2023 Leukaemia Treatment Self-Study PDF

Introduction to the pharmacological agents used to treat leukaemia. Dr. L Harmse. 2023 General note: This LT only deals with the drugs used in the various leukaemias and not with the specific treatment of each type. You can find more information on the specific treatment of each type of leukaemia i...

Introduction to the pharmacological agents used to treat leukaemia. Dr. L Harmse. 2023 General note: This LT only deals with the drugs used in the various leukaemias and not with the specific treatment of each type. You can find more information on the specific treatment of each type of leukaemia in De Piro’s Pharmacotherapy - a pathophysiologic approach, 12th edition chapter 157 (Acute Leukaemias) and chapter 158 (Chronic Leukaemias). This is available under Access Pharmacy at the WHS Library. Please note that there are several drugs/antibodies discussed that are not currently available in South Africa. I can highly recommend that you listen to the You-tube videos associated with these chapters. Only the content of your lecture and this learning topic is examinable. 1. Tyrosine kinase inhibitors Imatinib, dasatinib, nilotinib Imatinib is the most commonly used agent in the treatment of CML. It inhibits the BCR-ABL tyrosine kinase which is constitutively (continuously) active. Kinases are frequently overexpressed and/or overactive in many cancers. Imatinib induces remissions in more than 90% of CML patients in the chronic phase of the disease. Imatinib is also effective in other tumours that have related tyrosine kinase mutations: eg. Gastro intestinal stromal tumours (cKIT) and cancers that are driven by the platelet-derived growth factor receptor. Dasatinib or nilotinib is used in cases of imatinib failure or resistance. Mechanism of action (MOA) The inhibitors work by locking BCR-ABL kinase into an inactive state which prevents binding of the enzyme to it substrate or phosphate donor. Resistance to the inhibitors arise from point mutations that prevent binding of the drug to the enzyme. A small portion of Philadelphia chromosome positive patients with acute lymphoblastic leukaemia or CML in blast crisis are resistant to tyrosine kinase inhibitors prior to initiation of therapy. Kinetics Oral formulation. Maximal enzyme inhibition occurs at doses between 250-750 mg per day. Anti- acids reduce absorption. Food does not interfere. Elimination halflife: 18 and 40 hours for imatinib and its active derivative N-desmethyl imatinib. Metabolized by CYP3A4. NB! Other drugs that inhibit CYP4A4 increase imatinib concentration by 40%. Inducers of CYP3A4 like rifampicin lowers plasma concentration by 70%. Adverse drug reactions: Common: Myelosuppression, GIT distress ( diarrhoea, nausea, vomiting), Hepatotoxicity, rash. Fluid retention – causing oedema, pleural effusions, may progress to congestive heart failure. Nilotinib – prolong QT interval –caution patients cardiac arrhythmias 2. Alkylating agents 2.1 Cyclophosphamide Cyclophosphamide is a prodrug that is converted in the liver to an active nitrogen mustard that causes alkylation of DNA. This causes the covalent crosslinking between two separate DNA strands preventing the copying of the DNA. Indications: chronic lymphocytic leukaemia (CLL) Adverse drug reactions (ADRs): myelosuppressive, haemorrhagic cystitis caused by acrolein (a cyclophosphamide metabolite), cardiotoxic at high doses. Mesna and increased fluid intake (vigorous IV hydration) for management of haemorrhagic cystitis. 2.2 Busulfan Used in the palliative management advanced chronic myeloid leukaemia. Not used as treatment. Is important in the preparation for stem cell transplant since it is highly myelotoxic. ADR: severe myelosuppression, pulmonary fibrosis, GIT mucosal damage, hepatic veno-occlusive disease, CNS toxicities (convulsions) at high doses. 2.3 Bendamustine : Is an alkylating agent used in combination to treat CLL, non-Hodgkins to obtain remission of lymphoma, multiple myeloma. 