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
Intervention: Busulfan; Fludarabine
Intervention description: 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
Intervention MeSH terms: Fludarabine; Fludarabine phosphate; Busulfan
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 72.0
Sex: All
Minimum age: 16 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Busulfan; Fludarabine; Chimerism; Allogeneic stem cell transplantation (HCT); Myelodysplastic Syndromes; Leukemia Myeloproliferative disorders (MPD); Leukemia, Lymphocytic; Myeloma; Lymphoma; AUC; Hematologic malignancies

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.
    

Eligibility 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. Acute myelogenous leukemia (AML), Acute lymphoblastic leukemia (ALL), or
                  Non-Hodgkin's Leukemia (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. Myelodysplastic Syndrome (MDS), with IPSS >1

               3. Chronic myelogenous leukemia (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. Chronic lymphocytic leukemia (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: Diffusing capacity of lung for carbon monoxide (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
                  ml/min

               4. Hepatic: Total bilirubin less than or equal to 2 mg/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 nucleic acid test (NAT)

          -  Active central nervous system (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
             administration

          -  Prior use of MylotargR (gemtuzumab ozogamicin)

          -  Prior Hematopoietic Cell Transplantation (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
                  participants 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 (6 cm 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.)