This document discusses graft-versus-host disease (GVHD) and umbilical cord transplantation. It provides background on umbilical cord blood transplants and their relationship to GVHD. Specifically, it addresses several risk factors for GVHD following umbilical cord transplantation, including the degree of HLA matching between donor and recipient, GVHD prophylaxis regimens, and the use of anti-thymocyte globulin (ATG). The document analyzes studies on these topics and provides evidence that better HLA matching, use of mycophenolate for GVHD prophylaxis, and ATG administration may help reduce the risk of GVHD, though results are mixed.
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Graft-vs.-Host Disease and Umbilical Cord Transplantation
1. Graft-vs.-Host Disease
and Umbilical Cord
Transplantation
Amin M. Alousi, MD
Associate Professor of Medicine
Department of Stem Cell
Transplantation
GVHD
Disclosures: Therakos, research funding; All therapeutics are off-
label.
2.
3. Umbilical Cord Transplantation and GVHD
and
Donald Rumsfield . . .
ā There are known knowns; there
are things we know that we know.
There are known unknowns; that is
to say, there are things that we
now know we don't know.
But there are also unknown
unknowns ā there are things we do
not know we donāt know ā
āformer United States Secretary of
Defense, Donald Rumsfeld
4. What we know
What we do not know
What we do not know to
know that we may
never know
Umbilical Cord Transplantation and GVHD . . .
5. Things claimed to be known
That is things claimed to be a fact
Which are in fact,
wrong
Umbilical Cord Transplantation and GVHD
and Weapons of Mass Destruction . . .
6. Umbilical Cord Blood Transplants: Background
ļ± Unrelated Umbilical Cord transplantation has
expanded the donor pool for patients who do not
have an HLA-matched sibling or unrelated donor.
ļ± This is primarily due to the fact that HLA
mismatches are more āpermissibleā resulting in
rates of GVHD comparable to matched unrelated
donors.
ļ± However, outcomes have been hampered by
increased treatment-related mortality.
7. vs. MUD Peripheral Blood Less Acute and Chronic
Hazard Ratio p value
Acute GVHD 0Ā·57 0Ā·002
Chronic GVHD 0Ā·38 0Ā·001
vs. MUD Bone Marrow Less Chronic
Hazard Ratio p value
Acute GVHD 0Ā·78 0Ā·13
Chronic GVHD 0Ā·63 0Ā·01
vs. 1-ag MM PB or BM Less Acute and Chronic
Acute GVHD Hazard Ratio p value
vs. 7/8 Bone Marrow 0Ā·59 0Ā·01
vs. 7/8 Peripheral Blood 0Ā·57 0Ā·002
Chronic GVHD
vs. 7/8 Bone Marrow 0Ā·59 0Ā·01
vs. 7/8 Peripheral Blood 0Ā·49 0Ā·002
Eapen et al. Lancet Oncol. 2010
Single Unit 4-6/ 6 Matched Cord Blood vs. Adult Unrelated Donors
8. TRM Hazard Ratio p value
vs. MUD Bone Marrow 1Ā·69 0Ā·003
vs. MUD Peripheral Blood 1Ā·62 0Ā·003
vs. 1-antigen Mismatched BM 1Ā·06 0Ā·76
vs. 1-antigen Mismatched PB 0Ā·95 (0Ā·68ā1Ā·34) 0Ā·78
Eapen et al. Lancet Oncol. 2010
The Paradox
Less GVHD more Treatment Related Mortality (TRM)
Single Unit 4-6/ 6 Cord Blood vs. Unrelated Donor
9. Double Unit Umbilical Cord vs. Matched Related, Matched
Unrelated and Mismatch Unrelated Donor
Multivariable Analysis of Outcome
Acute GVHD Grades II-IV Relative Risk p value
Double UCB Donor 1.0
Matched Related Donor 1.08 0Ā·57
Matched Unrelated Donor 1.83 <0.01
Mismatch Unrelated Donor 2.35 <0.01
Less Acute than in MUD and Mismatch Unrelated Donor
Chronic GVHD Relative Risk p value
Double UCB Donor 1.0
Matched Related Donor 1.58 0Ā·03
Matched Unrelated Donor 1.71 0Ā·01
Mismatch Unrelated Donor 2.07 0.01
Less Chronic than in MRD, MUD and Mismatch Unrelated Donor
Transplant-related mortality (TRM) Hazard Ratio p value
Double UCB Donor 1.0
Matched Related Donor 0.31 <0.01
Matched Unrelated Donor 0.61 0.13
Mismatch Unrelated Donor 0.38 <0.01
But . . . Higher TRM than in MRD or MUD
Brunstein and Delaney. Blood. 2010
10. Risk Factors for GVHD following UCB transplantation:
Selection of Cord Units
Does degree of HLA matching impact GVHD
rates following umbilical cord transplantation?
