Large Diffuse B Cell Lymphoma

Transformation to large diffuse b-cell lymphoma. It's particularly troubling that there is no money for research into this affliction that affects so many CLL patients, especially since the risk is increased significantly with the use of FCR and other drug combinations that combine alkylating agents with purine analogs. This provides a potent mutagenic punch to the unstable CLL genome.

Contrary to Dr. Hamblin's glowing endorsement of FCR, and MD Anderson's love affair with the dangerous drug combination, stay away from this unless there is no other option. (Dr. Hamblin says anyone who has a serious side effect such as Richter's just 'gets the sticky end of the lollipop' a description I find insultive, dismissive, and arrogant.

For me, it's too late. but for those out there who are facing treatment decisions, choose something else. Especially with the prospect of an actual cure dangling tantalizingly in your faces.

Liver numbers have gone down on CAL-101

The good news is that my liver numbers, while still abnormal, are down considerably after I've reduced the dose of my CAL-101 from 3oo mg per day to 200.

The bad news is that my blood numbers are starting to deteriorate. My platelets have fallen drastically from 140,000 to 77,000. Dr. Kipps is worried and wants a new bone marrow biopsy. I told him I had one in the hospital last month. I told him I'd send him a copy (or rather, I'd ask UC Davis to send him the results). When I called Davis and asked them to fax a copy to Dr. Kipps, they offered to mail a copy to me. I said OK.

I read through the report and it's troubling. I have converted from about 11% 11q del to about 70%. Curiously, the rest of the CLL cells are positive for 13q14, which I've never seen in my reports before.

The worst part is that my cells are showing signs of 'clonal evolution' towards MDS.

The biggest mistake in my life (doing FCR based on glowing recommendation of Dr. Weirda) is perhaps coming back to haunt me. MDS is a killer, and should prevent most people from taking FCR, unless there are no other options. There were options for me, and I wish I had taken them.

In the era of CAL-101 and other kinase inhibitors, CLL may be a much more manageable disease. The CLL patient may be treated more like the chronic disease patient he is, rather than hitting him with the big guns.

Taking FCR may force mutations in the CLL cells that lead to terrible consequences. I know that Dr. Hamblin snarkily said that I 'just got the gummy side of the lollipop stick', but that flippant remark belies the terrible outcome for many FCR patients, who will die much earlier than they would if they eschewed that dangerous drug combination.

CAL-101... A week later

I had my second infusion of rituximab yesterday at Stanford. I'm happy to report that the infusion went well; no vomiting and no chills, as happened a week ago. My GERD is back; I assume this is due to the vomiting and/or the rituximab infusion.

My blood numbers were interesting. Since my disastrous bout with FCR, my counts have been very low, with the WBC ranging from 2100 to 2700 or so. This time, my white count is over 44,000. This fits with what I've learned about CAL-101, and also fits with my sudden and unexpected shrinking of my lymph nodes. The thinking is that this kinase somehow pushes CLL cells out of the lymph nodes and into the circulatory system, where it can be detected by a simple blood draw.

The rest of the numbers are about what I've been living with for the past few years. My hemoglobin count is a bit lower, from the high 12s to the high 11s. My platelets, though, are much higher. They've been hanging around the 90 neighborhood; now they are over 140, and in the normal range. This is the first time that's happened in years and years. In fact, I can't remember when it was in the normal range.

My absolute lymphocyte count is high, as one can imagine. My absolute neutrophil count is also up substantially, which is very nice. Dr. Kipps has been puzzled by the low neutrophil counts over the past two years, which have nevertheless not led to a single serious infection. He thought that maybe the neutrophils were 'hiding out' in the tissues somewhere. It appears that he was right.

I am taking 150 mg of CAL-101 twice a day since Wednesday of last week. It's not a difficult thing to remember, and I'm home in the morning and evening. I'm back on acyclovir and Septra, the first to forestall herpes infections, and the second to help prevent bacterial infection, primarily in the lungs.

I'm carrying on my normal activities, which include having a sewer and water line replaced at my rental house, and doing some painting and other minor repairs. I'm trying to stay away from sick people, crowds, and soil fungus.

So far, so good.

