Holy bendamustine, Batman! (B-R round two)

I have finished the second of my six bendamustine-rituximab treatments, and this time the regimen came with some "Kapow" and a little "Bam."

To guard against tumor lysis, my first treatment involved only two-thirds of the standard dose of bendamustine (aka Treanda); this time I had the full 100mg/m2. My reaction was significantly more intense than the easy-breezy first time around.

The bendamustine was administered last Tuesday and Wednesday. Tuesday also included the Rituxan, which brought forth infusion reactions unlike any I have had before. The ill effects of the bendamustine -- fatigue and low-level nausea -- didn't set in until Thursday night, and have only really abated today.

More on that later. First, there is good news to report. The higher dose has done a much more noticeable job on the nodes, almost returning my neck to its natural swanlike appearance, and reducing a large mass in the abdomen to a reasonable degree. I still have a long way to go with the nodes, but if this keeps up, I will have made significant progress by the time I'm through.

One question is how long the nodes will stay at their current size. Last time around, they began to bounce back in the week before my second treatment. By the time I sat down in the infusion chair, most of the progress that had been made thanks to the first round had been erased.

This is not a good sign, and it indicates how fast my disease is prone to grow. But my reaction to round two, with a much more noticeable node reduction than round one, makes me cautiously optimistic that the effort will hold this time. Which, fingers crossed, means round three should see an overall further reduction in the nodes.

I am hopeful that the cumulative effect of the treatments will largely shut down the CLL factory in the marrow as well as reducing it in the nodes, creating a smaller, more easily manageable disease.

A FISH story

For some time I have wondered if my disease has turned more aggressive, or whether it has reached a critical mass, like a snowball rolling downhill, gathering size until it gets so big that it is difficult to stop.

A first step was to get a new FISH test, which I did in April. Would there be a 17p deletion there, indicating more aggressive disease?

The results were a little surprising. My first FISH test, back in 2004, showed a "normal" karyotype, which meant the chromosomal damage was of a nature not probed for on the test. In 2006, the FISH came back positive for the 11q deletion on 24% of cells examined, not good news. 2007's FISH showed 11q in 36% of cells. 2008's FISH showed 11q on 53% of cells. In 2009, 11q was noted on 31% of cells examined. (Why the dip? Who knows? But it didn't change the basic picture: an 11q deletion that appeared to have increased in the number of cells over time. By the way, the deletion always showed up on one arm of the chromosome only, which was of some comfort, as it meant I still had some ATM function, ostensibly.)

2010 and 2011, the Revlimid years, were FISH-free as the disease was under control for most of the time. Then in April of this year came an interesting twist: the 11q was down to 8% and a new deletion, 13q, again on one arm of the chromosome, was found on 30% of cells examined.

That FISH test was from the peripheral blood. In July, I had a bone marrow biopsy, which showed 90% involvement by CLL. A FISH was performed on that sample. It showed no 11q deletion at all, and a 13q deletion on 42% of cells.

So, what does all this mean? It appears my 11q clones are in decline, which is good news. (Why that is, again, who knows? It appears to fly in the face of conventional wisdom. My hunch, which is a completely wild guess, is that my Revlimid treatments had something to do with it.)

The April FISH showed a double deletion (11q and 13q), which is not good news. And while 13q is considered the most benign of the deletions, there are a couple of flavors of 13q. One indicates more aggressive disease; the tests I had did not go beyond the basic probe, indicating a deletion of one arm of 13q14.3.

I don't think the handoff from 11q to 13q indicates an improvement in my disease. But this is about the best change I can hope for; it would seem to indicate that the disease is probably not more aggressive by nature than it was before.

So I am basically subscribing to the snowball theory, and only time will tell if I am right. Another point I am compelled to make: FISH tests are all well and good, but shy of showing a 17p deletion, the most important factor in deciding to treat the disease is your clinical condition.

On the way from Calais

The last time I recall feeling as nauseous as I did post-bendamustine was many years ago on a boat from France to England. This was in the pre-Chunnel days. I grew whiter and whiter as the white cliffs of Dover approached, barely managing to contain my nausea with each bumping wave.

