Date: September 10, 2007
Dr. Timothy G. Call – Mayo Clinic,
Dr. Terry J. Hamblin – Royal Bournemouth Hospital
Dr. Andrew R Pettitt – Liverpool University,
Dr. William G. Wierda – M. D. Anderson Cancer Center
Forward by Chaya Venkat – CLL Topics.
CLL may be the good cancer to have (not!), but it is sure as heck confusing. In a recent article (Catch 22 – The Transplant Minefield) we reviewed the bewildering and complex issues that go into making mini-allo transplant decisions. This is a continuation of that subject, with the feedback we received from four CLL experts.
Several important issues we raised in our article:
I feel strongly that our guys are put at risk when experts don’t communicate effectively with each other. We came across this thorny problem once before, when discussing the sorry lack of communication between CLL experts and dermatologists. I wish I had a dollar for every CLL patient who wrote me and said his/her dermatologist had no idea that CLL increases the risk of aggressive skin cancer. Or for every local oncologist who treated CLL patients with demonstrated history/risk of skin cancer with T-cell damaging drugs such as Campath and fludarabine, without so much as a second thought.
I get the feeling that not all transplant experts are up-to-date regarding modern molecular prognostic indicators in CLL and their impact on prognosis. And CLL experts may not have kept up with the changing trends (and improving success statistics, year after year) of transplant procedures, especially the new “mini-allo transplants”. Transplanters still think of CLL as one single monolithic disease, the “good cancer” to have, and therefore only in rare cases is it appropriate to transplant CLL patients. Oncologists, on the other hand, are only too aware of the horrors of GVHD and the mortality risks associated with heavy-duty full myeloablative transplants – without necessarily having kept up with the latest statistics using mini-allo approaches and better GVHD control techniques.
Don’t get me wrong – even with the kinder and gentler mini-allo versions, stem cell transplants are no picnic and there is definite risk of death, not to mention risk to quality of life, big time. No one in their right mind would even consider this option, unless they happen to have a particularly nasty version of this incurable (as in it might kill you) cancer. Researchers have yet to get a good handle on controlling GVHD without losing the precious graft-versus-leukemia effect that may actually CURE our guys once and for all. For the folks with good prognosis there are many less dangerous options to consider, if and when they need to do something.
Neither do I mean to tar all experts with the same brush. We are fortunate to have heard back from four world-class CLL experts on this subject, when we posed them the questions. I am deeply disappointed that none of the transplant experts we contacted were willing to comment on the record. Perhaps they are shy of publicity in the patient press, or just too busy. It has not been for a lack of my trying (nagging and guilt-tripping may be more appropriate words). If I hear from any of them in the future, we will be sure to publish their comments as well.
Please join me in thanking Drs. Tim Call (Mayo Clinic), Andrew Pettitt (Royal Liverpool and Broadgreen University Hospitals), Bill Wierda (M. D. Anderson Cancer Center) and our own Terry Hamblin.
Below are their thoughtful and candid comments on the subject. As you can see, it is still hard to define “Best Practices” in this complex and important area. But we are taking the first steps in getting consensus, by engaging these folks in discussion. As good scientists and researchers, each of our four experts keeps an open mind on the many complexities surrounding this subject. The message that comes through loud and clear is that we have many questions and not enough answers. Nor are we likely to develop a better understanding unless we get broad-based discussions among CLL and transplant experts, leading to well designed clinical trials. In the meantime, patients who need to make decisions now will have to do the best they can, shopping around until they find a transplant center which shares their point of view.
Division of Hematology
Mayo Clinic, Rochester, MN
You are asking the right questions, it just seems that the more transplants we do … the more questions I have and the less dogmatic I can be. Not whether or not we should be doing stem cell transplants in CLL patients, but exactly the questions you mention. Who – When – With what?? Hard to be definitive yet. I think the biggest need is for groups such as yours to "ring the bell" that there needs to be intercenter and cooperative group efforts quickly established to answer some of these questions in clinical trials. I am most interested in seeing what light the IWCLL abstracts/presentations/discussions may shed on this next week.
