The Expansion of Gastrointestinal-Associated αβ T Cell Clones in Peripheral Blood Associates with Severe Steroid Refractory GVHD

Abstract

Rabbit anti-thymocyte globulin (ATG) given with conditioning for allogeneic haematopoietic stem cell transplantation (alloHSCT) is effective in reducing the risk of chronic graft-versus-host disease (cGVHD). Whether conventional risk factors for cGVHD apply to ATG-conditioned alloHSCT is not known. Between the years 2004 and 2011, 356 adults (median age 48) from 3 centres received 4.5 mg/kg of Thymoglobulin prior to alloHSCT for haematologic malignancy (acute leukaemia 58%, chronic myeloid leukaemia 6%, other myeloid malignancy 15%, other lymphoid malignancy 21%). Donors were unrelated in 64%. Conditioning was myeloablative in 94%. Peripheral blood grafts were used in 97%. At 3 years, overall survival was 61.0% (95% CI 55.3-67.3%), cumulative incidence of relapse was 32.6% (95% CI 26.2-38.5%) and transplant-related mortality was 18.8% (13.2-24.1%). 342 patients were evaluable for the primary endpoint of cGVHD requiring systemic immunosuppression (cGVHD-IS). The cumulative incidence of cGVHD-IS at 3 years was 37.2% (95% CI 31.1-42.7%). On multivariate analysis, only prior grade 2-4 aGVHD (HR 3.08, 95% CI 2.10-4.52, P < .001) was associated with a significant increase in risk of cumulative incidence of cGVHD-IS. Recipient age of greater than 40 years was associated with significantly less cGVHD-IS (HR 0.66, 95% CI 0.45-0.97, P ¼ .03) in univariate but not multivariate analysis. The use of unrelated donors, donor age over 40, female donor/male recipient gender combination and recipient CMV seropositivity were not associated with increased cGVHD-IS. There was insufficient power to determine the effect of graft type (peripheral blood vs bone marrow) on cGVHD-IS, but the incidence did not appear higher in peripheral blood graft recipients. In summary, in this cohort, traditional pre-transplant risk factors for cGVHD were not predictive. In patients undergoing in vivo T-cell depleted alloHSCT, novel predictors of cGVHD may be needed.Chronic graft versus host disease (cGVHD) is a common complication of allogeneic stem cell transplantation (ASCT). Tacrolimus prophylaxis has been proven to be instrumental in the prevention of acute graft versus host disease (aGVHD) a common precursor to developing cGVHD. Our institution uses oral tacrolimus prior to ASCT because we perform ASCT in the outpatient setting and increases ease of administration. We retrospectively reviewed our experience in 94 consecutive patients (pts) who received ASCT from 10 /10 HLA matched donors, 47 were matched sibling donors (MSD) and 47matched unrelated donors (MUD) with a median age of 50 and 52 respectively. All patients received GVHD prophylaxis with tacrolimus started orally between day -3 and day -1 at a dose of 0.06mg/kg per day divided twice daily. Standard short course methotrexate (MTX) was prescribed for all pts (D1 dose 15mg/m2, D3, 6, and 11 doses at 10mg/ m2). Pts who had sub-therapeutic tacrolimus levels (less than 5ug/L) on the day of transplant (D0) were compared to pts who had therapeutic tacrolimus levels (greater than 5ug/ L) for inc...