Myeloablative umbilical cord blood transplantation for hematologic malignancies is comparable to unrelated

donor transplantation: a retrospective single center study

Filippo Milano, MD, PhD Clinical Research Division

Fred Hutchinson Cancer Research Center

Seattle, WA, USA

Background

Umbilical cord blood transplantation has become a widely and acceptable stem cell source for transplantation.

Several studies have shown comparable survival rates for both adult and pediatric cord blood transplant recipients when compared to unrelated donor transplantation. 1,3

Growing evidence of low incidence of relapse after cord blood transplantation. 4

1. Laughlin M. et al. N Engl J Med 2004; 4351: 2265–227.5 2. Eapen M. et al. Lancet 2007; 369: 1947–1954. 3. Brunstein C. et al Blood 2010; 116: 4693–4699. 4. Verneris M. Blood 2009; 114: 4293-4299.

Study design Between January 2006 and December 2012 we retrospectively analyzed

outcomes for 566 patients undergoing first allogeneic hematopoietic stem cell transplantation for hematologic malignancies with either cord blood (CBT) or unrelated donor (URD).

In the CBT group (n=112) selected cord blood units were required to be matched to the recipient at ≥ 4 of the 6 HLA loci based on intermediate resolution typing at HLA-A and –B and allele-level for HLA-DRB1.

All patients received a double CB graft except for 16 patients (14%) who received a single CB graft. In addition, 29 (26%) patients received an ex vivo expanded CB unit as part of either a single or double CBT.

In the URD group (n=447), patients received either HLA 10/10 (n=332) allele matched URD (MURD) or 1 (n=115) allele mismatched URD (MMURD).

Definitions/Statistical Methods

The primary endpoint was evaluation of disease free survival, relapse and non-relapse mortality.

Hematopoietic recovery was evaluated comparing time to neutrophil recovery (≥ 500/µl by day 45).

Chronic GVHD was assessed using old classification criteria.

The patient’s underlying disease was categorized as low, intermediate, high and very high-risk based upon previously described criteria*.

Time-to-event outcomes were compared between groups using Cox regression, and logistic regression was used for acute and chronic GVHD. All models were adjusted for age, race, year of HCT, disease risk and CMV serostatus.

*Armand Philippe et al. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood 2012; 120(4):905-13.

Patient characteristics (1) UCB

(n=112) MURD

(n=332) MMURD (n=115)

Age in years median, (range) 28 (0.6-67) 42 (1-67) 47 (2-65)

Gender, n (%) Female

52 (46)

141 (42)

50 (43)

Weight in kg median, (range) 70 (8-139) 75 (10-158) 79 (12-142)

Race, n (%) Caucasian Other

45 (45) 57 (55)

272 (87) 39 (13)

82 (75) 27 (25)

CMV serostatus, n (%) Pos Neg

75 (68) 35 (32)

173 (53) 153 (47)

60 (53) 52 (47)

Diagnosis, n (%) AML ALL MDS Myeloproliferative disorders CLL/Lymphoma Other

57 (51) 34 (30) 10 (9) 6 (5) 3 (3) 2 (2)

132 (40) 80 (24) 51 (15) 56 (17) 11 (3) 2 (<1)

50 (43) 26 (23) 15 (13) 22 (19)

2 (2) -

Patient characteristics (2) UCB

(n=112) MURD

(n=332) MMURD (n=115)

Stem cell source, n (%) UCB BM PB

112 (100)

- -

-

118 (36) 214 (64)

-

36 (31) 79 (69)

Disease risk, n (%) Low Intermediate High Very High

9 (8)

68 (61) 33 (29)

2 (2)

13 (4)

258 (78) 52 (16)

9 (3)

5 (4)

80 (70) 28 (24)

2 (2)

Conditioning regimen, n (%) FLU/CY/TBI 1320 cGy TREO/FLU/TBI 200 cGy BU with either Cy or Flu CY/TBI 1200 or 1320 cGy

83 (74) 29 (26)

- -

-

58 (17) 144 (43) 130 (39)

-

7 (6) 69 (60) 39 (34)

