The transplant and initial complications are past; now we need to watch and pray

I’ve been putting up a lot of short posts (I’ve primarily been using my old iPhone), and now I’ll just summarize the events of the past couple of days. There are photos throughout the posts that appear down below.

Beth received her transplant, from 9:45-10:30 on Wednesday evening, December 14^th. She received a very high number of stem cells (the range is 4 million to 8 million cells per Kg of body weight) — she had a young, strong donor, and she got the 8 million.

After the infusion of the new stem cells, she had a somewhat violent reaction, which lasted most of the night and the next day. Her fever went up to 103. Everyone’s initial response (all the medical folks) was that she was having an infection, and that is an appropriate place to look. Beth’s response was not common, but it happens. She seems to have settled down from that. They are continuing to give her two different antibiotics, Vancomycin, for staph infections, and Cefepime, which is good for pneumonia.

The next challenge will be that the effects of the chemotherapy (and I’m guessing they mean the Busulfan) really kick in on days 7-10. So we should be entering that phase now.

The purpose of the chemo was to destroy Beth’s existing bone marrow. This doesn’t happen all at once, but it happens over these 7-10 days. One of the doctors said that the existing marrow, while not yet “destroyed”, has been affected by the chemo and is not able to reproduce itself. And that’s where the new cells came in.

The new cells will begin to grow into new bone marrow. In the next couple of weeks, doctors will be looking for signs of engraftment, which occur probably during days 7-10 after the transplant. (These 7-10 days are different from the days 7-10 of chemo.)

30 days down the road, they will do another bone marrow biopsy and Chimerism testing to make certain that existing bone marrow is 100% donor and 0% Beth. If it’s something other than that, it would be a bad sign.

So we are not yet out of the woods. There is a 35% chance of relapse. But we know, too, that during the conditioning phase and afterward (by tweaking the response to the graft-vs-host effect – the effect by which the new tissues perceive Beth’s old marrow as enemy and continue to destroy it), the hope is that we achieve that 100% cure. But it’ll be a year or two before we know that.

The end is near

It’s about 6:00 now; I’m going to head back to the hospital to spend the night with Beth (I went in to work four hours today, and got a few things done).

Beth is going to get her first dose (of three) of Thymoglobulin, which, I understand, suppresses the immune system. She’ll also get the last doses of Fludabarbine and Busulfan. They’ve given her some “pre-medications”, which had her sleeping all day. We’ll see how she handles all this tonight.

For the next two days, then (the 13^th and 14^th), she’ll get the Thymoglobulin and the total body radiation, and the donor’s stem cells should arrive here the evening of the 14^th. By that time, our hope and expectation is that the leukemia-producing bone marrow will be completely destroyed.

Of course, then we have about a year dealing with issues such as engraftment, infections, and graft-vs-host symptoms, but the end of the leukemia is near.

A few more things we learned yesterday

Now that a donor has been recruited, Dr. Rossetti thinks that we will be able to “have stem cells by mid December”. No dates are firm yet, but we should be able to have a firm schedule in place by the end of next week.

Beth’s blood counts continue to be critically low – her white blood cells yesterday fell below 1.0 (“.94”) for the first time since I’ve been watching the numbers. And as I noted, her hemoglobin was 7.2, and her platelets were only 18 (again, lowest I’ve seen them). So today, Tuesday, she’ll go to Jefferson Hospital for her (7th of 7) injections of Vidaza, for two or more units of blood, and also, for platelets.

Beth’s bone marrow is defective, and every stem cell she produces is defective, and so the goal over the next few weeks (including the “intensive chemotherapy” and radiation) will be to bring her “as close to zero bone marrow” as she can get. The Vidaza, while not enabling her to produce good blood cells as promised, has at least gotten her most of the way there already. And that’s a good thing. [Also a “God” thing, as I had written at first.] The reason you want all of it gone is to reduce the chances of relapse down the road. And in addition to the “intensive chemotherapy”, the full body irradiation “cuts relapse rates 20%”, according to Dr. Rossetti. Every little bit helps.

Once the new stem cells are transplanted, then Beth’s numbers should begin to go in the right direction. Her white cells should begin to recover within 2-3 weeks. Engraftment should occur on or before day 30. Hemoglobin production should start in about three months. Anti-rejection drugs will be administered between days 35 and 90 – more or less to either to control or enable some “graft-vs-host” (GVH) effect. To some degree, the GVH has a “mopping up” effect – the immunity of the new stem cells will target and destroy any remaining defective bone marrow, or any remaining defective stem cells.

Too much, to be sure, can cause problems. But this is what the donor search has been all about: matching on precisely the right DNA characteristics, to give just enough, but not too much, GVH.

