PRINCIPLES OF CHEMOTHERAPY IN HEMATOLOGY.pptx

This slide will give you highlight on principles of chemotherapy in hematology.

1. PRINCIPLES OF CHEMOTHERAPY IN HEMATOLOGY By Hizkiel A. R3 March 12, 2024

2. Knowledge of drug actions, clinical toxicities, pharmacokinetics, and interactions is essential for the safe and effective administration of chemotherapy. Chemotherapy often targets the process of DNA replication. More recently, drugs have been introduced to target specific cellular processes, including receptor signaling, inhibition of oncoproteins, angiogenesis. Dose modification may be needed for patients with renal or hepatic dysfunction depending on the major route of drug clearance. 2

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4. Alkylating agents Bendamustine Busulfan Chlorambucil Melphan Mitomycin Procarbazine Cyclophosphamide Dacarbazine Ifosfamide Mechlorethamine Nitrosoureas(BCNU, CCNU) Temozolomide Thiotepa 4

5. Pharmacology Covalently bind to alkylating group to cellular molecules including DNA, RNA and proteins. Forms reactive carbonyl groups in plasma and with in tissues. Primary mechanism of cytotoxicity is, attack at electron rich sites on adenine or guanine (SN1 agents) in DNA. Block DNA replication and transcription leading to cell death. They are cell cycle non specific. Compromise genome integrity, induce mutagenesis. 5

6. Multiple enzymes repairs the genomic damage caused by alkylating agents. Ex: -methyl transferase. Overexpression of this enzyme produce resistance to nitrosurea , but not nitrogen mustard or cyclophosphamide.   6

7. Toxicity Alkylating agents shares common mechanism of action, but different pharmacokinetics, membrane transport properties, lipid solubility and chemical reactivity. Don’t show cross resistance. Toxicities varies significantly. Marrow suppression occurs in all hematopoietic cell types. Pattern of suppression varies from drug to drug. Relative platelet and stem cell sparing in cyclophosphamide. 7

8. Busulfan damaging stem cells. Hematopoietic depression produced by nitrosoureas is delayed by 3-6 weeks. Alopecia commonly occurs by cyclophosphamide. Nausea and vomiting are frequent in high dose, but decrease in low dose oral regimens. Pulmonary fibrosis in all, particularly in Busulfan and nitrosoureas. Isofosfamide CNS toxicity. Busulfan and nitrosoureas also cause CNS toxicity in higher doses. 8

9. Cystitis with cyclophosphamide and ifosfamide . Mercaptoethane sulfonate (MESNA) for all patients receiving ifosfamide and high dose cyclophosphamide to prevent cystitis. Hepatic toxicity in high dose thiotepa, cyclophosphamide, busulfan or BCNU. Renal toxicity seen with nitrosourea and ifosfamide . High does cyclophosphamide cause water retention. All causes gonadal atrophy and permanent loss of reproductive function. All are teratogenic and carcinogenic. 9

10. Increased risk of 2 nd cancers with melphan , procarbazine and cyclophosphamide. 10

11. Antimetabolites Azathioprine Cladribine Clofarabine Cytarabine Fludarabine Thioguanine Gemcitabine Hydroxyurea 6-mercaptopurine Methotrexate-MTX Pentostatin . 11

12. Prevents synthesis of molecules required for DNA synthesis. Cell cycle specific agents. Must present during S-phase of cancer cell cycle for cytotoxicity. Either by incorporation in to RNA/DNA or inhibition of enzymes necessary for nucleic acid production. Schedule of drug administration very important with these agents. Many are prodrugs. 12

13. Methotrexate and pralatrexate Mechanism of action Methotrexate is analog of folic acid. Pralatrexate is tight binding inhibitor of dihydrofolate reductase.(enzyme required for converting folate to its active form tetrahydrofolate. Methotrexate depletes purine and thymidine formation by inhibition of formation of tetrahydrofolate this leads to inhibition of DNA synthesis and subsequent cell death. 13

