Survival Statistics Based on Rai-Binet Staging May Need to Be Modified

If you are like the rest of humanity, right after your diagnosis with CLL and as soon as your brain started working again, the first question that you asked was this: "How long do I have to live?"

I hope your oncologist did the right thing, give you an honest, detailed answer and not brushed you off with the useless clichés about how CLL is the good kind of cancer to get. The honest answer would have been to tell you about the Rai and Binet staging systems, how these staging systems divide patients into low, medium and high risk categories, and the survival statistics associated with each category. If she/he had more than the standard 15 minutes to spare for you, you would also have learned the most important thing about statistics, that while it is good to know what your odds are, statistics do not guarantee outcome for a single patient. You may get lucky, far outlive predicted survival by a big margin, and then on the other hand you may end up at the wrong end of the stick, give up the fight sooner than expected.

But statistics are important, and the staging systems designed by Drs Rai and Binet have been extremely important in defining therapy decisions. Now comes new information that can change all that, stand the staging system on its head. If you thought you were in stage - 4 CLL, and based strictly on the advanced staging you were getting ready to kiss life goodbye, think again, and read this article. You may yet stick around long enough to die of old age.

Now that I have your attention, allow me to review the Rai and Binet staging systems, and save the new information for the end of the article.

Rai Staging System
Stage 0:	Your CBC shows absolute lymphocyte count is too high, more than 5.0 K. You probably have no other symptoms of leukemia, and the CLL was most likely diagnosed as a result of a routine blood test. Patients in Stage - 0 do not have swollen lymph nodes, spleen, liver. And you have hemoglobin, red blood cells and platelet numbers that are all in the normal ranges. Neutrophils are also "in the pink", and you have not noticed any higher frequency in getting infections.
Stage I:	By this stage, your lymph nodes are swollen (lymphadenopathy), but that is the only thing that has changed from Stage - 0. Everything else is still within the normal limits, and the spleen and liver are doing fine too.
Stage II:	Besides the swollen lymph nodes of Stage - 1, you have now graduated to where either your liver is swollen (hepatomegaly) or the spleen is swollen (splenomegaly). The CLL has now started impacting other organs of the body, in addition to the peripheral blood, lymph nodes and most likely the bone marrow as well.
Stage III:	The pivotal indication of Stage - 3 in the Rai classification system is anemia, there are too few red blood cells and too little hemoglobin. Since red blood cells are the only carriers of oxygen, not having enough red blood cells is pretty hard to miss. You will start to feel out of breath, tired after exertion, and generally not up to your old feisty self. This is considered such an important criteria that a patient is defined as Stage - 3 if he/she has significant anemia, even if the lymph nodes are hardly swollen, and the liver and spleen are doing OK too.
Stage IV:	Like Stage - 3 discussed above, the crucial criteria for putting patients in Stage - 4 is not having enough platelets (thrombocytopenia). The lymph nodes, liver, or spleen may be swollen, and there may be too few red blood cells (anemia). Typically, patients in Stage - 4 have all the bells and whistles, swollen lymph nodes, high WBC, swollen spleen and liver, anemia and thrombocytopenia.

Binet Staging System The Binet staging system is a little simpler, only three categories called Stages A, B and C.
Stage A:	Sure, your absolute lymphocyte count is too high, but red blood cells and platelets are still doing well. You have fewer than three areas of swollen lymph nodes.
Stage B:	Same as in Stage A, except that now there are three or more areas of swollen lymph nodes.
Stage C:	This is where the rubber meets the road, it does not matter how many swollen lymph nodes you have, the important thing is that your red blood cells are below normal (anemia) and/or your platelets have taken a dive (thrombocytopenia).

National Cancer Institute The National Cancer Institute recommends dividing CLL patients into three groups:
Low-risk group:	Rai Stage 0. These folks are expected to have, on the average life expectancy in excess of 14 years
Intermediate-risk group:	Rai Stage 1 and Stage 2, lumped together. The median life expectancy is around 8 years.
High-risk group:	Rai Stage 3 (anemia, defined as hemoglobin of less than 11) and Stage 4 (thrombocytopenia, platelets of less than 100 K).

As you can see, the definition of the high risk group in both the Binet and the Rai systems of staging depend upon anemia and thrombocytopenia. That is the crux of the present paper. It now appears we have to consider the why of low red blood cells and platelets, not just the how low. It actually makes sense, once we go through the logic of it.

