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Successful treatment of molecular relapse in NPM1-positive AML using 5-azacytidine

Leukemia volume 24, pages 236–237 (2010)Cite this article

Using contemporary therapeutic approaches, including stem cell transplantation (SCT), roughly 50% of young patients with acute myeloid leukemia (AML) can achieve long-lasting complete remissions (CRs). The individual prognosis of a patient depends, at least in part, on specific cytogenetic and molecular abnormalities. Genetic alterations in the nucleophosmin-(NPM)-1-gene are usually associated with a favorable prognosis, as long as they occur in the absence of FLT3-ITD mutations.1 NPM1 appears to be more stable than FLT3-ITD mutations during the course of the disease and may therefore be used as a marker for minimal residual disease (MRD).2 Increasing MRD levels after achieving CR are nearly uniformly followed by rapid overt AML relapse.3 Thereafter, a second CR may be achieved in some patients using intensive salvage chemotherapies. These approaches are often accompanied by significant toxicities and can therefore be offered only to a subset of medically fit patients. Furthermore, only a minority of patients will achieve long-lasting remissions under these circumstances even when treated with allogeneic SCT. This may be due to the fact that leukemic burden in relapsed patients is often too high to be controlled by chemotherapy and later by graft-versus-leukemia effects. Therefore, prevention of overt relapse by MRD-guided therapeutic interventions seems to be a reasonable approach. The possible agents for bridging patients with molecular relapse to allogeneic SCT should, in principle, fulfill two prerequisites: First, they should quickly and effectively prevent overt relapse. Second, they must not cause significant extramedullary toxicities that might render the patient unfit for transplantation. In fact, demethylating agents seem to meet both requirements. 5-aza-2-deoxycytidine and 5-azacytidine (aza) are clinically active in overt AML and MDS, respectively.4, 5 Toxicity is rather modest, with myelosuppression and nausea being the most frequent side effects. Both drugs have not been used so far in the treatment of MRD. Nevertheless, the above-mentioned therapeutic effectiveness and favorable risk profile prompted us to use 5-aza in a patient with molecular relapse of NPM1+ AML after previous induction chemotherapy followed by autologous transplantation.

A 56-year-old woman was diagnosed with AML FAB subtype M2 with an NPM1 mutation (type A) and an FLT3-ITD mutation (ratio of mutant FLT3 to wt FLT3=0.61). Initially she presented with hyperleukocytosis (84 000/ml) and was treated with double-induction chemotherapy using standard-dose cytarabin and daunorubicin (‘3+7’). Early treatment assessment showed good response (<5% blasts). Complete hematological remission (CR) was observed after the second induction therapy. Further, stem cells were harvested after one cycle of consolidation therapy using high-dose cytarabin (2 × 3 g/m2/day on days 1, 3 and 5). Four months after induction therapy, the patient received an autologous SCT after myeloablative conditioning (busulphan and cyclophosphamide).

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References

  1. 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: 4011–4020.

    Article  CAS  Google Scholar 

  2. Papadaki C, Dufour A, Seibl M, Schneider S, Bohlander SK, Zellmeier E et al. Monitoring minimal residual disease in acute myeloid leukaemia with NPM1 mutations by quantitative PCR: clonal evolution is a limiting factor. Br J Haematol 2009; 144: 517–523.

    Article  CAS  Google Scholar 

  3. Doubek M, Palasek I, Pospisil Z, Borsky M, Klabusay M, Brychtova Y et al. Detection and treatment of molecular relapse in acute myeloid leukemia with RUNX1 (AML1), CBFB, or MLL gene translocations: frequent quantitative monitoring of molecular markers in different compartments and correlation with WT1 gene expression. Exp Hematol 2009; 37: 659–672.

    Article  CAS  Google Scholar 

  4. Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 2007; 25: 3884–3891.

    Article  CAS  Google Scholar 

  5. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10: 223–232.

    Article  CAS  Google Scholar 

  6. O'Donnell PV, Luznik L, Jones RJ, Vogelsang GB, Leffell MS, Phelps M et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2002; 8: 377–386.

    Article  CAS  Google Scholar 

  7. Field T, Perkins J, Huang Y, Kharfan-Dabaja MA, Alsina M, Ayala E et al. 5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2009 (Epub ahead of print).

  8. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

    Article  CAS  Google Scholar 

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  1. University Hospital Carl-Gustav-Carus, Medical Clinic I, Dresden, Germany

    M Wermke, C Thiede, A Kiani, G Ehninger, M Bornhäuser & U Platzbecker

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  1. M Wermke
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Correspondence to U Platzbecker.

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Wermke, M., Thiede, C., Kiani, A. et al. Successful treatment of molecular relapse in NPM1-positive AML using 5-azacytidine. Leukemia 24, 236–237 (2010). https://doi.org/10.1038/leu.2009.204

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