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Searching for the “Perfect Stem Cell Transplant”
Sergio Giralt, MD Chief, Adult
BMT Service Professor of
Medicine Weill Cornell Medical College
Disclosures
Grant support: CELGENE
Honorarium: CELGENE ONYX GENZYME NOVARTIS MILLENIUM
Most important I am a transplanter
MDACC 2008
SCT and Cellular Therapies Richard Champlin Borje Andersson Roy Jones Elizabeth Shpall
Naoto Ueno Paolo Anderlini Jeffrey Molldrem John McMannis Chitra Hosing Uday Popat Martin Korbling Partow Kebriaei Issa Khouri Michael Andreef Steven Kornblau Muzaffar Qazilbash Yago Nieto APN’s PharmD. Research Nurses,
DataManagers, Fellows Symptom Research Charles Cleeland Shelley Wang Lori Williams Department of
Lymphoma/Myeloma Larry Kwak Donna Weber Michael Wang Robert Orlowski Raymond Alexanian Sheeba THomas
The TeamMSKCC SCT TEAMJuliet BarkerDavid ChungHugo Castro-MalaspinaJenna GoldbergKatherine HsuRobert JenqAnn JakubowskiGuenther KoehneHeather LandauMatt MatasarCraig MoskowitzEssie PapadopoulosMiguel PeralesDoris PonceCraig SauterJim YoungMarcel Van den BrinkRichard O’ReillyNancy KernanFarid BouladTrudy SmallSusan ProckopTHE BMT NURSES THE BMT PHARM DsTHE MSKCC RESEARCH STAFFMSKCC ADMINISTRATIVE SUPPORTTHE PATIENTS AND THEIR FAMILIES
What are the characteristics of the “perfect stem cell transplant?”
Essential Characteristics of the Perfect Transplant
Safe NRM rates consistently less than 5%
Effective Relapse rates of less than 10%
Easy Could be done in any mid-size to large
transplant program Minimal acute and long term side
effects Minimal disruption to patients quality
of life Cost-Effective
When compared to other alternative therapies
well almost perfect…
Perfect TransplantPipedream? Or Possibility?
Characteristic Number (n=153)
%
Male 84 55%
Female 69 45%
Bulk (≥ 5 cm) 46 30%
Relapsed/Refractory 101/52 66%/34%
Remission ≤ 1 year 37 24%
Extranodal disease 66 43%
B Symptoms 26 17%
Previous RT 79 52%
IFRT administered 115 75%
FI response
Positive 42 27%
Negative 110 72%
Pretransplant functional imaging in rel/ref HL Moskowitz et al Blood 2010; 116 (23): 4934-4937
Moskowitz, AJ. Blood 2010.
CALGB 100104, follow up to 04/17/2011
Median EFS: Stratified by Prior Lenalidomide UsePlacebo No Prior Len, 33 mo; Placebo Prior Len, 32 mo; Len No Prior Len, 39 mo; Len Prior Len, Not reached
What have we learned?With the right patient and the right prognostic factors + appropriate maintenance autografting for some diseases can approach our characteristics of the “perfect transplant”
Except….
Relapse prevention strategies may be essential
Still “not easy” (i.e. significant symptom burden and disruption of life.
N 109 Age 51 (24-75) Caucasian 83% Myeloma 60% PR/CR 80% M. D. Anderson Symptom Inventory
(MDASI) Administered at 6 time points:
Admission; Chemo; Day 0; Nadir; Recovery; Day 30
IVR or pencil and paper
Symptoms of Patients Undergoing Autologous SCT Anderson K et al BMT
Incidence of Moderate to Severe Symptoms
%
Biological Basis for Symptoms Post-SCT
30% of the variation in MDASI symptom interference scores was accounted for by the changes in white blood count and albumin levels Will reducing the days of absolute
neutropenia during an autologous SCT reduce symptom burden?