Below are some of my opinions/thoughts which I really must say are in constant flux.
We need to work together.
Leukemia. 2007 Jan;21(1):12-7.
Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus.
Dreger P, Corradini P, Kimby E, Michallet M, Milligan D, Schetelig J, Wiktor-Jedrzejczak W, Niederwieser D, Hallek M, Montserrat E
Chronic Leukemia Working Party of the EBMT. Department of Medicine V, University of Heidelberg, Heidelberg, Germany.
The aim of this project was to identify situations where allogeneic stem cell transplantation (allo-SCT) might be considered as a preferred treatment option for patients with B-cell chronic lymphocytic leukemia (CLL). Based on a MEDLINE search and additional sources, a consented proposal was drafted, refined and approved upon final discussion by an international expert panel. Key elements of the consensus are (1) allo-SCT is a procedure with evidence-based efficacy in poor-risk CLL; (2) although definition of 'poor-risk CLL' requires further investigation, allo-SCT is a reasonable treatment option for younger patients with (i) non-response or early relapse (within 12 months) after purine analogues, (ii) relapse within 24 months after having achieved a response with purine-analogue-based combination therapy or autologous transplantation, and (iii) patients with p53 abnormalities requiring treatment; and (3) optimum transplant strategies may vary according to distinct clinical situations and should be defined in prospective trials. This is the first attempt to define standard indications for allo-SCT in CLL. Nevertheless, whenever possible, allo-SCT should be performed within disease-specific prospective clinical protocols in order to continuously refine transplant indications according to new developments in risk assessment and treatment of CLL.
This abstract quoted above by Dr. Call appeared as an article in the journal Leukemia. This is an important article. Do write to us if you wish to locate and read the original full-text article.
Consultant in Haematology
Royal Liverpool and Broadgreen University Hospitals
Liverpool, United Kingdom
It may be helpful to outline my perspective with regard to CLL and transplantation. Although I have a specialist interest in lymphoid malignancy, because of the way our hematology services are configured I also see all CLL and lymphoma patients within a local population of about 4 million who are potential candidates for autologous or allogeneic transplants in order to guide them through the decision-making process. I also look after patients with a range of diseases during their transplants and see them afterwards in the follow-up clinic. So I guess I have a foot in both camps, although it should be stressed that I do not regard myself as a transplant expert at national or international level.
At the end of the day, there is no escaping the fact that an allograft amounts to a big gamble in which potential (but often poorly defined) long-term benefits are traded off against very real and significant short-term risks. Although reduced-intensity-conditioning (RIC) allografting is almost certainly safer than a ‘full’ transplant, the dangers are still substantial and it should in no way be regarded as a trivial procedure. It should also be stressed that our knowledge of what RIC allografting can achieve in the long term is still fairly limited. This notwithstanding, reduced intensity procedures have emerged as the ‘standard’ form of allo-transplantation in CLL, although there remains widespread disagreement about exactly how they should be performed.
There are essentially three possible outcomes following allografting: (1) the disease is cured (i.e. it stays away long term); (2) the disease is not cured but the patient survives the procedure; and (3) the procedure itself is fatal. It is always difficult to assign each of these outcomes with a precise probability value. However, taking an ‘average’ CLL patient (of course there is no such thing) who is in a reasonable remission (whatever this means), I find it helpful to think in terms of a ‘rule of fifths’, i.e. there is a 3-in-5 chance of the transplant working, a 1-in-5 chance of the disease relapsing, and a 1-in-5 chance of the transplant shortening the patient’s life due to complications. These figures are only crude approximations of the available data but nevertheless give patients and their families something simple and tangible to chew over. It goes without saying that patient selection has a profound impact on outcome, and these ‘guesstimates’ need to be modified according to the patient’s age and general fitness, the precise nature of his/her disease and its remission status, and of course donor considerations.