14. Resistance to methotrexate is related to increased levels of target enzyme DHFR. Pralatrexate expresses reduced folate carrier (RFC-1) which typically overexpressed in cancer cells . Pralatrexate undergoes polyglutamylation by foly-polyglutamte synthase and competitively inhibits DHFR and thymidylate synthase. 14

15. Clinical pharmacology MTX can be given oral, IV, SC, IM and intrathecal. Standard dose 7.5-20mg/m2. Bioavailability decreasing at higher doses. Primarily eliminated through kidney. Should not be given with renal insufficiency. Leucovorin rescue if clearance delayed. Retention of drug in ascites or pleural effusion can cause toxicity. Praletrexate half life 12-18 hours, dose reduction recommended in impaired renal function. 15

16. Toxicity Myelosuppression and mucositis is primary toxicities. High dose MTX result in renal failure. Adequate prehydration , alkalinization of urine and measurement of MTX concentration in high dose therapy to prevent AKI. Close monitoring of renal function recommended. Avoid coadministration of nephrotoxic drugs. Glucarpidase used in treatment of toxic MTX Concentration in patient with delayed drug clearance. 16

17. Chronic MTX administration associated with liver disease manifested by portal fibrosis and occasional cases of cirrhosis. Pulmonary toxicity. CNS toxicity in high dose specially with cranial irradiation. Intrathecal MTX- arachnoiditis. 17

18. Pyrimidine analogs Cytosine arabinoside- ara -C and liposomal ara -C , Gemcitabine, 5-azacytidine, decitabine. MOA Ara-C mediated DNA damage then induces apoptosis. Metabolized in the liver by enzyme cytidine deaminase. Half life 2-3 hours. Adequate capacity for clearance even in hepatic impairment. S-phase specific. Prolonged infusion or multiple day administration required for cytotoxicity. 18

19. Toxicity Continuous infusion or repeated administration for 24-48 hours results myelosuppression in ara -c in high dose. Nausea, vomiting and diarrhea after Ara-c in high dose. High dose ara -c , 3mg/m2 Q6-12 hours for 6-12 doses is associated with cholestatic jaundice and increased transaminases. Cerebral and cerebellar dysfunction, 20% in high doses of ara -c. More common in patients older than age 50 years and in patients with renal insufficiency. 19

20. Symptoms: mild ataxia, somnolence or inability to walk with out assistance. Steroid responsive conjunctivitis after high dose ara -c leads to routine use of prophylactic saline or steroid eye drops to prevent this. 20

21. Hydroxyurea MOA Inhibits ribonucleotide reductase- enzyme responsible for conversion of ribonucleotide required for DNA synthesis and repair. Kills cell selectively in the S-phase. Dose of 0.5-2g/d results rapid decline in peripheral white blood counts 2-5 days. Routine use in patients with significantly elevated leukemic blast counts or those with elevated platelet count. 21

22. Clinical pharmacology Well absorbed orally 90-100% bioavailability. Excreted in urine. Half life 4 hours. Renal failure drug doses should be reduced. 22

23. Toxicity Primary toxicity is myelosuppression. Occurs 2-5 days. Generally not sever. Reversal rapid following discontinuation of drug. Nausea, vomiting, anorexia, diarrhea can be seen. Dermatologic side effects; eczema, hyperpigmentation, dermal ulceration, skin carcinoma. 23

24. Purine antimetabolites 6-MP Azathioprine Nelarabine Fludarabine Cladarabine Clofarabine Purine analogs used in treatment of hematologic malignacy . 24

25. Guanine analogs are; 6MP, 6-thioguanine, azathioprine, nelarabine. Adenine analogs; cladribine, clofarabine and fludarabine. Interferes with DNA synthesis lead to termination of DNA chain elongation and inhibit DNA repair mechanisms. MOA of guanine analogs 6MP used in remission maintenance therapy for ALL. 6 thioguanine 2 nd line Agent for AML. Azathioprine prodrug of 6MP used as immunosuppressant. All terminates DNA synthesis. 25

