Chronic Lymphocytic Leukemia (CLL).

Chronic Lymphocytic Leukemia is the most common leukemia form observed in western countries to industrial development, affects more males and prefers the elderly over the age of 50 years. It can be defined as a monoclonal proliferation and uncontrolled of small lymphocytes that accumulate in the peripheral blood, bone marrow, lymph nodes and lymph organs.
More rarely affects extralymphatic locations. In a high percentage of cases the disease is diagnosed accidentaly by chance on the ground of a persistent peripheral lymphocytosis in asymptomatic patients or with clinical problems of other nature (often infections); and more rarely is the presence of lymphadenopaties e or hepatosplenomegaly to direct the physician toward the diagnosis.
The diagnosis of CLL is mostly manageable and it’s based essentially on the presence in the peripheral blood of a large number of lymphocytes, including in most patients between 5000/mmc and 150.000/mmc.
In percentage peripheral lymphocytes in the course of CLL represent 55-99% of the circulating elements, and they are morphologically indistinguishable from small normal lymphocytes but, unlike these, are particularly fragile, so as to deteriorate easily smear, giving rise to the so-called "Gumprecht shadows."

Collateral laboratory findings, very important are: the frequent confirmation of normocytic normochromic anemia, usually of insignificant entity; thrombocytopenia; and especially a hypogammaglobulinemia (0.7-0.8 g%), present in 50-75% of cases, that has increased in more advanced stages of the disease.
In the majority of cases (95-98%) neoplastic proliferation affects a single clone of B-lymphocytes (B-CLL). More rarely (5%) the nature of the leukemic lymphocytes is of type T (T-CLL).
Flow cytometry is the method of choice to confirm the CLL’s diagnosis, and makes use of specific reagents called monoclonal antibodies. The criteria for the diagnosis of B-CLL are based on weak expression of immunoglobulins of the surface of B lymphocytes (typically less than that of B lymphocytes normally circulating), by the expression of the markers CD19, CD20, CD23, CD5 in B lymphocytes
of the peripheral blood, bone marrow and lymphoid organs.

-Anatomo-clinical ratings and prognostic factors. The clinical picture and course of CLL are extremely variable existing, such as extremes of a wide spectrum of variations, forms for performance "aggressive" with poor prognosis in the short term and benign forms of protracted course. Retrospective studies are conducted by several authors to identify parameters correlated with the prognosis and therefore able to predict the course of the disease, survival, based on which, then set different treatment protocols. A substantial contribution to the resolution of the problem was given in 1975 by Rai et al., that have proposed a classification system in five clinical stages with different prognosis and life expectancy, based on clinical and laboratory findings obtained with standard diagnostic methods and then easily reproducible:
- Stage 0: bone marrow (40%) and peripheral lymphocytosis (15.000/mmc); median survival time: 12 years;
- Stage I: lymphocytosis associated with enlarged lymphonodes: median survival: 8 years;
- Stage II: lymphocytosis associated with spleno and/or hepatomegaly; median survival: 5.5 years;
- Stage III: Lymphocytosis associated with anemia (Hb <10 g / dl), median survival time: 2 years;
- Stage IV: lymphocytosis associated with thrombocytopenia (P1T <100,000 bcm), median survival time: 2 years.

Most recent attempts classified have reduced the number of stages, which appear to be more closely related to the prognosis of patients in them grouped. An International Working Group (International Workshop gold CLL) meeting in Paris in November 1979 and in Montreal in August 1980, based on a multiparameter analysis conducted on over 900 patient has proposed a new prognostic classification in three LLC stages (Binet et al.; 1981). Patients with anemia (Hb <10 g / dl) and /or thrombocytopenia (Plt <100,000 mm3) have a worse prognosis and are included in the group C.

The survival of the remaining patients (about 80%) is seen to depend by the clinical interest of the following five systems: spleen, liver, cervical, axillary and inguinal lymph nodes (regardless of the adenopathy is mono or bilateral). Patients with involvement of at least three of these areas form the group A, a better prognosis while subjects with 3 or more affected areas form the group B in intermediate prognosis. This new classification distinguishes:

CLINICAL STAGE A: less than 3 areas of interest absence of anemia or thrombocytopenia
CLINICAL STAGE B: involvement of 3 or more areas absence of anemia or thrombocytopenia
CLINICAL STAGE C: anemia (Hb <10 g / dl) and/or thrombocytopenia (P1T <100,000 bcm).

Among the many other prognostic factors taken into account in recent years by various scientists, deserve to be reported: the pattern of bone marrow infiltration (diffuse, nodular, interstitial); the phenotypic and immunological characteristics of lymphoid elements (especially nowadays importance has been given to the expression of ZAP-70 and CD38) and the gene pattern of immunoglobulin (been changed or not changed). All of them are parameters well correlated with the Rai staging system, and therefore able to predict, with likely confidence, the prognosis of patients with CLL.
In particular, an infiltrative pattern spread, the expression of ZAP-70 and CD38, and a set of non-mutated IgV genes, are the parameters associated with a lower life expectancy and therefore are defined as adverse prognostic factors. The forms of LLC which START from lymphocyte B naive present the genes which encode the variable part of the Ig-state non-mutated, express immunological markers such as CD38 and ZAP70, the lymphocyte count tends to double in a time interval less than 6 months, are marked with prognostically unfavorable cytogenetic abnormalities (trisomy 12, chromosome 11 deletion and alteration of chromosome 17 with mutations in the p53 gene), and have a clinical course in death in a few years, while the variant that starts with the B cell memory has a favorable prognosis (decades), doesn’t express CD38 and ZAP 70, often doesn’t present clonal cytogenetic abnormalities or it’s characterized by the presence of prognostically favorable cytogenetic abnormalities (chromosome 13), have a lymphocyte doubling time of more than 6 months, and have the genes for the IgV state changed.
In 10% of cases of CLL, the disease can develop into aggressive forms of lymphoma. This framework, called Richter's syndrome is characterized by the sudden onset of general symptoms (fever, night sweats, weight loss) with asymmetric increase of the size of the lymph nodes, hepatosplenomegaly and fast decay of clinical conditions; survival from the time of diagnosis, despite aggressive chemotherapy, is generally less than 1 year.
Nowadays there are numerous combinations of drugs able to successfully control the disease. There are also several monoclonal antibodies extremely effective in the control of the LLC, such as rituximab, MabCampath, ofatumumab. In the more aggressive cases the disease can be cured with allogeneic stem cell transplantation.
In recent years, scientific research is making great progresses both in diagnosis and therapy, in particular in the area of molecular biology (the study of epigenetics and microRNA), identification markers of angiogenesis (that is construction of blood vessels), and in the field of minimal residual disease by flow cytometry, which is essential for monitoring the response to drugs.

To conclude this brief overview, two general considerations:
- Who to entrust a patient with CLL? To medical specialists in hematology, updated and actively involved in scientific research, working in hospitals with a laboratory capable of performing on-site and in a short time the diagnostic morphological, cytogenetic and molecular features of which has been discussed;
- The rapid evolution of knowledge in medicine LLC confirms that scientific knowledge is never complete, but continues to progress in the hope of winning the battle against leukemia: BEAT LEUKEMIA!

Dr. Francesco Lanza, UO Director of Hematology, Istituti Ospitalieri Cremona

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