Download Cord Blood Transplantation: from the basics to what`s new

Cord Blood Transplantation:
from the basics to what’s new
2013 Hematopoietic Stem Cell Transplant for Advanced Practice Providers
Governor Hotel, Portland, Oregon
September 20, 2013
Dr. Shernan Holtan, MD
Milestones in the History of Cord
Blood Transplantation
Early Milestones in the History of Cord
Blood Transplantation (CBT)
• 1988: first CBT performed in 5-y/o boy with Fanconi Anemia
• CB donor was patient’s HLA-identical sibling, identified by prenatal testing to
be unaffected by FA
• Established proof of principle:
• Hematopoietic reconstitution can be achieved using umbilical cord blood hematopoietic
stem cells
• 1990: first HLA-mismatched CBT performed in 30-month old boy
with ALL in CR2
• 1992, 1993: initiation of cord blood banking programs
• 1993: first unrelated donor CBT in 3-y/o boy with T-ALL
• 1996: Kurtzberg et al and Wagner et al reported first series of unrelated
donor CBTs
Early Milestones in the History of Cord
Blood Transplantation (CBT)
• 1995: first CBT performed in adult patient with leukemia
• Experience reported in 1996, with 4 adults >21 years old
• 2005: first large series of double CBTs reported
• Transplanted between 2000-2003, pioneered by the University of Minnesota
• Double CBT now the standard of care for many adult CBT programs
• More than 20,000 CBTs have been performed to date
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Initial transplants limited to children, now adults
HLA-mismatched, unrelated setting, single vs double cord unit transplants
Worldwide inventory of CB units >500,000
NMDP estimates >95% patients can find at least 1 potential 4/6-matched CB
unit
www.marrow.org
Cord Blood as an Alternate Stem Cell
Source – Pro’s and Con’s
Benefits of CB
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•
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•
Extends donor pool
Lack of donor attrition
Shortened time to transplant
No safety risks for mother or child
with CB collection
• HLA-mismatch well tolerated
• Thought to be lower incidence of
(chronic) GVHD
- May be more treatment-responsive?
Concerns with CB
• Delay in engraftment
• Neutrophils
• Platelets
• Risk of graft failure
• Limited cell dose
• Total nucleated cell dose
• CD34+ cell dose
• Viral reactivations and infections
post transplant
• Delayed immune reconstitution
• No DLI available
Engraftment after CBT
• Early analyses described delay in engraftment in 562 patients
undergoing CBT1
• Neutrophil recovery (>500) : median 28 days
• Graft failure in 28%
• Platelet recovery ( >50,000): median 90 days
• Tolerable degree of acute and chronic GVHD
• 23% grade III/IV acute and 25% chronic
• Identified factors important to CB engraftment:
• Cell dose/kg body weight
• Total nucleated cell dose
• CD34+ cell dose
• Degree of HLA-match
1. Rubinstein P et al. NEJM 1998.
Delayed Engraftment after CBT
• ANC recovery delayed after single unit CBT:
• Pediatric patients1:
• ANC >500: day 32 with CBT versus day 18 for BMT
• Platelets >20,000: day 81 with CBT versus day 29 for BMT
• Adult patients2:
• ANC >500: day 27 for CBT versus day 18-20 for BMT
• Platelets >20,000: day 60 for CBT versus day 29 for BMT
1. Rocha V et al. Blood 2001.
2. Laughlin MJ et al. NEJM 2004.
Historical Comparison of CB vs BMT
Laughlin et al. NEJM 2004;351(22):2265.
 Lowest rates of TRM, treatment
failure, mortality among matched BMT
recipients
 No difference in outcomes after CBT
versus MM-BMT
CI Neutrophil Recovery
Contributors to Delayed Engraftment
• HLA-match
• Cell dose:
• 10-fold lower cell dose with CBT1
• BM or PBSC transplant: 2x10^6 CD34+ cells/kg
• Cord blood transplant: 1.37x10^5 CD34+ cells/kg for single cord
• Conditioning regimen2,3
• GVHD prophylaxis2
• Inherent difference with CB HSC compared to other stem cell sources?
