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

Approximately 30% of patients with acute myeloid leukemia (AML) have nucleophosmin-1 mutations (NPM1⁺), which are associated with a favorable prognosis.¹ However, the beneficial impact of this mutation decreases with increasing age in patients treated with standard intensive chemotherapy (IC) or hypomethylating agents (HMAs).² Newer 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 vs HMA †HMA plus VEN vs IC
	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] vs 3.7 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 vs 0.9 years; p < 0.001).  Furthermore, HMA plus VEN outperformed HMA monotherapy (median OS, NR vs 0.4 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% vs 27%, 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.