Successful treatment of chronic graft-versus-host disease (GvHD) often requires long-term systemic therapy (ST). Durable discontinuation of ST reflects the resolution of active chronic GvHD. We evaluated the factors associated with durable ST discontinuation, defined as cessation of all ST for ≥12 months, using data from two prospectively followed cohorts from the Chronic GvHD Consortium (n=684). Transplant sources were peripheral blood (89%), bone marrow (6.6%), and cord blood (4.4%) from HLA matched related (37.6%), HLA matched unrelated (45%), and other donor types (18%). Half of the patients received non-myeloablative conditioning. The median time from transplantation to chronic GvHD diagnosis was 7.7 months (range, 1.0–141.3) and the median time from chronic GvHD onset to enrollment into the cohorts was 0.9 months (range, 0.0-12.0). The cumulative incidence estimate of durable ST discontinuation was 32% (95% confidence interval: 28%-37%) at 10 years after enrollment into the cohort. Among patients who discontinued ST, the median time from chronic GvHD diagnosis to durable ST discontinuation was 3.6 years (range, 1.2-10.5). In multivariate analysis, patients who received myeloablative conditioning, had chronic GvHD manifested as moderate/severe lower gastrointestinal involvement, and had a higher (worse) Lee symptom overall score were less likely to attain durable ST discontinuation. In contrast, mild lower gastrointestinal involvement and cord blood (vs. peripheral blood) as the graft source were associated with a greater likelihood of ST discontinuation. Although a minority of patients can discontinue ST permanently, most patients require prolonged ST. Viewing chronic GvHD in this way has implications for management approaches.
Chronic graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT).1 It is a leading cause of non-relapse mortality in long-term survivors of allogeneic HCT,2 and is associated with impaired quality of life and lower performance status in patients.3,4
Approximately 30-50% of patients surviving for more than 100 days after allogeneic HCT will develop chronic GvHD and require treatment with systemic immunosuppression.1 Systemic immunosuppression can impair immunological function, increase the risk of opportunistic infections, and expose patients to the risks of medication-specific side effects such as those associated with chronic glucocorticoid therapy.
Successful therapy of chronic GvHD often requires longterm systemic therapy (ST). Previous studies of ST discontinuation reported rates as low as 27.7% and as high as 68%.5-7 The variation in rates of ST discontinuation may have resulted from the populations which were studied. Higher rates of discontinuation were observed in cohorts of patients with less heavily treated chronic GvHD from single institutions while lower rates were observed in cohorts of heavily pretreated patients from a quaternary referral center. Despite this variability, less severe chronic GvHD was associated with an increased likelihood of ST discontinuation across these studies. A significant limitation to the interpretation of these trials is that different definitions of ST discontinuation were used. Two studies defined ST discontinuation without specifying a minimal amount of time that the patient needed to be off ST6,7 while other studies defined successful discontinuation as 9 and 6 months off any ST.5,8
Approximately 50% of patients stopping ST for the first time will experience a flare in chronic GvHD symptoms at a median of 3.4 months (interquartile range, 2.3-8.0 months) and may require resumption of ST.8 Discontinuation of ST for a limited time may not represent true resolution of chronic GvHD. Therefore, we evaluated the durable discontinuation of ST, defined as discontinuation of ST for 12 or more months. This definition was proposed to ensure that patients were truly unlikely to flare and need to restart ST.
Subjects (n=684) came from two prospectively followed cohorts enrolled onto Chronic GvHD Consortium studies (NCT00637689, NCT01902576).
NCT00637689 “Improving outcomes assessment in chronic GvHD” was a cross-sectional study of chronic GvHD regardless of time since transplantation. The primary objective was testing of National Institutes of Health (NIH) recommended tools to assess chronic GvHD. Eligibility criteria included: (i) a clinical or histological diagnosis of chronic GvHD, and (ii) a need for ST. Severity of chronic GvHD was not an exclusion criterion. Clinical follow-up occurred at 3 months for incident cases, and every 6 months for the duration of the study. Long-term outcomes were determined through review of clinical charts. Six hundred and one subjects were accrued from 2007 to 2012.
NCT01902576 “Chronic GvHD response measures validation” was a prospective cohort study of patients with chronic GcHD starting new ST. The primary objective was testing of the NIH response criteria. Eligibility criteria included: (i) a diagnosis of chronic GvHD according to NIH consensus conference diagnostic and scoring criteria, and (ii) initiation of new ST for chronic GvHD. Severity of chronic GvHD was not an exclusion criterion. The patients had a clinical follow-up at 3, 6, and 18 months and if a new chronic GvHD treatment was started. Long-term outcomes were determined through review of the clinical charts. Three hundred eighty-three subjects were enrolled from 2013 to 2019.
