Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)
Condition: Myelodysplastic Syndromes; Myeloproliferative Disorders; Leukemia, Lymphocytic; Myeloma; Lymphoma
MeSH terms: Leukemia; Preleukemia; Leukemia, Lymphoid; Myelodysplastic Syndromes; Myeloproliferative Disorders
Study type: Interventional
Phase: Phase 4

Summary: 
      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 area under the
      plasma concentration time curve (AUC). Day 0 is the day of hematopoietic progenitor cell
      reinfusion. Supportive care will be based on institutional guidelines. Blood samples will be
      collected for dose modification based on the AUC levels. Dose escalation will proceed to
      determine the maximally tolerated level or AUC to evaluate the potential therapeutic benefit
      of higher doses of busulfan.
    

Detailed description: 
      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
      post-transplant.
    

Intervention name(s): Busulfan; Fludarabine
Intervention type(s): Drug; Drug
Intervention description(s): Bu IV (BusulfexR) over 3 hours on days -6, -5, -4, and -3. Day -6 and -5 doses for patients on Level 1 will be 170mg/m2. This dose is based on the dose used by DeLima (2004) adjusted proportionately to achieve an AUC of 6000uM-min. Subsequent daily doses for patients on Level 1 will be adjusted to achieve an average AUC of 6000uM-min.
Day -6 and -5 doses for patients on Level 2 will be based on the mean dose required on Level 1 to achieve target AUC then adjusted proportionally for new target AUC.
Subsequent daily doses will be adjusted to achieve target AUCs.; Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3
Other intervention name(s): Busulfex(R); Fludarabine Phosphate
Intervention MeSH terms: Fludarabine; Fludarabine phosphate; Busulfan
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Busulfan; Fludarabine; Chimerism; Allogeneic stem cell transplantation (HCT); Myelodysplastic Syndromes; Leukemia Myeloproliferative disorders (MPD); Leukemia, Lymphocytic; Myeloma; Lymphoma; AUC; Hematologic malignancies