Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

doi:10.3390/ijms19113492

Review

. 2018 Nov 6;19(11):3492.

doi: 10.3390/ijms19113492.

Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

Fabio Forghieri¹, Patrizia Comoli^{2

3}, Roberto Marasca⁴, Leonardo Potenza⁵, Mario Luppi⁶

Affiliations

¹ Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Via del Pozzo 71, 41124 Modena, Italy. fabio.forghieri@unimore.it.
² Pediatric Hematology/Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy. pcomoli@smatteo.pv.it.
³ Cell Factory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy. pcomoli@smatteo.pv.it.
⁴ Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Via del Pozzo 71, 41124 Modena, Italy. roberto.marasca@unimore.it.
⁵ Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Via del Pozzo 71, 41124 Modena, Italy. leonardo.potenza@unimore.it.
⁶ Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Via del Pozzo 71, 41124 Modena, Italy. mario.luppi@unimore.it.

PMID: 30404199
PMCID: PMC6274702
DOI: 10.3390/ijms19113492

Review

Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

Fabio Forghieri et al. Int J Mol Sci. 2018.

. 2018 Nov 6;19(11):3492.

doi: 10.3390/ijms19113492.

Authors

Fabio Forghieri¹, Patrizia Comoli^{2

3}, Roberto Marasca⁴, Leonardo Potenza⁵, Mario Luppi⁶

Affiliations

¹ Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Via del Pozzo 71, 41124 Modena, Italy. fabio.forghieri@unimore.it.
² Pediatric Hematology/Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy. pcomoli@smatteo.pv.it.
³ Cell Factory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy. pcomoli@smatteo.pv.it.
⁴ Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Via del Pozzo 71, 41124 Modena, Italy. roberto.marasca@unimore.it.
⁵ Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Via del Pozzo 71, 41124 Modena, Italy. leonardo.potenza@unimore.it.
⁶ Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Via del Pozzo 71, 41124 Modena, Italy. mario.luppi@unimore.it.

PMID: 30404199
PMCID: PMC6274702
DOI: 10.3390/ijms19113492

Abstract

Acute myeloid leukemia (AML) with NPM1 gene mutations is currently recognized as a distinct entity, due to its unique biological and clinical features. We summarize here the results of published studies investigating the clinical application of minimal/measurable residual disease (MRD) in patients with NPM1-mutated AML, receiving either intensive chemotherapy or hematopoietic stem cell transplantation. Several clinical trials have so far demonstrated a significant independent prognostic impact of molecular MRD monitoring in NPM1-mutated AML and, accordingly, the Consensus Document from the European Leukemia Net MRD Working Party has recently recommended that NPM1-mutated AML patients have MRD assessment at informative clinical timepoints during treatment and follow-up. However, several controversies remain, mainly with regard to the most clinically significant timepoints and the MRD thresholds to be considered, but also with respect to the optimal source to be analyzed, namely bone marrow or peripheral blood samples, and the correlation of MRD with other known prognostic indicators. Moreover, we discuss potential advantages, as well as drawbacks, of newer molecular technologies such as digital droplet PCR and next-generation sequencing in comparison to conventional RQ-PCR to quantify NPM1-mutated MRD. In conclusion, further prospective clinical trials are warranted to standardize MRD monitoring strategies and to optimize MRD-guided therapeutic interventions in NPM1-mutated AML patients.

Keywords: NPM1-mutated acute myeloid leukemia; allogeneic hematopoietic stem cell transplantation; clinical outcome; intensive chemotherapy; molecular minimal/measurable residual disease monitoring; prognostic thresholds and timepoints.

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Conflict of interest statement

F.F. served on advisory boards for Jannsen on the clinical use of decitabine in AML patients, M.L. served on advisory boards for Novartis on the clinical use of midostaurin. The other authors declare no potential conflicts of interest.

