Oral chronic graft-versus-host disease: current pathogenesis, therapy, and research.

Optimal management of complex autoimmune diseases requires a multidisciplinary medical team including dentists to care for lesions of the oral cavity. In this review, we discuss the presentation, prevalence, diagnosis, and treatment of oral manifestations in chronic graft-versus-host disease (cGVHD), which is a major late complication in patients treated by allogeneic hematopoietic stem cell transplantation. We assess current general knowledge of systemic and oral cGVHD and present general treatment recommendations based on literature review and our clinical experience. Additionally, we review areas where the understanding of oral cGVHD could be improved by further research and address tools with which to accomplish the long-term goal of providing better health and quality of life to patients with cGVHD.

Clinical evidence of a graft-versus-lymphoma effect against relapsed diffuse large B-cell lymphoma after allogeneic hematopoietic stem-cell transplantation.

BACKGROUND: A graft-versus-lymphoma effect against diffuse large B-cell lymphoma (DLBCL) is inferred by sustained relapse-free survival after allogeneic stem-cell transplantation; however, there are limited data on a direct graft-versus-lymphoma effect against DLBCL following immunotherapeutic intervention by either withdrawal of immunosuppression or donor lymphocyte infusion (DLI). MATERIALS AND METHODS: An analysis was carried out to determine whether a direct graft-versus-lymphoma effect exists against DLBCL. The analysis was restricted to patients with DLBCL, who were either not in complete remission at day +100 after allogeneic stem-cell transplantation or subsequently relapsed beyond this time point. RESULTS: Fifteen patients were identified as either not in complete remission (n = 13) at their day +100 evaluation or subsequently relapsed (n = 2) and were assessed for subsequent responses after withdrawal of immunosuppression or DLI. Eleven patients were treated with either withdrawal of immunosuppression (n = 10) or a DLI (n = 1) alone; four patients received chemotherapy with DLI to reduce tumor bulk. Nine (60%) patients subsequently responded (complete = 8, partial = 1). Six responses occurred after withdrawal of immunosuppression alone. Six patients are alive (range 42-83+ months) in complete remission without further treatment. CONCLUSION: The demonstration of sustained complete remission following immunotherapeutic intervention provides direct evidence of a graft-versus-lymphoma effect against DLBCL.

Chronic graft-versus-host disease in the era of reduced-intensity conditioning.

In the past decade the field of hematopoietic stem cell transplantation has entered a new era with the introduction of reduced intensity conditioning (RIC) regimens. The impact of RIC on the incidence of chronic graft-versus-host disease (GVHD) has not been evaluated systematically. Factors confounding such analyses include short follow-up in studies, absence of prospective comparison trials, use of a variety of RIC regimens, lack of uniform GVHD prophylaxis and lack of rigorous criteria for the diagnosis and staging of chronic GVHD. This review discusses factors that appear to influence the incidence and clinical presentation of chronic GVHD in the RIC transplantation era. Overall, RIC seems to decrease the incidence and severity of acute GVHD through day 100 post-transplant when compared to conventional conditioning; however, there is little evidence to suggest that chronic GVHD is reduced after RIC. For the more definitive assessments of chronic GVHD after RIC it will be important to study this question in prospective comparison trials with long duration of follow-up. The recent National Institutes of Health chronic GVHD consensus project recommendations provide now the critically needed standardized guidelines for the diagnosis, classification and staging of chronic GVHD.

Novel targets in the treatment of chronic graft-versus-host disease.

Despite advances that have improved survival after allogeneic hematopoietic stem cell transplantation (HCT), chronic graft-versus-host disease (GVHD) remains a leading cause of late morbidity and mortality after transplant. Current treatment options show limited efficacy in steroid-refractory disease, and there exists a paucity of robust data to guide management decisions. Lack of United States Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-approved agents in GVHD underscore the importance of developing novel therapies. Better understanding of the biology of chronic GVHD has provided novel targets for treatment, and structured guidelines in diagnosis and in clinical trial design have provided a common language and pathways for research in this area. These, combined with the surge of drug development in Oncology and Immunology, are factors that have contributed to the accelerating field of drug development and clinical research in chronic GVHD. In these exciting times, it is possible to foresee long awaited advances in the treatment of this devastating complication of HCT. This review will summarize the ongoing clinical development for novel therapies in chronic GVHD.

