How the donor DNA match works

When we talk about finding a “donor match” for Bethany, I’ve been using the term “DNA markers”, which is not technically inaccurate, but it is probably less specific than it could be.

What they’re really looking for are “HLA markers” or “human leukocyte antigen” markers that match. These markers “contain a large number of genes related to immune system function in humans.” And “the immune system uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person’s HLA type belongs to that person and therefore is not an invader.”

These are the little guys who can both kill off any remaining cancer cells, and cause the maddening array of graft vs host (GVH) difficulties that bone marrow transplant (BMT) patients must deal with.

The diagram here shows you probably as much as I could ever hope to tell you about them. I wish I’d had this diagram when talking with Renee at our first intake meeting. These markers are key among the ones that need to match in order to find a suitable donor.

As I’ve noted, Bethany has a rare “C” marker. I could not honestly tell you what that means, other than that it is a very important one. I am happy, at this point, to know as much as I do about it.

The last time I talked with Renee (on Monday), there was one person (among the four remaining candidates who matched 10/10 of these HLA markers) who had already submitted to the further blood testing that was needed, and a second one was scheduled for this testing.

Again, my understanding is that all of these four individuals had characteristics (older, females with multiple antigen-causing pregnancies, etc.) that made them less than ideal candidates. Though, as 10/10 matches, they are suitable.

There is a second group of four individuals, who match on the critical “C” marker, but may be mismatched in some other way. (These individuals might potentially become 8/10, 9/10, or 10/10 matches, but at least they will match the critical “C” marker). These folks are also being asked to undergo some further testing.

It’s a big process, and honestly, I wish things were a bit further along than they were. But 10 years ago, I don’t believe Bethany would have had the option of a transplant. She would simply have been forced to live out a short remaining life span, full of blood transfusions and a chemotherapy regimen that would eventually fail.

Account of a successful Bone Marrow Transplant

I may have posted some of this before, but there’s new information at the end, and it’s worth the telling.

At one point this past summer I logged into the discussion board at the Leukemia and Lymphoma Society. There are a lot of different types of leukemias, and CMML is one of the more rare ones. I came upon a thread entitled Looking for others with CMML.

(One writer writes, “There are so few people in the world with this disease, it is very scary”. Which is true.)

Most of the way down the second page of the discussion was a writer named “g-papaul”, who identified himself this way, with a post dated June 19, 2011:

I’m a 60 year old sales professional male getting annual physicals with blood tests. I was Diagnosed with CMML in Feb. 2011. My GP knew it required an oncologist and got the ball rolling. I’m from the Harrisburg, PA area and went to the best local oncologist I could find. The oncologist is affiliated with Johns-Hopkins, Baltimore, MD. My initial consultation with a transplant team at J-H was the end of March. March-April May were transfusions of blood and platelets as needed determined by my weekly blood draws at the oncologist. I also received 2 courses of Vidaza in preparation for the transplant. I was admitted to Johns-Hopkins on 6/13. On 6/15 started a 5 day run of Busulfan. Today 6/19 starts a 2 day run of Cytoxin. On 6/21 is the Bone Marrow Transplant from my donor brother. Then, 2 more days of Cytoxin. I start down the road to recovery and hopefully cured.

So he’s already into the “conditioning” phase – “intensive” chemotherapy, with the purpose of destroying the existing bone marrow, and two days away from a bone marrow transplant. Beth is due to follow a path like this one. He made several more postings. On July 8 we saw this:

I’m currently on DAY 17 after BMT. The BMT was uneventful and sort of just like getting another few units of blood. I rested for 2 days and then received 2 more days of Cytoxin. During the last day of Cytoxin you start to walk through the fires of hell. They start initiating bags of antibiotics, anti fungal anti microbials. I keep getting low grade fevers. They tell me it’s normal. Not all experience the same side effects. These drugs hit everyone differently. … I constantly feel like I have the flu. Just have to deal with it until around July 12. That’s the day projected to be the day my own marrow will be producing healthy cells.!