• Impaired homing versus engraftment
1. Gluckman E et al. Exp Hematol 2004.
2. Locatelli F et al. Blood 2003.
3. Gluckman E et al. BBMT 2007.
How to Improve Delayed
Engraftment after CBT?
How to Improve Delayed
Engraftment after CBT?
Development of Double Cord Blood Unit Transplantation
• 23 patients, median age 24 (13-53)
• 2 CB units given:
• 10 (43%) patients received 4/6-matched units
• 11 (48%) patients received at least one 5/6-match
• 2 (9%) patients received at least one 6/6-match
• Infused cell doses:
• Median cryopreserved TNC/kg = 4.8 x 10^7/kg
• Median infused TNC/kg = 3.5 x 10^7/kg
• Median infused CD34+/kg = 4.9 x 10^5/kg
• Ablative conditioning:
• 120 mg/kg Cyclophosphamide
• TBI 1320 cGy
• ATG  Fludarabine 75 mg/m2
• GVHD prophylaxis:
• Cyclosporine
• Methylprednisone  MMF
• All 21 evaluable patients achieved sustained
neutrophil engraftment
• Median of 23 days (range 15-41)
• Complete donor chimerism
• 76% with single donor dominance by day 21
• 100% by day 100
• No secondary graft failure
• Day 180 CI of platelet engraftment (>50,000) was 71%
Demonstrated feasibility and safety of double CB unit
transplantation as a means to improve engraftment
Established standard ablative conditioning regimen
with Cy/Flu/1320 TBI
• GVHD prophylaxis: CSA/MMF
 This regimen continues to be standard of care ablative conditioning
regimen for younger adult patients
Delayed Engraftment after CBT
• ANC recovery delayed after single unit CBT:
• Pediatric patients1:
• ANC >500: day 32 with CBT versus day 18 for BMT
• Platelets >20,000: day 81 with CBT versus day 29 for BMT
• Adult patients2:
• ANC >500: day 27 for CBT versus day 18-20 for BMT
• Platelets >20,000: day 60 for CBT versus day 29 for BMT
• Double unit CBT3:
• ANC >500: day 23
• CI of platelet engraftment to >50,000 was 71% by day 180
1. Rocha V et al. Blood 2001.
2. Laughlin MJ et al. NEJM 2004.
3. Barker JN et al. Blood 2005.
How to Improve Delayed
Engraftment after CBT?
Other Ways to Improve Engraftment?
Possible Methods to Improve Delayed
Engraftment
• Improve CB stem cell homing:
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•
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Diprotin A
C3a priming
Intra-bone infusion of CB
Modification of selectin ligands via enforced fucosylation
• Clinical Trial Options:
• Prostaglandin E2 (ProHema®):
• Goal to enhance homing and improve HSC proliferation
 Phase 2 Trial of ProHema® after ablative or RIC CBT
• CD133+ expansion in nicotinamide (NiCord®)
Possible Methods to Improve Delayed
Engraftment
• Overcome the limitation in cell dose:
• Double cord blood transplant
• Coinfusion of third party donor cells
• Haploidentical donor cells
• Ex vivo expansion of CB stem/progenitor cells
• Seattle group: Notch ligand expanded CB progenitor cells
 ANC recovery at day 12 versus 25 days for historical cohort
• MD Anderson / Baylor: Ex vivo expansion via mesenchymal
cell co-cultures
 ANC recovery at day 15 versus day 24 for CIBMTR matched
cohort
NEJM 2012;367:2305.
Post-CBT Complications
Immune Reconstitution after CBT
Prolonged T lymphopenia and relative expansion of B cells
and NK cells after CBT.
Komanduri K V et al. Blood 2007;110:4543-4551
©2007 by American Society of Hematology
Thymic regeneration failure after CBT.
Komanduri K V et al. Blood 2007;110:4543-4551
©2007 by American Society of Hematology
Post-CBT Complications
Infectious Complications
CMV Reactivation after CBT
• High rate of CMV reactivation
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•
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Reported rates between ~21% up to 100% 1-2
Incidence of CMV disease 6-21%2
Development of disease may be trend for inferior outcomes3
While there is early CD4+ CD8+ T-cell response to CMV, in correlative studies
these T-cells failed to achieve sufficient numbers in vivo to control CMV
reactivations4
• Optimal anti-CMV prophylaxis, surveillance, and treatment remain areas of
active debate
CBT patients likely require higher level of surveillance as well as
treatment/prophylaxis strategies
1.
