blood and marrow transplantation (bmt) update · 2020-03-02 · • 07/15: sibling (female)...

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 joseph.lau@roswellpark.org

Hematopoietic arrest at GMP stage by rST6G

MPO 200X

+ rST6G

saline CD34+ ex vivo

joseph.lau@roswellpark.org

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

joseph.lau@roswellpark.org

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 joseph.lau@roswellpark.org

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