Higher baseline mood disturbance scores were associated with higher MDASI scores at nadir and day 30 post-transplantation
Mood disturbance, quality of life, and family function were predictors of symptom-related interference
Pilot Trial of Multi Dose Stem Cell Infusion Post Autograft for
Myeloma. H.Landau PI
Day
0
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Day
9D
ay 1
0D
ay 1
1D
ay 1
2D
ay 1
3D
ay 1
4D
ay 1
5D
ay 1
6D
ay 1
7D
ay 1
8D
ay 1
9D
ay 2
0D
ay 2
1
0.0
5.0
10.0
15.0
20.0
25.0
30.0
Mean WBC Mean ANC
13
Neulasta or GCSF daily
FatigueFatigue 0-10
Median (Range)Time points MM Patients 11-105 Patients
Day -2 3 (0-8) N=34 1.5 (0-7) N= 18
Day +6 6 (0-10) N=34 4.5 (0-10) N=14
Day +11 4 (0-10) N=30 3 (0-10) N=16
Day +30 5 (0-9) N=27 4 (1-8) N=17
Day -2 Day +6 Day +11 Day +300
1
2
3
4
5
6
7
8
9
10
MM Patients11-105 Patients
Media
n F
ati
gue (
0-1
0)
Symptoms, Toxicities, and Cytokines Wang et al, J Clin Oncol
Cytokine blockade as a potential strategy to reduce symptom burden
0
1
2
3
4
5
6
Baseline Conditioning Regimen
Day of Transplant
Nadir of WBC Hospital Discharge
30 days post BMT
Mea
n o
f 5 M
ost
Sev
ere
Sym
pto
ms
Time
Symptom Severity by CD34 Positive Cells Infused
4 - 6x10^6 CD34 Cells/Kg
10 - 15x10^6 CD34 Cells/Kg
Randomized Phase II LD/HD CD34
Eligibility:Multiple myeloma > 60AmyloidosisCCI > 3High-dose melphalan Autograft
Randomize
Assessments:Q Day x 28 days Q Week Study EndToxicity Cytokines CytokinesMDASI Cognitive Cognitive
Fx Fx
3–5 million CD34+ cells/kg
High Dose vs Low Dose CD34
10–15 million CD34+ cells/kg
Symptom Measures for Studying Mechanism of Symptom Burden (Allo-
HSCT)
-20 -10 0 10 20 30 40 50 60 70 80 90 100
Sym
pto
m s
ever
ity
Fatigue
Pain
IL-6
Dry Mouth
Drowsy
Lack of Appetite
Sleep
0
1
2
3
4
5
6
7
8
10
IL-6 (p
g/m
L)
0
25
50
75
100
9
Days since Allogeneic Stem Cell Transplantation
Wang et al
Summary
In the setting of autologous SCT the main barriers to the almost perfect SCT remain a significant symptom burden associated with the procedure as well as the high relapse rate.
Novel strategies exploring post SCT maintenance as well as reduction of symptom burden are being actively explored.
Strategies employed to reduce symptom burden after autografting could be effective in reducing symptom burden after allografting.
What about allogeneic stem cell transplantation?
Is the perfect transplant possible?
Years
0 2 61 3 4 5
Probability of survival after HLA-matched sibling donor transplant for AML, age <20
years, by disease status, 1998-2008
Early (N=1,384)
SUM09_34.ppt
Intermediate (N=285)
Advanced (N=309)
0
20
40
60
80
100
10
30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
Pro
babili
ty o
f Surv
ival, %
P < 0.0001
Slide 28
Years
0 2 61 3 4 5
Probability of survival after allogeneic transplant for MDS, age <20 years,
by disease status and donor type, 1998-2008
Early, HLA-matched sibling (N=63)
SUM10_39.ppt
Early, unrelated (N=145)
Advanced, HLA-matched sibling (N=114)
Advanced, unrelated (N=190)
0
20
40
60
80
100
10
30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
Pro
babili
ty o
f Surv
ival, %
P = 0.002
Slide 32
Years
Probability of survival after HLA-matched sibling donor transplant for CML, by disease
status and transplant year, 1998-2008
0 2 61 3 4 5
SUM10_46.ppt
CP, 1998-2000 (N=2,302)
0
20
40
60
80
100
10
30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
Pro
babili
ty o
f Surv
ival, %
CP, 2001-2008 (N=2,412)
AP, 2001-2008 (N=314)
AP, 1998-2000 (N=301)
P < 0.0001
Slide 39
Years
0 2 61 3 4 5
Probability of survival after allogeneic transplant for severe aplastic anemia,
by donor type and age, 1998-2008
HLA-matched sibling, £20 y (N=1,388)
HLA-matched sibling, >20 y (N=1,408)
Unrelated, £20 y (N=562)
Unrelated, >20 y (N=532)
0
20
40
60
80
100
10
