3.1. CML

3.1.1. Definition

CML is a malignant clonal disorder of hematopoietic stem cells that results in increases in not only myeloid cells but also erythroid cells and platelets in peripheral blood and marked myeloid hyperplasia in the bone marrow.

3.1.2. Etiology

The diagnosis of CML is usually based on detection of the Philadelphia (Ph) chromosome. This abnormality, first described as a shortened chromosome 22 in 1960 and then as a t(9;22) translocation in 1973, is present in 95 percent of patients. Another 5 percent have complex or variant translocations involving additional chromosomes that have the same end result, which is fusion of theBCR (breakpoint cluster region) gene on chromosome 22 to the ABL (Ableson leukemia virus) gene on chromosome 9. The Ph chromosome is found in cells from the myeloid, erythroid, megakaryocytic, and B lymphoid lineages, indicating that CML is a stem-cell disease.

3.1.3. Epidemiology

CML occurs in all age groups, but most commonly in the middle-aged and elderly. Its annual incidence is 1–2 per 100,000 people, and slightly more men than women are affected. CML represents about 15–20% of all cases of adult leukemia in Western populations. [1] The only well-described risk factor for CML is exposure to ionizing radiation; for example, increased rates of CML were seen in people exposed to the atomic bombings of Hiroshima and Nagasaki[2] .

Leukemia is also rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women.

3.1.4. Pathogenesis and Pathophysiology

During the evolution to a blast crisis, a range of nonrandom, secondary chromosomal changes occur, including duplication of the Ph chromosome and trisomy 8. Mutations or deletions of tumor-suppressor genes such as p16 and p53 occur with variable frequency and presumably contribute to the malignant phenotype. The molecular consequence of the t(9;22) translocation is the creation of the fusion protein BCR– ABL, which is a constitutively active cytoplasmic tyrosine kinase. Depending on the site of the breakpoint in the BCR gene, the fusion protein can vary in size from 185 kd to 230 kd. Each fusion gene encodes the same portion of the ABL tyrosine kinase but differs in the length of BCR sequence retained at the N terminal. Nearly all patients with typical chronic-phase CML express a 210-kd BCR– ABL protein, whereas patients with Ph-positive acute lymphoblastic leukemia express either a 210-kd or a 190-kd BCR–ABL protein (the latter is sometimes referred to as 185/190 kd). Recently, a larger, 230- kd BCR–ABL fusion protein was found in a subgroup of patients with CML who presented with a lower white-cell count than is usual for the disease and in whom progression to blast crisis was slow.

The fact that fusion proteins of different sizes can be correlated with different outcomes has led to laboratory studies of the biologic activity of the proteins. The results indicate that the 190-kd BCR–ABL protein has greater activity as a tyrosine kinase and is a more potent oncogene than the 210-kd protein, suggesting that the magnitude of the tyrosine kinase signal affects the expression of the disease. The cloning of the Ph translocation has led to the development of highly sensitive and specific molecular probes that are valuable tools for monitoring responses to therapy. Quantitative cytogenetic information can be obtained by fluorescence in situ hybridization without the need to culture cells or analyze cells in metaphase.

Polymerase-chain-reaction (PCR) testing of peripheral-blood RNA is highly sensitive: it can detect 1 Ph-positive cell expressing the BCR–ABL fusion transcript in 10 to 10 normal cells. One consequence of these newer diagnostic tests has been the reclassification of the response to treatment on the basis of hematologic, cytogenetic, and molecular remissions. A hematologic remission indicates a return of peripheral-blood cell counts and bone marrow morphology to normal, whereas cytogenetic and molecular remissions indicate the disappearance of the Ph chromosome or the BCR– ABL gene, respectively. The favorable prognostic value of hematologic and cytogenetic remissions is clear, on the basis of data on survival among patients treated with interferon alfa, but the clinical value of molecular testing remains to be defined. Negative PCR results in patients treated by allogeneic bone marrow transplantation clearly predict a favorable outcome, but positive results are difficult to interpret, because of the extreme sensitivity of the PCR assay. For example, the results of PCR assays can remain positive in interferon-treated patients who are in complete cytogenetic remission and patients who have survived for several years after bone marrow transplantation, two subgroups with very favorable outcomes, presumably because small numbers of leukemic cells remain. Newly developed quantitative PCR assays allow monitoring of the level of BCR– ABL messenger RNA transcripts over time. On the basis of these assays, a progressive increase in minimal residual disease after allogeneic transplantation appears to predict eventual relapse.

