Biomarkers in chronic graft-versus-host disease: quo vadis?

Biomarkers are increasingly used for diagnosis and treatment of transplant-related complications including the first biomarker-driven interventional trials of acute graft-versus-host disease (GvHD). In contrast, the development of biomarkers of chronic GvHD (cGvHD) has lagged behind due to a broader variety of manifestations, overlap with acute GvHD, a greater variation in time to onset and maximum severity, and lack of sufficient patient numbers within prospective trials. An international workshop organized by a North-American and European consortium was held in Marseille in March 2017 with the goal to discuss strategies for future biomarker development to guide cGvHD therapy. As a result of this meeting, two areas were prioritized: the development of prognostic biomarkers for subsequent onset of moderate/severe cGvHD, and in parallel, the development of qualified clinical-grade assays for biomarker quantification. The most promising prognostic serum biomarkers are CXCL9, ST2, matrix metalloproteinase-3, osteopontin, CXCL10, CXCL11, and CD163. Urine-proteomics and cellular subsets (CD4+ T-cell subsets, NK cell subsets, and CD19+CD21low B cells) represent additional potential prognostic biomarkers of cGvHD. A joint effort is required to verify the results of numerous exploratory trials before any of the potential candidates is ready for validation and subsequent clinical application.

Conditioning regimens for allogeneic hematopoietic stem cell transplants in acute myeloid leukemia.

AML is currently the first indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT), as shown by international transplant registries. The conditioning regimens are classified as myeloablative conditioning, non-myeloablative or reduced intensity conditioning. Targeted radioimmunotherapy such as anti-CD45 antibody have also been added to the conditioning regimen in an attempt to improve tumor cell kill. Refinement of standard regimens has led to a reduction of non-relapse mortality, also in the older age group over 60 or 70 years of age. Relapse post allo-HSCT remains an important issue, especially for patients who undergo transplant with residual or refractory disease. In these patients, pre- and post-transplant interventions need to be considered.

A multicenter trial of myeloablative clofarabine and busulfan conditioning for relapsed or primary induction failure AML not in remission at the time of allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission. Seventy-one patients (median age: 56 years) received CloBu4. At day 30 after HCT, 90% achieved morphologic remission. The incidence of non-relapse mortality and relapse at 2 years was 25% and 55%, respectively. The 2-year overall survival (OS) and event-free survival (EFS) were 26% and 20%, respectively. Patients entering HCT in PIF had significantly greater EFS than those in relapse (34% vs 8%; P<0.01). Multivariate analysis comparing CloBu4 with a contemporaneous cohort (Center for International Blood and Marrow Transplantation Research) of AML not in remission receiving other myeloablative conditioning (n=105) demonstrated similar OS (HR: 1.33, 95% confidence interval: 0.92-1.92; P=0.12). HCT with myeloablative CloBu4 is associated with high early response rates and may produce durable remissions in select patients with AML not in remission.

Next-generation long-term transplant clinics: improving resource utilization and the quality of care through health information technology.

By the year 2020, potentially one-half a million hematopoietic cell transplant (HCT) recipients will need long-term follow-up care to address not only chronic GvHD but also multiple other late consequences of transplant. Despite this increase in patients, there will not be a concomitant increase in the HCT workforce. Thus, the future of long-term patient management will require a new 'next-generation' clinical model that utilizes technological solutions to make the care of the HCT patient efficient, safe and cost-effective. Guideline-based decision support will be embedded in clinical workflows. Documentation requirements will be reduced as automated data collection from electronic medical records (EMRs) will populate registries and provide feedback for a rapid learning health system. Interoperable EMRs will disseminate treatment protocols to multiple care providers in a distributed long-term clinic model, such that providers outside of the transplant center can provide services closer to the patient. Patients will increase their participatory role through patient portals and mobile devices. At Vanderbilt, we have responded to some of these future challenges by embedding guideline-based decision support, structuring clinical documentation and being early adopters of communication technology. This manuscript describes the current state of some of these innovations, and a vision for the future of the long-term transplant clinic.

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.

Six-month freedom from treatment failure is an important end point for acute GVHD clinical trials.

We studied the American Society for Blood and Marrow Transplantation (ASBMT) 6-month (m) freedom from treatment failure (FFTF) as a predictor of survival for patients with acute GVHD (aGVHD) requiring treatment. Adult patients undergoing allogeneic hematopoietic cell transplant (HCT) from February 2007 to March 2009 who were enrolled in a prospective biomarker clinical trial and developed aGVHD requiring systemic corticosteroids by day +100 were included (N=44). Six-month FFTF was defined as per the ASBMT guidelines (absence of death, malignancy relapse/progression or systemic immunosuppression change within 6 months of starting steroids and before chronic GVHD development). aGVHD was treated with systemic corticosteroids in 44 patients. Day 28 response after steroid initiation (complete response+very good partial response+partial response) occurred in 38 (87%) patients, but only 28 (64%) HCT recipients met the 6-m FFTF end point. Day 28 response predicted 6-m FFTF. Achieving 6-m FFTF was associated with improved 2-year (y) OS (81% vs 48%; P=0.03) and decreased 2-y non-relapse mortality (8% vs 49%; P=0.01). In multivariate analysis, 6-m FFTF continued to predict improved OS (hazard ratio, 0.27; P=0.03). The 6-m FFTF end point measures fixed outcomes, predicts long-term therapeutic success and could be less prone to measurement error than aGVHD clinical response at day 28.

