Chronic lymphocytic leukemia


This is a retirement disease: the average age of patients is 65 years, 2/3 of cases are over 60 years old at diagnosis;the cases observed before age 40 are exceptional. There is a discrete male predominance (61%).

A- Clinical manifestations:

1- Latency clinic:

The disease is often clinically latent and long. More than half of the cases were found by chance, on the occasion of prescribing a blood count in adults apparently healthy, with a variable lymphocytosis, usually between 5000 / mm3 and 50,000 / mm 3, but occasionally reaching several hundreds of thousands of cells per mm3. Symptomatic latency blood lymphocytosis, even when it reaches these values ​​is remarkable. Patients sometimes expressed in such circumstances a physical feeling of weariness. A low-grade fever, sweating, weight loss is unusual and should raise suspicion intercurrent or progressive complication of the disease.

2- Lymph Nodes:

Superficial lymph nodes are detected by palpation of the cervical areas, supraclavicular, axillary and inguinal. Their presence is inconsistent. The nodes are typically bilateral, long moderate volume, symmetric, painless, non-compression. The simultaneous achievement of several of these areas has prognostic implications. The deep lymph nodes are not systematically studied because of their usually asymptomatic and scarcity compressive events. The mediastinum traditionally seemingly unscathed on chest face and profile shots, often conceals lymphadenopathy if examined CT: ganglia are observed in the mediastinal paratracheal chains, mainly in the lodge and Baréty aorto-pulmonary window. They are rarely large (1-2 cm) and never compressive, unless transformation (Richter syndrome). Retroperitoneal lymphadenopathy have long been studied by lymphography. The review has the advantage of providing fairly precise images of pathological lymph nodes, where the end of a normal dotted ganglion is replaced by a more or less coarse speckled; the existence of lacunar images is unusual unless there is a transformation in Richter’s syndrome. Moreover, the persistence of the contrast agent in the affected nodes enables a scalable monitoring lesions for several months. Despite less definition of pathological lymph node images, CT has become today face lymphography for the exploration of abdominal and pelvic lymph node chains, because of the greater ease of implementation.

3- Splenomegaly:

Splenomegaly is often associated with lymphadenopathy. It can sometimes be isolated: this presentation is reputedly better prognosis, or at least to evolve slowly. However, the bulkiness of the spleen is sometimes indicates a more aggressive form called prolymphocytic, or other chronic lymphoproliferative diseases, which can be confusing especially if the blood count has not been carefully examined under the microscope an experienced cytologist.

4- Other signs of lymphoid swelling:

The volume increase pharyngeal tonsils is common but rarely causes dysphagia or signs of local compression. The lymphoid infiltration is actually present in most tissues but it is usually asymptomatic. Often it is described in a biopsy specimen performed for other reasons on a prostate lesion, pulmonary, digestive, etc .. The risk is too easily attributed to these lymphocytes infiltrate a tumor lesion role specific. However, there are symptomatic parenchymal locations of comments: kidney with proteinuria and nephrotic syndrome, skin type infiltrated papules, interstitial lung or pleural, osteolytic, meningeal. These observations are exceptional.

B- morphological examinations:

1- Complete blood count:

It shows an absolute increase in the number of small lymphocytes that there is nothing to distinguish from normal lymphocytes. This increase can be discreet at first, between 5000 and 10,000 / mm3, or significant at the first examination, exceeding 100,000 / mm3. Examination of the blood smear shows the usual presence of nuclear cadavers or “Gumprecht shadows.” The hyperlymphocytosis has no proper symptomatic accordingly; especially leukostasis phenomenon has little reality, except in rare cases when it exceeds 500,000 / mm3. It is possible, in the forms hyperlymphocytaires, detect changes in the ventilation-perfusion ratio when using sensitive methods.However, the hyperlymphocytosis can cause artifacts assays: blood gases can be changed by excessive oxygen consumption in vitro artifactual if we do not take care to refrigerate the sampling syringe to keep it at 4 ° C and practice without delay review. Similarly, an artificial hypoglycemia in vitro glucose consumption is possible if the sampling tube does not contain sodium fluoride (this blocks the mitochondrial respiratory chain, so aerobic glycolysis). In most cases, the granulocyte count (if care is taken to express it in absolute value), red blood cells and platelets shows normal values. The finding of anemia or thrombocytopenia is rare at diagnosis. Their presence alters the prognosis of the disease and justified to clarify if possible mechanism for the therapeutic measures required in such cases are not unique.

