Is There a (HLA) Soul-mate Out There, Just for You?

Turn on the TV these days and you are bombarded with ways of meeting your perfect soul-mate that matches you on umpteen criteria of compatibility. I wonder if these new fangled ways of finding your mate work any better, whether all these computer matched couples live happily ever after. You think?

Talking of compatibility, most of us chickens with CLL and hoping to get a stem cell transplant will be delighted to find a 10-point HLA (Human Leukocyte Antigen) matched donor, even if he or she does not share our taste in music and politics. If you are lucky enough to have siblings, that is the first place to start. Here are your odds of finding a perfect 10/10 match, depending on how many brothers and sisters you have.

Sibling Match Probability

What if your parents did not have the necessary foresight or stamina back in their youth to start a large family and you are an only child? Or if the meager one or two siblings they did provide you with are not a match? This is were we depend on the kindness of strangers. There are more than 10 million wonderful donors signed up in donor registries all over the world. Searching through them to find the single perfect match for you is no easy job. It takes time, patience and a transplant center that has access to the registries. But thanks to computerized databases, the job can be done reasonably efficiently.

Matching for hematopoietic (blood) stem cell transplant is done on the basis of HLA. Most centers now look for match on the following antigen markers: HLA-A, HLA-B, HLA-C, HLA-DRB and HLA-DQB. Since we get a set of two antigens for each HLA marker (one from our mothers and the second one from our fathers), that adds up to 5 x 2 = 10 antigens. A 10/10 match between you and your donor means you both match on each of the 5 sets of antigens, all 10 of them.

There are literally thousands of possibilities for each HLA type — and therefore zillions of combinations when we look at ten of them. Over the years our ability to type HLA has improved, from relatively crude “low resolution” categorizing to now more “high resolution” typing. As we said above, when considering adult matched unrelated donors, transplant centers would prefer to have a perfect 10 out of 10 match, at the high resolution level.

This is how the process works. First, the patient is typed to determine his (or her) HLA profile, at the high resolution level. All that is needed is a sample of blood and it is often possible to ship the tube via overnight mail. Next, any willing and able siblings are typed, as this is most often the best choice of donated stem cells. If no sibling match is found, the next step is to look for a matched unrelated adult donor (MUD). Chances of finding a MUD match are much better if you are of standard issue cookie-cutter ethnicity, since ethnic communities share many HLA types and it is much more likely you will find a good match. Minorities have much harder time finding suitable donors, since they are only sparsely represented in the donor banks. I know this from personal experience. Our hero “Harvey” was not fortunate enough to have a sibling match. After several months and mucho dollars, it was determined he had no MUD match anywhere in the world, not even at the ‘iffy’ 8 out of 10 level. The dollar cost of a protracted search for MUD donors is not trivial – you might want to check with your insurance company before you get started.

Harvey’s daughter matched exactly 5 out of 10. No more and certainly no less is expected from an offspring (if the match had been less than 5 out of 10, Serena would have had some explaining to do!) In special circumstances they do transplant patients with a 5/10 match, and these parent-child situations are called a haplo-identical match. Half-match, in plain English. Better than nothing but I would not go there if I did not have to.

How do the HLA typing results look? Here is an example:

harveyshlafinal.GIF

I know, it looks like so much gobbledygook. But getting a good match between you and your soon-to-be-enthroned donated immune system is very important — a matter of life and death you might say, with absolutely no exaggeration. High resolution HLA typing results typically have 4 digits, while the low resolution typing is restricted to the first two digits. For example, low resolution HLA-A results for Harvey would be 11 and 33. As you can see, the high resolution results go the extra distance, reporting 1101 and 3303. Any adult donor deemed a good match would have to match each of these HLAs, at this high resolution (4 digit) level. Transplant centers do sometimes use 9/10 matches, but with reluctance and when no better option is available. We will talk more about the perils of inadequate matching later on.

Some of the donor bank websites allow patients to punch in their own HLA typing and see if there are any matches out there for them. Unfortunately, sometimes this can be seriously misleading. Most of these search engines allow you to enter the low resolution typing only and that too not for all five sets. In other words, based on this partial and low resolution typing match, it is impossible to tell whether any of the prospective matches you find are actually going to pan out when rubber meets the road. There are other issues to consider. Is the donor healthy? Will he/she pass necessary screening for stuff like AIDS, hepatitis, etc? Duh, getting cured of CLL after a mini-allo transplant is not worth it, if in the process you have acquired AIDS.