A donor has been selected

We got a call today from the Transplant Coordinator, telling us that the donor has been selected. They actually select the third of the three donors we had been undergoing testing — the last one to come in. This is good news — when we saw Dr. Rossetti, he had liked that second one a lot. And he likes this one better. This first choice is a young female, not from the U.S., same blood type as Bethany. She will be contacted with the news, and if she agrees to do it, she will be scheduled for a complete physical exam. She will also be given a list of tentative dates for the procedure; the earliest of these will be about three weeks after the physical exam.

The donor goes through a five-day regimen of injections to (a) increase her production of stem cells and (b) force the stem cells out of the marrow and into the bloodstream. On the day of the transplant, the donor will be hooked up to a machine like a dialysis machine: blood will flow out of one arm, through the machine, which will “harvest” the stem cells, and the remaining blood will be put back into the other arm. This is about a 6-8 hour process for the donor. The stem cells will be stored in a bag very much like a regular unit of blood. Since the donor is outside of the US, they will be put on an international flight to Pittsburgh, and transported to the hospital.

By that time, Beth, also, will have undergone an 8-day regimen of intensive chemotherapy and full body radiation. The intention, again, is to destroy all of her damaged bone marrow. The hope is that the new stem cells will “engraft”, or set up shop, within 30 days, and begin to form new bone marrow within Beth’s bones. About that point, Beth will begin to face “rejection” issues — “graft vs host”. Some of this effect is good — the immunity effect of the new “graft” will, it is hoped, destroy any remaining damaged bone marrow and leukemia cells. This is vital, in fact, in preventing relapse. The unfortunate side is that the “graft vs host” also can have side effects that can be very serious, and can even lead to death (i.e., pneumonia and other infections become a very real danger.). And this danger lasts about a year.

Needless to say, Beth is very apprehensive about this. But at least we are moving forward now.

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.

What’s the greatest danger? (Part 2)

“Transplant is the only cure”
Once the decision has been made to go with the bone marrow transplant or stem cell transplant, an entirely different set of dangers arises from those faced because of the leukemia. In principle, the existing bone marrow is destroyed, and so the leukemia is destroyed. There is a significant possibility that it will return, but that danger is down the road.

The goal of this transplant is to completely eradicate her old, damaged bone marrow, and to replace it with new healthy and growing marrow that is capable of producing untainted blood cells. There is a great deal of danger in this process. Sometimes it seems to me that this is a case of “the cure is worse than the disease,” except the disease, CMML leukemia, is very bad indeed.

To eliminate the old bone marrow, Mom is going to be put through a regimen of “intense chemotherapy” (and note that the regular old kind of chemotherapy is bad enough for most people), with chemotherapy drugs with names like Fludarabine, Busulfan, and Thymoglobulin. These are still so far down the road that I haven’t yet looked them up. Then there are two day’s exposure to “total body irradiation”.

All of this will occur over a period of 6-8 days prior to the actual “transplant” (which in Mom’s case is then an infusion or a “graft” of stem cells from a non-related donor). In this process, not only is her bone marrow destroyed, but her immune system is destroyed.

For the first 30 days or so after the transplant, there is a danger that the graft will not “engraft”, that is, it will completely reject her system, but that risk is controlled with drugs, and it’s minimal. The larger possibility is that, with her depleted immune system, she will suffer from an infection. It can be bacterial, or viral, or fungal; she will likely develop “mouth sores”, she won’t be able to eat, and she’ll experience nausea, vomiting, and diarrhea. There are dangers of liver and kidney damage, and also pneumonia, which can be a killer.

There are drugs and antibiotics to deal with these. But still, the first 30 days is only the beginning.

When the “graft” becomes “engrafted,” there is a whole new set of dangers. Mom will have no immune system, and in essence, the “graft” will be in charge. The “graft” will have its own immunities, and they will have their way with her. There is a danger that they will reject her, in large and small ways. This is called graft vs host disease (GVH).

True, some of this GVH effect will do a clean-up job on any leftover bone marrow or leukemia from the old regime. In fact, “graft vs host” is what provides some of the magic of this transplant process. It’s often the final nail in the coffin of the leukemia.

Unfortunately, it’s also a killer in its own right. There are two phases: “acute”, while the actual “graft” is still moving around in there, and also “chronic”, beginning at approximately 100 days after the transplant, when the “son of graft” cells are taking over.

In all, the GVH period can last up to a full year or more. Symptoms may be as mild as a skin rash, but GVH can also affect major organs, and I have a friend whose wife died from GVH complications some two years down the road.

The good news is that, if Mom makes it down the road that far, there is an excellent, excellent chance that she will have beaten the leukemia and can look forward to a normal life span. There may be some lingering GVH symptoms – we’ve encountered a couple of people who can’t make tears.

But that’s a relatively minor thing to live with, compared to leukemia.

Bone Marrow Transplant

According to our doctor: “this is the only curative option”
In spite of all that has happened, we are still at the beginning of this process. What has happened up to this point is merely preparative. With this disease, all roads lead to the bone marrow transplant.

