Hematooncoloigic diseases

Hematooncoloigic diseases. Leukaemias. Lymphogranulomatosis. Agranulocytosis. Etiology, pathogenesis.

Clinical pattern. Treatment. The role of  a doctor-dentist   in treatment. Prophylaxis

 

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.

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 (Table see below) and of the WHO.

 

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.

Pathophysiology: The malignant cells of ALL are lymphoid precursor cells (ie, lymphoblasts) that are arrested in an early stage of development. This arrest is caused by an abnormal expression of genes, often as a result of chromosomal translocations. The lymphoblasts replace the normal marrow elements, resulting in a marked decrease in the production of normal blood cells. Consequently, anemia, thrombocytopenia, and neutropenia occur to varying degrees. The lymphoblasts also proliferate in organs other than the marrow, particularly the liver, spleen, and lymph nodes.

Frequency:

• In the US: ALL is the most common type of leukemia in children. In adults, it is less common than acute myelogenous leukemia (AML). In the United States, approximately 1000 new cases of ALL occur in adults each year.

• Internationally: The highest incidence of ALL occurs in Italy, the United States, Switzerland, and Costa Rica.

Mortality/Morbidity: Only 20-40% of adults with ALL are cured with current regimens.

Sex: ALL is slightly more common in men than in women.

Age: ALL is more 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.

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

• 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/L and are especially severe when it is less than 100/L.

• 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.

 

Hemorrhagic syndrome in leukemia

 

Gingival hyperplasy

Papulous and necrotic changes

Leucoplakia in leukemia

 

Causes:

• Less is known about the etiology of ALL in adults compared with AML. Most adults with ALL have no identifiable risk factors.

• An increased prevalence of ALL was noted in survivors of the Hiroshima atomic bomb but not in those who survived the Nagasaki atomic bomb. Most leukemias occurring after exposure to radiation are AML rather than ALL.

• Rare patients have an antecedent hematologic disorder (AHD) such as myelodysplastic syndrome (MDS) that evolves to ALL. However, most patients with MDS that evolves to acute leukemia develop AML rather than ALL.

• Increasingly, cases of ALL with abnormalities of chromosome band 11q23 following treatment with topoisomerase II inhibitors for another malignancy have been described. However, most patients who develop secondary acute leukemia after chemotherapy for another cancer develop AML rather than ALL.

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.

 

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

 

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

 

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

 

• Abnormalities in the prothrombin time/activated partial thromboplastin time/fibrinogen/fibrin degradation products may suggest concomitant DIC, which results in an elevated prothrombin time, decreased fibrinogen levels, and the presence of fibrin split products.

• A review of the peripheral blood smear confirms the findings of the CBC count.

• Circulating blasts are usually seen.

• Schistocytes are sometimes seen if DIC is present.

• A chemistry profile is recommended.

• Most patients with ALL have an elevated lactic dehydrogenase level and frequently have an elevated uric acid level.

• Liver function tests and BUN/creatinine determinations are necessary prior to the initiation of therapy.

• Appropriate cultures, in particular blood cultures, should be obtained in patients with fever or with other signs of infection without fever.

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.

• 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.

• 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.

• 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 stain negative 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.

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.

 

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

 

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
• 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.
• 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.
• In a large French study (French Group on Therapy for Adult Acute Lymphoblastic Leukemia 1987), patients with greater than 5% blasts in their bone marrow on day 15 had a lower response rate (34% vs 91%), worse disease-free survival, and worse overall survival than patients with low blast counts on day 15.
• Several other studies have shown that patients whose disease is in complete remission within 4 weeks of therapy have longer disease-free survival and overall survival than those whose disease enters remission after 4 weeks of treatment.
• Consolidation therapy
• 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).
• In a 1984 study reported by Hoelzer et al, subjects whose disease was in remission after induction received consolidation therapy consisting of dexamethasone, vincristine, and doxorubicin (Adriamycin), followed by cyclophosphamide, Ara-C, and 6-thioguanine beginning at week 20. Subjects also received maintenance therapy with 6-mercaptopurine and methotrexate during weeks 10-20 and 28-130. The median remission of 20 months was among the longest reported at the time.
• In the United Kingdom Acute Lymphoblastic Leukemia XA study, subjects were randomized to receive early intensification with Ara-C, etoposide, thioguanine, daunorubicin, vincristine, and prednisone at 5 weeks; late intensification with the same regimen at 20 weeks; both; or neither. The disease-free survival rates at 5 years were 34%, 25%, 37%, and 28%, respectively. These data suggest a benefit to early, rather than late, intensification.
• One study by the Cancer and Leukemia Group B (CALGB) did not show a benefit to consolidation therapy. Subjects whose disease was in complete remission were randomized to receive maintenance therapy or intensification with 2 courses of Ara-C and daunorubicin followed by maintenance. Remission duration and overall survival were not affected by the randomization.
• Because most studies showed a benefit to consolidation therapy, regimens using a standard 4- to 5-drug induction usually include consolidation therapy with Ara-C in combination with an anthracycline or epipodophyllotoxin.

