Continuing Education
Acute Lymphoblastic Leukemia of Childhood
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Acute Lymphoblastic Leukemia of Childhood
by
Shirley Hogan, PharmD.
Clinical Assistant Professor
University
of Mississippi School
of Pharmacy
Needs Statement: Therapy for acute lymphoblastic leukemia (ALL) of childhood has made great strides in recent years. Pharmacists need to understand the basics of the disease and the current treatment modalities available. Helping educate these patients, their parents and families can do much to reassure and support them during the difficult times that cancer brings.
Intended Audience: Any pharmacist who may come into contact with people whose lives are directly or indirectly affected by ALL.
Goal: To help pharmacists develop or enhance their understanding of the physiologic processes involved in Acute Lymphoblastic Leukemia of Childhood and the usual process of treatment, with emphasis on areas for pharmacist's focus.
Objectives: Upon completion of this article, the pharmacist should be able to:
Special note for on-line version of the lesson: As you read the lesson, you will encounter hyperlinked terms. Clicking on these links will take you to web sites that provide more information on the terms. In all instances (except tables and figures), you will be leaving the CE lesson to view material that is not considered part of the CE lesson, but nevertheless constitute information that should be helpful to you in understanding the lesson's topic.
A German physician, Virchow first used the term "leukemia", when he observed that some of his patients had a condition that led to "weisses blut", German for "white blood". This was later translated into Greek as "leukemia". The high number of white blood cells was thought to make the blood to actually appear white, and even though this was disproved, the term "leukemia" continues to describe this malignancy of the blood.
In the Preface to American Cancer Society Atlas of Clinical Oncology Adult Leukemias, the editor, Peter H. Wiernik, M.D. relates a personal story that summarizes the understanding of leukemia less than 50 years ago: "When I was a second-year medical student at the University of Virginia in 1962, the chairman of the Department of Medicine, the brilliant William Parson, presented a patient with acute myelocytic leukemia to us during one of his weekly professor rounds with students. The patient was a young man of 19 who was nervously smoking a cigarette as he sat up in bed to vomit blood, which was being lost at least as rapidly as it was being replaced. He was fully conscious and scared to death. He had been diagnosed about a week before we visited him, and in the hall Dr. Parson told us he would probably die of sepsis and hemorrhage within a few days and that there was nothing that could be done. I decided at that moment to spend the next 40 to 50 years learning all I could about the leukemias and to try my best to play some role in improving the outcome for future patients with those and other neoplasms."
Great advances in technology have occurred since the 1960's allowing a greater understanding of leukemia so that the diagnosis of the various types of leukemia is now accomplished on the molecular level. Knowing the sequence of the genetic code involved and how it has changed has led to effective treatment tailor-made to these specific changes. When these treatments are given as modules in sequence, cure expectancies overall are now > 70% with good-risk leukemias and >90% with good risk acute lymphoblastic leukemia (ALL) in children.
To understand leukemia, a review of some basic human cellular structures and processes is required. Research has provided us with the knowledge that cells need both the ability to divide and to "self-destruct" at the appropriate time. This allows a natural process that maintains the smooth and orderly functions of the body. The ability to self-destruct is referred to as apoptosis, a Greek word meaning "dropping off". It is speculated that breakdowns in the systems that control cell division/proliferation and facilitate apoptosis, contribute to cancer. For the most part, cancer develops from a single cell that previously appeared to be completely normal, but then starts to divide in an uncontrolled manner. All of the cells produced from this cell then carry the same defect, and continue to divide without control and lack the ability for apoptosis.
The leukemias share a number of consistent abnormal biologic characteristics with most other types of cancer; one fundamental feature is that of clonality. The molecular events required to produce clinical disease are assumed to be rare in relation to the number of "target" cells available. In the small number of individuals (~1%) who may develop a hematologic malignancy, only 1 cell is likely to experience the essential rare mutant event, or as assumed in the development of cancer, a sequential series of mutational events. The cellular and molecular phenotypic diversity of leukemia suggests that the disease can be viewed as a clonal lesion originating at different developmental levels and lineage compartments of hematopoiesis. The phenotype of the leukemia will reflect the level of differentiation/maturation achieved by these clones. The precise number of sequential cooperating mutations required to produce overt, clinical leukemia is not known, but the relatively short latency, especially in infancy and childhood, suggests it may be very few. Gene alterations in leukemia may result in loss or acquisition of function by multiple mechanisms including: 1) illegitimate recombination 2) loss or gain of genetic information or 3) point mutation. Genetic changes may also involve extra copies of particular chromosomes, such as hyperdiploidy in childhood ALL.
