228 Impact of Dose Intensification of FluBu2 to FluBu4 On Transplant Related Mortality, Relapse, and Survival After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia in Remission

Track: Contributed Abstracts
Wednesday, February 13, 2013, 6:45 PM-7:45 PM
Hall 1 (Salt Palace Convention Center)
John Magenau, M.D. , Adult Blood and Marrow Transplant Program, University of Michigan
Attaphol Pawarode, M.D. , Adult Blood and Marrow Transplant Program, University of Michigan
Daniel R. Couriel, M.D. , Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI
Gregory Yanik, M.D. , Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI
Shin Mineishi, M.D. , University of Alabama at Birmingham, Birmingham, AL
Thomas Braun, Ph.D. , Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI
Pavan Reddy, M.D. , Adult Blood and Marrow Transplant Program, University of Michigan
James L.M. Ferrara, M.D., D.Sc. , Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI
David Frame, PharmD , Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI
Sung Won Choi, M.D. , Pediatric Blood and Marrow Transplant Program, University of Michigan
Andrew C. Harris, M.D. , Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI
Carrie L. Kitko, M.D. , Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI
James A Connelly, M.D. , Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI
John Levine, MD, MS , Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI
Steven C. Goldstein, M.D. , Adult Blood and Marrow Transplant Program, University of Michigan

Reduced intensity conditioning (RIC) with fludarabine (Flu) and sub-myeloablative doses of busulfan (Bu) (< 8 mg/kg) has low transplant related mortality (TRM) compared to myeloablative (MA) conditioning, and is increasingly utilized in older and medically infirm pts. Flu with MA Bu (>8mg/kg) using pharmacokinetic (PK) dosing also has low TRM, but randomized comparisons to RIC are lacking. Therefore, we compared RIC and MA FluBu dosing on TRM, relapse and survival in remission AML. We reviewed AML pts receiving allogeneic hematopoietic stem cell transplant (HSCT) in remission (CR1/CR2) at the University of Michigan from 2003 – 2011. RIC (FluBu2) was flu 40mg/m2 x 4 days with IV Bu 3.2 mg/kg x 2 days. FluBu2 included TLI/TBI (200cGy) in 39% of cases, and ATG in one case. MA (FluBu4) was flu 40mg/m2 x 4 days with IV Bu 3.2 mg/kg x 4 days with PK adjustment to a target Css of 600-900 mcg/L (Seattle PK lab). FluBu4 had no TBI/TLI/ATG. Pt < 18 yrs, cords, prior HSCT and active AML were excluded. Cumulative incidence of GVHD, TRM and relapse were calculated with competing risks.  A total of 122 pts (FluBu2=71; FluBu4=51) were identified. Most primary GVHD prophy was tacro + MMF for FluBu2 (89%), and tacro + MTX for FluBu4 (86%).  FluBu2 pts were older (60 vs. 51; p<0.01), but donor type, HLA match, and disease risk (cytogenetics / FLT3 ITD) were not significantly different. There was a trend towards higher (≥ 3) comorbidity index scores in FluBu2 (42% vs. 25%; p=0.09).  All FluBu4 pts engrafted; two graft failures occurred (3%) in FluBu2. TRM did not differ at day 100 (FluBu2=0% vs. FluBu4=2%; p=0.3) or 1 yr (FluBu2=17% vs. FluBu4=10%; p=0.3), but by 3 yrs there was a trend towards greater TRM in FluBu2 (FluBu2=24% vs. FluBu4=10%; p=0.06). After adjusting for donor type, HLA match, age, and HSCT-CI the trend for greater TRM in FluBu2 remained (HR: 3.5, p = 0.04, 95% CI: 1.1 – 11.0). Pts with HSCT-CI ≥ 3, had similar TRM with FluBu2 (HR: 1.5, p=0.6, 95% CI: 0.4 – 5.7). Acute GVHD grade II-IV was not significantly different between FluBu2 and FluBu4 (38% vs. 24%; p=0.09). Chronic GVHD caused late deaths in 10% of FluBu2, and in 4% of FluBu4. There was no significant difference in relapse at 3 yrs (FluBu2=43% vs FluBu4=36%, p=0.5). Overall survival (OS) favored FluBu4 compared to FluBu2 (OS: 62% vs. 39%; p=0.02). This difference in OS was greater in intermediate risk AML (74% vs 50%; p = 0.07), compared to high risk AML (40% vs 28%, p=0.5). FluBu4 pts had a non-significant OS advantage after multivariate analysis including donor type, HLA match, and disease risk (HR: 1.75, p = 0.06, 95% CI: 1.0 – 3.1). In summary, MA conditioning with FluBu4 did not increase TRM compared to RIC with FluBu2. The potential survival benefit of FluBu4 in remission AML requires prospective validation.

3 yr Nonadjusted Outcomes

FluBu2 (N=71)

FluBu4 (N=51)

p-value

TRM

24%

10%

0.06

Relapse

43%

36%

0.5

OS

39%

62%

0.02

DFS

34%

54%

0.04

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