Graft-Versus-Host Disease and Graft-Versus-Tumor Response

Graft-Versus-Host Disease and Graft-Versus-Tumor Response

Joseph Pidala

Frederick L. Locke

Claudio Anasetti


Graft-versus-host disease (GVHD) is the most common treatment complication following hematopoietic stem cell transplantation (HSCT) from an allogeneic donor, and it is a major cause of recipient morbidity and mortality. GVHD results from the recognition of recipient tissue antigens by immune competent T cells transplanted with the graft. There is an acute form of GVHD with a rapid onset, usually early after transplantation, and a chronic form of GVHD with late onset. These two GVHD syndromes are largely distinct in pathogenesis, clinical manifestations, prevention, and treatment, and therefore are presented separately in this chapter. Donor cells in the graft also produce an immune response against targets in the recipient malignant cells, through a reaction that contributes substantially to the antitumor activity of allogeneic HSCT. Such a graft-versus-tumor (GVT) response is presented in the third section of this chapter.



The major source of treatment-related morbidity and mortality is GVHD. The incidence of clinically relevant (grade II to IV) acute GVHD ranges from 35% to 80%, with a higher incidence reported for recipients of unrelated donors compared to matched related donors.18, 19 The day 100 incidence of severe acute GVHD (grades III-IV) occurs in approximately 15%, but may be as high as 35% depending upon risk factors such as HLA disparity.5


Risk factors for the development of acute GVHD include T-replete transplant, recipient and donor HLA disparity, female donor for a male recipient, donor and recipient age, hematopoietic stem cell source (peripheral blood progenitor cells [PBPCs] > marrow > cord blood), graft cellular composition (worse with higher T-cell and CD34 cell numbers), higher conditioning intensity, diagnosis (worse with chronic myeloid leukemia), and immune response gene polymorphisms.20, 21 Predictive factors are of great interest to stratify patients prior to development of serious morbidity or mortality and to focus prevention upon the proper biological parameters.

HLA matching is critical to prevent acute GVHD. A single allele mismatch at HLA-A, HLA-B, HLA-C, or HLA-DRB1 increases the likelihood of acute GVHD development, and mismatch for multiple alleles compound the risk.5, 22

Female donor for a male recipient and donor parity are risk factors for the development of acute GVHD. The increased risk for male recipients of female as opposed to male donors is attributed to the recognition of H-Y mHAs by female donor T cells.23, 24 During pregnancy, female donors develop an immune response to the paternal mHAs of the fetus and mount a secondary, augmented T-cell alloimmune response against the same mHAs if expressed in the recipient.25

Increasing donor age is associated with increased risk for the development of severe acute and chronic GVHD, and worse mortality.26 Age of the recipient is also important with higher rates of acute GVHD in older compared to younger cohorts.20, 27

The rate of chronic GVHD in patients receiving PBPC grafts is higher compared to bone marrow; however, the association of PBPC with acute GVHD is not clearly established.28, 32 Unrelated cord blood transplant is associated with a low rate of acute GVHD when compared to transplant with similarly HLA mismatched adult donors.33, 34 Multiple factors may contribute to this effect; however, the low number of T cells in the graft and T-cell naive likely play a protective role.

The conditioning regimen used affects the incidence of acute GVHD. With high-dose intensity conditioning the incidence of acute GVHD is higher. For example, increasing doses of radiation can double the incidence of acute GVHD.35 Several large retrospective studies showed that reduced intensity regimens lead to reduced rates of grade II-IV acute GVHD when compared to higher intensity regimens.36, 37 Animal models suggest the correlation of the incidence of GVHD with intensity may be due to increased damage to host tissue and amplified release of cytokines followed by activation of APC.38 In addition, higher intensity regimens decrease the fraction of recipient T cells that persist after the regimen, leading to a lower barrier to donor engraftment and greater homeostatic re-population by donor T cells, which is associated with worse acute GVHD.39, 40