The nausea that set in last Friday never got to the barfing point, but it was uncontrollable with ondansetron (Zofran) tablets, which worked less well than Pepto-Bismol. To keep my kidneys flushing the dead CLL cells through, I needed to be drinking lots of water, and water is the last thing a sensitive stomach can tolerate. If I never see another can of Blue Sky New Century Cola again, it will be too soon. Needless to say, food was also rather unwelcome; I managed to lose some noticeable weight since nothing was appealing, although my stomach eventually discovered that macaroni and cheese was tolerable.

The fatigue was also way out of the ordinary. I would sleep 14 hours, on and off, and wake up tired. Today, Wednesday, is the first day that feels normal, both in terms of fatigue and nausea.

Although it sometimes felt as if my hemoglobin had taken a hit -- benadamustine can lower hemoglobin temporarily in about 90% of cases -- it turned out that wasn't the case. Comparing some numbers from the day before I started the second round to six days after I finished it: hemoglobin 10.8 before, 10.5 after; platelets 147 before, 138 after; absolute neutrophils 4.9 before, 5.4 after (as in the first round, I had a Neulasta shot on the day after completing treatment). The only dramatic change was in absolute lymphoctye count: 13.6 before, 2.1 after. I don't think my ALC has ever been so low.

UPDATE: My blood work from two weeks after treatment showed signs of decline in hemoglobin (down to 9.3) and platelets (110). Absolute lymphocyte count was 1.4, a new record low.

The rigors, minus the mortis

Last Tuesday's plan was to infuse the rituximab, then the bendamustine. My reaction to rituximab, a drug I have had countless times, was surprising. I was given prophylactic Benadryl and Solu-Medrol and expected pretty smooth sailing. About 15 minutes in, my face turned red and I felt some shortness of breath. This eventually abated, thanks to stopping the treatment, accompanied by some oxygen.

About 10 minutes after the infusion resumed, I experienced what the chemo nurses called "the rigors." This symptom was appropriately named, as it involved rigorous uncontrollable shaking. You can wear out your thigh muscles fast when this happens. Imagine having "the chills" but it's all coming from an internal place, so it doesn't matter how many blankets they pile on you, you still can't get warm. I think the rigors lasted about 15 or 20 minutes, during which time I found myself wondering whether this was what the passengers on the Titanic went through when they fell into the icy Atlantic. It finally abated, thanks to some more Solu-Medrol and Benadryl, as well as some Demerol. The Rituxan was stopped and I was given the bendamustine; reversing the order sometimes helps in such cases. Sure enough, when the Rituxan infusion was resumed later, it was completed without incident.

Why would someone who had managed to accommodate Rituxan for years with minor reactions, if any, suddenly develop these sort of symptoms? Again, who knows? With groundless abandon, I theorize that Revlimid changed something in my immune function. The Revlimid put an end to my autoimmune hemolytic anemia, but also led to a more hair-trigger allergy response in terms of skin rashes. Perhaps it also created a microenvironment less friendly to Rituxan.

My next sojourn in the chair is scheduled for mid-September. Keeping my eyes on the prize, I look forward to making more progress against the disease. But I'm not counting on an easy ride, and I will lay in a supply of macaroni and cheese, just in case.

Off to a good start with bendamustine and rituximab

I have just completed cycle one of six in my bendamustine and rituximab treatment and things are going well.

These drugs are also known as Treanda and Rituxan. "Treanda" sounds like a girl's name from the Maury show, but to my mind it is cyclophosphamide's big brother, an alkalyting agent with a powerful kick. Rituxan, of course, is the ubiquitous anti-CD 20 antibody that we CLLers have been using alone and in combination with chemotherapy for several years.

I'm pleased to report that the treatment is showing the signs of effectiveness that I had hoped for, with only a few bumps in the road. The best news is that it cleaned out my bone marrow enough on the first go-around that I am making more red blood cells and am getting out of the anemia rut that came with marrow impaction. I entered treatment with a hemoglobin of 7.8 and less than a week later I'm at 11.4.

Not a lot has been written about patient experiences with BR in chronic lymphocytic leukemia, so I will describe mine in some detail. Remember that this is an anecdotal report, and that your mileage will vary; but perhaps I'll be able to give you some idea of what BR is like, and some of the things to consider and watch out for.

My first thought is that how you manage treatment is important. This should be a no-brainer, but people with no brains are dishing out chemotherapy every day, sometimes to the great disadvantage of the patient.

