The Good, the Bad and the Ugly

I promised I will fill in the details of Harvey’s experience with Revlimid. It is by no means an “easy” drug, and patients and their doctors need to come up the learning curve on how to use it, what to expect, and how to monitor patients. But I think it is going to be an important drug in the treatment of CLL, especially for patients with poor prognostics. You can read our prior Revlimid articles on CLL Topics website by clicking here.

Revlimid is administered as an oral pill. Depending on the protocol, you will be asked to take one pill per day (dosages vary, and more about that later) for three weeks, with one week off for good behavior. Some protocols do not have the one week ‘holiday’, patients take the drug without breaks. I believe the dosages used in multiple myeloma were higher and these higher dosages did not sit so well with CLL patients in the earlier trials. Most of the new CLL / Revlimid protocols are in the daily 10mg to 15 mg range. There seems to be reason to expect good synergy between Revlimid and the other famous “R” drug, Rituxan. Several trials are exploring combination of R + R.

Revlimid is not yet FDA approved, your doctor cannot give you a script for it and get it for you from the local pharmacy. But you can get access to it readily through Celgene’s “RevAssist” program. Basically, they want to make sure you are not pregnant, not thinking about getting pregnant and if you are a guy, not thinking of getting anyone pregnant, before you touch this drug. Revlimid is an analog of thalidomide, the drug that was used in pregnant women several decades ago and caused horrific birth defects. If you can answer “none of the above” to the pregnancy questions, you will have no problem getting Revlimid even outside of clinical trials – just so long as your doctor approves. Make sure you get your insurance company on board – this is not a cheap drug.

Harvey got his Revlimid after getting a prescription from his local oncologist. Frankly, he had not heard of the stuff, certainly not for CLL patients. But he agreed when Harvey pointed out that a couple of top rated Revlimid / CLL experts were willing to speak up and recommend it for him. Folks, by now most of us know that in life and cancer therapy, we get what we can negotiate. As it turned out, having access to a couple of experts who have seen it all in terms of Revlimid side effects was very important in greasing the wheels. The other option would have been participating in one of the clinical trials – but that would have meant making many trips away from home.

Harvey started at 10mg/day, for 3 weeks, followed by one week holiday. The second cycle was a repeat of the first cycle (28 days). With the confidence gained in the first two cycles, with the permission of his expert advisers Harvey increased the dosage to 15mg/day for the third and final cycle. I strongly urge you to get expert guidance before you go to dosages higher than this.

Harvey went into the Revlimid therapy after 5 cycles of Humax-CD20 + fludarabine. His peripheral blood counts were fine, he felt energetic and fit. But the pesky lymph nodes were still there and it did not look like doing more HF was going to do much for him. At the completion of the three cycles of Revlimid most of his lymph nodes had melted away to nothing. There were a few 1.0-1.5cm nodes left behind, mere shadows of prior 3-4cm nodes. A bone marrow biopsy done last week showed his bone marrow is now squeaky clean. Very sensitive four color flow cytometry failed to detect any CLL cells in the bone marrow! Did the Revlimid work for him? Yes. It brought about significant reduction in his lymph nodes, an important step in getting ready for a stem cell transplant.

Was it easy? No, it was not. Harvey has been through dozens of infusions of Rituxan, Humax and most lately, fludarabine. The little Revlimid capsules were a whole new kettle of fish. For starters, within the first week of the first cycle, Harvey had the infamous “tumor flare” reaction. Revlimid is an immune modulator, an “imid“. It works by rattling the cage of the immune system, sounding off all sorts of alarm bells. the net result is that all the lymph nodes become enlarged and tender – as if you have a massive infection of some sort and your ‘glands’ swelled up. Some patients feel significant pain, but this was not the case with Harvey. He thinks it is because he is so macho, but I beg to disagree. The range of side effects seem to be quite wide, and there is no good way of predicting who is going to get an easy pass and who will be tested more acutely. Harvey lucked out, that’s my story and I am sticking to it.

In addition to the enlarged and tender to the touch lymph nodes, there was slight fever for a few days and general feeling of being under the weather – it felt a bit like having the flu. We were advised to monitor his body temperature daily, at the same time each day, and record it. Harvey typically has low body temperature, well below the “normal” 98.4 F. We were told to head out to the emergency room if his temperature went over 100.5 F. It never did. If this was all there was to the tumor flare, Harvey was pretty sure he was not going to sweat it!

