CCO_GVHDpostATL2022_Zeiser_Downloadable_2.pptx

Acute and Chronic GVHD:
A Deep Dive Into Current Approaches,
Near-Term Progress, and Future Directions
Supported by an educational grant from Incyte Corporation.

Robert Zeiser, MD
Professor of Medicine
Department of Hematology and Oncology
Director
Division of Tumor Immunology
Department of Internal Medicine
Freiburg University Medical Center
Freiburg, Germany
Management of Acute GVHD

Disclosures
Robert Zeiser, MD, has disclosed that he has received consulting fees
from Incyte, Mallinckrodt, and Novartis.

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Slide credit: clinicaloptions.com

Presentation Overview
 Patient case
 Clinical presentation and pathophysiology of acute GVHD
 Biomarkers as predictors for acute GVHD outcomes
 Treating acute GVHD

Patient Case
 A 65-yr-old female patient with no premedical
history presented to the emergency room due
to leukocytosis
‒ Lc: 269,000/µL; platelets: 43,000/µL;
Hb: 7.1g/dL; LDH: 2892 U/L
‒ Bone marrow: 86% blasts, FLT3-ITD mutated
and complex karyotype
 Induction “3 + 7” (cytarabine + daunorubicin)
+ midostaurin
‒ Induction failure (60% blast)
 Salvage therapy CLAM (cladribine, cytarabine,
mitoxantrone)
‒ Blast count: 23%
 PBSCT from unrelated HLA-matched (10/10)
donor
‒ Conditioning: fludarabine, thiotepa,
melphalan
‒ GVHD prophylaxis: everolimus,
mycophenolic acid
 GVHD progressed despite prednisone
2.5 mg/kg bodyweight for 5 days

Day 23 Post HSCT
 Acute GVHD grade IV
‒ Skin: grade IV°
‒ Intestines: grade III°
‒ Liver: grade 0°
Image courtesy of Robert Zeiser, MD. Slide credit: clinicaloptions.com
IMAGE NOT AVAILABLE

Start Ruxolitinib
Time Course: Soluble IL-2 Receptor
Image courtesy of Robert Zeiser, MD.
IL-2R
(U/mL)
Time (Days)

 Patient case
 Clinical presentation and pathophysiology of GVHD
 How to treat acute GVHD?

Zeiser. Blood. 2021;138:2165. Slide credit: clinicaloptions.com
Acute GVHD: Clinical Presentation
Classical Acute GVHD Target Organs
Skin: Keratinocytes
Liver: Bile duct epithelium
Intestines: Enterocytes
Paneth cells
Intestinal stem cells
L-cells
Nonclassical Acute GVHD Target Organs
CNS: Neurons
Astrocytes
Microglia
Lymph nodes: Lymph node stroma cells
Thymus: Thymus epithelial cells
Lungs: Bronchial epithelial cells
Kidney: Glomerula cells
Podocytes
Ovaries/Testes: Granulosa cells
Leydig cells
Bone marrow: Osteoblasts
Mesenchymal stroma cells

Microglia Activation in GVHD
Mathew. J Clin Invest. 2020;130:315. Slide credit: clinicaloptions.com
30
PC2
(13.04%)
20
10
0
-10
-20
-30
-50 -25 0 25
Untreated (n = 4)
Syn-HSCT (n = 4)
Allo-HSCT (n = 4)
PC1 (67.04%)
IMAGE NOT AVAILABLE

Paneth Cells
 Paneth cells produce α-defensins; GVHD disrupts
that production, resulting in a disruption of the
intestinal microbial ecology
Enterocytes
 In intestinal GVHD, antibacterial lectin is
upregulated, demonstrating reciprocal expression
of antimicrobial proteins
Intestinal Stem Cells
 IL-22 regulates sensitivity to GVHD and is
protective against immune-mediated tissue
damage
Hanash. Immunity. 2012;37:339. Eriguchi. Blood. 2012;120:223. Eriguchi. Biol Blood Marrow Transplant. 2013;19:1525. Slide credit: clinicaloptions.com
Target Cells of Intestinal Acute GVHD
5
Paneth
Cells
Per
Crypt
4
3
1
0
Naive Day 14 Day 35
Days After BMT
2
Day 7
Naive
Control
GVHD

