Day -9: Fludarabine Starts

Today we start Fludarabine, which is Zoe’s 2nd major chemotherapy medicine in the Reduced Intensity Conditioning (RIC) regimen. Fludarabine is designed to eliminate fast growing cells, any fast growing cells. Cells in the bone marrow are very fast growing so they are what will be most affected. Campath is a drug that specifically targeted Lymphocytes (virus fighting cells that are part of any normal immune system), whereas the Fludarabine will eliminate everything in the marrow. It may also finish off the last of her hair, but Maya was nearly bald until she was a year old, so we’re used to that.

It’s considered a well-tolerated medication, so we are hopeful that we won’t see anything at all this week, other than a drop in cell counts and perhaps some fatigue. So far that’s been the case.

Zoe’s counts came back up a bit over the weekend:

[spoiler name=”Click to see counts”]

  • WBC: 2.9
  • Hemo: 9.5
  • RBC: 3.12
  • Platelets: 730
  • Lymphocytes: 3%

[/spoiler]

We’ll continue Fludarabine until Friday. Also on Friday Zoe will get an additional Central Line placed, which means surgery. Hopefully the last major one.

We’ll be admitted to 5200, the Pediatric Blood and Marrow Transplant ward on Friday after surgery, and we will then begin the last medications before the transplant itself next Wednesday.

Zoe is handling all of this as well or better than we are. She’s a fantastic baby.

httpv://www.youtube.com/watch?v=OUK7rlXxYlk

Day -22: Starting Campath

We’re off and running now. Campath started today at 11:30am on a stepped dosing process, which means she gets an increasing dose every 15 minutes under observation until we reach the full test dose. The test dose will run for several hours, and is 20% of what she will receive the rest of the week.

Zoe was given pre-meds to help her manage the chemo: hydrocortisone (steroid), benadryl (antihistimine), tylenol (fever), and demerol (pain).

She is asleep, no surprise. We’re told to expect hives, rashes and fevers, so we will see how things go.

Zoe’s blood counts brought good news today, something we are grateful for on this day in particular. Her Creatinine, a marker of kidney function, is now down below .1, which is as low as can be measured. Her most recent test on Friday was .2, which means that her kidney function has improved measurably. Go Zoe!

The numbers:

  • WBC: 5.0
  • Hemo: 10.4
  • Sodium: 137
  • Platelets: 667
  • Seg Neutrophil: 38
  • Lymphocyte: 55
  • Creatinine: <0.1
  • Bilirubin: 0.5
  • AST: 37
  • ALT: 20
  • ANC: 1900

These are the numbers we’ll be following most closely from now on. The creatinine as mentioned is a marker of kidney function. Bilirubin is a marker for liver function, and it’s currently perfectly fine.

AST & ALT will be monitored to determine if we need to hold the Hydroxyurea. If they rise to 3x “normal” or mid-range, then we hold it. 3x “normal” is ~180 for AST, ~66 for ALT.

ANC means Absolute Neutrophil Count, which is a somewhat complicated calculation that measures immune system function. We can expect that to go up and down, but mostly down, during conditioning. After Zoe’s transplant this number will become our holy grail. We’ll be looking for her cell counts to go up and her ANC to rise and stay above 500, as I understand it. We’ll learn more about this closer to the transplant.

The campath will quickly reduce the Lymphocytes, which is what it is there to do. The “segs” will remain elevated and the ANC, which counts both, may therefore stay high initially. Eventually we expect it to go way down and not recover until after transplant.

Afternoon Update:

Zoe’s first day test dose went very well. No major reactions today. She had an elevated heart rate and very mild fever for about an hour, but was otherwise fine.

Because Zoe did so well, we will be giving her Dexamethasone for the next 3 days during Campath instead of the normal steroid given. This is because Dexamethasone penetrates the blood/brain barrier more effectively, and with HLH it can do more to suppress any abnormal cell activity than the traditional steroid given with RIC.

Tomorrow we continue the chemo and step up from the today’s test dose (which was 20% of normal strength) to the full dose. We expect if we’re going to see a reaction we should start seeing it tomorrow.

Reduced Intensity Conditioning & HLH

We’ve decided to go forward with the Reduced Intensity Conditioning (RIC) for Zoe. As I mentioned yesterday, it came up again in conversation with Dr. M, and after a long meeting at Duke where we discussed both the RIC and the “normal” or Ablative conditioning, we felt pretty strongly that this was the right approach.

Let’s back up a moment.

In our first meeting with Duke, we asked about the potential for a RIC process after doing a bit of research, but we didn’t have any cases to look at which were similar enough to Zoe’s to know if it was something that would work with HLH. At that time the idea was dismissed for the most part, since it’s not how they have done things with HLH patients, and they have had a good track record with their process.

Since then, we’ve spoken with or read about a few different cases where HLH patients took this approach, so we decided to bring it up again for consideration. This time the response was extremely positive, in fact Dr. P felt that it was the best approach having spoken to colleagues and done additional research since we first discussed it.