The cellular composition of the graft is linked to the incidence of GVHD. Despite the link between chronic GVHD and CD34 cell dose, conflicting studies outline the importance of CD34 cell dose on acute GVHD.41, 42 The preponderance of evidence suggests that there is no correlation between CD34 cell dose and the incidence of acute GVHD, whether the progenitor source is marrow or PBPC,43, 44, 45 although one study, looking at patients given cyclosporine as a prophylactic agent, revealed a positive association of CD34 dose with acute GVHD.46

Genetic polymorphisms of immune response genes are associated with an increased incidence of acute GVHD. Single nucleotide polymorphisms (SNPs) can alter cytokine binding domains, thereby altering affinity in a functional or nonfunctional way. Particular SNPs in genes coding IL-10, IL-6, IL-2, HPSE, CTLA-4, and MTHFR have all been identified as increasing the risk of clinically relevant or severe acute GVHD, likely via increased level or activity of these cytokines or receptors.47

Cytokine biomarkers correlate with the presence of acute GVHD and provide prognostic information independent of the severity of GVHD. Although not widely in diagnostic use, the panel which includes IL-2-receptor-alpha, TNF-receptor-1, IL-8, and hepatocyte growth factor, can confirm the diagnosis at the onset of clinical symptoms.48 An expanded 6 biomarker panel which also includes elafin, a skin-specific marker, and regenerating islet-derived 3-α, a gastrointestinal (GI) tract-specific marker was shown to predict response rate at day 28 after onset and survival at day 180 after onset, for patients with acute GVHD. This panel was predictive at 3 time points; onset, 2 weeks, and 4 weeks into therapy. Future clinical trials will determine if such stratification into high and low risks groups will lead to improved outcomes by capitalizing on the opportunity for early intervention.49


Acute GVHD response rates to high-dose steroid therapy are in the range of 50%, and achievement of response to steroids is the most important predictor of outcomes. Durable responses of a month or longer can be expected in about 30% and partial responses (PRs) in 20%. Lower intestinal acute GVHD has been linked to worse response rates compared to patients without lower intestinal manifestations.


The most common sites of involvement are skin, GI tract, and liver. Additional organ sites may be involved and clinicians should maintain a high degree of suspicion for acute GVHD as a
cause for any unexplained abnormalities in eyes, buccal mucosa, and lung. A biopsy of the presumptive site should be attempted whenever possible to confirm diagnosis, although histological manifestations can overlap with many inflammatory conditions confounding histological results. A pathologist familiar with acute GVHD is preferable, and appropriate immunohistochemical stains should be employed to rule out viral infection, particularly of the GI tract.

The onset and natural history of acute GVHD is variable depending on organ site, nature, and severity of disease. A hyperacute form, occurring in the first 14 days after transplant,50 is characterized by early onset of typical signs and symptoms, with a preponderance of patients, 90%, exhibiting skin involvement. In addition a higher percentage of patients are likely to experience stage III-IV disease (88% vs. 66%).51, 52

Most cases of acute GVHD manifest within the first 100 days following transplant. With the use of modern prophylaxis regimens including cyclosporine or tacrolimus, the onset is typically 20 to 25 days after cell infusion. With T-cell depletion, average onset is typically at 30 days, although it can be delayed several months as T cells reconstitute.53 NIH consensus criteria for chronic GVHD includes classification of acute GVHD occurring after day 100 (late-onset acute GVHD) and for patients manifesting signs and symptoms of both acute GVHD and chronic GVHD (overlap subtype of chronic GVHD).54 The severity of acute GVHD can easily be quantified using Keystone consensus grading criteria (Table 105.2).


Skin is the most commonly involved site of acute GVHD, being present 80% of the time at onset. A maculopapular rash is characteristic and may be described as a painful or pruritic sunburn. Characteristically involved sites include the back of the neck, palms, soles, dorsal surfaces of the extremities, and ears, although the rash can spread quickly to include the entire body. Although many cases are mild, severe manifestations can include bullous lesions and a clinical picture consistent with toxic epidermal necrolysis. Careful full-body examination allows for staging of acute GVHD by the Keystone consensus criteria. This scale is based upon percentage of body surface area (BSA) involvement. For example, when acute GVHD is confined to the skin and involves <50% of BSA, it is classified as grade I acute GVHD. Such a degree of involvement may require no more than topical steroids and frequent monitoring of symptoms (see “Primary and Secondary Therapy of Acute Graft-versus-host Disease” below). A biopsy of the skin can help to solidify the diagnosis, however, treatment is usually based on the clinical diagnosis.55







