This content is the property of the Advanced Practitioner Society for Hematology and Oncology (APSHO). It is made available for your personal use, educational advancement, or professional development. Unauthorized reproduction, publication, or alteration is prohibited. For permission to use for other purposes, please contact info@apsho.org

1. This content is the property of the Advanced Practitioner Society for Hematology
and Oncology (APSHO). It is made available for your personal use, educational
advancement, or professional development. Unauthorized reproduction, publication,
or alteration is prohibited. For permission to use for other purposes, please
contact info@apsho.org

2. Understanding
Chronic Graft-vs.-Host Disease

3. Table of Contents
• Objectives
• Overview of chronic graft-vs.-host disease (GVHD)
• Identifying chronic GVHD
• Treatment of chronic GVHD
• Care considerations
2

4. Objectives
• Understand the epidemiology of chronic GVHD, including incidence,
prevalence, and risk factors
• Understand the pathophysiology of chronic GVHD
• Identify clinical features of chronic GVHD, as well as exam findings and
diagnostics to support the diagnosis
• Identify common treatment modalities used for chronic GVHD, including
novel therapies
• Review care considerations for patients with chronic GVHD and the role
of the APP in the care of patients with GVHD
3

5. Overview of Chronic GVHD
4

6. Definitions: Acute GVHD
• Classic presentation
• Erythematous, maculopapular rash
• Nausea/vomiting, anorexia, profuse diarrhea, ileus
• Liver disease, specifically transaminitis with hyperbilirubinemia
• Typically occurs within first 100 days after transplant or donor lymphocyte
infusion (DLI)
• Late-acute GVHD
• Includes the above features but occurs beyond the first 100 days without
meeting criteria for chronic GVHD
• Hyper-acute GVHD
• Occurs before cellular engraftment and can be fatal
• Fever, insidious development of erythematous skin rash, transaminitis,
mucoid diarrhea
Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21:389-401.; Mitchell SA et al. Acute and chronic graft-versus-host disease. In S.A. Ezzone (Ed.), Hematopoietic stem cell transplantation: A manual
for nursing practice. 2nd ed. Oncology Nursing Society; 2013;103-153.
5

7. Definitions: Chronic GVHD
• Manifestations of autoimmune disease, involves multiple organ systems,
and does not have any clinical features of acute GVHD
• May include ocular, oral mucosa, skin, GI tract, liver, lungs, joints/fascia
• Overlap syndrome: Occurs when there are features of both acute and
chronic GVHD
• Acute features are typically transient, but chronic features are persistent
Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21:389-401.; Mitchell SA et al. Acute and chronic graft-versus-host disease. In S.A. Ezzone (Ed.), Hematopoietic stem cell transplantation: A manual
for nursing practice. 2nd ed. Oncology Nursing Society; 2013;103-153.
6

8. Epidemiology of Chronic GVHD
• Incidence: 30-70% of patients receiving an allogeneic transplant
HLA, human leukocyte antigen
DeFilipp Z et al. Blood Adv. 2021;5:4278-4284.
40% in patients who
received an HLA-
sibling transplant
>50% in patients who
received mismatched but
related transplants
70% in patients who
received matched but
unrelated transplants
• Most cases are diagnosed within the first year
• Median time to diagnosis: 4-6 months
• Leading cause of non-relapse morbidity and mortality in transplant
recipients
7

9. Risk Factors for Chronic GVHD
• History of acute GVHD
• HLA-mismatched unrelated donor
• Increased age of donor and/or recipient
• Use of non–T-cell-depleted donor cells
• Source of stem cells
• Donor sex mismatch
• Donor leukocyte infusion
Flowers MED, Martin PJ. Blood. 2015;125:606-615.
8

10. Pathophysiology of Chronic GVHD
Target tissue
destruction
APC, antigen-presenting cell; MHC, major histocompatibility complex
Mitchell SA et al. Acute and chronic graft-versus-host disease. In S.A. Ezzone (Ed.), Hematopoietic stem cell transplantation: A manual for nursing practice. 2nd ed. Oncology Nursing Society; 2013;103-153.;
Müskens K et al. Cells. 2021;10:2051.
Damage to host tissues with
conditioning chemotherapy
Donor T-cell activation
9

