Page 53 - Haematologica May 2022

Improved survival after acute GvHD
Figure 5. Three-year relapse incidence after aGvHD grades II-IV over time. Cumulative incidence estimates were calculated for relapse in a competing risks frame- work with NRM as a competing risk in the estimation of malignancy relapse.
year OS also increased over time in patients experiencing aGvHD grades III-IV, reaching 29% in the most recent HSCT cohort, independent of GvHD prophylaxis.
Previous studies reported an overall long-term survival of 10% to 25% in patients with severe aGvHD, defined as overall grades III to IV.17-20 Our survival rates compare favorably to Khoury et al. as well as El-Jawahri et al., who reported that longer time to aGvHD onset and younger recipient age were associated with improved OS,12,21 respectively. In our study, recipients of URD, patients not in CR at HSCT, and use of a female donor for a male patient were associated with increased mortality after aGvHD grades III-IV whereas recipients of RIC had a sig- nificantly lower mortality.
The significant improvement in outcome of patients over the past 25 years can also be seen in the decrease of three-year NRM from 47% in 1990-1995 to 36% in 2011- 2015 in patients experiencing aGvHD grades II-IV. The reduction in NRM over time is even more impressive when considering the significant changes in patient char- acteristics over recent decades, with an increase of medi- an recipient age from 35.4 to 52.3 years, more frequent use of URD (from 15.8% to 61.3%) and an increase in patients not in CR at HSCT from 27.3% to 32%, respec- tively. The reasons behind these impressive improve- ments are likely multifactorial, including improved pre- vention and treatment of infectious complications that are a main cause of morbidity and mortality of GvHD patients under long-lasting immunosuppressive treat- ment and improved supportive care practices.22 Of note is that infectious death in our study declined from 30.1% to 23.4% over time. McDonald et al., recently reported a sig- nificant reduction of NRM in a patient cohort undergoing HSCT between 2013 and 2017, compared to previous
years.23 No change in overall cytomegalovirus (CMV) infection, but a substantial reduction in higher level CMV DNAemia and in gram-negative bacteremia and invasive mold infections was observed. This supports the notion that the use of less intensive conditioning regimens and the availability and use of improved antifungal drugs as prophylaxis for high-risk patients may have contributed to this reduction. Of note, in our study, RIC administra- tion was also significantly associated with a lower risk for NRM. In recent years, clinicians have applied lower steroid doses for front-line therapy of aGvHD compared to the 1990s23,24 due to an increased awareness of steroid toxicity and increased NRM without improved response rates resulting from high-dose steroid treatment.25,26 Preclinical studies have revealed major pathophysiologi- cal pathways driving aGvHD and including tissue dam- age due to the administration of conditioning regimens or infection, alloreactivity seen as the body’s recognition of foreign major and minor histocompatibility antigens, and altered mechanisms of tissue repair and protection, such as microbiome dysregulation with a decline in protective microbial-derived metabolites.27 In recent years, more therapeutic strategies regarding aGvHD have become available in clinic, including the administration of costim- ulatory pathway blockade, targeted anti–interleukin-6 monoclonal antibodies, histone deacetylase inhibitors, kinase inhibitors and proteasome inhibitors, the anti- inflammatory protease inhibitor alpha-1-antitrypsin, CTLA-4 antagonism, CCR5 blockade, and adoptive regu- latory T cell transfer.27-34 These and other new strategies that are being developed will have a positive impact not only on response rates of aGvHD but also on the overall outcome of patients afflicted by this serious HSCT com- plication.
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