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My paper of the month - Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors

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Each month one member of the EBMT Scientific Council will select and comment a recent paper in the field of stem cell transplantation and cellular therapy that was published in high ranked journals.

For this month Newsletter, Jan Styczynski, Chair of the Infectious Diseases Working Party, comments on the publication entitled “Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors.”, published online in Bone Marrow Transplantation.

Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors

Authors: Jan Styczyński, Gloria Tridello, Linda Koster, Simona Iacobelli, Anja van Biezen, Steffie van der Werf, Małgorzata Mikulska, Lidia Gil, Catherine Cordonnier, Per Ljungman, Diana Averbuch, Simone Cesaro, Rafael de la Camara, Helen Baldomero, Peter Bader, Grzegorz Basak, Chiara Bonini, Rafael Duarte, Carlo Dufour, Jurgen Kuball, Arjan Lankester, Silvia Montoto, Arnon Nagler, John A. Snowden, Nicolaus Kröger, Mohamad Mohty & Alois Gratwohl for the Infectious Diseases Working Party EBMT

Bone Marrow Transplantation (Published: 27 August 2019)

Content of the paper: Infectious Diseases Working Party of EBMT analyzed data of 55,668 deaths in 114,491 patients with ALL, AML, or CML transplanted (83.7% allogeneic) between 1980-2015. Investigation was done in a landmark analysis for causes of death at day 30 (very early), day 100 (early), at 1 year (intermediate) and at 5 years (late), in two time-dependent cohorts: 1980-2001 and 2002-2015. According to the rules of the EBMT Registry, deaths were classified as caused by: relapse, GVHD, infections and "other". Infectious deaths were analyzed as bacterial, fungal, viral, parasitic, mixed and unknown infections. Mortality from all causes decreased from cohort 1 (1980-2001) to cohort 2 (2002-2015) in all post-transplant phases after auto-HCT. After allo-HCT, mortality from infections, GVHD, and toxicity decreased up to 1 year, but increased at 5 years; deaths from relapse increased in all post-transplant phases. Infections of unknown origin were the main cause of infectious deaths. Lethal bacterial and fungal infections decreased from cohort 1 to cohort 2, not unknown or mixed infections. Infectious deaths were associated with patient-, disease-, donor type-, stem cell source-, center-, and country- related factors. In conclusion, transplant centers have successfully managed to reduce death after HCT in the early and intermediate post-transplant phases, and have identified risk factors. Late post-transplant care could be improved by focus on groups at risk of relapse and better identification of infections of "unknown origin".

Commentary: This paper presents results of one of the largest ever study on HCT patients. It shows the data on changes of causes of deaths after HCT over 35 years in EBMT centers, with focus on deaths from infectious complications. The main message of the paper is that HCT outcomes were and can be improved. This study clearly shows that European transplant teams have successfully managed to reduce all-cause mortality after auto-HCT at all post-transplant time phases, and in the first 100 days after allo-HCT, despite an increase in the patient pre-transplant risk profile. However, data did not show a reduction of death afterwards and no reduced mortality from relapse after allo-HCT in the late post-transplant phase. Looking on infectious complications, the risk of death was higher with increasing age of patients, in advanced stage of leukemia, during first year after cord blood transplantation while peripheral blood as a stem cell source was associated with a lower rate of deaths in the first 100 days, but not afterwards. It suggests an additional indirect late GVHD effect of peripheral blood stem cells. The study indicates areas for improvements. The first step is to become aware of the reality, and to focus on preventable and reversible late complications. There is a need for improved strategies for: (1) targeted follow-up programs of reducing risk of relapse, especially for older patients; (2) better identification of causes and treatment of mixed and "unknown" infections through collaborative efforts. The major role of "allogeneicity" in death might lead to reconsider more carefully risk adapted indications for allogeneic HCT and improve prophylactic programs.