Benchmarks
We all use benchmarks in our everyday life, to make decisions without having to spend too much time thinking about things. Should you replace the tires on your car? Is it time to change the oil? There are reliable benchmarks for those decisions, making life easy for those of us who do not spend a lot of time thinking about our cars.
How about when to let your kids start driving? Now, that is a very much more nuanced decision and few good parents will rely solely on slam-dunk benchmarks. Age is one of the points that influence the decision, but most likely you will also consider whether the kid has sufficient maturity, whether you just found a stash of drugs in his bedroom, whether he/she is keeping up his grades in school etc. When to start CLL treatment falls into the second category, a little more important and complicated than when to change the oil in your car.
When is it time to start treatment?
Let us face it: local oncologists are very busy people. Majority of them treat a huge variety of cancers, including “solid” cancers like breast cancer, prostate cancer, lung cancer etc. With any luck your local guy sees a small number of blood cancers in his practice. Of these again many would be non-Hodgkin’s lymphoma, multiple myeloma etc. I doubt the average local oncology practice sees more than a couple of CLL patients on a regular basis.
What are the chances your local guy is going to use tried-and-true benchmarks to make therapy decisions quickly, rather than spend a lot of time worrying about subtle nuances that may be valid in your case? I think you get my drift, it is important that we understand the benchmarks a little better, dig down and get into the details so that we can make better choices when it comes to therapy time. Even if your local oncologist did not initially focus on the pesky details, perhaps you can get him interested if you ask the right questions, make therapy decisions that are a bit more tailored for your specific situation. Remember, in life and in CLL, the quality of care you get often depends on what you can knowledgably negotiate.
Rai and Binet Staging
No benchmark has more importance than staging, when it comes to CLL therapy decisions. Rai staging is used in the USA while Binet staging is used more often in Europe. Both are quite similar in the kind of things they focus on. Please refer to our earlier and detailed articles on the subject to get the exact features that go into defining the various stages in Rai and Binet systems. I strongly advise you to do so, since in this article I will focus entirely on late stage CLL. For your convenience the links to earlier articles are given at the end of this review.
Stage 4 (Rai) or Stage C (Binet) CLL
Whether you are using Rai or Binet staging, it goes without saying that late stage patients have multiple swollen lymph nodes and elevated white blood counts; perhaps they also have swollen spleens and livers. All of that is baked in the cake for late stage (Rai Stage 4 or Binet Stage C) patients. The big deal about late stage CLL are reduced platelets and red blood cell counts. Late stage CLL, the kind that gets your oncologist talking about time to start therapy, focuses on health of your platelet counts and your red blood cell parameters.
New platelets and red blood cells are made by blood stem cells in your bone marrow and no place else. As CLL progresses, the bone marrow is gradually infiltrated by CLL cells. In late stage CLL, the bone marrow might get so clogged with the useless CLL cells that there is no place left for proper function of the stem cells residing in the bone marrow. The result is that the marrow begins to experience increasing difficulty in manufacturing platelets and red blood cells. Think of these cell lines as the canaries in the coal mine. When the canaries begin to drop dead, an indication or too many toxins in the air, it is time for the miners to get out.
Same logic goes for using platelet counts and red blood cell counts as the trigger point for defining late stage CLL, end of “Watch & Wait” and start of therapy to roll back the CLL. Low platelet counts means clogged marrow unable to function, which in turn means you are Rai Stage 4 (Stage C Binet) and you had better get moving with therapy soon. Makes sense, right?
Not always. What if the low platelets and red blood cell counts are not due to a bone marrow clogged by CLL cells, but some other reason? This is where it gets interesting, where the tried-and-true benchmarks of Rai and Binet fail. Unless your local oncologist is paying attention and looking beyond slam-dunk benchmarks and looking for the reason why your platelet counts are low, you may be initiating the wrong therapy, for the wrong reasons.
Devil is in the Details
Let us get rid of some of the trivial reasons for low platelet counts right up front. Platelet counts are notoriously prone to measurement errors. Platelets tend to form clumps. That is their whole purpose in life, form clumps and clots, gradually slow down blood flow and prevent too much blood loss when you cut yourself shaving. That tendency to clump together makes it difficult for automated machines to count platelets accurately. A clump of platelets in the field of vision could be a single platelet, or it could be three or four platelets getting together and singing Kumbaya. How is a poor automated CBC machine to know the difference? Many labs follow up on an abnormal platelet count reported by automated machine with a manual check where a real live human being looks at the slide and counts the little suckers. As you can imagine, it is not all that hard for a trained tech to spot the clumps and make the proper adjustment to the counts reported.
We discuss this and many other trivial and not so trivial reasons why platelet counts may dip below the usual 100K specified for normal healthy range in our earlier articles. Heaven protect us from thoughtless / lazy oncologists who believes in therapy by numbers, using benchmarks without putting brain in gear first. I just heard from one patient whose doctor said he would start therapy the first time he sees platelets in the 100-125K range. How many ways is that plain stupid?