11. Pathophysiology of Chronic GVHD (cont’d.)
DAMP, damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern; TLR, toll-like receptor
Zeiser R, Blazar B. N Engl J Med. 2017;377:2565-2579.
Phase 1
10

12. Pathophysiology of Chronic GVHD (cont’d.)
Zeiser R, Blazar B. N Engl J Med. 2017;377:2565-2579.
Phase 2
11

13. Pathophysiology of Chronic GVHD (cont’d.)
Zeiser R, Blazar B. N Engl J Med. 2017;377:2565-2579.
Phase 3
12

14. Identifying Chronic GVHD
13

15. Subjective Signs and Symptoms
• Skin
• Rash
• Texture change
• Poikiloderma
• Nails
• Tenderness at the nail bed
• Oral mucosa
• Xerostomia
• Particularly painful dysgeusia
• Sensitivities to hot/cold, sweet/salty/acidic foods,
toothpaste
• Eyes
• Grittiness in the eyes
• Increased tearing/dryness
• Eye pain
• Photophobia
Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21:389-401.; Lee SL, Flowers MED. (2008). Hematology Am Soc Hematol Educ Program. 2008;2008:134-141.
Poikiloderma
14

16. Subjective Signs and Symptoms (cont’d.)
• GI tract
• Dysphagia
• Nausea, vomiting, anorexia, early satiety
• Unintentional weight loss
• Lungs
• Dyspnea on exertion
• Cough
• Wheezing
• Genitourinary
• Frequent UTI/UTI symptoms
• Dyspareunia
• Gynecologic
• Vulvar/vaginal dryness
• Erythema
• Tenderness
• External burning with urination
• Lichenification of labial tissue
UTI, urinary tract infection
Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21:389-401.; Lee SL, Flowers MED. (2008). Hematology Am Soc Hematol Educ Program. 2008;2008:134-141.
Dysphagia and early satiety are
symptoms are typically not present in
acute GVHD
15

17. Subjective Signs and Symptoms (cont’d.)
• Musculoskeletal
• Arthralgias, myalgias, typically in major joints
• Joint edema/tenderness
• Muscle cramping
• Hematopoietic
• Easy bruising or frank bleeding (epistaxis, hematuria, melena)
• Frequent infections
Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21:389-401.; Lee SL, Flowers MED. (2008). Hematology Am Soc Hematol Educ Program. 2008;2008:134-141.
16

18. Objective Signs: Skin
• Dyspigmentation
• Poikiloderma
• Lichen planus
• Hair loss
Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21:389-401.; Lee SL, Flowers MED. (2008).
Hematology Am Soc Hematol Educ Program. 2008;2008:134-141.
Hypopigmentation Lichen planus
Deep sclerosis
Lichen sclerosis Morphea-like sclerosis
• Sclerosis
17

19. Objective Signs: Skin (cont’d.)
https://www.frontiersin.org/files/Articles/838494/fimmu-13-838494-HTML/image_m/fimmu-13-838494-g001.jpg
https://bethematchclinical.org/post-transplant-care/chronic-gvhd/nails/
Nail splitting and atrophy
Desquamation
18

20. Objective Signs: Oral
• Oral mucosa
• Xerostomia
• Erythema
• As well as…
Be the Match. Chronic GVHD. https://bethematchclinical.org/post-transplant-care/chronic-gvhd. Accessed May 3, 2022.
Mucosal atrophy Ulceration
Mucoceles
Lichen planus
19

21. Objective Signs: Ocular
• Eyes
• Periorbital hyperpigmentation/edema
• Mucoid secretions
• Blepharitis
• Ocular sicca (severe ocular dryness)
Be the Match. Chronic GVHD. https://bethematchclinical.org/post-transplant-care/chronic-gvhd. Accessed May 3, 2022.
Ocular sicca
20