26. Clinical pharmacology of guanine nucleotides Oral absorption of 6MP is incomplete and highly variable. Low bioavailability 5-37%. Metabolized by xanthine oxidase in the liver. Concomitant use of xanthine oxidase inhibitor like allopurinol increases 6MP bioavailability 5x, increases toxicity. Undergoes 5- methylation by enzyme thiopurine methyl transferase to result less active 6 methyl mercaptopurine. Those with high TPMT results higher risk of relapse as result of rapid drug inactivation. Those with low TPMT results in advanced myelosuppression. 26

27. Nelarabine –for treatment of relapsed T-ALL and lymphocytic lymphoma . Water soluble prodrug of ara -G. Small amount cleared via kidney. Increased toxicity in patient with GFR <50ml/min. 27

28. Toxicity of guanine nucleotides Dose limiting toxicity is myelosuppression. Occurs 1-4 weeks after onset of therapy. Reversible when drug is discontinued. Immunity to infectious agents and vaccines are subnormal. GI mucositis and stomatitis is modest. Hepatotoxicity in 6MP is mild and reversible. Clinical picture of cholestatic jaundice. Elevations of transaminase may be seen. Frank hepatic necrosis and venooclusive disease-VOD can occur. 28

29. 6MP and azathioprine are potentially teratogenic. Drowsiness, seizure and peripheral neuropathy have been associated eith nelarabine use. 29

30. Mechanism of action of adenine nucleotide(fludarabine, cladribine, clofarabine) Fludarabine used to treat CLL and indolent refractory lymphomas. Results DNA deletions and mutations. DNA chain terminator. 30

31. Cladribine more cytotoxic to lymphocyte than fludarabine used to treat hairy cell leukemia. Clofarabine similar in structure to cladribine with addition of fluorine at the 2 carbon position of sugar moiety. Approved for treatment of refractory ALL and AML. 31

32. Clinical pharmacology of adenine nucleotide Fludarabine Excreted primarily in urine. In renal impairment clearance decreases. Oral bioavailability is excellent. Cladribine is cleared by kidney. Clofarabine 50% dose excreted unchanged in urine with in 24 hours. Half life is 7 hours. Dose reduction warranted in all 3 drugs with renal dysfunctions. 32

33. Toxicity of adenine nucleosides. Dose limiting toxicity of fludarabine is myelosuppression. Occurs median of 12-16 days. Cytopenia's may be prolonged. Nausea and vomiting in 36%. Fever in 60%. Infection in 33%. Peripheral sensorimotor neuropathy. Autoimmune hemolytic anemia- rare. 33

34. Hepatocellular toxicity with elevated transaminases. Mild reversible neurotoxicity at lower doses in older patients. Irreversible neurotoxicity syndrome in patients receiving high doses >40mg/m2/d for 5 days. Pulmonary toxicity characterized by Fever, cough, hypoxia and diffuse interstitial pneumonitis. Fludarabine is immunosuppressant and associated with increased risk of opportunistic infections. 34

35. Dose limiting toxicity of cladribine is myelosuppression. Grade 3 or 4 neutropenia in 50%. Fever in 2/3 of patients starting 5-7 days or during neutropenia. Cladribine suppresses CD4 lymphocytes. CD4/CD8 ratio may remain depressed up to 16 months. Associated opportunistic infections like candidiasis or aspergillus. Primary toxicity of clofarabine is myelosuppression leads to increased risk of infection. Mild nausea and vomiting. Pruritis and palmoplantar erythrodysthesia . Sever reversible hepatotoxicity in 15-40%. 35

36. Pentostatin Potent inhibitors of adenine deaminase. Active for treatment of chronic lymphoid malignancy particularly hairy cell leukemia. Inhibits DNA synthesis and impairs replication with arrest of cells in the G1 and S phase. 36

37. Clinical pharmacology Half life 3-15 hours. 40-80% of drug excreted unchanged in urine with in 24 hours. Dosage reduction should be considered for patient with renal impairment. Toxicity Therapy usually well tolerated at doses to treat hairy cell leukemia 4mg/m2 weekly 2x. Toxicity include worsening neutropenia, mild to moderate lethargy, anorexia, rash, reactivation of herpes zoster. Nausea and delayed emesis 37

