Reduced intensity conditioning increases risk of severe cGVHD: identification of risk factors for cGVHD in a multicenter setting

Reduced intensity conditioning increases risk of severe cGVHD: identification of risk factors for... Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality after allogeneic hemat- opoietic stem cell transplantation (HSCT). Aim is to identify risk factors for the development of cGVHD in a multicenter setting. Patients transplanted between 2000 and 2006 were analyzed (n = 820). Donors were HLA-identical siblings (57%), matched unrelated donors (30%), and HLA-A, B or DR antigen mismatched (13%). Reduced intensity conditioning (RIC) was given to 65% of patients. Overall incidence of cGVHD was 46% for patients surviving more than 100 days after HSCT (n = 747). Older patient age [HR 1.15, p < 0.001], prior acute GVHD [1.30, p = 0.024], and RIC [1.36, p = 0.028] increased overall cGVHD. In addition, RIC [4.85, p < 0.001], prior aGVHD [2.14, p = 0.001] and female donor to male recipient [1.80, p = 0.008] increased the risk of severe cGVHD. ATG had a protective effect for both overall [0.41, p < 0.001] and severe cGVHD [0.20, p < 0.001]. Relapse-free survival (RFS) was impaired in patients with severe cGVHD. RIC, prior aGVHD, and female-to-male donation increase the risk of severe cGVHD. ATG reduces the risk of all grades of cGVHD without hampering RFS. GVHD prophylaxis may be tailored according to the risk profile of patients. Keywords ATG  · Graft-versus-host disease (GVHD) · Risk factor Introduction Chronic graft-versus-host disease (cGVHD) remains one of the most severe complications after allogeneic hematopoietic stem cell transplantation (HSCT), affecting both the quality * Gabriel Afram of life and mortality of long-term survivors [1–4]. Its impact gabriel.afram@ki.se on morbidity and mortality varies depending on the severity Department of Hematology, Karolinska University Hospital and number of organs involved, allowing the classification Huddinge, Stockholm, Sweden of patients into mild, moderate, and severe cGVHD accord- Department of Hematology, Instituto de Biomedicina ing to the NIH, and identifying those at low, intermediate, de Sevilla (IBIS), Hospital Universitario Virgen del or high risk of developing GVHD-related morbidity and Rocío/CSIC/Universidad de Sevilla, Seville, Spain mortality. Chronic GVHD is associated with a graft-versus- Centre for Allogeneic Stem Cell Transplantation, Karolinska tumor effect (GVT) that decreases the risk of relapse after University Hospital Huddinge, Stockholm, Sweden transplant [5]. These findings emphasize the importance of Department of Hematology, Hospital de la Santa Creu i Sant appropriate management of cGVHD, which should be indi- Pau, Barcelona, Spain vidualized according to the patients’ characteristics. Department of Hematology, Hospital Universitario de Risk factors for cGVHD include high recipient age, prior Salamanca-IBSAL, Salamanca, Spain acute GVHD, female donor to male recipient [6], HLA dis- Department of Hematology, Hospital Clinico Universitario, parity between recipient and donor, and use of peripheral Valencia, Spain blood as a source of progenitor cells [7–9]. CGVHD is an Division of Hematology, Department of Medical Sciences, increasingly frequent complication after HSCT due, at least Uppsala University Hospital, Uppsala, Sweden Vol.:(0123456789) 1 3 79 Page 2 of 8 Medical Oncology (2018) 35:79 in part, to the more frequent use of peripheral blood stem HLA class I and II alleles [13]. Seventy-six percent received cells, higher age of recipients/donors, and increased use of peripheral blood hematopoietic stem cells (PBSC) from mismatched and unrelated donors. Recently, we retrospec- G-CSF stimulated donors, 20% received bone marrow grafts, tively classified a large cohort of patients in terms of cGvHD and 4% received cord blood grafts. subtype and severity according to the NIH proposal [10]. To the best of our knowledge, there are no data on cGvHD Conditioning risk factor analysis based on the cGvHD NIH classification. Various studies have attempted to identify the best strat- Myeloablative regimens were used in 34% of cases, the rest egy to prevent GVHD, and to date, only the use of in vitro or receiving reduced intensity conditioning (RIC). Forty-four in vivo T cell depletion has been shown to reduce the risk of percent received in vivo T cell depletion with anti-thymocyte cGVHD, although its impact on survival has been relatively globulin (ATG, Thymoglobulin, Genzyme, Cambridge, MA, limited in unselected series of patients [11]. Therefore, the USA) (n = 295) or Campath (n = 30). Patients at Karolinska prophylaxis regimen should be tailored on the basis of indi- (center A) received ATG (Thymoglobulin, Genzyme, Cam- vidual patient and transplant characteristics, and more effec- bridge, MA, USA) at a dose of 4–8 mg/kg. Patients from tive immunosuppressive strategies could benefit patients at Salamanca and Sant Pau (centers B and C) received ATG high risk of severe forms of cGVHD and low risk of relapse, at a dose of 7.5 mg/kg. ATG was administered for 3–4 days while the contrary could apply to patients at high risk of with the last dose given on day 1 or 2. ATG was adminis- relapse in the event of displaying a lower risk of cGVHD. tered to patients with unrelated donors, HLA-mismatched Our study aimed to highlight risk factors for developing donors, and those with non-malignant diseases. mild, moderate, and severe cGVHD in a multicenter setting. We retrospectively included 747 patients who had undergone GVHD prophylaxis and treatment HSCT between the years 2000–2006. Most patients received GVHD prophylaxis with cyclo- sporine A or tacrolimus combined with methotrexate Patients and methods (80%), while 11% received mycophenolate mofetil instead of methotrexate. The remaining 9% of patients received CyA Eight hundred and twenty patients undergoing HSCT at or tacrolimus combined with prednisone or other immuno- three different centers from January 2000 to December 2006 suppressive regimes. were included in this retrospective study. The analysis was First-line treatment for cGVHD was based on cyclo- restricted to those patients surviving more than 100 days sporine A or tacrolimus plus prednisone. Disease response after HSCT (n = 747). The