eMedicine Specialties > Pediatrics: General Medicine > Oncology

Acute Lymphoblastic Leukemia: Treatment & Medication

Author: Noriko Satake, MD, Assistant Professor, Department of Pediatrics, Section of Hematology/Oncology, University of California Davis School of Medicine, Davis Medical Center
Coauthor(s): Janet M Yoon, MD, Assistant Clinical Professor, Department of Pediatrics, Hematology/Oncology, University of California Davis Medical Center
Contributor Information and Disclosures

Updated: Aug 12, 2009

Treatment

Medical Care

Because leukemia is a systemic disease, therapy is primarily based on chemotherapy. Different forms of acute lymphoblastic leukemia (ALL) require different approaches for optimal results. Excluding mature B-cell acute lymphoblastic leukemia which is treated with short-term intensive chemotherapy, including high-dose methotrexate (MTX), cytarabine, and cyclophosphamide, acute lymphoblastic leukemia treatment typically consists of a remission-induction phase, intensification (consolidation) phase, and continuation therapy targeted at eliminating residual disease. The addition of cyclophosphamide and intensive treatment with asparaginase is also beneficial in the treatment of T-cell acute lymphoblastic leukemia.

• Tumor lysis syndrome
  • Before and during the initial induction phase of chemotherapy, patients may develop tumor lysis syndrome, which refers to the metabolic derangements caused by the systemic and rapid release of intracellular contents as chemotherapy destroys leukemic blasts. Because some cells can die before therapy, such metabolic changes can occur even before therapy begins.
  • Primary features of tumor lysis syndrome include hyperuricemia (due to metabolism of purines), hyperphosphatemia, hypocalcemia, and hyperkalemia. The hyperuricemia can lead to crystal formation with tubular obstruction and, possibly, acute renal failure requiring dialysis. Therefore, electrolyte and uric acid levels should be closely monitored throughout initial therapy.
  • To prevent complications of tumor lysis syndrome, patients should initially receive intravenous (IV) fluids at twice the maintenance rates, usually without potassium.
    • Sodium bicarbonate is added to the IV fluid to achieve moderate alkalinization of the urine (pH level, 7.5-8) to enhance the excretion of phosphate and uric acid. A urine pH level higher than this should be avoided to prevent crystallization of hypoxanthine or calcium phosphate.
    • The standard treatment for malignancy-associated hyperuricemia also includes allopurinol. By blocking the enzyme xanthine oxidase, allopurinol blocks uric acid formation. Patients at high risk for tumor lysis still need to excrete preexisting uric acid, which is unaffected by the use of allopurinol. 
    • Rasburicase, a recombinant urate oxidase, has demonstrated increased efficacy in pediatric patients at high risk for tumor lysis by catalyzing the enzymatic oxidation of uric acid to a much more urine soluble product, allantoin.
• Phases of therapy
  • The treatment of childhood acute lymphoblastic leukemia, with the exception of B-cell acute lymphoblastic leukemia, has 5 components: induction, consolidation, interim maintenance, delayed intensification, and maintenance. The goal of induction is to achieve remission or less than 5% blasts in the bone marrow. Induction therapy generally consists of 3-4 drugs, which may include a glucocorticoid, vincristine, asparaginase, and possibly an anthracycline. This type of therapy induces complete remission based on morphology in more than 98% of patients. However, the measurement of minimal residual disease (MRD) by flow cytometry or polymerase chain reaction has been shown to be much more specific and sensitive than morphologic examination of blast cells. 
  • The current pediatric acute lymphoblastic leukemia clinical trials have incorporated MRD as a criterion for determining rapid early responder versus slow early responder status during induction chemotherapy. Based on MRD measurements, treatment may be intensified in patients with high amounts of residual blasts (>1%).
  • Consolidation therapy is given soon after remission is achieved to further reduce the leukemic cell burden before the emergence of drug resistance and relapse in sanctuary sites (ie, testes, CNS). In this phase of therapy, the drugs are given at doses higher than those used during induction or the patient is given different drugs (ie, high-dose MTX and 6-mercaptopurine [6-MP]), epipodophyllotoxins with cytarabine, or multiagent combination therapy. Consolidation therapy also appears to improve the long-term survival of patients with standard-risk disease. The addition of intensive reinduction therapy after the completion of the induction phase is similarly beneficial for patients in both risk groups.
  • In interim maintenance, oral medications are administered to maintain remission and allow the bone marrow to recover. This occurs for 4 weeks and is followed by delayed intensification, which is aimed at treating any remaining resistant leukemia cells.
  • The last phase of treatment is maintenance. This consists of intrathecal MTX every 3 months, monthly vincristine, daily 6-MP and weekly MTX.
• Duration of therapy
  • Whereas B-cell acute lymphoblastic leukemia is treated with a 2-month to 8-month course of intensive therapy, achieving acceptable cure rates for patients with B-precursor and T-cell acute lymphoblastic leukemia requires approximately 2-2.5 years of continuation therapy. Attempts to reduce this time result in high relapse rates after therapy is stopped. In the current acute lymphoblastic leukemia clinical trials, the total duration of therapy for girls is 2 years from the start of interim maintenance and is 3 years from the start of interim maintenance for boys.
  • Most contemporary protocols include a continuation phase based on weekly parenterally administered MTX given with daily, orally administered 6-MP interrupted by monthly pulses of vincristine and a glucocorticoid. Although these pulses improve outcomes, they are associated with avascular necrosis of the bone. Patients with high-risk acute lymphoblastic leukemia may also benefit from intensified continuation therapy that includes the rotational use of drug pairs.