Excuse me Dr. Oncologist, but patients from some ethnicities have chronically low platelet counts. My husband was one such. Even prior to CLL diagnosis his platelet count was never much higher than 150K. The smart hematologist would pay attention to factors like that, look for robust and clear downward trend lines in platelet counts before making therapy decisions. If a patient started with healthy platelet counts and over a period of several months there was a clear and unmistakable trend downwards below healthy norms, then it is time to get excited. Please know that there is no immediate danger in low platelet counts. Chances are not high that you would immediately bleed to death if you get a small nick while shaving. No responsible doctor would initiate platelet transfusion unless the count goes below 25K or so, most often not until it gets into the teens. No experienced CLL expert would initiate therapy based solely on a single platelet count of between 100-125K, no other questions asked.
Autoimmune disease and CLL
Most of you know by now that there are two particular autoimmune diseases that happen frequently in CLL. The first and more common one is AIHA (autoimmune hemolytic anemia) – where perfectly good red blood cells are destroyed by your own immune system gone a little crazy and no longer able to tell the difference between friend and foe. The second is ITP (immune thrombocytopenic purpura) – where the immune system attacks and destroys good platelets before their time. Both of these autoimmune diseases are well documented in CLL and we have discussed them in earlier articles.
AIHA and ITP can cause devastatingly huge drops in red blood cell counts and platelet counts in a matter of days. AIHA is especially hard to miss. The sudden killing of all those red blood cells means an immediate onset of potentially deep anemia. You will no doubt experience some of the symptoms of your body struggling to get enough oxygen to the tissues without enough red blood cells to do the job properly: weakness, dizziness, difficulty going up the stairs, pounding of your heart and a startling deep reddish brown urine in the toilet bowl – colored by fragments of zillions of red blood cells killed – these are just some of the symptoms of sudden onset AIHA.
Both AIHA and ITP are serious issues that require careful intervention. No question about that. But here is the million dollar question: Do low platelet counts and/or red blood cell counts due to autoimmune disease have the same impact on CLL staging, compared to a clogged bone marrow unable to produce the platelets and red blood cells in the first place? Which is truly late stage CLL that generally requires initiation of therapy to control the CLL?
“Stage C or not Stage C”
That is the pithy title of the editorial in the recent issue of “Blood” journal, discussing the full length article on the same subject published in the same issue of the journal. You can read the editorial for free by clicking on the link. The abstract of the article it refers to is given below. Write to me if you wish to read it in full and I will show you how to get hold of it.
The authors had three major goals of this study: first, to get a handle on the prevalence of autoimmune disease (AIHA and ITP) in general CLL population; second, understand if patients with bad prognostic indicators are more likely to have autoimmune disease as well; last but not least, understand how cytopenias (low red blood cells and / or platelets) due to autoimmune disease compare with similarly low counts due to heavy infiltration of the bone marrow.
Blood. 2010 Aug 24. [Epub ahead of print]
Autoimmune cytopenias in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance.
Institute of Hematology and Oncology, Hematology Department, Hospital Clinic University of Barcelona, IDIBAPS, Barcelona, Spain;
We analyzed the prevalence, characteristics, clinical correlates, and prognostic significance of autoimmune cytopenia in patients with CLL. Seventy of 960 (7 %) unselected patients had autoimmune cytopenia, of whom nineteen were detected at diagnosis, three prior to diagnosis and 48 during the course of the disease. Forty-nine patients had autoimmune hemolytic anemia (AIHA), 20 immune thrombocytopenic purpura (ITP) and one both AIHA and ITP. A clear association was observed between autoimmune cytopenia and poor prognostic variables (i.e. high blood lymphocyte count, rapid blood lymphocyte doubling time, increased serum beta-2 microglobulin level, and high expression of ZAP-70 and CD38). Nevertheless, the outcome of patients with autoimmune cytopenia as a whole was not significantly different from that of patients without this complication. Furthermore, no differences were observed according to the time at which cytopenia was detected (i.e. at diagnosis, during the course of the disease). Importantly, patients with advanced (Binet C stage) disease due to an autoimmune mechanism had a significantly better survival than those in advanced stage related to a massive bone marrow infiltration (median survivals: 7.4 years vs. 3.7 years; p=0.02). These results emphasize the importance of determining the origin of cytopenia in patients with CLL for both treatment and prognostic purposes.
PMID: 20736453
For a change, this abstract is relatively easy to read and understand. That last couple of sentences in the abstract say it all. Here is the annotated version, to make sure you get the important points.
- Roughly 7% of CLL patients have to deal with autoimmune AIHA or ITP. A very small percentage have both!
- Patients with poor prognostic indicators (positive CD38, ZAP70; high B2M) are also more likely to have autoimmune disease during the course of their CLL career.
