treatment of chronic gvhd— progress to date and ......prelude “the era of the rock star is over....
TRANSCRIPT
Treatment of Chronic GVHD—Progress to Date and Challenges Ahead
Paul J. Martin, M.D.
Fred Hutchinson Cancer Research Center
University of Washington
Prelude
“The era of the rock star is over. We’re now in the era of the orchestra.”
―Connie Eaves, Ph.D. Thomas Lecture, ASH 2018
Discovery and Initial Characterization of Chronic GVHD
1980
• Kruger et al., Graft-versus-host disease. Am J Path, May 1971
• Shulman et al., Chronic cutaneous graft-versus host disease. Am J Path, June 1978
• Shulman et al., Chronic graft-versus-host syndrome…Am J Med, August 1980
20001990 2010 2020
– Keratoconjunctivitis sicca– Sialadenitis – Cutaneous sclerosis– Discoid lupus erythematosus– Cholestasis
– Limited and Extensive types– Progressive, late and de novo onset
First Movement—First Theme
Initial Prospective Clinical Trials
1980
• Sullivan et al. Prednisone and azathioprine….Blood, 1988
• Sullivan et al. Alternating-day cyclosporine and prednisone….Blood, 1988
20001990 2010 2020
Perc
ent
Surv
ival
First Movement—Second Theme
Identification of Prognostic Risk Factors
1980
• Wingard et al. Predictors of death from chronic GVHD….Blood, 1989
• Arora et al. Risk score predicts mortality….BBMT, 2015
20001990 2010 2020
Older patient age
Female donor, male recipient
HLA-mismatch
High disease risk category
Tacrolimus prophylaxis
Prior acute GVHD
Short interval from transplantation
Low performance score
High serum bilirubin concentration
Thrombocytopenia
Years from Onset
First Movement—Third Theme
Models of Chronic GVHD in Mice
1980
• Jaffee and Claman. Chronic GVHD as a model for scleroderma. Cell Immunol, 1983
• Hamilton and Parkman. Acute and chronic GVHD….in mice. Transplantation, 1983
20001990 2010 2020
Second Movement—First Theme
Pathophysiological Insights from Murine Models
1980 20001990 2010 2020
MacDonald KP, et al. Blood, 2017
• Alloactivated T cells from the graft
• Th17/Tc17 differentiation
• Defective negative selection in thymus
• Insufficient generation of Treg cells
• T and B cell axis– T cell help for B cells– Antibody production
• Macrophage activation and sequestration
• Profibrogenic cytokines
Third Movement
NIH Consensus Conferences
1980 20001990 2010 2020
Diagnosis and Staging
Pathology
Biomarkers
Measurement of Response
Supportive Care
Clinical Trial Design
Second Movement—Second Theme
Reports of Second-line Treatment Results—1990 through 2018*
1980 20001990 2010 2020
*N ≥10 patients
Number of Reports Number of ReportsRetrospectiveProspective
Second Movement—Third Theme
Controlled Trials of Initial Treatment—1980 to present
1980 20001990 2010 2020
First Author Arms Compared
DoubleBlind N Results
Sullivan Prednisone azathioprine Yes 179 Decreased survival
Koc Prednisone cyclosporine No 287 Steroid-sparing?
