Thursday, March 13, 2008

stem cell transplants - a personal history

I was first involved in a bone marrow transplant (BMT) in 1970. We attempted to transplant bone marrow into a toddler with aplastic anemia from an identical twin. It did not take and the child dies. Such a transplant is called a syngeneic transplant and I have never been involved in one since.

In 1983 I got involved in a an autologous bone marrow transplant (ABMT). This was a woman with untreatable ovarian cancer. The idea was to increase the dose of chemotherapy that we gave her. The most sensitive tissue to the toxicities of the alkylating agents is bone marrow, so we thought we could take this out of the equation by storing it in the fridge while she had a big dose of melphalan. The technology worked but the chemotherapy did not damage the cancer.

In 1985 I was given a grant to pursue the idea of ABMT in lymphoma. We had access to Campath - at that time a rat monoclonal antibody. The problem with ABMT in lymphoma is that there is often lymphoma in the bone marrow, so we thought we would be able to launder the marrow with Campath to clean out the lymphoma. This was more successful and we did our first CLL/SLL transplant in 1985. He was cured of his CLL/SLL but died 13 years later of lung cancer.

We transplanted several other patients at this time and some of these were very successful ans some are still alive. For patients with very heavily contaminated bone marrow, even Campath could not get it clean. We then saw a paper by Martin Korbling who described a patient with Burkitt lymphoma who had been treated by a stem cell transplant using stem cells harvested from the peripheral blood (PBSCT). We thought we could try the same thing, especially since I was President of the European Society for Haemapheresis at this time and new all about harvesting cells from the blood.

In fact stem cells had been harvested from the blood before in chronic myeloid leukemia, but that was thought to be a special case, where the disease seemed to consist of bone marrow spilling out into the blood. No-one had suspected that you could get marrow stem cells from the blood in other diseases.

In 1986 we had a patient whose bone marrow was solid with lymphoma (mantle cell lymphoma in fact) We were trying a new chemotherapy regimen, IMVP16, and we had the idea that during the recovery phase from the chemotherapy, stem cells might shower into the peripheral blood as they had with Korbling's case. Sure enough, we had an assay for bone marrow progenitor cells (CFU-GM) as after chemotherapy we found large numbers of these cells appearing. By this time Chris Juttner in Adelaide had done a stem cell transplant in AML so we went ahead in our patient. It was a great success and we put him into a complete remission that lasted for 18 months. This was the first PBSCT in the UK and we think the third or fourth in the world. We did two further such transplants and then published the three cases in a paper in the B J Haem. The important finding was that the neutrophils recovered much more quickly after a PBSCT than after an ABMT, 15 days compared to 24.

We then started doing autografts in myeloma. Having already given high doses of melphalan in this disease and nursing patients through 6 weeks of pancytopenia, we though we would be able to manage this safely. In order to generate the stem cell harvest we had to give 7g per square meter of cyclophosphamide, a huge dose, but the patients negotiated this safely. Again this was very successful, though others were worried about the large dose of chemotherapy, we found that we were able to harvest enough stem cells to do a double autograft in some patients.

Then an Italian group published the fact that instead of chemotherapy you could generate stem cells in the blood by giving the growth factors G-CSF or GM-CSF the whole field took off. In fact, even allogeneic transplants used peripheral blood stem cells as a preference. Because bone marrow transplants and peripheral blood stem cell transplants tend to get lumped together a new term was coined - human stem cell transplants (HSCT) which encompasses both.

We did our first allograft in 1985. She was a young mother with high count acute lymphoblastic leukemia. This disease has a terrible prognosis and we decided that she needed a transplant. Because the past 4 transplants that we had sent to London had all died of the procedure we decided that we couldn't do worse if we did it ourselves. In fact we did rather better, because at least the patient got home for a while. Unfortunately, she developed graft versus host disease and then interstitial lung disease and died a few months later. I met her daughter a few months ago. there were no recriminations; she though that we had done the best for her mum. She left the hospital in a white Rolls Royce in a blaze of publicity.

In this case her sister had been the donor - it was a matched sibling transplant. We went on to do several more transplants which were more successful, but unfortunately the powers that be decided that resources should be concentrated in a different center.

