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GRAFT VERSUS HOST DISEASE

Jennifer Peterson MSN, RN, BMTCN, OCN, WCC

Professional Practice Leader

Hematology/Hematopoietic Stem Cell Transplant

Department of Clinical Practice and Professional Education

How the Experts Treat Hematologic Malignancies

Las Vegas, NV

March 10, 2016

BMTCN REVIEW COURSE

DISCLOSURES

No Disclosures

Objectives

• Discuss risk factors for graft versus host disease (GVHD)

• Review organ systems affected by acute graft versus host

disease (aGVHD)

• Review organ systems affected by chronic graft versus

host disease (cGVHD)

• Discuss prevention and treatment strategies for GVHD

Note: the primary reference source for this course is Ezzone, S. (2013) Hematopoietic stem cell transplantation: a manual for nursing practice.

Oncology Nursing Society, Pittsburgh, PA

INTRODUCTION

• GVHD is an immunologic reaction of the donor immune cells against the host tissues

• Historically, it was divided based on the timing of occurrence

• Acute – within the first 100 days

• Chronic – after first 100 days

• More often is divided based on clinical features

• Classic acute GVHD

• Persistent, recurrent, late onset acute GVHD

• Classic chronic GVHD

• Overlap GVHD: • Features of both

GVHD

• Remains poorly understood

• Leading cause of non-relapse mortality in allo HCT recipients

• Increased morbidity Impaired QOL

• Escalation and prolonged use of immune suppression Infections

• Organ dysfunction

• Common problem after allo HCT

• GVHD occurs in up to 40% of sibling donor recipients and up to 70% of unrelated donor recipients

• Chronic GVHD occurs in 50% of 3-month survivors after allo HCT

• Separating GVHD from GVL

• Has many implications

GVHD Prophylaxis

• REGIMENS:

• Calcineurin inhibitor (Tacrolimus/Cyclosporine) + MTX

• Tacrolimus + Sirolimus is another frequently used combination • Randomized study showed comparable efficacy to Tacro/Siro

• Cellcept-based regimen

• Post-transplant Cytoxan • Unique for haploidentical HCT

• The addition of mini-dose MTX, ATG & Velcade • Mismatch cases with lower likelihood of relapse

• DURATION:

• Started before day 0

• Continue for at least 3-6 months:

• Depends on donor source

• Risk of disease relapse

• Occurrence of GVHD

Risk Factors for Acute GVHD

• Degree of (HLA) mismatch • HLA-A, -B, -C, and –DRB

• Gender disparity and donor parity • Female to male

• Multiparity Maternal allo-immunization

• Age of donor and recipient

• Intensity of conditioning regimen • Reduce intensity vs. myeloablative

• Source of graft • Peripheral blood vs. marrow vs. cord

Acute GVHD

• Skin

• GI tract

• Liver

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Acute GVHD

• Skin – Most common organ affected

– First to show symptoms

– Maculopapular rash often starting on palms and

soles

– Pt may complain of pain or itching to affected areas

– Usually correlates with engraftment; reduced intensity

have delayed onset of GVHD

– Rash becomes confluent as it progresses however,

blisters may form. Severe cases resemble burn

patients

• Differential diagnosis:

• Chemotherapy/radiation, drug, infection, engraftment

Acute GVHD

• GI tract • Upper GI: Nausea/vomiting, anorexia, weight loss

• Lower GI: Liquid diarrhea (may be bloody), abdominal

cramping, abdominal distension

• Differential diagnosis:

• Chemotherapy/radiation, medications, infections

Acute GVHD

• Liver • Increased bilirubin, alkaline phosphatase

• Transaminitis less common

• Differential diagnosis:

• Sinusoidal obstructive syndrome, infections, drug toxicities,

conditioning regimen effects, total parenteral nutrition, sepsis

Acute GVHD – Skin Presentation

Images used with permission: Elsevier Clinical Key © 2016

Grading of Acute Skin GVHD

Grade Description

I Rash <25% of body

II Rash 25% – 50% of body

III Generalized erythroderma or rash

>50% of body

IV Bullae formation and/or with

desquamation

Przepiorka D et al. Bone Marrow Transplant. 1995;15:825-8.

Grading of Acute Liver GVHD

Grade Description

I Bilirubin 2-3 mg/dL

II Bilirubin 3.1-6 mg/dL

III Bilirubin 6.1 – 15 mg/dL

IV Bilirubin > 15 mg/dL

Przepiorka D et al. Bone Marrow Transplant. 1995;15:825-8.

Grading of Acute Gut GVHD

Grade Description

I Diarrhea 500-1000 ml/day or persistent nausea,

vomiting or anorexia with biopsy proven upper GI

involvement

II Diarrhea 1000 - 1500 ml/day

III Diarrhea > 1500 mL/day

IV Severe abdominal pain with or without ileus or stool

with frank blood

Przepiorka D et al. Bone Marrow Transplant. 1995;15:825-8.

Overall Grade of Acute GVHD

Grade Skin Liver Gut

I I-II None None

II III I or I

III II-III or II-IV

IV IV IV

Przepiorka D et al. Bone Marrow Transplant. 1995;15:825-8.

