GVHD

Question 1

Settings that GVHD can occur in

Answer 1

• Most commonly due to transfer of foreign donor haematopoietic stem cells into a host recipient via an allogeneic haematopoietic stem cell transplant
• Other settings it can occur in:
  
  • Non-irradiated blood products to immuocompromised host
  • Maternal-foetal transmission
  • Solid organ transplantation

Question 2

Most important predictor of GVHD

Answer 2

HLA compatability between donor and recipient

40% HLA-identical develop, and 60-70% of mismatched develop

Question 3

What does using umbilical cord blood or peripheral blood do for risk of GVHD

Answer 3

Increasing use of umbilical cord blood and peripheral blood due to lower rates of GVHD, but has higher rates of non-engraftment

Question 4

Which is the preferred stem cell source

Answer 4

Peripheral blood

Peripheral blood has more rapid engraftment, but has increased risk of GVHD

Question 5

How does stem cell transplant work?

Answer 5

Donor: gets treated with GCSF, which mobilizes donor stem cells from the marrow into circulation –> then collected and infused into recipient

Question 6

What things affect natural history of GVHD

Answer 6

• T-cell depletion
• Total body irradiation for conditioning
• Donor lymphocyte infusions –> administered after to augment the graft versus tumour effect –> altered traditional acute and chronic, so it can induce acute after 100 days

Question 7

Risk factors for developing GVHD

Answer 7

• Donor
  
  • HLA incompatibility with recipient
  • Unrelated to recipient
  • Female with male recipient (especially multiparous)
• Recipient
  
  • Older aged
• Stem cell source
  
  • Peripheral blood > bone marrow > cord blood
  • T cell replete
• Other
  
  • Myeloablative conditioning regimen

Question 8

Pathogenesis of GVHD

Answer 8

1. Host APC activation from HSCT conditioning and consequent damage to host tissues
2. Donor T cells proliferate once come into contact with APC
3. Destruction of target tissues: occurs via cytotoxic T lymphocytes, NK cells and soluble factors (TNF, IFN-gamma, IL-1, nitric oxide)

• However, cGVHD often resembles autoimmune, suggesting B cell process, and rituximab helps –> ?B cells prime T cells to MHC antigens
• B cell activating factor of the TNF family (BAFF) correlate with cGVHD –> ANA, anti-dsDNA, anti-smooth muscle antibodies
• Early-onset cGVHD: 3-9 months: IFN-gamma, increased Tregs, and T cell cytokine response
• Late cGVHD: >9 months, lack of Th2 shift, BAFF, TLR9 induction, and also mixed Th1/Th17 signature with IFN-gamma and IL-17

Question 9

Clinical - Acute GVHD

Answer 9

• Usually 4-6 weeks post HSCT
• Morbilliform exanthem, with predilection for acral areas - dorsal hands and feet, palms, soles, forearms, ears, upper trunk
• Pruritus is variable
• Folliculocentric pattern may be seen
• Thrombocytopaenia –> looks haemorrhagic
• GIT:
  
  • Nausea
  • Voluminous diarrhoea
  • Abdominal pain
  • Liver: transaminitis, cholestasis, bilirubin elevation
• Stage 4 can look like SJS

Question 10

What is measured in the clinical staging of AGVHD

Answer 10

Skin
Liver - bilirubin
Gut - diarrhoea
Histology

Question 11

CGVHD cutaneous

Answer 11

• Stage 1 <25% BSA, 2 25-50%, 3 >50%, 4 generalized erythroderma
• skin and mucosa very common
• Most characteristic: reticulate pink to violet papules and plaques with overlying scale
• Often involve the dorsal aspects of the hands and feet, forearms, trunk but then can become widespread
• not associated with sclerodactyly, pinched facies or Raynauds like you see in systemic sclerosis
• deep-seated fibrosis of the subcutaneous fascia may present with insidious loss of joint range of motion or as nonspecific myalgias and cramping
• subtle rippling of the overlying skin may be present with a form, nodular texture noted with deep palpation

