Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: results from the AMLSG 09-09 trial

Abstract

Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1 mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TL) by RQ-PCR and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TL and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase III AMLSG 09-09 trial. 3733 bone marrow (BM) and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after two treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity consistently revealed as poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TL were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly higher proportion of patients achieving MRD negativity at EOT (56% vs 41%; P=.01). The betterreduction of NPM1mut TL after two treatment cycles in MRD-positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR 29.3% vs 45.7%, P=.009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction of NPM1mut TL across all treatment cycles leading to a significantly lower relapse rate. The AMLSG 09-09 trial was registered at www.clinicaltrials.gov as #NCT00893399.

Nucleophosmin1 and isocitrate dehydrogenase 1 and 2 as measurable residual disease markers in acute myeloid leukemia

“…The serial acquirement of somatic mutations in myeloid clone(s) was described as the multistep pathogenesis of AML. Several lines of evidence prove that NPM1 mutations are responsible for the definitive acute leukemic transformation, therefore considered as leukemia founder mutations: (i) NPM1 mutations are completely absent in the population without hematological malignancies even at a higher age [ [30][31][32][33][34][35][36][37][38][39]. The long observational period in our study allowed us to detect late AML relapses.…”

“…We were unable to test large number of RNA samples, which is a major limitation of our retrospective study. Ivey et al [57] demonstrated that RNA-MRD positivity in PB after induction (2 cycles) corresponded to higher cumulative incidence of relapse (MRC17 trial 3-year CIR: 82% versus 30%), similarly Balsat et al [58] (ALFA-0702 trial: 2-year CIR: 55% versus 21%); Hubmann et al [62] less than 3log-reduction in BM RNA-MRD (AMLCG 1999(AMLCG , 2004(AMLCG and 2008 trial: 2-year CIR 77.8% versus 26.4%,); Kapp-Schwoerer et al [34] less than 3-log 10 BM or PB RNA-MRD (AMLSG 09-09 trial 4-year CIR BM: 60% versus 28.5%; PB: 62.5% versus 33.9%). On the DNA level, we also observed that MRD positivity (less than 3log reduction) was associated with adverse outcome, and DNA-MRD after induction therapy is capable to identify high-risk NPM1 mut patients.…”

“…Although consensus exists about the importance of NPM1 MRD; broad range of heterogeneity was displayed concerning thresholds discriminating between low- and high-risk MRD. Studies comparing mutant NPM1 transcript levels parallel in bone marrow (BM) and peripheral blood (PB) samples identified strong correlation, but an average of 1-log higher sensitivity in BM [ 21 , 34 , 38 , 57 – 61 ]. In line with this observation, 3-log reduction of NPM1 mut / ABL1 transcript level was pointed as favorable prognostic indicator in BM, [ 21 , 59 , 60 ] but 4-log reduction was required in PB after induction therapy [ 57 , 58 ].…”

Rationale and Design of GnG-Trial: A Randomized Phase-III Study to Compare Two Schedules of Gemtuzumab Ozogamicin as Adjunct to Intensive Induction Therapy and to Compare Double-Blinded Intensive Postremission Therapy with or Without Glasdegib in Older Patients with Newly Diagnosed AML

“…AML achieving CR is known to be associated with a lower relapse risk. It can be considered a broad predictive biomarker useful to guide the patient's postremission management [41][42][43][44][45]. Thus, the ELN consensus recommends molecular MRD assessments for NPM1 mutations, RUNX1-RUNX1T1, CBFB-MYH11, and PML-RARA fusion transcripts at diagnosis, after two cycles of induction/consolidation therapy, and every 3 months, for 24 months after the end of treatment [4].…”

“…EFS has been accepted as primary endpoint for the approval of GO in rst line therapy in AML by the FDA and EMA [48]. EFS compared to OS provides the advantage to be measurable earlier and to be directly linked to the treatment under investigation [40][41][42][43][44][45][46][47][48][49][50][51]. In contrast to overall survival, where death is the only event of interest, EFS also includes failure to obtain complete remission and relapse from complete remission.…”