My drug vs. Pablo Escobar

I find it difficult to write science. My first drafts always include far too much detail. I get carried away. I can’t explain the drug without mentioning PD-1. I can’t mention PD without naming it directly. I can’t name it without explaining apoptosis. But then the drug has little to do with apoptosis and I just end up confusing myself. So, for the sake of simplicity, I shall not define PD-1. For those interested there is always Wikipedia.

Blood is composed of different cells. I have spoken of neutrophils, which fight bacteria, but I haven’t really mentioned lymphocytes, which is odd because I have a lymphocytic cancer. You’ll have to excuse me; I am bound to get out of my knowledge depth rather quickly. This may be why I haven’t mentioned lymphocytes before, a small knowledge gap there. Lymphocytes are the backbone of the immune system. There are two types of lymphocytes. B-cells, which find and remember pathogens, and T-cells, which do the killing. Within the T-cells there are many sub-types, but only two I wish to talk about today: regulators and effectors. The regulators ensure that your immune system does not fight itself. They deter the effectors, who want kill things. Usually the regulators are the good guys, maintaining a calm within the body. Sometimes they are complacent, leading to autoimmune diseases, and sometimes they are corrupt. You see, PD-1, perched on the outside of a cell, is much like Pablo Escobar paying off the cops. They even call it an immune checkpoint. Pablo uses his henchmen, ligands PD-L1 and PD-L2, to encourage more regulators, and assassinate effectors. Those effectors who survive turn up to the crime scene where they are swamped by regulators: “Move along, nothing to see here.” And so the cell survives when really it ought to die. My super-secret (or not so-secret) drug is a PD-1 inhibitor. It is an antibody (human IgG) that binds to PD-1 and prevents corruption. I don’t know Colombian history well enough to expand my Escobar metaphor. Perhaps I should have thought of that before I began.

It turns out that my subtype of Hodgkin’s lymphoma, along with a couple of other notable cancers, has an increased cellular PD-1 expression. I believe this is due to 9p24.1 over-amplification. This chromosomal mutation also leads to an upregulation of the JAK2 pathway (possibly my favourite pathway) which feeds back on itself to promote cell proliferation (i.e. cancer), produce more henchmen (PD-L1 and PD-L2), in turn recruiting more regulators. I guess the 9p24.1 mutation could be deemed cocaine. It would be great if my drug could destroy the cocaine, but it is limited in its abilities. All it can do is eliminate Pablo.

One half of chromosome 9 and its faulty ways

The catch, there is always a catch, is that PD-1 expression in small quantities is perfectly normal. In fact it is necessary. Unfortunately, my drug cannot distinguish between normal and abnormal levels. It binds not only to Escobar, but to every other Pablo in the body. This could lead to some overzealous effectors exterminating some rather essential cells. The key word there is could. It may not. We shall see.

A couple of months ago, my super-secret drug was approved by Medsafe. It is now officially safe to use in New Zealand. But not for my disease. For other cancers, cancers that have decent data sets. I rocked up to Wellington for my first treatment since my release to Nelson. It was going to be great; a quick scenic flight over the Marlborough Sounds, bloods taken, treatment initiated, a cheeky bone marrow, and an evening flight home. How naïve! Nothing ever runs according to plan. Surely I ought to have learned that by now. The drug hadn’t arrived. It should have, but it hadn’t, and nobody knew why. Maybe it will arrive tomorrow. Mike and I wait. I entertain my sister’s cat for a bit. Then her neighbour’s cat. Then a stray, who really is making a right nuisance of himself, but I am restless so I will tolerate his disobedience for a while. I know, I know I am reinforcing negative behaviour patterns. What are you gonna do? I sat on the couch, read, lay, rolled over, read, sat up, stood, oh a piece of candy, lay, rolled, sat, lay, stood, sat, paced, candy, paced. Where the bloody hell was this drug? Huh? There are only so many chin scratches one can give in a day. Wellington had quickly lost its charm. The drug did not arrive tomorrow. Perhaps the next tomorrow. No? Had they chosen kayak as a transportation method again? They hadn’t. It was a document issue. The drug had previously been imported as an experimental, unapproved drug. Since its approval status had changed, the import documents had also changed. I believe the drug was having a lovely little vacation in a customs lock-up somewhere in Auckland airport. I disputed the need for different paperwork; the drug is still unapproved for Hodgkin’s, it shouldn’t need the new paperwork. Apparently bureaucracy doesn’t work like that. The drug did arrive, it was just a week late. 

