The road ahead

I've met with my transplant/CLL doctor, Jose Leis, at the Mayo Clinic in Phoenix. He was pleased with my response to Ibrutinib -- dramatic shrinkage of abdominal nodes -- and laid out the course I will be following in the coming months.

For a transplant to have the best chance of success, he emphasized that I need to go into it with nodes no larger than 5 cm. I have a couple of abdominal masses that are well in excess of that, even after eight days of Ibrutinib. Dr. Leis pointed out that Ibrutnib can take a couple of months to reach its maximum effectiveness. So he wants me to stay on it for a few months before we even begin to think about transplant. 

I will likely have a CT scan at the end of that period, and it is possible my disease will be restaged. The hope is that Ibrutinib will do the heavy lifting and get those nodes down. I'll be seeing him once a month, and as we cross various bridges, we'll adjust things as we have to. It's possible that we may add Gazyva (obinutuzumab), the new anti-CD20 monoclonal, at some point, especially if the lymphocyte count in my blood rises dramatically, which is what can happen when Ibrutinib kicks the errant B-cells out of the nodes.

Meanwhile, a donor has been found. Somewhere out there is a man in his 40s who is, as Dr. Leis termed it, a 9.5 out of 10 match. The one allele where there is a mismatch, the DQ, is not clinically significant, according to the doctor. A six-month hold has been placed on the donor, which means he's reserved for me during that time. Let's hope he avoids flying anvils.

We discussed the prospect of Ibrutinib controlling DLBCL without a transplant. Dr. Leis told me this is unproven territory, and my tendency is to go for a transplant, with all the attendant risks. I will never be healthier than I am now, and DLBCL is not CLL. It can kill me, rapidly, and I can tell you from experience that it would be a horrible death, with tumors choking off the body's organs within a month or two. I don't want to die in a hospital, loaded with painkillers, living in a daze.

With most varieties of CLL, time is not of the essence. With aggressive Richter's and resulting DLBCL, the opposite is true. CLL can lead to a certain complacency, but aggressive DLBCL demands action. (The doctor pointed out that DLBCL arising from Richter's is often more aggressive than de novo DLBCL, which arises on its own.)

So things are going my way at the moment. Of course, as Dr. Leis pointed out, there is still a long road ahead, and there's no guarantee that something won't go wrong. But I feel that I'm in good hands, and on the right track. I'm looking forward to a couple of months during which I can gain my strength back following January's chemo, and be in good shape for a transplant.

At least so far, let my story be an example of what can happen when you don't give up. Marilyn was told by more than one doctor and chemo nurse since my Richter's exploded last April that I probably wasn't going to make it. 

Well, here I am, defying the odds. I am reminded of the bell curve. There's a good end of it, and that's where I want to be.

Riding the Richter's roller coaster

As the title of this post implies, things have changed since October, when it appeared I had achieved a pretty good response to treatment.

Seven weeks later, in December, I began to relapse, and it has been a tough slog ever since. I could regale you with all the details -- and perhaps someday I will, when I get a chance, which could be coning up soon. The one image I would like to leave you with is New Year's Eve, which I spent in the hospital getting chemo under my old insurance. At the stroke of midnight, my new insurance kicked in. Which, I think, may make me the first person in the country to use their new insurance under the Affordable Care Act. 

As required by the law, my new insurance provides for stem cell transplants, which my old insurance did not (which means, by the way, that Barack Obama may save my life). And so despite the relapse, I have some good news:

I am on track for an allogenic transplant within the next couple of months at the Mayo Clinic in Phoenix, AZ under the care of Dr. Jose Leis. Mayo has found three potential 10/10 donor matches, a far better pool than I expected given my unusual Jewish-Irish background. 

The success of any transplant depends on the tumor burden going in, and mine has been big. But the Hail Mary chemo I have done (more R-EPCH) has set the DLBCL back. And I have been approved for Ibrutinib, which was Dr. Leis' hope and mine. Studies have shown it to be effective in cases of relapsed aggressive DLBCL, which is what I have. It doesn't work in all cases, but it works in many, so there are still miles to go until I sleep in terms of conditioning for the transplant.

Despite the exhausting roller coaster ride of December and January, I may soon find myself cooped up for 70 days in what they call a transplant pod, with nothing better to do than blog about my experiences -- including some important things I have learned in the past ten years.

My thanks to all of you who have written; I simply haven't had the time to respond personally -- or to write this simple post -- until now. The good wishes of friends and family help keep me going. Most of all, I have the love and incredible strength of my wife, Marilyn. This is our fight. And to paraphrase Churchill, we will never surrender. There have been many truly dark hours, but I see dawn ahead.

I'm finally not feeling like crap

Greetings from the cancer ward of Banner Baywood Medical Center in Mesa, AZ, where I am undergoing round four of chemotherapy to combat aggressive B-cell lymphoma brought on by Richter's Transformation. Our arrival Monday -- Marilyn stays with me for all five fun-filled nights -- was like old home week, the friendly staff having seen me when things were at their worst back in April, and much-improved today. The fact that I had arrived on my own two feet, and not in a wheelchair, spoke volumes.

As I mentioned in my last post, Richter's Transformation came on with shock and awe in the middle of April. I put on an enormous amount of weight in a short time, gaining some 40 pounds in two weeks, and looking in the end like a bedraggled Sumo wrestler. My giant belly was mostly a collection of tumorous lymph nodes that had fused together into larger tumorous masses, and this led to edema in the legs, feet, and, ahem, scrotum and penis. Yes, folks, for awhile there I could have been a porn star. The tumors were interfering with the inferior vena cava and just about everything else in the middle and lower sections of my body.

I arrived at the ER at Banner Baywood on the morning of April 25 -- Marilyn and I had raced back to Arizona after seeing Dr. Thomas Kipps at UC San Diego, and Mesa is the home of my local oncologist, Dr. Droll. I had just found very obvious blood in my urine, and kidney damage was one of Dr. Kipps' main worries. I could tell in the eyes of the nurses and doctors that I looked like a true emergency case, so much so that one doctor took Marilyn aside and began to talk about hospice, which, as you might imagine, was not a welcome topic.

During the weeks prior to treatment, as my belly grew, pain grew with it. The burgeoning tumors put stress on my lower back, pushing against nerves there. This required that I sleep sitting up in a chair, and even then it took oxycodone to be pain-free. Laying on my back was an invitation to torture.

Unfortunately, one of the tools used to diagnose Richter's is a PET scan, which I had that first day in the hospital. The PET scan requires that you lay flat on your back and not move for 25 minutes, with your head stuck in a padded vise-like thing to keep you in place. It was the most painful experience of my life. That every moment was an eternity is a cliche, but true in this case. The nurse tried to take my mind off things by asking me questions about my work, my family, and my pets. Most of the time I was left to fend for myself. I sang the Star-Spangled Banner, which is good for about two minutes. I sang what I could remember of Warren Zevon's Werewolves of London. The refrain that was supposed to be ah-hoo, werewolves of London became OWWW! werewolves of London, belted out at the top of my lungs. 

