Hematology

Non-infectious complications after bone marrow transplant: acute graft-versus-host disease

Non-infectious complications after bone marrow transplant: acute graft-versus-host disease

What every physician needs to know about non-infectious complications after bone marrow transplant: acute graft-versus-host disease:

Acute graft-versus-host disease (aGVHD) is the most common and important complication of allogenic hematopoietic stem cell transplant (alloHCT).

AGVHD is an immunologically mediated disease occurring in an immunologically compromised host who has alloantigens that do not exist in the cell infusion or graft. AGVHD occurs at a median of 17 to 20 days after allogeneic mobilized peripheral blood grafts, but is later, following engraftment with marrow or umbilical cord graft sources. It may also be later following reduced intensity conditioning (RIC) regimens, that is, even beyond day 30 to 40.

Diagnosis and grading

Diagnosis of aGVHD is made clinically by the presence of symptoms and signs of dysfunction of three target organ systems (skin, liver, gastrointestinal tract). The diagnosis is best confirmed histologically as various other conditions (drug rashes, enteric infections, drug-induced cholestasis, or mild veno-occlusive disease of the liver (VOD) can mimic, or co-exist with aGVHD. The severity of organ involvement (staging) and number of organs, make up the clinical grade of aGVHD.

Incidence

Its incidence varies regarding the type of alloHCT.

  • Human leukocyte antigen (HLA)-identical sibling donor

- Up to 50% after human leukocyte antigen (HLA) identical sibling donor transplantation; moderate to severe aGVHD (grade II to IV) approximately 35 to 40%.

  • Unrelated donor (URD) transplant

- Up to 90%, (grade II to IV) approximately 40 to 50%.

  • Umbilical cord blood (UCB) transplant

- Single UCB, 38% and double UCB, 58% (grade II to IV). Mostly limited to stage three skin (clinical grade II).

  • After reduced intensity conditioning (RIC)

- After reduced intensity conditioning (RIC), aGVHD may be less common in UCB transplant. A recent meta-analysis revealed that a moderate to severe aGVHD rate was reduced by about 20% by non-myeloblative transplant or reduced-intensity conditioning transplant.

Risk factors

Donor/recipient HLA incompatibility is the most significant risk factor for developing aGVHD, though it is common even in HLA-identical sibling donor hematopoietic cell transplant (HCT), suggesting that other, minor histocompatibility antigens may initiate the allogeneic reaction, leading to aGVHD

  • Older recipient age

  • Donor/recipient sex mismatch (in particular female to male)

  • Graft source (peripheral blood greater than bone marrow greater than cord blood)

  • Inadequate immunosuppression post-HCT, such as low tacrolimus or cyclosporine serum levels, limited dose, or duration of mycophenolate mofetil (MMF)

  • Gene polymorphism: It has been shown that polymorphism affecting genes, involving cytokines (for example, IL-10, tumor necrosis factor [TNF]), immune response genes, drug metabolism, or DNA base excision repair pathways may be influence the risks of aGVHD, but these are early observations

What features of the presentation will guide me toward possible causes and next treatment steps:

Symptoms and signs of aGVHD

Skin, liver, and gastrointestinal (GI) tract are the three major organ systems involved in aGVHD. In addition, constitutional symptoms, including fever, fatigue, and weakness can occur.

Skin manifestations

Skin manifestations may vary from a mild erythematous maculopapular rash to bullae, even resembling toxic epidermal necrolysis. Malar, ears, neck, shoulders, and dorsal forearms/hands are most common, but any areas can be involved. AGVHD is one of only a few rashes that can involve the palms or soles.

Liver manifestations

AGVHD usually has a cholestatic presentation, with elevations in serum bilirubin and alkaline phosphatase greater than both aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

GI manifestations

GI manifestations include upper GI involvement with anorexia, nausea/vomiting, while small bowel and colon GVHD produces large-volume secretory diarrhea, abdominal cramping, in particular after oral intake. The volume of diarrhea is used to stage GI aGVHD. Lower gut GVHD symptoms (that is, diarrhea) need prompt investigation to confirm the diagnosis and start therapy, because early treatment may yield higher response rates. Stool cultures, endoscopy and biopsy can be helpful in confirming the diagnosis and recognizing other conditions which can mimic or exaggerate symptoms of aGVHD.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Laboratory studies required

  • Complete blood count

- CBC with differential (increased white blood cell [WBC] count can suggest infections, low platelet counts may indicate aGVHD or risks of GI bleed with GI aGVHD).

