blood and marrow transplantation (bmt) update · 2020-03-02 · • 07/15: sibling (female)...
TRANSCRIPT
Roswell Park Cancer Institute Blood and Marrow Transplantation
(BMT) Update
Philip McCarthy, M.D.
Blood and Marrow Transplant Program
Roswell Park Cancer Institute
2015
Disclosures for Philip McCarthy, MD The presentation will include off-label use of drugs for multiple myeloma treatment
Research Support/P.I. No relevant conflicts of interest to declare
Employee No relevant conflicts of interest to declare
Consultant Bristol Myers Squibb, Celgene, Janssen, Karyopharm, Millenium, Onyx, Sanofi, The Binding Site
Major Stockholder No relevant conflicts of interest to declare
Speakers Bureau No relevant conflicts of interest to declare
Honoraria Bristol Myers Squibb, Celgene, Janssen, Karyopharm, Millenium, Onyx, Sanofi, The Binding Site
Scientific Advisory Board No relevant conflicts of interest to declare
Roswell Park Cancer Institute
Disclosures
• The presentation will include off-label use of drugs for treatment of hematologic malignancies and cellular therapies
• Consultation, Advisory Board participation and Honoraria from The Binding Site, Bristol Myers Squibb, Celgene, Janssen, Karyopharm, Takeda/Millenium and Sanofi
Acute lymphocytic leukemia (ALL): Case Report • 01/14: 28 y.o. male: precursor B cell ALL, 6 cycles of Hyper-CVAD ,plan for
allogeneic BMT but delayed • 10/14: Bone marrow test: 78% blasts, CD 10+, CD20+, CD22+, partial trisomy
9 by FISH. Re-induced as per CALGB 10403 (dose intensive regimen for AYA patients)
• 11/14: Bone marrow test: 30% blasts, liposomal vincristine complicated by myopathy, started on prednisone
• 12/14: Goesto MSKCC for CD19 CAR-T-cell rx, 2 CAR-T cell infusions beginning 01/15
• 04/15: Bone marrow test: 78% blasts, Blinatumomab (bi-specific T-cell engager, CD3 and CD19) for 1 cycle
• 05/15: Hypercalcemia, acute kidney injury, Bone marrow test: 100% blasts, FLAG-IDA re-induction & liposomal vincristine, Bone marrow test: ~50% blasts
• 06/15: Severe abdominal pain/ileus, inotuzumab ozogamicin (anti-CD22 & calicheamicin) for 3 doses over 2 weeks, bone marrow test <1% blasts with molecular clonality and +MRD by flow (0.02%) Cytogenetics: Absent trisomy 9
• 07/15: Sibling (female) allogeneic blood stem cell transplant after fludarabine and melphalan, Day +22 bone marrow test NED by flow, 500/500 female cells & clonal B cell gene re-arrangement, Day +38 bone marrow aspirate NED by flow and cytogenetics, B cell gene rearrangement pending
Bone Marrow and Cord Blood Units
http://hematopoiesis.info/2008/10/04/private-cord-blood-banking-worth-your-money/
Mobilization of Stem Cells into the Peripheral Blood
Dreger et al BJH 1994
Types of Transplants
• Syngeneic – Identical twin
• Allogeneic – From another person
• family member (sibling, parent, other relative)
• unrelated donor
• Autologous – Self
RPCI BMT Program
• Autologous up to age 80 • Allogeneic
– Myeloablative up to age 60 – Reduced Intensity up to age 80
• Goal: Increasing patient access with decreasing mortality and improved outcome – Reduce the toxicity of chemotherapy and radiation
therapy – Reduce the toxicity of Graft-versus-Host Disease
(GvHD) and preserve the Graft-versus-Tumor (GvT) effect
RPCI Cord Blood Transplant Experience
• First CBT: May 1997, most recent CBT: Sept 2015
• 36 total, 33 Single CB, 3 Double CB, 7 alive, 6 disease free, 3 are >15 years from CBT
• Deaths: Infection n=8, Relapse of disease: n=7, GvHD n=5, RRT n=4, Cardiac disease n=2, hemorrhage n=1, second cancer n=1
• There are several strategies to overcome the risk of infection, relapse, severe GvHD and toxicity
