Sclerotic chronic GvHD (cGvHD) is one of the most severe complications after allo-hematopoietic stem cell transplantation (HSCT). Risk factors associated with this complication remain not very well defined. With the aim to define a pre-transplantation risk profile, we have conducted a French retrospective analysis in 705 consecutive patients between 2005 and 2010. Analyses to determine pre-transplantation risk factors included as variables: patient and donor age, kind of donor, HLA matching, ABO matching, sex-matching, diagnosis, stem cell source, gender, GvHD prophylaxis and antithymocyte globulin (ATG) in the conditioning regimen. The cumulative incidence of sclerotic cGvHD was 18% (95% CI, 16.6–19.6) 3 years after onset of cGvHD. In univariate analysis, we found a significantly lower number of sclerotic cGvHD form in patients transplanted from cord blood cells (P=0.0021), in patients with a one mismatched donor (P=0.041) and in patients who had received ATG in the conditioning regimen (P=0.002). In multivariate analysis, factors associated with an increased risk of sclerotic cGvHD were young patient age, multiple myeloma and PBSC as the stem cell source. ATG in conditioning regimen and cord blood unit as the stem cell source were associated with a lower risk.
Chronic GvHD (cGvHD) is one of the most severe complications after allogeneic hematopoietic stem cell transplantation (HSCT). Sclerotic cGvHD of the skin is characterized by inflammation and progressive fibrosis of the dermis and subcutaneous tissue. When sclerotic cGvHD is severe, contractures, severe wasting and chest wall restriction can occur.1, 2 Although sclerotic cGvHD is not an acute life-threatening manifestation, severe sclerotic cGvHD may lead to significant functional disability and morbidity.3 This form of cGvHD has a negative impact on the quality of life (QoL) for patients. The response to topical interventions is poor and sclerotic cGvHD is often refractory to systemic therapy.4, 5 The National Institutes of Health (NIH) Consensus Project proposed clear definitions of the sclerotic features of cGVHD.6 The incidence of sclerotic cGvHD is between 13 and 20% according to data from studies available in the medical literature.7, 8, 9 Despite its major impact on long-term morbidity and QoL, the risk factors for sclerotic cGvHD remain insufficiently studied. For cGvHD, the risk factors have been well known for the past 10 years: prior acute GvHD, PBSCs as stem cell source, the use of a female donor for a male recipient, older patient’s age, mismatched and unrelated donor.10
Previous series of patients had as the focus of interest the risk factors for sclerotic cGvHD and TBI in the reduced intensity conditioning (RIC) setting has been found as a risk factor in one study from the National Institute of Health (NIH) Clinical Center.4, 7 Recently, one large published retrospective study from Seattle shows a risk profile for sclerotic cGvHD.8 TBI with more than 450 cGy in the conditioning regimen and PBSC as the stem cell source were associated with an increased risk for sclerotic cGvHD, whereas patients with HLA-mismatched donors and ABO mismatch seem to have a protective profile. With the aim to define a pre-transplantation risk profile in a multicenter cohort of patients and to validate the American study on this point, we have conducted in France a retrospective analysis on 705 consecutive patients between 2005 and 2010 who received systemic therapy for cGvHD after a first allo-HSCT. We have compared patients with sclerotic cGvHD to patients with cGvHD without sclerotic features. Elucidation of pre-transplantation risks factor for this form of cGvHD would help to identify patients with high risk who can benefit from prevention procedures.
Materials and Methods
Subjects, definition of sclerotic cGvHD, diagnosis and NIH score of cGvHD
This retrospective study from seven centers in France included 705 consecutive adult and pediatric patients with a history of cGvHD according to the NIH consensus definition and who received a systemic treatment for this complication. All patients underwent a first allogeneic HCST with BM, PBSCs or cord blood unit (CBU) as stem cell source after myeloablative conditioning (MAC) or a RIC regimen for treatment of hematological malignancies or hemoglobinopathies between 2005 and 2010. Patients who had recurrent malignancy before the onset of cGvHD were excluded because immunosuppressive treatment might have been modified or DLI administered to produce graft-versus-tumor effect.
