Chronic graft-versus-host disease (GVHD) remains a serious complication after allogeneic hematopoietic stem cell transplantation (HCT). In 2005 the National Institutes of Health (NIH) established new criteria for chronic GVHD based on retrospective data and expert recommendations. We prospectively evaluated the incidence of NIH-defined chronic GVHD and its prognostic impact in 178 consecutive patients. The cumulative incidence of chronic GVHD at 3 years was 64, 48 and 16% for chronic classic GVHD and overlap syndrome. Prior acute GVHD and myeloablative conditioning were significantly associated with increased risk of chronic GVHD. Three-year survival (overall survival (OS)) for late-acute GVHD, chronic classic and overlap chronic GVHD when assigned on day 100 were 69, 83 and 73%. OS was significantly worse for patients with platelet counts below 100 g/l at onset of chronic GVHD (35% versus 86%, P<0.0001) and progressive as compared with de novo and quiescent onset of chronic GVHD (54.5% versus 89.5% versus 84%, P=0.022 and 0.001). Peak severity of chronic GVHD had no impact on non-relapse mortality (NRM) and OS. Recurrent acute GVHD, platelet counts below 100 g/l at diagnosis of chronic GVHD, progressive onset of chronic GVHD and advanced disease stage prior to HCT were significantly associated with increased NRM. This prospective analysis provides for the first-time data on the incidence rates of NIH-defined chronic GVHD categories and identified risk factors for the occurrence of chronic GVHD. A prognostic value of thrombocytopenia and progressive onset type of chronic GVHD for survival after HCT was observed in NIH-defined chronic GVHD.
Chronic graft-versus-host disease (GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (HCT), affecting up to 80% of patients otherwise cured of their underlying hematologic or oncologic disease.1, 2 Chronic GVHD substantially impairs patients’ quality of life and daily activities, and is the leading cause of late transplant-related mortality.3, 4 Affected patients can present a variety of clinical manifestations resembling autoimmune disorders.5 Historically, the presence of any symptoms of GVHD beyond 100 days after HCT was called chronic GVHD, even if the manifestations could not be distinguished from acute GVHD and chronic GVHD was stratified as limited and extensive.6, 7
In 2005 the National Institutes of Health (NIH) published consensus criteria for diagnosis, organ scoring and global assessment of chronic GVHD recommending the distinction of acute and chronic GVHD by clinical manifestations and not time after HCT.5 Furthermore, chronic GVHD was stratified into chronic classic GVHD presenting with manifestations that can be ascribed only to chronic GVHD and overlap syndrome that has diagnostic or distinctive chronic GVHD manifestations together with features typical of acute GVHD.5 Severity of chronic GVHD was graded by the NIH consensus according to number of organs involved and the degree of functional impairment in the affected organs.5 Currently, it is unclear whether pathophysiologic mechanisms involved in chronic classic GVHD differ from the ones leading to overlap syndrome.
As the proposed NIH criteria were based on expert opinion, retrospective analyses performed by several investigators assessed their validity.8, 9, 10, 11, 12 Reclassification of patients with GVHD beyond day 100 after HCT according to the NIH consensus criteria revealed persistent, recurrent or delayed (‘late’) acute GVHD in 9–37% of patients who historically would have been considered to have chronic GVHD.8, 9, 10, 11, 12 In three previous studies worse overall survival (OS) was observed in patients with late acute GVHD compared with those with NIH chronic GVHD,8, 10, 13 whereas in two others no statistically significant differences in OS were seen.9, 11 The discrepant results among these studies may be explained by inadequacies of medical records in documenting the presence or absence of diagnostic and distinctive manifestations of chronic GVHD according to NIH criteria. Therefore, prospective studies are needed to determine the impact of the NIH criteria on outcomes of patients with GVHD beyond day 100 after HCT. Furthermore, it is currently unclear whether survival rates are similar or different between the two newly defined subtypes of chronic GVHD. In addition, the impact of known risk factors such as progressive onset type of chronic GVHD and thrombocytopenia at diagnosis of chronic GVHD on survival and non-relapse mortality (NRM) has not been assessed yet in NIH-defined chronic GVHD.
Here, we present data on 178 patients transplanted at a single institution and prospectively assessed for presence or absence of chronic GVHD from day 100 after HCT. The aim of this study was to determine the incidence and outcomes of the various subtypes and severities of NIH-defined chronic GVHD and their impact on survival and NRM.
Materials and methods
Patients and trial conduct
Between June 2005 and October 2009 all consecutive patients given an allogeneic HCT at the Medical University of Vienna, Austria, and alive without malignant disease on day 101 after HCT were asked to participate in this study. Patients given a second allogeneic HCT, donor lymphocyte infusions or chemotherapy for a relapse after allogeneic HCT were excluded to constitute a homogenous cohort. Patients were censored prior to administration of donor lymphocyte infusions, post-transplant chemotherapy and second allogeneic HCT for relapse. Patients gave written informed consent in accordance with the Declaration of Helsinki. The study had the approval of the institutional review board of the Medical University of Vienna, Austria.
One-hundred seventy-eight patients with a median age of 40 (range, 20–65) years participated in the study and their characteristics are shown in Table 1.