RPCI BMT Program Outcomes
• Most recent outcomes report
• 1/1/2010-12/31/2012 with follow-up to 12/31/2013
• N=148 patients
• Actual 1-year survival rate = 70.9%
• Predicted 1-year survival rate = 62.2%
• 95% CI predicted 1-yr survival rate = 55.1%-69.6%
• Result: RPCI actual 1-year survival is statistically significantly higher than predicted
RPCI Transplant Center-Specific Survival Analysis 2014 Report (v 12 10
14)
Hematopoietic Stem Cell Transplantation - Classification -
Allogeneic
HLA-identical Other Unrelated sibling relative
Umbilical cord blood
Negative or positive selection
Ex vivo expansion
Donor
Graft Source
Graft manipulation
Bone Marrow
Peripheral Blood
Peripheral Blood
Bone Marrow
In vivo selection
Non-myeloablative
Conditioning Regimen Intensity
Reduced Intensity Myeloablative
Syngeneic Autologous
Courtesy M Pasquini, CIBMTR
Patient
Autologous BMT
Freezer
High dose Chemo +/-XRT
Blood or Marrow Collection
Allogeneic BMT
Donor Recipient
High dose Chemo +/-XRT
Graft-versus-Host Disease (GvHD) and Graft-versus-Tumor (GvT)
• Graft-versus-Host Disease (GvHD) is caused by the immune activation of donor cells recognizing recipient cells as foreign.
• Acute GvHD occurs ~ 100 days after BMT and affects Skin, GI tract and Liver.
• Chronic GvHD occurs after acute GvHD; up to 3 years following BMT.
• GvHD is the most frequent cause of mortality after allogeneic BMT.
• However, GvHD is accompanied by a Graft-versus-Tumor (GvT) effect that can result in eradication of the underlying cancer.
MECHANISM OF GVHD
APC
IL-1
T
IL-2R
T T
M
CTL NK
Target cell Death
Lymphokine dysregulation
Ag presentation
Cell activation
Clonal proliferation & differentiation
Afferent phase
Efferent phase
Courtesy of Mohamed Soliman RPCI Flow Cytometry
IL-2
T
GVHD is associated with GVL response
Years
Horowitz MM et al Blood 1990
0 2 4 6 1 3 5
0
20
40
60
80
100
Prob
ab
ilit
y o
f R
ela
pse,
%
T Depletion (n=401)
Twins (N=70)
No GVHD (n=433)
AGVHD Only (n=738)
AGVHD + CGVHD (N=485)
CGVHD Only (N=127)
Twins (N=70)
T Depletion (n=401)
No GVHD (n=433)
AGVHD Only (n=738)
CGVHD Only (N=127)
AGVHD + CGVHD (N=485)
No genetic disparity, No GVL
No T cells, Very little GVL
More GVHD, More GVL
Subclinical GVHD, Some GVL
Probability of Relapse After 2,254 HLA-identical Sibling Transplants for Early Leukemia, Slide Courtesy Wei Du
Transplant regimens Immunosuppression
Myelosuppression
Flu-Cy
Flu-Cy-ATG
Flu-low dose
TBI
Flu ATG
Cy-TBI
Bu-Cy Flu-Mel
Flu-Bu
Flu-Mel-TBI
Regimen Related Toxicity
Later Graft-versus Disease Effect Earlier Anti-Disease Effect
Allo Nonmyeloablative
Allo Reduced Intensity
Auto and Allo Myeloablative
Relapse
Bi-specific T-cell Engaging (BiTE) antibody therapy for cancer : Blinatumomab (anti-CD 19)
Nagorsen and Baeuerle Exp Cell Research 2011
ALL Activity: Schedule to be determined in NHL
Inotuzumab ozogamicin (Anti-CD22)
http://www.discoverymedicine.com/Alain-Beck/2010/10/16/the-next-generation-of-antibody-drug-conjugates-comes-of-age/
http://www.dddmag.com/articles/2013/05/antibody-drug-conjugates-carbon-14-labeling-requirements
Car T Cell: Clinical trial overview
Gene
transfer
8-11 days
4. Infuse
transduced
T cells to
eradicate
CD19+
tumor
CD19
Native TCR
19z1 CAR
Lymphodepleting
chemotherapy
Courtesy D Porter
Targeting CD19+ CLL with CAR-Modified T cells
• CARs combine an
antigen recognition
domain of antibody with
intracellular signaling
domains into a single
chimeric protein
• Gene transfer (lentiviral
vector) to stably express
CAR on T cells confers
novel antigen specificity
CAR, chimeric antigen receptor; TCR, T-cell receptor.