• Maintenance therapy
• 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.
• 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.
• Although maintenance appears necessary, using a more intensive versus less intensive regimen does not appear to be beneficial. Intensification of maintenance therapy from a 12-month course of a 4-drug regimen compared with a 14-month course of a 7-drug regimen (Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto 0183) did not show a difference in disease-free survival between the 2 groups.

• CNS prophylaxis
• 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.
• Cortes analyzed the prevalence of CNS leukemia in 4 consecutive clinical trials at the M.D. Anderson Cancer Center.
• In the first group, subjects received standard systemic chemotherapy without CNS prophylaxis. In the second, subjects received high-dose systemic chemotherapy and no CNS prophylaxis. The third group received high-dose systemic chemotherapy and intrathecal chemotherapy for high-risk subjects after achieving remission. The fourth group received hyperfractionated cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone (ie, hyper-CVAD protocol).
• All subjects received intrathecal chemotherapy starting in induction. High-risk subjects received 16 intrathecal treatments, and low-risk subjects received 4 intrathecal treatments.
• Overall, CNS relapse rates were 31%, 18%, 17%, and 3%, respectively.
• This study demonstrated that high-dose systemic chemotherapy reduces CNS relapse; however, early intrathecal chemotherapy is necessary to achieve the lowest risk of CNS relapse.

• Transplantation
• 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
• 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.
• 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.
• 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.
• In the Italian ALL R-87 study, 61 subjects with ALL in first relapse received induction chemotherapy with intermediate-dose Ara-C, idarubicin, and prednisone.
• Subjects whose disease was in remission were to receive consolidation chemotherapy and then BMT. Of these subjects, 56% achieved complete remission; however, only 9 of the responders underwent BMT.
• The remaining subjects did not undergo transplantations because of either early relapse or excessive toxicity.
• Of the 4 subjects who underwent allogeneic BMT, 3 were alive and achieved remission at 22, 43, and 63 months, whereas only 1 of the 5 subjects who underwent autologous BMT was alive.
• This study suggests that a small number of patients who experience relapse will survive long-term after allogeneic BMT. However, autologous BMT is less useful because it is associated with a high rate of relapse.

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

Diet: A neutropenic diet is recommended.

• No fresh fruits or vegetables may be eaten.

• All foods must be cooked.

• Meats are to be cooked until well done.

Activity: Activity may occur as tolerated by the patient, but the patient may not participate in strenuous activities such as lifting or exercise.

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.

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

Antineoplastics — Used for induction, consolidation, maintenance, and CNS prophylaxis: Vincristine (Oncovin, Vincasar), L-asparaginase, Methotrexate, Mercaptopurine, Cyclophosphamide, Cytosine arabinoside (Cytosar-U), Daunorubicin (Cerubidine), Idarubicin (Idamycin).

Colony-stimulating factors — Act as hematopoietic growth factors that stimulate development of granulocytes. Used to treat or prevent neutropenia when receiving myelosuppressive cancer chemotherapy and to reduce period of neutropenia associated with BMT. Also used to mobilize autologous peripheral blood progenitor cells for BMT and in management of chronic neutropenia: Filgrastim (Neupogen), Pegfilgrastim (Neulasta).

Prevention:

• While talking chemotherapy, patients with leukemia should avoid exposure to crowds and people with contagious illnesses, especially children with viral infections.

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.

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

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

• 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/L, 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.

Pathophysiology: The underlying pathophysiology consists of a maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this arrest is under study, but in many cases, it involves the activation of abnormal genes through chromosomal translocations and other genetic abnormalities.

This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of these cells, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, blood, and, frequently, the spleen and liver.

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.

Mortality/Morbidity:

• In 2005, an estimated 9000 deaths will occur in the United States. Of these, 5040 will occur in men and 3960 will occur in women. In adults, treatment results are generally analyzed separately for younger (18-60 y) and older (>60 y) patients.
• With current standard chemotherapy regimens, approximately 25-30% of adults younger than 60 years survive longer than 5 years and are considered cured.
• Results in older patients are more disappointing, with fewer than 10% of patients surviving long-term.

Race:

• AML is more common in whites than in other populations.

Sex:

• AML is more common in men than in women. The difference is even more apparent in older patients. This is likely because myelodysplastic syndromes (MDSs) are more common in men, and advanced MDS frequently evolves into AML. Some have proposed that the increased prevalence of AML in men may be related to occupational exposures.

Age:

• Prevalence increases with age. The median age of onset is 65 years. However, this disease affects all age groups.

Clinical diagnostic

History:

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

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

• 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).

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

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

• 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.

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

• 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.

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

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

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

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

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

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

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

• 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.

• 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.

• 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.

Causes:

• Although several factors have been implicated in the causation of AML, most patients who present with de novo AML have no identifiable risk factor.

• Antecedent hematologic disorders

• The most common risk factor is the presence of an AHD, the most common of which is MDS. MDS is a disease of the bone marrow of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years.

• Patients with low-risk MDS (eg, refractory anemia with normal cytogenetics findings) generally do not develop AML, whereas patients with high-risk MDS (eg, refractory anemia with excess blasts-type 2) frequently do develop AML.

• Other AHDs that predispose patients to AML include aplastic anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, and polycythemia vera.

• Congenital disorders

• Some congenital disorders that predispose patients to AML include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis.
• Usually, these patients develop AML during childhood; rarely, some may present in young adulthood.