number of patients included from was generally evaluated 5 weeks after initiation of treat- each center was: Karolinska (n = 425), Salamanca (n = 162) ment and subsequently every 3 months until cessation of and Sant Pau (n = 160). The study protocol was approved treatment. by the regional ethics committees (Regionala Etikprövn- All patients received antibacterial, antifungal, and anti- ingsnämnden, Stockholm and Comité Etico CEIM (Comité viral prophylaxis according to standard protocols at each de ética de la investigación con medicamentos) for Spain center. and was performed in accordance with the Declaration of Helsinki. Chronic GVHD was retrospectively categorized Statistical analysis according to the NIH consensus criteria [12]. The patients’ characteristics are summarized in Table 1. The incidence of chronic GVHD was estimated using an The median age at the time of transplantation was estimator of cumulative incidence curves. Patients were cen- 44 years (< 1–70). The most common diagnosis was acute sored at the time of death or last follow-up. Only patients leukemia (acute myeloid leukemia or acute lymphoblastic surviving more than 100 days after HSCT were included leukemia) in 34% of patients; chronic leukemia was diag- in the analysis and the competing event was death without nosed in 15% and lymphoma in 14%. chronic GVHD. Categorical parameters were compared using Chi-square test and continuous variables were com- Donors and stem cell source pared using the Mann–Whitney test. Multivariate predictive analyses were performed using Gray’s test and the propor- Fifty-seven percent of patients received sibling donor grafts, tional sub-distribution hazard regression model of Fine and 13% received grafts with one HLA-A, B, or DR antigen or Gray [14]. A stepwise backward procedure was used to con- allele mismatch, and 30% received grafts from HLA-A, B, struct a set of independent predictors. All predictors with a p and DR-matched unrelated donors. All patients and donors value below 0.10 in the univariate analysis were introduced were typed using PCR-SSP high-resolution typing for both into the multivariate model and sequentially removed if the 1 3 Medical Oncology (2018) 35:79 Page 3 of 8 79 Table 1 Characteristics of Factor No cGVHD cGVHD p value HSCT patients with or without chronic GVHD N = 409 338 Age 37 (< 1–69) 51 (< 1–70) < 0.001 Donor age 38 (0–74) 45 (0–77) < 0.001 Sex (male/female) 241/168 214/124 0.25 Donor sex (male/female) 239/164 179/152 0.18 Female to male 76 (19%) 89 (26%) 0.013 Disease stage (early/late) 180/199 129/195 0.04 Stem cell source (PBSC/BM/CB) 278/108/23 290/43/5 < 0.001 CD34 + cell dose (× 10 /kg) 6.8 (0.1–68) 6.7 (0.1 to − 19.9) 0.89 Donor Sibling 196 (48%) 242 (72%) < 0.001 MUD 153 (37%) 64 (19%) Mismatched 60 (15%) 31 (9%) 0.03 Conditioning MAC 165 (43%) 85 (26%) < 0.001 RIC 232 (57%) 245 (74%) ATG 233 (57%) 92 (27%) Diagnosis Non-malignant 53 (13%) 17 (5%) < 0.001 AML/ALL 90/52 (35%) 81/31 (33%) Ns CML/CLL 41/13 (13%) 36/21 (17%) Ns Lymphoma 55 (13%) 53 (16%) Ns MDS/MPS 36 (9%) 40 (12%) Ns Myeloma 29 (7%) 30 (9%) Ns Solid tumor 30 (7%) 13 (4%) Ns Other 10 (2%) 16 (5%) Ns Early stage CR1/CP1, Late stage beyond CR1/CP1, PBSC peripheral blood stem cells, BM bone marrow, CB cord blood, MUD matched unrelated donor, MAC myeloablative conditioning, RIC reduced intensity conditioning, ATG anti-thymocyte globulin, AML acute myeloid leukemia, ALL acute lymphoid leukemia, CML chronic myeloid leukemia, CLL chronic lymphoid leukemia, MDS myelodysplastic syndrome, MPS myeloproliferative syndrome p value was above 0.05. Risk factors included in the univari- was 29, 6, and 0%, respectively, for center A, B, and C. ate analysis were: patient and donor age, patient and donor Median time to onset for cGVHD was 5.7 (2.0–77) months sex, sex mismatch, disease stage, stem cell source, donor post-transplant. type, conditioning, ATG, diagnosis, center, GVHD prophy- ATG was administered at a frequency of 71, 13, and 1% laxis, CD34 + cell dose and prior aGVHD. All tests were in the three centers, respectively. The percentage of sibling two-sided. The type I error rate was fixed at 0.05 for factors donor transplants at each center was 42, 79, and 81%, respec- potentially associated with time-to-event outcomes. Analy- tively. Results were similar in terms of survival at the three ses were performed using the cmprsk package (developed centers [53% (48–58%), 49% (41–57%), 52% (45–59%), by Gray, June 2001), S-PLUS 6.2 software and Statistica respectively] as well as in terms of relapse-free survival software. (RFS) [46% (41–51%), 39% (31–47%), 42% (35–49%)] at 5 years. Results Risk factors for overall cGVHD The overall cumulative incidence of acute GVHD was In univariate analysis, significant risk factors for the devel- 56% and that of cGVHD was 48% (95% CI 44–52%). The opment of cGVHD included prior acute GVHD, RIC, incidence of cGVHD at the three centers A, B, and C was PBSC, sex mismatch, increased donor age, sibling donor, 32% (27–37%), 70% (63–77%), and 58% (50–66%), respec- and late disease stage (beyond first remission). The use tively. The percentage of children transplanted at each center of ATG was a protective factor (Fig.  1). In multivariate 1 3 79 Page 4 of 8 Medical Oncology (2018) 35:79 Fig. 2 Risk factor score for developing severe cGVHD including risk Fig. 1 Chronic GVHD incidence in patients treated with anti-thymo- factors from multivariate analysis with female donor to male recipi- cyte globulin (ATG) versus no ATG ent, reduced intensity conditioning (RIC), anti-thymocyte globulin (ATG) and prior acute GVHD analysis, the following variables significantly influenced the risk of overall cGVHD: use of ATG [HR = 0.41, 95% CI Table 2 Incidence of severe chronic GVHD after HSCT depending on number of risk factors (RF) and inclusion of anti-thymocyte glob- (0.32–0.52), p < 0.001], higher patient age (in 10-year incre- ulin (ATG) or not in the conditioning therapy. Only factors known at ments) [HR = 1.15, 95% CI (1.07–1.24), p < 0.001], prior time of transplantation were analyzed acute GVHD [HR = 1.30, 95% CI (1.04–1.63), p = 0.024] Severe cGVHD ATG (%) No ATG (%) p value and reduced intensity conditioning (RIC) [HR = 1.36, 95% CI (1.04–1.79), p = 0.028]. When analyzing risk factors for 1 RF 4 6 NS cGVHD after correcting