Going in with bulky disease and a bone marrow packed with CLL, my oncologist, Dr. Droll, felt it was best to start treatment at a lower dose and to do so in the hospital. I spent three nights at the lovely Banner Baywood, the name of which evokes a resort hotel (which no doubt would have been a lot cheaper), in Mesa, AZ. I was monitored for tumor lysis syndrome, which can occur when there is so much cell-kill that the kidneys are damaged. The hospital also kept track of my hemoglobin; bendamustine is known to reduce hemoglobin temporarily in about 90% of cases; it turned out that I needed four units of blood.

The photos I've posted show the room that was my home at Banner Baywood, which is a short walk from Dr. Droll's office. I was on the sixth floor cancer ward in a private room, since I was receiving chemotherapy and sharing a room could have, in theory, exposed the other patient to dangerous drugs The nurses could not have been nicer, and Marilyn stayed by my side the whole time, sleeping in a fold-out chair that reminded us of an uncomfortable cuchette that we once endured on an Italian train. I urged her to consider checking into a hotel, but love is stronger than a comfy mattress.

It helps to have a good caregiver with you, someone to watch you for infusion reactions that you may not be aware of, someone to keep an eye on what is being done, to get questions answered, to be there during the uncertain or scary times, and to raid the refrigerator at night when you want an egg salad sandwich.

Tuesday, July 24th began with a call from the hospital at 9:40 a.m.; a bed was ready. We pulled ourselves together and drove the two-and-a-half-hours to Mesa, a city east of Phoenix. We arrived at about 2:30 p.m. I was weighed, my height was recorded, and this was duly noted on the dry-erase board that serves as the information center in the hospital room.

I also had my vitals taken -- blood pressure, pulse, oxygen level, and temperature -- for the first of what seemed to be about six thousand times. One thing you learn quickly in the hospital is that you're not going to get a lot of uninterrupted sleep; there's always someone doing a vitals check, or drawing blood, or one of several other things that can leave you feeling very unrested. One morning between 6 a.m. and 9 a.m. we counted twelve visitors, including the chaplain, the "patient navigator" from the American Cancer Society, and, of course, the hospitalist. The hospitalist is the doctor who is in charge of the ward, although he had nothing to do with my treatment. I call him Dr. Ka-Ching, because I will no doubt owe him at least $500 for the 45 seconds he spent with me each day.

My first set of vitals put my blood pressure at 134/68, heart rate of 97, temperature of 36.8 Celsius (98.6), oxygen level of 95%. What's interesting is that once I started chemo these numbers immediately improved, and stayed improved, throughout my stay. My systolic pressure would typically be about 115, and the diastolic remained in the 60s and 70s. Oxygen level went up a tick, heart rate dropped into the 70s.

Dr. Droll came by and said he was lowering the bendamustine dose by one-third. Instead of 100 mg/m2, I received 65 mg/m2, which was modified by the hospital pharmacist to 125 mg per infusion. The doctor also said he wanted me to stop by the office on Friday for a Neulasta shot, which is a good precaution when using bendamustine. B can clobber the neutrophils, leaving the patient subject to all sorts of bad reactions that can put you in the ER.

To guard against tumor lysis, I was advised to continue on allopurinol (300 mg/day), which I had been taking for four days. (Please note that there can be some skin issues when allopurinol is used with bendamustine. I haven't had any problems, but it's something to watch for. According to an FDA warning letter to the drug's maker, Cephalon, "Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly.")

I was also advised to stay well hydrated, which would keep dead cells moving through the kidneys. I was put on a saline solution, dispensed at 150 mg per hour, with some variations in speed over the next few days, and my urine was monitored. I was asked to pee into a plastic urinal with numbers on the side, and the nurses duly recorded the volume to make sure that my output equaled my intake. Everything I drank was monitored as well.

Dr. Droll exited stage left, announcing that he was going on vacation, and that one of his partners would visit me each morning.

Rituximab, the big unknown, was infused first. I have lost track of how many infusions of Rituxan I have had since I first used it in 2004. I am guessing about two to three dozen, give or take a few. One of the big questions going in was whether R would work on me at all, as it had, over time, become less and less effective. But I had not had it in 2 1/2 years, and research shows that in the presence of bendamustine it can work in Rituxan-refractory patients.

I'm still waiting for the lobster.

Premeds consisted of 25 mg of Benadryl and two Tylenol. No steroids were given, which I questioned, since in all previous instances I had been given 125 mg of hydrocortisone or Solu-Medrol.  The chemo nurse said that steroids were in Dr. Droll's orders "if needed" and that at Banner Baywood it was routine practice not to give steroids as prophylaxis before infusing rituximab.