The PET scan measured glucose uptake by lymph nodes; mine was off the charts in a number of nodes, confirming the Richter's diagnosis. The largest lymph node aggregate mass measured 24 cm by 24 cm (about 10" by 10") and had a maximum glucose uptake value of 26.20, which is well beyond typical. This was followed by a biopsy of one of the nodes, which again confirmed the diagnosis. What I have is Diffuse Large B Cell Lymphoma (DLBCL) of the aggressive variety. This is Godzilla to CLL's Bambi. I still have CLL, but it's basically irrelevant.

Cut to eight days later, our arrival home. Emergency chemotherapy had knocked the tumors back in a big way -- I had lost 40 pounds, and soon lost 10 pounds more. I had managed to avoid kidney damage, including tumor lysis. The chemo also knocked me back in a big way. It was nothing like any chemo I had experienced before, and doing the simplest thing -- getting up out of a chair, for example -- required a Herculean effort.

The chemo in question was OFAR --oxaliplatin, fludarabine, cytarabine, and rituximab -- which had been recommended by Dr. Kipps, and was designed to be given every four weeks. OFAR has been the subject of two trials at MD Anderson, with the second trial also being done at UC San Diego and Ohio State. It's no miracle cure, but proponents say it may be better than R-CHOP, the current standard of care.

In my case, it created hideous quality-of-life issues and ultimately failed as a treatment. Between cycles I was left with an extreme lack of energy, both physical and mental, which did not improve over time. At one point I started eating less and less, and losing more and more weight, until this became a serious concern and Marilyn started pumping me full of high-calorie whey protein milkshakes. One challenge I was facing (and still am) is the loss of muscle mass. I didn't need to be losing more, and I need to regain the strength I have lost. It's no fun being too weak to get off the toilet without having to grab something to help you up.

I could have put up with all this, albeit with much bitching and moaning, had OFAR continued to work well. But I relapsed just shy of three weeks after the second treatment; the telltale signs included exhaustion, night sweats, and a lot of panting following almost any form of physical movement. I was also feeling a small crick in my back, tumors starting to settle against nerves again.

A change was called for, and at Dr. Droll's suggestion, it was to be R-EPOCH without the "O" (more on that later). Frankly, he had been suspicious of OFAR from the start. He's not a fan of MD Anderson studies, once joking that they should be published in The Journal of Irreproducible Results. He felt a protocol with adriamycin would be of the greatest benefit.  R-EPOCH includes adriamycin and is basically R-CHOP with the addition of etoposide, another potentially powerful drug.

And so I arrived at the hospital on Friday, June 21, for round three of chemo, which was also round one of R-EPCH. I looked like crap again, albeit without the Sumo belly. Dr. Droll was worried that I wasn't going to be up to the task ahead, that my heart might be as weak as my general constitution, and told Marilyn, privately, that he thought I only had a 50/50 chance of living through the weekend.

It turns out that Dr. Droll, while making good use of his cell phone, does not have a direct line to God. My heart rate was initially 144, and calmed down into the 80s a few hours later, after chemo began. My breathlessness abated. The next day I informed Dr. Droll, on one of his early-morning rounds, that reports of my death had been greatly exaggerated.

The "O" in R-EPOCH stands for oncovin, aka vincristine. I had bad peripheral neuropathy of the legs after using a small dose of vincristine in 2007; Dr. Droll said it was not an especially important part of the protocol and left it out.

My response to R-EPCH -- rituximab, etoposide, prednisone, cyclophosphamide, and doxorubicin, aka adriamycin, and who knows why they give it an "H" -- has been quite good, with the tumors getting smaller and no sign of a relapse between cycles. I feel much better, pretty much like normal, although limited to some extent by the low hemoglobin that is a cyclic side effect of the cell kill caused by the chemo. But I can drive, take things to the recycling center, shower with ease, cook breakfast, and leap 14 stairs in 14 bounds instead of 28 -- all things I could not do between rounds of OFAR.

Why did OFAR fail? There are no guarantees in the chemo business. OFAR worked wonders the first round, taking down the easy stuff, and thankfully most of that Sumo weight was easy stuff. But as with all chemo, the disease that's left over is harder to kill. This is where OFAR was not up to the task, and where R-EPCH evidently is. 

R-EPCH is done every three weeks, in the hospital, as the etoposide and adriamycin are infused together over a 96-hour period. Just about the only side-effect so far has been hair loss -- I expect to be bald in a few more weeks. I weigh 160 now and my belly, while still pronounced, is much less pregnant-looking. It's mushy, not taut with tumors. 

As I write this I am in the middle of chemo round four, and R-EPCH round two. Dr. Droll examined me this morning and said I am less nodey than he has ever seen me. The same man who said some three weeks ago that I might not live through the weekend now says he's pleased with my condition and the results of the chemo. My spleen is a little enlarged; that could be plain old CLL, about which we aren't too concerned. Only another PET scan, which measures that glucose uptake, can differentiate between the nodes that contain CLL and those comprised of DLBCL. Another bit of good news is that my LDH has dropped, from more than 500 when doing OFAR, to the 200s today. This indicates, most likely, that there is less tumor around to battle and destroy. Studies show that patients with LDH below 500 have better outcomes.

But I still have swollen nodes under the arms and in the abdomen. The possibility that the DLBCL nodes won't disappear completely is why the chemo may be followed by a stem cell transplant. More on that -- and the maddeningly absurd health insurance issues it entails -- later.  Transplants involve their own travails, but the silver lining is that they can be curative. Assuming I find a good matched unrelated donor, an allogenic transplant could cure both the CLL and DLBCL. Failing that, an autologous transplant could at least cure the DLBCL, putting me back to square one with CLL again, which doesn't seem so bad by comparison -- unless, of course, the CLL transforms a second time (!).

Longtime readers may note that I finally took the fludarabine plunge thanks to OFAR. And I am now experiencing the "red death," aka adriamycin, which is in fact red in color and which can, if overused, set up congestive heart failure down the road. These drugs are not lightweight, soft-glove treatments, but aggressive DLBCL is not a shy, retiring disease. I have had no hesitation in using whatever I need to use in order to fight this thing effectively. Funny how the nuclear option becomes an easy one when circumstances call for it.

So this is my new normal. Marilyn and I recently saw a lymphoma expert at UCLA -- Dr. Sven de Vos -- who said dose-adjusted R-EPOCH was his first choice for DLBCL, and that the transplant plan made a great deal of sense. This confirmed my feeling that I am on the right track. Dose adjustment basically means that they use blood tests to find out the nadirs of your neutrophils and platelets following therapy; if you have high nadirs, this means you can tolerate higher doses of therapy next time. Dr. Droll will adopt this strategy for future rounds. 

Meanwhile, there's nothing to do from here but "enjoy" the ride. The future, with all its high-stakes therapy and challenges, will still probably be an improvement over the recent past. The two months following mid-April were the most god-awful stressful of my adult life, and of Marilyn's. I have often said that the caregiver bears a greater burden, namely the prospect of losing their loved one and being left alone, missing an essential half. Top that with having to do everything -- all the driving, all the chores at home that I used to do, dealing with doctors and nurses, attending to me and my sometimes scary symptoms  -- and you have one exhausted person, running on fumes.