2.4 Chlorambucil : oral alkylating agent used in maintenance therapy CLL, lymphoma 3. Antimetabolites Antimetabolites are molecules with a structure similar to normal metabolites involved in the cell cycle. Since they are structurally similar to normal metabolites, they interact and inhibit the function of critical enzymes in the cell cycle. The antimetabolite class of cancer drugs play a KEY role in the treatment of the various leukaemia’s. 2.1 Folic acid analogs Methotrexate Methotrexate resembles the structure of folic acid, it binds and inhibits the enzyme dihydrofolate reductase causing a shortage of tetrahydrofolate. Tetrahydrofolate is the active coenzyme of folic acid and is essential in many biosynthetic reactions, eg the synthesis of DNA bases. since it is able to bind and transfer a single carbon groups between various bio-molecules. It is essential for the de novo synthesis of adenine and guanine. It also inhibits the function of thymidylate synthase, preventing the conversion of dUMP to dTMP causing cells to become deficient in thymidine. Collectively this inhibits the synthesis of DNA and cause cell death. Methotrexate is used to treat many cancers including acute lymphoblastic leukaemia. Adverse drug reactions: Common: myelosuppression, renal failure, pneumonitis and mucositis. In cancer, it is used at high doses and is followed by leucovorin rescue therapy to prevent life threatening toxicities. Leucovorin is active folinic acid that has a single carbon group bound to it and it is ready to partake in biosynthetic reactions. If you treat a patient on high dose methotrexate with folic acid it would not be converted to the active co-enzyme form since DHFR is inhibited. Adverse effects: Chronic long-term administration at low doses in the treatment of rheumatoid arthritis causes severe hepatotoxicity.(Note in RA folic acid is used to decrease the adverse effects since the dose is very low) High dose administration: myelosuppressive, hepatotoxic, mucositis Kinetics: administration = oral or IV, 50% plasma protein binding, complex kinetics, polyglutamation of the molecule ( addition of multiple glutamic acid residues to the molecule) helps to retain the drug in cells. Renal excretion. 2.2 Purine analogs 2.2.1 Cladribine Indication: Treatment of hairy cell leukaemia and B-cell chronic lymphocytic leukaemia MOA: Adenosine purine analog, active form is cladribine triphosphate. Incorporated into DNA and causes DNA strand breaks, and depletion of NAD and ATP, leading to apoptosis of cancer cells. Kinetics: given IV, plasma T½ =7 hours, renal excretion, crosses BBB (25% of plasma concentration) Adverse drug reactions: serious  severe myelosuppression, cumulative thrombocytopenia, decrease CD4+ counts. Others: nausea, fever, headache, fatigue, skin rashes, tumour lysis syndrome 2.2.2 Fludarabine Indication: Combined with cyclophosphamide / rituximab as first line or as second line in treatment of B-cell chronic lymphocytic leukaemia. MOA: Phosphorylated intracellularly to triphosphate form, inhibits DNA polymerase, DNA primase, DNA ligase, ribonucleotide reductase, incorporated into DNA and RNA, effective DNA chain terminator. Special consideration: Antimicrobial prophylaxis with cotrimazole and valaciclovir is recommended to prevent development of opportunistic infections. Kinetics: IV and orally, plasma T½ = 10 hrs, renal excretion Adverse drug reactions: common: severe myelosuppression  deplete CD4+ T cells  opportunistic infections, nausea and vomiting. Uncommon: chills& fever, malaise, anorexia, peripheral neuropathy 2.2.3 Mercaptopurine Indication: Used in combination therapy with methotrexate for maintenance therapy for acute leukaemias, especially acute lymphoblastic leukaemia. MOA: Mercaptopurine is an analogue of the natural purine, hypoxanthine. The enzyme hypo- xanthine guanine phosphoribosyl transferase (HGPRT) transfers a phosphoribosyl group to mercaptopurine to form 6-thioinosine monophosphate (T-IMP). T-IMP accumulates in the cell and (i) inhibits the de novo synthesis of new inosine monophosphate (adenine and guanine precursor), (ii) prevents conversion of IMP to adenosine and guanosine monophosphate. Kinetics: IV administration, T½ = 50 min, rapid metabolism by xanthine oxidase, DI with xanthine oxidase inhibitors (used to manage tumour lysis syndrome)  reduce mercaptopurine dose by 75% Adverse drug reactions: slow onset myelodepression. Patients with thiopurine methyltransferase mutations at risk for bone marrow aplasia, test before use for TPMT polymorphism. Anorexia, nausea vomiting, Adults: jaundice and hepatic enzyme elevations, predisposed to opportunistic infections, prolonged therapy – induce secondary acute myeloid leukaemia 3.3 Pyrimidine analogues Cytarabine NNB! Indication: Most important agent for the induction of remission in acute myeloid leukaemia (AML), CML in blast