2- Myelogram:

It shows an infiltration of small lymphocytes, constant in this condition, more than 30%. This infiltration is usually important percentage which randomizes the appreciation of the richness of other lineages. This restriction explains the difficulty of interpretation of bone marrow aspiration in cases of anemia or thrombocytopenia associated.

3- marrow biopsy:

Histologically infiltration may take several aspects: moderate interstitial nodules, has more or less dense and dotted with focal reinforcements. The density of this infiltration has no obvious translation on normal hematopoietic generation. However, it affects the overall prognosis of the disease forms dense infiltration and diffuse are less favorable than those interstitial or nodular infiltration.

4- Adénogramme:

He would show a dense monomorphic smears and small lymphocytes.

5- lymph node histopathological examination:

Histological examination of a lymph node, which is the key to diagnosis of non-Hodgkin lymphoma, has not been systematically studied in chronic lymphocytic leukemia, perhaps because the disease is blood first hematology and bone marrow in his expression. Sometimes discreetly or ignorance of hematological signs (blood count), these nodes are subject to a histopathological examination after lymphadenectomy: the appearance is that of a diffuse proliferation of small and monomorphic cells, erasing the normal architecture of lymph node, sometimes constituting pseudo-follicles blanks. Pathologists classify this as a lymphocytic lymphoma or small well differentiated lymphocytes. These nosological equivalencies are useful to know.

C- immunological tests:

They allow you to specify the type of lymphocyte proliferation and constituting existence, frequent manifestation of immunodeficiency and autoimmunity (see: For further 5).

1- lymphocytic immunophenotype:

These are monoclonal B lymphocytes. The study of membrane immunoglobulins always find a single type of light chain kappa or lambda. Heavy chains are usually very mu (IgM), sometimes type delta (IgD), often the two types associated. Typical alpha or gamma (IgG or IgA) are exceptional. One of the most faithful signs of the disease is the decrease in density of the membrane immunoglobulins from normal B lymphocytes. More recently, the availability of narrow specificity of monoclonal antibodies has allowed to recognize in their membrane coexpression of conventional B differentiation antigens (CD19, CD20), and an antigen conventionally expressed by T cells and a sub- population restricted B (CD5). This coexpression CD19-CD5 is a faithful sign of the disease. The expression of CD10 and CD25 antigens is negative. Without exception, the interest of these diagnostic markers is inversely proportional to the cytological experience in hematology specialist who carried out the examination of the blood count. They can however be useful to distinguish chronic lymphocytic leukemia chronic lymphocytic proliferations morphologically similar but distinct nosologically (Table I). Proliferation is rarely T-type: these forms are controversial classification and usually correspond to the appearance of a large granular lymphocyte leukemia.

2- humoral immunity:

Hypogammaglobulinemia is common. It can be separated, or wear on the 3 major classes of immunoglobulins (IgG, IgA, IgM). The antibody deficiency is also illustrated by the decline in anti-A and -B natural hemagglutinin, the difficulty of observing a vis-à-vis seroconversion a particular vaccine antigen. It is possible but uncommon to detect a peak serum monoclonal IgM, reflecting transitional forms with Waldenstrom’s macroglobulinemia (5% of cases).

3- cellular immunity:

Quantitative alterations of subpopulations of T-lymphocytes, in particular CD4, are discrete at the beginning of the disease, then asserts during evolution. It is difficult to distinguish the spontaneous alteration and treatment effects.Qualitatively, a cell cooperation default B / T is highlighted by the lack of expression of certain membrane antigens specifically involved in this function.

D- Karyotype:

The study of the karyotype is facing difficulties in obtaining analyzable mitotic and requires the use of laborious mitogenic processes. In these cases, the most common cytogenetic abnormalities are an anomaly of the long arm of chromosome 13 (q14) and trisomy 12. The recent introduction of techniques such as hybridization interphase fluorescence facilitates the identification of this anomaly (see: To deepen 6).

