Autologous Hematopoietic Cell Transplantation for Core-binding Factor (CBF) Acute Myeloid Leukemia (AML) in the First Complete Remission (CR1)
Autologous Hematopoietic Cell Transplantation for Core-binding Factor (CBF) Acute Myeloid Leukemia (AML) in the First Complete Remission (CR1)
Evaluation of efficacy of autologous hematopoietic cell transplantation (HCT) with
 core-binding factor (CBF) positive acute myeloid leukemia (AML) in the first CR (CR1).
5.2 AUTOLOGOUS PBSCS HARVESTING

 5.2.1. PBSCs will be collected during recovery phase after the second cycle of HDAC
 consolidation chemotherapy.

 5.2.2. For mobilization, recombinant human granulocyte- colony-stimulating factor (G-CSF,
 Filgrastim) will be given subcutaneously at a dose of 10 mcg/kg from day 9 of the 2nd HDAC
 cycle until the completion of harvesting.

 5.2.3. PBSCs harvesting will be performed via perm-cath or Quinton catheter, which will be
 inserted with fluoroscopy-guided before starting and will be removed after finishing harvest.

 5.2.4. Harvest will be initiated from the day when the peripheral absolute neutrophil count
 reach up to 0.2 x 109/mm3. Peripheral blood mononuclear cells will be collected by
 leukapheresis method with 'CS-3000' (Baxter, Deerfield, IL) or other compatible machine. Cell
 collection will be performed for at least 2 days and the duration of collection can be
 extended until a target CD34+ cell dose of 5 x 106/kg (in terms of body weight of recipient)
 is collected.

 5.2.5. If adequate numbers of CD34+ cells are not collected, the 3rd HDAC chemotherapy will
 be done and mobilization/harvest procedure will be repeated.

 5.2.6. Stem cells harvested from patient will be frozen in liquid nitrogen tank for future
 autologous HCT cell infusion.

 5.3.PRETRANSPLANT WORKUP FOR AUTOLOGOUS HCT 5.3.1. Pre-workup for checking the current
 disease status and feasibility for autologous HCT will be performed before the conditioning
 and infusion of autologous HCT.

 5.3.2. It is recommended that baseline workup for hematologic / non-hematologic status will
 be performed at least 1 month prior to the initiation of conditioning. Bone marrow aspirate/
 biopsy with cytogenetics and diagnostic lumbar puncture can be performed immediately before
 the initiation of conditioning.

 5.3.3. Pretransplant workup tests are listed in Appendix IV.

 5.4. CONDITIONING REGIMEN FOR AUTOLOGOUS HCT 5.4.1. On admission, 5.4.1.1.Menstruating women
 will be given norethindrone (Norlutate) 10mg po daily until platelet count is consistently
 over 100,000 /mcL.

 5.4.1.2.Actual body weight (ABW) for busulfan will be calculated using following guidelines;
 5.4.1.2.1.If ABW is less or equal to ideal body weight (IBW), use ABW. 5.4.1.2.2.If ABW is
 greater than IBW but ABW is within 120% of IBW, use IBW. 5.4.1.2.3.If ABW is 120% or greater
 than IBW, use IBW+25% (ABW-IBW). 5.4.1.2.4.IBW(ideal body weight) will be calculated in
 5.4.1.2.4.1.Male: 50 kg + 2.3kg (height[inch]-60) 5.4.1.2.4.2.Female: 45.5kg + 2.3kg
 (height[inch]-60) 5.4.1.2.4.3.1inch=2.54cm 5.4.2. On day -8, preparation drugs will be
 administered to patient as below; 5.4.2.1.Hydration with 0.9% normal saline will be started
 at 6PM and infused continuously at a rate of 100mL/hr through day -4.

 5.4.2.2.Allopurinol 300mg/day will be taken p.o. once a day from day-8 to -2. 5.4.2.3.Heparin
 100 U/kg/day in normal saline 500 mL will be infused continuously at a rate of 20mL/hr
 through day 20 (6pm). Heparin should be discontinued if there is clinically significant
 bleeding or aPTT level exceeds 1.2 time of the upper normal limit.

 5.4.2.4.Dilantin 15mg/kg (ABW) in normal saline 300cc will be infused continuously at a rate
 of 200mL/hr at 8PM, and then, 200mg will be taken p.o. twice a day through day -4. Dilantin
 level should be monitored in the morning of day-7 and -6 to maintain the level within 10 to
 20 mg/L.

 5.4.3. From day-7, conditioning drug will be administered to patient as below;
 5.4.3.1.Busulfan 3.2mg/kg/day in normal saline of 10 times the volume of busulfan will be
 infused continuously over 3 hours with an interval of 24 hours on days -7 to -5 (for 3 days).

 5.4.3.2.Etoposide 200mg/m2/day in normal saline 1000mL will be infused continuously over 5
 hours twice a day with an interval of 12 hours on day-3 to -2 (for 2 days).

 5.4.3.3.Antiemetics such as serotonin antagonist or lorazepam are allowed.

 5.5. AUTOLOGOUS PBSCS INFUSION 5.5.1. Autologous PBSCs will be infused on day0.
 5.5.1.1.Premedication including pheniramine maleate (avil) 45.5mg i.v., acetaminophen 600mg
 p.o., hydrocortisone 250mg i.v. and furosemide 20mg i.v. will be given 30 minutes before cell
 infusion.

