Late mortality and life expectancy of Allo-HSCT recipients in the past 40 years

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curable treatment option for patients with hematological malignancies and some other life-threatening diseases.
An estimated 10,000 patients in the United States receive Allo-HSCT each year
.

In the past 40 years, clinical practice of Allo-HSCT has undergone significant changes, including the use of Allo-HSCT for older patients; the use of alternative stem cell sources, such as peripheral blood stem cells (PBSCs) and cord blood; and the use of non-clear Medullary or reduced intensity pretreatment
.

Thanks to improvements in supportive care and management strategies for acute graft-versus-host disease (aGVHD), early transplant-related mortality has been significantly reduced, and the number of transplant survivors has increased
.

However, the long-term side effects of Allo-HSCT recipients such as secondary malignant tumors (SMN) and cardiovascular diseases (CVD) are worthy of attention
.

Based on this, some researchers have carried out a blood or bone marrow transplant survivor study (BMTSS) to analyze the cumulative impact of long-term complications and early mortality of Allo-HSCT recipients on life expectancy
.

Research Method BMTSS is a cohort study designed to examine the long-term outcome of patients who survived ≥ 2 years after Allo-HSCT at the University of Minnesota or the University of Alabama at Birmingham between January 1, 1974 and December 31, 2014
.

The cause of death that matches the pre-transplant diagnosis is classified as recurrence-related mortality (RRM)
.

All other causes of death are classified as non-relapse-related mortality (NRM)
.

Deaths caused by malignant diseases that are different from the pre-transplant diagnosis are classified as SMN-related
.

Deaths due to heart failure, coronary artery disease, arrhythmia, stroke, or other cardiovascular causes are classified as CVD-related
.

Deaths due to sepsis or other causes of infection are classified as infection-related
.

The researchers studied the trends of all-cause mortality and cause-specific mortality of recipients in three Allo-HSCT periods (1974-1989; 1990-2004; and 2005-2014) based on changes in transplant practice
.

Study results Patient characteristics: Overall, 4741 patients received Allo-HSCT between 1974 and 2014, and the survival time was ≥2 years
.

The median age of patients receiving Allo-HSCTBMT from 2005 to 2014 was 33 years
.

The median follow-up time after Allo-HSCT was 12 years
.

Acute myeloid leukemia (AML) is the most common indication (26.
3%) of Allo-HSCT.
Among them, 59.
2% of patients received transplantation from a related donor, and 47.
5% of patients' stem cells were derived from bone marrow
.

In the three periods, the median age of Allo-HSCT recipients showed an increasing trend (from 19.
5 years to 43.
0 years), receiving Allo-HSCT from unrelated donors (from 4.
8% to 55.
7%) and the high-risk subgroup receiving Allo-HSCT The proportion of patients (from 17.
9% to 33.
6%) is also increasing
.

In addition, the proportion of patients receiving systemic radiotherapy (TBI) (from 75.
6% to 51.
1%), myeloablative pretreatment (from 84.
2% to 36.
3%), and bone marrow-derived stem cells (from 99.
8% to 20.
5%) showed a downward trend; The incidence of chronic GVHD (cGVHD) increased (from 41.
6% to 49.
0%) (Table 1)
.

Table 1: Baseline characteristics of patients.
Mortality and life expectancy: The risk of all-cause death in this cohort is 8.
8 times higher than that of the general population (95% CI, 8.
4-9.
3)
.

The relative mortality rate was highest 2-5 years after Allo-HSCT (SMR, 34.
3; 95% CI, 31.
7-36.
9), and then declined, but 30 years or more after Allo-HSCT was still significantly higher than the general population (SMR , 5.
4; 95% CI, 4.
0-7.
1)
.

Over time, the relative mortality of patients after Allo-HSCT showed a downward trend, from 1974-1989 (SMR, 23.
4) to 2005-2014 (SMR, 5.
8) (P<0.
001)
.

The 2-35-year mortality rate after Allo-HSCT exceeded the expected population mortality rate, showing a U-shaped curve, with the shortest follow-up time (2 years after transplantation: 39.
4 deaths/1000 person-years) and the longest follow-up time (transplantation In the next 35 years: 31.
0 deaths/1000 person-years), the difference in the expected mortality of individuals is even greater
.

The mortality of patients after Allo-HSCT increases with age, and the mortality at all ages is higher than the expected mortality in the general population
.

In an analysis limited to a 10-year follow-up, the number of years of life lost for Allo-HSCT recipients in the three periods showed a downward trend (from 9.
9 years to 4.
2 years) (Table 2)
.

Table 2: Multivariate analysis of all-cause mortality risk factors.
Risk of late death: The 30-year overall survival (OS) rate of the entire cohort was 57.
8% (52.
5% to 80.
6%); 10-year all-cause late mortality related risk Factors include older age at Allo-HSCT, male, high-risk disease, use of PBSCs as a source of stem cells, and cGVHD history (Table 2)
.

After adjusting for all relevant demographic and clinical variables, it was found that within 3 periods, the HR of 10-year all-cause mortality showed a decreasing trend (P<0.
001) (Figure 1, Table 2)
.

A stratified analysis based on age (<18, 18-45 and >45 years) at Allo-HSCT showed that only in individuals aged <18 years of age who received transplantation, the reduction in late mortality according to the age of transplantation was statistically significant (P <0.
001) (Figure 2A); analysis stratified by stem cell source showed that individuals who received only bone marrow-derived stem cells had a statistically significant decrease in the late mortality rate during the transplant era (P<0.
001) (Figure 2B)
.

Figure 1: The trend of all-cause and cause-specific late death risks in Allo-HSCT recipients in different transplant eras.
Figure 2: The OS status of Allo-HSCT recipients in different transplant eras.
The risk of death from specific causes in allo-HSCT recipients: 1175 of the 1409 patients who died ( 83.
4%) withdrew due to death, including RRM (473 cases [40.
3%]), NRM (675 cases [57.
4%]) and external causes (27 cases [2.
3%])
.

The 30-year cumulative incidence of RRM was 12.
2% (95% CI, 11.
0%-13.
4%) (Figure 3A), and NRM was 22.
3% (95% CI, 20.
4%-24.
3%) (Figure 3B)
.

Figure 3: Conclusion of the study on cumulative mortality of Allo-HSCT recipients.
This cohort study showed that the late mortality of Allo-HSCT recipients has declined in the past 40 years; however, compared with the general population in the United States, life expectancy has not Recover to the expected speed
.

In addition, the reduction in the risk of late death appears to be limited to patients who received transplants at a younger age or patients who received bone marrow stem cells
.

Efforts to reduce disease recurrence, infection, SMN, CVD and lung diseases may have a positive effect on improving the prognosis of this population
.

References: Smita Bhatia, Chen Dai, Wendy Landier, et al.
Trends in Late Mortality and Life Expectancy After Allogeneic Blood or Marrow Transplantation Over 4 Decades: A Blood or Marrow Transplant Survivor Study Report.
JAMA Oncol.
2021 Sep 9.
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