for differences between patients 2 RF 4 24 < 0.001 receiving RIC or MAC, it is apparent that RIC patients 3 RF 7 40 0.01 still have higher cGVHD incidence [HR = 1.38, 95% CI (1.02–1.88), p = 0.038]. The analysis was done in order to eliminate confounding factors in each group. Table 3 Overall survival (OS) and transplant-related mortality (TRM) 5  years after HSCT, depending on the severity of chronic GVHD (95% confidence interval given in brackets) Risk factors for severe cGVHD Grade of cGVHD TRM OS No cGVHD 24% (19–29%) 51% (46–56%) The overall incidence of severe cGVHD was 14% (95% CI Mild 14% (8–20%) 72% (63–81%) 11–17%). In multivariate analysis, female donor to male Moderate 18% (11–25%) 71% (63–79%) recipient [HR 1.80 (95% CI 1.17–2.78), p = 0.008], RIC [HR Severe 31% (21–41%) 50% (39–61%) 4.85 (95% CI 2.40–9.83) p < 0.001], and prior aGVHD [HR p value < 0.001 < 0.001 2.14 (95% CI 1.34–3.42), p = 0.001] significantly increased All patients 22% (19–25%) 57% (53–61%) the risk of severe cGVHD while ATG had a protective effect [HR 0.20, (95% CI 0.11–0.37), p < 0.001]. Based on our findings, we developed a scoring system including significant risk factors from multivariate analysis was a significant protective effect from ATG on the inci- with regard to severe cGVHD incidence (Fig. 2). According dence of severe cGVHD at 5 years post-transplant (Table 2). to this scoring system, the risk of developing severe cGVHD was 3.1, 6.8, 26.4, and 40.4% at 5  years post-transplant Transplant‑related mortality (TRM), overall, among patients with one, two, three, or four risk factors. and relapse‑free survival Next, we conducted a multivariate analysis including only significant risk factors present at the time of transplanta- Concerning OS, the worst outcome was seen in patients tion. In this analysis, we found that patient age > 45 years, with severe cGVHD or no cGVHD. Similar results were female-to-male donation, and RIC increased the risk of observed concerning TRM. In this analysis, we found that severe cGVHD, while ATG remained a protective factor. the best outcomes were obtained in patients who developed When two to three of these risk factors were present, there mild–moderate cGVHD (Table 3). 1 3 Medical Oncology (2018) 35:79 Page 5 of 8 79 Relapse-free survival at 5 years was similar in patients developing mild or moderate cGVHD [59% (49–59%) vs. 64% (55–73%), respectively], but significantly higher in these same groups compared to patients without cGVHD or with severe cGVHD [RFS of 39% (34–44%) and 46% (35–57%), respectively; p < 0.001 for mild and moderate compared to severe or no cGVHD] (Fig. 3). ATG had no influence on RFS (Fig.  4). The risk of relapse or death was increased among patients with high-risk disease at transplantation [HR = 1.61, (95% CI 1.29–2.01), p < 0.001]. Interestingly, the best RFS was observed in patients with mild-to-moderate cGVHD irre- spective of disease stage at time of transplantation (Table 4). Discussion Fig. 4 Relapse-free survival in patients conditioned with or without anti-thymocyte globulin (ATG) Chronic GVHD remains the major cause of morbidity and mortality in long-term survivors after allogeneic stem cell conditioning regimen [19, 20]. Mechanisms involved in the transplantation. However, it is also correlated with a strong graft-versus-tumor effect. Thus, proper management of development of acute and chronic GVHD are not entirely congruent. In this regard, cGVHD is not simply the end patients should be based on individualized strategies taking into account the notion that the absence of cGVHD might stage of acute GVHD [21]. In accordance with this hypoth- esis, use of RIC might, in fact, decrease the risk of acute and hamper relapse-free survival while severe cGVHD leads to increased mortality due to infectious complications and increase the risk of chronic GVHD. It could be speculated that acute GVHD is mostly dependent on the cytokine storm organ failure [15–18]. In the current study, we identie fi d risk factors with regard mediated by the tissue injury induced by the high doses of chemoradiotherapy, which is avoided in the RIC setting. On to developing severe cGVHD, including female donor-to- male donor recipient, prior aGVHD and use of reduced the other hand, chronic GVHD would be more dependent on the persistence of host–origin antigen-presenting cells intensity conditioning. While the first two risk factors have previously been described, the latter requires further clarifi- that might trigger an alloresponse in donor T cells. The use of RIC favors the persistence of a mixed chimerism for a cation. In this regard, the finding of a higher risk of cGVHD among patients receiving RIC is somewhat surprising, since longer period post-transplant as compared to myeloablative conditioning. It could also be argued that since many centers previous studies have not been able to show a difference in terms of cGVHD incidence depending on the type of show a preference toward treating older patients with RIC mainly due to comorbidities, the median age in this patient group is higher compared to those treated with myeloabla- tive conditioning (MAC). This is also true in our study, and therefore, RIC patients are a higher-risk subpopulation for the development of cGVHD compared to MAC. Table 4 Relapse-free survival (RFS) in different grades of chronic GVHD according to disease stage Five-year RFS Early disease Late disease p value (%) (%) No cGVHD 45 36 0.09 Mild 72 48 0.016 Moderate 83 53 < 0.001 Severe 49 44 0.80 Fig. 3 Relapse-free survival dependent on severity of chronic GVHD Early stage CR1/CP1, Late stage beyond CR1/CP1 1 3 79 Page 6 of 8 Medical Oncology (2018) 35:79 In the present study, we have shown that the addition of the incidence of extensive cGVHD in patient groups younger ATG decreases the overall incidence of cGVHD without or older than 60 years [32]. hampering relapse-free survival, which is consistent with Most importantly, the current study allowed us to develop previous studies [6, 11, 17, 22–25]. a scoring system with clearly identifiable subgroups of Langston et  al. showed that the addition of ATG to patients at different risk of developing overall or severe fludarabine–melphalan in the RIC regimen for patients cGVHD. Remarkably, both severe cGVHD and no cGVHD receiving