All that you have read so far was typed over a month ago. The 31^st of May, so Word helpfully informed me. It seems like you have missed all of June. I would love to be able to declare myself extremely busy; moving on with life, running about town, running even. Alas, this is not quite true. Sometime in early June, Mike and I moved into our own place. We are living by ourselves for the first time in nearly a year. I am now struggling with life's everyday exhaustions. One load of laundry and a batch of dishes is enough to send me crawling back to bed with my tail between my legs. A 4pm fever leaves little energy for dinner preparation, which is usually left to Mike along with any other domestic duties I have missed. Suddenly it is eight-thirty, and I haul my sorry ass upstairs, for eight-thirty is now my bedtime. And repeat. The world is pretty much coming to an end if the vacuuming needs doing. As it does now. I have developed an attractive wheeze, a wheeze that turns into an emphysema like cough, enhancing my beauty. Oh winter and your cursed temperatures. To be fair, fevers are far more tolerable in winter than summer.

Ok, now that vile self-pity paragraph is done with. I guess I thought by complaining about it maybe everything would miraculously clear up, this searing back pain would cease, and I could start to enjoy things, anything, again. But it is like so many situations faced by so many people. Everything will be better when we move back to Nelson. Everything will be better when we get our own place. Everything will be better when…. No. There is no magic fix. There may never be a fix. It sure is hard work.

Right let’s pick this up a bit. Positives. Oh, my Hickman line has been removed. No more looking like something from a Kilgore Trout story. Also, I believe it has been over three months since my last blood transfusion. I got quite excited about that. Yus, my crossmatch sample is active for seven days now. The transfusionists out there get me. That is probably the end of the positives for now, we don’t want to overdo the excitement now do we? It might start me wheezing.    

Game changer

Sometimes, when my health is on the improve, I play a little game. It is a dangerous game. I pretend that all will turn out fine. That at some point, soon even, life will return to normal. We will rent a wee flat in Nelson, The Wood perhaps. Our cat will move back in with us. She will cease her biting ways. The flat will be near the city and we will walk or cycle to work. Ah, to work.  A job. Right. Becoming a contributing member of society again. Tricky business.

Our possessions are scattered throughout New Zealand. Various friends and family members are storing boxes filled with our crap; in garages, closets, chests, under beds, piled high in spare bedrooms. My books, my books are also scattered. I try to infiltrate the bookshelves of loved ones but usually, they too, end up in boxes. The books, not the loved ones. Gosh, things can get morbid mighty fast when grammar is overlooked. I must confess I never expected to open any of those stored boxes. It was all part of the game.

I left you in March (shit, was it that long ago?!) closely monitoring my fevers, platelets, haemoglobin and bilirubin. I started two blog entries but circumstances kept changing. My updates were obsolete before they were published. Like a newspaper. It is difficult to be witty and current. I’ve found opting for neither is the best approach. Anyway, there I was, March, obsessing over my bloods. I must apologise for I wasn’t exactly honest in my March post. Well it wasn’t complete dishonesty, it was more omission. Avoidance rather than evasion. Like Cameron. Allegedly. You see, the immunotherapy arrived at the eleventh hour, like a fairy-tale prince. I was a little too dependent on blood donations. Two bags a day, of both platelets and red cells. My bone marrow wasn’t working. It was packed full with Hodgkin’s cells. The marrow surrounding the Hodgkin’s cells becomes fibrotic and cannot produce any blood cells. My liver wasn’t working. Presumably, it too was packed with Hodgkin’s cells. I would like to thank all the blood donors out there. They kept me alive.