3.1.5. Clinical Manifestation and Diagnosis

The median age at presentation is 53 years, but all age groups, including children, are affected. Most patients also have thrombocytosis, which is consistent with the presence of a defect in a pluripotent hematopoietic stem cell. The typical symptoms at presentation are fatigue, anorexia, and weight loss, but about 40 percent of patients are asymptomatic, and in these patients, the diagnosis is based solely on an abnormal blood count (Table 1). The most common abnormality on physical examination is splenomegaly, which is present in up to half of patients. The natural history of CML is progression from a benign chronic phase to a rapidly fatal blast crisis within three to five years. The blast crisis is often preceded by an accelerated phase in which increasing doses of hydroxyurea or busulfan are required to lower the neutrophil count. In contrast to the maturation of CML cells during the chronic phase, during a blast crisis cells fail to mature and resemble the myeloblasts or lymphoblasts found in patients with acute leukemias.

3.1.6. Differential Diagnose

Differential diagnose of CML include :

Agnogenic Myeloid Metaplasia With Myelofibrosis Essential Thrombocytosis Myelodysplastic Syndrome Myeloproliferative Disease Polycythemia Vera

Problems to be considered include the following:

Acute myeloid leukemia Chronic myelomonocytic leukemia Chronic neutrophilic leukemia Thrombocythemia Leukemoid reactions from infections (chronic granulomatous [eg, tuberculosis]) Tumor necrosis

3.1.7. Treatment

During the chronic phase of CML, cytoreductive therapy is required in most patients to avoid thrombotic complications that can result from high circulating levels of neutrophils. Fortunately, CML cells are sensitive to several oral chemotherapeutic drugs.

Ninety percent of patients who are treated with hydroxyurea or busulfan have hematologic remissions. Hydroxyurea is preferred to busulfan because the median duration of

the chronic phase and median survival were significantly better in a comparative trial of long-term therapy to maintain the neutrophil count in the normal range .

Hydroxyurea is advantageous primarily because of its favorable toxicity profile rather than because it has a specific effect on CML cells. Treatment with either drug results in a negligible rate of cytogenetic response and has no effect on the rate of progression to blast crisis; therefore, these treatments must be considered palliative.

Allogeneic Bone Marrow TransplantationCML is a disease of hematopoietic stem cells. High-dose chemotherapy that destroys

the leukemic cells also destroys normal bone marrow and therefore must be followed by allogeneic bone marrow or stem-cell transplantation. Decades of follow-up data from multiple centers have confirmed that high-dose chemotherapy with busulfan and cyclophosphamide or combined chemotherapy with cyclophosphamide and fractionated total-body irradiation followed by allogeneic bone marrow transplantation is curative therapy in patients with CML in chronic phase. The International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation have recently reported survival rates of 50 to 60 percent among patients with CML in chronic phase who received chemotherapy alone or radiotherapy plus chemotherapy followed by transplantation of marrow cells from HLA-matched sibling donors. The largest single-institution experience is that of the Fred Hutchinson Cancer Center in Seattle, which reports a survival rate of 70percent at 10 years.

The success of allogeneic transplantation is age-dependent, being significantly lower in patients over the age of 40 years, primarily because of higher treatment-related mortality. Although age is clearly an important prognostic variable, transplantation decisions must be considered individually in the light of other variables that influence outcome, such as disease stage and the level of donor– recipient HLA matching. Because of the risk of transplantation-related mortality, it may be tempting to delay the procedure in patients with HLA-matched related donors until the disease progresses. This approach is inappropriate for two reasons. First, among patients with CML, those who undergo transplantation when the diseaseis in the chronic phase have a higher likelihood of survival than do those who undergo transplantation during the accelerated phase or blast crisis. Second, patients who undergo transplantation within the first year after diagnosis have a higher likelihood of survival than do those who undergo transplantation later, even if it is before progression to the accelerated phase.

These findings indicate that CML cells are capable of becoming resistant to high-dose chemotherapy and radiotherapy. Given that CML progresses steadily to a more malignant phenotype and that it is not possible to define the point in the chronic phase at which the likelihood of survival tends to decrease, allogeneic transplantation should be considered at the time of diagnosis in eligible patients with HLA-matched sibling donors. Unfortunately, only 15 to 20 percent of patients with CML are candidates for allogeneic transplantation from HLA-matched related donors because of age limitations and the low probability of having an HLA-matched sibling donor. This number can be increased to 30 percent through the use of HLAmatchedunrelated donors identified by bone marrow– donor registries.