Subjects selected for this analysis had either incident or prevalent chronic GvHD. Patients with prevalent chronic GvHD were limited to those within 12 months from diagnosis to allow evaluation of the defined endpoint of durable discontinuation of ST (off ST for at least 12 months). The treatments used are listed in Online Supplementary Table S1. Incident cases consisted of those enrolled less than 3 months after diagnosis of chronic GvHD (n=490; 70.6%), and prevalent cases comprised those enrolled 3-12 months after diagnosis of chronic GvHD (n=194; 28.4%). Subsetting according to incident and prevalent status was not significantly associated with the time to durable discontinuation of ST. Therefore, these two groups were combined for subsequent analyses.
Demographic and transplant characteristics are presented in Table 1 and Online Supplementary Table S2. This study was approved by the Institutional Review Boards of all participating centers, and all participants provided signed informed consent.
Descriptive statistics were used to summarize baseline demographic and chronic GvHD characteristics. Chronic GvHD was graded according to NIH severity scales. Baseline grade at enrollment, rather than most severe chronic GvHD status over the observed period, was used. The main endpoint was time to durable ST discontinuation, defined as the cessation of all ST for at least 12 months. Subjects who stopped ST but restarted for any reason within 12 months were considered to have been continuously on ST. These subjects did not meet the endpoint and were censored at last follow-up. The cumulative incidence of durable ST discontinuation was calculated with the competing risks of death and relapse of the disease for which HCT was performed.
Cox proportional hazards models were used to examine associations between durable ST discontinuation and transplant, clinical, and patient-reported variables, first in univariate models (Online Supplementary Table S3), and then in multivariate models. A stepwise procedure was used in the multivariate analysis, with entry into and exit from the model based on a P-value of 0.1, first with the transplant variables, then adding the clinical variables to the transplant model, then adding the patient-reported variables to the model including clinical plus transplant variables. Analyses were performed using SAS/STAT software, version 9.4 (SAS Institute, Inc, Cary, NC, USA).
Chronic graf-versus-host disease clinical and patient-reported outcomes
Chronic GvHD characteristics at enrollment are presented in Tables 2 and 3, and Online Supplementary Table S4. The median time from HCT until the diagnosis of chronic GvHD was 7.7 months (range, 1.0-141.3). The median time from the diagnosis of chronic GvHD to enrollment into the Consortium cohorts was 0.9 months (range, 0.0-12.0). Most patients were affected by moderate (51.2%) or severe (32.2%) chronic GvHD. Grade II-IV acute GvHD preceded the development of chronic GvHD in 51.6% of cases. The most common sites of chronic GvHD manifestations were the skin (63.6%), mouth (63.2%), and eyes (51.5%). Most patients had involvement of two or more sites. The median baseline Lee symptom overall summary scale score was 19.8 (range, 0.0-74.4). The median follow-up since transplantation for surviving patients was 95.3 months (range, 11.3-181.5).
Durable discontinuation of systemic therapy
The cumulative incidence of durable ST discontinuation among all patients was 24% (95% confidence interval [95% CI]: 21-28%) at 5 years and 32% (95% CI: 28-37%) at 10 years (Figure 1). Of the 519 subjects who initially stopped ST, 16 (3.1%) did not have sufficient follow-up to document ST discontinuation for ≥12 months. These subjects were considered not to have achieved durable ST discontinuation and follow-up was censored at the last contact. The NIH severity at enrollment among these 16 subjects was mild in 12.5%, moderate in 50% and severe in 37.5%. With regard to clinical outcomes at 5 years, 21% had died without relapse, 17% had relapsed from their underlying disease, 38% were alive but on ST, and 24% were alive and off ST. By 10 years, 27% had died without relapse, 18% had relapsed from their underlying disease, 23% were alive but on ST, and 32% were alive and off ST. The most frequent causes of non-relapse death were chronic GvHD, unknown, and infection (Online Supplementary Table S5). The median time from development of chronic GvHD until discontinuation of ST for at least 12 months was 3.6 years (range, 1.2-10.5). The median time from cohort enrollment until discontinuation of ST for at least 12 months was 3.4 years (range, 0.7-11.9).
