myeloablative umbilical cord blood transplantation for hematologic malignancies is comparable to...
TRANSCRIPT
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