ACUTE LEUKEMIA

Acute leukemia. Chronic lymphocytic leukemia. Chronic myeloid leukemia

Marrow is a spongy tissue where blood cell development takes place. It occupies the central cavity of bones. Iewborns, all bones have active marrow. By the time a person reaches young adulthood, the bones of the hands, feet, arms, and legs no longer have functioning marrow. The backbones (vertebrae), hip and shoulder bones, ribs, breastbone, and skull contain marrow that makes blood cells in adults. Blood passes through the marrow and picks up formed red and white cells, and platelets, for circulation.

  

This figure depicts an abbreviated diagram of the process of hematopoiesis. This process involves the development of functional blood and lymphatic cells from stem cells.

 

When the fully developed and functional cells are formed, they leave the marrow and enter the blood. In healthy individuals there are enough stem cells to keep producing new blood cells continuously.

Some stem cells enter the blood and circulate. They are present in such small numbers that they cannot be counted or identified in the usual type of blood counts. Their presence in the blood is important because they can be collected by a special technique and can be transplanted into a recipient if enough stem cells are harvested from a compatible donor.

Stem cell circulation, from marrow to blood and back, also occurs in the fetus. After birth, placental and umbilical cord blood can be collected, stored and used as a source of stem cells for transplantation.

In summary, blood cells are made in the marrow. When the cells are formed and functional, they leave the marrow and enter the blood. The red cells and the platelets carry out their respective functions of delivering oxygen and plugging up injured blood vessels throughout the body. The white cells (neutrophils, eosinophils, basophils, monocytes and lymphocytes) enter the tissues (for example, the lungs) to combat infections, such as pneumonia, and perform other immune functions.

Leukemia

Leukemia is a cancer of the marrow and blood. The earliest observations of patients who had marked elevation of their white cells by European physicians in the 19th century led to their coining the term weisses blut or white blood as a designation for the disorder. Later, the term leukemia, which is derived from the Greek words leukos, meaning white, and haima, meaning blood, was used to indicate the disease.

The major forms of leukemia are divided into four categories. The terms myelogenous or lymphocytic denote the cell type involved. Myelogenous and lymphocytic leukemia each have an acute or chronic form. Thus, the four major types of leukemia are acute or chronic myelogenous and acute or chronic lymphocytic leukemia.

Acute leukemia is a rapidly progressing disease that affects mostly cells that are unformed or immature (not yet fully developed or differentiated). These immature cells cannot carry out their normal functions. Chronic leukemia progresses slowly and permits the growth of greater numbers of more developed cells. In general, these more mature cells can carry out some of their normal functions.

The ability to measure additional specific features of cells has led to further subclassification of the major categories of leukemia. The categories and subsets allow the physician to decide what treatment works best for the cell type and how quickly the disease may progress.

Symptoms

nDamage to the bone marrow, by way of displacing the normal marrow cells with increasing numbers of malignant cells, results in a lack of blood platelets, which are important in the blood clotting process. This means people with leukemia may become bruised, bleed excessively, or develop pinprick bleeds (petechiae).

Leukemia. Symptoms

nWhite blood cells, which are involved in fighting pathogens, may be suppressed or dysfunctional, putting the patient at the risk of developing infections.

nFinally, the red blood cell deficiency leads to anemia, which may cause dyspnea. All symptoms may also be attributable to other diseases; for diagnosis, blood tests and a bone marrow biopsy are required.

Some other related symptoms

nFever, chills, and other flu-like symptoms

·        Weakness and fatigue

·        Loss of appetite and/or weight

·        Swollen or bleeding gums

·        Neurological symptoms (headache)

·        Enlarged liver and spleen

 Leukemia

–         Leukemia is clinically and pathologically split into its acute and chronic forms

–        

 

 

Acute leukemia is a rapidly progressing disease that affects mostly cells that are unformed or immature (not yet fully developed or differentiated). These immature cells cannot carry out their normal functions.

–         Acute forms of leukemia can occur in children and young adults. (In fact, it is a more common cause of death for children than any other type of malignant disease.)

–         Immediate treatment is required in acute leukemias due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. If left untreated, the patient will die within months or weeks.

 

Chronic leukemia progresses slowly and permits the growth of greater numbers of more developed cells. In general, these more mature cells can carry out some of their normal functions.

–         Typically taking months to years to progress, the cells are produced at a much higher rate thaormal cells, resulting in many abnormal white blood cells in the blood.

–         Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy.

 Furthermore, the diseases are classified according to the type of abnormal cell found most in the blood.

–         When leukemia affects lymphoid cells (lymphocytes and plasma cells), it is called lymphocytic leukemia.

–         When myeloid cells (eosinophils, neutrophils, and basophils) are affected, the disease is called myeloid ormyelogenous leukemia.

 

The major forms of leukemia are divided into four categories. The terms myelogenous or lymphocytic denote the cell type involved. Myelogenous and lymphocytic leukemia each have an acute or chronic form. Thus, the four major types of leukemia are acute or chronic myelogenous and acute or chronic lymphocytic leukemia.

 

Acute leukemias

Acute leukemias are clonal diseases of hematopoietic precursors with molecular genetic abnormalities. All hematopoietic cell lines may be affected. Proliferation of the leukemic cell clone replaces normal hematopoiesis in varying degrees. In acute myeloid leukemia (AML), it is most common for granulocytopoiesis and monocytopoiesis to be affected. Erythropoiesis is less frequently affected, and megakaryopoiesis rarely so. The distribution of the subtypes varies according to age. Acute lymphocytic leukemia (ALL) occurs predominantly in children, while AML has its peak in adults. The involvement of several myeloid cell lines is relatively common, but the simultaneous involvement of myeloid and lymphoid cell lines is very rare (hybrid and bilinear acute leukemias). WHO has recently proposed that the percentage of blasts in the bone marrow must be approximately 20 % to justify a diagnosis of acute leukemia. Examination of the peripheral blood is not essential for diagnosis but can provide important additional information. The diagnosis and classification (subtype assignment) always rely on the bone marrow. The most widely accepted system at present for the classification of AML is based on the criteria of the French-American- British (FAB) Cooperative Group and of the WHO.

Table 1. FAB classification of akute myeloid leukemia (AML), modified

Table 2. WHO classification of acute myeloid leukemias

 

 

Acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. ALL may be distinguished from other malignant lymphoid disorders by the immunophenotype of the cells, which is similar to B- or T-precursor cells. Immunochemistry, cytochemistry, and cytogenetic markers also may aid in categorizing the malignant lymphoid clone.

e common in children than in adults.

Clinical picture

History:

·                     Patients with ALL present with either (1) symptoms relating to direct infiltration of the marrow or other organs by leukemic cells or (2) symptoms relating to the decreased production of normal marrow elements.

o                                            Infiltration of the marrow by massive numbers of leukemic cells frequently manifests as bone pain.

o                                            This pain can be severe and is often atypical in distribution.

·                     Uncommonly (10-20%), patients may present with left upper quadrant fullness and early satiety due to splenomegaly.

·                     Other patients, particularly those with T-cell ALL, present with symptoms related to a large mediastinal mass, such as shortness of breath.

·                     Although patients may present with symptoms of leukostasis (eg, respiratory distress, altered mental status) because of the presence of large numbers of lymphoblasts in the peripheral circulation, leukostasis is much less common in persons with ALL than in persons with AML and occurs only in patients with the highest WBC counts, ie, several hundred thousand per microliter.

·                     Patients with ALL also present with symptoms related to a depletion of normal marrow elements. Symptoms of anemia are common and include fatigue, dizziness, palpitations, and dyspnea upon even mild exertion.

·                     Patients with ALL often have decreased neutrophil counts, despite an increased total WBC count. As a result, they are at increased risk of infection. The prevalence and severity of infections are inversely correlated with the absolute neutrophil count, which is defined as the number of mature neutrophils plus bands per unit of volume. Infections are common when the absolute neutrophil count is less than 500/mL and are especially severe when it is less than 100/mL.

·                     Patients with ALL often have fever without any other evidence of infection. However, in these patients, one must assume that all fevers are from infections until proven otherwise because a failure to treat infections promptly and aggressively can be fatal. Infections are still the most common cause of death in patients undergoing treatment for ALL.

·                     Approximately 10% of patients with ALL have disseminated intravascular coagulation (DIC) at the time of diagnosis, usually as a result of sepsis. Consequently, some patients may present with hemorrhagic or thrombotic complications. Bleeding symptoms are usually more often the result of a coexisting thrombocytopenia caused by marrow replacement. The thrombocytopenia, however, tends to be less severe than that observed in patients with AML.

Physical:

·                     Patients commonly have physical signs of anemia, including pallor and a cardiac flow murmur.

·                     Fever and other signs of infection, including lung findings of pneumonia, can occur. Fever should be interpreted as evidence of infection, even in the absence of other signs.

·                     Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. A large number of ecchymoses is usually an indicator of a coexistent coagulation disorder such as DIC.

·                     Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy.

·                     Occasionally, patients have rashes resulting from infiltration of the skin with leukemic cells.

Lab Studies:

·                     A CBC count with differential demonstrates anemia and thrombocytopenia to varying degrees. Patients with ALL can have a high, normal, or low WBC count, but usually exhibit neutropenia.

 

Pic.1 Small blasts. These may closely resemble lymphocytes but are distinguished by their finer chromatin structure and the occasional presence of nucleoli

 

Pic. 2 Different case showing blasts of varying sizes, some with pleomorphic nuclei. Panels a and b illustrate B-lineage ALL

 

Pic. 3. Peroxidase reaction. All lymphoblasts are negative and are interspersed with residual cells of granulocytopoiesis, whose proportion is more clearly demonstrated by the peroxidase reaction

 

Imaging Studies:

·                     Chest x-ray films may reveal signs of pneumonia and/or a prominent mediastinal mass in some cases of T-cell ALL.

·                     Multiple gated acquisition scan or ECG is needed when the diagnosis is confirmed because many chemotherapeutic agents used in the treatment of acute leukemia are cardiotoxic.

Other Tests:

·                     ECG is recommended prior to treatment.

Procedures:

·                     Bone marrow aspiration and biopsy are the definitive diagnostic tests to confirm the diagnosis of leukemia (see pict. 20-34). Immunophenotyping helps elucidate the subtype.

o                                            Aspiration slides should be stained for morphology with either Wright or Giemsa stain. The diagnosis of ALL is made when at least 30% lymphoblasts (FAB classification) or 20% lymphoblasts (WHO classification) are present in the bone marrow and/or peripheral blood.

o                                            In addition, slides should be stained with myeloperoxidase (or Sudan black) and terminal deoxynucleotidyl transferase (TdT), unless another method is used, such as flow cytometry.

o                                            Bone marrow samples should also be sent for cytogenetics and flow cytometry. Approximately 15% of patients with ALL have a t(9;22) translocation (ie, Philadelphia chromosome), but other chromosomal abnormalities also may occur, such as t(4;11), t(2;8), and t(8;14).

·                     A negative myeloperoxidase stain and a positive TdT is the hallmark of the diagnosis of most cases of ALL. However, positive confirmation of lymphoid (and not myeloid) lineage should be sought by flow cytometric demonstration of lymphoid antigens, such as CD3 (T-lineage ALL) or CD19 (B-lineage ALL), in order to avoid confusion with some types of myeloid leukemia (eg, M0, acute monocytic leukemia), which also staiegative with myeloperoxidase. Although more than 95% of cases of the L1 or L2 subtype of ALL are positive for TdT, TdT is not specific for ALL. TdT is present in some subtypes of AML such as M0. Additionally, TDT is absent in cases of L3 type ALL. However, TdT helps distinguish ALL from malignancies of more mature lymphocytes (ie, NHL).