30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
Pro
babili
ty o
f Surv
ival, %
P < 0.0001
SUM10_48.ppt
Slide 41
Causes of death after transplantations
done in 2003-2008
SUM10_22.ppt
Slide 20
Infection (17%)Other Cause
(19%)
Organ Failure (12%)
Primary Disease(35%)
IPn* (5%)
GVHD (12%)Infection(14%)
Other (22%)
GVHD (10%)
Primary Disease (43%)
IPn* (3%)
Organ Failure (8%)
Infection (5%)
Other Cause (17%)
Organ Failure (4%)
IPn* (1%)Primary Disease (73%)
*IPn = Idiopathic pneumonia syndrome
Autologous
Unrelated donor
HLA-identical sibling
TRIPLE P ALLOGRAFT
Push the drugs
Pour the cells
Pray that things work out
T Cell DepletionThe Facts
All pts CML
AMLALL
Acute LeukemiaCML
T Cell Depletion Study
Acute GVHD grades II–IVTCD 39% - Non TCD 63%
(p<.0001)Acute GVHD grades III–IV
TCD 18% - Non TCD 37% (p<.0001)Chronic GVHD at 2 years
TCD 29% - Non TCD 34% (p=NS)
CRITIQUESOld study (published 2005 but conducted 95-2000)
TCD methods obsolete (T10B9 or elutriation)
Marrow not PBHLA typing issues
Patient heterogeneityCML issue
T Cell depletion reduces regimen related toxicity.
Comparative Analysis of CD34+ Selected, T-Cell Depleted HLA-Matched Sibling Grafts on Allogeneic Hematopoietic Cell Transplantation for Patients with Acute Myeloid Leukemia in
Complete Remission
…. a more modern story.
Comparison Outline
Patients Randomized
N=600
No TransplantN=1
Received Transplant
N=599
Patients meeting eligibility
N=84
Eligibility Criteria:Age 18-65
HLA Match-SiblingPBSC
AML in CR1 or CR2
Patients Randomized
N=47
AML CR2N=19
AML CR1N=65
No TransplantN=1
Received Transplant
N=44
AML CR2N=7
AML CR1N=37
Patients meeting eligibility
N=44
BMT CTN 0101 BMT CTN 0303
Cumulative Incidences of Chronic GVHD
Pro
babili
ty, %
Years0 3
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
1 2
BMTCTN0303-0101-11_5.ppt
P<0.001
0303, 19% @ 2 years
0101, 50% @ 2 years
Cumulative Incidence of Leukemia Relapse
Pro
babili
ty, %
Years0 3
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
1 2
BMTCTN0303-0101-11_6.ppt
P=0.57
0303, 24% @ 2 years
0101, 27% @ 2 years
Cumulative Incidence of Treatment-related Mortality
Pro
babili
ty, %
Years0 3
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
1 2
BMTCTN0303-0101-11_8.ppt
P=0.95
0303, 21% @ 2 years
0101, 19% @ 2 years
Disease-Free Survival
Pro
babili
ty, %
Years0 3
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
1 2
BMTCTN0303-0101-11_10.ppt
P=0.6
0303, 55% @ 2 years
0101, 54% @ 2 years
Comparative Analysis of Graft Content post CD34+ Selection with CliniMacs (N=105) and
Isolex/E- (N=74)
4.74 x 103/kg 2.32 x 103/kg 1.53 x 103/kg 0.85x 103/kg
2.49 x 103/kg 0.78x 10 3/kg 1.52 x 103/kg 5.84 x 103/kg
CD3/kg CD4/kg CD8/kg CD56/16/kg0.00E+00
5.00E+03
1.00E+04
1.50E+04
2.00E+04
CliniMacsIsolex
MSKCC vs MDACC AML CR1TCD vs FLUBU non TCD
Characteristics Frequency, n (%)TCD, N=115 Unmodified, N=181 p
Time CR1 to transplant, days* 83 (12-304) 97 (8-455) 0.040Age, years * 52 (19-71) 48 (18-63) <0.001
>50 years 66 (57) 76 (42) 0.010Etiology
de novo 60 (52) 144 (80) <0.001Secondary 38 (33) 24 (13)Therapy-related 17 (15) 13 (7)
Cytogenetic risk status NSPoor 42 (37) 76 (42)
Donor typeMRD 56 (49) 103 (57)MUD 32 (28) 64 (35)MM 27 (23) 14 (8) <0.001
Graft typeBM 8 (7) 57 (32) <0.001PB 107 (93) 124 (68)
Outcome 3-year 18% (12%-27%) 25% (19%-33%) NS1-year CI NRM 18% (12%-27%) 13% (9%-19%) NS3-year CI NRM 24% (17%-34%) 16% (11%-23%) NS3-year KM RFS 58% (47%-67%) 60% (51%-67%) NS3-year KM OS 57% (47%-67%) 66% (58%-74%) NS
OS and EFS
In summary, modern TCD is associated with similar outcomes than non-TCD with a lower
risk of GVHD…
Why don’t they do better?Identify opportunities…
SC
AA
mm A
AA
A
mm
A
A
AA
A
A
A
A
A
Risk ProfileAny patients in which TCD is preferred?Any patients in which it may not work?