11. Factors Associated with Acute GVHD after Cord-Blood Transplantation
Gluckman E et al. N Engl J Med 1997.. Rubinstein P et al. N Engl J Med 1998.
12. Risk Factors for GVHD following Single and Double Unit UCB
transplantation: Selection of Cord Units
Factors associated with grade II-IV acute GVHD
multiple regression analysis
HLA matching
(engrafting unit)
RR of acute
GVHD (95% CI)
P
6/6 1.0
5/6 1.9 (0.9-4.2) .11
4/6 1.4 (0.7-3.2) .36
MacMillan et al. Blood. 2009; 113: 2410-15.
13. Risk Factors for GVHD following UCB transplantation: Selection
of Cord Units: Impact of C-locus.
ļ± Cords historically are selected based on intermediate-resolution
typing at the HLA-A and B loci and allele-level typing at DRB1.
ļ± Recently, the relative importance of matching at HLA C has been
retrospectively studied.
ļ± TRM was higher in:
ļ§ Patients with 6/6 match unit but mismatched at HLA-C
versus those matched at C.
ļ§ Patients with 5/6 match unit + second mismatch at HLA-C
versus those matched at C.
ļ± However, mismatching at the C-locus (or any other loci) did not
impact the rates of acute or chronic GVHD.
Eapen et al. Lancet Oncol. 2011; 12: 1214-21.
14. Hazard Ratio for TRM and OS
associated with a single mismatch at HLA- A, B, C or DRB1
versus a match in that locus in the presence of
0, 1, 2 or 3+ mismatches at other loci.
Treatment Related Mortality Overall Survival
Eapen et al. Lancet Oncol. 2011; 12: 1214-21
Single Mismatch at locus vs. Match at that locus
plus 0 or 1 other mismatches:
Higher TRM
Single Mismatch at locus vs. Match at that locus
plus 0 or 1 other mismatches:
Overall Survival Not Impacted
15. Cumulative incidence of Acute GVHD Grade III/IV: Impact of
matching based on allele level typing
HLA-A,-B,-DRB1 HLA-A,-B,-C,-DRB1,-DQ
Ponce et al. BBMT. 2013.
Roughly 1/3rd pts retrospectively
found to be < 4/6 match
16. Risk Factors for GVHD following UCB transplantation:
Selection of Cord Units
Does degree of HLA matching impact GVHD
rates following umbilical cord transplantation?
Answer: Perhaps (when units are poorly
matched at allele level typing)
17. Risk Factors for GVHD following UCB transplantation:
GVHD Prophylaxis Regimens
Does Using Methotrexate matter?
Is Mycophenolate Better?
Does the Dose of Mycophenolate Matter?
What about Rappamune (Sirolimus)?
18. Methotrexate in GVHD prophylaxis lowers the
likelihood of Neutrophil recovery.
Herr A et al. Blood 2010;116:1849-1856
Hazard Ratio of 0.48
(95% CI, 0.31-0.73; p<0.001) on
MV analysis
19. Use of Mycophenolate (MMF) in GVHD Prophylaxis
ā¢ In the Non-Cord setting, most studies have shown comparable
rates of acute GVHD with CNI + MTX versus CNI + MMF.