There are countless wrinkles and details I don't have time to get into -- take, for example, my sudden allergy to allopurinol, which led to a whole-body rash, fever, and night at the Sedona ER -- but suffice it to say that for week after week, it seemed that every day brought a new stress, a new concern, a new reason not to get enough sleep.

After we saw Dr. de Vos, we took a few days "off," as it were, to enjoy California. Marilyn grew up in L.A., and we met at UC Santa Cruz in 1977, and later lived in Berkeley. In our youth we traveled the state, from the shores of Big Sur to magnificent Yosemite to the redwood coast in the north. It was rejuvenating to reconnect to the good times in our past, to enjoy old memories, and to create new ones. 

Our experiences were simple. We enjoyed the cool, foggy ocean air, which was 45 degrees colder than the 115 degree temperature in Phoenix, which we had driven through on our way to L.A. Fog tends to blur the fireworks on July 4, but the spirit of celebration could not be dimmed. It was nice to be around people who were having a good time.

We ate chile verde at a place in Santa Maria that we had eaten at 25 years ago and found that it was just as good today. Sometimes you can go home again.

We saw San Francisco with a garland of fog, and the tops of the buildings, including the  Transamerica pyramid, peeking into the sunny sky above. It's still a beautiful city, in a beautiful setting. Oakland, where we used to live also, shows new signs of life, and we stumbled upon a huge collection of food trucks gathered for a festival at the art museum.

These things served as a reminder of what I'm fighting for: the simple gift of more days on this beautiful Earth, with the beautiful loved one with whom I have been so fortunate to share my life. 

Where there's a will, my friends, there's a way.

April nightmare; May resolve

When last I wrote, things were looking pretty good. I had gotten a better-than-expected result from bendamustine and rituximab. I was planning on seeing expert Dr. Thomas Kipps at UC San Diego on April 25 to discuss maintenance ideas or what to do at relapse; perhaps one of the BTK inhibitor trials would be a possibility. 

And, of course, the day was getting tantalizingly close when I would be able to purchase new and better health insurance from the exchanges that will come online October 1, with the new insurance effective January 1, 2014. The new insurance, I hoped, would cover treatment at a major CLL center or two (such as UC San Diego) and would cover a stem cell transplant, if needed, which my current insurance does not.

I had managed to play for time in somewhat difficult circumstances, and was content. Until one day, around the very end of March or beginning of April, I awoke with a crick in my back.

Sometimes while sleeping I can end up in a contorted position that causes back pain. When this happens, I try to be careful for a few days to lay in such a way as to help my back muscles. Usually the pain diminishes and the problem is solved.

That's what I expected to happen here. The pain persisted, though. I had a routine appointment with Dr. Droll, my Phoenix-area oncologist, on April 5. I recall trying to get comfortable in bed the night before, and making a mental note that the pain was still there. Well, I had moved a couple of heavy boxes, against my better judgment; maybe I had put new strain on the muscles.

The CBC for the appointment showed an unusual result: my platelets had dropped from the 150s to 89. This was not the first time this had happened. Such fluctuations often occurred during my BR chemo. Dr. Droll had been wondering if I had ITP, so this might have fit that pattern. As with so many anomalous blood results on so many tests over the years, it made sense to wait for the next test, to see if this was a one-time blip or the start of a pattern.

There was also a mistake on the bloodwork. I had gone to Sonora Quest with a standing order that included LDH, or lactate dehydrogenase. The evidently dyslexic phlebotomist had input "HDL" into the computer, not LDH. So I was left with a count of cholesterol, not a reading of tissue breakdown, which is a marker of whether a cancer is growing.

Now, for those who don't know, a drop in platelets along with an elevation in LDH can be a sign of Richter's Transformation. I was aware of this, and had been on the lookout for any sign of Richter's since completing BR. Richter's can be a bit hard to disagnose, but other symptoms can include abdominal discomfort, fatigue, and sudden tumor growth.

On all those counts, I felt fine. I could detect no tumor growth. My weight had not changed significantly. I had weighed 185 in December, which is pretty normal for me. I then settled into the low 190s, probably the result of letting myself go, diet-wise. I was not adverse to the occasional dessert involving Scotch and a shortbread cookie.

A repeat CBC on April 15 showed platelets back up to 156, leading me to wonder if the one-time drop had just been an anomaly. The LDH was just mildly elevated at 247 -- two points over the reference range of 112-245. This was a little unusual, but I knew I had some abdominal nodes left over from BR, and I supposed I could be starting to relapse, and I figured I would discuss this with Dr. Kipps.

Meanwhile, the pain in my back had become worse. I could no longer sleep on my right side, just the left. I went to see my primary care doctor, who ordered an X-ray. Sure enough, it showed a compressed disc in the L5, S2 region of the spine. Ugh, I thought, this is a new and unwelcome health thing to deal with. But it did, ostensibly, explain the pain, which was becoming so bad that I needed oxycodone to fall asleep.

Simultaneously, though, I developed rapid weight gain. Between April 12 and 16 I gained 10 pounds. My belly began to look distended. This raised the Richter's warning flag. Every day it seemed to get bigger. On Saturday, April 22 I went to the Sedona ER. An X-ray came back showing what the ER doc took to be a great deal of ascites. This was followed by a CT scan, which confirmed, informally, what we had been suspecting. My abdomen was filled with a huge tumorous mass. The obvious guess was Richter's Transformation.

This was not good news, but I am not one to bemoan my fate. I don't dwell on "why me?" Shit happens, and so does Richter's, to upwards of 10% of CLLers. Nobody knows why, but it does seem to come if you have had the disease for a long time, and it had been almost ten years since my diagnosis. Having abdominal nodes could be a factor, and I have had them for years. It's possible that the Epstein-Barr virus could contribute, and I had mononucleosis as a child, so EBV is still kicking around in my system somewhere. Maybe BR set up the environment for it; if you read the BR studies closely, you will note that there are always reports of Richter's on follow-up. 

I figured that if this was Richter's, there would be no better place to be than in Dr. Kipps' office three days later. The pain in my back was now severe and I was unable to sleep laying down. I had to sit up in a chair and rest my head on a pillow on the dining room table. The belly continued to grow. I looked like I was pregnant with twins. For those who are used to the slow pace of CLL, which can come in on little cat feet, this was a shocking experience. Richter's had arrived with all the aplomb of Godzilla tearing through Tokyo.  

Preparing for San Diego proved to have its comic moments. The night before we were to leave I suddenly realized that none of my pants would fit. Marilyn had to run to Wal-Mart at 1 a.m. to buy a selection of size 44 and 46 slacks and sweat pants. I managed to find a pair of pants that could be buttoned. Exhausted, we headed off the next day for the eight-hour drive to the sea.

Ironically, we had originally planned to make a mini-vacation of our visit. We had booked a room near the beach in Encinitas, north of San Diego. I could see the waves in the distance through the window. Talk again about the best-laid plans . . . I was in no shape to walk the beach. Everything, even the simplest task, took extraordinary effort to accomplish, and the back pain was ferocious.

My visit with Dr. Kipps is a blur in my memory. He took one look at all bloated 216 pounds of me -- and it was a look of concern -- and suspected what was happening. The exact diagnosis would have to be confirmed by PET/CT scan and lymph node biopsy. It was clear to him that diagnosis and treatment could not wait. Among other things, he was worried that the tumor could be on the verge of causing some kind of kidney damage. 

