Acute Graft Versus Host Disease

(aGVHD)

Teaching session

1 July, 2004

Meg Browning

Definition of terms GVH(D): Graft-versus-host (disease). The set of symptoms

that occur when the immune cells from a graft (marrow, organ, even transfusion) react against the recipient.

MHC: major histocompatibility complex; the primary proteins that identify “self.” We currently measure 10 genetic alleles for such proteins. These genes sort together, so you get them as sets from your parents, not as individual proteins.

Syngeneic: matching exactly (e.g., identical twins) Allogeneic: not matching at some level (a “matched sibling”

is still allogeneic!) Autologous: (autogeneic, sadly, isn’t a word): from self

A brief note on “acute” and “chronic” The classic definition is whether or not the patient is

within the first 100 days after transplant; thus, “acute” GVH occurs before day 100.

There are pathological differences, as seen on biopsy, between disease states that would be considered chronic vs. acute

The red skin rash we see is acute; the chronic skin disease is more like scleroderma

Profuse watery diarrhea is consistent with acute; wasting is more chronic

Boring “historical perspective” slide

A fatal syndrome of skin abnormalities and diarrhea (or wasting, in newborns) given allogeneic spleen cells after irradiation (or in the newborns, at all).

Primary disease was the same thing after irradiation itself.

This was in the 1950’s, and in mice.

Primarydisease

Secondarydisease(GVHD)

1966 (original, Billingham) definition Criteria for the development of GVHD: The graft must contain immunologically competent

cells. Still true

The host must possess alloantigens that are lacking in the graft (must appear foreign). True in the parenthetical explanation

The host must be incapable of mounting an effective anti-graft reaction, at least for a period of time. True as long as you emphasize “effective.”

Picky technical slide #1

Picky technical slide #2graft

The antigen-presentingcell recognizes a foreigncell, processes it, and presents antigen. The T cell is activated, leading to prolif-

eration, cytokine production, etc.

IL-1

TNF

IFN

IL-2foreign cell(non-self)

Trick Question

Can recipients of autologous (and/or syngeneic) transplants still get GVHD?

Yes. (OK, so it loses something when I warn you it’s a

trick.) How?

possibly thymic damage, and/or regulatory imbalance

What creates a GVHD set-up?(or lack thereof)

alloreactivity degree of mismatch strength of mismatch

sex mismatch donor parity age

recipient age 20%, 30%, and 80% at <20, 45-50, and >50

donor age

stem cell source cord: ?less marrow PBSC: more chronic whether T cell depleted

microbes particularly herpes family

conditioning immune suppression organ damage

prophylaxis

Acute GVHD Occurs within the 1st 100 days post-transplant; typically between

days 4+ and 40. Triad of dermatitis, enteritis, and hepatitis

ocular symptoms, pneumonitis, and hemorrhagic cystitis may also occur acutely, as may thrombocytopenia and anemia.

40% of all HLA-matched recipients still get GVHD! GVHD increases the risk of sepsis and certain other complications aGVHD patients are more likely to have cGVHD There is no racial or gender predilection GVHD may decrease the likelihood of relapse

Skin is usually first Red to violet lesions, often starting on palms and soles. May hurt or

itch. Becomes confluent over cheeks, ears, neck, trunk; papules may form. In severe cases, bullae and epidermal necrosis occur.

DDx: scalded skin syndrome (infection), viral exanthem, chemo/radiation effects, drug allergy.

Biopsy or serial biopsies are helpful in Dx. Biopsy findings are graded, not staged

Liver or GI involvement is unusual WITHOUT skin involvement

More skin GVH issues Staging:

1: < 25% of the BSA is involved 2: 25-50% BSA 3: 50-100%, as erythroderma 4: vesicles and bullae

Higher stages are more likely to develop chronic skin GVH

Hyperacute GVH: fever, erythroderma (may be pruritic), and desquamation prior to engraftement (before day 14).

An arm with aGVHD

Liver Next most commonly involved Cholestatic jaundice; does NOT usually progress to liver

failure DDx: VOD, infection, drug toxicity The bile duct damage is characteristic, but biopsy is not

typically needed. Staging:

1: bili 2-3 2: bili 3-6 3: bili 6-15 4: bili >15

Gut Diarrhea (green, water, mucoid; may contain cells and fecal

casts), intestinal bleeding, crampy abdominal pain, ileus Upper tract disease is less common, and occurs in older

patients. Requires Bx for diagnosis. Barium studies show increased transit time and loss of

haustral folds Histology is quite variable. DDx: residual chemo effects, infection Staging:

1: diarrhea 500-1000* cc of stool/day OR persistent nausea 2: 1000-1500* cc 3: >1500* cc 4: pain +/- ileus*stool volumes were determined in adults.

