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D. Fuerst et al.
on the outcome with hematopoietic stem cell transplan- tation in a setting with competing risks. We adjusted these variables in a piecewise-constant manner for the time-dependent effects, extending standard Cox-regres- sion models in order to obtain more accurate risk esti- mates. For transplant-related mortality these were advanced disease stage, year of transplantation, source of stem cells, conditioning intensity and KPS. All these effects were highly significant (P<0.001). Year of trans- plantation before 2001, advanced disease stage, myeloab- lative conditioning and a poor KPS were associated with significantly increased early mortality after transplanta- tion. This observation is related to effects induced by tis- sue damage caused by the acute toxicity of condition- ing.14-16 After resolution of the acute toxicity these effects diminish.17 We estimate the time to resolution of acute toxicity to be around 4 months after transplantation according to the results obtained for the predictors condi- tioning intensity and KPS. The strikingly high transplant- related mortality risk for patients with a poor KPS in the first 4 months (HR: 2.10) substantially decreased in patients surviving this critical phase (HR: 1.37). Our data further suggest that improvements in transplantation pro- cedures and supportive care over time affect mainly mor- tality early after transplantation.18 Such a relationship may not be obvious in a Cox-regression approach with- out time-dependent effects. Peripheral blood stem cells as a graft source were associated with a lower risk of trans- plant-related mortality in the first year after transplanta- tion but a higher risk thereafter. The protective effect of peripheral blood stem cell grafts is most likely due to the faster engraftment of these stem cells as compared to bone marrow, leading to a shorter period of aplasia and decreased vulnerability to infections.19 It has been report- ed that transplantation with peripheral blood stem cell grafts leads to an increased incidence of chronic graft-ver- sus-host disease, which in turn may explain the higher
Table 7. Comparison of hazard ratios of selected covariables.
risk of transplant-related mortality more than 1 year after transplantation.20 Our analysis reveals here that the trans- plantation biology of bone marrow and peripheral blood stem cells is determined by two opposing effects, which would not have been detected in a more conventional analysis. Our approach enables a better understanding of the dynamic risk changes after hematopoietic stem cell transplantation.
Death from other causes summarizes deaths due to relapse or progression of disease and deaths unrelated to hematopoietic stem cell transplantation. With regards to this endpoint, time-dependent effects for disease stage, year of transplantation (2006-2013), conditioning intensi- ty and a poor KPS were detected.21,22 For disease stage, a considerably higher risk of death from other causes was observed in the first 10 months after transplantation, which reflects the higher incidence of relapse in patients in late disease stage.23 This is consistent with the results for relapse incidence within the composite endpoint of disease-free survival. This risk is considerably decreased in patients surviving more than 10 months after trans- plantation. Such information might allow physicians to reassure patients reaching this phase of follow-up. Patients transplanted in recent years had a slightly lower risk of transplant-related mortality and death from other causes in the first 8 months after transplantation, with no significant difference afterwards, which is most likely attributable to optimization in conditioning treatments and supportive care.24 Similarly, reduced intensity condi- tioning led to a lower early mortality in the first 4 months and a higher risk afterwards, highlighting the divergent effects on toxicity and relapse incidence.25 This cutpoint provides an estimate for the duration of conditioning tox- icity after hematopoietic stem cell transplantation. A poor KPS is evoked by more severe disease burden and comor- bidity. These problems can cause relapse and death from other causes. Consequently a poor KPS was associated
Covariable
Intermediate disease stage first 10 months
after 10 months
Advanced disease stage first 5 |10| 8 months after 5 |10| 8 months
Year of transplant 2001-2005 first 8 months
after 8 months
Year of transplant 2006-2013 first 8 months
after 8 months
RIC (vs. MAC) first 4 months after 4 months
KPS <80 (vs. 80-100) first 4 months after 4 months
TRM
DOC
Relapse
P-value HR P-value HR
NRM
P-value
<0.001 <0.001
<0.001 0.654
<0.001
0.907
<0.001 0.299
<0.001
HR
1.32
1.69 1.42
0.58 0.94
0.44
0.78
0.78 1.10
2.10
1.37
P-value HR <0.001
2.35 1.45
<0.001 3.39 <0.001 2.07
1.10
<0.001 0.487
<0.001 0.88
0.013 1.13
<0.001 0.89 0.090 1.11
<0.001 2.75
0.004 1.34
<0.001 1.87 <0.001 <0.001 1.52 <0.001
<0.001 2.92 <0.001 <0.001 1.73 <0.001
1.42 1.75
0.082
0.95 0.391 0.67 1.21 0.025 1.04
0.041 0.82 <0.001 0.56
0.073 1.10 0.273 0.99
1.13 <0.001
0.130 0.76 0.024 1.06
<0.001 2.10 <0.001 2.29
TRM: transplant-related mortality; DOC: death of other cause; NRM: non-relapse mortality; HR: hazard ratio; MAC: myeloablative conditioning; RIC: reduced intensity condition- ing; KPS: Karnofsky performance score.
<0.001 1.26 0.021
1.26 0.028
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haematologica | 2018; 103(9)