The patients who received prophylactic DLI or DLI after transplantation were excluded in this study. Patients had given written consent allowing the use of medical records for research in accordance with the Declaration of Helsinki.
Initially, we did not have all the information about sclerotic cGvHD and cGvHD to conduct this study in the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) database. A questionnaire has been sent to the referring transplant physician from the seven centers in the aim to obtain the missing data. Sclerotic cGvHD was defined by deep cutaneous sclerosis with dermal and subcutaneous tissue sclerosis, fasciitis or joint contracture.
Referring HSCT physicians completed the questionnaire with documentation of patients with sclerotic cGvHD among cGvHD patients identified for each center in the SFGM-TC database. Clinical evidence of sclerotic-type cGvHD was determined by a transplant physician with experience in each center and according to the NIH definition.6
For sclerotic cGvHD patients, histological documentation and percent of body surface area skin involvement has been documented in the questionnaire. For all cGvHD patients, HSCT physicians completed the questionnaire with the NIH cGvHD (0–3) organ-specific scores for 7/8 organs (skin, mouth, eye, liver, gastro-intestinal tract, lungs, joints-fascia and female genital tract) according to the NIH Consensus Criteria.6
All complementary data have been documented in the data capture form for this study and have been added to the whole database by the central data manager of the SFGM-TC. After that, the cohort of patients with sclerotic features has been compared with the cohort of patients with cGvHD without sclerotic features in the aim to looking for pre-transplantation risks factors of sclerotic cGvHD.
The primary endpoint of the study was sclerotic cGvHD at any time among all patients with cGvHD. The analysis was carried out until November 2012.
The covariates used for the univariate and multivariate were defined at the beginning of the study. The univariate analysis was performed with a Fine & Gray test. Analyses to determine pre-transplantation risk factors included as covariates: patient age at engraftment, diagnosis, status at engraftment, kind of donor, HLA matching, ABO matching, sex-matching, CMV matching, stem cell source, GvHD prophylaxis, conditioning regimen, TBI and antithymocyte globulin (ATG) in the conditioning regimen. The Fine & Gray competing risks regression was used to identify risk factors for sclerotic cGvHD.11 Survival analysis was represented with a landmark analysis. The level of significance was set at 5% and the results were described with a confidence interval of 95%. All the statistical analysis was executed with the survival and cmprsk libraries of the R program (version 2.15).
We retrospectively analyzed 3135 patients who underwent allogeneic HSCT between 2005 and 2010 and were registered in the SFGM-TC database. For our study, we selected from the database 705 adult and pediatric patients who presented a history of cGvHD after a first allogeneic HSCT and who received a systemic treatment for this complication. Among these 705 patients, 134 patients (19%) presented sclerotic features at initial diagnosis (n=76, 57%) or after the onset of cGvHD (n=58, 43%). Most patients (96%) with sclerotic features had histological confirmation by punch biopsy in this study. All patients with sclerotic lesions had more than 30% skin surface involved at diagnosis of sclerotic cGvHD and the global NIH cGvHD (0–3) severity score was 2 (moderate) for 19 patients (14%) and 3 (severe) for 115 patients (86%). For cGvHD patients without sclerotic lesions, the global severity score was 1 (mild) for 336 patients (59%), 2 (moderate) for 84 patients (15%) and 3 (severe) for 151 patients (26%). Concerning acute GvHD, there were 239 (42%) patients with aGvHD grade⩾2 in the cGvHD cohort and 64 (48%) in the sclerotic cGvHD cohort (P=0.25). The median patient age was 48.8 years (range, 3–70.3) and the median donor age was 40.6 years (range, 0–81.5).
The patients and transplantation characteristics are described for the two cohorts of patients in Table 1.