2.
3.
4.
Takami A et al. Haematologica 2005.
Walker CM et al. BBMT 2007.
Beck JC et al. BBMT 2010.
McGoldrick et al. Blood 2013.
Other Infectious Complications after HCT?
• Epstein-Barr virus
• Adenovirus disease
• Fungal infections
• RIC study found invasive fungal infection in 14/128 patients2
• 13/14 with probable invasive pulmonary aspergillosis
• 3-year CI of invasive aspergillosis was 10.2%
• Median onset of IFI was day 20 (range 1-82)
• Mortality rate of IFI was 86%
• Multivariate analysis revealed steroids >0.2 mg/kg was a significant risk factor for
invasive aspergillosis
1.
2.
Sauter C et al. BBMT 2011.
Miyakoshi et al. BBMT 2007.
Benefits of CBT
Enhanced Graft-Versus-Leukemia Effect?
Probability of leukemia relapse for all patients
based on the number of units infused.
Verneris M R et al. Blood 2009;114:4293-4299
©2009 by American Society of Hematology
Verneris M R et al. Blood 2009;114:4293-4299
©2009 by American Society of Hematology
Analysis of risk factors for
outcomes after unrelated cord
blood transplantation in adults
with lymphoid malignancies: a
study by the Eurocord-Netcord
and lymphoma working party
of the European group for
blood and marrow
transplantation.
J Clin Oncol. 2009 Jan 10;27(2):256-63. Epub 2008 Dec 8.
Rodrigues CA, Sanz G, Brunstein CG, Sanz J, Wagner JE, Renaud M, de Lima M, Cairo MS, Fürst S, Rio B, Dalley C, Carreras E, Harousseau JL, Mohty M, Taveira D, Dreger
P, Sureda A, Gluckman E, Rocha V.
Sideri et al. Haematologica 96(8);2011.
Brunstein C G et al. Blood 2010;116:4693-4699
©2010 by American Society of Hematology
Brunstein C G et al. Blood 2010;116:4693-4699
• Relapse rates significantly lower following dCBT
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dCBT (15%, 95% CI 9-22%)
MRD (43%, 95% CI 35-52%)
MUD (37% , 95% CI 29-46%)
MMUD (35%, 95% CI 21-48%)
• Early TRM was highest following dCBT
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dCBT (34%, 95% CI 25-42%)
MRD (24%, 95% CI 17-39%)
MUD (14%, 95% CI 9-20%)
MMUD (27%, 95% CI 15-39%)
Pro’s / Con’s of Double CBT
• Double CBT associated with higher incidence of acute GVHD (58% vs
39% double vs single)
• Not higher TRM or chronic GVHD for single versus double CBT
• TRM after onset of acute GVHD significantly lower in double CBT
compared to single CBT
• 20% vs 39% at 1-year
• Lower leukemia relapse for patients with good disease status in CR1,
CR2
Sideri et al. Haematologica 2011.
MacMillan et al. Blood 2009
How to Extend CBT to Older
Patient Population?
How to Extend CBT to Older
Patient Population?
Reduced Intensity Conditioning Regimens
• Reduced intensity conditioning:
• Fludarabine 200 mg/m2
• Cyclophosphamide 50 mg/kg
• TBI 200 cGy
• GVHD prophylaxis with CSA/MMF
• Required > 3 x 10^7 TNC/kg
• 110 patients, median age 51 years (17-69)
• 85% received double CBT
• HLA-match:
• 124 (61%) 4/6-match
• Median infused doses:
• TNC/kg = 3.7 x 10^7
• CD34/kg = 4.7 x 10^5
• CD3/kg = 1.1 x 10^7
• Neutrophil engrafted in 92% of patients
• Median of 12 days (0-32)
• No difference between recipients of 1 versus 2 units
• CI of sustained engraftment 85%
• Primary graft failure = 7; secondary graft failure = 8
• CI of platelet recovery by day 180 = 65%
• Occurred at median of 49 days
• Double unit chimerism detectable in marrow of 43% of
patients at day 21, 9% at day 100, 0% at 1-year
Optimal Reduced Intensity Regimen
• Remains an area of active investigation
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Melphalan-containing regimens
TBI/Fludarabine
Treosulfan
ATG-containing regimens
Benefits of CBT
Less, or More Treatment-Responsive Graft-Versus-Host
Disease?
