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Molecular MRD status as a predictor of outcome in patients with NPM1-mutated acute myeloid leukemia (AML)

Mar 30, 2020
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Measurable residual disease (MRD) assessed prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a predictor of relapse and outcome.1 Thus, determination of MRD is of growing interest and its adoption in standard clinical practice could be useful to guide treatment decisions. At the 46th annual meeting of the European Society for Blood and Marrow Transplantation (EBMT) the AML Hub will hold a Satellite Symposium (August 30, 2020, 8:30am, IFEMA – Feria de Madrid, ES) to discuss the latest developments of MRD assessments in the context of HSCT.

Mutations in the nucleophosmin (NPM1) gene are present in a large subgroup of patients with AML who have normal cytogenetics.2 In this study, published in Blood, Richard Dillon and colleagues used reverse-transcription quantitative PCR (RT-qPCR) to assess pretransplant MRD in patients with NPM1-mutated AML enrolled in the UK National Cancer Research Institute (NCRI) AML17 study. They then examined the effects of MRD status on the outcomes of these patients.3

Study design3

  • The study enrolled 3,215 patients (aged 16–77 years) eligible for intensive chemotherapy:
    • 861 had a mutated NPM1 and of these 530 provided samples for MRD assessment
    • In total 107 patients received allo-HSCT and were included in the study. These patients were transplanted:
      • In first remission (CR1), 52% (n= 56)
      • After molecular relapse (MR), 28% (n= 30)
      • In second remission (CR2) after morphological relapse, 20% (n= 21)
  • Pre-HSCT peripheral blood (PB) and bone marrow (BM) samples were taken in the 60 days prior to HSCT (median time, 29 days; range, 5─57):
    • Patients MRD negative before HSCT, 54% (n= 58)
    • Of 48 patients who were receiving additional chemotherapy before HSCT for molecular or hematological relapse, 27 achieved MRD negativity
  • As a risk factor, FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) status4 at diagnosis was also evaluated

Results3

After a median follow-up of 4.9 years (range, 1.0─8.4 years) after transplant:

  • Forty-two (39%) patients died (21 because of relapse)
  • 2-year overall survival (OS) was:
    • 68% for patients transplanted in CR1
    • 63% for those transplanted after MR
    • 57% for patients transplanted in CR2

Overall survival differences between MRD-negative and MRD-positive patients

The 2-year OS was evaluated in MRD-negative vs MRD-positive patients:

  • Overall, 83% vs 45%; median OS (mOS) not reached (NR) vs 10.5 months (hazard ratio [HR], 3.60; 95% confidence interval [CI], 1.92─6.77; p < 0.0001)
  • PB samples, 81% vs 30%; mOS NR vs 7.4 months (HR, 8.30; CI, 3.77─18.20; p < 0.0001)
  • 5-year OS in BM samples, 84% vs 49%; mOS NR vs 13.1 months (HR, 3.17; CI, 1.54─6.54; p = 0.002)

Using a threshold of 200 copies of mutant NPM1 transcripts per 105 ABL (control gene) in the PB sample or 1000 copies in the BM sample, patients were split into three groups: negative, low, and high number of copies. The 2-year OS was evaluated and results are reported in Table 1.

Table 1. Differences in overall survival according to pretransplant molecular MRD status

BM, bone marrow; CI, confidence interval; MRD, measurable residual disease; PB, peripheral blood

 

 

MRD status

2-year overall survival

PB sample

BM sample

Combined

Negative, (n)

81% (73)

84% (37)

83% (58)

Low, (n)

54% (13)

56% (32)

63% (30)

High, (n)

12% (17)

22% (9)

13% (19)

Hazard ratio

(CI)

2.81

(1.96─4.02)

2.87

(1.69─4.86)

2.83

(1.92─4.19)

p value

< 0.0001

< 0.0001

< 0.0001

Effect of FLT3-ITD status on outcomes

According to FLT3-ITD status, 34 patients were FLT3-ITD positive and 73 negative. FLT3-ITD status was associated with outcome only in patients with low levels of MRD, with a 2-year OS in patients FLT3-ITD positive vs FLT3-ITD negative of 25% (mOS, 7.1 months) vs 77% (mOS, NR) (HR, 6.14; CI, 1.50─25.13; p = 0.01)

A prognostic model incorporating MRD status and FLT3-ITD has been developed and 83 patients have been assigned to:

  • High-risk group: patients with high levels of MRD, and patients with low levels of MRD plus FLT3-ITD at diagnosis (n= 27; 2-year OS, 17%; mOS, 6.5 months)
  • Low risk group: all the other patients (n= 56; 2-year OS, 82%; mOS, NR; HR, 13.2; CI, 5.80─30.2; p < 0.0001)

Effects of donor source, conditioning regimen or T-cell depletion on outcome

Donor source or conditioning regimen do not correlate with outcome. On the contrary, in the MRD-positive group, T-cell depletion was significantly associated with inferior survival (2-year OS, 34% vs 100%, in patients who did undergo T-cell depletion vs who did not, respectively; HR, 3.78; CI, 1.57─19.2; p= 0.003).

Conclusions3

This study confirms the prognostic value of MRD assessment:

  • Patients with NPM1-mutated AML, MRD negative by RT-qPCR pre-HSCT have a better outcome than MRD positive patients, regardless of FLT3 status
  • MRD-positive patients with high levels of MRD and/or the presence of an FLT3-ITD mutation have a poor prognosis. In these high-risk patients might be useful reducing the levels of MRD before HSCT and further studies are required to investigate these approaches
  1. Schwind S. et al. Use of minimal residual disease in acute myeloid leukemia therapy. Curr Treat Options Oncol. 2020 Jan 30; 21(1):8. DOI: 1007/s11864-019-0695-5

  2. Falini B. et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005 Jan 20;352(3):254-66. DOI: 1056/NEJMoa041974

  3. Dillon R. et al. Molecular MRD status and outcome after transplantation in NPM1-mutated AML. Blood. 2020 Feb 27;135(9):680-688. DOI: 1182/blood.2019002959

  4. Daver N. et al. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019 Feb;33(2):299-312. DOI: 1038/s41375-018-0357-9

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