Discussion
The main finding in the study was that the number of patients being treated with allogeneic stem cell transplantation has increased, whilst one-year survival has improved and relapse-free and GVHD-free survival is more common.
The increase in transplants is a result of several factors. The main reasons are probably the ageing population, with leukaemia mainly affecting older patients, and the removal of the upper age limit for transplantation. The number of transplants in Norway was previously lower than in other European countries. While Norway carried out 15 to 20 transplants per 1 million inhabitants in 2013–14, the corresponding figure for Sweden, Finland and Denmark was 20 to 30 transplants (4). Activity in Norway is now on a par with other Nordic countries (5). The extent to which new forms of treatment can replace transplantation will determine the need for the service going forward. For lymphoma and B-lymphoblastic leukaemia, treatment with chimeric antigen receptor T-cell therapy is an option for some patients, but this treatment is not yet available for other haematological diseases.
An important prerequisite for more patients being offered a transplant was a reduction in treatment-related mortality. Mortality after 100 days decreased from 20 % in the period 1985–2012 (2) to 8 % in period 3 of the study. The most likely reason for this is the changes in pre-transplant treatment, with increased use of treosulfan. Compared with busulfan, treosulfan causes less organ toxicity, and several studies demonstrate better tolerance and at least as good an antileukemic effect in people over the age of 60 (6, 7).
The reduction in acute GVHD and severe chronic GVHD has probably also contributed to the improvement in survival from period 1 to period 3. Reduction of chronic GVHD is particularly important for quality of life and long-term survival (8). Treatment with anti-thymocyte globulin was introduced as prophylaxis for GVHD in period 1. Anti-thymocyte globulin induces a dose-dependent reduction of T cells. A balanced reduction of donor T cells is necessary to maintain the antileukemic effect whilst also preventing GVHD (9). A total dose of 4–6 mg/kg has been shown to effectively reduce GVHD without simultaneously increasing the risk of relapse (10, 11). Although the frequency of chronic GVHD has been reduced and is on par with other studies, a further reduction is desirable because of the reduced quality of life associated with the disease.
An expected side effect after the introduction of anti-thymocyte globulin treatment was several cases of Epstein-Barr virus reactivation. However, increased use of anti-thymocyte globulin does not appear to have impacted on the risk of cytomegalovirus reactivation. The proportion of invasive fungal infections was reduced, which was presumably a result of milder pre-transplant treatment and the introduction of prophylaxis for mould infections (12).
Both GVHD and treatment-related mortality are impacted by the choice of donor. What constitutes an optimum donor and stem cell source is open to debate. An HLA-identical sibling donor has been considered better than a matched unrelated donor, but new data suggest that young matched unrelated donors yield better outcomes (13, 14). An unrelated donor is now used for the majority of patients. Since the siblings of older patients are older too, the ageing population will also influence the choice of donor.
One of the weaknesses of the study was the short observation time, particularly for the last two-year period. Relapses mainly occurred in the first year after the transplant. The estimate for both chronic GVHD and relapse would be rather different if the observation time was longer. Another possible bias in the study is the change in the practice for reporting cases of chronic GVHD during the COVID-19 pandemic (in period 3). All patients need to be evaluated at least every three months at the transplant centre. This ensures consistent reporting, particularly for chronic GVHD, where it can be difficult to differentiate between mild, moderate and severe cases. During the pandemic, some patients preferred to have their check-ups at a local hospital rather than Oslo University Hospital in order to avoid using public transport.
The Unit for Allogeneic Stem Cell Transplantation at Oslo University Hospital is accredited under the European Society for Blood and Bone Marrow Transplantation (EBMT) quality system, and reports data to their quality register on an ongoing basis. The findings in this study are comparable to the results at other centres (15, 16). This review of data from an internal quality register showed that the number of allogeneic stem cell transplants has increased over the past six years, while survival has improved and the risk of complications has been reduced.