Influence of NPM1 and FLT3-ITD status on outcome in relapsed/refractory AML patients receiving salvage therapy including gemtuzumab ozogamicin

Acute myeloid leukemia (AML) encompasses a group of very heterogeneous diseases both in terms of presentation and outcome. Thus far, cytogenetic abnormalities are widely recognized as the most important prognostic factors and serve as basis for treatment decision algorithms. The AML subgroup without cytogenetic abnormalities accounts for around 40–50% of all AML cases.1 In this subgroup, two particular gene alterations have been shown to confer prognostic relevance. On one hand, internal tandem duplications of the fms-related tyrosine kinase 3 gene (FLT3-ITD+) have been associated with poor outcome. On the other hand, mutations in the nucleophosmin gene (NPM1+) have been associated with a favorable outcome (reviewed in Bacher et al.2). Therefore, assessment of these two factors allowed for identifying a particularly favorable subgroup of patients. Indeed, AML patients presenting with a mutation for NPM1 without concomitant FLT3-ITD can have a better outcome compared with patients presenting with other combinations. Moreover, a recent study from the German–Austrian AML Study Group1 proposed to classify these patients in the favorable risk leukemia group similar to the core-binding factor AML subgroup, in which allogeneic stem cell transplantation in first complete remission (CR) is not recommended anymore. However, all the above-mentioned studies have considered NPM1/FLT3-ITD status at diagnosis and to the best of our knowledge no series has focused on the effect of the NPM1/FLT3-ITD status at the time of disease relapse, especially in terms of response to salvage therapy and overall outcome. We have previously shown that salvage chemotherapy including gemtuzumab ozogamicin (GO) is a valid option for the treatment of relapsed/refractory CD33+ AML patients.3 With this background, the aim of this report was to investigate the influence of the NPM1/FLT3-ITD status on outcome in relapsed/refractory AML patients with normal karyotype who received a salvage regimen using GO as monotherapy or in combination with other agents.

For this purpose, we analyzed the outcome of 57 AML patients with normal karyotype treated in four institutions (Nantes, Marseille, Bordeaux and Angers) in France, between 2001 and 2009. Patients received GO as monotherapy or in combination with other chemotherapeutic agents at time of relapse (n=36) or in the setting of refractory disease (n=21). There were 26 men and 31 women with a median age of 52 (range, 20–70) years at time of leukemia diagnosis. The French–American–British distribution included 2, 13, 15, 11, 12 and 1 AML cases from the M0, M1, M2, M4, M5 and M6 subgroups, respectively. Three cases were considered as unclassified. In addition, five patients had secondary AML. All patients were CD33+ with a median CD33 expression level of 98%. As salvage treatment, 46 patients received the MIDAM regimen (GO: 9 mg/m2 at day 4+cytarabine 1 g/m2 every 12 h for days 1–5+mitoxantrone 12 mg/m2 per day for days 1–3).3 In two patients receiving the MIDAM regimen, mitoxantrone was omitted to avoid cardiac toxicity. Four patients received GO as monotherapy at 9 mg/m2 (n=3) or at 6 mg/m2 (n=1). The five remaining patients received GO 3–9 mg/m2 combined with other chemotherapeutic agents (cytarabine+VP16+GO, n=2; cytarabine+idarubicin+GO, n=2; cytarabine+amsacrine+GO, n=1). After salvage therapy, 25 patients could proceed and receive consolidation with an allogeneic stem cell transplant.

In this series, all patients could be screened in the blood or bone marrow for mutations in the FLT3 gene (ITD mutations) and in the NPM1 gene at diagnosis as previously described.4, 5 Same proportion of refractory patients was observed in the favorable NPM1+/FLT3-ITD− group compared with the others patients (36%, n=5/14 vs 37%, n=16/43). Probability of overall survival (OS) was calculated using the Kaplan–Meier estimates. The log-rank test was used for univariate comparisons.

In this series, with a median follow-up of 23.3 (range, 2.3–94.5) months for surviving patients, OS was 46.5% (95% CI, 33.6–59.9) at 2 years. CR, relapse and death rates according to disease and NPM1/FLT3-ITD status, and causes of death are detailed in Table 1. The CR rate was higher in patients with NPM1+/FLT3-ITD− status (85 vs 60% for all others, P=0.16) whereas the relapse rate was lower in this subgroup (33 vs 42% for all others, P=0.87) but the differences were not significant. Conversely, the death rate was significantly lower in patients with NPM1+/FLT3-ITD− (28 vs 65%, P=0.02). As a consequence, OS was significantly higher in this subgroup, in comparison to patients from the other subgroups (P=0.026; Figure 1a).

Table 1 CR, relapses and death rates depending on disease and NPM1/FLT3 status
Figure 1
figure1

Comparison of overall survival (OS): (a) between NPM1+/FLT3− patients and others, and (b) between the different NPM1/FLT3 combinations.

To the best of our knowledge, this is likely among the first largest series that assessed the role of the NPM1/FLT3-ITD status as prognostic factor for cytogenetically normal AML patients receiving salvage therapy in the refractory or relapsed setting. Recently, Meloni et al.6 reported a single case describing the outcome of a 19-year-old woman who relapsed 5 years after diagnosis of AML. Of note, this patient presented with two different karyotypes (del(13;14) and t(4) then normal karyotype, respectively) and NPM1/FLT3-ITD status (NPM1+/FLT3-ITD+ and NPM1+/FLT3−, respectively) between diagnosis and relapse. The patient received a combination of cytarabine, idarubicin and GO as salvage therapy and could achieve a second CR, suggesting a favorable effect for the NPM1+/FLT3− status at relapse.6 Results from the current analysis suggest the favorable effect of an NPM1+/FLT3-ITD− status is still retained at relapse or when receiving treatment for a refractory disease. However, one should bear in mind, that all patients from our series received GO, which was not able to improve the dismal prognosis of patients without the favorable mutation status (Figure 1b). Others strategies including, for example, an anti-FLT3 inhibitor such as sorafenib may prove more usefulness.7

One caveat of our study is that we have studied the molecular status of the patients only at diagnosis, and not at time of relapse immediately before salvage therapy. However, this is unlikely to be a major concern as NPM1 mutation status is shown to be very stable in the course of the disease (relapse or refractory disease) suggesting that it could be used as a marker for monitoring of minimal residual disease.8 However, FLT3-ITD status has shown more variability, but the overall de novo acquisition of a FLT3-ITD mutation was reported to be <5% in the favorable NPM1+/FLT3-ITD− subgroup.8

In all, and although this needs to be confirmed in a prospective setting refractory/relapsed AML patients with a normal caryotype and a NPM1+/FLT3-ITD− are likely to remain in a ‘favorable prognosis’ category when receiving salvage therapy. Such information is of major interest for patients counseling and for the design of salvage therapy approaches.

Conflict of interest

The authors declare no conflict of interest.

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Chevallier, P., Prebet, T., Pigneux, A. et al. Influence of NPM1 and FLT3-ITD status on outcome in relapsed/refractory AML patients receiving salvage therapy including gemtuzumab ozogamicin. Leukemia 24, 467–469 (2010). https://doi.org/10.1038/leu.2009.214

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