E- Diagnostic Practice:

The majority of these tests are not essential to the diagnosis of the disease in clinical practice, and have no interest in the prospective studies of this disease. In practice, the diagnosis is based on simple arguments: an adult, chronic lymphocytosis small lymphocytic, exceeding 5,000 / mm3 for several months, made of small cells of normal appearance is a major criterion if the morphological examination is by a competent specialist. It is conventional to involve the demonstration of bone marrow infiltration by these cells, criterion exceptionally in default if lymphocytosis is significant. The interest of immunophenotypic study is related to the possibility of confusion with some forms of non-Hodgkin lymphoma (follicular lymphoma leukemia forms of mantle cell lymphoma, splenic lymphoma called villous lymphocytes) and forms borders with macroglobulinemia Waldenstrom or leukemia prolymphocytaires say: the best criteria for chronic lymphocytic leukemia are coexpression CD19 / CD5, the low density of membrane immunoglobulin expression of the CD23 antigen, the lack of expression of CD10 and CD25. This expression of membrane markers profile is used by some to establish a score for assessing the likelihood of diagnosis. Table I summarizes the main varieties of chronic lymphoproliferative diseases that can, by their clinical presentation and (or) cytological, confusing.


The disease course is variable: some cases develop slowly or remain remarkably stable over very long periods (sometimes decades), others get worse in a few months. The evolution is punctuated by infectious complications, tumors, autoimmune and bone marrow failure.

A- Infections:

They are the most common cause of hospitalization and mortality in these patients. They depend granulocytopenia, spontaneous or iatrogenic alteration of cellular and humoral defenses. These contributing factors are often combined. Bacterial infections are especially bronchopulmonary, favored by progressive hypogammaglobulinemia and granulocytopenia: repetition may make the bed bronchiectasis that evolve on their own behalf, promoting the recurrence of infectious episodes. Viral infections, mycobacterial and protozoa depend mainly on the impaired cellular immunity, whether spontaneous or iatrogenic: reduction in blood levels of CD4 cells is particularly pronounced with drugs such as fludarabine, corticosteroids and the monoclonal antibody being evaluated (anti-CD52). The causative virus of the herpes group include: shingles, herpes recurrent peri-orificiels, cytomegalovirus pneumonia. Tuberculosis is not uncommon, especially in the population of older patients often escaped the mandatory vaccination with BCG. Protozoan (Toxoplasma gondii, Pneumocystis carinii) are sometimes observed at a terminal stage. Infections fungi: Candida, Aspergillus, Cryptococcus have pulmonary tropism, sometimes neuroméningé or septicaemic: these cases are most often detected only post mortem.

B- Tumor Progression:

Signs of lymphoid swelling remain for a long time not pronounced in the majority of patients. Where are bulky lymphadenopathy at diagnosis or become still evolving, the pathological type of proliferation is hardly changes: the glands keep an appearance diffuse infiltration by small lymphocytes. Over time, a contingent of nucléolées lymphoid cells (prolymphocytes) appears in the blood, bone marrow and lymph nodes for most patients, but these cells are still a minority (<20%): they must not speak of acute transformation. These cases must be distinguished leukemia say prolymphocytaires B whose diagnosis is evoked by a proportion of prolymphocytes immediately important in the blood (> 50%). Histological transformation (Richter syndrome) is rare. It must be mentioned if the lymph nodes become large, compressive, sensitive or are accompanied by local or systemic inflammatory manifestations (fever, sweats, weight loss). The histological or cytological monotony of ganglion is then modified by a large immunoblastic proliferation aspect cells or recalling Sternberg cells.

C- Autoimmunity:

Of autoimmune manifestations can reveal disease or complicate evolution. They are dominated by the anti-erythrocyte autoimmunity. This can be limited to a positive direct Coombs test without excessive hemolysis. The actual incidence of autoimmune hemolytic anemia is estimated between 5 and 10%. This complication is rarely indicative of chronic lymphocytic leukemia, usually detected evolving, and seems favored by immunosuppression and use of certain treatments (particularly fludarabine) in previously multitraités patients. The majority of cases are hot type, anti-Rh. Cases of cold antibodies are rare. This complication worsens the prognosis of the disease mainly by the treatment makes it necessary (corticosteroids in the forms to hot antibodies, immunosuppressive when glucocorticoid or corticorésistance and forms antibodies to cold). Some cases of aplastic anemia depend on an autoimmune PRCA likely mechanism. This mechanism is difficult to prove in this field: the direct Coombs test is generally positive, but there is no hyperhemolysis license. The examination of bone marrow erythroblasts shows little (<5%), but this test is difficult to interpret in the presence of a significant lymphocytic infiltration. The frequent correction of anemia by a non cytostatic immunosuppressive therapy (eg, cyclosporine) reinforces the hypothesis of a demonstration of anti-erythroblast autoimmunity in these cases. Other autoimmune manifestations are much more rare: a few cases of immune thrombocytopenic purpura, or association with rheumatoid arthritis, Sjogren’s syndrome, lupus disease are reported but are anecdotal.