However, the survival rate among recipients of transplants from unrelated donors identified by the National Marrow Donor Program is substantially lower than that among recipients of transplants from related donors. Recent results from a Seattle study are better, particularly in patients who were 50 years of age or younger

who received a transplant matched for HLA-A, B, and DRB1 by molecular studies. Molecular typing allows a distinction to be made between subtypes of serologically related but immunologically distinct HLA antigens. Although this strategy appears to improve survival, it will decrease the number of patients with CML for whom an appropriate donor can be found.

3.1.8. Prognosis

A follow-up on patients using imatinib published in the New England Journal of Medicine in 2006 showed an overall survival rate of 89% after five years.[3] In 2011, an independent study performed in 832 CML patients worldwide reported that the group of patients who achieve a stable cytogenetic response with imatinib shows an overall survival rate of 95.2% after 8 years, which is similar to the rate in the general population. Only 1% of patients died because of leukemia progression.[4]

4.1. CLL

4.1.1. Definition

Chronic lymphocytic leukemia (CLL), the most frequent form of leukemia in Western countries, is characterized by the clonal proliferation and accumulation of neoplastic B lymphocytes in the blood, bone marrow, lymph nodes, and spleen.

4.1.2. Etiology

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease of unknown etiological origin. CLL is the only B cell malignancy where a characteristic chromosomal translocation is not involved in cancer initiation. Therefore, the cause of tumorigenesis in CLL patients and the type of cell that is transformed are two questions that have intrigued researchers for decades. However, evidence suggests the CLL cell may be derived from B-1 cells. These B-1 cells, thought to develop during neonatal maturation as a link between innate and adaptive

immunity, share multiple phenotypic and genetic patterns with CLL cases. These include signaling molecules sensitivity and expression patterns, B-cell receptor (BCR) specificity, and a unique immune-modulatory phenotype. Through understanding the biological relevance of B-1 cells in immune development and regulation, we may further understand the molecular mechanisms underlying the complexity of CLL. With this understanding, we can provide more optimal care to patients based on their unique diagnosis and pathologic disease course. In this review, based on our current understanding of CLL cells and B1 cells we hypothesize that CLL cells are originated from B1 cells.[5]

4.1.3. Epidemiology

CLL is a disease of older adults, with a median age of 70 years at the time of diagnosis. [6]

Though less common, CLL sometimes affects people between 30 and 39 years of age. The incidence of CLL increases very quickly with increasing age.

In the United States during 2012, about 16,060 new cases are expected to be diagnosed, and 4,580 patients are expected to die from CLL.[7] Because of the prolonged survival, which was typically about ten years in past decades, but which can extend to a normal life expectancy, the prevalence is much higher than the incidence.

CLL is very rare in Asian countries, such as Japan and China, and may account for as few as 10 percent of all leukemias in those regions.[6]

Subclinical "disease" can be identified in 3.5% of normal adults, [8] and in up to 8% of individuals over the age of 70. That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown.

Rates of CLL are somewhat elevated in people exposed to certain chemicals. Under U.S. Department of Veterans' Affairs regulations, Vietnam veterans who served in-country or in the inland waterways of Vietnam and who later develop CLL are presumed to have contracted it from exposure to Chemical Weapons and may be entitled to compensation.

4.1.4. Pathogenesis and Pathophysiology

The molecular pathogenesis of CLL is unknown; there are no specific genetic abnormalities and, unlike other lymphoproliferative disorders, balanced chromosomal translocations are rare. Despite the absence of any common genetic alteration to all CLL patients, several recurrent genetic defects have been found in CLL cells. Using FISH, chromosomal alterations have been found in approximately 80% of CLL patients, the most commonly occurring being the deletion of 13q14, the trisomy of chromosome 12, the deletion of 11q and, finally, the deletion of 17p, which seems to clearly influence the choice of specific treatment. It has been repeatedly demonstrated that patients with the 17p deletion respond poorly to most drugs used routinely in the treatment of this disease.

