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Busulfan Dose Escalation Study Based on AUC in the Setting of Busulfan/Fludarabine Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation (HCT)

Phase 4
16 Years
65 Years
Not Enrolling
Myelodysplastic Syndromes, Myeloproliferative Disorders, Leukemia, Lymphocytic, Myeloma, Lymphoma

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Trial Information

Busulfan Dose Escalation Study Based on AUC in the Setting of Busulfan/Fludarabine Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation (HCT)

Patients will receive anti-seizure prophylaxis beginning on day -7. Pre-transplant
conditioning will include Fludarabine and dose-escalated Busulfan on days -6, -5, -4, and
-3. Daily treatment doses will be adjusted to achieve target AUCs (area under the plasma
concentration time curve). Day 0 is the day of hematopoietic progenitor cell reinfusion.

Supportive care will be based on institutional guidelines. In an effort to prevent
hepatotoxicity, ursodiol will be given to patients. During chemotherapy patients will not
receive concurrent metronidazole, itraconazole, or be given acetaminophen.

Blood samples will be collected at specific times after Dose 1 and Dose 4 and dose
modification will be determined or based on the desired AUC levels. Doses 3 and/or 4 will
be adjusted to achieve an average daily Busulfan AUC over the 4 treatment days.

Dose escalation will proceed through 3 dose levels to determine the maximally tolerated
level or AUC to evaluate the potential therapeutic benefit of higher doses of busulfan.

Graft assessment, processing, and characterization will be done as per institutional
guidelines. Donor-recipient chimerism (two genetically distinct types of blood cells) will
be characterized by samples obtained pre-transplant and on days 30+/- 7, 90+/-7 and 360+/-30

Inclusion Criteria

Inclusion Criteria - Recipient:

- HLA A, B, C, DRB1 8/8 or 7/8 matched related or unrelated donor. HLA-DQ mismatches
are not considered ie they are allowed in addition to these.

- Histologically confirmed diagnosis by pathologic review

- Diagnosis of any of the following:

1. AML, ALL, or NHL, in first remission with high risk of relapse, refractory to
primary chemotherapy, or after first relapse; acute biphenotypic or
undifferentiated leukemia is also included

2. MDS, with IPSS >1

3. CML, with GleevecR-refractory or intolerant chronic phase, or beyond chronic
phase by morphology or cytogenetics

4. Myeloproliferative disorders, including Ph-negative CML, myelofibrosis and
chronic myelomonocytic leukemia (CMML)

5. Multiple myeloma, refractory to two or more lines of therapy.

6. CLL, refractory to fludarabine

7. Hodgkin's disease, refractory to primary chemotherapy or after first relapse

8. Karnofsky performance status 70-100%

- Organ function:

1. Pulmonary: DLCO greater than 50%

2. Cardiac: left ventricular ejection fraction greater than 45%

3. Renal: creatinine clearance (measured or calculated) equal or greater than 50

4. Hepatic: total bilirubin less than or equal to 2mg/dL, (Gilbert and other
syndromes with increased indirect bilirubin should be allowed); serum
transaminases less than two times the upper limit of normal.

- Signed informed consent form in accordance with institutional policies

Exclusion Criteria - Recipient:

- Pregnant or lactating women

- HIV or seropositive, confirmed by NAT

- Active CNS malignancy

- Patients with current uncontrolled bacterial, viral or fungal infection (currently
taking medication with evidence of progression of clinical symptoms or radiologic
findings) are ineligible.

- Unfavorable psychosocial evaluation or history of poor compliance to prescribed
medical care

- Current use of metronidazole or acetominophen, unless medically necessary; patients
must discontinue use of these agents at least 7 days prior to the start of BusulfexR

- Prior use of MylotargR (gemtuzumab ozogamicin)

- Prior HCT

- Prior chest or abdominal irradiation with greater than 1800 cGy

- Presence of any of the following comorbid conditions:

1. History of myocardial infarction or coronary artery disease requiring
catheterization or stent placements less than six months prior to enrollment.
All subjects with history of myocardial infarction or coronary artery disease
must have clearance by a cardiologist to be enrolled

2. Congestive heart failure (even if symptomatically controlled)

3. Peripheral vascular disease (including intermittent claudication or history of
bypass for arterial insufficiency)

4. Untreated thoracic or abdominal aneurysm (6cm or more)

5. History of any cerebrovascular accident including transient ischemic attacks

6. Dementia

7. Connective tissue/rheumatologic disorders with active disease

8. Diabetes uncontrolled by medication (including insulin)

9. Hemiplegia/paraplegia

10. History of prior malignancy (excluding nonmelanoma skin or cervical carcinoma
after curative resection) less than 5 years from enrollment with the following
exception. Cancer treated with curative intent less than 5 years will be
reviewed on a case-by-case basis by the Principal Investigator.

11. History of renal failure requiring renal replacement therapy (e.g.,
hemodialysis, peritoneal dialysis, etc)

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Non-relapse Mortality

Outcome Description:

The number of subjects dead due to causes unrelated to relapse within the first 100 days post transplant

Outcome Time Frame:

100 days

Safety Issue:


Principal Investigator

Teresa Field, PhD, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute


United States: Institutional Review Board

Study ID:




Start Date:

August 2005

Completion Date:

February 2012

Related Keywords:

  • Myelodysplastic Syndromes
  • Myeloproliferative Disorders
  • Leukemia, Lymphocytic
  • Myeloma
  • Lymphoma
  • Busulfan
  • Fludarabine
  • Chimerism
  • Allogeneic stem cell transplantation (HCT)
  • Myelodysplastic Syndromes
  • Leukemia Myeloproliferative disorders (MPD)
  • Leukemia, Lymphocytic
  • Myeloma
  • Lymphoma
  • AUC
  • Hematologic malignancies
  • Leukemia
  • Leukemia, Lymphoid
  • Lymphoma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders



H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida  33612