1. Treatment

2. Phases of treatment Induction chemotherapy Postremission therapy *Initial goal: quickly induce CR *Therapy depends on patient age

3. Induction chemotherapy Cytarabine + anthracycline – Mode of action: Cytarabine – s-phase specific antimetabolite, interferes w/ DNA synthesis Anthracycline – DNA intercalators, inhibit topoisomerase II leading to DNA breaks – Adminitration: Cytarabine – continuous IV infusion for 7 days Anthracycline (daunorubicin) – IV on days 1,2 & 3 (the 7 & 3 regimen) * cytarabine + idarubicin – may be superior to danaurubicin in younger patients * addition of etoposide – may improve CR duration

4. Induction chemotherapy Cytarabine toxicity – Myelosupression – Pulmonary toxicity – Irreversible cerebellar toxicity Occur more commonly in patients w/ renal impairment or those over the age of 60

5. Induction chemotherapy Bone marrow exam after induction therapy – Determine if leukemia has been eliminated – >5% blast w/ >20% cellularity – re-treat patient – Failed to attain CR after 2 induction – allogeneic stem cell transplant

6. Induction chemotherapy Patients who do not achieve CR: – Drug resistant leukemia – Fatal complications of bone marrow aplasia – Impaired recovery of normal stem cells

7. Supportive Care Recombinant hematopoietic growth factors – To lower infection rate – For elderly patients w/ complicated courses, those receiving post remission regimens, patients w/ uncontrolled infections, those participating in clinical trials Multilumen right atrial catheters – For administration of IV medications and transfusions, for blood drawing Adequate prompt blood bank support – Platelet transfusion – maintain at >10,000-20,000/μL – RBC transfusion – Hg level >8g/dL

8. Complications Infections – major cause of morbidity and death – Candidiasis – oral nystatin, clotrimazole – Herpes simplex virus – acyclovir Fever – Empirical broad spectrum antibacterial & antifungal antibiotics Imipenen-cilastin Antipseudomonal semisynthetic penicillin + aminoglycoside Third generation cefalosporin w/ antippseudomonal activity Double β lactam combinations

9. Treatment of PML Tretinoin – Induces differentiation of leukemic cells bearing the t(15;17) – Complication: retinoic acid syndrome Fever, dyspnea, chest pain, pulmonary infiltrates, pleural and pericardial effusion, hypoxia Treatment: glucocorticoids, chemotherapy, supportiveb measures Cytarabine + daunorubicin – Complication: DIC Tretinoin + anthracycline – Safest and most effective treatment Arsenic Trioxide *RT-PCR amplification of the t(15;17) chimeric gene - predict relapse

10. Postremission Therapy To eradicate residual leukemic cells to prevent relapse and prolong survival Based on age ( 55-65) Younger patients – Intensive chemotherapy – Allogeneic or autologous SCT Older patients – Attenuated intensive therapy Chemotherapy Reduced intensity allogeneic SCT

11. Relapse Patients are rarely cured w/ further standard dose therapy – Allogeneic SCT – for eligible patients – Autologous SCT rescue Factors predicting response at relapse: – Length of previous CR – Initial CR was achieved w/ 1 or 2 courses of chemotherapy – Type of postremission therapy Patients have poor outcome

12. Relapse Innovative approaches – new drugs or immunotherapy Decitabine – Elderly patients Gemtuzumab ozogamicin – Toxicity – myelosuppression, infusion toxicity, venoocclusive disease – Pretreatment w/ glucocorticoids

13. Algorithm for treatment of AML Induction therapy Daunorubicin + Cytarabine + Etoposide Complete remission No complete remission t(8;21) or inv 16Low risk normal karyotype High risk normal karyotype, others (both options available High risk karyotype 3-4 cycles of high dose cytarabine 3-4 cycles of high dose cytarabine or autologous SCT Allogeneic SCT Investigational therapy Yes: Alloigeneic SCT No: investigational therapy

14. No complete remission Patient candidate for allogeneic SCT and has suitable donor Yes: Alloigeneic SCT No: investigational therapy