Lentiviral vector
T cell
CD19
Native TCR
Tumor cell
CTL019 cell
Dead tumor cell
Anti-CD19 CAR construct
Courtesy D Porter
BMT CTN 1101
0603
0604
Treatment Regimens
BMT CTN 0603/0604 Non-relapse mortality and relapse
Cu
mu
lati
ve I
ncid
en
ce,
%
100
0
20
40
60
80
Months Post Transplant 0 8 16 32 24 4 12 36 28 20 40
8%
cord
haplo
28%
Months Post Transplant 0 8 16 32 24 4 12 36 28 20 40
cord
haplo
50% 52% 58%
36% 34% 32%
Non-relapse mortality Relapse
The results of BMT CTN 0603 and 0604
provide equipoise for a randomized
phase III clinical trial with progression-
free survival as the primary endpoint
BMT CTN 1101 Hypothesis: Two year PFS is similar
after related haplo-BM donor transplantation
or after dUCB transplantation.
BMT CTN 1101 Schema Patient > 18 and <70 yrs.
Acute leukemia or lymphoma
Available both1) 4-6/6 HLA-matched
UCB units
2) 4-6/8 HLA matched
related donor
Adequate organ function
Performance score >70
Double UCB Haplo-BM
Randomization
Stratified by Transplant Center
The Hematopoietic Stem Cell (HSC)
35
• Hematopoiesis is a
hierarchical process with
HSCs at the apex
• 1012 new blood cells
produced daily
• HSCs differentiate into
multipotent progenitors
(MPP) and eventually
produce all blood cells
Self-Renewal HSC
MPP
Differentiation
Mature Blood Cells
Courtesy of M Nemeth
HSC Proliferation is Associated with
Differentiation
36
15
Figure 1.4: Increased cellular proliferation is associated with hematopoietic differentiation. The majority of long-term hematopoietic stem cells (LT-HSCs) are in the quiescent G0 phase of the cell cycle (G0). The proportion of cells actively proliferating increases as LT-HSCs differentiate, resulting in a substantial increase in the number of cells as a percentage of whole bone marrow. In the mouse, this represents greater than a 100-fold expansion from less than 0.01% of bone marrow to greater than 1.0%.
1.6 Molecular regulators of HSC quiescence
LT-HSC quiescence is regulated through both cell-extrinsic and intrinsic factors.
We will return to cell-extrinsic regulators of HSC quiescence in the next section, 1.7 The
HSC niche maintains LT-HSC quiescence. Cell intrinsic factors include transcription
regulatory factors (e.g. Hif- Foxo3a, Scl, and Pten), cell cycle regulatory factors (e.g.
p21, p27, p57), and regulators of metabolic activity (e.g., Atm, mTOR) 131, 137, 144-164.
Quiescent HSCs also exhibit low levels of reactive oxygen species (ROS) and metabolic
activity.