22. Objective Signs
• Lungs
• Wheezing with auscultation
• Cough
• Genitourinary
• Lichen planus/sclerosis features
• Fissures or ulcers
• Phimosis or scarring of the male urethra
• Musculoskeletal
• Joint stiffness, contractures
• Fasciitis: restricted range of motion,
edema, peau d’orange appearance
Be the Match. Chronic GVHD. https://bethematchclinical.org/post-transplant-care/chronic-gvhd. Accessed May 3, 2022.; Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21:389-401.
Peau d’orange appearance
21

23. Evaluation of Skin or Fascial Tightening
Lee S et al. Biol Blood Marrow Transplant. 2015;21:984-999.
• Flexibility scale should be used
at each visit
• Photos should be taken at
baseline and during treatment
22

24. Diagnostics
Labs
• Routine
• CBC w/differential
• CMP w/LDH
• Upon clinical suspicion
• GI GVHD  Pancreatic enzymes
• Lung  Sputum culture (infection)
• Frequent infections  IgG level
• Myositis  Aldolase level, CK level
• Renal  UA to assess proteinuria
Imaging/Tissue
• Skin  Incisional/punch biopsy
• GI  EGD, colonoscopy
(w/biopsies)
• Liver  Abdominal ultrasound
• Lung  CT chest
• Joints/Fascia  EMG
• Eyes  Schirmer test
CBC, complete blood count; CMP, complete metabolic panel; CK, creatinine kinase; EGD, esophagogastroduodenoscopy; EMG, electromyography; LDH, lactate dehydrogenize; UA, urinalysis
Lee SL, Flowers MED. (2008). Hematology Am Soc Hematol Educ Program. 2008;2008:134-141.
23

25. Special Diagnostics: Pulmonary Function Tests
(PFTs)
• Assess lung volumes and
spirometry
• Looking for a restrictive and/or
obstructive pattern
• Key values for GVHD
• FEV1
• FVC
• FEV1/FVC ratio
• RV
• DLCO (corrected)
DLCO, diffusing capacity for carbon monoxide; FEV, forced expiratory volume; FVC, forced vital capacity; RV, residual volume
https://step2.medbullets.com/pulmonary/120664/pulmonary-function-tests
24

26. Grading Chronic GVHD: NIH Consensus 2014
• Overall scoring: based on severity
and organ system(s) involved
• Organ site scoring: each individual
site is scored 0-3, including
performance status (KPS or ECOG)
ECOG, Eastern Cooperative Oncology Group; KPS, Karnofsky Performance Scale; NIH, National institutes of Health
Khanna D et al. J Scleroderma Relat Disord. 2017;2:11-18.
25

27. Grading Chronic GVHD: NIH Consensus 2014
National Comprehensive Cancer Network. (2022). Hematopoietic Cell Transplantation (Version 1.2022). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf.
26

28. Skin GVHD: The Rule of Nines
Khanna D et al. J Scleroderma Relat Disord. 2017;2:11-18.
27

29. Skin GVHD: Modified Rodnan Score
Khanna D et al. J Scleroderma Relat Disord. 2017;2:11-18.
28

30. NCCN Organ Scoring
National Comprehensive Cancer Network. (2022). Hematopoietic Cell Transplantation (Version 1.2022). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf.
29

31. NCCN Organ Scoring (cont’d.)
National Comprehensive Cancer Network. (2022). Hematopoietic Cell Transplantation (Version 1.2022). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf.
30

32. NCCN Organ Scoring (cont’d.)
National Comprehensive Cancer Network. (2022). Hematopoietic Cell Transplantation (Version 1.2022). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf.
31

33. Treatment of Chronic GVHD
32

34. Topical and Local Therapies: Skin
Intact Skin
• Ointments > lotions
• Steroid agents
• Neck down  triamcinolone 0.1%,
clobetasol 0.05%
• Face, axillae, groin  hydrocortisone 1-
2.5%, desonide 0.05%
• Consider wet wraps
• Lubricants/emollients
• Antihistamines
• Extracorporal photopheresis (ECP)
• Psoralen and long-wave UV (PUVA)
Non-Intact Skin
• Topical antimicrobials (for infection
prevention)
• Protective films and dressings
• Wound care
Wolff D et al. (2010) Biol Blood Marrow Transplant. 2010;16:1611-1628.; Slater S. Acute graft-versus-host disease. In: Maziarz RT, Slater S (eds.). Blood and marrow transplant handbook: Comprehensive
patient care. Springer; 2011:167-188.
33