These biological findings have greatly changed the perception of the disease and have introduced into routine practice immunologic, cytogenetic, and molecular diagnostic tools combining specificity and sensitivity. These diagnostic tools have aided in recognizing clinical differences in infant, childhood and adult ALL and point to the existence of leukemias that are distinct in terms of their cellular origins, molecular disorder, and drug responsiveness. In addition to their value at diagnosis these unique molecular markers, due to their clonal uniqueness and use of sensitive screening methods, are useful in monitoring treated patients for elimination, persistence or reemergence of the leukemia clone.
Human blood contains many different mature cell types, each with a different and unique set of specialized properties and life supporting functions. Due to the relatively short life span of these cells, billions are lost from the system each day, yet their numbers are usually maintained at a constant level. Our bodies achieve this by continuous production in the marrow and lymphoid tissue of new, mature blood cells from more primitive precursors through a complex, balanced system, in which the regulation of cell differentiation, proliferation and death determines the rate of mature cell output. The regulated production of mature cells to meet changing physiologic needs is a general feature of tissues characterized by continual turnover. This system, that allows a high degree of cell amplification and specialization, arises from a relatively small pool of self-maintaining pluripotent hematopoietic stem cells. Understanding of these events in molecular terms is the result of many years of research. The evidence from this extensive research shows that hematopoietic cell differentiation involves the regulated and sequential activation and silencing of genes encoding various transcription factors. In addition, data now show that some of the earliest steps in the hematopoietic cell differentiation process involve changes in either expression and/or signaling capacity of cell surface receptors for different growth factors and cell adhesion molecules that participate in the regulation of hematopoiesis. Understanding this new data has directed recent research with the anticipation of finding new treatment options.
The major categories of leukemia are described in terms of lineage and degree of maturation of the predominant malignant cells. Therefore, there are lymphoid and myeloid leukemias, with each of these being divided into multiple subtypes on the basis of cellular morphology and genetic markers. Acute and chronic leukemias were originally distinguished by the rapidity of the clinical course. When improved cell staining techniques were introduced it was found that rapidity of progression correlated inversely with the degree of maturation of the predominant malignant cell, with blastic leukemia being the most rapidly fatal. The introduction of effective therapy has changed the original meanings of acute and chronic, which are now determined by the morphologic, immunologic, and genetic characteristics of the leukemia cells at the time of diagnosis instead of the time frame of the clinical pathway.
Leukemia can occur at any age, from infancy to old age. Although it occurs, overall, with nearly equal frequency among races and genders, there are differences in frequency among gender and ethnic groups within certain subtypes of leukemia. Acute lymphoblastic leukemia is the most frequently diagnosed malignant disease of childhood, and the discussion at this point will focus on this childhood subtype of leukemia.
Lymphoid leukemia is the result of neoplastic clonal proliferation of lymphoid cells at different stages of maturation. Acute lymphoid leukemias are characterized by the immunophenotypic and antigen-receptor gene configuration of immature B or T cells. In addition to the genetic abnormalities associated with leukemogenesis (chromosomal translocations and gene fusions) leukemic cells often express cell markers in combinations that are not found during normal lymphopoiesis; these aberrant immunophenotypes can be exploited to monitor response to treatment and track residual leukemic cells in patients. The growth requirements and response to stimuli of leukemic cells are often markedly different than those of their normal counterparts.
Acute lymphoblastic leukemia (ALL) accounts for one-fourth of all childhood cancers and approximately 75% of all cases of childhood leukemia. Between 2,500 and 3,500 children are diagnosed with ALL in the United States each year. The peak incidence for ALL occurs between age 2 and 5 years. The incidence of ALL is higher among boys than girls with this difference at its greatest in pubertal children.