The cumulative incidence of sclerotic cGvHD from time of allogeneic HSCT was 14% (95% confidence interval (CI), 13–15.5) 1 year after onset of cGvHD, 17.5% (95% CI, 16–19) after 2 years and 18% (95% CI, 16.5–19) after 3 years (Figure 1).
The median time from allo-HSCT to cGvHD was 5.1 (0.9–47.6) months and the median time from allo-HSCT to sclerotic cGvHD was 6.8 (1.8–41.5) months with a significant P-value (P<0.0001) between the two groups calculated by Wilcoxon-Mann-Whitney test.
Survival analysis, transplant-related mortality and relapse
The probabilities of survival at 6 months, 12 months, 24 months and 48 months after the diagnosis of cGvHD for cGvHD patients without sclerotic features were 83% (80–86), 75% (71–78), 67% (63–71) and 53% (48–58), respectively, and for sclerotic cGvHD patients were 98% (96–100), 94% (90–98%), 83% (77–90) and 71% (63–81), respectively.
There were 519 patients alive at 9 months after transplantation, 147 patients without cGvHD, 300 patients with cGvHD without sclerotic features and 72 patients with sclerotic cGvHD. The probabilities of survival at 12 months, 24 months and 48 months based on the cGvHD status at 9 months after transplantation for patients without cGvHD were 98% (97–100), 91% (86–96) and 80% (72–89), respectively; for cGvHD patients without sclerotic features, the probabilities of survival were 94% (91–97), 82% (77–87) and 63% (56–70), respectively; and for sclerotic cGvHD patients, the probabilities of survival were 99% (96–100), 88% (80–96%) and 75% (65–87), respectively.
Moreover, for the survival analysis, a landmark analysis has been realized with the cGvHD status at 9 months after transplantation (Figure 2). This analysis has been realized at 9 months because the median time from allogeneic-HSCT to sclerotic cGvHD was 6.8 months. The landmark analysis shows that patients with cGvHD without sclerotic features have an inferior survival compared with the two other groups of patients.
The TRM at 12 months was 10% and 0% for cGvHD patients and patients with sclerotic form, respectively; at 24 months, 18% and 6% respectively; and at 36 months, 19% and 14%, respectively (P=0.04). The causes of death in the two groups are described in the Table 2.
Ninety-two (16%) patients in the cGvHD cohort without sclerotic form experienced relapse after the onset of the cGvHD and 14 (10%) in the sclerotic cGvHD group. The incidence of relapse at 1 year was 5% and 11%, at 2 years was 9% and 15% and at 3 years was 9.5% and 18% after allogeneic HSCT for sclerotic cGvHD group and cGvHD cohort, respectively, (P=0.014).
Risk factors for the development of sclerotic cGvHD
In a univariate analysis, we found a significantly lower number of the sclerotic cGvHD form in patients transplanted from cord blood cells (P=0.024), in patients with one-mismatched donor (P=0.041) and in patients who had received ATG in the conditioning regimen (P=0.002). The univariate analysis is presented in Table 3 with all factors studied, P-values and hazard ratios (HR).
The multivariate analysis identified two factors associated with an increased risk of sclerotic cGvHD: diagnosis of multiple myeloma versus acute leukemia (HR, 2.09; 95% CI, 1.022–4.3028; P=0.043) and HSC source: PBSC versus BM (HR, 1.75; 95% CI, 1.01–3.0556; P=0.045). The two factors associated with a significantly lower risk of sclerotic cGvHD were the use of rabbit ATG in the pre-transplantation conditioning regimen (HR, 0.476; 95% CI, 0.2706–0.8081; P=0.0065) and cord blood as stem cell source (HR, 0.1104; 95% CI, 0.0123–0.9914; P=0.049) (Figure 3). Concerning age, it was considered as a continuous variable in the statistic model (HR, 0.98; 95% CI, 0.9679–0.9979; P=0.026). Older age is protective for sclerotic cGvHD and younger age increases the risk of developing sclerotic cGvHD.
