Page 47 - Haematologica May 2022

Improved survival after acute GvHD
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) has been increasingly used to cure malignant and benign hematologic diseases.1 Transplanted T-cells from the donor can recognize and eradicate hematologic malignan- cies through the immunologic graft-versus-leukemia effect. Unfortunately, donor conventional T-cells recognize normal recipient tissues and attack them, causing graft-versus-host disease (GvHD); this is the major cause of non-relapse mor- tality (NRM) following HSCT: GvHD is commonly reported in 40-60% of patients following HSCT.2,3 Despite advances in GvHD prophylaxis, current pharmacological approaches fail to completely prevent acute GvHD (aGvHD).4-6 Corticosteroids remain the established first-line therapy, however only around 50% of patients with aGvHD achieve complete responses7 and prognosis of steroid-refractory patients is dismal.8 Therefore, aGvHD and its associated infectious complications and organ toxicities contribute sub- stantially to morbidity and early mortality following HSCT.
Over recent decades, transplant practices have changed markedly with recipient age increasing, the use of unrelated and mismatched donors, reduced-intensity conditioning (RIC) and peripheral blood stem cells (PBSCs) as the pre- dominant graft source.9,10 Furthermore, improvements in supportive care measures such as novel antimicrobial agents and diagnostic procedures have also had an impact on HSCT outcome over time.
Retrospective analyses have revealed an improvement in the survival of more recent transplant recipients.9,11 Gooley et al., observed reduced incidences of aGvHD grades III-IV, less major organ injury and a reduction in life-threatening infections in the early stages following HSCT in recently- transplanted HSCT patients.11 Khoury et al. reported improved survival over time for transplant recipients after myeloablative conditioning with aGvHD given tacrolimus- based GvHD prophylaxis. This was most evident for patients with grade II aGvHD.12
To date, analyses on changes in survival outcome over time in an aGvHD-affected patient cohort given various conditioning regimen intensities are lacking. Therefore, we conducted a large registry study to assess whether outcome of HSCT patients experiencing severe aGvHD has improved over time.
Methods
Data collection
This was a multicenter, retrospective study performed by the Transplant Complications and Chronic Malignancies Working Parties of the European Society for Blood and Marrow Transplantation (EBMT). Data on transplantations were obtained from the EBMT registry. A total of 590 transplant centers con- tributed patients. The study was approved by the scientific board of both EBMT working parties.
Patient selection
Patients were 18 to 80 years of age with hematological malig- nant disease and received a first allograft between 1990 and 2015 from a HLA-identical sibling or matched or mismatched unrelated donor. Both myeloablative and RIC regimens, and any disease stage at HSCT, were included. Recipients of in-vitro T-cell deplet- ed grafts, haplo-identical transplants and cord-blood transplants were excluded. The maximal severity of aGvHD for each patient was used in all analyses.13
Study endpoints
The primary endpoints were aGvHD grades II-IV following HSCT and overall survival (OS) after aGvHD grades II-IV, with events defined as death from any cause after experiencing aGvHD grades II-IV. Secondary endpoints were incidence of aGvHD grades III-IV following HSCT; OS after aGvHD grades III-IV; NRM after aGvHD grades II-IV, defined as death occurring before signs of progression or relapse; relapse and progression after aGvHD II- IV, defined as recurrence and continuation of the original disease, respectively, following aGvHD II-IV and disease-free survival (DFS) after aGvHD II-IV, and defined as survival after aGvHD II- IV in the absence of signs of progression or relapse. For outcomes following aGvHD, only the subset of patients experiencing aGvHD were analyzed. In this subset, the starting point was the date of aGvHD onset. A clock-back approach was used, i.e., the timescale starts from the date of aGvHD onset rather than the date of HSCT.
Statistical analysis
The primary comparison concerned outcomes in transplanta- tion periods 1990-1995, 1996-2000, 2001-2005, 2006-2010, and 2011-2015. Cumulative incidence estimates were calculated for aGvHD, relapse and NRM, in a competing risks framework. NRM was a competing risk in the estimation of malignancy relapse, and relapse was a competing risk for estimation of NRM. For aGvHD, only mortality was considered a competing event. Baseline char- acteristics were compared across these transplant periods and test- ed by means of c2 tests for categorical variables and Kruskal-Wallis tests for continuous variables. Univariate analyses compared the outcomes OS, DFS, NRM, and relapse incidence between the five time cohorts. The probabilities of OS and DFS for all patients were calculated using the Kaplan Meier estimator. Group differences were tested by means of log rank test and Gray’s test. The median follow-up was estimated by reverse Kaplan-Meier estimator. Multivariable analyses were performed using Cox proportional hazards regression models for OS and RFS. Cause-specific hazards models were applied in the analysis of aGvHD, relapse and NRM. Each of the outcomes was analyzed using the same covariate structure. Covariates included were age at transplant (continuous in decades), transplantation year (in decades), conditioning inten- sity (reduced vs myeloablative), donor type (unrelated vs HLA identical), graft source (bone marrow (BM) vs PBSC), patient- donor gender match (male/female, female/male, and female/female vs male/male), antithymocyte globulin (ATG) and alemtuzumab. Models were stratified by malignant disease (Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Multiple Myeloma (MM), Myeloproliferative Disorder (MPE) and Other. Hazard ratios including 95% confidence intervals and P-values are provided. Analyses were done in R, version 3.6.0, using survival, prodlim and cmprskpackages.
Results
Patients
Between 1990 and 2015, 102,557 patients with a medi- an age (range) of 47.6 (18-83.8) years with malignant dis- ease received a first allogeneic HSCT. Conditioning was myeloablative in 55.8% and RIC in 44.2% of patients. Of note is that 50.6% of patients had an HLA-identical sibling and 49.4% a matched or mismatched unrelated donor. The stem cell source in 79.2% of patients was PBSC and BM in 20.8% of patients. Cyclosporine-based GvHD pro- phylaxis was given in 77.2% of patients; of these patients,
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