partially matched URD transplants does not had a similar adverse impact on outcome. Based on these increase the rates of relapse or infection. The same study did data, mild or moderate cGVHD show a desirable GvL effect not show any difference with regards to cGVHD incidence in without increasing the mortality from the procedure. Inter- the two groups with Fu–Mel–ATG versus Flu–Mel [26]. One estingly we found that in patients with more advanced dis- recent report shows that a fludarabine-containing RIC regi- ease stages the difference in RFS became less prominent, men with the addition of ATG is effective and safe for adults perhaps suggesting that this patient group relapses before a up to the age of 69 [27]. Investigation of the effect of ATG significant GvL effect is obtained. All together, these data in a matched related donor myeloablative setting has shown suggest that patients at higher risk of severe cGVHD should beneficial effects with reduction in both severe aGVHD and be identified in order to have a favorable influence on long- cGVHD, which translated into higher survival [28]. term outcomes via the use of more intense immunosuppres- Nevertheless, the use of pretransplant ATG as GVHD sive strategies, such as the use of ATG. In this regard, the prophylaxis in patients receiving grafts from URD has been lack of conclusive data regarding the impact of the use of discussed for years, and although most studies have shown a ATG on survival in most previously reported randomized significant reduction in acute GVHD and cGVHD, they have studies could be attributed to the lack of selection criteria, lacked evidence concerning a potential benefit on overall such that, according to our data, older males with female survival [11, 13, 24, 25, 29]. A GITMO group showed a sig- donors receiving RIC transplants would benefit the most nificant reduction in the incidence of grades III–IV aGVHD from receiving this prophylaxis. Pretransplant identification and extensive cGVHD, but this positive effect was counter - of patients at risk of developing graft-versus-host disease balanced by the increased risk of infections. In a follow-up remains an unmet medical need. In this regard, even among analysis of this study, encouraging results included a reduced patients receiving transplantation from HLA-identical risk of chronic lung dysfunction, protection against exten- donors, the risk of GVHD varies greatly among individuals. sive chronic GVHD, and an improved quality of life [21]. In Recently, Sorror et al. [33] reported that the pretransplant this prospective setting, there was no significant difference comorbidity index predicts the risk of severe aGVHD and between the two groups regarding relapse and long-term subsequent mortality. In the current study, we developed a survival. scoring system for cGVHD including risk factors known at These data contrast with a recent report from CIBMTR the time of transplant: RIC, female-to-male donation and describing lower overall survival, lower disease-free sur- patient age > 45 years. Patients with these three risk fac- vival, and an increased risk of relapse in patients receiving tors had an incidence of severe cGHD of 40% at 5 years, in vivo T-cell depletion [30]. This difference might be due while the same patients had a cumulative incidence of 7% at to the heterogeneous nature of the population included in the 5 years when they received ATG. Accordingly, the scoring CIBMTR study, in which patients received different prepa- system allows the tailoring of strategies to prevent cGVHD rations of ATG, dosage, conditioning regimens and donor in the early post-transplant period and in the long-term types. In addition, the type of conditioning determines the follow-up. Furthermore, we also identified RIC, female-to- effect of the antibody therapy since, according to Soiffer male donation, prior acute GVHD and not receiving ATG et al., there is a deleterious effect of in vivo T cell deple- as GVHD prophylaxis as risk factors for developing severe tion among patients undergoing RIC. Furthermore, both the cGVHD. This information would be of the greatest use for dosage and the preparation of ATG seem to be important in modifying immunosuppression during the post-transplant terms of transplant outcomes [13, 24, 25, 31]. In this regard, follow-up period. In this regard, these patients should be most studies have shown that an intermediate dose of rabbit- carefully monitored and might benefit from receiving early ATG (Thymoglobulin, Genzyme) ranging from 5 to 8 mg/kg treatment once signs or symptoms of cGVHD appear. leads to a positive reduction in severe aGVHD and cGVHD In conclusion, in the current study, we identified sub- without impairing relapse or long-term survival. groups of patients with different risk of cGVHD; these In addition, in the current study, we show that increasing parameters might help to tailor GVHD prophylaxis and man- patient age significantly influences the incidence of cGVHD, age immunosuppression in the long term. but only up to 50 years, which is consistent with a recent Author’s contribution GA and HH designed the study, wrote first draft, study including 206 patients who underwent RIC allo-HSCT and collected data for the Swedish patient cohort. JAPS contributed as plus 5 mg/kg r-ATG. 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Russell JA, Turner AR, Larratt L, Chaudhry A, Morris D, Brown 2013. https ://doi.org/10.1016/j.bbmt.2013.11.030. C, et al. Adult recipients of matched related donor blood cell 33. Sorror ML, Martin PJ, Storb RF, Bhatia S, Maziarz RT, Pul- transplants given myeloablative regimens including pretransplant sipher MA, et al. Pretransplant comorbidities predict severity of antithymocyte globulin have lower mortality related to graft-ver- acute graft-versus-host disease and subsequent mortality. Blood. sus-host disease: a matched pair analysis. Biol Blood Marrow 2014;124(2):287–95. h t t p s : / / d o i . o r g / 1 0 . 1 1 8 2 / b l o o d - 2 0 1 4 - 0 1 - Transpl. 2007;13(3):299–306.55056 6 (Epub 2014 May 5). 29. Bacigalupo A, Lamparelli T, Bruzzi B, Guidi S, Alessandrino PE, Bartolomeo P, et al. Antithymocyte globulin for graft-versus-host 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Medical Oncology Springer Journals
