Pediatric Acute Lymphoblastic Leukemia Medication
- Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP; Chief Editor: Jennifer Reikes Willert, MD more...
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) or cyclophosphamide and cytarabine. Drugs used for intensification include cytarabine, cyclophosphamide, etoposide, dexamethasone, asparaginase, doxorubicin, MTX, 6-MP, and vincristine. Continuation therapy is based on oral 6-MP and MTX with pulses of vincristine and glucocorticoid (prednisone or dexamethasone). Intrathecal chemotherapy includes primarily MTX, which may also be combined with hydrocortisone and cytarabine (“triple-intrathecal therapy”). Imatinib is also approved for children newly diagnosed with Ph+ ALL.[35, 14]
It is important to note that corticosteroids can adversely suppress the function of the hypothalamic-pituitary-adrenal (HPA) axis and such suppression can have adverse effects on a patient's ability to respond to different stresses, such as severe infection. A Cochrane Database review of 7 studies showed adrenal insufficiency occurred in nearly all ALL patients in the first days after cessation of glucocorticoid therapy. Although the majority of patients recovered within a few weeks, a small number of patients had adrenal insufficiency lasting up to 34 weeks.
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 act at specific phases of the cell cycle, whereas others (ie, alkylating agents, anthracyclines, cisplatin) are not phase-specific. Cellular apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic agents.
Vincristine is a chemotherapeutic agent derived from the periwinkle plant. This agent acts by inhibiting microtubule formation in mitotic spindles, causing metaphase arrest.
Extracts of Escherichia coli or Erwinia L-asparaginase impair asparagine synthesis. Asparaginase is lethal to lymphoblasts that cannot synthesize the essential amino acid asparagine.
Catalyzes deamidation of asparagine to aspartic acid and ammonia, thereby reducing circulating levels of asparagine. Lack of asparagine synthetase activity results in cytotoxicity specific for leukemic cells that depend on an exogenous source of the amino acid asparagine. Indicated as part of a multiagent chemotherapeutic regimen for patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E coli –derived asparaginase. It is estimated that 15-20% of patients with ALL develop a hypersensitivity to E coli –derived asparaginase, which extrapolates to approximately 450-600 children in the United States annually.
Daunorubicin is an anthracycline that intercalates with DNA and interferes with DNA synthesis.
Methotrexate is a folate analogue that competitively inhibits dihydrofolate reductase, thus inhibiting DNA, RNA, and protein synthesis.
Mercaptopurine is a synthetic purine analogue that kills cells by incorporating into DNA as a false base.
Cytarabine is a synthetic analogue of nucleoside deoxycytidine. This agent undergoes phosphorylation to arabinofuranosyl-cytarabine-triphosphate (ara-CTP), a competitive inhibitor of DNA polymerase.
Etoposide inhibits topoisomerase II and breaks DNA strands, causing cell proliferation to arrest in the late S or early G2 portion of the cell cycle.
Cyclophosphamide is chemically related to the nitrogen mustards. When this drug is used as an alkylating agent, the mechanism of action of its active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.
Nelarabine is a prodrug of 9-beta-D-arabinofuranosylguanine (ara-G). This agent is converted to the active arabinofuranosyl-guanine-5'-triphosphate (ara-GTP), a T-cell–selective nucleoside analogue. Leukemic blast cells accumulate ara-GTP, which allows for incorporation into DNA, leading to inhibition of DNA synthesis and cell death.
Nelarabine was approved by the US Food and Drug Administration [FDA] as an orphan drug to treat T-cell lymphoblastic lymphoma (a type of non-Hodgkin lymphoma [NHL]) that does not respond or that relapses with at least 2 chemotherapy regimens.
Clofarabine is a purine nucleoside antimetabolite that inhibits DNA synthesis and is indicated for relapsed or refractory acute lymphoblastic leukemia in pediatric patients. Pools of cellular deoxynucleotide triphosphate are decreased by inhibiting ribonucleotide reductase and terminating DNA chain elongation and repair. This agent also disrupts mitochondrial membrane integrity.
Imatinib is a selective BCR-ABL tyrosine kinase inhibitor. It is approved for children newly diagnosed with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body’s immune response to diverse stimuli. These agents are significantly toxic to lymphoblasts, and two thirds of patients with pediatric ALL who receive steroid therapy alone go into remission.
Prednisone is a corticosteroid and an important chemotherapeutic agent in the treatment of acute lymphoblastic leukemia (ALL). This agent is used in induction therapy and is also given as intermittent pulses during continuation therapy.
Dexamethasone is another corticosteroid that acts as an important chemotherapeutic agent in the treatment of ALL. Like prednisone, this agent is used in induction and reinduction therapy and is also given as intermittent pulses during continuation therapy.
Prophylactic antimicrobial drugs are given to prevent infection in patients receiving chemotherapy.
Sulfamethoxazole and trimethoprim inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. All immunocompromised patients can be given cotrimoxazole to prevent Pneumocystis carinii pneumonia (PCP).
Immunocompromised patients who do not tolerate cotrimoxazole due to myelosuppression may receive IV pentamidine to prevent Pneumocystis carinii pneumonia (PCP).
These agents may change the permeability of the fungal cell, resulting in a fungicidal effect.
Fluconazole may be used in patients at high risk (eg, infant ALL) to prevent fungal infections. It is a synthetic triazole that inhibits fungal cell growth by inhibiting CYP-dependent synthesis of ergosterol, a vital component of fungal cell membranes.
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