Chronic graft-versus-host disease: implications of the National Institutes of Health consensus development project on criteria for clinical trials.

Chronic graft-versus-host disease (GVHD) has been a difficult problem to address and clinical research in this area lags behind other innovations in hematopoietic stem cell transplantation (HCT). Recently the international transplant community has focused more on chronic GVHD. This new focus is well represented by the development of the National Institutes of Health sponsored chronic GVHD consensus project, which has unified the transplant community's approach to chronic GVHD through the activities of focused working groups. From December 2005 through May 2006, a series of consensus documents have been published addressing the areas of diagnosis and staging, histopathology, strategies for the development and validation of biomarkers, response criteria, ancillary therapy and supportive care and the design of clinical trials. This paper summarizes and discusses these reports, focusing specifically on diagnosis and scoring and response criteria. Although these documents represent a huge effort by the research community, they must be prospectively implemented and validated. These new criteria should advance the standards and uniformity of chronic GVHD clinical research. The ultimate success of this project is dependent on whether these recommendations move the field forward. This is an opportunity for the transplant community to unite and make a significant impact in chronic GVHD.

Prevalence and determinants of fatigue in patients with moderate to severe chronic GvHD.

Although fatigue is common after allogeneic hematopoietic cell transplantation, little is known about fatigue in patients with chronic GvHD (cGvHD). The aim of this study was to explore factors associated with fatigue in cGvHD. Data were drawn from a sequentially recruited, cross-sectional study of adults with moderate or severe cGvHD (n=263). Respondents were classified as fatigued or not fatigued based on their response to a single item regarding loss of energy from the Lee cGvHD Symptom Scale. In univariate analysis, factors significantly associated with fatigue included performance status, number of prior cGvHD therapies, cGvHD symptom bother, self-assessed physical and mental health, nutritional status, walk velocity and self-reported physical activity. There were no significant associations between fatigue and disease-related cGvHD variables. Multivariable logistic regression demonstrated that being less active and having pulmonary and/or muscle/joint symptoms were independently associated with fatigue. In conclusion, clinically significant fatigue was prevalent in more than one-third of subjects with cGvHD, and was disabling. Absence of association with measures of cGvHD severity underscores the need to elucidate the pathogenesis of fatigue and its relationship with inflammatory activity. Pulmonary and muscle/joint symptoms and physical inactivity represent potential targets for intervention in clinical studies.

Oral disease profiles in chronic graft versus host disease.

At least half of patients with chronic graft-versus-host-disease (cGVHD), the leading cause of morbidity and non-relapse mortality after allogeneic stem cell transplantation, have oral manifestations: mucosal lesions, salivary dysfunction, and limited mouth-opening. cGVHD may manifest in a single organ or affect multiple organ systems, including the mouth, eyes, and the skin. The interrelationship of the 3 oral manifestations of cGVHD with each other and with the specific manifestations of extraoral cGVHD has not been studied. In this analysis, we explored, in a large group of patients with cGVHD, the potential associations between: (1) oral mucosal disease and erythematous skin disease, (2) salivary gland dysfunction and lacrimal gland dysfunction, and (3) limited mouth-opening and sclerotic skin cGVHD. Study participants, enrolled in a cGVHD Natural History Protocol (NCT00331968, n = 212), underwent an oral examination evaluating: (1) mucosal cGVHD [NIH Oral Mucosal Score (OMS)], (2) salivary dysfunction (saliva flow and xerostomia), and (3) maximum mouth-opening measurement. Parameters for dysfunction (OMS > 2, saliva flow ≤ 1 mL/5 min, mouth-opening ≤ 35 mm) were analyzed for association with skin cGVHD involvement (erythema and sclerosis, skin symptoms), lacrimal dysfunction (Schirmer's tear test, xerophthalmia), Lee cGVHD Symptom Scores, and NIH organ scores. Oral mucosal disease (31% prevalence) was associated with skin erythema (P < 0.001); salivary dysfunction (11% prevalence) was associated with lacrimal dysfunction (P = 0.010) and xerostomia with xerophthalmia (r = 0.32, P = 0.001); and limited mouth-opening (17% prevalence) was associated with skin sclerosis (P = 0.008) and skin symptoms (P = 0.001). There was no association found among these 3 oral cGVHD manifestations. This analysis supports the understanding of oral cGVHD as 3 distinct diseases: mucosal lesions, salivary gland dysfunction, and mouth sclerosis. Clear classification of oral cGVHD as 3 separate manifestations will improve clinical diagnosis, observational research data collection, and the definitions of outcome measures in clinical trials.

