Feasibility and Efficiency Study of Leukemic Cell Mobilization With Plerixafor Injection

• Quantification of leukemic progenitor cells after administration of Plerixafor as a myeloablative preparative regimen for a patient with AML undergoing a stem cell transplantation. [ Time Frame: one year ] [ Designated as safety issue: No ]
  Quantification of CXCR4 positive cells before and after administration of the first and subsequent doses of Plerixafor mesure andNumber of Participants with adverse Events as a measure of safety and tolerability.
• Quantification of leukemic progenitor cells after administration of Plerixafor as a myeloablative preparative regimen for a patient with AML undergoing a stem cell transplantation. [ Time Frame: One Year ] [ Designated as safety issue: No ]
  Qutification of hypermethylation status of Mobilized cells and number of paticipants with adverse event as a measure of safety and Tolerability.
• Quantification of leukemic progenitor cells after administration of Plerixafor as a myeloablative preparative regimen for a patient with AML undergoing a stem cell transplantation. [ Time Frame: one year ] [ Designated as safety issue: No ]
  Qutification of candidates for leukemic cell population s using a marker panel by flowcytometry.
• Quantification of leukemic progenitor cells after administration of Plerixafor as a myeloablative preparative regimen for a patient with AML undergoing a stem cell transplantation. [ Time Frame: one year ] [ Designated as safety issue: No ]
  Qutification of leukemic cells with suitable cytogenic or molrecular markerand number of participants with adverse events measure of safety and tolerability.
• Number of Participants with Adverse Events as a Measure of Safety and Tolerability will be evaluated in the study. [ Time Frame: one year ] [ Designated as safety issue: No ]
  Qutification of normal clonogenic hemopoietic progenitors and number of participants with adverse events as a measure of safety and tolerability.
• Number of Participants with Adverse Events as a Measure of Safety and Tolerability will be evaluated in the study. [ Time Frame: one year ] [ Designated as safety issue: No ]
  overall and Leukemia free survival at 1 year and number of Adverse events as a measure of safety and tolerability.

The study will be conducted as a single center Phase I/II study to evaluate the safety of administering Plerixafor administered as part of a myeloablative preparative regimen (Institutional Protocol:Fludarabine 50mg/m2/da x 4 days, Busulfan 3.2mg/kg/day x 4 days, TBI 400cGy in divided fractions) for stem cell transplant recipients with AML and to determine whether or not residual leukemic stem cells can be mobilized. Three patients will be enrolled into each of 4 sequential cohorts. Patients in the first cohort will receive 1 dose of Plerixafor (240mcg/kg sc) prior to administration of the first dose of Fludarabine and Busulfan. If tolerated it is planned to escalate the number of Plerixafor doses in the subsequent cohorts to 2. 3. and 4 to be administered before the respective 2nd, 3rd, and 4th dose of chemotherapy.

The study will be conducted as a single center Phase I/II study to evaluate the safety of administering PLERIXAFOR as part of a myeloablative preparative regimen (Institutional Protocol: FBT(400) - FLUDARABINE 50mg/m2/d x 4 days, BUSULFAN 3.2mg/kg/day x 4 days, TBI 400cGy in 2 fractions) for stem cell transplant recipients with Acute Myeloid Leukemia (AML) and to determine whether or not residual leukemic stem cells can be mobilized. Three patients will be enrolled into each of 4 sequential cohorts. Patients in the first cohort will receive 1 dose (240mcg/kg SC) of PLERIXAFOR ( MOZOBIL, formerly known as AMD3100) prior to administration of the first dose of FLUDARABINE and BUSULFAN It is planned to escalate the number of PLERIXAFOR doses in the subsequent cohorts to 2. 3. and 4 to be administered before the respective 2nd, 3rd, and 4th doses of chemotherapy. As primary endpoint the study will establish the toxicity of combined administration of PLERIXAFOR and the preparative regimen at each dose level. Secondary endpoints will include quantification of CXCR4 positive cells and candidates for leukemic disease propagating cells before and after administration of PLERIXAFOR. Mobilized cells will be examined for the ability to undergo apoptosis. Clinical parameters including SAE, OS and LFS are part of the evaluation.

The comparison of cell populations in peripheral blood before and after PLERIXAFOR may facilitate a better definition of minimal residual disease in patients deemed morphologically in a complete remission. The assessment after completion of the preparative regimen will provide a measurement of minimal residual disease prior to the transplant. The assessment of residual leukemic cells with respect to apoptosis will define their responsiveness to the administration of FLUDARABINE and BUSULFAN. The obtained information will facilitate development of a new platform to optimize preparation of patients for a transplant. Eg. Insufficient mobilization of leukemic cells may be addressed in future studies by combining mobilization strategies. Similarly, if cells are shown to be apoptosis resistant one may be able to include apoptosis inducing small molecules.

The study will be performed on patients undergoing myeloablative allogeneic stem cell transplants (PBSC or BM) from related or unrelated donors for the treatment of patients with AML in remission.

• cohort 1
  Patients in Cohort 1 will be followed with daily Flowcytometric studies to quantify CXCR4 positive cells.The samples will be obtained before the following doses of FLUDARABINE and BUSULFAN. Eighteen hrs (range 18 -20 hrs) after start of the last dose of FUDARABINE andBUSULFAN and before the first dose of TBI a PB sample as well as bone marrow aspirate and biopsy will be obtained to repeat the studies as conducted prior to the first dose of PLERIXAFOR
  Intervention: Drug: Plerixafor (mozobil)
• Cohort 2
  Patients in Cohort 2 will receive the second dose of PLERIXAFOR 24 hrs after the first dose. A PB sample for a CBS and Flowcytometry will be drawn prior to the dose. Nine hrs later a further study sample for Flowcytometry will be obtained prior to administration of the second dose of FLUARABINE and BUSULFAN. Flowcytometric studies will be repeated on day 3 and 4. Eighteen hrs (range 18 - 20 hrs) after start of the last dose of FLUDARABINE and BUSULFAN and before the first dose of TBI a PB sample as well as bone marrow aspirate and biopsy will be obtained to repeat the studies as conducted prior to the first dose of PLERIXAFOR.
  Intervention: Drug: Plerixafor (mozobil)
• cohort 3
  Cohort 3: Administration of PLERIXAFOR (240mcg/kg sc) before the first, second, and third dose of FLUARABINE and BUSULFAN
  Intervention: Drug: Plerixafor (mozobil)
• Cohort 4
  Administration of PLERIXAFOR (240mcg/kg sc) before all four doses of FLUDARABINE and BUSULFAN
  Intervention: Drug: Plerixafor (mozobil)

Inclusion Criteria:

• Patients with AML in remission.
• Availability of a suitably matched related or unrelated donor
• Age 18-60 years
• Eligibility for a myeloablative transplant using the Institutional protocols R-FBT(400)-CSMF as preparative regimen for related donors and U-FBT(400)-CP(30)CS for unrelated donors.
• Eligible subjects who are illiterate will be offered participation in the study

Exclusion criteria:

• Patients aged 61years or older
• Patients not eligible for the preparative regimens R-FBT(400)-CSMF or U-FBT(400)-CP(30)CS
• Pregnant or lactating females
• Creatinine of .>2x normal
• Bilirubin, AST, ALT > 2x normal
• MUGA of <50%