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Medicine & Public Health; Oncology; Hematology; Pathology; Internal Medicine
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Abstract

Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality after allogeneic hemat- opoietic stem cell transplantation (HSCT). Aim is to identify risk factors for the development of cGVHD in a multicenter setting. Patients transplanted between 2000 and 2006 were analyzed (n = 820). Donors were HLA-identical siblings (57%), matched unrelated donors (30%), and HLA-A, B or DR antigen mismatched (13%). Reduced intensity conditioning (RIC) was given to 65% of patients. Overall incidence of cGVHD was 46% for patients surviving more than 100 days after HSCT (n = 747). Older patient age [HR 1.15, p < 0.001], prior acute GVHD [1.30, p = 0.024], and RIC [1.36, p = 0.028] increased overall cGVHD. In addition, RIC [4.85, p < 0.001], prior aGVHD [2.14, p = 0.001] and female donor to male recipient [1.80, p = 0.008] increased the risk of severe cGVHD. ATG had a protective effect for both overall [0.41, p < 0.001] and severe cGVHD [0.20, p < 0.001]. Relapse-free survival (RFS) was impaired in patients with severe cGVHD. RIC, prior aGVHD, and female-to-male donation increase the risk of severe cGVHD. ATG reduces the risk of all grades of cGVHD without hampering RFS. GVHD prophylaxis may be tailored according to the risk profile of patients. Keywords ATG  · Graft-versus-host disease (GVHD) · Risk factor Introduction Chronic graft-versus-host disease (cGVHD) remains one of the most severe complications after allogeneic hematopoietic stem cell transplantation (HSCT), affecting both the quality * Gabriel Afram of life and mortality of long-term survivors [1–4]. Its impact gabriel.afram@ki.se on morbidity and mortality varies depending on the severity Department of Hematology, Karolinska University Hospital and number of organs involved, allowing the classification Huddinge, Stockholm, Sweden of patients into mild, moderate, and severe cGVHD accord- Department of Hematology, Instituto de Biomedicina ing to the NIH, and identifying those at low, intermediate, de Sevilla (IBIS), Hospital Universitario Virgen del or high risk of developing GVHD-related morbidity and Rocío/CSIC/Universidad de Sevilla, Seville, Spain mortality. Chronic GVHD is associated with a graft-versus- Centre for Allogeneic Stem Cell Transplantation, Karolinska tumor effect (GVT) that decreases the risk of relapse after University Hospital Huddinge, Stockholm, Sweden transplant [5]. These findings emphasize the importance of Department of Hematology, Hospital de la Santa Creu i Sant appropriate management of cGVHD, which should be indi- Pau, Barcelona, Spain vidualized according to the patients’ characteristics. Department of Hematology, Hospital Universitario de Risk factors for cGVHD include high recipient age, prior Salamanca-IBSAL, Salamanca, Spain acute GVHD, female donor to male recipient [6], HLA dis- Department of Hematology, Hospital Clinico Universitario, parity between recipient and donor, and use of peripheral Valencia, Spain blood as a source of progenitor cells [7–9]. CGVHD is an Division of Hematology, Department of Medical Sciences, increasingly frequent complication after HSCT due, at least Uppsala University Hospital, Uppsala, Sweden Vol.:(0123456789) 1 3 79 Page 2 of 8 Medical Oncology (2018) 35:79 in part, to the more frequent use of peripheral blood stem HLA class I and II alleles [13]. Seventy-six percent received cells, higher age of recipients/donors, and increased use of peripheral blood hematopoietic stem cells (PBSC) from mismatched and unrelated donors. Recently, we retrospec- G-CSF stimulated donors, 20% received bone marrow grafts, tively classified a large cohort of patients in terms of cGvHD and 4% received cord blood grafts. subtype and severity according to the NIH proposal [10]. To the best of our knowledge, there are no data on cGvHD Conditioning risk factor analysis based on the cGvHD NIH classification. Various studies have attempted to identify the best strat- Myeloablative regimens were used in 34% of cases, the rest egy to prevent GVHD, and to date, only the use of in vitro or receiving reduced intensity conditioning (RIC). Forty-four in vivo T cell depletion has been shown to reduce the risk of percent received in vivo T cell depletion with anti-thymocyte cGVHD, although its impact on survival has been relatively globulin (ATG, Thymoglobulin, Genzyme, Cambridge, MA, limited in unselected series of patients [11]. Therefore, the USA) (n = 295) or Campath (n = 30). Patients at Karolinska prophylaxis regimen should be tailored on the basis of indi- (center A) received ATG (Thymoglobulin, Genzyme, Cam- vidual patient and transplant characteristics, and more effec- bridge, MA, USA) at a dose of 4–8 mg/kg. Patients from tive immunosuppressive strategies could benefit patients at Salamanca and Sant Pau (centers B and C) received ATG high risk of severe forms of cGVHD and low risk of relapse, at a dose of 7.5 mg/kg. ATG was administered for 3–4 days while the contrary could apply to patients at high risk of with the last dose given on day 1 or 2. ATG was adminis- relapse in the event of displaying a lower risk of cGVHD. tered to patients with unrelated donors, HLA-mismatched Our study aimed to highlight risk factors for developing donors, and those with non-malignant diseases. mild, moderate, and severe cGVHD in a multicenter setting. We retrospectively included 747 patients who had undergone GVHD prophylaxis and treatment HSCT between the years 2000–2006. Most patients received GVHD prophylaxis with cyclo- sporine A or tacrolimus combined with methotrexate Patients and methods (80%), while 11% received mycophenolate mofetil instead of methotrexate. The remaining 9% of patients received CyA Eight hundred and twenty patients undergoing HSCT at or tacrolimus combined with prednisone or other immuno- three different centers from January 2000 to December 2006 suppressive regimes. were included in this retrospective study. The analysis was First-line treatment for cGVHD was based on cyclo- restricted to those patients surviving more than 100 days sporine A or tacrolimus plus prednisone. Disease response after HSCT (n = 747). The number of patients included from was generally evaluated 5 weeks after