  • Liver function tests (elevated liver enzymes and bilirubin) are essential

  • Hemolysis markers

- Hemolysis markers (for example, haptoglobin, lactate dehydrogenase [LDH], reticulocyte count) can indicate microangiopathic hemolytic anemia (MAHA)/thrombotic thrombocytopenic purpura (TTP), which can result from cyclosporine A [CsA] or tacrolimus (particularly with sirolimus), which is a serious complication of these GVHD prophylaxis drugs.

What conditions can underlie non-infectious complications after bone marrow transplant: acute graft-versus-host disease:

Differential diagnosis

(See Table I)

Drugs

Liver dysfunction is common with high dose conditioning chemotherapy, antifungal agents (fluconazole and voriconazole), total parenteral nutrition, and CsA; GI, MMF can cause nausea or diarrhea; skin rash can be cause by many drugs including antibiotics

Infection

CMV, hepatic candidiasis, and sepsis may be associated with liver dysfunction; lower GI symptoms, mainly diarrhea can be caused by Clostridiumdifficile, viruses (adenovirus, rotavirus, CMV) or rarely, cryptosporidium.

Miscellaneous

Iron overload from prior transfusions or unrecognized hemachromatosis can cause elevation in liver function tests and can coexist with aGVHD.

Table I

Differential diagnosis of GIT (gastrointestinal tract) GVHD
Diagnosis Features Comments
Acute GVHD Epithelial cell apoptosis is more prominent in the regenerative compartment of the cryptNot prominent inflammation (neutrophils) in lamina propria, but increased eosinophils can be seenExploding cryptic cellsVillous blunting and loss of crypts (mucosal denudation) Signs can be minimal, look for other organ evidence of GVHD involvement
Preparative regimen Epithelial cell apoptosis Increased mitotic activity Crypt cell regeneration Early phase
Cytomegalovirus (CMV) Epithelial cell apoptosisNuclear inclusions can rarely be detected Carefully assess because both GIT GVHD and CMV can coexist
Cryptosporidium parvum Epithelial cell apoptosis Positive microbiological evidence (flourescent-Ab [antibody] or polymerase chain reaction [PCR] assays may be needed)
MMF GIT toxicity Colitis with increased crypt cell apoptosis.Focal ulcersMixed inflammatory infiltration in lamina propria Correlation between timing of MMF initiation and the onset of signs/symptoms might be helpful Sometimes discontinuation of MMF might be necessary to evaluate its effect on signs/symptoms
CGVHD Destruction of crypts or glands.Villous atropyLamina propria fibrosisUlcersApoptosis in glandular epithelial cellsUpper esophageal webs  

When do you need to get more aggressive tests:

Histopathology

AGVHD diagnosis is made clinically. However, tissue biopsies are very useful to confirm the diagnosis and exclude other complications or factors in the differential diagnosis.

  • Skin and GI biopsies are relatively easy and safe, compared to liver biopsies (most patients are at risk for bleeding). The histological hallmark of acute GVHD is apoptosis of the proliferative and regenerative cell layer of the epidermis or epithelium of intestinal or biliary tract

  • In the skin, this manifests as basal epidermal cell vacuolization with dyskeratosis

  • In advanced GI aGVHD, apoptotic cells contain intracytoplasmic vacuoles, filled with nuclear dust and debris, so-called “exploding crypt” cells. Villous blunting and loss of crypts can occur

  • In the liver, lymphocytic inflltration of small bile ducts, epithelial cell dropout, and cholestasis in zone three of the liver acinus are histological changes compatible with aGVHD.

Bone marrow aspirate and biopsy is generally not informative for diagnosis of aGVHD, but may be helpful if there are significant cytopenias of unknown etiology.

What imaging studies (if any) will be helpful?

A computed tomography (CT) scan of the abdomen can be helpful, by showing luminal dilatation with thickening of the wall of the small bowel (“ribbon sign”), engorgement of the vasa recta adjacent to affected bowel segments, stranding of the mesenteric fat, large-bowel wall thickening, bowel dilatation proximal to thickened wall segments, ascites, periportal edema, mucosal enhancement, and serosal enhancement. In severe cases with ileus, air/fluid levels can be detected.

None of these findings are specific for aGVHD, but reflect diffuse enteric inflammatory injury. Abdominal Doppler ultrasound might help to exclude veno-occlusive disease (VOD) disease of the liver, if suspected.

CT of the chest can be useful to exclude any active invasive fungal infections or pneumonia, which can present with fever and elevated bilirubin.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Therapy for aGVHD

Therapy for aGVHD should include two components: immunosuppression to decrease the T-cell induced inflammatory tissue injury, and appropriate supportive care.