Chronic GVHD after CBT
• Relatively mismatched donor source with CBT
• Reported increased incidence of acute GVHD after dCBT
• Literature has suggested a potentially lower overall incidence of
chronic extensive GVHD after CBT
• Reported incidences vary widely:
• 10-20% to 89% after ablative single and double CBT
• ~12% to 40% after reduced intensity CBT
Chronic GVHD after CBT
• Mechanisms for the potential difference in chronic GVHD after CBT, compared
with other stem cell sources, remain to be defined.
• CB T-cells have been reported to have greater immune tolerance to HLA-mismatch, generally
thought to be due to the overall immaturity of the immune cells
• Decreased cytotoxicity of cord blood CD8+ T-cells
• Impaired allogeneic activation with subsequent decreased production of interferon-γ
• Defective Th1 responses of CB T-cells related to differential expression and activation of
transcription factors
• Impaired cord blood dendritic cell maturation and cytokine production
Response Rate to Treatment of Chronic
GVHD after CBT
• Arora et al. evaluated presentation and response to
treatment in 170 patients with chronic GVHD
• Complete response (CR): resolution of all reversible signs and
symptoms of cGVHD.
• Partial response (PR): improvement in 1 or more organs of
involvement and no evidence of worsening in any organ.
• Progression: defined as worsening in 1 or more organs of
involvement to be more severe than at baseline.
• Compared URD, predominately HLA-matched marrow
(n=123), versus CBT (n=47)
Arora M et al. BBMT 2007.
Response Rate to Treatment of Chronic
GVHD after CBT
Time Point
URD Response Rate CB Response Rate
p value
2-months
48%
74%
0.005
6-months
49%
78%
0.001
1-year
51%
72%
0.03
2-years
47%
70%
0.05
• Higher response rates among recipients of CBT
• Similar incidence and timing of discontinuation of
immunosuppression
• Higher NRM after chronic GVHD following URD
transplant
• 27% versus 11% (URD versus CB) at 1-year (p=0.055)
Arora M et al. BBMT 2007.
Historical Classification of Chronic GVHD
Limited
_ Localized skin involvement or
_ Hepatic dysfunction due to chronic GVHD, or
_ Localized skin involvement and hepatic dysfunction
Extensive
• Generalized skin involvement, or
_ Findings of limited chronic GVHD plus




Aggressive hepatitis, bridging necrosis, cirrhosis, or
Ocular sicca, or
Oral involvement, or
Involvement of any other organ
Shulman, Sullivan, Weiden et al. Am J Med. 1980; 69:204
Slide courtesy of Dr. Mary Flowers.
2005 NIH Consensus Criteria for
Classification of Chronic GVHD
• Proposed new criteria for the diagnosis and classification of chronic
GVHD for clinical trials
• Goals were to:
(1) Establish criteria for diagnosis of the disease, emphasizing the distinction
between acute and chronic GVHD
(2) Define criteria for scoring the severity of clinical manifestations in affected
organs
(3) Propose categories describing the overall severity of the disease and the
indications for treatment
 NIH consensus criteria have been evaluated in the conventional donor setting in several large series.
 In the CBT setting, NIH consensus criteria have only been evaluated prospectively in 1 study of CBT patients.
Filipovich AH et al. BBMT 2005.
Estimated Probability of Acute GVHD after CBT
Newell LF et al. BBMT 2013.
Estimated Probability of Chronic GVHD after CBT
Newell LF et al. BBMT 2013.
Characteristics of Chronic GVHD, According to NIH Criteria, Among
Patients Who Were Alive and Without Relapse Between 80-100 Days
after CBT
Characteristic
Number of evaluable patients
Persistent, recurrent, or late acute GVHD, No.
Persistent
Recurrent
Late
NIH Chronic GVHD subcategories, No.
