Acute GvHD: Are You Avoiding These Common Treatment Pitfalls?

Allogenic hematopoietic stem cell transplantation (allo-HSCT) can be curative for many patients with hematologic malignancies. However, graft-versus-host disease (GvHD) remains one of the most common complications and one of the leading causes of death after unrelated HSCT. GvHD triples mortality rates. GvHD occurs when T-cells from the donated tissue recognize the patient as foreign and mount an immune attack. GvHD can be acute or chronic. Acute GvHD (aGvHD) usually presents within 100 days after transplantation and commonly affects the skin, gastrointestinal system, and liver. About 80% of patients with refractory aGvHD die. Chronic GvHD (cGvHD) typically presents beyond 100 days post-transplant, although it can occur at any time.

Risk factors for the development of GvHD includes incompatible HLA mismatch, stem cells from the peripheral blood rather than the bone marrow or umbilical cord, older age of the recipient and/or donor, ineffective GvHD prophylactic regimen, CMV serostatus, a multiparous female donor to a male recipient, and an intense preconditioning regimen.

Because of the life-threatening consequences of GvHD, appropriate prophylaxis is necessary. Click and to learn more about current and emerging prophylactic strategies and treatments options for acute GvHD.

However, despite prophylaxis, up to 59% of allo-HSCT recipients will develop aGvHD. Proper staging, grading, and risk evaluation are important when considering treatment selection. Organ involvement (skin, liver, upper GI, and lower GI) is staged from 0 to 4 based on presentation and symptoms:

Stage	Skin (Active Erythema Only)	Liver (Bilirubin)	Upper GI	Lower GI (Stool Output/Day)
0	Not active (erythematous) GvHD rash	<2 mg/dL	No or intermittent nausea, vomiting, or anorexia	Adult: <500 mL/day or <3 ep/day Child: <10 mL/kg/day or <4 ep/day
1	Maculopapular rash <25% BSA	2 to 3 mg/dL	Persistent nausea, vomiting, or anorexia	Adult: 500 to 999 mL/day or 3 to 4 ep/day Child: 10 to 19.9 mL/kg/day or 4 to 6 ep/day
2	Maculopapular rash 25% to 50% BSA	3.1 to 6.0 mg/dL		Adult: 1000 to 1500 mL/day or 5 to 7 ep/day Child: 20 to 30 mL/kg/day or 7 to 10 ep/day
3	Maculopapular rash >50% BSA	6.1 to 15 mg/dL		Adult: >1500 mL/day or >7 ep/day Child: >30 mL/kg/day or >10 ep/day
4	Generalized erythroderma (>50% BSA) + bullous formation and desquamation >5% BSA	>15 mg/dL		Severe abdominal pain with or without ileus, or grossly bloody stool (regardless of stool volume)

Harris AC, et al. Biol Blood Marrow Transplant. 2016;22(1):4-10.

 

The disease is then graded according to a variety of recognized grading systems:

Severity	Glucksberg1		CIBMTR2		MAGIC3
Mild	I	Stage 1-2 skin involvement; no liver or gut involvement; ECOG PS 0	A	Stage 1 skin involvement; no liver or gut involvement	I	Stage 1-2 skin without liver, upper GI, or lower GI involvement
Moderate	II	Stage 1-3 skin involvement; Stage 1 liver and/or gut involvement; ECOG PS 1	B	Stage 2 skin involvement; Stage 1-2 gut or liver involvement	II	Stage 3 rash and/or Stage 1 liver; Stage 1 upper GI; Stage 1 lower GI
Severe	III	Stage 2-3 skin, liver, and/or gut involvement; ECOG PS 2	C	Stage 3 skin, liver, or gut involvement	III	Stage 2-3 liver and/or Stage 2-3 lower GI with Stage 0-3 skin, and/or Stage 0-1 upper GI
Life-threatening	IV	Stage 1-4 skin involvement; Stage 2-4 liver or gut involvement; ECOG PS 3	D	Stage 4 skin, liver, or gut involvement	IV	Stage 4 skin, liver, or lower GI involvement with Stage 0-1 upper GI
1. Glucksberg H, et al. Transplantation. 1974;18(4):295-304. 2. Rowlings PA, et al. Br J Haematol. 1997;97(4):855-864. 3. Harris AC, et al. Biol Blood Marrow Transplant. 2016;22(1):4-10.

Patients are then determined to be of standard or high risk based on the number of organs involved and staging:

GvHD Risk Score	1 Organ	2 Organs	3 Organs
Standard Risk	Stage 1-3 skin Stage 1-2 GI	Stage 1-3 skin + Stage 1 GI Stage 1-3 skin + Stage 1-4 liver	— —
High Risk	Stage 4 skin Stage 3-4 GI Stage 1-4 liver	Stage 1-3 skin + Stage 2 GI Stage 1-2 lower GI + Stage 1-3 liver Stage 3-4 GI + Stage 1-3 skin Stage 3-4 GI + Stage 1-4 liver	Stage 1-3 skin + Stage 1-2 GI + Stage 1-3 liver Stage 1-3 skin + Stage 3-4 GI + Stage 1-4 liver
MacMillan ML, et al. Biol Blood Marrow Transplant. 2015;21(4):761-767.

 

Treating aGvHD can be complicated as providers try to balance the graft-versus-tumor effect while suppressing the graft-versus-host effect. Click here to learn about some of the common pitfalls of treatment and how to avoid them, as well as emerging therapies in the frontline and steroid refractory settings.