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New Treatments for Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia is the most common form of leukemia in Western countries, with about somewhere between 8,500 and 12,000 new cases a year, depending on who you read and what you believe. It is characterized by a plethora of small mature-appearing lymphocytes in the peripheral blood mixed with these chronic lymphocytic leukemia.

I have on purpose selected very characteristic examples of these diseases but it isnít always so easy. So weíve had to develop some diagnostic criteria for CLL. We did this sort of arbitrarily, requiring an absolute lymphocytosis of more than 5,000. The morphology being primarily small mature-appearing lymphocytes and a bone marrow containing at least 30% lymphocytes. Now, that does not mean that you need to do a bone marrow to make the diagnosis of CLL. This is done in most, if not almost all patients, by the peripheral blood smear. But a bone marrow is useful in certain circumstances, such as to assess the other progenitor cells; how many megakaryocytes and nucleated red cells.

CLL is characterized by expression of B-cell markers, CD19, 20 or 23. It also co-expresses CD5 which used to be thought to be a T-cell marker but is now known to be present on a minor sub-clone of normal B-cells. And the CD5 positive B-cells are seen in increased numbers in patients with autoimmune diseases such as rheumatoid arthritis, lupus, post-allogeneic bone marrow transplants.

Thatís all well and good. How do I remember it? This is sort of a diagrammatic approach to the CLL-like disorders. The patient has a lymphocytosis of at least 5,000. You do a careful examination of peripheral blood smear and then you do your imuno-phenotyping. If the cells are CD5 positive and CD20 negative, then these are T-cell chronic lymphoid leukemias. If they are CD5 positive and CD20 positive then your three options are CLL, CLL that has transformed to prolymphocytic leukemia, or mantle cell lymphoma in a leukemic phase. And you distinguish the CLLís and the mantle cells in two ways. One, the mantle cells donít express CD23, and two, mantle cells express CD20.

Okay, the patient shows up with CLL. What can we expect? Well in general, nothing. Most patients with CLL are diagnosed serendipitously at the time of a routine examination. More than half the patients are totally asymptomatic and without physical findings when they are diagnosed. But during the course of their disease they will, or are likely to, develop lymphadenopathy, hepatosplenomegaly.

Anybody who has taken care of more than one patient with CLL knows that they are all different. The first patient may show up in your office. You follow this patient for years, for decades, they never need treatment, they do just fine living a normal life. The next patient shows up, looks kind of the same initially and dies within a matter of months from their disease despite your best therapeutic intents. Well the first successful form of categorizing patients was Dr. Kanti Rai staging system, published almost 25 years ago, in which he had five stages. Zero is lymphocytosis only and associated with a reasonably normal life span compared with an age-matched control population. Stage I is lymphocytosis with lymphadenopathy, II with splenomegaly and/or hepatomegaly, III with anemia and IV with thrombocytopenia that are not immune-related. Well, I always have trouble memorizing five staging systems, so fortunately Dr. Rai subsequently modified his system.

The Rai classification is used throughout most of the world, except France and a few European countries. There they use the Binet system. Dr. Binet developed a system in the late 70ís, early 80ís, composed of three stages. The reason I show you this, even though it wonít be on the Boards, is because several of the slides I will be using subsequently employ the Binet system. And the Binet system is stage A, fewer than three involved node areas. B, three or more involved node areas and C with anemia and/or thrombocytopenia and the median survival.

But even within clinical stages there are marked differences in patient outcome and there are a number of prognostic factors which have been looked at in an attempt to separate patients into risk groups. Older patients do worse, those with advanced stage do worse, males do worse, blacks do worse, and patients with an impaired performance status do poorly. Patients with a diffuse pattern of bone marrow involvement appear to do worse than those with a non-diffuse pattern but it also correlates very nicely with stage and I donít think it is independent. The doubling time is widely used. That means, the patient shows up in your office, you check the lymphocyte count, you follow them over a period .

These are some data from the M.D. Anderson showing a very nice correlation between serum beta to microglobulin. As it goes up the response rate goes down and the five year survival goes way down. So beta 2 is not just useful in myeloma, itís also useful in indolent lymphomas and in chronic lymphocytic leukemia. When we used to give our CLL talks we used to say, "Trisomy 12 is the most common cytogenic abnormality in CLL, occurring in around 20-25% of patients" Ö wrong. We now have found out, using more sophisticated techniques, that A: trisomy 12 is not the most common cytogenetic abnormality, and B: itís not found in 20-25% of patients. This is a slide of a fluorescent in situ hybridization, or FISH. And this was a patient using standard cytogenetic techniques, had a normal karyotype.

Moving on to the treatment aspect. This slide shows the remarkable progress we have made over a series of decades in the treatment of CLL. Going from the 60ís to the 70ís to the 80ís you can see two things. One, we aint made a whit of progress and two, there is no plateau on the tail of these curves, which demonstrates that CLL is an incurable disorder which leaves the treating physician with two decisions; not only how to treat patients but when to treat patients. Toward the latter, the French cooperative group - Dr. Binet and co-workers - did a series of large randomized studies, most recently published in the New England Journal. In this study they compared, in patients with Binetís stage A disease, daily oral chlorambucil or no initial therapy. As you can see, there was no difference in time to progression to more advanced stage and there was no difference in survival. But the group that got earlier intervention with daily chlorambucil had a much greater likelihood.