initiation of treat- each center was: Karolinska (n = 425), Salamanca (n = 162) ment and subsequently every 3 months until cessation of and Sant Pau (n = 160). The study protocol was approved treatment. by the regional ethics committees (Regionala Etikprövn- All patients received antibacterial, antifungal, and anti- ingsnämnden, Stockholm and Comité Etico CEIM (Comité viral prophylaxis according to standard protocols at each de ética de la investigación con medicamentos) for Spain center. and was performed in accordance with the Declaration of Helsinki. Chronic GVHD was retrospectively categorized Statistical analysis according to the NIH consensus criteria [12]. The patients’ characteristics are summarized in Table 1. The incidence of chronic GVHD was estimated using an The median age at the time of transplantation was estimator of cumulative incidence curves. Patients were cen- 44 years (< 1–70). The most common diagnosis was acute sored at the time of death or last follow-up. Only patients leukemia (acute myeloid leukemia or acute lymphoblastic surviving more than 100 days after HSCT were included leukemia) in 34% of patients; chronic leukemia was diag- in the analysis and the competing event was death without nosed in 15% and lymphoma in 14%. chronic GVHD. Categorical parameters were compared using Chi-square test and continuous variables were com- Donors and stem cell source pared using the Mann–Whitney test. Multivariate predictive analyses were performed using Gray’s test and the propor- Fifty-seven percent of patients received sibling donor grafts, tional sub-distribution hazard regression model of Fine and 13% received grafts with one HLA-A, B, or DR antigen or Gray [14]. A stepwise backward procedure was used to con- allele mismatch, and 30% received grafts from HLA-A, B, struct a set of independent predictors. All predictors with a p and DR-matched unrelated donors. All patients and donors value below 0.10 in the univariate analysis were introduced were typed using PCR-SSP high-resolution typing for both into the multivariate model and sequentially removed if the 1 3 Medical Oncology (2018) 35:79 Page 3 of 8 79 Table 1 Characteristics of Factor No cGVHD cGVHD p value HSCT patients with or without chronic GVHD N = 409 338 Age 37 (< 1–69) 51 (< 1–70) < 0.001 Donor age 38 (0–74) 45 (0–77) < 0.001 Sex (male/female) 241/168 214/124 0.25 Donor sex (male/female) 239/164 179/152 0.18 Female to male 76 (19%) 89 (26%) 0.013 Disease stage (early/late) 180/199 129/195 0.04 Stem cell source (PBSC/BM/CB) 278/108/23 290/43/5 < 0.001 CD34 + cell dose (× 10 /kg) 6.8 (0.1–68) 6.7 (0.1 to − 19.9) 0.89 Donor Sibling 196 (48%) 242 (72%) < 0.001 MUD 153 (37%) 64 (19%) Mismatched 60 (15%) 31 (9%) 0.03 Conditioning MAC 165 (43%) 85 (26%) < 0.001 RIC 232 (57%) 245 (74%) ATG 233 (57%) 92 (27%) Diagnosis Non-malignant 53 (13%) 17 (5%) < 0.001 AML/ALL 90/52 (35%) 81/31 (33%) Ns CML/CLL 41/13 (13%) 36/21 (17%) Ns Lymphoma 55 (13%) 53 (16%) Ns MDS/MPS 36 (9%) 40 (12%) Ns Myeloma 29 (7%) 30 (9%) Ns Solid tumor 30 (7%) 13 (4%) Ns Other 10 (2%) 16 (5%) Ns Early stage CR1/CP1, Late stage beyond CR1/CP1, PBSC peripheral blood stem cells, BM bone marrow, CB cord blood, MUD matched unrelated donor, MAC myeloablative conditioning, RIC reduced intensity conditioning, ATG anti-thymocyte globulin, AML acute myeloid leukemia, ALL acute lymphoid leukemia, CML chronic myeloid leukemia, CLL chronic lymphoid leukemia, MDS myelodysplastic syndrome, MPS myeloproliferative syndrome p value was above 0.05. Risk factors included in the univari- was 29, 6, and 0%, respectively, for center A, B, and C. ate analysis were: patient and donor age, patient and donor Median time to onset for cGVHD was 5.7 (2.0–77) months sex, sex mismatch, disease stage, stem cell source, donor post-transplant. type, conditioning, ATG, diagnosis, center, GVHD prophy- ATG was administered at a frequency of 71, 13, and 1% laxis, CD34 + cell dose and prior aGVHD. All tests were in the three centers, respectively. The percentage of sibling two-sided. The type I error rate was fixed at 0.05 for factors donor transplants at each center was 42, 79, and 81%, respec- potentially associated with time-to-event outcomes. Analy- tively. Results were similar in terms of survival at the three ses were performed using the cmprsk package (developed centers [53% (48–58%), 49% (41–57%), 52% (45–59%), by Gray, June 2001), S-PLUS 6.2 software and Statistica respectively] as well as in terms of relapse-free survival software. (RFS) [46% (41–51%), 39% (31–47%), 42% (35–49%)] at 5 years. Results Risk factors for overall cGVHD The overall cumulative incidence of acute GVHD was In univariate analysis, significant risk factors for the devel- 56% and that of cGVHD was 48% (95% CI 44–52%). The opment of cGVHD included prior acute GVHD, RIC, incidence of cGVHD at the three centers A, B, and C was PBSC, sex mismatch, increased donor age, sibling donor, 32% (27–37%), 70% (63–77%), and 58% (50–66%), respec- and late disease stage (beyond first remission). The use tively. The percentage of children transplanted at each center of ATG was a protective factor (Fig.  1). In multivariate 1 3 79 Page 4 of 8 Medical Oncology (2018) 35:79 Fig. 2 Risk factor score for developing severe cGVHD including risk Fig. 1 Chronic GVHD incidence in patients treated with anti-thymo- factors from multivariate analysis with female donor to male recipi- cyte globulin (ATG) versus no ATG ent, reduced intensity conditioning (RIC), anti-thymocyte globulin (ATG) and prior acute GVHD analysis, the following variables significantly influenced the risk of overall cGVHD: use of ATG [HR = 0.41, 95% CI Table 2 Incidence of severe chronic GVHD after HSCT depending on number of risk factors (RF) and inclusion of anti-thymocyte glob- (0.32–0.52), p < 0.001], higher patient age (in 10-year incre- ulin (ATG) or not in the conditioning therapy. Only factors known at ments) [HR = 1.15, 95% CI (1.07–1.24), p < 0.001], prior time of transplantation were analyzed acute GVHD [HR = 1.30, 95% CI (1.04–1.63), p = 0.024] Severe cGVHD ATG (%) No ATG (%) p value and reduced intensity conditioning (RIC) [HR = 1.36, 95% CI (1.04–1.79), p = 0.028]. When analyzing risk factors for 1 RF 4 6 NS cGVHD after correcting for differences between patients 2 RF 4 24 < 0.001 receiving RIC or