Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)

Phase 4

Completed

Conditions: Myelodysplastic Syndromes
Myeloproliferative Disorders
Leukemia, Lymphocytic
Myeloma
Lymphoma

Brief 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.

Recruitment & Eligibility

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Arm && Interventions

Group	Intervention	Description
AUC 9000	Fludarabine	AUC Level 3: 9000 +/- 900 uM-min Fludarabine 40mg/m2 IV over 1 hour
AUC 7500	Fludarabine	Busulfan AUC Level 2: 7500 +/- 750 uM-min Fludarabine 40mg/m2 IV over 1 hour
AUC 6000	Busulfan	Busulfan AUC Level 1: 6000 +/- 600 uM-min Fludarabine 40mg/m2 IV over 1 hour
AUC 6000	Fludarabine	Busulfan AUC Level 1: 6000 +/- 600 uM-min Fludarabine 40mg/m2 IV over 1 hour
AUC 7500	Busulfan	Busulfan AUC Level 2: 7500 +/- 750 uM-min Fludarabine 40mg/m2 IV over 1 hour
AUC 9000	Busulfan	AUC Level 3: 9000 +/- 900 uM-min Fludarabine 40mg/m2 IV over 1 hour

Primary Outcome Measures

Name	Time	Method
Non-relapse Mortality	100 days	The number of participants dead due to causes unrelated to relapse within the first 100 days post transplant.

Secondary Outcome Measures

Name	Time	Method
Severe Venous Occlusive Disease (VOD)/ Sinusoidal Obstructive Syndrome (SOS)	100 days	The number of subjects with severe VOD / SOS; severity staged according to criteria set forth by McDonald G.B., Hinds M.S., Fisher L.D., et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255-267. Assessed within the first 100 days post transplant.