35. Topical and Local Therapies: Eyes and
Oral Mucosa
Eyes
• Artificial tears – preservative free
• Warm compresses, eyelid care
• Punctal plugs
• Cyclosporine drops (Restasis)
Oral Mucosa
• Rinses – dexamethasone,
clobetasol
• Gels – clobetasol, tacrolimus
• ECP
• Supportive care
• Salivary stimulants/substitutes
• Fluoride treatments
Wolff D et al. (2010) Biol Blood Marrow Transplant. 2010;16:1611-1628.
34

36. Topical and Local Therapies: GI, Liver
Upper GI
• Dysphagia  lubrication
• Nausea, anorexia, early satiety
• Antiemetics
• Appetite stimulants
• Beclomethasone/corn oil
Lower GI
• Diarrhea
• *RULE OUT INFECTION*
• Antidiarrheals
• Budesonide
Wolff D et al. (2010) Biol Blood Marrow Transplant. 2010;16:1611-1628.
Liver
• Ursodiol
• Beclomethasone
35

37. Topical and Local Therapies: Lung
• Inhaled corticosteroids
• Albuterol PRN for dyspnea, wheezing
• Fluticasone/budesonide BID
• Salmeterol/formoterol BID
• Leukotriene inhibitors  montelukast
• Oral antimicrobials  azithromycin
• Systemic therapy
BID, twice a day; PRN, as needed
Wolff D et al. (2010) Biol Blood Marrow Transplant. 2010;16:1611-1628.
36

38. Topical and Local Therapies: Genitalia
• Good genital hygiene
• Emollients, lanolin cream to external genitalia
• Vaginal moisturizers or bacteriostatic gels
• Topical estrogen replacement (for vaginal GVHD)
• Tacrolimus, clobetasol gels
• Pelvic floor physical therapy to prevent permanent vaginal stenosis
Wolff D et al. (2010) Biol Blood Marrow Transplant. 2010;16:1611-1628.
37

39. Systemic Therapies
• Corticosteroids (prednisone)
• First-line therapy
• Dosing: 0.5-2 mg/kg/day
• Duration: 2-4 weeks
Wolff D et al. (2010) Biol Blood Marrow Transplant. 2010;16:1611-1628.; Lee SL, Flowers MED. (2008). Hematology Am Soc Hematol Educ Program. 2008;2008:134-141.
Prompt response
Treats multiple organs
simultaneously
Benefits
Adrenal insufficiency
Increased infection
risk
Avascular necrosis
Osteoporosis
Risks*
* Primarily with long-term use
38

40. Secondary Therapies
• Prophylaxis against encapsulated bacteria is routinely used due to
increased risk of infection related to immunosuppression
• Some patients may be already taking some of the therapies listed as secondary
• Criteria for starting a secondary therapy
• Worsening signs or symptoms of chronic GVHD despite steroid therapy
• Development of new signs or symptoms in a previously unaffected organ
• Absence of improvement after 1 month of 1 mg/kg/day prednisone
• Inability to decrease prednisone below 1 mg/kg/day within 2 months
• Treatment-related toxicity
Flowers MED, Martin PJ. Blood. 2015;125:606-615.
39

41. Secondary Therapies: Tacrolimus
• Calcineurin inhibitor (CNI)
• Inhibits the activation and proliferation of T cells
• Used primarily as prophylaxis
• BID dosing, requires therapeutic trough monitoring (goal 4-10 ng/mL)
• Example of side effects
• Electrolyte abnormalities
• Transaminitis
• Hypertension
• Nephrotoxicity
• Thrombotic microangiopathy
Antin JH, Raley DY. (Eds.). Manural of stem cell and bone marrow transplantation (2nd ed.). Cambridge University Press; 2013.
40