Koc Cyclosporine/prednisone thalidomide Yes 51 Toxicity
Arora Cyclosporine/prednisone thalidomide No 54 No benefit
Martin Calcineurin inhibitor/prednisone mycophenolate mofetil Yes 151 No benefit
Gilman Calcineurin inhibitor/prednisone hydroxychloroquine No 54 No benefit
Carpenter Sirolimus/prednisone calcineurin inhibitor No 138 No benefit
Second Movement—Third Theme
Investigator-initiated Studies with Industry Collaborators
1980 20001990 2010 2020
Collaborator Studies
Astellas 1
Astex 1
Bristol-Myers Squibb 1
Celgene 1
Genentech 1
Genzyme 1
Hoffmann-La Roche 1
Maco Pharma SAS 1
Medipost 1
Millennium 4
Novartis 8
Prometheus 3
Roche Laboratories 1
Seattle Genetics 1
Indication
Initial treatment 5
High risk or Steroid-refractory 1
Steroid-refractory 19
Nu
mb
er
Year Study Started
Agents Tested
Abatacept Imatinib
Alefacept Lenalidomide
Alemtuzumab Mesenchymal stem cells
Bortezomib Mycophenolate mofetil
Brentuximab vedotin Nilotinib
ECP Panobinostat
Erismodegib Pentostatin
Everolimus Rituximab
IL-2 ± Treg or ECP Vismodegib
0
2
4
6
8
10
Studies with Industry Collaborators
Third Movement
Industry-sponsored Trials for Steroid-refractory Chronic GVHD
1980 20001990 2010 2020
Drug Sponsor Phase Enrollment
AMG 592 Amgen 1 - 2 124
KD025 Kadmon 2 126
SNDX-6352 Syndax 1 30
Ibrutinib Janssen (Japan) 3 19
Ibrutinib Pharmacyclics 1 – 2 44*
Ruxolitinib Incyte 3 324
KD025 Kadmon 2 88
Ibrutinib Pharmacyclics 1 - 2 45
ECP Kiadis 1 - 2 20
ECP Mallinckrodt 2 72
*Pediatric
Third Movement
Approval of Ibrutinib for Second-line Treatment—August 2, 2017
1980 20001990 2010 2020
Pathophysiology ManifestationsOnset of Response
Inflammation Cutaneous erythema Weeks
Oral lichenoid changes
Diarrhea
Abnormal liver function
Fibrosis Cutaneous sclerosis Months
Fasciitis and joint disease
Panniculitis
Destruction Oral and ocular sicca Not seen
Bronchiolitis obliterans
Vitiligo
• Defined trajectory of disease before enrollment
• Cutaneous erythema or oral changes required for eligibility
• Response assessment not confounded by other new treatment at or after enrollment
• Study product was well tolerated during long-term administration
Percent SuccessEndpoint Ibrutinib
6-month FFS-CR/PR 45
Third Movement
Approval of Ibrutinib for Second-line Treatment—August 2, 2017
1980 20001990 2010 2020
Pathophysiology ManifestationsOnset of Response
Inflammation Cutaneous erythema Weeks
Oral lichenoid changes
Diarrhea
Abnormal liver function
Fibrosis Cutaneous sclerosis Months
Fasciitis and joint disease
Panniculitis
Destruction Oral and ocular sicca Not seen
Bronchiolitis obliterans
Vitiligo
• Defined trajectory of disease before enrollment
• Cutaneous erythema or oral changes required for eligibility
• Response assessment not confounded by other new treatment at or after enrollment
• Study product was well tolerated during long-term administration
Percent SuccessEndpoint Ibrutinib Benchmark
6-month FFS-CR/PR 45 40
Third Movement
Industry-sponsored Trials for Initial Treatment of Chronic GVHD
1980 20001990 2010 2020
Drug Sponsor Phase Enrollment
Ruxolitinib Novartis 2 42*
Itacitinib Incyte 3 266
Ibrutinib Pharmacyclics 3 186
Arsenic trioxide Medsenic 2 24
Entospletinib Gilead 2 66
ECP Mallinckrodt 1 60
Third Movement
*Pediatric; also includes steroid-refractory
Progress to Date—Perspective 2019
1980 20001990 2010 2020
• Disease and clinical course are now well characterized
• Complex pathophysiology is much better understood
• Many investigational agents are available for treatment
• Strong infrastructure for clinical trials is available
• Resources are available through industry collaboration
• Regulatory approval pathway has been established
First Three Movements
Progress to Date—Perspective 2019
1980 20001990 2010 2020
• Disease and clinical course are now well characterized
• Complex pathophysiology is much better understood
• Many investigational agents are available for treatment
• Strong infrastructure for clinical trials is available
• Resources are available through industry collaboration
• Regulatory approval pathway has been established
• Mainstay of initial treatment is still calcineurin inhibitor and prednisone
• Best choice of subsequent treatment is still undefined
BUT
First Three Movements
Challenge No. 1—Tolerability of Long-Term Treatment
2019 20212020 2022 2023
Death or Relapse During Treatment
Treatment Continuing
Treatment Ended
Risk Factors for Prolonged Treatment