 5.5.1.2.PBSCs will be infused via saline infusion set without in-line filters. 5.5.1.3.Vital
 sign should be checked 4 times with 15 minutes of interval, 4 times with 30 minutes, and then
 4 times with 1 hour. Electrocardiogram monitoring will be performed from the start until the
 completion of PBSCs infusion.

 5.5.1.4.Following medications should not be administered simultaneously with PBSCs;
 5.5.1.4.1.Lipid-containing total parenteral nutrition fluid 5.5.1.4.2.Conventional or
 liposomal amphotericin 5.6. SUPPORTIVE CARE 5.6.1. Recombinant human G-CSF (rhG-CSF) 450㎍ in
 100 mL of D5W will be infused intravenously over 30 minutes from day 5 till ANC>3,000/㎕.

 5.6.2. Ciprofloxacin 500mg will be given p.o. twice a day (for selective bowel
 decontamination) from day 1 till ANC>3,000/㎕. With the first fever spike, ciprofloxacin can
 be replaced with broad spectrum antibiotics.

 5.6.3. Micafungin 50mg will be infused intravenously once a day from day1 till ANC>3,000/㎕.

 5.6.4. Acyclovir 250mg/m2 will be infused twice a day from day1 till ANC>3,000/㎕.

 5.6.5. In case of oral mucositis, sodium bicarbonate/saline mouthwash will be applied four
 times a day until resolved.

 5.6.6. Clotrimazole or Canesten® powder can be applied to groin, axilla, and perianal area
 twice a day from day-8 until engraftment.

 5.6.7. All cellular blood products must be transfused after leukocyte filtration and
 irradiation.

 5.6.8. For woman of childbearing potential, adequate consultation for ovarian protection can
 be sought. For man who intend to have child(ren) in future, sperm banking can be recommended
 and performed.

 5.7. EVALUATION DURING TREATMENT 5.7.1. CBC with differential count, ALT/AST, bilirubin with
 BUN/Cr, and electrolyte will be checked once daily.

 5.7.2. Chemical battery with BUN/phosphorus, LDH and level of magnesium will be checked three
 times a week.

 5.7.3. Coagulation battery with fibrinogen/d-dimer will be checked at day 0, 7, 14, 21 and
 once a week thereafter until discharge.

 5.7.4. Protein C, antithrombin III, t-PA antigen, and PAI-1 antigen will be checked at day 0,
 7, 14, and 21.

 5.7.5. Urinalysis will be checked once a week. 5.7.6. Chest X-ray will be checked once a week
 routinely and more frequently according to patient's condition.

 5.7.7. Blood galactomannan (aspergillosis antigen, GM) assay can be recommended to be checked
 once a week until ANC>3,000/ according to the physician's decision.

 5.8. POST-HCT FOLLOW-UP INCLUDING MRD MONITORING 5.8.1. Patients will be followed with
 physical examination and appropriate blood test including CBC at least every 3 months for 3
 years, every 6 months for the next 2 years, and then annually thereafter.

 5.8.2. Toxicities related to treatment will be assessed and reported according to NCI CTCAE
 v3.0.

 5.8.3. Minimal residual disease (MRD) monitoring with RQ-PCR for AML1/ETO or CBFβ/MYH11 will
 be performed before autologous HCT (bone marrow and peripheral blood, 1 month after
 autologous HCT (bone marrow and peripheral blood), and thereafter, every 3 months (peripheral
 blood only) until 3 years after autologous HCT.

 5.8.4. If RQ-PCR is not available, RT-PCR and/or FISH can be used for MRD monitoring
Inclusion Criteria:

 -  Patients with CBF positive AML in CR1. CBF AML includes t(8;21)(q22;q22)
 [AML1(RUNX1)/ETO(CBFα2T1)], inv(16)(q13q22) (CBFβ/MYH11),t(16;16)(p13;q22)
 (CBFβ/MYH11) Using RT-PCR, FISH, or standard karyotype analysis technique.

 -  Patients who plan to receive the second cycle of HDAC consolidation chemotherapy.

 -  15 years old or older and 65 years or younger

 -  Adequate performance status (Karnofsky score of 70 or more).

 -  Adequate hepatic and renal function (AST, ALT, and bilirubin < 3.0 x upper normal
 limit, and creatinine < 2.0 mg/dL).

 -  Adequate cardiac function (left ventricular ejection fraction over 40% on heart scan
 or echocardiography)

 -  Signed and dated informed consent must be obtained from patient.

 Exclusion Criteria:

 -  Presence of significant active infection

 -  Presence of uncontrolled bleeding

 -  Any coexisting major illness or organ failure

 -  Patients with psychiatric disorder or mental deficiency severe as to make compliance
 with the treatment unlike, and making informed consent impossible

 -  Nursing women, pregnant women, women of childbearing potential who do not want
 adequate contraception

 -  Patients with a diagnosis of prior malignancy unless disease-free for at least 5 years
 following therapy with curative intent (except curatively treated nonmelanoma skin
 cancer, in situ carcinoma, or cervical intraepithelial neoplasia)