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Leukemia
OVERVIEW: Proliferation and accumulation of abnormal immature blood cell progenitors (blasts) in the bone marrow and other tissues. The outstanding characteristic is the development of marrow failure. Intracerebral leukostasis may develop if the blood blast count becomes greatly elevated.
Leukemia is classified according to the type of blast and according to the course, if untreated:
• Acute lymphoblastic leukemia (ALL)
• Acute nonlymphoblastic leukemia (ANLL)
• Chronic myelocytic leukemia (CML)
• Chronic lymphocytic leukemia (CLL)
System(s) affected: Hemic/Lymphatic/Immunologic
Genetics: Unknown, some are familial
Incidence/Prevalence in USA: The yearly incidence is 13.2:100,000 in males and 7.7:100,000 in females
Predominant age:
• 70% occurs in adults, mostly CLL and ANLL. 30% in children, mostly ALL.
• With the current cure rate especially good for childhood ALL, it is estimated that by the year 2010, one in 1,000 young adults (15-45 years of age) in the USA will be a childhood ALL survivor
Predominant sex: Males > Females
SIGNS AND SYMPTOMS: • Mostly nonspecific and related to marrow failure or infiltration
• Fever
• Bleeding (e.g., petechiae, purpura, easy bruising, or oozing)
• Bone pain, pallor, fatigue
• Splenomegaly
• Hepatosplenomegaly
• Lymphadenopathy
• If CNS is involved, symptoms of increased intracranial pressure can be present
• Gingival swelling
CAUSES: Precise causes unknown
RISK FACTORS: • Genetic and chromosomal abnormalities (e.g., trisomy 21, breakage and translocation, especially t9,22. Also AML, MLL, etc. genes)
• MLL gene for mixed lineage leukemia located on chromosome 11q23. Its abnormalities and rearrangements are easier detected with FISH (fluorescent in situ hybridization) or PCR (polymerase chain reaction). Most rearrangements in this gene result in aggressive AML, secondary AML (after chemotherapy), and infant leukemia. Example: t(11;19)(q23;p13) (MLL-ENL).
• t(12;21)(p13,q22) detected by FISH and by screening for TEL/AML1 rearrangement by PCR is now known to be the most common rearrangement in childhood ALL and carries a favorable prognosis.
• Radiation exposure
• Immunodeficiency states
• Chemical and drug exposure (nitrogen mustard and benzene)
• Preleukemia
• Cigarette smoking
DIAGNOSIS DIFFERENTIAL DIAGNOSIS: • Viral induced cytopenia, lymphadenopathy and organomegaly
• Immune cytopenias
• Drug induced cytopenias
• Other marrow failure and infiltrative diseases: aplastic, hypoblastic and refractory anemias; paroxysmal nocturnal hemoglobinuria; myelodysplastic syndromes, Gaucher's disease, etc.
LABORATORY: • CBC, differential, platelets show subnormal RBC, neutrophils, and possibly subnormal platelets
• In some types, no circulating leukemic blasts are necessary to be present to establish the diagnosis. If 2 of the 3 above parameters are affected, or only one profoundly decreased, bone marrow failure should be ruled out.
• Reticulocyte count < 0.5
• Sedimentation rate usually elevated
• Chemistries LDH, and uric acid can be elevated
• Immunoglobulins IgG can be low or rarely elevated
• Coagulation profile can be normal or prolonged especially in promyelocytic leukemia (ANLL subtype)
Drugs that may alter lab results: Chemotherapy agents, especially corticosteroids. Don't prescribe these before finalizing the bone marrow studies. Some leukemic blasts are very sensitive and can have massive cell kill from as little as one dose of corticosteroids.
Disorders that may alter lab results: N/A
PATHOLOGICAL FINDINGS: • The marrow will be hypercellular and the normal architecture effaced
• The percentage of leukemic cells compared to the remainder of the cell population is usually more than 30%
• Liver, spleen, and kidneys can be enlarged and infiltrated with leukemic cells
SPECIAL TESTS: Spinal tap may reveal fluid with leukemic cells
IMAGING: • Chest x-ray may reveal a large mediastinal mass
• Ultrasonography or CT scan of the abdomen may discover organomegaly
DIAGNOSTIC PROCEDURES: • Bone marrow studies are necessary to make the final diagnosis
• Aspirates are stained with a buffered Wright's stain and provide good resolution for cell morphology
• Biopsies are demineralized, sectioned and stained with hematoxylin-eosin (H&E) stain. They provide valuable information for cellularity, architecture, and megakaryocytic series.