Rash on <25% of skin

Bilirubin 2-3 mg/dl

Diarrhea >500 ml/d or persistent nausea


Rash on 25-50% of skin

Bilirubin 3-6 mg/dl

Diarrhea >1000 ml/d


Rash on >50% of skin

Bilirubin 6-15 mg/dl

Diarrhea >1500 ml/d


Generalized erythroderma with bullous formation

Bilirubin >15 mg/dl

Severe abdominal pain with or without ileus



Stage 1-2




Stage 3 or

Stage 1 or

Stage 1


Stage 2-3 or

Stage 2-4


Stage 4 or

Stage 4

Functional Grading





Rash on <50% of skin


Rash on <50% of skin or

Bilirubin 2-3 mg/dl or

Diarrhea >500 ml/d or persistent nausea


Generalized erythroderma with bullous formation or

Bilirubin >3 mg/dl

Diarrhea >1000 ml/d

Criteria for grading given as minimum degree of organ involvement required to confer that grade.

Grade IV may also involve lesser organ involvement but with extreme decrease in performance status. From Przepiorka D, Weisdorf D, Martin P, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 1995;15:825-828.


Liver acute GVHD is typically characterized by involvement of the bile duct epithelium, resulting in cholestasis. Bilirubin and alkaline phosphatase elevation, accompanied by cholestatic jaundice are the typical manifestations. Direct hepatocyte damage is rare, absent a more chronic fibrosis, although transaminitis often occurs. Hyperbilirubinemia must be distinguished from other common post-transplant complications such as toxicity from preparative chemotherapeutics, sinusoidal obstructive syndrome (also called hepatic veno-occlusive disease), and occasionally fulminant viral hepatitis. Sinusoidal obstructive syndrome is characterized by hyperbilirubinemia, portal hypertension, and weight gain due to third spacing of fluids. Portal hypertension is part of the clinical picture of sinusoidal obstructive syndrome, and not a manifestation of acute GVHD in patients without underlying liver disease. Doppler assessment of portal hypertension, measurement of the hepatic vein occlusive pressure, and if necessary histological examination, are critical in resolving the differential diagnosis. A transjugular liver biopsy is preferable to transcutaneous biopsy, as portal pressures can be measured. Acute GVHD produces cholestatic hepatitis, with histology showing frequent acidophilic bodies evolving to bile duct exocytosis and disruption. As the disease progresses beyond day 100 post-transplant, portal fibrosis is seen with increasing bile duct dropout.56 This is in contrast to sinusoidal obstructive syndrome, which is characterized by occluded hepatic venules, sinusoidal fibrosis, and hepatocyte necrosis.57

Gastrointestinal Tract

Anorexia, nausea, and vomiting are the most common symptoms of GI acute GVHD, but diarrhea, abdominal pain, and hemorrhage are symptoms of serious lower-tract disease. Almost any site along the tract can be involved. Unexplained GI symptoms such as mouth ulcers or ileus can be caused by acute GVHD. Endoscopy with biopsies of the upper and/or lower tract should be obtained for persistent symptoms, inasmuch as histology provides critical information. The differential diagnosis of uppertract GVHD includes herpes simplex, cytomegalovirus, or candida esophagitis, stomach ulcer, and peptic gastritis or duodenitis. The differential diagnosis of lower tract disease includes enteritis from C. difficile, cytomegalovirus, Norfolk viruses, cryptosporidium, giardia, or enteric pathogens such as Salmonella, and side effects of irradiation or medications including cytotoxic chemotherapy, tacrolimus, and mycophenolate mofetil among others. Radiologic findings by computed tomography (CT) scan can include thickening of the esophageal, small, or large bowel wall; adjacent vasa recta engorgement; mesenteric fat stranding; or mucosal enhancement.58 Radiologic modalities should not be relied upon for confirmation of diagnosis. Upper or lower endoscopy affords both a visual examination of the mucosa which may exhibit edema, erythema, ulceration, and mucosal sloughing, as well as the opportunity to obtain tissue for histology. Classic microscopic findings include epithelial crypt apoptotic bodies and lymphocytic infiltration. Involved mucosa can be noncontinuous and a lack of findings or a low degree of severity at one level does not rule out other areas or degrees of involvement.59


