Tucked under the passenger seat of our Prius was a black folder stuffed with articles and studies that weighed the risks and rewards of a transplant. Taken together, Marilyn and I hoped they would help provide an answer to the question: When is a transplant a good idea, and am I at that point? At the very least, we hoped to learn enough to be able to walk into the NCI and have an adult conversation.
The day before our meeting in Bethesda, we sequestered ourselves in our hotel room and read. And read. Avoiding temptations like The Simpsons Movie on HBO, we spent the day awash in Post-Its and highlighters, scribbling notes and occasionally announcing epiphanies.
Some of the articles were especially helpful in getting the lay of the land. Among these were a CLL Topics piece called What Say You Dr. Expert?; an overview by Dr. Andrew Pettitt written for the UK CLL Support Association; and a paper entitled Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus, which reflects the views of European experts (there is no US equivalent). The latter is hard to get hold of but I can send you a PDF if you write to me.
The bottom lines, as near as we could tell, are these (and I would encourage you to find your own hotel and do your own reading and reach your own conclusions):
- Allogeneic transplants are still too risky to undertake without serious thought and thorough investigation. There is a two-thirds or better chance that you’ll get a long term remission or a cure. But it doesn’t take a math genius to realize that there is a fair chance of death or relapse, not to mention the possibility of significantly reduced quality of life due to graft vs. host disease (GVHD).
- Prognostic tests (aka “biological risk factors” or “biomarkers”) alone (FISH, IgVH, ZAP-70, CD38) are insufficient grounds to undertake a transplant, except perhaps in the case of 17p-deleted patients, whose disease is by its very nature resistant to most chemo and likely to be aggressive and result in early death. As the European paper states, “. . . an adverse prognosis suggested by biological risk factors must be substantiated by an unfavorable clinical course.”
- The favorability of your clinical course is generally determined by how well you respond to purine-analogue based therapy (i.e., fludarabine or pentostatin). If you don’t respond well, or if you relapse within two years after combination therapy such as FCR or PCR, you are a good candidate for a transplant. (If you respond to FCR for at least two years, you’ll likely be given FCR again.) A short period (less than 12 months) between diagnosis and the need for treatment is another sign of aggressive disease, though I think it can be argued that since we are all diagnosed at different points in our disease progression, this is something of a moving target.
Dr. Pettitt makes a useful point: “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.”
- The 17p deletion indicates non-functionality of the p53 pathway, in which the 11q deletion is also implicated. The less the p53 pathway functions, the more the body is incapable of killing mangled, mutant cells even with chemotherapy, and therefore the more aggressive the disease. Dr. Terry Hamblin makes the point that “TP53 functional assays might be better than FISH.” Such an assay may be very helpful in further determining whether your CLL is reaching the point of getting out of control. Apparently such an assay is not easy to come by -- welcome to CLL.
- Doctors tend to agree that 17p-deleted patients are better off having a transplant when they achieve their first remission. For the rest of us, they tend to think it should be after the second remission and some might even advise waiting a bit longer, depending upon the patient’s age, general health, prognostics, ability to respond to chemo, duration of remission, and ways in which the disease may be impinging on quality of life.
To see just how unclear the thinking is on this one, the Europeans note: “Although conclusive evidence for CLL is still lacking, experience from other entities suggests that the success rate of the allo-SCT can decrease as the number of pretreatment cytotoxic lines [English translation: chemo regimens] grows. This implies that it might be advisable to consider allo-SCT in eligible patients as soon as criteria for poor-risk CLL are fulfilled. However, the available body of evidence does not allow sound recommendations on this issue.”
- So, in the absence of conclusive evidence, what can we infer from the data we have? Does it make sense to transplant sooner rather than later?
There are two big arguments for not waiting too long. One is that your general health is likely to be better the younger you are, and that means fewer comorbidities and a better chance of successfully undergoing the rigors of transplant. The second argument, and the conventional wisdom, is that CLLers going into transplant with a CR -- which is more likely to be achieved if you have not had too many "pretreatment cytotoxic lines" and become too resistant to drugs -- stand a better chance of success. From what I can tell, this is true. A 2007 study at the Hutch in Seattle showed that none of seven CLLers with a CR relapsed in the first 14 months, while out of 75 CLLers who didn’t have a CR, 31% relapsed.
But that is not the end of the discussion because the risk of death is high enough -- and the success rate of non-CR patients is good enough -- to make waiting a little longer a reasonable course of action for some. It all depends on how you want to play the risk game: transplant sooner and risk not having time you would have had otherwise; transplant later and, having maximized your time already, assume a somewhat greater risk of not having any more of it. This is the crappy craps game you'll have to play.