D- Bone marrow failure:

The marrow failure events may be present immediately at diagnosis: in fact, it is likely that early cytopenias (initial stages C) depend on complex mechanisms and still incompletely understood (medullary maturation-dependent inhibition of cytokines, self immunity). Bone marrow failure is usually a late manifestation dependent multiple treatments received by patients. It limits its use and causes its own complications: infections, bleeding, transfusion dependence.


Some prognostic factors are predictive of overall survival.

A- prognostic classifications to:

Much work has been devoted to the identification of prognostic criteria, including emerging classifications by stages: they have the advantage of simplicity of practical application (these classifications require only clinical data and blood count) and reproducibility. Two classifications share the favors of clinicians (Tables II and III): the classification in 3 stages ABC, developed in France by JL Binet et al, favored by French hematologists;. the classification in 5 stages, developed in the US by K Rai et al., has more than the Anglo-Saxons. By applying the ABC classification, the median survival of patients with stage A is greater than 120 months and approaches to subjects over 60 years, the survival of a healthy population of the same age. The median Patients with stage B of the order of 70 months that patients with stage C is about 40 months.

B- Other prognostic criteria:

The identification of validated prognostic criteria is one of the current goals of clinical research. The doubling time of blood lymphocytosis less than 12 months, bone marrow infiltration by diffuse type biopsy, an increase in the serum of the soluble fraction of the CD23 receptor or beta-2 microglobulin levels, the existence of cytogenetic abnormalities including 17p and 11q have an unfavorable prognosis. The interest of these prognostic criteria compared to the above classifications is being evaluated.

Principles of treatment:

There is no known example of a patient cured of this condition. Current treatments used to regress the lymphoid intumescence events in most patients: even in cases where a complete tumor regression was observed (disappearance of clinical manifestations of lymphoid intumescence, pathological blood lymphocytes, the bone marrow), one can detect the presence of residual clonal cells in all patients using ultrasensitive methods (PCR) amplifying the genes of the variable regions of the immunoglobulin heavy chain specific for the clone, and repeating as necessary. The objective of the current therapeutic research is based on the assumption that the fullest possible tumor reduction (disappearance of all significant residual disease) produces a benefit in terms of survival. The current median survival are indeed difficult to accept for a high proportion of patients still ‘young’ chronic lymphocytic leukemia stages B or C.

A- Stage A:

These patients should not be treated unless symptomatic progression: their overall survival similar to that of a healthy population of the same age, is not changed. Above all, the administration of Chloraminophène could eventually promote the development of therapeutic resistance in the event of disease progression; Incidence increased cancer however, are not yet formally established.

B- Stages B and C:

The goal of treatment is to achieve and maintain the most complete tumor regression as possible at the price of the lowest possible toxicity. The choice of treatment in these cases is still debated, and several ongoing trials are trying to assess the advantages and disadvantages of each.

1- Treatments available:

• Chloraminophène (2 mg capsules): it is the oldest drug used. It is used either in continuous prescription at a dose of 0.1 mg / kg / d, discontinuous prescription at a dose of 0.25 mg / day, 5 consecutive days every 4 weeks in combination with prednisone. A response is observed in 6 to 9 months, featuring in most cases a regression of lymphocytosis in a third of cases partial or complete regression of clinical signs (lymphadenopathy and splenomegaly), but the bone marrow infiltration persists in all case. Some authors propose in prospective trials using continuous heavy doses (10 mg / m2 / day) until a maximum response; the response time is shorter and higher response rate.

• polychemotherapies: most proven combines adriamycin (25 mg / m2), cyclophosphamide, vincristine and prednisone (CHOP). Administered monthly, it provides a partial or complete regression of clinical signs and blood counts in 75% of cases, spinal normalization in 10% of cases. Tolerance is suitable, alopecia is the most common side effect. The risk of cardiomyopathy dependent adriamycin is very low if the heart against-indications are respected, that of sensorimotor neuropathy dependent vincristine is low neurological monitoring is regular.