Cutting through a lot of important detail to get to the bare bones of the concept, there are two possible reasons why you may have low numbers of these two important cell lines, red blood cells and platelets. One is a lot more serious than the other.

One reason could be that your bone marrow is completely shot, either because of the cancer itself and/or the effect of prior harsh chemotherapy treatments. For these or other reasons, the stem cells have given up. No more production, the factory is burned to the ground. A bone marrow biopsy would reveal a graveyard type of scenario, no new baby cells being produced, nothing happening. There is no way to fix dead bone marrow, except to replace it with a new bone marrow from some one else, new stem cells to take over the job of producing vital cell lines. BMTs are no joke, they carry significant risk of death just from the procedure itself. While modern procedures and new approaches such as the non-myeloablative allogeneic bone marrow transplants ("mini" transplants or "BMT lite") have made the odds better, it is still a very serious procedure.

The other reason for low red blood cells and low platelets could be that although they are being produced normally back at the "factory", (bone marrow), they are not being allowed to do their job properly and in fact they are getting destroyed before their time. The destruction could be due to improper functioning of the spleen, for example. People with large swollen spleens due to CLL infiltration could have good, perfectly normal platelets destroyed there. In such cases, splenectomy (surgical removal of the spleen) is often recommended. While this is major surgery, and no one wants to leave behind a piece of their original equipment in the operating room, splenectomy has surprisingly excellent results and few complications if done early enough. In other words, many patients live just fine without a spleen, so if this were the main reason for the anemia and thrombocytopenia, it can be corrected without turning the world upside down.

Another reason for low platelets or red blood cells could be autoimmune disease. Even though CLL is a B-cell cancer, when your system is choke full of these malignant cells, they manage to corrupt a lot of other systems as well. Under normal circumstances, the body depends on antibodies and effector cells such as T-cells and macrophages to protect itself from foreign invaders. When things go wrong, as in advanced stages of CLL, everything gets subverted to some degree. Autoimmune disease is one face of this subtle corruption from within. Antibodies may be produced that attack red blood cells and platelets, and effector cells may home in on these unfortunate cells and kill them. The careful distinction between "self" and "non-self" breaks down, and the very defenses that should keep us safe start attacking various parts of the body.

If this is the reason for the anemia and thrombocytopenia in late stage CLL, it too can be fixed by fixing the source of the problem, the large numbers of CLL cells causing havoc with other systems of the body. Most patients respond well to therapy, and reduction in tumor burden is accompanied by reduced levels of autoimmune disease. Once the huge numbers of CLL cells are out of the picture, red blood cells and platelets are allowed to do their jobs in peace, and their numbers recover.

So, there is a big difference in the two sources for possible anemia and thrombocytopenia. The first one, a dead or dying bone marrow, is pretty serious stuff and has serious impact on survival statistics. The second source, which has to do with untimely destruction of red blood cells and platelets, even though they are being produced OK in the bone marrow, can be corrected by splenectomy, CLL therapy, or even growth factors like EPO to increase production of red blood cells. Heck, we know of several people who survived on just plain transfusions red blood cells and platelets to get them over the hump, while therapy, splenectomy and EPO, etc., have a chance to kick in.

Incidentally, the second abstract below suggests that contrary to popular myth, anemia and thrombocytopenia are normal consequences of progression of CLL, and not often caused by or responsive to treatment with the popular drug of choice, Fludarabine.

The abstract below reports on 132 patients with CLL/SLL. Careful analysis showed that if the anemia and thrombocytopenia were due to autoimmune disease, as in AIHA (autoimmune hemolytic anemia) and ITP (immune thrombocytopenia), there was no significant penalty. If these patients had been put in the high risk category based strictly on anemia and thrombocytopenia as per the Rai and Binet staging systems, they would have been miscast in the role. On the other hand, if the anemia and thrombocytopenia were due to bone marrow failure, then the risk of death was significantly higher and the "high risk" classification is justified.

Makes sense, right? It is not enough to know you have anemia and/or thrombocytopenia. It is also important to know why, so that you can be correctly placed in the appropriate risk category. This is a subtlety that is not presently captured by the Rai or Binet staging systems.

May all of you with thin blood (low platelets) and pale with anemia have "only" autoimmune disease, not bone marrow failure.