Improving T Cell Depletion
Induction RegimensDifferent for TCD?Role of pre SCT IS?
Maintenance
Risk Profile
Prep RegimenNovel radiotherapyNew antibodies
Supportive Care
Graft Characterization
Improving Immune-Reconstitution
Facts Infection major
cause of treatment failure after TCD SCTs
Most fatal infections occur after engraftment.
Pre-emptive therapy can make a difference
Observations Improved immune-
reconstitution correlates with improved outcomes.
Strategies to improve immune reconstitution can be explored clinically Androgen ablation KGF Cytokines Stem cell dose
Immune Reconstitution After CD34 Selected Allo PBSCT (BMT-CTN 0302)
Devine et al, BBMT 17:1343;2011
Comparison of median CD4 cells/ul post unrelated HCT, ablative regimenT.Small & M.Perales unpublished data
0-2m 2-4m 4-6m 6-9m 9-12m 12-18m
18-24m
24-36m
0
200
400
600
800
1000
1200
1400 Double cord
conv BM
conv PB
SBA-E-
CD34+E-
Clinimacs
0-2m 2-4m 4-6m 6-9m 9-12m 12-18m 18-24m 24-36m0
200
400
600
800
1000
1200
1400Double cord
conv BM
conv PB
SBA-E-
CD34+E-
Clinimacs
Children, <18 yr Adult, >18 yr
Months post Unrelated donor transplantation
Patient Characteristics Number
Total 375
Age: range median
2-6840
Disease (%) AML MDS ALL CML NHL
150 (40%) 36 ( 10%) 85 (23%) 55 (15%) 49 (13%)
Remission status, no of patients (%) complete remission 1 >complete remission 1
178 (47%)197 (53%)
Evaluating the effect of immune recovery on OS and relapse in TCD allogeneic transplants
Goldberg J et al.
Improved immune recovery predicts improved OS/Relapse Risk
J Goldberg/M. Perales/G Heller
Immune recovery parameters assessed as continuous variables over time
Factor Hazard Ratio for death
p-value
ALC 0.88 0.006CD4 0.79 <0.001CD8 0.83 <0.001NK NS NSCD45RA 0.77 <0.001PHA 0.76 0.064
Hazard Ratio for relapse
p-value
0.51 <0.0010.55 <0.0010.53 <0.001NS NS0.67 0.0020.49 0.010
Strategies to enhance T cell reconstitution following allo-HSCT
Keratinocyte Growth Factor (KGF)
• Fibroblast growth factor-7 (FGF-7) produced by thymic stroma and thymocytes
• FGFR2IIIb: epithelial tissues including thymic epithelial cells, hepatocytes, gut epithelium and skin keratinocytes.
• FGFR2IIIb-/- mice: decreased thymic cellularity and abnormal T cell development .