  • Improvements in relapse-free survival gained by intensification with anthracyclines or epipodophyllotoxins must be weighed against the late sequelae of these agents, which include cardiotoxicity and treatment-related acute myeloid leukemia.
• CNS disease
  • CNS disease is divided into the following:
    • CNS 1 - Absence of blasts on cytospin preparation of cerebrospinal fluid (CSF), regardless of the number of WBCs
    • CNS 2 - WBC count of less than 5/mL and blasts on cytospin findings, or WBC count of more than 5/mL but negative Steinherz-Bleyer algorithm findings (used to assess traumatic taps)
    • CNS 3 - WBC count of 5/mL or more and blasts on cytospin findings and/or clinical signs of CNS leukemia such as facial nerve palsy, brain/eye involvement, and hypothalamic syndrome (Additional intrathecal therapy is only given for CNS 3 disease.)
  • If the patient has blasts in the peripheral blood and the lumbar puncture is traumatic (containing >5/mL WBCs and blasts), CNS disease (CNS 3) is present if CSF WBC count divided by the CSF RBC count is more than 2 times blood WBC count divided by the blood RBC count.
  • Treatment of subclinical CNS leukemia is an essential component of acute lymphoblastic leukemia therapy.
  • Although cranial irradiation effectively prevents overt CNS relapse, concern about subsequent neurotoxicity and brain tumors has led many investigators to replace irradiation with intensive intrathecal and systemic chemotherapy for most patients. This strategy has produced excellent survival outcomes, with CNS relapse rates of less than 2% in some studies.
  • Whether cranial irradiation is necessary for patients with very high-risk acute lymphoblastic leukemia (patients with BCR-ABL or MLL gene rearrangements) is unclear.
  • Pui et al conducted a clinical trial in children with newly diagnosed acute lymphoblastic leukemia to determine if prophylactic cranial irradiation can be safely omitted from treatment to avoid irradiation consequences with effective risk-adjusted chemotherapy.³
    • The duration of continuous complete remission in 71 of 498 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received irradiation. The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04).
    • Certain populations were significantly associated with poorer event-free survival (ie, CNS leukemia or traumatic lumbar puncture with blast cells at diagnosis, high level of minimal residual disease after 6 wk of remission induction).
    • Risk factors for CNS relapse include genetic abnormality, CNS involvement at diagnosis, and T-cell immunophenotype.
    • The researchers concluded that prophylactic cranial irradiation can be safely omitted in many children with acute lymphoblastic leukemia.
• High-risk patients
  • Optimal treatment for patients with very high-risk acute lymphoblastic leukemia has not been found.
  • Some centers recommend allogeneic stem-cell transplantation (SCT) soon after first remission is achieved. For patients without a matched family donor, transplantation of marrow from an unrelated donor is a reasonable treatment option. Results of SCT, often reported from single institutions, have been inconsistent and sometimes disappointing. Large, multi-institutional, controlled trials are clearly needed to determine the effectiveness of this therapy for patients without a matched donor.
• Treatment of relapse: In general, relapsed acute lymphoblastic leukemia cells acquire resistance to exposed chemotherapy drugs. Therefore, treatment of relapse is intensive and often includes SCT. However, the outcome of relapse is poor.
• Molecular targeted therapy
  • A drug targeted at the underlying molecular defect that is unique to certain leukemias can have potent and specific antileukemic activity while producing minimal toxicity to normal cells.
  • The best example of molecular targeted therapy is imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor.
    • Imatinib has demonstrated significant anti-leukemic activity and is now a standard front-line treatment for Ph-positive chronic myeloid leukemia (CML).^4,5,2,6
    • Imatinib has shown efficacy in Ph-positive acute lymphoblastic leukemia, and combination regimens with imatinib and conventional chemotherapy or SCT have been evaluated in clinical trials.
    • Because the poor prognosis of Ph-positive acute lymphoblastic leukemia has been related to a slow response to induction therapy, imatinib has been added during early treatment phases to improve therapeutic response. Adult data in Ph-positive acute lymphoblastic leukemia has demonstrated excellent results using this approach.
    • Imatinib has been shown to be safe and efficacious in children with advanced Ph-positive acute lymphoblastic leukemia, raising the possibility of incorporating its use into front-line therapy prior to SCT. Although some evidence suggests this approach could improve overall outcome, the low incidence of childhood Ph-positive acute lymphoblastic leukemia (2-4% of childhood acute lymphoblastic leukemia cases) makes evaluating its efficacy in a randomized trial difficult.
• Genetic studies and future challenges
  • More than 80% of children with acute lymphoblastic leukemia now can be cured. However, the cause of treatment failure in the remaining 20% of patients is largely unknown.
  • Because of the diverse nature of the disease, use of risk-directed therapy for all patients on the basis of molecular and pharmacogenetic characterization of the leukemic cells at the time of diagnosis is favored.
  • Studies using microarray gene expression analysis, improved multiparameter flow-cytometric analysis, quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), genomics, proteomics and sophisticated bioinformatics hold promise for providing important clues to the mechanisms behind leukemogenesis and response and resistance to current therapies. Future goals include the use of these technologies to identify additional biologic subsets of acute lymphoblastic leukemia that require specifically targeted therapies.