During routine follow-up visits in the Outpatient Clinic of the BMT Unit of the Medical University of Vienna, Austria, patients were assessed for presence of chronic GVHD according to the NIH consensus recommendations,5 including physical exams; laboratory tests (complete blood counts and differential, liver and renal function tests); examination by an ophthalmologist in case of clinical complaints; gynecological examination in case of clinical complaints and examination by a dermatologist in case of skin manifestations among others. All patients had pulmonary function tests prior to start of conditioning therapy for allogeneic HCT, and starting on day 100 after HCT, every 3 months and in case of decrease of forced expiratory volume in 1 s (FEV1) >10% as compared with the value prior to HCT, a high-resolution CT scan of the lungs and bronchoalveolar lavage (BAL) with transbronchial biopsy were performed. In case of gastrointestinal symptoms, including weight loss, nausea, vomiting and diarrhea, endoscopic examinations of the gastrointestinal tract by biopsies and CT scan of the abdomen were performed.
All patients underwent HCT following standard of care or institutional review board-approved protocols. Myeloablative conditioning consisted in the vast majority of patients of cyclophosphamide at 120 mg/kg and total-body irradiation of 13.2 Gy. For dose-reduced conditioning, fludarabine-containing chemotherapy regimens were administered to 63 patients and fludarabine in combination with total-body irradiation of 2 Gy to five, respectively. Forty-one patients administered dose-reduced conditioning according to the FLAMSA protocol (fludarabine, cytarabine, amsacrine, total-body irradiation of 4 Gy and cyclophosphamide)14 received anti-thymocyte globulin on days −3 and −2 as part of their conditioning. Ten patients with Hodgkin's lymphoma were administered alemtuzumab as part of their dose-reduced conditioning regimen. Patients received a median of 6.6 (range, 1.33–14) × 106 CD34+ cells per kg body weight (b.w.) on day 0. Standard GVHD prophylaxis with either cyclosporine-A and methotrexate (MTX) after myeloablative conditioning, or cyclosporine-A with or without mycophenolate mofetil after dose-reduced conditioning, was used. All patients received antimicrobial and antifungal prophylaxis according to institutional guidelines. Patients were monitored for cytomegalovirus reactivation by PCR assays, and were treated preemptively with ganciclovir as described.15 After engraftment anti-infectious prophylaxes were administered to all patients as recommended.15
Diagnosis and treatment of acute and chronic GVHD
Acute GVHD was graded weekly until day 100 after HCT and thereafter every 2–3 weeks during routine controls in the Outpatient Clinic by using the modified Glucksberg criteria.16Acute GVHD was subdivided into classic acute GVHD occurring within 100 days of HCT, persistent (defined by features of unresolved acute GVHD beyond day 100 after HCT), recurrent (defined as recurrence of acute GVHD after day 100) and late-onset (defined by features of acute GVHD first observed after day 100). All patients with cutaneous manifestations of acute GVHD had skin biopsies confirming the diagnosis. All patients with persistent nausea and/or diarrhea had endoscopic examinations of the gastrointestinal tract, including biopsies to confirm the diagnosis of acute GVHD of the gut. Only patients with elevation of bilirubin levels were assigned to the category acute GVHD of the liver.
Treatment of acute GVHD grades II–IV consisted of methylprednisolone at 2 mg/kg b.w. for a minimum of 7 days followed by a taper every 5–7 days in responding patients. The vast majority of steroid-refractory acute GVHD patients were referred to extracorporeal photopheresis.
Chronic GVHD was graded according to the NIH consensus criteria and subdivided into chronic classic (defined as presence of chronic GVHD features alone) and overlap syndrome (defined as presence of features of both acute and chronic GVHD).5 Patients with maculopapular rash without lichenoid or sclerotic cutaneous manifestations and/or features of biopsy-proven acute GVHD of the gut were assigned to the category overlap syndrome of chronic GVHD when they had other diagnostic signs of chronic GVHD present in addition. Only esophageal web, strictures or stenosis in the esophagus, exocrine pancreatic insufficiency and chronic wasting syndrome were considered to be chronic classic GVHD of the gut. If patients had marked elevations of transaminases with or without cholestasis, with diagnostic signs of chronic GVHD, they were assigned to the category chronic classic GVHD. Pulmonary scoring of all patients was performed by using both the NIH symptom scale as well as pulmonary function tests, starting prior to conditioning for allogeneic HCT and repeating the tests from day 100 after HCT every 3 months for 2 years. Severity of lung involvement was graded according to the symptom scale and FEV1. In close cooperation with our pulmonary specialists, all other potential lung diseases, including infections, allergic reactions, cardiac diseases, infectious or allergic sinusitis, were excluded before the diagnosis of lung involvement by chronic GVHD was established. We used the following criteria for diagnosis of bronchiolitis obliterans syndrome: absence of infection, another chronic GVHD manifestation, FEV1 below 75% predicted or decline more than 10% compared with the value prior to HCT, and signs of obstruction (FEV1/FVC ratio below 0.7 or air trapping in high-resolution CT scan of the lung).
Quiescent onset of chronic GVHD was defined as absence of all symptoms of acute GVHD for at least 2 weeks and discontinuation of steroid therapy or steroid dose of 0.1–0.2 mg/kg b.w. (equaling 10–12 mg absolute dose of methylprednisolone) during taper of steroids for acute GVHD. Progressive onset of chronic GVHD was defined as presentation of diagnostic signs of chronic GVHD within 2 weeks of presence of symptoms of acute GVHD or therapy with steroids at doses above 0.5 mg/kg b.w. for treatment of acute GVHD.