Then came the real stuff, at least in Harvey’s case. He broke out in a rash, all over his chest, back, thighs, upper arms. The rash looked red and angry, sort of like a bad case of prickly heat. AND it itched something fierce. Poor guy had a hard time resting or sleeping and it drove him crazy. Our experts recommended Benadryl, lots of it. He was gulping down couple of tablets of the stuff every four hours. The rash and itch lasted for 3 days and gradually faded away. This was the first cycle, we figured this was the last of the rash and there would be no recurrence of it in the subsequent cycles . Not so. He had a similar rash on the second and third cycle as well, but this time we knew what to do and initiated the Benadryl right away. That seemed to help in limiting the duration and severity of the rash.

Our experts told us to keep a close watch on his blood counts and we did. A CBC and Chem panel (electrolytes, liver, kidney function etc) were done each week. Harvey become neutropenic, and self-administered Neupogen shots every time his absolute neutrophil count (ANC) went below 1K. Red blood cell counts dipped as well, hemoglobin going down to 12 for the first time in his career. Both the lower red blood cell count as well as general fatigue associated with Revlimid made it harder for him to maintain his regular work-out schedule. Serena watched over him as he slept 10-12 hours each night and took afternoon naps, very unlike his usual self. By the end of the second cycle the red blood counts had recovered, and the fatigue too went away gradually. Perhaps because of the increased dosage, the third cycle introduced a new wrinkle: reduced platelet counts. Harvey never had very high platelet counts, even before the CLL diagnosis. His platelets ranged between 150- 200K. For the first time in his CLL journey, his platelet counts dipped down to 90K. Nothing to get excited about, people do fine with platelet counts in this region and they do not even think about transfusions until the counts get well below to the 10-20K range. I am recounting these details to let you know Revlimid is associated with reduced red blood cell counts, neutropenia and thrombocytopenia (low platelets), and this should not come as a surprise to you.

With next to no T-cells left over after the fludarabine therapy and neutropenia because of the Revlimid, Harvey had little home grown protection against opportunistic infections. He therefore continued his previous prophylactic regimen of Bactrim (broad spectrum antibiotic, terrific for protecting against pneumonia), Valtrex (to prevent Herpes viral reactivation) and itraconazole (anti-fungal). None of this stuff is particularly friendly to the liver, hence the need to monitor liver functions on a regular basis. At one point in the second cycle of the Revlimid therapy Harvey’s liver functions (ALT and AST) spiked over the normal range. The expert advice was to continue taking daily Revlimid but drop the three prophylactic drugs above for a week. Blood tests done a week later confirmed the liver enzymes were coming back down, and a few days later the prophylactics were gradually re-introduced. There was no further recurrence of ALT and AST spiking after that.

The tumor flare reaction is unexpected and different from the usual stuff – and this is perhaps what makes it scary. Here we are, trying to shrink Harvey’s lymph nodes, and they were getting larger by the day! Sort of counter-intuitive and scary. I am told Harvey had a relatively easy time of it and other patients may experience more pain and distress as a result of the “flare”. It is important to monitor blood counts and protect against opportunistic infections. With the nasty flu season going on while he was on Revlimid, Harvey became a bit of a hermit. Fortunately there was no reason not to go out hiking his favorite mountain trails and still avoid crowds.

Bottom line, Revlimid seems to work by a different mechanism than drugs such as fludarabine – and that is perhaps its biggest value to patients who fail more conventional therapy. Patients with Refractory CLL have few good choices. Typically, these are patients with poor cytogenetics (such as 11q and 17p deletions on FISH test) or who have had plenty of chemotherapy up to that point and may have acquired poor cytogenetics as a result of clonal evolution. Harvey hoped he would be among the lucky minority of patients with 11q deletion that got a good response to RF therapy (well, HF in his case). But that did not happen. The other choices were Campath +/- high dose steroids. That sledgehammer combination has its own drawbacks. We were intrigued by what we were hearing from our expert counselors regarding the results they were seeing with Revlimid therapy in some of their 11q deleted CLL patients and we decided to see if Harvey too would get a good response.

This time, Harvey lucked out. Will Revlimid word for every 11q deleted patient? How about even tougher cases with documented 17p deletions? We do not know. That is what clinical trials are for, to get desperately needed answers to questions such as these. I wish this drug was not so darn expensive, I wish local oncologists were more familiar with it, I wish patients were better monitored while they took this drug, I wish we understood more about how it works. But this much seems to be clear. It is an important addition to our arsenal. For patients looking to get a good remission going into a transplant, as Harvey was, Revlimid can be an important bullet.

Be well,