Surgical Care

Surgical care is generally not required in the treatment of acute lymphoblastic leukemia, except for the placement of a central venous catheter. Such catheters are used for administering chemotherapy, blood products, and antibiotics, and for obtaining blood samples.

Consultations

Numerous consultations should be obtained, depending on the clinical circumstances of patients with newly diagnosed acute lymphoblastic leukemia.

• Pediatric oncologist: Refer all patients to a subspecialist to direct their care.
• Pediatric surgeon: Patients require placement of a central venous catheter.
• Psychosocial team: Involve psychologists and social workers in the care of patients with acute lymphoblastic leukemia to aid them and their families in navigating all of the difficult issues surrounding their care.
• Radiation oncologist: Depending on their risk group, some patients require craniospinal radiation as part of the treatment plan.
• Other subspecialists: Consultations with other specialists (ie, infectious disease specialist, nephrologist) may be appropriate, depending on the clinical circumstances.

Diet

Because of the use of MTX, avoid folate supplementation.

Medication

Drugs commonly used during remission induction therapy include dexamethasone or prednisone, vincristine, asparaginase, and daunorubicin. Consolidation therapy often includes methotrexate (MTX) and 6-mercaptopurine (6-MP). Drugs used for intensification or continuation include cytarabine, cyclophosphamide, etoposide, dexamethasone, asparaginase, doxorubicin, MTX, 6-MP, and vincristine. Intrathecal chemotherapy includes MTX, hydrocortisone, and cytarabine.

Antineoplastics agents

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then finally a mitotic cell division (ie, phase M).