Besides the presence or absence of specific genetic aberrations, several pieces of evidence point to a key role of the microenvironment in the survival of leukemic cells. CLL cells rapidly undergo spontaneous apoptosis when cultured ex vivo, suggesting that the microenvironment found in specific anatomic locations, particularly bone marrow and lymph

nodes, plays an important role in the regulation of death and proliferation of neoplastic cells. Antigenic stimulation through the B-cell receptor (BCR) also has a central role in promoting the survival of CLL cells. Moreover, CLL cells have stereotyped BCRs, using immunoglobulin heavy-chain variable gene families in a restricted distribution. This phenomenon suggests that CLL cells recognize common antigens, and that these antigens have an important role in the development and progression of the disease.

4.1.5. Clinical Manifestation and Diagnosis

The median age of patients at diagnosis is 65 years, with only 10 to 15 percent under 50 years of age. In most series, more men than women are affected. The course of the disease is variable. Whereas some patients with CLL have a normal life span, others die within five years after diagnosis. During the past few years, important advances have been made in the understanding of the biology, natural history, and treatment of CLL.

The hallmark of CLL is an increased white-cell count with about 95 percent small lymphocytes. To make the diagnosis, careful review of a good-quality peripheral-blood smear is thus essential. Accepted requirements for diagnosis include absolute lymphocytosis, with most lymphocytes being small and mature in appearance; a characteristic immunophenotype of the lymphocytes (i.e., low-density surface-membrane immunoglobulin, Cd5+, CD19+, CD20+, CD23+, FMC7-/+, and CD22-/+); and infiltration of the bone marrow by lymphocytes. Although diagnostic thresholds for both lymphocytosis and bone marrow infiltration have been proposed, these are arbitrary. CLL can be diagnosed whenever there is an absolute increase in lymphocytes in blood and their morphology and immunophenotype have the characteristic features of the disease. The French–American–British classification system proposed three morphologic types based on the proportion of atypical lymphocytes in blood: typical CLL, in which more than 90 percent of the lymphocytes are small; CLL–prolymphocytic leukemia, in which the proportion of prolymphocytes is between 11 and 54 percent; and atypical CLL, in which there is a heterogeneous lymphoid-cell morphology but the proportion of prolymphocytes is less than 10 percent. Again, these criteria are arbitrary. Although there are atypical cases of CLL, other lymphoproliferative disorders should be carefully considered before atypical CLL is diagnosed. In this regard, analysis of the immunophenotype of the neoplastic B cells, as well as cytogenetic and molecular data, may be useful. Atypical lymphoid-cell morphology, for example, is more frequent in patients with trisomy 12. On the other hand, prolymphocytic leukemia should not be regarded as a variant of CLL but as a separate entity that is characterized by a high white-cell count with a predominance of prolymphocytes in blood (i.e., >54 percent) with a typical phenotype (i.e., surface-membrane immunoglobulin++, CD19+, CD20+, CD23-/+, FMC7+), splenomegaly, resistance to therapy, and poor outcome. This is in contrast with CLL–prolymphocytic leukemia, in which the clinical features and immunophenotype are much closer to those of CLL.

4.1.6. Differential Diagnose

Differential diagnose of CLL include

Acute Lymphoblastic Leukemia Hairy Cell Leukemia Lymphoma, Diffuse Large Cell Lymphoma, Follicular Lymphoma, Lymphoblastic Lymphoma, Mantle Cell Lymphoma, Non-Hodgkin Small Lymphocytic Lymphoma T-Prolymphocytic leukemia (Former T-CLL)

4.1.7. Treatment

The diagnosis of CLL does not imply the need for therapy. A number of indications justify treatment in CLL, including constitutional symptoms, bulky lymphadenopathy, and splenomegaly causing compressive problems; however, prognostic factors are the most useful tools in decisions about therapy in a given patient.

At present, there is no curative therapy for CLL. This, coupled with the potentially indolent course of the disease and the advanced age of many patients, makes palliation of symptoms and prolongation of survival reasonable therapeutic goals in most patients with CLL requiring therapy. However, in younger patients with poor-risk factors, experimental approaches aimed at achieving cure are warranted. Current treatment possibilities according to prognostic factors and other variables are discussed below.

