Pharmacological Agents in Leukemia Treatment

Pharmacological Agents Used to Treat Leukemia

• Imatinib is a tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML). It inhibits the BCR-ABL tyrosine kinase, which is consistently active in many cancers.
• Imatinib induces remissions in over 90% of CML patients in the chronic phase.
• Other tyrosine kinase inhibitors like dasatinib or nilotinib are used when imatinib fails or is resistant.
• Tyrosine kinase inhibitors work by preventing the enzyme from binding to substrates or phosphate donors.
• Resistance to these inhibitors can arise from mutations that prevent drug binding.
• Imatinib is administered orally at doses between 250-750mg per day. Food does not impede absorption.
• Imatinib's half-life is 18-40 hours.
• CYP3A4 metabolizes imatinib. Other drugs that inhibit CYP3A4 increase imatinib concentration. Inducers of CYP3A4 (like rifampicin) lower plasma imatinib concentration.
• Common adverse drug reactions include myelosuppression (low blood cell count), gastrointestinal distress (diarrhea, nausea, vomiting), liver toxicity, and rash.
• Fluid retention (edema), pleural effusions, and congestive heart failure are also possible side effects.

Alkylating Agents

• Cyclophosphamide is a prodrug that is converted to an active nitrogen mustard in the liver.
• It causes alkylation of DNA, leading to covalent cross-linking between DNA strands, preventing DNA replication.
• Cyclophosphamide is used in the treatment of chronic lymphocytic leukemia (CLL).
• Adverse drug reactions include myelosuppression (low blood cell count), hemorrhagic cystitis, and cardiotoxicity (at high doses). Mesna and increased fluid intake are used to manage hemorrhagic cystitis.

Antimetabolites

• Methotrexate is a folic acid analog that inhibits dihydrofolate reductase, decreasing tetrahydrofolate, an essential coenzyme in DNA synthesis.
• This reduces the synthesis of DNA, eventually causing cell death.
• Methotrexate is used in the treatment of acute lymphoblastic leukemia.
• Common adverse effects include myelosuppression, renal failure, pneumonitis, and mucositis. Leucovorin rescue therapy can help prevent severe toxicities when used with high doses of methotrexate.
• Long-term use of low doses of methotrexate in rheumatoid arthritis can cause severe liver toxicity

Plant Products

• Vincristine is used in acute leukemia, childhood leukemia, and lymphomas.
• It acts during mitosis by binding to beta-tubulin, interfering with microtubule formation, and thus stopping cell division.
• Adverse reactions include neurological toxicity, constipation, and myelosuppression among other effects.
• Doxorubicin, Daunorubicin, and Idarubicin are cytotoxic antibiotics used in acute leukemia.
• These intercalate with DNA, generating free radicals and preventing DNA replication, or preventing re-ligation of DNA strands.
• These cause cardiotoxicity.

Other Drugs

• Fludarabine is used in combination therapy with cyclophosphamide/rituximab as a first or second-line treatment for B-cell chronic lymphocytic leukemia. It inhibits DNA polymerase, DNA primase, and DNA ligase, incorporated into DNA and RNA.
• Mercaptopurine is used in combination therapy with methotrexate to treat acute leukemia, especially acute lymphoblastic leukemia. It is an analogue of the natural purine, hypoxanthine.
• Cytarabine (Ara-C) is used to treat acute myeloid leukemia, acute promyelocytic leukemia, and high-grade lymphoma. It is an analog of 2' deoxycytidine. Active form is incorporated into DNA and interferes with base pairing, inducing apoptosis.
• Venetoclax is a drug that targets Bcl-2, an anti-apoptotic protein, which is overexpressed in some leukemias, notably CLL. In normal cells, Bcl-2 prevents intrinsic apoptosis. Venetoclax binds to and inhibits Bcl-2, stimulating apoptosis in cells that overexpress Bcl-2.
• Ibrutinib inhibits Bruton's tyrosine kinase (BTK). BTK is involved in B-cell activation pathway, stimulating the PIP3-PKC pathway in B-cell leukemia, and contributes to anti-apoptotic signaling, (NF-KB). Ibrutinib inhibits growth factor signaling, thereby inhibiting cell division and decreasing anti-apoptosis signaling.
• Midostaurin is a small molecule tyrosine kinase inhibitor used in AML, which is positive for FLT-3
• Additionally, there are monoclonal antibodies like Rituximab (targets CD20) and Obinutuzumab (targets CD20).