42. Secondary Therapies: Sirolimus
• Used in both prevention and treatment of GVHD
• Macrolide antibiotic: Inhibits response of B and T lymphocytes
• Once daily dosing, requires therapeutic trough monitoring (goal
5-15 ng/mL)
• Example of side effects
• Thrombocytopenia
• Leukopenia
• Peripheral edema
• Increased serum creatinine
Slater S. Acute graft-versus-host disease. In: Maziarz RT, Slater S (eds.). Blood and marrow transplant handbook: Comprehensive patient care. Springer; 2011:167-188.
41

43. Secondary Therapies: Cyclosporine
• Calcineurin inhibitor that prevents IL-2 gene expression and impairs the
activation of T cells
• Used as both prophylaxis and GVHD treatment
• BID dosing, require therapeutic trough monitoring (goal 200-300 ng/mL)
• Example of side effects
• Posterior reversible encephalopathy syndrome (PRES)
• Hypertension
• Nephrotoxicity
• Thrombotic microangiopathy
Antin JH, Raley DY. (Eds.). Manural of stem cell and bone marrow transplantation (2nd ed.). Cambridge University Press; 2013.
42

44. Steroid-Sparing Agents: Ibrutinib
Ibrutinib
• Inhibits Bruton tyrosine kinase in B
cells and IL-2-inducible T-cell kinase
in T cells
• 2017 multicenter, open-label study:
Best overall response was 67%
• 71% of responders showed sustained
response for ≥20 weeks
• Responses observed across involved
organs evaluated
Miklos D et al. (2017). Blood. 2017;130:2243-2250.
43

45. Ibrutinib Dosing
• Starting dose: 420 mg daily
• Dose adjustments for hematologic toxicity
• ≥ Grade 3 neutropenia with infection or fever, or
grade 4 toxicity: Hold therapy, resume dosing at the
starting dose upon recovery
• Dose adjustments for nonhematologic toxicity
• ≥ Grade 3 toxicity: Hold therapy, resume dosing at
the starting dose upon recovery
Imbruvica (ibrutinib) [prescribing information]. South San Francisco, CA: Pharmacyclics LLC; October 2021.
Occurrence of toxicity Chronic GVHD
Usual initial dose 420 mg once daily
First occurrence Restart at 420 mg once daily
Second occurrence Restart at 280 mg once daily
Third occurrence Restart at 140 mg once daily
Fourth occurrence Discontinue ibrutinib
Ibrutinib Dose Modification Levels for Adverse
Reactions in Chronic GVHD
44

46. Steroid-Sparing Agents: Ruxolitinib
Ruxolitinib
Zeiser R. et al. N Engl J Med. 2021;385:228-238.
• Janus kinase 2 inhibitor: Interrupts signaling
leading to inflammation and tissue damage
in acute GVHD and chronic GVHD
• 2021 REACH3 study: Patients with
glucocorticoid-refractory or -dependent
chronic GVHD
• Ruxolitinib led to significantly greater overall
response, failure-free survival, and symptom
response
45

47. Ruxolitinib Dosing
• Starting dose: 10 mg BID
• Dose adjustment
recommendations
• GFR 15-59: 5 mg BID
• GFR <15, dialysis-dependent:
10 mg daily after dialysis
* If ruxolitinib-related
GFR, glomerular filtration rate
Jakafi (ruxolitinib) [prescribing information]. Wilmington, DE: Incyte Corporation; September 2021.
Adverse reaction Ruxolitinib dosing recommendation
Hematologic
Platelets
<20,000/mm3
Reduce by 1 dose level
• If resolved within 7 days, may increase to initial dose level
• If not resolved within 7 days, then maintain dose at 1 dose level
lower than initial dose
ANC* <750/mm3 Reduce by 1 dose level
• Resume at initial dose level upon recovery
ANC* <500/mm3 Hold for up to 14 days
• Resume at 1 dose level lower upon recovery
• May resume initial dose level when ANC >1000/mm3
Others
Grade 3 Continue at 1 dose level lower until recovery
Grade 4 Discontinue
Ruxolitinib Dose Modification Levels for Adverse Reactions in
Chronic GVHD
46