• More subtle genetic disorders, including polymorphisms of enzymes that metabolize carcinogens, also predispose patients to AML. For example, polymorphisms of NAD(P)H:quinone oxidoreductase (NQO1), an enzyme that metabolizes benzene derivatives, are associated with an increased risk of AML. Particularly increased risk exists for AML that occurs after chemotherapy for another disease or for de novo AML with an abnormality of chromosomes 5, 7, or both. Likewise, polymorphisms in glutathione S-transferase are associated with secondary AML following chemotherapy for other malignancies.

• Familial syndromes

• Germ-line mutations in the gene AML1 (RUNX1, CBFA2) occur in the familial platelet disorder with predisposition for AML, an autosomal-dominant disorder characterized by moderate thrombocytopenia, a defect in platelet function, and propensity to develop AML.

• Mutation of CEBPA (the gene encoding CCAAT/enhancer binding protein, alpha; a granulocytic differentiation factor and member of the bZIP family) was described in a family with 3 members affected by AML.

• Some hereditary cancer syndromes, such as Li-Fraumeni syndrome, can manifest as leukemia. However, cases of leukemia are less common than the solid tumors that generally characterize these syndromes.

• Environmental exposures

• Several studies demonstrate a relationship between radiation exposure and leukemia.

• Early radiologists (prior to appropriate shielding) were found to have an increased likelihood of developing leukemia.
• Patients receiving therapeutic irradiation for ankylosing spondylitis were at increased risk of leukemia.
• Survivors of the atomic bomb explosions in Japan were at a markedly increased risk for the development of leukemia.
• Persons who smoke have a small but statistically significant (odds ratio, 1.5) increased risk of developing AML. In several studies, the risk of AML was slightly increased in people who smoked compared with those who did not smoke.
• Exposure to benzene is associated with aplastic anemia and pancytopenia. These patients often develop AML. Many of these patients demonstrate M6 morphology.

• Prior exposure to chemotherapeutic agents for another malignancy

• As more patients with cancer survive their primary malignancy and more patients receive intensive chemotherapy (including bone marrow transplantation [BMT]), the number of patients with AML increases because of exposure to chemotherapeutic agents. For example, the cumulative incidence of acute leukemia in patients with breast cancer who were treated with doxorubicin and cyclophosphamide as adjuvant therapy was 0.2-1.0% at 5 years.
• Patients with prior exposure to chemotherapeutic agents can be divided into 2 groups: (1) those with prior exposure to alkylating agents and (2) those with exposure to topoisomerase-II inhibitors.

• Patients with a prior exposure to alkylating agents, with or without radiation, often have a myelodysplastic phase prior to the development of AML. Cytogenetics testing frequently reveals -5 and/or -7 (5q- or monosomy 7).

• Patients with a prior exposure to topoisomerase-II inhibitors do not have a myelodysplastic phase. Cytogenetics testing reveals a translocation that involves chromosome band 11q23. Less commonly, patients developed leukemia with other balanced translocations, such as inversion 16 or t(15;17).

• The typical latency period between drug exposure and acute leukemia is approximately 3-5 years for alkylating agents/radiation exposure but only 9-12 months for topoisomerase inhibitors.

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

• 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.

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

• Peripheral blood smear

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

• Circulating blasts are usually seen.

• Schistocytes are occasionally seen if DIC is present.

 

Two type I blasts. The cytoplasm is devoid of granules

 

Blood smear in AML. Undifferentiated blasts with scant cytoplasm

 

 

 

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

 

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

 

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

 

• Chemistry profile

• Most patients with AML have an elevated lactic dehydrogenase level and, frequently, an elevated uric acid level.

• Liver function tests and BUN/creatinine level tests are necessary prior to the initiation of therapy.

• Appropriate cultures should be obtained in patients with fever or signs of infection, even in the absence of fever.

• Perform HLA or DNA typing in patients who are potential candidates for allogeneic transplantation.

• Bone marrow aspiration (see pict. 20-34)

• A blast count can be performed with bone marrow aspiration. Historically, by French-American-British (FAB) classification, AML was defined by the presence of more than 30% blasts in bone marrow. In the newer World Health Organization (WHO) classification, AML is defined as the presence of greater than 20% blasts in the marrow.

• The bone marrow aspirate also allows evaluation of the degree of dysplasia in all cell lines.

• Flow cytometry (immunophenotyping) can be used to help distinguish AML from acute lymphocytic leukemia (ALL) and further classify the subtype of AML. The immunophenotype correlates with prognosis in some instances.

• Cytogenetic studies performed on bone marrow provide important prognostic information and are useful to confirm a diagnosis of APL, which bears the t(15;17) and is treated differently.
• 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:

• 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.
• 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.
• 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.

