Early transplantation-related mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia

This study was a nationwide, population-level, historical cohort study of patients with acute leukemia who underwent allo-HCT. This data was obtained from the claims database of the NHIS of the Republic of Korea. South Korea has a universal health coverage system provided by the central government, which has been unified since 2000. The NHIS provides health insurance to more than 99% of the population. Accordingly, the NHIS has a comprehensive health database for diagnoses, treatments, procedures, and prescriptions. They provide these extensive data for use in research after the approval process. This study also obtained death related data, including the cause of death from Statistics Korea, which has a comprehensive database in connection with the NHIS. In South Korea, death registration is usually completed and confirmed by a physician. The institutional review boards of Kosin University Gospel Hospital approved this study and granted a waiver of informed consent from the study participants owing to the nature of the data from which private information was deleted. All methods were carried out in accordance with relevant guidelines and regulations along with the approval.

We selected patients diagnosed with acute leukemia who received allo-HCT from 2003 to 2015. This study includes data on both adults and pediatric patients. Transplant data registered with the NHIS were from patients who reached complete remission prior to transplantation. The recipients and donors were typed at the allelic level for HLA-A, HLA-B, HLA-C, and HLA-DRB1 including those with fully matched or single-HLA locus mismatched transplants.

The conditioning intensity was defined as MAC when the total body irradiation (TBI) was administered for 4 days or longer, or when busulfan was administered for 3 days or longer. In contrast, the cases in which TBI was administered for less than 4 days or busulfan for less than 3 days were classified as reduced-intensity conditioning (RIC). Rabbit anti-thymocyte globulin (ATG; Sanofi-Aventis, Cambridge, MA) was administered to patients at various dosages to prevent GVHD. ATG was given in equally divided doses for 2 or 3 days from day − 3. All patients received calcineurin inhibitors, including cyclosporine or tacrolimus, with or without short-term methotrexate as immunosuppressants to prevent GVHD. Prophylaxis against infections included low-dose acyclovir, trimethoprim−sulfamethoxazole, antifungal agents (such as fluconazole), antibiotics (such as levofloxacin), and preemptive therapy with ganciclovir for patients with cytomegalovirus infection (on the basis of antigen or DNA testing). Half of the patients received ursodiol as prophylaxis against cholestasis.

The objectives of this study were to determine the CIRs of early TRM at 50 and 100 days after transplantation and to identify the causes of death and risk factors for early TRM. The CIR of early TRM was reported at a specific time after the transplant (day 50 and 100) in a landmark approach. Patients who underwent two or more transplants in that period were analyzed for the last transplant. The probabilities of mortality were estimated using cumulative incidence curves. We used the chi-square test for categorical data and independent t-test for continuous data. The causes of death were reported within 50 days of allo-HCT. We used maximally selected log-rank statistics in the maxstat function of the R software (version 3.3.2) to identify the optimal threshold to assess the survival outcomes for age and time from diagnosis to transplantation. We selected the optimal age and time from diagnosis cut-offs to be 40 years and 9 months, respectively. The probability of overall survival was estimated by the Kaplan−Meier method. Logistic regression was used for multivariate analysis. The statistical analysis was performed using the R statistical software (version 3.4.4; R Foundation for Statistical Computing) and SAS statistical analysis software (version 9.4; SAS Institute Inc., Cary, NC, USA). P-values < 0.05 with 2 sided test were considered statistically significant.

The characteristics of 5395 patients in the two transplant periods (from 2003 to 2009 and from 2010 to 2015) are shown in Table 1. The mean age of all patients was 35.9 ± 16.6 years (range, 0–72 years) at the time of transplantation, and 55.1% were male. The mean age at the time of transplantation has also increased from 31.8 to 38.3 years. Since 2010, the period from diagnosis to transplantation has been longer than that in the past. The number of patients who have had two or more transplants has also increased. However, the number of patients who required a high number of red blood cell (RBC) and platelet transfusions before transplantation decreased. Iron chelation was performed in some patients whose ferritin level was 1000 ng/mL or higher due to red blood cells transfusion. The number of patients who received iron chelating agents before transplantation increased from 5.2 to 20.1%.

The graft source of HCT in Korea has been changed. The use of peripheral blood increased from 55.8 to 85.8% and bone marrow decreased from 39.0 to 11.0%. The use of MAC decreased from 74.5 to 58.0%, while the use of RIC increased from 25.5 to 42.0%. TBI and busulfan-based conditioning regimens were used in approximately one-third and two-thirds of the patients, respectively. The number of patients who used ATG increased from 18.6 to 57.3%.

Accounting all, 151 and 442 patients died at 50 and 100 days after allo-HCT, respectively. The CIRs of early TRM were 2.9 and 8.3%, respectively (Fig. 1, Table 2). The CIRs of early mortality were significantly lower in those under 20 years of age. The median follow-up duration was 5.7 years (1–14.9). The 5-year overall survival (OS) rates were 54 ± 1% and 52 ± 1% in the transplantation periods of 2003–2009 and 2010–2015, respectively (p = 0.270). The 5-year OS rates for patient under 20 years of age were 56.7 ± 2.2% and 61.4 ± 2.6% in the transplantation periods of 2003–2009 and 2010–2015, respectively (p = 0.023, Supplemental Fig. 1). The 5-year OS rates for adults were 52.1 ± 1.3% and 49.0 ± 1.1% in the transplantation periods of 2003–2009 and 2010–2015, respectively (p = 0.104).

The common causes of early TRM within 50 days of allo-HCT are described in Supplemental Table 1. Infection-related death (66.9%) was the most common cause, such as pneumonia (43.7%) and sepsis (21.9%). Organ failure-related death (16.6%) was also common, including that due to kidney (7.3%), multi-organ (6.0%), and liver toxicity (2.6%). Other causes related to bleeding included intra-cranial hemorrhage (5.3%) and unknown causes (11.3%).

The detailed results of the CIRs of early TRM at 50 and 100 days (according to other variables) are shown Table 2 and Fig. 2. Since 2010, the early mortality did not change between the two periods. There was no significant difference in early TRM within 50 days according to age. However, the TRM at 100 days was higher in those 40 years old or older (< 40 vs ≥40; 7.1 vs. 9.4%, p = 0.003). Early mortality was significantly higher in patients with more than 9 months between diagnosis and transplantation (CIRs of TRM at 50, 100 days; 6.0, 13%, respectively). In addition, patients who underwent one or more previous transplantations showed significantly higher CIRs of early TRM at 50 and 100 days (9.4, 17.2%, respectively).

The CIRs of early TRM were significantly lower in patients who received previous iron chelation therapy at 50, 100 days (0.3, 1.8%, respectively) compared to that of those who did not receive iron chelation therapy. The average number of RBC transfusions was higher in the iron chelation group (6.4 ± 8.9 vs 3.7 ± 5.4, data was not shown) than it was in other groups. The CIRs of early TRM were higher for patients whose graft source was cord blood at 50 and 100 days (6.1, 18.3%, respectively) than they were in patients with other graft sources.

The detailed results of univariate and multivariate analysis of early TRM at 50 and 100 days according to other variables are shown in Supplemental Table 2 and Table 3. The independent high-risk factors of early TRM included older age (≥40 years), longer duration from diagnosis to transplantation, previous transplantations, and cord blood transplantation. In particular, previous iron chelation therapy was an independent low-risk factor for early TRM (HR, 95% CI at 50 and 100 days; 0.07, 0.02–0.29, p < 0.001; 0.17, 0.10–0.29, p < 0.001).