It was established that treatment could not be done at UCSD because of insurance issues; I would return to Arizona the next day, and Dr. Kipps would contact Dr. Droll, which he did both by phone and fax. "Therapy in the next several days appears to be imperative," he concluded in the fax.

The back pain I was experiencing, it turns out, was not the result of a compressed disc. It was the result of a tumor pressing against nerves in my spine, something I never would have guessed when, just a few weeks before, I had awoken with a crick in my back.

This concludes Part 1. So as not to leave you in too much suspense, it did indeed turn out to be Richter's Transformation to aggressive Diffuse Large B Cell Lymphoma. CLL is now the least of my worries. The plan is to achieve the best remission possible, then move on to a stem cell transplant. I have undergone two rounds of treatment (OFAR) with what appears to be a good degree of success. After the first round, my weight dropped to 175. A CT scan before the second treatment showed a massive reduction in node size.

Needless to say, my world has turned upside down. The new normal is considerably more risky and difficult than the old one. Despite all this, there is reason for hope. People do beat Richter's. In Part 2, I will share my treatment experiences, and discuss some of the challenges ahead. 

 

Bendamustine and rituximab: the verdict

The results are in. After five cycles of bendamustine (Treanda) and rituximab, which ended in mid-November, I can report that the treatment worked better than I expected.

As you may recall, I entered into it last July feeling a little desperate. My marrow was 90% impacted with CLL, my hemoglobin had dropped into the 7s, my platelets were dipping below 100, and thanks to swollen lymph nodes my abdomen looked like it was ready to give birth to three or four alien babies. You know, the big, ugly Sigourney-Weaver-attacking kind.

When chemo began I did not know what to expect. I knew a CR (complete response) was out of the question. I just hoped I wouldn't get a HAR (half-assed response), one so ultimately poor and useless that it would render all the time, pain, and money not worth it.  Especially in someone as heavily pretreated as myself, that kind of response was entirely possible. The disease tends to become more refractory to treatment as time goes on; you don't want a big, ugly failure to confirm your worst fears.

Well, I've now had a follow-up bone marrow biopsy and CT scan. And the bone marrow result was one I did not expect: a CR in the bone marrow, courtesy of a 5-color flow cytometry.

The CLL clones are there, just in numbers too few to analyze. The flow cytometry reveals "no specific diagnostic abnormality." Susupicious B cells comprise "approximately 0.1% of the total cellularity," or "too few to accurately assess clonality."

I have to admit that I just about fell out of my chair upon hearing the news. I was hoping, at best, for maybe 20% CLL in the marrow, a significant reduction, to be sure. But not one that pushes my CLL back to pre-diagnosis levels.

The CT scan of chest, abdomen and pelvis came out about as well as I might have hoped, but with less stellar results: Numerous swollen nodes are still there, especially in the retroperitoneum of the abdomen. The largest node is 6 x 4 cm, or about 2.4 x 1.6 inches. There are two others about that size, as well as numerous smaller ones.

What I am grateful for is that no huge cluster or mass of nodes was found; one can only wonder how bad things must have been at the start of chemo.

The spleen was also enlarged, 10 x 6 x 17 cm. 

An added bonus on the CT was what wasn't found: "The liver, spleen, gallbladder, pancreas, adrenal glands, and kidneys are unremarkable. . . . Lungs are clear." In other words, no new wrinkles to challenge me on top of the CLL.

Four months after therapy my peripheral blood continues to look good, with an absolute lympohoctye count of 0.8, hemoglobin of 12.3, and platelets at 153.

Like Caesar's Gaul, CLL is divided into three parts: the marrow, the peripheral blood, and the nodes. It appears that chemo pretty much flushed it out of the first two. It remains a problem and a challenge in the nodes and spleen, which is what I would have expected given my history. And my B2M remains high at 5.1, which indicates the disease won't be staying out of those other two compartments forever.

So now, the challenge is maintaining -- or building upon -- the remission I have. I had a good visit with Dr. Thomas Kipps in San Diego in January. More on that in my next post, as well as some thoughts as to where to go from here. 

But the headline is that the chemo was worth it and that the disease has been dealt a significant blow.

Red cell rebound

I knew I was feeling more energetic recently when, after going up and down the stairs moving a dozen cardboard boxes, I didn't feel especially winded.

Contrast this with not all that long ago, when just getting myself up the 14 steps was challenge enough.

My latest CBC confirms what I suspected -- some six weeks after finishing Round 5 of bendamustine and rituximab, my red cells have recovered to the levels they were at before marrow impaction by CLL forced me into chemo.

With a hemoglobin of 13.3, I feel like a new man, or at least not an old one. After living for more than a year with steadily declining red counts that put me in the 7s at one point, I realize now the subtle effect that growing anemia can have. At a hemoglobin of 11 I can feel almost normal, but lacking the energy edge of 13. At 9 I can function, but need a nap and am loathe to take on physical projects. At 7, well, it's a strain to climb the stairs.

Platelets are at 134, about where they were when all this began. Absolute lymphocytes are at 1.8. Lymph nodes are significantly reduced and my weight is in the low 170s, where it has not been in two decades. I look a lot less pregnant -- sorry folks, no alien baby will be bursting forth this year.

So, my initial verdict on BR is that it worked pretty well on me. Considering that I am ten years into this fight and have had multiple treatments, it was reassuring to see that I responded and responded well.

I'll be paying a visit to CLL expert Dr. Thomas Kipps next week and will be curious about his take on my response, as well as the state of my abdominal lymph nodes via a thorough physical examination. 

I'll also ask him about possible maintenance treatments and/or treatments at relapse, including what may be available in clinical trials. One thing I am certain of is that I do not want the disease to get out of hand as it did in 2012; B-R has not been easy and there is no guarantee that I will respond well to it in the future. 

My local oncologist is floating the idea of Campath, aka alemtuzumab, for maintenance. He's aware that it doesn't do much on nodes larger than 5 cm, which I may still have somewhere. And since bulky disease has always been my problem, I am a little loathe to go this direction.

What's more, Campath is severely immunosuppressive, killing off T cells as well as B cells, and leaving some CLLers with all the immunity of your average AIDS patient. I have had pretty good quality of life when it comes to avoiding nasty infections, and I am not disposed to open myself up to juggling pneumonia, shingles, and who-knows-what-else.

The extensive rash I wrote about in my last post has finally gone away with the help of a two-week course of oral dexamethasone. The biopsy came back as "hypersensitive dematitis" with no sign of CLL infiltration. Which is what I figured before the dermatologist punched holes in my skin.

My oncologist thinks the rash might have been an allergy to Rituxan, perhaps less so an allergy to bendamustine. But no one knows for sure. 

So I have one last question for Dr. Kipps: Is it worth doing the last round of B-R, and doing it more than a month behind schedule? My tendency is to go for it, if this is my best shot at using it to nail down the best remission possible, perhaps without the R, just to stay on the safe side of any possible rash. 

Meanwhile, I still have more boxes to move. It's the simple things in life that count and it's good to feel like a human being again.

