WORKUP	Section 5 of 11
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Lab Studies:

• Peripheral blood findings show a typical leukoerythroblastic blood picture, with circulating immature cells from the bone marrow (see Image 4).

• 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.

• 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.

• 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.

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

• 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 5) 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.

• 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 5). 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.

• 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 6) 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.

• 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.

• 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.

• 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.

• 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.

	TREATMENT	Section 6 of 11
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Medical Care: The 3-fold goals of treatment of CML have changed markedly in the past 10 years; they are to achieve a hematologic remission (normal CBC count and physical examination, ie, no organomegaly), to achieve cytogenetic remission (normal chromosome returns with 0% Ph-positive cells), and, most recently, to achieve molecular remission (negative PCR result for the mutational BCR/ABL m-RNA). The latter is an attempt for cure and prolongation of patient survival.

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

• 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 CML positive for the Ph chromosome. This drug was approved rapidly by the US Food and Drug Administration because of the following results:
  • 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).

  • The decision to choose the initial treatment or primary therapy for chronic-phase CML is difficult since the advent of the tyrosine kinase inhibitor imatinib (Gleevec), formerly known as STI571.

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

    • 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 <.001). The estimated rates of complete cytogenetic response were 76.2% and 14.5%, respectively (P <.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 <.001). 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 CML.

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

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

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

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

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

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

• Busulfan (Myleran) is an alkylating agent that has traditionally been used to keep the WBC counts less than 15,000 cells/mL. However, the myelosuppressive effects may occur much later and persist longer, making maintaining the numbers 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 of higher than 300,000 cells/mL, and it can alleviate acute symptoms of leukostasis, hyperviscosity, and tissue infiltration. Leukapheresis usually reduces the WBC count only temporarily and is often combined with cytoreductive chemotherapy for more lasting effects.

• Interferon alfa was the treatment of choice for most patients with CML who are too old for bone marrow transplantation (BMT) or who do not have a matched bone marrow donor. Interferon alfa is given at an average of 3-5 million IU/d subcutaneously after hematologic remission with hydroxyurea.
  • The cytogenetic response is monitored every 3-6 months by karyotyping or by fluorescence in situ hybridization to count the percent of bone marrow cells with Ph-positive cells.

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

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

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

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

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

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

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

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.

Consultations: These patients 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	Section 7 of 11
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The medications used for patients with chronic-phase CML include a myelosuppressive agent to achieve hematologic remission, which requires 1-2 months of treatment. Once the patient goes into hematologic remission, the goal of treatment is to suppress the Ph-positive hematopoietic clone in the bone marrow for a cytogenetic remission and, hopefully, a molecular remission. This entails the use of interferon alfa or a BMT.

Treatment is determined by (1) the age of the patient, (2) the presence of an HLA-matched donor willing to donate bone marrow, and (3) the Sokal score. The 3 categories of the Sokal score are (1) low risk, which is less than 0.8; (2) intermediate risk, which is 0.8-1.2; and (3) high risk, which is greater than 1.2.

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

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

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

Drug Name	Hydroxyurea (Hydrea) -- Inhibitor of deoxynucleotide synthesis and DOC for inducing hematologic remission in CML. Less leukemogenic than alkylating agents such as busulfan, melphalan (Alkeran), or chlorambucil. Myelosuppressive effects last a few days to a week and are easier to control than with alkylating agents; busulfan is associated with prolonged marrow suppression and can cause pulmonary fibrosis.
Adult Dose	Initial dose: 30 mg/kg/d at an average of 1000-1500 mg/d PO in 500-mg tabs Can be given at higher doses in patients with extremely high WBC counts (>300,000/mL) and adjusted accordingly as counts fall and platelet counts drop; dose can be given as a single daily dose or divided into 2-3 doses at higher dose ranges
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; thrombocytopenia is dose-limiting factor in using hydroxyurea; do not administer if platelet counts <50,000/mL; administer under advisement in patients with counts <100,000/mL; anemia may be aggravated by medications, and concomitant irradiation is contraindicated
Interactions	Neurotoxicity can occur when administered concurrently with fluorouracil
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor blood counts and adjust doses accordingly; some patients may be sensitive and present with fever, chills, and elevation of liver enzymes, which disappear after stopping drug; skin ulcers may be seen in long-term use; caution in patients with renal impairment

Drug Name	Busulfan (Myleran) -- Potent cytotoxic drug which, at recommended dosage, causes profound myelosuppression. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Adult Dose	4-8 mg/d PO; may administer up to 12 mg/d; maintenance dosing range is 1-4 mg/d to 2 mg/wk; discontinue regimen when WBC count reaches 10,000-20,000/mL; resume therapy when WBC reaches 50,000/mL
Pediatric Dose	0.06-0.12 mg/kg/d or 1.8-4.6 mg/m2/d; titrate dose to maintain WBC count >40,000/mL; reduce dose by 50% if WBC count is 30,000-40,000/mL; discontinue if WBC count <20,000/mL
Contraindications	Documented hypersensitivity; severely depressed bone marrow function; breastfeeding; failure to respond to previous treatment
Interactions	CYP3A3/4 enzyme substrate; acetaminophen, cyclophosphamide, itraconazole, and thioguanine may increase toxicity; phenytoin may decrease levels
Pregnancy	X - Contraindicated in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; may cause pulmonary fibrosis; if WBC count is high, hydration and allopurinol should be used to prevent hyperuricemia

