Competing-risk outcomes after hematopoietic stem cell transplantation from the perspective of time-dependent effects

Abstract

The success of hematopoietic stem cell transplantation is determined by multiple factors. Additional complexity is conferred by covariables showing time-dependent effects. We evaluated the effect of predictors on competing-risk outcomes after hematopoietic stem cell transplantation in a time-dependent manner. We analyzed 14951 outcomes of adult patients with hematologic malignancies who underwent a first allogeneic transplant. We extended the combined endpoints of disease-free and overall survival to competing-risk settings: disease-free survival was split into relapse and non-relapse mortality. Overall survival was divided into transplant-related mortality, death from other causes and death from unknown causes. For time-dependent effects we computed estimators before and after a covariable-specific cut-point. Patients treated with reduced intensity conditioning had a constantly higher risk of relapse compared to patients treated with myeloablative conditioning. For non-relapse mortality, patients treated with reduced intensity conditioning had a reduced mortality risk but this effect was only seen in the first 4 months after transplantation (hazard ratio: 0.76, P<0.001) and not afterwards. Graft source exhibited a time-dependent effect on both transplant-related mortality (in first year: hazard ratio 0.70, P<0.001; after first year: hazard ratio 1.47, P=0.002) and non-relapse mortality (in first 8 months: hazard ratio 0.75, P<0.001; after first 8 months: hazard ratio 1.38, P<0.001). Patients with a poor Karnofsky performance score (<80) had a considerably higher risk of all endpoints in the first 4 months. The competing-risk analysis for overall survival and disease-free survival allows resolution of effects with different vectors early and later after stem cell transplantation, as shown for graft source. This information may be useful in risk assessment of treatment choices and for counseling patients on an individual basis.

The Human Leukocyte Antigen-DPB1 Degree of Compatibility Is Determined by Its Expression Level and Mismatch Permissiveness: A German Multicenter Analysis

“…Time-dependent effects of other clinical covariates were also modeled and are shown in Table S1 in Supplemental Material. These time-dependent covariables resemble effects that were explored and published previously (24,27).…”

“…For the endpoints NRM, aGvHD and relapse, cumulative incidence curves for competing risk data were generated and compared with the method of Gray ( 23 ). For multivariate analyses cause specific Cox models have been used, allowing for adjustment of time-dependent covariate effects in a piecewise constant manner ( 24 ). The breakpoints were chosen graphically ( 22 ).…”

The complexity of stem cell transplants: can we improve our understanding?

“…In a study published in this issue of Haematologica, Fuerst and colleagues have added a fourth level of complexity: they hypothesized that the effect of different covariates may be different at different intervals from transplantation, and this is exactly what they found. 1 One example is the stem cell source: bone marrow and peripheral blood as sources of stem cells have been compared in numerous prospective and retrospective studies, including meta-analyses, to define which is better, and results have often been conflicting. Again the complexity of transplantation does not make comparisons easy: in the first randomized study 2 of patients with low-risk disease, receiving a myeloablative regimen and HLA identical sibling grafts, the hazard risk (HR) of death was 1.20 for recipients of peripheral blood compared to bone marrow (P=0.2).…”

“…Fuerst and colleagues offer a new way of looking into this particular issue: they found that peripheral blood has a significant protective effect on non-relapse mortality early after transplantation, and a significant detrimental effect later on. 1 The time point for a change of effect on non-relapse mortality was set at 8 months: this means that patients receiving peripheral blood grafts had a lower non-relapse mortality within 8 months (HR: 0.75) and a higher non-relapse mortality beyond 8 months after transplantation (HR:1.38), which were both highly significant effects (Figure 1). There was no protective effect of peripheral blood on relapse, which is the competing event (Figure 1).…”