2/15/18. Biology of Chronic GVHD. Disclosures. Objectives BMT Pharmacists Conference. Paul J. Martin, M.D.

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1 2018 BMT Pharmacists Conference Biology of Chronic GVHD Paul J. Martin, M.D. Member, Fred Hutchison Cancer Research Center Professor of Medicine, Division of Oncology University of Washington Disclosures Neovii (Fresenius): Clinical Investigator, Research Funding; Pfizer: DSMB Member, Consultancy; Procter and Gamble: Stock, Ownership Interest None of these financial arrangements are related to my discussion of treatment for GVHD No agent other than ibrutinib has received regulatory approval for treatment of chronic GVHD in the U.S. Discussion of all other medications is off-label Objectives Describe biological pathways in the pathogenesis of chronic graft-versus-host disease Evaluate the current trends in clinical trials of treatment for chronic GVHD. Identify drugs of particular interest for treatment of chronic GVHD. Assess quality criteria in the interpretation of clinical trial results 1

2 Initial Pathogenesis of Acute and Chronic GVHD Schroeder MA, et al. Dis Model Mech. 2011;4: Antigen Presentation and T Cell Activation in Acute GVHD Schroeder MA, et al. Dis Model Mech. 2011;4: Trafficking and Tissue Injury in Acute GVHD Schroeder MA, et al. Dis Model Mech. 2011;4:

3 Distinctive Early Events in cgvhd Schroeder MA, et al. Dis Model Mech. 2011;4: Activation of B cells in cgvhd Schroeder MA, et al. Dis Model Mech. 2011;4: Fibrotic Mediators in cgvhd Schroeder MA, et al. Dis Model Mech. 2011;4:

4 Distinctive Biological Pathways in cgvhd MacDonald KP, et al. Blood. 2017;129:13-21 ARS Question #1 Which of the following is NOT considered a distinctive early event leading to the development of cgvhd? A. Increased number of TREG cells B. Thymic injury C. Dysregulated B cell immunity Goals of Treatment for cgvhd Reduce symptom burden Control objective manifestations of disease activity Preserve function by preventing damage and impairment Improve overall survival With sustainable benefit until systemic treatment is no longer needed Without causing disproportionate harm related to the treatment itself Martin PJ, et al. Biol Blood Marrow Transplant. 2015;21:

5 Continuous Recalibration of Systemic Treatment Martin PJ, et al. Biol Blood Marrow Transplant. 2015;21: Dimensions of Response Trajectory of change before enrollment Criteria Categorical Minimal absolute change Minimal relative change Stabilization Duration and continuity of response Concomitant treatment At enrollment After enrollment Accounting for complications other than GVHD Before enrollment After enrollment Expected Time to Onset of Response Pathophysiology Onset of Response Manifestations Inflammation Weeks Cutaneous erythema Oral lichenoid changes Diarrhea Abnormal liver function Fibrosis Months Cutaneous sclerosis Fasciitis Panniculitis Destruction Not seen Oral and ocular sicca Bronchiolitis obliterans Vitiligo 5

6 Some Benchmarks for First and Second-line Treatment Trials Percent Success Outcome First-line Second-line 3-month complete or partial response (intent-to-treat) 6-month complete or partial response (intent-to-treat) 55 a 45 a 6-month failure-free survival 68 b 56 c 12-month failure-free survival 54 b 36 d 45 c 12-month failure-free survival with CR/PR 15 e 12-month overall survival b,d,e 85 c End of systemic treatment within 12 months 5 b 2 c Mean prednisone dose at 3 months (mg/kg/day) 0.28 d a Martin PJ, et al. Biol Blood Marrow Transplant 2011;17: b Inamoto Y, et al. Blood. 2014;124: c Inamoto Y, et al. Blood. 2013;121: d Martin PJ, et al. Blood 2009;113: e Martin PJ, et al. Blood 2017;130: Clinical Benefit of Failure- Free Survival with CR/PR at 1 Year CR/PR vs. SD/PD/New Rx HR, 2.75; 95% CI, ; P < IST=Immunosupressive treatment; CR/PR=Complete or partial response; SD/PD=Stable or progressive disease; New Rx=Secondary system treatment of cgvhd before the landmark; HR=Hazard ratio Martin PJ, et al. Blood. 2017;130 (3): Clinical Benefit of Failure- Free Survival with CR/PR at 1 Year CR/PR vs. SD/PD/New Rx HR, 0.19; 95% CI, ; P=0.02 IST=Immunosupressive treatment; CR/PR=Complete or partial response; SD/PD=Stable or progressive disease; New Rx=Secondary system treatment of cgvhd before the landmark; HR=Hazard ratio Martin PJ, et al. Blood. 2017;130 (3):

