What is the treatment mortality rate of hematopoietic stem cell transplantations (HSCT) in patients with varying demographics and disease statuses?

Treatment Mortality Rates in Hematopoietic Stem Cell Transplantation

Treatment-related mortality (TRM) in HSCT varies substantially by transplant type, conditioning intensity, and timing of assessment, with contemporary data showing day-100 TRM rates of 1.9% for autologous HSCT and 6.1% for allogeneic HSCT, though rates increase significantly over longer follow-up periods. 1

Defining Treatment-Related Mortality

TRM encompasses death from any cause other than disease relapse or progression, including deaths from organ toxicity, conditioning regimen complications, infections, and graft-versus-host disease (GVHD). 1 This metric is critical for evaluating the safety profile of the transplant procedure itself, separate from disease control. 1

Contemporary Mortality Rates by Time Point

Early Mortality (Day 100)

• Autologous HSCT: 1.9% TRM 1
• Allogeneic HSCT: 6.1% TRM 1
• Reduced-toxicity conditioning in pediatrics: 3% TRM by day 100 2

Intermediate and Long-Term Mortality

• 1-year TRM: Ranges from 13.6% in reduced-toxicity pediatric cohorts 2 to 21-36% depending on conditioning intensity and donor source 3
• 5-year outcomes: Mortality from infections, GVHD, and toxicity actually increases at 5 years compared to earlier timepoints 4

Critical Risk Factors Affecting TRM

Conditioning Intensity

Myeloablative conditioning carries substantially higher TRM than reduced-intensity conditioning (RIC). 1 Historical myeloablative regimens were associated with TRM rates of 40-45%, while contemporary RIC has achieved TRM rates under 3% in selected populations. 1 Patients over 60 years should receive RIC regimens rather than myeloablative conditioning due to 50% transplant-related mortality with myeloablative approaches in this age group. 3

Age-Related Mortality

Patients >13-16 years have significantly higher TRM rates compared to younger patients. 1, 5 However, age alone should not be an exclusionary factor, as comorbidities and disease status are equally critical determinants. 6, 3

Disease-Specific Mortality Patterns

Myelodysplastic Syndromes (MDS):

• Lower-risk patients (WPSS score) achieve 5-year overall survival of 80% following allogeneic HSCT 6
• Survival declines progressively with increasing WPSS scores: 65% (intermediate), 40% (high risk), and 15% (very high risk) 6
• Non-relapse mortality in older adults (60-70 years) with RIC shows no increase compared to younger patients 6

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL):

• TRM rates of 17% with allogeneic HSCT and 0% with autologous HSCT at 5 years 6
• Treatment-related mortality of 27-32% reported in various phase II studies combining imatinib with HSCT 6
• Matched sibling allogeneic HSCT: 27% TRM; matched unrelated donor HSCT: 39% TRM 6

Temporal Trends in Mortality

Mortality from all causes has decreased significantly over time. After autologous HSCT, mortality decreased across all post-transplant phases when comparing 1980-2001 to 2002-2015 cohorts. 4 After allogeneic HSCT, mortality from infections, GVHD, and toxicity decreased up to 1 year, though deaths from relapse increased in all post-transplant phases. 4

Major Causes of Treatment-Related Death

The leading causes of excess deaths in rank order are: 7

• Second malignancies and recurrent disease
• Infections (particularly of unknown origin) 4
• Chronic GVHD 4
• Respiratory diseases 7
• Cardiovascular diseases 7

Infections of unknown origin remain the main cause of infectious deaths. 4 While lethal bacterial and fungal infections decreased from earlier to more recent cohorts, unknown or mixed infections did not show similar improvement. 4

Special Population Considerations

Older Adults (≥60 Years)

A prospective trial of 372 patients aged 60-75 years with nonmyeloablative conditioning showed no association between age and non-relapse mortality, overall survival, or progression-free survival. 6 Comorbidities and disease status, rather than age alone, should determine eligibility. 6

Pediatric Patients

Reduced-toxicity conditioning in 100 consecutive pediatric recipients demonstrated 3% TRM by day 100 and 13.6% for the entire study period. 2 However, primary graft failure occurred in 16% overall, with significantly higher rates (31.4%) after umbilical cord blood transplantation. 2

Inborn Errors of Immunity (Adolescents/Adults)

In 329 patients aged 15-62.5 years, overall survival at 5 years was 71% with TRM contributing to the mortality burden. 8 Neither age nor donor type significantly affected outcomes, but the number of IEI-associated complications did. 8

Long-Term Survival Context

Patients surviving 5 years without disease recurrence have an 80.4% estimated survival at 20 years post-transplant. 7 However, mortality rates remain 4- to 9-fold higher than the general population for at least 30 years after transplantation, yielding an estimated 30% lower life expectancy. 7

Common Pitfalls to Avoid

• Do not use myeloablative conditioning in patients over 60 years, as RIC provides equivalent efficacy with substantially lower toxicity 3
• Do not exclude patients based solely on age, as multivariate analyses demonstrate that comorbidity burden and disease status are more predictive than chronological age 6, 3
• Do not underestimate late mortality risk, as TRM from infections and GVHD actually increases at 5 years compared to earlier timepoints 4
• Recognize that chemotherapy-naive umbilical cord blood transplant recipients have significantly higher graft failure rates (46.7% vs 9.5%), which impacts overall mortality 2