GVHD Prophylaxis, n(%) CSA+MMF FK506+MTX FK506+MMF+CY Other

112 (100)

- - -

-

58 (88) 23 (7) 15 (5)

-

114 (99) -

1 (1)

Age distribution

Overlap UCBT URD

Neutrophil engraftment

0.2

.4.6

.81

Prob

abilit

y

0 20 40 60 80 100Days after HCT

Non-Matched Cryopreserved

Median=19 days

PB Median=17 days

Partially Matched Median=11 days

Conventional CBT Median=23 days

BM Median=21 days

Univariate analysis (Overall Mortality) Hazard Ratio

(95% CI) p-value

Gender Female Male

1

1.25 (0.93-1.67)

-

0.14

CMV serostatus Neg Pos

1

1.25 (0.93-1.67)

-

0.14

Years of HCT* 0.89 (0.83-0.96) <0.01

Age* 1.01 (1.00-1.02) 0.01

Disease risk Low Intermediate High Very High

1

1.19 (0.58-2.43) 1.93 (0.92-4.07) 3.18 (1.19, 8.47)

-

0.64 0.08 0.02

Stem cell source BM CORD PBSC

1

0.92 (0.60-1.41) 1.08 (0.78-1.50)

-

0.71 0.64

Donor CORD 10/10 MURD 9/10 MMURD

1

1.02 (0.69-1.50) 1.53 (0.99-2.36)

-

0.92 0.05

* Modeled as continuous variable

Univariate analysis (Non-Relapse Mortality) Hazard Ratio

(95% CI) p-value

Gender Female Male

1

1.37 (0.93-2.01)

-

0.11

CMV serostatus Neg Pos

1

1.20 (0.82-1.76)

-

0.35

Year of HCT* 0.89 (0.81-0.98) 0.02

Age* 1.03 (1.01-1.04) <0.01

Disease risk Low Intermediate High Very High

1

0.68 (0.33-1.42) 1.16 (0.53-2.55) 3.35 (1.21- 9.26)

-

0.30 0.70 0.02

Stem cell source BM CORD PBSC

1

1.05 (0.62-1.81) 1.08 (0.70-1.67)

-

0.85 0.49

Donor CORD 10/10 MURD 9/10 MMURD

1

0.87 (0.53-1.40) 1.37 (0.80-2.35)

-

0.56 0.26

* Modeled as continuous variable

Univariate analysis (Relapse) Hazard Ratio

(95% CI) p-value

Gender Female Male

1

1.15 (0.78-1.69)

-

0.49

CMV serostatus Neg Pos

1

1.19 (0.80-1.75)

-

0.39

Year of HCT* 0.91 (0.83-1) 0.06

Age* 1.00 (0.99-1.01) 0.65

Disease risk Low Intermediate High Very High

1

1.00 (0.99-1.01) 1.70 (1.11-2.58) 2.08 (0.65- 6.61)

-

0.64 0.01 0.21

Stem cell source BM CORD PBSC

1

0.54 (0.28-1.05) 1.17 (0.76-1.79)

-

0.07 0.49

Donor CORD 10/10 MURD 9/10 MMURD

1

2.03 (1.10-3.75) 2.20 (1.11-4.39)

-

0.02 0.02

* Modeled as continuous variable

Disease Free Survival

HR (95% CI) p-value Cord Blood 1.0

MURD 1.02 (0.67-1.55) 0.92 MMURD 1.30 (0.81-2.10) 0.27

DFS at 4 years

CORD 69%

MURD 61%

MMURD 52%

Risk of Overall Mortality as function of age

Non-relapse mortality

HR (95% CI) p-value Cord Blood 1.0

MURD 0.71 (0.42-1.21) 0.21 MMURD 0.92 (0.50-1.69) 0.79

NRM at 4 years

CORD 20%

MURD 21%

MMURD 27%

Risk of Non-Relapse Mortality as function of age

Relapse

HR (95% CI) p-value Cord Blood 1.0

MURD 2.44 (1.29-4.63) 0.006 MMURD 2.32 (1.12-4.81) 0.02

Relapse at 4 years

CORD 12%

MURD 22%

MMURD 31%

Risk of Relapse as function of age

Acute GVHD

HR (95% CI) p-value Cord Blood 1.0 MURD BM 0.71 (0.52-0.97) 0.03 MURD PB 0.66 (0.50-0.88) 0.004