We’ve rewritten the plan entirely at this point.

About RIC

Reduced Intensity Conditioning is a process traditionally used for patients who cannot handle the standard ablative (high dose) conditioning in advance of a Bone Marrow or Stem Cell Transplant. It often involves an entirely different set of medications designed to achieve the same goal, but with less damage to the body.

The goal of the conditioning is to prepare the bone marrow for the new cell material, either donated bone marrow or stem cells. If the transplanted material does not take or “graft”, then the process has to be repeated or restarted.

Different diseases require different levels of conditioning. Some require the high dose or ablative conditioning to ensure that the disease is wiped out in the body before beginning. Others, such as immune disorders or non-malignant diseases, might require less intense conditioning since there is not something that has to be eliminated, rather the bone marrow is being prepared for new cell material. Partial elimination might be enough in these cases.

In short, ablative conditioning completely wipes out the bone marrow. RIC can either partially wipe it out, leaving some material but making enough room for the new transplant material, or completely wipe it out, giving the same results of the ablative therapy without the additional risks.

Advantages and Disadvantages

The advantages of RIC are numerous. For starters, all of the disadvantages of normal high-dose conditioning are reduced or eliminated.

  • The patient has less increased risk of future malignancy
  • Higher chance of remaining fertile
  • Reduced damage to the organs
  • Less chance of growth retardation and/or puberty delay

Disadvantages are few.

  • Chance of needing to repeat or restart the transplant procedure if graft fails
  • Longer conditioning process
  • Chance of relapse with some conditions or diseases

So why not do RIC? Well, a patient may not qualify for it due to their disease, or they may prefer to take a more conservative approach. RIC is newer and less tested, and the process is still being refined. Traditional conditioning is well tested and established, and it is a more sure approach in terms of the graft.

RIC and HLH

RIC has a relatively short history with HLH so far, due in part to the relative immaturity of HLH research. There are studies, and in some transplant hospitals they do RIC with HLH, but keep in mind that there are very few HLH patients in any given year. This makes it hard to accumulate results.

What sporadic results there are have been fairly positive, as best I can tell. Outcomes seem to be as good or better than ablative conditioning, and Dr. P confirmed our impressions in our discussion. Dangers still exist with any transplant: Graft Versus Host Disease and risk of infection are the two biggest and are no less dangerous on RIC.

Most of the existing studies I was able to find do not use cord blood stem cells as the transplant material however, making the specific combination of Unrelated Cord Blood, RIC and HLH exceedingly rare.

Zoe will be the first HLH case treated with RIC at Duke. They have treated numerous other conditions with RIC however, and the process is very similar. The medications are all well tested and established. The precautions are all in place for GVHD and infection as they would be in any transplant situation, and the team at Duke is great.

What does this mean for Zoe?

Zoe is in about as strong a position as any child could be going into a transplant with HLH. Her organs are in good shape, she has no fever, no other known infections. If there were ever going to be a successful case to do RIC with a cord blood transplant in an HLH patient, we like to think that Zoe is it.

This is a more modern treatment and gives her the greatest chance of walking away from this unscathed. I strongly suspect that HLH will be treated with RIC increasingly, given what I’ve been reading about the results. There just doesn’t seem to be a significant downside.

Worst case scenario related to RIC, she doesn’t graft and we have to start over with conditioning and a new transplant. Obviously GVHD and infection present other worst cases unrelated to the conditioning process.

This means we’ll be starting Zoe on Campath in a couple weeks in the outpatient clinic. After a week of that, she’ll have a week off, then we start the heavier chemo medications and Zoe will be admitted.

Our optimism is now at it’s highest point since we began this journey. We still have a hard path ahead, but we feel better than ever that we’re getting the best treatment we can for Zoe and that our advocacy is working in her favor.

Those Difficult Thursdays

Thursdays are our clinic days, and in recent weeks Michelle has been going in by herself, feeling that there is no point having two of us out of commission for the day. She’s right of course, but I’ve come to feel that I’m not as in touch with what’s going on, so I’m in with her today. I’d be here alone and give her a break, except that she has to be here to feed Zoe pretty regularly.

Being in the hospital again, even for a day, brings back all the recent memories of Zoe’s worst days. Michelle has remained accustomed to it, but I’m feeling pretty stressed being here, having had a couple weeks away from it. Hopefully, we will be done with this phase soon. Our day is spent waiting and worrying about infection in the lobby, getting labs drawn and vitals, and then sitting in a curtained and claustrophobic observation room for hours while Zoe gets her VP-16.

Compared to her days as an inpatient, it’s not bad, but a sad reminder of what Zoe is going through. At home things seem almost normal many days.

