Unveiling prognosis in patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax through novel risk stratification

Abstract

Several genetic risk classification systems based on response to older acute myeloid leukemia patients treated with less-intensive regimens, especially venetoclax (VEN) + hypomethylating agent (HMA), are proposed recently. VEN+HMA improved the outcome of cytogenetic adverse-risk AML, AML with some of MR mutations and/or clonal hematopoiesis (CH) related mutations. DNMT3A^mut, IDH1/2^mut and NPM1^mut were defined as “VEN sensitive mutations”. DDX41^mut is identified as a particularly favorable-risk group. Even multi-hit TP53 status did not negatively affect overall survival (OS) of DDX41-mutants. Signaling gene mutations (FLT3-ITD^pos and K/NRAS^mut) are classified as intermediate risk, consistent with their biological associations as mediators of VEN resistance.

The median age at diagnosis for patients with acute myeloid leukemia (AML) is 68 years. Elderly patients, due to comorbidities and adverse genetic mutations, are often unsuitable for intensive chemotherapy or exhibit resistance to standard chemotherapy. Venetoclax (VEN) in combination with a hypomethylating agent (HMA), such as decitabine or azacitidine (AZA), is the preferred treatment regimen. The European LeukemiaNet (ELN) previously stratified AML risk based on patients younger than 60 years who received anthracycline-based intensive chemotherapy with cytarabine [1], a classification that does not apply to AML patients receiving lower-intensity therapies, including VEN+HMA [2]. Increasingly, studies have focused on the impact of genetic mutations on treatment response and survival in AML patients treated with VEN+HMA [[3], [4], [5], [6], [7], [8], [9], [10], [11]].

Currently, five prognostic models have been developed to predict survival in newly diagnosed AML patients receiving low-intensity therapy, defining novel genetic risk stratifications (Table 1): (1) ELN 2024 Genetic Risk Stratification [12]: Based on data from patients receiving low-intensity therapies (Table 2, Table 3), favorable prognosis is defined as a median overall survival (OS) >24 months, poor prognosis as a median OS of 5-8 months, and intermediate prognosis for other patients. Favorable-risk mutations include NPM1^mut, IDH1/2^mut and DDX41^mut; intermediate-risk mutations include signaling pathway mutations (FLT3-ITD^pos and K/NRAS^mut); and TP53^mut is classified as high-risk. (2) Refined ELN 2024 risk stratification [20]: Based on VEN+HMA therapy, NPM1^mut, IDH1/2^mut, and DDX41^mut are classified as low-risk, demonstrating a favorable response to VEN+HMA induction therapy with a median OS of 34.8 months. However, only 8.6 months in other favorable-risk AML patients as per the ELN 2024 classification suggests that other genetic mutations may be more appropriately classified as intermediate-risk [20]. FLT3-ITD^pos, NRAS^mut and other unclassified mutations are categorized as intermediate-risk, while KRAS^mut, PTPN11^mut and TP53^mut are classified as high-risk. The median OS for low-, intermediate-, and high-risk groups is 34.8, 13, and 5.4 months, respectively, refining the ELN 2024 classification, which previously defined low-risk as a median OS >2 years. (3) Mayo Genetic Risk Model [21]: Based on VEN+HMA therapy, the 3-year OS for low-, intermediate-, and high-risk groups is 67%, 33%, and 0%, respectively. In addition to genetic mutations, adverse cytogenetics and KMT2Ar are incorporated into risk stratification. Unlike the ELN 2024 classification, only IDH2^mut (excluding IDH1^mut) is considered favorable, and only KRAS^mut (excluding NRAS^mut) impacts survival. Moreover, RUNX1^mut, which is not included in other models, influences CR/CRi rates. (4) VIALE-A Four-Gene Prognostic Model [3]: Based on VEN+AZA therapy, patients are stratified into three groups according to the mutational status of TP53, FLT3-ITD, KRAS and NRAS. The high-benefit, intermediate-benefit, and low-benefit groups have median OS of 26.5, 12.1 and 5.5 months, respectively. (5) Hokkaido Leukemia Network Risk Stratification [22]: Based on VEN-based regimens, patients with DAMT3A^mut, NPM1^mut, or IDH1/2^mut achieve CR/CRi rates exceeding 80% and are classified as having “VEN-sensitive mutations” with favorable prognosis. Patients with complex cytogenetics or TP53^mut are categorized as high-risk. Notably, in Japan, the widespread use of FLT3 inhibitors (gilteritinib and quizartinib) has mitigated the adverse prognosis associated with FLT3-ITD^pos.

