Saturday, November 13, 2010

CHRONIC MYELOGENOUS LEUKEMIA

Introduction
Background

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.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Leukemia.
Pathophysiology

Chronic myelogenous leukemia (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.

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 chronic myelogenous leukemia (CML) phenotype through processes that are not yet fully understood.1,2,3,4,5,6,7,8

The presence of BCR/ABL rearrangement is the hallmark of chronic myelogenous leukemia (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.
Frequency
United States

Chronic myelogenous leukemia (CML) accounts for 20% of all leukemias affecting adults. It typically affects middle-aged individuals. Although uncommon, the disease also occurs in younger individuals.
International

Increased incidence of chronic myelogenous leukemia (CML) was reported among individuals exposed to radiation in Nagasaki and Hiroshima after the dropping of the atomic bomb.
Mortality/Morbidity

Generally, 3 phases of chronic myelogenous leukemia (CML) 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 is 3-5 years.

* Most patients with chronic myelogenous leukemia (CML) present in the chronic phase, characterized by splenomegaly and leukocytosis (see image below) with generally few symptoms.
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Blood film at 400X magnification demonstrates leu...
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.

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Blood film at 400X magnification demonstrates leu...

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.
* 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.
* After an average of 3-5 years, chronic myelogenous leukemia (CML) 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, chronic myelogenous leukemia (CML) 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, chronic myelogenous leukemia (CML) may appear as a disease of new onset in elderly individuals.

Clinical
History

* The clinical manifestations of chronic myelogenous leukemia (CML) are insidious and are often discovered incidentally when an elevated white blood cell (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 with chronic myelogenous leukemia (CML) may have low-grade fever and excessive sweating related to hypermetabolism.
* The disease has 3 clinical phases, and chronic myelogenous leukemia (CML) 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 the chronic phase has lasted for longer than 9.5 years in patients who respond well to interferon alfa therapy. Furthermore, the addition of imatinib mesylate in recent years has dramatically improved the duration of hematologic and, indeed, cytogenetic remissions.
o Some patients with chronic myelogenous leukemia (CML) 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%), basophils (>20%), and platelet counts less than 100,000 cells/μL unrelated to therapy. Promyelocytes and basophils are shown in the image below.
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Blood film at 1000X magnification shows a promyel...
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.

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Blood film at 1000X magnification shows a promyel...

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 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. Thus, signs of transformation or accelerated phase in patients with chronic myelogenous leukemia are poor control of blood counts with myelosuppression or interferon, increasing blast cells in peripheral blood with basophilia and thrombocytopenia not related to therapy, new cytogenetic abnormalities, and increasing splenomegaly and myelofibrosis.
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.

Physical

* Splenomegaly is the most common physical finding in patients with chronic myelogenous leukemia (CML).
o In more than 50% of the patients with CML, the spleen extends more than 5 cm below the left costal margin at time of discovery.
o The size of the spleen correlates with the peripheral blood granulocyte counts (see image below), with the largest spleens being observed in patients with high WBC counts.
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Blood film at 1000X magnification demonstrates th...
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.

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Blood film at 1000X magnification demonstrates th...

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.
o 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/μL. Upon funduscopy, the retina may show papilledema, venous obstruction, and hemorrhages.

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.Differential Diagnoses

Agnogenic Myeloid Metaplasia With Myelofibrosis
Myelodysplastic Syndrome
Myeloproliferative Disease
Polycythemia Vera
Other Problems to Be Considered

Acute myeloid leukemia
Chronic myelomonocytic leukemia
Chronic neutrophilic leukemia
Essential thrombocytosis/thrombocythemia
Leukemoid reactions from infections (chronic granulomatous [eg, tuberculosis])
Myelodysplasia
Tumor necrosis
Workup
Laboratory Studies

* Peripheral blood findings in patients with chronic myelogenous leukemia (CML) show a typical leukoerythroblastic blood picture, with circulating immature cells from the bone marrow (see image below).
o

Bone marrow film at 400X magnification demonstrat...
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.

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Bone marrow film at 400X magnification demonstrat...