"What strange corner of Mesa have I stumbled onto?," I wondered. But I figured I'd go along with the program, when in Rome and all, having never had a really bad reaction to Rituxan. Sometimes during the first infusion, about 40 minutes in, I would get a flushed face or some tightness in the throat. A couple of times this led to a temporary halt in the infusion, and/or giving more steroids. Then things would calm down and be uneventful the rest of the way.

Sure enough, about 40 minutes in, I began to react. This involved profuse sweating and shortness of breath, and I do mean shortness of breath. My blood oxygen level dropped into the high 80s. Not since I almost drowned in a swimming pool as a child have I felt that close to being unable to breathe. It was scary. I was hooked up to oxygen and the nurse proceeded to go about getting some steroids in me. I was given 40 mg of Solu-Medrol, the maximum that Dr. Droll's orders indicated. I needed more, and this took a little while to arrange, since Dr. Droll's Partner had to be reached by phone to agree to exceed the dose set by Dr. Droll, which he did. Another 100 mg of Solu-Medrol was administered and it worked.

Suffice it to say that Dr. Droll and I are going to have a conversation about Rituxan premeds and that at least two chemo nurses at Banner Baywood are now aware that CLL patients ought to be given steroids as prophylaxis when Rituxan is used. 

The good news is that Rituxan showed signs of working almost immediately. In the old days, when I used it as a single agent, there would be some tumor flare in my neck after a couple of hours. The area with the nodes would also turn a little red. The idea is that the body was responding to an area where there was now an antibody, cell-kill was ensuing, and this was part of the process by which the nodes were reduced. In later infusions, when I wasn't sure that Rituxan was working, this reaction would be absent. But sure enough, it was happening again, and I had not yet had bendamustine, so it was not the product of that drug's influence. Call it chance, call it luck, but it was a very good sign.

Bendamustine was started at 12:47 a.m. In the hospital they can give chemo 24/7, and they do. The Rituxan had taken forever, from 5:20 p.m. to 11:30 p.m. Premeds for the B consisted of 12 mg of dexamethasone and 24 mg of ondansetron (generic for Zofran, an anti-nausea drug), as well as 40 mg of Lovenox to prevent clotting.

The B was started at 10 ml/hour and was raised incrementally to 400 ml/hour, and it took an hour and a half to infuse. The chemo nurse kept track of the vein in my left arm into which all of this was pouring; I have never had a port, and I am evidently some sort of God when it comes to having good veins, but she wanted to make sure the vein did not blow, which can happen with rapid bendamustine infusions.

All went well. She may as well have been infusing me with water for all the reaction I had, which was no reaction at all. After the Rituxan it was anticlimactic, and I had had enough drama for one evening.

There was, however, to be no rest for the weary. I entered the hospital with a hemoglobin of 7.8 and Dr. Droll's orders called for a red blood cell transfusion if the hemoglobin was below 8. So I was given two units of blood, taking about three-and-a-half hours each.

The blood was irradiated, CMV negative, with leukocytes removed, so it was about as pure as it was possible to get. I had no infusion reactions and did finally manage to get some sleep, although the entire process was not finished until about 9:30 a.m. the next day.

I should note that these days, at least at Banner Baywood, the patient armband has a UPC code; nurses use a scanner on it that verifies who a drug is for (and no doubt adds it to the bill.) This also tells them if a drug is contraindicated with another that the patient has been given. A separate armband is used for blood products. When blood was transfused, two nurses would come in and, in addition to the scan, repeat my name, date of birth, blood type, and so on to verify that the right person was getting the right stuff. I appreciated this attention to detail. There is enough to worry about when doing chemo without having to worry that you're being given something by mistake.


Day Two involved the second and last bendamustine infusion as well as two more units of blood. All were uneventful in terms of infusion reactions.

The blood was ordered because my hemoglobin, which had been raised by 1.6 points thanks to the first two units, had again slipped below 8. Given that bendamustine takes a toll on hemoglobin in 89% of cases, it was not surprising that the number didn't hold. (My platelets were taking a hit as well, having been 127 upon admission and 71 on discharge. This drop occurs in 77%-86% of cases. Absolute neutrophils actually increased, which is something of an anomaly, from 1.82 to 2.42. Neutropenia is reported in 75%-86% of cases.)