MMURD BM 0.86 (0.54-1.34) 0.49 MMURD PB 0.98 (0.70-1.39) 0.93

HR (95% CI) p-value Cord Blood 1.0 MURD BM 0.76 (0.40-1.42) 0.39 MURD PB 0.63 (0.35-1.11) 0.11

MMURD BM 1.27 (0.55-2.94) 0.57 MMURD PB 1.29 (0.68-2.44) 0.44

Chronic GVHD

HR (95% CI) p-value Cord Blood 1.0 MURD BM 0.64 (0.42-0.97) 0.04 MURD PB 0.91 (0.63-1.32) 0.61

MMURD BM 0.74 (0.41-1.34) 0.31 MMURD PB 1.08 (0.68-1.70) 0.44

0.2

.4.6

Pro

babi

lity

0 1 2 3Years after HCT

p=0.10

Unrelated matched 26%

Cord Blood 16%

0.00

0.25

0.50

0.75

1.00

Pro

babi

lity

0 1 2 3Years after HCT

p=0.94

Cord Blood 54%

Unrelated matched 59%

Treo/Flu/TBI – UCB vs URD

Relapse

0.2

.4.6

Pro

babi

lity

0 1 2 3Years after HCT

p=0.07

Unrelated matched 14%

Cord Blood 29%

Non-Relapse Mortality

Disease Free-Survival

0.2

.4.6

Prob

abilit

y

0 1 2 3 4 5Years after HCT

Cord Blood 21% Unrelated Mismatched 21%

Unrelated Matched 14%

0.2

.4.6

Pro

babi

lity

0 1 2 3 4 5Years after HCT

Cord Blood 11%

p=0.003

Unrelated Mismatch 34%

Unrelated Matched 24%

0.00

0.25

0.50

0.75

1.00

Prob

abilit

y0 1 2 3 4 5

Years after HCT

Cord Blood 67%

Unrelated matched 60%

Unrelated Mismatched 45%

p=0.03

p=0.83

High-dose TBI – UCB vs MURD vs MMURD

Disease Free-Survival

Non-Relapse Mortality Relapse

0.00

0.25

0.50

0.75

1.00

Pro

babi

lity

0 2 4 6Years after CBT

Disease free survival in UCBT by disease

DFS at 4 years

ALL 78%

MDS/CML 74%

AML 62%

AML

MDS/CML

ALL

Conclusions Disease free survival, relapse free survival and non-relapse mortality

after CBT were not inferior to those observed after URD transplantation.

Speed of engraftment in CBT recipients receiving ex-vivo expanded cells was similar to what observed after peripheral blood and bone marrow.

“Younger” CBT patients appear to have an advantage over “younger” URD patients in terms of lower risk of overall mortality, however this advantage appears to disappear for “older” patients.

Relapse occurred less frequently for CBT recipients when compared to both MMURD and MURD.

The risk of chronic GVHD was lower for patients receiving MURD with BM but similar between the other groups.

Things to do….

Add other variables to the analysis: - HCT-CI score - Presence of minimal residual disease at time of

transplantation - Evaluation of allele mismatching among the

MMURD Use NIH GVHD classification for all patients

Future directions

Results are encouraging but can we do better? The use of non-matched cryopreserved ex-vivo

expanded CD34+ cells might reduce the early mortality due to the delayed hematopoietic recovery and potentially increase GVL effect (Protocol 2603)

How we do improve access to transplant for all patients in need? Set-up a randomized study between CBT and URD

recipients

ACKNOWLEDGEMENTS

Colleen Delaney

Ted Gooley Bau Ellie

Rachel Salit Riffkin Ivy

Ziegler Denise

Fred Appelbaum Ann Woolfrey

Boglarka Gyurkocza Bob Whiterspoon

Paul O’Donnell Joachim Deeg

Harrington Liz Adrienne Papermaster

Connie Nakano Lisa Getzendaner

Celia Evans