Thymoglobulin Decreases the Need for Immunosuppression at 12 Months after Myeloablative and Nonmyeloablative Unrelated Donor Transplantation: CBMTG 0801, a Randomized, Controlled Trial

Abstract Background: Randomized trials (RCT) have shown that anti-thymocyte globulin (ATG) decreases the incidence and severity of chronic graft-versus-host disease (cGVHD) following unrelated donor transplants, but it is not used universally. We conducted a multicenter RCT to test whether the addition of Thymoglobulin® (TG) to both myeloablative (MA) and nonmyeloablative (NMA) preparative regimens results in a decrease in use of immunosuppression for cGVHD, leading to improvements in quality of life but without an increase in mortality, disease relapse or serious infections. Methods: Multicentric (Canada and Australia, 12 centres), open label RCT, in patients having transplantation from unrelated donors for a hematologic malignancy. Inclusion criteria: age 16-70, MA or NMA preparative regimen, bone marrow or peripheral blood graft, fully major histocompatibility complex (MHC) matched (HLA-A, B, C and DRB1) or 1-antigen/allele mismatched donor. Subjects were allocated by minimization procedure to TG or No Thymoglobulin® (NoTG). The TG arm received 0.5, 2.0, 2.0 mg/kg of TG on days -2, -1 and +1 respectively. Analyses were on a modified intention-to-treat basis for patients actually transplanted. The primary end-point was freedom from cGVHD at 12 months from transplantation defined as withdrawal of all systemic immunosuppressive agents (IST) without resumption up to 12 months after transplantation. Secondary end-points included relapse, serious infections, acute and chronic GVHD, overall survival (OS), and quality of life (QoL). QoL measures included Life Happiness Rating, Affect Balance Scale, FACT-BMT, EuroQol 5D, Center for Epidemiologic Studies-Depression Scale, Chronic GVHD Symptom Scale, and the Illness Intrusiveness Ratings Scale, collected prior to randomization and at 12 months. Treatment group comparisons, adjusted for baseline values, were made using logistic regression, analysis of covariance or the Cox proportional hazards model; in the presence of competing risks the method of Fine and Gray was implemented. Results: Data were locked on July 7, 2014. Two hundred and three (203) subjects consented and were randomized; seven were non-evaluable (6 withdrew before transplant, 3 having relapsed; 1 withdrew consent day 139), leaving 196 subjects for analysis. One subject was later found ineligible but was analyzed. Study populations were balanced for clinical risk factors. Sixty-seven percent (67%) received myeloablative conditioning, and 88% peripheral blood. Eighty-three percent (83%) were 8/8 HLA matched. Overall, freedom from IST at 12 months was twice as high in the TG group 37.4% vs. 16.5%, p=0.0001, even after adjusting for clinical factors: odds ratio 4.25 (95% CI, 1.87 – 9.67); p=0.006 or separately analyzing the MA and NMA groups. Acute GVHD (I-IV) and moderate/severe NIH grades of cGVHD were higher in the NoTG group, while relapse, non-relapse mortality, serious infections and OS were not significantly different. CGVHD (mild/mod/severe) was borderline significant using Fine and Gray (p=0.12; HR=0.65 95% CI (0.38 – 1.11) but the Cox result was significant p=0.01 (HR=0.48 95% CI (0.27 -0.85). Life Happiness was higher and Chronic GVHD Symptoms lower in the TG group as compared to the NoTG group (p=0.014 and 0.017 respectively); no other measure differed significantly. Conclusions: Addition of TG to the conditioning regimen for unrelated donor transplantation results in twice the likelihood of being alive and off immunosuppression at 12 months after transplantation, and is associated with modest improvements in some aspects of QoL. This benefit is seen without an increase in relapse, serious infections or non-relapse mortality. Our data support the use of TG in both MA and NMA preparative regimens before unrelated donor transplantation.TableTG N=97NoTG N=99p-valuePRIMARY ENDPOINTFreedom from IST at 12 mos37.4%16.5%0.001Myeloablative Subanalysis37.9%19.7%0.02Nonmyeloablative Subanalysis36.4%9.7%0.01SECONDARY ENDPOINTSAcute GVHD I-IV58.6%73.2%0.012cGVHD (NIH criteria)22.4%33.4%0.01 (Cox) 0.12 (Fine and Gray)cGVHD (NIH) Mod/Severe4.4%31%0.0001Serious infections38.4%37.1%0.85Relapse10.1%13.4%0.27Non-relapse mortality (12 mo)19.2%24.1%0.45Survival (12 mo)74.7%64.5%0.16Life Happiness Rating (QoL)*7.405.970.014GVHD Symptom Scale (QoL)*14.9520.930.017* Other QoL measures not significant Disclosures Walker: Sanofi: Research Funding. Off Label Use: Thymoglobulin which is the intervention in this randomized trial. Kuruvilla:Sanofi Aventis: Honoraria. Popradi:Sanofi: Honoraria.

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