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

Table I

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.]