Book 6, Chapter 1, Verse 2
The Muses have not been kind to me.
For almost two weeks I have been trying to get the second part of my venetoclax story written and sent. I have written, revised, rewritten it and then decided my stuff was too detailed, tedious and boring. I rewrote the whole thing, only to lose it to a power surge during a thunderstorm. Arrgh! So I’ve modified a previous version and here it comes. Here’s the deal; if you’re interested in the problems we encountered in just trying to get into the trial, keep on reading. But if you’re just interested in the venetoclax study itself, skip down to the “Ramping Up the Venetoclax” part.
JUMPING THROUGH HOOPS
I met Doc Thompson in the first week of May and that’s when he signed me up for the venetoclax study. That was quick and easy. It also turned out to be just about the only quick and easy part of this process. He introduced me to our hard-working research nurse, Blanche, who was in charge of integrating me into the study protocol. Blanche immediately started butting her head against several walls. She had to get approval from our insurance carriers to get me into the study, then try to get permission from the sponsor to waive having to repeat all the preliminary tests I’d had done just nine weeks previously, make appointments for any tests I still needed to get done and then, finally, when all this had been done, she had to get the sponsor (in this case, Abbott Pharmaceuticals or their biologics branch, AbbVie) to review my labs and other studies and agree that I was fit for the venetoclax protocol. We thought it might take a couple of weeks. It took well over a month!
Blanche first had to get insurance approval for me to be in the study. Yes, when you’re in a research study, the drug company will pay for the “study drug,” and also for any strictly research tests that are done in connection with the study (like drug levels in your blood, etc.) but your insurance is expected to pick up the tab for any “routine” testing which has to be done. But I had just had a battery of expensive tests done within a couple months of signing up for the venetoclax protocol. Remember that I had a couple days’ worth of tests, including the bone marrow biopsy, CT scans, EKG, echocardiogram, numerous blood tests (you can’t believe how much some of these specialty blood tests cost) and more when I signed up for the nivolumab study in March. Would insurance pay to get them done again? Would the sponsor waive the requirement to repeat them after such a short period of time?
Blanche thought it might take a few days to a week to get the insurance approval. But it took a couple of weeks or more. I didn’t like the waiting. I was getting worried, seriously worried about the progression of my disease. By now, after all the delays I'd experienced (see my previous blog entry) I had been relapsing for something approaching nine months. The daily aching of my lymph nodes in my armpits reminded me that I was sick. I worried out of proportion to the length of time it was taking, but I now knew that some 17p folks like me have “explosive” relapses when they fail the ibrutinib and I also knew that I apparently only had a 60% chance of responding to the venetoclax in the best of circumstances. In other words, I had perhaps a 40% chance of dying fairly soon. I was getting physically ill with these thoughts. But, there really wasn’t much else to do. I was scared. I feared that something was going to happen while we were waiting for all these approvals which would knock me out of the study.
After anxiously emailing Blanche a few times, inquiring about the (to me) prolonged time it was taking to get the insurance approval, she finally got it a couple weeks later. Great news! But, meanwhile, the sponsor refused to waive any of the preliminary studies. So, I had to be scheduled for all of the ones I’d just completed plus more. Blanche ran into a scheduling nightmare trying to schedule, again, manifold blood tests, a PET scan, the echocardiogram, EKG, another bone marrow biopsy and more.
Up until recently it had been fairly easy to schedule things like that, as each nurse could apparently do their own scheduling. But, in March of this year M. D. Anderson inflicted a new electronic records system on the staff. Ostensibly this is to make everything easier for the staff. In practice, it has made so many things harder, slower and more complicated for them and the patients, too. I could write a whole chapter on the changes I’ve seen at M. D. Anderson just in recent months. I love the place. I love the staff. But I have found myself getting angry with “the system” and how staff and patients alike have been getting jerked around in recent months. Appointments appear and disappear randomly, tests ordered never make it to the lab, medication orders don’t find their way to the pharmacy. Sometimes the computer doesn’t even know where we’re “authorized” to get our blood pressure and weight taken, as if it should make any difference at all. But that’s all I’m going to say in these pages.
