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1478 High Risk Mutations in Critical Genes Do Not Significantly Affect Remission Rates and Minimal Residual Disease Clearance in Acute Myeloid Leukemia Patients Receiving CPX-351 Induction

Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemias: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, Drug development, Diseases, Treatment Considerations, Myeloid Malignancies, Technology and Procedures, Measurable Residual Disease , Molecular testing
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Fabio Guolo, MD, PhD1,2, Carola Riva3*, Maria Chies, MD4*, Chiara Vernarecci, MD5*, Ylenia Azzanelli, MD6*, Nicoletta Colombo, PhD2*, Sara Rosellini7*, Alessia Parodi7*, Elisabetta Tedone2*, Enrico Carminati, PhD2*, Francesco Puglisi4*, Clara Nurra4*, Giuseppina Fugazza8*, Michele Cea9,10*, Roberto Massimo Lemoli, MD11,12* and Paola Minetto, MD2

1Hematology Unit, Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
2IRCCS Ospedale Policlinico San Martino, Genoa, Italy
3Clinic of Hematology, Department of Internal medicine (DiMI), University of Genoa, Genova, AL, Italy
4Clinic of hematology, Department of Internal medicine (DiMI), University of Genoa, Genoa, Italy
5Clinic of hematology, Department of Internal medicine (DiMI), University of Genoa, Genova, AL, Italy
6Clinic of Hematology, Department of Internal medicine (DiMI), University of Genoa, Genoa, Italy
7Servizio di Citofluorimetria, Dipartimento di Anatomia Patologica, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
8Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
9IRCCS Ospedale Policlinico San Martino, Genova, Italy
10Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genova, Italy
11Clinic of Hematology, University of Genoa, Genoa, Italy
12Clinica Ematologica, Dipartimento di Oncologia e Ematologia, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

Background and aims

The better understanding of the molecular basis of Acute Myeloid Leukemia (AML) allowed to identify critical gene mutations related to a higher risk of treatment failure in patients receiving conventional 3+7 chemotherapy. Consequently, the presence of at least one mutation among TP53, ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 confers adverse risk according to the recent European LeukemiaNet (ELN) 2022 classification.

In patients receiving less intensive treatment with hypomethylating agents plus Venetoclax (HMA+VEN), RUNX1, FLT3-ITD, N/KRAS, CBL, and KIT mutations have also been reported to predict treatment failure.

In the last years new drugs have been approved for the treatment of AML. CPX-351 showed superior efficacy if compared to conventional 3+7 in secondary AML (s-AML), and adverse risk mutations are particularly common in this context.

However, data concerning the prognostic relevance of adverse risk mutations in CPX-351 treated patients are lacking. Furthermore, a fraction of s-AML patients may be eligible to both CPX-351 and HMA-VEN induction, and there are no data about the efficacy of CPX-351 in s-AML patients with gene mutations predictive of HMA-VEN failure.

This study therefore aimed to explore the prognostic relevance of adverse risk mutations or mutational patterns linked to high risk of treatment failure with either conventional chemotherapy or with HMA-VEN in a cohort of elderly patients with s-AML treated with CPX-351.

Methods

The study involved 85 patients (median age 69, range 37-77) with s-AML or t-AML according to WHO 2016 classification, treated in our Center with CPX-351.

NGS was performed using the Myeloid Solution panel by SOPHiA Genetics, encompassing 34 critical genes mutations. Samples were processed on an Illumina MiSeq platform and analysis was performed with SOPHiA DDM® Software.

Minimal Residual Disease (MRD) was analysed in all patients achieving complete remission (CR) with multicolour flow-cytometry (MFC), with a threshold of 0.1%.

Results

Cytogenetic analysis showed high or intermediate risk karyotype in 48 (57%) and 37 patients (43%), respectively. Fifty-three patients (62%) showed high risk gene mutations, as defined by ELN 2022 risk score, and 64 patients (75%) displayed molecular aberrations predictive of resistance to HMA-VEN. Median number of gene mutations for single patient by NGS was 5 (range 2-10) and 45 patients had high mutational burden (≥ 4 mutations, 53%). Most frequent mutations were: CBL (79 %), CEBPA (59%), TET2 (41%), RUNX1 (39%), ASXL1 (29%), DNMT3A (29%), SRSF2 (29%), TP53 (26%). ELN 2022 risk score was favourable, intermediate or unfavourable in 3 (3%), 28 (33%) and 54 (64%) patients, respectively. After cycle 1, 66 patients (78%) achieved CR, with MFC-MRD negativity obtained in 48/66 responding patients (72%). Three patients (3.8%) died before response assessment, mainly due to infections.

Uni and multivariate analysis showed that both CR and MRD negativity rate were not affected by the ELN 2022 high-risk mutations or by any other gene mutation (p=n.s.). Furthermore, CR and MRD negativity were also unaffected by adverse cytogenetics or by the presence of high mutational burden or HMA-VEN resistance profile (p=n.s.).

After a median follow up of 42.1 months (CI 95%; 31-62 months), median OS was 19 months (CI 95% 15.89-20.69), whereas 2-year OS was 40.2%.

OS was not affected by any of the high-risk mutations, high mutational burden, or by the presence of HMA-VEN resistance profile (p=n.s.). Multivariate OS analysis showed that negative MRD was the strongest independent prognostic factor (p<0.05).

In landmark analysis, patients achieving CR and proceeding to allogeneic stem cell transplantation consolidation (HSCT) (n=23) within 3 months from CR (n=8) had a significantly better outcome if compared to CR patients who did not receive HSCT (n=41) or proceeded to transplant later (n=15, p<0.03).

Conclusions
CPX-351 is able to induce MRD negative CR in a large proportion of s-AML patients, with a lower impact from the presence of adverse risk features or HMA-VEN resistance profile. However, as the deep response achieved may be not durable, early HSCT consolidation is strongly advised in order to achieve long term survival.

Disclosures: Lemoli: Jazz Pharma: Speakers Bureau.

*signifies non-member of ASH