MAC, it is apparent that RIC patients 3 RF 7 40 0.01 still have higher cGVHD incidence [HR = 1.38, 95% CI (1.02–1.88), p = 0.038]. The analysis was done in order to eliminate confounding factors in each group. Table 3 Overall survival (OS) and transplant-related mortality (TRM) 5  years after HSCT, depending on the severity of chronic GVHD (95% confidence interval given in brackets) Risk factors for severe cGVHD Grade of cGVHD TRM OS No cGVHD 24% (19–29%) 51% (46–56%) The overall incidence of severe cGVHD was 14% (95% CI Mild 14% (8–20%) 72% (63–81%) 11–17%). In multivariate analysis, female donor to male Moderate 18% (11–25%) 71% (63–79%) recipient [HR 1.80 (95% CI 1.17–2.78), p = 0.008], RIC [HR Severe 31% (21–41%) 50% (39–61%) 4.85 (95% CI 2.40–9.83) p < 0.001], and prior aGVHD [HR p value < 0.001 < 0.001 2.14 (95% CI 1.34–3.42), p = 0.001] significantly increased All patients 22% (19–25%) 57% (53–61%) the risk of severe cGVHD while ATG had a protective effect [HR 0.20, (95% CI 0.11–0.37), p < 0.001]. Based on our findings, we developed a scoring system including significant risk factors from multivariate analysis was a significant protective effect from ATG on the inci- with regard to severe cGVHD incidence (Fig. 2). According dence of severe cGVHD at 5 years post-transplant (Table 2). to this scoring system, the risk of developing severe cGVHD was 3.1, 6.8, 26.4, and 40.4% at 5  years post-transplant Transplant‑related mortality (TRM), overall, among patients with one, two, three, or four risk factors. and relapse‑free survival Next, we conducted a multivariate analysis including only significant risk factors present at the time of transplanta- Concerning OS, the worst outcome was seen in patients tion. In this analysis, we found that patient age > 45 years, with severe cGVHD or no cGVHD. Similar results were female-to-male donation, and RIC increased the risk of observed concerning TRM. In this analysis, we found that severe cGVHD, while ATG remained a protective factor. the best outcomes were obtained in patients who developed When two to three of these risk factors were present, there mild–moderate cGVHD (Table 3). 1 3 Medical Oncology (2018) 35:79 Page 5 of 8 79 Relapse-free survival at 5 years was similar in patients developing mild or moderate cGVHD [59% (49–59%) vs. 64% (55–73%), respectively], but significantly higher in these same groups compared to patients without cGVHD or with severe cGVHD [RFS of 39% (34–44%) and 46% (35–57%), respectively; p < 0.001 for mild and moderate compared to severe or no cGVHD] (Fig. 3). ATG had no influence on RFS (Fig.  4). The risk of relapse or death was increased among patients with high-risk disease at transplantation [HR = 1.61, (95% CI 1.29–2.01), p < 0.001]. Interestingly, the best RFS was observed in patients with mild-to-moderate cGVHD irre- spective of disease stage at time of transplantation (Table 4). Discussion Fig. 4 Relapse-free survival in patients conditioned with or without anti-thymocyte globulin (ATG) Chronic GVHD remains the major cause of morbidity and mortality in long-term survivors after allogeneic stem cell conditioning regimen [19, 20]. Mechanisms involved in the transplantation. However, it is also correlated with a strong graft-versus-tumor effect. Thus, proper management of development of acute and chronic GVHD are not entirely congruent. In this regard, cGVHD is not simply the end patients should be based on individualized strategies taking into account the notion that the absence of cGVHD might stage of acute GVHD [21]. In accordance with this hypoth- esis, use of RIC might, in fact, decrease the risk of acute and hamper relapse-free survival while severe cGVHD leads to increased mortality due to infectious complications and increase the risk of chronic GVHD. It could be speculated that acute GVHD is mostly dependent on the cytokine storm organ failure [15–18]. In the current study, we identie fi d risk factors with regard mediated by the tissue injury induced by the high doses of chemoradiotherapy, which is avoided in the RIC setting. On to developing severe cGVHD, including female donor-to- male donor recipient, prior aGVHD and use of reduced the other hand, chronic GVHD would be more dependent on the persistence of host–origin antigen-presenting cells intensity conditioning. While the first two risk factors have previously been described, the latter requires further clarifi- that might trigger an alloresponse in donor T cells. The use of RIC favors the persistence of a mixed chimerism for a cation. In this regard, the finding of a higher risk of cGVHD among patients receiving RIC is somewhat surprising, since longer period post-transplant as compared to myeloablative conditioning. It could also be argued that since many centers previous studies have not been able to show a difference in terms of cGVHD incidence depending on the type of show a preference toward treating older patients with RIC mainly due to comorbidities, the median age in this patient group is higher compared to those treated with myeloabla- tive conditioning (MAC). This is also true in our study, and therefore, RIC patients are a higher-risk subpopulation for the development of cGVHD compared to MAC. Table 4 Relapse-free survival (RFS) in different grades of chronic GVHD according to disease stage Five-year RFS Early disease Late disease p value (%) (%) No cGVHD 45 36 0.09 Mild 72 48 0.016 Moderate 83 53 < 0.001 Severe 49 44 0.80 Fig. 3 Relapse-free survival dependent on severity of chronic GVHD Early stage CR1/CP1, Late stage beyond CR1/CP1 1 3 79 Page 6 of 8 Medical Oncology (2018) 35:79 In the present study, we have shown that the addition of the incidence of extensive cGVHD in patient groups younger ATG decreases the overall incidence of cGVHD without or older than 60 years [32]. hampering relapse-free survival, which is consistent with Most importantly, the current study allowed us to develop previous studies [6, 11, 17, 22–25]. a scoring system with clearly identifiable subgroups of Langston et  al. showed that the addition of ATG to patients at different risk of developing overall or severe fludarabine–melphalan in the RIC regimen for patients cGVHD. Remarkably, both severe cGVHD and no cGVHD receiving partially matched URD transplants does not had a similar adverse impact on