Happy Thanksgiving

Another Thanksgiving has come. I hope all have a blessed and wonderful day of thanksgiving. I'm personally thankful that my wife is recovering and getting better every week. I'm doing OK. My counts are still below normal because of permanent damage caused by my stupid foray into FCR-land.

I had a severe inner-ear infection a couple of weeks ago. It seems to have abated, but it's left me with a nasty cause of tinnitus. For those who have been lucky enough not to have experienced this 'ringing in the ear', it's a constant (in my case) high-pitched buzzing, caused by long-term exposure to loud noise (not my problem) and infection.

It's very annoying, and it's accompanied by hearing loss. I have an appointment in January with the ENT doc, but there's nothing they can do. Medical science has a long way to go.

Anyway, hope things are better with you all. Be thankful for what we do have.

Steady as she goes

Saw Dr. Kipps on the 19th. My CLL is holding steady. My lymph nodes, which popped up a bit before the last visit in September, are now about the same size. Obviously I still have CLL, and it still is active, but luckily it is behaving itself, and not creating too many problems now. (Actually, not any problems that I can see. My energy level is back up to where it was before flavopiridol, and I've not had any infections or other complications. So I now have a six-week reprieve.

Counts are still terrible because of my disastrous dalliance with FCR. My marrow is permanently ruined. As bad as that is, it also limits my choice of further treatment. Counts have to high enough (especially neutrophils) to successfully sign up for clinical trials.

I do have a minor ear infection that I'm getting antibiotics for. One of the many annoyances (let it stay minor!!!) that come with CLL. You just can't fight off infections well.

The past month has been a good one, for me.

My Marrow has been "Chewed Up" by FCR

I saw a CLL doctor for yet another opinion, this time a doc at Stanford. We discussed my situation, especially in light of Dr. Kipps' recommendation that I start a search for a donor for a much-feared stem cell transplant (the survival figures are not as high as I'd like).

I had to wait over an hour to see him, which seems to be par for the course for busy CLL types. I gave a brief rundown of my history, and the fact that I've had four treatments; HDMP+R, ISF-35 (direct nodal injection), the idiotic FCR, and flavopiridol. According to his labs, the slight improvement in my numbers noted at UC Davis has disappeared, but I think some of that can be ascribed to different labs. I like Davis' lab, because I always have better numbers there.

He said there were two drugs in trials at Stanford that he likes for CLL: Cal-101 and another drug that he didn't even mention the name/number of. Something like PCI something or another. I'd pass the name along, but he didn't pass it along to me. (Searching the web I do find two candidates: PCI-32765 & PCI-45292, both Bruton's Tyrosine Kinase inhibitors.)

We then talked about why my marrow has never recovered. The doc said my marrow was 'chewed up' by FCR. I asked if there was anything I could do to make it better. He said, 'no'. He also said, 'they never mention that when they publish glowing reports about FCR.'

So, in addition to a heightened risk for Richter's tranformation, and myelodysplastic syndrome, our non-friend FCR can 'chew up' your marrow. Wonderful. Apparently, FCR has left me with a permanently scarred and chewed up marrow. Sweet!

The doc is going to send me the protocol for Cal-101, which he seems to like a lot. It apparently doesn't give many people a complete remission, but it does help shrink swollen lymph nodes.

Besides my chewed up and spit out marrow, the abdominal nodes may or may not be making a comeback, so this might work well. We will see. I see Dr. Kipps soon as well. And, joy, I get another bone marrow biopsy! That will make number 16. I wonder what the record is? I wonder if I have any marrow left in my hip after all of the sucking and drilling?

Counts holding somewhat steady

A quick post: I've put myself on bi-weekly instead of weekly blood tests. The counts have improved to a certain extent, after the flavopiridol trial I was on last year/this year.

My hemoglobin count has improved to 12.0, after running in the 10s and 11s for the past two and one have years, after the poor decision to do FCR. My white count is now in the normal range, so no more neupogen or neulasta shots, for the time being. My platelets are also in the normal range, the first time in years (albeit low normal). I've been feeling pretty good, with no infections and no major problems.

So, as I've indicated before, flavopiridol (Alvocidib) is a great success for me.