After appropriate examinations diagnosis of chronic GVHD was established followed by assessment of severity of all organ manifestations and global severity scoring. Assessments for presence of chronic GVHD and its severity were repeated every 3 months or in case of change of immunosuppressive/immunomodulatory therapy, prior to therapeutic changes.
Patients with isolated oral, ocular or mild skin involvement by chronic GVHD were treated with topical immunosuppressants such as topical steroids. Patients with moderate or severe chronic GVHD received systemic immunosuppressive therapy except four patients with moderate chronic GVHD and high risk for relapse who were administered only topical therapies. First-line therapy for chronic GVHD consisted of methylprednisolone at 0.5–1 mg/kg b.w. in 20 patients, a calcineurin inhibitor plus steroids in 53, sirolimus plus steroids in 2, topical psoralen plus ultraviolet A irradiation plus steroids in 2, extracorporeal photopheresis plus steroids in 1 and extracorporeal photopheresis plus calcineurin inhibitor plus steroids in 16, respectively. Salvage therapy of steroid-refractory chronic GVHD patients included extracorporeal photopheresis, mycophenolate mofetil and other immunosuppressants.
The study was designed as a prospective cohort study including 178 patients who were followed longitudinally. Data were analyzed as of 1 September 2010. Fisher's exact test was used to examine the significance of the association between two variables. The events analyzed were calculated from the time of HCT by using Kaplan–Meier estimates. NRM was defined as any death in the absence of the underlying malignancy. Cumulative incidence of NRM was estimated by using the Kaplan–Meier method with adjustment for relapse as a competing risk event. Relapse was defined as recurrence of malignancy after achievement of complete remission or any progression of malignant disease. OS was calculated from day 0 of HCT to the day of death from any cause or last follow-up. Patients were censored at the date of last contact.
The subtype of GVHD was assessed at study entry around day 101 after allogeneic HCT, at onset of chronic GVHD and at peak severity. In case of transitions from late acute GVHD to chronic GVHD, a date of onset of chronic GVHD was assigned and the patient was considered as having chronic GVHD thereafter. Cumulative incidences of acute and chronic GVHD were estimated by considering relapse/progression and death as competing risk events.17 Failure times were counted from 100 days after HCT, whereas chronic GVHD with onset time before 100 days was counted from the onset time. Follow-up was censored at the time when patients underwent donor lymphocyte infusions. Kaplan–Meier survival analysis was performed by SPSS test. SPSS version 16 (IBM Company, Chicago, IL, USA) was used for the statistical analyses. Cox proportional cause-specific hazard models were used to assess the association of patient and transplant covariates with relapse and NRM.
For outcome analysis, the proportional sub-distribution hazards’ regression model of Fine and Gray17 was used. In order to investigate the relation of relevant covariables on acute GVHD or on chronic GVHD, univariate competing risk regressions using NRM and relapse as competing events were calculated. For the outcome analysis of relapse, the same covariables were studied and competing events were NRM and vice versa for the outcome analysis of NRM. Univariate significant influence factors were studied in multivariate analyses. These analyses were performed by using R 2.11.1 (using the cmprsk package). Differences were considered statistically significant at a P-value <0.05.
GVHD incidence and severity according to NIH criteria
At study entry on day 101 after HCT, 11 patients each (6.2%) had recurrent or persistent acute GVHD. In 10 patients (5.6%) acute GVHD was first diagnosed a median of 120 (range, 101–133) days after HCT, thus, fulfilling the criteria of late-onset acute GVHD. The cumulative incidence of acute GVHD was 63% (95% confidence interval (CI), 56–71%). For classic acute, persistent acute, recurrent acute and late-onset acute GVHD, the cumulative incidences were 49% (95% CI, 42–56%), 6.2% (95% CI, 2.6–9.7%), 3.9% (95% CI, 1.1–6.7%) and 4.5% (95% CI, 1.4–7.5%), respectively.
One hundred and fifteen of 178 patients (65%) presented chronic GVHD a median of 152 (range, 67–490) days after HCT (Table 2). On day 101 after HCT 55 patients had already chronic GVHD, including 42 (76%) with chronic classic GVHD and 13 (24%) with overlap syndrome. The median time to onset of chronic classic GVHD was 159 (range, 99–490) days as compared with 111 (range, 67–167) in patients with overlap syndrome (P<0.0001). Among the 32 patients with persistent, recurrent or late-onset acute GVHD, 20 later transformed to chronic classic GVHD and four to overlap syndrome.
The most frequent organ manifestations of chronic GVHD at onset were skin (48%), mouth (39%), liver (33%) and eyes (30%). No significant differences in organ manifestations and severity between chronic classic GVHD and overlap syndrome were observed (Table 2). Significantly more patients with overlap syndrome had progressive onset of chronic GVHD compared with patients with chronic classic GVHD (62% versus 7%, P=0.001). Seventeen patients (15%) had platelet counts below 100 g/l at onset of chronic GVHD, with no significant difference between chronic classic GVHD and overlap syndrome (P=0.8). Seventy-three patients (63%) had a Karnofsky performance score of ⩾90% at onset of chronic GVHD.