Pseudoautologous blood stem cell transplantation for refractory chronic graft-versus-host disease.

A female patient with AML received an allogeneic BMT from her brother. She experienced two relapses managed with chemotherapy and donor leukocyte infusions. The patient subsequently developed extensive therapy-refractory chronic GVHD. Pseudoautologous blood stem cell transplantation was performed as a salvage treatment for chronic GVHD. Her blood stem cells were easily mobilized with cyclophosphamide and G-CSF. The conditioning regimen was well tolerated and consisted of 200 mg/kg cyclophosphamide and horse-derived antithymocyte globulin. A total of 4.03 x 10(6)/kg CD34+ cells were infused and hematological recovery was rapid. Chronic GVHD improved with the ability to taper steroids. Nine months post transplantation the patient died from leukemia.

Organ dysfunction following stem cell transplantation: relationship to plasma cytokine concentrations.

Patients receiving high-dose preparation for stem cell transplantation are at risk for organ dysfunction (OD). Signs of early OD include hypoxia, mental status changes, and liver dysfunction. These early signs have not been correlated with potential cytokine mediators. We compared plasma concentrations of IL-6, TNF-alpha, and IL-10 in OD patients and controls. Cytokines were measured before preparation, 5 days before OD, day of OD, and 5 days after OD. TNF-alpha and IL-10 were not measurable prior to preparation. IL-10 was more likely to be measurable in OD patients than in controls 5 days prior to onset of OD (P = 0.039), on the day of OD (P = 0.023), and 5 days later (P < 0.0001). TNF-alpha was more likely to be measurable only on the day of OD (P = 0.0035). IL-6 was significantly elevated in OD patients at all time points. Patients who had measurable IL-6 on admission were 5.1 times more likely to develop OD (95% CI = 1.4-17.9; P = 0.011). Five days prior to OD for each 100 pg/ml increase in IL-6, patients were 2.75 times more likely to develop OD (95% CI = 1.3-5.8; P = 0.0087). The early elevation of IL-6 in patients who develop OD may help identify a high risk group where preventive therapies can be evaluated.

Topical corticosteroid therapy for cicatricial conjunctivitis associated with chronic graft-versus-host disease.

A retrospective chart review was performed on seven patients treated with topical ocular corticosteroid therapy for progressive cicatricial conjunctivitis associated with chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. A clinical grading criteria for conjunctival GVHD based on the degree of cicatrization was developed and patients graded prior to therapy. During the treatment course, the dose and frequency of topical corticosteroids and clinical outcomes were recorded. A complete response was defined as a complete resolution of the conjunctival hyperemia with either total resolution of the conjunctival fibrovascularization or presence of inactive conjunctival scarring. Prednisolone acetate 1% eye drops were used in a total of eight courses of therapy in seven patients. A complete response was documented in all seven patients with a total treatment duration of 7 weeks (median, range: 3-16 weeks). Additional studies are required to determine the long-term safety and efficacy of topical corticosteroids for cicatricial conjunctivitis associated with ocular GVHD in the context of a randomized, prospective clinical trial.

Intensive immunoablation and autologous blood stem cell transplantation in patients with refractory rheumatoid arthritis: the University of Nebraska experience.

