Many months after my visit to the NCI/NIH to discuss a stem cell transplant trial, I received a call from the clinical nurse in charge of finding donors for trial participants. In the 15 or so minutes we talked, Jennifer Wilder could not have been more helpful.
While I was rejected for the trial, one of the benefits of applying for it was that I was able to get a much better handle on my donor match situation. Before the trial, all I had to go on was a preliminary search of the National Marrow Donor Program (NMDP) database, which indicated there were 22 potential 6/6 matches at low resolution on the microscope.
That’s like looking through Mr. Magoo glasses and saying there are objects in the sky twinkling at night without knowing which are stars, which are planets, and which are airplanes passing by.
For their part, the NIH needed to do enough searching at high resolution to see what the prospect of a 10/10 matched unrelated donor would be, as that level of match is required for participation in the trial. It is also generally accepted as the desirable standard at all transplant centers. Their effort would have cost me thousands of dollars had I been paying for it out of pocket.
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More on the results in a minute, but first a little background:
The bottom line when it comes to adult stem cell transplants is what sort of match you can get, and not all matches are created equal.
Sibling matches, for example, can mean less Graft vs. Host Disease (GVHD), which is what can happen when your new immune system comes into contact with your old one. But this also tends to mean less Graft vs. Leukemia effect (GVL), in which the new immune system takes on the CLL cells. Engraftment is harder since the CLL cells stick around, and relapse is more likely. Statistics show that if you are rolling the dice on a cure, your brother’s or sister’s stem cells are not the best way to go.
Matched unrelated donors are preferred -- those wonderful people who volunteer to help others in need. You’d think that out of some six billion people on earth there would be more than 10 million such donors, but those who need transplants are small in number and the need for donors does not get much publicity. (That prospective donors are often charged a small fee for testing does not help; one wonders what would happen if people were paid a small fee to agree to enlist, but that is another post for another day.)
A 10/10 match -- or better -- means the stage is set for a pretty good chance of engraftment and possibly cure. At the low end, Dr. Steven Pavletic of the NCI told me, an 8/8 match is acceptable. But it’s not desirable, and it’s something I would think twice about if it were all I could muster.
Then there’s the cord blood transplant, in which the rules change a bit: The level of match is not as important since the stem cells are pretty much unformed and adaptable to your system. Double cord blood transplants are a new thing, performed in adults at only a few centers. Dr. Paveltic described them as being riskier than unrelated, which indeed appears to be the consensus as of now.
A word is in order here about the mysteries of HLA -- Human Leukocyte Antigen -- typing, the complexities of which have caused smoke to come out of my ears as well as several other orifices on more than one occasion. For those of you who want to focus on the locus, the following are some links that provide further information, one from Wikipedia, one from CLL Topics and two from the NMDP, the first one for patients, the second one for professionals. (And aren’t we patients professional researchers at this point?)
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Despite the statistics on CLL outcomes, the reflexive procedure at transplant centers seems to be to look for a sibling match first and then to look for an unrelated donor if that fails. I’ve got two brothers and a sister but each of them is a half-sibling. All are willing to donate their stem cells to my cause, none of which would be helpful. So thank you Rick, Dan, and Julie, but a sibling match is out.
Wilder told me that they found 15 6/6 unrelated matches at high resolution, looking at loci A, B, C, DRB1, DRB3, and DQB1. Two potential matches “would probably fall off for ethnic or other reasons," leaving me with a pool of 13.
(Ethnicity is important in all this, and I am a bit of an odd combination. My paternal grandparents were Russian Jews, who escaped the rule of Tsar Nicholas II and came to America shortly before the Russian Revolution. My mother was adopted, which I only learned following her death in 1977; after much searching, I narrowed her birthplace to the Irish immigrant community around Crown Point, New York. So I am something of an Irish Jew, evidently, which explains my demented sense of humor but which also puts me in a distinct ethnic minority.)
Of those 13 potential matches, they had additional data on four -- enough to get close to determining a 10/10 match. Of those, there is a 50% chance of one perfect match, Wilder said. The other three would be about a 10% chance of a 10/10 match. What lurks in the “mystery nine" would have to be determined through further testing.
Beyond this, there were 10 mismatched donors, probably only one of which might be as high as a 9/10 match.
Wilder said the odds of a successful transplant with a 9/10 match are “fairly decent.” The rule of thumb is that for every mismatch, successful outcomes drop by 9%.
A mismatch of one number at a locus is called an allele mismatch, she said, which is what I appear to have in three places when compared to the usual results for Caucasians. A mismatch of both numbers is called an antigen mismatch. Wilder said that an allele mismatch is not as bad as an antigen mismatch (fun reading here.)
“Do some mismatches matter more than others?” I asked.
The consensus is “yes,” Wilder said, but nobody agrees on what they are. For example, studies suggest that a mismatch at locus A-0205 is important but these studies are from Japan and could be important only within the confines of the Japanese ethnic group.
I have three “less common alleles,” she said, which means “a less common combination of numbers.” But she described my alleles as “nothing that’s all that rare.”
Obviously they’re rare enough to turn finding a 10/10 match into a bit of work.