Standard chemotherapy won’t help her. Bethany’s bone marrow is damaged, so even if chemotherapies could be given that would put her into “complete remission,” that is, to eliminate all the cancerous effects from her blood, it wouldn’t last, because her bone marrow is damaged, and her damaged bone marrow would continue to replicate the leukemia process. My understanding is that these treatments work for a while, but they will eventually fail.

So, as Dr. Rossetti reminds us, “The only curative option remains allogeneic (non-related donor) transplantation.” And as a part of this process, there are still several milestones that we need to look forward to.

Finding a donor
Even though we have a number of potential donor matches, we still haven’t found that ideal person. They are looking for someone who can match on 10/10 DNA markers. So far, there are six potential “10/10” matches, but none of these is ideal. Most, for example, are older females, who have had children; antigens developed during pregnancies that can contribute to complications during the process that follows.

The dangers, as I understand it, are not that the cancer is less cured. The danger is that the graft vs. host complications will be more severe. So the donor search process is an attempt to minimize that part of it.

The “Bone Marrow Transplant” (BMT)
This is the biggie. The bone marrow transplant is a “transplant” in the same sense of a kidney or heart transplant. Something old is removed, and something totally new is put in. However, unlike a traditional transplant, which is usually a one-time surgical procedure, this one is a longer term process. Much longer.

To get out the old, they can’t just open her up and take out the bone marrow. They have to kill it, and they’ll do it with “intensive chemotherapy” and full body radiation. This process will last a little over a week, and if it sounds harsh, it is.

Simultaneously, the selected donor will be given Neupogen injections for 5-6 days, to prompt his or her stem cells to move from the bone marrow to the blood; on day five of the Neupogen injections, they’ll be hooked up to a dialysis-type of unit; blood will flow out one arm, the stem cells will be harvested by a machine, and then the blood will flow back into the other arm.

When enough stem cells are collected, the bag of stem cells will be flown into Pittsburgh, where Bethany will have already been prepared by the process described above. The implantation of the cells process itself is simple. Some of the blogs I’ve read have even described it as a bit of a let-down, just something like another blood transfusion. But the results are spectacularly different.

“Engraftment”: First 30 Days
Many things can go wrong during this first phase. If we were to go to UPMC, this would be an inpatient process, lasting four to six weeks. At West Penn, they say that patients respond better by being home. (Dani wouldn’t be permitted into the hospital; they’re pretty firm about that.) So Beth will be permitted to go home every evening, and then will need to return to the medical short stay unit, every day for 30 days.

(Note to Highmark: Our understanding is that we will be required to pay the $30.00 co-pay each and every day we show up there. Is there some way that you can streamline this clunky procedure? West Penn is already saving you oodles of cash by making this an outpatient procedure; the least you can do is streamline your paperwork to make it easier for a patient who’s near death.)

During this time, the chemo is still raging; Beth’s hair will fall out, she’ll experience nausea, vomiting and diarrhea, won’t be able to eat. Her immune system will have been wiped out. She’ll be ultra-sensitive to infections, and it’s very likely she’ll need to be admitted to treat infections anyway.

The expectation is that the new stem cells will go to where they’re needed most, that is, into the now-dead bone marrow, and set up shop. This is called engraftment. As part of the daily checking, is checking for signs that this is happening. There is about a 5% chance that engraftment will fail.

Acute “Graft vs. Host Disease” (GVHD): 30 days-100 Days
During this time, Beth’s immune system will be severely depleted, but the expectation is that the new stem cells will have their own immunity. To some degree, this is very desirable, because the new immune system can kill off any remaining cancer in the bone marrow.

But on the other hand, the new stem cells can, to one degree or another, begin to reject Beth’s own tissue. This is called Graft vs. Host Disease. Symptoms can range from simple skin rashes and mouth sores, to more complicated issues dealing with organs such as kidneys, liver, and lungs. Often, I am told, the symptoms from the anti-rejection drugs can be worse than the GvH symptoms themselves.

She will also be susceptible to infections during this time period, including pneumonia, which can be life-threatening.

Chronic GVHD: +100 days to One Year
After 100 days, the new stem cell engraftment will have begun producing its own new stem cells, and for some reason, a whole new round of “rejection” can occur. Too, some of them can be fatal. Marrow.org has prepared a brief presentation that walks through this phase of the process.

The ideal outcome
The ideal outcome, then is simply to get all through all of this. Most of the GvH symptoms will diminish over time. There is still some danger of relapse at this point. But from what Dr. Rossetti tells us, if you can get past the two-year mark, the chances of living out a normal life-span are excellent.

One survivor who I’ve been in contact with has told me about the “survivor dinners,” where “There are a lot of people who are many years past transplant and look great and do not have any ongoing issues”. That’s something we can look forward to.

Here, again, is the prognosis:

30% cure;
20% immediate complications;
15% major longer-term complications;
35% chance of relapse.

Please keep us in your prayers, and please, also, consider helping us out financially.