Cell-division rates vary for different tumors. Most common cancers grow slowly compared with normal tissues, and the rate may be decreased in large tumors. This difference allows normal cells to recover from chemotherapy more quickly than malignant ones and is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are specific to phases of the cell cycle, whereas others (ie, alkylating agents, anthracyclines, cisplatin) are not. Cellular apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic agents.

Prednisone (Deltasone)

Corticosteroid. Important chemotherapeutic agent in treatment of ALL. Used in induction and reinduction therapy. Also given as intermittent pulses during continuation therapy.

Dexamethasone (Decadron, Dexone)

Corticosteroid. Important chemotherapeutic agent in treatment of ALL. Used in induction and reinduction therapy. Also given as intermittent pulses during continuation therapy.

Vincristine (Oncovin, Vincasar)

Chemotherapeutic agent derived from periwinkle plant. Inhibits microtubule formation in mitotic spindle, causing metaphase arrest.

Asparaginase (Elspar, Kidrolase)

Extracts of Escherichia coli or Erwinia L-asparaginase impair asparagine synthesis. Lethal to cells that cannot synthesize essential amino acid asparagine.

Daunorubicin (Cerubidine)

Anthracycline that intercalates with DNA and interferes with DNA synthesis.

Methotrexate (Folex PFS, MTX)

Folate analog that competitively inhibits dihydrofolate reductase, inhibiting DNA, RNA, and protein synthesis.

Mercaptopurine (Purinethol, 6-MP)

Synthetic purine analog that kills cells by incorporating into DNA as false base.

Cytarabine (Cytosar-U)

Synthetic analog of nucleoside deoxycytidine. Undergoes phosphorylation to arabinofuranosyl-cytarabine-triphosphate (ara-CTP), competitive inhibitor of DNA polymerase.

Etoposide (Toposar, VePesid)

Inhibits topoisomerase II and breaks DNA strands, causing cell proliferation to arrest in late S or early G2 portion of cell cycle.

Cyclophosphamide (Cytoxan)

Chemically related to nitrogen mustards. 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.

Nelarabine (Arranon)

Prodrug of deoxyguanosine analog 9-beta-D-arabinofuranosylguanine (ara-G). Converted to active 5'-triphosphate, arabinofuranosyl-guanine-5'-triphosphate (ara-GTP), T-cell–selective nucleoside analog. Leukemic blast cells accumulate ara-GTP. This allows for incorporation into DNA, leading to inhibition of DNA synthesis and cell death.
Approved by US Food and Drug Administration [FDA] as orphan drug to treat T-cell lymphoblastic lymphoma (type of non-Hodgkin lymphoma [NHL]) that does not respond or that relapsing with at least 2 chemotherapy regimens.

Clofarabine (Clolar)

Purine nucleoside antimetabolite that inhibits DNA synthesis. Pools of cellular deoxynucleotide triphosphate decreased by inhibiting ribonucleotide reductase and terminating DNA chain elongation and repair. Also disrupts mitochondrial membrane integrity. Indicated for relapsed or refractory ALL in pediatric patients.

Prophylactic antimicrobials

These drugs are given to prevent infection in patients receiving chemotherapy.

Sulfamethoxazole and trimethoprim (Cotrim, Septra, Bactrim, SMZ/TMP)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. All immunocompromised patients should be treated with cotrimoxazole to prevent Pneumocystis carinii pneumonia (PCP).

Nystatin (Nilstat)

Used to prevent fungal infections in mucositis. Fungicidal and fungistatic antibiotic from Streptomyces noursei; effective against various yeasts and yeastlike fungi. Changes permeability of fungal cell membrane after binding to cell membrane sterols, causing cellular contents to leak.
Treatment should continue until 48 h after symptoms disappear. Not substantially absorbed from GI tract.

Clotrimazole troches (Mycelex)

May be used instead of nystatin to prevent fungal infections. Broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing death of fungal cells.

Itraconazole (Sporanox)

Used to prevent fungal infections in high-risk patients. Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP-dependent synthesis of ergosterol, vital component of fungal cell membranes. Bioavailability greater for PO solution than for cap.

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