7 Trends in Trials of Treatment for cgvhd New interest from industry sponsors Wider selection of targets based on pathophysiology Larger sample size in some studies Trends in Funding Sources Phase 2 Studies Interval No Outside Support Academic Lead Public Support Industry Support Industry Lead Any Industry Support (N = 10) (N = 10) 5 2 3* (N = 16) *1 trial also had public support 3 trials also had public support Abstracted from ClinicalTrials.gov Approved Agents Tested in Phase 2 with Industry Support Trial Status and Agent Tested Launch Indication Target Enrollment Completed ECP 2002 Steroid-refractory skin disease 72 Pentostatin 2004 Refractory disease 51 Bortezomib 2008 Initial treatment 22 Pomalidomide 2009 Steroid-refractory disease 13 Active, not recruiting Bortezomib 2010 Steroid-refractory disease 25 IL Steroid-refractory disease 35 Everolimus 2012 Initial treatment 38 Nilotinib (after imatinib) 2012 Steroid-refractory disease 65 Ofatumumab 2012 Initial treatment 44* Pomalidomide 2012 Steroid-refractory disease 34 Ibrutinib nd, 3rd or 4th-line treatment 45* ECP plus IL Steroid-refractory disease 25 Ixazomib 2015 Steroid-refractory disease 50 *phase 1-2 Abstracted from ClinicalTrials.gov 7

8 Approved Agents in Trials Recruiting with Industry Support Agent Tested Launch Phase Indication Target Enrollment Abatacept Steroid-refractory disease 22 Carfilzomib Steroid-refractory disease 20 Vismodegib 2015 Pilot Steroid-refractory scleroderma 12 Obinutuzumab Prevention 200 Arsenic trioxide Initial treatment 24 Fostamatinib Prevention 18 Ibrutinib Initial treatment 186 Ixazomib Prevention 46 Ruxolitinib Steroid-refractory disease 324 Abstracted from ClinicalTrials.gov Recruiting for Studies with Unapproved Agents Agent Tested Launch Phase Indication With Industry Support Target Enrollment T-regulatory cells plus IL Steroid-refractory disease 25 KD nd, 3rd or 4th-line Rx 48 Entospletinib Initial treatment 100 AZD Bronchiolitis obliterans 34 TH9402 photochemotherapy Steroid-refractory disease 25 Baricitinib Steroid-refractory disease 31 Without Industry Support T-regulatory cells plus sirolimus Steroid-refractory disease 35 T-regulatory cells (n = 3) & 1-2 Steroid-refractory disease Mesenchymal stem cells (n = 5) , 2, 3 2 nd and 1 st -line treatment Abstracted from ClinicalTrials.gov ARS Question #2 Currently, research in cgvhd is at standstill because there is no interest from industry sponsors and there are few medications available due to limited targets based on pathophysiology. A. True B. False 8

