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Simultaneous occurrence of acute myeloid leukaemia with mutated nucleophosmin (NPM1) in the same family

Leukemia volume 23, pages 199–203 (2009)Cite this article

Acute myeloid leukaemia (AML) with mutated nucleophosmin (NPM1), accounting for about 30% of adult de novo AML1 and 7% of childhood AML,2 displays distinctive biological and clinical characteristics.3 We report for the first time on the clinical, pathological and molecular features of NPM1-mutated AML which developed almost simultaneously (at an interval of only 2 months) in a father and his daughter, and discuss the biological significance of this finding.

His daughter (SV), aged 7 years, presented in June 2006, because routine blood tests showed Hb 8.9 g per 100 ml, platelets 195 000 per mm3, and a WBC count of 46 920 per mm3 with 90% blasts. The morphological features (Figure 2a) and positivity for myeloperoxidase of a fraction of blast cells (not shown) indicated an AML without maturation, according to the WHO classification. Leukaemic cells were CD34 negative (Figure 2b). Cytogenetics showed a normal karyotype (46, XX). Molecular studies revealed an NPM1 gene mutation of type B (insertion of 4 bp CATG after nucleotide 1018 of the reference sequence, GenBank accession number NM_002520), which is one of the most common NPM1 mutation variants in childhood AML.4 Further studies also revealed an internal tandem duplication of the FLT3 gene (FLT3-ITD). The patient was treated according to the high-risk arm of the Associazione Italiana Ematologia Oncologia Pediatrica protocol LAM 2002/01 (Supplementary Materials). Complete haematological remission was followed by autologous PBSC transplantation (December 2006; Supplementary Materials). Bone marrow biopsy (February 2007) showed about 15% leukaemic cells. Rescue therapy was immediately started according to the I-BFM-SG protocol but only the first FLAG (fludarabine, cytarabine, granulocyte-colony stimulating factor) cycle was administered because of severe neutropenia. In April 2007, bone marrow biopsy showed massive infiltration by leukaemic cells exhibiting the original morphological and phenotypic characteristics (myeloperoxidase positivity, CD34 negativity). In May 2007, the child underwent a haploidentical PBSC transplant from her mother at the Division of Pediatric Oncology and Haematology, and Haematopoietic Stem Cell transplantation Unit of the University of Perugia, Italy (Supplementary Materials). A CR was sustained from June to November 2007. As bone marrow biopsy in December 2007 indicated AML had relapsed, the patient was treated with a donor lymphocyte infusion (5 × 105 per kg). In February 2008, bone marrow biopsy showed massive leukaemic infiltration. Molecular analyses confirmed the presence of NPM1 and FLT3-ITD mutations. In March 2008, the child received unmanipulated bone marrow stem cells from the same donor after conditioning with treosulfan, thiotepa and clofarabine. She developed grade II acute graft-versus-host disease and achieved a CR with a full-donor type chimerism.

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Acknowledgements

Supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), MIUR PRIN and Fondazione Cariplo (to GC and AB). LLN was supported by IBISCUS. This work was supported by MIUR (Ministero Università e Ricerca) through a FIRB grant RBLA03ER38 and funds to Interdisciplinary Center for Biomolecular Studies and Industrial Applications (CISI) and Department of Biomedical Sciences and Technologies, University of Milan, Italy. We thank Dr GA Boyd for editorial assistance. B Falini has applied for a patent on the clinical use of NPM mutants.

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Author notes

  1. G Cazzaniga and L Lo Nigro: These authors contributed equally to this work.

Authors and Affiliations

  1. Centro Ricerca Tettamanti, Clinica Pediatrica, Ospedale San Gerardo, Università di Milano-Bicocca, Monza, Italy

    G Cazzaniga & A Biondi

  2. Center of Pediatric Haematology Oncology, University of Catania, Catania, Italy

    L Lo Nigro & E Mirabile

  3. Institute of Biomedical Technologies (ITB), National Research Council (CNR), Milan, Italy

    I Cifola

  4. Institute of Haematology, Ospedale Ferrarotto, University of Catania, Catania, Italy

    G Milone & F Di Raimondo

  5. MLL Munich Leukemia Laboratory, Munich, Germany

    S Schnittger & T Haferlach

  6. Ospedale Cannizzaro, Catania, Italy

    F Costantino

  7. Section of Haematology and Immunology, IBit Foundation, University of Perugia, Perugia, Italy

    M P Martelli, E Mastrodicasa, F Aversa & B Falini

Authors
  1. G Cazzaniga
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  14. B Falini
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Corresponding author

Correspondence to B Falini.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Cazzaniga, G., Lo Nigro, L., Cifola, I. et al. Simultaneous occurrence of acute myeloid leukaemia with mutated nucleophosmin (NPM1) in the same family. Leukemia 23, 199–203 (2009). https://doi.org/10.1038/leu.2008.170

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