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.

NCI risk classification

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.