The European paper has a table that covers seven different studies of patients who underwent transplant. For each study, the percentage of fludarabine-refractory patients is given. I was surprised to see that there were not huge differences in overall survival between studies that had high percentages of fludarabine-refractory folks and those that didn’t. In one study of 73 patients, 82% of whom were fludarabine refractory -- which we can take as a rough guide for how many may have entered transplant without a CR -- the relapse rate was 28% after two years. Indeed, the relapse rate after two years seems to be about 30% in many studies.
Despite the Hutch’s figures on that rather small group of seven patients, there is no guarantee that a CR patient will not relapse. or will not die for some other reason. Having a CR does not protect you from complications and early death (in the first 100 days), which is something around 7%. Nor is it a guarantee against transplant-related mortality, where you might well have a leg up on the non-CR people, but which runs about 15% to 20% in the first two years among all CLLers.
My conclusion is that while a CR is preferable, the desire to attain it does not necessarily trump everything else in making the transplant decision. Statistics are significant from the angle that you look at them. The Hutch study indicates that 69% of non-CR patients had NOT relapsed. The European study shows that after two years 70% out of a heavily-fludarabine-refractory group had not relapsed. My guesstimate is that going into transplant with a CR might add another 10% or 15% to those numbers in your favor. That should not be dismissed, nor should it be seen as the certain difference between life and death. In the end, luck is going to play a crucial role in your outcome.
- For those of us playing softball with CLL by using single-agent Rituxan and the like, it may be hard to define “first” and “second” remission. Most of the experts assume you’ll be using purine-analogue-based combination therapy. How many relapses after Rituxan does it take to equal the “first” or “second” relapse that the experts talk about? All I can suggest is that you look at your ongoing responsiveness to Rituxan, and any additional chemo, as a guide. Eventually, because of AIHA, I needed to graduate to something stronger, the R-C(V)P I had at the end of 2007. I am making an educated guess that my relapse from that regimen will constitute the equivalent of “first” relapse.
- I am making that inference in large part because I seem to respond well to drugs. I always have, be it allergy medication or chemotherapy. The experts agree that disease resistance on the part of CLL will build; the question is at what rate. When there are signs that responsiveness is significantly diminishing, it’s time to think about transplant. Remember Dr. Pettitt’s point about resistance to fludarabine trumping all biomarkers; when the drugs stop working on you, nothing else is going to matter.
- The art of medicine is definitely in play here, as you can tell by reading “What say you, Dr. Expert?” There are the vagaries of the bell curve, the idiosyncratic individual CLL that may give you a break, or maybe not. Ultimately, as I see it, and as I think a lot of the doctors see it, your responsiveness to therapy, your quality of life, and your clinical course and status (e.g, is your marrow still functioning reasonably well?; can you fight off infections?) are the practical factors that outweigh all others. The path to a transplant does not go like clockwork; there is always the need to finesse.
To illustrate that point, here are thoughts from two doctors about the dangers of starting too early and starting too late:
“I had a young patient (50 years old) with unfavorable prognostic factors who was anxious to go to transplant,” Dr. William Wierda of MD Anderson wrote. “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 is something that I would not like to consider for a 45-year-old with five children.”
Dr. Hamblin points out the dangers of waiting too long: “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.”
- So there is definitely a sweet spot, a best window of opportunity for transplant. Not too early (17p excepted, perhaps) and not too late. While you’re still responsive to therapy, but not while you still have a lot of bullets left. While you’re young and fit enough to cope with the rigors of transplant, but, um, not while you’re young and fit enough to enjoy good quality of life while controlling your CLL with chemotherapy.
To quote Dr. Pettitt again: “At the end of the day, allografting amounts to a big gamble in which short-term risks are traded off against potential long-term gains. The dilemma is not only one of whether or not to have an allograft, but also when to have one. Thus, transplants consistently achieve the best results in patients who have not received too much in the way of previous treatment and are in remission at the time of transplantation. On the other hand, allografting has the potential to shorten as well as prolong life. This is very much an area where there are no clear answers, and under these circumstances patient choice is of paramount importance.”
Which is why I always say: Go with your intuition.
Our feelings were validated when we returned home and a new CBC showed that my lymphocyte count was still stable, my red counts had climbed to mid-normal, and best of all I was finally Coombs negative, meaning the AIHA was now less likely to return.
In Part 3, I’ll report on my interview with Dr. Steven Pavletic, transplant protocol chair at the NCI, and his conclusions about my case and insights into the transplant process.