Immune-Genomic Evolution in AML Spontaneous Remission: A 66-Patient Pooled Analysis and Longitudinal Clonal Tracking

Background/Objectives: Spontaneous remission (SR) of acute myeloid leukemia (AML) offers unique clinical insights into host anti-tumor immunity. However, the comprehensive clinical landscape and molecular dynamics of blast clearance and subsequent relapse remain unclear. This study aimed to elucidate these dynamics. Methods: We conducted a two-phase observational study: a systematic pooled analysis of 66 adult AML SR cases (1990-2024) to define clinical triggers and outcomes and longitudinal molecular tracking of two institutional cases to map clonal shifts (with immune profiling for Patient 1 and genomic tracking for both). Results: In the pooled analysis, infection was the predominant trigger, accounting for 78.6% (95% CI: 65.6-88.4%) of SR events. The dataset showed male predominance and monocytic leukemia enrichment (57.6% [95% CI: 44.1-70.4%]), suggesting lineage-specific susceptibility. SR duration and relapse risk were independent of the infection trigger, AML subtype, or age. When integrated with these clinical patterns, institutional tracking was consistent with a biphasic evolutionary model: an acute IL-8 surge alongside NKT and CD4+ T cell activation coincided with blast clearance, as observed primarily in Patient 1. Subsequently, the emergence of TP53 or NRAS mutations within persistent DNMT3A-mutated clones during relapse raised the hypothesis that unresolved chronic inflammation could potentially exert selective pressure favoring resistant subclones. Such interpretations remain correlational and require prospective validation. Conclusions: Our findings outline a clinical-evolutionary framework for AML SR. Remission durability likely relies on balancing acute immune activation with underlying clonal stability. These observational insights highlight complex immune-genomic crosstalk, generating hypotheses for future prospective investigations.