- In general, autoimmune disease did not decrease overall survival statistics much. Median overall survival for Stage A patients who went on to develop autoimmune disease was 9-10 years, same as for patients who did not develop this complication. You guys out there with AIHA or ITP, breathe easy. No extra penalty points for your autoimmune disease, according to these researchers.
- The “why” of low platelet or red blood cell counts (“cytopenias”) is important in properly staging CLL. Low counts due to autoimmune disease is not the same thing as low counts due to significantly infiltrated marrow.
- Patients who are “Stage C – autoimmune” are likely to live quite a bit longer than those with “Stage C – infiltrative”.
- As the graph below points out, the median survival of “Stage C – autoimmune” is more than 7 years. For “Stage C – infiltrative”, median survival is less than 4 years. Of course, these are statistics based on this large cohort study. Your own mileage may vary, depending on your own specific situation.
- In fact, a patient “Stage C – autoimmune” can be treated for that (with steroids such as prednisone, IVIG, Rituxan etc) and once the autoimmune disease is under control, the patient is often no longer in Stage C, may be kicked downstairs back to a more reassuring Stage B or even Stage A.
The graph below shows the survival probability of patients over time, depending on their staging. For your convenience, they have drawn a horizontal line across at the 50% level. Where it cuts the different curves gives the median survival (Median survival means 50% of the patients are alive at that point, 50% are dead). As you can see, the blue line representing early Stage A patients cuts the median line at about 10 years. Next in line are the Stage B folks, red curve in the graph below.
The shortest time (roughly 4 years) is for “Stage C – infiltrative group”, the full black curve right at the bottom. This group is the truly late stage CLL folks. Above that is the broken black curve, for “Stage C – autoimmune” folks. They have below normal platelets or red blood cells due to autoimmune disease, not because they have infiltrated bone marrow. These guys fare a lot better than the “Stage C – infiltrative” folks, with a median survival of more than 7 years.
Treating autoimmune disease versus CLL control
Game plans for controlling autoimmune disease are very different than those for cleaning out a heavily infiltrated bone marrow. Autoimmune disease is usually handled by daily doses of steroids such as prednisone. Splenectomy (surgical removal of the spleen) is often surprisingly effective in reversing the ravages of autoimmune disease. When (if) the patient develops resistance to prednisone therapy, it is usual to initiate Rituxan therapy as a single agent or in combination with dexamethasone (another steroid like prednisone) and / or cyclophosphamide, vincristine etc. Sometimes intravenous immunoglobulin infusions (IVIG) help.
While the onset of AIHA or ITP can be very sudden and the symptoms scary as all heck, we do have methods of handling them and their onset does not significantly influence overall survival odds. On the other hand, low platelet counts and low red blood cell counts because the bone marrow is heavily infiltrated and the blood stem cells can no longer produce these cell lines – that is indeed the definition of late stage CLL requiring end of W&W and start of therapy.
For example, when the bone marrow is no longer working, there are only two ways of having enough red blood cells for your body to keep breathing. A quick but very short term way of getting around the problem is a red blood cell transfusion, getting red blood cells from blood donors to do the job for you. Transfusions are not a long term solution. In a matter of days patients will need another transfusion because the previously infused cells have died on the job. Patients who are transfusion dependent face huge difficulties of many sorts – trust me, you don’t want to walk in their shoes if you can possibly help it.
The second option is to clear out the bone marrow, kill most of the CLL cells messing it up, so that the marrow can get back to work. Since no one wants to become transfusion dependent, the real option for late stage CLL is just that: start therapy to get rid of the CLL cells in the bone marrow, so it can get back to work.
Getting the bone marrow up and working is the major reason for start of therapy. The white blood counts in the CBC reports that patients get fixated on are not really all that important and even the ugly swollen lymph nodes can be ignored for a while. The bone marrow and the precious blood stem cells living there – these are the truly unique resource of your body and no one can live long without reasonably good functioning of the bone marrow.
Someone is bound to ask me the question, so I will address it right away. How about when therapy fails and the bone marrow gets re-infiltrated? Does this not make therapy as an option of clearing the bone marrow just as temporary? You bet. Everything in life is temporary, my friends. In the end, all of us die. That is the only real guarantee in life. The real question is not whether it is temporary, the real question is how temporary. Running in front of a speeding truck is extremely temporary. Transfusion dependence is very temporary. Chemotherapy that gives you a deep and long remission is a whole lot less temporary. Not doing anything when you are in late stage CLL, whether it be due to autoimmune disease or infiltrated bone marrow? Now that falls into the category of very temporary indeed. Not quite as quick as running in front of the truck, but a close second.