Transplant, clinical, and patient-reported variables evaluated for association with durable ST discontinuation are presented in Online Supplementary Table S3. In the multiple regression model (Figure 3), patients who received an umbilical cord blood transplant were 2.08 times (95% CI: 1.07-4.04, P=0.03) and those who received a bone marrow transplant were 1.80 times (95% CI: 1.00-3.24, P=0.05) more likely to discontinue ST compared to patients who received a peripheral blood stem cell transplant. Patients with mild lower gastrointestinal (GI) involvement were 1.76 (95% CI: 1.05-2.96, P=0.03) times more likely to discontinue ST. Patients who underwent myeloablative conditioning (hazard ratio [HR]=0.62, 95% CI: 0.44-0.87, P=0.006), those with moderate to severe lower GI involvement (HR=0.25, 95% CI: 0.06-1.0, P=0.05), and those with a higher Lee symptom summary score at enrollment (HR=0.82 per 10-point increase, 95% CI: 0.70-0.96, P=0.01) were less likely to discontinue ST. The chance of discontinuing ST decreased by 18% for every 10-point increase in the Lee symptom scale overall score. Results were qualitatively similar when the analysis was limited to incident cases. In an analysis including NIH overall chronic GvHD severity and excluding individual organ involvement because of overlapping content, those with severe chronic GvHD were less likely to durably discontinue ST (HR=0.53, 95%CI: 0.31-0.90, P=0.02) than those with mild or moderate severe GvHD. The presence and severity of individual organs involved by chronic GvHD, including the lungs, was not associated with the probability of ST discontinuation.
Recipient age, recipient and donor HLA mismatching, and transplants with male recipients of grafts from female donors, all factors which have been associated with the development of chronic GvHD, were not associated with the probability of achieving durable ST discontinuation.
Upon developing moderate or severe chronic GvHD, patients and their caregivers face a great deal of uncertainty about the duration and success of ST. With a median follow up of almost 8 years, we found that the majority (67%) of patients with chronic GvHD are unable to discontinue ST for more than 12 months.
In previous studies, differences in the populations studied and different definitions of what constituted ST discontinuation may have resulted in variability in the discontinuation rates that were reported.5-7 We used a multi-institutional cohort of incident and prevalent cases of chronic GvHD that were within 1 year of diagnosis in order to reduce center bias, and further reduced variability by requiring follow-up for at least 12 months to ascertain that ST discontinuation was durable. This duration was proposed to be long enough to classify patients as having discontinued ST without a significant risk that resumption of ST would be necessary. To our knowledge, this is the largest study with the longest follow-up performed to date exploring the issue of ST discontinuation.
Similar to prior studies, we found that less severe chronic GvHD and use of umbilical cord blood grafts were associated with a shorter time to ST discontinuation.5-7 Previous studies did not use validated patient-reported instruments to measure the severity of chronic GvHD. We demonstrated that more severe chronic GvHD symptoms, as indicated by higher (worse) Lee symptom scores, were associated with a decreased probability of durable ST discontinuation, consistent with the effect of increased disease burden and emphasizing the importance of measuring patient-reported outcomes. It is intuitive that more symptomatic patients would be less likely to stop ST.
Notably, our observed rate of ST discontinuation (24% at 5 years) was closest to that from a quaternary referral center (27.7% at 5 years) with a high number of heavily treated chronic GvHD cases in their clinical population and which similarly defined ST discontinuation as requiring 6 (rather than 12) months without any therapy.5 In contrast, the population we studied was composed of 71.9% incident cases of chronic GvHD, many of whom had not progressed to second-line therapy. These results suggest that other than having a biomarker indicative of chronic GvHD, a mandatory 6- to 12-month observation period is needed to support the conclusion that ST has been discontinued permanently.
Most patients are unable to discontinue ST for at least 12 months. Patients who received peripheral blood grafts, received myeloablative conditioning, had a higher (worse) Lee symptom score, and moderate/severe lower GI involvement were less likely to achieve durable ST discontinuation.
We observed contradictory effects from lower GI chronic GvHD severity on the likelihood of discontinuing ST: mild lower GI chronic GvHD increased and moderate/severe lower GI chronic GvHD decreased the likelihood compared to no lower GI chronic GvHD. We were unable to separate the effects of moderate versus severe lower GI chronic GvHD because of the small number of cases wth severe lower GI-GvHD, limiting our interpretation of the data. An association between low levels of short chain fatty acids at around day +100 and subsequent development of chronic GvHD was recently reported, implying a role for the microbiome in chronic GvHD.9 Although association is not causation, it is possible that mild lower GI chronic GvHD may reflect an underlying perturbation in the microbiota that is more amenable to intervention by non-chronic GvHD ST such as changes in antibiotics, diet, or hospitalization. Further investigation on this subject will be necessary.
We also found that many factors (age, HLA mismatch, recipient/donor sex mismatch) associated with the development of chronic GvHD were not associated with the likelihood of ST discontinuation, suggesting that the pathophysiology of chronic GvHD treatment and control may differ from its development.