38. Histone deacetylase inhibitors Vorinostat Romidepsin Penobinostat Belinostat Histone acetylase transferase (HAT)- are enzymes that acetylate histone molecules resulting in opening of the chromatin; thereby allowing transcription factors access to DNA promoter regions.s 38

39. Histone deacetylase (HDAC)- family of enzymes remove acetyl groups from histone proteins leading to condensation of DNA and inactivation gene transcription. Increase HDAC activity has been associated with a decrease in tumor suppressor or gene expression. Romidepsin , vorinostat and belinostat are approved for treatment of cutaneus T-cell lymphomas. 39

40. 5-Azacytidine and decitabine are methyl transferase inhibitors that block methylation in some cancers. Activates tumor suppressor gene. Approved for the treatment of MDS and AML Who are not candidates for remission induction treatment. MOA: inhibition of HDAC induces genes that cause apoptosis or differentiation. Also induce oxidative damage. Have anti angiogenic effects. Disrupts cell cycle check points. 40

41. Specific mechanism of antineoplastic activity remains uncertain. Vorinostat available as oral 100mg capsule. Given with food. Romidepsin and belinostat given IV. Both excreted in urine. Vorinostat has short half life , 2 hours. Decitabine and 5-azacytidine rapidly inactivated by hepatic metabolism. Half life 4 hour and 30 minutes. Continuous treatment over several days recommended. Dose adjustment for hepatic and renal insufficiency not studied. 41

42. Toxicity Most common toxicities include nausea, vomiting, diarrhea, thrombocytopenia, anemia and taste disorders. Dose limiting side effects are generally thrombocytopenia and dehydration. Pulmonary emboli in 4-5% receiving vorinostat . QT prolongation. Primary toxicity of decitabine and azacytidine is myelosuppression. GI toxicities including nausea, vomiting and constipation are seen usually transient in nature 1-4 days. Improve over time. 42

43. Microtubular agents Two general classes Vincas and taxanes . Vinca alkaloids block microtubular formation. Taxanes (docetaxel, Ixabepilone and pacitaxel ) Stablizes microtubulin bundles leading to their dysfunction. Taxanes not used in hematology. 43

44. Vinca alkaloids (vinblastine, vincristine and vinorelbine). Binds to tubulin and prevents the formation of micro tubulin apoprotein that is essential for maintenance of cellular shape and for formation of the mitotic spindle. Cells arrested in metaphase. Initiation of apoptosis during M-phase of the cell cycle. All are metabolized by liver via hepatic cytochrome P-450 CYP3A4. Excreted in bile. 44

45. Drugs that block CYP3A4 results in toxicities. Dose should be reduced in hepatic dysfunction. Liposomal vincristine has longer half life. Approved for IV use in relapsed Ph- ALL. 45

46. Toxicity Vincristine causes little myelosuppression. Dose limiting and most frequent toxicity is neurotoxicity manifested by asymmetric, distal, sensory motor neuropathy. Loss of DTR in lower extremities . Paresthesia's of the finger and toes common early findings. Neuropathies of motor cranial nerves. Continued use results further motor neuropathy which may be partially reversible when the drug is stopped. Other effects such as constipation, cramps and paralytic ileus. 46

47. Dose limiting toxicity of vinblastine is thrombocytopenia and leukopenia. Onset of myelosuppression tends to occur earlier with this agent than other antineoplastic s. Leukocyte nadir typically seen by day 4-7 and recovery by day 10-14. Sever neurotoxic symptoms are unusual with vinblastine. Associated with myalgias and autonomic neuropathy manifested by orthostatic hypotension. Dose limiting toxicity of vinblastine is myelosuppression. 47

48. Less neurotoxic than vincristine. Injection site reaction of erythema, pain and vein discoloration occur in one third of patients. Sever vein toxicity in 2%. All vincas are potent vesicants. Sever local tissue damage associated with extravasation of these drugs in soft tissues. Should never be administered intrathecally. 48

49. Monoclonal antibodies Rituximab, ofatumumab, and Obinutuzumab. Bind to protein CD20 expressed in human B-lymphocyte surface. CD20 is expressed in all B-cell malignancies except myeloma and majority ALL. Several mechanism of cytotoxicity. Antibody half life ranges from 30-400 hours for rituximab. 7 days for ofatumumab 28 days for obinutuzumab . 49

