Friday, August 19, 2016

Ramping Up The Venetoclax

Dave’s Great Adventure
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.


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!


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

Sunday, August 7, 2016

Nivolumab, pneumonia and venetoclax!

Book 6, Chapter 1, Verse 1

Nivolumab, pneumonia and venetoclax!

“Life is a crooked line. It’s rarely what you plan.” –Chuck Slaughter, founder of TravelSmith

Or, as I’ve quoted many times before in this long story, “If you want to hear God laugh, tell Him your plans.”

Indeed, my life and plans have not been a straight line. I have settled in several times to write an update to my story, only to have our plans change…over and over again in the past six months. I will try to tell you of all these permutations of our plans in a somewhat condensed form, but those long-time readers of my stuff know that it is hard for me to tell stories succinctly. I always seem to render them in excruciating detail. I can’t help myself. Hey, I diagnosed myself with “hypergraphia” several years ago. I guess it doesn’t heal itself!

Last January it looked like I was relapsing. The folks at M. D. Anderson made plans for me to get a huge number of tests and to return in a month for follow-up. And indeed, on my return a month later, the manifold tests showed that I was indeed relapsing, that I was failing my wonder drug, ibrutinib. I’d long known that it was possible to relapse on ibrutinib, but I had done so well for so long, I was thinking I’d have many more good years on this drug. I knew of some folks who have been on it five years or more and continue to do well. I’d hoped to be one of them.

But, since I was relapsing, we had to come up with a plan for my next treatments. I mentioned at the end of my “Book Five” that Doc Keating was considering trying the checkpoint inhibitors on me. To that end, I was signed up for a clinical trial which combined the ibrutinib with a checkpoint inhibitor called nivolumab (trade name Opdiva) which is already on the market and shows success against lung, kidney and melanoma skin cancers. It had not, however, been used against leukemias except in a very few small trials. But it looked promising.

In February, I signed all the appropriate paperwork usually associated with clinical trials (laying out all the known and unknown risks). I also was scheduled for a whole raft of new tests to make sure I was eligible and qualified to be in this clinical trial, for which you have to be sick enough, but not TOO sick, to get in. The tests, which were scheduled for early March, included about a dozen tubes of blood being drawn, another bone marrow biopsy, CT images of my abdomen, chest and head and neck, an EKG and, finally, a cardiac echogram. I believe just getting eligible for the study set my insurers (the taxpayers of America—thank you very much!) back about $10,000 or so. All the tests went well so I was scheduled to begin the trial, which was the nivolumab in combination with my recently failed ibrutinib, later in March. But let me digress for just a moment in telling this story.

Initially I had great interest in getting into the nivolumab plus ibrutinib study. It sounded exciting (any drug that can help you stave off certain death HAS to be exciting, I think) but the more I thought about it, the less I liked the idea. I could find close to nothing in the medical literature showing that nivolumab had significant effects against CLL cells, and I knew already that my CLL cells weren’t responding to the ibrutinib any longer. “What was the point,” I thought to myself. But, I was scheduled to begin the study at the end of March and we went forward with the plan.

Then the trajectory of our plans went sideways. Our family had a long-planned trip to Alaska set up for mid-March, just before the start of the “nivo” study. We were headed to Fairbanks, the better to see the Northern Lights, plus we had plans to go dog sledding, snow-machining, flightseeing and more. We had a wonderful time up there as I mentally prepared myself for the upcoming study to start.

But, as we flew home from Alaska, I developed a fever. Followed by shaking chills. Followed days later by a persistent and vicious cough. I thought I had a bad cold. After about ten days of this, it was time to go back to Houston to start my new trial. There I saw my nurse practitioner, Jackie, who asked some questions and listened to my chest for a few seconds. “Do you want to be admitted?” she asked. “Hell, no!” I responded. I still believed I had just a bad cold and maybe a little post-viral bronchitis. But Jackie ordered a chest X-ray. It showed “double pneumonia,” pneumonia in both lungs! When the X-ray results came back, Jackie told me-- didn’t ask me-- “You’re getting admitted!” They ended up growing both the bacterium Pseudomonas and the virus human meta-pneumovirus out of me.