One approach does not fit all late stage CLL
I hope I have convinced you why proper staging of late stage CLL is important. We have now learned there are two distinctly different versions of late stage (Rai Stage 4 or Binet Stage C) disease. Treating “Stage C – infiltrative” with daily doses of prednisone is hardly the right thing to do. It will not do much to relieve the over-crowding in the bone marrow and get it working properly again. Single agent Rituxan does not do a whole lot either for getting good marrow clearance. What will get the marrow clear is more heavy duty options such as chemoimmunotherapy combinations (FCR, FR, PCR etc) or newer therapy options such as Revlimid, CAL-101 etc.
On the other hand, autoimmune disease (AIHA, ITP) are reasonably controlled in most patients with nothing more than prednisone or single agent Rituxan. Relapsed autoimmune disease that has become resistant to these two frontlines may need couple more things thrown at it. But I hope you agree it is not reasonable to initiate full blown FCR therapy as primary control for taking care of “Stage C – autoimmune” disease. There is no doubt that autoimmune disease is scary and its long term control is complicated. But it is important that we do not confuse the low counts resulting from autoimmune disease with low counts due to heavily infiltrated marrow. Different reasons, different causes, different prognoses and different methods of best treating them. They why is important because it gives us a better handle on how to treat it, and with what.
Below are some links to previous articles on this subject that you may find interesting. I have given the dates of publication in parenthesis. Oy vey! I have been writing this stuff for too many years! This lot should be enough to keep you busy reading for a while.
Staging Does Not Predict Survival (2003)
CLL Staging: Dawn of a New Era (2005)
CLL Staging: Devil is in the Details (2010)
When Platelet Counts Start Dropping (2009)
Splenectomy to Control Autoimmune Disease (2009)
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24 comments on "Late Stage CLL"
Thanks Chaya,all that invaluable information you’ve given us over the years, please keep it coming.
My question is, are there any survival statistics for second time treatments? All the figures seem to be for first time treatments only. Although these look promising for long remissions for FCR, I wonder what the prognosis is for 2nd and third time round chemo?
Molly:
Patients who have relapsed after first round of chemoimmunotherapy such as FCR, especially if they got only a shallow response that lead to a short remission, do not have a great many good choices. Please look up an earlier article titled “Life after FCR”. Very often the best “salvage therapy” option for such patients is a mini-allo stem cell transplant.
Of course, some patients who relapsed after a nice long remission following FCR continue to have good response to second and third round therapies. I think a lot depends on the individual situation, whether clonal evolution has taken place since the first FCR therapy.
One of the reasons why we do not have robust survival statistics for FCR relapsed patients is that FCR is a relatively new approach and many patients get long remissions from it. It will be awhile before enough numbers of post-FCR patients are available who have then gone through second line salvage therapy and then relapsed for a second time.
Although late stage, I don’t fit into the mold here. AIHA yes, for 2 years now and very scary. Everytime the steroids were reduced the AIHA came back with a vengence. My spleen was removed in July this year and it was thought to be working. My PLT were as high as 611 at one point. Then the symptoms of AIHA came back, together with a chest infection and I was hospitalised again. My RBC was 75 and I needed another transfusion. So my splenectomy failed and I am now on Azathioprine (an immune suppressant) running together with Prednisolone in the hope that the Azathioprine will take over from the steroids. We will know if this is working by Christmas. I think perhaps it’s not. I am also having a lot of breathlessness and am having lung function tests this week. There is not a lot of mention anywhere of splenectomy failure and further treatment for AIHA. My WBC is currently about 73,000. I am now in my 11th year of CLL with FC, Campath and FCR behind me.
Chaya…First…a little rare, long overdue compliment from me…
Keep up the good work. I don’t reply often anymore as I’m still in remission, and don’t have a lot of questions. But don’t let my lack of response fool you into thinking I don’t read every article with great interest, and pass on those I think may interest friends and family.
Your latest article above helped me to understand what I hope were the reasons that my doctor progressed with my treatment the way she did. I first had MCD (Minimal Change Disease) in 2005 (a year after I was initially diagnosed with CLL) and then a year later, AIHA. I was successfully treated with massive doses of prednisone for both (my neighbor, who was a doctor at the U of R, was concerned that the dosage may have been TOO high! Thankfully, he was wrong!). That was followed a year later with PCR, which when that was over, was followed with Campath.
I had all the negative prognostic markers, although my platelets never got below 96. Including a very high cholesterol count over 440 (no typo…440…it returned to my normal 185 after the prednisone had fixed the MCD).
Neither the anemia or the kidney problems have recurred (and so far, the CLL either), so I have to believe my doctor knew (or guessed) the effect this sequence of treatment would have…even five years ago when it all started with the MCD.
I tried to keep her informed of everything of interest that I was finding out from your websites, thinking that I may have been introducing something new, but looking back on it all now, it looks like she’s been keeping on top of things despite (or maybe “because of” ) my suggestions. She is a hematologist at the U of R, and she and her team do treat a good number of CLL patients. From my experience they had already seen a number of the reports that you’ve mentioned. We still do discuss the pros and cons of topics I bring up.