50. Obinutuzumab approved for use in CLL and follicular lymphoma. Obinutuzumab has superior efficacy compared to rituximab. 50

51. Toxicity Sever toxicity rare. Infusion reactions results mild nausea, chills, rigors, tachycardia, fever and skin rash with in 1-3 hours. Slow infusion to reduce those reactions on 1 st time infusions. Serious infusion reactions like bronchospasm, hypotension, acute respiratory distress syndrome and shock in <1%. Decrease in subsequent infusions. Grade 3-4 neutropenia in 2-6%. Anemia in 1-3%. Thrombocytopenia in 1-2%. 51

52. B-cell lymphocytes reduced for 6 months. Increased risk for sinusitis and pneumonia. Late onset neutropenia 40-350 days in 3-7%. Tumor lysis in large tumor burden. Reactivation of hepatitis B and ILD have been reported. PML is black box warning.. 52

53. Alemtuzumab Monoclonal antibody directed against CD52. Administered as slow infusion or SC. Reactions common. Sever local reactions in SC injection. Results in myelosuppression and long term immunosuppression. Near universal lymphocytopenia. High risk of opportunistic infection. Risk of opportunistic infections. 53

54. Brentuximab Monoclonal antibody against CD30. Should be avoided in renal impairment CrCl <30ml/min. Toxicity Infusion reaction in 10%. Occasional anaphylaxis. Peripheral neuropathy improves with drug discontinuation 20-50%. Fatigue, fever, nausea and diarrhea and neutropenia. High incidence of pulmonary toxicity when combined with bleomycin. 54

55. Daratumumab Approved for previously treated multiple myeloma. Anti CD38. Not studied in patient with hepatic and renal impairment. Toxicity Infusion reaction >20%. Fatigue, nausea, back pain, pyrexia, cough, upper respiratory tract infection. Median time for infusion reaction is 1.5 hours. 55

56. Elbtuzumab Indicated combination with lenalidomide and dexamethasone for MM. Most frequent reaction is pneumonia, pyrexia, respiratory tract infection, anemia, PE and acute renal failure. Elevations in liver enzyme constant with hepatotoxicity. Infusion reactions in 10%. 56

57. Balinatumumab Indicated for relapsed or refractory B-cell ALL, including for minimal residual disease(MRD) positivity in ALL. Doesn’t require dose adjustment for renal and hepatic impairment. Toxicity Pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia and constipation in 20%. Black box warning for cytokine release syndrome(CRS) and neurological toxicities. 57

58. Neurotoxicity in 50%. Median time of onset is 7 days. 58

59. Gemtuzumab ozagamicin Monoclonal antibody to the CD33 antigen. Approved for use in newly diagnosed or relapsed AML. Toxicity Infusion related reactions. Profound neutropenia and thrombocytopenia occurred in 98%. Hyperbilirubinemia in 29%. 59

60. Inotuzumab ozogamicin Humanized anti CD22. Approved for treatment of relapsed or refractory B-cell ALL. Common toxicities include nausea, headache, neutropenia and thrombocytopenia. Hepatotoxicity . Liver function should be monitored during therapy. 60

61. Programmed death receptor -1 Nirolumab , pembrolizumab. Indicated for treatment of multiple solid tumors and ALL. Humanized monoclonal antibodies that block the programmed death receptor-1 (PD-1). Mean elimination time is 24 days. Doesn’t require dose adjustment for renal and hepatic impairment. 61

62. Toxicity Cough, fatigue, nausea, pruritis, decreased appetite and constipation. Arthralgia and diarrhea. Pneumonitis, colitis and hepatitis require therapy interruptions. Colitis and pneumonitis 3.5 months after therapy begins and stay for 1 month. Onset of hepatitis 1.5 month duration 2month. 62

63. Molecular targeted therapies Retinoids All trans retinoic acid/tretinoin(ATRA). Binds to one or more nuclear receptors or decrease proliferation and induces differentiation of APL. Metabolized by hepatic P450 microsomal enzyme system. Toxicity Many patients tolerates. Syndrome characterized by Unexplained fever, leukocytosis, dyspnea with interstitial pulmonary infiltrates, peripheral edema, pleuropericardial effusion, hypotension and ARF in 20-25%. 63