• Marrow cell suspension used for:
• Cytochemistries (e.g., myeloperoxidase and Sudan black are positive in myeloblasts)
• Immunophenotyping especially useful for lymphoid leukemia and can indicate whether it is monoclonal or polyclonal, B lymphocytes or T lymphocytes, early or late, etc.
• Chromosome studies will show the ploidy and/or the presence of a translocation which is of prognostic value
• Immunofluorescent stain for terminal deoxyribonucleotidyl transferase (TdT), another marker that differentiates between myeloid and lymphoid blasts
TREATMENT APPROPRIATE HEALTH CARE: • Consult with a chemotherapist
• Induction for acute leukemia treatment requires inpatient care
GENERAL MEASURES: • Assessment of liver, heart, and kidney functions and performance status
• In acute leukemia induction, establish good hydration and urine flow (especially in ALL patients)
• Give platelet transfusion if platelet count is
< 20,000 or if patient is having bleeding symptoms
• Avoid aspirin products
• Give packed red blood cells transfusion if patient is symptomatic from the anemia (e.g., orthostatic hypotension, dizziness, fatigue, hyperactive precordium) or if a cerebral or a cardiopulmonary problem is present
• If the absolute neutrophil count (ANC) < 1000, exert close temperature monitoring. (ANC = WBC x (Percentage of Polys + Bands) / 100). If patient becomes febrile (even low grade fever), appropriate cultures should be taken and patient placed on broad spectrum IV antibiotics covering pseudomonas and gram positive bacteria.
• Isolation (when the ANC is low) has no value because majority of the infecting agents in this situation are the patient's own normal flora of the skin, mouth, or gut
• In promyelocytic leukemia (ANLL subtype), patients are especially at risk for DIC when treatment is started. Heparinization is indicated with close followup of coagulation parameters.
SURGICAL MEASURES: • Bone marrow transplant
• Allogenic bone marrow transplantation in first remission for ANLL is advocated if a matched sibling is available. Autologous bone marrow transplant is also acceptable in first remission.
• Allogenic or autologous bone marrow transplant is acceptable in first remission in high risk ALL, especially in adults. They are acceptable in second remission for childhood ALL.
• Early studies using an allogenic non-related match donor seem to be promising and might replace the autologous route when a full sibling match is not available
ACTIVITY: Ambulatory as tolerated
DIET: • Ensure adequately balanced calorie/vitamin intake
• Follow weight closely
PATIENT EDUCATION: • Prognosis and treatment toxicity.
• Leukemia Society of America: 33 Third Ave. New York, NY 10017, (212)573-8484
• NCI (Bethesda, Maryland) has pamphlets and telephone education
• You and Leukemia, A Day At A Time by Dr. Lynn S. Baker, W. B. Saunders Co.
MEDICATIONS DRUG(S) OF CHOICE: Change frequently as result of research
• ALL
• Induction: vincristine plus prednisone plus asparaginase with or without doxorubicin or daunorubicin. CNS prophylaxis, intrathecal methotrexate with or without cranial irradiation. Cyclophosphamide is added for adult ALL.
• Maintenance: vincristine, prednisone, mercaptopurine (6-mercaptopurine) daily and methotrexate weekly for 2-3 years
• Intensification with IV methotrexate without rescue for children or with IV cyclophosphamide, cytarabine, 6-mercaptopurine, 6-thioguanine with or without 3 weeks of induction like regimen is used for both adult and children ALL.
• ANLL
• Induction: cytarabine plus daunorubicin, cytarabine plus idarubicin or cytarabine plus mitoxantrone. Idarubicin seems to be superior to daunorubicin in the treatment of ANLL. Yeast derived granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor(G-CSF) do not stimulate leukemia cell growth; but help in the resolution of marrow hypoplasia associated with chemotherapy.
• Maintenance: combined agents and high dose cytarabine. High dose Ana-c with timed sequence.