ā¢ In the non-myeloablative adult donor setting, CNI + MMF is
often employed to minimize toxicity associated with MTX.
ā¢ Similarly, because of the concern of engraftment in cords
when MTX is used, most centers (at least within the U.S.) have
replaced MTX with MMF.
ā¢ In the cord setting, there is limited evidence supporting this
approach with no comparisons of CNI+MTX versus CNI+MMF.
20. Factors Single Double P
Total N= 80 N=185
Conditioning < .01
Myeloablative 61 (76%) 78 (42%)
Nonmyeloablative 19 (24%) 107 (58%)
Use of ATG in the conditioning < .01
Yes 46 (58%) 49 (26%)
No 34 (43%) 136 (74%)
GVHD prophylaxis < .01
CSA/MP 46 (58%) 4 (2%)
CSA/MMF 33 (41%) 181 (98%)
CSA/MTX 1 (1%) 0
Factors associated with grade II-IV acute GVHD: multiple regression
Factor RR of acute GVHD (95% CI) P
ATG in conditioning
No 1.0
Yes 0.5 (0.3-0.9) .02
MMF as GVHD prophylaxis
No 1.0
Yes 0.5 (0.2-1.3) .14
ATG only given in
those patients
not getting MMF
Even with no ATG
in the MMF group
trend for less
acute GVHD
Addition of MMF to CNI: trend for lower acute
GVHD when compared to CNI + steroids
MacMillan et al. Blood. 2009. 113: 2410-15
21. MMF Twice Daily or Thrice Daily Dosing?
ā¢ Thrice daily versus Twice daily dosing of
MMF was found to be associated with
better PKās in the setting of non-
myeloablative, MUD transplants.
ā¢ Poor Donor T-cell chimerism was seen in
patients with low MPA Css but no
association with acute GVHD incidence.
ā¢ Based on this analysis some have
recommended thrice daily dosing for
prophylaxis in NMA transplants.
ā¢ Not extensively studied in the umbilical cord
setting.
ā¢ MMF may cause neutropenia and in the
non-transplant setting this has been shown
to be dependent on drug levels.
Giaccone et al. Blood. 2005. 106: 4381.
22. Letter to Editor: Delayed neutrophil engraftment in cord blood
transplantation with intensive administration of mycophenolate for
GVHD prophylaxis
Single-Unit Cord Blood Transplant BMT
b.i.d. Dosing t.i.d. Dosing b.i.d. Dosing t.i.d. Dosing
No. of Patients 13 15 9 8
Median age, yrs 49 (21-66) 52 (20-66) 42 (32-58) 48.5 (35-59)
Sex, male/female 5/8 9/6 6/3 6/2
Diagnosis
AML
ALL
MDS
NHL
Others
1
5
6
1
0
2
5
5
1
2
2
2
4
0
1
0
2
3
3
0
Conditioning
Myeloablative
Non-Myeloablative
9
4
6
9
8
1
5
3
Median CD34+ cells,
X 106/kg (range)
P
0.10 (0.04-0.21) 0.09 (0.03-0.19) 1.30 (0.74-2.60) 1.05 (0.23-3.70)
0.67 0.53
Neutrophil Engraftment
Median period, days
P
17 (14-18) 22 (14-41) 11 (9-17) 11 (8-14)
0.016 0.696
Okamura et al. BMT.2011. 46: 148-149.