64. Patinets with four of those symptoms have sever differentiation syndrome called retinoic acid syndrome. Those with 3 have intermediate syndrome. Occurs more frequently in patients with elevated WBC or renal insufficiency. Treated with steroids. Pseudotumor cerebri, hyperlipidemia and abnormal liver function tests have been observed. Headache, xeroderma, rash and dry mucous membrane. Significant teratogenic. 64

65. Arsenic Trioxide Used for the treatment of APL Half life 17 hours. Distributes through out the body. No dosage guideline for patients with hepatic and renal insufficiency. Toxicity Most common side effects nausea, rash, fatigue, fever, headache, diarrhea and mild hepatotoxicity. Life threatening toxicities include hypokalemia 13%, hyperglycemia 10% , the APL differentiation syndrome and cardiotoxicity, QT prolongation. Myelosuppression is low 65

66. Bexcaroten Approved for therapy of cutaneous T-cell lymphoma. Available as topical gel or as oral capsule. Half life 4-7 hours. Toxicity Most common is hyperlipidemia 82%. Hypercholesterolemia 30% Central hypothyroidism 29%. Headache 20%. Asthenia 16%. 66

67. Pruritis 13%. Leukopenia 11%. Side effects common at higher doses ; pancreatitis, result from hyperlipidemia. Use lipid lowering agent and thyroid replacement often required. 67

68. Signal transduction inhibitors Inhibit a tyrosine kinase associated with signal transduction molecules activated in cancer cells. Imatinib mesylate Inhibits the tyrosine kinase of BCR-ABL, KIT and PDGF. Given orally at doses 400-800mg/d. Bioavailability 98%. Half life 18 hours Cleared by P-450. Drugs that alter CYP3A4 has potential to alter clearance of all BCR-ABL TKI. 68

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70. Toxicity Mild nausea 70%, diarrhea 56% and fluid retention are common. Edema managed by diuretics or dose reduction. Hematologic toxicity is mild associated with advanced stage- CML blast crisis. Abnormal LFT. 70

71. Dasatinib It can bind both active and inactive ABL kinase domains . Inhibit BCR-ABL mutations resistant to imatinib. Also inhibit SCR kinase 100-300x more potent than imatinib. Given orally 100-400mg/d. Metabolized in the liver by CYP3A4 . H2 blocker and PPI should not used. 71

72. Toxicity Fluid retention, nausea, vomiting and diarrhea. Pleural effusions in 8%. Myelosuppression is common 50% grade 3 or 4. Thrombocytopenia 35-80%, grade 3 or 4. QT prolongation. Correct hypokalemia and hypomagnesemia. 72

73. Nilotinib 30x more potent than imatinib. Inhibits KIT and PDGF. Neither nilotinib nor dasatinib is effective against T3151 mutants. Given orally dose 300-400mg bid. Half life 15-17 hours. Metabolism mainly hepatic. 73

74. Toxicity Mild skin rash 22%, fatigue 16%, nausea 13%, pruritis 9%. Peripheral edema and pleural effusions seldom occurs. Grade 3 or 4 thrombocytopenia 25% and neutropenia 9%, elevated transaminase 6%, QT prolongation. 74

75. Bosutinib Kinase inhibitor of both ABL and SRC. Doesn’t target KIT orPDGFR Doesn’t act on T315I or V299L mutation. Given orally at dose of 400mg/d with food. For newly diagnosed chronic phase CML and 500mg for others. Diarrhea 70% is most frequent side effects. 75

76. Ponatinib Multi target kinase inhibitors of ABL and members of PDGFR, FGFR and VEFGF. The only BCR-ABL inhibitor that is effective against T315I mutations. Vascular complications including arterial and venous thrombosis in 27%. Initial recommended dose 45mg po/d with or with out food. Aspirin for those with preexisting CVS risk factor or heart failure. Metabolism primarily hepatic through CYP3A4. Hepatotoxicity including liver failure and death. Monitor LFT . Common toxicities include myelosuppression rash and headache. 76