Two patients with severe rheumatoid arthritis (RA) were treated with high dose chemotherapy and autologous blood stem cell transplantation. Hematopoietic stem cells mobilized readily with cyclophosphamide and granulocyte-colony stimulating factor. Both patients achieved an American College of Rheumatology (ACR) 50% response before starting high dose therapy. The transplantation regimen included 200 mg/kg cyclophosphamide and 6 doses of equine antithymocyte globulin. Transplantation was well tolerated and both patients recovered neutrophils on day 7 post-transplant. At one month post-transplant both patients had an ACR response of 80%. Both individuals relapsed at 6 months and responded well to a combination of disease modifying antirheumatic drugs that was previously ineffective. At 12 months ACR responses were 80% and 60%, respectively. The first patient developed a flare at 18 months when she was found to be hypothyroid; she regained an 80% ACR response at 24 months with therapy of hypothyroidism. The second patient progressed relentlessly 15 months post-transplant. Immunological reconstitution showed a continuous inversion of the ratio of CD4 and CD8 lymphocytes with a predominant expansion of memory T cells.

Treatment of relapse after autologous blood stem cell transplantation for severe rheumatoid arthritis.

There is little information about the clinical course of patients with rheumatoid arthritis (RA) who relapse after autologous blood stem cell transplantation (ASCT). We describe 6 patients with severe RA who received ASCT in 3 US centers. Duration of followup was between 24 and 42 months posttransplant. Five patients achieved major responses but relapsed 3-22 months posttransplant. Two patients with relapse improved remarkably after restarting disease modifying antirheumatic drugs (DMARD). Two patients developed a mild RA flare at 3 and 5 months posttransplant and improved spontaneously. All 4 patients who improved after an initial disease flare remained highly functional at 14-22 months posttransplant. All patients in this study were anti-tumor necrosis factor (TNF) drug naive; all received a TNF blocker as a second line posttransplant salvage therapy, but only 3 responded. Future ASCT strategies need to focus on improving the durability of the early posttransplant responses.

Comparative analysis of FoxP3(+) regulatory T cells in the target tissues and blood in chronic graft versus host disease.

Activation and migration of regulatory T cells (Treg) into tissue is critical in control of inflammation, but has not been examined extensively in chronic graft versus host disease (cGVHD). In parallel studies of tissues and blood, we determined that FoxP3(+) T cells increased in proportion to T effectors (Teff) in tissue infiltrates in oral and cutaneous lichenoid cGVHD. These FoxP3(+) cells expressed distinguishing phenotypic and functional markers of Treg (CD3(+), CD4(+), CD27(+), ICOS(+) and CD39(+)), not found on FoxP3(-) Teff. Both Teff and FoxP3(+) Treg expressed T-bet and the chemokine receptor CXCR3, however, consistent with a common mechanism of chemokine-mediated migration into tissue. Furthermore, functional markers (ICOS and CD39) and chemokine receptors (CXCR3) were both present in a higher proportion of FoxP3(+) cells in tissues than in peripheral blood, consistent with recruitment and activation of Treg in cGVHD target tissues. Finally, the 'activated' CD45RA(-)FoxP3(hi) subset of Treg cells, which highly express functional markers, were found in comparable frequencies in cGVHD patients and normal controls, despite a significant deficit in naive 'resting' Treg. These findings are consistent with Treg capacity to upregulate functional markers and traffick into tissue in cGVHD.

Uptake and use of recommendations for the diagnosis, severity scoring and management of chronic GVHD: an international survey of the EBMT-NCI Chronic GVHD Task Force.

In 2005, the National Institutes of Health (NIH) consensus conference published a series of papers recommending methods to improve the conduct of clinical trials in chronic GVHD. Although the NIH recommendations were primarily aimed at strengthening research, several papers addressed issues relevant for clinical practice, particularly diagnosis, severity scoring, and ancillary and supportive care practices. We conducted an international survey to assess the uptake of these recommendations, identify barriers to greater use and document the use and perceived effectiveness of available treatments. The response rate for the American survey of 1387 practitioners was 21.8%, and it was 24.6% for 407 centers surveyed in Europe, Asia, Australia and Africa. Most respondents were familiar with the NIH consensus recommendations (94-96%) and used them in practice. Multiple barriers to greater use were reported. Besides lack of time (55-62%), unfamiliarity with the recommendations, scarcity of evidence supporting the impact of recommendations on outcomes, insufficient training/experience in chronic GVHD management and inaccessibility of subspecialists were also endorsed. Systemic corticosteroids were reported to be the most effective treatment for chronic GVHD, but many others were perceived to have moderate or great success. Therapeutic management of steroid-refractory chronic GVHD was identified as the highest priority for research.