And so it was that I spent April Fools’ Day on the 16th floor of the M. D. Anderson hospital wing. Unlike the long-ago April Fools, who were celebrating New Year’s Day in April, not yet having heard about the change from the Julian to the Gregorian calendar, I knew the correct date. I just didn’t know when I’d be able to start my new study drug, the “nivo”. I was sick enough that it couldn’t be administered, but I really wanted to get going with something. I could feel lymph nodes in my neck and underarm areas growing, seemingly on a weekly basis.

But the study was postponed while I was tied to a hospital bed with an IV pumping in industrial strength antibiotics I’d never heard of before (ever hear of linezolid or cefepime?). I spent four days on the ward and then another five weeks on various oral antibiotics, trying to get well enough to start up the trial of nivo. All the time I was impatient to get going on the study. My nodes were getting bigger all the time and aching daily.

Then the trajectory changed again. I went back to M. D. Anderson in early May to see Doc Keating to see if I was finally well enough to start the study. We were running out of time, as the cluster of tests I’d done in early March were going to “expire” after 60 days and those days were about used up. But, Doc Keating wasn’t there. He was out recovering from back surgery, having been involved in a freak incident. As I hear it, there had been a car fire in the hospital parking garage and someone, driving too fast to get away from it, almost ran Doc Keating down. He dove out of the way, injuring his back and ended up requiring surgery.

So, instead I saw his protégé, Dr. Phillip Thompson, another Aussie who specializes in CLL and who is being groomed to take over for Doc Keating. Doc Keating is now working part-time and is slowly, very slowly heading into retirement. It was great to meet Doc Thompson after having only heard about him from other patients lately. If you see any of the patent Power videos concerning updates in CLL, you’re probably seen a lot of Doc Thompson in recent months.

Dr. Thompson examined me, felt the enlarged nodes in my neck, under my arms and in my belly (he could tell they were there though I could not) and we talked about the nivo study, for which I was still signed up. But Doc Thompson said that the early results of that study weren’t encouraging, that the response rate wasn’t very good. He felt that it was disappointing that they weren’t better, because in theory the nivo should be a great treatment for CLL. But, since it wasn’t working out well, he suggested I enter into a study of another drug called ABT-199 (also known by its generic name, venetoclax).

I’d been hearing more and more about venetoclax lately and in fact, knew that it had been approved for certain CLL patients just the month before. It’s been in development for about as long as ibrutinib, but some early problems in its testing phase set it back. This stuff really works! It works, maybe, too well in some cases. There were a few deaths of some patients early on because this stuff kills off CLL cells so fast that the cellular debris and the inflammatory chemicals in the CLL cells overwhelmed some folks’ kidneys and immune systems in a condition called “tumor lysis syndrome.” It’s nothing to mess around with.

I was happy to hear that I could sign up for a venetoclax study. I had actually wanted to get into one the previous February when I signed on to the nivo study, but there were no venetoclax studies open at the time. I knew it was a wonderful drug for CLL and I also knew that the docs administering it were exceptionally careful in giving it now, knowing full well the deadly complications it could bring on. And so I signed on to the study.

Only then did I go looking for recent updates on the drug and folks in my condition. You will remember that I have the deadly 17p chromosome deletion and I also now have failed the ibrutinib after more than three years. I looked up recent studies of folks like me who were taking venetoclax. There was one such study. It flatly stated that patients who have this chromosome abnormality AND who have failed ibrutinib have a “dismal” prognosis. They had recently started a study using venetoclax on some of these patients. At the time of publication they had signed up 18 study patients. Four of them were already dead six months into the study. And, the overall response rate was said to be about 60%. That left 40% of those patients with little hope. That scared me. It really scared me. So, as I entered into the study I wondered if I’d be one of the lucky 60% who at least showed some response to this drug, which apparently was now my last and best hope for survival, or whether I’d be one of the 40% for whom there would be little hope.

--Next; slowly and carefully starting the venetoclax…and maybe a transplant?


“Experience is the comb that life gives you after you’re bald.” –Chinese proverb