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/μL. 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 (ALP). 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).
* The bone marrow is characteristically hypercellular, with expansion of the myeloid cell line (eg, neutrophils, eosinophils, basophils) and its progenitor cells. Megakaryocytes (see image below) are prominent and may be increased. Mild fibrosis is often seen in the reticulin stain.
o

The Philadelphia chromosome, which is a diagnosti...
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.

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The Philadelphia chromosome, which is a diagnosti...

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.
* 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 chronic myelogenous leukemia (CML), found in almost all patients with the disease, 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 above). The latter is presumably responsible for the cellular transformation in chronic myelogenous leukemia (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.
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.
o The new technique of fluorescence in situ hybridization (FISH) uses labeled probes that are hybridized to either metaphase chromosomes or interphase nuclei, and the hybridized probe is detected with fluorochromes. This technique, a rapid and sensitive means of detecting recurring numerical and structural abnormalities, is illustrated below.
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Fluorescence in situ hybridization using unique-s...
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.

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Fluorescence in situ hybridization using unique-s...

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 Chronic myelogenous leukemia (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 chronic myelogenous leukemia (CML), such as newly diagnosed acute lymphocytic leukemia (ALL) or nonlymphocytic leukemia, may also 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 chronic myelogenous leukemia (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 radiologic imaging is not necessary.

Histologic Findings

The diagnosis of chronic myelogenous leukemia (CML) is based on the histopathologic findings in the peripheral blood and the Ph1 chromosome in the bone marrow cells.Treatment
Medical Care

The 3-fold goals of treatment of chronic myelogenous leukemia (CML) have changed markedly in the past 10 years. They are: (1) to achieve a hematologic remission (normal complete blood cell [CBC] count and physical examination [ie, no organomegaly]), (2) to achieve cytogenetic remission (normal chromosome returns with 0% Ph-positive cells), and, most recently, (3) to achieve molecular remission (negative PCR result for the mutational BCR/ABL m-RNA). The last is an attempt for cure and prolongation of patient survival.