• Fludarabine (injectable ampoules iv 50 mg): purine analog that is used in monthly courses at a dose of 25 mg / m2, 5 days. The responses are comparable to those obtained by the above association. Side effects are different: alopecia is exceptional, but the immunosuppressive effects are stronger (prolonged depletion of CD4 lymphocytes).This medication affects occurrence of autoimmune hemolytic anemia, especially among multitraités patients.

2- being evaluated treatments:

• Immunotherapy: it uses monoclonal antibodies directed against certain antigens of these cells (CD52, CD20). This type of treatment is currently being evaluated and looks promising to complete the effect of initial chemotherapy.

• Intensive Treatments: strong chemotherapy followed by autologous bone marrow transplantation are encouraging results in young patients, especially in cases of resistance to conventional treatments. The beneficial effect seems especially that of the total radiation by packaging. Currently being considered instead of these therapeutic methods in subjects with age is consistent with the morbidity of these treatments.

C- symptomatic treatments:

Symptomatic treatments are paramount: precise and appropriate antibiotics if possible in case of bacterial infection, preventive gamma globulin for some. Attenuated vaccines are contreindiqués. The flu shots are not actually against-indicated but have uncertain effectiveness. The tetanus and polio vaccines are used without apprehension. Some cases of anemia may warrant special treatment: the cases of autoimmune hemolysis, justifying strong corticosteroid therapy (1 mg / kg / day) and prolonged several weeks. In the case of autoimmune PRCA, corticosteroids, immunosuppressants (cyclosporine) have success to their credit. Irradiation of the spleen low dose (5-10 Gy) in case of voluminous splenomegaly may be a useful adjunct.

Highlights to include:

• Chronic lymphocytic leukemia is the most common hematological malignancies in adults in the West. It has no known cause or precipitating factor. It is characterized by the progressive infiltration of bone marrow, blood, lymphoid organs by a small B cell clone

• The proliferation kinetics of this clone is usually slow, and there is an apparent paradox between this property and the sometimes major tumor development of the disease: in reality, it is thought that the disease is more proliferative than accumulative.


1 / Epidemiology:

The geographical distribution of the disease is special. In the West, this is the most common hematological malignancies: its incidence is 1 to 3 new cases per year per 100,000 inhabitants. However, this form of leukemia is exceptional in the Far East, and its frequency is very low among Asian immigrants in the United States.

2 / etiological factors:

No predisposing factors, genetic or acquired, have been reported to date: the study of markers HLA (human leukocyte antigen) does not detect association with a particular phenotype. Exposure to radiation or toxic, including benzene, does not seem concerned. The evocation of a risk linked to exposure to electromagnetic fields currently lacks any convincing basis. The familial cases are rare. In these related cases, gene sequencing of the variable parts of the heavy chains (VH) has not resulted in detection of common immunogenetic characteristics.

3 / Origin and nature of leukemic cells:

Pathological monoclonal cells derived from a subpopulation of cells which is believed to correspond to the perifollicular ring of nodes. These cells have the particular feature of co-express markers of differentiation B (CD19, CD20, CD23), but also a type of T antigen (CD5) restricted to this subpopulation B: coexpression of these two types of marker identifies a population of said cells autoreactive that would be closely involved in the ordering of the recognition and immunological tolerance of the self. The initial differentiation of normal B cells is linked to a rearrangement of their immunoglobulin genes event, obligatory step and characteristic of this differentiation (rearrangement of VDJ sequences). This rearrangement specific to each cell is one of the phases of acquisition of immunological diversity of B cells and each cell selects a directory in its specificity expresses the antibody it produces. at this stage, the antibodies present on the membrane of cells are IgD type and (or) IgM, “polyreactive” that is to say capable of simultaneously recognize several antigens with low affinity. These cells “naïve” then migrate within the follicle B, or after an antigenic contact, they undergo additional somatic mutations of genes of variable portions. These phenomena alter the affinity characteristics: it becomes strong and specific. In the case of chronic lymphocytic leukemia, all cells have operated the same VDJ rearrangement, which means they belong to the same clone. In usual cases, the cells express on their surface polyreactive IgM immunoglobulins. The additional somatic mutations are rare, which means that the event triggering the disease affects a cell B “naive” or “immature” (immunologically sense: the morphology of these cells with a mature cell appearance). However, recent data show that this aspect of cells “naïve” is far from the rule is observed in some cases a high frequency of somatic mutations, suggesting a malignant transformation process to a more advanced stage of differentiation.