I want to thank you again for putting this complex disease, and equally complex treatments, together in a way that we can all understand it, and in a form where we can confidently discuss it with our doctors. I’m glad I found you! Keep it up!
When scientists cite “median survivals of 7.4 years vs 3.7 years” for Stage C autoimmune and Stage C infiltrative, do they mean with or without treatment? Thanks.
Chaya,
Thank you for your timely article, always full of valuable information.
It is so kind and thoughtful of you to keep us informed.
I continue to look forward to your articles.
As Always, Many, many Blessings.
Rita
Manhatten:
That would be 7.4 years and 3.7 years respectively for patients after they reached Stage C – autoimmune and Stage C – infiltrative respectively, with appropriate treatment in each case.
Since a good deal of time passes in W&W and more time passes while the patient gradually progresses from Stage A through Stage B and finally Stage C, the total of all that time plus the 3.7 years post therapy after Stage C – infiltrative adds up (roughly) to the median overall survival of about 10 years we are seeing in CLL population.
The thing to focus on is that these are population statistics, how the odds add up for the general group of CLL patients. I don’t want any of you looking at these numbers and thinking it defines your personal scenario. Each man is a unique individual, a statistic of one, and as I like to put it, your mileage may vary depending on your particular situation.
The good news to recognize too is that just a while ago the slam dunk median survival for CLL in general was 7 -8 years. Now it has become 8-10 years. That is a two year improvement in overall median survival for the community at large, nothing to sneeze at.
I really need help deciding my first-time therapy. I am 78 yrs, had a heart attack 2 yrs ago(3 stents) and in for more evaluation this week owing to abnormal stress test. I have squamous cell carcinomas removed every 3 months or so for past several years and also have glaucoma.
I was diagnosed with CLL in 1996, my WBC is now 212, platelets 81 and hemaglobin 10.8(chart shows slow downward progression over time of platelets and hemaglobin) Am on plavix and baby asprin so no clumping of platelets skewing the count. My oncologist suggested Fludarabene + rituxan, or CVP or bendamustine. I am concerned about tumor lysis syndrome – would it be better to start on the less toxic, take-at-home chlorambucil to get a slower kill of WBC (together with allopurinol and an anti viral since I could get shingles a second time) or do I choose the best bang for the buck? That paper on the elderly with comorbidities suggested chlorambucil. I want quality of life for whatever my remaining years are. I am active during the morning but wiped out rest of day. PLEASE HELP WITH COMMENTS AND/OR ADVICE.
Heather
Dear Chaya,
Thanks a lot for the wonderful articles and support you render to all of us fellow CLLers. You have a special gift of explaining complex and sophisticated things in a clear way. This article is just another example.
I’ve been following your articles since 2002 when I was diagnosed at Stage I with 13q14 deletion and 16K WBC. Since then my CLL progressed to 170K WBC (140K Lymph)in March this year (a rapid surge from 70K in 18 months), swollen lymph nodes (not much really) and reduced platelets (140K). My doctor insisted on immediate treatment and I started chemo in March with R-FMC scheme (Rituxan, Fludara, Mitoxantrone, Cyclophosphan). My WBC dropped to 60k after the first round and after the second round – to 1.7K (100 times!). However, my platelets followed suit – dropped to 70K. When the time came to start my third round my doctor and the head of the hematology deprtment of the clinic I was treated at told me that they will not start the third round unless my platelets get back to a safe level. That was in late May. I did not get any therapy since, my WBC counts are climbing slowly (or not so slowly) and are now at 20K. My platelet count is currently at 110K. My RBC has always been in the normal range. My lymph nodes are not felt or seen. My cytogenetics was checked in November and was found unchanged – 13q14. The doctors in the clinic say that my platelets are still too low to continue chemo. They put me at Stage 2 now (despite the platelets). One option they are contemplating now is leukeran – to keep my WBC down. I am at a loss and do not know – should I turn to another clinic or follow the advice of my doctors (they’ve been monitoring me for almost 9 years).
Julia Rastopchina, Russia
Chaya,
Thanks for the article; it clearly lays out what I may have ahead of me- at some point in the near or somewhat distant future. Based on your paragraph below I have several “questions”:
“Single agent Rituxan does not do a whole lot either for getting good marrow clearance. What will get the marrow clear is more heavy duty options such as chemoimmunotherapy combinations (FCR, FR, PCR etc) or newer therapy options such as Revlimid, CAL-101 etc.”
1. Are the newer therapy options (Revlimid) really an option at this point as front line treatment or are they only available in select clinical trials? What level of damage do they do to the bone marrow?
2. Is the likely current medical preference of going with the proven approach (FCR etc.) based on a medical paradigm that needs to change and embrace newer approaches quicker or at least offer the patient that option? It is clear to me that there are no definitive answers on CLL and each case is different so how do we make sure each case is viewed that way?