Numerous transcription factors are able to regulate adult HSC quiescence. The
transcription factor stem cell leukemia protein (Scl) encoded by TAL1 maintains HSC
Long-term HSCs (LT-HSCs) are quiescent (G0)
Courtesy of M Nemeth
Hypothesis
37
Wnt5a
Quiescence
LT-HSC Function
Ryk
HSC
Ryk mediates the effect of Wnt5a on HSC proliferation
and long-term function
Courtesy of M Nemeth
38
0
10
20
30
Control Wnt5a Wnt5a
+ α-Ryk
α-Ryk
% G
0
p < 0.01
p < 0.05
p < 0.05
Effect of Ryk Inhibition on Quiescence
Courtesy of M Nemeth
Summary
39
Wnt5a
Quiescence
LT-HSC Function
Ryk
HSC
Blockade of Ryk inhibits the effect of Wnt5a on HSC
proliferation and long-term function
a-Ryk
X
Povinelli and Nemeth
Stem Cells, 2014
Povinelli, et al
Exp Hematol, 2015
Courtesy of M Nemeth
Hematopoietic Stem Cell Ontogeny
AGM: aorta-gonads-mesonephros FL: Fetal Liver WBM: Whole bone marrow
http://daleystem.hms.harvard.edu/
Slide courtesy of Dr. Vladislav Sandler, HemoGenyx LLC
CD
14
4+C
D45
+C
D3
4+
CD144+CD45+CD34+ Adult Hemogenic Endothelium (AHE) Cells are found in cord blood Postnatal Hemogenic Endothelium (PHE) is a better name for these cells in the cord and cord blood. The prediction of engraftment of one of two CB units may depend on the CD34+ and CD34+CD144+ cells. Slide courtesy of Dr. Vladislav Sandler, HemoGenyx LLC
hC
D4
5+ (
% o
f to
tal)
5 weeks
CD144+CD45+CD34+ AHE Cells From Umbilical Cord Engraft in Immune-Compromised Mice
0
2
4
6
8
10
45
50
55
60
65h
CD
19
+ (
% o
f to
tal
hC
D4
5+)
hC
D3
3+ (
% o
f to
tal
hC
D4
5+)
0
2
4
6
8
Every circle is a separate NOD mouse (Taconic) Slide courtesy of Dr. Vladislav Sandler, HemoGenyx LLC
Intrinsic and Extrinsic
Modes of Glycosylation
Intrinsic Glycosylation Extrinsic Glycosylation
ST6Gal-1: a GlycosylTransferase mediating attachment of sialic acid residues
- Abundant intracellularly
- Abundant as a freely circulating, catalytically active protein in blood
Joseph Lau [email protected]
rST6G infusion mitigates acute inflammation
Acute airway inflammation elicited by oropharyngeal instillation of NTHI
rST6G mitigated inflammation by at least 2 ways 1. Suppressed new inflammatory cell production 2. Suppressed release of inflammatory mediators
Manipulating circulating ST6Gal-1
• Depleting circulating ST6Gal-1 (e.g. by Mab) – Enhance hematopoietic repopulation after myeloablative events
• Raising circulating ST6Gal-1 (e.g. by rST6G) – Myeloproliferative syndromes
– Suppression of inflammation
Joseph Lau [email protected]
Target cell
perforin
granzymes
cytotoxic granules
TNF-a
IFN-g
Molecular pathways that contribute to GVH and GVL activity
Apoptosis Van den Brink et al Nat Rev. 2002
FasL-Fas
T cell
Apoptosis
T cell
Target cell
Granzyme B (GzmB)
Perforin
Courtesy W Du, N Leigh, X Cao
GzmB is required for allogeneic CD8+ T cells to cause lethal GVHD
TCD-BM WT/GzmB-/- CD8+T
129/SVJ (H-2b) BALB/C (H-2d)
Bian et al, J Immunol. 2013; 190:1341-1350
0 2 0 4 0 6 0 8 0
0
2 0
4 0
6 0
8 0
1 0 0 B M on ly n =8
W T C D 8 n = 1 8
G z m B -/- C D 8 n = 1 8
P = 0 .0 0 7 1 v s W T
(A )
T im e a fte r B M T in je c tio n (d a y s )
% S
urv
iva
l
Courtesy W Du, N Leigh, X Cao
GzmB-/- CD8+ T cells exhibit significantly enhanced GVL effect
TCD-BM WT/GzmB-/- CD8+T
129/SVJ (H-2b) BALB/C (H-2d)
A20: Aggressive Mouse B cell NHL
Bian et al, J Immunol. 2013; 190:1341-1350
This result was repeated with different donor and host combinations and three more tumor models.
