Wednesday, August 01, 2012

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.


Anonymous said...

I'm so glad to hear things have gone well. You are due for some good events. I also appreciate the information you are giving us. There's a question that I may need treatment (first time in 17+ years) and my doctor leans toward BR at the moment. We'll see in the next few months.

I'm glad Marilyn stayed with you. Wives like to watch over our loved ones ;-)

All the best to you both,
Deb in Chicagoland

Anonymous said...

David thanks for this detailed report. I'm 38, diagnosed 8 months ago, also a former hack and have bulky disease which is now moving quite rapidly. I'm facing treatment and, with bad prognostic markers, my doctor is investigating BR. It's not approved for use here in Australia on our health system so the hospital will be importing it from Germany (cost to me approximately $7,000 USD). It's the lymph nodes in my neck which are causing me most grief. Starting to look like a hamster, it'a getting difficult to find a comfortable way to sleep (neck brace anyone?) and my energy levels have dropped rapidly. My blood test this well flagged a spike in LDH levels as well as a doubling in my lymphocyte count from two months ago. My specialist is very excited about Ibrutinib - just a shame I won't be eligible for any trials at this stage but they are getting all the ducks in order for a possible stem cell transplant in the future as my sister is a match. Good luck with the treatment and thanks again for the detailed account! Very best wishes, Deborah in Melbourne

stew (WORCESTER) UK said...

Good luck David, early days but sounds like its working well , such a help to have a detailed insight into treatment, it will let the rest of his know what to expect if we have the same or similar treatment , A message to deborah(above comment ) diagnosed similar time and similar age, im a little bit older . A lot of similarities, if you ever want to e mail let me know deborah .
Good Luck David
United Kingdom

Anonymous said...

I'm so glad to hear this all went well and you're feeling better - what great news - I love your final picture - no doubt you will "Live Long and Prosper" :)

Sherry Gardner said...

Happy to know the drug combo is helpful and not too toxic, Dave. You might think about the possible role of the steroids in elevating your sugars. The first time I had Rituxan + high-dose methylprednisolone at Mayo, I was hospitalized so I could eat a good diabetic diet and so sugars could be monitored four times/day. They did increase, and a touch or two of insulin got them back in line. I felt pretty good throughout the course of treatment. Eight months later, same treatment,but without hospitalization and without monitoring of sugars, and I felt worse and recovery was slower. Something to consider. Best of luck to you!
Sherry Gardner

Anonymous said...

Hi Stew - yes would love to hear from you. My email is - while I'm now living in Oz I'm a fellow Pom (makes the Olympics a lot of fun in our house!). Been here 5 years and have 3 children aged 8, 5 and 2. Thanks David for bringing us all together. Hope you're still feeling well. Cheers Deborah

Anonymous said...

David, I am heading towards my third bendamustine+ofatumumab month in Sydney... The experience has been very similar, the thing is I had some rash, diarrhea, extreme fatigue, and also had to be supported by blood trasfusions and neupogen. But in 10 days after the treatment I am getting fine. Thiking of going skiing for the weekend, something I have managed to do just a month ago after 2.5 years being unable to do so.

We might compare notes if you wish, I'm on gz at ipksolutions dot com. It's Greg Z from the CLL list.
BTW I had to buy Bendamustine in Germany myself as well. cost 25% from the US price!

charlotte said...

Thanks David for your very thorough diary. Hope things are continuing to go well for you.
My husband has had CLL for about 4 years and his WBC's are up to 183,000 and he has not had any chemo yet. His MD gave us a handout on Bendamustine. I have also recently had a mastectomy and so I am sure they are going to suggest chemo for me also. I think it would be kind of tough for us both to do it at the same time. Do you have any further words of wisdom?

David Arenson said...

Hi, Charlotte.

Bendamustine can be tough, especially in the few days following the infusion. My wife, Marilyn, has had to do extra duty as caregiver during those times. Depending on what your chemo is like and how severe the symptoms associated with it, you might at least want to stagger things so that you're not having chemo the same week as your husband. Usually, after B & R, I am feeling back to normal about five or six days after the last infusion.

Whatever you decide, my best to you both.