Dr. Droll's Partner stopped by with another theory; perhaps I was being so well hydrated to avoid tumor lysis that it was causing the hemoglobin number to drop. It is true that if you want to increase your hemoglobin on a CBC, going into the test dehydrated will help. So he cut the flow rate of the saline solution to 60 ml/hour and said he wanted me to stay in the hospital one more day to monitor the situation. This prospect was not greeted with huzzahs by me or my loved one -- the chemo nurse was amused to learn that a sweet-looking lady can curse like a sailor -- but we understood the reasoning.

Sure enough, the next morning, my hemoglobin was 9.0 and I was a free man.

I feel significantly better following the chemo. That's the bottom line, after all. I have a great deal more energy, thanks in part to that 11.4 hemoglobin. I feel as if I have my life back; I can do things around the house again, run errands and not get winded, and so on. I'm not ready to run any marathons, but things feel more normal than they have in some time. Perhaps the CLL was taking an overall toll on my system that helped account for my low energy on top of the low hemoglobin; putting it in check has done more in a short time than I expected. It is interesting that my heart rate dropped so dramatically -- from the 90s to the 70s -- after therapy.

My major challenges are the lymph nodes and bone marrow. There are five more cycles to go and I am optimistic that I will have a significant reduction in nodes. Odds are very good that I am among the bulkier CLL patients ever to use BR. My nodes tend to be smaller, but they fuse together in clumps when left unchecked. Treatment then breaks them up. Already the neck nodes are noticeably and significantly reduced. The masses that were under my arms are now individual, smaller nodes, though still significant. My abdomen has slimmed down and I look a mere seven months pregnant instead of nine. I have lost about five pounds, much of which is probably lymph node weight.

My white blood count, which is really the least of my problems, dropped from 71.7 to 12.1 on discharge and 8.2 four days after discharge. Platelets have begun to recover as well, now at 112, up from 71 at discharge. The Neulasta bumped absolute neutrophils up to 4.7. The hemoglobin, which was 9.0 after the last two units of blood, is at 11.4 four days later. That is the highest it has been since last December and I am surprised, in a good way, at the rapid turnaround.

I managed to avoid tumor lysis syndrome as well. I picked up a few things from the nurses on what they look for. In extreme cases they see signs of mental confusion, but I was no more confused than I usually am. They also pay attention to creatinine levels, uric acid, and electrolytes such as potassium, magnesium, calcium, and phosphorous. At one point my magnesium and phosphorous were a little high and calcium a little low, but nothing to worry about. The other numbers remained within the normal reference range. 

One thing I noticed on the tests that has been little-discussed is a rise in blood glucose levels. Back when I used to do RCD -- rituximab, cyclophosphamide, and dexamethasone -- to combat autoimmune hemolytic anemia, my glucose levels would rise. My oncologist at the time, Dr. Meng, said this was mainly due to the cyclophosphamide, which can cause hyperglycemia (although I am sure the steroids contributed as well).

Diabetes is not an issue for me and in a fasting state I test out at normal glucose levels. I can eat a turkey sandwich before a blood test and still have a glucose level that's not far over 100. But in the hospital, where I was not fasting, the glucose was coming back at 229, then 185, then 175. (Four days later it was 109 in a fasting state.) Given that bendamustine is an alkalyting agent like cyclophosphamide, those of you with blood sugar issues may want to keep an eye on things if you opt for BR.

I have found a few good resources on BR. There aren't many out there for a therapy that is becoming increasingly common. The best I have found on dosage and side effects is this document from the Veteran's Administration. The ever-helpful BC Cancer Agency also has a good PDF on bendamustine. The best paper on BR is Bendamustine Combined With Rituximab in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group. The abstract can be found here. If you want more than the abstract, send me a note at clldiary at yahoo dot com. I'm not always swift about replies but I promise to get back to you.

I am looking forward to my next treatment, which will be in Dr. Droll's office, with full-strength bendamustine. I'll report on what happens then, and whether I experience any delayed reactions to the treatment I have already had. Some patients have reported nausea, fevers, fatigue, rashes, constipation, diarrhea, and severe neutropenia. Some of this is a matter of luck (or lack of it) and I think age may also have something to do with how easily the medicine goes down. It's easier to handle heavy-duty chemo at 55 than at 75. Whatever your age, of course, the important thing is that it works. So far, so good.