Molecular Detection of Minimal Residual Disease before Allogeneic Stem Cell Transplantation Predicts a High Incidence of Early Relapse in Adult Patients with NPM1 Positive Acute Myeloid Leukemia

Abstract

We analyzed the impact of alloHSCT in a single center cohort of 89 newly diagnosed NPM1mut AML patients, consecutively treated according to the Northern Italy Leukemia Group protocol 02/06 [NCT00495287]. After two consolidation cycles, the detection of measurable residual disease (MRD) by RQ-PCR was strongly associated with an inferior three-year overall survival (OS, 45% versus 84%, p = 0.001) and disease-free survival (DFS, 44% versus 76%, p = 0.006). In MRD-negative patients, post-remissional consolidation with alloHSCT did not provide a significant additional benefit over a conventional chemotherapy in terms of overall survival [OS, 89% (95% CI 71–100%) versus 81% (95% CI 64–100%), p = 0.59] and disease-free survival [DFS, 80% (95% CI 59–100%) versus 75% (95% CI 56–99%), p = 0.87]. On the contrary, in patients with persistent MRD positivity, the three-year OS and DFS were improved in patients receiving an alloHSCT compared to those allocated to conventional chemotherapy (OS, 52% versus 31%, p = 0.45 and DFS, 50% versus 17%, p = 0.31, respectively). However, in this group of patients, the benefit of alloHSCT was still hampered by a high incidence of leukemia relapse during the first year after transplantation (43%, 95% CI 25–60%). Consolidative alloHSCT improves outcomes compared to standard chemotherapy in patients with persistent NPM1mut MRD positivity, but in these high-risk patients, the significant incidence of leukemia relapse must be tackled by post-transplant preemptive treatments.

Venetoclax induces rapid elimination of NPM1 mutant measurable residual disease in combination with low‐intensity chemotherapy in acute myeloid leukaemia

“…Two elderly patients considered unfit for HSCT remain alive at 6 and 12 months respectively. As detectable NPM1 mut ‐MRD levels prior to HSCT are associated with inferior outcomes, 6–8 it would seem reasonable to consider venetoclax‐based therapy to try to attain a molecular CR before transplantation 9,15 …”

“…Molecular relapse or progression after completion of therapy is invariably associated with clinical relapse 1,3,4 . Detection of NPM1 mut ‐MRD prior to allogeneic haematopoietic stem cell transplantation (HSCT) is associated with inferior survival 5–8 …”

Modelling the Effects of MCM7 Variants, Somatic Mutations, and Clinical Features on Acute Myeloid Leukemia Susceptibility and Prognosis

“…Acute myeloid leukemia (AML) is characterized by a phenotypic and genetic heterogeneity. Several chromosomal rearrangements, somatic mutations, and epigenetic aberrations have been described to be implicated in the AML susceptibility, pathogenesis, prognosis, evolution, overall survival (OS), or in the treatment response of AML patients [1][2][3][4][5].…”

Flow cytometric immunophenotypic alterations of persistent clonal haematopoiesis in remission bone marrows of patients with NPM1‐mutated acute myeloid leukaemia

“…Therefore, monitoring AML MRD has become increasingly part of standard care for patients with AML. MRD assessment can be performed using multicolour flow cytometry (MFC) immunophenotyping or by molecular methods, the latter including next generation sequencing (NGS) or ultrasensitive methods such as digital droplet polymerase chain reaction (PCR), single molecule molecular inversion probe capture or other sequencing methods incorporating error correction schemes based on molecular barcoding 1–9 . In the recent consensus guidelines by the European LeukemiaNet MRD Working Party for AML MRD, 10 MFC monitoring of MRD is recommended for all AML subtypes, using the approach of identification of classic leukaemia‐associated immunophenotypes (LAIP) 11 and identification of immunophenotypic deviation from normal.…”