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

• To determine the FAB type of the leukemia, slides are also stained with myeloperoxidase (or Sudan black), 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
• M4eo – Myelomonocytic with eosinophilia
• M5 – Monoblastic leukemia
• M5a – Monoblastic without differentiation
• M5b – Monocytic with differentiation
• M6 – Erythroleukemia
• M7 – Megakaryoblastic leukemia

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.
• 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.
• These regimens require adequate cardiac, hepatic, and renal function.
• Using these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% enter remission following a second course of therapy.
• 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.
• 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.
• Some studies suggest an advantage to BMT.
• In a Dutch study, patients received either allogeneic BMT or autologous BMT based on the availability of a sibling donor matched via human leukocyte antigen (HLA). This study demonstrated a decreased rate of relapse at 3 years for patients receiving allogeneic BMT versus autologous BMT (34% vs 60%, respectively; P = .03) and an increased overall survival rate at 3 years for patients receiving allogeneic BMT versus autologous BMT (66% vs 37%, respectively; P = .05). However, the median age of patients who received allogeneic BMT was 10 years younger that those who received autologous BMT.
• In the Medical Research Council AML 10 trial, patients without an HLA-matched donor received 4 courses of intensive chemotherapy followed by either no further treatment or autologous BMT. In this study, the number of relapses was lower for patients receiving autologous BMT versus no further treatment (37% vs 58%, respectively; P <.001), and the rate of disease-free survival at 7 years was improved for patients receiving autologous BMT versus no further treatment (53% vs 40%, respectively; P = .04). However, no improvement in the overall survival rate at 7 years was observed for autologous BMT versus no further treatment (57% vs 45%, respectively; P = .2).
• In a European Organization for Research and Treatment of Cancer/Gruppo Italiano Malattie Ematologiche Maligne dell’Adul study, patients with an HLA-identical sibling underwent allogeneic BMT. Other patients randomly received either autologous BMT or a second course of intensive chemotherapy with high-dose araC and daunorubicin. The disease-free survival rate at 4 years was 55% for patients who received allogeneic BMT, 48% for patients who received autologous BMT, and 30% for patients who received intensive chemotherapy (P = .04). Again, the overall survival rate was similar in all 3 groups because patients who relapsed after chemotherapy had a response to subsequent autologous BMT.
• Several other studies have failed to show any advantage to BMT.
• In a study by Groupe Ouest Est Leucemies Aigues Myeloblastiques, patients as old as 40 years with a matched donor received allogeneic BMT. All other patients received a course of consolidation chemotherapy with high-dose araC and an anthracycline and then randomly received either a second course of consolidation chemotherapy or autologous BMT. In this study, the type of postremission therapy had no effect on outcome.
• In a US Intergroup study, patients in remission with a matched donor received allogeneic BMT. Other patients randomly received either autologous BMT or one additional course of high-dose araC. In this study, the survival rate was better for patients receiving chemotherapy without BMT compared with the other groups
• In view of these conflicting results, the following recommendations can be made:
• Patients with good-risk AML, ie, t(8;21) and inversion of chromosome 16(inv16), have a good prognosis following consolidation with high-dose araC and should be offered such therapy. This is given as araC at 3 g/m² twice a day on days 1, 3, and 5 of each cycle, repeated monthly (after recovery from the previous cycle) for 4 consolidation cycles. Transplantation should be reserved for patients who relapse.
• Patients with high-risk cytogenetics findings are rarely cured with chemotherapy and should be offered transplantation in first remission. However, these patients also are at high risk for relapse following transplantation.
• The best approach for patients with intermediate-risk cytogenetics findings is controversial. Some refer patients in first remission for transplantation, whereas others give consolidation chemotherapy with high-dose araC for 4 courses and reserve transplantation for patients who relapse.
• Prior to referral for allogeneic transplantation, a suitable donor must be identified. Ideally, this is a fully HLA-matched sibling; however, most patients do not have such a donor. In these patients, alternatives include transplantation using a matched unrelated donor or using cord blood. Newer studies are examining the possibility of transplanting across HLA barriers (ie, with haploidentical-related donors) via intensive conditioning regimens and high doses of infused CD34⁺ donor cells.

• 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.
• 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 acute promyelocytic leukemia