phase, acute promyelocytic leukaemia, high grade lymphoma. MOA: Analog of 2’ deoxycytidine. Activated to the triphosphate form and competes with CTP for binding and incorporation into DNA. Interferes with base pairing in newly synthesised DNA. Incorporated Ara-CMP potently inhibit DNA polymerase and prevents elongation of the DNA strand. Stimulates apoptotic cell death. Kinetics: IV, plasma T½ = 10 min, rapid bolus infusions and/or continuous IV for 5-7 days. Intrathecal administration of liposomal AraC has sustained release in CSF. Adverse drug reactions: Potent myelosuppression, GI, stomatitis, conjunctivitis, hepatic enzyme elevations 4. Plant products 4.1 Vincristine Indication: Acute leukaemia, childhood leukaemia and lymphomas. MOA: Act specifically during mitosis. Binds specifically to β-tubulin and blocks polymerisation with α–tubulin preventing the formation of microtubules. Cells require the formation of microtubules to form the mitotic spindle. Cell division arrests in metaphase and cells enters apoptosis. Kinetics: IV only, hepatic metabolism metabolites excreted in the bile, dose reduction in hepatic failure, plasma T½= 20 hrs. Adverse drug reactions: Vincristine is tolerated better by children than adults who frequently experience severe neurological toxicity. Avoid extravasation. Sensory changes, severe constipation (follow prophylactic program). Mild myelosuppression. Contraindicated for intrathecal administration – fatal irreversible coma and death. 5. Cytotoxic antibiotics – anthracylines There are three drugs in this class used in the treatment of acute leukaemias: Doxorubicin, daunorubicin and idarubicin Mechanism of action (i) Intercalate with DNA - this causes distortion of the DNA backbone – RNA and DNA polymerase cannot bind – inhibit DNA replication and transcription. (ii) Form complex with topoisomerase II and DNA – prevents re-ligation of DNA strands. (iii) Generate free radicals that produce hydrogen peroxide and hydroxyl reactive groups  DNA oxidation (iv) Exposure of cells to anthracyclines cause apoptosis Cardiotoxicity These agents can cause irreversible acute cardiotoxicity which presents as arrhythmias and dose related cardiomyopathy. Patients must have adequate left ventricular function and must be closely monitored during and after treatment. This group of drugs are contraindicated in patients with pre-existing cardiac disease or hepatic and renal impairment. Of the three agents, idarubicin is the least cardiotoxic. The compound dexrazoxane, an iron chelator, protects against the cardiac toxicity which is caused by the free radical formation. Other ADRs: myelosuppression, photosensitivity, extravasation causes tissue necrosis, red colour urine, stomatitis, GI effects (N&V), alopecia and rash. Kinetics: doxorubicin and daunorubicin  IV route, idarubicin IV and oral, does not cross the blood brain barrier, hepatic metabolism, biliary excretion, variable plasma T½s 6. Monoclonal antibodies 6.1 Alemtuzumab is a humanized monoclonal antibody (IgG1). It binds to the CD52 protein found on normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages and a small population of granulocytes. Indications: B-cell chronic lymphocytic leukaemia not responsive to fludarabine and alkylating agents. Its expense limits it use. MOA: Bind CD52 on cell surface and deplete leukaemic and normal cells by direct antibody- dependent lysis. Adverse drug reactions: lymphopenia, and may also become anaemic and thrombocytopenic 6.2 Rituximab is a mouse chimeric antibody that binds to the CD20 receptor on B-cells causing the destruction of the B-cells by stimulating antibody dependent cellular cytotoxicity (NK cells macrophages), apoptosis, and the activation of the complement system. It is used in combination with cyclophosphamide and fludarabine in the initial treatment of CLL. Can be given subcutaneously. 6.3 Obinutuzumab is a new humanized monoclonal antibody targeting the CD20 receptor. Use in CLL, follicular lymphoma. Very expensive. 7. Asparaginase Asparaginase is an enzyme of bacterial origin, used to treat ALL. It hydrolyses circulating L- asparagine (amino acid) to aspartic acid and ammonia. ALL is deficient in the enzyme asparagine synthase causing an inhibition of protein synthesis. Normal cells are able to synthesize the amino acid. The main ADR is a hypersensitivity reaction to the enzyme since it is of bacterial origin. There is an increased risk of both clotting and bleeding since there are changes to various clotting factors. There is also a risk for pancreatitis, renal toxicity and mental depression. 