Norona. Blood. 2020;136:1442. Slide credit: clinicaloptions.com
Could L-Cells Be a Target of GVHD?
15
Mean
GLP-2
+
Cells
in
10hpf
(40x),
n
10
5
0
Untreated C57BL/6 (n = 5)
Untreated BALB/c (n = 10)
d10 BALB/c_TBI/Syn BM/Tc (n = 10)
d10 BALB/c_Chemo/allo-BM/Tc (n = 10)
d10 57BL/6_TBI/allo-BM/Tc (n = 10)
d10 BALB/c_TBI/allo-BM/Tc (n = 10)
P <.0001
P <.0001
P = .0016
P <.0001
P <.0001
1.5
Relative
Cldn4
Expression
1.0
0.5
0
Untreated (n = 10)
TBI/Syn BM/Tc (n = 10)
TBI/allo-BM/Tc (n = 10)
P = .0001
P = .005
2.5
2.0 15
Relative
GLP-2R
Expression
10
5
0
Untreated (n = 10)
TBI/BM/Tc D2 (n = 6)
P = .0945
P = .0347
P = .0006
P = .0001

 Patient case
 Clinical presentation and pathophysiology of acute GVHD
 How to treat acute GVHD?

Amphiregulin as a Monitoring Biomarker for aGVHD:
Study Design
 Data from 2 prospective clinical trials
‒ UMN cohort of patients receiving
uhCG/EGF (N = 51)
‒ REACH1 cohort of patients with
steroid-refractory aGVHD receiving
second-line ruxolitinib (N = 60)
 Longitudinal plasma samples drawn on
Days 0, 7, 14, 28, and 56
‒ UMN: AREG by ELISA, ST2 and REG3-α
by bead-based multiplex
‒ REACH1: AREG, ST2, and REG3-α by
microfluidic immunoassay
 Biomarker concentrations compared
across response groups
 Change of biomarkers from BL to
study days analyzed
 Biomarker cutoffs predictive of OS
identified in UMN cohort and tested
for validity in REACH1 cohort
Pratta. ASH 2021. Abstr 259. Slide credit: clinicaloptions.com

Baseline Characteristics
Pratta. ASH 2021. Abstr 259.
Characteristic
UMN (uhCG/EGF)
First-line
High-Risk Cohort
(n = 26)
Second-line
Cohort
(n = 26)
Median age, yr (range) 61 (22-72) 62 (2-69)
Male, n (%) 19 (73) 20 (77)
aGVHD clinical grade at
enrollment, n (%)
 II
 III
 IV
2 (8)
21 (81)
3 (12)
9 (35)
8 (31)
9 (35)
Characteristic
REACH1
Ruxolitinib
Cohort
(N = 60)
Median age, yr (range) 52 (18-73)
Male, n (%) 31 (52)
MAGIC aGVHD grade, n (%)
 II
 III
 IV
22 (36.7)
24 (40.0)
14 (23.3)

Biomarkers Over Time
 UMN cohort (uhCG/EGF)
‒ In patients with CR at Day 28,
AREG fell 3-fold from BL to Day 56
‒ Mean 98 vs 32 pg/mL; P = .006
‒ In patients with PR or no response
at Day 28, no change in AREG
over time
‒ Limited to no change in ST2 and
REG3-α
 REACH1 cohort (ruxolitinib)
‒ In patients with CR at Day 28, AREG fell
2.8-fold from BL to Day 56
‒ Mean 174.7 vs 63.6 pg/mL; P = .007
‒ In patients with PR at Day 28, AREG fell
2.0-fold from BL to Day 56
‒ Mean 288.2 vs 146.1 pg/mL; P = .017
‒ In patients with PD, no change in AREG
over time
‒ Limited to no change in ST2 and REG3-α
Pratta. ASH 2021. Abstr 259. Slide credit: clinicaloptions.com

Biomarker Cutoffs Associated With Rapidly Fatal Course
Biomarker Cutoff
Median Survival, Days
AREG Cutoff 212 pg/mL ST2 Cutoff 292 ng/mL REG3-α Cutoff 13.5 ng/m
High
AREG
Low
AREG
P
Value
High
ST2
Low
ST2
P Value
High
REG3-α
Low
REG3-α
P Value
UMN (uhCG/EGF) NR 62 .006 NR 239 <.001 NR 416 .01
Biomarker Cutoff
Median Survival, Days
AREG Cutoff 336 pg/mL ST2 Cutoff 188 ng/mL REG3-α Cutoff 3.6 ng/m
High
AREG
Low
AREG
P
Value
High
ST2
Low
ST2
P Value
High
REG3-α
Low
REG3-α
P Value
REACH1 (ruxolitinib) NR 74 .005 -- -- .09 -- -- .03