Patients with ALL present with signs and symptoms that reflect inadequate hematopoiesis due to leukemic cell invasion of the bone marrow. Symptoms of anemia, bleeding, and infection are the usual reasons for seeking medical attention. Pallor, fatigue and loss of appetite are commonly reported by the parents of children with ALL. They may also report repeated episodes of infection or infections that do not respond to usually effective treatment. Bleeding or bruising, as a result of diminished platelets is also a common initial finding. Physical exams may reveal petechiae and ecchymoses in the skin or mucous membranes, and bone tenderness due to leukemic infiltrations or hemorrhage that stretches the periosteum. Liver, spleen, and lymph nodes are the most common sites of extramedullary involvement, with more than half having an enlargement of one or more of these sites at diagnosis. A variety of abnormal non-hematologic laboratory results may be found in patients newly diagnosed with ALL. These findings along with their degree of abnormality reflect the leukemic cell burden, the extent of extramedullary spread, or the excessive proliferation and destruction of the leukemic cells. Elevated serum uric acid and serum lactate dehydrogenase frequently occur and correlate with leukemic cell burden.
A definitive diagnosis of ALL is dependent on an examination of the bone marrow, which may be replaced by leukemic lymphoblasts. Diagnosis requires 25% lymphoblasts in the bone marrow. A number of initial clinical and laboratory findings have been associated with predicting outcome, but the most basic and reliably agreed upon are age and white blood cell (WBC) count at diagnosis. Children aged 1-9 years with a WBC less than 50,000/microL are designated standard risk and children 10 years or older or with WBC greater than 50,000 (regardless of age) are designated high risk. Infants less than 1 year have an increased risk of treatment failure and are therefore also considered high risk. The risk of treatment failure and/or relapse may be further defined by cytogenetic findings. These include hyper- or hypo- diploidy and translocations, and have treatment outcome implications. Hyperdiploidy (>50 chromosomes) is associated with a decreased chance of relapse whereas, hypodiploidy (<46 chromosomes) is associated with poorer outcome.
Since the 1970's, when surface markers were first used to characterize ALL in terms of cell origin and stage of differentiation, three immunologic subsets have been recognized: T-cell, B-cell and B-cell precursor. Despite very different clinical presenting features and different leukemic cell burdens, the difference in prognostic distinctions among the ALL subtypes has decreased with risk-directed treatment. For determining this treatment one must distinguish T-cell and mature B-cell cases from all other B-lineage (B-cell precursor) cases. B-cell precursor cases comprise approximately 80-85% of childhood ALL and generally have the better outcomes.
The recognition that ALL is a heterogeneous disease and that children can be stratified into various risk groups has profoundly influenced therapy. Combination chemotherapy remains the primary treatment modality, but the choice of the agents in the combination is tailored to the distinct subtype identified in each patient group. Although the specific approaches to patients in each subtype or risk group may vary somewhat, current ALL treatment regimens divide therapy into four main categories: 1) remission induction, 2) CNS prophylaxis, 3) consolidation or intensification and 4) maintenance therapy.
The aim of initial ALL treatment for all subtypes and risk groups is induction of remission. The approach to treatment of B-cell and T-cell patients differs at different centers, but most currently treat these separately from B-precursor patients. The treatment regimens for B-cell and T-cell leukemia usually are more short-term and intensive than those for B-precursor and the chemotherapy agents used may vary at different centers, but B-precursor ALL treatment is very much standardized and very little difference is seen amongst centers across the United States. The discussion of treatment will therefore focus on B-precursor ALL.
Prior to starting chemotherapy, supportive care measures need to be instituted. Febrile patients, with or without a documented infection, need treatment with a broad-spectrum antibiotic until infectious disease can be excluded. Patients with anemia may require transfusions with packed red cells, especially in view of the need to draw a relatively large volume of blood for laboratory studies and the bone marrow suppression due to the leukemia itself and following the chemotherapy drugs. Thrombocytopenia is a common presenting symptom of ALL, but active bleeding is rare. Guidelines for prophylactic platelet transfusions vary according to treatment site, but a general rule is to transfuse platelets if below 5 x 109/L. Attention to fluid and electrolyte balance is important. Intravenous hydration is necessary for all patients prior to and during chemotherapy treatment to ensure adequate kidney filtration and aid in removal of cell lysis products. Tumor lysis syndrome results from the rapid death of predominantly malignant cells and is an indication that treatment is working. This rapid lysis of cells releases intracellular contents into the systemic system faster than the body can eliminate them with an end result of hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia. Addition of sodium bicarbonate to the IV fluids along with allopurinol is necessary to treat or prevent hyperuricemia. The sodium bicarbonate alkalinizes the urine to prevent crystallization and the allopurinol inhibits the formation of uric acid. A recent addition to hyperuricemia treatment/prevention is the use of recombinant urate oxidase that converts uric acid to allantoin, a readily excretable metabolite with a 5-10 fold higher solubility than uric acid.
