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Advances in the molecular assessment of measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) have led to the inclusion of MRD-negative molecular complete remission (CR) as a new response criterion in the 2017 European LeukemiaNet AML recommendations.1 One of the most common genomic alterations in AML is a mutation in the gene encoding nucleophosmin (NPM1mut). NPM1mut represents an ideal marker for monitoring MRD because it is stable and homogeneous, and studies have shown that the transcript levels are prognostic.
Early results from the phase III AMLSG 09-09 trial (NCT00893399; previously reported on the AML Hub) showed that addition of gemtuzumab ozogamicin (GO) to intensive chemotherapy failed to provide significant improvement in event-free survival (EFS) in patients with NPM1mut AML.2 There was, however, evidence of anti-leukemic activity. In an explorative study published in Blood, Silke Kapp-Schwoerer et al. evaluated NPM1mut transcript levels and determined the impact of NPM1mut MRD and GO treatment on the prognosis of patients participating in the AMLSG 09-09 trial.3
The study comprised 3,733 bone marrow (BM) and 3,793 peripheral blood (PB) samples from 469 patients with newly diagnosed NPM1mut AML within the AMLSG 09-09 trial. Inclusion criteria included availability of a diagnostic and at least one subsequent BM or PB sample, and achievement of a CR or CR with incomplete blood count recovery (CRi) after induction therapy.
Patients were treated with intensive chemotherapy plus all-trans retinoic acid (ATRA) with or without GO.
NPM1mut transcript levels (TL) were determined by quantitative reverse transcription polymerase chain reaction (RQ-PCR) after two treatment cycles: at the end of treatment (EOT) and during follow-up. Because the primary endpoint of the trial (improved EFS) was not met, cumulative incidence of relapse (CIR) was the endpoint used to assess the prognostic impact of NPM1mut MRD.
Gene–gene interactions between NPM1mut and other frequent mutations, including the gene encoding DNA methyltransferase 3A (DNMT3Amut) and internal tandem duplications of FLT3 (FLT3-ITD), have been observed in NPM1mut AML but the prognostic impact is unclear. In this study, the authors also evaluated the impact of NPM1mut/DNMT3Amut interactions on NPM1mut TL, MRD negativity, and CIR.
The baseline characteristics of study patients are shown in Table 1. Clinical and disease features were well balanced between study arms; the only significant difference was in DNMT3A mutational status (DNMT3Amut), which was higher in the GO arm than in the standard arm. FLT3-ITD were underrepresented overall since patients with this mutation were assigned to an alternative trial, (AMLSG 16-10, previously reported on the AML Hub). Post remission, 84% of patients received ≤ 3 cycles of high-dose cytarabine, 7% had an allogeneic hematopoietic cell transplant in the first CR or CRi, and 9% did not receive consolidation therapy.
Table 1. Baseline patient characteristics3
DNMT3A, DNA methyltransferase 3 alpha; FLT3, fms-like tyrosine kinase receptor 3; GO, gemtuzumab ozogamicin; ITD, internal tandem duplication; TKD, tyrosine kinase domain. *For patients with BM blasts < 20%, AML diagnosis was established based on extramedullary disease or ≥ 20% peripheral blood blasts. |
|||
Characteristic |
Standard arm (n = 237) |
GO arm (n = 232) |
p value |
---|---|---|---|
Median age at diagnosis (range) |
58.6 (20.9–78.4) |
57.5 (19.3–82.3) |
0.67 |
Sex, male, % |
49 |
44 |
0.23 |
Type of AML, % |
|
|
0.64 |
De novo |
91 |
89 |
|
Secondary |
7 |
9 |
|
Therapy related |
2 |
2 |
|
Cytogenetics, % |
|
|
0.65 |
Normal karyotype |
89 |
86 |
|
Other karyotypes |
10 |
14 |
|
Complex karyotype |
0 |
0 |
|
FLT3-ITD, % |
|
|
0.22 |
FLT3-ITD negative |
83 |
87 |
|
FLT3-ITD low |
6 |
7 |
|
FLT3-ITD high |
11 |
6 |
|
DNMT3A, % |
|
|
0.06 |
Wildtype |
58 |
47 |
|
Mutated |
42 |
53 |
|
FLT3-TKD, % |
|
|
0.16 |
Wildtype |
90 |
85 |
|
Mutated |
10 |
15 |
|
Table 2. Statistically significant prognostic factors identified in multivariate analysis3
CI, confidence interval; DNMT3A, DNA methyltransferase 3 alpha; HR, hazard ratio; FLT3-ITDhigh, fms-like tyrosine kinase receptor 3-internal tandem duplication with high allelic ratio; GO, gemtuzumab ozogamicin; MRD, measurable residual disease. *Increase of 10 years. |
||||
Bone marrow |
After two treatment cycles |
At end of treatment |
||
---|---|---|---|---|
Variable |
HR (95% CI) |
p value |
HR (95% CI) |
p value |
MRD positive |
1.82 (1.01–3.26) |
0.04 |
2.41 (1.55–3.77) |
0.0001 |
FLT3-ITDhigh |
2.17 (1.13–4.18) |
0.02 |
2.36 (1.03–5.44) |
0.04 |
DNMT3Amut |
2.73 (1.72–4.34) |
< 0.0001 |
2.14 (1.29–3.53) |
0.003 |
Age* |
1.48 (1.25–1.76) |
< 0.0001 |
1.51 (1.24–1.85) |
< 0.0001 |
GO treatment |
0.58 (0.39–0.84) |
0.004 |
0.63 (0.40–1.00) |
0.05 |
Peripheral blood |
After two treatment cycles |
At end of treatment |
||
Variable |
HR (95% CI) |
p value |
HR (95% CI) |
p value |
MRD positive |
3.12 (2.04–4.97) |
< 0.0001 |
5.50 (3.44–8.79) |
< 0.0001 |
FLT3-ITDhigh |
2.41 (1.1–4.94) |
0.016 |
3.06 (1.38–6.80) |
0.005 |
DNMT3Amut |
3.01 (1.86–4.89) |
< 0.0001 |
3.27 (1.85–5.80) |
< 0.0001 |
Age* |
1.52 (1.28–1.82) |
< 0.0001 |
1.31 (1.06–1.62) |
0.01 |
GO treatment |
— |
— |
0.62 (0.38–1.02) |
0.057 |
This exploratory analysis supports a role for early reduction of NPM1mut TL in lowering relapse rates and demonstrates the prognostic relevance of MRD monitoring in patients with NPM1mut AML. The addition of GO to standard intensive chemotherapy led to reduced NPM1mut TL and higher rates of MRD negativity, which translated into lower CIR and superior relapse-free survival. The authors conclude that monitoring MRD with NPM1mut TL is a valuable tool for assessing risk of relapse and efficacy of novel treatments in NPM1mut AML.
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