77. Ibrutinib Inhibits bruton tyrosine kinase- BTK. Decreases malignant B-cell proliferation and survival. Metabolism primary hepatic CYP3A4. Common toxicities include diarrhea, nausea and fatigue and peripheral edema. Treatment related thrombocytopenia and Atrial fibrillation. Given at doses 420mg/d po for CLL or wandestrom macroglobulinemia, higher dose 560mg for relapsed marginal zone lymphoma or mantle cell lymphoma. Acalabrutinib is 2 nd generation BTK approved for relapsed mantle cell lymphoma or other B-cell neoplasma . 77

78. Idelalisib Phosphoinositide 3-kinase inhibitors. Used in treatment of CLL with combination of rituximab. For relapsed follicular lymphoma. Dose 150mg bid. Undergoes hepatic metabolism. Commonly described toxicities include diarrhea, nausea, fever and cough. Less common but sever toxicities includes serious hepatotoxicity, colitis, pneumonitis and intestinal perforations. 78

79. Midostaum Multi target TKI with activity activity against FLT3, and KIT. Approved for use in AML at doses of 50mg bid. 100mg po bid for systemic mastocytosis or mast cell leukemia. Cytopenia in AML treated common. Diarrhea, nausea, elevated liver functions, hypokalemia, hyponatremia and hypocalcemia in <20% manageable. 79

80. Proteasome inhibitors Bortezomib, carfilzomib and Ixazomib . Bortezomib and Ixazomib reversibly inhibit proteosome. Carfilzomib inhibit irreversibly. Metabolized in liver. Dose adjustment not needed in renal insufficiency. Toxicity Most frequent is herpes zoster reactivation, myelosuppression (neutropenia/thrombocytopenia) and peripheral neuropathy. Peripheral neuropathy of bortezomib sensory neuropathy affecting hands and feet in stocking and glove distribution and is painfull . 80

81. Incidence is higher in bortezomib than carfilzomib. Reversible in most cases. Resolves 5-6 months latter after discontinuation. Incidence reduced by less frequent dosing like weekly Vs twice/week and SC administration. Patients should be simultaneously on antiviral prophylaxis for prevention of herpes zoster reactivation. Not associated with secondary malignancies. 81

82. Topoisomerase II inhibitors Doxorubicin, daunorubin , Idrarubicin , mitoxantrone and etoposide Topoisomerase enzymes are needed for DNA replication chromosome condensation and chromosome segregation. Anthracyclines (doxorubicin, daunorubicin and idrabicin ) Clearance is through hepatic metabolism and biliary excretion. Urinary excretion account 10%. Dose reduction recommended for jaundiced patients. Less cardiotoxicity with liposomal doxorubicin. Liposomal combination daunorubicin and cytarabine in fixed ratio 1:5 have been approved for use in treatment related AML with myelodysplasia related changes. 82

83. Toxicity Acute dose limiting toxicity is myelosuppression. Nadir leukocyte count expected around 10-14 day. Full recovery 21-28 days. Other acute systemic toxicities include nausea, vomiting, alopecia and mucositis. Local tissue reaction with extravasation. The most serious is cardiotoxicity. Dose dependent congestive cardiomyopathy. Leads to congestive heart failure 83

84. Dose dependent congestive cardiomyopathy leads to congestive heart failure. Late onset cardiomyopathy appears months to years after treatment is completed. With dose <350mg/m2, HF is seen in <5%. Continuous infusion reduce the risk of HF. 84

85. Mitoxantrone Better antineoplastic activity and less toxicity than doxorubicin. Hepatic metabolism is primary clearance and 6-11% by kidney. Toxicity Dose limiting toxicity, myelosuppression. Other potential toxicities, nausea, vomiting, alopecia and cardiotoxicity. 85

86. Epipodophylotoxins -Etoposide Excreted via urine and liver. Clearance modestly decreases with in patients with renal dysfunction, but not hepatic obstruction. Available as oral capsule. Bioavailablity 40-80%. Toxicity Bone marrow suppression. Dose dependent nausea or vomiting and alopecia. 86