All the findings:

• LP like
• morphoea like
• scleroderma like
• fasciitis –> subcutaneous rippling of skin with joint contractures, Groove sign - path of vascular structures of fascial bundles
• other: psoriasiform, eczematous, dyshidrotic, SCLE, pit rosea, eczema craquelee, ichthyosis like, KP like, dyspigmetation, vitiligo
• angiomatous nodules - rare
• ulcerations: from long standing fibrosis
• patterned hyperpigmentation

Question 12

CGVHD mucous findings

Answer 12

LP like
Mucocele like

Oral mucosa: keratotic plaques, LP like, restriction of oral opening due from sclerosis, gingivitis, mucositis, pseudomembranes, ulcers, xerostomia, mucosal atrophy, mucocele

Genital: 50% female patients - burning, pruritus, dyspareunia
Erythema, fissuring to labial resorption and fusion
Vaginal scarring, shortening, narrow of vaginal canal
LP like
Risk of hematocolpos
Male genital less common - balanoposthitis, LP like, phimosis

Question 13

CGVHD nails and hair

Answer 13

ridging, thinning, splitting, brittleness, onycholysis, dorsal pterygium, anonychia

new onset alopecia, alopecia areata, premature greying

Question 14

What’s the difference between AGVHD and CGVHD

Answer 14

traditionally used to be acute <100 days, chronic >100 days but now changing regimens means you can get both at the same time

Question 15

AGVHD histology

Answer 15

• widespread keratinocyte necrosis
• Basal layer hydropic degeneration
• Band like lymphohistiocytic infiltrate in the upper dermis
• however can just be confined to the hair follicle
• Features overlap with viral and drug, which makes diagnosis more tricky

Question 16

CGVHD histology

Answer 16

• may resemble aGVHD with additional features of epidermal orthokeratosis and hypergranulosis
• Sclerotic subtypes may have concurrent epidermal features, or just sclerosis of the dermis, subcutaneous tissue and/or fascia
• Thickening of SC fat septae indicates a deep-seated sclerosis
• MRI might be helpful for fascial involvement

Question 17

DDx for AGVHD

Answer 17

• Drug
• Viral
• Engraftment syndrome: poorly understood, nonspecific erythematous skin eruption, fever, pulmonary oedema, elevated BNP. You see in autologous or allogenic, associated fever, no diarrhoea, but get pulmonary oedema, weight gain, rarely encephalopathy, responds every well to steroids, usually 10-12 days post transplant
• Toxic erythema of chemotherapy (although more palmoplantar)

Question 18

Ddx for CGVHD

Answer 18

• Lichenoid drug

- Autoimmune connective tissue disease

Question 19

AGVHD

Answer 19

• If limited cutaneous: topical steroids, but most require systemic
• First line: oral pred or IV methyl pred, added to ongoing prophylactic GVHD therapy with a systemic calcineurin inhibitor (tacrolimus, cyclosporine)
• Results in disease control in about 50% of patients
• If don’t respond to steroids, have a high risk of mortality
• Second line therapies: MMF, TNF alpha blockers

Question 20

CGVHD treatment

Answer 20

• no single therapy proven to be superior
• Local: topical steroids or calcineurin inhibitor
• If you apply tacro under occlusion can lead to toxic drug levels
• Small series: phototherapy with PUVA, UVB, NBUVB, UVA
• Systemic steroids first line: unfortunately 50% won’t respond
• Other options: hydroxychloroquine, MMF, imatinib, rituximab, ruxolitinib, acitretin, ECP
• Ocular symptoms: site specific therapies - special contacts
• Physical therapy for ROM
• Photoprotection - typically on photosensitizing agents - bactrim, levofloxacin, voriconazole
• Educate regarding skin cancer risk
• MDT: ophthal, gyny, oral medicine, physiatry, derm