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.

It's chemo time

Treatment starts Tuesday. I have decided to go with bendamustine and rituximab (aka Treanda and Rituxan), the first round of which will be given in the hospital so I can be monitored for tumor lysis.

As readers of this blog know, I have been looking for a kinase inhibitor trial for some time. A series of events out of my control has kept me out of trials, and my clinical condition now demands something bigger and stronger.

I was invited into the CAL-101 plus ofatumumab trial at UCLA last August, only to be told that there was a mistake by the company that organizes the trials and that the slot didn't actually exist. Had this worked out, it would have been ideal, since I was still at Stage 2 with ample hemoglobin and platelets. It would probably have been a seamless transition from the lenalidomide (Revlimid) I was on, and it probably would have forestalled the situation I now find myself in. At last count, hemoglobin was 7.9, platelets were 96, and the lymph nodes are bigger than ever. My spleen is 6 cm below the costal margin and the liver is, in the words of my oncologist, Dr. Droll, "pronounced."

In March, I was invited into the ABT-199 trial at the University of Arizona Cancer Center. I went there for the testing that is required before entering the trial, only to find out that there was now a problem between the drug company, Abbott, and UA. Since then I have been able to piece together some of the story; it appears that a failure to do something right at UA lead to the suspension of recruitment there. Which left me with nothing other than the promise that I would have first crack when a slot opened in the AVL-292 trial, in which UA was also participating.

The slot for AVL-292 finally opened, and I was faced with a difficult fact: Hemoglobin of 9.0 is required for admission, and while mine had been a steady 9.2 for months, it dropped to 8.5 and now 7.9. So I wasn't going to get in the trial regardless.

The cart before the horse

This all dragged on much longer than anticipated, and as it did my hemoglobin began to head south. It became apparent to me that between my failing marrow and disease bulk, using a kinase inhibitor would be like trying to stop a house from burning down with a garden hose. Even if it addressed the nodes to some extent, it was almost assuredly not going to address the marrow, or do so with much depth and rapidity, and that is probably the worst problem I have at the moment.

I went in for a bone marrow biopsy on Thursday; I haven't heard the official results, but the person who did the BMB -- and all she does is BMBs, day in and day out -- said my marrow was "packed." I'm not surprised.

(For BMB fans, of which there are none, it is worth noting that they put me under for the procedure with propofol, as well as using lidocaine on my hip. This is the way to go as far as I'm concerned. I woke up a few minutes early and felt her digging the needle around in my hip bone; it was much more pleasant being knocked out.)

Ultimately, it makes a lot more sense to deliver as big a blow as I can to the disease now, and then follow up with a trial, probably a kinase inhibitor, as maintenance afterward. I might also consider using lenalidomide as maintenance; perhaps at a low dose I could tolerate it, and with less disease burden it might not be as overreactive in terms of tumor flare as it proved to be last November.

The choice

Basically, there are two choices for Big Chemo these days: FCR or BR. In my case, given the low hemoglobin and the fact that I had autoimmune hemolytic anemia from 2007 to 2010, FCR is just too risky. While the CR can moderate fludarabine's ability to trigger AIHA, it is still a risk, and one that someone with a hemoglobin of 7.9 should not take.

Bendamustine is newish, at least in practice in the U.S., and is supposed to be less myelosuppressive than FCR. Reading anecdotal case histories, one finds that most patients get through it with good results. There are exceptions, usually when neutrophils crash, triggering bad reactions, which is why using Neulasta during treatment makes some sense.

The most reputable paper on BR comes from the German CLL Study Group, which examined the treatment in a tough group of relapsed and refractory patients. The abstract is available here. For those who don't know, bendamustine was developed in East Germany. After reunification, it attracted the interest of researchers and drug companies. An alkalyting agent like cyclophosphamide, it also seems to have properties similar to purine analogues like fludarabine.

The full paper from the German group is worth reading. Bendamustine can work on those who are fludarabine-refractory, with 45.5% responding. It can also work on those who have had  rituximab, and I have had plenty in years past. Of seven patients who had previously received rituximab, five responded with a partial remission.

A disturbing fact involves Richter's Transformation. Four of 78 patients were diagnosed with Richter's Transformation after the end of treatment. The authors imply this was unrelated to treatment, but I'm not so sure. Richter's can be set up by profound immunosuppression resulting from treatment; just because it doesn't show up until later doesn't mean treatment had nothing to do with it.

The bottom line is that all therapy comes with risks; kinase inhibitors are not risk-free, as Chaya Venkat makes clear in a recent report at CLL Topics Updates.

What I can expect

Based on the German data and my clinical situation, I am hoping for a partial remission that significantly reduces the nodes and clears out the marrow to a great extent. I am not anticipating a CR, despite the optimistic words of Dr. Daruka Mahadevan at UA, who said BR would "clean me out."

This is why maintenance should be initiated soon after I complete BR in December. I need to keep the disease in check through some means; if there has been a lesson for me in my experience since November, it is "don't let up."

I will report on BR in some detail as I experience it; little has been written, even anecdotally, about patient experiences with the drug, and it is here to stay as a major player in CLL.

I'll be doing the first round in the hospital so I can be monitored 24/7 for tumor lysis. In someone with my disease bulk, so many CLL cells could die so quickly that my kidneys might be at risk. Both Dr. Mahadevan and Dr. Droll thought this was a good idea, and I can't argue. As much as I don't like the hospital, I like my kidneys. I also expect that Dr. Droll will go with a lower-than-usual dose of bendamustine in the beginning, another way to guard against potential problems.

And so the next chapter begins in my CLL Diary. I am looking forward to the treatment, which I hope will restore some of the quality of life that I have lost. I had seven years of relatively easy CLL; when things head south, one is reminded of how difficult (and, yes, how potentially deadly) this disease can be.

Black thumbs, passing arms, and high fevers

Time for an update, as the saga drags on.

I have a new theory, which I'll call Dave's Black Thumb. It goes like this: If there is a doctor in Arizona that I like, they will eventually leave their practice and probably the state.

The first to go, in 2006, was Dr. Susan Partyka, known as "Dr. Chopin" in the blog. In January of this year it was Dr. Lesley Meng ("Dr. Belle.")

Which brings us to the present. Earlier this year, when Dr. Meng left, I found a new oncologist, but I also found another doctor to consult with who was conducting some interesting clinical trials of kinase inhibitors. This was Dr. Daruka Mahadevan at the University of Arizona Cancer Center in Tucson. (I paid out of pocket for to see him because my insurer, Merciless Healthcare Group, doesn't cover either of the state's preeminent cancer centers, the other being Mayo Clinic in Scottsdale.) Dr. Mahadevan was UA's CLL guy, and we hit it off immediately. He's smart, an honest arbiter of treatments, showed a willingness to fight for his patients, and was worth the $500. And now he, too, has flown the coop and departed the state for points unknown.

This means the reset button has been pressed, and now I need to see a new doctor in Tucson, who will be the new investigator for the one remaining trial (AVL-292) they expect to open "in a few more weeks." If I had a quarter for every time I have been told "a few more weeks" I really could buy a cup of coffee. (My last post went into problems with the trial that would have been the first choice, ABT-199.)   