cGvHD is a complex multi-organ disorder that remains an important cause of late mortality and has a major impact on QoL after allogeneic HSCT.12, 13 In contrast to acute GvHD, cGvHD is a poorly understood process and appears to involve donor B cells.14 cGvHD has clinical features similar to autoimmune diseases and a variety of collagen disorders like systemic sclerosis.15 The excess production of collagen is a characteristic for both systemic sclerosis and sclerotic cGvHD. In animal models, pro-fibrotic cytokines (TGF-beta and PDGF) have a role of effector molecules inducing fibrosis. Sclerotic lesions in this model are blocked by inhibitors of TGF-beta; consequently, this cytokine seems to be important in the development of sclerosis.16, 17, 18
Several risk factors for cGvHD are reported and confirmed in the medical literature: prior acute GvHD, PBSC as stem cell source, the use of female donors for male recipients, older patients, mismatched and unrelated donor.9 Concerning sclerotic cGvHD, the literature only contained single-center studies and studies with relatively small cohorts of patients. One of them, from the University of Udine, reports dose of CD3+ cells at time of HSCT and at time of cGvHD, the pigmentation of the skin, eosinophilia and immune markers as the risk factors.4
In a study from the NIH in 2011, TBI in RIC regimen was also identified as a risk factor for sclerotic cGvHD.7 In these studies, there were mixed factors studied (clinical factors and laboratory markers) and studies with a large number of patients are needed to understand the implication of each factor. Recently, in a large retrospective study from Seattle, a first risk profile for sclerotic cGvHD was reported: PBSC as stem cell source and TBI in the conditioning regimen increased the risk of sclerotic cGvHD, and protective factors are ABO mismatch and HLA mismatching.8
In our study, we found PBSC as stem cell source, young patient age and multiple myeloma as risk factors but not TBI in RIC or MAC conditioning regimen. Our results show that the profile of risk factors associated with sclerotic cGvHD is different compared with the profile of risk factors for cGvHD except for PBSC.
The observation that PBSCs are a risk factor for sclerotic cGvHD is consistent with results of numerous previous studies evaluating risk factors for cGvHD and with the American study of Inamoto for sclerotic cGvHD.8, 9, 19, 20, 21 In a recent murine model, there is evidence that IL-17A controls the infiltration of macrophages into skin and has a role in cutaneous fibrosis. The use of G-CSF for collecting PBSC grafts causes an amplification of IL-17 and that process has a major role in sclerosis after allogeneic PBSC transplantation.22 This observation in murine model needs further immunological investigations in human to be confirmed.
Concerning young age and multiple myeloma, there are some limitations to take into account. In this cohort, patients with multiple myeloma underwent allogeneic stem cell transplantation in a tandem auto-allo-SCT procedure or after a RIC procedure. The stem cell source was PBSC in both procedures. Multiple myeloma is linked to RIC procedure and PBSC. In the same way, young age is linked to MAC regimen, 12 Gy TBI and acute leukemia. The results on age and multiple myeloma require careful interpretation because of the retrospective design of the study and several links with other parameter. Further prospective studies are needed to determine whether these results stay true.
The protective effect of ATG in the conditioning regimen is consistent with several reports that found a decreased risk of cGvHD.23, 24, 25 The link between ATG use and the decreased risk of cGvHD is not completely understood. There is evidence in mouse models that the thymus is damaged by prior chemotherapy, conditioning regimen, TBI, acute GvHD and age-related atrophy. The appropriate negative selection of undesirable T cells that recognize donor or recipient allo-antigens is impaired. Anti-thymocyte globulin, by depleting donor T cells or by interfering with their activation by recipient allo-antigen allows a decrease risk of GvHD. There is also evidence in the recent literature that ATG promotes the expansion of CD4+CD25highFOXP3+ regulatory T cells, which are protective against cGvHD.26, 27, 28
In this study, CBUs are associated with a lower incidence of sclerotic cGvHD and to the best of our knowledge, this is the first observation of a protective effect of CBU in this form of cGvHD. Several studies on CBU show a lower incidence of aGvHD and cGVHD.29, 30 CBUs are not analysed in the American study of Inamoto. Further prospective investigations in CBU cohorts will be necessary to confirm this observation.