* A new approach to treatment of chronic myelogenous leukemia (CML) is to directly inhibit the molecular cause of the disease, that is, using a protein-tyrosine kinase inhibitor that inhibits the bcr-abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Ph chromosome translocation abnormality.
* STI571, or imatinib mesylate (Gleevec), inhibits proliferation and induces apoptosis by inhibiting tyrosine kinase activity in cells positive for BCR/ABL and fresh leukemic cells in chronic myelogenous leukemia (CML) that is positive for the Ph chromosome.1,2,5,9,10 This drug was approved rapidly by the US Food and Drug Administration (FDA) because of the following results:
o With imatinib at 400 mg/d orally in patients with newly diagnosed Ph-positive CML in the chronic phase, the complete cytogenetic response rate is 70% and the estimated 3-year survival rate is 94%. With higher doses of 800 mg/d, the complete cytogenetic response rate increases to 98%, the major molecular response rate is 70%, and the complete molecular response rate is 40-50%.
+ In patients in the chronic phase who were previously treated with interferon and whose treatment failed or who were unable to tolerate therapy, a complete hematologic remission was achieved in 88% (532 patients), with a major cytogenetic response (ie, complete remission in 0%, partial remission in 1-35%, Ph-positive metaphases) in 49% of patients.
+ Among 235 patients in the accelerated phase, the hematologic response was 65% (28% complete remission), and the cytogenetic response was 21%. Patients in myeloid blast crisis (260 patients) achieved a hematologic response rate of 26% (4% complete remission) and a major cytogenetic response rate of 13.5% (5% complete remission).
o The decision to choose the initial treatment or primary therapy for chronic-phase CML is difficult, because the advent of the tyrosine kinase inhibitor imatinib.
o For patients with chronic-phase chronic myelogenous leukemia (CML), imatinib at 400 mg/d is the best candidate for primary therapy, because it induces a complete hematologic response in almost all patients and causes a high cytogenetic response rate. Overall survival data comparing it with interferon are shown below.
+ A study comparing the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed, chronic-phase CML randomly assigned 1106 subjects to receive imatinib (553 subjects) or interferon alfa plus low-dose cytarabine (553 subjects).11
+ After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0-35% of cells in metaphase positive for the Ph chromosome) at 18 months was 87.1% in the imatinib group and 34.7% in the group given interferon alfa plus cytarabine (P <0.001).11 The estimated rates of complete cytogenetic response were 76.2% for the imatinib group and 14.5% in the interferon alfa group (P <0.001). At 18 months, the estimated rate of freedom from progression to accelerated-phase or blast-crisis CML was 96.7% in the imatinib group and 91.5% in the combination-therapy group (P <0.0001). Imatinib was better tolerated than combination therapy. + The conclusions of this study in terms of hematologic and cytogenetic responses, tolerability, and the likelihood of progression to accelerated-phase or blast-crisis CML, were that imatinib is superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed, chronic-phase chronic myelogenous leukemia (CML).11 o Treatment of patients with CML in the accelerated phase or in blast crisis has been dismal. However, data have shown that imatinib can induce a hematologic response in 52-82% of patients, but the response is less frequent and less durable, being sustained for at least 4 weeks in only 31-64% of patients. o The complete response rate is lower, at 7-34% of patients. Karyotypic response occurs in 16-24%, and complete cytogenetic response is observed in only 17%. Higher doses (ie, 600 mg/d) result in improved response rates, cytogenetic response, and disease-free and overall survival. o In Ph-positive acute lymphoblastic leukemia, the combination of chemotherapy plus imatinib is associated with a 2-year survival rate of 60%. o Resistance of chronic myelogenous leukemia (CML) cells to imatinib is emerging through multiple mechanisms such as overexpression of BCR/ABL and mutations of the abl gene.7,8,12 Resistance can be overcome by increasing the imatinib dose, by developing more selective bcr-abl kinase inhibitors, and developing new non–cross-resistant drugs. * Myelosuppressive therapy, which was formerly the mainstay of treatment to convert a patient with chronic myelogenous leukemia (CML) from an uncontrolled initial presentation to one with hematologic remission and normalization of the physical examination and laboratory findings, may soon fall out of favor as the new agents prove to be more effective with fewer adverse events and longer survival. * Hydroxyurea (Hydrea), an inhibitor of deoxynucleotide synthesis, is the most common myelosuppressive agent used to achieve hematologic remission. The initial blood cell count is monitored every 2-4 weeks, and the dose is adjusted depending on the WBC and platelet counts. Most patients achieve hematologic remission within 1-2 months. This medication causes only a short duration of myelosuppression; thus, even if the counts go lower than intended, stopping or decreasing doses usually controls the blood counts. Maintenance with hydroxyurea rarely results in cytogenetic or molecular remissions. * Busulfan (Myleran) is an alkylating agent that has traditionally been used to keep the WBC counts less than 15,000 cells/µL. However, the myelosuppressive effects may occur much later and persist longer, making maintaining the numbers within normal limits