4 / Mechanisms of proliferation:

The disease has long been a mystery as to how tumor development, paradoxical for the potential of these cells slowed division.We now know that the disease depends as much, and perhaps even more, a slowdown in the process of senescence and cell death (apoptosis) their excessive proliferation: the disease is more proliferative than accumulative. However, the cellular mechanisms of this imbalance are still unclear in chronic lymphocytic leukemia.In most cases of malignant lymphoid proliferation of B lineage, the carcinogenesis seems closely related to the activation of a proto-oncogene (usually by chromosomal translocation): depending on the case, activation of proto -oncogène results in excessive synthesis of an activation protein of the cell cycle (the case of C-MYC in Burkitt’s lymphoma, BCL1 of in mantle cell lymphoma), or a protein of inhibition of apoptosis (case Bcl2 in the case of follicular lymphoma). But none of molecular carcinogenesis of this type have been identified to date in the case of chronic lymphocytic leukemia. Overexpression of oncogene Bcl-2 is observed in the cells, but it does not result from a translocation as in the case of follicular lymphomas (one evokes an inactivating default hypomethylation of the gene), and the increase appears Bcl2 contingent in the malignant transformation mechanism of cell chronic lymphocytic leukemia. Some tumor proliferation are associated with the loss of anti-oncogene function (the vector is that of the retinoblastoma). For example, one of the key steps in the cell division cycle is exercised by the p53 protein schematically, this protein has the function of blocking the progress of the cycle (G1 to S phase transition) whether any DNA lesions have not been properly repaired before mitosis. The mutation of p53 causes a loss of control and this allows division of abnormal cells. Such mutations have been detected in a small proportion of cases of chronic lymphocytic leukemia (10-15%). However, they seem to be more an evolutionary step that initial event in this disease: the mutations of p53 mainly involve advanced forms, multitraitées.

5 / mechanism of immune alterations:

Many current work suggest the existence of an anomaly in the interaction between antigen presenting cells and T cells in chronic lymphocytic leukemia: in particular, the activation of many functions of T cells depends on the stimulation of a membrane receptor of T cells (CD 40) by the specific ligand for this receptor (CD40 L) present on antigen presenting cells. This interaction depend membrane expression and activation (modulation) of molecules involved in the activation or control many immune functions cytokine receptors, adhesion proteins, histocompatibility antigens … This interaction is abnormally low in chronic lymphocytic leukemia. It could explain, at least in part, the immunological abnormalities observed in this disease (cellular and humoral immune deficiency, autoimmune manifestations).

6 / chromosomal abnormalities:

Two main types of chromosome damage acquired (somatic) are frequently observed in the B cell chronic lymphocytic leukemia. Trisomy 12 is detected in 10-15% of cases if it is sought by the karyotype, 20% of cases if it is sought by interphase fluorescence. It is unclear whether it plays a role in the genesis of the disease. It seems more likely associated with atypical cytological or immunological presentation. The 13q12 and 13q14 abnormalities (deletions or microdeletions) seem to result from an early event in the disease. They could be associated with the loss of an anti-oncogene function. It shows a microdeletion few hundred bases within these regions 25 to 50% of cases, depending on the technique used. Additional cytogenetic abnormalities are detected less frequently: 17p abnormalities (mutations and deletions of p53) seem associated with a stage of tumor progression (Richter syndrome, prolymphocytic transformation). 11q23 abnormalities are detected in younger subjects and more rapid disease progression. Recent work and need to be confirmed found these abnormalities in hematopoietic stem cells (population CD34 +) in some patients, if these facts are confirmed, they evoke a disease development mechanism in several steps, where prior alteration stem cell facilitate the emergence of a clonal proliferation of B lymphoid cells

Strong Points to remember:

• The diagnosis is based on simple arguments: chronic lymphocytosis small lymphocytic> 5000 / mm3 for several months.

• The evolution is variable. Some cases develop slowly. It can be sprinkled with infectious complications, autoimmune and bone marrow failure.

• The goal of treatment is to achieve and maintain tumor regression as complete as possible.