Multivariate Analysis of Survival
 Day 28 response and AREG were significantly associated with survival
in both cohorts in multivariate analysis
Variable
UMN (uhCG/EGF)
RR P Value
Day 28 response
(no response vs CR/PR)
4.94 .02
AREG >212 pg/nL 4.17 .03
ST2 >292 ng/mL 2.50 .13
REG3-α >13.5 ng/mL 4.40 .10
Variable
REACH1 (Ruxolitinib)
RR P Value
Day 28 response
(PD vs CR/VGPR/PR)
9.14 <.0001
AREG >336 pg/nL 2.72 <.05
ST2 >188 ng/mL 0.39 .17
REG3-α >3.6 ng/mL 0.36 .21

EBMT/ELN Treatment Guidelines for Acute GVHD
Corticosteroid resistance
aGVHD
(based on clinical symptoms or signs)
Grade ≥II
Systemic
methylprednisolone
2 mg/kg divided BID for 7 days
Taper dose;
optimal rate is not
defined
Second-line therapy
If GI aGVHD:
Add nonabsorbable oral steroid
If skin aGVHD:
Add topical steroids
or
Clinical study
Stop treatment
when all signs of
GVHD disappear
Gold standard is
systemic
steroid therapy
Taper steroid
doses as soon as
major improvement
is seen
Major
improvement
No response after 7 days
or
Clear progression after 5 days
Penack. Lancet Haematol. 2020;7:e157. Slide credit: clinicaloptions.com

Response to Steroids in Patients With aGVHD
Steroids are effective
in only 40% of patients
with aGVHD
Only 30% of patients with
aGVHD have a long-lasting
response to steroids
Murray. The European Blood and Marrow Transplantation Textbook for Nurses: Under the Auspices of EBMT. 2018:221-251. Slide credit: clinicaloptions.com

Does GVHD Impact Survival?
Westin. Adv Hematol. 2011;2011:601953. Slide credit: clinicaloptions.com
Overall Survival in Steroid-Responsive and Steroid-Refractory aGVHD
Cumulative
Proportion
Surviving
0.4
0
0.2
1.0
0.8
0.6
0 10 20 30 40 50 60 70 80 90
Time Since Transplantation (Mo)
HR at 2 yr: 0.5
P <.001
CR or PR
Other

Can We Reduce GVHD by JAK1/2 Targeting?
Spoerl. Blood 2014;123:3832. Slide credit: clinicaloptions.com
100
Percent
Survival
80
60
20
0
0 40 60
Time After Allo-HSCT (Days)
40
20 80 100
P <.0001
BM only (n = 10)
Vehicle (n = 21)
Ruxolitinib (n = 20)
0
0.9
0.8
0.7
Weight
Ratio
0 20 30
10
Time After Allo-HSCT (Days)
Ruxolitinib (n = 6)
Vehicle (n = 9) GVHD
Histology
Score
4
3
1
0
8 14 29
Days Post Allo-HSCT
2
Small Intestine
Vehicle Ruxolitinib
P <.0001
P <.0001P <.0001 4
3
1
0
8 14 29
2
Large Intestine
P <.0001
P <.0001
P <.0002 4
3
1
0
8 14 29
2
Liver
P = .0002
P = .0002
P = .0002

Safety and Efficacy of Ruxolitinib vs BAT in Patients
With SR aGVHD: REACH2 Phase III Study Design
 Multicenter, open-label, randomized trial
 Primary endpoint: ORR at Day 28
 Key secondary endpoint: durable ORR at Day 56
Patients ≥12 yr of age
with grade II, III/IV
SR aGVHD; evidence
indicating myeloid
engraftment with ANC
>1000/mm3 and
platelets
≥20,000/mm3
(N = 309)
Ruxolitinib 10 mg BID +
steroids ±
calcineurin inhibitors
(n = 154)
BAT* +
steroids ±
(n = 155)
Ruxolitinib 10 mg BID +
steroids ±
BAT +
steroids ±
Day 1 Day 28
Screening 6 Mo
Day 56 18 Mo
Core Treatment Phase Extension Phase
At 6 mo:
Secondary
analysis
for
OS and NRM
At 18 mo:
Final analysis
of
safety and
efficacy
*Patients randomized to BAT arm could cross over to ruxolitinib arm if primary endpoint not attained or response
lost with disease progression, mixed response, or no response and requiring further systemic immunosuppressive therapy.
Zeiser. NEJM. 2020;382:1800.