Blanche set about trying to schedule all the needed tests, which required a great deal of coordination, some tests being able to be done only after others had been completed. She worked, I worried. Days went by, another week went by. Finally, we got a phone call from Blanche. It was about 5:15PM and we were watching the news. The stars had aligned and she had everything scheduled for me. She told us we needed to be in Houston THE NEXT MORNING to start the three days of required tests and scans! We threw some clothes in our bags and headed out, making hotel reservations en route. We didn’t arrive until after 11PM that night, but I was oh-so-glad to be getting going on the study. This was the start of seven consecutive weekly 600 mile round trips to Houston.
Getting the testing done was actually fairly straightforward and, except for a lot of wasted time sitting around, went well. People in the know at M. D. Anderson tell me that the “M. D.” in the name stands for “Most of the Day.” There can be a lot of waiting at many appointments, but I’m happy to wait. I was very happy to get the testing behind us because Blanche had me scheduled, finally, to start the drug the following week, the first week in June. After completing all the required tests, we left for home on Friday, with plans to return the following Monday, with the drug trial to begin on Tuesday.
After just enough time at home to wash clothes and get some cash, we headed back down I-45 on Monday. Our appointments hadn’t yet been made but Blanche was going to set them up as soon as the sponsor looked over my test results and gave the final approval. We waited for the call to let us know what we were supposed to do. We got the call while in the hotel room in Houston, on Tuesday morning, but it wasn’t the call we wanted. Bad news. The start of the drug testing had to be postponed. My tests were still in processing and weren’t yet ready. “Go home,” we were told, and we’ll try again next week.
Home we went, now waiting for yet another call to let us know that everything was ready. The call came. More bad news. Abbott/AbbVie wasn’t happy with the PET/CT scan, which had been done without IV contrast. We’d have to repeat it, this time with some sort of iodine contrast material (which is injected into a vein at the time of the CT scan). To save us yet another trip to Houston, Blanche added this additional CT scan onto the next week’s schedule, on the Monday before I was to start the protocol. We came back the next week, did the CT scan with contrast and everyone was now happy. We were finally in!
RAMPING UP THE VENETOCLAX
Venetoclax is a great drug. It’s a powerful drug. It’s too powerful to be used casually. In its early studies, some patients died. Doctor Thompson tells a story of one of the first patients he treated with venetoclax in the early trials. The patient had a white count of about 100,000, high, but not unusual for a CLL patient (normal white counts are about 6,000, +/- 3,000 or so). The standard dose of venetoclax is 400mgs, but to be careful, they gave this patient only a half dose; 200mgs. Eight hours later the patient’s white blood cell count was only 1,000!
SCIENCE LESSON FOLLOWS: Let me explain what that means. It does NOT mean that, in dropping from 100,000 to, 1,000, the drug killed off 99,000 white blood cells. When you have a number in your blood tests, like the 100,000 number above, what it means is that the test shows there are 100,000 white blood cells per every milliliter (or “cc,” they’re the same thing) of blood in your body. The average adult has about five liters (or 5,000 milliliters) of blood in his/her body. So, a white blood cell count of 100,000 means that person actually has 100,000 white blood cells/ml x 5,000mls of blood in the body, or 5,000,000,000 total white blood cells. That’s 5 BILLION white blood cells! So, in this case, when the venetoclax rapidly dropped this patient’s count from 100,000 to 1,000, it actually had rapidly killed off about 4,950,000,000 white blood cells, give or take a few dozen, in just a few hours.
That’s all well and good, but all those dead white blood cells and their contents have to go somewhere. These cells have proteins, electrolytes (like potassium) and a lot of inflammatory chemicals. These things can clog up and damage the kidneys, cause heart rate irregularities and more. They can cause what’s called “tumor lysis syndrome” (TLS). That’s basically just dissolving too much “tumor” in too short a time for the body to handle the debris (this can happen with other drugs and other tumors as well).
I mentioned that a number of patients have died as a result of being treated with venetoclax. That’s not good news, obviously, for lots of folks. So, to minimize this very significant risk, the drug manufacturer has wisely made it hard to give venetoclax to CLL patients. It has put a number of restrictions of who can give the drug and how they can give it. First (as I understand it), any doctor who is going to give the drug has to go through specific training sponsored by the manufacturer. Secondly, those patients who are to receive the drug and who are considered to be at “high risk” for TLS, must be admitted to the hospital during the early stages of therapy so they can be very carefully monitored (described below). Those not admitted are still required to be carefully monitored with additional blood testing and exams. In every case, the drug is initially given in very small doses and “ramped up” very carefully and deliberately over five weeks.