Validation of the National Institutes of Health chronic GVHD Oral Mucosal Score using component-specific measures.

Oral chronic GVHD (cGVHD) is a common, late complication of alloSCT that is associated with significant patient morbidity. The NIH Oral Mucosal Score (NIH OMS) was developed to assess oral cGVHD therapeutic response, but has not been fully validated. This study's purpose was to conduct a rigorous construct validity and internal consistency analysis of this score and its components (erythema, lichenoid, ulcers, mucoceles) using established measures of oral pain, oral function, oral-related quality-of-life, nutrition and laboratory parameters in 198 patients with cGVHD. The construct validity of the NIH OMS was supported: a moderate correlation was observed between NIH OMS and mouth pain (rho=0.43), while a weaker correlation was observed with low albumin (rho=-0.26). Total NIH OMS, erythema and lichenoid components were associated with malnutrition, oral pain and impaired oral QOL, while ulcers were only associated with oral pain. No associations were found between mucoceles and any indicator evaluated, including salivary function or xerostomia. Kappa determined between scale components was low overall (all 0.35), supporting a conclusion that each component measures a distinct manifestation of oral cGVHD. This study supports the use of the NIH OMS and its components (erythema, lichenoid and ulcerations) to measure clinician-reported severity of oral cGVHD.

Investigator feedback about the 2005 NIH diagnostic and scoring criteria for chronic GVHD.

The 2005 National Institutes of Health (NIH) consensus criteria for chronic GVHD have set standards for reporting. Many questions, however, have arisen regarding their implementation and utilization. To identify perceived areas of controversy, we conducted an international survey on diagnosis and scoring of chronic GVHD. Agreement was observed for 50-83% of the 72 questions in 7 topic areas. There was agreement on the need for modifying criteria in six situations: two or more distinctive manifestations should be enough to diagnose chronic GVHD; symptoms that are not due to chronic GVHD should be scored differently; active disease and fixed deficits should be distinguished; a minimum threshold body surface area of hidebound skin involvement should be required for a skin score of 3; asymptomatic oral lichenoid changes should be considered a score 1; and lung biopsy should be unnecessary to diagnose chronic GVHD in a patient with bronchiolitis obliterans as the only manifestation. The survey also identified 26 points of controversy. Whenever possible, studies should be conducted to confirm the appropriateness of any revisions. In cases where data are not available, clarification of the NIH recommendations by consensus is necessary. This survey should inform future research in the field and revisions of the current consensus criteria.

Malnutrition in patients with chronic GVHD.

Malnutrition is a known complication of chronic GVHD (cGVHD), but has not been well described in the context of organ-specific manifestations and the recent National Institutes of Health (NIH) criteria. Here, 210 cGVHD patients were analyzed, in a cross-sectional study design, for demographics, transplant-related history, clinical assessments, symptoms, function, quality-of-life, laboratory values and survival in order to determine their associations with nutritional status. Most patients had long-standing, moderate or severe cGVHD and had failed many lines of therapy. Twenty-nine percent (60/210) of subjects were malnourished, using the subjective Patient-Generated Subjective Global Assessment (PG-SGA) questionnaire and evaluation. No demographic or transplant characteristics were associated with malnutrition; cGVHD of the lungs, gastrointestinal (GI) tract and mouth, NIH global score, cGVHD symptoms, worse functioning, low albumin, poorer survival and low BMI were associated with malnutrition. A predictive model was developed from all variables of significance: cGVHD of the lungs, GI tract, mouth and BMI accurately predicted 84.2% of malnourished patients as well as 87.2% of well-nourished patients. The PG-SGA questionnaire may be a useful tool in diagnosing nutritional deficits in cGVHD patients undergoing one-time evaluations. Longitudinal prospective studies should assess the utility of nutritional support interventions in cGVHD.

