RISK FACTORS: Radiation exposure, Immunodefi ciency states, Chemical and drug exposure (nitrogen mustard and benzene), Preleukemia, Cigarette smoking
RISK FACTORS
β’ Genetic and chromosomal abnormalities (e.g., trisomy 21, breakage and translocation, especially t9,22. Also
AML, MLL, etc. genes)
β’ MLL gene for mixed lineage leukemia located on chromosome 11q23. Its abnormalities and rearrangements
are easier detected with FISH (fl uorescent 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).
β’ 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.
β’ Radiation exposure
β’ Immunodefi ciency states
β’ Chemical and drug exposure (nitrogen mustard and benzene)
β’ Preleukemia
β’ Cigarette smoking
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) Ββ¬ 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
patients 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 fi rst remission for ANLL is advocated if a matched sibling is
available. Autologous bone marrow transplant is also acceptable in fi rst remission.
. Allogenic or autologous bone marrow transplant is acceptable in fi rst 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. No intense or contact sports nor aspirin due to low platelets
DIET
β’ Ensure adequately balanced calorie/vitamin intake
β’ Follow weight closely
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. Add cyclophosphamide 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 Granulocytemacrophage 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 (ARA-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 relapse
. 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), are showing great promise in refractory CLL. Fludarabine as a first 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
. STI571 a specific inhibitor of the BCR-ABL (oncogene) tyrosine kinase has substantial activity in both
chronic and blast crises in CML and in Philadelphia chromosome-positive ALL
. High dose cytarabine with or without daunorubicin
Precautions:
β’ Administration of chemotherapy agents should be by skilled and specifi cally trained individuals. IV vincristine, daunorubicin, and doxorubicin may lead to chemical burns in the event of extravasation.
β’ 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.
β’ Avoid anthracyclines if patient has a pre-existing cardiac problem
β’ Close monitoring of the WBCβs, polys, RBC and platelets is required especially in CML (chronic phase or ALL maintenance) in order not to induce profound myelotoxicity
β’ 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.
PATIENT MONITORING
β’ 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.
β’ Follow uric acid level and urinary function
β’ Physical evaluation, including weight and blood pressure, should be done with every treatment and as
frequently as once a week
POSSIBLE COMPLICATIONS
β’ Side effects of chemotherapy
β’ Rarely in lymphoid leukemia, acute tumor lysis syndrome may develop leading to hyperuricemia, hyperkalemia , hyperphosphatemia, hypocalcemia, and/or uric acid nephropathy
β’ Late onset cardiomyopathy has been described in children treated with standard dose anthracyclines
EXPECTED COURSE/PROGNOSIS
β’ ALL remission rate is very good. In children, long term survival is the rule.
β’ AML remission rate is 60-80%, with only 20-40% long term survival
β’ CML invariably transforms into the acute phase within 2 years (median of 45 months). Afterward, survival rate is poor.
β’ CLL usually is asymptomatic for several years especially Rai, stages 0-II. In Raiβs 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.
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