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 in approximately 50% of alloHCT recipients. The time to develop aGVHD varies based upon graft source and conditioning intensity, with a median onset of 17 to 20 days after allogeneic mobilized peripheral blood grafts. Onset may be 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. AGVHD can even develop as late as 6 month post-HCT (late-onset aGVHD) or occur at the same time as chronic GVHD (overlap syndrome). Even with modern tissue matching and supportive care, one in five allogeneic HCT recipients dies from complications of GVHD.

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. The pattern of organ involvement can help risk stratify patients into a standard-risk or high-risk group. Severity of aGVHD may also be determined on the basis of serum biomarkers of inflammation and tissue damage.

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

Overall, aGVHD is a clinical diagnosis, although some routine laboratory studies may help guide supportive care or risk stratification.

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)

Table I.

Diagnosis	Features	Comments
Acute GVHD	Epithelial cell apoptosis is more prominent in the regenerative compartment of the crypt Not prominent inflammation (neutrophils) in lamina propria, but increased eosinophils can be seen Exploding cryptic cells Villous 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 apoptosis Nuclear 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 ulcers Mixed inflammatory infiltration in lamina propria	Correlation between timing of MMF initiation and the onset of signs/symptoms might be helpfulSometimes discontinuation of MMF might be necessary to evaluate its effect on signs/symptoms
CGVHD	Destruction of crypts or glands. Villous atropy Lamina propria fibrosis Ulcers Apoptosis in glandular epithelial cells Upper esophageal webs

(Adapted from Washington, Jagasia. Human Pathology. 2009.)

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 Clostridium difficile, 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.

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 infiltration 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. Approximately 50% of patients with have a complete or partial response to steroids 4 weeks after starting 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), second-line immunosuppression is started. 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. However, only 20% of patients with steroid-refractory aGVHD have durable responses to second-line therapy. Most of these patients die within 6 to 12 months.

Mesenchymal stromal cells

Mesenchymal stromal cells may be available for compassionate use after steroid failure for helping induce tolerate and provide wound healing factors. This therapy is available for compassionate use in children, but it is not approved for adults given lack of efficacy data.

Investigational agents

Patients with steroid-refractory aGVHD should be enrolled in clinical trials given lack of approved agents and poor prognosis. Agents currently under evaluation include lymphocyte trafficking inhibitors (e.g., natalizumab, vedolizumab), complement inhibitors (ALXN1007), JAK inhibitors (ruxolitinib), alpha-1 antitrypsin, and tolerizing hormones (e.g., human chorionic gonadotropin). A few studies showed that intra-arterial (inferior and/or superior mesenteric arteries) infusion of very high dose methylprednisone may salvage some patients.

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. Different techniques are used (negative selection of T cells ex vivo, positive selection of CD34+ stem cells ex vivo, targeted or nonspecific antibodies against T cells, e.g., ATG or alemtuzumab, or post-transplant cyclophosphamide).

Decreased aGVHD with T-cell depletion is 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 does 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 or UCB 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 after UCB transplant.

Ursodiol prophylaxis

Ursodiol prophylaxis might decrease incidence of VOD and severe liver a GVHD.

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 (standard risk) aGVHD is characterized by limited organ involvement and carries a good prognosis.

Severe (high risk) GVHD has extensive multiorgan involvement with significant morbidity and poor survival.

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.

Pathophysiology

Pathogenesis

Phase I: Initiation Phase

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

Phase II: Expansion, Trafficking, and Effector Phase

Recognition of these changes at tissue level leads to activation, expansion, and trafficking of T cells to aGVHD target tissues. 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.

Phase III: Treatment Phase

Once steroid treatment begins, 3 primary immunologic outcomes are possible: the aGVHD inflammatory response (1) is completely resolved after therapy, (2) partially responds clinically, but incompletely resolves immunologically, leading to what may be a persistent state of “injurious resolution” with ongoing immune deficiency or evolves into chronic GVHD, or (3) progresses despite therapy (i.e., the patient is steroid-refractory).

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?

Blood-based biomarkers for risk stratification

Fecal calprotectin

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, B, Basu, S. “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. “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, K, 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.]

MacMillan, ML, Robin, M, Harris, AC. “A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality”. Biol Blood Marrow Transplant.. vol. 21. 2015. pp. 761-767. [This manuscript provides that a risk scoring system predicts response to therapy in acute GVHD]

Levine, JE, Braun, TM, Harris, AC. “A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study”. Lancet Hematol. vol. 2. 2015. pp. e21-29. [This manuscript reviews biomarkers for acute GVHD]

Adam, B, Koldehoff, M, Ditschkowski, M. “Endoscopic and Histological Findings Are Predicted by Fecal Calprotectin in Acute Intestinal Graft-Versus-Host-Disease”. Dig Dis Sci.. 2016 Mar 19. [This manuscript reports fecal calpotectin is useful marker to predict endoscopic and histological findings in GI-GVHD]

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