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References

1. Tomlinson B., Lazarus H.M. Enhancing acute myeloid leukemia therapy—Monitoring response using residual disease testing as a guide to therapeutic decision-making. Expert Rev. Hematol. 2017;10:563–574. doi: 10.1080/17474086.2017.1326811. - DOI - PubMed
1. Ossenkoppele G., Schuurhuis G.J. MRD in AML: Does it already guide therapy decision-making? Hematol. Am. Soc. Hematol. Educ. Program. 2016;2016:356–365. doi: 10.1182/asheducation-2016.1.356. - DOI - PMC - PubMed
1. Hourigan C.S., Gale R.P., Gormley N.J., Ossenkoppele G.J., Walter R.B. Measurable residual disease testing in acute myeloid leukemia. Leukemia. 2017;31:1482–1490. doi: 10.1038/leu.2017.113. - DOI - PubMed
1. Buccisano F., Maurillo L., Del Principe M.I., Di Veroli A., De Bellis E., Biagi A., Zizzari A., Rossi V., Rapisarda V., Amadori S., et al. Minimal residual disease as a biomarker for outcome prediction and therapy optimization in acute myeloid leukemia. Expert Rev. Hematol. 2018;11:307–313. doi: 10.1080/17474086.2018.1447378. - DOI - PubMed
1. Araki D., Wood B.L., Othus M., Radich J.P., Halpern A.B., Zhou Y., Mielcarek M., Estey E.H., Appelbaum F.R., Walter R.B. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia: Time to move toward a minimal residual disease-based definition of complete remission? J. Clin. Oncol. 2016;34:329–336. doi: 10.1200/JCO.2015.63.3826. - DOI - PMC - PubMed

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[1] Tomlinson B., Lazarus H.M. Enhancing acute myeloid leukemia therapy—Monitoring response using residual disease testing as a guide to therapeutic decision-making. Expert Rev. Hematol. 2017;10:563–574. doi: 10.1080/17474086.2017.1326811. - DOI - PubMed

[2] Tomlinson B., Lazarus H.M. Enhancing acute myeloid leukemia therapy—Monitoring response using residual disease testing as a guide to therapeutic decision-making. Expert Rev. Hematol. 2017;10:563–574. doi: 10.1080/17474086.2017.1326811. - DOI - PubMed

[3] Ossenkoppele G., Schuurhuis G.J. MRD in AML: Does it already guide therapy decision-making? Hematol. Am. Soc. Hematol. Educ. Program. 2016;2016:356–365. doi: 10.1182/asheducation-2016.1.356. - DOI - PMC - PubMed

[4] Ossenkoppele G., Schuurhuis G.J. MRD in AML: Does it already guide therapy decision-making? Hematol. Am. Soc. Hematol. Educ. Program. 2016;2016:356–365. doi: 10.1182/asheducation-2016.1.356. - DOI - PMC - PubMed

[5] Hourigan C.S., Gale R.P., Gormley N.J., Ossenkoppele G.J., Walter R.B. Measurable residual disease testing in acute myeloid leukemia. Leukemia. 2017;31:1482–1490. doi: 10.1038/leu.2017.113. - DOI - PubMed

[6] Hourigan C.S., Gale R.P., Gormley N.J., Ossenkoppele G.J., Walter R.B. Measurable residual disease testing in acute myeloid leukemia. Leukemia. 2017;31:1482–1490. doi: 10.1038/leu.2017.113. - DOI - PubMed

[7] Buccisano F., Maurillo L., Del Principe M.I., Di Veroli A., De Bellis E., Biagi A., Zizzari A., Rossi V., Rapisarda V., Amadori S., et al. Minimal residual disease as a biomarker for outcome prediction and therapy optimization in acute myeloid leukemia. Expert Rev. Hematol. 2018;11:307–313. doi: 10.1080/17474086.2018.1447378. - DOI - PubMed

[8] Buccisano F., Maurillo L., Del Principe M.I., Di Veroli A., De Bellis E., Biagi A., Zizzari A., Rossi V., Rapisarda V., Amadori S., et al. Minimal residual disease as a biomarker for outcome prediction and therapy optimization in acute myeloid leukemia. Expert Rev. Hematol. 2018;11:307–313. doi: 10.1080/17474086.2018.1447378. - DOI - PubMed

[9] Araki D., Wood B.L., Othus M., Radich J.P., Halpern A.B., Zhou Y., Mielcarek M., Estey E.H., Appelbaum F.R., Walter R.B. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia: Time to move toward a minimal residual disease-based definition of complete remission? J. Clin. Oncol. 2016;34:329–336. doi: 10.1200/JCO.2015.63.3826. - DOI - PMC - PubMed

[10] Araki D., Wood B.L., Othus M., Radich J.P., Halpern A.B., Zhou Y., Mielcarek M., Estey E.H., Appelbaum F.R., Walter R.B. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia: Time to move toward a minimal residual disease-based definition of complete remission? J. Clin. Oncol. 2016;34:329–336. doi: 10.1200/JCO.2015.63.3826. - DOI - PMC - PubMed

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Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

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Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

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