Transplants and the treatment balancing act

If we’re smart, we CLLers look down the road and think ahead. A question we should be prepared to answer is this: Might I need a stem cell transplant at some point, or is there a reasonable possibility that I can ride this thing out without one?

Chances are, if you are younger than 60 and have unmutated chronic lymphocytic leukemia, you might well need a transplant if you want to become the eccentric old codger you were meant to be. I, for one, look forward to spending my 80s with Marilyn and too many cats while yelling at kids to get off my lawn. I have no intention of letting CLL interfere with those golden years.

Further signs that you might need a transplant -- and, by the way, transplants are now being done on patients well into their 60s if they are in otherwise good health -- are these: Risky abnormalities per FISH test, such as 17p, 11q, and perhaps Trisomy 12; ZAP-70 and/or CD38 positivity; clinical symptoms that show disease progression on many fronts; relapse from treatment, especially after a shorter-than-average remission.

For such young-uns with uncooperative CLL, the stem cell, or bone marrow, transplant is a light at the end of the tunnel. For some, this light may have the characteristics of an oncoming train, but I prefer to look at it as a potential cure.

Harvey ponders the path to success

Anyone looking down this road should keep up with Harvey’s Journal at CLL Topics. Harvey is a somewhat hypothetical fellow who is about to undergo a cord blood transplant. A recent journal entry, Planning for Success, describes the logic of achieving a CR ("complete response") prior to transplant, as well as the ways in which our treatment choices over time can reduce our ability to achieve that CR. The facts presented led to a little surprise and consternation among some readers.

Chaya Venkat, the Topics writer who, like Elwood P. Dowd, enjoys the delusion that there is a Harvey in the house, cites a study from the Fred Hutchinson Cancer Center. It shows that entering a transplant with bulky disease puts you at a disadvantage: after two years, 14% of patients with lymph nodes less than 5 cm at transplant had relapsed, compared to 52% of those with nodes greater than 5 cm. She further cites another study from the Hutch, albeit with a small sample, showing that, in her words, “the risk of relapse in CLL patients going into the transplant with full blown CR was zero, none, nada.” If you think about it, that makes sense: the less CLL the new immune system has to fight, the better the odds of achieving a successful graft vs. leukemia effect.

Chaya also provides data from a 2005 study by MD Anderson, which I have discussed in the past and which can be found in detail here. It shows the CR rates in previously treated patients who are given FCR, which is today’s gold standard of chemotherapy. While 70% of those using FCR as their first treatment get a CR, that number drops in previously treated patients: to 29% in those who have used single-agent Rituxan; to 28% in those who have used an alkalyting agent such as chlorambucil or cyclophosphamide; to 24% among those who have used fludarabine and cyclophosphamide together. Table 3 of the study has details on fludarabine sensitivity: 31% of those considered sensitive achieved CRs, as opposed to just 5% of those who were refractory to the drug. (A note here: Only seven patients in the study had used single-agent Rituxan. That's not a huge sample but it's the only one we've got.)

So what is a patient -- especially one who thinks they might need a transplant one day -- to do?

The treatment conundrum

The question of which treatments to have, and in what order to have them, is much debated among patients -- I have written my share about it in this blog -- as well as their doctors. As Dr. Terry Hamblin has pointed out, the studies are just not there to show us what combination, and in what order, leads to the longest overall survival.

Chaya delineates the problem as it relates to transplant: “Getting that CR ahead of the transplant may prove to be more difficult than you thought. Waiting too long to make the transplant decision may end up costing you. If you become a truly refractory 'salvage' case, it may not be possible for you to get a good remission no matter what you try. Too few bullets left, and too strong an enemy, the window of opportunity to get a successful transplant may not last forever.”

Dr. John Byrd has been quoted as saying that your first treatment is the most important because your first remission will be your best. And if transplant success were the foremost goal, then we would all have transplants following our first treatment, and we would all insure that our first treatment is the one that gives us the best chance of a CR.

Indeed, the day may come when 1) we can predict a person's disease accurately enough, and 2) transplants are safe enough, to make that a routine course of action for those with aggressive disease.

