Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse

Hubmann, Max; Köhnke, Thomas; Hoster, Eva; Schneider, Stephanie; Dufour, Annika; Zellmeier, Evelyn; Fiegl, Michael; Braess, Jan; Bohlander, Stefan K.; Subklewe, Marion; Sauerland, Maria-Cristina; Berdel, Wolfgang E.; Büchner, Thomas; Wörmann, Bernhard; Hiddemann, Wolfgang; Spiekermann, Karsten

doi:10.3324/haematol.2014.104133

Cited by 69 publications

(72 citation statements)

References 34 publications

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“…3,13,14 In addition, the risk of relapse may be better defined with the use of leukemia-specific molecular markers (e.g., mutated NPM1) as targets for detection of submicroscopic levels of leukemia, so-called minimal residual disease, after therapy. 15 Although the presence of minimal residual disease can provide prognostic information, [16][17][18][19][20][21][22] it is unclear whether such identification is useful in the context of systematic molecular profiling. Moreover, questions have been raised about the assessment of minimal residual disease in routine practice, given the clonal complexity of AML.…”

mentioning

confidence: 99%

Assessment of Minimal Residual Disease in Standard-Risk AML

Ivey

Hills

Simpson³

et al. 2016

N Engl J Med

674

595

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BACKGROUNDDespite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. METHODSWe used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. RESULTSMolecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status. CONCLUSIONSThe presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors.

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mentioning

confidence: 99%

Assessment of Minimal Residual Disease in Standard-Risk AML

Ivey

Hills

Simpson³

et al. 2016

N Engl J Med

674

595

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“…14 Additionally, NPM1 and CEBPA mutations and FLT3 internal tandem duplications (FLT3-ITDs) were tested by standard methods. [23][24][25][26][27] Genotyping of T lymphocytes was performed for selected patients as described in the Supplement.…”

Section: Genetic Analysesmentioning

confidence: 99%

“…23,28 Eleven additional patients had other types of NPM1 mutations, and no qPCR assay was available for these. Flow cytometric MRD assessment, based on detection of leukemia-associated immunophenotypes, was performed using FACSCalibur (BD Biosciences, San Jose, CA, USA; 60 patients) or NAVIOS (Beckman Coulter, Brea, CA, USA; 21 patients) instruments.…”

Section: Minimal Residual Disease Assessmentmentioning

confidence: 99%

Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia

Rothenberg‐Thurley

Amler²,

Goerlich³

et al. 2017

Leukemia

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Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ≥1 mutation during remission at a variant allele frequency of ≥2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (p<.0001) and, in multivariate analyses adjusting for age, genetic risk, and allogeneic transplantation, with inferior relapse-free survival (hazard ratio, 2.34; p=.0039) and overall survival (hazard ratio, 2.14; p=.036). Patients with persisting mutations had a higher cumulative incidence of relapse before, but not after allogeneic stem cell transplantation. Our work underlines the relevance of mutation persistence during first remission as a novel risk factor in AML. Persistence of pre-leukemic clones may contribute to the inferior outcome of elderly AML patients. Allogeneic transplantation abrogated the increased relapse risk associated with persisting pre-leukemic clones, suggesting that mutation persistence may guide postremission treatment.

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“…Ответ длительно сохраняется при проведении консолидации цитарабином в вы-соких дозах. Тем не менее более чем у 40 % из них в дальнейшем все же развиваются рецидивы, включая группу NPM1/FLT3wt [30].…”

Section: Introductionunclassified

“…Однако оптимальный уровень к настоящему времени не определен. Значения в разных источниках варьируют от 3 до 5 log [14,30,33]. В настоящее время большинство исследователей рассматривают NPM1 как высокоспецифичный [34][35][36] и стабильный маркер оценки МОБ [14,[37][38][39][40][41].…”

Section: Introductionunclassified

Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia

Гиршова¹,

Budaeva²,

Ovsyannikova³

et al. 2017

Клиническая онкогематология

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Background. Acute myeloblastic leukemia (AML) with NPM7 mutation amounts to 30 % of all AML and is characterized by good prognosis with the exception of cases with FLT3-/TD mutation. Despite the good prognosis, the likelihood of relapses in patients with NPM7 mutation may significantly differ. Thus, the estimation of the minimal residual disease (MRD) after chemotherapy and during follow-up is becoming increasingly important. This approach will make it possible to predict the sensitivity of a tumoral clone to chemotherapy. Aim. To evaluate the prognostic value of highly specific marker (NPM7 mutation) and non-specific marker (WT1 overexpression) of MRD, as well as to identify the correlation between the levels of NPM7 and WT7 at different stages of therapy and in the follow-up period. Materials & Methods. The research included 14 patients with AML. All patients had the NPM7 mutation and WT7 overexpression: 50 % of patients had additional molecular markers (BAALC overexpression, FLT3-/TD, DNMT3A, and MLL mutations). Real-time PCR was used for long-term monitoring of WT7 expression levels and NPM7 mutation. Results. The median decrease of NPM7 levels after the induction therapy was 3 log. All patients had relapses, NPM7 mutation, and lower rates of OS/RFS, which significantly correlated with prognostically negative molecular markers. There were no statistically significant differences in RFS in groups with the decrease of WT7 expression level < 2 log and ≥ 2 log on day 28 of treatment. At the same time, the decrease of WT7 expression by > 2 log was associated with significant differences in early relapses, which correlated with the decrease of NPM7 levels (> and < than 3 log) is revealed. RFS rates were higher in patients with WT7 expression level of < 100 per 104 copies ABL on day 28 and WT7 of < 250 per 104 copies ABL on day 14 of treatment. WT7 expression was significantly lower on days 14 and 28 in patients with NPM7 decrease of > 3 log on day 28. The decrease in WT7 expression of < 100 per 104 copies ABL on day 28 was more common in patients with isolated NPM1 mutation, compared to patients with additional negative molecular markers. Conclusion. The decrease in NPM1 levels after the induction therapy may serve as reliable prognostic marker of RFS and OS rates. New correlation between the degree of NPM1 reduction and the presence of additional molecular markers was established. Highly specific (NPM1 mutation) was shown to be more specific compared to non-specific markers ( WT1 overexpression). The research showed the predictive value of a lower limit level of WT1 on day 28 of treatment (100 per 104 copies ABL), and for the first time, the importance of the early assessment WT1 expression reduction on day 14 of induction therapy.

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Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse

Cited by 69 publications

References 34 publications

Assessment of Minimal Residual Disease in Standard-Risk AML

Assessment of Minimal Residual Disease in Standard-Risk AML

Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia

Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia

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