Clinical Outcomes in De Novo Versus Secondary NPM1-Mutated AML

Introduction Nucleophosphomin-1 (NPM1) mutated AML is a molecularly defined subtype typically associated with more favourable treatment response rates and prognosis. Within chronic phase myeloid neoplasms, including MDS and MPN, NPM1 is observed less frequently, and previous studies have suggested an association between the presence of an NPM1 mutation and a rapid rate of progression to acute leukemia. AML evolving from a prior myeloid neoplasm is generally associated with unfavourable treatment response rates and survival outcomes. However, it is unclear if NPM1 mutations remain a positive prognostic indicator within secondary AML (sAML). At present, there are limited studies investigating potential differences in the survival outcome of NPM1-mutated sAML.

Methods This study included adults diagnosed with de novo and secondary NPM1-mutated AML first seen at Princess Margaret Cancer Center between January 1, 2000, and April 21, 2021. The primary outcome was overall survival (OS), comparing patients with de novo versus sAML.

Secondary AML was defined as those with a previously diagnosed chronic phase myeloid malignancy that preceded the diagnosis of AML. Patients who were found to have prolonged, unexplained cytopenias of at least 6 months duration prior to AML diagnosis were included in this category as suspicious for preceding MDS.

OS was calculated from date of AML diagnosis, and leukemia-free survival (LFS) was calculated from the date of achieving CR1. Patients who received allogeneic hematopoietic stem cell transplant (HSCT) prior to progression to AML were not included in the survival analysis. Kaplan-Meier survival curves were generated for OS and LFS, and differences were tested using the log-rank test.

Results Of the 575 NPM1-mutated patients eligible for inclusion in our study, 40 (7%) patients had a confirmed diagnosis of a preceding chronic myeloid neoplasm, and 14 (2%) additional patients were considered to be suspicious of preceding MDS. Preceding confirmed myeloid neoplasm diagnoses included MDS (n=18, 45%), CMML (n=14, 35%), MPN (n=4, 10%), therapy-related myeloid neoplasm (n=2, 5%), atypical CML (n=1, 3%), and MDS/MPN unclassifiable (n=1, 3%). Prior to AML progression, 22 (55%) patients received disease-specific treatment including azacytidine (n=7, 18%), erythropoiesis stimulating agents (n=8, 20%), hydroxyurea (n=6, 15%), ruxolitinib (n=1, 3%) and HSCT (n=2, 5%). Median time to progression to sAML was 3.2 months (0.1-79.3).

Compared to de novo AML, there was no significant difference in sex (p=0.39), ELN 2017 risk (p=0.10), presence of FLT3-ITD (p=0.38), or karyotypic abnormalities (p=0.16). Patients with sAML were more likely to be at an advanced age (≥70 years) at time of AML diagnosis (39% vs 22%, p=0.01), and were also more likely to have mutations in RUNX1 (14% vs 3%, p=0.01), CBL (9% vs 2%, p=0.04), and NRAS (26% vs 11%, p=0.02). There was a significant difference in first-line AML treatment in sAML compared to de novo AML (p<0.0001), with fewer patients receiving induction therapy (67% vs 84%) and more patients receiving hypomethylating agent-based therapy (22% vs 3%).

There was no significant difference observed between patients with NPM1-mutated de novo versus sAML in LFS (2-year LFS 48% sAML vs 52% de novo AML, p=0.74) or OS (2-year survival 46% sAML vs 56% de novo AML, p=0.14) (figure 1).

Conclusion While previous studies have demonstrated poor clinical outcomes within sAML, there are limited investigations studying outcomes specifically within secondary, NPM1-mutated AML. In our study, no significant differences in OS or LFS were observed between NPM1-mutated de novo and sAML, suggesting that evolution from a preceding myeloid malignancy is not a predictor of poor prognosis.

Our study demonstrated a short time to progression to sAML in most patients which further supports the consideration of NPM1 as an AML-defining mutation. Variations in treatment during the MDS/MPN stage, as well as the heterogeneity in preceding diagnoses, including polycythemia vera, may have contributed to longer progression latency observed in some cases. Future studies investigating the impact of NPM1 variant allele frequency on the rate of sAML progression are planned.

Gupta:Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board; BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board; Sierra Oncology: Consultancy; Roche: Other: Participation on a Data Safety or Advisory board; AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board. Richard-Carpentier:Astellas: Consultancy, Honoraria, Other: Advisory Board Participation; AbbVie: Consultancy, Honoraria, Other: Advisory Board Participation; Pfizer: Consultancy, Other: Advisory Board Participation; BMS: Other: Advisory Board Participation; Taiho: Other: Advisory Board Participation. Schimmer:Medivir AB: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Otsuka Pharmaceuticals: Consultancy, Honoraria; UHN: Patents & Royalties: the use of DNT cells to treat AML. Schuh:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Phebra: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva Pharmaceutical Industries: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Yee:Forma Therapeutics: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astex: Research Funding; GlaxoSmithKline: Consultancy; Abbvie: Honoraria; Bristol-Myers Squibb/Celgene: Consultancy; Shattuck Labs: Consultancy; TaiHo: Consultancy; Jazz: Consultancy, Research Funding; F. Hoffmann La Roche: Consultancy, Research Funding; Geron: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Takeda: Consultancy; Pfizer: Consultancy; Karyopharm: Research Funding; Treadwell: Research Funding; Astellas: Consultancy.