Early and Stable Disease

Patients with early, stable CLL should not be treated unless symptoms develop or the disease progresses. This strategy is based on two kinds of evidence. First, patients with early and stable disease may survive as long as normal subjects of the same age. Second, treatment of patients in an early stage (Binet stage A or Rai stage 0) with chlorambucil, either continuously or intermittently, delays the rate of disease progression but does not increase survival. Moreover, in one study continuous treatment with chlorambucil was associated with a shorter survival because of the high incidence of epithelial cancers.

Advanced CLL with a Large Tumor Burden and Bone Marrow Failure

Chlorambucil (e.g., at a dose of 6 to 8 mg orally daily; 0.4 to 0.8 mg per kilogram of body weight orally every two weeks) should be still considered the standard treatment. Treatment is given as long as the patient responds, usually for no less than 8 to 12 months. Response rates range from 40 to 70 percent, but complete responses are rare. In recent trials, the combination of chlorambucil and prednisone has not yielded better results than treatment with chlorambucil alone. Although patients treated with combination-chemotherapy regimens have higher response rates, survival is not prolonged.

The role of maintenance treatment in CLL has never been extensively investigated. Usually, treatment is discontinued once a response has been achieved and is restarted when there is disease progression. In most instances, renewed treatment results in a poorer response than initial treatment, probably because of the overexpression of mdr genes and p53 gene

mutations. For patients with no response to standard therapy or a relapse after such therapy, purine analogues, particularly fludarabine, are the treatment of choice .

Cytopenias Due to an Immune Mechanism or Hypersplenism

Patients with cytopenias due to an immune mechanism should be treated with a corticosteroid, with cytotoxic agents added only if there is no response after four to six weeks of treatment. Alternative treatments include high-dose immune globulin, cyclosporine, splenectomy, and low-dose radiation to the spleen.The latter two approaches may also be useful in cases of hypersplenism. Rarely, pure red-cell aplasia may be associated with CLL. Excellent treatment results have been reported with cyclosporine.

Treatment of Systemic Complications

Hypogammaglobulinemia is frequent in CLL and is the chief cause of infections. In a randomized study, high-dose immune globulin (400 mg per kilogram intravenously every three weeks) prevented infections but had no effect on survival. Cost–benefit considerations make the routine use of immune globulin in all patients with hypogammaglobulinemia debatable. Lower doses of immune globulin (i.e., 250 mg per kilogram every four weeks or 10 g every three weeks) may be as effective as high doses. Infections have to be treated with broad-spectrum antibiotics, and clinicians must keep in mind the possibility of opportunistic infection. Vaccines are considered to produce a suboptimal response because the immune system is impaired. Recombinant hematopoietic growth factors (e.g., granulocyte–macrophage colony-stimulating factor and granulocyte colony-stimulating factor) may overcome neutropenia related to treatment. Finally, erythropoietin may be useful to treat anemia that is unresponsive to other measures.

New Treatment Approaches

Purine Analogues

Purine analogues (pentostatin [2'-deoxycoformycin], fludarabine, and 2-chlorodeoxyadenosine) are highly active against CLL. Their mechanisms of action are complex, but include the induction of apoptosis. For patients with no response to initial therapy, fludarabine (25 mg per square meter of body-surface area intravenously for five days every four weeks) is the treatment of choice, with a response rate ranging from 17 to 74 percent (rate of complete response, 0 to 20 percent). The response rates are higher in patients who responded to previous therapies and who have not had extensive treatment. Preliminary results of ongoing trials comparing fludarabine with combinations of cyclophosphamide, doxorubicin, vincristine, and prednisone and cyclophosphamide, doxorubicin, and prednisone show a higher response rate for fludarabine; whether this will translate into longer survival remains to be seen.

The main toxic effect of purine analogues is myelosuppression; acute tumor lysis syndrome and autoimmune hemolytic anemia have also been documented. Opportunistic infections (e.g., cytomegalovirus, toxoplasma, Pneumocystis carinii, legionella, and listeria) occur because of the decrease in CD4+ cells induced by these agents. Because patients treated with purine analogues and prednisone have more opportunistic infections than those treated with purine analogues alone, prednisone should be omitted from regimens containing purine

analogues. Although there is no proof of their effectiveness, oral antibiotics can be used as prophylaxis.

The role of purine analogues in untreated patients is being investigated. Preliminary results show rates of complete response ranging from 25 to 74 percent for fludarabine and 2-chlorodeoxyadenosine. Pentostatin has been investigated less thoroughly. A U.S. trial comparing chlorambucil with fludarabine as first-line therapy has recently completed the accrual of patients, but no data are yet available.