Table 1.

Novel genetic risk classification for acute myeloid leukemia patients receiving less-intensive therapies.

Risk Stratification	Genetic mutations			Year	NO	Age (ys)	Therapies	Overall time (months)			CR/CRi (%)
	Fav	Int	Adv					Fav	Int	Adv	Fav	Int	Adv
ELN2024[12]	NPM11 IDH21 IDH12 DDX41 Others 1	FLT3-ITD2 NRAS2 KRAS2	TP53	2024	Review of literatures[4, 7, 11, 13-19]		HMA-baseda	>24	Others	5-8	67	67	56
ELN2024 Revised [20]	NPM13 IDH23 IDH13 DDX413	FLT3-ITD4 N-RAS4 Others 4	KRAS PTPN11 TP53	2024	430	72 (20-89)	HMA+VEN	34.8	13	5.4	-	-	-
Mayo [21]	-	-	-	2025	400	73 (19-98)	HMA+VEN	-	-	-	-	-	-
Response Predictors	NPM15 IDH25 DDX415	-	TP536 FLT3-ITD6 RUNX16		378	-	-	-	-	-	87b	63c;73d	44e
OS scoring system 7	IDH2	TP53 K-RAS Adverse Karyotype	KMT2Ar		391	-	-	NR	19.1	7.1	-	-	-
VIALE-A[3]	Others	FLT3-ITD N/K-RAS	TP53	2024	392	76 (49–91)[13] 74 (65-86) [16]	AZA+VEN	26.5	12.1	5.5	73	52	46
Hokkaido [22]	NPM18 IDH1/28 DNMT3A8	Others	CK/TP53mut 9	2023	89	75 (57-90)	VEN-based f	NR	-	-	-	-	-

1. FLT3-ITD^neg, NRAS^wt, KRAS^wt, TP53^wt; 2. TP53^wt; 3. N/KRAS^wt, PTPN11^wt, FLT3-ITD^neg, and TP53^wt; 4. K-RAS^wt, PTPN11^wt, and TP53^wt; 5. Favorable; 6. Unfavorable; 7. OS scoring system: IDH2^wt = 1 point; TP53^mut= 1 point; K-RAS^mut = 1 point; ELN 2022 Adverse Karyotype = 1 point; KMT2A rearrangement = 2 points; 8. VEN-sensitive mutation; 9. Lacks a VEN-sensitive mutation. a. Receiving HMA monotherapy, HMA/VEN, or AZA/IVO (for IDH1^mut AML); not apply to patients who have received prior treatment with an HMA; b. Favorable without unfavorable; c. Neither favorable nor unfavorable; d. Favorable with unfavorable; e. Unfavorable without favorable; f. 85 patients received VEN+azacitidine; 4 patients received VEN+cytarabine. Abbreviations: ys, years; Fav, Favorable; Int, Intermediate; Adv, Adverse; ELN, European Leukemia Net; HMA, hypomethylating agent; AZA, azacitidine; VEN, venetoclax; CR, complete remission; CRi, CR with incomplete haematological recovery; KMT2Ar, KMT2A rearrangement; CK/TP53mt, Complex karyotype and /or TP53 mutation; VEN, venetoclax; AZA, azacitidine; NR, not reached; OS, overall time.