• Promyelocytic leukemia:
• All-trans-retinoic acid (ATRA) promotes maturation to normal granulocyte and provide remissions with lower toxicity
• Arsenic is showing success in relapsed promyelocytic
• CLL. An anti-CD33 monoclonal antibody has the potential for eradicating minimal residual disease.
• Chlorambucil with or without prednisone used only if symptomatic or cytopenic. Fludarabine and cladribine (2-CDA), recently FDA approved, are showing great promise in refractory CLL. Fludarabine as a 1st line therapy was effective with 81% response rate and 2-CDA in a small study showed 85% response rate. New agents such as somatostatin analog, cyclosporine, theophylline have significant activity in CLL.
• Added measurements for CLL management can include: splenectomy, leukophoresis, radiation therapy, pentostatin and 2'-deoxycoformycin
• Hairy cell leukemia - Interferon
• CML
• Chronic phase, allogenic bone marrow transplantation. If not possible, busulfan, hydroxyurea, or interferon alpha can prolong survival.
• Acute phase - daunorubicin plus cytarabine plus vincristine plus prednisone with or without thioguanine, or
• High dose cytarabine with or without daunorubicin
Contraindications: No absolute contraindication due
Precautions:
• Administration of chemotherapy agents should be by skilled and specifically trained individuals. IV vincristine, daunorubicin, and doxorubicin may lead to chemical burns in the event of extravasation.
• If liver injury, the toxicity of vincristine, anthracyclines and antimetabolites can be pronounced. If liver injury is advanced and hyperbilirubinemia is present, avoid those medications or reduce dosage.
• Anthracyclines can cause cardiomyopathy. Avoid them if patient has a pre-existing cardiac problem.
• Close monitoring of the WBC's, polys, RBC and platelets is required especially in CML (chronic phase or ALL maintenance in order not to induce profound myelotoxicity
• Patients will be immunosuppressed during treatment. Avoid live vaccines. Administer varicella-zoster, or measles immunoglobulin as soon as exposure of a patient at risk becomes known.
Significant possible interactions: Allopurinol accentuates the toxicity of 6-mercaptopurine
ALTERNATIVE DRUGS: N/A
FOLLOW UP PATIENT MONITORING: • Repeat bone marrow studies every week or every other week during induction of acute leukemia. Less frequently later. Also perform if a relapse is suspected.
• Follow uric acid level and urinary function
• Physical evaluation, including weight and blood pressure, should be done with every treatment and as frequently as once a week
PREVENTION/AVOIDANCE: No intense or contact sports and no aspirin due to low platelets and RBC
POSSIBLE COMPLICATIONS: • Side effects of chemotherapy
• Rarely in lymphoid leukemia, acute tumor lysis syndrome may develop leading to hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and/or uric acid nephropathy
• Late onset cardiomyopathy has been described in children treated with standard dose anthracyclines
EXPECTED COURSE AND PROGNOSIS: • ALL remission rate is very good. In children, long term survival is the rule.
• AML remission rate is 60-80%, with only 20-40% long term survival
• CML invariably transforms into the acute phase within 2 years (median of 45 months). Afterward, survival rate is poor.
• CLL usually is asymptomatic for several years especially Rai, stages 0-II. In Rai's series the mean interval (in stages 0-II) is 5.3 years from diagnosis until therapy was needed. Median overall survival in CLL is thought to be 9 years.
MISCELLANEOUS ASSOCIATED CONDITIONS: N/A
AGE-RELATED FACTORS:
Pediatric: Tolerate intense treatments better
Geriatric:
• Do not tolerate allogenic bone marrow transplant. Age 50 is usual cut off for transplant.
• Autologous transplant may be tried in patients >50, if no organ failure is present and performance status is good
• Adding granulocyte-macrophage colony stimulating factor (GM-CSF) to induction for ANLL patients 60 years significantly reduced toxicity and made induction a feasible option in this patient profile
Others: N/A
PREGNANCY: Chemotherapy is a viable option in the 2nd and 3rd trimesters. Refer patient to an oncologist.
SYNONYMS: N/A
ICD-9-CM: 204.0 ALL
202.4 Hairy-cell leukemia
205.0 AML
206.0 AMoL
204.1 CLL
205.1 CML or chronic granulocytic leukemia
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