Molecular Determinants of Treatment Response and Outcomes in Acute Myeloid Leukaemia with mutated NPM1

Abstract

Mutations in the nucleophosmin (NPM1) gene occur in ~30% of adult AML, where they define a distinct disease subtype associated with relatively favourable prognosis. Outcomes are impacted by age, mutations in FLT3-ITD and DNMT3A, and adverse karyotype. Measurable residual disease (MRD) after induction chemotherapy is strongly associated with relapse and survival, but its interaction with baseline prognostic factors and their combined impact on treatment decisions is not well established. Chapter 1 of this thesis describes a large cohort of younger patients with NPM1 mutated AML, comprehensively analysing the relationship between clinical features, genomic abnormalities and MRD response. Factors associated with poor MRD responses are identified, as are those remaining prognostic in patients achieving MRD negativity. Chapter 2 demonstrates that blood MRD results can identify patients who benefit from allogeneic transplant in first remission. For MRD negative patients, survival is not improved by transplant regardless of baseline prognostic factors. Chapter 3 is the first description of the impact of molecular MRD in patients receiving venetoclax-based therapies for NPM1 mutated AML. MRD is highly prognostic, with patients achieving MRD negativity in bone marrow having excellent outcomes, including those who electively stopped therapy. Chapter 4 and appendix 1 explore the treatment of molecular relapse, which is known to predict impending haematological relapse, demonstrating high response rates and low toxicity with FLT3 inhibitors and venetoclax-based therapies. Chapter 5 addresses another unresolved issue in classification of NPM1 mutated AML, showing that therapy-related and de novo disease have similar clinical and genomic features, suggesting they should be considered the same disease. In conclusion, the results described in this thesis provide practice-influencing clarification of the molecular determinants of treatment response and outcomes in NPM1 mutated AML.