Table 2.

Data from acute myeloid leukemia patients receiving less-intensive therapies which ELN 2024 risk classification developed based on.

Ref	NO	Age (ys)	ECOG PS	AML Population	Therapies	Genetic mutations			OS (months) CR/CRi (%)
						Fav	Int	Adv	Fav	Int	Adv
[13] *	286	76 (49–91)	2-3 (45%)	ND	VEN+AZA	Adverse karyotype secondary AML high-risk molecular mutations		-	-	-	-
[13]**	-	-	-	-	-	Intermediate karyotype IDH1 /2		-	-	-	-
[13]	145	76 (60–90)	2-3 (44%)	ND	AZA	-	-	-	-	-	-
[14]	240	≥ 65	≤ 2	ND	AZA	Adverse karyotype	-	FLT3 TET2	-	-	-
[15]	604	77 (59–94)	51% ≥ 2	Non-intensively treated	Guadecitabine Azacitidine Decitabine LDAC	DDX41	Others	FLT3-ITD TP53 SRSF2	-	-	-
[17]	431	76 (49–91)	0–2 (≥75 ys); ≥0–3 (18-74 ys)	ND	VEN+AZA (n=286) AZA (n=145)	IDH1/2 MRD <10-3	-	-	-	-	-
[4]	81	74 (62-87)	-	ND	VEN+HMA (n=58) VEN+LDAC (n=23)	NPM1	Others	TP53 FLT3-ITD	-	-	-
[9]	77	69 (22–86) 73 (61–81)	-	ND (n=38) R/R (n=39)	VEN+AZA	ASXL1 IDH SFSR2	Others	TP53 RAS Adverse karyotype	-	-	-
[11]*	301	73 (19–95)	-	ND	VEN+HMA	NPM1 IDH2 DDX41	Others	TP53 FLT3-ITD RUNX1	91%a	65%b 57%c	36%d
[11]**			-	-	-	ASCT	Others	Adverse karyotype Absence of CR/CRi TP53 Absence of IDH2mut	28.9ms	9.6ms	3.1ms
[7]	179	75 (61-89)	-	ND	VEN+HMA	Others	FLT3-ITD K/N-RAS	TP53	86% 30ms	54% 12ms	59% 5ms
[18]	314	74 (25-90)	-	Secondary (n=111) De novo (n=203)	VEN+HMA (n=166) HMA (n=148)	ASCT Secondary AML SFmut	Others	TP53	-	-	-

a. Favorable without unfavorable; b. Neither favorable nor unfavorable; c. Favorable with unfavorable; d. Unfavorable without favorable; * CR/CRi predictors; ** OS predictors. Abbreviations: Ref, reference; NO, number; ys, years; ms, months; OS, overall time; Fav, Favorable; Int, Intermediate; Adv, Adverse; ELN, European Leukemia Net; HMA, hypomethylating agent; AZA, azacitidine; VEN, venetoclax; ECOG PS, Eastern Cooperative Oncology Group performance status; ND, New diagnosed; R/R, relapsed and/or refractory; LDAC, Low-dose cytarabine; MRD, measurable residual disease; ASCT, allogeneic stem cell transplants; CR, complete remission; CRi, CR with incomplete haematological recovery; INT, intensive therapy; SF^mut: Mutations in splicing factor (SF) genes: SRSF2, U2AF1, SF3B1, and ZRSR2.

Table 3.

Data from new diagnosed AML patients receiving less-intensive therapies which ELN 2024 risk classification developed based on.