Comorbidity burden in patients with chronic GVHD.

Chronic GVHD (cGVHD) is associated with mortality, disability and impaired quality of life. Understanding the role of comorbidity in patients with cGVHD is important both for prognostication and potentially for tailoring treatments based on mortality risks. In a prospective cohort study of patients with cGVHD (n=239), we examined the performance of two comorbidity scales, the Functional Comorbidity Index (FCI) and the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). Both scales detected a higher number of comorbidities at cGVHD cohort enrollment than pre-hematopoietic cell transplant (HCT) (P<0.001). Higher HCT-CI scores at the time of cGVHD cohort enrollment were associated with higher non-relapse mortality (HR: 1.21:1.04-1.42, P=0.01). For overall mortality, we detected an interaction with platelet count. Higher HCT-CI scores at enrollment were associated with an increased risk of overall mortality when the platelet count was ≤ 100,000/µL (HR: 2.01:1.20-3.35, P=0.01), but not when it was >100,000/µL (HR: 1.05:0.90-1.22, P=0.53). Comorbidity scoring may help better to predict survival outcomes in patients with cGVHD. Further studies to understand vulnerability unrelated to cGVHD activity in this patient population are needed.

Measurement of oral chronic GVHD: results from the Chronic GVHD Consortium.

Oral chronic GVHD (cGVHD) is a serious complication of alloSCT. Scales and instruments to measure oral cGVHD activity and severity have not been prospectively validated. The objective of this study was to describe the characteristics of oral cGVHD and determine the measures most sensitive to change. Patients enrolled in the cGVHD Consortium with oral involvement were included. Clinicians scored oral changes according to the National Institutes of Health (NIH) criteria, and patients completed symptom and quality-of-life measures at each visit. Both rated change on an eight-point scale. Of the 458 participants, 72% (n=331) had objective oral involvement at enrollment. Lichenoid change was the most common feature (n=293; 89%). At visits where oral change could be assessed, 50% of clinicians and 56% of patients reported improvement, with worsening reported in 4-5% for both the groups (weighted kappa=0.41). Multivariable regression modeling suggested that the measurement changes most predictive of perceived change by clinicians and patients were erythema and lichenoid, NIH severity and symptom scores. Oral cGVHD is common and associated with a range of signs and symptoms. Measurement of erythema and lichenoid changes and symptoms may adequately capture the activity of oral cGVHD in clinical trials but require prospective validation.

Long-term follow-up of informal caregivers after allo-SCT: a systematic review.

Currently, more than 40000 patients undergo allogeneic hematopoietic SCT (HSCT) annually throughout the world, and the numbers are increasing rapidly. Long-term survival after allogeneic-HSCT (allo-HSCT) has also improved significantly since its inception over 40 years ago due to improved supportive care and early recognition of long-term complications. In long-term follow-up after transplantation, the focus of care moves beyond cure of the original disease to late effects and quality of life. Nearly one-fourth of the long-term survivors are likely to have chronic consequences of HSCT, which require frequent help by caregivers, particularly informal caregivers such as spouses, partners or children. The physical and psychosocial consequences for patients undergoing HSCT have been extensively reported. There has, however, been far less investigation into the long-term follow-up of caregivers of HSCT recipients. This article provides an overview on addressing caregiver issues after HSCT. The rapidly growing population of long-term HSCT survivors creates an obligation not only to educate patients and physicians about the late complications observed in patients but also to follow up caregivers for their psychosocial support needs.

Expression of α4ß7 integrin on memory CD8(+) T cells at the presentation of acute intestinal GVHD.

Acute intestinal GVHD remains a major source of morbidity after allogeneic hematopoietic cell transplantation (HCT). α4ß7 integrin is a cell surface molecule that mediates lymphocyte trafficking to intestinal tissue. In this analysis, peripheral blood was collected at the time of presentation of symptoms of acute GVHD and before any treatment. In all, 45 samples were collected and divided into three groups on the basis of subsequent evaluation: intestinal GVHD (n=15), skin GVHD (n=20) and no GVHD (n=10). Two patients developed intestinal GVHD after DLI. The no-GVHD group comprised 10 patients who presented with suspicious symptoms, but evaluation yielded other etiologies. Analysis by flow cytometry showed that intestinal GVHD patients had a significantly higher percentage of α4ß7 integrin-expressing memory CD8(+) T cells (median 7.69%; lower and upper quartiles, 1.06% and 11.64%, respectively) compared with patients with skin GVHD (1.26%; 0.57% and 2.49%) and no GVHD (0.96%; 0.44% and 1.85%), P=0.03. No differences were found in α4ß7 expression in any CD4(+) T-cell subsets or naive CD8(+) T cells. This study adds to the evidence that α4ß7 integrin is involved in lymphocyte trafficking in acute intestinal GVHD.