more difficult. Long-term use can cause pulmonary fibrosis, hyperpigmentation, and prolonged marrow suppression lasting for months. * Leukapheresis using a cell separator can lower WBC counts rapidly and safely in patients with WBC counts greater than 300,000 cells/µL, and it can alleviate acute symptoms of leukostasis, hyperviscosity, and tissue infiltration. Leukapheresis usually reduces the WBC count only temporarily and is often combined with cytoreductive chemotherapy for more lasting effects. * Interferon alfa was the treatment of choice for most patients with chronic myelogenous leukemia (CML) who are too old for bone marrow transplantation (BMT) or who do not have a matched bone marrow donor. Interferon alfa is given at an average of 3-5 million IU/d subcutaneously after hematologic remission with hydroxyurea. o The cytogenetic response is monitored every 3-6 months by karyotyping or by fluorescence in situ hybridization to count the percentage of bone marrow cells with Ph-positive cells. o The goal is 100% normal cells after 1-2 years of therapy. Patients with MRD BCR/ABL positive) should be kept on maintenance therapy as long as they continue to have MRD. o Cytogenetic improvement has been observed in 70% of patients treated for longer than 3 months, with the median of Ph'-positive cells declining from 100% to 65% (range 0-95%). Complete suppression of the Ph' chromosome was observed in 20% of patients. * BMT should be considered early in young patients (<55 y) who have a matched sibling donor.13,14 o All siblings should be typed for human leukocyte antigen (HLA)-A, HLA-B, and HLA-DR. If no match is available, the HLA type can be entered into a bone marrow registry for a completely matched unrelated donor. o The mortality rate associated with BMT is 10-20% or less with a matched sibling and 30-40% with an unrelated donor. The bone marrow registry approximates the cure rate for patients with chronic myelogenous leukemia (CML) at 50%. o Transplantation is recommended within 1 year of diagnosis or after a 1-year trial of interferon therapy without a complete or significant cytogenetic remission. o Most patients with MRD after transplantation require interferon maintenance therapy anyway, or they may require a reinfusion of T cells collected from the donor. * Transplantation has been relegated to patients who do not achieve molecular remissions or show resistance to imatinib and failure to second-generation bcr-abl kinase inhibitors such as dasatinib. Mechanisms for resistance to imatinib are: (1) BCR-ABL amplification, and (2) BCR-ABL– independent mechanisms such as: (A) Src family of kinase activation and (B) additional molecular events. * Previous exposure to imatinib before transplantation does not adversely effect posttransplant outcomes such as overall survival and progression-free survival with 90% engraftment, higher relapsed mortality (24%) and lower graft versus host disease (GVHD) (acute, 42%; chronic, 17%).15 * Treatment decisions involving the use of interferon, BMT, or investigative options for younger patients with chronic myelogenous leukemia (CML) are extremely complex and in constant flux. Individualized decisions should be made in conjunction with consultation with physicians familiar with the recent literature. Surgical Care * Splenectomy and splenic irradiation have been used in patients with large and painful spleens, usually in the late phase of chronic myelogenous leukemia (CML). o This is rarely needed in patients whose disease is well controlled. o 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. Consultations Patients with chronic myelogenous leukemia (CML) should be under the care of hematologists and oncologists. Selected patients should be seen by experts in a BMT program in a tertiary care center. Medication Cortes et al studied the efficacy of dasatinib as initial therapy for early chronic phase chronic myeloid leukemia.16 Fifty patients were randomized to receive dasatinib 100 mg qd or 50 mg bid for at least 3 months. No difference was noticed between treatment arms regarding outcome. Of the 50 patients, 49 (98%) achieved a complete cytogenetic response (CCyR), and 41 (82%) achieved a major molecular response (MMR).16 The projected event-free survival rate at 24 months was 88%, and all patients were alive after a median follow-up time of 24 months. The medications used for patients with chronic-phase chronic myelogenous leukemia (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 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. Antineoplastic 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. Spleen size correlates with WBC counts, and it shrinks as WBC counts approach the reference range. Also, intermediate and myeloblast cells disappear from the circulation. Hydroxyurea (Hydrea) Inhibitor of deoxynucleotide synthesis and DOC for inducing hematologic remission in CML. Less leukemogenic than alkylating agents such as busulfan, melphalan (Alkeran), or chlorambucil. Myelosuppressive effects last a few days to a week and are easier to control than with alkylating agents; busulfan is associated with prolonged marrow suppression and can cause pulmonary fibrosis. * Dosing * Interactions * Contraindications * Precautions Adult Initial dose: 30 mg/kg/d at an average of 1000-1500 mg/d PO in 500-mg tabs. Can be given at higher doses in patients with extremely high WBC counts (>300,000/µL) and adjusted accordingly as counts fall and platelet counts drop; dose can be given as a single daily dose or divided into 2-3 doses at higher dose ranges
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Neurotoxicity can occur when administered concurrently with fluorouracil