We found that the incidence of sclerotic cGvHD reached 18% at 3 years in a cohort of consecutive patients with cGvHD; this observation is very close to the incidence of 20% in the American study from Seattle on sclerotic cGvHD. The median time from allo-HSCT to sclerotic cGvHD was 6.8 (1.8–41.5) months in this study. In the medical literature, the shortest time reported for development of sclerotic cGvHD was 5 months.4 We found an earlier time for onset of sclerotic cGvHD compared with reported data, but the comparison is not easy because the time for onset of sclerotic cGvHD is not always available in large studies but in case reports. One hypothesis could be that the patients who had a cutaneous acute GvHD with no resolution and followed by cGvHD had more sclerotic cGvHD than the other patients, but the proportion test is not significant (P=0.58) in our cohort to prove that. A large multi-center prospective study on sclerotic cGvHD in MAC and RIC setting is needed to confirm this result concerning the time for onset of sclerotic cGvHD.
We expected a poor survival for sclerotic cGvHD patients but OS is better for the sclerotic group of patients than for cGvHD group with a lower rate for both TRM and relapse in the sclerotic group. Survival might be related to new strategies that have been recently developed for the treatment of this severe form of cGvHD, as for instance rituximab or imatinib.31, 32 In this study, these findings are secondary points and need confirmation from other retrospective and prospective studies.
Moreover, the impact on QoL was not evaluated in this study, but we would like to follow up on this study by sending QoL questionnaires to the physicians in the participating centers and to the patients who are still alive. Concerning the use of questionnaires, that is a limitation to note because the recall required annotation of details by investigators.
In conclusion, we validate previous studies showing that PBSCs are a risk factor for sclerotic cGvHD and we identified protective factors (ATG and CBU) for sclerotic cGvHD. New strategies in the future to prevent sclerotic cGvHD based on this pre-transplantation risk profile could be developed in prospective studies. Moreover, immunologic reconstitution and immunologic mechanisms that account for the increased and decreased risk of sclerotic cGvHD warrant future investigations.
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We would like to thank the members of the Société Française de Greffe de Moelle et de Thérapie cellulaire (SFGM-TC), the SFGM-TC data manager Nicole Raus and all collaborators who contributed to patient recruitment, data registration and quality control of the study. Marie Detrait would like to thank François Duhoux (MD,PhD) for the reading of the manuscript and advices.
MD designed the study, collected and analyzed data, and wrote the manuscript. SM performed the statistical analysis and contributed to the redaction of the manuscript. MD and FB; RPL; IYA and LM; RC; RT and SV; JOB and PC completed questionnaires for their centers. RPL and GS; FB, MD and MM; IYA and LM; RC and DB; RT, SV and NM; JOB; PC and MMo were the principal contributors of clinical data from the seven centers. NR sent data capture forms to the centers, collected clinical data from questionnaires and performed the extraction of clinical data. MM has been the supervisor of the study. RPdL, RC, FB, MMo, NM and GS read and commented on the manuscript.
The authors declare no conflict of interest.
This study was presented as an oral session during the 39th Annual Meeting of the European Group for Blood and Marrow Transplantation in London, UK, April 7–10, 2013 (Bone Marrow Transplant April 2013; Vol 48 (Supp2): S1-S574 (abstract 0326)).
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Detrait, M., Morisset, S., Peffault de Latour, R. et al. Pre-transplantation risk factors to develop sclerotic chronic GvHD after allogeneic HSCT: A multicenter retrospective study from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Bone Marrow Transplant 50, 253–258 (2015). https://doi.org/10.1038/bmt.2014.244
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