Title: Umbilical Cord Blood transplantation in acute leukemias
1Umbilical Cord Blood transplantation in acute
leukemias
- Pablo Ramirez, M.D.
- DiPersio Lab
- Grand Rounds, March 2009
2Clinical case
- 26 yo pt
- AML, complex cytogenetics
- CR after 73 induction chemotherapy
- No siblings
- 2 unrelated donors 6/8 HLA matched
- 6 UCB units gt4/6 HLA matched
- What are the options?
3High risk cytogeneticsmatched donor vs chemo
EORTC/GIMEMA Blood 20031021232-1240
4Impact of HLA mismatch on OS
Lee, Blood 2007 1104576-83
5(No Transcript)
6No family HLA matched donor 67
options
Haploidentical family donor Most have
donors Not widespread
Volunteer Unrelated donor 50-70 matched donor
Unrelated cord donor
7Cord blood-derived stem cell source
Boxmeyer et al Potential application of UCB HSC
for Clinical transplantation
Wagner et al First unrelated UCBT in a child
with leukemia
Rubinstein First UCB bank New York
Ende et al First human infusion of UCB in a pt
with ALL
1972 1974 1988 1989 1993
1994
Knudtzon et el First evidence of the Presence of
primitive and committed HSC
Gluckman et al First sibling UCB transplantation
in a pt with FA
8- 300K public UCB units available worldwide
- Over 8K UCBT worldwide
- National Cord Inventory
- 9 asian
- 16 African-American
- 14 multirace
- 40 CB units released are for pts of racial
minorities.
9Collection, processing and storage of UCB
- Collection in utero or after delivery
- Same total blood volume, CD34 and TNC
- Ballen et al. Transfusion 2002421261-1267
- Removal of excess of RBC and plasma
- TNC count, CFU, relevant ID, HLA, ABO, Rh,
genetic diseases or traits - Freezing rate and thawing process
10Biology UCBTmore questions than answers
- UCB T-cells biology Clin Immunol 2008
- Lower incidence of acute and chronic GVHD
- Lower lymphocyte counts?
- Limited response of naïve T-cells
- Less citotoxicity and proliferation
- Reduced cytokine production
- Significant GVL response
- Slower immune reconstitution
- Higher amount of Treg
- More suppressive in vitro
11- Stem cells Clin Immunol 2008
- Slower hematologic engraftment
- Lower counts of CD34
- Higher proliferation rate than adult HSC
- Mouse models
- Higher engraftment capacity compared to mobilized
HSC - Niche Blood 2007 Stem Cells 1998
- Cytokine and adhesion molecules milieu?
- Oxigenation ? normoxia vs hypoxia
- VLA4/VCAM-1 interaction ? survival advantage
- Umbilical/placental niches?
12Transplantation with UCB children
- Ablative conditioning
- No randomized studies UCBT vs unrelated donors
- Majority of the data ? registries and series
- CTN trial comparing 1 vs 2 units
13Outcomes unrelated UCB vs BM children with
acute leukemiaCIBMTR-USA
- TRM
- Higher (comp to BM)
- 2 Ag mm UCB
- RR 2.31 p0.0003
- 1 Ag mm low CD34 dose UCB
- RR 1.88 p0.045
- Relapses
- Lower
- 2 Ag mmUCB
- RR 0.54 p0.0045
- 503 children UCBT
- 282 uBM recipients
- acute leukemias
- Primary end point
- 5 year LFS
- mBM is the standard
- 8 allele match
Wagner et al. Lancet 20073691947-1954
14Probability of LFS
60
33-45
15- These data and others support HLA-matched and 1
or 2 antigen HLA-mismatched UCB in children with
acute leukemia who need transplantation - Better HLA matching and higher cell doses
significantly decrease the risk of TRM - Threshold gt 2.5 x 107 /kg TNC
- How much HLA disparity?