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; thrombocytopenia is the dose-limiting factor in using hydroxyurea; do not administer if platelet counts are <50,000/µL; administer under advisement in patients with counts <100,000/µL; anemia may be aggravated by medications, and concomitant irradiation is contraindicated * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Monitor blood counts and adjust doses accordingly; some patients may be sensitive and present with fever, chills, and elevation of liver enzymes, which disappear after stopping the drug; skin ulcers may be seen in long-term use; caution in patients with renal impairment Busulfan (Myleran) Potent cytotoxic drug which, at recommended dosage, causes profound myelosuppression. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. * Dosing * Interactions * Contraindications * Precautions Adult 4-8 mg/d PO; may administer up to 12 mg/d; maintenance dosing range is 1-4 mg/d to 2 mg/wk; discontinue regimen when WBC count reaches 10,000-20,000/µL; resume therapy when WBC reaches 50,000/µL Pediatric 0.06-0.12 mg/kg/d or 1.8-4.6 mg/m2/d PO; titrate dose to maintain WBC count >40,000/µL; reduce dose by 50% if WBC count is 30,000-40,000/µL; discontinue if WBC count <20,000/µL * Dosing * Interactions * Contraindications * Precautions CYP3A3/4 enzyme substrate; acetaminophen, cyclophosphamide, itraconazole, and thioguanine may increase toxicity; phenytoin may decrease levels * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; severely depressed bone marrow function; breastfeeding; failure to respond to previous treatment * Dosing * Interactions * Contraindications * Precautions Pregnancy X - Contraindicated; benefit does not outweigh risk Precautions Regularly examine patient's hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; may cause pulmonary fibrosis; if WBC count is high, hydration and allopurinol should be used to prevent hyperuricemia Tyrosine Kinase Inhibitors Tyrosine kinase inhibitors elicit strong tyrosine kinase inhibition activity of the BCR/ABL abnormality in all phases of chronic myelogenous leukemia (CML). Imatinib mesylate (Gleevec) Specifically designed to inhibit tyrosine kinase activity of bcr-abl kinase in Ph-positive leukemic CML cell lines. Well absorbed after oral administration, with maximum concentrations achieved within 2-4 h. Elimination is primarily in feces in form of metabolites. * Dosing * Interactions * Contraindications * Precautions Adult Chronic phase: 400 mg/d PO with food and large glass of water; may increase to 600 mg/d if no severe adverse effects or severe non–leukemia-related neutropenia or thrombocytopenia, disease continues to progress (any time), hematologic response is not satisfactory (after at least 3 mo treatment), or a loss of previously achieved hematologic response occurs. Accelerated phase or blast crisis: 600 mg/d PO with food and large glass of water; may increase to 800 mg/d (400 mg bid) if no severe adverse effects or severe non–leukemia-related neutropenia or thrombocytopenia, disease continues to progress (any time), hematologic response is not satisfactory (after at least 3 mo treatment), or a loss of previously achieved hematologic response occurs. Pediatric Not established * Dosing * Interactions * Contraindications * Precautions CYP3A4 inhibitors (ketoconazole increases distribution of imatinib); CYP3A4 substrates (simvastatin increases maximum concentration of imatinib by a 2- to 3.5-fold factor); CYP3A4 inducers (phenytoin decreases AUC by approximately one fifth of typical AUC); likely to increase blood levels of drugs that are substrates of CYP2C9, CYP2D6, and CYP3A4/5 * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Dose must be reduced if grade 3-4 neutropenia or thrombocytopenia develops or levels of transaminases or bilirubin become elevated Dasatinib (Sprycel) Multiple tyrosine kinase inhibitor. Inhibits growth of cell lines overexpressing BCR -ABL. Orphan drug indicated for chronic myeloid leukemia (CML) in individuals resistant to or intolerant of previous therapy (eg, imatinib [Gleevec]). Has been able to overcome imatinib resistance resulting from BCR -ABL kinase domain mutations. * Dosing * Interactions * Contraindications * Precautions Adult Chronic phase: 100 mg PO qd (morning or evening); may increase to 140 mg PO qd if inadequate response Advanced phase (accelerated phase, myeloid, or lymphoid blast