Background:

AML with mutated NPM1 (NPM mut AML) represents a distinct subtype of AML generally characterized by favourable prognosis. Nevertheless, several studies disclosed a biological and molecular heterogeneity of NPM mut AML.

Despite only FLT3-ITD mutation and adverse karyotype are currently validated for risk stratification, observation from different studies suggested that other molecular features could be associated with poor outcome.

The co-mutation of DNMT3A has firstly been suggested to negatively influence prognosis in AML-NPM1, especially if a concomitant FLT3-ITD mutation is present.

More recently, the European LeukemiaNet 2022 (ELN) classification included mutations of SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR and STAG (collectively defined as secondary-type mutations, STM) in the adverse risk group, based on studies showing poor prognosis also in the novo AML. However, it is not clear whether the STM are able to overcome the positive prognostic value of NPM1 mutation.

Moreover, most information on the prognostic role of concomitant mutations comes from trials with standard 3+7 chemotherapy and several reports have shown that NPM mut AML patients may benefit from more intensive induction strategy such as fludarabine-high dose cytarabine and idarubicin regimen (FLAI).

Our group has reported that FLAI may overcome the negative prognostic impact of FLT3-ITD in NPM mut AML, but there are still no data on the impact of other concomitant mutations in NPM mut AML patients in this context.

Aims:

The aim of this study was to assess the prognostic impact in term of minimal residual disease (MRD) clearance and survival of concomitant STM and/or DNMT3A mutation in a cohort of NPM mut AML treated with FLAI.

Methods:

the study included 44 patients (median age 56 years range 29-59) affected by AML with NPM1 mutation defined according to WHO2022 classification, treated in our center with FLAI between January 2013 and January 2023.

Next generation sequencing (NGS) was performed using the Myeloid Solution panel by SOPHiA Genetics, encompassing 34 critical genes mutations. Sample were processed on Illumina MiSeq platform and analysis was performed with SOPHiA DDM® Software. MRD was analysed in all patients achieving complete remission (CR) by reverse transcription polymerase chain reaction (RT-PCR).

Results

Six/44 (14%) patients had STM, whereas 9 patients (21%) had DNMT3A mutations, 3 of them had both DNMT3A and STM. FLT3-ITD was detected in 18/43 patients (42%). Median number of mutations for patient was 2 (range 0-9). Three/44 (7%) patients had high risk cytogenetics (complex hyperdiploid karyotype in all cases).

After cycle 1, 41 patients achieved a complete remission (94%), 2 were resistant (4%) and 1 (2%) died before disease evaluation. NPM MRD after cycle was negative in 34/41 (83%) responding patients. Both CR rate and MRD negativity were not affected by the presence of STM, DNMT3A, FLT3-ITD or a high-risk karyotype. Notably, the two patients that showed resistance to FLAI had normal cytogenetics and did not have STM or DNMT3A mutation, but were the only patients in the cohort showing a KMT2A mutation.

After a median follow-up of 59 months (CI 95% 41.32-68.6), median overall survival (OS) and median disease-free survival (DFS) were not reached. Five patients relapsed, 1 with overt hematological relapse whereas the other four showed MRD relapse only. A total of six patients (14%) received allogeneic stem cell transplantation (HSCT) in our cohort, 2 patients (4%) in first CR, and 4 (9%) as a consolidation of successful reinduction of a MRD relapse.

Overall, 5 patients died (11%), 3 because of resistant disease, one during induction and one because of SARS-CoV2 infection in MRD negative CR status.

OS and DFS were not affected by the presence of STM, DNMT3A, FLT3-ITD or high-risk cytogenetics (p=n.s.), whereas achieving a negative MRD after cycle 1 resulted in a significative longer OS and DFS (p<0.05).

Conclusions

FLAI was able to induce MRD negative CR and a long survival in the vast majority of NPM mut AML patients, regardless of concomitant STM, DNMT3A or FLT3-ITD mutations. Only a small minority of patients required HSCT in our cohort, significantly less compared to what is commonly reported with conventional 3+7. KMT2A mutations were rare in our cohort but seemed to be related to resistance to FLAI, but larger studies are needed to confirm this finding.

Disclosures

Lemoli:Jazz Pharma: Speakers Bureau.

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2024
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