When I started going to Kings College Hospital, I linked up with the biggest transplant center in the UK, one run by my old research fellow who had done our first allograft with us back in 1986. The majority of transplants done there are matched unrelated transplants (MUD) where the donors come from a volunteer donor panel. Sometimes these are known as volunteer unrelated donor transplants (VUD). To some extent this has made transplants more available, but still, because most hematologic diseases occur in older patients, most are unsuitable for standard transplants.

I remember going to a lecture about 10 years ago when the lecturer proposed that transplants work not by rescuing patients after a massive dose of chemotherapy, but by an immune attack on the tumor, the so-called graft-versus-leukemia effect. Therefore it wasn't really necessary to blast the patient with radiotherapy, simply to immunosuppress him enough for the graft to become established. This 'mini-tranplants' began. These are sometimes known as reduced intensity conditioning (RIC) transplants, and sometimes non-myeloablative grafts. There are various regimens used for the conditioning. In Seattle they use low-dose total body irradiation, but in other centers they rely on a small dose of fludarabine to immunosuppree, and in the UK they often use Campath. Patients up to the age of 70 can be safely transplanted, which brings patients with MDS and CLL into the transplantable range.

Still to be solved is the problem of ethnic minority volunteer donors. One solution seems to be cord-blood donors. Cord blood doesn't need to be so tightly matched and one or two mismatches are often perfectly acceptable. This extends the number of possible donors and even with patients who are half Serb and half Nigerian a donor can be found. Kings has started a cord blood program. Often the graft is not large enough for an adult transplant and in these cases two cords must be used. Only one will transplant, but the second sustains the first while it is expanding. One disadvantage of cord transplants is the risk of EBV driven lymphomas which occurs in 20%. The risk can be elimnated if rituximab is given with the graft, but this will likely make the recipient hypogammaglobulinemic for life.

Transplants are getting better all the time but the problems are not yet solved. There are patients that sail through the procedure with little problem, for others the procedure is lethal. We know some of the factors that influence outcome, but not all. Because the risk is uncertain we are reluctant to recommend it except where the alternative is definitely worse, but often that is a matter of judgement.


Chonette said...

I just love the detail of your historical chronology on your writing.
I was surprice to learn that only 19 transplants of CLL had been done at the Royal Free Hospital, I thought it was very little, but reading your blog it makes me more aware of how new the technology is for RIC-MUD-SCT.
Yes it is a very personal decision and all things have to be considered, but maybe it is worth the risk if at least the experience will help future patients, I am sure each transplant leaves a positive learning for doctors.
Thanks for relating your personal history on transplants.
Keep it going

Anonymous said...

You mention the 'powers that be'. I assume that's the government in the NHS.

Also, you don't mention this time the miserable life some (all?) transplant patients have after their transplant. You mentioned in a previous post the two patients who chose death over graft versus host disease. I know of one person who, several years post-transplant, still has serious skin problems due to G-v-HD, to the extent that they won't/can't leave the house without wearing a knit cap, scarves, and over-all body covering (not a problem in Taliban countries I suppose).

But definitely life-changing and not in a good way.

Is the transplant worth the time, pain and suffering, and money???

Some CLL folks blithely discuss a transplant as just another treatment, but I think it is so much more than that.

Terry Hamblin said...

The powers that be were teaching hospital experts who thought that a teaching hospital should do teh transplants even though our unit had a much better academic record. It was this epsiode that made me realize that you can't fight the system. My transplanter coolleague promptly decamped to Chicago.

No, I haven't commented on likely outcomes in this article - I was using it to explain the various abreviations to ACOR members.

Anonymous said...

I enjoy the historical perspective.

I often think that if I had had CLL a hundred years ago, I would be dead by now.

Even though there is no cure, treatments do matter and do add years of good quality of life for the patient.

Anonymous said...

Thank you for the history Dr. Hamblin. I have spent over seven months preparing for a mini BMT- at Ohio State University-to have it called off due to other ailments... a cancerous kidney. It is expected that I might once again climb the BMT tree- if so I do it with extrme reluctance.

God Bless,

Randy Shannon