Comparison of allogeneic stem cell transplantation and non-transplant approaches in elderly patients with advanced myelodysplastic Syndrome: optimal statistical approaches and a critical appraisal of clinical results using non-randomized data

TY - JOUR

T1 - Comparison of allogeneic stem cell transplantation and non-transplant approaches in elderly patients with advanced myelodysplastic Syndrome: optimal statistical approaches and a critical appraisal of clinical results using non-randomized data

AU - Brand, Ronald

AU - Putter, Hein

AU - van Biezen, Anja

AU - Niederwieser, Dietger

AU - Martino, Rodrigo

AU - Mufti, Ghulam

AU - Onida, Francesco

AU - Symeonidis, Argiris

AU - Schmid, Christoph

AU - Garderet, Laurent

AU - Robin, Marie

AU - van Gelder, Michel

AU - Finke, Jürgen

AU - Bornhäuser, Martin

AU - Kobbe, Guido

AU - Germing, Ulrich

AU - de Witte, Theo

AU - Kröger, Nicolaus

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Allogeneic stem cell transplantation (ASCT) from related or unrelated donors may cure patients with myelodysplastic syndromes (MDS), a heterogeneous group of clonal stem cell disorders. We analysed 384 elderly patients (55-69 years) with advanced MDS who received either ASCT (n=247) and were reported to The European Group for Blood and Marrow Transplantation (EBMT) or a non -transplant approach (n=137) reported to the Düsseldorf registry. Besides an attempt to answer the question of "comparison", the purpose of this work is to explain the difficulties in comparing a non-transplant with a transplant cohort, when death before transplant is likely but unknown and the selection of patients for transplant is based on assumptions. It shows which methods are almost always biased and that even the most sophisticated approaches crucially rely on clinical assumptions. Using the most appropriate model for our data, we derive an overall univariate non-significant survival disadvantage for the transplant cohort (HR: 1.29, p = 0.11). We show that such an "average" hazard ratio is however misleading due to non-proportionality of the hazards reflecting early treatment related mortality, the occurring of which is logically correlated with the interval between diagnosis and transplant creating a disproportional drop in the (reconstructed) survival curve of the transplanted patients. Also in multivariate analysis (correcting for age > 60 (HR: 1.4, p = 0.02) and abnormal cytogenetics (HR: 1.46, p = 0.01)), transplantation seems to be worse (HR: 1.39, p = 0.05) but only in the (incorrect but commonly applied) model without time varying covariates. The long term (time depending) hazard ratio is shown to be virtually 1 and overall survival is virtually identical in both groups. Nonetheless no conclusion can be reached from a clinical point of view without assumptions which are by their very nature untestable unless all patients would be followed from diagnosis.

AB - Allogeneic stem cell transplantation (ASCT) from related or unrelated donors may cure patients with myelodysplastic syndromes (MDS), a heterogeneous group of clonal stem cell disorders. We analysed 384 elderly patients (55-69 years) with advanced MDS who received either ASCT (n=247) and were reported to The European Group for Blood and Marrow Transplantation (EBMT) or a non -transplant approach (n=137) reported to the Düsseldorf registry. Besides an attempt to answer the question of "comparison", the purpose of this work is to explain the difficulties in comparing a non-transplant with a transplant cohort, when death before transplant is likely but unknown and the selection of patients for transplant is based on assumptions. It shows which methods are almost always biased and that even the most sophisticated approaches crucially rely on clinical assumptions. Using the most appropriate model for our data, we derive an overall univariate non-significant survival disadvantage for the transplant cohort (HR: 1.29, p = 0.11). We show that such an "average" hazard ratio is however misleading due to non-proportionality of the hazards reflecting early treatment related mortality, the occurring of which is logically correlated with the interval between diagnosis and transplant creating a disproportional drop in the (reconstructed) survival curve of the transplanted patients. Also in multivariate analysis (correcting for age > 60 (HR: 1.4, p = 0.02) and abnormal cytogenetics (HR: 1.46, p = 0.01)), transplantation seems to be worse (HR: 1.39, p = 0.05) but only in the (incorrect but commonly applied) model without time varying covariates. The long term (time depending) hazard ratio is shown to be virtually 1 and overall survival is virtually identical in both groups. Nonetheless no conclusion can be reached from a clinical point of view without assumptions which are by their very nature untestable unless all patients would be followed from diagnosis.

KW - Aged

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Myelodysplastic Syndromes

KW - Prognosis

KW - Stem Cell Transplantation

KW - Transplantation, Homologous

KW - Treatment Outcome

U2 - 10.1371/journal.pone.0074368

DO - 10.1371/journal.pone.0074368

M3 - SCORING: Journal article

C2 - 24116002

VL - 8

SP - e74368

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 10

ER -