eMedicine Specialties > Hematology > Stem Cells and Disorders
Chronic Myelogenous Leukemia: Treatment & Medication
Updated: Feb 6, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
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:
- 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, because the advent of the tyrosine kinase inhibitor imatinib.
- 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
- 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.
- 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.
- In Ph-positive acute lymphoblastic leukemia, the combination of chemotherapy plus imatinib is associated with a 2-year survival rate of 60%.
- 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.
- 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%.
- 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.
- 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.
- 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.13,14
- 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.
- 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%.
- 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.
- 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).
- 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
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
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.
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
Neurotoxicity can occur when administered concurrently with fluorouracil
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
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.
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
CYP3A3/4 enzyme substrate; acetaminophen, cyclophosphamide, itraconazole, and thioguanine may increase toxicity; phenytoin may decrease levels
Documented hypersensitivity; severely depressed bone marrow function; breastfeeding; failure to respond to previous treatment
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.
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
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
Documented hypersensitivity
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.
Adult
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 alternative medication with no or minimal enzyme inhibition or induction is recommended.
Pediatric
Not established
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)
None known
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); swallow tab whole, do not crush or cut
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.
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
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)
Documented hypersensitivity; long QT syndrome; uncorrected hypokalemia or hypomagnesemia
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 typesof 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.
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 established
Theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity.
Documented hypersensitivity
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
Elderly patients do not tolerate treatment as well as younger individuals; caution in patients with 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 the total dose.
More on Chronic Myelogenous Leukemia |
| Overview: Chronic Myelogenous Leukemia |
| Differential Diagnoses & Workup: Chronic Myelogenous Leukemia |
 Treatment & Medication: Chronic Myelogenous Leukemia |
| Follow-up: Chronic Myelogenous Leukemia |
| Multimedia: Chronic Myelogenous Leukemia |
| References |
| Further Reading |
| « Previous Page | Next Page » |
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Keywords
chronic myelogenous leukemia, CML, myelogenous leukemia, chronic granulocytic leukemia, Philadelphia chromosome–positive myeloproliferative disorder, myeloproliferative disorders, lymphoblastic leukemia, leukemia, leukocytosis, splenomegaly, blast crisis, enlarged spleen, lymphoproliferative disorder, blood cell cancer, Philadelphia chromosome, Ph chromosome, BCR/ABL, BCR-ABL
