advances in prevention of GVHD by different investigational and approved methods of graft modulating, drugs, chemotherapy, analysis of published data, improved survival, future direction. different sources of stem cell and strategies to prevent mortality and morbidity

1. Recent Advancement in Prevention
and Management of Chronic GVHD
Speaker- Dr. Sudip Roy
Moderator- Prof. M. Bhattacharyya

2. • Introduction
• Pathogenesis and classification of GVHD
• Recent advanced in GVHD prevention
• Recent advances in management of chronic GVHD
• Conclusion

3. Introduction
• Systemic disorder
• Graft's immune cells recognize the host as foreign and attack
the recipient's body cells
• Cell-mediated reaction of donor origin against recipient tissue

4. Incidence of GVHD
CIBMTR WORKING COMMITTEE FOR GRAFT-VERSUS-HOST DISEASE Orlando, February 16, 2023

6. Understanding GVHD
Donor Graft-
Immune cells + Stem Cells
•Help to prevent blood cancer relapse
(GVL)
•Attack healthy host tissue- GVHD
•Hematopoietic reconstitution
•Immune reconstitution

9. Types of GVDH
Acute GVHD
• classically within 100 days
• strong inflammatory component
• m. c. targets are-
• gut,
• skin and
• liver
Chronic GVHD
• After 100 days, m.c. 6 months to 2
years
• autoimmune and fibrotic features
• Like lupus or rheumatoid features
• target-
• skin, subcutaneous tissue
• oral mucosa
• salivary and lacrimal gland
• Lung, gut, liver and joints

10. Risk Factors for GVHD
• Degree of HLA Mismatch
• Sex mismatch ( Female donor to male recipient)
• Transplant conditioning intensity
• GVHD prophylaxis regimen
• Graft source (highest risk in PBSC)
Rimando et all, "How I prevent GVHD in high-risk patients: posttransplant cyclophosphamide and beyond." Blood, The Journal
of the American Society of Hematology 141.1 (2023): 49-59.

11. GVHD Prophylaxis
• From the start of conditioning
• Optimum prophylaxis is unknown but the most
commonly used regimens are-
– Cyclosporine or Tacrolimus with Methotrexate
– Sirolimus with Tacrolimus
– Cyclosporine with MMF
– Tacrolimus, Rapamycin and MMF
Shernan G. Holtan et al, Optimizing Donor Choice and GVHD Prophylaxis in Allogeneic Hematopoietic Cell Transplantation. JCO 39, 373-385(2021).

12. Drugs Mechanism of action
Cyclosporine Inhibit T cell activation (# IL2)
Tacrolimus Calcineurin inhibitor, # IL2
Methotrexat
e
Inhibit dihydrofolate reductase to suppress T cell
response and proliferation
Sirolimus Inhibit mTOR to block IL2
MMF Inhibit IMP to suppress cell mediated immune
response
ATG Both donor and recipient T cell depletion
Rapamycin Increase tolerance by increasing Treg cells
Conventional drugs for GVHD prophylaxis
IL-2 control the differentiation
and homeostasis of both pro-
and anti-inflammatory T cells
controls
Ram R, Storb R. Pharmacologic prophylaxis
regimens for acute graft-versus-host disease:
past, present and future. Leuk Lymphoma. 2019
Aug;54(8):1591-601

13. Advances in GVHD prevention
Justin Jiang et all; Trend in Survival in Patients Undergoing Allogeneic Stem Cell Transplantation: An Institutional Experience. Blood 2022; 136 (Supplement 1): 15

14. Recent advances in GVHD prevention
• Post transplant cyclophosphamide
• Maraviroc
• Abatacept
• Exosomes, MDSC and iTreg
• Immune cell modification in graft

15. PTCy (Post Transplant Cyclophosphamide)
Mystery explained: How a common chemo drug thwarts graft rejection in bone marrow transplants - 11/14/2013. (n.d.). Hopkinsmedicine.org

16. Cumulative incidence of aGVHD and cGVHD

19. Cumulative incidence of chronic extensive GVHD GVHD free, relapse-free survival (GRFS)

20. Outcome of prospective studies using PT-Cy
Mussetti A. Is Post-Transplant Cyclophosphamide the New Methotrexate? Journal of Clinical Medicine. 2021; 10(16):3548.

21. Maraviroc
• Maraviroc is CCR5 antagonist
• Indicated to treat HIV-1
• Prevent HIV-1 to entry into
CD4 cells
Latinovic, O., Kuruppu, J., Davis, C., Le, N., & Heredia, A. (2009). Pharmacotherapy of HIV-1
infection: Focus on CCR5 antagonist maraviroc. Clinical Medicine. Therapeutics, 1, CMT.S2365.

26. • Moderate/severe cGVHD was 0% on the ABA and 65.8% on the MTX-Tac arm
• No statistically significant difference in the rates of OS, DFS and infection was
noted

27. Strategy of graft manipulation

29. Peter Lang; Transplantation of highly purified CD34+ progenitor cells from unrelated donors in pediatric leukemia. Blood 2003; 101 (4): 1630–1636

30. Cantilena CR, Distinct Biomarker Profiles in Ex Vivo T Cell Depletion Graft Manipulation Strategies: CD34+ Selection versus CD3+/19+ Depletion in Matched Sibling Allogeneic Peripheral Blood Stem Cell Transplantation. Biol Blood Marrow
Transplant. 2018 Mar;24(3):460-466

32. EVENTS
Cummuliative incidence of cGVHD 8.1%
5-year cumulative incidence of non-relapse mortality 5.2%
5 years cumulative incidence of relapse 22.7%
projected 10-year overall survival 75.4%
projected 10-year disease-free survival 71.6%

