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Venetoclax in combination with hypomethylating agents for the treatment of older patients with NPM1-mutated acute myeloid leukemia

May 18, 2020

Approximately 30% of patients with acute myeloid leukemia (AML) have nucleophosmin-1 mutations ( NPM1 +), which are associated with a favorable prognosis. 1However, the beneficial impact of this mutation decreases with increasing age in patients treated with standard intensive chemotherapy (IC) or hypomethylating agents (HMAs). 2Newer studies have also shown venetoclax (VEN)-based treatment regimens to be efficacious in the treatment of NPM1 +AML. 3,4

Curtis A. Lachowiez and colleagues have recently published the results of a retrospective study in the journal Blood Advances, which compares HMA plus VEN, HMA monotherapy, or IC treatment regimens for older patients (> 65 years) with NPM1 +AML. 5

Study Design

  • Eligible patients were identified as those with a diagnosis of NPM1 +AML who had received frontline AML therapy at the MD Anderson Cancer Center between 2007 and 2019
  • Patients were stratified into cohorts based on the per-protocol induction therapy received: HMA plus VEN, HMA, or IC (defined as receipt of cytarabine plus anthracycline)
  • Patients treated with IC in combination with targeted therapeutics (fms-like tyrosine kinase 3 [FLT3], isocitrate dehydrogenase 1 and 2 [IDH1, IDH2] inhibitors) were included, and additional chemotherapeutic agents such as fludarabine or cladribine were allowed
  • HMA cohort included those treated with HMA monotherapy (azacitidine or decitabine) or with the combination of an FLT3 inhibitor (FLT3i)
  • The aim of this study was to retrospectively evaluate the outcomes of patients with NPM1 +AML including:
    • Response to therapy, assessed using the European LeukemiaNet criteria
    • Overall survival (OS), calculated as time from the start of induction therapy to the date of death or last follow-up
    • Measurable residual disease (MRD) status in composite complete response (CRc; complete response [CR] + CR with incomplete count recovery [CRi]) by 8-color multiparameter flow cytometry

  Patient characteristics

  • Of a total of 446 patients with NPM1 +AML identified, 303 were included in the analysis as seen in Figure 1(n = 28 HMA plus VEN; n = 47 HMA; n = 228 IC)

Figure 1. Percentage of patients included in each cohort

HMA, hypomethylating agents; IC, intensive chemotherapy; VEN, venetoclax

 

  • 143 patients were excluded as they received induction regimens that could not be classified into one of the three treatment regimens
  • The IC cohort had a higher representation of younger patients compared with the HMA or HMA plus VEN cohort (median ages: 55, 72, and 71 years respectively; Table 1)

Table 1. Baseline patient demographics

AML, acute myeloid leukemia; HMA, hypomethylating agents; IC, intensive chemotherapy; VEN, venetoclax

*HMA plus VEN vs IC

Data are n

 

HMA plus VEN

(n = 28)

HMA

(n = 47)

IC

(n = 228)

p

Median age, years

71

72

55

0.0001

< 55

-

-

114

 

55–65

2

8

89

 

> 65

26 (median, 72)

39 (median, 75)

25 (median, 68)

0.0040*

Performance status

 

 

 

 

0–1

15

23

180

0.0002

2–3

9

13

27

 

AML subtype

 

 

 

 

De novo

25

35

213

0.0010

Secondary

1

6

4

-

Treated secondary

2

6

11

-

 

Results

  • CRc rates at 1-year median follow-up were 96%, 36%, and 89% of HMA plus VEN, HMA, and IC patients, respectively
  • CR rates stratified by age ( Table 2), showed that patients aged > 65 years with NPM1 +AML, treated with HMA plus VEN achieved a high CR rate compared with patients receiving IC regimens

Table 2. Treatment outcomes

CR, complete response; HMA, hypomethylating agents; IC, intensive chemotherapy; MRD, measurable residual disease; VEN, venetoclax

*HMA plus VEN vsHMA

HMA plus VEN vsIC

 

HMA plus VEN

(n = 28)

HMA

(n = 47)

IC

(n = 228)

p

% CR by age, y

 

 

 

 

< 55

89

55–65

100

13

88

0.067*

1.000

> 65

88

28

56

<0.001*

0.013

Total

89

26

85

<0.001*

0.778

MRD negativity

75

27

79

0.011*

0.593

 

  • When patients of all ages were included in the analysis, OS was not significantly different between HMA plus VEN compared with IC (median OS, not reached [NR] vs3.7 years respectively; p = 0.292)
  • In patients aged > 65 years, HMA plus VEN demonstrated a significant improvement in OS compared with IC (median OS, NR vs0.9 years; p < 0.001).  Furthermore, HMA plus VEN outperformed HMA monotherapy (median OS, NR vs0.4 years; p < 0.001).
  • After a median follow-up of 1 year, 80% of patients age > 65 years treated with HMA plus VEN survived, compared with 36% of patients treated with IC and 12% of patients treated with HMA
  • MRD analysis by flow cytometry showed that MRD negativity was achieved in a substantial portion of patients treated with HMA plus VEN, compared with HMA monotherapy (75% vs27%, respectively; Table 2), indicating this regimen can induce deep remissions

Conclusions

These results provide further evidence of the improved outcomes of using HMA combinations over HMA monotherapy as a treatment for older patients with NPM1 +AML. However, the authors acknowledge that limitations of this study include its retrospective nature, as well as small sample sizes for the HMA plus VEN, and HMA cohorts. 

  1. Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107(10):4011-4020. DOI: 1182/blood-2005-08-3167
  2. Ostronoff F, Othus M, Lazenby M, et al. Prognostic significance of NPM1mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report. J Clin Oncol. 2015; 33(10):1157-1164. DOI: 1200/JCO.2014.58.0571
  3. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. DOI: 1182/blood-2018-08-868752
  4. Bisaillon R, Moison C, Thiollier C, et al. Genetic characterization of ABT-199 sensitivity in human AML. Leukemia. 2020;34(1):63-74. DOI: 1038/s41375-019-0485-x
  5. Lachowiez CA, Loghavi S, Kadia TM, et al. Outcomes of older patients with NPM1-mutated AML: current treatments and the promise of venetoclax-based regimens. Blood Adv. 2020;4(7):1311-1320. DOI: 1182/bloodadvances.2019001267