23. Sirolimus and Tacrolimus for GVHD prophylaxis in
Double Cord Transplant following Flu-Mel-ATG
Days -8 -7 -6 -5 -4 -3 -2 -1 0
FLUDARABINE 30 mg2 / day X 6 days
Mel
100
mg/m2
**ATG
1.5
mg/kg
ATG
1.5
mg/kg
ATG
1.5
mg/kg
ATG
1.5
mg/kg
INFUSE
TWO
CORD
UNITS
Tacrolimus (level 5-10 ng/ml)
Sirolimus* (level 3-12 ng/ml)
* Oral Loading Dose of 12mg then once daily to maintain level
** Moving forward, ATG dose lowered to 1.0mg/kg Cutler et al. BMT. 2011. 46: 659-67.
24. Patient and Graft Characteristics
N 32 patients
Age in years (range) 53 (19-67)
Weight in kg (range) 75.9 (52-113)
Diagnosis
NHL
AML
Hodgkin Disease
MDS
CLL
ALL
CML/MPD
10
9
5
4
1
1
2
High Risk Malignancy 20 (63%)
Previous Transplantation 9
HLA Match (A, B, DR)
4/6, 4/6
4/6, 5/6
5/6, 5/6
5/6, 6/6
16
13
2
1
Umbilical Cord Blood Cell Dose
Cord Unit 1, TNC/kg, median X 107 (range)
Cord Unit 2, TNC/kg, median X 107 (range)
Combined, TNC/kg, median X 107 (range)
2.67 (1.87-3.91)
2.33 (1.51-3.94)
5.16 (3.66-7.58)
ā¢ Day 100 Acute GVHD was 9.4% and
chronic was 12.5%.
ā¢ No Deaths caused by GVHD
ā¢ No Cases of TMA or VOD
ā¢ 100 day and 2-yr NRM: 12.5 and 34%
ā¢ This related favorably to previous
reported acute GVHD incidence rate of
40% using CSA+MMF and similar dUCBT
conditioning regimen.
Cutler et al. BMT. 2011. 46: 659-67.
Neutrophil
Engraftment:
21 days (13-70)
25. Risk Factors for GVHD following UCB transplantation:
GVHD Prophylaxis Regimens
Does Using Methotrexate matter?
Avoid
Is Mycophenolate Better?
Probably Yes
Dose the Dose of Mycophenolate Matter?
Unknown at least for Cord Transplants
What about Rappamune (Sirolimus)?
Encouraging Results in Double UCT following
Flu-Mel-ATG conditioning
26. Risk Factors for GVHD following UCB transplantation:
ATG or No ATG
Should ATG be given in UCB Transplantation?
27. Risk Factors for GVHD following UCB transplantation:
ATG or No ATG
ļ± Use of ATG has been shown to reduce the rate of acute GVHD
II-IV by 50% (RR=0.5; 0.3-0.9, p=0.02).
ļ± Limited studies suggest ATG may increase risk for infections,
specifically viral (adenovirus and EBV).
ļ± Both out of concern for infections and to promote recovery of
thymopoiesis (immune reconstitution) some centers have
removed ATG from conditioning.
28. Risk Factors for GVHD following UCB transplantation:
ATG or No ATG
ļ± MSKCC has adopted removal of ATG and recently published
their experience.
ļ± Engraftment was not impacted by removal of ATG.
ļ± Cumulative Incidence of Grade II-IV acute GVHD was
comparable to other reports of DUCBT at 43%.
ļ± Concerning was rate of severe Grade III/IV acute GVHD with
more than half cases of GVHD > Grade III (19 of 31 cases).
Sauter/ Barker. BBMT. 2011. 17: 1460-71.
29. ā¢ 75% of patients free from serious infections after day 120.
ā¢ However, despite removal of ATG, viral infections remain and associated with GVHD:
ā¢ All EBV Infections happened within the context of GVHD/Steroids.
ā¢ All Cases of Adenovirus colitis happened within the context of GVHD/steroids.
ā¢ All late CMV infections occurred within the context of GVHD/steroids.
MSKCC experience with ATG-free ablative and non-ablative,
Double Umbilical Cord Transplant in 72 patients
Sauter/ Barker. BBMT. 2011. 17: 1460-71.
30. Risk Factors for GVHD following UCB transplantation:
ATG or No ATG
Should ATG be given in UCB Transplantation?