It's not a cure, though. Everyone seems to relapse, and hardly anyone gets a complete remission out of it. My latest bone marrow biopsy shows CLL still present, and my spleen may have increased in size a bit. Nothing, though, that causes me any problems.

The average remission (which is in my case a partial remission) lasts 12 months for most CLL patients, and 9 months for those who have the 11q deletion, which is unfortunately my situation. However, one of the interesting things about Alvocidib is that is almost always works as well upon re-treatment. The treatment lasts eight months, and if I get nine months of remission, I could conceivably get eight plus nine months (17 months) for the first go-around, and another 17 months the second. This means I could perhaps get a total of THREE YEARS of decent health out of Alvocidib! For someone in my condition whose prognosis is regarded as 'grim', I think that qualifies as a miracle of sorts, thought Dr. T.H. probably wouldn't think so.

Anyway, I'm not cured, my CLL is still here, and my misguided use of FCR has made me much more vulnerable to MDS or Richter's, so I'm not out of the woods yet. However, at 12 months and counting after beginning Alvocidib, feeling good enough that CLL isn't pressing on my mind daily, is a great thing.

Would I do Alvocidib again? I'd say the pay-off is worth it.

An update

I have been feeling OK, though my WBC is still very low, and my hemoglobin and platelets are below normal.

I suspect that there is something awry with my stem cells. They are not producing enough of most everything. This is called marrow failure, which is a term that describes what is obviously happening, but explains nothing beyond that. Little is known about marrow failure, except causes. Radiation is one big killer of blood-forming stem cells (hematopoietic stem cells), chemical poisons are another. A third cause is...chemotherapy! In other words, FCR.

It is possible this would have occurred on its own, since CLL allows more cancers to grow unabated. But since my counts crashed on the fourth cycle of that toxic regime, it's definitely linked to FCR.

Folks, please think about avoiding FCR if you can. Reserve it for when you have relapsed and are looking at a stem cell transplant. The combination of the 'F' and the 'C' (fludarabine and cyclophosphamide (cytoxan)) apparently are a potent producer of marrow failure, aplastic anemia and myelodysplastic syndrome (MDS). All of these are killers (six months to two years). Knowledge of these cancers is about where CLL was in 1995. It's terrible.

There are many other options out there. I made a serious mistake, being encouraged to try it by MD Anderson and seduced by the high complete remission data, etc. But everyone eventually fails FCR, and then the prognosis is 'grim'. Learn from my lesson.

Meanwhile, Dr. Kipps has been silent. I've been sending my blood numbers to them down in San Diego, but I've not heard anything. I am going to be prepared for an MDS diagnosis by making an appointment to see a doc at Stanford, where they have an MDS center, and a robust (as far as I know) stem cell transplant center.

Penultimate Flavopiridol Treatment

It was my next-to-last flavopiridol (Alvocidib) treatment last Wednesday. I did probably the best I've done to date with the side effects.

I've been having nausea with every treatment starting mid-way through the eight-month treatment. This time was a little different. I started to feel queasy toward the end of the treatment. I was very late in getting the bags of the chemo; they were busy at UCSD and short-handed. So it was late in finishing up. My nurse Dan (who is great) took over when he got there (I think it was his late day or something; he did stay late).

But about an hour before I was released I started thinking I was going to throw up. Nothing happened. But I've noticed I've gotten some phlegm that starts going during the treatment. Anyway, I did finish the treatment without throwing up. Usually I make it to the motel before I throw up (if I do; it's about 50-50 that I do).

This time, I was 'unplugged' and going out the door when the nausea hit. I made it to the restroom at the Moores cancer center, but then I threw up. It's only one episode of multiple heaves (sorry for the grossness). Once I've thrown up, it's over for good. So I can't complain too much. And, to be honest, if I try to maintain, I just am nauseated for a longer period of time. So, just be done with it!

Once I got to the hotel, I was OK. I did have the diarrhea, but it wasn't too bad this time for some reason.

Fasting: I do fast the day of treatment. There is no reason to eat something, just to have it come up later. I also don't eat anything Thursday morning or afternoon. Believe me, I don't want to eat, so it's easy to fast.

Results look OK but I'm still dealing with low neutrophils, as a direct result of FCR. I wish I'd never done FCR.