I can't wait forever

Keep in mind that my disease has become much worse since last November and that I needed treatment in January, really. My hemoglobin has plateaued at about 9.2, which is just enough to get me around but not enough to do any meaningful physical activity. I think twice before walking up the stairs, for example. I tire easily and need to sleep more than usual.

My new local onc, who I think I'm going to call "Dr. Droll" because he has a dry sense of humor, has kept me going during this trial search with huge doses of pulsed steroids, which is a stop-gap of limited usefulness, not any kind of solution. This involves taking 40 mg of dexamethasone for four days every ten days, ostensibly. (I do it about every three weeks, when I feel baseballs forming under my arms again.) This regimen is used on myeloma patients. When I saw him recently and mentioned how much I hated the steroid regimen, his comment was "They don't clamor for it." 

The platelets dropped to 85 at one point but thanks to the steroids have been hanging around 120. The lymph nodes have gotten worse than ever (though surprisingly my spleen is almost petite). Left unchecked for awhile, the nodes clump together in masses under my arms and in my abdomen. The steroids knock them back some, then they bounce back after a few weeks. It's clear that my marrow is impacted and that the nodes need attention.

Dr. Mahadevan's suggestion for a conventional treatment was bendamustine-rituximab. Dr. Droll has the same point of view. Mahadevan said he "wouldn't give me fludarabine with a 10-foot-pole" because of my history of AIHA. I am not overenthused about bendamustine, but I do see the logic and it is less myelosuppressive than fludarabine. Either can lead to such lovely conditions as Richter's Transformation, and I have a lot of deep abdominal nodes.

It is exactly because the kinase inhibitors can do an excellent job of shrinking the nodes with much less toxicity that I have held on this long to search for a trial. But how long is it safe to continue waiting to get into one while taking enough steroids to revive the dead?

Which brings us to the Hail Mary pass I have thrown, which may result in some good news, and which may not, and I won't know until mid-July. I'm going somewhere a little further afield than Tucson, and I'll see what happens there.

But the window on this is closing; no trial soon = bendamustine-rituximab.

104 degrees

And I don't mean the weather. I have just finished a week, most of it spent in bed, with fevers that ranged from 99 to 104. Besides fever, the main symptom was exhaustion. My lymph nodes did not swell up beyond their already swollen point, which is usually what happens when I have a cold or flu. In a CLLer with limited immunity a fever of 104 is not a good sign. Marilyn wrapped me in an electric blanket and stuffed me under the comforter and we agreed that if it was not down within an hour, it was off to the ER. But it dropped, and I stayed home.

The good news is I got over It, whatever It was. The fever began while I was continuing on prophylactic meds for the steroids, although I was off the steroids, but the Bactrim, Augmentin, Fluconazole, and Acyclovir did not prevent It nor cure It. My own immune system overcame It, which is a very good sign.

And that's where things stand. I'll update you in a month.

Hurry up and wait

Those of us with chronic lymphocytic leukemia are familiar with the concept of "watch and wait," which means being a patient patient while your disease take its course. This can involve a certain degree of dis-ease (pun intended) as you and your doctor lurk about, waiting for just the right moment to begin treatment, should that become necessary. 

Of late I feel like I've been experiencing something called "hurry up and wait," which is what you do when your disease definitely needs treatment but you are waiting for the best treatment option to make itself available, which is supposed to happen Any Day Now.

"Watch and wait" drives Type A personalities a little bit crazy, which isn't really a problem for me. "Hurry up and wait," on the other hand, can be a bit of a challenge.

In my case, since the end of the Revlimid era last November, the CLL has taken a turn for the worse, compounded by departing doctors, insurance runarounds, and potential clinical trials that have proven to be trials in more ways than one. I've written about some of this, and am here to provide a little update now.

The good news is that Any Day Now there should be an opening in a kinase inhibitor trial with my name on it. I've been waiting on two such choices for a while. 

The first, which I'll call Trial One, almost came to fruition six weeks ago. In fact, I was all dressed up for extensive testing for a trial slot, only to arrive and find I had no place to go. Seems an "adverse event" in the trial of said inhibitor had just raised a big red flag at corporate headquarters and further patient accrual was being put off. All this happened in real time as I sat in my hotel, or in the Vietnamese restaurant adjacent to my hotel. Eventually I was sent home with the knowledge that while Trial One was probably out for the forseeable future, there was a Trial Two that would have an opening in another month, give or take.

And, so, here I wait at home, far from pho, disappointed but cautiously optimistic that I might make it into the second trial, in which no adverse events have been reported to date, at least that I know of.

You could argue that I am lucky the adverse event in Trial One didn't happen to me. It was an unexpected case of severe tumor lysis, apparently, which means massive, immediate die-off of leukemia cells that, uncontrolled, can damage the kidneys. Trials are called trials for a reason, and as much as we like to think of ourselves as intelligent, forward-thinking patients, we are also in fact risk-taking lab rats when we sign on the dotted line. So maybe I dodged a bullet by not making it into Trial One, which would not have been so disappointing had the principal investigator not been so genuinely enthusiastic about its potential to help me.

Now, I could go into names of drugs and names of doctors here, but what I have heard is second-hand, and I'm not in the business of reporting such things as absolute fact. This is a blog, not journalism, and there is a huge difference between the two that I still hold somewhat sacred, having worked in the news business back when double-checking the facts counted for something.

To keep my CLL at bay while waiting for trials, I have been taking huge pulsed doses of steroids every few weeks. My new local hem/onc calls it the "myeloma dose" -- 40 mg of dexamethasone daily for four days. The advantage is that it does reduce the nodes temporarily, and it has bettered my platelets a bit (they're now at 101) while perhaps also keeping my hemoglobin steady in the low 9s, which isn't so awful once you get used to it. Plus the steroids leave your system in under six days, and the prophylactic meds (antibiotics, antivirals, antifungals) also leave quickly, meaning that you can be ready to qualify for a clinical trial without a long delay.

Since 2007, I've had a fair amount of experience with steroids, about which I plan to write at some point soon. I think they're a good but problematic stop-gap, and nothing more. Steroids are a potentially useful component in any "hurry up and wait" strategy, but they're no way to live.

The late Dr. Terry Hamblin once pointed out that in end-stage cases he would prescribe steroids once a month just to keep the patient going, and I can see how, when all else fails, it beats the alternative. 

Fortunately, we now have more alternatives, such as the kinase inhibitors, as well as Revlimid for those who can tolerate it, not to mention the supercharged T cells being studied at such places as the University of Pennsylvania.

Which brings us to the real game to win here. I call it "slow down and wait." By that I mean, allow science to outpace your CLL by just enough that it can save your life. I feel like I'm cutting it close on this one, but there really is no other choice, except to go marching off to the Relapsed-and-Refractory Factory and await the end.

Call me irresponsible, accuse me of "dithering" in the face of my own unplanned obsolescence, but I am not comfortable with following a conventional wisdom that can change from one day, or week, or month, to the next. In CLL, action can mean progress, but it can also mean the illusion of progress. Doing something just to do something may not always be the most rational course. So I often find myself taking my chances with inaction.

