Do you know your “Risk Bucket“?
A while back I wrote about a CLL patient whose oncologist changed his Rai staging from a comforting Stage – 1 to scary Stage – 4 in one fell swoop, because his latest blood test listed his platelet count at 96K. (“When platelet counts start dropping”). This is no small deal. Based on the changed Rai stage, his oncologist also recommended immediate start of chemotherapy. Talk about acting without putting brain in gear first. As we pointed out in our article there are many reasons (some of them very trivial) why the platelet counts were a tad low on that particular blood test. Some are important, some are trivial. It is important that you and your oncologist understand the details before making therapy decisions!
However, even when the red blood cells and / or platelet counts are legitimately low and a real cause of worry, it does not automatically imply dire consequences. Researchers have now identified clear deficiency in the Rai and Binet staging systems when it comes to dealing with “cytopenias” – reduced hemoglobin level due to insufficient red blood cells (anemia), and platelets (thrombocytopenia). Both of these systems depend on thrombocytopenia (low platelets) as a trigger for putting patients into the last and most advanced stage of CLL.
Rai and Binet Staging
Before we analyze this important abstract authored by very credible experts it is important to know how the Rai and Binet staging systems work. Rai staging (invented by Dr. Kanti Rai, the grand old man of CLL who heads the group at Long Island Jewish Hospital) is used in the USA. Binet staging is used more often in Europe. Both systems use increased lymphocyte counts, swollen lymph nodes, anemia and thrombocytopenia as the trigger points.
The Binet staging system is a little simpler, it has just three stages. It too focuses on swollen lymph nodes, anemia and thrombocytopenia
What do the staging systems have to do with your risk classification? Here is how the NCI uses staging information to put patients into low, intermediate and high risk categories.
Notice that Rai, Binet and NCI systems all focus on anemia (low hemoglobin levels due to reduced red blood counts) and thrombocytopenia (low platelet counts) as indications of increased risk. What has changed is that now we are interested not just in how low the hemoglobin levels and platelet counts are, we are interested in the reason behind the drop.
The Prognostic Significance of Autoimmune Cytopenias in Patients with Chronic Lymphocytic Leukemia
Carol Moreno, Kate E Hodgson, Pau Abrisqueta, Gerardo Ferrer, Montse Elena, Arturo Pereira, Francesc Bosch and Emili Montserrat
Clinical staging systems are the backbone for assessing prognosis in patients with chronic lymphocytic leukemia (CLL). Clinical stages, however, are assigned without taking into consideration the mechanisms of the disease.In this regard, the prognosis of patients with advanced (Binet C, Rai III, IV) stage due to immune cytopenia is controversial. To address the prognosis of patients with CLL in advanced clinical stage due to immune mechanisms, we studied two groups of patients with and without autoimmune cytopenia.
The first group consisted of 62 patients (39 men, median age 65 yrs; range 33-89) with advanced stage due to autoimmune cytopenia(stage C “immune”). Autoimmune hemolytic anemia (AIHA) was defined as a hemoglobin level <10g/dLand either a positive direct antiglobulin test (n=37) or indirect signs of hemolysis including a high reticulocyte count, low haptoglobin levels, increased LDH and bilirrubin levels (n=7). Immune thrombocytopenia (ITP) was defined as a platelet count < 100.000/mm3with normal megakaryocytes in bone marrow or no reticulocytopenia, no enlarged spleen and no chemotherapy within the last month from study entry (n=18).
The control group included 96 patients (59 men, median age 68 yrs; range 28-90) with stage C disease with no signs of immune-mediated cytopenia. Demographics, clinical characteristics and duration of follow-up were similar in both groups. When considered from the time of diagnosis, patients with stage C ”immune” disease had a significantly better survival than those in stage C due to bone marrow infiltration (median survivals: 89 months vs. 45 months; p=0.04). In contrast, the prognosis of 12 patients who developed immune cytopenia during the course of the disease was not different from that of 42 patients who had progressed to stage C with no evidence of autoimmunity, neither when considered from the time of diagnosis (median survivals: 110 months vs. 101 months; p=0.71) nor from the point at which cytopenia (either autoimmune or infiltrative in origin), was detected (median survivals: 51 months vs. 63 months; p=0.102). When the analysis was restricted to the 62 patients with autoimmune cytopenia, no significant differences in survival were observed according to the time at which the autoimmune disorder was detected, i.e. at diagnosis or during the course of the disease (median survivals: 89 months vs.103 months; p=0.38). Of note, 11 out of the 18 patients with stage C “immune” disease at diagnosis responded to corticosteroids and, as a result, switched to stage A, whereas only 8 out of 53 patients with stage C due to bone marrow infiltration had a similar response to chemotherapy. In summary, this study shows that the outcome of patients with CLL who present with advanced clinical stage differs according to the origin of the cytopenia (i.e., immune vs. infiltrative)and emphasizes the importance of determining the origin of the cytopenia when evaluating patients with CLL and “advanced” clinical stage. These results also make a case for including a stage C “immune” group in the prognostic categorization of patients with CLL.