• Palifermin is FDA approved for mucositis• KGF prevents GVHD in mouse models• KGF had no effect on GVHD in phase II trial
Alpdogan, O. et al. Blood 2006;107:2453-2460
KGF administration enhances thymopoiesis and peripheral T-cell development in 18-month-old mice
BM, thymic, and splenic cellularity were significantly increased after allogeneic BMT and leuprolide acetate treatment
Goldberg, G. et al. Journal of Imm. 2009; 182:5846-5854
Combination Immunoregenerative Therapy (CIT) to enhance thymic function following allo-HSCT
Randomized phase II protocol, 3 arms 1:1:1 Arm 1: controlTCD TBI based PBSCTNO KGF/NO LUPRON
Arm 2: KGF armTCD TBI based PBSCTPre/post KGF/NO LUPRON
Arm 3: KGF + Lupron armTCD TBI based PBSCTPre/post KGF/LUPRON pre and 3 mos post
Primary endpoint: CD4 count at 6 mosSecondary endpoints:OS at 2 yrsTRM at 6 mosIncidence of infectionsIncidence of relapseMucositis endpoints
Stem cell dose and immune-reconstitution
Trudy Small MDMiguel Perales MDJenna Goldberg MD
CD4 reconstitution TCD HLA matched sibHCT by CD34 cell dose
1-2m 2-4m 4-6m 6-9m 9-12m0
400
800
1200
1600
1-2m 2-4m 4-6m 6-9m 9-12m0
400
800
1200
1600
1-2m 2-4m 4-6m 6-9m 9-12m0
400
800
1200
1600
1.67-4.9 5-10 >10 million/kg
90%
50%
10%
Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.
Pulsipher, M. A. et al. Blood 2009;114:2606-2616
Figure 3 Overall survival after URD-PBSC transplantation by CD34+ dose
Figure 3. Overall survival after URD-PBSC transplantation by CD34+ dose. CD34+ cell doses higher than 4.5 x 106/kg recipient weight improved overall survival compared with lower doses. (A) Overall survival after MA transplantation (P = .020 at 3 years for Medium vs Low; P = .489 at 3 years for Medium vs High). (B) Overall survival after RI/NMA transplantation (P = .045 at 3 years for Medium vs Low; P = .157 at 3 years for Medium vs High). Low indicates no greater than 4.5 (n = 142, MA; n = 80, RI/NMA); Medium, 4.5 to 9.5 (n = 183, MA; n = 102, RI/NMA); High, greater than 9.5 (n = 110, MA; n = 54, RI/NMA) (x 106 CD34+/kg).
Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.
Pulsipher, M. A. et al. Blood 2009;114:2606-2616
Figure 2 Cumulative incidence of GVHD after URD-PBSC transplantation by quartile (Q) of CD34+ dose
Figure 2. Cumulative incidence of GVHD after URD-PBSC transplantation by quartile (Q) of CD34+ dose. Higher CD34+ cell doses did not increase the incidence of GVHD. (A) Grades III-IV acute GVHD after MA transplantation (P = .599 at 180 days); (B) grades III-IV acute GVHD after RI/NMA transplantation (P = .305 at 180 days); (C) chronic GVHD after MA transplantation (P = .068 at 2 years); (D) chronic GVHD after RI/NMA transplantation (P = .189 at 2 years). MA: Q1 indicates no greater than 3.8; Q2, 3.8 to 6.2; Q3,6.2 to 9.5; Q4, greater than 9.5; RI/NMA: Q1, no greater than 3.6; Q, 3.6 to 5.9; Q3, 5.9 to 9.4; Q4, greater than 9.4 (x 106 CD34+/kg).
Can we explore megadoses of stem cells after allogeneic stem cell
transplantation?
Percentile 1st Collection Total Collections
50th 8.5 x 106/kg 9.2 x106/kg
80th 3.85 x106/kg 4.3 x106/kg
90th 2.3 x 106/kg 3.6 x106/kg
With current guidelines and collection techniques unlikely to be able to explore giving more than 10 x 10 e 6 CD34 per kg.Unless ….We collect more than once.How could this really help improve SCT outcome?
Secondary Graft Failure
Larocca et al
CD34 Selected Stem Cell Boosts for Patients with Poor Graft FunctionOverall Survival - Medical Score Rosenzweig & Castro-Malaspina
Outpatient no organ dysfunctionInpatient, afebrile, no organ dysfunctionFebrile. no organ dysfunctionOrgan dysfunction
Conditioning Regimen
TCD or Non-TCD allograft
Week 6-8 Recollect Stem Cell Donor-CD34
select and infuse
-9 -8 -7 -6 -5 -4 -3 -2 -1 0 Week 1 +2 +3 +4 +5 +6 +7
1ry EndpointsFeasibility: 60% of donors will be able to have a 2nd stem cell collection within 6-8 weeks of original stem cell collection.2ry EndpointsImmune reconstitution parametersInfectionsGraft functionGVHDRelapse-EFS and OS
Pilot Trial of Supplemental CD34 Infusions in Recipients of HLA Matched Related Allogeneic Stem Cell Transplants
Fractionating stem cell infusionsHypothesis: Fractionated stem cell infusions will enhance engraftment by increasing the number of stem-cells that find a functioning hematopoietic “niche” and successfully proliferate when compared to bulk infusions.
