Believe It Or Not, This is the Kinder / Gentler Version

I promised to tell you all about the details of Harvey’s mini-allo transplant. Mini-allo transplants (also known as non-myeloablative or Reduced Intensity Conditioning, RIC) are not quite as intense as the full myeloablative variety of transplants. This post goes into the details and if this level of detail is not your cup of tea, please feel free to skip the early parts, go right to the bottom of it to see how Harvey is faring.

The Minneapolis preconditioning protocol has three drug components that are the mainstay of their preconditioning protocol:

  • fludarabine,
  • cyclophosphamide
  • total body radiation.
  • and, for a select few, they also add ATG (anti-thymocyte globulin).

These are the main players, but there are a host of supporting drugs that play important roles. I will try to explain the details of this protocol with special attention to dosages, the why and how of it. The devil is indeed in the details and there is a definite advantage in selecting a transplant center that has been around the block a few times; even more important, a nursing staff that is well trained to be meticulous in adhering to best practices. That is perhaps the thing I like most about U of Minnesota hospital at Fairview. The staff is very strict with themselves, in terms of following protocols, but very flexible when it comes to allowing patients to get as comfortable as possible. Going through a transplant is tough enough on patients and families. Who needs a drill sergeant nurse with deficiencies in the empathy department?

Getting Ready, the Night Before

Making good use of the catheter installed just hours before, Harvey had a constant drip of prophylactic medications overnight. In addition to the flush of saline when nothing else was being pumped in, he had 200 mg of fluconazole (anti-fungal), 500 mg of levaquin (broad spectrum anti-bacterial), 640 mg of acyclovir (anti-viral) and 300 mg of ursodiol (drug to protect the liver). The last one (ursodiol) is repeated three times per day. These protective drugs seem to be a daily feature of the protocol, I am happy to say.

You might say Harvey was loaded for bear, prepped and protected for all sorts of nasty contingencies. Protecting the liver is an important thing to do, since so many of the drugs used in the transplant process have some level of toxicity to this important organ. Believe it or not, I heard of a CLL patient that needed a liver transplant, after he went through a stem cell transplant to cure his CLL. Two for the price of one, poor guy.

Why Fludarabine ?

Most CLL patients are familiar with fludarabine. Most of us have had it on one or more occasions, most of us end up opting for a transplant because we have become refractory to this important firewall drug and there are few other good choices left. So, the logical question is why do transplant protocols use fludarabine, if most of their patients are likely to be be refractory to it going in?

Aha, that is because they are trying to benefit from one of the most infamous nasty side effects of fludarabine treatment. We have hammered away at the heavy duty immune suppressing effects of fludarabine. Dr. Terry Hamblin minces no words, he says fludarabine treated CLL patients are on par with AIDS patients when it comes to immune competency. Fludarabine kills T-cells. That is the single biggest reason why using this drug causes immune suppression. T-cells are our front line troops when it comes to attacking and killing foreign substances like viruses and other pathogens. Loss of T-cells lays us wide open to viral infections such as pneumonia or painful attacks of shingles.

That is precisely why fludarabine is such a good drug to use ahead of a transplant. When you think about it, it all makes sense. The new graft (cord blood units or adult donor stem cells) coming in are “foreign” material, and to any self-respecting “host” T-cells remaining in the patient’s body the graft looks like dangerous invaders that must be killed at any cost. Patients with too many of their own T-cells remaining in the body prior to the infusion of the new graft run the risk of graft failure , where the precious new immune system is killed before it has a chance to settle down and do some good. Graft failure was not such a big deal in prior years, since most protocols used full myeloablative preconditioning – heavy handed chemo that was not likely to leave behind too many T-cells to worry about. With the advent of “kinder and gentler” mini-allo transplants that do not include T-cell toxic drugs such as fludarabine, there is a possibility that a few T-cells may escape getting killed and that increases the risk of graft failure. Some institutions use Campath in their preconditioning since it too does a terrific job of killing T-cells.

The dosage of fludarabine given in the Minnesota protocol is 40mg/m2 for five days (Days -6 through -2). Harvey had his first dose of fludarabine yesterday, his day -6. One gets used to this method of counting days, DAY ZERO being the all important day when the baby cord blood units are infused. The fludarabine dosage of 40mg/m2 is not all that different from the dosages we have seen in standard combos such as FR (fludarabine + Rituxan). Harvey tolerated it without missing a beat.

In Harvey’s case, the fludarabine dosage was adjusted downward by 20%. This was because when they did his blood tests in the morning they found his creatinine level was 1.1. This is quite within the normal range of kidney function, but U of M looks for a creatinine level of 1.0. Picky picky! Since our bodies get rid of fludarabine and its waste products by dumping them into the urine, kidney function is very important in calculating the right dose. For people whose kidneys are a little slow in getting the job done (reflected in increased creatinine level), there is a longer delay in getting rid of fludarabine. This means the drug lingers in the body longer than normal, and less of it needs to be given.

