Induction-Related Mortality in Adults with Acute Lymphoblastic Leukemia (ALL) Treated in Two Consecutive Protocol Eras 1998-2006 and 2007-2016

Abstract

Induction mortality is the price adult acute lymphoblastic leukaemia pays for the intensity that cures it. Successive protocol generations raised dose intensity to
improve remission depth, and in older adults the toxicity outran the benefit. The most instructive recent evidence comes from cooperative groups that compared
consecutive protocol eras directly and found that reducing intensity in middle-aged patients lowered early death without loss of disease control.
Objectives: To review the published evidence on induction-related mortality in adults with acute lymphoblastic leukaemia across consecutive protocol
generations: how rates have changed, which patients carry the risk, what they die of, and what protocol modifications have demonstrably reduced it.
Material and Methods: Narrative review of cooperative group trials, population-based registry analyses and single-centre cohorts indexed in PubMed and the
major haematology journals. Studies were eligible if they reported induction or treatment-related mortality in a defined leukaemia population, or compared
outcomes between consecutive treatment protocols. No new patient data were generated and no patients were recruited; every rate and effect estimate quoted is
one published by the original investigators.
Results: In a direct comparison of two consecutive cooperative group protocols enrolling 787 and 743 adults respectively, the induction death rate fell from 6 to 3
per cent (p = 0.005). The reduction was confined to patients aged 45 to 59 years, in whom it fell from 11 to 3 per cent (p = 0.001) after de-escalation of
asparaginase, anthracycline and corticosteroid dosing, at the cost of a higher requirement for a second induction course (9 against 5 per cent). Excess intensity is
demonstrably harmful in this age group: in a prospective trial giving pegylated asparaginase within a five-drug induction to 90 adults of median age 46.5, sixteen
died during induction, and age above 40 years carried an odds ratio for induction death of 18.5 (95% CI 2.02-169.0). Reported induction mortality ranges from 7
to 11 per cent in high-resource trial settings to 20 to 50 per cent in some Latin American series, with 13.4 per cent in one Hispanic adult cohort. Infection
accounts for the majority of deaths, at 68 per cent in a population-based analysis and 64.1 per cent in a Hispanic cohort.
Conclusion: The fall in induction mortality between protocol generations is attributable to age-adapted de-escalation rather than to better supportive care alone,
and the benefit is concentrated in middle-aged adults. Reporting induction mortality as a single figure for an adult trial conceals an age gradient steep enough to
determine whether a protocol is safe.
Abbreviations: ALL – Acute Lymphoblastic Leukaemia, AYA – Adolescent and Young Adult, BFM – Berlin-Frankfurt-Münster, CR – Complete Remission,
HSCT – Haematopoietic Stem Cell Transplantation, IRM – Induction-Related Mortality, MRD – Minimal Residual Disease, Ph – Philadelphia Chromosome,
TRM – Treatment-Related Mortality, TKI – Tyrosine Kinase Inhibitor, WBC – White Blood Cell Count.
Keywords: Acute Lymphoblastic Leukaemia; Induction Mortality; Treatment-Related Mortality; Age-Adapted Chemotherapy; Protocol Era