Impact of donor and recipient Epstein-Barr Virus serostatus on outcomes of allogeneic hematopoietic cell transplantation: a systematic review and meta-analysis
Michalina Kołodziejczak et al
Ann Hematol. 2021 Mar;100(3):763-777. doi: 10.1007/s00277-021-04428-9. Epub 2021 Jan 25.
Epstein Barr virus (EBV) is an ubiquitous virus which infects the majority of the population and then remains latent in B cells. In the immuno-compromised state post-HCT EBV can reactivate and cause a range of complications. It is routinely screened for pre-transplant in both patients and donors and there has been an indication from previous EBMT studies that survival and other outcomes may be impacted by EBV serostatus, but statistical power and conclusions are limited.
This study combined the three EBMT studies to undertake a meta-analysis with greater numbers i.e. 26,650 patients with haematological cancers and non-malignant diseases undergoing allogeneic HSCT. The rate of EBV seropositivity was 85.1%, including 86.6% and 83.6% among transplant recipients and healthy donors, respectively. The main findings are that in patients undergoing allogeneic HCT, positive EBV serology in both pre-transplant EBV-positive donors and recipients is associated with a significant increase in development of subsequent GVHD, along with a decreased survival and increased relapse in EBV seropositive patients. More specifically, recipient EBV seropositivity increased the risk of cGVHD by 12%, de novo cGVHD by 17%; increased NRM by 11%, increased RI by 11%, decreased OS by 14%, and decreased RFS by 11%, whilst donor EBV seropositivity increased the risk of cGVHD by 17%, de novo cGVHD by 14%, and aGHVD by 5%. There was no significant effect of recipient EBV serostatus on NRM.
Although there are several methodological limitations, including the small number of ‘comparator’ EBV serostatus R−/D− patients, and definitive conclusions cannot be made, this study of a large number of patients generates interesting data to guide further studies in this area. What the data means clinically and mechanistically is also to be determined i.e. whether the baseline recipient EBV serostatus (positive/negative) is a ‘nonspecific’ indicator leading to long-term adverse clinical outcomes rather than anything EBV specific, or whether donor and recipient serostatus can usefully identify patients at the higher risk of long-term clinical events or help with donor selection also remains to be defined.
Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends over 30 years
Passweg JR et al
Bone Marrow Transplant. 2021 Feb 23. doi: 10.1038/s41409-021-01227-8. Online ahead of print.
Every year since 1990 the EBMT activity survey has reported trends in activity and this was a very special 30th edition. Based in Basel, the survey is separate from the more detailed EBMT registry reporting, and captures activity data across the indications from a greater range of centres, including centres who are associate EBMT members and non-members both within and outside Europe. In 1990 there were 4234 patients from 143 centers in 21 countries. Since then, the annual survey has been updated to incorporate progress in clinical practice and new technology to capture trends in HCT activity, including cell therapy. The survey now reflects the growth of HCT in Europe to over 800,000 transplant and cell therapy procedures.
This year’s report, based on the 2019 activity survey data, summarises the changes in activity and indications since the 2018 survey and also over the last 30 years. In 2019, 700 centres responded – a 96% return rate, covering 82% of EBMT members. 48,512 first transplants were reported in 43,581 patients with 19,798 HCT (41%) were allogeneic and 28,714 (59%) autologous HCT. Overall, there was a 2.2% increase in transplant activity since 2018, but the number of paediatric patients decreased by 3.3%. As expected, the main indications for allogeneic HCT were myeloid malignancies for allogeneic HCT, and, for autologous HCT lymphoid malignancies, especially myeloma. Regarding trends in donor type, haploidentical donors increased by 17.8%, and cord blood decreased by 1%. Growth in cellular therapies, such as CART cells, increased to 1134 reported patients for 2019. Access to transplant in different countries is also reflected by transplant rates and centre density e.g. ranging from 0.2 in Nigeria to 476 per 10 million in Israel for allogeneic HCT, with 5 countries not reporting any allogeneic transplants.
However, the major value in this recent report is the summary of the last 30 years, which provides not only an impressive historical testament to the progress in our specialty, but important trends for clinicians and those involved in health service planning and patient access to transplant and cell therapy procedures.
Conditioning intensity before allogeneic haematopoietic stem cell transplantation: a quality control audit
Alois Gratwohl et al
Br J Haematol. 2021 Mar;192(6):e151-e154. doi: 10.1111/bjh.17369. Epub 2021 Feb 22.
Reduced intensity conditioning (RIC) has become ‘routine’ in our day-to-day clinical practice for allogeneic HCT. The biggest driver for its introduction and increasing use has been reduction in early complications, symptomatic and supportive care needs of patients and early treatment related mortality and its use has extended allogeneic transplantation to older and frailer patients.
However, the ‘creeping’ development of RIC has arguably progressed in our ‘routine’ practice with not as much scrutiny as necessary. This paper is a thought-provoking ‘quality control audit’ drawing on data from the EBMT Activity Survey to look critically at the evolution of RIC based transplantation across contributing countries from 2000 to 2018. During this time period, the proportion of RIC transplants increased initially from 20 to 40%, but after 2010 stabilised between 38 and 41%.
Looking specifically at 2018, where 19,630 allogeneic transplants were registered (38% as RIC), a substantial variation in clinical practice across different countries was noted. For example, in the 33 countries reporting more than 50 allogeneic HSCT, the proportion of RIC transplants (of total allogeneic transplant activity) ranged widely from 1.7% to 83% (median 39.1%). This variation in practice is all the more remarkable as transplant rates for AML, the most frequent indication for allogeneic HCT, were relatively consistent across these countries. Some explanations for the heterogeneity are attempted, including economic factors, but individual clinical decision-making factors within clinical teams and national HCT communities need further exploration.
There are clear limitations to this analysis, including limited data available from the EBMT Activity Survey and what is defined and reported as a RIC transplant.
Overall, this ‘quality control audit’ generates more questions than answers, but highlights a need for greater standardization and harmonisation of HCT protocols and decision making, better definitions of conditioning intensity and higher quality data reporting (including assessments of what is ‘elderly’, ‘frail’, and other comorbidities used to justify transplant technique). This will enable some very practical clinical questions to be addressed as well as informing future audit and benchmarking processes.