Critical Care Medicine

Non-infectious complications Post-BM/PSC Transplant: Graft rejection/graft failure

Graft failure

Synonym

Graft rejection

Related conditions

Marrow aplasia

Pancytopenia

1. Description of the problem

Graft failure and graft rejection are life-threatening complications after allogeneic SCT. This results in pancytopenia and a high risk of infection and bleeding complications. The risk of graft failure or rejection has decreased over the years with more effective transplant procedures, but when this occurs, mortality rates remain high.

It is important to try and distinguish graft failure, which potentially could be reversed with additional donor stem cells, from graft rejection, which might require intensification of immunosuppression or procedures to further eliminate any residual host immunity (such as donor lymphocyte infusions).

Primary graft failure occurs by day 28 after transplant when there is:

-- pancytopenia

-- marrow aplasia

-- an absolute neutrophil count of less than 500/ul (with no other cause of myelosuppression)

Late graft failure develops beyond day 28 after transplant, typically after hematopoietic recovery, and also is manifested by:

-- pancytopenia

-- marrow aplasia

-- an absolute neutrophil count of less than 500/ul (with no other cause of myelosuppression)

Graft rejection is also manifested by pancytopenia. While this is often difficult to diagnose, molecular chimerism testing is important to help define graft failure from graft rejection.

Finding donor chimerism decrease over time without concurrent relapse is often suggestive of rejection.

For graft failure, the initial management is transfusion support.

Myeloid growth factors (G-CSF, GM-CSF) may be of some use.

It is important to rule out other causes of graft failure such as infection (in particular CMV, herpes viruses) and medication use.

2. Emergency Management

For graft failure, the initial management is transfusion support.

Myeloid growth factors (G-CSF, GM-CSF) may be of some use.

It is important to rule out other causes of graft failure such as infection (in particular CMV, herpes viruses), and medication use.

Transfusions as needed

A bone marrow evaluation is necessary but results are dependent on timing of suspected graft failur/rejection.

Donor chimerism analysis

Review medication list and eliminate any myelosuppressive medications as possible.

Test for CMV reactivation.

Test for herpes viruses (HSV, HHV6) and parvovirus.

Begin myeloid growth factor (G-CSF or GM-CSF).

If graft rejection is suspected, it is always difficult to determine if the patient requires additional immunosuppression (to inhibit immune-mediated rejection) or less immunosuppression (to enhance the "graft-vs.-host" reaction of donor T cells against residual host immune cells. In some cases, additional donor T cells (donor lymphocyte infusions [DLI]) are given to try and reverse rejection by providing enhanced donor immunity. At other times, additional donor stem cells may be given if concern is for graft failure rather than immune-mediated rejection.

3. Diagnosis

Primary graft failure is a lack of engraftment with pancytopenia, marrow aplasia, and an absolute neutrophil count of less than 500/ul (with no other cause of myelosuppression) at day 28 after transplant.

Late graft failure is also manifested by pancytopenia and marrow aplasia that develops after initial hematopoietic recovery and at a later time course after transplant.

Graft rejection is often difficult to distinguish from graft failure and is presumed to be immunologic rejection by the host of the donor cells. In this case, finding donor chimerism decrease over time without concurrent relapse is often suggestive of rejection.

How do I know this is what the patient has?

Primary graft failure is a lack of engraftment with pancytopenia, marrow aplasia, and an absolute neutrophil count of less than 500/ul (with no other cause of myelosuppression) at day 28 after transplant. A bone marrow evaluation is done (though often hypocellular) to rule out recurrent disease, and occasionally unusual infections as a cause of pancytopenia. Occasionally findings of early hematopoietic recovery will be identified, suggesting delayed engraftment (rather than failed engraftment).

There is no single test to identify (or distinguish) graft failure or graft rejection.

Differential diagnosis

Delayed or late-onset pancytopenia after allogeneic SCT can be caused by:

-- Infections that result in stem cell toxicity or myelosuppression such as CMV, EBV, HSV, HHV6

-- Myelosuppression or maturation arrest from medications (antibiotics or others)

Confirmatory tests

Bone marrow evaluation.

Chimerism studies (note that in graft rejection, falling donor chimerism is often seen). In graft failure, these studies may still show a high percentage of donor cells despite having minimal hematopoiesis.

4. Specific Treatment

First-line therapy would be transfusion support.

Growth factors (G-CSF +/- GM-CSF)

Avoid myelosuppressive medications (in particular, if possible: ganciclovir, sulfamethozole, vancomycin, linezolid, ACE inhibitors).

Treat any infections.