phase): 140 mg PO qd; may increase to 180 mg qd if inadequate response Coadministration with strong CYP3A4 inhibitors: Decrease daily dose to 20 mg from 100 mg/d, or decrease to 40 mg from 140 mg/d Coadministration with CYP3A4 inducers: May need to increase dose (monitor for toxicity) If clinically viable, an alternative medication with no or minimal enzyme inhibition or induction is recommended Pediatric Not established * Dosing * Interactions * Contraindications * Precautions CYP450 3A4 substrate and inhibitor; CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, grapefruit juice) may increase serum concentrations; CYP3A4 inducers (eg, dexamethasone, phenytoin, rifampin, phenobarbital, carbamazepine, St John's wort) may decrease serum concentrations; coadministration with antacids or other drugs that decrease gastric pH (eg, H2 blockers [famotidine], proton pump inhibitors [omeprazole]) may decrease AUC and Cmax; may increase plasma levels of CYP3A4 substrates (eg, alfentanil, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, ergot alkaloids, simvastatin); coadministration with other drugs that prolong QT interval (eg, class Ia or III antiarrhythmics) may increase risk for Torsades de Pointes * Dosing * Interactions * Contraindications * Precautions None known * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Adverse effects include fluid retention (including pleural effusion), bleeding, diarrhea, rash, pyrexia, infections, headache, fatigue, and nausea; frequently causes anemia, neutropenia, or thrombocytopenia; because of extensive liver metabolism, caution in patients with hepatic impairment (may need to decrease dose); caution with coexisting QT interval prolongation; swallow tab whole, do not crush or cut; may take with or without food Nilotinib (Tasigna) Inhibits BCR/ABL kinase. In vitro, inhibits BCR/ABL –mediated proliferation of murine leukemic cell lines and human cell lines derived from Philadelphia chromosome – positive chronic myeloid leukemia. Under the conditions of the assays, was able to overcome imatinib resistance resulting from BCR/ABL kinase mutations in 32 of 33 mutations tested. In vivo, shown to reduce tumor size in a murine BCR/ABL xenograft model. Indicated for Philadelphia chromosome–positive chronic myeloid leukemia in adults whose disease has progressed or who cannot tolerate other therapies that include imatinib. * Dosing * Interactions * Contraindications * Precautions Adult 400 mg PO bid 1 h ac or 2 h pc with water only; administer about 12 h apart; swallow whole (do not chew or crush) Pediatric Not established * Dosing * Interactions * Contraindications * Precautions CYP3A4, CYP2C8, CYP2C9, and CYP2D6 inhibitor; CYP2B6, CYP2C8, and CYP2C9 inducer; coadministration with other drugs known to prolong QT interval (eg, class III antiarrhythmics [amiodarone, dofetilide, sotalol], tricyclic antidepressants, verapamil, erythromycin, moxifloxacin, thioridazine) increases risk of life-threatening arrhythmias and sudden death; avoid coadministration with strong CYP3A4 inhibitors (eg, grapefruit, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), which may increase serum levels, thereby increasing QT interval; avoid coadministration with strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John's wort) * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; long QT syndrome; uncorrected hypokalemia or hypomagnesemia * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions May prolong QT interval, leading to life-threatening arrhythmias and possible sudden death; this risk is lowered by taking without food, avoiding grapefruit products, and confirming that potassium and magnesium levels are within normal limits; if QTc >480 ms, withhold and analyze concurrent medications, serum potassium levels, and magnesium levels (reduce dose according to prescribing information); food increases bioavailability, thus administer on empty stomach to avoid elevated serum levels and toxicity; common adverse effects include myelosuppression (obtain CBC count q2wk for 2 mo, then monthly), rash, headache, nausea, and itching; may cause hepatic toxicity, edema, and pancreatitis; females of childbearing potential should use effective contraception; caution in the presence of liver impairment; withhold drug with ANC <1 X 109/L, platelet count <50 X 109/L, or serum lipase, amylase, bilirubin, or hepatic transaminase levels >grade 3
Interferons