Maximum grade was reached after a median of 6 (range, 1–16) months after onset of chronic GVHD and consisted of mild in 17 (15%), moderate in 36 (31%) and severe in 62 (54%) patients. Most frequent peak organ manifestations were skin in 86%, liver in 59%, oral mucosa in 59% and eyes in 58%, respectively (Table 2). Peak severity of organ manifestations according to global severity of chronic GVHD is shown in Figure 1. Only 18 (16%) and 50 (43%) patients had a Karnofsky performance score of ⩾90 and ⩾80% at peak severity of chronic GVHD.
The cumulative incidence of chronic GVHD at 3 years was 64% (95% CI, 56–75%). It was 48% (95% CI, 38–56%) for chronic classic GVHD and 16% (95% CI, 10–24%) for overlap syndrome, respectively. In univariate competing risk regression analysis, prior acute GVHD (hazards ratio (HR) 2.76, 95% CI, 1.6–4.77, P<0.0001) was significantly associated with increased risk of chronic GVHD, whereas use of dose-reduced conditioning regimen (HR 0.52, 95% CI, 0.34–0.82, P=0.0043) was significantly associated with decreased risk of chronic GVHD. Donor type and stem cell source had no significant impact on occurrence of chronic GVHD. Of note, the CD34+ cell dose transplanted was not significantly different between patients with and without chronic GVHD. Age below or equal to 40 years was significantly associated with decreased chronic classic GVHD (HR 0.54, 95% CI, 0.44–0.87, P=0.0124). In univariate competing risk regression analysis, only use of dose-reduced conditioning (HR 0.08, 95% CI, 0.01–0.57, P=0.0119) was significantly associated with decreased risk of overlap syndrome.
In multivariate analysis, only use of myeloablative conditioning was significantly associated with increased risk of chronic GVHD (HR 1.55, 95% CI, 1.04–2.31, P=0.0317).
Fifty-four of 178 patients (30%) died within the median follow-up period of 31 (range, 3–69) months including 3 with acute GVHD, 26 without chronic GVHD, 17 with chronic classic GVHD and 8 with overlap syndrome at study entry.
Three-year OS for the whole cohort was 72.5%. When assigned on day 100 to either late acute (persistent acute, recurrent acute, late-onset acute GVHD combined) GVHD or chronic GVHD, 3-year OS for patients with late acute GVHD and chronic GVHD were 69 and 80%, and not significantly different, as shown in Figure 2a. Three-year survival for late-acute GVHD, chronic classic and overlap chronic GVHD when assigned on day 100 were 69, 83 and 73% as shown in Figure 2b. Patients without chronic GVHD with late acute GVHD excluded had significantly worse 3-year OS compared with those with chronic classic GVHD with late acute GVHD excluded (62% versus 83%, P=0.003). Of note, 3-year OS was not significantly different for patients with chronic GVHD present on day 100 after HCT as compared with patients with later onset of disease (P=0.351).
When patients with late acute GVHD transitioning into chronic GVHD at later time points than day 100 after allogeneic HCT were assigned to the respective chronic GVHD subcategory, 3-year OS for chronic classic and overlap syndrome were 82 and 69%, and not significantly different, as shown in Figure 2c. However, patients without chronic GVHD had significantly worse 3-year OS compared with chronic classic GVHD (P=0.002).
OS according to GVHD severity and other risk factors
Three-year OS for mild, moderate and severe chronic GVHD at onset were 93%, 79% and 62.5%, and significantly different between mild and severe (P=0.007), respectively. Three-year OS according to maximum severity of chronic GVHD was 88, 83 and 74% for mild, moderate and severe chronic GVHD, and thus, not significantly different, as shown in Figure 3a, when patients with initial persistent, recurrent or late-onset acute GVHD who later transitioned into chronic GVHD were included in the analysis. Three-year survival according to maximum severity of chronic GVHD was 87, 78 and 80% for mild, moderate and severe chronic GVHD, and not significantly different when patients with late acute (persistent acute, recurrent acute, late-onset acute GVHD combined) GVHD were excluded from the analysis. No significant differences in 3-year OS according to severity of chronic GVHD were observed between chronic classic GVHD and overlap syndrome at both onset as well as peak severity. Furthermore, patients with progressive onset type of chronic GVHD had significantly worse 3-year survival compared with de novo (54.5% versus 89.5%, P=0.022) and quiescent type of onset (54.5% versus 84%, P=0.001) as shown in Figure 3b. Three-year OS was also significantly worse in patients with platelet counts below 100 g/l at onset of chronic GVHD (35% versus 86%, P<0.0001) (Figure 4). Furthermore, 3-year OS was significantly worse in patients with a Karnofsky performance score below 90% as compared with ⩾90% at onset of chronic GVHD (67% versus 86%, P=0.024). Karnofsky performance score at peak severity of chronic GVHD had no significant impact on 3-year OS (P=0.772).
In Cox regression analysis including all patients, only advanced disease stage prior to allogeneic HCT (P=0.025), absence of chronic GVHD (P=0.030) and severe form of chronic GVHD at onset (P=0.022) had a significant negative impact on OS. When focusing on the cohort of chronic GVHD patients, platelet counts below 100 g/l at onset of chronic GVHD had a significantly negative impact on OS (P<0.001), whereas other variables, including severity of chronic GVHD at peak, history of acute GVHD, occurrence of late acute GVHD, age, donor type, stem cell source, disease stage and conditioning, had no significant influence on OS. Of note, no significant differences in survival probabilities according to main severe organ manifestations of chronic GVHD were observed.