Neutropenia

Since my unfortunate decision to undergo FCR (fludarabine, cyclophosphamide and rituximab), my neutrophil count has hit rock bottom, and pretty much stayed there. In fact, the low white blood count was the reason I only did four of the normal six cycles.

The neutropenia improved since January 2009, which coincided with the end of the four-cycle treatment. In the spring of 2009, I was on neupogen or neulasta for several months, with the low point being reached when my absolute neutrophil count plummeted to 106, well below the dangerous level of 500.

I did not need neutrophil support in the late spring, summer, and fall of 2009. However, beginning in late November, my neutrophils have dropped to dangerous levels again.

My counts are buoyed by the colony support factors neupogen/neulasta, with each course lasting 2-4 weeks. However, it may be that I am now neupogen/neulasta dependent, which is dangerous. Dangerous because artificially stimulating the production of neutrophils can lead to myelodysplastic dysplastic syndrome (MDS) or even the aggressive leukemia acute myelogenous leukemia (AML).

I'm hoping and praying that this does not happen.

Other than boosting my level of exercise, I know of no way to increase the production of the stem cells that were damaged by FCR.

That is one reason I have soured on the idea of using FCR. A well-known (though I had not heard of it prior to researching marrow failure) side effect of fludarabine in combination is secondary MDS, more difficult to treat than de novo MDS.

Live and learn. Though the learning might be easier than the living, if things go against me.

Even without MDS, I am perpetually at higher risk for infection being frequently neutropenic.

Not a happy place to be in.

OTOH, the flavopiridol/Alvocidib is still apparently working, though the side effects associated with the drug has not. I am scheduled for the last treatment in this fifth cycle on Wednesday, February 3.

Is FCR Losing its Golden Luster?

It's not been too long ago that I, among many others, dubbed FCR (fludarabine, cyclophosphamide, and rituximab) as the 'gold standard' in treating CLL. The basis for that claim was the fading significance of chlorambucil (Leukeran) in treating CLL, at least in the United States. (It remains a popular drug in the UK and elsewhere.) Also, monotherapy with fludarabine has been linked to autoimmune hemolytic anemia (AIHA) a serious complication of CLL that is characterized by the development of antibodies to a patient's own red blood cells. Combination therapies such as FCR, which add other drugs to fludarabine, appear to be free of the risk of initiating and promoting AIHA.

The complete remission rates of FCR, reported primarily out of MD Anderson, are extremely impressive, and far exceed that of chlorambucil. For example, at the 2007 ASCO meeting (American Society of Clinical Oncologists, a major cancer group), MD Anderson reported on the long-term results of 300 patients who were treated with FCR at the institution. The group reported that 72% of patients enjoyed a Complete Remission, 11% obtained a nodular PR (PRn) & 12% ended up with a Partial Remission. Saving the calculation, that is a phenomenal over-all response rate of 95%. In spite of the immune suppression associated with the drug combination, infections were manageable with prophylactic antiviral, antifungal, and antibiotic drugs.

However, the long-term survival pattern showed no plateau, meaning that the rate of death did not level off at any point, meaning that most if not all patients would eventually fail FCR. Quoting the study: "Median Times to Progression (TTP) were 80 months for CR (n=216), 80 months for PRn (n=32) & 27 months for PR (n=36), with 77%, 65% and 28% projected to be progression-free at five years; projected 5 yr survival were 90%, 81% and 37% respectively."

These data are superior to single agent fludarabine, and fludarabine in combination with cyclophosphamide (FC) or mitoxantrone (FM).
(www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=36113)

The down side? Well, it is not a cure, nor does it appear to have that potential. There are some very long-term survivors, out 10 years or more. But based on projections, it is possible, if not likely, that most everyone will eventually relapse. And even in the case of those who have deep, long-term molecular remissions (data not available in the 2007 ASCO abstract, but has been reported to be about 32% in complete responders, meaning the over-all MR rate is about 24%) it is expected that they, too, will fall out of remission down the line.
(http://tinyurl.com/lgxy3q)


So, what will replace FCR as the 'gold standard'? It must be noted that this is a moving target. For decades, chlorambucil was termed the gold standard, even though complete remission rates were only about 5-10%. Then single agent fludarabine took that exalted spot.

