Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti–T-cell globulin ATG-Fresenius

Abstract

Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD).Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] ‫؍‬ 1.21, P ‫؍‬ .47, and HR ‫؍‬ 0.68, P ‫؍‬ .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR ‫؍‬ 0.84, P ‫؍‬ .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity. (Blood. 2011; 117(23):6375-6382) IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used worldwide as a curative therapy for malignant and nonmalignant hematologic disorders. Chronic graft-versushost disease (cGVHD) is the leading cause of nontransplantation mortality and morbidity after allogeneic HSCT. 1-3 cGVHD is a multiorgan disease resembling autoimmune disorders, such as scleroderma or systemic lupus. 4,5 Its incidence and prevalence are rising because of transplantation practices known to be associated with increased risk of cGVHD. 4,6 Indeed, older patients now undergo HSCT, and more transplantations are being performed from unrelated donors and/or with peripheral blood stem cells instead of bone marrow. Furthermore, the reduced-intensity conditioning (RIC) regimens developed during recent years have also led to higher numbers of transplantations performed worldwide. 7,8 However, although the acute GVHD (aGVHD) rate appears lower after RIC, the incidence of cGVHD seems to be unaffected. 9 Altogether, cGVHD thus remains the most challenging complication after allogeneic HSCT. 10 The main risk factor for developing cGVHD is the previous occurrence of aGVHD. 11 Thus, transplantation physicians have focused on decreasing the rate of aGVHD to lower nonrelapse mortality (NRM) associated with both aGVHD and cGVHD. However, although calcineurin inhibitors (cyclosporine or tacrolimus) in association with methotrexate have proven to decrease the aGVHD rate in randomized studies and although new regimens, such as the association of rapamycin with tacrolimus, seem to l...

Identification of risk factors for bronchiolitis obliterans syndrome after reduced toxicity conditioning before hematopoietic cell transplantation

“…The protective effect of ATG on chronic lung dysfunction has been demonstrated in prospective randomized trials. 30,31 Other authors have reported an association of extensive cGVHD with BOS. 3,32 However, cGVHD besides BOS and aGVHD, both of which were previously identified as a risk factors for BOS in heterogeneous groups of transplanted patients, 3,33 could not be shown to be significantly associated with BOS in our patient cohort.…”

IL15 levels on day 7 after hematopoietic cell transplantation predict chronic GVHD

“…How ATG, given peritransplant, prevents cGVHD, [13][14][15]20,31,44,45 which typically develops at X3 months post transplant, has been a mystery. The correlation between ATG and IL15 levels and the inverse correlation between IL15 levels and CD8 T-cell counts ( Figure 3) and the published inverse correlation between day 7 or 28 ATG levels and day 28 CD8 T-cell counts 37 suggest that ATG kills or prevents expansion of CD8 T cells, some of which (alloreactive CD8 T cells?)…”

“…Prophylaxis of cGVHD using T-cell depletion ex vivo (for example, by graft enrichment for CD34 cells) or in vivo (for example, using alemtuzumab or polyclonal anti-T-cell antibodies like rabbit antithymocyte globulin (ATG)) is more efficacious than treatment. [9][10][11][12][13][14][15] However, the prophylaxis has side effects (for example, viral infections 16 ). Therefore, it would be desirable to give prophylaxis or preemptive therapy only to patients at high risk of developing cGVHD.…”

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)

“…[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.…”