Lung complications following allogeneic transplant can be of cardiac, infectious, vascular, or immune nature. Infections and pulmonary embolism should always be entertained in the differential diagnosis of a transplant patient with shortness of breath, hypoxia, or new infiltrate. Volume overload and cardiogenic pulmonary edema is another mechanism of respiratory distress. Immune-mediated processes should be entertained when infectious work-up is negative, or CT scanning is not consistent with infectious processes. Diffuse alveolar hemorrhage has long been recognized as a post-transplant complication and occurs in approximately 10% of patients, with myeloablative regimens associated with a higher incidence. Patients manifest with dyspnea (92%) accompanied with mild to severe bleeding into the alveoli, although hemoptysis is seen in a minority (15%) of cases. Fever can be a presenting symptom (67%) and diagnosis is typically made following bronchoscopy. Patients often require ventilatory support and mortality rates can reach 70%.60, 61 Lung wedge resection or video-assisted thoracoscopic biopsy should be entertained for patients where an organism is not identified and diagnostic uncertainty remains. Bronchiolitis obliterans with organizing pneumonia (BOOP) is seen in up to 2% of patients during the post-transplant period. Although not considered a manifestation of GVHD,62 biopsy-proven BOOP occurs at a median of 108 days after transplant and can display a wide range of severity and reversibility. It is typically a restrictive lung disease with radiographic findings showing peripheral patchy consolidation, ground glass infiltrates, and nodular opacities. BOOP after transplant is associated with GVHD and steroid therapy affords a chance for improvement.63, 64


Primary therapy for acute GVHD consists of high-dose steroids (the equivalent of 1 to 2 mg/kg/day of prednisone, with a taper initiated as soon as patients have a major decrease in GVHD signs or symptoms). This standard is based upon historical empirical evidence and randomized controlled data which suggest no advantage to prednisone-equivalent steroid doses of >2.5 mg/kg/day and no disadvantage for 1 mg/kg/day for grade II acute GVHD.92

Standardized consensus response criteria for acute GVHD clinical trials are defined as a complete response, with resolution of all signs and symptoms of disease and normalization of laboratory values, and a very good partial response (VGPR), which allows for residual nonbullous erythematous rash on <25% of BSA, occasional nausea or vomiting, and a reduction of bilirubin to <25% of baseline at enrollment.93 The definition of VGPR (Table 105.3) allows for confounding variables that clinicians must recognize while monitoring for resolution of acute GVHD such as residual GI and hepatic toxicities from conditioning or prophylactic medicines and the recognition of erythema or darkening skin as resolving skin lesions. Prolonged high-dose steroid use leads to a significant degree of morbidity and mortality, and the tapering of these drugs must take precedence once symptomatology and abnormal laboratory data recede.



No rash, or residual erythematous rash involving <25% of the body surface, without bullae (residual faint erythema and hyperpigementation do not count)


Total serum bilirubin concentration <2 mg/dl or <25% of baseline at enrollment


Tolerating food or enteral feeding

Predominantly formed stools

No overt gastrointestinal bleeding or abdominal cramping

No more than occasional nausea and vomiting

From Endpoints for Clinical Trials Testing Treatment of Acute Graft-Versus-Host Disease: A Consensus Document. from Martin PJ, Bachier CR, Klingemann HG, et al. Endpoints for clinical trials testing treatment of acute graft-versus-host disease: a joint statement. Biol Blood Marrow Transplant 2009;15:777-784.

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Oct 21, 2016 | Posted by in HEMATOLOGY | Comments Off on Graft-Versus-Host Disease and Graft-Versus-Tumor Response
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