Another extremely important issue to be factored into the equation is that, irrespective of the final outcome, the procedure is very likely to have a negative impact on quality of life for a year or more owing to frequent hospital attendances and the problems associated with graft-versus-host disease (GVHD) and infection.
Transplantation for CLL is one of those areas in medicine where there are no absolute rights or wrongs, just shades of grey. Under these circumstances my personal belief is that patients and their families should play a central role in the decision-making process. The role of biomarkers in helping with transplant decisions is an integral part of the 'first step' of my transplant counseling process, i.e. to make sure the patient understands the likely outcome of his/her disease without a transplant. In my opinion, 17p- is the only biomarker that is reliably bad enough to justify transplantation in first remission (although patients with 17p- affecting only a minority of cells should probably undergo further analysis for p53 mutation and functional impairment to be sure one is dealing with a bona fide p53 defect). I should stress that I would not use any biomarker as a reason to start treatment earlier than usual as there are occasional 'high-risk' patients (including those with 17p-) who defy the rules and remain well and stable for a long period of time.
It is very important to remember that the clinical and therapeutic context has a major impact on the prognostic value of some biomarkers. For example the real strength of IgVH gene mutation, CD38 and ZAP70 is in predicting time to progression in newly diagnosed patients with early-stage disease. In patients who have already progressed to the point of requiring treatment, these biomarkers have a relative weak effect on outcome whereas 17p deletion retains its profound adverse prognostic effect. As for patients who are resistant to fludarabine-based regimens, this probably trumps all biomarkers, which therefore become redundant in this setting.
Having made sure that the patient understands the likely outcome of his/her disease without a transplant, the next step is to explain the theory, logistics, potential benefits, risks and side effects of transplantation, and then to weigh up the pros and cons of having versus not having a transplant within the context of the patient’s specific circumstances. The aim of this discussion is to allow the patient to be able to make a properly informed decision about which way to go. In other words I see my role as providing information and guidance rather than simply saying ‘yes’ or ‘no’. My dual insight into the two worlds of CLL and transplantation no doubt makes this process easier for me than it would otherwise be, and in situations where CLL and transplantation are dealt with by separate medical teams, mutual dialogue would be extremely important.
Whether a transplant is the right way forward for an individual patient will depend largely on his/her priorities, personal circumstances and attitude to risk. Faced with the same information, different patients will come to different conclusions based on these various considerations, and I see nothing wrong in this. In my experience this approach inevitably results in sensible decisions being made, provided no punches are pulled when explaining the negative side of things. Of course, life would be much easier if there was some randomized data concerning the effectiveness and toxicity of allografting in CLL. However, randomized transplant studies are notoriously difficult to perform owing to the profound imbalance between the treatment arms and the understandable preference of patients and doctors to make the issue of transplantation one of choice rather than one of ‘heads or tails’. So for the foreseeable future, it looks as though we will have to make do with single-arm data and apply the usual caution when comparing outcome in different patient cohorts.
Assistant Professor of Medicine
MD Anderson Cancer Center
University of Texas, Houston, TX
Subject: Re: A case history for your review
I hope you are well. Certainly, you are busy.
I think this is a well written article and addresses some important points.
I have a few considerations for you as follows:
This patient is 45 years old, much younger than the median age at diagnosis for CLL (72 years old). This patient has 17p del, which is seen in approximately 5% of patients receiving initial therapy. I think it is important to have discussions that are relevant to a broader group, particularly, older patients. Much of the time, they and their doctor do not realize transplant is an option.
I consider the treatment (SCT) for this patient "experimental", so I hope it is being done on a clinical trial. In fact, I would encourage you to emphasize that treatment advances can only be made through clinical trials. Clinical trials are how we learn if patients benefit from a particular treatment. They help to minimize or eliminate the situation this patient in, searching for information and answers. These are questions that we are not able to scientifically able to answer at this time and won't be able to adequately answer without clinical research.