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

Interferon alfa-2a (Roferon A) or alfa-2b (Intron A)

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

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

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

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

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

Not establishedFollow-up
Further Inpatient Care

* Allogeneic bone marrow or stem cell transplantation is the best treatment for cure of chronic myelogenous leukemia (CML). Unfortunately, this procedure has a high mortality rate because of the induction and long-term complications. Several types of BMT are available, and most data are from allogeneic transplantations from HLA-matched sibling donors and a few syngeneic transplantations from an identical twin. Data show that allogeneic transplantations have better results than syngeneic transplantations because of some graft versus leukemia effects.
o Allogeneic BMT is currently the only proven cure for chronic myelogenous leukemia (CML). Ideally, it should be performed in the chronic phase of the disease rather than in the transformation phase or in blast crisis. Candidate patients should be offered the procedure if they have a matched or single–antigen-mismatched related donor available. In general, younger patients fare better than older patients.
o Allogeneic BMT with matched unrelated donors has yielded very encouraging results in this disease. The procedure has a higher rate of early and late graft failures (16%), grade III-IV acute graft versus host disease (50%), and extensive chronic graft versus host disease (55%). The overall survival rate ranges from 31% to 43% for patients younger than 30 years and from 14% to 27% for older patients. Benefits and risks should be assessed carefully with each patient.
* Autologous BMT is investigational, but, relatively recently, chemotherapy combinations or interferon have been found to induce a cytogenetic remission and allow harvesting of Ph-negative CD34 hematopoietic stem cells from the patient's peripheral blood.
* Other attempts to collect specifically normal stem cells are currently being investigated. The role of allogeneic hematopoietic stem cell transplantation in newly diagnosed chronic myelogenous leukemia (CML) has been relegated to the back with the availability of imatinib therapy. However, it has been suggested that patients with "poor-risk" Sokal scores but good risk for allogeneic hematopoietic stem cell transplantation be transplanted early or upfront, but no current consensus exists on these issues. However, a widely accepted consensus is patients who progress beyond chronic phase on imatinib should be offered hematopoietic stem cell transplantation if this is an option.
* Management of lymphoid and myeloid blast crisis: In patients with chronic myelogenous leukemia (CML) in blast crisis who are imatinib naive, the drug is used in combination to standard acute myelogenous leukemia or acute lymphoblastic leukemia induction-like regimens. However, because a high percentage of imatinib-resistant mutations exists in these patients, relapses occur more frequently and at an earlier time from induction. Thus, all efforts are made to take these patients for an allogeneic hematopoietic stem cell transplantation as possible.

