Ellie's Bone Marrow Transplant Plan

We recently had the final BMT coordination meeting with the head oncologist which went for over 2 hours. I feel like I aged about 5 years over those two hours. It was draining but we now have (almost) all the information we need before commencing conditioning week on 20 June.
 
The last piece of the puzzle is the brain complication. We will have a meeting with the head radiologist next week to discuss whether Ellie should have brain radiation prior to BMT. This is because of the unknown matter (suspected necrotic tissue) where the AML chloroma used to be. Our understanding now is that it’s a question of whether the juice is worth the squeeze. Brain radiation comes with its own list of serious side effects. Given we don’t know if there are active AML cells in the brain, it could all be for nothing and result in more long-term damage. We’re not comfortable with radiation unless absolutely necessary but it’s a conversation we need to have.
 
As for the bone marrow transplant. BMT is fascinating and terrifying at the same time.
 
Ellie is scheduled for the transplant to occur on 27 Jun; D-0 (I didn’t make that up, it’s how BMT events are tracked). Pre-transplant conditioning week starts at D-7 and the whole process is expected to take around 6 weeks. For that time, Ellie will be held in protective isolation in a pressurised isolation room to minimise the risk of exposure to practically everything. The slightest bacteria, even normal bacteria on her own skin or food will result in infection which will have severe consequences.
 
Prior to conditioning week, Ellie will have baseline testing on her heart, brain, lungs, kidneys, eyes, teeth, and hearing. This is because the chemotherapy and most of the other medications she needs have serious side effects, including major organ failure. This is a serious worry for us and is why they describe BMT as being a critical turning point in treatment. In theory, BMT will cure the cancer and it’s our last option; the focus then changes from fighting the cancer to surviving the transplant.
 
The theory
 
From around D-6 Ellie will undergo Myeloablative chemotherapy, receiving ‘huge amounts’ of Busulphan and Cyclophosphomide chemotherapy, and Anti-Thymocyte Globulin (ATGAM) to completely destroy her bone marrow. This is different to previous chemotherapy which attacked the AML cells and healthy cells in the blood and CSF. The purpose of destroying her bone marrow is to wipe out her immune system to prevent her body rejecting the graft cells. A healthy immune system would recognise the graft cells as foreign and quickly destroy them. The first week of treatment is generally well tolerated until her bone marrow is wiped out and side-effects start to kick in.
 
Myeloablative therapy does three things: makes space for the new cells to grow, is the last attempt to destroy any residual AML cells, and gets rid of the immune system. While Ellie is in morphological remission (no AML detected), there may still be residual AML cells in her blood. If there is even one AML blast cell remaining at the time of transplant, the transplant could fail in terms of curing the cancer.
 
When the bone marrow is destroyed and Ellie’s immune system has shut down, she will essentially be kept alive by several medications and through isolation. The transplant occurs by injecting around 25ml of graft stem cells into her central line over a couple of minutes. Apparently, aside from a terrible taste and smell which generally brings on immediate vomiting, the actual transplant is anti-climactic. In simple terms, the graft cells slowly make their way to the long bones and bed-down for around 2 weeks until engraftment commences.
 
During the period in which engraftment hasn’t yet occurred is when Ellie will be ‘extremely sick’. She’s guaranteed to be febrile, vomiting, have mucositis, need morphine, naso-gastric feeds, and total parenteral nutrition (TPN). Hopefully this just lasts a few weeks. We have seen her extremely sick during initial induction therapy in 2021 however, the team keep reinforcing this point to us. We understand their way of communicating well enough to know we need to brace ourselves for this period. Plan for the worst and hope for the best sums up BMT.
 
The average time for engraftment to commence is 14 days. Once engraftment commences, the theory is that the graft cells begin to generate new (healthy) white cells to build a new immune system, replacing the destroyed system. At the same time, they could recognise any residual AML cells as foreign, and attack them as the immune system grows. However, this is not guaranteed and there is no real way of knowing if this occurs.
 
During engraftment, and up to D+100, one of our major concerns is Graft v Host Disease (GvHD) which is where the graft white cells recognise they’re in a foreign body and start to attack Ellie’s healthy cells. This can result in major complications and is life-threatening. That said, there is a balance in GvHD because it is also what can result in the destruction of residual AML cells (Graft v Leukaemia effect (GvL)). The optimal result is a small degree of GvHD but not too much. It was described to us that there are benefits to GvHD however, we would never attempt to promote/stimulate it with specific medications in BMT because the risk is too high.
 
If everything goes well, we should see Ellie start to turn the corner between D+21 to D+30 where her cell count begins to increase. Engraftment success is determined by neutrophil count of >0.5 for 3 consecutive days. When released from isolation after around 6 weeks, or when her counts have sufficiently recovered, and providing there are no other major complications, she will be released to come home for the majority of her recovery. During this period, she will need to attend clinic appointments at the hospital 3 times per week for the first several months and this will eventually taper down. Her central line can be removed (again) after about 3 months. She will need to remain isolated at home for 6 months and cannot attend school or any populated places until her immune system has recovered. The oncology team has described her immune system as transitioning from a baby to a toddler during this period. After this time, she should be able to build-up to recommencing school however, the entire recovery period is thought to be 12-18 months.
 