This new drug arrived and promptly terminated my liver failure. The bone marrow response was a little slower, but I have maintained a haemoglobin in the low 90s for at least four weeks now without any transfusions. Go team! Thrombopoietin (TPO) is the hormone that stimulates platelet production in the marrow. In a wicked feedback cycle, the liver produces the majority of TPO. The red blood cell equivalent, Erythropoietin (EPO), is produced by the kidneys. By having liver failure there was minimal production of TPO, which was fine at the time because my bone marrow was also failing and would have done fuck all with such stimulus, but once the two began working again it was interesting to watch my haemoglobin rise whilst my platelets lagged behind. I was reliant on platelet transfusions for about a week longer than red cells. In Wellington, protocol is to keep platelets above 20 for patients with fevers. You are not allowed to shave your legs until your count reaches 50. I am unsure if that is actually documented in the official SOP. These are the pesky issues I worry about now that the chemo is out of my system. Did I hear somebody say first world problem?

My consultant informed me he was rather impressed with my blood. I blushed. This is probably deemed showing off in an anaemic ward. But my cells had done me proud. I still take it personally when my haematological results amaze, fucked up, I know, I know. It is the nerd within me. Or the nerd that is me. Anyway, so impressed was my consultant that during an impromptu meeting he released us from Wellington. Mike and I were free to live in Nelson on a full time basis with me returning to Wellington once a fortnight for treatment. We were shocked. This was completely unexpected. More unexpected than the marrow failure. We had to take a moment or two to recover. Despite the southerly cutting through my now functioning marrow, Wellington had grown on me. Stockholm Syndrome perhaps?

  

Mitre Peak, Milford Sound

This occurred a few weeks back. Since then I have been a little distracted trying to cram the rest of my life into four weeks. Christchurch, Queenstown, Fiordland, Omakau – ok so that one doesn’t feature in Lonely Planet. I am still cramming. How does a Mid-May overnight tramp in Nelson Lakes sound? Great, let’s do it. Now. Let’s do it now. Tramping has a different definition in New Zealand, although both involve a sleeping bag and no showers. My fevers persist, however monitoring these has been complicated by menopausal flushes. Fun fact: your temperature does not rise during a hot flush. It does with a fever. Initially I was pleased; menopause is a process all women go through, I felt it was my duty as a woman to experience it. After a month of continual hot flushes I declared it unfair ­– the first time throughout my journey I have said such a thing. Still, my glowing red face does provide a conversation piece with women over forty-five.

It turns out merging back into reality is time consuming, exhausting, and rather difficult. My procrastinations are interrupted by self-imposed distractions. Looking for a flat in The Wood is not as romantic as it sounds. My cat still bites. And a job? Ha! I can’t even commit to a haircut. And I need to. I really need to.

     

Small windows of opportunity

It is odd how the mind works. Over the last few days my rigors and fevers have improved, I have had periods of undisturbed sleep and, other than a couple of humours qualms, I am deemed ‘well’ by the haematology team. And yet, when I sat to type this, tears flowed faster than the words. For no reason. I am not sad, a little tired yes, but not upset. Perhaps the previous months have caught up on me, or perhaps I just found Biffy Clyro particularly sentimental today. I don’t know. But if you can imagine your screen as a sheet from my little black book, there would be small salty droplets marking it. Not as authentic as a coffee ring, I grant you; well I’ll give you creative license to add whatever features you wish. I was hoping to provide an insightful blog post during our last limbo period, you know, an overly descriptive piece regarding my thoughts and feelings on various aspects of medicine and life. One of my sisters simply loves these entries. Unfortunately, I didn’t have the strength or energy to do such a thing so you have all been saved. For now.