Immunosuppressive therapy mainly targets T-cells and the cytokine amplified tissue injury; corticosteroids are the cornerstone of initial therapy for acute GVHD.

  • Topical steroids

Topical steroids are used for limited skin aGVHD; oral non-absorbable steroids (for example, beclomethasone) can supplement therapy for early-stage GI GVHD.

  • Systemic steroids

Intravenous (IV) methylprednisolone 1 to 2mg/kg/day is most common agent used for moderate to severe, or multiorgan aGVHD. The initial response rate is 30% to 50% after 4 weeks of therapy.

  • Patients with lesser severity and single-organ involvement

Patients with lesser severity and single-organ involvement tend to be more responsive to therapy; some reports suggest that GVHD following unrelated donor HCT is more resistant to therapy.

  • Steroid-resistant patients

In steroid-resistant patients (progression after 3 to 5 days, no response in 7 to 10 days, require added therapy. Most often used are anti-thymocyte globulin (ATG), MMF, pentostatin, the TNF-α receptor blockers etanercept or infliximab and the interleukin-2 (IL-2) receptor inhibitor denileukin diftitox or phototherapy (for skin GVHD) may yield responses in 20 to 60%. Generally, second line agents are added to corticosteroids, though the steroid doses may be lowered. Sirolimus may be added to, or replace calcineurin inhibitors. After a clinical response, the goal of therapy is to gradually taper the steroids first.

  • Mesenchymal stromal cells

Mesenchymal stromal cells may be available for compassionate use after steroid failure, but not after failure of second line agent. Phase II experience suggests that they may modulate the severity of aGVHD, but no controlled trials prove their efficacy. The best methods for their preparation, use and longterm safety are unknown.

Supportive care

In addition to effective immunosuppression, supportive care including antimicrobial, nutritional, and other support is critical to improve survival in patients with aGVHD. In patients on high dose steroid, anti-fungal prophylaxis with fluconazole, or if non-yeast fungi (Aspergillus) are of concern, then oral extended spectrum azoles (posaconazole or voriconazole) may be preferred. GI distress may limit their absorption. In patients receiving ATG or alemtuzumab based anti T-cell therapy, viral infections (for example, CMV, Epstein-Barr virus, etcetera) should be closely monitorized, preferably by frequent blood tests.

In patients with continuous fever with unknown source of infection, CT of the chest and sinuses should be performed to exclude fungal or other infections, in particular fungal infections. Hyperalimentation is frequently needed for patients with advanced GVHD, especially in those with involvement of the gastrointestinal tract.

What other therapies are helpful for reducing complications?

Prophylaxis of graft-versus-host disease

T-cell depletion

T-cell depletion has effectively decreased aGVHD rate. Three different techniques are used (negative selection of T cells ex vivo, positive selection of CD34+ stem cells ex vivo, and targeted or nonspecific antibodies against T cells (for example, alemtuzumab [particularly in nonmyeloablative {NMA} transplants, anti-thymocyte globulin {ATG} or antilymphocyte globulin {ALG}, in particular in unrelated donor alloHCT) in vivo.

Decreased aGVHD was offset by high rates of graft failure, relapse of malignancy, infections, and Epstein-Barr virus (EBV) associated lymphoproliferative disorders. Therefore, although aGVHD rates decreased, overall survival did not improve. Partial T-cell depletion (for example, CD8+ T cells) has been tried in clinical studies with some success.

Immunosuppressive drugs

The most common method to prevent GVHD is administering immunosuppressive drugs, starting before stem cell infusion. In this regard, a combination of methotrexate and a calcineurine inhibitor (for example, cyclosporine or tacrolimus) has been standard. After NMA transplants, MMF has replaced methotrexate in many centers.

Corticosteroids have not shown to improve overall survival because it is not used routinely in prophylaxis. Mammalian target of rapamycin (mTOR) inhibitor sirolimus has been shown to be effective in aGVHD prophylaxis.

Ursodiol prophylaxis

Ursodiol prophylaxis might decrease incidence of severe liver aGVHD.

Administering regulatory T cells

Administering regulatory T cells is being investigated to decrease GVHD.

What should you tell the patient and the family about prognosis?

Mild to moderate (grade I or II) aGVHD is characterized by limited organ involvement and carries an excellent prognosis.

Severe (grade III or IV) GVHD has extensive multiorgan involvement with significant morbidity and poor survival.

Gut aGVHD may be the most resistant to treatment.

AGVHD may completely resolve or progresses to chronic GVHD.