What could go wrong?
 
On the face of it, the whole process seems reasonable. We can do another 8 months in isolation – no problems at all. Unfortunately, there is considerable risk of major complications during transplant. As I said before, the focus switches from fighting cancer to surviving the transplant. This is not only due to the transplant itself, but several dangerous medications which can lead to major long-term health problems.
 
Aside from all the standard side effects of chemotherapy, some of the more severe complications Ellie is at risk of include veno-occlusive disease, capillary leak syndrome, cytomegalovirus, and major organ failure; particularly respiratory, heart, and renal failure. Many of the more dangerous medications and chemotherapies are particularly harsh on the heart, lungs, and kidneys. Complications in the major organs could occur early, or onset later in life, so we will need to be vigilant in monitoring for symptoms and be prepared to manage life-long chronic conditions.
 
Transplant rejection is concerning however, we have been reassured it is highly unlikely due to Ellie’s immune system being in such a poor condition. Transplant rejection (different to GvHD) is when Ellie’s immune system recognises the graft cells as foreign and attacks them, causing the transplant to fail. This would mean we need to repeat the transplant with the backup umbilical cord which I spoke about in the previous post. Given the state of Ellie’s immune system, it’s unlikely she has the ability to reject the graft. If by D+25 there are no signs of engraftment, the team will start planning for transplant with the second cord.
 
GvHD is of more concern to us due to the likelihood of occurrence. We understand it almost always happens however, the degree varies significantly, and it could commence early, or within 100 days of transplant. GvHD more commonly attacks the skin, liver, and gut. It can present in mild symptoms (grade 1 GvHD) such as mild skin rashes, to life-threatening (grade 4 GvHD) severe skins conditions, and severe liver, stomach, and intestinal problems.
 
Our head oncologist described managing the transplant and treating the side effects as walking a tightrope. To me, it seems more like an impossible balancing act, on one leg, while juggling a dozen knives blind-folded. For every major complication or side effect, there is of course, medication to treat. However, each medication has side effects that are just as bad, or worse, and so there is another medication to counter the last one, and so on.
 
For example:
 
Cyclosporin is used to treat GvHD however, damages the kidneys and can result in kidney failure.
 
Cyclophosphamide is critical in conditioning therapy to prevent transplant rejection however, damages the lining of the bladder and can lead to haemorrhagic cystitis, for which there is no treatment. It also increases the risk of heart damage, lung damage, and secondary cancers.
 
Busulphan which is also critical in conditioning therapy, can result in seizures, veno-occlusive disease, and lung fibrosis.
 
Most of the antibiotics and anti-fungals (which Ellie has taken since the start) help to prevent serious infection however, also result in impaired kidney function and drug-induced liver injury.
 
It certainly feels like the calm before the storm. Ellie feels good right now, happy, chatty, and cheeky. Knowing what we’re about to put her through is very unsettling.
 
The silver linings
 
In our last post, we explained that Ellie will have stem cell transplant from umbilical cord blood (UCB) which came from the US and is a perfect 8/8 HLA match. We now know the age of the cord, being from 2018. An HLA matched umbilical cord is about the next best thing after a matched sibling donor. While studies show that events of chronic GvHD and organ complications are least likely with a matched sibling donor, matched UCB is next best when compared to other donor methods.
 
We also learned yesterday that UCB transplant is not commonly done in Australia. In fact, our team at the Sydney Children’s Hospital, Randwick is the only team in the country that routinely does it. There are only 4 hospitals that can do it (Randwick, Westmead, Brisbane, Melbourne) though not all routinely. This is because the Randwick Kid’s Cancer Centre has a habitual relationship with the Minneapolis Pediatric Cancer Center whereby, they send oncologists to learn UCB transplant. Our team now have over 25 years of UCB experience. They are convinced UCB transplant is the future of HSCT in paediatric AML and they’re in the process of publishing a study which presents the favourable data. We’ve read some of it and the data is encouraging.
 
While the reality of BMT makes for some tough reading, there are silver linings to be found. At the end of the marathon meeting, I asked the head oncologist to end on a high note with some good news. He started by saying “we have a fairly good chance of pulling this off.” He followed up with several other highlights however, I was distracted by thinking how terrible his choice of words was.
 
From our perspective, we’re fortunate that we have the opportunity for transplant because Ellie achieved morphological remission and because of advances in modern medicine; we’re lucky to have one final chance at curing Ellie’s cancer; we have a great 8/8 HLA matched umbilical cord donor; we have the best health care team looking after her, and the only team who have UCB donor experience; and we have the continued love and support of our family and friends which is honestly, what keeps us going.
 
We know Ellie will continue to fight hard, like she always has, and will beat cancer again.
 
PC