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

Drug Name	Imatinib mesylate (Gleevec) -- Specifically designed to inhibit tyrosine kinase activity of bcr-abl kinase in Ph-positive leukemic CML cell lines. Well absorbed after oral administration, with maximum concentrations achieved within 2-4 h. Elimination is primarily in feces in form of metabolites.
Adult Dose	Chronic phase: 400 mg/d PO with food and large glass of water; may increase to 600 mg/d if no severe adverse effects or severe non–leukemia-related neutropenia or thrombocytopenia, disease continues to progress (any time), hematologic response is not satisfactory (after at least 3 mo treatment), or a loss of previously achieved hematologic response occurs Accelerated phase or blast crisis: 600 mg/d PO with food and large glass of water; may increase to 800 mg/d (400 mg bid) if no severe adverse effects or severe non–leukemia-related neutropenia or thrombocytopenia, disease continues to progress (any time), hematologic response is not satisfactory (after at least 3 mo treatment), or a loss of previously achieved hematologic response occurs
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	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
Pregnancy	D - Unsafe in pregnancy
Precautions	Dose must be reduced if grade 3-4 neutropenia or thrombocytopenia develops or levels of transaminases or bilirubin become elevated

Drug Name	Dasatinib (Sprycel) -- Multiple tyrosine kinase inhibitor. Inhibits growth of cell lines overexpressing BCR-ABL. Orphan drug indicated for chronic myeloid leukemia (CML) in individuals resistant to or intolerant of prior therapy (eg, imatinib [Gleevec]). Has been able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations.
Adult Dose	70 mg PO bid; continue until disease progression or no longer tolerated Chronic-phase CML: Escalate dose to 90 mg PO bid Advanced-phase CML: May increase to 100 mg PO bid Coadministration with CYP3A4 inhibitors: 20-40 mg PO qd Coadministration with CYP3A4 inducers: May need to increase dose If clinically viable, an alternate medication with no or minimal enzyme inhibition or induction is recommended
Pediatric Dose	Not established
Contraindications	None known
Interactions	CYP450 3A4 substrate and inhibitor; CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) 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)
Pregnancy	D - Unsafe in pregnancy
Precautions	Adverse effects include fluid retention (including pleural effusion), bleeding, diarrhea, rash, pyrexia, infections, headache, fatigue, and nausea; frequently causes anemia, neutropenia, or thrombocytopenia; because of extensive liver metabolism, caution in patients with hepatic impairment (may need to decrease dose); swallow tab whole, do not crush or cut

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

Drug Name	Interferon alfa-2a (Roferon A) or alfa-2b (Intron A) -- Both are recombinant alpha interferons with some minor amino acid differences but are considered equivalent modalities in treatment of CML. Roferon A comes in single (3-, 6-, 9-, and 36-MIU strength) or multidose vials (9- or 18-MIU strength). Intron A comes in multidose pens of 18 MIU (delivers 3 MIU/dose), 30 MIU (5 MIU/dose), and 60 MIU (10 MIU/dose), with each pen good for 6 doses. Elderly patients who cannot tolerate adverse effects may be started at half the recommended starting dose.
Adult Dose	Approximately 5 million/m2/d SC until complete cytogenetic remission (100% Ph-negative BM cells by FISH) Remission can occur within 1-2 y from onset of therapy; individual maximally tolerated dose can be obtained by starting at 3 MIU or 1.5 MIU qd and increasing by 3 MIU/d qmo until tolerance or cytogenetic remission
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Elderly patients do not tolerate treatment as well as younger individuals; caution in brain metastases, severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, or compromised CNS; can cause severe mood disturbance in some patients, including clinical depression; caution in history or predisposition to depression; most acute adverse effects are flulike symptoms, which can be alleviated by taking acetaminophen for fever and muscle aches and giving injections at night before bedtime; occasionally, patients may have some psychiatric effects (psychoses) or intolerance due to chronic fatigue; LFT results may be affected with liver enzyme elevation, which is alleviated by decreasing total dose

	FOLLOW-UP	Section 8 of 11
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Further Inpatient Care:

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

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

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

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

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

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

Further Outpatient Care:

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

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

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

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

• 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.

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

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

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

• 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).

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

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

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.

• 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).

• 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.

Patient Education:

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

	MISCELLANEOUS	Section 9 of 11
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Medical/Legal Pitfalls:

• Failure to diagnose and treat 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 these patients 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.

• 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. Since 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.

• 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.

	PICTURES	Section 10 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Caption: Picture 1. 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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Caption: Picture 2. 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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Caption: Picture 3. 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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Caption: Picture 4. 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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Caption: Picture 5. 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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Caption: Picture 6. 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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	BIBLIOGRAPHY	Section 11 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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Chronic Myelogenous Leukemia excerpt