Definition of Transplant-Related Mortality (TRM) in HSCT
Transplant-related mortality (TRM) is defined as death occurring from any cause other than disease relapse or progression following hematopoietic stem cell transplantation. 1, 2
Core Definition and Scope
TRM encompasses all deaths directly attributable to the transplantation procedure and its complications, excluding deaths from the underlying malignancy itself. 2, 3 This includes:
- Deaths from graft-versus-host disease (GVHD) - representing approximately 25% of all deaths after allogeneic HSCT 3
- Deaths from infectious complications - accounting for approximately 11% of deaths, though this varies by time period and patient population 3, 4
- Deaths from organ toxicity and conditioning regimen-related complications 1
- Deaths from other transplant-related causes - representing approximately 34% of deaths 3
Temporal Framework for TRM Assessment
TRM is typically assessed at specific time points post-transplant, which helps stratify risk and evaluate outcomes:
- 100-day TRM: The most commonly reported early mortality metric, ranging from 1.9% for autologous HSCT to 6.1% for allogeneic HSCT in contemporary series 5
- Very early mortality (day 30): Captures immediate post-transplant complications 4
- Early mortality (day 100): Standard benchmark for acute transplant complications 1
- Intermediate mortality (1 year): Reflects extended complications including chronic GVHD 4
- Late mortality (beyond 1 year): Captures long-term transplant-related complications 6, 4
Historical Context and Trends
TRM rates have decreased substantially over time, particularly in the early post-transplant period. 2, 4 For allogeneic HSCT in acute myeloid leukemia, the relative risk of TRM decreased to 0.5 for matched sibling donors and 0.73 for unrelated donors when comparing 2000-2004 to earlier eras. 2
Historical myeloablative conditioning was associated with TRM rates of 40-45% in some populations 1, while contemporary reduced-intensity conditioning has achieved TRM rates under 3% in selected populations. 1
Major Contributors to TRM
Infectious Complications
- Infections remain a leading cause of TRM, with cumulative incidences of 1.6% for viral, 1.5% for bacterial, and 1.3% for fungal infections in late post-transplant deaths 6
- The majority (66%) of lethal infections occur within 18 months after HSCT 6
- Infections of unknown origin represent the main cause of infectious deaths 4
GVHD-Related Deaths
- Acute GVHD increases the relative risk of late infectious death by 7.19-fold 6
- Chronic GVHD increases the relative risk by 6.49-fold 6
Conditioning Regimen Toxicity
- Myeloablative conditioning carries higher TRM than reduced-intensity approaches 1
- Total body irradiation protocols may have direct neurotoxic effects contributing to mortality 1
Risk Factors for Higher TRM
Key factors associated with increased TRM include: 1, 6
- Age: Patients >13-16 years have significantly higher TRM rates 1, 7
- Donor type: Mismatched or unrelated donors carry 3.86-fold increased risk 6
- CMV infection: Increases risk 4.69-fold 6
- Conditioning intensity: Myeloablative regimens carry higher TRM than reduced-intensity 1
- Disease status: Chemotherapy-resistant disease increases mortality risk 1, 7
Clinical Significance
TRM is distinguished from overall mortality specifically to evaluate the safety and toxicity profile of the transplant procedure itself, separate from disease control. 2 This distinction is critical for:
- Comparing different transplant approaches and conditioning regimens 1
- Counseling patients about transplant-specific risks versus disease-related risks 1
- Evaluating improvements in transplant care over time 2, 4
- Making treatment decisions, particularly when TRM rates approach or exceed disease-related mortality 1
A critical caveat: TRM rates vary dramatically based on patient population, disease type, conditioning regimen, donor source, and institutional experience, making direct comparisons between studies challenging without careful attention to these variables. 1, 4