• Acute promyelocytic leukemia (APL) is a special subtype of AML. APL differs from other subtypes of AML in that patients are, on average, younger (median age 40 y) and most often present with pancytopenia rather than with elevated WBC counts. In fact, WBC counts higher than 5000 cells/mL at presentation are associated with a poor prognosis.
• APL is the subtype of AML that is most commonly associated with coagulopathy due to disseminated intravascular coagulation (DIC) and fibrinolysis. Therefore, aggressive supportive care is an important component of the treatment of APL. Platelets should be transfused to maintain a platelet count of at least 30,000/mL (and preferably 50,000/mL). Administer cryoprecipitate to patients whose fibrinogen level is less than 100 g/dL.
• The bone marrow demonstrates the presence of more than 30% blasts resembling promyelocytes. These cells contain large dense cytoplasmic granules along with varying numbers of Auer rods.
• Although the initial diagnosis is based on morphology, the diagnosis is confirmed based on cytogenetic and molecular studies. Do not delay treatment pending the results of confirmatory tests.
• In more than 95% of cases, cytogenetics testing reveals t(15;17)(q21;q11). Molecular studies reveal the PML/RARa rearrangement. Patients with either t(15;17) or the PML/RARa rearrangement respond well to all-trans-retinoic acid (ATRA) and chemotherapy.
• A small percentage of patients have other cytogenetic abnormalities, including t(11;17)(q23;q11), t(11;17)(q13;q11), t(5;17)(q31;q11), or t(17;17). Patients with t(11;17)(q23;q11) are resistant to ATRA. Older studies using standard chemotherapy regimens without ATRA showed that approximately 70% of patients achieved CR and 30% were disease free at 5 years. Induction failures were due to deaths resulting from hemorrhage caused by DIC, with few actual resistant cases.
• In the 1980s, reports from China, France, and the United States demonstrated that most patients with APL could enter remission with ATRA as the single agent. Unfortunately, in the absence of further therapy, these remissions were short-lived. In addition, a new toxicity, the retinoic acid syndrome, was discovered. The retinoic acid syndrome results from differentiation of leukemic promyelocytic cells into mature polynuclear cells and is characterized by fever, weight gain, pleural and pericardial effusions, and respiratory distress. The syndrome occurs in approximately 25% of patients, and, in the past, was fatal in 9%.
• Subsequently, the early addition of chemotherapy resulted in a reduction of deaths caused by retinoic acid syndrome. Studies have also demonstrated that the addition of chemotherapy (idarubicin and araC) to ATRA results in remissions in more than 90% of patients. As many as 70% of these patients are long-term survivors.
• Currently, the most standard approach is the combination of ATRA and anthracycline-based chemotherapy. Chemotherapy is most effective when added early in induction (ie, day 3) rather than after attainment of CR. Initiate chemotherapy on day 1 of therapy for patients with high WBC counts (eg, >5000/mL). Once patients with APL are in remission, the standard approach is consolidation therapy with 2 courses of idarubicin and araC. Maintenance therapy with ATRA, 6-MP, and methotrexate is effective in preventing relapses compared with no maintenance therapy; however, the optimal schedule of this therapy is not yet determined.
• Patients who relapse can be retreated with chemotherapy plus ATRA, depending on the duration of their first remission and cardiac status. Arsenic trioxide is also highly active. Arsenic trioxide induces CR in 85% of patients. Toxicities include the APL differentiation syndrome (similar to that seen with ATRA), leukocytosis, and abnormalities found on ECG. Evaluate patients in second remission for allogeneic or autologous stem cell transplantation.
• Newer studies are examining the need for araC (ie, treatment with idarubicin and ATRA alone) iewly diagnosed patients. For example, the GIMEMA AIDA regimen (ie, idarubicin 12 mg/m² on days 2, 4, 6, and 8 combined with ATRA 45 mg/m² daily until remission) yields remissions in 95% of patients.
• Another trend is the development of risk-adapted approaches to consolidation therapy. In the Programa para el Estudio de la Terapéutica en Hemopatнa Maligna (PETHEMA) study, patients with intermediate and high risks of relapse (ie, whose baseline WBC count was >10,000/mL or platelet count was <40,000/mL) received 3 courses of consolidation therapy with ATRA and increased doses of anthracyclines (idarubicin month 1, mitoxantrone month 2, idarubicin month 3).
• Other areas of investigation include the use of arsenic in front-line therapy (with or without chemotherapy) and the use of gemtuzumab ozogamicin as consolidation therapy.

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

 

AML, M2 subtype, prior to treatment

 

 

Severe cytopenia following two cycles of chemotherapy

 

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

 

 

Complete remission after an additional four weeks’ therapy

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.

Antineoplastics — These agents are used for induction or consolidation therapy: Cytosine arabinoside, cytarabine (Cytosar-U), Daunorubicin (Cerubidine), Idarubicin (Idamycin), Mitoxantrone (Novantrone), Gemtuzumab ozogamicin (Mylotarg), Arsenic trioxide (Trisenox).

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.

Prognosis:

• Prognosis relies on several factors.

• Increasing age is an adverse factor because older patients more frequently have a prior antecedent hematologic disorder (AHD) along with comorbid medical conditions that compromise the ability to give full doses of chemotherapy.

• Prior AHD is associated with a poor outcome to therapy. The most common AHD is myelodysplastic syndrome (MDS).

• Cytogenetic analysis of the bone marrow is one of the most important prognostic factors. Patients with t(8;21), t(15;17) or inversion 16 have the best prognosis, with long-term survival rates of approximately 65%. Patients with normal cytogenetics findings have an intermediate prognosis and have a long-term survival rate of approximately 25%. Patients with poor-risk cytogenetics findings (especially -7, -5) have a poor prognosis, with a long-term survival rate of less than 10%.

• Other cytogenetic abnormalities, including +8, 11q23, and miscellaneous, have been reported to be intermediate-risk in some series and poor-risk in others.

• The presence of an FLT3 mutation is associated with a poorer prognosis. Mutations in CEBPA are associated with a longer remission duration and longer overall survival. Mutations in NPM are associated with an increased response to chemotherapy.

 

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

 

Bypass of CLL has three stages:

1. Initial (slight increasing of lymphatic nodes one or two groups, leucocytosis no more than 30 – 50 х 10⁹/l, working capacities preserved.

2. Unrolled (increasing leucocytosis, progressing generalized enlargement of lymph nodes, relapsing infections, and autoimmune cytopenia).

3. Terminal – malignant transformation with expanding of leucosis process out of the borders of hemopoetic system.

 

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:

·        Localized or generalized lymphadenopathy

o   Splenomegaly (30-40% of cases)

o   Hepatomegaly (20% of cases)

·        Petechiae

·        Pallor

 

 

 

Lymphadenopathy

 

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.