Modern Understanding of Anemia and Thrombocytopenia
Let us assume all the trivial reasons (like the lab tech had a bad hair day that day and messed up the results) are not involved. This abstract zeros in on two important and very different reasons why the patient may be suffering from crashing hemoglobin and red blood cell counts and / or platelet counts.
One reason for low red blood cell or platelet counts is that the bone marrow is not working as it should. You must realize that the bone marrow is a very unique and precious organ, it is the single location where blood stem cells reside, which in turn are the only cells that can create brand new red blood cells and platelets. If the bone marrow environment is messed up (for example, cluttered with too many useless CLL cells) or the blood stem cells have been damaged in some way (many chemotherapy drugs damage blood stem cells), production of new red blood cells and / or platelets comes to a screeching halt. As old cells in blood circulation get worn out and die, there are no new troops to replace them. If this is the cause of anemia or thrombocytopenia, the only way to fix it is to somehow make the bone marrow a healthy environment once again and allow stem cells living there to do their job.
The second important reason for cytopenias (anemia or thrombocytopenia) identified in this abstract is autoimmune disease. CLL patients are prone to two specific kinds of autoimmune disease: AIHA (autoimmune hemolytic anemia) and ITP (immune thrombocytopenia). In such cases the bone marrow is still doing its job and producing new red blood cells or platelets. The reason why counts are low is because an out of kilter immune system cannot tell the difference between friend and foe, killing off perfectly good red blood cells and platelets in a mad frenzy.
The authors point out that low counts due to autoimmune disease is the lesser of the two evils. Autoimmune disease can be controlled by appropriate immune suppressing drugs to bring the berserk immune system under control. But a damaged bone marrow and / or damaged stem cells is a whole lot more dangerous. If it is a matter of clearing out the bone marrow of its hordes of CLL cells getting in the way, it may be possible to achieve that with appropriate therapy. However, if the stem cells have been damaged in some way, the choices are limited. One can wait it out, hope that the stem cells gradually recover and get back to work. But if the damage is irreversible and stem cells are dead or unable to recover sufficiently to do their work, the only choices left are transfusions or a stem cell transplant.
Here is how the median survival differed between patients who had cytopenias (haemoglobin less than 10.0 and / or platelet counts less than 100) because of autoimmune disease or bone marrow infiltration. Notice the big (statistically significant) difference between survival of the two groups when the cytopenias were present right from the get-go. But if the cytopenias developed later on as the disease progressed, it did not matter a great deal whether this was due to autoimmune disease or bone marrow infiltration.
Moral of the story, Rai and Binet staging can be off the mark by a lot when predicting risk in advanced cases (Rai Stage III –IV or Binet Stage C), because neither of these two systems take into account the reason for the cytopenias.
That is not to say crashing red blood cell counts or platelets due to autoimmune disease is something to be taken casually. The sudden onset of symptoms can be very scary. Please refer to earlier articles on AIHA and ITP to learn more about these dangerous complications. All this article is saying is that autoimmune disease can be managed with appropriate drug therapy, and when mayhem caused by berserk immune system has been stopped the patient can be re-staged to a lower risk category. But a compromised bone marrow is a wake up call to prompt action. Hopefully the bone marrow can be brought back to health, get it working right again by clearing out the CLL cell infiltration. Not all drugs are effective at clearing the bone marrow and it is important to make therapy choices carefully.
In the worst case scenario if the cytopenias are due to damage of the stem cells, even if there is no CLL infiltration of the bone marrow, the cytopenias may last a long time. This could be one of the reason why patients have long lasting cytopenias after aggressive chemotherapy. Majority of the CLL cells have been killed, but in the process sufficient damage may have been done to the stem cells to cause cytopenias. If the damage is reversible, gradual recovery of the stem cells will be accompanied by gradual recovery in haemoglobin levels and platelet counts. If stem cell recovery is no longer possible, the next step is a stem cell transplant – bringing in healthy stem cells from a willing and matched donor.
13 comments on "CLL Staging: Devil is in the Details"
Thank you for this important update.