Inconclusive evidence, removal seems to result in higher
GVHD (especially grades III/IV) and this may negate the
desired benefit (protection from infections- especially viral).
31. Risk Factors for GVHD following UCB transplantation:
Single or Double Unit Cord Transplant?
One or Two Cords, if GVHD is the only
consideration?
32. BMT CTN 0501: Single vs. Double UCB in
Pediatric Patients
ā¢ Multi-center randomized study of 1 (n=113) vs. 2 units (n=111).
ā¢ Conditioning: Flu/Cy/TBI (1320 cGY)
ā¢ GVHD Prophylaxis: CSA/MMF
ā¢ Median TNC: 4.8 vs. 8.8 X 107/kg
Single UCB Double UCB p- value
Overall Survival @ 1 year 71% 66% 0.13
Relapse @ 1 year 12% 14% 0.37
NRM @ 1 year 20% 22% 0.45
Neutrophil Recover at day 42 89% 87% 0.08
Platelet Recovery at day 180 80% 72% 0.06
Acute GVHD II-IV at day 100 57% 57% 0.94
Acute GVHD III/IV at day 100 14% 23% 0.03
Any Chronic @ 1 year 32% 30% 0.64
Higher
Acute GVHD
III/IV; but
no impact
on NRM
33. Risk Factors for Grade II-IV Acute GVHD following unrelated donor
umbilical cord transplantation (multiple regression analysis)
Factor RR for acute GVHD (95% CI) P
Number of Donors
One
Two
1.0
2.0 (1.2-3.4) 0.01
Conditioning Regimen
Myeloablative
Nonmyeloablative
1.0
1.7 (1.1-2.5) 0.01
ATG in Conditioning
No
Yes
1.0
0.5 (0.3-0.9) 0.02
MMF as prophylaxis
No
Yes
1.0
0.5 (0.2-1.3) 0.14
HLA-Match (engrafted unit)
6/6
5/6
4/6
1.0
1.9 (0.9-4.2)
1.4 (0.7-3.2)
0.11
0.36
University of Minnesota examined the relative risk of acute GVHD in 265
consecutive UCB transplants (Single / Double Unit UCBT: 80 / 185) in patients
> 10 years of age between 1994-2006.
MacMillan M L et al. Blood. 2009. 113:2410-2415
34. Cumulative incidence of Grade II-IV acute GVHD:
2-Fold Increased Risk in Double UCBT
MacMillan M L et al. Blood. 2009. 113:2410-2415
35. Maximum stage of acute GVHD by organ system in
recipients of a single and double UCB transplant
Higher Incidence in Double solely due to > skin Stage 3
MacMillan M L et al. Blood. 2009. 113:2410-2415
Lower GI Upper GI
36. Cumulative incidence of TRM at 1 year after
transplantation: TRM always worst after Single Unit
All Patients Patients with Grade II-IV acute
GVHD
ā¢ If you get acute GVHD, better to have 2 cord.
ā¢ In MV analysis, only factor impacting TRM following acute
GVHD was receipt of Double versus Single (RR 0.4; 0.2-0.9, p=0.03).
ā¢ While Risk of Grade III/IV GVHD was similar between Single versus
Double, TRM was twice as high in those who get it following Single Unit UCBT.
(Single 43% vs. Double 20%, p=0.06)
MacMillan M L et al. Blood. 2009. 113:2410-2415
37. Caution: Recent Results from MSK
examining GVHD after DUBCT
Characteristic Value
Median Age, years 37 (1-69)
Diagnosis
Acute Leukemia
Lymphoma/ CLL
MDS/ CML/ other MPD
58%
37%
5%
Conditioning
Ablative
RIC
NMA
49%
28%
23%
GVHD Prophylaxis
CNI + MMF 100%
ATG 0%
Patient Characteristics (n=115)
38. Grades II to IV and III to IV acute GVHD at day 180
Ponce et al. BBMT. 2013.