But we are not there yet, and transplants are still risky: There is a 20% chance that a transplant will shorten your life and another 20% chance of relapse, those statistics according to UK CLL expert Dr. Andrew Pettitt. (The good news, according to Pettitt, is that 60% are successful.) With the possible exception of 17p-deleted patients, those with the most aggressive CLL, most top doctors hesitate to recommend a transplant at first remission. They are more commonly recommended at second remission in patients with rather aggressive -- perhaps I should say "assertive" -- disease. Still other doctors, those who do not see the transplant glass as half full, recommend transplants only as a last resort, after any number of therapies have been tried. In all these instances, treatment with something as conditioning for the transplant will be required.

And if there is one thing we do know -- just look at that MD Anderson data -- it is that treatment with any drug(s) sets up a disease resistance situation where second treatment is likely to be less effective.

Acceptable (?) risks

So, if we assume that for most of us a transplant at the outset is too risky but may become a desirable risk later, how do we plan? How do we still get treated but avoid becoming salvage patients on whom nothing really works?

There are a couple of points worth noting here:

First, there is no guarantee of getting a CR with your first treatment, even if you use FCR. Thirty percent fail to get a CR in such cases.

Second, according to MDA, 25% of pretreated patients achieve a CR with FCR. Who does the best? Single-agent Rituxan users (29%) and the fludarabine sensitive (31%).

How do you know how you will respond? You don't, but we can hazard a couple of guesses. If you are 17p deleted, you will have a harder time getting a CR. Those with huge lymph nodes may have trouble since it is that much harder to get rid of them. The NCI guidelines say you don't need to treat lymph nodes until they achieve a mass of 10 cm, but as a practical matter many patients report problems reducing nodes that big to an acceptable size. Keep that in mind if you, like me, have a largely node-centered disease (which is, by the way, a trademark of the 11q deletion).

Speaking of nodes, let us recall the data from the Hutch: 14% with nodes of less than 5 cm relapsed. 52% relapsed whose nodes were greater than 5 cm.

Given the risks of a transplant, and the fact that you may be able to keep the disease at bay for many years with treatment, does this data suggest what might be the reasonable standard, the compromise point, which one should aim for? In other words, preserving your ability, to the best of your ability, to reduce your nodes to below 5 cm (and perhaps to get a CR to boot)?

I think "yes" is a reasonable conclusion. I also think the data suggest that two things will be of particular help in preserving this ability: using Rituxan as your treatment of choice and maintaining your sensitivity to fludarabine.

(As always, my opinions are my own: There are wiser people who may well disagree with me. You could be reading the ravings of a madman here; remember that propensity for copious quantities of cats.)

The treatment blue plate special

Harvey the Hypothetical had six years of good quality of life (QOL) with the “soft glove” monoclonal antibodies Rituxan and HuMax-CD20 -- especially helpful as he had no donor match and had to wait until cord blood transplants could be made reasonably safe.

Rituxan and HuMax are not free lunches, as Chaya points out, but I think they at least qualify as the blue plate special. To paraphrase Churchill, they are the worst drugs to use, except for all the others. These monoclonals can plug the holes in the dike without being as immunosuppressive as the alternatives, without being mutagenic, and without building quite so much disease resistance. (Cases of especially aggressive disease, such as the 17p deleted, are the exception here. Studies suggest that 17p-deleted CLL clones are pretty resistant to Rituxan, as well as to fludarabine; in these cases, the start-with-big-guns then straight-to-transplant-at-remission plan makes some sense.)

The MDA data show a CR of only 5% for the fludarabine refractory. It is possible to become fludarabine refractory after your first treatment, although you may luck out and respond two, three, or more times. In the 2004 ASH Education Book, Dr. Byrd noted that "at the time of relapse from initial response to fludarabine, 40% can be retreated and will respond again to the same regimen." He went on to say that "ultimately, virtually all CLL patients who are treated become fludarabine-refractory." (It is generally accepted, by the way, that if you achieve a long remission the first time, your chances of a good response the second time are improved.)

So, are you better off playing for time by using single-agent Rituxan? Or should you start your treatment career with FCR, which obviously carries a greater risk of making you fludarabine refractory? (Of course, even Rituxan can make your disease somewhat resistant to fludarabine; CLL is not black and white. Our stock in trade is shades of gray.)

