Friday, January 28, 2011

T-depleted transplants - the UK experience

The point about RIC transplants is that they use the transplanted immune system to attack the host's leukemia. This graft-versus-leukemia (GVL) effect is difficult to separate from the graft-versus-host-disease (GVHD) that usually accompanies it. As we saw yesterday with the report of the German study chronic GVHD is very common and it can be very debilitating; so much so that I have had patients who have committed suicide rather than continue with it. I remember a teenager with ALL whose GVHD made him look like an old man of 80+. He drowned himself.

One way of attempting to prevent GVHD is to deplete the T cells from the graft, but this carries the risk of graft failure and relapse because some T cells are necessary for the graft to survive and in getting rid of the T cells you are apt to abolish GVL withe the GVHD. The German study seemed to have suffered from both problems, though the number of T-depleted transplants was small and the figures were not reliable.

In the October 21st issue of Blood Steve MacKinnon and his colleagues from teh Royal Free Hospital presented the results of a study in which he titrated the dose of alemtuzumab used to T-deplete. Most people use 100mg of alemtuzumab (5 days of 20mg/d infused into the recipient before the transplant) and this is the experience of MacKinnon and of the German group I wrote about yesterday. Previous British experience has been that the incidence of grade 2 to 4 acute GVHD has been 2% to 20% and with chronic GVHD has been 0% to 13%. The disadvantage of this approach has been slower immune reconstitution and therefore more frequent infections and possibly a lesser GVL effect.

In this study they have titrated down the dose of alemtuzumab. In four cohorts they used 60mg, 40mg, 30mg, or 20mg. 106 patients were transplanted - a mixture of AML, CLL, myeloma, NHL and Hodgkin's disease. There were 15 patients with CLL. All the donors were HLA matched siblings. The conditioning regimen was 5 days of fludarabine 30mg/sq m/d and one day of melphalan 140 ng/sq m. This is probably slightly more intense than the fludarabine/cyclophosphamide regimen used by the Germans.

There was a marked difference between those who received 20mg of alemtuzumab and those who received more than 20mg. The follwing differences were statistically significant. Grade 2-4 acute GVHD, 16% v 5%; extensive chronic GVHD 24% v 9%.

The two year progression-free survival was 60% and overall survival 73%. Full donor chimerism was 81% at 2 years. The non-relapse mortality was 15% at 2 years.

The use of alemtuzumab allows DLI to be used to eliminate mixed chimerism and therefore abort early relapse, without too great a risk of GVHD. Selected T cells may also be infused to protect against re-activated CMV infections and possibly other viral infections.

In future T-depleted transplants in the UK will be with 30mg rather than 100mg of alemtuzumab. It has to be recognized that this study was in a number of different diseases and teh CD52 positive tumors like CLL and NHL would adsorb more alemtuzumab than the myelod tumors, but even so 30mg seems to be enough.


Unknown said...

Amazing input from 2 high quality trials Terry. Thank you for your contribution

Chonette said...

Thank you for writing about this, since my SCT I have been very interested in the different preconditioning protocols done across the transplant centers.
I dreaded all those GVHD problems and I consider myself fortunate to have sailed through with just a few expected problems.
I have great respect for the McKinnon team.
I am doing well and having a beak in sunny Merida Mexico. All test good and only on peniciline and Acyclovier now.

Brian Koffman said...

Thanks for a thoughtful review of an important subject.
You said that T cells were important for engraftment. I thought it was the T cells that blocked engraftment and I have always felt my lack of ATG with an unrelated donor was a factor in my losing my graft

Terry Hamblin said...

T cells in the host block engraftment, T cells in the graft enhance it.