Further Outpatient Care

* Management of early or chronic phase: The standard treatment of choice is now imatinib mesylate (Gleevec), which is a specific small-molecule inhibitor of BCR/ABL in all phases of chronic myelogenous leukemia (CML). Ninety percent of patients with CML in Western countries are diagnosed in the early or chronic phase of the disease.
* More than 80% of newly diagnosed patients with chronic myelogenous leukemia (CML) in the chronic phase will achieve a complete cytogenetic response (CCR) with the standard dose of 400 mg/d of imatinib. The probability of progression-free survival is strongly correlated with the level of response, approaching 100% in those patients who achieve molecular remission (a reduction of BCR/ABL mRNA by at least 3-log at 12 mo).
* In patients with chronic-phase CML whose interferon therapy had failed, the CCR was 41% at 18 months and 52% at 40 months, with a progression-free survival at 2 years of 76%. Progression to an accelerated phase or blast crisis had a peak at 2 years of 7.6%, but the incidence remains constant over the years at an average of 2%.
o High Sokal risk predicts poorer outcome, but on-treatment response parameters generally override pretherapeutic prognostic variables. Sokal score (based on age, spleen size, platelet and peripheral blood blast counts) is well correlated with the likelihood of achieving CCR: 91% for low-, 84% for intermediate-, and 69% for high-risk patients.
o Standard monitoring of response includes full blood counts, cytogenetics (or FISH), and quantitative reverse transcriptase (RT)-PCR for BCR/ABL mRNA. The more sensitive tests are done when the previous less sensitive tests become negative (ie, cytogenetics and FISH), and, thus, they should be tailored to the level of response attained by a given patient.
o The standard therapeutic milestones to be achieved in the patients are (1) a complete hematologic response (normal CBC and no evidence of extramedullary disease) at 3 months, (2) a minor cytogenetic response (36% to 65% Ph+) at 6 months, (3) a major cytogenetic response (0% to 35% Ph+) at 12 months, and (4) a complete cytogenetic response (0% Ph+) at 18 months.
o Failure to achieve these milestones should trigger a reassessment of the therapeutic strategy. Most patients with CCR remain positive for RT-PCR, indicating the presence of MRD. Discontinuation of the drug in these patients is usually followed by relapse, suggesting that imatinib fails to eradicate leukemic stem cells in these patients.
o Early intensification with the use of high doses of imatinib (800 mg/d) or imatinib in combination with cytarabine or interferon alfa may induce higher rates of RT-PCR negativity, but this still needs to be confirmed in further studies.
o The criteria for major molecular response (MMR) is >3-log reduction of BCR/ABL mRNA, and for complete molecular response (CMR), it is negativity by RT-PCR. Because a good correlation exists between BCR/ABL mRNA in bone marrow and peripheral blood, this can be monitored from peripheral blood samples.
o At 12 months with CCR, patients can be classified according to their molecular response into those with MMR (>3-log) or <3-log reduction of transcripts (98% vs 90% progression-free survival).
o Limited data are available on patients with CCR or MMR who discontinued their treatment with imatinib (5 of 6 patients had reappearance of Ph+).
o Patients should be screened for mutations of the BCR/ABL kinase domain whenever there is an indication of loss of response to imatinib at whichever level. Primary hematologic resistance to imatinib occurs in approximately 5% of cases that fail to achieve complete histologic remission (CHR), and 15% show primary cytogenetic resistance in the chronic phase. Secondary or acquired resistance (loss of previous response) is 16% at 42 months and increases to 26% in those previously treated with interferon, and is 73-95% in the accelerated or blast phase.

Prognosis

* Historically, the median survival of patients with chronic myelogenous leukemia (CML) from the time of diagnosis was 3-5 years, and, until recently, no known therapy was 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-risk groups (average survival of 5-6 y), intermediate-risk groups (average survival of 3-4 y), or poor-risk groups (average survival of 2 y). 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 chronic myelogenous leukemia (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 chronic myelogenous leukemia (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.
* The prognosis of patients with chronic myelogenous leukemia (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, showed that the median survival with busulfan is 6 years (50 patients); with hydroxyurea, 6.5 years (55 patients); and with interferon alfa, 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 chronic myelogenous leukemia (CML).

Miscellaneous
Medicolegal Pitfalls

* Failure to diagnose and treat chronic myelogenous leukemia (CML) early with new modalities may be a cause for malpractice charges.

Special Concerns

* The discovery of new agents presently under study, such as tyrosine kinase inhibitor therapy, may prove valuable in prolonging the survival of patients with chronic myelogenous leukemia (CML) and may provide them with an eventual cure. Physicians should refer their patients to tertiary care centers for clinical trials involving these therapies.
* Development of secondary or acquired imatinib resistance and the mechanisms responsible are due to BCR/ABL mutations. The molecular mechanism for primary imatinib resistance is unknown.
o Kinase-domain mutations in BCR/ABL represents the most common mechanism of acquired resistance to imatinib occurring in 50-90% of cases, of which 40 different mutations have currently been described. Because imatinib binds to the ABL kinase domain in the inactive, or closed, conformation to induce conformational changes, resistance occurs when the mutation prevents the kinase domain from adopting the specific conformation upon binding.
o The development of 2 novel BCR/ABL inhibitors, dasatinib (BMS-354825) and AMN107, are more potent inhibitors of BCR/ABL than imatinib, and moreover, they exhibit significant activity against all resistant mutations except BCR/ABL/T315I mutation.

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