Busulfan Monotherapy as Conditioning for Autologous Hematopoietic Progenitor Cell Transplantation

• Successful Autologous Stem Cell Collection [ Time Frame: At time of stem cell collection ] [ Designated as safety issue: No ]
  Number of subjects who were able to collect at least 2 million CD34+ cells/kg
• Severe Regimen-related Toxicity [ Time Frame: up to 100 days post translant ] [ Designated as safety issue: Yes ]
  Number of participants with severe regimen-related toxicity within 2 years posttransplant. Severe regimen-related toxicity was defined as CTC (version 3)grade 4.
• 1 Year Event-free Survival [ Time Frame: 1 year post transplant ] [ Designated as safety issue: No ]
  Number of participants alive and without disease relapse at 1 year posttransplant
• 1 Year Overall Survival [ Time Frame: 1 year post transplant ] [ Designated as safety issue: No ]
  Number of participants alive at 1 year posttransplant

• Rate of successful autologous stem cell collection
• Rate of severe regimen-related toxicity
• Event-free survival measured from the time at which criteria are met for CR until the first date that recurrent or progressive disease is objectively documented, or death from any cause occurs
• Overall survival measured from time of CR to the time of death

During the pre-transplantation phase (following completion of consolidation chemotherapy), patients will begin to receive G-CSF at 10 mcg/kg twice daily; leukapheresis will also be given until a target goal for recipient body weight is obtained, or up to a maximum of 5 days. Conditioning/Preparative therapy will follow PBSC collection for up to 30 days with Busulfan IV daily x 4 days; subsequent doses will be adjusted based on pharmacokinetic (plasma level)monitoring. Following 1 day of rest, stem cell reinfusion will begin with supportive care. During follow-up, patients will be monitored out to 730 days.

1. Pre- Transplantation Phase -

   1. Twenty-four to 48 hours following completion of consolidation chemotherapy, patients will begin to receive G-CSF at 10 mcg/kg twice daily subcutaneously. Alternatively, patients may receive G-CSF alone (same dose) as mobilization therapy.
   2. Leukapheresis will begin day 4 of G-CSF administration and proceed according to institutional guidelines. Leukapheresis will continue until a target goal for recipient body weight is obtained, or up to a maximum of 5 days. A minimum recipient body weight is required to proceed to transplantation.

2. Transplantation Phase

   a. Conditioning/Preparative therapy - up to 30 days following PBSC collection, patients will begin conditioning therapy with Busulfan IV daily x 4 days (transplantation days -5,-4,-3,-2). The day -5 and -4 dose will be 130mg/m2; subsequent doses will be adjusted based on pharmacokinetic monitoring.

   • Busulfan plasma level monitoring, collected around the first dose of busulfan b. Stem cell reinfusion - following 1 day of rest, previously collected autologous peripheral blood stem cells will be infused.
   • The administration of supportive measures (e.g. intravenous fluids, antihistamines) during stem cell reinfusion will be performed according to institutional guidelines.

3. Supportive care

   1. Antibiotic prophylaxis- according to hospital/institutional guidelines, and at the discretion of the treating physician.
   2. Growth factor support
   3. Transfusion support
   4. Prophylaxis for busulfan-induced seizures

4. During follow-up, patients will be seen at least weekly for the first month and there after periodically out to 730 days posttransplant. The following medical procedures will be done:

   • Medical history and physical exam (including concurrent meds, vital signs, performance status and weight)
   • Standard labs
   • Bone marrow aspirate and biopsy

• Drug: G-CSF

  Mobilization Option 1:Twenty-four to 48 hours following completion of consolidation chemotherapy, patients will begin to receive G-CSF at 10 mcg/kg twice daily subcutaneously.

  Mobilization Option 2: If patients have recovered hematologically from consolidation chemotherapy, they may receive G-CSF at 10 mcg/kg twice daily subcutaneously.

  Other Name: filgrastim or NeupogenR
• Drug: Leukapheresis
  leukapheresis
• Drug: Busulfan
  Busulfan IV daily x 4 days (transplantation days -5,-4,-3,-2). The day -5 and -4 dose will be 130mg/m2
  Other Name: Busulfan (MyleranR, Busulfex™)
• Procedure: Stem cell reinfusion
  autologous stem cell transplant

Inclusion Criteria:

• Patients must have had histologically confirmed diagnosis of AML, in 1st complete remission, by a pathologic review at the H. Lee Moffitt Cancer Center and Research Institute. Any induction/consolidation regimen is permitted.

• General Inclusion Criteria:

  1. Age 56-74
  2. Able to give informed consent
  3. Hepatic and renal function: normal bilirubin, AST and ALT less than or equal to 2x normal limits, serum creatinine less than or equal to 1.5x normal
  4. Left ventricular ejection fraction (LVEF) must be in normal range
  5. FEV1 AND DLCO greater than or equal to 50% predicted (at planned time of transplantation)
  6. ECOG PS less than or equal to 2 (at planned time of transplantation)

• Disease Specific Inclusion Criteria:

  1. Adverse-risk karyotype (del 5/5q, 7/7q, 3q, greater than or equal to 3 abnormalities):
  2. Intermediate-risk karyotype [46 XY, +8, -Y, +6, or any other isolated (<3 total) non-random abnormality not included in the adverse-risk category or favorable-risk category below]
• AML arising from antecedent hematologic disorder (e.g. MDS)
• Secondary AML (t-AML)

Exclusion Criteria:

• Acute Promyelocytic Leukemia(FAB M3) subtype
• Presence of (8;21) translocation or inversion 16/t(16;16) cytogenetic phenotype (i.e. favorable-risk AML)
• Eligible for and willing to undergo matched-sibling allogeneic transplantation
• Greater than 2 induction regimens required to achieve complete remission
• Duration of > 8 weeks between completion of induction chemotherapy and initiation of consolidation chemotherapy
• No prior malignancy is allowed, except for adequately treated basal cell (or squamous cell) skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for at least 5 years.
• Prior extensive radiation therapy (>25% of bone marrow reserve)
• Concomitant radiation therapy, chemotherapy, or immunotherapy
• Intrinsic impaired organ function (as stated above)
• Active infection
• Positive serum pregnancy test in women who have not yet reached menopause (no menstrual periods for >12 months or who have not undergone tubal ligation or complete hysterectomy.
• Women who are breast-feeding
• Positive HIV testing
• Presence of CNS leukemia
• Uncontrolled insulin-dependent diabetes mellitus or uncompensated major thyroid or adrenal gland dysfunction
• Physical or psychiatric conditions that in the estimation of the PI or his designee place the patient at high-risk of toxicity or non-compliance