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 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.

A Visit to Duke Part 1: Surviving the Transplant

On Friday we traveled to Durham to visit Duke Medical Center and meet with part of the team there who will likely be handling Zoe’s Stem Cell Transplant. Overall it was a great visit, very positive and we gained a good deal of insight into the process.

Because of the wide-ranging nature of what we discussed, I’d like to break it up some and cover what’s going on with more than one post.

First, the SCT itself and what we now know we can expect.


Let’s talk a little about statistics. Briefly. Not my favorite subject either, believe me.

I have previously discussed the mortality rates for children going through a Stem Cell Transplant (SCT) based on both the research I’ve done and on the numbers I was given from Duke originally. As expected though, context helps put those numbers in perspective, and the outlook is not nearly as poor as we might have feared.

The problem is sample size — in this case, the amount of children who have had the procedure at Duke. The sample size for HLH is very small, and as such even one poor outcome skews the result vastly. Only 8-20 children are estimated to develop HLH per year, making it hard to get a clear picture.

I could say that 50% of the cars on my block are blue, for example, and that might be a true statement. But if there are only 2 cars on my block (2 in the sample), does that 50% begin to seem like a misleading number? In some cases, it might.

In the case of the SCT procedures done at Duke on patients with HLH, the number is 14. Of those, 5 did not survive long term. What we now know however is that there are a lot of factors that make that number less frightening.

  • All of the patients who did not survive long-term had their procedure prior to the year 2000
  • Since 2000, many things have changed with regard to medicines and procedures, reducing the risks
  • All of the HLH patients at Duke since 2000 have survived
  • All of the patients who did not survive have factors that distinguish their cases from that of Zoe or perhaps other more recent HLH babies.

Of the patients that did not survive:

  • One died in 1991, prior to both the HLH-94 and HLH-2004 protocols — his treatment was simply not as effective because not as much was understood about the disease, and he lost a long fight
  • One died of a fungal infection — since the time of that patient’s death, a medication called Vfend has become a standard part of treatment, and would likely have saved that child had they had that medication at the time. Zoe takes Vfend 2x a day.
  • Two died due to viral infections they had at the time of their transplant — that means they went into the procedure in poor health, likely because they had no other choice

My notes are incomplete on the 5th, but the overall point of the discussion at the time was that there were clear reasons that each child did not make it. It was not simply a matter of Russian roulette — these children were not at their best or were lacking medicines that, had they been born today, could have saved their lives.

Gives you new respect for medical research.

With this information in mind, the 70% survival rate begins to seem like a problematic number. The real number is likely much higher. The risks are still very much present, but we are no longer going into this feeling like our chances of losing Zoe are so high as to be soul crushing.


The two risks most on the mind of Dr. P are Graft Versus Host Disease and infection (bacterial, viral, etc). The risk of GVH is mitigated somewhat by the type of material to be used in Zoe’s transplant, cord blood. Cord blood procedures are understood to have a lower risk of Acute GVH vs. donated marrow procedures. The risk is there, but lessened.

The risk I had most been fearing was that of VOD, a specific complication of the transplant procedure. I have been living in fear of it due to the fact that several of the HLH children whose stories are public on the web did not survive it. I was greatly relieved to hear that Duke has access to a medication that takes much of the danger of that off the table. It is not FDA approved, however it is available to some hospitals on a “compassionate” basis. Duke is among the hospitals testing it, and they hope to see its FDA approval so that it will be in use more widely. Regardless, Dr. P felt confident that VOD would not be as risky for Zoe as it has for other children in the past.

So. 99% of patients survive the conditioning regimen. 90-95% of patients achieve a graft of the transplanted cells. Slowly, slowly, our fears are being replaced by facts.

Zoe will begin her procedure in the best health we can hope for while still fighting the disease — no known infections, good overall health and, by the time of the procedure, good counts (we hope). Risk of bacterial infection greatly reduced. Risk of GVH reduced. Risk of VOD greatly reduced.

Reasons for hope indeed.

Other Factors

There are a lot of questions we’ve been asking ourselves.

What can we do to help Zoe survive this?

Is she getting the right treatment?

Is Duke the best possible hospital for her transplant?

We want her to have every chance, so we regularly beat ourselves up trying to be sure we’re not making mistakes. The answers are hard to come by though.

What we know is this: we are doing everything we can for Zoe within our power. We are researching everything as best we can and challenging Zoe’s doctors (nicely! :)) when we aren’t sure of something, to be sure they are and be sure we understand why they are.

And, we now know that Duke is as good if not the best at pediatric transplants in the US. They do more unrelated (cord blood, marrow) pediatric BMT and SCT procedures than anyone in the country from what I understand. We feel we are in the best hands for the procedure that Zoe is going to have.

Right in the Middle

So, where are we?

First, a few updates. Zoe had a good day on Friday for her VP-16 dose. No adverse reactions this time, they gave her Benadryl at the start and did a 3hour drip instead of 2 or 4, and it worked out just fine.

Michelle was able to meet with Dr. W and the good new news is that Zoe’s immune system has made a sufficient recovery to put her out of immediate danger of infection from normal day-to-day life.

We are allowed outside. We are allowed to eat in (uncrowded) restaurants. It’s like Life 2.0.

The pertinent number, the one that gave us this new freedom, is her SEG Neutrophil count. Hers is 2.1, where 1.0-9.0 is considered normal. Great, great news.