New treatment possibilities may allow the achievement of remission at the molecular level. Therefore, to evaluate patients' responses to therapy, in addition to standard clinicohematologic methods, cytofluorometry and molecular-biology techniques are needed. This information may be useful in planning treatment strategies such as autotransplantation. Although in the future fludarabine or other purine analogues will probably replace chlorambucil as standard therapy in CLL, for now such an approach should be confined to clinical trials. Finally, the role of purine analogues in combination with other cytotoxic agents (e.g., cyclophosphamide) or biologic-response modifiers (e.g., interferon) is being investigated.

Transplantation of Hematopoietic Progenitors

Data on the largest series of allotransplantations, involving 54 patients, have been collected by the European and International Bone Marrow Transplant Registries (Michallet M, et al.: unpublished data). The median age of the patients at transplantation was 41 years (range, 21 to 57). Before transplantation most patients received a conditioning regimen consisting of cyclophosphamide and total-body irradiation as well as cyclosporine and methotrexate as prophylaxis against graft-versus-host disease. Of the 54 patients, 38 (70 percent) entered remission and 24 (44 percent) were alive a median of 27 months (range, 5 to 80) after transplantation. The probability of survival at three years was 46 percent (95 percent confidence interval, 32 to 60 percent). Five patients died of progressive leukemia (9 percent) and 25 of treatment-related complications (46 percent). This contrasts with the 10 percent mortality rate reported in recent studies from single institutions; the difference is probably due to differences in patient-selection criteria. The results are better in patients with stable disease that is responsive to therapy than in those with progressive disease. Relapses, sometimes as late as four years after transplantation, may occur.

There are several reports on autotransplantation in CLL. About 40 patients have been described. All the patients had advanced disease before transplantation, and all received cyclophosphamide and total-body irradiation as part of the conditioning regimen. In about half the patients the bone marrow graft was purged with monoclonal antibodies against B cells (CD19, CD20, CD10, and CD5). The follow-up is too short to draw conclusions.

Although results are promising, transplantation should still be considered an experimental procedure. Opportunistic infections (e.g., toxoplasmosis) are an additional concern. Transplantation, however, should be considered in any young patient with high-risk CLL.

Biotherapy

Interferon alfa does produce a response, albeit not a complete response, in patients with early disease who have not received prior therapy. Thus, it might potentiate the responses achieved

with chemotherapy. The effectiveness of monoclonal antibodies, either alone (e.g., CAMPATH 1-H) or conjugated with toxins (e.g., B4-blocked ricin), cytotoxic agents, or radioisotopes (e.g., iodine-131), is being investigated; the response obtained is usually partial and transient. Monoclonal antibodies might be useful as a treatment for minimal residual disease. Interleukins (e.g., interleukin-2, 4, and 6) are under study. Interleukin-2 has proved to have limited clinical activity and substantial toxicity at high doses. Preliminary experiments in mice suggest that antisense oligonucleotides specific for interleukin-10, a potent stimulator of the growth of neoplastic B lymphocytes, might be clinically useful.

4.1.8. Prognosis

In several recent series, the median survival of patients with CLL was about nine years, although individual survival varies. Clinical stages, bone marrow histopathological findings, blood lymphocyte counts, lymphocyte doubling time, and cytogenetic abnormalities are good predictors of survival. In addition, blood lymphocyte morphology; serum concentrations of lactate dehydrogenase, thymidine kinase, beta2-microglobulin, CD23, and CD25; and the presence of p53 mutations have been found to be of prognostic value in some studies Transformation of the disease into large-cell lymphoma (Richter's syndrome) carries a poor prognosis, with a median survival of less than one year after its appearance. Similarly, CLL–prolymphocytic leukemia has a poorer prognosis than classic CLL. Finally, a response to therapy is associated with longer survival.

Clinical staging systems are easy to use, and their prognostic value has been widely validated. However, they do not provide information on the likelihood of progression in a given patient. In this regard, other variables may provide prognostic information. For example, among patients with early-stage CLL, those with a pattern of diffuse infiltration of bone marrow on histopathological analysis or rapidly increasing lymphocyte counts (or both) are likely to have progression and shorter survival, whereas those without diffuse infiltration of bone marrow and with low, stable blood lymphocyte counts usually have an indolent, nonprogressive, smoldering disease.

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