If falling donor chimerism suggesting immunologic rejection, consider additional immunosuppression.

Determine if graft rejection and consider DLI.

Determine if graft failure/loss and consider additional donor stem cells with or without immunosuppressive conditioning.

Drugs and dosages

GCSF 5-10 ug/kg

GM-CSF 250 ug/M2

Refractory cases

For refractory cases, consider second SCT with same or alternate donor.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

After a myeloablative allogeneic SCT, the prognosis for graft rejection is usually poor, with survival rates only approximately 30% at one year.

WIth the increased use of a non-myeloablative conditioning, the incidence of graft rejection is higher. However many of these patients will experience autologous hematopoietic recovery.

Incorrect diagnosis

The diagnosis may be incorrect if the bone marrow shows >5% cellularity or early hematopoietic recovery despite pancytopenia.

Follow-up

Frequent monitoring of blood counts, chimerism studies, and follow-up bone marrow biopsy. Monitoring for infection and GVHD is essential.

Pathophysiology

Graft rejection is a major cause of graft failure and is due to an immune response of residual post immune cells against donor hematopoietic cells. This is suspected when residual host T cells are present in the presence of marrow aplasia and pancytopenia.

Graft failure, independent of immunologic rejection, may be caused by inadequate or insufficient numbers of donor hematopoietic stem cells. It can be caused by toxin exposure (often medications such as antibiotics) or infections. Infections most commonly associated with graft rejection include CMV, HHV6 and perhaps HSV and parvovirus.

Immune mechanisms are most often considered to be due to surviving recipient T cells despite the conditioning therapy. Experimental evidence also suggests that NK cells can participate in immune-mediated rejection. It is unclear if anti-HLA antibodies result in rejection, but this may be a concern particularly when the patient and donor are HLA-mismatched (such as in the setting of umbilical cord blood transplant or haploidentical transplant).

Epidemiology

Graft failure/rejection occurs in <1% of recipients of matched sibling bone marrow or stem cell grafts treated with a myeloablative conditioning regimen. It is more common in recipients of unrelated donor or mismatched stem cell grafts (such as those common with umbilical cord blood) and may occur in 5-10% of patients depending on the degress of mismatch. A low cell dose in the stem cell product increases the risk of graft rejection/failure.

The risk of rejection increases in patients sensitized presumably to HLA antigens by prior blood transfusion or even pregnancy. Recipients of non-myeloablative conditioning regimens are also at higher risk of graft failure/rejection that is dependent on the immunosuppressive intensity of the conditioning.

Since many cases of graft rejection are immune-mediated, they can be overcome by a higher T-cell dose in the donor graft. T-cell depletion of the donor graft (as GVHD prophylaxis) increases the risk of rejection.

Prognosis

Graft rejection/failure is often a life-threatening complication. Many patients die of infectious complications before adequate or effective therapy is initiated, or often therapy for graft failure is ineffective or results in life-threatening risks.

In one detailed study over a 10- year period, the 1-, 2- and 5-year survival rates after diagnosis of graft failure were 31%, 24% and 15%. Patients who experience autologous reconstitution (often after non-myeloablative conditioning) are more likely to enjoy prolonged survival than patients who have no autologous hematopoietic reconstitution.

Special considerations for nursing and allied health professionals.

NA

What's the evidence?

Rondon, G, Saliba, RM, Khouri, I. "Long-Term Follow-Up of Patients Who Experienced Graft Failure Postallogeneic Progenitor Cell Transplantation. Results of a Single Institution Analysis. Biology of Blood and Marrow Transplantation". Journal of the American Society for Blood and Marrow Transplantation. vol. 14. 2008. pp. 859-866.

Large retrospective single-institution study examining the long-term follow-up of patients who experienced graft failure after allogeneic stem cell transplant over a 10-year period. 68 patients with graft failure were identified out of 1726 patients who underwent transplant.

Mattsson, J, Ringden, O, Storb, R. "Graft Failure after Allogeneic Hematopoietic Cell Transplantation. Biology of Blood and Marrow Transplantation". Journal of the American Society for Blood and Marrow Transplantation.. vol. 14. 2008. pp. 165-170.

Excellent review on the risks and pathophysiology of graft failure.

Lowsky, R, Messner, H, Appelbaum, F, Forman, S, Negrin, R, Blume, K. "Mechanisms and treatment of graft failure". Thomas' Hematopoietic Cell Transplantation (4th ed). John Wiley & Sons. 2010. pp. 1203-1218.

Comprehensive and very up-to-date review on the pathophysiology, risk factors, and treatment for graft failure.

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