I was considered to be “high risk.” Anyone with a white blood cell count over 25,000 or an enlarged lymph node over 5cms (about 2 inches) in size was defined as high risk. My white count was 34,000 and I had at least one node that was 8cms, or about three inches in diameter, among the dozens of enlarged nodes I had in my belly, chest, neck and under my arms. So, I got admitted to the hospital to start the drug.
While in the hospital I had an IV going continuously, giving me an extra two liters (about a half gallon) of fluids every day, plus the fluids I got in my diet and all the water the nursing staff kept pushing me to drink. I also got to collect all the “output” for them to measure, in a process I called “Operation Golden Flow.” They needed to know that all those fluids were coming out and not building up in my body somewhere. All this was designed to make sure my kidneys were working well and dealing with the cellular debris which was being created by the drug.
And I got stuck a lot. I had labs drawn before I took my first dose of the venetoclax and then every four hours for 12 hours, followed by several other tests during the next 36 hours. This was to check for any early signs of TLS and to look for how well the drug was working. I also had more tests before and after my second dose the next day.
I have mentioned how carefully and deliberately the drug is “ramped up.” This is how we started. The standard dose of venetoclax is 400mgs per day. But, for a new patient, the initial dose, given for the first full week, is only 20mgs. That’s only 5% of the standard dose. But, even at that miniscule dose, it started working. Within days, I could feel my nodes first swell a bit with inflammation induced by the drug, and then start to shrink.
I was discharged from the hospital after about 48 hours or so, and after another blood count the following day, we went back home, with me taking the 20mgs daily at home. But we came back in a week and I was admitted yet again, with the same routine except that this week my dose was increased to 50mgs daily. Same routine; blood tests before and every four hours after the drug was given, the IV going continuously and measuring all my urine output. Thereafter, I was allowed to increase my dose, weekly, as an outpatient, going from the 50mgs dose to 100mgs, then to 200mgs and finally to the final 400mgs dose, each time staying at the new dose for one week. And each week we were back in Houston for exams, labs and follow-up. In fact, every time we increased my dose I had blood tests done before the new dose, then 8 hours later and again in 24 hours, before being allowed to take the second dose of the new amount. They were exceptionally careful. And I’m very happy about that.
I’ve now been on the venetoclax for about 10 weeks. My white count now is actually low, but adequate, at about 2,600. My red cell count has come back from being a low 28% (normal for a male is more like 45%) up to the mid-30s. And my clotting cells, the platelets are back up to 100,000 for the first time in years (normal is 150,000 to 300,000 or so, but 100,000 is more than adequate for clotting). All the nodes in my armpits have disappeared and I presume the ones in my belly have too. And I can report that there are few to no side effects. No nausea (which is the most common side effect), no joint pains like the ibrutinib caused, no hair loss, no rashes…nothing but some minor fatigue. Good news all around. I guess.
When I first started on the venetoclax in June, even before my first hospital admission, Doc Thompson mentioned in passing that at some point we should probably talk about a stem cell transplant. Now, I know that I may have to cross that bridge sometime in the battle against my disease, but I didn’t expect it to be very soon, since the venetoclax holds a lot of hope for folks like me. But, after just two months on the drug, he again mentioned, more strongly, his interest in having me see the transplant team, so well am I doing. Everything is going just great…and he wants me to see about getting a transplant!
But for a transplant to have the best chance of succeeding, I need to be in a good remission. We will soon see how good a remission I am getting into. To that end, on August 23rd, which is our 47th wedding anniversary, I will be face down on a procedure table at M. D. Anderson with a large bore needle stuck deeply into my hip, drawing out some bone marrow to see how much disease is left in there. I’ll also be getting more blood tests and CT scans of my belly, chest and neck, looking for tumors. We’ll see, very soon, what shows up and where this will lead.
Next: The rationale for going for a potentially risky transplant while you’re doing just great on a newly approved drug!
“If you think health care is expensive today, just wait until it’s free.” P. J. O’Rourke