·                     In cases of acute leukemia that are MPO negative, TdT positive, the distinction between AML and ALL is made based on the analysis of flow cytometry results. Patients with AML demonstrate myeloid markers such as CD33, whereas patients with ALL demonstrate lymphoid markers. Further confusion arises because some patients with ALL have aberrant expression of myeloid markers, such as CD13. However, if the cells are TdT-positive, myeloperoxidase-negative, and CD33-negative and demonstrate lymphoid markers, the leukemia is considered ALL.

·                     Studies for bcr-abl analysis by polymerase chain reaction or cytogenetics may help distinguish patients with Philadelphia chromosome positive ALL from those with the lymphoid blastic phase of chronic myelogenous leukemia. Most patients with Ph+ ALL have the p190 type of bcr-abl, whereas patients with lymphoid blastic CML have the p210 type of bcr-abl.

·                     Newer studies are analyzing ALL subtypes by gene expression profiling. In children with ALL, Bogni et al distinguished 3 groups of patients. Interestingly, one of these groups had a significantly increased risk of developing treatment-related AML following chemotherapy for their ALL.

Histologic Findings:

French-American-British Classification

·                     L1 – Small cells with homogeneous chromatin, regular nuclear shape, small or absent nucleolus, and scanty cytoplasm; subtype represents 25-30% of adult cases

·                     L2 – Large and heterogeneous cells, heterogeneous chromatin, irregular nuclear shape, and nucleolus often large; subtype represents 70% of cases (most common)

·                     L3 – Large and homogeneous cells with multiple nucleoli, moderate deep blue cytoplasm, and cytoplasmic vacuolization that often overlies the nucleus (most prominent feature); subtype represents 1-2% of adult cases

The WHO classifies the L1 and L2 subtypes of ALL as either precursor B lymphoblastic leukemia/lymphoblastic lymphoma or precursor T lymphoblastic leukemia/lymphoblastic lymphoma depending on the cell of origin. The L3 subtype of ALL is included in the group of mature B-cell neoplasms, as the subtype Burkitt lymphoma/leukemia.

Cytogenetic abnormalities occur in approximately 70% of cases of ALL in adults. These abnormalities included balanced translocations as occur in cases of AML. However, abnormalities of chromosome number (hypodiploidy, hyperdiploidy) are much more common in ALL than in AML.

 

Table 3. Common Cytogenetic Abnormalities in ALL

 

Table 4. Effect of Chromosome Number on Prognosis

 

Eighty-five percent of cases of ALL are derived from B cells. The primary distinction is between (1) early (pro-B) ALL, which is TDT positive, CD10 (CALLA) negative, surface Ig negative; (2) precursor B ALL, which is TDT positive, CD10 (CALLA) positive, surface Ig negative; and (3) mature B cell (Burkitt) ALL, which is TdT negative, surface Ig positive. Fifteen percent of cases are derived from T cells. These cases are subclassified into different stages corresponding to the phases of normal thymocyte development. The early subtype is surface CD3 negative, cytoplasmic CD3 positive, and either double negative (CD4^–, CD8^–) or double positive (CD4⁺, CD8⁺). The latter subtype is surface CD3 positive, CD1a negative, and positive for either CD4 or CD8, but not both.

 

Table 5. Immunophenotyping of ALL Cells – ALL of B-Cell Lineage (85% of cases of adult ALL)

*Cytoplasmic immunoglobulin
†Surface immunoglobulin

Pic. 5. Diagnostic workup of a patient with pre–B-cell acute lymphoblastic leukemia. Bone marrow aspiration revealed French-American-British L2 morphology.

 

Table 6. Immunophenotyping of ALL Cells – ALL of T-Cell Lineage (15% of cases of adult ALL)

 

Treatment

Medical Care: Currently, only 20-30% of adults with ALL are cured with standard chemotherapy regimens. Consequently, all patients must be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy. Traditionally, the 4 components of ALL treatment are induction, consolidation, maintenance, and CNS prophylaxis. Other aspects of treatment are also discussed.

·                     Induction therapy

o                                            Standard induction therapy typically involves either a 4-drug regimen of vincristine, prednisone, anthracycline, and cyclophosphamide or L-asparaginase or a 5-drug regimen of vincristine, prednisone, anthracycline, cyclophosphamide, and L-asparaginase given over the course of 4-6 weeks.

o                                            Using this approach, complete remissions are obtained in 65-85% of patients. The rapidity with which a patient’s disease enters complete remission is correlated with treatment outcome.

·                     Consolidation therapy

o                                            The use of consolidation chemotherapy is supported by several studies. In 1987, Fiere et al compared consolidation therapy with daunorubicin and cytosine arabinoside (Ara-C) versus no consolidation therapy in adults with ALL. The 3-year, leukemia-free survival rate was 38% for subjects receiving consolidation and maintenance therapy compared with 0% for those receiving maintenance therapy without consolidation (P <.05).

·                     Maintenance therapy

o                                            The effectiveness of maintenance chemotherapy in adults with ALL has not been studied in a controlled clinical trial. However, several phase 2 studies without maintenance therapy have shown inferior results compared with historical controls.

o                                            A CALGB study of daunorubicin or mitoxantrone, vincristine, prednisone, and methotrexate induction followed by 4 intensifications and no maintenance was closed early because the median remission duration was shorter than in previous studies. A Dutch study using intensive postremission chemotherapy, 3 courses of high-dose Ara-C in combination with amsacrine (course 1), mitoxantrone (course 2), and etoposide (course 3), without maintenance, also yielded inferior results.

·                     CNS prophylaxis

o                                            In contrast to patients with AML, patients with ALL frequently have meningeal leukemia at the time of relapse. A minority of patients have meningeal disease at the time of initial diagnosis. As a result, CNS prophylaxis with intrathecal chemotherapy is essential.

o                                            Cortes analyzed the prevalence of CNS leukemia in 4 consecutive clinical trials at the M.D.Anderson Cancer Center.

·                     Newer approaches

o                                            Standard induction regimens are modeled after pediatric programs and were originally developed when supportive care was significantly inferior to what is available today. Few antibiotics were available, and transfusion capabilities were minimal. Consequently, milder regimens were designed in an attempt to minimize early deaths during induction.

o                                            With the addition of third-generation cephalosporins and sophisticated blood-banking techniques, the ability to support patients through a pancytopenic phase has increased dramatically. As a result, the use of more intensive induction approaches is being studied. Two notable examples are the Memorial ALL-2 protocol and the hyper-CVAD protocol.

o                                            The ALL-2 protocol uses an intensive, high-dose, mitoxantrone-based, AML-style induction regimen. In a phase 1 study of high-dose mitoxantrone combined with high-dose Ara-C, Arlin et al reported that 8 of 8 patients newly diagnosed with ALL and 8 of 10 patients with ALL who relapsed achieved complete remission.

·                     Treatment of Philadelphia chromosome positive ALL

o                                            In the past, Ph+ ALL was treated with the same regimens as other types of ALL, with poor results. However, imatinib inhibits the bcr-abl fusion protein of Ph+ ALL and thus allows targeted therapy of this disease. As a single agent, imatinib has limited activity.

o                                            In an early study of patients with Ph+ ALL or CML in lymphoid blast crisis, only 4 of 20 patients had a complete response, and all patients progressed in less than 6 months. Several newer studies are demonstrating improved outcomes when imatinib is added to chemotherapy.

·                     Transplantation

o                                            Relatively few studies have compared transplantation with chemotherapy in adults with ALL. In a study by the Groupe Ouest Est d’etude des Leucenies et Autres Maladies du Sang, subjects younger than 45 years who had a sibling donor and whose disease was in remission were assigned to allogeneic transplantation. The remaining subjects received methylprednisolone, Ara-C, mitoxantrone, and etoposide chemotherapy followed by autologous bone marrow transplantation (BMT). For subjects undergoing allogeneic BMT, the rate of freedom from relapse was 70% at 4 years. However, because of transplant-related complications, the event-free survival rate was only 33%. No toxic deaths occurred in the subjects who underwent autologous BMT. However, the event-free survival rate was only 17% at 4 years because of a high rate of relapse.

·                     Treatment of relapsed ALL

o                                            Patients with relapsed ALL have an extremely poor prognosis. Most patients are referred for investigational therapies. Young patients who have not previously undergone transplantation are referred for such therapy. Reinduction regimens include the hyper-CVAD protocol and high-dose Ara-C–based regimens.

o                                            As noted above, the hyper-CVAD regimen is based on hyperfractionated cyclophosphamide and intermediate doses of Ara-C and methotrexate. In a study at the M.D. Anderson Cancer Center of 66 patients with relapsed ALL, the complete remission rate was 44% and median survival was 42 weeks.

o                                            Arlin et al reported that 8 of 10 patients with relapsed ALL achieved complete remission with high-dose Ara-C and high-dose mitoxantrone. A similar regimen using a single high dose of idarubicin in combination with Ara-C (the Memorial ALL-3 protocol) resulted in complete remission rates of 58-78% in patients who experienced relapse.

·                     Newer drugs

Ø     A number of new drugs are currently in development for the treatment of ALL. A few examples are as follows.

Ø     Clofarabine is a novel nucleoside analogue that was recently approved for the treatment of pediatric patients with refractory or relapsed ALL. Clofarabine inhibits DNA synthesis at both DNA polymerase I and at RNA reductase. Overall response rates average 25%.

Ø     506U78 (nelarabine [Arranon]) is a novel purine nucleoside that is a prodrug of ara-G. It was approved as an orphan drug by the FDA in October, 2005. Complete responses are reported in 31% of patients and in 54% of patients with T-cell ALL. The dose-limiting toxicity of this drug is neurotoxicity.

Ø     Dasatinib is a dual ABL-SARC inhibitor that differs from imatinib in that it binds to both the active and inactive form of the ABL kinase. Dasatinib is active against most bcr-abl mutations (except T315I) that render the kinase resistant to imatinib. In a preliminary study, 8 of 10 patients with Ph+ ALL had a major hematologic response and major cytogenetic response to dasatinib. However response durations were brief.

Ø     Supportive care with replacement of blood products

Ø     Patients have a deficiency in the ability to produce normal blood cells, and they need replacement therapy. This deficiency is temporarily worsened by the addition of chemotherapy. All blood products must be irradiated to prevent transfusion-related graft versus host disease, which is almost invariably fatal.

Ø     Packed red blood cells are given to patients with a hemoglobin level of less than 7-8 g/dL or at a higher level if the patient has significant cardiovascular or respiratory compromise.

Ø     Platelets are transfused if the count is less than 10,000-20,000/mL. Patients with pulmonary or gastrointestinal hemorrhage receive platelet transfusions to maintain a value greater than 50,000/mL. Patients with CNS hemorrhage are transfused to achieve a platelet count of 100,000/mL.

Ø     Fresh frozen plasma is given to patients with a significantly prolonged prothrombin time, and cryoprecipitate is given if the fibrinogen level is less than 100 g/dL.

o                                            Supportive care with antibiotics

o                                            Supportive care with growth factors

Surgical Care: Placement of a central venous catheter, such as a triple lumen, Broviac, or Hickman catheter, may be necessary.

The medications used to treat acute leukemia cause severe bone marrow depression. Only physicians specifically trained in their use should administer these medications. In addition, access to appropriate supportive care is required.

Drug Category: Corticosteroids — May be used during induction, consolidation, and/or maintenance therapy.

 

Drug Category: Antineoplastics — Used for induction, consolidation, maintenance, and CNS prophylaxis.

 

 

 

 

 

 

 

 

 

 

 

 

 

Complications:

·                     Death may occur as a result of uncontrolled infection or hemorrhage. This may occur even after the use of appropriate blood product and antibiotic support.