outcome. Based on these increase the rates of relapse or infection. The same study did data, mild or moderate cGVHD show a desirable GvL effect not show any difference with regards to cGVHD incidence in without increasing the mortality from the procedure. Inter- the two groups with Fu–Mel–ATG versus Flu–Mel [26]. One estingly we found that in patients with more advanced dis- recent report shows that a fludarabine-containing RIC regi- ease stages the difference in RFS became less prominent, men with the addition of ATG is effective and safe for adults perhaps suggesting that this patient group relapses before a up to the age of 69 [27]. Investigation of the effect of ATG significant GvL effect is obtained. All together, these data in a matched related donor myeloablative setting has shown suggest that patients at higher risk of severe cGVHD should beneficial effects with reduction in both severe aGVHD and be identified in order to have a favorable influence on long- cGVHD, which translated into higher survival [28]. term outcomes via the use of more intense immunosuppres- Nevertheless, the use of pretransplant ATG as GVHD sive strategies, such as the use of ATG. In this regard, the prophylaxis in patients receiving grafts from URD has been lack of conclusive data regarding the impact of the use of discussed for years, and although most studies have shown a ATG on survival in most previously reported randomized significant reduction in acute GVHD and cGVHD, they have studies could be attributed to the lack of selection criteria, lacked evidence concerning a potential benefit on overall such that, according to our data, older males with female survival [11, 13, 24, 25, 29]. A GITMO group showed a sig- donors receiving RIC transplants would benefit the most nificant reduction in the incidence of grades III–IV aGVHD from receiving this prophylaxis. Pretransplant identification and extensive cGVHD, but this positive effect was counter - of patients at risk of developing graft-versus-host disease balanced by the increased risk of infections. In a follow-up remains an unmet medical need. In this regard, even among analysis of this study, encouraging results included a reduced patients receiving transplantation from HLA-identical risk of chronic lung dysfunction, protection against exten- donors, the risk of GVHD varies greatly among individuals. sive chronic GVHD, and an improved quality of life [21]. In Recently, Sorror et al. [33] reported that the pretransplant this prospective setting, there was no significant difference comorbidity index predicts the risk of severe aGVHD and between the two groups regarding relapse and long-term subsequent mortality. In the current study, we developed a survival. scoring system for cGVHD including risk factors known at These data contrast with a recent report from CIBMTR the time of transplant: RIC, female-to-male donation and describing lower overall survival, lower disease-free sur- patient age > 45 years. Patients with these three risk fac- vival, and an increased risk of relapse in patients receiving tors had an incidence of severe cGHD of 40% at 5 years, in vivo T-cell depletion [30]. This difference might be due while the same patients had a cumulative incidence of 7% at to the heterogeneous nature of the population included in the 5 years when they received ATG. Accordingly, the scoring CIBMTR study, in which patients received different prepa- system allows the tailoring of strategies to prevent cGVHD rations of ATG, dosage, conditioning regimens and donor in the early post-transplant period and in the long-term types. In addition, the type of conditioning determines the follow-up. Furthermore, we also identified RIC, female-to- effect of the antibody therapy since, according to Soiffer male donation, prior acute GVHD and not receiving ATG et al., there is a deleterious effect of in vivo T cell deple- as GVHD prophylaxis as risk factors for developing severe tion among patients undergoing RIC. Furthermore, both the cGVHD. This information would be of the greatest use for dosage and the preparation of ATG seem to be important in modifying immunosuppression during the post-transplant terms of transplant outcomes [13, 24, 25, 31]. In this regard, follow-up period. In this regard, these patients should be most studies have shown that an intermediate dose of rabbit- carefully monitored and might benefit from receiving early ATG (Thymoglobulin, Genzyme) ranging from 5 to 8 mg/kg treatment once signs or symptoms of cGVHD appear. leads to a positive reduction in severe aGVHD and cGVHD In conclusion, in the current study, we identified sub- without impairing relapse or long-term survival. groups of patients with different risk of cGVHD; these In addition, in the current study, we show that increasing parameters might help to tailor GVHD prophylaxis and man- patient age significantly influences the incidence of cGVHD, age immunosuppression in the long term. but only up to 50 years, which is consistent with a recent Author’s contribution GA and HH designed the study, wrote first draft, study including 206 patients who underwent RIC allo-HSCT and collected data for the Swedish patient cohort. JAPS contributed as plus 5 mg/kg r-ATG. In this study, there was no difference in 1 3 Medical Oncology (2018) 35:79 Page 7 of 8 79 second author. MR and RM conducted statistical analysis. TC-V and 11. Bacigalupo A, Lamparelli T, Barisione G, Bruzzi P, Guidi S, Ales- OLG conducted data collection for Spanish cohort. DC, LLC and LV sandrino PE, et al. Thymoglobulin prevents chronic graft-versus- conducted clinical management and critical review for patients added host disease, chronic lung dysfunction, and late transplant-related from Salamanca. JS conducted data collection and clinical management mortality: long-term follow-up of a randomized trial in patients together with JLP, IG and AE for patients from Barcelona. OR is pro- undergoing unrelated donor transplantation. Biol Blood Marrow fessor at the HSCT unit at Karolinska Huddinge and contributed with Transpl. 2006;12(5):560–5. experience-based input. PL was at the time head of the department of 12. 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Medical OncologySpringer Journals

Published: Apr 25, 2018

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