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A Phase 1 Study of Targeted, Dose-Escalated Intravenous Busulfan in Combination with Etoposide As Preparative Therapy for Autologous Stem Cell Transplant in Acute Myeloid Leukemia

Track: Poster Abstracts
Wednesday, February 26, 2014, 6:45 PM-7:45 PM
Longhorn Hall E (Exhibit Level 1) (Gaylord Texan)
Gabriel N. Mannis, MD , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Lloyd E Damon, MD , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Weiyun Ai, MD, PhD , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Charalambos Andreadis, MD, MSCE , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Karin ML Gaensler, MD , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Lawrence D Kaplan, MD , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Aaron C Logan, MD, PhD , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Anuj Mahindra, MD , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Rebecca L. Olin, MD, MSCE , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Peter Sayre, MD , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Catherine C Smith, MD , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Jeffrey M Venstrom, MD , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Jeffrey L Wolf, MD , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Thomas G Martin, MD , Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
Introduction:

Busulfan (BU) and etoposide (VP) have been employed as preparative therapy for autologous stem cell transplantation (autoSCT) in adults with acute myeloid leukemia (AML) for over 20 years. Toxicity and safety significantly improved with the transition from oral to intravenous (IV) BU and the use of pharmacokinetic (PK)-based dosing. In an attempt to enhance outcomes following autoSCT, we designed a Phase I study with the following objectives: 1) to determine the maximum tolerated dose (MTD) of targeted, dose-escalated IV BU in combination with VP- 60mg/kg and 2) to achieve BU levels within +/- 10% of goal in >80% of patients (pts) after dose-adjustment (DA).

Methods:

Patients with AML in CR1 meeting all eligibility criteria including, ECOG 0-1, age 18-69, good organ function, and adequate stem cells stored (>3 x 10e6 CD34 following consolidation chemotherapy (HDAC+VP)) were prospectively enrolled.  Three cohorts (targeted AUC 1250, 1400 and 1550 mMol*min were planned with Cohort 1 (C1) receiving IV BU at 0.9mg/kg, Cohort 2 (C2) at 1 mg/kg and Cohort 3 (C3) at BU 1.1mg/kg. PK studies were performed after doses 1 (day -10), 4, and 12, with DA occurring with doses 2 and 11 of 16 total doses. VP was given IV on day -3 with autoSCT on day 0. Palifermin and standard antimicrobial prophylaxis were used.

Results:

To date, 12 pts have undergone autoSCT with targeted, dose-escalated IV BU. Median age 50 (range 24-61). Cytogenetics were diploid in 5 (1 FLT3+, 2 FLT3 WT, 2 FLT3 unknown). The remaining 7 pts had t(9;11) (2), +21 (2), t(8;21), 9q-, and 1 failed. TRM was 0% and engraftment robust; mean ANC >500/uL and platelets >20,000/uL was 11 (range 10-13) and 30 days (range 13-124), respectively. 

All pts received a DA after dose #1 and 7 (58.3%) prior to dose #11. The mean final AUC was 1243 (range 1151-1361) for C1 and 1464 (range 1401-1558) for C2.  All pts in C1 were within 10% of the target AUC in C1 (range -2.8 to +8.2%) versus 83% in C2 (range +0.1 to +10.1%). PK studies revealed BU accumulation at dose 12, with the final AUC exceeding goal by a mean of 14.9% (range 1-35%). Grade 3-4 mucositis occurred in 50% in C1 and in 66% in C2.  Grade 3 hepatic dysfunction was observed in 33% in C1 and in none in C2. 

As of October 2013, 50% of pts are alive and relapse-free. Median relapse-free survival (RFS) for the entire study group is 12.6 months (range 2.2-28.9). In C1, RFS is 33% (median13.1 months; range 3.0-28.9) vs. 66% in C2 (median 12.2 months; range 2.2-20.6). Non-relapse mortality (NRM) was 0% at 100 days post-autoSCT.

Conclusions:

Targeted, dose-escalated IV BU in combination with VP as preparative therapy for autoSCT in AML is safe, with mucositis being the most significant toxicity, limiting escalation to C3. An AUC target of 1400 was deemed the maximum acceptable dose. Serum BU levels accumulate, with higher-than-expected final AUC despite interval DA based on PK studies. Increased BU AUC target is associated with improved RFS at one year.

Disclosures:
Nothing To Disclose
See more of: Poster Session 1: Autologous Transplants
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