·                     The most common complication is failure of the leukemia to respond to chemotherapy. These patients do poorly because they usually do not respond to other chemotherapy regimens.

Prognosis:

·                     Patients with ALL are divided into 3 prognostic groups.

o                                            Good risk includes (1) no adverse cytogenetics, (2) age younger than 30 years, (3) WBC count of less than 30,000/mL, and (4) complete remission within 4 weeks.

o                                            Intermediate risk does not meet the criteria for either good risk or poor risk.

o                                            Poor risk includes (1) adverse cytogenetics [(t9;22), (4;11)], (2) age older than 60 years, (3) precursor B-cell WBCs with WBC count greater than 100,000/mL, or (4) failure to achieve complete remission within 4 weeks.

 

Acute Myelogenous Leukemia

Acute myelogenous leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow.

Frequency:

·                     In the US: Estimates predict 11,960 new cases of AML in the United States in 2005 (6530 men and 5430 women).

·                     Internationally: AML is more commonly diagnosed in developed countries.

Clinical diagnostic

History:

Ø     Patients present with symptoms resulting from bone marrow failure, organ infiltration with leukemic cells, or both. The time course is variable.

Ø     Some patients, particularly younger ones, present with acute symptoms over a few days to 1-2 weeks.

Ø     Others have a longer course, with fatigue or other symptoms lasting from weeks to months. A longer course may suggest an antecedent hematologic disorder (AHD) such as myelodysplastic syndrome (MDS).

Ø     Symptoms of bone marrow failure are related to anemia, neutropenia, and thrombocytopenia.

Ø     The most common symptom of anemia is fatigue. Patients often retrospectively note a decreased energy level over past weeks.

Ø     Other symptoms of anemia include dyspnea upon exertion, dizziness, and, in patients with coronary artery disease, anginal chest pain. In fact, myocardial infarction may be the first presenting symptom of acute leukemia in an older patient.

Ø     Patients often have decreased neutrophil levels despite an increased total WBC count.

Ø     Patients present with fever, which may occur with or without specific documentation of an infection. Patients with the lowest absolute neutrophil counts (ie, <500 cells/mL and especially <100 cells/mL) have the highest risk of infection.

Ø     Patients often have a history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics.

Ø     Patients present with bleeding gums and multiple ecchymoses. Bleeding may be caused by thrombocytopenia, coagulopathy that results from disseminated intravascular coagulation (DIC), or both.

Ø     Potentially life-threatening sites of bleeding include the lungs, gastrointestinal tract, and the central nervous system.

Ø     Alternatively, symptoms may be the result of organ infiltration with leukemic cells.

Ø     The most common sites of infiltration include the spleen, liver, and gums.

Ø     Infiltration occurs most commonly in patients with the monocytic subtypes of acute myelogenous leukemia (AML).

Ø     Patients with splenomegaly note fullness in the left upper quadrant and early satiety.

Ø     Patients with gum infiltration often present to their dentist first. Gingivitis due to neutropenia can cause swollen gums, and thrombocytopenia can cause the gums to bleed.

Ø     Patients with markedly elevated WBC counts (>100,000 cells/mL) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status). Leukostasis is a medical emergency that requires immediate intervention.

Ø     Patients with a high leukemic cell burden may present with bone pain caused by increased pressure in the bone marrow.

Physical:

·                     Physical signs of anemia, including pallor and a cardiac flow murmur, are frequently present.

·                     Fever and other signs of infection can occur, including lung findings of pneumonia.

·                     Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. Petechiae are small, often punctate, hemorrhagic rashes that are not palpable. Areas of dermal bleeding or bruises (ie, ecchymoses) that are large or present in several areas may indicate a coexistent coagulation disorder such as DIC. Purpura is characterized by flat bruises that are larger than petechiae but smaller than ecchymoses.

·                     Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy. Occasionally, patients have skin rashes due to infiltration of the skin with leukemic cells (leukemia cutis). Chloromata are extramedullary deposits of leukemia. Rarely, a bony or soft-tissue chloroma may precede the development of marrow infiltration by AML (granulocytic sarcoma).

·                     Signs relating to leukostasis include respiratory distress and altered mental status.

Lab Studies:

·                     CBC count with differential demonstrates anemia and thrombocytopenia to varying degrees. Patients with acute myelogenous leukemia (AML) can have high, normal, or low WBC counts.

·                     Prothrombin time/activated partial thromboplastin time/fibrinogen/fibrin degradation products

o                                            The most common abnormality is disseminated intravascular coagulation (DIC), which results in an elevated prothrombin time, a decreasing fibrinogen level, and the presence of fibrin split products.

o                                            Acute promyelocytic leukemia (APL), also known as M3, is the most common subtype of AML associated with DIC.

·                     Peripheral blood smear

o                                            Review of peripheral blood smear confirms the findings of the CBC count.

o                                            Circulating blasts are usually seen.

o                                            Schistocytes are occasionally seen if DIC is present.

 

Pict. 6 Two type I blasts. The cytoplasm is devoid of granules

 

Pict. 7 Blood smear in AML. Undifferentiated blasts with scant cytoplasm

  

Pict. 8 Peroxidase reaction in the same patient. All blasts in the field are strongly positive

 

Pict. 9 Bone marrow from the same patient shows pronounced maturation (more than 10 %)

 

Pict. 10 Very strong peroxidase reaction in the same patient. This case demonstrates that bone marrow examination is necessary for an accurate classification

 

Pict. 11 Schematic diagram and partial karyotype of the translocation t(8;21)(q22;q22), found predominantly in the M2 subtype of AML

 

Pict. 12 Schematic diagram and partial karyotype of the t(3;12)(q26;p13), which is found in AML and MDS. Changes in the short arm of chromosome 12 (12p), like t(6;9) [below t(3;12)], may be associated with increased basophilic granulocytes in the bone marrow. A similar increase is occasionally found in the M4 subtype in the absence of detectable anomalies

  

·                     Recently, several molecular abnormalities that are not detected with routine cytogenetics have been shown to have prognostic importance in patients with AML. When possible, the bone marrow should be evaluated for the following abnormalities:

o                                            Fms-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene in persons with AML and is constitutively activated in one third of AML cases. Internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3 exist in 25% of AML cases. In other cases, mutations exist in the activation loop of FLT3. Most studies demonstrate that patients with AML and FLT3 mutations have a poor prognosis.

o                                            Mutations in CEBPA are detected in 15% of patients with normal cytogenetics findings and are associated with a longer remission duration and longer overall survival.

o                                            Mutations iucleophosmin (NPM) are associated with increased response to chemotherapy in patients with a normal karyotype.

·                     Gene-expression profiling is a research tool that allows a comprehensive classification of AML based on the expression pattern of thousands of genes.

Imaging Studies:

·                     Chest radiographs help assess for pneumonia and signs of cardiac disease.

·                     Multiple gated acquisition (MUGA) scan is needed once the diagnosis is confirmed because many chemotherapeutic agents used in treatment are cardiotoxic.

Other Tests:

·                     Electrocardiography should be performed prior to treatment.

Procedures:

·                     Bone marrow aspiration and biopsy are the definitive diagnostic tests.

o                                            Aspiration slides are stained for morphology with either Wright or Giemsa stain.

o                                            To determine the FAB type of the leukemia, slides are also stained with myeloperoxidase (or Sudanblack), terminal deoxynucleotidyl transferase (TdT) (unless performed by another method [eg, flow cytometry]), and double esterase

·                     Bone marrow samples should also be sent for cytogenetics testing and flow cytometry.

·                     Patients with APL should have their marrow evaluated for the PML/RARa genetic rearrangement.

·                     When possible, the bone marrow should be evaluated for FLT3 mutations.

Histologic Findings: The older, more traditional, FAB classification is as follows:

·                     M0 – Undifferentiated leukemia

·                     M1 – Myeloblastic without differentiation

·                     M2 – Myeloblastic with differentiation

·                     M3 – Promyelocytic

·                     M4 – Myelomonocytic

o                                            M4eo – Myelomonocytic with eosinophilia

·                     M5 – Monoblastic leukemia

o                                            M5a – Monoblastic without differentiation

o                                            M5b – Monocytic with differentiation

·                     M6 – Erythroleukemia

·                     M7 – Megakaryoblastic leukemia

The newer WHO classification is as follows:

·                     AML with recurrent genetic abnormalities

o                                            AML with t(8;21)(q22;q22), (AML1/ETO)

o                                            AML with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13)(q22),(CBFB/MYH11)

o                                            APL with t(15;17)(q22;q12), (PML/RARa) and variants

o                                            AML with 11q23 (MLL) abnormalities

·                     AML with multilineage dysplasia

o                                            Following myelodysplastic syndrome (MDS) or MDS/myeloproliferative disease (MPD)

o                                            Without antecedent MDS or MDS/MPD but with dysplasia in at least 50% of cells in 2 or more lineages

·                     AML and MDS, therapy related

o                                            Alkylating agent or radiation-related type

o                                            Topoisomerase II inhibitor type

o                                            Others

·                     AML, not otherwise classified

o                                            AML, minimally differentiated

o                                            AML, without maturation

o                                            AML, with maturation

o                                            Acute myelomonocytic leukemia

o                                            Acute monoblastic or monocytic leukemia

o                                            Acute erythroid leukemia

o                                            Acute megakaryoblastic leukemia

o                                            Acute basophilic leukemia

o                                            Acute panmyelosis and myelofibrosis

o                                            Myeloid sarcoma

  

Table 7. Common Cytogenetic Abnormalities in AML

*Refers to 3-5 different cytogenetic abnormalities, depending on the classification used

 

Table 8. Cytogenetic Abnormalities in APL

 

Table 9. Immunophenotyping of AML Cells

 

Treatment

Medical Care: Current standard chemotherapy regimens cure only a minority of patients. As a result, evaluate all patients for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy as described below.

Treatment of acute myelogenous leukemia (excluding acute promyelocytic leukemia)

·                     Induction therapy: Various acceptable induction regimens are available.

o                                            The most common approach is called ”3 and 7,” which consists of 3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone), combined with 100 mg/m² of arabinosylcytosine (araC) as a 24-hour infusion daily for 7 days. Idarubicin is given at a dose of 12 mg/m²/d for 3 days, daunorubicin at 45-60 mg/m²/d for 3 days, or mitoxantrone at 12 mg/m²/d for 3 days.

o                                            These regimens require adequate cardiac, hepatic, and renal function.

o                                            Using these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% enter remission following a second course of therapy.

o                                            Alternatively, high-dose araC combined with idarubicin, daunorubicin, or mitoxantrone can be used as induction therapy in younger patients. The use of high-dose araC outside the setting of a clinical trial is considered controversial. However, 2 studies demonstrated improved disease-free survival rates in younger patients who received high-dose araC during induction.

·                     Consolidation therapy in younger patients: In patients aged 60 years or younger, treatment options for consolidation therapy include high-dose araC, autologous stem cell transplantation, or allogeneic stem cell transplantation.

o                                            High-dose araC therapy: Mayer et al conducted a randomized study of 3 different doses of araC in patients with acute myelogenous leukemia (AML) who achieved remission after standard “3 and 7”induction chemotherapy. Patients received 4 courses of araC at one of the following doses: (1) 100 mg/m²/d by continuous infusion for 5 days, (2) 400 mg/m²/d by continuous infusion for 5 days, or (3) 3 g/m² in a 3-hour infusion every 12 hours on days 1, 3, and 5. The probability of remaining in continuous complete remission (CR) after 4 years in patients aged 60 years or younger was 24% in the 100-mg group, 29% in the 400-mg group, and 44% in the 3-g group (P = .002). The outcome in older patients did not differ. Based on this study, high-dose araC for 4 cycles is a standard option for consolidation therapy in younger patients.