Classic
Overlap
Unclassified *
Days from transplant to diagnosis of GVHD, median (range):
Persistent acute
Recurrent acute
Late acute
Classic chronic
Overlap chronic
Chronic GVHD associated with severe morbidity
Bronchiolitis obliterans
Scleroderma/Joint contractures
Esophageal stricture
Serositis
68
25
3
20
2
31
7
24
2
82 (80-97)
141 (77-599)
118 (102-134)
123 (91-363)
114 (80-412)
2
0
1
5
* Treated with immunosuppression for cryptogenic organizing pneumonia at day 123 post-transplant (n=1), and for anasarca at day 309 after
transplant (n=1).
Probability of Discontinuation of Immunosuppression
Financial Costs of CBT
Comparison of CBT vs MRD Transplant
• U Minnesota group compared costs of HCT within first 100 days:
• MRD: n=67 ablative, n=54 nonmyeloablative
• CBT: n=63 ablative, n=110 nonmyeloablative
• Comparable 100-day probabilities of overall survival, TRM
• Delayed ANC recovery with CBT
• Greater incidence of graft failure with CBT
• Median cost per day survived:
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$1016 for ablative MRD
$2082 for ablative CBT
$612 for nonmyeloablative MRD
$1156 for nonmyeloablative CBT
Majhail et al. BBMT 2009.
Comparison of CBT vs MRD Transplant
• Factors associated with higher costs within first 100 days in multivariate
analysis:
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Graft failure
Need for dialysis
Mechanical ventilation
Ablative CBT
• Longer inpatient stay with associated costs (i.e. pharmacy, room, blood draws, etc)
• Due to longer time to engraftment
Authors connote that this study did not address long-term costs of CBT:
Given potential for less (severe) / more treatment responsive GVHD after CBT, will this
translate into lower costs over an extended period of time?
Majhail et al. BBMT 2009.
Cost Effectiveness of Single vs Double CBT in France
• Adult patients, acute leukemia in CR, 2002-2009, n=134
• In myeloablative setting:
• Similar total cost
• Greater cost of CB units for doubles
• Increased hospitalizations for singles (increased infections, increased relapse)
• In RIC setting:
• Higher total cost for double CBT
• Greater cost of CB grafts with doubles
• Increased hospitalizations for GVHD with doubles
Rocha V et al, 2012 International Cord Blood Symposium
Future Directions in CBT
How to Select CB Units?
• Traditionally based on HLA-match, TNC/kg cell dose, unit quality
• HLA-A and –B typing at antigen level, high resolution typing for HLA-DRB1 alleles
• Minimum 4/6-matched, each > 1.5 x 10^7 TNC/kg
• 6/6-match: minimum single unit dose required > 3 x 10^7/kg
• 5/6-match: > 4 x 10^7/kg
• 4/6-match: > 6 x 10^7/kg
Ongoing studies on benefit of further high resolution typing, effect of HLA-C
matching
How to Select CB Units?
• Higher CD34+ viability
• Part of benefit of double CBT is increased likelihood of transplanting at least 1 good unit
• Not all banks are the same
• Lower CD34+ viability from less commonly used banks (range 36-94% versus >70-90% with
commonly used banks)
• CD34 dose important for engraftment, not necessarily for single donor dominance
• Unit-unit match, patient-unit match no effect
• Speed of neutrophil engraftment related to CD34+ dose
• Potential dose-dependent effect TNC, CD3+
Other Factors ?
• Effect of HLA-C matching: Eapen et al. The Lancet Oncology
2011;12(13):1214.
• More significant for 6/6-matched CBT
 TRM 9% with C-match vs. 26% with C-MM
• Also for 5/6-matched CBT
 TRM 32% with C-match vs. 44% for C-MM
• NIMA:
• Improved NRM, LFS ?
• Donor-specific antibodies:
• Associated with increased TRM, decreased engraftment
Future Questions / Directions
• Number of CB units to infuse
• Is double CBT the standard for adult patients
• Ideal conditioning regimens
• Ablative regimens
• RIC regimens
• Third party donor cells?
• Manipulation of CB stem cells
• Generation of NK cells, CMV specific T-cells, etc
• Novel methods to improve homing / engraftment
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PGE2-modulation
Fucosylation
CD26/DPP4 inhibition
Copper chelation
Questions?