Umbilical Cord Blood transplantation in acute leukemias - PowerPoint PPT Presentation

Loading...

PPT – Umbilical Cord Blood transplantation in acute leukemias PowerPoint presentation | free to view - id: 12430e-MjU2Z



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Umbilical Cord Blood transplantation in acute leukemias

Description:

Umbilical Cord Blood transplantation in acute leukemias. Pablo Ramirez, M.D. DiPersio Lab ... Umbilical/placental niches? Transplantation with UCB: children ... – PowerPoint PPT presentation

Number of Views:357
Avg rating:3.0/5.0
Slides: 41
Provided by: pablor9
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Umbilical Cord Blood transplantation in acute leukemias


1
Umbilical Cord Blood transplantation in acute
leukemias
  • Pablo Ramirez, M.D.
  • DiPersio Lab
  • Grand Rounds, March 2009

2
Clinical 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?

3
High risk cytogenetics matched donor vs chemo
EORTC/GIMEMA Blood 20031021232-1240
4
Impact of HLA mismatch on OS
Lee, Blood 2007 1104576-83
5
(No Transcript)
6
No family HLA matched donor 67
options
Haploidentical family donor Most have
donors Not widespread
Volunteer Unrelated donor 50-70 matched donor
Unrelated cord donor
7
Cord 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.

9
Collection, 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

10
Biology UCBT more 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?

12
Transplantation 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

13
Outcomes unrelated UCB vs BM children with
acute leukemia CIBMTR-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
14
Probability 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

16
Transplantation 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

17
Comparison between UCBT-uBMT 2004 European
database analysis 1 unit
18
Comparison between UCBT-uBMT European database
analysis
  • Neutrophil recovery
  • cGVHD

Rocha et al. NEJM 20043512276-2285
19
Comparison between UCBT-uBMT European database
analysis
  • TRM
  • Relapse GVL

Rocha et al. NEJM 20043512276-2285
20
Comparison between UCBT-uBMT European database
analysis
  • OS
  • LFS

Rocha et al. NEJM 20043512276-2285
21
Comparison between UCBT-uBMT 2004 American
database analysis 1unit
22
Comparison between UCBT-uBMT American database
analysis
  • Neutrophil recovery
  • Platelet recovery

23
Comparison between UCBT-uBMT American database
analysis
  • LFS
  • OS

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

25
Comparison of uBM, PB and UCB Eapen 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

26
(No Transcript)
27
Conclusions from these studies and 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

28
Approaches 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

29
Transplantation of 2 partially HLA-matched UCB
units (U of MN) Myeloablative
  • Demographics
  • Neutrophil engraftment

Barker et al. Blood 20051051343-1347
30
Always one cord predominated Potential
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
31
  • GVHD
  • DFS

Barker et al. Blood 20051051343-1347
32
Transplantation of 2 partially HLA-matched UCB
units (U of MN) RIC
  • Demographics
  • Graft characteristics

Brunstein et al. Blood 20071103064-3070
33
Hematologic recovery
  • Netrophils
  • Platelets

34
  • Chimerism
  • aGVHD

II-IV
III-IV
35
  • 3-year TRM
  • 3-year EFS

2 UCB
1 UCB
36
1 vs 2 cords Blood March, 2009 UMN, 265 pts
Higher incidence of grade II-IV aGVHD
Higher incidence grade II-IV aGVHD per
conditioning regimen
37
1 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

38
Conclusions
  • 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

39
Unresolved 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
About PowerShow.com