Administration of a phosphorus binder such as aluminum hydroxide or calcium carbonate in a patient with low calcium levels may be necessary to treat/prevent hyperphosphatemia and consequent hypocalcemia. Removal of potassium from IV fluids during initial induction treatment is usually adequate to prevent hyperkalemia.
Other supportive care measures include prophylactic use of trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia and the placement of chemo-ports or other indwelling catheters for ease in administration of chemotherapy and withdrawal of blood samples. Even though children have an advantage in terms of long-term disease outcome within all diagnostic groups of leukemia they may be susceptible to changes of physical and intellectual growth. These are less of a problem for their adult counter-parts and are therefore sometimes overlooked; therefore, endocrinologic, neurologic, psychiatric, and educational testing and counseling should begin as soon as possible after diagnosis.
The goal of remission induction treatment is to rapidly achieve a complete remission, most often described as a normocellular bone marrow with < 5% lymphoblasts and normal peripheral blood values. Achievement of a complete remission by this definition is a basic premise of antileukemic treatment and a proven prerequisite for prolonged survival and should be accomplished in ~28 days. Treatment typically includes administration of prednisone, vincristine and L-asparaginase. Dexamethasone has been researched as an improvement over prednisone due to laboratory data revealing a possible advantage in potency and increased efficacy in penetrating the blood-brain barrier. More recent data, however, show that dexamethasone may be associated with greater acute and long-term toxicity so that its use is now reserved for the well-controlled research setting. The efficacy of this 3-drug combination may be enhanced by the addition of an anthracycline such as daunorubicin. Because the use of a fourth drug or additional drugs may increase the incidence of toxic effects during induction, most centers reserve these additions for the higher risk patients.
Each of these agents has well-known toxicity profiles, and pharmacists working with these patients need to ensure that proper monitoring parameters are used to identify adverse events and that appropriate dosage adjustments are made when necessary. The relatively high dose of prednisone used may precipitate a loss of glucose control and necessitate the use of insulin during the induction phase of treatment. Careful monitoring of blood glucose during treatment is necessary, but also at the completion of the prednisone course to ensure the insulin is discontinued as the glucose returns to normal.
Vincristine is well known for having neurotoxic effects and monitoring should include observation of the patient's gait to identify "foot-drop" caused by loss of the deep-tendon reflex. Monitoring the frequency of bowel movements allows for identification of neurotoxicity involving the GI tract since constipation can be a dose-limiting toxicity. A patient may experience fever after vincristine administration (up to 24 hr later) and the knowledge of this cause of fever may prevent unnecessary use of antibiotics.
L-asparaginase has a relatively high rate of hypersensitivity reactions associated with its administration. Patients and caregivers need to be educated as to the signs/symptoms of these type reactions and the importance of reporting these immediately. Pancreatitis has an ~15% occurrence rate related to L-asparaginase use, therefore amylase and lipase values should be recorded at baseline before starting treatment and rechecked at the first indication of abdominal pain. Occurrence of pancreatitis precludes further administration of L-asparaginase. Changes in coagulation factors possible with L-asparaginase require the monitoring of PT/PTT and fibrinogen prior to each dose. There are two purified preparations of the enzyme asparaginase: one from Escherichia coli and one from Erwinia carotovora. The E. coli preparation is the most readily available at this time. The Erwinia preparation, when available allows substitution in the event of hypersensitivity to the E. coli preparation, but its availability has been sporadic recently. A polyethylene glycol (PEG) conjugated preparation of E. coli derived asparaginase is also available, though it too has had supply problems. The extended half-life of this product makes it an attractive alternative from the patient's point of view, since it requires fewer IM injections. It is important to consider this pharmacokinetic difference when calculating equivalent doses.