Despite my relapse, my situation still fell within the BCSH guidelines. But the lines were a little blurry, the directions a little vague, and by the end you cannot help but think the document is simply shrugging at you. That being said, we were left with three treatment options. The first was to continue with Brentuximab. I was all for this, but my reasoning was purely emotional. I desperately wanted this cool ass drug to work. But it hadn’t. They scanned me to prove it. I’ve been told the unused portion will be transferred to another patient. They may have said this to ease my guilt. The second option was Gemcitabine; another chemotherapy agent. My cells, however, seem suspiciously resistant to chemotherapy, so I imagine this thought pattern was discarded rather quickly.

Seemingly, this left one final option: a double stem cell transplant. But wait, there was an outsider. An option that, travelling feverishly back from the Coromandel, I had not considered. No one, I imagine, had considered it. Around the time I relapsed a drug company began offering a new unregistered drug to refractory Hodgkin’s lymphoma patients for free. I did not meet the criteria but my consultant opted to apply anyhow. It sounds like he had to compose a novel. Upon completion of his manuscript, he returned and said he was not hopeful at all, don’t hold your breath, this will never be accepted. We forgot about it and concentrated on the original final option.

A double stem cell transplant. There are two types of stem cell transplants. Autologous, using my own stem cells, and allogenic using donor cells. The first is a way to administer high dose chemo. The second has further curative aspects. The donor cells work to eliminate the cancerous cells. Because they’re foreign cells, they can recognise that Hodgkin’s cells aren’t normal. It’s like the donor cells walk into a masquerade ball, have a quick look around and cannot believe Hero could be so foolish; that is clearly Don Pedro not Claudio, and they hope Beatrice is leading Benedict on because his disguise really isn’t that great. Then they kill them all. Yes I turned it into a tragedy. Are you lost? I think I am.  

Where was I? Right a back-to-back stem cell transplant. It was finally going ahead. Global emails had been sent; this was the consensus. First up would be the autologous with some BEAM to eliminate as much disease as possible. Then when I recover, say after two months, they would smash me with the allogenic. Hopefully, in that two month period they would find a donor for the allogenic transplant. The donor cells need genetically similar, HLA matched, as we say in the industry. Although I have two sisters, I again landed on the wrong side of statistics. Neither are suitable donors. They tell me somebody in Germany is a full match. Germany have a strong donation culture. Many people donate stem cells more than once in their life. And they donate all around the world. Even with my occupation, I was unaware of this need for donors. I cannot believe I was never on a register. Don’t worry, my stem cell harvest post is imminent, so I can implore everyone to join the donor registry. Anyway, they had two months to sort out Germany. I myself was facing six months of incapacitation, and that is not hyperbolic, it is necessity. Further disease staging was performed, namely another bone marrow, but don’t worry I asked for the gas again. Always ask for the gas.

My stem cell transplant was scheduled for Friday. We had an appointment with my consultant Wednesday for consenting and a final rundown on the procedure. I’d booked my last supper at a classy Wellington restaurant for that evening. But the consultant had a bombshell. You know before the Shakespeare tangent, the HLA tangent, the Germany tangent, there was that drug application made. The one we had all given up on. Yeah that one. Well it had been approved. My consultant explained that we were now in uncharted territory, probably somewhere off Bermuda. In a triangle. The global medical consensus (there had been more emails) was to continue with the transplants. The Wellington team felt they should continue with the transplants. My consultant was neutral, or at least portrayed neutrality, and the decision was ours to make. We had three hours.

I am not an apt enough wordsmith to convey how serious this decision was. It was the biggest of our lives, although, granted, we have had few of those lately. I am often asked if my medical background helps with my treatment. Well it obviously hasn’t helped physically. As far as understanding goes, it has definitely been beneficial when communicating with clinicians, and it has possibly helped me to rationalise my disease, although ignorance would have made relapses much easier emotionally. In this situation, my occupation and my affinity for nerding out, helped substantially. I had heard about this drug before leaving the UK, I knew it was in development, but I never expected it to be available to me. I had read about it, knew the uber cool science behind it, the potential side effects, the results from the small (very small) clinical trial, and to know all this, and to be able to absorb further information rapidly, was priceless. So, our question remained, do we opt for the conventional treatment, the one the experts are suggesting, the one with a known curative possibility; or, or, do we opt for this new drug, with little long-term data, with little data at all, a drug nobody in the haematology department has used, an experiment really.

