Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Favorable outcomes for allogeneic hematopoietic cell transplantation in elderly patients with NPM1-mutated and FLT3-ITD-negative acute myeloid leukemia

Bone Marrow Transplantation volume 55, pages 473–475 (2020)Cite this article

Subjects

Nucleophosmin1 (NPM1) is the most frequently encountered mutation in acute myeloid leukemia (AML) with normal karyotype (NK) [1, 2]. In the European LeukemiaNet and other prognostic classifications [3], AML patients harboring the NPM1 mutation (NPM1m) in absence of FLT3-ITD (FLT3-ITD-negative) are in the favorable genetic group. In fact, a large subset of these patients can be cured with chemotherapy regimens that include repeated cycles of consolidation with high-dose cytarabine following initial cytarabine-anthracycline-remission induction [2, 4,5,6]. These results led to a general recommendation against early transplant in NK-AML patients with a NPM1m/FLT3-ITD-negative leukemic genotype. However, most of the available data supporting the favorable impact of this genetic profile on younger patients (<60 years old) [4, 5, 7]. The incidence of NPM1m/FLT3-ITD-negative AML was comparable in the German Acute Myeloid Leukemia Cooperative Group analysis across age including elderly patients, however, increased age (≥60 years) was associated with inferior overall survival (OS) [6]. Becker et al. previously reported that although older patients (≥60 years) with NK-AML had better outcomes [CR, disease-free survival (DFS), and overall survival (OS)] if NPM1 is mutated compared to NPM1 wild-type, yet long-term outcomes were extremely poor for NPM1m older patients with 3-years overall survival (OS) and disease-free survival (DFS) of only 29 and 19%, respectively [8]. The authors did not comment on how many patients received allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR1) in this cohort. Similar dismal long term outcomes were reported in another study in elderly patients with NPM1m/FLT3-ITD-negative, mainly due to high relapse rate after achieving CR in the absence of alloHCT consolidation [9].

Thus, we conducted a retrospective analysis to evaluate the outcomes of these older patients who underwent alloHCT in CR1 between 2011 and 2018. Among 233 AML patients ≥60 years old transplanted in CR1 during this period, 17 (7%) had NPM1m/FLT3-ITD-negative disease. The median age was 66 years (range; 61–73). More patients were transplanted between 2017 and 2018 than in previous years (10 versus 7). The majority of cases had de novo AML (n = 14) while two patients had secondary AML arising from myelodysplastic syndrome and one patient had therapy-related AML. Cytogenetics were NK in all patients but two; one with trisomy 8 and one with deletion (5) (q22q35). Recurrent associated somatic mutations in this cohort included FLT3-TKD (n = 6), TET2 (n = 5), DNMT3A (n = 3), IDH 1 or 2 (n = 3), and MLL2 (n = 2). The median presenting white blood cell count (WBC) was 40 k/µL (1.1–137), and 6 patients had initial WBC > 50 k/µL. All patients were induced with standard 7 + 3 regimen except for one who received induction with venetoclax and azacitidine. Three patients required a second induction to achieve remission. Thirteen patients had pre-transplant minimal residual disease (MRD) evaluated by either multicolor flow cytometry (MCF) at a reference laboratory [n = 11] and/or by quantitative polymerase chain reaction (PCR) for NPM1 mutation [n = 8]. PCR was negative in all cases while MCF was positive in 2 (18%) patients before transplant.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352:254–66.

    Article  CAS  Google Scholar 

  2. Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, Schaich M, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107:4011–20.

    Article  CAS  Google Scholar 

  3. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  Google Scholar 

  4. Dohner K, Schlenk RF, Habdank M, Scholl C, Rücker FG, Corbacioglu A, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106:3740–6.

    Article  Google Scholar 

  5. Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111:2776–84.

    Article  CAS  Google Scholar 

  6. Buchner T, Berdel WE, Haferlach C, Haferlach T, Schnittger S, Müller-Tidow C, et al. Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Myeloid Leukemia Cooperative Group. J Clin Oncol. 2009;27:61–69.

    Article  Google Scholar 

  7. Schlenk RF, Dohner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909–18.

    Article  CAS  Google Scholar 

  8. Becker H, Marcucci G, Maharry K, Radmacher MD, Mrózek K, Margeson D, et al. Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study. J Clin Oncol. 2010;28:596–604.

    Article  CAS  Google Scholar 

  9. Scholl S, Theuer C, Scheble V, Kunert C, Heller A, Mügge LO, et al. Clinical impact of nucleophosmin mutations and Flt3 internal tandem duplications in patients older than 60 yr with acute myeloid leukaemia. Eur J Haematol. 2008;80:208–15.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, USA

    Ibrahim Aldoss, Ryotaro Nakamura, Amandeep Salhotra, Anthony S. Stein, Vinod Pullarkat, Stephen J. Forman & Guido Marcucci

  2. Department of Computational & Quantitative Medicine, City of Hope, Duarte, CA, USA

    Dongyun Yang

Authors
  1. Ibrahim Aldoss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryotaro Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dongyun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amandeep Salhotra
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anthony S. Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vinod Pullarkat
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stephen J. Forman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guido Marcucci
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Designated the study, IA, RN and GM; Data collection, IA and DY; Analysis, IA, DY, RN, AS, VP, ASS, SJF and GM, Writing, IA, RN and GM; Review & Editing, all authors.

Corresponding author

Correspondence to Ibrahim Aldoss.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aldoss, I., Nakamura, R., Yang, D. et al. Favorable outcomes for allogeneic hematopoietic cell transplantation in elderly patients with NPM1-mutated and FLT3-ITD-negative acute myeloid leukemia. Bone Marrow Transplant 55, 473–475 (2020). https://doi.org/10.1038/s41409-019-0553-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-019-0553-x

This article is cited by

Search

Advanced search

Quick links