This is an important detail any time you are given fludarabine, not just in the transplant setting. If your creatinine level is significantly higher than than 1.0, you should make sure your doctor is taking this into account before deciding on the right dose for you. Over and beyond the prophylactic anti-viral, anti-fungal and antibacterials Harvey got overnight, the pre-medications given just before fludarabine are Zofran (anti nausea) and decadron (aka dexamethasone, a steroidal drug similar to prednisone)

Cyclophosphamide (aka Cytoxan)

Fludarabine and cyclophosphamide seem to go together well, sort of like peas and carrots. Many popular chemo combinations such as FCR, FC, and CFAR take advantage of the synergy between these two drugs. A lot of CLL patients are familiar with cyclophosphamide (“Cytoxan”) for that reason. But I doubt any of our guys would have gotten cyclophosphamide at the dose it is given in the transplant preconditioning setting. U of M uses a single dose of cyclophosphamide on Day -6, a whopping 50mg/kg. Harvey is a big man in a small package, he weighed in at a svelte 64.2 kg when they took his weight yesterday. So, doing the math, he got a massive dose of 50×64 = 3,200 mg of cyclophosphamide.

Cyclophosphamide is not a friendly drug, especially when it is given in such as high dose. So, there are special precautions for it. One of the issues is that cyclophosphamide can damage the bladder. Once again, the body tries to get rid of the toxic drug by means of dumping it into the bladder, as urine. If the stuff is allowed to sit around in the bladder for long periods, serious bladder damage can occur. Hemorrhagic cystitis is a dangerous side effect, where your bladder turns to mush as a consequence of close encounter with toxic materials, especially byproducts of chemotherapy agents such as cyclophosphamide. It can be a fatal complication if not treated properly.

Fortunately, a simple and low-tech solution works remarkably well. Get rid of the contaminated urine by peeing every two hours or sooner! For 24 hours after cyclophosphamide is administered, the nurses (and yours truly) kept an eagle eye on Harvey, we made sure he made the trip to the bathroom at least every two hours. The urine was monitored closely for any signs of blood. In order to produce the copious amounts of urine, Harvey was encouraged to drink liquids frequently (he also got quite a lot of liquids just from the various iv drips going in).

Among the special pre-medications for cyclophosphamide is Mesna. This gives additional protection beyond frequent emptying of the bladder, worth remembering if you have bladder issues and just cannot stay away from cyclophosphamide therapy. Zofran (anti-nausea) and decadron (to reduce inflammation) are given as well.

Since we are talking of the importance of peeing every two hours, it is important to point out that all of the liquid going in and going out makes for potential imbalances in blood electrolytes. Our bodies need to have very stable levels of electrolytes such as potassium, sodium, calcium, magnesium etc. for proper function. The staff here monitor these values closely and at the slightest deviation from the norm they are quick to hook up another bulging bag of potassium chloride or whatever. Last night Harvey got a few leg cramps, enough to trigger additional potassium and magnesium infusions. If on the other hand there is an increase in body weight suggesting water retention, a small dose of diuretic (“Lasix”) is sufficient to take of it.

Anti-Thymocyte Globulin (ATG)

Most patients coming to the transplant center have had multiple rounds of chemotherapy of one kind or another and therefore their immune systems have been ravaged by the time they get here. But a subset of patients (such as Harvey) have not had excessive amounts of fludarabine or similar T-cell killing drugs. The amount of fludarabine given in the preconditioning regimen is considered insufficient for these guys, extra precautions are needed to get any remaining T-cells.

That job falls to ATG, anti-thymocyte globulin. “Thymocytes” is another name for T-cells, reflecting their passage through the thymus as part of their education. ATG is therefore nothing less than a specific T-cell killer.

It is sort of interesting how they make ATG. Human T-cells are injected into a horse (or rabbit). The horse responds to this outrage by doing all it can to kill the foreign T-cells. In the process of doing it, the horse’s body produces immunoglobulins (Igs) targeted to attach themselves to the offending human T-cells, mark them for death by the rest of the horsey immune system (complement mostly). I don’t think they have to kill the horses, just “milk” their blood and collect the anti-T cell globulins. Sometimes rabbits are used instead of horses.

ATG is similar to Rituxan and Campath in the sense that it too is an immunoglobulin product. But unlike Rituxan and Campath, it is not a monoclonal antibody, it is instead a polyclonal antibody. It is not fixated on a single marker (CD20 for Rituxan and CD52 for Campath). ATG is a mix of many different kinds of immunoglobulins, created by our offended horse (or rabbit) to tag all sorts of markers exhibited by human T-cells. Since these markers are not the exclusive property of T-cells, other human cell lines too may have one or more of the markers and therefore targeted by ATG. In other words, think of ATG as a broad spectrum antibody (as opposed to the very narrowly targeted Rituxan) and it therefore kills many cell lines, even though the main target of its wrath is T-cells.

ATG Therapy: Risks and Rewards

As we mentioned above, ATG is used primarily to kill any remaining host T-cells, so that they are not around to attack and destroy the new graft coming in. The major advantage of ATG therapy prior to transplant is therefore prevention of graft failure, which is a very good thing. Think about it, they have just killed the immune system you were born with, and now you have this brand new immune system that is supposed to get settled and take care of you for the rest of your life. Last thing you want is to have the precious new immune system killed. Graft failure is one of the components of overall mortality statistics and reducing this risk factor is a very good thing to do.