Fifty-four patients died, including 32 (59%) of relapse, 7 (13%) of infection, 12 (22%) of GVHD and 3 (6%) of cardiovascular failure. Two of 54 patients had late acute (1 persistent acute and 1 late-onset acute) GVHD on day 101 after allogeneic HCT and died of acute GVHD and infection. One patient with late-onset acute GVHD died of relapse.
NRM included 9 of 60 patients (15%) without chronic GVHD, 7 of 89 patients (8%) with chronic classic GVHD and 4 of 26 patients (15%) with overlap syndrome. According to severity at onset of chronic GVHD, NRM affected 10 of 32 patients (31%) with NIH severe chronic GVHD and 1 of 53 patients (2%) with NIH moderate chronic GVHD, and was significantly different (P=0.001). According to peak severity of chronic GVHD, all non-relapse deaths (11 of 62, 18%) were in the patient cohort with severe chronic GVHD. When compared with NRM of patients with no chronic GVHD (9 of 60, 15%), no significant difference was observed.
Three-year cumulative NRM with relapse as a competing risk for all patients was 14% (95% CI, 8–20%). When calculated according to the disease status on day 101 after allogeneic HCT, 3-year cumulative NRM was 11% (95% CI, 5–17%) in patients with chronic GVHD compared with 18% (95% CI, 4–30.5%) in patients without chronic GVHD. Three-year cumulative NRM was 9% (95% CI, 1–17%) and 14% (95% CI, 1–29.5%) in patients with chronic classic GVHD and overlap syndrome. It was 21.5% (95% CI, 5–38%) in patients with late acute (persistent acute, recurrent acute, late-onset acute GVHD combined) GVHD. When patients with late acute GVHD transitioning into chronic GVHD at later time points than day 100 after allogeneic HCT were assigned to the respective chronic GVHD subcategory, 3-year NRM was 11% (95% CI, 5–17%) in patients with chronic GVHD compared with 19% (95% CI, 6–32%) in patients without chronic GVHD. Furthermore, 3-year NRM was 10% (95% CI, 3–17%) and 16% (95% CI, 1–30%) in patients with chronic classic GVHD and overlap syndrome, respectively.
In competing risk regression analysis of all patients, advanced disease stage prior to HCT (HR 2.46, 95% CI, 1.04–5.8, P=0.0397) and recurrent acute GVHD (HR 4.15, 95% CI, 1.43–12.08, P=0.009) were significantly associated with increased risk of NRM. There was a trend of increased risk of NRM in overlap syndrome as compared with chronic classic GVHD (HR 3.04, 95% CI, 0.93–9.99, P=0.0663). Compared with progressive onset type, quiescent onset type had significantly lower risk of NRM (HR 0.24, 95% CI, 0.08–0.7, P=0.0097). NRM was also significantly higher in chronic GVHD patients with platelet counts below 100 g/l (HR 3.05, 95% CI, 1.13–8.22, P=0.0272). Of note, history of acute GVHD; occurrence and severity of chronic GVHD both at onset and at peak intensity; different organ manifestations of chronic GVHD and pre-transplant variables such as conditioning, donor type and stem cell source had no significant impact on NRM.
In multivariate competing risk analysis of all patients, only quiescent onset type was significantly associated with decreased risk of NRM (HR 0.16, 95% CI, 0.05–0.52, P=0.0020) whereas platelet counts below 100 g/l were significantly associated with increased risk of NRM (HR 6.70, 95% CI, 1.50–29.87, P=0.0126).
Fourteen patients with chronic GVHD (12%) died of relapse, including 4 with mild (13%), 7 with moderate (13%) and 3 with severe (9%) chronic GVHD at onset. According to peak severity, 2 patients with mild (12%), 4 with moderate (11%) and 8 with severe (13%) chronic GVHD died of relapse. No significant differences between these cohorts with regard to relapse-related deaths were observed.
The 3-year cumulative incidence of relapse with NRM as a competing risk was 19.5% (95% CI, 13–26%) for the whole cohort. When calculated according to the disease status on day 101 after allogeneic HCT, 3-year incidence of relapse was 13% (95% CI, 4–21%) and 14% (95% CI, 1–30%) for patients with chronic classic GVHD and overlap syndrome. Of note, in patients without chronic GVHD 3-year cumulative incidence of relapse was 35% (95% CI, 21–48%) compared with 13% (95% CI, 6.5–19%) in patients with chronic GVHD. Furthermore, 3-year incidence of relapse was 13% (95% CI, 1–25%) in patients with late acute (persistent acute, recurrent acute, late-onset acute GVHD combined) GVHD. When patients with late acute GVHD transitioning into chronic GVHD at later time points than day 100 after allogeneic HCT were assigned to the respective chronic GVHD subcategory, 3-year relapse incidence was 32% (95% CI, 19–45%) in patients without chronic GVHD compared with 13% (95% CI, 6.5–19%) in patients with chronic GVHD. Three-year relapse incidence was 12% (95% CI, 5–19%) and 16% (95% CI, 1–30%) for patients with chronic classic GVHD and overlap syndrome, respectively.