3. Might not there already be drugs available that make Wait and Watch the suboptimal approach? Are there any clinical trials readdressing this question?
Thanks to you and all others on this site for allowing me ask questions and be able to make educated decisions as my CLL journey takes off….
Dear,dear Chaya,
This article is definitely an indepth response to my concerns that I recently asked you about. I do thank you for posting this info as doctors really cannot convey all that a patient needs to know in time allotted to them. Enjoy the holidays…..you are doing a wonderful service.
Thank you Chaya for the priceless information that your updated letters give us.
Stay well,
Monique
Interesting article. Stage C infiltrative can mean different things to different doctors. I consulted a CLL specialist after my hematologist suggested starting treatment due to falling platelets (100 to 80 range over nine months), while being otherwise asymptomatic except for fatigue, with ALC in 25K range and Hg normal at 15. BMB revealed a 70% infiltration of the hypercellular marrow (80% overall cellularity) with decreased normal trilineage hematopoiesis, presumably the source of the falling platelets.
The CLL specialist suggested waiting further but my hematologist recommended moving forward with FCR, since it would depress platelets and it would be safer to start treatment from a higher level.
I ultimately followed my hematologist’s advice and just completed FCR with platelets falling to a measured low of 44 during treatment. Looking back, I am glad we initiated FCR rather than waiting further as I experienced two febrile neutropenia (neutrophils at a vary healthy level prior to treatment) and one anemia event caused by FCR.
Also my B2M had been steadily increasing to 4 prior to treatment. I am recovering slowly and am glad it is all over.
I hope you will cover PCR and T-cell measurement after FCR treatment in a future article. Keep up the good work !
Thank you for your ongoing work that keeps us informed.
This article really hit home for me. And because of it I have some questions. I was classified as indolent, no bad markers, except for 13Q, mutated, and negative for Zap 70 and 38.
My lymph nodes on both sides of my neck began to swell about a yr ago. This spring a CT scan revealed to abdominal nodes 5-6cm. Around July I decided to get off the cymbalta that I was taking and thought I was having a reaction to that – severe dizziness that curtailed anything I was doing. My onc. dismissed the deep circles around my eyes as allergies. Went to my pc and started a regimen of Levaguin along with Mucinex (there were alot of allergens at the time). Had my blood drawn.
What is confusing to me is that my WBC had fallen into normal range but my platlets had fallen from 97 to 47 in 3 months and it showed anemia. (My onc. told me that we would have to watch my platlets – no question there). Last week I had my blood drawn again – platlets 57 but more anemic, spacey, weak, and can feel my heart pounding, and resting pulse 80. I was thinking of AIHA but my onc. said no to that because the heptoglobulin was normal. My B2M was only 3.9 and my LDH was lower than normal. However, my onc. did say that I will probably go into treatment in about 3 mo. I am going in for a CT scan this coming week (I know too much radiation is not good but for abdominal nodes, how else can you tell what is going on?) My spleen is enlarged and he wants to find out how much. He did say that my bone marrow is packed (no BMB)
Now, after all that history, what I am thinking is that the Levaquin precipitated all this.???? Thrombocytopenia is one of the side effects. Is it possible to recover to previous labs if I wait long enough?
I do trust my onc. because he does have a lot of experience with this kind of Leukemia (live in the heart of cancer country-La.)I was going to try to make it to a specialist but don’t think I could make it the way I am feeling. And he does consider how robust you are feeling.
Thanking you for any comment that you would have. Sorry to make this sooo long.
Heather:
You are very right to focus on quality of life issues in deciding upon therapy options. Age is an unavoidable consideration, as are existing other health conditions.
Relatively high WBC, but more importantly a gradual decrease in platelet count and hemoglobin levels points to a “Stage C – infiltrative” disease, which needs to be treated. Clearing out the bone marrow would certainly help with restoring better function of stem cells, which in turn will hopefully address the anemia issues and therefore improve the quality of life.
From what little I read of your situation, chlorambucil is an entirely valid approach. It may not give you a deep or very long remission, but most people think it is relatively easy to tolerate. Bendamustine and fludarabine containing combination regimens are pretty potent and not always easy to tolerate. I am not sure how your local oncologist sees it, but to my mind you may be considered ineligible for FCR – both on account of age and comorbidities.
I worry that we are giving “glib” answers and pat advice in complicated situations. If I may make a suggestion, please send an email to Dr. Terry Hamblin. He is a world-class expert, very well informed about the right scenarios for chlorambucil use and generous about providing pro-bono help (even while he is going through chemotherapy himself!). Send me an email Heather, if you do not have his email address.
Juliaras:
FCR + Mitoxantrone is pretty aggressive choice of therapy, no wonder your counts have taken a beating. This combination was tried at M. D. Anderson a few years ago (you can look up our reviews of it on http://www.clltopics.org, seach for key word mitoxantrone). Their recent paper said there was no increase in response rates over FCR, but the mitoxantrone may likely have added to toxicity issues.