Addition of a fourth drug, daunorubicin, to the 3-drug regimen increases the risk for toxicity, but improves the remission rate for higher risk patients. The dose of this anthracycline is kept to a minimum to reduce the risk of cardiotoxicity, which is related to the patient's cumulative dose. Monitoring for this adverse effect is accomplished with baseline and pre-course echocardiograms. Since the cardiotoxic effects of the anthracyclines may not surface until much later in life, it is important to ensure that these patients continue to be monitored after treatment is complete.
As treatments for ALL became more efficacious, it was recognized that CNS recurrence had to be prevented for improvement in overall success rates to occur. CNS preventive treatment is based on the premise that the CNS acts as a haven in which leukemic cells can exist undetected. These leukemic cells are protected by the blood-brain barrier from the therapeutic concentrations of the chemotherapy given systemically. This portion of treatment might more correctly be called CNS treatment rather than prophylaxis since it is assumed that leukemic cells already exist in the CNS, though they may be undetected. Early successful attempts at CNS relapse prevention involved craniospinal radiation and then later attempts included craniospinal radiation with methotrexate administered intrathecally. This combination of radiation and intrathecal methotrexate is still used for some high-risk patients at some centers, but the idea of avoiding cranial irradiation grew from concerns that radiotherapy is responsible for many of the long-term adverse CNS events observed in these patients. The most recent studies have shown that intensive intrathecal therapy given early during induction and consolidation is effective treatment for lower risk and when continued into the maintenance phase is effective for intermediate-risk ALL. CNS irradiation is now reserved for those at high risk for CNS relapse. Methotrexate is the chemotherapy agent used most often for this intrathecal treatment. When the conventional dosing method based on body surface area was changed to a pharmacologically validated algorithm based on age there was improved efficacy and decreased toxicity. Pharmacists must remember that only preservative-free preparations of methotrexate, or any other drug given intrathecally, must be used.
Even when patients attain "remission" as previously defined, they will still have leukemic cells that will require further treatment to prevent relapse.
This is the beginning of the consolidation or intensification phase of treatment. Consolidation therapy is a period of intensified treatment given as soon as induction is complete and remission is confirmed. Most treatment centers administer some type of consolidation therapy, but many combinations exist and the treatment chosen is dependent on the risk group at diagnosis. The most commonly used chemotherapy agents include: high dose IV methotrexate, prolonged administration of weekly asparaginase, vincristine and prednisone pulses, and 6-mercaptopurine. Pharmacists should carefully monitor the administration of high dose IV methotrexate to ensure patient safety. The addition of leucovorin rescue based on serum concentrations of methotrexate allows larger more effective doses to be administered with minimal toxicity. The drug interaction between trimethoprim-sulfamethoxazole and methotrexate requires that the trimethoprim-sulfamethoxazole be withheld during the methotrexate administration and until monitoring of serum concentrations is complete.
ALL is unique among human malignancies in that it requires prolonged continuation treatment for 2.5 to 3 years post remission. The combination of methotrexate and 6-mercaptopurine (6MP) constitutes the principal elements of most maintenance therapy regimens. The optimal schedule of administration of the two drugs is different. Methotrexate is more effective when administered intermittently, whereas, 6MP appears to have optimal efficacy with daily administration. Compliance problems over this extended treatment time may also affect outcomes, so that pharmacists should monitor compliance with refills for these patients closely.
Relapse is defined as the reappearance of leukemic cells at any site in the body. Most relapses occur during treatment or within the first 2 years off treatment. Time to relapse and the site of the relapse are important predictors of outcome. With reference to time, the longer time from end of treatment to relapse, the better chance for good outcome. Relapse while still on treatment has a worse prognosis than relapse occurring when treatment is completed. This time relationship supports the idea that relapse while still on treatment or shortly after finishing treatment would suggest drug resistance, whereas relapse further out from the end of treatment would suggest a true recurrence and that the same drugs used initially would be efficacious again. Bone marrow transplantation is usually considered in patients after a second relapse or after a first relapse if prognostic factors indicate a high risk for second treatment failure.
There is continuing research with the goal of curing all children with ALL and accomplishing this goal with minimal long-term toxicity. Each time further refinement in prognostic factors is accomplished; treatment can also be refined for these well-defined risk groups. This will allow children to receive adequate treatment for the best chance of cure with minimized toxicity and the best quality of life.
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http://www.nci.nih.gov/cancerinfo/