1. Presented BY : Group 5, PharmD. Supervised by : Dr. Nashaat.

2.  Resistance to imatinib is still a problem,mainly in patients in the accelerated Or blast crisis phases of the disease.  Resulting in : relapse or no progression (persistence). Imatinib resistance divided into the broad categories of primary and secondary resistance: 1- Primary resistance to imatinib, defined as an inability to achieve landmark response, is comprised of the 2% of patients who fail to achieve hematologic response and 8-13% who fail to achieve major or complete cytogenetic response using early chronic phase CML treated with imatinib at diagnosis as a benchmark. 2- Patients with secondary resistance—those who achieve but subsequently lose relevant response—is most straightforward for overt relapse such as loss of cytogenetic or hematologic response and progression from chronic to advanced-stage disease.

3. Mechanisms of Imatinib resistance: 1. Over-expression of BCR/ABL & BCR/ABL point mutations in imtinib resistant leukemia: the relapse is characterized by reactivation of BCR/ABL kinase activity. 2. c-Kit & PDGFRa point mutations in GIST: an “enzymatic site” activating mutation which affects that catalytic portion of the KIT receptor kinase is associated with resistant to imatinib.

4. Mechanism of Imatinib resistance: 3. P-glycoprotein up regulation: i.e. over expression of multidrug resistance P-gp (efflux pump). 4. Alpha acid glycoprotein binding of imatinib: the plasma protein alpha 1 acid glycoprotein (AGP) has been proposed to bind to imatinib & prevent imatinib from reaching its target. Strategies to overcome imatinib resistance: 1- Combination therapy with imatinib: to improve response includes; the standard chemotherapeutic agents : cytosine arabinoside, daunorubicin, interferon alpha. 2- Modulation of imatinib dosing: by administration of higher (than conventional) doses of imatinib. 3- Second line therapy: Nilotinib, Dasatinib.

5. It is a selective BCR/ABL tyrosine kinase inhibitor, also it inhibits the receptor tyrosine kinases platelet-derived growth factor receptor (PDGF-R) and c-kit, a receptor tyrosine kinase mutated and constitutively activated in most gastrointestinal stromal tumors (GISTs). Nilotinib

6. Dasatinib It binds to multiple conformations of the ABL kinase, dasatinib inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-B. By targeting these kinases, dasatinib inhibits the overproduction of leukemia cells in the bone marrow of patients with CML and Ph+ALL and allows normal red cell, white cell, and blood platelet production to resume.

7. DasatinibNilotinib SPRYCEL®Tasigna ® Brand name Oral,tabOral, cap.Route of administration treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib. treatment of adults with Philadelphia chromosome- positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. Philadelphia chromosome- positive chronic myelogenous leukemia in adult patients resistant or intolerant to prior therapy. Ph+ acute lymphoblastic leukemia. Systemic mastocytosis Hypereosinophilic syndrome. Indications

8. DasatinibNilotinib 94% protein bound. eliminated primarily by hepatic metabolism and excreted in feces. excreted <1% in the urine. primarily metabolized by CYP3A4; mean half life ≈ 4 to 6 h. not altered in absorption with co-administration of food. A – AUC ↑ 82% when given after high fat meals. D – 98% protein bound. M – hepatic: oxidation and hydroxylation. E – 90% eliminated in feces; t 1/2 = 17 hrs. PKs

9. DasatinibNilotinib 70 mg orally twice a day, Chronic phase CML: 100 mg once daily. Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL: 70 mg twice daily. Administered orally, with or without a meal. Tablets should not be crushed or cut. 400 mg orally twice daily,approximately 12 hours apart and should not be taken with food. Dose Rifampicin, phenytoin, clozapine, digoxin, simvastatin, famotidine. Clarithromycin, moxifloxacin, telithromycin, Phenytoin, ketoconazole, itraconazole, voriconazole, cloazapine, ritonavir, midazolam, digoxin Drug- drug interactions

10. DasatinibNilotinib Myelosuppression. Bleeding related events. Fluid retention. QT prolongation. QT prolongation and Sudden Deaths. Myelosuppression. Elevated serum lipase. Hepatotoxicity. Electrolyte abnormalities. ADVERSE REACTIONS Diarrhea, anorexia, colitis….Rash, Prorates, Nausea Neutropenia, Thrombocytopenia Side effects Breast feeding.Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome, & breast feeding. Contraindications Category D Pregnancy

11. DasatinibNilotinib Myelosuppression: Severe thrombocytopenia, neutropenia, and anemia may occur and require dose interruption or reduction. Monitor complete blood counts regularly Bleeding Related Events (mostly associated with severe thrombocytopenia): CNS hemorrhages, including fatalities, have occurred. Severe gastrointestinal hemorrhage may require treatment interruptions and transfusions. Black Box Warning Tasigna prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome, Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Warning

12. DasatinibNilotinib Use SPRYCEL with caution in patients requiring medications that inhibit platelet function or anticoagulants. Fluid Retention. QT Prolongation. Use SPRYCEL with caution in patients with hepatic impairment. Patients should avoid food 2 hours before and 1 hour after taking dose. Use with caution in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. Warning