0 5 10 15 20 251100 7
1100 8
1100 9
1101 0
1101 1
BM only
129/SvJ WT CD8
GzmA-/- CD8
GzmB-/- CD8
*
(A)
Time after A20 and BMT injection (days)
Tu
mo
r b
urd
en
(p
ho
ton
s/s
ec)
*p<0.05
0 20 40 60 800
25
50
75
100
129/SvJ WT CD8 n=8P<0.0001 vs BM only
GzmA-/- CD8 n=8
P=0.7666 vs WT
GzmB-/- CD8 n=8
P=0.0015 vs WT
BM only n=6
(B)
Time after A20 and BMT injection (days)%
S
urv
ival
Courtesy W Du, N Leigh, X Cao
0 2 0 4 0 6 0
0
2 0
4 0
6 0
8 0
1 0 0
B M o n ly n = 8
W T C D 4 + T e ff n = 1 2
G z m B -/- C D 4 + T e ff n = 1 2
T im e a fte r B M T in je c tio n (d a y s )
Pe
rc
en
t s
urv
iva
l
*
* p = 0 .0 2 9 6
Donor T cell dose: 5×104
GzmB diminishes the ability of CD4+Teff cells to cause lethal GVHD
BALB/C (H-2d)
MHC-mismatched
C57BL/6 (H-2b)
Courtesy W Du, N Leigh, X Cao Du et al, J Immunol Accepted for publication
GzmB diminishes the ability of CD4+Teff cells to cause lethal GVHD
T im e a fte r B M T in je c tio n (d a y s )
Pe
rc
en
t s
urv
iva
l
0 2 0 4 0 6 0
0
2 0
4 0
6 0
8 0
1 0 0
B M o n ly n = 1 0
W T C D 4 + T e ff n = 1 2
G z m B -/- C D 4 + T e ff n = 1 3
* P = 0 .0 3 8 5
*
51
MHC-matched Minor antigen-mismatched
C57BL/6 (H-2b) 129/SVJ (H-2b)
Courtesy W Du, N Leigh, X Cao Du et al, J Immunol Accepted for publication
BALB/C (H-2d)
MHC-mismatched
C57BL/6 (H-2b)
A20 mouse Luciferase-expressing lymphoma cells
T im e a fte r A 2 0 a n d B M T in je c t io n (d a y s )
Tu
mo
r b
urd
en
(p
ho
ton
s/s
ec
)
0 1 0 2 0 3 0
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
1 0 1 0
B M o n ly n = 5
W T C D 4 + T e ff n = 5
G z m B -/- C D 4 + T e f f n = 9
p = 0 .0 5 4
Donor T cell dose: 1×104
GzmB is required for CD4+Teff cell-mediated optimal GVL response
Courtesy W Du, N Leigh, X Cao Du et al, J Immunol Accepted for publication
GzmB diminishes the ability of CD4+Teff cells to cause lethal and pathological GVHD.
GzmB contributes to the optimal GVL activity of CD4+Teff cells.
GzmB plays opposite roles in CD4+ Teff vs. CD8+ T cell in mediating GVHD and GVL effect.