Abstracts:

Autoimmune cytopenia does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma

Division of Hematology/Oncology, Department of Medicine, Central Arkansas Veterans Healthcare System (CAVHS) and University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is characterized by an acquired immune defect that can cause autoimmune complications, including anemia and thrombocytopenia. We conducted an observational study of the epidemiology, clinical presentation and significance of autoimmune complications of CLL/SLL in 132 patients from a large population (>45,000 veterans), in which at least 90% of patients with CLL/SLL have been previously identified. Over a period of 12.5 years, 12 patients (9.1%) had autoimmune complications; of these, 6 (4.5%) had autoimmune hemolytic anemia (AIHA), 5 (3.8%) had immune thrombocytopenia (ITP), and 1 (0.8%) had pure red blood cell aplasia (PRBA). All 6 cases of AIHA had a positive direct immunoglobulin test for IgG and C3d. In 6 patients, CLL/SLL was an incidental finding at the time of presentation with autoimmune cytopenia. Nine out of 10 patients responded to immunosuppressive therapy, which was complicated by serious infection in 7 cases, one of which was fatal. The major cause of mortality in patients with autoimmune complications of CLL/SLL was secondary malignancy. Survival of patients with immune cytopenia was not significantly different from CLL/SLL patients without immune cytopenia. Among patients with anemia or thrombocytopenia, mortality was significantly higher in those with bone marrow failure compared to an autoimmune etiology. We show that in a non-referred population with a high incidence of CLL/SLL, autoimmune cytopenia can occur early in the natural history of the disease. These data suggest that the Rai and Binet classifications for CLL need to be modified for patients with autoimmune cytopenia. Am. J. Hematol. 74:1-8, 2024. Published 2024 Wiley-Liss, Inc.

Autoimmune hemolytic anemia in chronic lymphocytic leukemia patients treated with fludarabine.

Di Raimondo F, Giustolisi R, Cacciola E, O'Brien S, Kantarjian H, Robertson LB, Keating MJ.

Autoimmune hemolytic anemia (AHA) is a frequent complication of chronic lymphocytic leukemia (CLL). Although the pathogenesis of AHA is still unknown, an imbalance of normal residual T cells is believed to play a central role. Since fludarabine is reported to affect primarily T lymphocytes, we conducted a retrospective study to evaluate the incidence and outcome of AHA in 112 CLL patients treated with fludarabine alone. Eight patients had AHA before therapy; only one achieved remission of both CLL and AHA after fludarabine alone. In the other seven patients, we observed no effect or even a worsening of AHA, although the CLL was responding to fludarabine. Five patients developed AHA from 1 to 19 months after fludarabine therapy while the CLL was responding. One additional patient developed pure red cell aplasia (PRCA) 3 months after starting therapy. Most patients in both groups responded to steroids or other immunosuppressive therapy. The study showed that in these patients, AHA evolved independently of CLL and was not affected by fludarabine.

A member followed up the preceding article with a question on whether falling platelet numbers in CBCs are the only indication of a bone marrow failure and whether falling platelet numbers necessarily imply a bone marrow failure.

A falling platelet count does not, repeat does not mean irrevocable bone marrow failure. As I have written before, reduced platelet numbers can be due to a variety of causes, I touched on some of the more prominent ones.

Even when there is no autoimmune disease, and the reduction in platelets (or other cell lines) is indeed due to decreased production of the cells in the bone marrow, that does not automatically mean the marrow is dead. It can be just that the marrow is so heavily infiltrated with CLL cells that there is no room left for growth of new platelets or RBCs, etc. The stem cells may be perfectly fine and viable, we just need to clean out the marrow to give some room for the right cell lines to be created. This is where therapy comes in. Reducing the tumor burden, especially in the bone marrow, will have a good response in this case.

Irrevocable bone marrow damage is obviously serious business, but one should not jump to that conclusion without strong evidence. In many cases, the anemia or thrombocytopenia is due to reasons other than bone marrow failure, and can be treated without resorting to a BMT. That was the whole point of the article, that the old Rai and Binet staging systems did not differentiate between the two conditions: anemia and/or thrombocytopenia due to bone marrow failure (serious) versus anemia and thrombocytopenia due to reasons other than bone marrow failure (not so serious, can be handled).

Disease Characteristics