87. At high doses mucositis is dose limiting. Liver toxicity , fever and chills are also seen with high dose therapy. The most serious toxicity is development AML. Also occurs in other topoisomerase II inhibitors with low frequency. Leukemia develops early 2-5 years. 87

88. Platinum analogs Cisplatin, Carboplatin and oxaplatin Are heavy metal complexes that induce tumor cell kill by cross linking DNA strands in a manner analogs to the alkylating agents. 2 nd line agents for the treatment of lymphomas. Renal excretion 70-90% for carboplatin Carboplatin dose should be calculated based on individual creatinine. Oxaplatin is also excreted via kidney in 50%. 88

89. Toxicity Toxicity profiles differs for all the drugs. Myelosuppression is rare with cisplatin. Nephrotoxicity is dose related. Manifested by azotemia and electrolyte disturbances primarily hypomagnesemia and hypokalemia. Reduced by pre and post treatment hydration and diuresis. Neurotoxicity from cisplatin is cumulative dose related usually begins “stocking-glove” type PN. Toxicity of carboplatin is dose limiting myelosuppression. Renal and ototoxicity's less frequent comparing to cisplatin. 89

90. Nausea and vomiting is mild to moderate. Oxaplatin results in neurotoxicity that is both acute and chronic. Reversible cumulative peripheral sensory neuropathy is primary dose limiting factors of oxaplatin therapy. Ototoxicity and nephrotoxicity are uncommon. 90

91. Other chemotherapy agents in hematology Pagaspargase Inhibition of protein synthesis when cells are depleted of aspargine . Toxicity Decrease in circulating level of albumin clotting factors, insulin and lipoprotein. Synthesis of anticoagulant decreased. Hypersensetivity . Toxic reactions include cerebral dysfunction 25%, vomiting, chills, pancreatitis 15%. 91

92. Bleomycin Can be administered subcutaneously IM and IV. Instilled in to pleural and pericardial space as sclerosing agent in malignant effusion. Toxicity Not myelosuppressive. Fever with in 48 hours in 25%. Most prominent toxic effect is chronic interistial pneumonitis which may continue to fibrosis, hypoxia and death. Risk factors are individual who took >400mg, advancing age>70 years, underlying lung disease and previous radiation to chest. 92

93. Enasidenib Selective inhibitor of isocitirate dehydrogenase 2(IDH2). An enzyme mutated in fraction of cases of AML. Used in treatment of relapsed AML harboring IDH2 mutation. Dose 100mg po/d. Possible toxicities; nausea, diarrhea, hyperbilirubinemia and electrolyte disturbance. Differentiation syndrome; fever, edema, dyspnea or multiorgan dysfunction. When suspected corticosteroid therapy should be initiated. 93

94. Ventoclax Oral selective small molecule inhibitor of BCL-2. BCL-2 Is antiapoptotis protein that mediates tumor cell survival. Approved for use in relapse or deletion 17P associated CLL. Undergoes hepatic metabolism via CYPE3A4 and CYP3A5. High risk of Tumor lysis syndrome. Patient should receive adequate hydration. Lysis monitoring. Upward titration of daily dose every week for 5 weeks to standard 400mg daily dose. Nausea, diarrhea and neutropenia. 94

95. Immunomodulators Thalidomide, lenalidomide and pomalidomide. Immunomodulatory wide potential antineoplastic. Particularly against MM. Pomalidomide and lenalidomide with fewer side side effects. Specific mechanism of action unknown. 95

96. Toxicity Potent teratogen. Pregnancy is absolute contraindications. Negative pregnancy test before starting treatment. Use two effective forms of birth control. Have pregnancy test every 4 weeks. Breast feeding prohibited. Men must use condom. 96

97. Common toxicities Neuropathy, somnolence and constipation. Neuropathy is 38% at 6 months and 73% at 12 months. Tingling or painful distal paresthesia’s in 5-20%. Venous thrombosis seen in 2-23%. Constipation >50%. Reversible myelosuppression, neutropenia and thrombocytopenia. Increased risk of development of 2 nd malignancies. 97

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