ATG hangs around in the body for more than just a few days. Which brings us to the second effect of ATG: it kills some of the T-cells coming in with the graft as well. These are the donor T-cells we are talking about, not the host T-cells long dead and gone. Killing donor T-cells has two effects. First, it reduces the risk of acute GVHD. Graft-versus-host disease happens when the newly arriving donor T-cells look around, see a lot of stuff around them that looks sort of foreign and decide to attack. Perfectly innocent cells lining the gut, mouth, skin, liver, kidneys etc can be attacked and killed in this process. High grade GVHD can cause significant mortality, it certainly impacts quality of life. Taking these frisky donor cells down a peg or two makes all the difference in GVHD incidence.

But there is a price to pay (there always is), for the assistance of ATG in reducing graft rejection and GVHD. As we know by now, T-cells are needed to protect against infections. Fewer donor T-cells to get started doing this job (because some of them have been killed off by the ATG) means patients are more at risk of infections and have to be monitored more carefully. This is particularly true of viral reactivations and patients given ATG therapy are closely monitored for CMV and EBV reactivation.

I am guessing here, but I would think much of the above discussion is also true of patients who have Campath as part of their pre-conditioning regimen. Campath is also a good T-cell killer, and unlike garden variety chemo like fludarabine, it too hangs around the body for several weeks. In other words, it too is likely to kill a portion of the donor T-cells as they come in with the graft, and therefore it too is likely to impact GVHD and risk of infection.

Last but by no means least, T-cells are involved in the all important GVL (graft-versus-leukemia) effect, the single biggest reason for doing stem cell transplants. Without GVL, the whole process of pre-conditioning etc is nothing more than a whole bunch of heavy duty chemotherapy. You may get good clearance of CLL cells as a result, but it is only GVL that can keep a watchful eye out for any CLL cells hidden in the nooks and crannies of your body and kill them as soon as they are seen. Think of pre-conditioning chemo as sort of carpet bombing of the enemy - it kills off most of the bad guys (as well as some perfectly innocent and righteous citizens). GVL following shortly after is akin to well trained troops with good intel going house to house through all the neighborhoods on a search and destroy mission to kill any bad guys still hiding out.

Where is this leading us? ATG (and drugs like Campath) may kill so many of the incoming T-cells that there are fewer T-cell troops available right away to do the search-and-destroy mission of GVL. Over time this will be remedied as the new stem cells get settled down and start producing newly minted T-cells. But it is important to know that for patients going into transplant with poorly controlled and aggressive disease, reduced T-cell coverage and therefore inadequate GVL immediately after transplant may make all the difference. Risk of relapse of the original cancer increases with use of ATG therapy. See what I mean, there is no free lunch? Fortunately, unlike acute leukemias, most CLL patients in good remission do not have this run-away freight train type situation, and can afford to wait a few days for the GVL to kick in.

The Minnesota protocol mandates ATG for patients who have not had conventional chemotherapy drugs in the past 3 months. Revlimid does not count, therefore Harvey had to have ATG. The dosage is 15mg/kg body weight, given twice a day, for three days (Days -6, -5 and -4). The pre-medications for ATG therapy are Tylenol, Benadryl and methylprednisolone. Most of us who have had any sort of a antibody therapy, whether it is Rituxan or Campath, know that there are infusion related side effects and they have to start the process very slowly, gradually ramping up to full speed. Same story with ATG. Among the popular side effects are “shake & bake”, rigors, chills, hives.

Our Hero Has a Tough Night

Harvey’s first ATG infusion took 7 hours. The second one was quicker, and happened while he slept. Barring a short episode of chills, he tolerated the first three infusions on Day -6 with no problem.

We were congratulating ourselves on how well our hero was tolerating the pre-conditioning. He sailed through the infamous high dose cyclophosphamide with nothing more dramatic than several bouts of hiccups (did you know this is one of the less frequent documented side effects of cyclophosphamide?), got through 3 out of 6 ATG infusions with no problems, fludarabine is a known drug he has tolerated very well in the past, we were almost home free through this phase of the protocol! Serena went home to grab some shut-eye, do the laundry etc. As you would expect, all hell broke loose right away. We are talking major league diarrhea, vomiting, and a spike in temperature to 102.4. Since Harvey typically runs around 97 degrees (most CLL patients seem to have slightly below average temperature, I never understood why), temperature of 102.4 is a big deal. They hustled him off downstairs to get a chest X-ray, stool, blood and urine are being cultured as I write.

This morning things seem to have settled down. There is still remnants of the diarrhea, but the fever is gone and so too the nausea. I understand they will add two additional iv antibiotics to his already impressive list of protective agents, just to make sure any impending infection is chased off.

Gotta run, the docs are doing their rounds and I have questions to ask. I will try to write an update on Harvey’s situation later today or tomorrow.

Be well,

Chaya