Stem cell transplantation

In order to define the best postremission therapy for young patients, several large, randomized studies have compared allogeneic bone marrow transplantation (BMT), autologous BMT, and chemotherapy without BMT. Unfortunately, the results of these studies are conflicting.

·                     Consolidation therapy in older patients: No standard consolidation therapy exists for patients older than 60 years. Options include a clinical trial, high-dose araC in select patients, or repeat courses of standard-dose anthracycline and araC (2 and 5; ie, 2 d of anthracycline and 5 d of araC). Select patients can be considered for autologous stem cell transplantation or nonmyeloablative allogeneic transplantation.

o                    Nonmyeloablative allogeneic transplantation

§                     Although allogeneic stem cell transplantation is a potentially curative treatment option for patients with AML, all age groups have a significant risk of death from the procedure. The risk of death increases with age, particularly in patients older than age 40 years. However, the median age of patients with AML is 65 years; therefore, only a small percentage of patients with AML are candidates for such aggressive therapy.

§                     Following ablative allogeneic transplantation, death occurs due to sepsis, hemorrhage, direct organ toxicity (particularly affecting the liver; ie, venoocclusive disease [VOD]), and graft versus host disease. In an attempt to reduce these toxicities, several investigators have developed new, less toxic conditioning regimens known as nonmyeloablative transplants or mini-transplants. These transplants use conditioning drugs that are immunosuppressive to allow engraftment of donor cells with less direct organ toxicity than that of standard transplants. Patients who receive these transplants often also have less severe acute graft versus host disease than patients who receive standard transplants. These two factors result in a day 100 mortality rate of less than 10%.

§                                                                     The tolerability of these regimens allows patients aged 70 years or younger to undergo transplantation. However, patients who receive nonmyeloablative transplants still develop significant chronic graft versus host disease, which can be fatal. In addition, relapse rates following nonmyeloablative transplants appear to be higher than those following standard transplants. Further studies are ongoing to determine the best role for these transplants in patients with AML.

Treatment of relapsed acute myelogenous leukemia

·                     Patients with relapsed AML have an extremely poor prognosis. Most patients should be referred for investigational therapies. Young patients who have not previously undergone transplantation should be referred for such therapy.

·                     Estey et al reported that the chances of obtaining a second remission with chemotherapy correlate strongly with the duration of the first remission. Patients with an initial CR duration of longer than 2 years had a 73% CR rate with initial salvage therapy. Patients with an initial CR duration of 1-2 years had a CR rate of 47% with initial salvage therapy. Patients with an initial CR duration of less than 1 year or with no initial CR had a 14% CR rate with initial salvage therapy. Patients with an initial CR duration of less than 1 year (or no initial CR) who had no response to first-salvage therapy and received a second or subsequent salvage therapy had a response rate of 0%. These data stress the need to develop new treatment options for these patients.

 

Therapy-Induced Changes in Acute Leukemias

 

Pict. 13  AML, M2 subtype, prior to treatment

 

 

Pict. 14 Severe cytopenia following two cycles of chemotherapy

   

Pict. 15 Higher-power view of a small focus of granulocytopoietic regeneration with young promyelocytes. It can be difficult to distinguish betweeormal and leukemic precursors at this stage

 

 

Pict. 16 Complete remission after an additional four weeks’ therapy

 

Newer therapies

·                     Gemtuzumab ozogamicin

o                                            Gemtuzumab ozogamicin is a monoclonal antibody against CD33 (a molecule present on most AML cells but not oormal stem cells) conjugated to calicheamicin (a potent chemotherapy molecule). Gemtuzumab ozogamicin is currently approved by the Food and Drug Administration in the United States for the treatment of patients with CD33-positive AML in first relapse who are aged 60 years or older and who are not considered candidates for other cytotoxic chemotherapy.

o                                            Sievers reported the results of gemtuzumab ozogamicin administration in 142 patients with AML who were in their first relapse and who had no history of an antecedent hematologic disorder (AHD). Sixteen percent of patients obtained a formal complete response. An additional 13% of patients met criteria for complete response but did not have the required platelet recovery. Toxicity included infusion reactions, myelosuppression, and hepatic toxicity.

Surgical Care: Placement of a central venous catheter (eg, triple lumen, Broviac, Hickman) is necessary.

Diet: Patients should be on a neutropenic diet (ie, no fresh fruits or vegetables). All foods should be cooked. Meats should be cooked completely (ie, well done).

Activity: Patients should limit their activity to what is tolerable, with no strenuous activities (eg, lifting, exercise).

Medications cause severe bone marrow depression. Only physicians specifically trained in their use should use them. In addition, access to appropriate supportive care (ie, blood banking) is required.

Drug Category: Antineoplastics — These agents are used for induction or consolidation therapy.

 

 

 

 

 

 

Further Inpatient Care:

·                     Patients require readmission for consolidation chemotherapy or for the management of toxic effects of chemotherapy.

Further Outpatient Care:

·                     Patients should come to the office for monitoring of disease status and chemotherapy effects.

Transfer:

·                     Patients are best treated at a center whose staff has significant experience in the treatment of leukemia. Patients should be transferred to an appropriate (generally tertiary care) hospital if they are admitted to hospitals without appropriate blood product support, leukapheresis capabilities, or physicians and nurses familiar with the treatment of leukemia patients.

Deterrence/Prevention:

·                     While receiving chemotherapy, patients should avoid exposure to crowds and people with contagious illnesses, especially children with viral infections.

Complications:

·                     Death may occur because of uncontrolled infection or hemorrhage. This may happen even after use of appropriate blood product and antibiotic support.

·                     The most common complication is failure of the leukemia to respond to chemotherapy. The prognosis for these patients is poor because they usually do not respond to other chemotherapy regimens.

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) results from an acquired injury to the DNA of a single cell, a lymphocyte, in the marrow. This injury is not present at birth. Scientists do not yet understand what produces this change in the DNA of CLL patients.

This change in the cell’s DNA confers a growth and survival advantage on the cell, which becomes abnormal and malignant (leukemic). The result of this injury is the uncontrolled growth of lymphocytic cells in the marrow, leading invariably to an increase in the number of lymphocytes in the blood. The leukemic cells that accumulate in the marrow in chronic lymphocytic leukemia do not impede normal blood cell production as profoundly as in the case of acute lymphocytic leukemia. This important distinction from acute leukemia accounts for the less severe early course of the disease.

Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. It is the most common form of leukemia found in adults in Western countries.

 

Pathophysiology

·The cells of origin in the majority of patients with CLL are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells. Morphologically in the peripheral blood, these cells resemble mature lymphocytes. B-CLL lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20, CD21, and CD24 monoclonal antibodies. In addition, they express CD5, which is more typically found on T cells. Because normal CD5+ B cells are present in the mantle zone (MZ) of lymphoid follicles, B-cell CLL is most likely a malignancy of an MZ-based subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural autoantibodies.

·        B-CLL cells express extremely low levels of surface membrane immunoglobulin, most often immunoglobulin M (IgM) or IgM and immunoglobulin D (IgD). Additionally, they also express extremely low levels of a single immunoglobulin light chain (kappa or lambda).

·        Recent studies have demonstrated that bcl2, a protooncogene, is overexpressed in B-CLL. The protooncogene bcl2 is a known suppresser of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite the frequent overexpression of bcl-2 protein, genetic translocations that are known to result in the overexpression of bcl2, such as t(14;18), are not found in patients with CLL.

·        An abnormal karyotype is observed in the majority of patients with CLL. The most common abnormality is deletion of 13q, which occurs in more than 50% of patients. Patients showing 13q14 abnormalities have a relatively benign disease that usually manifests as stable or slowly progressive isolated lymphocytosis. The presence of trisomy 12, which is observed in 15% of patients, is associated with atypical morphology and progressive disease. Deletions of bands 11q22-q23, observed in 19% of patients, are associated with extensive lymph node involvement and aggressive disease. More sensitive techniques have demonstrated abnormalities of chromosome 12. Approximately 2-5% of patients with CLL exhibit a T-cell phenotype.

·        CLL also should be distinguished from prolymphocytic leukemia, in which more than 65% of the cells are morphologically less mature prolymphocytes.

 

Frequency

·        In the US: More than 17,000 new cases are reported every year.

·        Internationally: Unlike the incidence of CLL in the Western countries, which is similar to that of the United States, the disease is extremely rare in Asian countries (ie, China, Japan), where it is estimated to comprise only 10% of all leukemias.

 

Mortality/Morbidity

·        The natural history is heterogeneous.

·        Some patients die rapidly, within 2-3 years of diagnosis, because of CLL complications.

·        The majority of patients live 5-10 years, with an initial course that is relatively benign but followed by a terminal progressive and resistant phase lasting 1-2 years. During the later phase, morbidity is considerable, both from the disease and from complications of therapy.

 

Race: The incidence is higher among whites compared to African Americans.

 

Sex: The incidence is higher in males than in females, with a male-to-female ratio of 1.7:1.

 

Age:

·        CLL is a disease that primarily affects elderly individuals, with the majority of cases reported in individuals older than 55 years.

·        The incidence continues to rise in those older than 55 years.

·        Recently, individuals aged 35 years or younger are being diagnosed more frequently.

Causes and Risk Factors

 As in the case of most malignancies, the exact cause of CLL is uncertain.

The protooncogene bcl2 is known to be overexpressed, which leads to suppression of apoptosis (programmed cell death) in the affected lymphoid cells.

CLL is an acquired disorder, and reports of truly familial cases are exceedingly rare.

Unlike the other three major types of leukemia, chronic lymphocytic leukemia is not associated with high-dose radiation or benzene exposure. First-degree relatives of patients with the disease have about a threefold greater likelihood of getting the disease than other people. This should be put into perspective, however. For example, the 60-year-old sibling or offspring of a patient with chronic lymphocytic leukemia would have three chances in 10,000 of developing the disease compared with the one chance in 10,000 for a 60-year-old person without a family history of the disease. The disease is very uncommon in individuals under 45 years of age. At the time of diagnosis, 95 percent of patients are over age 50, and the incidence of the disease increases dramatically thereafter (see Figure 3).

  

The horizontal axis shows the age at diagnosis of Americans who develop chronic lymphocytic leukemia. Age is grouped into 5-year periods. The vertical axis represents the number of new cases of chronic lymphocytic leukemia per 100,000 people in a particular 5-year age grouping. The risk of chronic lymphocytic leukemia becomes measurable after age 40 and increases dramatically over succeeding decades. The data are from the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program, 2004.

 

Symptoms and Signs

Early in the disease, chronic lymphocytic leukemia often has little effect on a person’s well being. The disease may be discovered after finding an abnormal blood count during the course of a periodic medical examination or while the patient is under care for an unrelated condition. The report of an elevated white cell count is the most common clue that leads a physician to consider the diagnosis of chronic lymphocytic leukemia.

The symptoms of chronic lymphocytic leukemia usually develop gradually. Patients tire more easily and may feel short of breath when physically active, as a result of anemia. They may lose weight. The leukemic lymphocytes (white cells) can accumulate in the lymphatic system and the lymph nodes and spleen may become enlarged. Patients may experience infections, sometimes recurrent, of the skin, lungs, kidneys, or other sites.

History

·        Patients with CLL present with a wide range of symptoms and signs at presentation. Onset is insidious, and it is not unusual for this disorder to be discovered incidentally after a blood cell count is performed for another reason.