NHANES III equations enhance early detection and mortality prediction of bronchiolitis obliterans syndrome after hematopoietic SCT.

Bronchiolitis obliterans syndrome (BOS) is a serious complication of chronic GVHD (cGVHD) following HSCT (hematopoietic SCT). The clinical diagnosis of BOS is based on pulmonary function test (PFT) abnormalities including: FEV1<75% predicted and obstructive FEV1/VC ratio, calculated using reference equations. We sought to determine if the frequency of clinical diagnoses and severity of BOS would be altered by using the recommended NHANES III vs older equations (Morris/Goldman/Bates, MGB) in 166 cGVHD patients, median age 48 (range: 12-67). We found that NHANES III equations significantly increased the prevalence of BOS, with an additional 11% (18/166) meeting diagnostic criteria by revealing low FEV1 (<75%) (P<0.0001), and six additional patients by obstructive ratio (vs MBG). Collectively, this led to an increase of BOS incidence from 17 (29/166) to 29% (41/166). For patients with severe BOS, (FEV1<35%), NHANES III equations correctly predicted death 71.4% vs 50% using MGB. In conclusion, the use of NHANES III equations markedly increases the proportion of cases meeting diagnostic criteria for BOS and improves prediction of survival.

NIH response criteria measures are associated with important parameters of disease severity in patients with chronic GVHD.

Lack of standardized criteria measuring therapeutic response remains an obstacle to the development of better treatments for chronic GVHD (cGVHD). This cross-sectional prospective study examined the concurrent and predictive validity of 18 clinician-reported ('Form A') and 8 patient-reported ('Form B') response measures proposed by NIH criteria. Concurrent parameters of interest were NIH global score, cGVHD activity, Lee symptom score and SF36 PCS. Patient cohort included 193 adults with moderate-to-severe cGVHD. Measures associated with the highest number of outcomes were lung function score (LFS), 2-min walk, grip strength, 4-point health-care provider (HCP) and patient global scores, 11-point clinician- and patient-reported global symptom severity scores, and Karnofsky performance score (KPS). Measures associated with survival in univariate analyses led to a Cox model containing skin erythema, LFS, KPS, eosinophil count and interval from cGVHD diagnosis to enrollment as jointly associated with survival. In conclusion, 4-point HCP and patient global scores and 11-point clinician- and patient-reported global symptom severity scores are associated with the majority of concurrent outcomes. Skin erythema is a potentially reversible sign of cGVHD that is associated with survival. These results define a subset of measures that should be prioritized for evaluation in future studies.

Active thrombopoiesis is associated with worse severity and activity of chronic GVHD.

Chronic GVHD (cGVHD) is a major complication of allogeneic hematopoietic SCT. Post transplant thrombocytopenia in patients with cGVHD has been associated with poor outcome and its etiology is unclear. We investigated whether thrombopoiesis, assessed via measurement of the absolute immature platelet number (AIPN) in the blood, is impaired in cGVHD, and whether the level of thrombopoiesis correlates with the severity and activity of cGVHD as assessed via the National Institutes of Health (NIH) organ scoring system. We used a cohort of 110 well-characterized cGVHD patients, including 83 (75%) with severe cGVHD per NIH global score. Higher AIPN was associated with active therapeutic intent (P=0.026), lower Karnofsky score (P=0.0013), worse joint/fascia cGVHD (P=0.0005) and worse skin cGVHD (P=0.0044). AIPN correlated with platelet counts and was not correlated with ANC, WBC, C-reactive protein (CRP), absolute lymphocyte count (ALC), albumin, total and average NIH scores, or number of prior systemic therapies. AIPN values for cGVHD patients substantially overlapped those of the normal population. Higher AIPN, as marker of active thrombopoiesisis, was associated with worse severity and activity of cGVHD, especially skin and joints/fascia manifestations. Among patients with stable moderate or severe cGVHD, there was no evidence of hypoproduction of platelets. Future studies should further investigate the role of thrombopoiesis in cGVHD.