One of my uncommon alleles is that A-0205. If you HLA-type 100 Caucasians, most will have 0201. Another uncommon allele that I have is at locus DRB1; I have 1305, and most would be 1302. Each of these counts as a mismatch. So a mismatch on the A-0205 alone means a 9/10 match, a mismatch on both the above means 8/10, etc. Transplanters do have an order of preference for where the mismatches are, but I didn’t get into the details.
Wilder said the bottom line for me is that with continued searching and typing of more donors, I would have a pretty good chance of finding a 10/10 match, with the prospect of a 9/10 in the background.
She searched databases worldwide. Wilder noted that people do join databases and a search in another year or two could “pop up some perfect matches.”
Which was polite of her to say, but my one perfect match, if there is one, could also get hit by a truck.
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I have a case of CLL in which nothing is easy. I don’t have indolent disease. I don’t have horribly aggressive disease. I have progressing disease with fairly mild clinical symptoms, if you discount episodes of hemolysis due to AIHA, which isn't exactly easy to do. But my marrow is still pretty healthy, I don't have B symptoms such as fatigue and night sweats, and I am not prone to frequent or severe infections.
Alas, I have three out of four poor biological markers -- IgVH mutational status, ZAP-70 and FISH are all bad; CD38 remains good.
December's FISH test showed no new deletions beyond the 11q, and my 11q deletion appears to be stable when compared to results from 2007 -- the deletion shows up on just over half of cells tested. It also appears that I still have some ATM (programmed cell death) functionality. ATM is located on the long arm of chromosome 11, hence the tag of 11q. (It is not present on the short or “p” arm of the chromosome.) Monoallele deletion -- which is what I have -- means the relevant bit is broken off of the long arm of one of the set of two chromosomes #11. Biallele deletion means that both of the chromosomes 11 have lost the ATM gene. It stands to reason, and appears to be born out clinically, that the monoallele deletion is the half a loaf that is better than none; how long it will stay that day, given the vagaries of clonal evolution, is anyone's guess.
The downside of my 11q is that I also have extensive abdominal lymph nodes, as my CT scan of last month made clear. They're not impinging on anything important, but they have grown into a 13 cm by 15.5 cm mass, helping driving the disease, and a mass of that size is an indicator for treatment, according to the NCI guidelines.
I know where all this eventually leads -- transplant or die -- but it is not a pell mell rush, and so there is a little wiggle room along the way in terms of the what and when of treatment.
And what I learned from Wilder is that I’m not on Easy Street when it comes to finding a 10/10 donor, either. Still, she made it clear that there's a realistic chance. So let’s hope the one or maybe two or three people in the world’s donor databases who qualify enjoy quiet evenings at home with their air purifiers and heart-healthy diets.
Is this a slim reed on which to plan a long-term strategy?
The way I see it, the alternatives do not change because of the donor match situation. Basically, I can ride along doing chemo until nothing works on me anymore and I earn my scarlet “S” for “Salvage patient,” at which point I can make my peace with the world and go out gracefully.
Or I can go for a transplant at the best level of match I can get, even if it is not ideal: 9/10 perhaps, or cord blood, or maybe that 10/10 after all.
There is an anonymous quote I ran across that sums up my opinion: “There are always two choices. Two paths to take. One is easy. And its only reward is that it's easy.”
Dragging out the chemo is the “easy” choice here, but in a way it is also the hardest. It is a personal statement that “I accept that CLL will shorten my life, and that I will live three, five, maybe eight more years.”
Making the “hard” choice to go for transplant is saying, “I know there is a reasonable chance that I could be cured of CLL and I am willing to accept the risk of getting killed in the process, or living with inconvenience afterward, in order to have a longer life.”
In my humble opinion, and it is only that, so long as transplant is a viable alternative with a reasonable chance of success, the “easy way out” is akin to writing a suicide note.
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But knowing that finding a perfect match will be a bit dicey does make me wonder about the advisability of jumping sooner rather than later. In making this decision, I am juggling a lot of balls in the air, or twirling a lot of plates on sticks, or tap dancing on the backs of several hungry alligators -- pick your metaphor.
As Dr. Pavletic told me, people don’t get healthier with age. I have no comorbidities (other cancers or diseases) that might reduce my chances of success. My heart and lung function are good. I am still chemosensitive, so my chances of getting a CR, or close, are decent, though hardly guaranteed. There will never be a better time than now, Pavletic said. As a reminder, he estimated that I have a 70% chance of a cure or long-term remission, perhaps a 15-20% chance of death, based on a 10/10 match. This tracks with everything I have heard for a patient in my situation.
Then again, despite my CLL and AIHA, I am enjoying pretty good quality of life. I’m 52. I can wait until I’m 55 or even a bit older before taking the leap. This guarantees me a few more years, time to enjoy life before risking that life. What I risk in waiting is the arrival of a comorbidity, watching the disease grow more stubborn and resistant to therapy, things that might ultimately reduce my chances of transplant success. What I gain in waiting is knowing that, barring a flying anvil with my name on it, I will probably be alive in three years. I am not risking a one in five chance of death.
This is a tough one. Push is starting to come to shove. Your thoughts are welcome.
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