Dual T-cell depletion with ATG and PTCy combined with cyclosporine (CsA) in peripheral blood (PB) reduced intensity conditioning (RIC) allo-HSCT results in an impressive control of clinically relevant GVHD.
We aim to share the largest and unique single center experience using this novel GVHD combination in allo-HSCT for hematological malignancies.
Between October 2015 and April 2019, 365 consecutive adult recipients underwent PB RIC allo-HSCT. Conditioning regimen consisted on fludarabine, busulfan and 200 cGy of total body irradiation. For GVHD prophylaxis all cases received ATG, PTCy (50mg/kg/24h x 2 doses on day +3 and +4) and CsA since day +5.
Two hundred fifty-nine (71%) recipients, transplanted between 2015 and May 2018, received a total dose of 4.5mg/kg of rabbit-ATG (given on day -3,-2 and -1). In May 2018, the protocol was reviewed and refined decreasing the dose of ATG to a total of 2mg/kg (given on day -3 and -2). A total of 106 (29%) recipients received the lowered dose of ATG.
Data was collected retrospectively and updated on July 2019. Cumulative incidence (Cum.Inc) of GVHD, CMV and EBV reactivation analysis was assessed accounting relapse and death as competing events. The multivariate analysis for OS and RFS was controlled by the following significant variables in the univariate analysis: age at transplant, disease risk index (DRI) (low and moderate v's high and very high), Karnofsky performance status (>80% v's ≤80%), HCT-CI score ≥3 and donor type.
Baseline characteristics and main post-transplant information and outcome are summarized in Table 1 and 2.
The cum.Inc of grade II-IV and grade III-IV at day +100 was respectively 14% (95 confidence interval (CI) 11.1-18.4) and 4.7% (95% CI 2.8-7.2). The cum.Inc of moderate and severe chronic GVHD at 1 year was 13% (95% CI 9.7-16.8). ATG dose and donor type did not influence acute/chronic GVHD rates (Table 3).
The cum.Inc of CMV and EBV reactivation at day +180 was comparable between the two cohorts that received different dose of ATG (P>0.05). However, in the cohort that received a lower dose of ATG (2mg/kg), no CMV disease was documented and the percentage of probable or proven EBV-post-transplant lymphoprolipherative disease (P/P-PTLD) was only 3.7%. The percentages of CMV disease and P/P-PTLD in the group that received a dose of ATG of 4.5 mg/kg were respective 4.6% and 8.8%.
Overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM) and the cumulative incidence (cumInc) of acute GVHD of the entire cohort and according to the ATG dose are shown in the Table 2 and the Table 3. OS and RFS curves of all 365 patients and stratified according to donor type are shown in the Plots 1 to 4.
In the multivariate analysis, age at transplant [(HR 1 (95% CI 1.01-1.02); P=0.046], high and very high DRI score [HR 1.8 (95% CI 1.2-3.6); P=0.001], KPS ≤80% [HR 1.8 (95% CI 1.2-2.7); P=0.001], and HCT-CI score ≥3 [HR 1.4 (95% CI 1.01-2.09); P=0.042] were significant risk factors for worse OS. Donor type was not a significant parameter for OS (P>0.05).
In the multivariate analysis of risk factors for RFS, high DRI score [HR 1.7 (95% CI 1.2-2.4); P=0.002], and a KPS ≤80% prior allo-HSCT [HR 2 (95% CI 1.4-2.8); P<0.001] were significant risk factors for worse RFS. To receive grafts from a 10/10 MUD was a significant parameter for better RFS [HR 0.6 (95% CI 0.4-0.9); P=0.046].
Dual T-cell depletion with ATG and PTCy provides an impressive control of GVHD with acceptable relapse rates using PB stem cell grafts independently of the donor type. This observation suggests that the present combination overcomes the HLA-barrier and its effect on GVHD.
Acute GVHD rates are effectively controlled with a dose of ATG of only 2mg/kg when it is combined with PTCy and CsA. Further investigations need to be done to better define the efficacy of a lower dose of ATG controlling chronic GVHD in this setting.
Further investigations and refinements need to be done to improve survival rates in those recipients with higher DRI score and worse KPS ≤80% prior transplantation.
Michelis:CSL Behring: Other: Financial Support. Mattsson:Gilead: Honoraria; Therakos: Honoraria; Celgene: Honoraria.
Asterisk with author names denotes non-ASH members.