9 Targets and Agents of Particular Current Interest Non-lymphocyte targets: Hedgehog inhibitors Neutrophil elastase inhibitors Block T activation & cytokine-induced lineages: JAK inhibitors (Ruxolitinib, Baricitinib) Proteasome inhibitors CTLA4-Ig fusion protein Block trafficking of effectors from LN: Ponesimod (S1P1R) Tregs: IL-2 1. APC activated, move to LN 2. APC activate Th1, Th17, Tfh T cells 3. Tfh support Ab-producing B cells 4. T-& B-cells infiltrate tissue 5. Ab deposition and cytotoxic attack 2 thymopoiesis: KGF IGF IL-7 Steroid blockade Deplete B cells: Rituximab Block B activation: Belimumab (BAFF) Fostamatinib (Syk) Cerdulatinib (Syk) Ibrutinib (BTK) Im A, et al. Leukemia. 2017;31: Targets and Agents of Particular Current Interest Non-lymphocyte targets: Hedgehog inhibitors Neutrophil elastase inhibitors Block T activation & cytokine-induced lineages: JAK inhibitors (Ruxolitinib, Baricitinib) Proteasome inhibitors CTLA4-Ig fusion protein Block trafficking of effectors from LN: Ponesimod (S1P1R) Tregs: IL-2 1. APC activated, move to LN 2. APC activate Th1, Th17, Tfh T cells 3. Tfh support Ab-producing B cells 4. T-& B-cells infiltrate tissue 5. Ab deposition and cytotoxic attack 2 thymopoiesis: KGF IGF IL-7 Steroid blockade Deplete B cells: Rituximab Block B activation: Belimumab (BAFF) Fostamatinib (Syk) Cerdulatinib (Syk) Ibrutinib (BTK) Im A, et al. Leukemia. 2017;31: Interleukin-2 (IL-2) Mechanism of Action Thymus Secondary Lymphoid Organs Makek TR, et al. Nat Rev Immunol. 2004;4:

10 Low-dose IL-2 for Steroid-refractory cgvhd Design Single arm, open-label study Eligibility Active cgvhd despite 4 weeks of treatment with 0.25 mg/kg/day prednisone in prior 12 months 2 prior lines of treatment Stable treatment for 4 weeks before enrollment No concurrent treatment with sirolimus and calcineurin inhibitor (CNI) Treatment IL-2, 1 x 10 6 IU/m 2 /day for 12 weeks Extended treatment allowed after 4-week hiatus Statistical hypothesis CR/PR 0.40 at 12 weeks with null hypothesis 0.20 Number of patients enrolled 35 Koreth et al. Blood. 2016;128: Low-dose IL-2 for Steroid-refractory cgvhd: Results Compared to Benchmark Percent Success Outcome Benchmark IL-2 3-month complete or partial response (intent-to-treat) 57 6-month complete or partial response (intent-to-treat) 6-month failure-free survival 56 NR 12-month failure-free survival 45 NR 12-month failure-free survival with CR/PR 12-month overall survival End of systemic treatment within 12 months 2 NR Mean prednisone dose at 3 months (mg/kg/day) NR=NOT REPORTED Koreth et al. Blood. 2016;128: Adverse Events During Treatment with IL-2 Koreth et al. Blood. 2016;128: Adverse Event Percent of Patients Myalgia 3 Arthralgia 6 Constitutional symptoms 9 Fatigue 3 Thrombocytopenia 6 Hyperglycemia 12 Neuropathy 3 RSV infection 3 Streptococcus infection 3 Pulmonary embolism 6 Aspergillus pneumonia 3 10

11 Targets and Agents of Particular Current Interest Non-lymphocyte targets: Hedgehog inhibitors Neutrophil elastase inhibitors Block T activation & cytokine-induced lineages: JAK inhibitors (Ruxolitinib, Baricitinib) Proteasome inhibitors CTLA4-Ig fusion protein Block trafficking of effectors from LN: Ponesimod (S1P1R) Tregs: IL-2 1. APC activated, move to LN 2. APC activate Th1, Th17, Tfh T cells 3. Tfh support Ab-producing B cells 4. T-& B-cells infiltrate tissue 5. Ab deposition and cytotoxic attack 2 thymopoiesis: KGF IGF IL-7 Steroid blockade Deplete B cells: Rituximab Block B activation: Belimumab (BAFF) Fostamatinib (Syk) Cerdulatinib (Syk) Ibrutinib (BTK) Im A, et al. Leukemia. 2017;31: Ruxolitinib Mechanism of Action Teshima, et al. Blood. 2014;123: Ruxolitinib for Steroid-refractory cgvhd Design Retrospective survey Eligibility Refractory to glucocorticoid treatment for 3 weeks Treatment addition of ruxolitinib 5-10 mg/day Statistical hypothesis none Number of patients enrolled 41 Zeiser et al. Leukemia. 2015;29:

12 Ruxolitinib for Steroid-refractory cgvhd: Results Compared to Benchmark Percent Success Outcome Benchmark Ruxolitinib 3-month complete or partial response (intent-to-treat) 6-month complete or partial response (intent-to-treat) 85* 6-month failure-free survival 56 NR 12-month failure-free survival 45 NR 12-month failure-free survival with CR/PR 12-month overall survival End of systemic treatment within 12 months 2 NR Mean prednisone dose at 3 months (mg/kg/day) *Responses occurred at 1 to 25 weeks; 2 patients had recurrent or progressive chronic GVHD after response. Median follow-up was 22 (range, 3 to 135) weeks. NR=NOT REPORTED Zeiser et al. Leukemia. 2015;29: Adverse Events During Treatment with Ruxolitinib Adverse Event Percent of Patients CMV reactivation 15 Grade 3 4 cytopenia 7 Grade 2 4 cytopenia 10 Recurrent malignancy 2 Zeiser et al. Leukemia. 2015;29: Targets and Agents of Particular Current Interest Non-lymphocyte targets: Hedgehog inhibitors Neutrophil elastase inhibitors Block T activation & cytokine-induced lineages: JAK inhibitors (Ruxolitinib, Baricitinib) Proteasome inhibitors CTLA4-Ig fusion protein Block trafficking of effectors from LN: Ponesimod (S1P1R) Tregs: IL-2 1. APC activated, move to LN 2. APC activate Th1, Th17, Tfh T cells 3. Tfh support Ab-producing B cells 4. T-& B-cells infiltrate tissue 5. Ab deposition and cytotoxic attack 2 thymopoiesis: KGF IGF IL-7 Steroid blockade Deplete B cells: Rituximab Block B activation: Belimumab (BAFF) Fostamatinib (Syk) Cerdulatinib (Syk) Ibrutinib (BTK) Im A, et al. Leukemia. 2017;31:

13 Ibrutinib Mechanism of Action Nakasone H, et al. Int J Hematol. 2015:101: Ibrutinib for Steroid-refractory cgvhd Design Single arm, open-label study Eligibility 1 to 3 prior treatments Steroid-dependent: prednisone 0.25 mg/kg/day for 12 weeks or Steroid-refractory: prednisone 0.5 mg/kg/day for 4 weeks Erythematous rash > 25% of body surface or oral score > 4 Stable prior systemic immunosuppressive treatment for 14 days Treatment ibrutinib added at 420 mg/day Statistical hypothesis CR/PR at any time 50% Number of patients enrolled 42 Miklos et al. Blood 2017;130: Ibrutinib for Steroid-refractory cgvhd: Results CR/PR at any time in 28/42 (67%) patients CR at any time in 9/42 (21%) patients Among Responders 21/28 tapered prednisone to <0.15 mg/kg/day 5/28 ended steroid treatment during administration of ibrutinib 20/28 had response sustained for >20 weeks Miklos et al. Blood 2017;130:

14 Duration of Response Among Responders CR PR SD No Evaluation PD D/C Ibrutinib Exit from Study Miklos et al. Blood. 2016;128:LBA-3 Ibrutinib for Steroid-refractory cgvhd: Results Compared to Benchmark Percent Success Outcome Benchmark Ibrutinib 3-month complete or partial response (intent-to-treat) 43 6-month complete or partial response (intent-to-treat) 45 6-month failure-free survival month failure-free survival month failure-free survival with CR/PR 12-month overall survival 85 NR End of systemic treatment within 12 months 2 2 Mean prednisone dose at 3 months (mg/kg/day) 0.27* *median NR=NOT REPORTED Miklos et al. Blood 2017;130: Adverse Events During Treatment with Ibrutinib Miklos et al. Blood 2017;130: Percent of Patients Adverse Event All Grades* Grade 3 5 Fatigue Diarrhea Muscle spasms 29 0 Nausea 26 0 Bruising 24 0 Upper respiratory infection 19 0 Pneumonia Fever 17 5 Headache 17 5 Fall 17 0 *incidence > 15% 14