Felfly H, Trudel M: BJH; 146:646:2010
Felfly et alOne Cell Dose
Cell Dose e7 Number of Doses
Time to infusion
engraftment Wbc chimerism
XRT Level 2 2 1 4 4/21 37
4 1 4 5/12 48
5 1 4 5/8 76
2 1 52 2/13 38
5 1 52 3/8 27
Multi Dose
XRT Level 2 4 2 6/7 73
4 3 5/5 51
4 4 6/6 72
XRT Level 1 6 2 1/7 34
6 3 7/7 29
6 4 7/7 27
Any Hematologic MalignancyUndergoing Allogeneic SCT10/10 or 9/10 matched donor
Unmanipulated or TCD
RegisterOn protocol
IF DONOR COLLECTS MORE THAN 7 x 10e6 CD34RANDOMIZE
GROUP 1BULK INFUSIONALL CELLS DAY 0
vsGROUP 2
FRACTIONATED INFUSIONSDAY 0
4 x 10 e 6 CD34 Day 0 REST INFUSED ON DAYS 2-4-6-8EQUALLY DIVIDED DOSES OF CD34
IF COLLECTION LESS THAN 7 x 10e6 CD34
ALL CELLS ON DAY 0-
ALL FRACTIONATED INFUSIONS CD34 SELECTED
D30 primary endpoint assessment of
ALC T cell SubsetsTime to ALC 500Infusional Toxicities
D360 secondary endpoint assessment of immune reconstitution
parametersGraft functionInfectons
Acute and chronic GVHDSurvival and Relapse
Bulk vs Fractionated Allogeneic Stem Cell Infusion Protocol
Improving Immune-Reconstitution
Improving Immune-Reconstitution
Recombinant human interleukin-7 (CYT107) enhances T-cell recovery without causing graft-versus-host disease following T-cell depleted allogeneic hematopoietic stem
cell transplantation M.Perales MD
Memorial Sloan-Kettering Cancer Center
Interleukin 7 (IL-7)
Required for T cell development (lymphoid precursor to memory T cell) and peripheral T cell homeostasis.
Enhances T cell reconstitution in HSCT recipients in mouse models (increased thymopoiesis and homeostatic proliferation of transferred and de novo generated mature T cells, and decreased peripheral T-cell apoptosis).
Dose-dependent expansion of CD4+ and CD8+ T cells in initial clinical trials (patients with solid tumors or HIV infection).
Alpdogan et al, Blood 2001;98:2256-226; Alpdogan et al, J. Clin. Invest. 2003; 112:1095–1107; Rosenberg et al, J Immunother 2006;29:313–319; Sportes et al, J Exp Med 2008; 205: 1710-1714; Levy et al, J. Clin. Invest. 2009; 119:997–1007; Sereti et al, Blood 2009: 113:6304-6314; Sportes et al, Clin Cancer Res 2010; 16: 727–735.
Memorial Sloan-Kettering Cancer Center
a: Pt 14-203 removed after single injection for biopsy-proven drug rash (evaluable for toxicity)b: Chemo=Busulfan/ Melphalan/ Fludarabine; TBI=TBI/ Thiotepa + Cyclophosphamide (n=3) or Fludarabine (n=1) – All patients received ATGc: Baseline T cell counts represent mean of two consecutive tests pre-treatment
Patient Characteristicsa
Age (median) 60 years (range 27-67 years)
Gender M=6/ F=6
Disease AML n=9
MDS n=2
CML n=1
Regimenb TBI n=4
Chemotherapy n=8
Donor MRD n=7
MUD n=4
MMUD n=1
Median Day of rhIL-7 start post BMT 103 days (range 60-244 days)
Baseline T cell counts (median)c
CD3+CD4+ 69/mm3 (range 0 – 272 /mm3)
CD3+CD8+ 32/mm3 (range 0 – 299 /mm3)
CD4+CD45RA+ 0 (range 0 – 17 /mm3)
Memorial Sloan-Kettering Cancer Center
Injection of rhIL-7 (CYT107) after TCD allo-HSCT was not associated with significant toxicities
Main toxicities possibly/probably related to CYT107: Injection site reactions in 2/10 patients Grade 2 skin biopsy-proven hypersensitivity rash in 3/10 patients;
patient 14-203 with rash after 1st injection was removed from the study
Low-grade fever in 2/10 patients Splenomegaly noted on CT in one patient
No patients developed GVHD No patients developed anti-IL7 antibodies or neutralizing
