Mutational spectrum of de novo NPM1-mutated acute myeloid leukemia patients older than 75 years

Figures & data

Table 1. Characteristics of the 22 AML patients older than 75 with mutated NPM1.

Variable	Number	Mean	Median	Range
Gender
Female	12
Male	10
Age at diagnosis	22	83	84	76–93
WBC count at diagnosis (10^9/L)	22	78	27	1–400
Blasts by morphology in PB at diagnosis (%)	22	42	31	0–99
Blasts by morphology in BM at diagnosis (%)	16	48	52	10–90
Blasts by flow cytometry in PB at diagnosis (%)	6	83	85	68–94
Blasts by flow cytometry in BM at diagnosis (%)	16	55	58	14–96
NPM1 VAF% in PB samples	6	38	37	31–47
NPM1 VAF% in BM samples	16	33	32	14–44
FLT3-status
ITD	6
TKD	3
wt	13
Karyotype^a
Normal	10
isolated trisomy 8	1
-X [25]^b, inv(9) [25]^b	1
del(5q) [21], add(9) [2]	1
missing data	9
Treatment
Intensive chemotherapy	2
5-azacytidine	4
Low dose cytarabine	2
Hydroxycarbamide	7
Best supportive care (no cytotoxic drugs)	7

BM: bone marrow; ITD: internal tandem duplication; PB: peripheral blood; TKD: tyrosine kinase domain; VAF: variant allele frequency; WBC: white blood count; wt: wild-type.

^aKaryotype from 25 mitoses.

^bPossible constitutional variants.

Table 2. Detailed characteristics of the two patients receiving intensive chemotherapy with daunorubicin and cytarabine (DA).

	Patient 1	Patient 2
Gender	male	female
Age at diagnosis	77	76
Phenotype	CD34-/HLA-DR-	CD34-/HLA-DR+
Mutations at diagnosis	NPM1, IDH2 and SRSF2	NPM1 and IDH2
NPM1 type	A	A
FLT3-ITD	no	no
WBC at diagnosis	1.4 × 10^9/L	1.9 × 10^9/L
Blasts in BM at diagnosis by morphology (%)	54	50
Blasts in PB at diagnosis by morphology (%)	0	42
Karyotype	normal	45,X,-X,inv(9)(p11q13)c
Comorbidity	Angina pectoris	Cardiovascular disease and high blood pressure
Induction / consolidation	3 cycles of intensive chemotherapy	4 cycles of intensive chemotherapy
Stem cell transplantation	No	No
Complete remission	Yes, by 4 weeks	Yes, by 4 weeks
Relapse	Relapse 1 at day 595^a; relapse 2 at day 1397	No
Survival	Dead of disease at day 1577	Alive at day 1622^b after diagnosis

BM: bone marrow; ITD: internal tandem duplication; PB: peripheral blood; WBC: white blood count.

^aTreatment with 5-azacytidine after first relapse.

^bEnd of follow-up in December 2020.

Figure 1. AML-associated mutations, immunophenotypic characteristics and karyotype of 22 NPM1-mutated AML patients. Each column represents a single patient. ‘APL-like’, ‘Acute promyelocytic leukemia’-like phenotype i.e. CD34-/HLA-DR-. Five patients displayed two different TET2 mutations and one patient two different BCOR mutations.

Figure 2. Gene mutation frequencies (%) of TET2, DNMT3A, IDH2, FLT3-ITD and SRSF2 in NPM1-mutated AML comparing data from the present study (n = 22; leftmost) with those of another cohort of older patients by Renaud et al. [29] (n = 17; middle left) and two series of younger AML patients by Papaemmanuil et al. [4] (n = 418, middle right) and Ivey et al. [28] (n = 223, rightmost). p-values as determined by Fisher’s exact test are shown for comparisons of the gene mutation frequencies with those of the present study.

Figure 3. Variant allele frequency (VAF%) of coexisting mutations in DNA methylation genes (DNMT3A, TET2 and IDH2) compared to NPM1 VAF% among the 22 AML patients. Three patients (#1, 11 and 19) lacked a mutation in either of these genes. For TET2, two different mutations were found in five patients, displayed by different symbols (patients #2, 5, 10, 12 and 20). All NPM1 VAF% values are connected with a gray line for easier read-out.

Tate JG, Bamford S, Jubb HC, et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 2019;47(D1):D941–D947.

 PubMed Web of Science ®Google Scholar

Renaud L, Nibourel O, Marceau-Renaut A, et al. Comprehensive molecular landscape in patients older than 80 years old diagnosed with acute myeloid leukemia: a study of the French Hauts-de-France AML observatory. Am J Hematol. 2019;94(1):E24–E27.

 PubMed Web of Science ®Google Scholar

Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–2221.

 PubMed Web of Science ®Google Scholar

Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374(5):422–433.

 PubMed Web of Science ®Google Scholar