We met with Dr. M first thing this morning to discuss a few things and check in. I’d sent an email to Dr. M and Dr. W on Friday to ask a few questions, foremost among them what contact they’ve had with the team at Cincinnati Children’s Hospital, the U.S. experts on HLH. It’s a touchy issue — I don’t want them to think we are unhappy with our care, we aren’t at all, but I do want to be sure we have the most current information for Zoe before we close the book on her pre-transplant care. It is a rare disease and I feel sure that new information can appear that could help her, given how poorly researched it is relative to other conditions.

We should hear back from Dr. Filipovich soon.

Vitals today:

  • WBC: 12.4
  • RBC: 2.82
  • Hemo: 8.8
  • Platelets: 781k
  • SEG Neutrophil: 8.6
  • Ferritin: 700

Great results overall. Her Ferritin is back down from it’s brief spike, and it is being attributed to the skipped etoposide week (to let her immune levels recover). This means we can continue to taper her steroids, and I have in hand the next few days’ doses, after which she will be done with it, hopefully forever. It will take time to burn off the extra weight she has put on and for her cheeks to go down.

This means we will put a plan in place to move ahead with the transplant fairly soon. If there is a bed at Duke PBMT, we could begin her “work-up” in the next week or two, putting us in the hospital for conditioning somewhere in early June. It’s where we want to be. Doing it during the summer lessens the impact on our work and lessens the impact on Maya’s preschool attendance.

By fall we hope to be having our best year ever as Zoe returns to health. In the meantime, it looks like our mean old Thursday visits will be coming to an end soon.

HLH: A Simple Description

In order to properly discuss or write about some of the more complicated aspects of this disease, I feel I need to try and post as simple an explanation of it as possible. It’s not as simple as I would like because it’s such a complicated set of problems, but I’ve tried to include the basic facts everyone interested should know.

Overview:

  • HLH is a rare disorder of the immune system. It is also commonly referred to as a disease. It’s rarity is currently understood to be approximately 1 in 1 million children as many as one in 50,000 children, with recent studies suggesting it is even more common than previously believed.
  • There are two forms of the disease. The primary form is FHL, also known as Familial HLH. The secondary form is simply known as HLH. Both forms are treated in the same manner medically, with the exception of the additional need for a Bone Marrow or Stem Cell transplant to cure the primary form.

Description:

  • When the body has an infection, certain specialized cells activate and fight off the infection. These cells are part of our Immune System. Among these cells are T-Cells and Histiocytes, which when activated cause an inflammatory reaction in the body.
  • In most people when an infection(a cold, flu, other virus or a bacterial infection for example) has been eliminated, the inflammatory reaction that helps eliminate them is turned off and the Immune System returns to it’s “Steady State” or normal state. In HLH patients, the inflammatory reaction does not turn off and causes the symptoms of HLH.
  • Our Bone Marrow produces our blood cells, including infection fighting cells. As the inflammation persists abnormally, the Histiocyte cells attack or “eat” the other blood cells in the bone marrow, causing a severe drop in cell counts. This means that the patient is exposed to normal infections, but has no way to fight those infections off.
  • Typical symptoms of HLH itself can include: Fever, Pallor, Jaundice, Liver and Spleen enlargement, and Neurological symptoms such as irritability and seizures. Not all symptoms appear in all patients initially.
  • Because symptoms vary widely and can be associated with other infections, HLH is very difficult to diagnose. It is an especially dangerous disease undiagnosed, with a fatality rate of 100% over a course of approximately 2 months. 100% of patients will die in 2 months if untreated.
  • Patients have a better chance of survival of this disease the earlier they are diagnosed and treated. The longer the disease continues, the more damage the body does to itself. Because the treatment itself is hard on the body and the disease often affects young children, if the body is too badly damaged, recovery can be difficult even when treated properly.

Treatment:

  • HLH is currently treated with a protocol or treatment program called HLH-2004. This program was created by an international team of doctors in 2004 to attempt to address the poor survival rates of patients with HLH. Prior to that point, a program known as HLH-94 was used.
  • HLH-2004 involves a chemotherapy regimen (a set medicines given to the patient) to stop or suppress the inflammation in the body, bringing the disease under control.
  • Once the disease is under control — once the immune system has “cooled off” — symptoms can begin to fade and the patient’s immediate danger from HLH itself is lessened. The patient is still at very high risk from normal infections due to the damaged immune system.
  • Infection presents the greatest risk to patients with HLH after it has been diagnosed and treated.
  • In the primary form of HLH, known as FHL, remission is only temporary. A Bone Marrow or Stem Cell transplantation is required for long term survival.
  • In the secondary form of HLH, the disease can be permanently resolved with the HLH-2004 program in some cases.

The question many parents want an answer to most, “what are our chances”,  is very hard to answer. I know I spent a lot of time trying.

That answer is there is no easy answer. It depends strongly on how early diagnosis and treatment took place and what underlying conditions are present. In short: your doctor should be the one to even try to answer that because it really is dependent on the unique situation of each child.

More information is available at Histiocyte.org as a starting point. I’ve posted articles I’ve found to be useful in the Links section above as well.