38. Recent advances in management of
Chronic GVHD

39. Why chronic GVHD is important?
• Heterogeneous and pleomophic disease
• ≥ 3 organs involved in diagnosis
• Treatment involves prolonged immunosuppression (2- 3.5 yr)
• High morbidity and negative long-term impact on quality of life
• Associated with late mortality

40. Targets of cGVHD Therapy
Treatment of cGvHD has three different goals
– Reduce the activated status of B and T cells
– Play an anti-inflammatory effect
– Slow down the rate of fibrosis

41. Zachariah DeFilipp; Nonrelapse mortality among patients diagnosed with chronic GVHD: an updated analysis from the Chronic GVHD Consortium. Blood Adv 2021; 5 (20): 4278–4284

42. Mechanistic approach for treatment of cGVHD
Corey S. Cutler; Mechanistic approaches for the
prevention and treatment of chronic
GVHD. Blood 2017; 129 (1): 22–29

43. Standard 1st line therapy
Systemic Corticosteriods
– Prolonged treatment course
– Overall response is 50% in 2-3 years
– Mortality is >60% without additional therapy
Garnett C. Treatment and management of graft-versus-host disease: improving response and
survival. Therapeutic Advances in Hematology. 2022;4(6):366-378

44. Recently published data for conventional therapy
Therapy ORR, % Survival, %
Extracorporial photopheresis 65-70 70-78 at 1 yr
Rituximab 66-86 72 at 1 yr
Imatinib 22-79 75 in 1.5 yr
Pentostatin 53-56 34-60 in 1.5 yr
Mycophenolate mofetil 26-64 67-96 in 1 yr
mTOR inhibitor (rapamycin) 76 72 in 3 yr
IL-2 52 NA
CIBMTR Guide Book 2023

45. Beyond initial therapy
1. Steroid refractory chronic GVHD
– Progress while on ≥ 1mg/kg/day pred for 1-2 weeks
– Stable cGVHD on 0.5mg/kg/day pred for >4 weeks
2. Steroid-dependent chronic GVHD
– Pred >0.25mg/kg/day needed to prevent recurrence or
progression
– Unsuccessful attempt to tapper tried 2 occasions separated by 8
weeks
Martin PJ et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. The 2014 Clinical Trial Design Working
Group Report. Biology of Blood and Marrow Transplantation [Internet]. 2015 Aug 1;21(8):1343–59.

46. FDA approved 3 drugs for steroid refractory cGVHD
– Ibrutinib
– Ruxolitinib
– Belumosudil

47. FDA approved Ibrutinib for 2nd line therapy on 2nd August, 2017

49. Ruxolitinib
Robert Zeiser, Gérard Socié; The development of ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. Blood Adv 2020; 4 (15): 3789–3794

51. Belumosudil
www.rezurockhcp.com
• Inhibitor of Rho-associated coiled-coil
kinase 2 (ROCK2)
• Belumosudil binds to and inhibits
the serine/ threonine kinase activity of
ROCK2
• ROCK2 regulates multiple profibrotic
process
• Myofibroblast activation
• Stress fiber formation

52. ORR by organ system in the ITT population

53. Axatilimab
https://syndax.com/

55. Diagnostic Biomarkers
sBAFF Increased in active cGVHD
CXCL9 Increased at diagnosis
CXCL10 Increased in 6 and 12 months
Biomarker panel:ST2, MMP3,CXCL9, OPN Increased at diagnosis
MMP3 Increased at diagnosis

56. Response Biomarkers
sBAFF If increased after 1 month of ECP, poor
prognosis
ST2 If increased after 2-4 month of ECP, poor
prognosis
Prognostic Biomarkers
CXCL9 Increased in severe disease
Reg3α Increased in severe disease
MMP9 Increased in severe disease

57. Multidrug Resistant GVHD
• MDR-GVHD was defined as no improvement in GVHD after
more than 2 types of treatments
• Regardless of GVHD prophylaxis

58. Treatment outcome of MRD- HSCT
With conventional therapies, median OS is <7 months from diagnosis
Experimental treatment modalities ORR, %
Mesenchymal stem cell infusion 72%
Ruxolitinib 67%
IL2 receptor antibody 82%
Schmidt-Hieber M, Fietz T, Knauf W, Uharek L, Hopfenmüller W, Thiel E, Blau IW. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-
refractory acute graft-versus-host disease. Br J Haematol. 2023 Aug;130(4):568-74

59. Duration of therapy in cGVHD
• 50% of patients are cured within 7 years
• 10% require continued systemic therapy beyond 7 years
• Overall 40% patients experience relapse and mortality
Mary E. D. Flowers, Paul J. Martin; How we treat chronic graft-versus-host disease. Blood 2021; 125 (4): 606–615.

61. Possible therapeutic approaches for steroid-resistant/refractory
cGvHD patients according to the NCCN and EBMT 2020 guidelines

62. Ongoing studies evaluating novel drug agents in patients with cGvHD
Till Sept, 2023

63. Conclusion
• GVHD is invariable in AlloHSCT without immunosuppression
• Prolonged usages of non-specific immunosuppression caused an
increased risk of life-threatening infections
• PT-Cy, graft manipulation, Abatacept, and Maraviroc may help
prevent GVHD
• >50% patients with cGVHD needs 2nd line therapy beyond high dose
corticosteroids
• Ibrutinib, Ruxolitinib and Belumosudil are approved for cGVHD
therapy