Diagnosis of Acute GVHD

• Diagnosis is predominantly based on clinical findings &

exclusion of other causes

• Biopsy can be helpful for excluding other etiologies

• GI tract (EGD, flex sigmoidoscopy)

• Skin biopsy

• Not very sensitive or specific

• Liver biopsy

• Done if etiology is not clear

• Transjugular approach is safer

Acute GVHD Treatment

• Initiated once GVHD is suspected or confirmed

• Corticosteroid remains the standard first line therapy

• Randomized studies failed to show benefit of combining other agents

• Starting Solu-Medrol dose 1-2mg/Kg

• 10mg/kg was not superior to 2mg/kg

• 1mg/kg might be enough for grade II disease

• Grade I skin GVHD • Managed with topical therapy + optimizing immunosuppression

levels

• Non-absorbable steroid are very useful adjuvant therapy in GI GVHD

• Survival correlates directly with the response to initial therapy

Salvage Therapy for Steroid Resistant aGVHD

• m-TOR inhibitor- • Sirolimus

• Extracorporeal photopheresis (ECP)

• Anti-TNF antibodies- • Infliximab, Etanercept

• Infliximab: Begin gtt within 3 hrs from preparation, and infuse at least over 2hrs. Risk of hypersensitivity reaction. Monitor vital signs closely

• Cellcept

• IL2 inhibitors- • Basiliximab

• Hypersensitivity reaction, monitor vital sign

• Nucleoside analogues- Pentostatin • Infuse over 15 minutes, and pre-infusion hydration is given usually

• Rituximab • Infused over 4 hrs, and associated with risk of hypersensitivity reaction

Topical Agents for Cutaneous GVHD

• Topical Steroids

• Different potency

• Triamcinolone acetone 0.1% cream

• Apply twice daily

• Do not use on face

• Calcineurin inhibitors:

• Tacrolimus cream 0.03% or 0.1%

• Apply twice daily

Refractory aGVHD

• Steroid refractory defined as

• GVHD progression after 3 days of therapy

• No improvement in 1 week of therapy

• No resolution in 2 weeks of therapy

• Second-line treatment characterized by

1. High failure rate

2. Significant toxicities

3. Poor survival

• No standard of care for second or beyond therapy

• No data for efficacy for one regimen over another

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Nursing Management :Acute GVHD

Skin

• Skin cleansing

• Moisturize skin/Avoid drying lotions

• Topical antihistamines

• Topical steroids

• Analgesics

• Maintain mobility with passive Range of Motion (ROM)

• Educate patient to avoid sun exposure and dehydration

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Nursing Management: Acute GVHD

Gut

• Maintain fluid and electrolyte balance

• Sitz baths for comfort

• Prevent rectal fissures

• Administer platelets as needed/ordered

• Nutritional support

• Protective barrier on rectal area

Chronic GVHD

• Pathophysiology of chronic GVHD not well understood

• Leading cause of non-relapse related mortality for patients > 2 yrs post allogeneic transplant

• Associated with: • Decreased quality of life

• Impaired functional status

• Ongoing need for immunosuppressive medications

• Risk factors • History of acute GVHD

• Similar factors for acute GVHD

• Infusion of DLI for treatment of recurrent disease

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Chronic GVHD

Increased incidence due to:

• History of acute GVHD

• Mismatched donor

• Older recipient age

• Use of peripheral blood as stem cell source

• Infusion of donor lymphocytes for treatment of recurrent malignancy

Signs and Symptoms of cGVHD

Filipovich AH et . Biol Blood Marrow Transplant.

2005;11:945-56. Socie G et al. Blood. 2014;124:374-84.

Skin Changes

Images used with permission: Elsevier Clinical Key © 2016

Oral Manifestations of cGVHD

Lichenoid changes Mucocele

Images used with permission: Elsevier Clinical Key © 2016

NIH scoring for cGVHD

Organ/site grading

0 No involvement

1 (Mild) No significant impairment

2 (Moderate) Significant impairment of daily activity

3 (Severe) Major disability

Overall grading

Mild One or two involved organs with a score of 1 and no

pulmonary involvement

Moderate Involvement of 3 organs with a score of 1, at least one

organ with a score 2 or pulmonary GVHD with a score 1

Severe Score of 3 in any organ or site or patient who have

pulmonary GVHD scoring 2 or 3

Filipovich AH et . Biol Blood Marrow Transplant.

2005;11:945-56. .

Treatment for cGVHD

• Infection is leading cause of death for patients with chronic GVHD

• Patient education is essential

• Prophylaxis treatment

• Viral and pneumocystis pneumonia prophylaxis should be continued while on immunosuppression

• Mold prophylaxis should be given for patients on prolonged high dose steroid

• Patients should receive prophylaxis antibiotics prior to dental procedures to prevent endocarditis

• Monitor for CMV infection closely

• Revaccination after 6-12 months of HCT and after stopping IS

• IVIG replacement for hypogammaglobulinemia

Treatment for cGVHD

• Mild cGVHD

• May not require treatment

• Wait and watch

• Severe cGVHD

• Topical agents

• Systemic agents

• Prednisone is first line treatment at doses 0.5-1mg/kg

• No consensus on second line therapy

• Extracorporeal photopheresis

• Supportive care

Organ-specific management and

supportive care in cGVHD

• Cutaneous

• Topical therapy – steroid or topical calcineurin inhibitors • Regular moisturizers for xerosis • Annual skin check by dermatologist

• Increased risk of skin cancer • ECP is effective in skin GVHD • Physiotherapy for scleroderma like cases

• Ocular

• Artificial tears • Lubrication • Topical anti-inflammatory (steroid/cyclosporine emulsion) treatment • Referral to specialist for change in vision • Occlusive eyewear to prevent evaporation

• Oral

• Dexamethasone elixir • Artificial saliva • Salivary stimulants • Adequate hydration

Organ-specific management and supportive

care in cGVHD

• GI

• Topical steroid

• Optimizing nutrition

• Genital • High potency topical steroid (female)

• Use of dilators

• Early referral to specialist in difficult cases

• Lungs • Prophylactic antimicrobial therapy

• Oxygen

• Inhaled steroid/immunosuppressants