- HLA match partially compensates low TNC dose
16Transplantation with UCB adults
- Favorable results in children
- Single institutions or database analysis
- No prospective studies yet
- Some questions
- Feasibility
- Impact on OS, EFS
- Impact on GVHD, GVL
- Impact of low dose of TNC/CD34
- Role of RIC
17Comparison between UCBT-uBMT2004 European
database analysis 1 unit
18Comparison between UCBT-uBMTEuropean database
analysis
Rocha et al. NEJM 20043512276-2285
19Comparison between UCBT-uBMTEuropean database
analysis
Rocha et al. NEJM 20043512276-2285
20Comparison between UCBT-uBMTEuropean database
analysis
Rocha et al. NEJM 20043512276-2285
21Comparison between UCBT-uBMT2004 American
database analysis 1unit
22Comparison between UCBT-uBMTAmerican database
analysis
23Comparison between UCBT-uBMTAmerican database
analysis
Plt0.001
P0.001
24- GVHD
- Acute II-IV (p0.04)
- 51 mmBMT
- 48 mBMT,
- 40 UCBT
- Chronic
- 50 UCBT
- 40 mmBMT
- 35 mBMT
- TRM
- 65 mmBMT
- 63 UCBT
- 46 mBMT
- Relapse
- Similar between 3 groups
25Comparison of uBM, PB and UCBEapen et al, ASH
2008
- 1240 adults gt16 years
- AML n707
- ALL n533
- BM and PB T-cell replete and 7/8 or 8/8 HLA
matched (A,B,C and DRB1) - Cords were gt4/6 HLA matched (A,B and DRB1)
- Neutrophil engraftment
- 78 at 42 days UCB
- 94 at 42 days PB/BM
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27Conclusions from these studiesand other databases
- UCB is feasible in adults with adequate number of
cells - Lower risk of GHVD despite greater HLA disparity
- The standard still is matched related or
unrelated PB/BM but if not matched donor,
outcomes are similar for UCBT - Significant delays in neutrophil engraftment and
higher TRM - Unresolved aspects
- Dose, conditioning regimen, long term effects,
GVHD prophylaxis? - How to reduce the high mortality associated to
the procedure? - How to reduce the delayed engraftment?
- Real advantage over MUD?
- Best combination cell dose/HLA disparity
28Approaches to improve rates and kinetics of
engraftment
- Dual transplants haplo CD34 UCB or MSC
- Ex vivo UCB expansion prior to infusion
- Cord stem cell mobilization
- Double cords
29Transplantation of 2 partially HLA-matched UCB
units (U of MN)Myeloablative
Barker et al. Blood 20051051343-1347
30Always one cord predominatedPotential
contributors
- CD3?no
- CD34?no
- Matching?no
- Sequence of infusion?no
- Mouse model?no
- Shipping and processing?maybe
- Rate of infusion? maybe
- Order of infusion?aybe
- Adhesion molecules
- ? unknown
Barker et al. Blood 20051051343-1347
31Barker et al. Blood 20051051343-1347
32Transplantation of 2 partially HLA-matched UCB
units (U of MN)RIC
Brunstein et al. Blood 20071103064-3070
33Hematologic recovery
34II-IV
III-IV
352 UCB
1 UCB
361 vs 2 cordsBlood March, 2009 UMN, 265 pts
Higher incidence of grade II-IV aGVHD
Higher incidence grade II-IV aGVHD per
conditioning regimen
371 year TRM
All pts
Grade II-IV aGVHD
- Risk factors for aGVHD
- 2 units
- RIC
- No ATG
- No MMF
- Risk factors for TRM
- 1 unit
38Conclusions
- Clinical experience is improving
- Lower TRM
- Improvement in results in adults
- Better pt selection, greater TNC dose infused,
better treatment of complications - Important role of double cords and RIC
- 8/8 matched PB or BM still is the first choice
for adults with acute leukemias that require SCT - Partially matched UCB with adequate cell dose is
an alternative for the large proportion of pts
for whom an 8/8 matched unrelated donor is not
identified or requires an urgent transplant
39Unresolved questions in UCBT
- Minimum TNC dose for each level of mismatch?
- Minimum TNC dose of 2.5 x 107 /kg
- Should CD34 dose be considered in unit
selection? - Optimal conditioning regimen
- Direct comparison single vs double cords
- BMT CTN RCT 2-21 yo, 110 pts, 5-year accrual
- Long term immune reconstitution
- GVHD, GVL
- Best method to study HLA serology, PCR?
- Mechanisms of engraftment?
- Costs UCB vs MUD
40- New strategies are needed to improve
hematopoietic recovery and reduce early TRM after
UCBT - Only a RCT UCB vs BM could exclude potential
selection bias - Logistics
- Few patients with both donor types
- Ethical considerations
- In the absence of RCT the efficacy of UCBT over
BM graft cannot be definitely stated