Stay well,
Monique
Your article caught my attention as my platelet count has been in the 80-100 range over the last few months. A BMB has revealed 70% marrow infiltration and slightly reduced hematopoietic cell function. Except for fatigue, I am asymptomatic so that should put me in an ‘atypical’ Stage IV, as I do not have swollen lymph nodes, spleen or liver or high WBC (ALC is around 30).
Local oncologist suggesting FCR treatment this year while CLL specialist says wait further. Considering starting FCR treatment once platelets get closer to 50 which may be this year. According to your stats I would have something like 4 years to live but then again FCR should provide an average remission of say 6 years as I have mutated IGHV, trisomy 12 and no 11p/17q deletions. I am also considered to have ‘atypical CLL’, with a small possibility of it being SMZL or LPL lymphoma. Bottom line: individual cases can deviate from typical behavior and this adds to uncertainty and anxiety about what the future holds.
Paul:
You are absolutley right in your analysis that individual cases cannot be predicted with certainty from general patient population statistics. This is specially true with atypical cases like you.
The best take home message from this for you is that increasing bone marrow infiltration is not going to go away on its own and your therapy choices have to be made in the context of what works in bone marrow clearance. For example, single agent monoclonal antibody such as Rituxan is not known for its ability to clear bone marrow. Which is perhaps why both your local guy and CLL expert are recommending FCR.
Thank you for clearing up the staging information. I am a CLL pt. since 2002 at age 49. I recently had thyroid cancer surgery inwhich they removed 52 lymph nodes from my neck. They told me I have a lymphproliferative disorder.(Which in all my reading of CLL never heard of before) Do you have any information on this? The other thing that I found interesting is that after surgery I received radioactive Iodine, prior to this treatment my WBC were 80 thousand and now are 38 thousand. My RBC’s are in normal limits. Thanks Anna
Dear Chaya,
Thanks for this. It does appear to validate the choice of NOT accepting any chemotherapy, particularly as the stuff kills cells indiscriminately. That precious stuff, bone-marrow, needs to be protected!
Makes my doumbfounded reaction to some bloke saying I should be grateful to have been diagnosed (accidentally through Breast-screening) so that I could have chemotherapy!
There is no intention to treat, nad I definitely don’t want any! Rather scary isn’t it, when chemo is seen as a “gift” you are lucky to have a chance to get, without having any indication for need!
Have a much better 2010, with love, Mette
What happens when your numbers are “good” and your lymph nodes can’t be filled with the touching of the oncologist hands? My lungs are damaged due to much pneumonia (broncheaectisis)? A pocket of CLL filled the outside of my left lung and I had to immediately start CVP a year ago. So far so good. Oncologist claims Rai stage 0. My IGM and IGA is very low. I am on 48 units of IVIG every three weeks. I contibute my IVIG to my so called quality of life. Thank God for doctors other than oncologists. My infectious disease doctor has saved my life so far.
Without you, I would be lost. I thank you daily for you help and input. Don’t ever think you are not loved and or needed. I pray for you.
Janice
Flowood, MS
Dear Chaya,
I have learnt so much about CLL / SLL from this site and am very grateful for the sence of empowerment that you give. Diagnosed with SLL aged 50 years, 2 ½ years later I am still on watch and wait and feeling fine. How does staging apply to SLL when bloods are ‘normal’ but with numerous moderately enlarged nodes. Bone marrow results – now 2 years old showed nodular involvement? Is it like Paul an atypical stage 1V.
Kind regards, keep up the good work.
Mary
ellieoak
“Lymphoproliferative disease” is a catch-all phrase for all kinds of blood cancers where lymphocyte counts are high. Examples are CLL, NHL, MCL, HCL and a bunch of others. Further testing (especially flow cytometry) is needed to fine tune the diagnosis further to one kind of B-cell cancer.
Mette:
No one in their right mind would have chemotherapy unless they had (1)cancer (2)the other option is the cancer getting more and more out of control (3) possibility of death in the absence of chemotherapy. Unfortunately, all of our members have CLL – still considered an incurable cancer. In the context of this particular article, uncontrolled AIHA or ITP can kill patients very quickly, sometimes in a matter of weeks or months and very often a lot more quickly than the underlying CLL. How do they control AIHA and ITP? By using chemotherapy drugs such as dexamethasone, cyclophosphamide, Rituxan, vincritine.
Recent work on chemoimmunotherapy combinations such as FCR have shown increased overall survival. I know my husband would have died a lot sooner if he had not had chemotherapy. The one and only curative option, stem cell transplants, is not possible without first undergoing chemotherapy. Once again, it is a matter of playing the cards we are dealt to best advantage and that sometimes means choosing the lesser of two evils.