This study is limited by its reliance on clinical examination/practice to determine chronic GvHD status and on the 12-month waiting period to determine when chronic GvHD had been fully treated and was unlikely to recur. Practitioners may be less likely to discontinue and more likely to restart ST in patients with manifestations of severe chronic GvHD. This was controlled by the long 12-month waiting period which allowed an adequate time off therapy to ensure that chronic GvHD flares were unlikely. Indeed, only a small proportion of subjects (3%) restarted systemic therapy within the 12-month period in this study. Of these, the minority had severe chronic GvHD, suggesting that practitioner anxieties about stopping ST in subjects with severe chronic GvHD are less likely to bias the outcomes. Within a single institution and across a multiinstitutional consortium there may be slight variations in chronic GvHD-related definitions. Unfortunately, a clearcut biomarker of chronic GvHD status, which could provide additional precision, is not yet available, despite the application of powerful discovery and analytical techniques. The 12-month waiting period was not based on the underlying pathophysiology of tolerance induction after allogeneic HCT but rather was a practical cutoff based on the observed time to restart ST. It may still be possible to completely taper ST after many years.
The applicability of this study is limited by the population studied. A diagnosis of chronic GvHD was required for inclusion. Consequently, patients at low risk of developing chronic GvHD, such as young children or those who received post-transplant cyclophosphamide, antithymocyte globulin, or in vivo/ex vivo T-cell depletion as acute GvHD prophylaxis are not well represented. Our findings may not be applicable to these specific populations when they do not develop chronic GvHD. Finally, our findings are based on the clinical course of patients who agreed to participate in observational research. Despite these limitations, we believe our results are still valid and generalizable to patients under treatment with chronic GvHD.
Our findings suggest that for most patients, ST is likely to be a long-term proposition and that there is a much lower probability of being able to discontinue treatment than had been anticipated from earlier studies.6,7 Chronic GvHD may behave more like an ongoing autoimmune disease without resolution than a temporary state in which eventual tolerance is expected. Viewing chronic GvHD in this way has implications for management approaches and the development of therapeutic agents for chronic GvHD. The goal of defining a regimen that minimizes (rather than discontinues) ST or fosters operational immunological tolerance may need to be given higher priority to avoid the see-saw of stopping and restarting ST. Similarly, addressing the factors that contribute to persistent immune deficiency may improve outcomes by decreasing the risk of infections, a major cause of death.
- Received August 12, 2021
- Accepted March 24, 2022
No conflicts of interest to disclose.
GLC, LO, SJL, and MA designed the research, analyzed the data, and wrote the manuscript. All authors provided subjects, and read, critiqued, and revised the paper.
For access to data, please contact Stephanie Lee,
This research was supported by grants CA118953 and CA163438 to SJL.
We thank the patients who participated in the Chronic GVHD Consortium studies and the clinical staf of each member institution.
- Arora M, Cutler CS, Jagasia MH. Late acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016; 22(3):449-455. https://doi.org/10.1016/j.bbmt.2015.10.018PubMedPubMed CentralGoogle Scholar
- Wingard JR, Majhail NS, Brazauskas R. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2011; 29(16):2230-2239. https://doi.org/10.1200/JCO.2010.33.7212PubMedPubMed CentralGoogle Scholar
- Hamilton BK, Storer BE, Wood WA. Disability related to chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2020; 26(4):772-777. https://doi.org/10.1016/j.bbmt.2019.10.019PubMedPubMed CentralGoogle Scholar
- Pidala J, Kurland B, Chai X. Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood. 2011; 117(17):4651-4657. https://doi.org/10.1182/blood-2010-11-319509PubMedPubMed CentralGoogle Scholar
- Curtis LM, Pirsl F, Steinberg SM. Predictors for permanent discontinuation of systemic immunosuppression in severely affected chronic graft-versus-host disease patients. Biol Blood Marrow Transplant. 2017; 23(11):1980-1988. https://doi.org/10.1016/j.bbmt.2017.08.005PubMedPubMed CentralGoogle Scholar
- Stewart BL, Storer B, Storek J. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood. 2004; 104(12):3501-3506. https://doi.org/10.1182/blood-2004-01-0200PubMedGoogle Scholar
- Perez-Simon JA, Encinas C, Silva F. Prognostic factors of chronic graft-versus-host disease following allogeneic peripheral blood stem cell transplantation: the National Institutes Health scale plus the type of onset can predict survival rates and the duration of immunosuppressive therapy. Biol Blood Marrow Transplant. 2008; 14(10):1163-1171. https://doi.org/10.1016/j.bbmt.2008.07.015PubMedGoogle Scholar
- Lee SJ, Nguyen TD, Onstad L. Success of immunosuppressive treatments in patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2018; 24(3):555-562. https://doi.org/10.1016/j.bbmt.2017.10.042PubMedPubMed CentralGoogle Scholar
- Markey KA, Schluter J, Gomes ALC. The microbe-derived short-chain fatty acids butyrate and propionate are associated with protection from chronic GVHD. Blood. 2020; 136(1):130-136. https://doi.org/10.1182/blood.2019003369PubMedPubMed CentralGoogle Scholar
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