Sunday, November 16, 2008

My visit to the NCI, Part 2 - The expert consensus on transplants

Readers will recall that in Part 1, I had approached the National Cancer Institute about a transplant clinical trial, a possible donor had been identified, and I was asked to meet with a transplant doctor to determine what to do next. Marilyn and I set out from Arizona on a road trip to Bethesda, MD, where the NCI -- and possible salvation from CLL -- awaited.

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.
After mulling over these points, Marilyn and I concluded that I was not yet ready to take the leap. While my 11q deletion is not the best of news -- though even 11q is not monolithic, so to speak, and there are better and worse variations that we are only beginning to understand, some of which Dr. John Byrd is testing for at his lab in Columbus -- my better-than-expected response to what was essentially mild chemotherapy was proof that my clinical course was not sufficiently unfavorable, at least not yet, to justify the risk.

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.


Anonymous said...

At last a REAL CLL post and not a sob story about politics.

I suggest you have your transplant soon. Obama will take options away from you. Just wait and see.

No transplant for me! I've seen up close and personal what the results can be. It is not pretty. In fact, it's like one of those sci-fi horror movies. Talk to a transplant nurse in an unguarded moment and see whether she would have one. I'll bet she'll say no.

I have a relative who used to work at the Hutch and would never consider it.

Also remember that CLL care is getting better every year (though not fast enough, of course).

Then, of course, there is socialized medicine a-coming!

David Arenson said...

I know other people who share your distaste for transplants, who swear they'll never get one, and I know people who have done well with them. I think it's all a matter of what you're prepared to put up with and the risk you're willing to take. Arriving at the NCI, which looks as imposing as its name, helped remind me how serious a step it would be. I'm still prepared to take it, if and when the time comes, so long as I am not handicapped to start with by something like a poor HLA match, etc. The risk is big, and so is the reward. I'd rather go out fighting if there is a reasonable hope of success but I'm not going to jump before I have to.

Anonymous said...

As usual, this is a well written summary and should serve others as a good resource for that which, unfortunately, still remains something of a crap shoot.

The pros and cons have been well laid out. the concept of hitting the 'sweet spot' is the most important, as that time will vary for each individual along with the vagaries of their own particular version of the disease (and the influence of whatever types of treatment they have previously had).

For any one considering the possibility of taking this step it still pays to lay the groundwork and begin investigating possibilities early enough that any move to proceed to HSCT is not done under duress as it can take a long time to locate a suitable donor. When the stars line up correctly and the 'sweet spot' has been reached it is best to be able to act or not reasonably quickly, so as to avoid the need for further 'salvage' type therapy which may serve to diminish the chances of success for a post "sweet spot" HSCT.

You have done your homework and this blog has served us all well.

Good luck,


Anonymous said...

This is DWCLL again...I forgot to mention that as you point out, even when the stars line up and all due diligence has been done, a large element of skill on the part of the transplant team and, perhaps, an even larger component of luck on the part of the patient still plays a huge role in determining outcomes. This is not a game for the faint of heart, though I suspect that many lucky people have sailed though HSCT without even recognizing all of the sharks and alligators in the water.

Once again,

Good luck,


Anna L. Conti said...

Thank you for taking the time to lay this out so clearly (the topic is complicated but your summary is quite lucid.)

Anonymous said...

A lot of hard work David. Emotionally taxing, I know, for you and Marilyn. I support in full your choice/choices that the two of you have made. It is important to understand how your personal CLL reacts to treatment. 17p deletion is a scary thing but treatment is coming that will even hit a home run with that deletion.
I look at it as the ultimate "waiting" game. How many of us can wait for the cure? I hope that Tom can. I am not sure how quickly 17p deletion % goes upward. At the last test, Tom's was still in small numbers, although I don't even know what the numbers are yet. Do small % of this deletion cause any problems? More questions, more unknowing.
Thanks so much for keeping us all in your loop. You do rock my world.
Hi Marilyn!!!!!

Jenny Lou

Anonymous said...

When considering possible treatment options, there are no right or wrong answers. In a way, I found that that fact made it easier for me to decide things. I've had a harder time deciding which peanut butter to buy at the supermarket than in choosing some of my treatment options. When in the process of thinking about my choices, on the one hand I'd be saying "My life could depend on how I choose," and so the choice seemed fraught with life-and-death implications. But on the other hand I'd say, "But nobody knows which is the better choice, and no matter how hard I study the data I'm not going to uncover the hidden key." So, in a very real sense, it doesn't really matter how you choose. Ultimately, as David implies, you just cut the Gordian knot with your sword of intuition.


Anonymous said...

Thanks for sharing what you have learned. For those in a similar boat (i.e. between a rock and a hard place), your research is much appreciated!

PS I read that you are a UCSC alumni. Too bad you didn't go to college where the weather's a bit warmer, you know, some place like UCSB!

Signed, UCSB CLL'er!

Anonymous said...

Another thing that many people don't think about is the support they are going to need from family.

I probably wouldn't qualify for a transplant because my wife also has a very serious disease and gets hospitalized once or twice or more a year.

Difficult to take care of a transplant patient when you yourself is in the intensive care unit.

Brian Koffman said...

Excellent discussion. I would add that the not only is mortality lower when you have your transplant earlier with fewer comorbidities, but you are likely to have an easier time of it
Be well


"I suggest you have your transplant soon. Obama will take options away from you. Just wait and see."

I partook in Japanese "socialized" medicine for 14 years and may return to Japan because of it. They have more options than we do it seemed to me even though their medical system isn't always as plush with amenities as our.