 

Depending on the stage in lymphocytic cell development in which the malignant transformation occurs, the leukemic cells may be principally B cells, T cells, or NK cells. Most patients have a B cell type of leukemia. A minority have T or NK cell types. These distinctions may be accounted for by the malignant transformation occurring after the common lymphocyte has differentiated into one of the three specific types of lymphocytes. The malignant event (mutation of DNA) could occur at the point at which the early specialized lymphocytes were formed or thereafter.

 

Determining the immunophenotype of the lymphocytes in the blood or marrow is important. This distinguishes whether the lymphocytes that accumulate are derived from a malignant transformation of a lymphocyte in the B cell developmental pathway or the T cell developmental pathway (see Figure 3). The T cell type of disease, called T cell chronic lymphocytic leukemia, is very infrequent. It affects the skin, nervous system, and lymph nodes more often and may be more rapidly progressive than is the B cell type. (See also Other Related Lymphocytic Leukemias). Immunophenotyping also permits assessment of whether the lymphocytes in the blood are derived from a single malignant cell (in other words, whether they are monoclonal). The test for monoclonality is important because it distinguishes leukemia from the very infrequent increase in the blood lymphocytes in adults that is not the result of a malignant transformation characteristic of cancer. This test is especially important if the lymphocytes in the blood are only slightly elevated.

Another very important test that is performed is the measurement of the concentration of gamma globulins (immunoglobulins) in the blood. Immunoglobulins are proteins called antibodies that the B cells of healthy individuals make to protect themselves from infection. They are often deficient in persons with chronic lymphocytic leukemia. The leukemic B lymphocytes do not make protective antibodies effectively. At the same time, the leukemia acts to prevent remaining normal lymphocytes from doing so. This inability to make antibodies efficiently causes CLL patients to be susceptible to infections.

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.

·         

 

 

Peripheral blood smear showing CLL cells

 

 

 

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.

 

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

 

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.

Other measurements may aid the physician in determining if treatment is warranted. The expression of CD38, when present as a marker on CLL cells, is associated with more progressive disease. The degree of elevation of serum ß 2-microglobulin, a protein that is shed from CLL cells, is associated with a greater extent of disease. Chromosome abnormalities in CLL cells, especially three rather than two chromosomes number 12 (trisomy 12) and additional other abnormalities of chromosomes are associated with more progressive disease. Nonmutation of the immunoglobulin (Ig) heavy chain gene (H) variable region (v) gene, abbreviated IgHv, also suggests the likelihood of progressive disease. Zeta-associated protein 70 (ZAP-70), contained inside CLL cells, when increased, is associated with more rapidly progressive disease.

Since no single feature is precisely predictive of progression in an individual patient, the physician considers all the findings, especially a decrease in blood hemoglobin level, an increase in white cell count, an increase in lymph node or spleen size, as well as the biochemical and genetic markers noted above, to assess the need for treatment. The physician may observe the patient at intervals to see if the disease remains stable or progresses before deciding on treatment. The reason for this approach is that some patients may go for very long periods without disease progression and may be able to pursue all activities, and early treatment in such patients has not lead to long-term benefit.

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.

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

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

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

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

·        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.

·        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.

·        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.

·        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.

 

The IWCLL has recommended integrating the Rai-Sawitsky and Binet systems as follows: A(0), A(I), A(II), B(I), B(II), C(III), and C(IV).

 

Disease Course

Some patients with chronic lymphocytic leukemia have minimal changes in their blood cell counts: a slight increase in blood lymphocytes and little or no decrease in red cells, normal white cells, and platelets. These patients may remain stable for relatively long periods (years). Patients with minimal changes in their blood may have few related problems, such as infections. These patients usually are not treated.

When patients learn that they have leukemia but will not receive treatment, they may become concerned. A decision to delay treatment should not produce concern. Chronic lymphocytic leukemia (and its closely related variants) is the major type of leukemia that can be stable and not disturb the patient’s well being for prolonged periods without treatment. Untreated patients are followed periodically to be sure progression is not occurring. They also are advised to seek medical assistance if they develop a fever or other signs of infection or illness.

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.

 

 

Some CLL patients produce a type of antibody that works against their own cells. These autoantibodies are usually directed against the patient’s own red cells or, less often, platelets, and cause the cells to be removed from the blood rapidly. This effect can worsen anemia or markedly decrease platelet levels. A test called the antiglobulin, or Coombs’ test, is used to identify the autoantibodies. Treatment with prednisone is sometimes needed to improve this type of anemia, which may be referred to as autoimmune hemolytic anemia, or improve the low platelet count, which may be referred to as immune thrombocytopenia.

A small proportion of CLL patients have a change in their disease that causes it to behave like a more rapidly progressive lymphoma. This pattern has been referred to as a Richter transformation, after the physician who first called it to medical attention. Lymph node enlargement may be more apparent, fever and weight loss more prominent, and tumors of lymphocytes may develop in sites other than lymph nodes. In effect, the CLL transforms into an aggressive lymphoma. It is usually not a second disease but a change in character of the CLL cells. Transformations of this type can be seen in most hematologic malignancies, such as chronic myelogenous leukemia, which may transform into acute leukemia.