·        Predisposition to repeated infections such as pneumonia, herpes simplex labialis, and herpes zoster

·        Enlarged lymph nodes

·        Early satiety and/or abdominal discomfort related to an enlarged spleen

·        Mucocutaneous bleeding and/or petechiae secondary to thrombocytopenia

·        Tiredness and fatigue secondary to anemia

 

Basis of clinical diagnostics of CLL is lymphadenopathy, splenomegaly, hepatomegaly, infiltration by tumoral lymphocytes of pleura, gastrointestinal tract (with simulation of stomach tumor, intestinal polyposis), prostate, bones and joint with development of osteoporosis and osteolisis of vertebra and pelvic bones; perivascular infiltration of retine of eye, middle ear, vestibular apparatus, nervous system (hemiplegia, meningisms, paralysis of cranial nerves), skin (lymphocytic tumoral erythema, macropapules, exematous placodes, rarely – specific skins leukemia’s, erythrodermia, prurigo). From general features – hyperhydrosis, weight loss, undue fatigue.

 

Physical:

Ø     Localized or generalized lymphadenopathy

Ø     Splenomegaly (30-40% of cases)

Ø     Hepatomegaly (20% of cases)

Ø     Petechiae

Ø     Pallor

Diagnosis

To diagnose the disease, the blood and, in most cases, the marrow cells are examined. The white cell count is increased in the blood. The increase is the result of an increase in blood lymphocytes. A marrow examination also will show an increase in the proportion of lymphocytes, often accompanied by some decrease in the normal marrow cells. In addition, a sample of marrow cells is examined to determine if there is an abnormality of chromosomes. The examination of cells to determine if an abnormality of chromosomes is present is referred to as a cytogenetics analysis. Low platelet counts and low red cell counts (anemia) may be present but are usually only slightly decreased in the early stage of the illness.

Lab Studies

 

· CBC count with differential shows absolute lymphocytosis with more than 5000 lymphocytes/mL. Some authors consider this to be a prerequisite for the diagnosis of CLL and classify cases that would otherwise meet the criteria as small lymphocytic lymphoma/diffuse well-differentiated lymphoma.

· Microscopic examination of the peripheral blood smear is indicated to confirm lymphocytosis. It usually shows the presence of smudge cells, which are artifacts due to damaged lymphocytes during the slide preparation.

· Peripheral blood flow cytometry is the most valuable test to confirm CLL.

· It confirms the presence of circulating clonal B-lymphocytes expressing CD5, CD19, CD20(dim), CD 23, and an absence of FMC-7 staining.

· Consider obtaining serum quantitative immunoglobulin levels in patients developing repeated infections because monthly intravenous immunoglobulin administration in patients with low levels of immunoglobulin G (<500 mg) may be beneficial in reducing the frequency of infectious episodes.

· The differential diagnosis of CLL includes several other entities, such as hairy cell leukemia, which is moderately positive for surface membrane immunoglobulins of multiple heavy-chain classes and typically negative for CD5 and CD21. Prolymphocytic leukemia has a typical phenotype that is positive for CD19, CD20, and surface membrane immunoglobulin and negative for CD5. Large granular lymphocytic leukemia has a natural killer cell phenotype (CD2, CD16, and CD56) or a T-cell immunotype (CD2, CD3, and CD8). The pattern of positivity for CD19, CD20, and the T-cell antigen CD5 is shared only by mantle cell lymphoma.

Pict. 17 Peripheral blood smear showing CLL cells

 

Pict. 18 This is a microscopic view of bone marrow from a person with chronic lymphocytic leukemia; it shows predominantly small, mature lymphocytes

 

Imaging Studies:

·  Liver/spleen scan may demonstrate splenomegaly.

·  Computed tomography of chest, abdomen, or pelvis generally is not required for staging purposes. However, be careful to not miss lesions such as obstructive uropathy or airway obstruction that are caused by lymph node compression on organs or internal structures.

 

Picture 19. Peripheral smear of a patient with chronic lymphocytic leukemia, small lymphocytic variety.

 

Picture 20. This is a peripheral smear of a patient with chronic lymphocytic leukemia, showing the large lymphocytic variety. Smudge cells also are observed. Smudge cells are the artifacts produced by the lymphocytes damaged during the slide preparation.

 

Procedures:

·        Bone marrow aspiration and biopsy with flow cytometry is not required in all cases but may be necessary in selected cases to establish the diagnosis and to assess other complicating features such as anemia and thrombocytopenia. For example, bone marrow examination may be necessary to distinguish between thrombocytopenia of peripheral destruction (in the spleen) and that due to marrow infiltration.

·        Consider a lymph node biopsy if lymph node(s) begin to enlarge rapidly in a patient with known CLL to assess the possibility of transformation to a high-grade lymphoma. When such transformation is accompanied by fever, weight loss, and pain, it is termed Richter syndrome.

   

Determining Disease Stage

CLL patients are assessed as having a specific stage of disease to judge disease progression and the need for treatment. Several staging classifications have been proposed. The Rai or Binet staging systems are commonly used. These systems consider:

·                     The elevation of blood and marrow lymphocyte counts;

·                     The size and distribution of lymph nodes;

·                     The spleen size;

·                     The degree of anemia and the extent of the decrease of the blood platelet count.

Staging:

Two staging systems are in common use, the Rai-Sawitsky in the United States and the Binet in Europe. Neither is completely satisfactory, and both have been often modified. Because of its historical precedent and wide use, the Rai-Sawitsky system is described first, followed by the Binet. The International Workshop on Chronic lymphocytic Leukemia (IWCLL) system is listed last.

The Rai-Sawitsky staging system divides CLL into 5 Stages, 0-IV.

Ø     Stage 0 is lymphocytosis in the blood and marrow only, with a survival of longer than 120 months.

Ø     Stage I is lymphocytosis and adenopathy, with a survival of 95 months.

Ø     Stage II is lymphocytosis plus splenomegaly and/or hepatomegaly, with a survival of 72 months.

Ø     Stage III is lymphocytosis plus anemia (hemoglobin <10 g), with a survival of 30 months.

Ø     Stage IV is lymphocytosis plus thrombocytopenia (platelets <100,000), with a survival of 30 months.

 

The Binet staging system uses 3 stages, A, B, and C.

Ø     Stage A requires a hemoglobin of greater than or equal to 100 g/L, platelets greater than or equal to 100 X 10-9, and fewer than 3 lymph node areas involved (Rai-Sawitsky stages 0, I, II). Survival is longer than 120 months.

Ø     Stage B requires hemoglobin and platelet levels as in stage A and 3 or more lymph node areas involved (Rai-Sawitsky stages I and II). Survival is 61 months.

Ø     Stage C is a hemoglobin less than 100 g/L, platelets less than 100 X 10-9, or both (Rai-Sawitsky stages III and IV). Survival is 32 months.

 

Disease Course

Progression of CLL may take several forms. Accumulation of leukemic lymphocytes in marrow and blood can lead to progressive decrease in blood hemoglobin and platelet count. Progressive enlargement of lymph nodes, especially in the abdomen, can result in compression of neighboring structures such as the gastrointestinal tract or urinary tract. Severe immunoglobulin deficiency, sometimes coupled with a low neutrophil count, can lead to recurrent infections. Some signs of progressive disease are shown in Table 10.

 

 

The main principles of CLL treatment:

Ø     Patients’ regimen.

Ø     Cytostatic therapy.

Ø     Medical lymphocytopheresis.

Ø     Radial therapy.

Ø     Splenectomy

Ø     Glucocorticoid agents.

Ø     Treatment of infectious complications.

Treatment of stage I, stage II, stage III, and stage IV chronic lymphocytic leukemia may include the following:

Ø    Watchful waiting when there are few or no symptoms.

Ø    Monoclonal antibody therapy.

Ø    Chemotherapy with 1 or more drugs, with or without steroids or monoclonal antibody therapy.

Ø    Low-dose external radiation therapy to areas of the body where cancer is found, such as thespleen or lymph nodes.

Ø    A clinical trial of chemotherapy and biologic therapy with stem cell transplant.

Ø    A clinical trial of biologic therapy.

Ø    Treatment of refractory chronic lymphocytic leukemia may include the following:

Ø    A clinical trial of chemotherapy with stem cell transplant.

Ø    A clinical trial of a new treatment.

 

Medical Care:

At the time of diagnosis, most patients do not need to be treated with chemotherapy unless they have weight loss of more than 10%, extreme fatigue, fever related to leukemia, night sweats, progressive marrow failure, autoimmune anemia or thrombocytopenia not responding to prednisone, progressive splenomegaly, massive lymphadenopathy, or progressive lymphocytosis. Progressive lymphocytosis is defined as an increase of greater than 50% in 2 months or a doubling time of less than 6 months.

Those patients who have more progressive disease (higher numbers in the staging system) are usually treated with chemotherapy and monoclonal antibodies.

Chemotherapy
The drugs most commonly used to treat progressive chronic lymphocytic leukemia are shown in Table 11. Drug combinations are sometimes used, depending on the patient’s health status, age, and the apparent rapidity of disease progression. Fludarabine or cladribine are usually the first drugs used because clinical trials have found them to be more effective than other options.

 

 

Patients at stage 0 whose disease is stable require only periodic follow-up. Early treatment has not been demonstrated to be advantageous.

Ø     Prednisolone alone, usually in a dose of 20-60 mg daily initially, with subsequent gradual dose reduction, may be useful in patients with autoimmune manifestations of the disease.

Ø     Nucleoside analogs (ie, fludarabine, cladribine, and pentostatin) include a new group of drugs with major activity against indolent lymphoid malignancies, including CLL.

Ø     Fludarabine is the most extensively studied and currently is the most commonly used second-line therapy in CLL.

Ø     Responses to treatment with chlorambucil and prednisone are observed in 38-47% of patients.

Ø     Patients treated with fludarabine have much higher rates (80%) of overall responses and a 37% complete remission rate.

Ø     Studies using purine analogs, especially fludarabine, compared to alkylator-based therapies have shown that the response rates are superior and the progression-free interval is longer, but evidence to show prolonged overall survival is premature.

Ø     The combination of fludarabine and cyclophosphamide has shown higher response rates, but direct comparative trials of fludarabine and cyclophosphamide to fludarabine alone are lacking.

Ø     The combination of fludarabine and chlorambucil recently has been shown to result in more infections than either single agent alone.

Ø     Various combination regimens have shown improved response rates in several randomized trials but failed to show any survival advantage. Common combination regimens include chlorambucil and corticosteroids; cyclophosphamide, doxorubicin, and prednisone (CAP); cyclophosphamide, vincristine, and prednisone (CVP); and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

Ø     Chlorambucil (alkylating agent) and fludarabine (antimetabolite) are commonly used in the treatment of CLL. Purine analogs and, in particular, fludarabine are very active against CLL. Fludarabine produces remissions in a significant proportion of patients. It appears to induce apoptosis in malignant lymphocytes upon exposure.

Ø     Chemotherapy for CLL typically is given in an outpatient setting.

Ø     Some patients require admission if they develop febrile neutropenia.

Ø     This is treated in the usual fashion by giving broad-spectrum intravenous antibiotics after obtaining blood cultures.

Ø     The antibiotics commonly used on empiric grounds are ceftazidime, cefepime, or imipenem.

Ø     If patients have indwelling central venous access devices and appear septic, consider adding vancomycin.

 

 

Monoclonal Antibody Therapy

Several monoclonal antibodies that kill malignant lymphocytes and were introduced as treatments for lymphoma may be useful in the treatment of CLL (Table 2). These antibodies are made by biotechnology methods and target the leukemic lymphocytes, causing them to die after attachment. Most chemotherapeutic agents affect cells of normal tissues as well as the CLL cells. The monoclonal antibodies may affect related, normal lymphocytes but spare most other tissues, limiting their undesirable effects. On average, the side effects are less when the monoclonal antibodies rituximab (Rituxan^®) or alemtuzumab (Campath^®) are used. (These agents are the two monoclonal antibodies that are most useful in treating CLL.)

