Early Infection after Allogeneic Transplant Increases NRM without Influencing Relapse Rate

Intro: Relapse post allogeneic transplant is the leading cause of early mortality in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Known risk factors of relapse include persistent disease at the time of transplant, use of anti-thymocyte globulin, reduced intensity conditioning, and absence of chronic graft versus host disease (GVHD). Early infection has been reported to increase non-relapse mortality (NRM) while protecting against hematologic disease relapse (Auletta et al., Blood 2016). We sought to determine the influence of patient features and post-transplant early infection (bacterial, fungal, and viral) on acute GVHD, relapse, and mortality.

Methods: Adult patients (N=146) with myeloid disorders (AML, MDS, MPN/CMML) who received an initial allogeneic transplantation from 2013-2018 at Oregon Health & Science University were retrospectively identified and followed until 6/30/20 for acquired infections, hematologic relapse, and survival outcomes. Time-to-event endpoints, starting from transplant date, were modeled with Cox regression for single events (overall survival [OS], cause-specific hazards for competing events) and Fine-Gray subdistribution regression for events with a competing risk (early infection vs. death, acute GVHD vs. death, relapse vs. NRM). Infection status (one or more confirmed infections) in the first 100 days post-transplant was considered as a time-dependent covariate.

Results: Among 146 adult patients, 77% had AML, 54% were male, and the median age was 59 years (range 18 - 72). The Karnofsky score was 90-100 in 44% and 60-80 in 51% of patients. Using 2017 ELN risk guidelines for AML and IPSS-R for MDS and MDS/MPN, 11% of patients were classified as low risk, 33% as intermediate, and 50% as adverse. The median time from diagnosis to transplant was 5 months (range 2 - 203). At the time of transplant, 63% of patients had attained some degree of response (i.e., complete remission [CR] or hematologic improvement). However, 66% had minimal residual disease (defined as persistent cytogenetic abnormalities or leukemia-associated mutations detected by NGS). Fifty-one percent of patients had myeloablative conditioning and 90% received peripheral blood stem cell grafts with methotrexate and calcineurin-based GVHD prophylaxis. Donors were HLA-matched in 86% of patients, with haploidentical and umbilical cord blood grafts representing 10% and 3%, respectively. Forty-six percent of donors were positive for cytomegalovirus (CMV).

Seventy-five percent (n=109) of patients had at least one infection in the first 100 days after transplant. Cumulative incidence rates of any infection are displayed in Table 1. The median time from transplant to first infection was 22 days, ranging from 0 to 73 days. Forty-three patients (29%) relapsed during study follow-up. The median time from transplant to relapse was 6.1 months (IQR 3.1 - 12.0). Over a median follow-up time of 18.7 months, 78 patients (53%) died, with median time to death of 4.1 months after transplant. Forty-six (59%) of the deaths were attributed to causes other than hematologic disease (i.e., infection, GVHD, other cancer).

Low prognostic risk and total body irradiation during conditioning were associated with early infection (Table 2). In the multivariable setting, a higher rate of death was associated with male gender (HR=1.67; p=0.040), having at least a 6-month lag between diagnosis and transplant (HR=2.79; p<0.001), and contracting an infection of any type (HR=2.54; p=0.003; Table 3).

There was no association between early infection and acute GVHD, which occurred in 85 patients (58.2%) with a median time to onset of 34 days. A greater incidence of acute GVHD was related to older recipient age (HR=1.88 for ≥50 years vs. <50; p=0.014), being male (HR=2.62; p<0.001), not having achieved a CR (HR=1.66; p=0.020), and undergoing transplant ≥ 6 months after diagnosis (HR=1.72; p=0.014). Infection did not correlate with the rate of relapse (HR=1.02, p=0.942) but significantly elevated the rate of NRM (HR=5.72, p<0.001). Time-independent variables associated with a higher probability of relapse were failure to attain a pre-transplant CR (HR=1.87; p=0.038) and having a CMV-positive donor (HR=2.11; p=0.016).

Conclusion: Our retrospective study found that post-transplant early infection in AML and MDS/MPN patients did not impact relapse rate but drastically increased the rate of NRM.