Organ Involved N (%)
Gastrointestinal
Upper Only
Lower Only
Upper & Lower
49 (80%)
14 (29%)
9 (18%)
26 (53%)
Skin
Stage II
Stage III
Stage IV
39 (64%)
20 (51%)
17 (44%)
2 (5%)
Liver 9 (18%)
39. Is GVHD worst after DUCBT?
ā¢ Caution should be used when interpreting
single-center reports.
ā¢ Many factors can influence GVHD including
use of ATG, Different Conditioning Regimens
and difference in reporting/ confirming GVHD.
40. Risk Factors for GVHD following UCB transplantation:
Single or Double Unit Cord Transplant?
One or Two Cords, if GVHD is the only consideration?
Children: One seems to be as good (or better than 2, less Grade
III/IV).
Adults: Would not base this on risk for GVHD
Acute GVHD rates are higher with 2 cords, but
TRM lower (in one single-center report) and other factors
(engraftment) probably more important.
41. Is Treatment-Related Mortality Following development of
acute GVHD influence by stem cell source?
Is it worst for recipients of Cords?
42. Recipients of Single or Double UCB who develop acute
GVHD do not have higher TRM when compared to
acute GVHD after receipt of another donor source.
MacMillan et al. Blood. 2010. 115: 5412-7.
Treatment Related Mortality after Acute GVHD Based on Donor
Donor Type
Relative Risk
(95% CI) p
Matched Sibling 1.O (reference)
Matched Unrelated Donors 1.42 (0.92-2.20) 0.11
Unrelated or Sibling Mismatched 1.88 (1.34-2.63) <0.001
Single Umbilical Cord 1.18 (0-72-1.94) 0.52
Double Umbilical Cord 0.74 (0.44-1.2) 0.21
43. Is Acute GVHD after UCB more
responsive to treatment?
45. Ponce et al. BBMT. 2013.
ļ± Is Upper GI GVHD after cords more Responsive to
Budesonide?
ļ§ Original Work in Seattle with Non-Absorbable steroids
suggested that they do not work when administered alone
(randomized study with beclomethasone called for
concurrent treatment with brief period of systemic
steroids).
ļ§ What does day 28 response mean for entity upper GI
GVHD? How can you have a PR?? How do you assess this
response retrospectively?
ļ§ Think suggestion that Budesonide-alone results in āhigh
day 28 responseā needs to be interpreted with significant
caution.
46. Is Cord GVHD More Steroid Responsive?
ļ± Japanese Registry paper suggested patients with acute GVHD
after a UCBT were more likely to ārespondā than after MRD,
MUD, or MM Unrelated.
ļ± However, āresponseā was defined as not receiving second-line
therapy and results should be interpreted cautiously.
ļ± Series from Univ. of Minnesota (MacMillan et al. Blood. 2009)
suggest acute GVHD might be more responsive to steroids.
47. Is Acute GVHD after UCB more
responsive to treatment?
Answer: Maybe, certainly not worst
48. Does Chronic GVHD rates and
presentation differ following Umbilical
Cord Transplantation?
49. Chronic GVHD following Umbilical Cord
Transplantation
ā¢ Chronic GVHD is leading the cause of late Non-Relapse Mortality
after transplantation.
ā¢ Recently Peripheral Blood was found to result in higher rates of
chronic GVHD than Bone Marrow in Matched Unrelated Donor
recipients.
ā¢ UCB results in lower rates of chronic GVHD when compared to
MUD.
ā¢ Main Risk factors for Chronic GVHD following Cord is h/o Acute
GVHD (especially severe).
ā¢ By NIH Criteria, the classic form of chronic is low in cord recipients
(5%) with late acute (71%) and Overlap (24%) variants
predominating. Alsultan et al. BMT. 2011. 46: 668-75.