In competing risk regression analysis, occurrence of chronic GVHD (HR 0.33, 95% CI, 0.17–0.66, P=0.0017), chronic classic GVHD (HR 0.29, 95% CI, 0.13–0.67, P=0.0038), quiescent onset type of chronic GVHD (HR 0.32, 95% CI, 0.15–0.70, P=0.0042) and late acute GVHD (persistent acute, recurrent acute, late-onset acute GVHD combined) (HR 0.33, 95% CI, 0.11–0.96, P=0.0410) significantly decreased the risk of relapse. Of note, disease stage had no influence on relapse.
In multivariate analysis, only presence of chronic GVHD (HR 0.19, 95% CI, 0.08–0.45, P<0.0001) was associated with decreased relapse rate.
Our study of 178 patients assessed serially after allogeneic HCT revealed a cumulative incidence of NIH-defined chronic GVHD of 64% at 2 years. To our knowledge this is the first report on the use of the NIH consensus criteria for the diagnosis and staging of chronic GVHD5 in a prospective study including the distinction between chronic classic GVHD and overlap syndrome, with cumulative incidences of 38% and 12% at 3 years, respectively. In retrospective analyses incidences of chronic classic GVHD and overlap syndrome reportedly were 42–87% and 13–30%,8, 10, 11, 12, 18, 19 with the main limitation that up to 48% of patients originally classified as chronic GVHD according to Seattle criteria had to be reclassified as acute GVHD when using the NIH criteria (Table 3).8, 10, 11, 12 Thus, our study presents for the first time accurate incidences on the two new categories of chronic GVHD in a cohort of consecutive patients treated at a single institution.
Severity at onset of chronic GVHD and distribution of organ manifestations were not significantly different between patients with chronic classic GVHD and overlap syndrome. Skin, mouth, liver and eyes were most commonly involved as has also been reported recently by Arai et al.20 in a prospective study validating the NIH consensus chronic GVHD global severity score. These investigators, however, observed higher rates of skin (63% versus 48%), mouth (62% versus 39%), eye (51% versus 30%), gastrointestinal (27% versus 2%), liver (50% versus 33%), joint (26% versus 1%) and genital (13% versus 1%) manifestations of chronic GVHD at enrolment compared with our study. Furthermore, lung involvement reportedly was 50%, with an additional 5.7% of patients with bronchiolitis obliterans syndrome as compared with 7% of patients at onset and 18% of patients at peak of chronic GVHD in our study. As Arai et al. do not provide any details on how many patients’ lung involvement was graded with the symptom scale, FEV1 or lung function score, the assessment of chronic GVHD could have been different in the two studies. Pulmonary scoring of all our patients was performed by using both the NIH symptom scale as well as FEV1 from the serial pulmonary function tests that were started prior to conditioning for allogeneic HCT and repeated from day 100 after HCT every 3 months for 2 years. All pulmonary function tests were performed at the same institution by using the same reference equations used for all calculations. In close cooperation with our pulmonary specialists, all other potential lung diseases were excluded before the diagnosis of lung involvement by chronic GVHD was established. Serial examinations also allowed valuable comparisons and confirmed the patients’ course. We did not use the lung function score as it does not separate obstructive and restrictive lung manifestations, and has not been validated yet. Furthermore, Arai et al.20 enrolled only patients with an indication for systemic treatment into their study and thus, patients with very mild chronic GVHD who only needed topical therapy were not represented. We, however, present all patients with chronic GVHD, including those with mild forms. In the cohort reported by Arai et al., only 53% of cases were classified as incident (enrolment less than 3 months after chronic GVHD diagnosis), which is in contrast to our study including all patients from the day of onset of chronic GVHD in the analyses.
Onset of overlap syndrome as compared with chronic classic GVHD was significantly earlier after HCT. Significantly more patients with overlap syndrome had progressive onset of chronic GVHD compared with patients with chronic classic GVHD as has been reported previously in a retrospective analysis.10
In our study, history of acute GVHD was a significant risk factor for chronic GVHD, which is in line with previous reports.1, 21, 22, 23 Whereas other investigators observed a significant increase in chronic GVHD after allogeneic HCT by using a mismatched or unrelated donor,1, 23, 24 this was not the case in our study. As donors were selected based on high-resolution typing of human leukocyte antigen (HLA)-A, B, C, DRB1, DRB3/4/5 and DQB1 as reported previously,25 and only a minority of 10% of patients had an HLA-mismatched unrelated donor, our study most likely did not have the statistical power to assess HLA mismatching as a risk factor for chronic GVHD. In multivariate analysis we observed a significantly lower risk for chronic GVHD after reduced-intensity conditioning. As the majority of patients had received anti-thymocyte globulin as part of dose-reduced conditioning, our results confirm previous findings on decreased rates of chronic GVHD after in vivo T-cell depletion.23, 26 Recently, Soiffer et al.27 reported significantly lower 3-year rates of chronic GVHD in patients administered alemtuzumab-containing and anti-thymocyte globulin-containing regimens for reduced-intensity allogeneic HCT in 1676 adults with hematologic malignancies. Our data in a far smaller cohort of patients are in line with these findings. Surprisingly, in our study grafting with growth factor-mobilized blood cells was not significantly associated with increased risk for chronic GVHD as has been reported by others.23, 28 However, the median CD34+ cell dose transplanted in our cohort was below 8 × 106/kg, which was reported to be the cut-off for increased risk of developing clinical extensive chronic GVHD.29 Furthermore, Arai et al.20 observed no association of conventional risk factors for development of chronic GVHD such as age, gender match, donor type, stem cell source or disease status with global severity categories of chronic GVHD.