Is your prospective donor willing to go through the actual process of donation or was it a momentary fit of generosity that caused him/her to register? It takes a lot of work, attention to detail and patience to nail down all these contingencies. One horror story I heard reported the patient was put through all the steps of the transplant preconditioning etc, only to have the donor change his mind 24 hours before he was to show up at the hospital for stem cell collection. I am sure this does not happen frequently, but I am equally sure pre-transplant patients worry about their MUD donors having a change of heart.

There are more than 10 million volunteers registered in bone marrow registries worldwide. But this is not enough and a substantial percentage of patients who need a matched donor for their stem cell transplant still cannot find one. In an important Dutch study it was found that 59% of the patients (with easy-to-fit Northern European ancestry) found an matched unrelated donor (MUD), 11% had no such luck and in the case of an unlucky 30%, their disease progressed beyond help while they waited for a potential donor. These statistics become a lot more grim if you consider patients with more exotic parentage. Way too many people in the US who need a blood stem cell transplant cannot get one because they cannot find a suitable donor, more so than in European countries or Japan. Perhaps it has to do with the immigrant nature of our population — our people come from every corner of the world and most of us do not have common ancestry. Inadequate donor recruitment among minority communities is another stumbling block. Statistics for finding good MUD matches are grim if you are belong to the Black, Hispanic, Indian (either the ‘dot’ and ‘feather’ variety), Chinese, Korean (general Oriental) communities.

No Time to Waste?

Making the decision to pull the trigger and opt for a stem cell transplant is not an easy task. The process is admittedly complex, carries significant risk of death and costs an arm and a leg. In my experience, when the going gets tough, the tough dither. Several transplant experts I interviewed bemoaned the fact that most of the patients they see have been through every chemotherapy known to man and finally come to the transplant shop only as a last ditch “Hail Mary” effort.

Since that is the case and denial is an understandable aspect of human nature, many patients do not have time to waste when they have finally made the big transplant decision. If you do not have a well matched sibling that will drop everything and come to your rescue at the drop of a hat, how long will it take to find a suitable matched but unrelated adult donor? Well, that depends on your ethnicity and your luck. If your “ethnic tribe” is well represented in the donor registries, you may be in luck. If you are of more exotic ethnicity and they broke the mold after you were assembled, you might be whistling in the dark. Finding the perfect soul-mate HLA adult MUD match can take anywhere from a few weeks to many long months. Sometimes too long to be of much good to an advanced stage cancer patient, sometimes forever.

This is one of the biggest reason why using umbilical cord blood units to transplant adult patients is receiving so much attention. The time difference between finding an adult MUD donor compared to finding suitable cord blood units can be weeks if not months. That may not sound like much for normal people. But if you are a cancer patient whose disease is fairly galloping along, things are quite a bit different. You worry that the hard-won remission may be fail while you sit biting your fingernails. Waiting another few weeks or months can feel like an eternity — all the while hoping and praying that they will find a generous stranger willing and able to donate perfectly matched stem cells that can save your life.

Why Is It Easier to Find Well-matched Cord Blood Units?

The major advantage of stem cells from cord blood is that they are not as finicky as adult stem cells. For starters, cord blood units do not have to be matched across five sets of HLA. Instead it is acceptable to look at only three of them: HLA-A, HLA-B and HLA-DR. Once again, there are two of each kind to consider, so we are talking of 3 x 2 = 6 HLA points of compatibility to consider. A ’6 out of 6′ cord blood match is considered perfect. But not too many patients can get that, with our present level of inventory in the cord blood banks. Here is the good news: perfectly acceptable and successful cord blood transplants are done with only 4 out of 6 matches. Finding an acceptable 4 out of 6 match using cord blood is a far cry from the 10/10 match needed to transplant adult donor stem cells. Last but not least, most centers require the matching only at the “low resolution” (2 digit) level, making it far easier to find good matches for most patients. Several experts I spoke with agreed that the chances of finding sufficiently well matched cord blood units is very high, very few patients are turned away for lack of matches.

Below is how Harvey made out, when they did the search for matching cord blood units. University of Minnesota (and other cord blood transplant centers as well) requires low level resolution match is required for HLA-A and HLA-B markers, but high resolution (4 digit) match is needed for HLA-DRB.

Cord Blood Matches

As you can see, Harvey has found two cord blood units with 4 out of 6 HLA match (highlighted in yellow). Since he already had his own HLA typing done from when he was looking for an adult MUD match, the process of finding these units was a piece of cake. Unlike chasing down potential adult donors, the cord blood units were already in the bag as it were, literally. Most often, the cord blood registry banks have detailed virology done while processing the cord blood units, which means there are fewer surprises and hurdles to cross on that front as well.

Why two cord blood units? Aha, that is a very important question and we will be writing about it in great detail later on.

You guys with me so far? In the next few entries we will discuss some of the other transplant jargon.

Be well,

Chaya