I think that the best initial treatment for CLL might very well be high-dose methylprednisolone plus rituximab (HDMP+R). I had a discussion with a couple of nurses at UC San Diego, where Dr. Kipps has a great deal of experience with the drug combination, and they said they just don't use FCR too much any more. Instead, they do a lot of HDMP+R. I have to admit that off-handed comments by several oncology nurses isn't definitive proof, but it is very interesting that, at least in one institution, FCR has seemingly fallen out of favor.

So what does HDMP+R have going for it? For one thing, it doesn't damage the bone marrow like fludarabine does. Fludarabine has a deserved reputation for enhancing the fatal rates of infection for up to two years. This is due primarily as a consequence of prolonged neutropenia. Grade 3/4 neutropenia were encountered in FCR. That makes the patient much more likely to have a serious illness, or even death.

First developed as a salvage regime for those patients with refractory CLL (and still used for this application), patients were given five cycles of the drug combination. It was not for the faint of heart. Numerous infections occurred and deaths were reported. The regime was tailored for a less-impacted crowd; as an initial treatment for CLL patients. The duration of the regime was shortened to three cycles.

A report in 'Leukemia' 2008 reported that in patients who were refractory to fludarabine and had adverse genetics, fully 93% of patients responded to the combination, and 36% had a complete remission. This compares favorably to the FCR regime. The paper states that median survival "has not been reached after a median follow up of 40 months."
(http://tinyurl.com/m9ropo)

There are also anecdotal reports that some patients who have completed HDMP+R have begun to normalize their immune system, as reported in a previous blog post here. That is simply astounding to me; I am unaware of this happy development in anything less than a stem cell transplant.

It also should be noted that adding a Campath 'chaser' to those who responded to the drugs, and did not develop bulky lymph nodes, may have enhanced responses.
(www.geocities.com/m_mcghan/ourpage.html?20066)


Another development in CLL needs to be reported as well: 'FCR-lite'. This regime seems quite promising, with good results in spite of the reduction of the dose of fludarabine and cyclophosphamide, and an increase in the dose of rituximab. Reports are that the side effects are lessened compared with FCR, and the responses seem to be (at least initially) almost on par.

The paper states: "The OR and CR rates were 100% and 79%, respectively, using the 1996 NCIWG guidelines and 100% and 77% using the 2008 guidelines. Median duration of complete response was 22.3 months (range, 5.2 to 42.5 months) and none of the complete responders have relapsed. Grade 3/4 neutropenia was noted in 13% of the cycles of therapy."
(www.jco.ascopubs.org/cgi/content/abstract/27/4/498)
(www.medicalnewstoday.com/articles/138141.php)

It must be noted this trial was in untreated patients, most of whom had early stage CLL (only 16% had stage 3 or 4 CLL). (I'm not sure why a stage 1 CLL patient was even treated, but 40% were here.) That might be considered 'stacking the deck', and making comparisons with FCR and HDMP+R difficult if not impossible.

The bottom line: It may be premature to dethrone FCR as the gold standard, but recent advances in research suggest that we might need to rethink exactly who's on top in caring for CLL patients.

Should you fast before chemo?

There is evidence that you might be doing yourself a favor it you do.

Me? I'm so addicted to food that when I fast, all I think about is food. I could fast one day. Two days? I've had to do it before a colonoscopy that I had late in the day one time. All I could think about was food.

I think it would be worth a try!

I'm through with FCR, so this advice comes a bit late for me.

When it's your life, this might be something to at least run by your onc doc.

Stable, so far

Two plus months from my last FCR cycle, my marrow is damaged, but I am doing OK in spite of that. I've managed to avoid infections (knock on wood) and am working and carrying on a relatively normal existence.

I still have low platelets, low WBC, am neutropenic, but as of the results of the last blood test I've seen shows, the hemaglobin has come back and is now in the 12.5 range, which is a lot better than the 7.9 range I was in last fall.

I see Dr. Kipps later this month. I'll have a BMB and get his usual thorough exam. I know I have not had a molecular remission, nor a complete remission, since I still have enlarged nodes. We will see what kind of partial remission I'm in.