In our prospective study, the 3-year survival of patients with chronic classic GVHD and overlap syndrome was 82 and 69%, and not significantly different. Whereas Kim et al.12 observed a significantly different 5-year GVHD-specific survival of 87 and 70% in patients with chronic classic GVHD and overlap syndrome, others reported no significant differences in survival of these two new chronic GVHD entities (Table 3).9, 10, 11 Jagasia et al.8 observed a significantly worse 3-year survival of patients with any features of acute GVHD, including overlap syndrome, as compared with chronic classic GVHD. Considering inadequacies of medical records in documenting the presence or absence of diagnostic and distinctive manifestations of chronic GVHD according to the NIH consensus criteria, and differences in historical criteria used to make the diagnosis of chronic GVHD at various transplant centers, these retrospective analyses have clear limitations. We confirm the worse survival of patients with persistent, recurrent or late onset acute GVHD,8, 10, 11 but observed no significantly worse survival in patients with overlap syndrome of chronic GVHD. Our data obtained prospectively provide the first evidence that these two new entities of chronic GVHD have similar survival and that a distinction between late acute GVHD and overlap syndrome is of importance for patient outcome. Of note, recurrent acute GVHD was significantly associated with increased risk of NRM as has been reported previously in retrospectively reclassified patient cohorts.10, 19 Furthermore, the increased NRM in patients with overlap syndrome as compared with chronic classic GVHD has to be interpreted cautiously as the numbers of patients affected are small.
Three-year survival in patients with mild, moderate or severe chronic GVHD at onset was 93, 79 and 62.5%, and significantly different. Furthermore, no significant differences in survival were observed when correlated with peak intensity of chronic GVHD, which is in contrast to reports on retrospective analyses.12, 18 Perez-Simon et al.18 observed a significantly worse 5-year survival of 46% in patients with severe chronic GVHD as compared with 83 and 77% in moderate and mild chronic GVHD. We observed no significant impact of severity of chronic GVHD at its peak intensity on NRM, confirming reports by Jagasia et al.8 However, it has to be kept in mind that the NIH consensus group's original purpose of diagnosing and staging of chronic GVHD was to define the need for systemic treatment and to reflect clinical effects of chronic GVHD on the patient's functional status, and not to predict outcomes.5 Thus, the NIH consensus project was originally developed based on expert opinion and retrospective data analyses as a tool to be used in clinical trials, with the understanding that the criteria could be revised as they underwent evaluation.5 Although patients with chronic GVHD were treated on a routine daily basis with immunosuppressive agents and immunomodulatory strategies according to the recently published recommendations of the German/Austrian/Swiss consensus group on chronic GVHD,30, 31 this therapeutic strategy was not a comparative trial on therapy of chronic GVHD. Thus, any impact of severity of chronic GVHD on transplant outcome should be investigated in the future in therapeutic clinical studies. In addition, it has to be considered that our prospective study was performed on patients with newly diagnosed chronic GVHD and thus, some patients’ characteristics could not be comparable to the ones defining patients with long-lasting chronic GVHD in recently published retrospective analyses. Furthermore, the lack of association of severity of chronic GVHD with NRM could be potentially due to the limited follow-up in our study and may be more pronounced after a longer follow-up period. Of note, in the two retrospective analyses revealing significantly worse OS in patients with severe chronic GVHD compared with mild and moderate one, median follow-up were 46 and 37 months, and thus, longer than in our study.11, 12
Most interestingly, platelet counts below 100 g/l had a significant negative impact on survival after allogeneic HCT as has been reported previously by investigators using the revised Seattle criteria of chronic GVHD32, 33, 34, 35, 36, 37, 38, 39 or reclassifying their chronic GVHD patient cohort according to the NIH consensus criteria.9
In our study progressive onset type of chronic GVHD was significantly associated with worse survival and increased NRM. Several investigators demonstrated this association in patients with historically defined chronic GVHD32, 33, 34, 35, 36, 37, 40 or in patient cohorts reclassified according to the NIH criteria.18 As persistent acute GVHD may have many features similar to progressive onset type of chronic GVHD, reclassification of historically defined chronic GVHD cohorts according to the NIH criteria can be highly problematic and most likely includes a substantial number of patients with acute GVHD as has been reported by several investigators.8, 9, 10, 11, 41 Thus, our prospective study provides for the first time accurate data on the impact of progressive onset type of NIH-defined chronic GVHD on survival and NRM after allogeneic HCT.