“What if” scenarios.

The prognosis is very poor in patients who do not respond to second line treatment. Almost all patients with severe gut aGVHD patients will not survive. These patients should be enrolled in a clinical trial if available. A few studies showed that intra-arterial (inferior and/or superior mesenteric arteries), very high dose methylprednisone may salvage some of these patients.

Other potential agents and treatments are being evaluated in trials include a monoclonal antibody against CD147 expressed on T and B cells (approximately 40% overall response in early phase studies) and alefacept selectively effect CD2 and thus memory effector T cells (approximately 70% overall response in early phase studies).

Pathophysiology

Pathogenesis

Phase I

Mainly this phase is composed of two parts: Tissue damage secondary to preparative regimen and increased secretion of cytokines by activated host cells, which may upregulate major histocompatibility (MHC) antigens.

Phase II

Recognition of these changes at tissue level by T cells and activation of T cells. Studies in murine and humans have shown that regulatory T cells (Tregs) can also be critical in pathogenesis of aGVHD, however this issue remains controversial.

Phase III

Alloreactive T cells undergo expansion and differentiation. These activated T cells migrate to aGVHD target tissues (for example, skin, gut, liver). In the last phase, these effector T cells cause destruction of the target tissues.

What other clinical manifestations may help me to diagnose non-infectious complications after bone marrow transplant: acute graft-versus-host disease?

N/A

What other additional laboratory studies may be ordered?

N/A

What’s the evidence?

Shi-Xia, X, Hai-Qin, X, Xian-Hua, T, Bo, F, Xiang-Fen. "Comparison of reduced intensity and myeloablative conditioning regimens for stem cell transplantation in patients with malignancies: a meta-analysis". Clinical Transplantation. vol. 25. 2011. pp. E187-198 .

[A meta-analysis demonstrates that allogeneic hematopoietic cell transplantation (alloHCT) following reduced intensity conditioning is associated with less aGVHD, compared to alloHCT with myeloablative conditioning regimens.]

Oran, B, Wagner, JE, Defor, TE, Weisdorf, DJ, Brunstein, CG. "Effects of conditioning regimen intensity on acute myeloid leukemia outcomes after umbilical cord blood transplantation". Bone Marrow Transplant. vol. 17. 2011. pp. 1327-1334.

[Demonstrates aGVHD rates in UCB transplant.]

Pérez-Simón, JA, Díez-Campelo, M, Martino, R. "Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft-versus-host disease after allogeneic transplantation". Br J Haematol. vol. 130. 2005. pp. 394-403.

[This study shows that intensity of conditioning regimen affects the frequency of GVHD.]

Arora, M, Lindgren. "Polymorphisms in the base excision repair pathway and graft-versus-host disease". Leukemia. vol. 24. 2010. pp. 1470-1475.

[Demonstrates polymorphism in genes involved repair pathway is important in aGVHD.]

Choi, SW, Levine, JE, Ferrara, JL. "Pathogenesis and management of graft-versus-host disease". Immunol Allergy Clin North Am. vol. 30. 2010. pp. 75-1 .

[Excellent review on pathogenesis of aGVHD by Ferrara et al.]

Socié, G, Blazar, BR. "Acute graft-versus-host disease: from the bench to the bedside". Blood. vol. 114. 2009. pp. 4327-36.

[Excellent review of acute GVHD from international authors.]

MacMillan, ML, Weisdorf, DJ, Brunstein, CG. " Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors". Blood. vol. 113. 2009. pp. 2410-5.

[Describes the risk factors for GVHD after UCB transplant.}

Levine, JE, Paczesny, S, Mineishi, S, et. "Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease". Blood. vol. 111. 2008. pp. 2470-2475 .

[Demonstrates the efficacy of etanercept plus methylprednisolone as initial therapy for aGVHD in a phase II trial.]

Le, Blanc, Frassoni, F, Ball, L. "Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study". Haematologica. vol. 92. 2007. pp. 627-34.

[Demonstrates the efficacy of mesenchymal stem cells in steroid resistant aGVHD.]

Alousi, AM, Weisdorf, DJ, Logan, BR. "Blood and Marrow Transplant Clinical Trials Network. Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network". Blood. vol. 114. 2009. pp. 511-7.

[Compares various treatment options for aGVHD in a phase II trial.]

Washington, K, Jagasia, M. "Pathology of graft-versus-host disease in the gastrointestinal tract". Human Pathology. vol. 40. 2009. pp. 909-917.

[This manuscript reviews pathologic features of GVHD in the gastrointestinal tract.]
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