Infusion of monoclonal antibodies into a vein may cause transient fever, chills, and low blood pressure. The monoclonal antibodies target a protein on the lymphocyte cell surface. In the case of rituximab, the target is referred to as CD20 and in the case of alemtuzumab, the target is CD52. These monoclonal antibodies have been used most frequently in CLL patients who do not or no longer respond to chemotherapy. Because they have a very good effect in a proportion of patients, they are being studied for use as initial treatment either alone or with chemotherapy.

Therapy with monoclonal antibodies has been evaluated in patients with CLL. The most useful agent in clinical trials so far appears to be CAMPATH-1H, an antibody directed at CD52. Rituxan (rituximab) also is effective as a second-line or third-line treatment and may assume a more prominent role in the future.

Stem Cell Transplantation

This is a treatment option for carefully selected younger patients who can be matched with a marrow donor. A special form of stem cell transplantation that uses very low doses of pretreatment radiation and/or chemotherapy to prepare the patient to receive the donor marrow is being studied. This treatment is referred to as nonablative or mini transplant because it does not lead to severe decreases in blood cell counts and can be used in older persons. It does not ablate or wipe out the blood forming function of the marrow. The beneficial effects develop gradually over months and are thought to result from an immune attack by the donor’s lymphocytes against the chronic leukemia cells. Eventually the donor marrow and immune cells become dominant. This approach is experimental.

 Chronic myelogenous leukemia

 

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells. CML is a tumor arisen from one mutate predecessors-cells of mielopoiesis, morphological substrate of which, as a rule, is three- sprouts proliferation, which displays that with prevalentsurplus excrescence of cells of granulocytes row, also has a place moderate cell proliferation of erytrocytes and megacariocytes sprouts.  This peculiarity is associated with that these sprouts develop from one matter – predecessors-cells of mielopoiesis.

 

Pathophysiology: CML is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9; t(9;22). The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph) chromosome after the city of discovery.

 

Pict. 21 The Philadelphia chromosome as seen by metaphase FISH

 This translocation relocates an oncogene called abl from the long arm of chromosome 9 to the long arm of chromosome 22 in the BCR region. The resulting BCR/ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The expression of this protein leads to the development of the CML phenotype through processes that are not yet fully understood.

The presence of BCR/ABL rearrangement is the hallmark of CML, although this rearrangement has also been described in other diseases. It is considered diagnostic when present in a patient with clinical manifestations of CML.

 

Causes:

· The initiating factor of CML is still unknown, but exposure to irradiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki.

· Other agents, such as benzene, are possible causes.

Among etiological factors the most essential are physical and chemical mutagens, viruses, congenital or acquireed defects of immune defense. However in majority of cases (87 %) the cause of  beginnings of leucocytosis growth is chromosomal pathology (Philadelphia chromosome).

In some cases the conditions of “slip out” are created of mutant from under immune control. As a result, happened to be outside of organism control, a mutant cell continues uncontrolledly to “reproductive”, that brings to fast accumulation of tumoral tissues and forcing out healthy haemopoiesis.

 

CLINICAL

History:

· The clinical manifestations of CML are insidious and are often discovered incidentally when an elevated WBC count is revealed by a routine blood count or when an enlarged spleen is revealed during a general physical examination.

· Nonspecific symptoms of tiredness, fatigue, and weight loss may occur long after the onset of the disease. Loss of energy and decreased exercise tolerance may occur during the chronic phase after several months.

· Patients often have symptoms related to enlargement of the spleen, liver, or both.

o  The large spleen may encroach on the stomach and cause early satiety and decreased food intake. Left upper quadrant abdominal pain described as “gripping” may occur from spleen infarction. The enlarged spleen may also be associated with a hypermetabolic state, fever, weight loss, and chronic fatigue.

O  The enlarged liver may contribute to the patient’s weight loss.

·  Some patients may have low-grade fever and excessive sweating related to hypermetabolism.

·  The disease has 3 clinical phases, and it follows a typical course of an initial chronic phase, during which the disease process is easily controlled; followed by a transitional and unstable course (accelerated phase); and, finally, a more aggressive course (blast crisis), which is usually fatal.

O Most patients are diagnosed while still in the chronic phase. The WBC count is usually controlled with medication (hematologic remission). This phase varies in duration depending on the maintenance therapy used. It usually lasts 2-3 years with hydroxyurea (Hydrea) or busulfan therapy, but it has lasted for longer than 9.5 years in patients who respond well to interferon alfa therapy. Recently, the addition of imatinib mesylate has dramatically improved the duration of hematologic and indeed cytogenetic remissions.

O Some patients progress to a transitional or accelerated phase, which may last for several months. The survival of patients diagnosed in this phase is 1-1.5 years. This phase is characterized by poor control of the blood counts with myelosuppressive medication and the appearance of peripheral blast cells (>15%), promyelocytes (>30%) (see Image below), basophils (>20%), and platelet counts less than 100,000 cells/mL unrelated to therapy. Usually, the doses of the medications need to be increased. Splenomegaly may not be controllable by medications, and anemia can worsen. Bone pain and fever, as well as an increase in bone marrow fibrosis, are harbingers of the last phase.

 

Picture 23. Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils.

 

Picture 23. Chronic Myelogenous Leukemia (A) Myeloblasts,(B) Neutrophilic Myelocyte. (C) Neutrophilic Metamyelocyte. (D) Band neutrophil. (E) Basophil.

 

O Acute phase, or blast crisis, is similar to acute leukemia, and survival is 3-6 months at this stage. Bone marrow and peripheral blood blasts of 30% or more are characteristic. Skin or tissue infiltration also defines blast crisis. Cytogenetic evidence of another Ph-positive clone (double) or clonal evolution (other cytogenetic abnormalities such as trisomy 8, 9, 19, or 21, isochromosome 17, or deletion of Y chromosome) is usually present.

· In some patients who present in the accelerated, or acute, leukemia phase of the disease (skipping the chronic phase), bleeding, petechiae, and ecchymoses may be the prominent symptoms. In these situations, fever is usually associated with infections.

 

In CML flowing they pick out the next stages initial, unroll and terminal.

· For todays understanding initial stage is that disease stage, when only small part of cells of granulocytes sprout is tumoral, and majority are the cells of normal hemopoiesis. As a rule, this stage has never diagnosed, because specific clinical disease symptoms of disease are absents.

·  Unroll stage is manifestation of total generalisation of tumoral cells in marrow with forcing out of healthy haemopoiesis sprout. Clinical symptoms in this stage are crescent general weakness, rapid fatigue, hyperhydrosis, weight loss, increase of temperature, osseous and articulate pains, spleen and livers enlargement which one can be combined into syndrome of tumoral intoxication.

· Terminal stage starts when a monotonously flowing monoclone tumor turns into policlone. Under this sharp there is increase of amount of tumoral cells, that with each following mutation lose ability to differentiatie, the manifestation of what is sharp increasing of cells amount of granulocytes row of different ripening degrees. Metastatic spreading of these cells, adapted to survival for boundary paths of haemopoietic system, brings about appearance of metaplastatic hearths of tumoral growth in liver, skin, bone, lymph node and oth., with clinical features of dysfunctions of these organs and systems. The most threatful features of terminal stage is blastogenic crises.  A clinical picture of CML consists from tumoral intoxication syndrome, syndrome of tumoral metaplasy, syndrome of metabolitic distebance. The cells substrate of tumor are leucocytosis for a counting of immature cells of granulocytes row, metaplastic anaemia and tromcytopenia, pletora of marrow for a counting of tumoral granulocytessprout.

 

Stages of CML

 

 

Physical:

· Splenomegaly is the most common physical finding in patients with CML.

· In more than half the patients with CML, the spleen extends more than 5 cm below the left costal margin at time of discovery.

· The size of the spleen correlates with the peripheral blood granulocyte counts (see Image below), with the biggest spleens being observed in patients with high WBC counts.

 

Picture 24. Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil.

 

 

· A very large spleen is usually a harbinger of the transformation into an acute blast crisis form of the disease.

· Hepatomegaly also occurs, although less commonly than splenomegaly. Hepatomegaly is usually part of the extramedullary hematopoiesis occurring in the spleen.

· Physical findings of leukostasis and hyperviscosity can occur in some patients, with extraordinary elevation of their WBC counts, exceeding 300,000-600,000 cells/mL. Upon funduscopy, the retina may show papilledema, venous obstruction, and hemorrhages.

 

 Lab Studies:

· Peripheral blood findings show a typical leukoerythroblastic blood picture, with circulating immature cells from the bone marrow.

 

Picture 25. Bone marrow film at 400X magnification demonstrates clear dominance of granulopoiesis. The number of eosinophils and megakaryocytes is increased.

  

· The increase in mature granulocytes and normal lymphocyte counts (low percentage due to dilution in the differential count) results in a total WBC count of 20,000-60,000 cells/mL. A mild increase in basophils and eosinophils is present and becomes more prominent during the transition to acute leukemia.

O These mature neutrophils, or granulocytes, have decreased apoptosis (programmed cell death), resulting in accumulation of long-lived cells with low or absent enzymes, such as alkaline phosphatase. Consequently, the leukocyte alkaline phosphatase stains very low to absent in most cells, resulting in a low score.

O Early myeloid cells such as myeloblasts, myelocytes, metamyelocytes, and nucleated red blood cells are commonly present in the blood smear, mimicking the findings in the bone marrow. The presence of the different midstage progenitor cells differentiates this condition from the acute myelogenous leukemias, in which a leukemic gap (maturation arrest) or hiatus exists that shows absence of these cells.

O A mild-to-moderate anemia is very common at diagnosis and is usually normochromic and normocytic.

O The platelet counts at diagnosis can be low, normal, or even increased in some patients (>1 million in some).

· Bone marrow is characteristically hypercellular, with expansion of the myeloid cell line (eg, neutrophils, eosinophils, basophils) and its progenitor cells. Megakaryocytes (see Image above) are prominent and may be increased. Mild fibrosis is often seen in the reticulin stain.

· Cytogenetic studies of the bone marrow cells, and even peripheral blood, should reveal the typical Ph1 chromosome, which is a reciprocal translocation of chromosomal material between chromosomes 9 and 22. This is the hallmark of CML, found in almost all patients with CML, and is present in CML throughout its entire clinical course.

O The Ph translocation is the translocation of the cellular oncogene c-abl from the 9 chromosome, which encodes for a tyrosine protein kinase, with a specific breakpoint cluster region (bcr) of chromosome 22, resulting in a chimeric bcr/c-abl messenger RNA that encodes for a mutation protein with much greater tyrosine kinase activity compared with the normal protein (see Image below). The latter is presumably responsible for the cellular transformation in CML. This m-RNA can be detected by polymerase chain reaction (PCR) in a sensitive test that can detect it in just a few cells. This is useful in monitoring minimal residual disease (MRD) during therapy.

 

Picture 26. The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows).

 

O Karyotypic analysis of bone marrow cells requires the presence of a dividing cell without loss of viability because the material requires that the cells go into mitosis to obtain individual chromosomes for identification after banding, which is a slow, labor-intensive process. The new technique of fluorescence in situ hybridization (see Image below) uses labeled probes that are hybridized to either metaphase chromosomes or interphase nuclei, and the hybridized probe is detected with fluorochromes. This technique is a rapid and sensitive means of detecting recurring numerical and structural abnormalities.