Safety and Efficacy of Ruxolitinib vs
BAT in Patients With SR aGVHD: REACH2 Results
Zeiser. NEJM. 2020;382:1800.
HR*: 0.46 (95% CI: 0.35-0.60)
Mo
Patients
Without
Treatment
Failure
(%)
*HR for relapse or hematologic disease progression, non–relapse-related
death, or additional new systemic therapy for aGVHD.
Treatment
Median Failure-Free
Survival, Mo
Ruxolitinib 5.0
Control 1.0
Partial response
Complete response
Day 28 Overall Response
Patients
(%)
0
20
40
60
80
100
62.3
39.4
Ruxolitinib
(n = 154)
Control
(n = 155)
34.4
27.9 20.0
19.4
P <.001
Day 56 Durable
Overall Response
0
20
40
60
80
100
39.6
21.9
Ruxolitinib
(n = 154)
Control
(n = 155)
26.6
13.0 5.8
16.1
P <.001
0
20
40
60
80
100
0 2 4 6 8 10 12
Ruxolitinib
Control
Censored data
Duration of Failure-Free Survival

REACH 2: 6-Mo Follow-Up
Duration of Response and Event-Free Survival
Duration of Response Event-Free Survival
Mohty. EBMT 2021. Abstr O067.
100
Probability
of
Loss
of
Response
(%)
80
60
20
0
0 4 6
Mo
40
2 8 10 12 16 18
14 20 22
Censored
Competing event
BAT
RUX
37.34% 37.34%
8.73% 10.16%
6 Mo 12 Mo
100
EFS
(%)
80
60
20
0
Mo
40
0 4 6
2 8 10 12 16 18
14 20 22
BAT
RUX
24 26 28
Censoring times
8.18 vs 4.17 mo
HR: 0.80 (95% CI: 0.60-1.08)
Median (RUX vs BAT)
RUX: 87/154
BAT: 95/155
Events
FFS
(%)
100
80
60
20
0
40
Failure-Free Survival
4 6
2 8 10 12 16 18
14 20 22
0 24 26 28
Mo
4.66 vs 1.02 mo
HR: 0.49 (95% CI: 0.37-0.63)
P <.0001
Median (RUX vs BAT)
RUX: 99/154
BAT: 124/155
Events
Censoring times
BAT
RUX

Novel Approaches for GVHD
 Bendamustine
 IL-2
 Defibrotide
 Atorvastatin
 Leronlimab (CCR5)
 Tocilizumab
 CD24f
 Bortezomib
 Fecal transplant
 Vedolizumab
 Itacitinib
 Canabidiol
 CD40L blockade
 Tildrakizumab (anti-IL23p19)
 Expanded regulatory T-cells
 Basiliximab
 Telmisartan
 RGI 2001 (α gal-cer
[CD1d ligand])
 MSC
 Panobinostat
 Carfilzomib
 Rituximab
 Milatuzumab (anti-CD74)
 Maraviroc
 Brentuximab vedotin

CD6 Blockade With Steroids as
Initial Therapy for Severe Acute GVHD
 Binding of CD6/ALCAM important for1:
‒ Immune synapse formation
‒ Optimal costimulation and activation
‒ Trafficking into tissues
 EQ001 (itolizumab), a humanized IgG1 mAb, binds CD6 and blocks
interaction with ALCAM; inhibits activity and trafficking of T-cells
without causing T-cell depletion
‒ Itolizumab approved for treatment of psoriasis in India2
 EQUATE trial3: phase Ib/II study evaluating safety, tolerability,
pharmacokinetics, pharmacodynamics, and clinical activity of itolizumab
in patients with newly diagnosed acute GVHD (estimated N = 100);
currently enrolling
1. Consuegra-Fernandez. Autoimmun Rev. 2018;17:493. 2. Krupashankar. J Am Acad Dermatol. 2014;71:484. 3. NCT03763318.
IMAGE NOT AVAILABLE

IL-22 “GI Protectant” With Steroids as
Initial Therapy for GI GVHD
 F-652: recombinant fusion protein of human IL-22 dimer and human IgG2 Fc with an extended t1/2
 Phase II trial with steroids2
1. Hanash. Immunity. 2012:37:339. 2. Ponce. TCT 2020. Abstr 68. 3. NCT04539470.
Day 28 Response Rate
10
8
6
4
2
0
Stage 1 Stage 2 Stage 3-4
Responder
Nonresponder
Lower GI aGVHD Stage
Patients,
n
CR (n = 13)
VGPR
(n = 3)
PR
(n = 3)
No Response (n = 8)
IMAGE NOT AVAILABLE