48. Steroid-Sparing Agents: Belumosudil
• Selective Rho-associated coiled-coil–
containing protein kinase 2 (ROCK2)
inhibitor.
• ROCK signaling plays a central role in
multiple fibrotic pathways
• 2021 ROCKstar study: Best overall
response rate for daily and BID
dosing was 74% and 77%
• High response rates observed in all
subgroups
• The median duration of response was
54 weeks
• 44% of subjects remained on therapy for
≥1 year
Cutler C et al. Blood. 2021;138:2278-2289.
47

49. Belumosudil Dosing
• Starting dose: 200 mg daily
• Dose adjustment recommendations:
• None required for baseline renal or hepatic disease
• Adjusting for toxicity (hepatotoxicity):
ULN, upper limit of normal
Rezurock (belumosudil) [prescribing information]. Warrendale, PA: Kadmon Pharmaceuticals LLC; July 2021.
Toxicity Grade Dose Adjustment
AST or ALT elevation
Grade 3 (5-20x ULN)
Hold until recovery to grade 0-1 then resume at recommended
dose
Grade 4 (>20x ULN) Discontinue permanently
Bilirubin elevation
Grade 2 (1.5-3x ULN)
Hold until recovery to grade 0-1 then resume at recommended
dose
Grade 3-4 (>3x ULN) Discontinue permanently
Other adverse reactions
Grade 3
Hold until recovery to grade 0-1 then resume at recommended
dose
Grade 4 Discontinue permanently
48

50. Alternative and Adjunctive Therapies
National Comprehensive Cancer Network. (2022). Hematopoietic Cell Transplantation (Version 1.2022). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf.
49

51. Care Considerations
50

52. GVHD Treatment Sequelae
• Hyperglycemia/Cushing disease
• Osteoporosis
• Avascular necrosis
• Adrenal insufficiency
• CMV reactivation/chronic infection
CMV, cytomegalovirus
51

53. Infection Prevention
• Vaccination
• No vaccines while on immunosuppression (unless CD4 count is at least 200) or
having an active GVHD flare
Bacterial
• Encapsulated bacteria/PJP pneumonia:
TMP-SMX, dapsone, atovaquone,
inhaled pentamidine
• If ANC < 500, add gram negative
coverage with levofloxacin
Viral
• VZV: valacyclovir
Fungal
• Only if ANC < 500
• Posaconazole is preferred
• Voriconazole or fluconazole are
acceptable
• Isavuconazonium may be considered
patients with previous fungal infections.
52

54. Financial and Emotional Constraints
• Drug cost and availability
• Consider grant programs, expanded access programs
• Copay cards
• Frequency of clinic visits, lab monitoring
• Struggle of chronic illness
• Risks and benefits of treating GVHD
• Anxiety and depression
53

55. How “WE” Treat GVHD
54

56. Treating Chronic GVHD Is a Team Effort
• A team-oriented approach is essential to successful management of
GVHD.
• APPs are often the first to detect signs and symptoms of chronic GVHD,
and they are primarily involved in the ongoing management of the
patient.
• Responsible for adjusting dosage, starting tapers, consult with MD colleagues for
consideration of treatment changes.
• Clinical pharmacists are useful for assistance with therapeutic drug
monitoring, drug-drug interactions, and the creation of taper schedules.
• Invite the patient to be an active participant in their own care.
55

57. Contributors
LEAD AUTHOR
Adrianne Maurer, MSN, RN, AG-ACNP
, BMTCN
Fred Hutchinson Cancer Center
REVIEWER
Kristi Wiggins, MSN, ANP-BC, AOCNP®
Duke University Medical Center
REVIEWER
Pamela Lee, MSN, RN, FNP-BC
University of California, San Francisco
56

58. Receive Your Certificate of Participation
Visit apsho.org/surveys/?id=cGVHD for information on how to receive your
certificate of participation for this APSHO Educator Module.
57