches in the major histocompatibility genes. Even with a cord blood this is too much to ask, especially if the patients is over 30.

So the bottom line for CLL patients is if you need a transplant to survive, then a double cord blood transplant is an option, and you might be able to manage a one or two locus mismatch, but probably not three.

On the other hand there is no prospect of saving your baby's cord blood for your own future use - there are likely to be too many mismatches. However, by all means offer your baby's cord blood for the bank. There are no ethical dilemmas over this, it would otherwise be thrown away. And you never know when you might need to make a withdrawal. And withdrawal of a cord blood that is a better match than your own child's would be.

This is the only type of treatment that can cure CLL. For patients who are young enough and who have a donor the results are encouraging enough now to think about it as a possibility. Campath is a useful drug and it works in p53 deleted cases, but its place in therapy has nor yet been defined. I would certainly think about using it with curative intent following complete remission after first line therapy in cases with high risk prognostic markers. However, as one more treatment after failing several other rounds it will only buy a little more time.

There are several other experimental treatment that can be tried in patients who have failed first line therapy, but at the moment a mini-allograft is the best hope of cure in this group of patients. As I have stressed many times, cure is not the only therapeutic ambition in treatment and for some patients long term palliation is a better bet. Drugs like Revlimid, 17-AAAG, anti-CD23, bcl-2 antisense and several others in the pipeline might all have a role to play in CLL treatment, but if I were younger than I am with CLL that had relapsed after a fludarabine/rituximab plus combination and poor prognostic markers I would at least want to discuss a mini-allo with my physician to place it in the batting order among the possible treatments.

An allograft is the transplantation of someone else's bone marrow stem cells into a patient. In order to do this the patient's immune system must be suppressed.

The original concept was to treat bone marrow disease by replacing the diseased bone marrow with healthy bone marrow. It involved first killing the diseased marrow with radiotherapy (total body irradiation) and then transplanting the healthy marrow (actually this was not a transplant like a kidney or heart transplant. No operation was invoved. Bone marrow was sucked out of the donors pelvic bones, filtered to remove the particles, then reinfused into the patient's vein like a blood transfusion.)

The total body irradiation served two purposes - to kill the diseased marrow and to immunosuppress the patient so that the donated marrow was not rejected.

In order for this to work, the donor and patient had to have the same tissue type. This meant that they had to be a brother or sister.

Despite this it was a very hazardous procedure and many patients died. When I was doing them in the 1980s we were pleased to have 50% survive. The main hazards were infection - viruses, bacteria and funguses; radiation damage to the lungs; and graft versus host disease. This last was when the immune system of the donor, which had been transplanted with the marrow, started to reject the patient. It causes rash, diarhea and liver damage.

Because this was such a dangerous treatment some of us thought we could transplant the patient's own bone marrow - a so called autograft. The idea was that we would get a patient in remission and then harvest the patient's own bone marrow and freeze it down. Sometimes the bone marrow wasn't involved and we could harvest the marrow before beginning treatment, and even if it were involved we could launder it before freezing by treating it with a monoclonal antibody. This was my first experience with Campath. We also experimented at this time of harvesting the marrow stem cells from the peripheral blood (this would be 1985-6) and found it to be the preferable method because it shortened the period in hospital by 10 days.

Autografting seemed to work well. It was much safer, fewer than 5% died of the procedure. But relapse was much more likely than with an allograft, despite the fact that just as much total body irradiation was given.

It was then that we began to suspect that as well as there being a graft-versus-host effect, there was also a graft-versus-leukemia effect. The idea was floated that this was the main beneficial effect of an allograft. Perhaps all that radiotherapy was not really necessary. So it proved. It is possible to do an allograft with immunosuppressive treatment only. CLL patients will be familiar with the most immunosuppressive drugs: fludarabine and Campath.

In CLL in the UK we are doing these reduced intensity conditioning allografts (or mini-allografts using fludarabine and Campath conditioning. Graft versus host disease is very low and because the procedure is much safer we can now extend the age up to 60 or even 65, rather than confining it to the under-40s. In the US they don't tend to use Campath, but other immunosuppressive regimens are used including low dose total body irradiation, total nodal irradiation and anti-thymocyte globulin.