Allo-SCT for high-risk AML-CR1 in the molecular era: impact of FLT3/ITD outweighs the conventional markers.

Seventy-nine patients with AML in CR1 received allo-SCT between May 2006 and May 2011, and the prognostic impact of FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) mutation was evaluated in the context of other clinical prognostic factors. Patients with FLT3/ITD + AML had significantly inferior DFS (2-year DFS: 19% vs 64%, P = 0.0027), increased risk of relapse (1-year: 59% vs 19%, P = 0.01), and a trend towards decreased OS (P = 0.08) compared with patients without FLT3/ITD. Multivariate analysis confirmed FLT3/ITD + independently predicted a shorter DFS (HR, 3.0; 95% CI), 1.4-6.5; P = 0.01) and increased risk of relapse (HR, 4.9; 95% CI, 2.0-12.3, P = 0.01). Time to relapse in patients with FLT3/ITD + was short with 100-day cumulative risk of 45% (95% CI, 33-57). Our data suggest that the poor prognostic implication of FLT3/ITD positivity remains even after early allo-SCT in patients with FLT3/ITD + AML, and patients remain at high risk of early relapse. FLT3/ITD positivity also outweighs other conventional prognostic markers in predicting relapse.

Prevalence and risk factors associated with development of ocular GVHD defined by NIH consensus criteria.

We studied 172 patients for development of ocular graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT) from 2002 to 2009. Ocular GVHD was diagnosed in 60 patients (38%), with 27 (16%) being diagnosed at days 100 and 33 (23%) beyond day 100 for a 2-year cumulative incidence of 35% (95% confidence interval (CI), 28-43). The positive and negative predictive values of a Schirmer I test score (using 5 mm as a cutoff) in predicting ocular GVHD (day 100) were 41 and 82%, respectively. In patients with ocular GVHD beyond day 100, extraocular manifestations of GVHD preceded the development of ocular GVHD in most patients (27 of 33, 81%). Prior acute skin GVHD (odds ratio 2.57, 95% CI 1.17-5.64, P=0.019) and male recipients of female donors (odds ratio 2.57, 95% CI 1.09-6.06, P=0.03) were independent risk factors for ocular GVHD. We recommend comprehensive ocular evaluation rather than a screening Schirmer's test to establish the diagnosis of ocular GVHD. Early diagnosis and preventive strategies in high-risk populations need to be studied in clinical trials to prevent devastating impact on quality of life in patients with prolonged ocular GVHD.

Palifermin for the reduction of acute GVHD: a randomized, double-blind, placebo-controlled trial.

This prospective, randomized, double-blind, placebo-controlled study evaluated the efficacy of palifermin to reduce the incidence of severe (grade 3-4) acute GVHD after myeloablation and allo-SCT. Adults who received allo-SCT for hematologic malignancies received placebo or palifermin 60 µg/kg daily on three consecutive days before conditioning and a single dose of 180 µg/kg after conditioning, but often 1 or 2 days before allo-SCT. Subjects received MTX (plus CYA or tacrolimus) on days 1, 3, 6 and 11. Acute GVHD was evaluated once weekly and oral mucositis was evaluated daily. Subjects were randomly assigned to placebo (n=78) or palifermin (n=77). Conditioning included TBI in approximately half of the subjects (48% placebo, 51% palifermin). The primary efficacy end point, subject incidence of grade 3-4 acute GVHD, was similar between treatment groups (17% placebo, 16% palifermin). Grade 3-4 oral mucositis (73% placebo, 81% palifermin) and other secondary efficacy end points were similar between treatment groups. The most commonly reported treatment-related adverse events were skin/s.c. events such as rash, pruritus, and erythema. This exploratory study of acute GVHD after myeloablation and allo-SCT did not provide evidence of a treatment effect with this dosing regimen of palifermin.

Long-term outcome after autologous or allogeneic stem cell transplantation in patients with recurrent follicular lymphoma.

Thirty-five consecutive patients with follicular lymphoma (FL) receiving SCT at our institution between January 2000 and December 2010 were included in this study. At the time of presentation, 30 (86%) had advanced stage disease and 25 (71%) received three or more chemotherapy regimens prior to transplantation. In all, 12 (34%) patients were in complete response pre-SCT following salvage therapy. At the time of analysis (median follow-up 6 years from diagnosis and 4 years from transplantation), 24 patients were alive with an estimated 5-year OS and PFS of 66.5 and 53%, respectively. OS and PFS in patients receiving auto-SCT (91.7%, 73.3%) were superior compared with patients receiving allo-SCT (53.9%, 43%). Our data support early use of auto-SCT in patients with FL and suggest the need to improve allo-SCT outcome. Integrating novel agents in a combined modality approach may improve long-term outcome in FL.