"Slow down and wait" involves a certain amount of powerlessness, of accepting things you probably cannot change, among them the possibility that Fate might throw something at you, for good or ill. By making wise (or just plain lucky) treatment choices you might be able to control the disease long enough to buy more time, but there are no guarantees, since the disease can always take a turn for the worse at a whim. As to the pace of scientific progress -- and the availability of its fruits in your locale -- that is all luck, pure and simple. 

So far, I've been fortunate that science has done more since my diagnosis in 2003 than I, or perhaps anyone else, might have expected. My disease behaved decently until last fall, and now has settled into a new plateau, worse than it was but not getting worse, at least yet.

And Any Day Now, well, I hope to be trying a new treatment that might just control this thing. So I'm hurrying up and waiting in order to slow down and wait some more. Welcome to CLL.

Revlimid, in retrospect

Now that my year-and-a-half experiment with Revlimid -- aka lenalidomide -- is likely done for good, I think it's appropriate to sum up what I've learned.

Blogs tend to blurt out information that gets disconnected after awhile; my training as a feature writer tells me to sum up and provide context. For those chronic lymphocytic leukemia patients considering Revlimid, I hope my anecdotal experience might be of some use, which is why I am writing this.

I say "anecdotal" with all the usual warnings, as in YMMV -- Your Mileage May Vary -- and with this drug, it probably will. 

Pills are small and easy to take, but this one is not, on so many levels. For a little capsule that's supposed to be an "immunomodulator," it can easily provide more grinding fits and challenges than regular chemo. In CLL, lenalidomide comes with a wide degree of patient tolerance issues. One of them ultimately derailed the drug for me, but until it did, this stuff was almost golden.

Today, it is being eclipsed by the buzz about kinase inhibitors with license-plate names: CAL-101, ABT-199, AVL-292, PCI-32765, and so on. These drugs are in trials with promising results; while they may end up being a first choice over lenalidomide for many patients, in some cases they may not. Revlimid is here to stay for CLL, and it is a useful option to have. I used it from March 2010 until November 2011, with three months off starting in March 2011.

Revlimid modulates the immune system. Somehow. And in people with weakened immunity, such as CLL, this can do a couple of great things. One, it can cut down on infections, sinus and otherwise. In fact, it has been suggested that low doses of lenalidomide can be given to older people -- not necessarily CLLers, just older people who tend to get sicker easier -- as a means of keeping the immune system more functional. I have been fortunate in my CLL career not to have been especially infection-prone, despite my immunoglobulins being in the tank for nine years. While on Revlimid I was infection free -- not even a sinus minus clogging up my yap.

Revlimid normalized my blood counts, and it has done this for a lot of people. My absolute lymphocyte count wasn't too high to start with, as most of my disease is located in my 11q-deleted lymph nodes. But at one point my CBC became picture-perfect, frame-able even. You couldn't tell by the numbers that anything was wrong.

And this is a really big deal -- while using Revlimid, my very nasty, recurring case of autoimmune hemolytic anemia resolved. From the moment that the AIHA was diagnosed in March 2007, until Revlimid put a stop to it, I was bedeviled by serious hemolysis and treatments that began to fail, one after another, until I was left getting pretty heavy chemo (Rituxan, dexamethasone, and cyclophosphamide) as frequently as every three months. And there was some question about how long that could continue before a splenectomy became a necessity.

Dr. Asher Chanan-Khan, probably the country's leading lenalidomide-CLL researcher, told me in an e-mail before I started the drug that he had seen two actively hemolyzing patients -- hemolysis means your macrophages are eating your own red blood cells, which they will continue to do until you have none left and die --  whose hemolysis resolved while on Revlimid.

My own experience has led me to prosthelytize on these pages more than once, and so let me shout it out again for all my AIHA fellow-sufferers to hear: Please, please, consider Revlimid, especially if you are finding that the usual treatments (steroids, rituximab) are failing. If it does for you what it did for me, you'll have enough red blood cells to do some serious dancing in the streets. After a year of Revlimid, my hemoglobin was back up to 15.1 -- the exact number it was at on the day of my CLL diagnosis in 2003. I turned Coombs negative and remain so at this moment.

Revlimid also reduced my lymph nodes to a noticeable degree. I would say -- and I am guessing, since some nodes are more palpable than others -- by up to about half. In a nodey guy like me, that is great news. It took a long time. But it was slow and steady. And in CLL, slow and steady is often all you need to win the race, or at least to stay where you need to be when in competition with the growth of the disease.

Now, here's a real Revlimd success story. I have a friend with 11q-deleted CLL who went into a Revlimid clinical trial as frontline treatment. His lymphocyte count had reached a half-million (that's not a typo). In the trial, patients are upped from 5 mg daily to 25 mg daily over time, if they can tolerate it. And my lucky friend proved able to tolerate it, and to get the benefit from the maximum dosage. 

By the end of his two-year stint, his counts had normalized, what nodes were left were barely palpable, his hemoglobin was high, and a bone marrow biopsy showed improvement. Platelets were a bit low, but you can't have everything, and he's been told they should recover. He had found himself an excellent way to start out controlling his CLL without burning any bridges. He has had treatment, but not chemotherapy, which sets up disease resistance. From all indications, he can go on to do any other treatment out there, or take advantage of a new treatment that comes along, and he can expect it to work as well on him as if he had never been treated. (And, of course, he can always do more Revlimid at relapse.)

That is great news in the Second Chance department, which is so important in CLL,  and which cannot be understated. Preserving a second chance is what I was trying to do with single-agent Rituxan back in the days before Revlimid. That turned out not to work. Once you've done single-agent Rituxan, you have diminished your response to future treatments. It's not a free ride. But since Revlimid is an immunomodulator and works on totally different principles from chemotherapy, it does not appear to set up disease resistance. (Not that it won't make changes in the immune system, and only time will tell if there's something important about it that researchers and patients have been missing so far.)  But if I were starting out and needing treatment, I would seriously consider Revlimid for the Second Chance reason, as well as for its potential to do the job in the blood, nodes, and marrow that needs to be done.

And if I had been through the chemo mill, and was pretty much out of Second, Third, and Fourth chances, I would also look into Revlimid. There are some CLLers out there who have been kept alive for years now with daily doses of Revlimid. Fate has allowed them to tolerate it, and it works as well on the nasty 17p-deleted CLL clones that are left after the Chemo Wars as on the "nice" ones you tend to find more of at the start. For these people, Revlimid truly is golden.  

Dosages are tricky. Not everyone can tolerate 25 mg. Celgene, the drug's maker, has recommended that as a routine matter, CLLers not be given more than 10 mg daily. Some patients are coasting along at 5 mg, in maintenance. Some can tolerate 10, some higher. Some can't tolerate it at all.

In my case, doses as low as 5 mg have caused problems. I'll get into that in a minute. Suffice it to say that the higher the dose you can take, the more the drug will probably be able to do for you. Finding that right dose, and watching out for symptoms that could indicate drug intolerance, requires a great deal of patience. It helps to have a doctor who has used the drug in CLLers, or at least in those for whom it was originally intended, patients with MDS. You need to be aware of your body and on top of symptoms if you are going to experiment with it, and let's face it -- in CLL, Revlimid is still experimental.