 

Picture 27. Fluorescence in situ hybridization using unique-sequence, double-fusion DNA probes forbcr (22q11.2) in red and c-abl (9q34) gene regions in green. The abnormal bcr/abl fusion present in Philadelphia chromosome – positive cells is in yellow (right panel) compared with a control (left panel).

  

Imaging Studies:

· Typical hepatomegaly and splenomegaly may be imaged by using a liver/spleen scan. Most often, these are so obvious that radiological imaging is not necessary.

· Histologic Findings: Diagnosis is based on the histopathologic findings in the peripheral blood and the Ph1 chromosome in the bone marrow cells.

 

Pic.28  Oil immersion field demonstrating myeloid cells of all degrees of maturity

 

Pict. 29. This high-power microscopic view of a blood smear from a person with classical CML shows predominantly normal-appearing cells with intermediate maturity

 

Pict. 30. Low power view showing marked hypercellularity with a broad-spectrum of myeloid and erythroid cell types and marked myeloid hyperplasia

 

  TREATMENT    

A treatment program of CML includes:

· Cytostatic therapy (monotherapy, polychemotherapy).

· Treatment by alpha-interferonum

· Radial therapy.

· Leukocytoferesis.

· Splenectomy.

· Symptomatic therapy.

· Marrow transplantation.

Treatment of CML depends on disease stage and prognostic criterioa of lifetime at the moment of diagnosis establishment.

Attached to insignificant expressed clinicohematological features and satisfactory general state of patients common strengthen therapy is recommended, full value feeding, rich on vitamins, rational work and rest regime, clinical supervision.

In unroll stage of disease cytostatic therapy (mono or polychemotherapy). Is used in which appearance it was taken depends on prognostic factors of disease.

Monotherapy of CML. Agent of choice in treatment of CML is hydroxyurea (hedrea-litaliz). This agent inhibits one of key ferments into biosintesis of DNA – ribonuclease – diphosphatreductase and predominantey influences the pool of leukemis cells growing rapidly, block S and G-1 stages of mitotic cycle. Preparation isproduced in capsules on 0,5 g and is administrated in initial dose 20-40 mg/kg/ day, a sustaining dose is 15-30 mg/kg, and attached to progressing increas to 40-60 mg/kg on day.

Treatment effectiveness is values after 6 weeks, through treatment duration is not limited. As a rule,hydroxyurea is well carried, however there is possible development of dyspeptic phenomen, neurulogic violations, skin allergic reactions, rarely-stomatitis, leucopenia, trombocytopenia.

Contraindication of hydroxyurea:

–  leucopenia (amount of leucocites less than 3 х 10^⁹/l);

– thrombocytopenia (less than 100 х 10^⁹/l).

Attached to absence of the effect from hydroxyurea patient is prescribed mielosan (busulphan, mileran), that operates on predecessors-cell and stopes production of leukemic cells. It is prodused in pills on 0,002 g, usedin dependence on leucocytes level in daily dose 2-8 mg. Mielosan effect usually begins to appear not early than on 10- day from the beginning of aueption, and normalization of hemogram and decreasing of spleen size come on 3-6 treatment week after obtaining at general dose – 250-300 mg.

On obtaining remission and decreasing of leucocytes level less than18 х 10⁹/l, they switeh to sustaining doses on 2 mg 1-2 times a week.

For reaching more rapid effect mielobromolum is used 250 mg/day.

For fixing of remission combination of cytosar with hydroxyurea, methotrexate is recommended,thioguaninum, cyclophosfane and vincristinum, rubromicinum.

Polychemotherapy of CML:

Is pertormed at unroll stages of CML attached to presence of criterioa of high risk.

Advisible is application of scheme “7 + 3″ (cytosar in dose 100mg/m2 – 7 days, rubomicini in dose 45 mg/m2 – 3 days).

More frequently we used the AVAMP schemes and CVAMP (arabinosid (cytosin-arabinosid) -30 mg/m² i/v in 1 and 8 days; Vincrastinum 2 mg/m² i/v on 3- and 10- days, ametopretinum (metotrexatum) 20 mg/m² i/v on 2, 5 and 9 days, 6-mercaptopurinum – 60 mg/m² from 1 to 10 day; prednisolonum 40 mg/m² from 1-го to 10- day).

 Medical Care: The 3-fold goals of treatment of CML have changed markedly in the past 10 years; they are to achieve a hematologic remission (normal CBC count and physical examination, ie, no organomegaly), to achieve cytogenetic remission (normal chromosome returns with 0% Ph-positive cells), and, most recently, to achieve molecular remission (negative PCR result for the mutational BCR/ABL m-RNA). The latter is an attempt for cure and prolongation of patient survival.

 A new approach to treatment of this disease is to directly inhibit the molecular cause of the disease, ie, using a protein-tyrosine kinase inhibitor that inhibits the bcr-abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Ph chromosome translocation abnormality.

For patients with chronic-phase CML, imatinib at 400 mg/d is the best candidate for primary therapy because it induces a complete hematologic response in almost all patients and causes a high cytogenetic response rate. Overall survival data comparing it with interferon are shown below.

 Treatment of CML patients in the accelerated phase or in blast crisis has been dismal. However, recent data show that imatinib can induce a hematologic response in 52-82%, but the response is less frequent and less durable, being sustained for at least 4 weeks in only 31-64%.

  The complete response rate is lower, at 7-34%. Karyotypic response occurs in 16-24%, and complete cytogenetic response is observed in only 17%. Higher doses (ie, 600 mg/d) result in improved response rates, cytogenetic response, and disease-free and overall survival.

In Ph-positive acute lymphoblastic leukemia, the combination of chemotherapy plus imatinib is associated with a 2-year survival rate of 60%.

Resistance of CML cells to imatinib is emerging through multiple mechanisms such as overexpression of BCR/ABL and mutations of the abl gene. Resistance can be overcome by increasing the imatinib dose, by developing more selective bcr-abl kinase inhibitors, and developing new non–cross-resistant drugs.

  Myelosuppressive therapy, which was formerly the mainstay of treatment to convert a patient with CML from an uncontrolled initial presentation to one with hematologic remission and normalization of the physical examination and laboratory findings, may soon fall out of favor as the new agents prove to be more effective with fewer adverse events and longer survival.

Hydroxyurea (Hydrea), an inhibitor of deoxynucleotide synthesis, is the most common myelosuppressive agent used to achieve hematologic remission. The initial blood cell count is monitored every 2-4 weeks, and the dose is adjusted depending on the WBC and platelet counts. Most patients achieve hematologic remission within 1-2 months. This medication causes only a short duration of myelosuppression, so even if the counts go lower than intended, stopping or decreasing doses usually controls the blood counts. Maintenance with hydroxyurea rarely results in cytogenetic or molecular remissions.

 Busulfan (Myleran) is an alkylating agent that has traditionally been used to keep the WBC counts less than 15,000 cells/mL. However, the myelosuppressive effects may occur much later and persist longer, making maintaining the numbers withiormal limits more difficult. Long-term use can cause pulmonary fibrosis, hyperpigmentation, and prolonged marrow suppression lasting for months.

 Leukapheresis using a cell separator can lower WBC counts rapidly and safely in patients with WBC counts of higher than 300,000 cells/mL, and it can alleviate acute symptoms of leukostasis, hyperviscosity, and tissue infiltration. Leukapheresis usually reduces the WBC count only temporarily and is often combined with cytoreductive chemotherapy for more lasting effects.

 Interferon alfa was the treatment of choice for most patients with CML who are too old for bone marrow transplantation (BMT) or who do not have a matched bone marrow donor. Interferon alfa is given at an average of 3-5 million IU/d subcutaneously after hematologic remission with hydroxyurea.

 The cytogenetic response is monitored every 3-6 months by karyotyping or by fluorescence in situ hybridization to count the percent of bone marrow cells with Ph-positive cells.

 The goal is 100% normal cells after 1-2 years of therapy. Patients with MRD BCR/ABL positive) should be kept on maintenance therapy as long as they continue to have MRD.

 Cytogenetic improvement has been observed in 70% of patients treated for longer than 3 months, with the median of Ph’-positive cells declining from 100% to 65% (range 0-95%). Complete suppression of the Ph’ chromosome was observed in 20% of patients.

 BMT should be considered early in young patients (<55 y) who have a matched sibling donor.

The mortality rate associated with BMT is 10-20% or less with a matched sibling and 30-40% with an unrelated donor. The bone marrow registry approximates the cure rate for patients with CML at 50%.

 Transplantation is recommended within 1 year of diagnosis or after a 1-year trial of interferon therapy without a complete or significant cytogenetic remission.

 Most patients with MRD after transplantation require interferon maintenance therapy anyway, or they may require a reinfusion of T cells collected from the donor.

Treatment decisions involving the use of interferon, BMT, or investigative options for younger patients with CML are extremely complex and in constant flux. Individualized decisions should be made in conjunction with consultation with physicians familiar with the recent literature.

 

MEDICATION

 

The medications used for patients with chronic-phase CML include a myelosuppressive agent to achieve hematologic remission, which requires 1-2 months of treatment. Once the patient goes into hematologic remission, the goal of treatment is to suppress the Ph-positive hematopoietic clone in the bone marrow for a cytogenetic remission and, hopefully, a molecular remission. This entails the use of interferon alfa or a BMT.

Treatment is determined by:

(1) the age of the patient,

(2) the presence of an HLA-matched donor willing to donate bone marrow, and

(3) the Sokal score.

The 3 categories of the Sokal score are (1) low risk, which is less than 0.8; (2) intermediate risk, which is 0.8-1.2; and (3) high risk, which is greater than 1.2.

The Sokal score is calculated for patients aged 5-84 years by hazard ratio = exp (0.011 (age – 43) + 0 .0345 (spleen – 7.5 cm) + 0.188 [(platelets/700)2 – 0.563] + 0.0887 (% blasts in blood – 2.1).

The choice of treatment is determined by the prognosis and the age of the patient. Most patients have no matched donor or are too old for BMT; interferon alfa is the drug of choice in these patients.

Drug Category

· Myelosuppressive agents — To control the underlying hyperproliferation of the myeloid elements, a myelosuppressive agent is necessary to bring down WBC counts and, occasionally, elevated platelet counts. Size of the spleen correlates with WBC counts, and it shrinks as WBC counts approach reference range. Also, intermediate and myeloblast cells disappear from the circulation.

Drug Name

· Hydroxyurea (Hydrea) — Inhibitor of deoxynucleotide synthesis and DOC for inducing hematologic remission in CML. Less leukemogenic than alkylating agents such as busulfan, melphalan (Alkeran), or chlorambucil. Myelosuppressive effects last a few days to a week and are easier to control than with alkylating agents; busulfan is associated with prolonged marrow suppression and can cause pulmonary fibrosis.

· Adult Dose Initial dose: 30 mg/kg/d at an average of 1000-1500 mg/d PO in 500-mg tabs

· Can be given at higher doses in patients with extremely high WBC counts (>300,000/mL) and adjusted accordingly as counts fall and platelet counts drop; dose can be given as a single daily dose or divided into 2-3 doses at higher dose ranges

· Pediatric Dose Not established

· Contraindications Documented hypersensitivity; thrombocytopenia is dose-limiting factor in using hydroxyurea; do not administer if platelet counts <50,000/mL; administer under advisement in patients with counts <100,000/mL; anemia may be aggravated by medications, and concomitant irradiation is contraindicated

· Interactions Neurotoxicity can occur when administered concurrently with fluorouracil

· Pregnancy C – Safety for use during pregnancy has not been established.