In other patients the change in their disease may more closely resemble prolymphocytic leukemia. The cells in the blood may change to be composed predominantly of another type of white cell, called prolymphocytes. The spleen may enlarge further and the patient may become less responsive to treatment. Prolymphocytic leukemia is more rapidly progressive than chronic lymphocytic leukemia, but less progressive than acute lymphocytic leukemia.

Very rarely, the pattern of CLL may mimic that of acute lymphocytic leukemia.

In total, of the changes to a more aggressive pattern described above affect only a small proportion of CLL patients.

The main principles of CLL treatment: 

·        Patients’ regimen.

·        Cytostatic therapy.

·        Medical lymphocytopheresis.

·        Radial therapy.

·        Splenectomy

·        Glucocorticoid agents.

·        Treatment of infectious complications.

 

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.

 

 

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.

Patients with CLL demonstrate autoimmune anemia and or thrombocytopenia up to 25% of the time, and, at the same time, immune incompetence is present, characterized by a progressive profound hypogammaglobulinemia.

 

This hypogammaglobulinemia eventually develops in almost all patients, predisposing them to a number of infections, the most common being bacterial pneumonias.

 

Patients showing frequent bacterial infections associated with hypogammaglobulinemia are likely to benefit from monthly infusions of intravenous immunoglobulins. In a randomized double-blind study, intravenous immunoglobulin, 400 mg/kg, or placebo was administered every 3 weeks for 1 year in 84 patients. The study showed significant reductions in the bacterial infections in the group treated with immunoglobulins, but no statistically significant difference was observed in the number of life-threatening infections requiring parenteral antibiotics.

 

The autoimmunity in B-CLL is observed much more commonly in patients treated with fludarabine, which is known to suppress the circulating CD4+ T cells.

Extremely high white blood cell counts (>300,000/mL) may produce a hyperviscosity syndrome with altered central nervous system function and/or respiratory insufficiency. Leukocytapheresis and urgent therapy with prednisone and chemotherapy may be required. Virtually all patients requiring therapy also should be given allopurinol to prevent uric acid nephropathy.

 

Surgical Care:

·        Refractory splenomegaly and pancytopenia is a common problem in patients with advanced CLL that occasionally necessitates splenectomy.

·        Substantial improvements in hemoglobin and platelet counts are observed in up to 90% of patients undergoing splenectomy.

·        All patients who are to undergo splenectomy should be immunized at least a week in advance with Pneumovax and Haemophilus and Neisseria meningitides vaccines.

 

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 prevalent surplus 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.

 

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.

 

Frequency:

·        In the US: CML accounts for 20% of all leukemias affecting adults. It typically affects middle-aged individuals. Although uncommon, the disease also occurs in younger individuals.

·        Internationally: Increased incidence was reported among individuals exposed to radiation in Nagasaki and Hiroshima after the dropping of the atomic bomb.

 

Mortality/Morbidity: Generally, 3 phases of the disease are recognized. The general course of the disease is characterized by an eventual evolution to a refractory form of acute myelogenous or, occasionally, lymphoblastic leukemia. The median survival of patients using older forms of therapy was 3-5 years.

 

·        Most patients present in the chronic phase, characterized by splenomegaly and leukocytosis (see Image below) with generally few symptoms. This phase is easily controlled by medication. The major goal of treatment during this phase is to control symptoms and complications resulting from anemia, thrombocytopenia, leukocytosis, and splenomegaly. Newer forms of therapy aim at delaying the onset of the accelerated or blastic phase.

 

 Blood film at 400X magnification demonstrates leukocytosis with the presence of precursor cells of the myeloid lineage. In addition, basophilia, eosinophilia, and thrombocytosis can be seen. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

 

·        After an average of 3-5 years, the disease usually evolves into the blast crisis, which is marked by an increase in the bone marrow or peripheral blood blast count or by the development of soft tissue or skin leukemic infiltrates. Typical symptoms are due to increasing anemia, thrombocytopenia, basophilia, a rapidly enlarging spleen, and failure of the usual medications to control leukocytosis and splenomegaly. The manifestations of blast crisis are similar to those of acute leukemia. Treatment results are unsatisfactory, and most patients succumb to the disease once this phase develops. In approximately two thirds of cases, the blasts are myeloid. However, in the remaining one third of patients, the blasts exhibit a lymphoid phenotype, further evidence of the stem cell nature of the original disease. Additional chromosomal abnormalities are usually found at the time of blast crisis, including additional Ph chromosomes or other translocations.

·        In many patients, an accelerated phase occurs 3-6 months before the diagnosis of blast crisis. Clinical features in this phase are intermediate between the chronic phase and blast crisis.

 

Age:

·        In general, this disease occurs in the fourth and fifth decades of life.

·        Younger patients aged 20-29 years may be affected and may present with a more aggressive form, such as in accelerated phase or blast crisis.

·        Uncommonly, CML may appear as a disease of new onset in elderly individuals.

 

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.

 

Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

 

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 granulocytes sprout.

 

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.

·       

HEPATOSPLENOMEGALY

 

·        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.

 

 

 

Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

 

·        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 (see Image below).