Revlimid can also make you feel kind of out of it. Before I get into more serious tolerance issues, one thing my friend and I both noticed, and that some others have noticed, too, is that lenalidomide can bring a certain dullness to your life. I wouldn't say fatigue, necessarily. But this drug is the enemy of multi-tasking. It can lead to a lack of focus or sharpness. You can operate heavy machinery, you can go to work, you can do all the things you normally do, but somehow you do these things slower, or somewhat more detached, or in a somewhat foggy world involving less concentration. This is not a good-time, party drug. When Marilyn and I flew back East for my step-mom's big 70th birthday bash, I stopped taking Revlimid a few days before. I knew that if I were off of it, I'd be enjoying the party and making conversation. If I were on it, I'd be sitting in a corner trying to remember who so-and-so was from a distance. Suffice it to say that lenalidomide is no help with libido, either. While not everyone reports these sorts of symptoms, It's ongoing use could lead to a somewhat lower quality of life in some respects. That's not enough to make it not a choice, but it's potentially part of the experience (and for some it does get better over time.)

Revlimid can lead to serious clotting issues. This is one of those things that Celgene is very up-front about, and that the nurses who dispense the drug are always reminding you of.

By now, if you've read CLL Diary, you know that clotting was my problem, and that this shifted the risk-reward scale in favor of abandoning lenalidomide. To recap, I have a family history of clotting troubles. My mother died of a pulmonary embolism at 57,  just two years older than I am now. Her older son -- my older half-brother -- suffered several strokes, one of which took his life this past July at the age of 66. I saw him become bedridden and incontinent, barely able to move one hand, hardly able to swallow, eventually surviving through a stomach plug. I saw him decline, both physically and mentally. One night, a few weeks before he died, in a moment of frightening clarity, he shouted something from the hospital bed that had been set up in his living room: "What a miserable existence!"

It is possible to live with CLL and have good quality of life. In the QOL department, there are many worse conditions to have, not all of them cancerous. Staring my brother's fate in the face, I was ever reminded that worse things could await me if I were not careful.

I had two transient ischemic attacks, aka mini-strokes, while on lenalidomide, and then a third incident that probably qualified as something of the same. The first incident came about four months in, while I was on 10 mg daily, and involved about ten minutes of aphasia, or language difficulty. It resolved completely, and I ignorantly chalked it up to "chemo brain" and put it out of my mind. 

The second attack came some some months later, after things had been going so well that my oncologist gave me the go-ahead to up the dose to 15 mg daily. We wanted to go in and get at those nodes. After a week or so, the same language difficulty appeared again, also for about ten minutes. This time I went to see the doc, and she put two and two together, and clotting issues took center stage.

Which is why, like my lucky friend, who underwent a supervised trial in which Coumadin was required prophylaxis, I would not advise anyone to go on Revlimid without also going on Coumadin, or warfarin. Even if you don't think you have a clotting problem, it is wise to guard against it. If it is good enough for Dr. Chanan-Khan's patients, it should be good enough for your doctor's, too. Like any prophylactic drug we CLLers take -- such as allopurinol, acyclovir, or Bactrim -- it is designed to guard against a problem occurring. And at a low dose, such as 2 mg daily, it should not present a problem for most people. It is insane not to do it, IMHO.

The third incident occurred in September of last year, and came and went over the course of a week. By that time, I was on higher doses of warfarin, which were not improving my clotting time much at all, and lower doses of Revlimid, such as 5 mg three times a week. I felt a transient numbness on the left side of my mouth, sort of the way you feel after you've been to the dentist and the Novocaine has started to wear off. Simultaneously, I also felt this numbness in my left hand. This resolved after about 15 minutes, but it came and went for short periods during the following week.

Finally, of course, there is the story of my lenalidomide gotterdammerung and the abscessed lymph node, catalogued a few posts back complete with messy photos. Despite a year-and-a-half of being on the drug (and sometimes off of it), resuming it at 5 mg just four days in a row caused such unholy tumor flare as to land me in the hospital.

Which leads me to a final point: Revlimid can do unanticipated things to the immune system. In my case, it appeared to goose it up over time. There was a three-month period, starting in March 2011, when I was off the drug. I was, in part, expecting to get a slot in a kinase inhibitor trial, which did not pan out, and I needed to be "drug free" for 28 days before starting the trial.

Just before resuming Revlimid after this hiatus, I came down with a case of hives. This was unusual, since my allergies don't usually take that form. It resolved with Benadryl (speaking of Zombie drugs) and I went on to restart Revlimid at a general course of 5 mg three days a week. Over the course of the last summer, I was constantly getting hives, several times a week. Move me to a spot with a new allergen, and it would start. Let me get a little sweaty in Arizona in the summer -- which is impossible not to do -- and the the hives would come again. It was all easily controlled; in fact I began taking Allegra every other day just to keep it away. But something in my immune reaction was more hair-trigger, way more prone to act quickly than it had been in the past.

My theory -- and, again, this is anecdotal guesswork -- is that Revlimid, which had rewritten my immune system in some good ways, also rewrote it in some more dangerous ones. A recent paper by Dr. Chanan-Khan and others discusses mechanism of action at some length, and basically points out that lenalidomide works best when there are lots of NK and T-cells present. (The latter, little marvels, also surveil against squamous cell skin cancer, another problem I've had, and something common to CLLers; Revlimid appears to have kept a lid on those, too.)

The paper, Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response, is worth reading if you're thinking of taking the lenalidomide leap. It appeared in the May 15, 2011 issue of Cancer, which is published by the American Cancer Society. Now, here is where I teach you to fish. Most journals that usually charge for articles will provide one free for the personal use of a patient if you just write and ask. In this case, contact canceredoff at cancer.org. 

Tumor flare, the paper explains, predicts response in Revlimid. There is a two-thirds chance that you will encounter it. From the very beginning, tumor flare was always a challenge for me. It came on big when I first started the drug, then remained at a lower but tolerable level during treatment as the ongoing battle with the nodes was engaged. What happened at the end with the abscess was one for the record books. Again, just a guess, but I wonder if the Revlimid had created in me a condition by which my immune system overreacted when the Revlimid itself was re-introduced at a 5 mg sustained dose, higher than I had been taking for some time.

Talk about ironic. In many ways, I responded very well to Revlimid, perhaps a little too well. It created too much fire to play with.

But it got me through a rough patch when I needed it, and it saved my ass in 2010 and much of 2011, getting me in a bumpy fashion to the great hope of 2012, kinase inhibitors.

So, thank you Celgene. And if you, fellow patient, are in the right position to tolerate it, Revlimid could be an important option for treatment. Just consider that it may not be easy, and do expect the unexpected.

(A final note: readers will recall that I began my Revlimid regimen in 2010 along with infusions of ofatumumab, aka Arzerra. The Arzerra was stopped after September's dose as the Revlimid appeared to be doing most of the work; I was on (and off) Revlimid for another eleven months after the Arzerra ended, so I do not think it clouds the story much. The one thing it may have done is mitigate the tumor flare I experienced at the beginning; perhaps it also served to keep the immune-goosing effects of the Revlimid somewhat in check.)