Grading: the overall dealgrade skin

stageliver stage

gut stage

function impaired

0 (none) 0 0 0 0

I (mild) 1-2* 0 0 0

II (moderate) 1-3 1 1 +

III (severe) 2-3 2-3 2-3 ++

IV (life threat’g) 2-4 2-4 2-4 +++

*officially recorded as “+,” but I find the numbers easier to see

How do we treat GVHD?

Prevent it!!

GVHD Prevention To review briefly: match well (antigens, ?

CMV), T-deplete (?), condition lessThese suggestions are all very well for GVHD, but

have to be balanced with what is good (well, bad) for the underlying disease

Prevent infection Immunosuppress post-transplant Consider antibody prophylaxis

Antibody prophylaxis IVIG helps on 2 fronts

Prevents certain infections Reduces the frequency of aGVHD, at least in adults

no, I don’t actually know how

ATG has not yet been proven helpful on a sustained basis, but is sometimes used as part of immunosuppression

Other agents such as anti-cytokine products are now being used and tested – more on those if we have time.

Immunosuppress MTX, the old standby MTX + CSA MTX + CSA + PRED CSA + PRED CSA FK506 + CSA It’s difficult to interpret a lot of this data, as it is either very

small numbers or compared across different prep regimens, types of transplant, ages, etc.

Not only the agents, but the doses and length of therapy are all open to question.

What do we use? Aplastic anemia (non-

TBI-based prep)

Haploidentical donor – old protocol

Haplo, new protocol

Unrelated donor, T-depleted graft (with TBI)

CSA/MTX

CSA/ATG

Nothing!

CSA/MP taper

NOTE: Can substitute FK506 (tacrolimus) for CSA in most cases

Prevent infection An area where the nursing staff has particularly great opportunity

to make a difference BMT diet: NOT proven. SAA patients conditioned with CSA

alone benefited from aseptic guts. Hand washing is well-proven, but not for GVH Limiting sick staff is a hot topic, again “just” for overall infection Surveillance cultures are still recommended, and antimicrobials Mouth cares: may actually be helpful, though it is unclear exactly

how infectious mucositis and mucous membrane GVH involvement are related

Matching for CMV: another hot topic, as it may be better from a relapse perspective NOT to.

OK, now what if we truly do have to treat it.

Initial therapy Treat all patients with grade II or greater. Methylprednisolone (IV steroid) is the primary

treatment of choice. Boluses may range from 1-60 mg/kg/day. Taper based on response.

Continue GVH prophylaxis (such as CSA) during therapy, plus of course infection prophylaxis (especially TMP/SMX).

CSA is generally not a great treatment, nor ATG. However, some patients will respond, especially to CSA + methylpred.

New kids on the block Mycophenolate mofetil (MMF, Cellcept) is becoming

more established in the treatment of aGVHD. It kills lymphocytes.

Newer on the block is anti-IL-2R, aka anti-CD25, or daclizumab (Zenapax).

Salvage therapies Anti-TNF-alpha, or infliximab (Remicade), which works for

aGVHD (especially gut) but leads to increased fungal infections. (We have mostly used it for cGVHD, here.)

Anti-CD25 (CD25 is a surface marker for activated T cells), or daclizumab (Zenapax): a current NIH study

Many others in adult patients, mostly with around 30% response rates and very poor “cure” rates

Anti-CD3 (anti-T cell) antibodies have been tried in various forms, but thus far with as many complications as successes (for this; they’re useful in solid tumor rejection)

Ultraviolet radiation and psoralens are currently considered “salvage” as well.

Remember when you didn’t want to see this? Don’t you like it better now?

graft

IL-1

TNF

IFN

IL-2foreign cell(non-self)

Cellcept

Zenapax

Remicade

A few words about chronic GVHD By definition, occurs after day 100, but usually occurs

between 3 and 18 mos post-BMT. 30% of matched-sib transplants (all comers, not just

peds) Around 50% of those with > grade 1 acute GVH will go

on to develop chronic GVHD; 10-20% mortality. In general, diagnosis and treatment are similar to acute;

however, grading is usually as “limited” versus “extensive.”

What’s happening now FK506 (tacrolimus, Prograf) is becoming more important

in BMT, and may be particularly successful in steroid-resistant patients. (Probably works by decreasing cytokine production and lymphocyte activation.)

New antibodies and combinations of these newer therapies are keeping the basic science folks busy. Around our campus, cellular therapies are also being studied.

So, in 2-3 years, the amount of information on GVH prevention and/or therapy may double.