8. Hydroxycarbamide (hydroxyurea) Indication: CML and other cancers, sickle cell disease and thalassemia MOA: Inhibits ribonucleotide reductase. This enzyme converts ribonucleotides to deoxy- ribonucleotides (change the ribose sugar of nucleotides to a deoxyribose sugar). The conversion of ribonucleotides to deoxyribonucleotides is a rate limiting step in the biosynthesis of DNA. Cells arrest near the G1 – S interphase which makes them more susceptible to radiation therapy. ADRs: MILD ADRs - myelosuppression, interstitial pneumonitis, cutaneous vasculitic ulceration (in patients cotreated with interferon). Kinetics: orally, plasma T½ = 3.5-4 hrs 9. Glucocorticosteroids As result of their ability to suppress mitosis and cause lysis of lymphocytes, glucocorticosteroids are used as cytotoxic agents in the treatment of acute leukaemia in children and lymphomas in children and adults. Their antitumour effects are mediated by cytoplasmic receptor binding and activation of apoptosis. Remissions occur more rapidly with glucocorticosteroids than with cytostatic agents but the duration of the remission is brief. Glucocorticosteroids are always used in combination with cytostatic agents and is a valuable component of therapy. Dexamethasone is used in conjunction with radiotherapy to reduce oedema in critical areas such as the superior mediastinum, brain and spinal cord. Please review your other lectures on the pharmacology of the glucocorticosteroids (Respiratory block). 10. Tretinoin Only indication is to induce remission in promyelocytic leukaemia (APL). Highly effective in treating APL.Tretinoin is a natural metabolite of retinol which is structurally related to vitamin A. It induces maturation of the pro-myelocytes and is highly effective in treating APL. Absolutely contraindicated in pregnancy Cause retinoic acid syndrome – impaired cardiac contraction, hypotension, hypoxaemia. 11. New drugs used for leukaemia: 11.1 Venetoclax Venetoclax is the first of a new class of cancer drugs. It binds to Bcl-2 an apoptotic inhibitor protein overexpressed in some leukaemias like CLL. Bcl-2 overexpression inhibits normal apoptosis to take place. Venetoclax inhibits this anti-apoptotic function. In normal cells the formation of Bax-Bax dimers or Bak-Bax dimers cause permeabilization of the mitochondrial outer membrane which leads to intrinsic apoptosis (via the release of cytochrome c and apoptosome formation). Bcl-2 prevents intrinsic apoptosis by binding to Bax, preventing Bax dimer formation and mitochondrial pore formation. Venetoclax mimics Bax and binds to Bcl-2 allowing apoptotic cell death. It is only effective is cancers that are overexpressing Bcl-2 – currently used in AML, CLL It is used in combination treatments as resistance is common. Unfortunately, its cost is currently limiting its use. Kinetics: given orally in tablet form. ADRs: has a high risk for tumour lysis syndrome Cost limits its use 11.2 Ibrutinib Inhibits Bruton’s tyrosine kinase in B cells. BTK is part of B-cell activation pathway and stimulates the PIP3 -PKC pathway in B-cell leukaemia. BTK inhibition decreases growth factor signalling and NF-ĸB signalling thereby inhibiting cell division and decreasing anti-apoptosis signalling. (The NF-ĸB pathway enhances the synthesis of anti-apoptotic proteins) Kinetics: oral, drug interactions are common – avoid CYP3A4 inducers or inhibitors – or adjust dose. CI pregnancy Adverse effects: numerous common ADRs :neutropenia, thrombocytopenia, pyrexia, bleeding , rash pneumonia, respiratory tract infections, tumour lysis syndrome. Serious: Atrial fibrillation, second primary malignancy eg. non-melanoma skin cancers 11.3 Midostaurin Small molecule multi-kinase inhibitor used in combination therapy in newly diagnosed AML patients positive for FLT-3 (FLT-3 is a tyrosine kinase). Adverse effects include leukopenia, nausea, mucositis, diarrhoea, musclo-skeletal pain. References: Available at the WHSL library under “Access Pharmacy” 1. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition Chapters 157 and 158 2. Brunton L, Chabner B, Knollman B; Goodman and Gillman’s: The Pharmacological Basis of Therapeutics 14th Edition, Chapters 69, 70, 71 and 72. 3. The South African Medicines Formulary. 14th edition Published by UCT. pp 392-416