Other vitals:

  • WBC: 6.2 (way up)
  • RBC: 2.73
  • Hemo: 8.3
  • Platelets: 447k

Where does that leave us?

Well, right in the middle I would say. We’re now mostly clear of the danger from the onset of the disease, and with continuing treatment we should stay clear for a little while. The fevers are gone, the organ enlargement is gone, the histiocytes in her spinal fluid are gone, and her platelets are well clear of the danger of internal bleeding now.

Once we have confirmation about the genetic testing, we will know more about the Stem Cell Tranplant, but we’re working on the assumption that she will need one to be cured. We have a huge decision ahead, depending on test results, as I’ve mentioned previously. It’s a little scary, but we feel considerably better than we did a few weeks ago. We know more now, and we’ve had more conversations with our doctors to answer questions we didn’t even know we had back when Zoe was sicker.

Our next step is to meet with the doctors at Duke, ask our long list of questions, and try to come to a firm decision about the transplant. That should happen late next week, and we hope to get news on the remaining genetic tests “soon”.

In the meantime we’ll be keeping up with Zoe’s meds, checking in twice weekly with the hospital, and hoping for continued improvement.

And I’m (not so) secretly hoping the chipmunk cheeks take a hike too.


FHL, or, Familial HLH

Now that I’ve attempted to lay out some basic information for understanding HLH, I’d like to take a look at the real issue: the difference between FHL and HLH.

When I began reading up on this disease it took quite some time to understand where FHL, or Familial HLH, fit in to the picture. When literature or doctors talk about the disease, they tend to refer to it simply as HLH. Over time I’ve come to realize there are a variety of reasons for this, not least of which is the difficulty in diagnosing which of the forms of HLH a patient has. So, let’s take a look at the two forms side by side.

HLH, or Hemophagocytic Lymphohistiocytosis, is the name for the immune disorder. It can come in one of two forms: Familial HLH, also called FHL, and Acquired HLH, usually referred to simply as HLH.


  • Is the primary, or most common, form of HLH
  • Is also known as Familial HLH
  • Is caused by a genetic defect passed to the child by parents who are carriers; children of parents who each are carriers (as they must be for the child to have the disease) have a 1 in 4, or 25%, chance of getting FHL.
  • Is rare for two reasons primarily: because it requires two parents who both carry the recessive genetic defect to mate and pass on the gene (only a 25% chance); and because it goes undiagnosed often enough with 100% fatality, so as to seem more rare than it likely is.
  • Is generally found in very young children; this is because it manifests itself when the child has an immune response (such as to a cold) and once it manifests is fatal if untreated. Kids who have FHL get sick as kids always do at some point, and they don’t survive unless treated. So, it’s not usually found in older kids — it’s either treated successfully or it is fatal.
  • Is fatal if uncured. This means that the disease can be put in remission temporarily through the HLH-2004 protocol, but will return worse and likely with fatal results if uncured.
  • Can only be cured with a Bone Marrow Transplant, or a Stem Cell Transplant.
  • Requires genetic testing to positively confirm


  • Is the secondary, or less common, form of HLH
  • Is also known as Acquired HLH
  • Is caused by an immune disorder resulting from another condition putting the immune system under severe strain
  • Patients who have HLH are usually slightly older children (>1yr), though it has been seen in infants as well
  • Is able to be treated successfully with HLH-2004, and often resolves itself permanently once it and the underlying condition are treated
  • Cannot be positively confirmed through genetic testing

The Diagnosis Problem

HLH, in either form, is rapidly fatal. Within two months of the disease manifestation, an untreated (undiagnosed) child will die 100% of the time.

Therefore, diagnosis of the particular form of the disease is not the most pressing issue, but instead the focus is on treating the patient as soon as possible to control the immune response before it destroys the body.

Once the disease is under control, a determination has to be made as to whether a Bone Marrow Transplant (BMT) or Stem Cell Transplant (SCT) will be needed. This is where it really gets tricky, and why distinguishing between the two forms is so vital. FHL requires a BMT/SCT to be cured, whereas Acquired HLH does not.

Both BMT and SCT are highly dangerous procedures, not due to the transplant itself but to the difficulty the patient has with accepting the new cells and surviving the side effects. Survival rates for children appear to be in the neighborhood of 70%, with some variation depending on the type of transplant cells used. The numbers never look “good” though, for these procedures — the risk is always too high.

Therefore deciding to get a BMT or SCT is a tough decision, and unfortunately diagnosis of FHL is not always able to be positively confirmed. What has to happen is the tests must be done, and the overall picture must be looked at.

Factors that are considered:

  • Results of genetic testing: Sometimes will positively confirm the disease, however because we do not yet know all of the genes to test it does not always confirm it
  • Results of Soluble IL-2 test: Over 10,000 tends to be a marker for FHL
  • Results of NK cell count test: Low or absent counts are a marker for HLH in general, but not specifically FHL or HLH
  • Age of the patient: due to the manner in which Acquired HLH manifests, very young patients without an underlying condition tend to be assumed to have FHL

It is unfortunately not possible to positively confirm Acquired HLH, only FHL. Therefore, to make a decision the doctor and parents will need to look at all of the information and test results before deciding on the need for the transplant.

Click to enlarge

Here is a chart sometimes used to understand the process for diagnosing FHL. Please note: HCT is the acronym for the medical term for Bone Marrow or Stem Cell Transplant

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.


  • 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.


  • 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.


  • 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 as a starting point. I’ve posted articles I’ve found to be useful in the Links section above as well.