CD8+ T cells CD4+ Teff cells
GVHD
GVL response
GzmB-/- GzmB-/-
Courtesy W Du, N Leigh, X Cao Du et al, J Immunol Accepted for publication
Housing temperature-induced stress is suppressing murine GVHD through β2-adrenergic receptor
signaling
C 5 7 B L / 6 B A L B / c
0 1 0 2 0 3 0 4 0
0
5 0
1 0 0
2 2 ° C T C D - B M
D a y s p o s t a l l o H C T
Pe
rc
en
t s
ur
viv
al
3 0 ° C T C D - B M
2 2 ° C T C D - B M + P a n T
3 0 ° C T C D - B M + P a n T
##
No
re
pin
ep
hr
in
e in
pla
sm
a (p
g/m
L)
P r e a l l o H C T P o s t a l l o H C T
0
1
2
3
4
2 2 ° C
3 0 ° C
**
Leigh N, Kokulus K et al Submitted to JI 2015
Propranolol, β1 and 2-adrenergic blocker worsens GvHD at room temperature receptor signaling
Leigh N, Kokulus K et al Submitted to JI 2015
##
0 2 0 4 0 6 0
0
5 0
1 0 0
D a y s p o s t a llo H C T
Pe
rce
nt
su
rviv
al
2 2 °C + P B S
2 2 °C + P ro
3 0 °C + P B S
3 0 °C + P ro
#
C 5 7 B L /6 to ta l B M B A L B /c
The effect of temperature on GvHD is mediated in part by the β2-adrenergic system
Leigh N, Kokulus K et al Submitted to JI 2015
IC I 1 1 8 ,5 5 1 - 2 a n ta g o n is t
0 2 0 4 0 6 0
0
5 0
1 0 0
D a y s p o s t a llo H C T
Pe
rc
en
t s
urv
iva
l
2 2 °C + P B S
2 2 °C + IC I
3 0 °C + P B S
3 0 °C + IC I
## #
S a lb u ta m o l- 2 a g o n is t
0 2 0 4 0 6 0
0
5 0
1 0 0
D a y s p o s t a llo H C TP
erc
en
t s
urv
iva
l
2 2 °C + P B S
2 2 °C + S a l
3 0 °C + P B S
3 0 °C + S a l
#
• Understanding the patient’s immune status pre/post alloHSCT may lead to the design of strategies to control disease and prevent relapse
• Can protective immune reconstitution to prevent infections occur without the development of GvHD following alloHSCT?
• Can the GvT/GvL effect be preserved while eradicating the morbidity and mortality of GvHD
• Can CBT be enhanced to decrease the risk of infection
• Can other therapies enhance the host’s ability to eradicate disease and/or have direct anti-tumor effects ? – Antibodies +/- conjugate; +/- IMiD,
– Targeted cellular therapies for Hematologic malignancies
– Targeted Checkpoint Inhibition
Conclusions
People and Services who make the BMT program possible
• S Balderman
• G Chen
• C Ho
• M Ross
• M Aungst
• K Arnold
• J Bertolo
• M Burgess
• M Everett
• A Kobel
• J Lex
• A Phillips
• P Paplham
• S Flavin
• H McAdoo
• S Stack
• H Werner
• K Farrell
• H Jacobson
• S Oakley
• K West
• J Pleskow
• M Cimino
• T Hahn
• S Schinnagel
• S Zhao
• M Steward
• D Swinnich
• D Cipolla
• K Dubel
• P Lipka
• S Siconofi
• C Warren
• L Yoerg
• T Glow
• RKumpf
• G Wilding
• ID service
• Rad Onc Service
• Radiology Svc
• Surgery Svc
• Pathology Svc
• Lab Medicine
• Stem Cell Lab
• Apheresis Unit
• Managed Care and
• Finance Svc
• P Wallace
• L Sucheston Campbell
• J Henwood
• L Regan
• S Boehm
• C Paddon
• J Kapinos
• A Singh
• Medical Oncology Fellows
• 5 East, 5 North and 6 North Nursing and Secretarial Staff
• Hospitalist Staff
• F Hernandez
• E Wang
• A Adjei
• J Lau (C Dougher)
• M Nemeth (B Povinelli)
• V Sandler
• X Cao Lab (W Du, N Leigh, R O’Neill)
• E Repasky (K Kokulus),
• S Holstein
• P Wallace
• Y Zhang
• Support by RPCI Alliance, RPCI Core Grant, NCI, NHLBI and B and E McCarthy