One of the balancing acts is to pick a therapy that the patient can tolerate, so that all cycles of proposed therapy can be administered. If the regimen is so potent that it has to be discontinued after just two cycles, that is not a good balance, since it leaves the patient half-way to a good remission.
I am not suggesting you leave your doctors that have been taking care of you for 9 years. But it may be appropriate for you to get better informed about your therapy choices and become more actively involved in the decision making. No doubt your doctors would also feel more comfortable administering mutually agreed upon regimens. I am not familiar with Russian healthcare systems so I cannot suggest specific options for your consideration.
Marathon:
CLL is a rapidly changing field. Drugs like Revlimid are gradually making their debut, both as single agents and in combination with other drugs. While still in clinical testing, Revlimid is also available outside of clinical trials. My husband PC had Revlimid therapy after FC-ofatumumab failed completely in his case. He had Revlimid outside of clinical trials and a three month regimen got him an excellent response. That was in 2008. I guess it is a matter of what you can negotiate with your doctor and your insurance company.
No doubt the FCR as gold standard paradigm will change as we get more clinical trial results and more therapy options.
With the exception of the Revlimid chemoprevention trial approach for high risk patients that we reviewed on this site, there are few drugs that make W&W sub-optimal in early stage CLL patients. There is always EGCG (green tea extract). Drugs such as perifosine (also reviewed on this site) may be an exception to the W&W rule, when and if we get positive results to their clinical trials. Until and unless we get drugs with high efficacy with low toxicity, there is not much reason for treating early stage patients. W&W is still the best choice for early stage and unsymptomatic patients – it does the least harm. Down the road some of the kinase inhibitors in clinical trial right now (CAL-101, for example) may fit the bill of high efficacy and low toxicity enough that W&W becomes an outmoded approach. We are not there, yet.
roserd:
I tend to agree with your oncologist, for what that is worth. I think your low platelet counts and obvious anemia – even the relatively low white cell count – are the result of a highly infiltrated bone marrow. Broad spectrum cytopenia of this sort is usually due to bone marrow dysfunction. In your case this dysfunction is probably due to massive infiltration. Therapy chosen for its ability to reduce bone marrow CLL infiltration should help restore proper function, which in turn means the stem cells can start making all the cell lines needed for health and life. Yes, levaquin is immune suppressive. But the situation is well beyond that now, and I am willing to bet your oncologist has it right, it is a case of heavy CLL infiltration of the bone marrow.
roserd
Whilst your oncologist and Chaya may well be correct, if I was in your position (and I am a CLL patient not a doctor) I would wish to be more certain that my low platelets/anaemia were indeed due to bone matrrow infiltration. If I was in your position I would do all I could to seek a second opinion from a specialist haematologist (eg Dr Hamblin)
Regards
Antony
roserd
In reading your post I had a similar response to Antony above. If I were you, I would get a second opinion from a CLL expert: arrange for him/her to obtain a BMB and then get their opinion. It would seem the best way to confirm marrow infiltration is by a bone marrow biopsy, which when done by an experienced technician, is not to be feared. And if it is confirmed as infiltration, then you also have a baseline for measuring part of the success of your CLL treatment. If it isn’t infiltration, then that expert may have other treatment ideas. I’m just a patient, like you, but want all of the measurable parameters on the table before making a treatment choice.
With such outstanding articles and before my comments on the topic I would hate to have Chaya need to ask subscribers for money so that we may all benefit from her wit & wisdom not to mention the time she has to put in to keep up on all things CLL. After this post I’ll be showing my appreciation with a donation.
As Chaya points out, the numbers aren’t the whole story and doctors vary in their approach to treatment. I never had “B” symptoms and have an email from a very CLL savvy expert at NIH who stated that in his opinion though I qualified for treatment I had the “option to wait”, this in regard to an email I had sent to him stating I would have to drop out of the CLL Natural History study I was enrolled in because I had decided that I needed treatment. My condition at the time was bulky disease, High B2M (5600), Absolute Lymphocyte Count (ALC) 300+, HgB hovering above 10. My decision to push on with treatment was based on my concern that the CLL was degrading my kidney function.
Just over one month prior to my TX in July ’09 my creatinine spiked to 1.6 which was the first time it had gone above what was considered high normal. (at diagnosis Sept.’06 my kidney function was excellent) The NIH doc had cautioned to me to monitor my platelets and if they dropped to a sustained level between 90 and 95 that TX should be started as he did not like platelets below 90 to initiate therapy.
Curiously enough, not any doctor other than my family doc raised concern over my rising creatinine and corresponding drop in GFR. While any one test can be a lab error or an anomaly I had always provided my doctors with updated (Chaya’s) Charts by which one could see a very slow but persistent saw tooth pattern of creatinine rise/GFR impairment.