antibodies Pt 14-301 developed an EBV-PTLD after treatment and
responded to treatment with rituximab 9/12 patients remain alive with median follow-up of 16
months (2 patients with high-risk AML died of relapse, Pt 14-203 died of PML 23 months after IL-7 injection)
Memorial Sloan-Kettering Cancer Center
rhIL-7 (CYT107) increases CD4+ T cell counts post TCD allo-HSCT
Median rise in CD4+ T cells: 76% at day 21 (range 0 to 35-fold increase)
Absolute CD4+ T cells
0 5 100
200
400
60010 mcg/kg20 mcg/kg30 mcg/kg
Week on Study
Cel
l/µL
CD4+ T cells - Ratio/Baseline
0 5 10
1
10
10010 mcg/kg20 mcg/kg30 mcg/kg
Week on StudyR
atio
/bas
elin
e
Memorial Sloan-Kettering Cancer Center
rhIL-7 (CYT107) does not increase NK or CD19+ cell counts post TCD allo-HSCT
NK cells
0 5 10
1
10
10010 mcg/kg20 mcg/kg30 mcg/kg
Week on Study
Rat
io/b
asel
ine
CD19+ cells
0 5 10
1
10
10010 mcg/kg20 mcg/kg30 mcg/kg
Week on StudyR
atio
/bas
elin
e
Other factors in searching for the “perfect SCT”
OPTIMIZING DONOR SELECTION
Dose effect of donor KIR3DS1: overall survival
HR 0.63
HR 0.88
P=0.03
Venstrom Blood 2010
Overall Mortality TRM Relapse Grade II-IV aGvHD
ALL(n=237)
0.85(0.61-1.19, p=.35)
0.79(0.52-1.20, p=.27)
1.10(0.62-1.93, p=.75)
0.60(0.34-1.07, p=.08)
AML(n=306)
0.66(0.49-0.89,p=.006)
0.64(0.44-0.94, p=.02)
0.70(0.43-1.14, p=.15)
0.53(0.31-0.87, p=.01)
CML(n=390)
0.81(0.61-1.09, p=.16)
0.76(0.55-1.04, p=.09)
1.02(0.57-1.80, p=.96)
0.86(0.53-1.42, p=.42)
MDS(n=154)
1.10(0.72-1.67, p=.66)
1.28(0.81-2.01, p=.29)
1.03(0.42-2.52, p=.94)
1.00(0.49-2.03, p=.99)
Effect of donor 3DS1 is more pronounced in AML
Venstrom Blood 2010
Other factors in searching for the “perfect SCT”
OPTIMIZING CONDITIONING REGIMEN
AML/MDS
PK Adjusted dose AUC 6000 µMol-min
Fixed dose 130 mg/m2, results inan average AUC ~5000 µMol-min
Pharmacokinetic Dose Guidance of IV Busulfan with Fludarabine with Allogeneic Stem Cell Transplantation Improves Progression Free Survival in Patients with AML and MDS ; Results of a
Randomized Phase III Study Andersson BS, deLima M, Saliba RM, et al ASH 2011
The dose adjusted group will have an average dose escalation of ~20% and a consistent AUC at that level.
0 10 20 30 40 50 60 70 80
Months Post Transplant
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumu
lative
Pro
portio
n Sur
viving
Pro
gres
sion F
ree Adjusted, N=111
Fixed, N=124
P 0.03
0 10 20 30 40 50 60 70 80
Months Post Transplant
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumu
lative
Prop
ortion
Surv
iving
Prog
ressio
n Free
Adjusted, N=71
Fixed, N=68
P 0.4Remission at Transplant
EFS Curves
0 10 20 30 40 50 60 70 80
Months Post Transplant
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0C
um
ula
tive
Pro
po
rtio
n S
urv
ivin
g P
rog
ress
ion
Fre
eActive Disease at Transplant
Adjusted, N=40
Fixed, N=46
P 0.03
0 10 20 30 40 50 60 70 80
Months Post Transplant
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumu
lative
Prop
ortion
Survi
ving P
rogres
sion F
ree
High Risk MDS
Fixed N=13, 15%
Adjsuted N=11, 60%
P at 2 yrs 0.002
0 5 10 15 20 25 30 35 40 45 50 55 60
Months Post Transplant
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cumu
lative
Prop
ortion
Survi
ving P
rogres
sion F
ree
Low Risk MDS
Adjusted N=15, 60%
Fixed N=12, 64%
P at 2 yrs 0.9
Adjusted vs Fixed Busulfan
Preventing relapse post allo
Is it possible?
