P97 Busulfan/sulfolane metabolic ratio on the third day of conditioning may predict the event-free survival in children receiving busulfan based conditioning prior to hematopoietic stem-cell transplantation

BackgroundBusulfan (Bu) is widely used as a component of myeloablative conditioning regimen before hematopoietic stem cell transplantation (HSCT) in children. Obtaining the ratio of Bu to its metabolite sulfolane i.e. metabolic ratio (MR) may serve as an indicator of Bu GSH conjugating capacity of an individual.ObjectiveTo evaluate the utility of Bu MR to predict EFS in children undergoing allogeneic HSCT.MethodsTwo different cohorts with children receiving Bu in four times daily (QID, n=44) and once daily doses (QD, n=13) at St. Justine’s Hospital, Montreal were studied. Bu and Su levels were measured on day 3 of the conditioning regimen at the end of infusion (dose 9 in QID or dose 3 in QD dosing). EFS was defined from the time of transplant until death, relapse, or rejection, whichever occurred first. A receiver-operator characteristic curve (ROC) of Bu MRs was analyzed in relation to EFS. Cutoff values were defined based on the Youden´s J statistic.ResultsTwenty-two males and 22 females aged from 0.1 to 19.9 years (mean±SD: 7.2 ± 5.7) from Bu QID cohort had the mean MR of 5.9 (SD: 3.2). A cut off value of 4.9 in MR was chosen in ROC analysis in this cohort, with better sensitivity (71%) and specificity (70%) for EFS prediction (p=0.01, AUC= 0.7 (95% CI= 0.6–0.8). In QD cohort nine females, and four males aged between 0.4 and 15.8 years (6.7±5.1) had the mean MR of 29.3 (SD: 16.6). In ROC analysis, a cut off value of 25.06 was chosen with better sensitivity (100%) and specificity (100%) for EFS prediction (p=0.003; AUC=1.0).ConclusionThe Bu MR on day 3 above 4.973 and 25.06 were associated with worse EFS in children undergoing HSCT and received Bu in QID and QD dosing schedules, respectively.Disclosure(s)Nothing to disclose

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Pre-Transplant Test Dose vs. PK Studies during Conditioning Regimen To Target iv Busulfan in Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v110.11.3006.3006 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3006-3006

Author(s):

Sandeep Chunduri ◽

Rakesh Beri ◽

Lisa C. Dobogai ◽

Elizabeth Hurter ◽

Christina Mactal-Haaf ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Conditioning Regimen ◽

Test Dose ◽

Hematopoietic Stem ◽

Blood Samples ◽

The Mean

Abstract In this study we tested the efficacy of a test dose of iv busulfan in targeting blood levels of this drug during the conditioning regimen prior to an allogeneic hematopoietic stem cell transplant. We analyzed blood samples of 22 patients undergoing allogeneic hematopoietic stem cell transplantation with a busulfan-based conditioning regimen. Patients received a test dose of busulfan at 0.8 mg/kg as a 60 minute intravenous infusion. Serial blood samples were drawn at eight time points: 15 minutes before dose, at end of infusion, 15 minutes after completion, 30 minutes after completion, 60 minutes after completion, 2 hours after completion, 4 hours after completion, and 6 hours after completion. Pharmacokinetics (PK) studies were then performed at the Seattle Cancer Care pharmacokinetics laboratory. The AUC was determined using WinNonlin Professional software. The conditioning dose of busulfan was calculated by multiplying the test dose in mg/AUC × 4800. After the first dose of busulfan was administered, the same protocol was used to test busulfan PK. If the Busulfan AUC was therapeutic (between 4800 μM*min and 5200 μM*min) then the same dose was continued. If the Busulfan AUC was low or high then the third and fourth doses of busulfan were adjusted. The test dose of 0.8 mg/kg intravenous did not have any hematological side effects. The mean historic dose (solely based on weight) was 3.2 ± 0.1 mg/kg and the mean dose based on the test dose was 3.5 ± 0.5 mg/kg (p=0.02). In 12 patients where we also analyzed PK after the first day of conditioning regimen, AUC values of busulfan obtained during test dose and after day 1 dose were not different (p=0.7). The mean dose of busulfan based on test dose was 3.5 ± 0.6 mg/kg while the final dose based on day 1 busulfan PK was 3.6 ± 0.7 mg/kg (p=0.9). Nevertheless, in 2 CML patients who were on treatment with dasatinib or nilotinib at the time of the test dose, a higher AUC was observed (AUC 6065 and 6200, respectively). A pre-transplant busulfan test dose can be safely performed anytime prior to transplant and allows targeting the dose of busulfan efficiently, thus avoiding the requirement of PK studies during the conditioning regimen.

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