Let's look a little further at the MDA study: Let's add together the percentage who got either a CR or an NPR (nodular partial remission -- patients with no swollen lymph nodes who would have achieved a CR but for some nodules in the bone marrow). The responses were as follows: 58% in Rituxan users; 40% in those who had alkalyting agents; 39% in the FC group; 48% in the fludarabine-sensitive group; and just 16% among the fludarabine refractory.

The takeaway here is that those who did best -- and now we're talking half of previously-treated patients that managed to get rid of those pesky nodes -- were those who had used single-agent Rituxan and those who were fludarabine sensitive.

So, if I were playing the odds, using Rituxan while trying to preserve fludarabine sensitivity by not using it is the way I would go. In fact, it is the way I had been going, until AIHA intervened and forced me to use cyclophosphamide and a touch of vincristine. (Not everyone should play it this way; Rituxan is still a soft-glove treatment and if you arrive at the treatment door needing something stronger to deal with the problems your disease is handing you, by all means use it.)

It is important to note that your previous treatment is not the only factor that influences your ability to get a CR or NPR with FCR. Do read the MDA article, which I linked to above; it goes into other significant factors, including age, stage, and number of previous treatments. For example, your chance of a CR with FCR is reduced significantly if you have had more than two previous treatments. (Does single-agent Rituxan, with its lighter touch, carry the same weight as other treatments, I wonder?)

Type A personalities, welcome to the seventh circle of hell

We can parse the data all we want, but it's important to remember that what Rowan and Martin of TV's Laugh In called the “fickle finger of fate” is also at play here. Harvey, for example, was not particularly fludarabine-sensitive out of the gate, while many patients are. None of us knows how we are likely to respond to drugs, despite what statistics may tell us.

The good news is that Harvey managed to get close to a CR with Revlimid, got those nodes down to well under 5 cm, which is also the cutoff point at which Campath will work on nodes. Since we’re talking hypotheticals here, he perhaps could have followed up with Campath to clear the nodes further, though this sets up a risk of immunosuppression, infection, and viral reactivation. HDMP was another option that he did not use that might have shrunk the nodes significantly. He could have opted for R-CHOP (or H-CHOP) or Hyper-CVAD. (One consideration, of course, is that the more immunosuppressive, toxic drugs you use to nuke the CLL with, the greater the chances of a side effect or complication. And transplants are complicated enough as it is.)

My point is that there are several ways to search for that node reduction and/or CR when the time comes (and, like all CLL treatments, each comes with its risks and rewards). And in the interim I think there is a reasonable middle ground -- exactly the ground Harvey has trod. He got close to a CR after six years of good QOL with monoclonals, and he saved fludarabine for the end. That last gamble didn't work out as well as he hoped, but welcome to CLL.

Hindsight is 20/20: At the beginning of his CLL career, Harvey had only the favorable 13q deletion and was IgVH mutated to boot, so it seemed his disease course would be rather indolent, in which case a transplant seemed unthinkable. It was only as time went on and clonal evolution to 11q occurred and his mutated status proved less significant than problematic clinical symptoms that the transplant option became more attractive. This concept -- “things can change” -- is important to keep in mind. It bolsters Chaya’s argument that one should not wait too long; I can tell you from personal experience, as well as the experience of many patients I know, that once the disease starts to progress, things do not get better. They get worse.

One of the biggest challenges of living with the "new normal" of CLL is that we are forever making decisions without knowing what our disease will do, or what the drugs will do. This is not a disease for Type A personalities. Fortunately, I have always been more of a roll-with-the-punches type of guy. My view is that we patients are dealing in real time, and we make the best choices we can. We should not fault ourselves for making one choice and then finding out that "had I known what I could not possibly have known I might have done things differently."

Chaya's journal entry gives us good food for thought. There is no such thing as a CLL treatment that is risk free or that will not have consequences down the road. No matter what you do, there is no treatment that will not make retreatment more difficult. It is all a matter of balancing the risks and the rewards, playing the odds, and a little luck.

And speaking of which, good luck to Harvey as he heads north to a cure! I confess to having seen him myself a few times. Must be chemo brain . . .