Alemtuzumab Administration in Reduced Toxicity Conditioning (RTC) Regimens Prior to Allogeneic Hematopoietic Cell Transplantation (AlloHCT). What Matters Most – Timing or Donor Source?

Introduction:  The optimal timing of Alemtuzumab administration during RTC regimen is not well studied. Proximal administration may lead to more in vivo T cell depletion, decreasing GVHD but potentially increasing graft failure (GF) and delaying immune reconstitution.  Intermediate administration may improve engraftment but could lead to higher rates of GVHD.  We compared two centers’ experiences studying the schedule of Alemtuzumab within Busulfan/Fludarabine RTC regimen.

 Methods:  Pts ≤21 years old undergoing alloHCT for malignant and non-malignant conditions using a Busulfan-12.8-16mg/kg (Css- 600-900ng/ml)/Fludarabine (160-180mg/m2)/Alemtuzumab (45-54mg/m2) regimen were included.  Pts received Alemtuzumab either Days -6 to -2 (proximal group [PG]) or from Days -12 to -9 (intermediate group [IG]). 

Results:  37 pts were included in PG and 39 in IG.  Donor Sources in PG were related=20 (54%) and unrelated=17 (46%) vs. 14 (36%) and 25 (64%) in IG, respectively (p<0.001). Five pts (14%) in PG had an underlying malignancy vs 2 pts (5.1%) in IG.  Stem Cell Sources in PG were: BM=18 (49%), PBSC=4 (11%), related CB=3 (8%), unrelated CB (UCB)=12(32%); in IG, BM=27 (69%), PBSC=12 (31%).  To maximize the homogeneity, the UCB in the PG group were analyzed separately.  Kinetics of immune reconstitution are in Table 1 (excludes UCB). The incidence of viremia in PG vs. IG was comparable, p=0.3. Significantly higher CMV disease was seen in PG vs. IG (16.7% vs. 2.6%, p= 0.03), respectively.   Higher TRM was seen in IG vs. PG:  12.8% vs.  0%(p=0.06), respectively.  Rates of GF were comparable (p=1), while PG had a higher incidence of grade II-IV acute GVHD (32% vs. 12.8%, p=0.1). The OS at 1 year in PG was 96% vs. 79.5%(p=0.07) in IG. 

Day

Whole Blood Chimerism

CD4(cells/uL)

CD8(cells/uL)

CD56(cells/uL)

PG

IG

p

PG

IG

p

PG

IG

p

PG

IG

p

30

91.8± 21.8

93.4±19.8

0.765

25.8±48.3

76.25±92.97

0.198

6.4±10.4

105.0±99.5

0.142

146.7±104.1

66.8±77.8

0.189

100

94.2 ±7.8

95.8±4.6

0.399

51.0±38.1

113.0±84.1

0.001

77.2±116.5

203.5±258.1

0.020

256.8±138.4

217.1±125.1

0.270

180

93.0±6.2

92.7±12.1

0.911

148.8±134.3

283.6±163.6

0.003

156.0±146.3

399.8±358.9

0.004

252.9±148.7

260.2±132.5

0.857

365

89.9±10.0

91.9±15.7

0.574

583.7±346.8

784.1±589.1

0.280

593.9±564.9

599.6±367.4

0.974

350.8±377.0

285.0±204.5

0.508

In the UCB sub-analysis of PG pts (n=12), compared to remaining donor sources (n=25), a higher incidence of viral disease (33% vs. 16%, p=0.4), viral reactivation (58% vs. 32%, p=0.1), and GF (p=0.0001) and TRM (p=0.008 ) was noted, respectively. The 1 yr OS in the UCB cohort was 67%, p=0.03.

Discussion: Pts receiving PG had delayed immune reconstitution which did not impact OS.  Chimerism was comparable between the two groups.  The optimal timing of Alemtuzumab administration remains unclear; however, UCB is associated with inferior outcomes. Larger studies evaluating outcomes and health care utilization/cost are needed.