My concern over the state of my kidneys was born out in a renal failure event following cycle two of RF concurrent TX which raises an important question to the staging guidelines of when to treat. CLL can affect and manifest in problems outside of the blood arena. Serious situations can develop for our kidneys our hearts, liver, eyes etc. and when these conditions show up it is prudent to at least get a specialist doctor on board to help in the decision process and who will be familiar with your case should treatment exacerbate the condition in question. Even though I was concerned, I failed myself in waiting too long EVEN THOUGH THE CLL ITSELF may not have been an immediate threat. I also failed to get a Nephrologist on board prior to my TX as I relied on my Oncologist to know when this should be done. Bottomline: All co-morbidities should be taken into consideration as equal threats to our lives and QOL when decisions to treat are made.
Question: Is the rise in RDW a further indicator of marrow stress as described by “stage-C infiltrative” or can this occur with “stage-C autoimmune” as well? I had noticed the RDW begin to rise from 12 for the first time to 15 jumping rapidly to 18+ when my ALC had reached 240+ and not that distant in time when my marrow was tested to be diffusely infiltrated at 91%.
WWW
Thank you, Chaya. I’ll look into different therapy options. The info about mitoxantrone is interesting – thanks again!
Waynewells:
Thanks.
RDW stands for “red blood cell distribution width”. What it measures is the distribution in size of red blood cells. Newly minted baby red blood cells are larger than adult red blood cells that have been around for a while. In a healthy patient under normal conditions, there is a certain proportion of adult cells and baby cells, giving a size distribution that is considered normal.
When red blood cells are being destroyed for some reason (say autoimmune disease, bleeding disorder or some other reason), the orders go out to the bone marrow to make new red blood cells to make up for the deficit. A healthy bone marrow able to oblige will respond to the orders and make a lot more baby red blood cells. These larger cells will increase the size distribution of red blood cells present in the body – in other words, RDW will increase. This tandem effect of increasing RDW with decreased red blood cell counts is one indication that the bone marrow is still able to produce new cell lines on command.
A heavily infiltrated bone marrow (or one where the blood stem cells have taken a huge beating, a dangerous case of insufficient hematopoiesis or inability to make new blood cells) is not able to respond to the orders to make new red blood cells in a hurry – in such cases RDW will not increase even if red blood cell counts are down. Procrit or other epo drugs may help the process in some cases, by increasing the urgency of the command to make more red blood cells.
There are many other reasons for RDW changes, especially in combination with changes in MCV – some of them dietary or absorption deficiencies such as vitamin B12 deficiency, iron absorption issues etc. Anemia is complicated business with many potential reasons. It needs to be checked out by a competent physician.
I have a question regarding cbc: My husband’s has monthly blood tests at time of IVIG checking white, red and platelets. The white cells are broken down as: wbc, lymphocytes, mid and gran. He is in progressive disease now, but still W&W.
My question is about the “gran”. The number of cells falls below the normal range, but the % falls above the range. I am trying to figure out how the actual count can be blow, but the % of cells can be high? Just seems strange to me. We see doc on Monday, but I am interested in any feedback there may be. Thanks!
His RBC is good, and his platelets are low, but still ok.
I think what is most important is the absolute value of the granulocytes. If your blood report shows granulocytes but not neutrophils you can calculate your neutrophils pretty easily. However, my oncologist just takes the granulocyte number as equal to the neutrophils. Since I am fairly picky, I like to figure out the exact number. Here is how you do it. The section of the report called “manual differential” should have values for “seg” and “band.” First add these up. Now take the value for WBC and multiply it by ten. Finally multiply these two numbers. You should get a number between 2,000 (2.0) and 8,000 (8.0). If it goes below 500 (0.5), then it’s pretty serious and a doctor will advise using neupogen or the like. There is very good info on this site about when to use it and when not to. Look up GCSF in the search box.
I hope this is helpful.
Dear Chaya,
What Harley says goes for me too. I’m in a good remission, so I don’t have many comments, but I do still read every article with great interest.
I have to say— my heart sank when I read your parting comment, “I have been writing this stuff far too many years.” Yes it’s been many, but hopefully not far too many!
My experience with CLL goes against the typical treatment and remission outcome. So I’m hoping that mentioning it here will give hope to some readers.
I was diagnosed in 2002. Had treatment in 2004/5 with FR.
After only 18 months I was in need of a second treatment.
In 2006/7 I signed up for a clinical trial that bought me a little time. Then in 2008 I needed treatment again.
I chose PCR, because at the time it was still thought to be less immunosuppressant than FCR and I thought it would be good to vary my poisons.
Now two years later there are still no signs of progression.
So it just goes to show that it is possible to get a longer progression-free period after your second treatment.
Wishing good news for us all coming out of the upcoming ASH convention.
Cheers,
HL
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