· Precautions Monitor blood counts and adjust doses accordingly; some patients may be sensitive and present with fever, chills, and elevation of liver enzymes, which disappear after stopping drug; skin ulcers may be seen in long-term use; caution in patients with renal impairment

Drug Name

· Busulfan (Myleran) — Potent cytotoxic drug which, at recommended dosage, causes profound myelosuppression. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

· Adult Dose 4-8 mg/d PO; may administer up to 12 mg/d; maintenance dosing range is 1-4 mg/d to 2 mg/wk; discontinue regimen when WBC count reaches 10,000-20,000/mL; resume therapy when WBC reaches 50,000/mL

· Contraindications Documented hypersensitivity; severely depressed bone marrow function; breastfeeding; failure to respond to previous treatment

·   Precautions Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; may cause pulmonary fibrosis; if WBC count is high, hydration and allopurinol should be used to prevent hyperuricemia

Drug Category

· Tyrosine kinase inhibitors — Imatinib mesylate, or STI571, in oral formulation is an agent with strong tyrosine kinase inhibition activity of the BCR/ABL abnormality in all phases of CML.

Drug Name

· Imatinib mesylate (Gleevec) — Specifically designed to inhibit tyrosine kinase activity of bcr-abl kinase in Ph-positive leukemic CML cell lines. Well absorbed after oral administration, with maximum concentrations achieved within 2-4 h. Elimination is primarily in feces in form of metabolites.

· Adult Dose Chronic phase: 400 mg/d PO with food and large glass of water; may increase to 600 mg/d if no severe adverse effects or severe non–leukemia-related neutropenia or thrombocytopenia, disease continues to progress (any time), hematologic response is not satisfactory (after at least 3 mo treatment), or a loss of previously achieved hematologic response occurs

·  Accelerated phase or blast crisis: 600 mg/d PO with food and large glass of water; may increase to 800 mg/d (400 mg bid) if no severe adverse effects or severe non–leukemia-related neutropenia or thrombocytopenia, disease continues to progress (any time), hematologic response is not satisfactory (after at least 3 mo treatment), or a loss of previously achieved hematologic response occurs

· Contraindications Documented hypersensitivity

· Precautions Dose must be reduced if grade 3-4 neutropenia or thrombocytopenia develops or levels of transaminases or bilirubin become elevated

Drug Name

· Dasatinib (Sprycel) — Multiple tyrosine kinase inhibitor. Inhibits growth of cell lines overexpressing BCR-ABL.

· Orphan drug indicated for chronic myeloid leukemia (CML) in individuals resistant to or intolerant of prior therapy (eg, imatinib [Gleevec]). Has been able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations.

· Adult Dose 70 mg PO bid; continue until disease progression or no longer tolerated

· Chronic-phase CML: Escalate dose to 90 mg PO bid

· Advanced-phase CML: May increase to 100 mg PO bid

· Coadministration with CYP3A4 inhibitors: 20-40 mg PO qd

·        Coadministration with CYP3A4 inducers: May need to increase dose

·        If clinically viable, an alternate medication with no or minimal enzyme inhibition or induction is recommended

· Contraindications None known

· Precautions Adverse effects include fluid retention (including pleural effusion), bleeding, diarrhea, rash, pyrexia, infections, headache, fatigue, and nausea; frequently causes anemia, neutropenia, or thrombocytopenia; because of extensive liver metabolism, caution in patients with hepatic impairment (may need to decrease dose); swallow tab whole, do not crush or cut

Drug Category

· Interferons — Alfa, beta, and gamma are the 3 types known to date. Alfa group has been found to inhibit propagation of Ph-positive hematopoietic clone, allowing return of normal cells in bone marrow.

Drug Name

· Interferon alfa-2a (Roferon A) or alfa-2b (Intron A) — Both are recombinant alpha interferons with some minor amino acid differences but are considered equivalent modalities in treatment of CML. Roferon A comes in single (3-, 6-, 9-, and 36-MIU strength) or multidose vials (9- or 18-MIU strength). Intron A comes in multidose pens of 18 MIU (delivers 3 MIU/dose), 30 MIU (5 MIU/dose), and 60 MIU (10 MIU/dose), with each pen good for 6 doses.

· Elderly patients who cannot tolerate adverse effects may be started at half the recommended starting dose.

·  Adult Dose Approximately 5 million/m2/d SC until complete cytogenetic remission (100% Ph-negative BM cells by FISH)

· Remission can occur within 1-2 y from onset of therapy; individual maximally tolerated dose can be obtained by starting at 3 MIU or 1.5 MIU qd and increasing by 3 MIU/d qmo until tolerance or cytogenetic remission

· Contraindications Documented hypersensitivity

· Precautions Elderly patients do not tolerate treatment as well as younger individuals; caution in brain metastases, severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, or compromised CNS; can cause severe mood disturbance in some patients, including clinical depression; caution in history or predisposition to depression; most acute adverse effects are flulike symptoms, which can be alleviated by taking acetaminophen for fever and muscle aches and giving injections at night before bedtime; occasionally, patients may have some psychiatric effects (psychoses) or intolerance due to chronic fatigue; LFT results may be affected with liver enzyme elevation, which is alleviated by decreasing total dose

Further Inpatient Care:

· Allogeneic bone marrow or stem cell transplantation is the best treatment for cure of this disease. Unfortunately, this procedure has a high mortality rate because of the induction and long-term complications. Several types of BMT are available, and most data are from allogeneic transplantations from HLA-matched sibling donors and a few syngeneic transplantations from an identical twin. Data show that allogeneic transplantations have better results than syngeneic transplantations because of some graft versus leukemia effects.

O  Allogeneic BMT is currently the only proven cure for CML. Ideally, it should be performed in the chronic phase of the disease rather than in the transformation phase or in blast crisis. Candidate patients should be offered the procedure if they have a matched or single–antigen-mismatched related donor available. In general, younger patients fare better than older patients.

O Allogeneic BMT with matched unrelated donors has yielded very encouraging results in this disease. The procedure has a higher rate of early and late graft failures (16%), grade III-IV acute graft versus host disease (50%), and extensive chronic graft versus host disease (55%). The overall survival rate ranges from 31-43% for patients younger than 30 years and from 14-27% for older patients. Benefits and risks should be assessed carefully with each patient.

· Autologous BMT is investigational, but, recently, chemotherapy combinations or interferon have been found to induce a cytogenetic remission and allow harvesting of Ph-negative CD34 hematopoietic stem cells from the patient’s peripheral blood.

· Other attempts to collect specifically normal stem cells are currently being investigated. The role of allogeneic HSCT iewly diagnosed CML has been relegated to the back with the availability of imatinib therapy. However, it has been suggested that patients with “poor-risk” Sokal scores but good risk for allo-HSCT be transplanted early or upfront, but no current consensus exists on these issues. However, a widely accepted consensus is patients who progress beyond chronic phase on imatinib should be offered HSCT if this is an option.

· Management of lymphoid and myeloid blast crisis: In CML patients in blast crisis who are imatinib naive, the drug is used in combination to standard AML or ALL-induction-like regimens. However, since a high percentage of imatinib-resistant mutations exists in these patients, relapses occur more frequently and at an earlier time from induction. Thus, all efforts are made to take these patients for an allogeneic HSCT as possible.

Further Outpatient Care:

· Management of early or chronic phase: The standard treatment of choice is now imatinib mesylate (Gleevec), which is a specific small-molecule inhibitor of BCR/ABL in all phases of CML. In 90% of patients with CML in the Western countries are diagnosed in the early or chronic phase of the disease.

· More than 80% of newly diagnosed patients with CML in the chronic phase will achieve a complete cytogenetic response (CCR) with the standard dose of 400 mg/d of imatinib. The probability of progression-free survival is strongly correlated with the level of response, approaching 100% in those patients who achieve molecular remission (a reduction of BCR/ABL mRNA by at least 3-log at 12 mo). In patients with chronic-phase CML who had failed IFN therapy, the CCR was 41% at 18 months and 52% at 40 months with a progression-free survival at 2 years of 76%. Progression to an accelerated phase or blast crisis had a peak at 2 years of 7.6%, but the incidence remains constant over the years at an average of 2%.

O High Sokal risk predicts poorer outcome, but on-treatment response parameters generally override pretherapeutic prognostic variables. Sokal score (based on age, spleen size, platelet and PB blast counts) is well correlated with the likelihood of achieving CCR: 91% for low, 84% for intermediate, and 69% for high-risk patients.

O Standard monitoring of response includes full blood counts, cytogenetics (or FISH), and quantitative RT-PCR for BCR/ABL mRNA. The more sensitive test are done when the previous less sensitive tests become negative (ie, cytogenetics and FISH), and so they should be tailored to the level of response attained by a given patient.

O The standard therapeutic milestones to be achieved in the patients are (1) a complete hematologic response (normal CBC and no evidence of extramedullary disease) at 3 months, (2) a minor cytogenetic response (36% to 65% Ph+) at 6 months, (3) a major cytogenetic response (0% to 35% Ph+) at 12 months, and (4) a complete cytogenetic response (0% Ph+) at 18 months.

o  Failure to achieve these milestones should trigger a reassessment of the therapeutic strategy. Most patients with CCR remain positive for RT-PCR indicating the presence of minimal residual disease (MRD). Discontinuation of the drug in these patients is usually followed by relapse, suggesting that imatinib fails to eradicate leukemic stem cells in these patients.

O  Early intensification using high doses of imatinib (800 mg/d) or imatinib in combination with cytarabine or IFN-alpha may induce higher rates of RT-PCR negativity, but this still needs to be confirmed in further studies.

O The criteria for major molecular response (MMR) is > 3-log reduction of BCR/ABL mRNA and complete molecular response (CMR) is negativity by RT-PCR. Since a good correlation exists between BCR/ABL mRNA in BM and PB, this can be monitored from peripheral blood samples.

O At 12 months with CCR, patients can be classified according to their molecular response into those with MMR (>3-log) or <3-log reduction of transcripts (98% vs 90% progression-free survival).

O Limited data are available on patients with CCR or MMR who discontinued their treatment with imatinib (5 of 6 patients had reappearance of Ph+).

O Patients should be screened for mutations of the BCR/ABL kinase domain whenever there is an indication of loss of response to imatinib at whichever level. Primary hematologic resistance to imatinib occurs in approximately 5% of cases who fail to achieve CHR, and 15% show primary cytogenetic resistance in the chronic phase. Secondary or acquired resistance (loss of previous response) is 16% at 42 months and increases to 26% in those previously treated with IFN, and is 73-95% in the accelerated or blast phase.

 

 

References.

A – Main:

1. Davidson’s Principles and practice of medicine (21^st revised ed.) / by Colledge N.R., Walker B.R., and Ralston S.H., eds. – Churchill Livingstone, 2010. – 1376 p.

2. Harrison’s principles of internal medicine (18^th edition) / by Longo D.L., Kasper D.L., Jameson J.L. et al. (eds.). – McGraw-Hill Professional, 2012. – 4012 p.

3. The Merck Manual of Diagnosis and Therapy (nineteenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 2011.

4. Web -sites:

a) http://meded.ucsd.edu/clinicalmed/introduction.htm

b) http://emedicine.medscape.com/

 

B – Optional:

a. Lawrence M. Tierney, Jr. et al: Current Medical Diagnosis and treatment 2000, Lange Medical Books, McGraw-Hill, Health Professions Division, 2000.

b. On Line Resources:

http://image.bloodline.net/category.html

http://www.merckmanuals.com/professional/hematology_and_oncology/anemias_caused_by_deficient_erythropoiesis/decreased_erythropoiesis.html

http://www.merckmanuals.com/professional/hematology_and_oncology/anemias_caused_by_hemolysis/overview_of_hemolytic_anemia.html?qt=&sc=&alt=

http://bestpractice.bmj.