Monday, October 08, 2007

Del 11q23

I am responding to one of my correspondents up front because not everybody reads the 'comments' on this blog. 'Anonymous' has misinterpreted the situation with del 11q23, which means I have made myself insufficiently clear, and I apologise.

Up to 20% of patients with CLL have del 11q23 at diagnosis, and more acquire it as the disease progresses. On the piece of chromosome that is deleted is the gene that codes for the the protein that is missing in a strange congenital disease called ataxia telangectasia. The gene is known as ATM (which stands for 'mutated in Ataxia Telangectasia). We know the gene is involved in the same apoptosis-inducing pathway as p53, but it seems that whereas a defect in only one of the two p53 genes is necessary to cripple this pathway, both ATM genes have to be damaged or missing to achieve the same effect. You can read in more detail about it here.

The importance of this pathway is that most of the drugs that kill CLL cells do so by making use of it. This is true for fludarabine, chlorambucil and rituximab. The only exceptions we are sure of are Campath (alemtuzumab) and high dose steroids. Flavopiridol also by-passes this pathway, but a safe and effective way of giving it is still being developed. Revlimid (lenalidamide) might also be useful in this situation, but comprehensive results are not in. HuMax is another antibody not fully tested in this situation.

Clinical trials have shown that most patients that are primarily resistant to fludarabine combinations have a defect of p53. On the other hand patients with del 11q tend to respond well, but they also tend to relapse earlier than other patients. This may be because there is an increased tendency for these patients to acquire an ATM defect on the other chromosome 11. The problem then becomes how should such patients be retreated. Another round of FCR or perhaps PCR will put most patients back in remission, but being exposed to these drugs a second time raises risk of immunodeficiency and marrow failure. Perhaps these patients should be the ones in whom clinical trials of newer agents should take place. Drugs like HuMax, Revlimid and flavopiridol might be tried. Newer drugs that inhibit the enzyme PARP1 look promising in the laboratory, and I hope they will shortly make an appearance in the clinic.

Some would argue that such patients should be treated with Campath and high dose steroids. This regimen would likely work as well as it does for p53 deleted patients, though it cannot at the moment be justified for use as first line treatment in those who have never been treated. The problem with Campath and steroids is that responses are likely to last less than 18 months, and this regimen is best used in preparation for a later low intensity allograft.

I have been criticised as being unduly pessimistic about stem cell transplants. I might respond that that is because transplanters are unduly optimistic. To a man with a hammer, everything looks like a nail. But I want to reflect the truth, not opinion. It is true that a stem cell allograft is probably the only treatment that offers a cure in CLL, even in those with bad-risk cytogenetics. There is a sufficient graft-versus-leukemia effect to be confident that when it works patients can enjoy a long and healthy life. However, it is risky. Transplant-related-deaths used to account for 40% of patients when full intensity conditioning was used. It was higher in CLL then in other conditions because the patients tended to be older, they were already immunodeficient and it was usually done as a last resort when all sorts of other body poisons had been administered. It had been hoped that the introduction of reduced intensity conditioning would reduce the treatment-related mortality.

What has happened is that the age at which transplants are attempted has increased. It is quite commonplace for patients up to the age of 70 to be offered a transplant, whereas 50 used to be the absolute upper age limit and most were unhappy about anyone over 40. The reason for increasing the age is that patients would no longer have to withstand total body irradiation or high dose cyclophosphamide and busulphan. Instead they might simply receive immunosuppressive treatment such as fludarabine and Campath. That being said there is not just one type of reduced intensity conditioning, and no-one has worked out what is best for CLL. At Seattle the use low-dose total body irradiation; at Kings College, London they use fludarabine, busulphan and Campath. At University College, London they have been doing a trial to see how little Campath they can manage with. Others use anti-lymphocyte globulin. There are many possibilities. So when you sign up for a reduced intensity allograft - also known as a mini-allograft - you are taking part in experimental therapy.

The problem that transplanters are grappling with is graft-versus-host disease. This first shows itself as a rash, typically involving the palms of the hands and soles of the feet, and if that is all it is it can usually be managed - indeed those who have grade I GVH have the best outcome. But it also involves the gut (causing diarrhea), the liver and other organs. Acute GVH can be avoided by removing the T cells (Campath does a very good job), but abolishing GVH gets rid of the graft versus leukemia effect and without that, relapse is inevitable. So you need some T cells, and indeed, if the disease shows signs of relapsing the transplanters add some back as a donor lymphocyte infusion. Keeping the balance between too many and too few T cells is the transplanters' art. Too many and the graft versus host disease becomes uncontrollable, too few and not only is relapse likely, but viral infection - especially from CMV becomes a danger. Even if acute GVH is avoided, chronic GVH can be very difficult to live with.