Urinary-Derived Human Chorionic Gonadotropin/
Epidermal Growth Factor for aGVHD: Study Design
 Prospective phase II trial
 Primary outcome: Day 28 response
 Secondary outcomes: safety, survival, exploratory metabolomics analysis, biomarkers
uhCG/EGF 2000 units/m2 SC
every other day x 7 days +
High-dose steroids*
(n = 22)
Patients with
life-threatening
aGVHD; creatinine
<2.5x ULN; LVEF ≥35%
Holtan. ASH 2021. Abstr 261. NCT02525029.
uhCG/EGF 2000 units/m2 SC
(steroid dependent) or 5000 units/m2 SC
(steroid refractory) every other day x 14 days +
SoC immunosuppression*
(n = 22)
*Responders eligible to receive optional maintenance doses
twice weekly x 5 wk.
First line: Minnesota High Risk
Second line: no response
to first line or GVHD flare

uhCG/EGF for aGVHD: Baseline Characteristics
Characteristic First-line High Risk (n = 22) Second Line (n = 22)
Median age, yr (range) 61 (22-72) 62 (2-69)
Median Karnofsky score (range) 60 (30-90) 50 (20-100)
Male, n (%) 16 (73) 17 (77)
Graft source, n (%)
 Marrow
 Peripheral blood stem calls
 Umbilical cord
5 (23)
8 (36)
9 (41)
8 (36)
9 (41)
5 (23)
Conditioning, n (%)
 Myeloablative
 Reduced intensity
10 (45)
12 (55)
5 (23)
17 (77)
Median post-transplant day of
enrollment, n (IQR)
57 (34-118) 123 (76-209)
Holtan. ASH 2021. Abstr 261. Slide credit: clinicaloptions.com

uhCG/EGF for aGVHD: GVHD Severity at Baseline
Characteristic, n (%) First-line High Risk (n = 22) Second Line (n = 22)
aGVHD organ stage
at enrollment
 Skin
– 0
– 1
– 2
– 3
– 4
 Lower GI
– 0
– 1
– 2
– 3
– 4
 Liver
– 0
– 1
– 2
– 3
– 4
13 (59)
3 (14)
1 (5)
4 (18)
1 (5)
1 (5)
1 (5)
5 (23)
13 (59)
2 (9)
19 (56)
1 (5)
0
2 (9)
0
12 (55)
1 (5)
3 (14)
4 (18)
2 (9)
8 (36)
3 (14)
3 (14)
2 (9)
6 (27)
18 (82)
1 (5)
3 (14)
0
0
Holtan. ASH 2021. Abstr 261.
Characteristic First-line High Risk (n = 22) Second Line (n = 22)
aGVHD clinical stage
at enrollment, n (%)
 2
 3
 4
2 (9)
17 (77)
3 (14)
9 (41)
5 (23)
8 (36)
Median albumin,
g/dL (range)
2.7 (1.9-3.4) 2.5 (0.9-4.0)
Concomitant
GVHD therapy
Steroids (n = 22)
ATG (n = 4)
Etanercept (n = 1)
Ruxolitinib (n = 5)
Sirolimus (n = 4)
Steroids (n = 8)

uhCG/EGF for aGVHD: Day 28 Response
(Primary Outcome) and Survival Outcomes
 Median OS for entire cohort: 1.2 yr
 2-yr survival 67% vs 12% for responders vs nonresponders, respectively; P <.01
Outcome, n (%)
First-line High Risk
(n = 22)
Second Line
(n = 22)
All Patients
(N = 44)
CR 64 50 57
PR 0 23 11

uhCG/EGF for aGVHD: Adverse Events and
Metabolomic Analysis (Exploratory)
 1 dose-limiting toxicity: cerebral venous sinus thrombosis; treated successfully with
anticoagulation
 23/44 (52%) patients died
‒ aGVHD (n = 9)
‒ Relapse (n = 9)
‒ Infection (n = 3)
‒ Organ damage (n = 2)
 Metabolomics analysis (exploratory) identified possible associations between
blood metabolites and response to therapy
‒ Higher linoleic acid levels associated with higher CR/PR rates
‒ Higher lactic acid levels associated with treatment failure

Conclusions
 There is evidence that acute GVHD affects not only the intestinal
tract, liver, and skin, but also the CNS, thymus, ovaries, and
multiple other organs
 2-yr OS of patients with steroid-refractory acute GVHD is below 40%
 Ruxolitinib was approved by the FDA for SR-aGVHD in 2020
 Amphiregulin is promising as an aGVHD biomarker
 Novel regenerative approaches such as IL-22 and GLP-2 treatment in
addition to immunosuppression may help improve the outcome of
patients with SR-aGVHD

clinicaloptions.com/oncology
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