I had a young patient (50 yo) with unfavorable prognostic factors who was anxious to go to transplant. He was in CR after his initial treatment. He was transplanted by one of the other transplanters here at MDACC. I was somewhat relieved that he had a sister who was a full match and expected this would reduce his risk for complications. This patient died during transplant, before he had a chance to be discharged from the hospital. I have had many others that have been successfully transplanted, however, this one patient, and the painful conversations I had with his wife after his death, have clearly affected my view of transplant and when to transplant. This something that I would not like to consider for a 45 year old with 5 children.
I think it is very important for patients and their family to have a better understanding of transplant. Patients need better education about what a transplant involves in terms of work-up, the actual procedure, and the extensive in-patient and out-patient follow-up. You might think about having some information on your website from patient who were transplanted 1, 2, 3 years, or more, ago. Details of their experience, decision process, positive and negative experiences, etc. I think this would provide a realistic and balanced perspective. There are patients out there you could contact. If you need some names, I would be happy to provide some.
I hope you find these comments constructive.
Royal Bournemouth Hospital
Bournemouth, United Kingdom
Thanks for asking about Richard's case. As you know, I now regularly attend at Kings College Hospital in London, which is the biggest mini-allo center in the UK. I have been following a number of patients who were transplanted for CLL. The thing that stands out for me is that transplanting too late is a disaster. I have seen patients who remain in hospital for over a year after their transplant before they die. They fluctuate between CMV reactivation and GVHD. The treatment for one makes the other one worse. What is common to these patients is that they were transplanted late in their disease.
What makes CLL so much worse than other conditions for which mini-allografts are performed is how immunosuppressed the patients are before the transplant. Patients with CLL are immunodeficient from the start in a way that patients with say, MDS are not. Fludarabine, the drug that is used in most regimens for inducing a remission, is extremely immunosuppressive, producing AIDS-like levels of CD4+ cells for around 2 years. If the patient has been previously exposed to CMV or EBV, the reactivation of one of these herpes viruses is on the cards. Most guidelines have suggested that allografting should be reserved for patients refractory to fludarabine containing regimens or those who relapse within one year. This seemed like good advice at the time, since the risks of transplant in CLL are so great that one would not want to expose a patient to them if there was a reasonable chance of prolonged good quality life on immunochemotherapy alone.
Remember that before mini-allo's, allografts in CLL carried a treatment related mortality of 40%. It had been hoped that mini-allo's would reduce this, but on what has been revealed so far, this has not been the case. Of course this might be because the inclusion criteria have been extended to include older, sicker patients.
However, we now have a prognostic indicator that predicts poor response to fludarabine. Patients who have p53 deletions by FISH do not respond well. Purine analogues, alkylating agents and rituximab all require an intact p53 pathway to kill CLL cells. FCR does not kill p53 deficient calls. I really do not expect FCHuMax to be much better.
I need to spell out some caveats about p53.
I would certainly like to see Richard having a mini-allo in first remission, but I am concerned that done outside the confines of a randomized controlled trial we will not be able to influence any other center, nor the insurance companies. Certainly, a small phase II trial is warranted, but within a short time a randomised phase II, looking at TRM and relapse rate needs to be done. This should not be onerous and would produce a quick result. The problem is that in giving advice here we are extrapolating from insufficient evidence.
There is one other important point. In Richard's case the p53 deletion was present at presentation. This only occurs in about 5% of cases. Overall, about 30% of CLLs eventually become p53 deleted, and obviously these cannot be treated with up front transplants. We still need to pursue treatments that do not allow this to happen.
At the moment I would not recommend allograft in first remission in patients with other poor risk markers like del 11q and unmutated VH genes, though if we can push towards cures of >70% I could have my mind changed. The other thing that needs to be considered which none of the three centers did is the severity of chronic GVHD. I have had two patients commit suicide with severe chronic GVHD. These patients do not appear in the GVHD or the TRM lists, but Richard meet someone with chronic GVHD and discuss the problems before he commits to a transplant.
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