Is it a gift to have a chance at having chemotherapy? That too depends on one’s perspective. Today I replied as best as I could to a heartbreaking letter (from India) from a loving husband whose wife has aggressive CLL – and they have no money, husband recently fired from his job and has no health insurance. For this young mother the chance of getting necessary chemotherapy would indeed be a gift.
Mississippi_Woman:
It sounds like you have SLL, a variety of CLL that has the disease focused in the lymph nodes and not in the blood. Low immunoglobulins, frequent infections and especially lung and respiratory infections are the classic hallmark of CLL. I am glad you have a good infectious disease doctor. That is very important, especially in your case. But down the road you will also need an oncologist, since you do have cancer. Developing a good working relationship with our oncologists is not always easy. But it is necessary. If necessary, keep “shopping” until you find one that can work with you.
doreensll:
SLL is a little harder to stage using the more common CLL based staging systems. In your shoes I would still look for development of anemia and /or thrombocytopenia to alert me to bone marrow infiltration or autoimmune disease. Particularly in the case of SLL it is important to keep an eye on the size of the nodes. Bulky nodes (usually defined as larger than 5cm in diameter) would rule out some important therapy options since the drugs involved are not able to reduce such large nodes.
I suggest you talk to your doctor about the need for CT scans at regular intervals to judge the size of nodes buried deep in your belly – these cannot be felt by physical palpitation alone. Once again it is a matter of balancing risks: avoiding unnecessary radiation exposure versus getting a heads-up on when to initiate therapy because the nodes are getting too large.
When I was diagnosed with CLL 3 months ago I was moderately anemic with a hemogloblin less than 10. (All abnormalities were found on incidental bloodwork. I realized that my being out of breath was due to anemia when I had been blaming myself for being out of shape.)
My doctor recommended iron pills and recent bloodwork showed my hematocrit and hemoglobin back up in the normal range, confirming a diagnosis of iron-deficiency anemia.
Thank you Chaya for all you do.
doggeedoc:
I am glad your doctor is on top of things.
Folks, this ASH2009 abstract and my review of it are based on the assumption that all other reasons for low platelets and red blood cells (and therefore low hemoglobin) have been ruled out. As in “doggeedoc” case, anemia could be due to other reasons besides CLL. Same goes for platelets too. We discussed many of these non-CLL related causes in earlier articles.
Ellieoak, I was diagnosed with CLL 3 1/2 years ago the week after my 45th birthday. During prognostic testing the PET scan discovered a small tumor on my thyroid which turned out to be malignant. My WBC was at 50K at diagnoses and then decreased to 22K after I had my thyroid removed. I have often wondered if my WBC (130K in Sept 09) would reduce if I took a hiatus from synthroid for a few weeks. I know I would feel terrible but I think I would chose it over chemo.
I have not done it and when I brought it up to my endocrinologist she just reminded me how terrible I felt.
It could also just have been a coincidence without any medical/scientific substantiation.
Once again Chaya you have come through for us. I was diagnosed in 2003 at 51 yrs old. My platelets were 89.0 last CBC in December 2009. WBC 31.2 and of course this puts my lymphocytes and percentage higher as well. On this last report I noticed a new reading included because it was high. It was RDW-SD which was 51.7. Normal range being 36.4-46.3. What is this reading and what bearing does it have on my CLL? I am still considered in the watch and wait stage. Last time my platelets were above 100K was in June 2009. I am involved in a clinical trial in Bethesda this April. I will be having my evaluation done then and from there we will see where it leads me for further study on W&W patients. I have my next oncologist appt the end of this month. I try to keep as positive as possible and do stay in shape with exercise in walking, biking,kayaking and swimming when the weather is warmer. I hope to be around for quite some time and maybe there will be a cure soon. My brother in law also has CLL and they feel it was due to Viet Nam and agent orange back in the 60’s. He will be in line for a possible BMT this spring. This disease is so unpredictable.We are hoping he has a match and that he will be able to get through it and be with us for another long while. I do appreciate this web site and bring many of the articles to my oncologist’s attention. Bless you for all you do for us and helping us to be more assertive with our health.
Anita
Speaking of BMT, I have a question, in case anyone has an idea about it. My husband’s doctor said he is not eligible for BMT because his disease would return too quickly to make the rise worthwhile. At diagnosis 6 years ago he had very advanced, agressive disease. He is still going strong, so he is getting good care, but I am curious about the whole thing. What circumstances would cause the risk to be not worth the process because the disease would return too quickly?
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