Well, I am a scientist after all. I am always up for an experiment. And the biology behind it sounds solid. After a three hour stroll around Newtown and far too many coffees, we announced that we would try the new drug. I was so close to having that bloody stem cell transplant I’d nearly declared it to the online world. But this time I turned the bastard down. It was at least on my terms. And I still went out for my classy dinner.

         

There were further reasons that lead us to our conclusion, reasons that may seem less than rational. The drug is offered through a “Compassionate Access Scheme”. It had barely opened for Hodgkin’s patients when I re-re-relapsed, and remained open only a few weeks. I believe it has now closed. Such a narrow window, and yet I had slid through. It was almost my duty to give it go. Those who know me will be well aware of my spiritual and religious beliefs. If anyone thought there was a slim chance that I was agnostic, I am not. The more I am compelled to reflect on my mortality, the more I believe that when I die, that is it. I am not coming back as a cat, I never consider the pearly gates, nor Dante; all I imagine is nothing. Definitely an atheist, sorry guys. So I do not believe in fate, but I do believe that if an opportunity opens up, like this window, well I should probably take it. Ok, maybe I will return as a cat burglar given my apparent window obsession. Obviously all my clinical data will be collected, so I can flatter my ego with the belief that I am contributing to future medical advances. Liv, the ultimate humanitarian. I spoke of my medical background, and clinical trials, and science, and making an informed decision quickly; but it was predominately personal reasons that lead us to our final outcome. I found it quite difficult to go against medical consensus.

A new drug, a distended abdomen and who's that sexy beast in the mirror? 

The drug is in my veins now. It took two weeks of further paperwork before it was cleared, and I was too afraid to update the blog in case everything fell through. As you’ve probably gathered, plans have a tendency to change at the last minute. And I didn’t have the energy to type a retraction. I probably would have Fairfaxed out. During these two weeks my disease progressed rapidly. I suffered unresolvable nocturnal fevers resulting in terrible mornings. The drug infusion itself (one hour, once a fortnight) was an enjoyable anti-climax. Unfortunately, the following day was one of those terrible mornings. I had a pleasant mustard complexion and a yellow glow in my eyes. They admitted me, and to be honest I didn’t argue. They were concerned that these were side effects, however I knew it was all disease. That night my fevers were again unresolvable. This caused quite a stir in the morning. I informed my nurse I had a fever. She knew. She’d been watching me for five minutes. My resting heart rate was over 150. The alert team were called. About six doctors and five nurses streamed into my little cubical. All the while I was mumbling “But this is just normal morning fevers, this isn’t the drug.” I made a joke about dying. It fell flat. Not funny in a cancer ward. They pumped me full fluids, and more fluids, and more fluids. Too many fluids. Eight kilograms too many. And it all ended up in my legs. I won’t be climbing through any windows for a while. I have to lift my elephantine limbs off the bed. My underwear are two sizes too small and I spend my days with elevated feet, wondering if it is acceptable to simply forgo trousers. It is rather comical. Mainly because my fevers have eased and this is probably my biggest ailment. Oh that and my spleen! Yes you get to hear about that again. My spleen is massive and painful, as is my liver. Both are enlarged to the extent that I was used as a training abdomen. Twice. A medical student was ecstatic because one of his goals was to palpate a spleen. What can I say? I aim to please.

So this is long. But it is current. I was only discharged Monday. I know I have been deliberately coy about the drug. I am yet to receive confirmation as to whether I can name it, hence I haven’t. And the New Zealand media are currently a little sensitive about cancer treatment. I am itching to launch into the science behind it; patience Liv. Basically, it is not chemotherapy, it is immunotherapy. It works to turn my immune system against the cancerous cells. This is why I am feeling pretty positive about it all. Chemo wasn’t working, this might. And how else can I feel?