In my reading about stem cell transplants, I have found it difficult to find much comment about chronic GVH. One text book (Handin, Lux and Stossel) says "It is the most insidious of transplantation complications and, in some respects, the most difficult to handle." Characteristically it involves the skin which develops a condition akin to scleroderma, with thinning, scarring, and ulcer formation. Hair loss is a feature as well as photosensitivity and depigmentation. There is an absence of saliva and tears. Muscle and joint pains, inflamed tendons, joint contractures, strictures of the gullet, sore mouth, liver damage and cirrhosis, and failure of the immune system are all problems that occur. Of course, it is not severe in everyone, but it is quite common. In a study from Nashville two thirds of patients had some degree of chronic GVH and in a third of these it was classified as severe.

This is what Peter Dreger, the leader of the German stem cell transplant program, said at the IWCLL meeting in London, "Allo-SCT from matched-related or matched unrelated donors can be highly effective in patients with otherwise resistant CLL. With modern strategies, non-relapse mortality can be kept to ~20% or lower, but the morbidity asociated with graft-versus-host disease remains a significant problem. Due to the absence of controlled trials in defined disease settings, however, it is unclear what the real impact of allo-SCT in the treatment of CLL might be, and whether it can change the natural history of poor-risk CLL. A randomized phase III trial addressing these issues, as well as the optimum time of transplantation is currently being prepared by the German CLL study Group."

The difficulties of reduced intensity stem cell allografts in CLL are reflected in the outcome data. No-one has huge experience, but there are a number of reports of 30-70 patients treated at single centers or groups of centers. Treatment-related-mortality varies from 18% to 39% and two year survival from 51% to 80%. There is no way of selecting out who does it best, because none of the studies is really a clinical trial, there are no standard entry criteria and some of the studies (including one of the largest with the best results) used several kinds of conditioning regimes over the period of the study.

So I am not against stem cell transplants any more than I am against marriage. And you know what the Book of Common Prayer says about marriage, " is not by any to be enterprised, nor taken in hand, unadvisedly, lightly or wantonly ... but discreetly, advisedly, soberly and in the fear of God."


Anonymous said...

I guess the take home message is, if you're going to get CLL, get it 20 years from now...

It's a sobering message. Having CLL is certainly not for sissies.

I suppose the only reason for doing it is a strong will to survive, knowing that you really will be never the same again.

We need better treatments so that we can avoid the specter of a transplant. Short of that, chose treatments that don't raise the risk of further genetic damage, I suppose.

Anonymous said...

BTW, a PARP1 inhibitor, ABT-888 is currently in clinical trials at the National Cancer Institutes in Maryland. See

Several other PARP1 inhibitors are also under study, though clinical trials are not planned at the present time, unfortunately.

David Arenson said...

" . . . patients with del 11q tend to respond well, but they also tend to relapse earlier than other patients. This may be because there is an increased tendency for these patients to acquire an ATM defect on the other chromosome 11. The problem then becomes how should such patients be retreated."

I have noticed, anecdotally, that some 11q patients do better than others. From what you are saying, the presence of a defect on the second chromosome may be an important factor in duration of response to treatment.

This implies that patients with a defect on just one chromosome will have lengthier remissions, perhaps approaching that of other patients (?), while those with a second defect are in another boat. (It is almost as if 11q patients can be divided into two groups, those with merely a bad prognosis and those with a worse prognosis.)

Would a FISH test of both chromosomes be a wise step before considering retreatment, or for that matter fromtline treatment?

Can you recommend any studies of 11q in CLL for further reading?

Finally, is a defect on the second chromosome pretty much an inevitability over time, either by clonal evolution or as a side effect of treatment?

Terry Hamblin said...

The defect on the second chromosome is a mutation not a deletion; it wouldn't show on FISH, but requires sequencing of the gene. that is wahat Tanya Stankovic has done, but it is a research technique not easily transferable to the routine laboratory.

At the moment this is still one of a number of possibilities for the heterogeneity of del 11q patients, but I think it is most likely. We do not know how inevitable this development is.

My longest survivor with del 11q lived 334 months after diagnosis.