 

 

 

Bone marrow film at 400X magnification demonstrates clear dominance of granulopoiesis. The number of eosinophils and megakaryocytes is increased. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

 

 

·        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.

 

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). Courtesy of Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine.

 

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.

 

 

Fluorescence in situ hybridization using unique-sequence, double-fusion DNA probes for bcr (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). Courtesy of Emmanuel C. Besa, MD.

 

o   Two forms of the BCR/ABL mutation are present, depending on the location of their joining regions on bcr 3′ domain. Approximately 70% of patients who have the 5′ DNA breakpoint have a b2a2 RNA message, and 30% of patients have a 3’DNA breakpoint and a b3a2 RNA message. The latter is associated with a shorter chronic phase, shorter survival, and thrombocytosis.

o   CML should be differentiated from Ph-negative diseases with negative PCR results for BCR/ABL m-RNA. These diseases include other myeloproliferative disorders and chronic myelomonocytic leukemia, which is now classified with the myelodysplastic syndromes.

o   Additional chromosomal abnormalities, such as an additional or double Ph-positive chromosome or trisomy 8, 9, 19, or 21; isochromosome 17; or deletion of the Y chromosome, have been described as the patient enters a transitional form or accelerated phase of the blast crisis as the Ph chromosome persists.

o   Patients with conditions other than chronic-phase CML, such as newly diagnosed acute lymphocytic leukemia or nonlymphocytic leukemia, also may be positive for the Ph chromosome. Some consider this the blastic phase of CML without a chronic phase. The chromosome is rarely found in patients with other myeloproliferative disorders, such as polycythemia vera or essential thrombocythemia, but these are probably misdiagnosed CML. It is rarely observed in myelodysplastic syndrome.

·        Other laboratory abnormalities include hyperuricemia, which is a reflection of high bone marrow cellular turnover and markedly elevated serum vitamin B-12–binding protein (TC-I). The latter is synthesized by the granulocytes and reflects the degree of leukocytosis.

 

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.

 

Oil immersion field demonstrating myeloid cells of all degrees of maturity

 

 

 

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

 

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 is produced 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);

–                                 trombocytopenia (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, used in 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 10^9/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).

 

Surgical Care:

 

·        Splenectomy and splenic irradiation have been used in patients with large and painful spleens, usually in the late phase of the disease.

·        This is rarely needed in patients whose disease is well controlled.

·        Some authors believe that splenectomy accelerates the onset of myeloid metaplasia in the liver. Splenectomy is associated with high perioperative morbidity and mortality rates because of bleeding or thrombotic complications.

 

  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.

 

 

·        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: Hydroxyurea (Hydrea) , Busulfan (Myleran),

·        Tyrosine kinase inhibitors:  Imatinib mesylate (Gleevec, ) Dasatinib (Sprycel)

 

Prognosis:

 

·        Historically, the median survival of patients with CML from the time of diagnosis was 3-5 years, and, until recently, no known therapy was been shown to alter this survival rate. As treatment improved, the need to stage patients according to their prognoses became necessary to justify procedures with high morbidity and mortality, such as BMT.

·        Staging of patients is based on several analyses using multiple variate analysis between the association of pretreatment host and leukemic cell characteristics and their corresponding patient’s survival. The findings from these studies classify patients into good-, intermediate-, or poor-risk groups, with an average survival of 5-6 years, 3-4 years, and 2 years, respectively. A combined prognostic model, incorporating previous models such as the Sokal score, has been devised using the number of poor-prognosis characteristics: stage 1 is for 0 or 1+, stage 2 is for 2+, stage 3 is for 3 or more, and stage 4 is for diagnosis at blastic phase.

o   Poor prognosis in patients with CML is associated with several clinical and laboratory factors, including older age, symptomatic presentation, poor performance status, African American descent, hepatomegaly, splenomegaly, negative Ph chromosome or <BCR/ABL, anemia, thrombocytopenia, thrombocytosis, decreased megakaryocytes, basophilia, or myelofibrosis (increased reticulin or collagen).

o   Several therapy-associated factors may indicate a poor prognosis in patients with CML, including longer time to hematologic remission with myelosuppression therapy, short duration of remission, total dose of hydroxyurea or busulfan, or poor suppression of Ph-positive cells by chemotherapy or interferon alfa therapy.

·        Recently, the prognosis of patients with CML has improved from an expected median survival of 3 years and a 5-year survival rate of less than 20% to a median survival of 5 or more years and a 5-year survival rate of 50-60%. The improvement is due to earlier diagnosis, improved therapy with interferon and BMT, and better supportive care. A German study of 139 low-risk patients with CML, according to the Sokal index, shows that the median survival with busulfan is 6 years (50 patients), with hydroxyurea is 6.5 years (55 patients), and with interferon alfa is approximately 9.5 years (34 patients), indicating improvement in survival with new therapy.

·        Some patients with molecular remissions from interferon alfa may be cured, but this can only be established over time.

·        The new and active tyrosine kinase inhibitor, imatinib, is associated with a higher response rate and better tolerance of adverse effects. It may replace interferon as first-line therapy. Long-term remissions remain to be seen, and imatinib will be reevaluated in the near future to determine its role in the treatment of CML.