Later, he said:

The chemo side effects are all they say they are. … You feel like you got run over by a bus! Have to stay positive since they only last about 2 weeks. Then the miracle begins…Day 18 after transplant. Blood counts start appearing 50 here, 110 there and keep growing. Not by leaps & bounds but by 20-30 points. Several transfusions of red cells and platelets. A little rash here & there (a little GVHD is a good thing)…

I may have posted this much of his story already. Since that last posting, there was not another comment from him until yesterday. And here’s the key … here’s the thing we’re looking forward to:

I felt it was time to offer a follow up to my BMT to cure my CMML. I was released from Johns-Hopkins on August 19th to go home. Home…a wonderful place to recuperate. No more IV drugs that tear you up. Only a few in pill form to prevent various infections. We had a whole house HEPA filter system and a reverse osmosis water system on our well water installed. I DO NOT leave the house or go in the basement without an N95 mask. If I’m going to the store or doctor I wear disposable gloves too. Wash hands frequently. I finally started eating the last week of August after 6 weeks of eating nothing. I lost 80 LB and feel great…. The diet has been expanding but not my waist line. I’ve learned to eat all over again. I will not return to 290 LB!!! There are positives out of this ordeal. My Osteo arthritis is gone. (They said it could be temporary or long term). I don’t need Blood Pressure or Cholesterol meds anymore. I don’t need to sleep with a C-PAP machine. All of the anti bacterials & fungals fed me IV cured my athlete’s foot and one nail infected with a fungal infection…they rebuilt me! I currently visit my local Oncologist every 2 weeks for chec ups. He says the recovery is text book.

There’s not a lot of good medical news about CMML. But here’s anecdotal evidence that the process works, and works well. There are a couple of differences with our situation. Most notably, this individual has a related donor. But it’s a very hopeful story.

Beth was crying last night when I got home

She woke up yesterday with a new pain in her spleen. An enlarged spleen is one of the symptoms of CMML (chronic myelomonocytic leukemia). This Detailed Guide to CMML by the American Cancer Society is one of the best that I’ve found, and it gives a fairly complete overview of this disease. I’ve also found this 2005 summary from the National Institutes of Health (NIH) : “Intensive chemotherapy alone is of little benefit, and stem cell transplantation is the only curative modality in the small number of eligible patients, although outcome remains suboptimal.”

That doesn’t strike me as too hopeful, though it is easy simply to be bewildered by this disease. As medical science has learned more and more about it through DNA, it has been found to be more rare than at first thought. Originally, Beth was diagnosed with MDS (a pre-leukemia with certain tell-tale signs), but after a second biopsy, her diagnosis was changed to CMML (more specifically dysplastic CMML-2).

One thing that you don’t see much of is the prognosis for CMML patients who undergo a Bone Marrow Transplant (BMT). That’s because the population of these patients is so small. There are only about 1,100 cases diagnosed each year — and 90% of them in people over 60 who can’t have the BMT.

I’ve also found this overview in the France-based Atlas of Genetics and Cytogenetics in Oncology and Haematology :

The median survival for patients with CMML is about 24 months. … Of adult patients who underwent allogeneic bone marrow transplantation the disease-free survival was 39% at 3 years.

But this disease is so rare, the population upon which this study was based is very very small. I believe it is only in the 10s of patients. (They didn’t even study “hundreds” of CMML patients with CMML).

An oncology textbook notes that:

Median survival in CMML is approximately 12 months, with a range from approximately 1 to more than 60 months. …Unfortunately, at this time, unless the patient is a candidate for imatinib therapy or stem cell transplantation, long-term salutary therapeutic effects are uncommon.

But even for those who receive a stem cell or bone marrow transplant, the NIH says:

Allogeneic hematopoietic SCT (HST) offers the only curative potential for patients with chronic myelomonocytic leukemia (CMML). However, there is a paucity of data addressing this approach in CMML. The disease is a relatively under-represented myelodysplastic (MDS)/myeloproliferative subtype among transplant eligible patients. Non-randomized studies suggest that long-term remissions are achievable when using myeloablative or reduced intensity conditioning transplantation. Allogeneic SCT for CMML is often reported as part of MDS registry data. The largest series in adult patients reported a disappointing long-term relapse-free survival (RFS) of 18%. The Fred Hutchinson Cancer and Research Center group reported a 40% long-term RFS for a mixed group of adults and children with CMML who were transplanted over two decades. In this study, we performed a literature search and reviewed available data for adult CMML patients undergoing HST. The dearth of data that span two decades with changing transplant practices prohibited us from performing a formal meta-analysis. However, we elected to present the current status of HST in adult CMML patients. Carefully selected CMML patients may have the most benefit from this curative approach.

Really, this seems to be all that’s available out there.