50. Umbilical Cord Recipients who get Chronic GVHD are
more likely to respond to GVHD therapy than MUDās
Predictors of Chronic GVHD response at 2 months following Diagnosis
Predictor Odds Ratio (95% CI) P
Umbilical Cord Blood versus MUD 3.8 (1.3-11.1) 0.02
De novo or Quiescent Onset 3.2 (1.1-9.3) 0.03
Predictors of Chronic GVHD response at 2 years following Diagnosis
Umbilical Cord Blood versus MUD 6.6 (1.9-23.3) 0.003
De novo or Quiescent Onset 3.8 (1.1-12.8) 0.03
Arora et al. BBMT. 2007. 13: 1145-1152.
51. Overall Survival, Disease-Free Survival, Relapse and Non-relapse Mortality in
Patients who develop Chronic GVHD after UCB vs. MUD
Non-relapse Mortality following Chronic GVHD:
lower in recipients of UCB vs. MUDās.
27 vs. 11% at 1 year
Arora et al. BBMT. 2007. 13: 1145-1152
52. Discontinuation of Immunosuppressive Medications:
Despite Higher Response Rates in UCB Cumulative Incidence
and Timing of Discontinuation Similar to MUDās
Roughly 1/4th of Chronic GVHD patients on immunosuppressive medications beyond 4 years
Arora et al. BBMT. 2007. 13: 1145-1152.
53. Can we utilize properties of
Umbilical Cords to treat or prevent
GVHD?
Prophylactic infusion of Ex-Vivo
Expanded 3rd party Cord Blood Treg
prevents GVHD
54. Studies demonstrate that cord blood as compared to adult
blood is an improved source for Treg-cell isolation and culture.
ā¢ Previous studies have shown that ex vivo polyclonally expanded
Treg cells can be effective in preventing or suppressing GVHD.
ā¢ In some models, Treg cells can prevent GVHD and still allow GVL.
ā¢ Consequently, T reg cells could have a potential role in clinical
immunosuppressive therapy in transplantation, provided human
Treg cells could be isolated and expanded to generate sufficient
numbers for in vivo infusion.
ā¢ Adult human Treg studies are impeded by contamination of CD25
dim expressing T-cells.
Godfrey et al. Blood. 2005. 105: 750-758.
55. Cultured cord bloodāderived CD4+CD25+ cells markedly suppress
MLRs. Analysis of suppressor cell function in MLR assays by
proliferative inhibition.
57. -18
MMF
UCB
stem &
T cells
Phase I Treatment Plan for Human UCB Tregs
CSA or Rapa
Phase I semi-log dosing:
1 ā 30 x 105/ kg/dose
Non-myeloablative
conditioning
UCB TregsTreg cell
UCB
culture
UCB Tregs
0 +1-9 ... -3 ...
Days Post-Transplant
+15
58. Grade II-IV
Acute GVHD
CumulativeIncidence
Historical
60%
Treg
43%
0.0
0.2
0.4
0.6
0.8
1.0
P = 0.05
Viral + Fungal
Infections
Days Post-Transplant
Historical
67%
Treg
39%
0 20 40 60 80 100
P = 0.02
Relapse
at 1 year
P = 0.43
Historical
48%
Treg
35%
0 180 360270900 20 40 60 80 100
Major Outcomes of Phase I Treatment Plan
Primary Endpoint: No Dose-Limiting Toxicities Seen
59. Lab of Simrit Parmar, MD
Xiaoying Liu
Shawndeep Tung
Simon Robinson
MD Anderson Cancer Center
Dept. of SCTCT
Richard Champlin, MD
EJ Shpall, MD
Marcos DeLima, MD
Yago Nieto, MD
Simrit Parmar, MD
Partow Kebriaei, MD
Uday Popat, MD
Nina Shah, MD
Roy Jones, MD, PhD
Borje Andersson, MD
Martin Korbling, MD
Paolo Anderlini, MD
Issa Khouri, MD
Chitra Hosing, MD
Muzaffar Qazilabsh, MD
Stefan Ciurea, MD
Geath Al-Atrash, DO, PhD
G. Rondon, MD