15 ARS Question #3 KM is a 45 year old man who is Day +280 after an HLAmatched unrelated transplant for treatment of AML. He currently has cgvhd of the skin, mouth, eyes, and lungs. Treatment was started with Prednisone 1 mg/kg/day 6 weeks ago, and when the dose was tapered, the cgvhd flared. Which of the following would be the preferred next step to help treat KM s cgvhd? A. Increase the dose of Prednisone back to 1 mg/kg/day B. Add Mycophenolate 1000 mg three times daily C. Add a calcineurin inhibitor D. Add Ibrutinib 420 mg once daily Controlled Studies of First-Line Treatment Author Sullivan (1988) Koc (2002) Koc (2000) Arora (2001) Martin (2009) Gilman (2012) Carpenter (2016) Arms Compared Prednisone ± azathioprine Prednisone ± CSP CSP/Prednisone ± thalidomide CSP/Prednisone ± thalidomide CNI/Prednisone ± MMF CNI/Prednisone ± hydroxychloroquine Sirolimus/Prednisone ± CNI CSP=cyclosporine; CNI=calcineurin inhibitor; MMF=mycophenolate mofetil Double Blind N Results Yes 179 Decreased survival No 287 Limited benefit Yes 51 Toxicity No 54 No benefit Yes 151 No benefit No 54 No benefit No 138 No benefit Targets and Agents of Particular Current Interest Non-lymphocyte targets: Hedgehog inhibitors Neutrophil elastase inhibitors Block T activation & cytokine-induced lineages: JAK inhibitors (Ruxolitinib, Baricitinib) Proteasome inhibitors CTLA4-Ig fusion protein Block trafficking of effectors from LN: Ponesimod (S1P1R) Tregs: IL-2 1. APC activated, move to LN 2. APC activate Th1, Th17, Tfh T cells 3. Tfh support Ab-producing B cells 4. T-& B-cells infiltrate tissue 5. Ab deposition and cytotoxic attack 2 thymopoiesis: KGF IGF IL-7 Steroid blockade Deplete B cells: Rituximab Block B activation: Belimumab (BAFF) Fostamatinib (Syk) Cerdulatinib (Syk) Ibrutinib (BTK) Im A, et al. Leukemia. 2017;31:

16 Bortezomib Mechanism of Action Nakasone H, et al. Int J Hematol. 2015:101: Bortezomib for Initial Treatment of cgvhd Design Single arm, open-label study Eligibility Initial diagnosis of cgvhd requiring systemic treatment No systemic glucocorticoid treatment within past 4 weeks Treatment bortezomib 1.3 mg/m 2 days 1, 8, 15, 22 Three 35-day cycles Prednisone at 0.5 to 1 mg/kg/day Statistical hypothesis CR/PR 0.60 at 15 weeks with null hypothesis 0.30 Number of patients enrolled 22 Herrera et al. Biol Blood Marrow Transplant. 2014;20: Bortezomib for Initial Treatment of cgvhd: Results Compared to Benchmark Percent Success Outcome Benchmark Bortezomib 3-month complete or partial response (intent-to-treat) month complete or partial response (intent-to-treat) 45 NR 6-month failure-free survival 68 NR 12-month failure-free survival month failure-free survival with CR/PR 15 NR 12-month overall survival End of systemic treatment within 12 months 5 23* Mean prednisone dose at 3 months (mg/kg/day) *ended treatment with prednisone estimated NR=NOT REPORTED Herrera et al. Biol Blood Marrow Transplant. 2014;20:

17 Adverse Events During Treatment with Bortezomib Adverse Event Percent of Patients Abnormal liver function tests 9 Hyperglycemia 14 Renal failure 5 Coccidiomycosis 5 Grade 3 neuropathy 5 Recurrent malignancy 5 Herrera et al. Biol Blood Marrow Transplant. 2014;20: Targets and Agents of Particular Current Interest Non-lymphocyte targets: Hedgehog inhibitors Neutrophil elastase inhibitors Block T activation & cytokine-induced lineages: JAK inhibitors (Ruxolitinib, Baricitinib) Proteasome inhibitors CTLA4-Ig fusion protein Block trafficking of effectors from LN: Ponesimod (S1P1R) Tregs: IL-2 1. APC activated, move to LN 2. APC activate Th1, Th17, Tfh T cells 3. Tfh support Ab-producing B cells 4. T-& B-cells infiltrate tissue 5. Ab deposition and cytotoxic attack 2 thymopoiesis: KGF IGF IL-7 Steroid blockade Deplete B cells: Rituximab Block B activation: Belimumab (BAFF) Fostamatinib (Syk) Cerdulatinib (Syk) Ibrutinib (BTK) Im A, et al. Leukemia. 2017;31: Rituximab Mechanism of Action Nakasone H, et al. Int J Hematol. 2015:101:

18 Rituximab for Initial Treatment of cgvhd Design Single arm, open-label study Eligibility Initial diagnosis of cgvhd requiring systemic treatment No prednisone at doses 1 mg/kg/day Treatment rituximab 375 mg/m 2 /week x 4 Second cycle allowed if response not adequate Prednisone at 1 mg/kg/day followed by taper Cyclosporine to maintain trough at ng/ml Statistical hypothesis CR/PR 0.85 at 1 year with null hypothesis 0.60 Number of patients enrolled 24 Malard et al. Blood. 2017;130: Rituximab for Initial Treatment of cgvhd: Results Compared to Benchmark Percent Success Outcome Benchmark Rituximab 3-month complete or partial response (intent-to-treat) 55 6-month complete or partial response (intent-to-treat) 45 6-month failure-free survival month failure-free survival month failure-free survival with CR/PR month overall survival End of systemic treatment within 12 months 5 58* Mean prednisone dose at 3 months (mg/kg/day) *ended treatment with prednisone estimated Malard et al. Blood. 2017;130: Adverse Events During Treatment with Rituximab Adverse Event Percent of Patients Infections 29 Grade 3 4 lymphopenia 50 Grade 3 4 neutropenia 21 Hyperglycemia 4 Renal failure 4 Thrombotic microangiopathy 4 Transient global amnesia 4 Recurrent malignancy 4 Malard et al. Blood. 2017;130:

19 ARS Question #4 JD is a 62 year old woman who is Day after an HLAmatched related transplant for treatment of myelodysplastic syndrome. She had Grade II acute GVHD of the skin and gut that resolved during steroid treatment. When the prednisone dose reached 0.15 mg/kg/day, she developed oral ulcers, dry eyes, and severe diarrhea. What would be the most appropriate treatment for cgvhd? A. Increase the dose of prednisone to 1 mg/kg/day B. Begin treatment with prednisone at 2 mg/kg/day C. Begin treatment with prednisone at 1 mg/kg/day plus MMF D. Enroll the patient in a clinical trial Summary Understanding of pathophysiology has improved Trial designs and endpoints have been developed Therapeutic targets have been identified Pharmaceutical industry interest has increased Candidate agents are being tested FDA has approved ibrutinib for second-line treatment Challenge for the Future Linkage of pathophysiology with clinical manifestations Target single pathway or multiple pathways? Im A, et al. Leukemia. 2017;31:

20 Special Acknowledgments Mary Flowers Paul Carpenter Yoshi Inamoto Stephanie Lee Shawn Chai Barry Storer NIH Consensus Conference on Chronic GVHD U.S. FDA, Division of Hematology Products National Cancer Institute: CA18029 and CA98906 Recommended Reviews Cutler CS, Koreth J, Ritz J. Mechanistic approaches for the prevention and treatment of chronic GVHD. Blood. 2017;129: MacDonald KPA, Blazar BR, Hill GR. Cytokine mediators of chronic graft-versus-host disease. J Clin Invest. 2017;127: Im A, Hakim FT, Pavletic SZ. Novel targets in the treatment of chronic graft-versus-host disease. Leukemia. 2017;31: MacDonald KPA, Betts BC, Couriel D. Emerging therapeutics for the control of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2018;24: Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. New Engl J Med. 2017:377: BMT Pharmacists Conference Biology of Chronic GVHD Paul J. Martin, M.D. Member, Fred Hutchison Cancer Research Center Professor of Medicine, Division of Oncology University of Washington 20