We observed significantly worse 3-year survival of patients without chronic GVHD as compared with patients with any form of chronic GVHD both when analyzing patients according to their GVHD status on day 100 after allogeneic HCT as well as when transition of late acute GVHD into chronic or no chronic GVHD was considered. This is in accordance with findings of Jagasia et al.8 reporting significantly worse OS of 44% in patients without chronic GVHD compared with 60% in patients who developed GVHD after day 100. Although the causes of death were not significantly different compared with patients with GVHD after day 100, in this retrospective analysis, patients without GVHD had a significantly shorter time to death compared with patients with GVHD after day 100.8 In our prospective study occurrence and severity of chronic GVHD both at onset and at peak intensity, and different organ manifestations of chronic GVHD, had no significant influence on NRM, whereas presence of any chronic GVHD significantly decreased risk for relapse both in competing risk regression analyses as well as in multivariate analysis. Recently, Inamoto et al.42 using the NIH consensus criteria retrospectively in 2656 patients showed that chronic GVHD was not associated with an increased risk of early or late mortality but a reduction in risk of relapse. Besides chronic GVHD we observed a significant association of late acute GVHD (persistent acute, recurrent acute, late-onset acute GVHD combined) with decreased risk of relapse, which has also been reported by Inamoto et al.42 in a larger patient cohort. Other investigators reported an association of risk of relapse with only acute GVHD43 or only chronic GVHD.19, 44 Of note, disease stage prior to HCT had no significant impact on risk of relapse in our study. In view of the low relapse rates and the powerful impact of any GVHD on disease recurrence, our study most likely did not have the statistical power to assess disease stage as a risk factor for relapse.
Besides survival and NRM other endpoints, including side effects and duration of systemic medications, relief of symptoms, prevention of disability, quality of life, time to withdrawal of systemic immunosuppressive treatment without exacerbation of residual disease manifestations and developing immunologic tolerance, should be important goals in the management of chronic GVHD. Previous studies have shown a median duration of systemic treatment for chronic GVHD of up to 3 years.1, 2, 35 Besides uniform criteria for diagnosis and staging of chronic GVHD, the NIH consensus group developed documents on chronic GVHD assessment both by clinicians as well as patients, and chronic GVHD-nonspecific ancillary measures, including assessments of functional impairments and quality of life.45 Although these documents represent a huge effort by the research community, they are based on expert opinion and have to be prospectively implemented and validated to advance the standards and comparability of chronic GVHD research, and hopefully thereby improving patient outcome in the near future. Recently, Herzberg et al.46 validated the Human Activity Profile Questionnaire in patients after allogeneic HCT as suggested by the NIH consensus group for measurement of physical functioning. Currently, the Chronic GVHD Consortium in the United States is conducting a multicenter, prospective, longitudinal study designed to validate and refine the recommendations of the NIH consensus conference and to provide improved tools for clinical trials in chronic GVHD.47 Although this study will evaluate the natural history of chronic GVHD under currently used treatment regimens, and will evaluate prognostic factors and surrogate endpoints for therapeutic response, treatment is not standardized and the study is conducted during routine clinical practice. Within the German/Austrian/Swiss consortium on chronic GVHD we recently assessed the usefulness of the NIH consensus criteria for patient care in clinical practice by conducting a survey of current practices of diagnosis, staging and overall grading of chronic GVHD, and three meetings with participants representing 88% of all allogeneic HCT activities in Germany, Austria and Switzerland.48 For definitions of chronic GVHD as well as overall and organ-specific severity staging, high rates of acceptance were obtained among the vast majority of participants. Furthermore, most NIH recommendations were deemed to be highly suitable for clinical routine, which is in line with our experience as this prospective study was performed during routine patient visits in the Outpatient Clinic of our BMT unit. Mucocutaneous assessments, serial pulmonary function tests even in clinically asymptomatic patients and referral to specialist consultants such as ophthalmologists were shown to be highly suitable during routine clinical practice and were easily performed in 3 months’ intervals. Most discussions arose in the assessment of isolated GVHD of the liver after day 100 after HCT and its assignment to either late acute or chronic GVHD. Most likely we will not be able to resolve this issue with future clinical studies alone but will need blood biomarkers or molecular studies of liver biopsies, which we plan to perform within our consortium in the near future.
In conclusion, this study provides for the first time prospective data on the incidence rates of NIH-defined chronic GVHD categories and identified risk factors for the occurrence of chronic GVHD. Thrombocytopenia and progressive onset type of chronic GVHD were significantly associated with worse survival. Our findings can provide the basis for risk-adapted strategies for treatment of NIH-defined chronic GVHD patients.
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We thank Dr Peter Bauer from the Institute of Medical Statistics of the Medical University of Vienna for his assistance in statistical analyses. The study was supported by European Commission Grant 037703 STEMDIAGNOSTICS and a grant by Austrotransplant.
HTG designed the research study, analyzed and interpreted the data, and co-authored the manuscript; ZK performed the clinical research, collected and analyzed data; AB, SE, LV and PK performed clinical assessments of chronic GVHD according to the NIH criteria; VP, KK, GS, UJ and JN performed assessments of defined organ manifestations of chronic GVHD according to the NIH consensus criteria; EP performed the statistical analyses; RK and NW were involved in clinical assessments and therapy of patients.
The authors declare no conflict of interest.
Preliminary data of this manuscript were presented at the Annual Meeting of the European Group for Blood and Marrow Transplantation in March 2010 in Vienna, Austria.
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Kuzmina, Z., Eder, S., Böhm, A. et al. Significantly worse survival of patients with NIH-defined chronic graft-versus-host disease and thrombocytopenia or progressive onset type: results of a prospective study. Leukemia 26, 746–756 (2012). https://doi.org/10.1038/leu.2011.257
- chronic graft-versus-host disease
- NIH criteria
- progressive onset type
- risk factors
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