Older donor age
Recipient HLA mismatch
Mobilized blood graft
Previous late acute GVHD
High serum bilirubin concentration
High prednisone dose at onset
Female donor for male recipient
High number of involved sites
Vigorito et al. Blood, 2009
Fourth Movement
Challenge No. 2—Short-Term Prognostic Endpoints
2019 20212020 2022 2023
Failure-free survival: survival without new systemic treatment or recurrent malignancy
Fourth Movement
Challenge No. 2—Short-Term Prognostic Endpoints
2019 20212020 2022 2023
CR/PR
Fourth Movement
Challenge No. 2—Short-Term Prognostic Endpoints
2019 20212020 2022 2023
Months from Landmark
6-month Landmark
Perc
ent
Surv
ival
CR/PR
SD/PD
New Rx
Fourth Movement
Challenge No. 2—Short-Term Prognostic Endpoints
2019 20212020 2022 2023
Martin et al. Blood, 2017
Months from Landmark Months from Landmark
12-month Landmark6-month Landmark
CR/PR vs. SD/PD/New RxHR, 0.19; 95% CI, 0.05-0.77;
P=0.02
Perc
ent
Surv
ival
CR/PR
SD/PD
New Rx
Fourth Movement
Challenge No. 2—Short-Term Prognostic Endpoints
2019 20212020 2022 2023
100 Patients Receive Initial Systemic Treatment
58 alive without new systemic treatment or relapse (FFS)
17 with FFS-CR/PR
P = 0.58
6 Months
12 Months
P = 0.29
Baseline
Fourth Movement
Challenge No. 2—Short-Term Prognostic Endpoints
2019 20212020 2022 2023
100 Patients Receive Initial Systemic Treatment
75 alive without new systemic treatment or relapse (FFS)
38 with FFS-CR/PR
P = 0.58 0.75
6 Months
12 Months
P = 0.29 0.50
Baseline
Fourth Movement
Challenge No. 3—Right Drug, Right Patient, Right Time
2019 20212020 2022 2023
Cluster Number Characteristics Frequency (%)
1 Ocular predominant 9
2 Sclerotic 10
3 Liver-predominant-Moderate 9
4 Mixed Phenotype-Intermediate Risk 34
5 Erythema Predominant 17
6 Mixed phenotype-High Risk 12
7 Liver-predominant-Severe 10
Gandelman et al. Haematologica 2019
Fourth Movement
Challenge No. 3—Right Drug, Right Patient, Right Time
2019 20212020 2022 2023
Pathophysiological Mechanism Available Therapeutic Agents
Th17/Tc17 differentiation JAK inhibitors (ruxolitinib, itacitinib), ROCK inhibitors (KD025)
Insufficient generation of Treg IL-2, AMG592, KD025, ruxolitinib, ECP
T and B cell axisBTK inhibitors (ibrutinib), SYK inhibitors (fostamatinib), KD025,anti-CD19/20, proteasome inhibitors
Macrophage activation and sequestration anti-CSF-1R (SNDX6352 and others)
Profibrogenic cytokines pirfenidone
BiomarkerClinical Cluster
Fourth Movement
Challenge No. 3—Right Drug, Right Patient, Right Time
2019 20212020 2022 2023
Pathophysiological Mechanism Other Possible Agents
Th17/Tc17 differentiationAntibodies: IL-12p40 (ustekinumab), IL-17 (secukinumab, ixekizumab, brodalumab), anti-IL-22
Insufficient generation of Treg
T and B cell axis anti-IL-21, anti-ICOS, anti-CD40L, bcl6 inhibitors
Macrophage activation and sequestration
Profibrogenic cytokines anti-TGFβ
BiomarkerClinical Cluster
Fourth Movement
Challenge No. 4—Immunological Resolution of the Disease
2019 20212020 2022 2023
3.5 years
Fourth Movement
Challenge No. 4—Immunological Resolution of the Disease
2019 20212020 2022 2023
3.5 years 1.5 years
Fourth Movement
Continuing the Music
2019 20212020 2022 2023
Patients & Clinicians
Clinical Investigators
Laboratory InvestigatorsBiostatisticians
Industry Sponsors
Academic Community
FDA and Patients NIH and other Funding Agencies
Fourth Movement
Credits• Mary Flowers• Stephanie Lee• Barry Storer• Yoshi Inamoto• Paul Carpenter
• Georgia Vogelsang• Steve Pavletic• Howard Shulman• Keith Sullivan• Defu Zeng• NIH Consensus Conference Participants• Authors
• National Cancer Institute• National Heart, Lung Blood Institute• National Institute of Allergy and Infectious Diseases
One Final Thought
“The greatest enemy of knowledge is not ignorance, it is the illusion of knowledge.”
―Daniel J. Boorstin: The Discovers: A History of Man’s Search to Know His World and Himself*
*Quotation courtesy of Georgia Vogelsang
A Second Final Thought
“The greatest enemy of knowledge is not ignorance, it is the illusion of knowledge.”
―Daniel J. Boorstin: The Discovers: A History of Man’s Search to Know His World and Himself
*Quoted by Joshua D. Mezrich: When Death Becomes Life
“I cannot give any scientist of any age better advice than this: the intensity of the conviction that a hypothesis is true has no bearing on whether it is true or not.”
―Peter Medawar: Advice to a Young Scientist*