Low dose 5-Azacitidine will decrease the relapse
rate after allogeneic transplantation.
Study Aim
To determine the safest dose and schedule combination of azacitidine given after allogeneic transplant.
Hypothesis
Protocol 2005-0417
Median age = 60 ( range, 24 – 67 )
Median comorbidity score : 3 (range, 0-8)
Chemotherapy regimens prior to HSCT (median = 2)
AML from MDS : 73% MDS : 5% AML : 22%
Median bone marrow blasts at transplant : 10% (0-86%)
CR at HSCT : 20%
Protocol 2005-0417
Patient characteristics
Cancer 2010.
Global DNA methylation (LINE assay (bisulfite pyrosequencing) : No dose was found to significantly affect global methylation
Guillermo Garcia-Manero’s laboratory
30
35
40
45
50
55
60
Dose 8mg/m2
Dose 16mg/m2
Dose 24mg/m2
Dose 32mg/m2
Leandro Silva
Azacitidine maintenance – MTD : 32 mg/m2
5 10 15 20 25 30 35 40 45
Months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cum
ula
tive P
roport
ion S
urv
ivin
g
Median follow-up is 16 months
Survival - patients that received AZA
50% unrelated donor HSCT -96 cycles delivered – safe.
Median follow-up = 16 months
Protocol 2005-0417
- Azacitidine was well tolerated
- Approximately 60% of the patients (heavily pre-treated, refractory etc) were able to receive at least one cycle
- At least 4 cycles at 32 mg/m2 could be delivered.
- Randomized protocol 2008-0503 is ongoing :
32 mg/m2 daily X 5 days, every 30 days, for 1 year, versus no maintenance.
Goodyear et al Blood 2012
27 patients (median age 59) Median follow up 7 months (3-21) 11 sib, 16 VUD CR1=18, CR2=7, relapse 2
•Control cohort: FMC 50 no AZA
- Induction of an increase in circulating T-regs in the early post transplant period
- Induction of a memory T cell-mediated response in the bone marrow to putative tumour antigens
Building the Perfect Stem Cell Transplant
Building the Perfect Stem Cell Transplant
• Peri-Post SCT• Phase I-Conditioning
– Condition intensity– Optimizing dose– Optimizing stem cell product
• TCD• KIR
• Phase II-Cytopenic Phase– Novel GVHD prevention strategies
• Bortezomib based• Sirolimus based
– Aggressive management of symptom burden
• Palifermin• Cytokine blockade• Stem Cell dose and schedule
– Enhance immune-reconstitution• IL-7• CTL’s• Supplemental stem cell infusions
• Phase III-Early recovery– Preemptive therapy of GVHD-
Biomarker targeted• Phase IV-Early Convalescence
– Enhance immune reconstitution– Viral monitoring– Pre-emptive therapy– Prophylactic CTL’s– Anti-relapse maintenance
• Cells• Drugs
• Phase V-Late Convalescence– Anti-relapse maintenance– Biomarker identification of chronic
GVHD risk for pre-emptive therapy – Biomarker identification with early
intervention of late side effects.
Myeloid Malignancies
Lymphoid Malignancies
Myeloma and Plasma Cell Disorders
Advanced Cellular Therapies (CAR and CTL’s)
Germ Cell
Cord Blood ProgramGVHD & Immune-reconstitution
Supportive Care and Survivorship
SummarySummary
• If we want to make a quantum leap in SCT outcomes we will need to explore all strategies that can result in incremental improvements. These include strategies concerning supportive care, viral and MRD monitoring, cellular therapies and post transplant maintenance.
• The concept of a “Almost Perfect Transplant” (80-90% success with low risk disease and 50% or more with high risk disease) should be achievable within our lifetime.
• The tools are there it is a question of putting them together. Many obstacles exist, none impossible to surmount.
• Continued performance of Triple P transplants (Push the drugs-Pour the cells-Pray that it all works out) will not move us forward.
• Strong collaborations between industry, academic centers, basic and clinical science researcher should be the way forward.
