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Myeloablative umbilical cord blood transplantation for
hematologic malignancies is comparable to unrelated
donor transplan...
Background
 Umbilical cord blood transplantation has become a
widely and acceptable stem cell source for
transplantation....
Study design
 Between January 2006 and December 2012 we retrospectively analyzed
outcomes for 566 patients undergoing fir...
Definitions/Statistical Methods
 The primary endpoint was evaluation of disease free survival,
relapse and non-relapse mo...
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 (...
Patient characteristics (2)
UCB
(n=112)
MURD
(n=332)
MMURD
(n=115)
Stem cell source, n (%)
UCB
BM
PB
112 (100)
-
-
-
118 (...
Age distribution
Overlap UCBT URD
Neutrophil engraftment
0.2.4.6.81
Probability
0 20 40 60 80 100
Days after HCT
Non-Matched
Cryopreserved
Median=19 days
PB...
Univariate analysis (Overall Mortality)
Hazard Ratio
(95% CI)
p-value
Gender
Female
Male
1
1.25 (0.93-1.67)
-
0.14
CMV ser...
Univariate analysis (Non-Relapse Mortality)
Hazard Ratio
(95% CI)
p-value
Gender
Female
Male
1
1.37 (0.93-2.01)
-
0.11
CMV...
Univariate analysis (Relapse)
Hazard Ratio
(95% CI)
p-value
Gender
Female
Male
1
1.15 (0.78-1.69)
-
0.49
CMV serostatus
Ne...
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 y...
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 y...
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...
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 (...
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 ...
0.2.4.6
Probability
0 1 2 3
Years after HCT
p=0.10
Unrelated matched 26%
Cord Blood 16%
0.000.250.500.751.00
Probability
0...
0.2.4.6
Probability
0 1 2 3 4 5
Years after HCT
Cord Blood 21% Unrelated Mismatched
21%
Unrelated Matched 14%
0.2.4.6
Prob...
0.000.250.500.751.00
Probability
0 2 4 6
Years after CBT
Disease free survival in UCBT by disease
DFS at 4 years
ALL 78%
M...
Conclusions
 Disease free survival, relapse free survival and non-relapse mortality
after CBT were not inferior to those ...
Things to do….
Add other variables to the analysis:
- HCT-CI score
- Presence of minimal residual disease at time of
tran...
Future directions
Results are encouraging but can we do better?
 The use of non-matched cryopreserved ex-vivo
expanded CD...
ACKNOWLEDGEMENTS
Colleen Delaney
Ted Gooley
Bau Ellie
Rachel Salit
Riffkin Ivy
Ziegler Denise
Fred Appelbaum
Ann Woolfrey
...
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Myeloablative Umbilical Cord Blood Transplantation for Hematologic Malignancies is Comparable to Unrelated Donor Transplantation: a Retrospective Single Center Study

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Transcript of "Myeloablative Umbilical Cord Blood Transplantation for Hematologic Malignancies is Comparable to Unrelated Donor Transplantation: a Retrospective Single Center Study"

  1. 1. 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
  2. 2. 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.
  3. 3. 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).
  4. 4. 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.
  5. 5. 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) -
  6. 6. 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)
  7. 7. Age distribution Overlap UCBT URD
  8. 8. Neutrophil engraftment 0.2.4.6.81 Probability 0 20 40 60 80 100 Days after HCT Non-Matched Cryopreserved Median=19 days PB Median=17 daysPartially Matched Median=11 days Conventional CBT Median=23 days BM Median=21 days
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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%
  13. 13. Risk of Overall Mortality as function of age
  14. 14. 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%
  15. 15. Risk of Non-Relapse Mortality as function of age
  16. 16. 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%
  17. 17. Risk of Relapse as function of age
  18. 18. 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
  19. 19. 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
  20. 20. 0.2.4.6 Probability 0 1 2 3 Years after HCT p=0.10 Unrelated matched 26% Cord Blood 16% 0.000.250.500.751.00 Probability 0 1 2 3 Years after HCT p=0.94 Cord Blood 54% Unrelated matched 59% Treo/Flu/TBI – UCB vs URD Relapse 0.2.4.6 Probability 0 1 2 3 Years after HCT p=0.07 Unrelated matched 14% Cord Blood 29% Non-Relapse Mortality Disease Free-Survival
  21. 21. 0.2.4.6 Probability 0 1 2 3 4 5 Years after HCT Cord Blood 21% Unrelated Mismatched 21% Unrelated Matched 14% 0.2.4.6 Probability 0 1 2 3 4 5 Years after HCT Cord Blood 11% p=0.003 Unrelated Mismatch 34% Unrelated Matched 24% 0.000.250.500.751.00 Probability 0 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
  22. 22. 0.000.250.500.751.00 Probability 0 2 4 6 Years after CBT Disease free survival in UCBT by disease DFS at 4 years ALL 78% MDS/CML 74% AML 62% AML MDS/CML ALL
  23. 23. 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.
  24. 24. 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
  25. 25. 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
  26. 26. 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
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