One unfortunate note is that we are dealing with a sick dog. He has been diagnosed with hemangiosarcoma, which is a cancer of the blood vessel cells. He has a massive spleen that could rupture with fatal results at any time. We've been offered surgery with the hope he may live another few months, but since he is 16, has an undetermined secondary mass in his stomach, we probably won't put our old guy through that.

Spring has come early again to Sacramento, with the fruit trees blossoming with all vigor.

Going on from here

Since my counts haven't recovered, we've stopped pretending that I'm going to get my fifth and sixth cycle of FCR. It has been rather stupid the way the infusion center has been handling it; I've gone in three straight weeks, been hooked up to the IV line, and then they draw blood, find out my counts are too low, then they apologize all over the past and are sad my counts are horribly low, etc., then I change plans and go into work. I should have gone in the day before, had a blood draw, then they could have called me

I go to the infusion center prepared with a giant bottle of Gatorade (2 liter), partially frozen to stay cool all day, a few of my 'Issac Asimov's Science Fiction Magazine', which I have been buying in bulk from e-bay. It's a lot cheaper than to buy the latest versions, so I save money. It's also interesting to read a magazine from the 1980s, when Reagan was still president, Islamic terror attacks weren't a problem, gas was $1.25 a gallon, when Asimov was alive, when I didn't have cancer....

The stories are timeless, though. There are some topical references of course (computers weren't as ubiquitious in the 80s, there was no internet, 'green' meant what you ate for dinner, and so on). But by and large, the stories remain quite readable and enjoyable. Asimov's is one of the primary place for future award-winning stories and authors to appear. Some are clunkers, of course, but many are enjoyable and a few outstanding.

It makes the time go by quickly and pleasantly. Sometimes my wife sneaks a treat into my backpack. This time, it was M&Ms. Thanks, Sweetie!

Getting back to the CLL... I see the local onc doc (who I guess is a hematologist, but who sees, obviously, few CLL patients) on Monday. We will discuss what to do from here. My guess is...nothing. I suppose we will track my counts for the next months, pray I don't get sick, and just soldier on until the inevitable happens.

My counts are truly terrible. My neutrophils were only 0.5 on February 2, 0.9 on the 9th, and back down to 0.6 on Wednesday the 20th. My platelets have never recovered either, but truth be told, my platelets haven't broken 100 since about 2006, when I had the high-dose methylprednisolone plus rituximab. (I was looking at some old test results I've kept, and my platelets shot up to something like 876 for one test, before settling back down to the low 100s, and then declining from there. Currently, they are in the low 70s. Everyone else besides the onc doc freaks at those numbers.

Oddly, my hemaglobin has remained decent. Below normal (what else is new) but decent. As I remember they are about 12.5 or so. Certainly no difficulties at this point in time with that.

My abdominal nodes are still there. I don't think they've changed one bit during the FCR. My other nodes have largely disappeared, which is nice. I HATE having nodes. I hate it. It's an ever-present reminder of my disease. I acquired the 11q deletion after the HDMP+R trial I as on in mid-2006. Not a pleasant thing to have. The abdominal nodes can be quite painful at times.

I have been tired, but that's something we CLLers always face. I have been trying to do a bit more exercise, since that is important for over-all health and can't hurt as I try to get my marrow to recover.

I see the CLL expert in San Diego in late March. I was supposed to have finished the six cycles by then, but obviously that's not going to happen. I want to ask about maintenance therapy. Many papers have suggested that rituximab, Campath, or Revlimid can be used to help prolong complete and partial remission. Sometimes, maintenance can even push a partial remission into a complete one. I'm not a candidate for Campath with my 'massive' abdominal nodes, and Rituxan would probably be nixed for that as well. Revlimid may be a possiblity, and since they've lowered the dose to 1/10 what they started out with, side effects have declined and tolerability has improved. This is my preference as of now.

I also am scheduled for a bone marrow biopsy in San Diego. I will pray that it comes out improved, or at least not gotten worse. It's going to be a stressful time, not only psychologically, but physically since the biopsies have gotten more and more painful as time has gone on. I hope I can get some pain medication this time!