Therapies	Population	NO	Age (ys)	ECOG PS (%)	CR/CRi (%)	DoR (ms)	OS (ms)
IVO+AZA[23]	IDH1mut	72	76 (58-84)	2 (36%)	54	-	24
AZA		74	75.5 (45-94)	2 (32%)	16	-	7.9
AZA+VEN[6]	IDH1/2mut	81	76 (64-90)	2-3 (43.2%)	79	29.5	24.5
AZA		28	77.5 (62-90)	2-3 (32.1%)	10.7	9.5	6.2
AZA+VEN	IDHmut	-	-	-	66.7	-	15.2
AZA		-	-	-	9.1	-	2.2
AZA+VEN	IDH2mut	-	-	-	86	-	NR
AZA		-	-	-	11.1	-	13
AZA+VEN[5]	FLT3mut	42	75 (49-91)	2-3 (59.5%)	67	17.3	12.5
FLT3-ITDpos		-	-	-	63	-	9.9
FLT3-ITDposNPM1mut		-	-	-	70	NR	9.1
FLT3-ITDposNPM1wt		-	-	-	57.9	10.1	-
FLT3-TKDmut		-	-	-	77		19.2
AZA		22	75 (65-85)	2-3 (11%)	36	5	8.6
AML with poor-risk cytogenetics			-	-	-	-	-
AZA+VEN[8]	TP53mut	54	-	-	41	6.5	5.2
	TP53wt	50	-	-	70	18.4	23.4
AZA	TP53mut	18	-	-	17	6.7	4.9
	TP53wt	22	-	-	23	8.5	11.3
DDX41 mutated AML		96	69 (21-90)	-	87	-	49
VEN+ low intensity[10]		25	-	-	88	91% (2-year-OS)
Low intensity		11	-	-	81.8	60% (2-year-OS)

Abbreviations: NO, number; ys, years; ECOG PS, Eastern Cooperative Oncology Group performance status; DoR, duration of remission; OS, overall time; ms, months; IVO, Ivosidenib; AZA, azacitidine; VEN, venetoclax; CR, complete remission; CRi, CR with incomplete haematological recovery.

The Mayo Genetic Risk Model and VIALE-A Four-Gene Prognostic Model also predict the response to VEN+HMA induction therapy for newly diagnosed AML based on different genetic mutations, specifically the complete remission (CR) rate and complete remission with incomplete hematologic recovery (CRi) rate. These rates are 87%, 73%, 63%, and 44% in groups with favorable without unfavorable, neither favorable nor unfavorable, favorable with unfavorable and unfavorable without favorable mutations, respectively [21]. In the VIALE-A Four-Gene Prognostic Model, the CR/CRi rates for the high-benefit, intermediate-benefit, and low-benefit groups are 73%, 52%, and 46%, respectively [3]. However, according to the ELN 2024 guidelines [12], the CR/CRi rates for low-, intermediate-, and high-risk groups are 67%, 67%, and 56%, respectively. The Mayo Genetic Risk Model also predicts the OS after achieving CR/CRi with VEN+HMA treatment: 3-year OS for the low-risk, intermediate-risk, and high-risk groups is 80%, 44%, and 0%, respectively [21].

Favorable genetic mutations include NPM1^mut, IDH1/2^mut, DDX41^mut and DNMT3A^mut. The ELN 2024 guidelines indicate that DDX41^mut AML has a favorable prognosis, unaffected by signaling pathway mutations or TP53^mut; IDH1^mut AML is only favorable when treated with AZA+ivosidenib (IVO), and is unaffected by signaling pathway mutations [12]. However, in other models [20,22], IDH1^mut AML also shows favorable prognosis with VEN+HMA therapy. In addition to TP53^mut, FLT3-ITD^pos and K/NRAS^mut, RUNX1^mut AML shows poor response to VEN+HMA induction therapy [21]. The ELN 2024 guidelines do not consider adverse cytogenetics to impact survival, but the Mayo Genetic Risk Model suggests that adverse cytogenetics and KMT2Ar are associated with poor prognosis [21], while the Hokkaido model in Japan classifies complex cytogenetics as poor prognosis [22]. All five risk stratification models indicate that TP53^mut AML has a poor prognosis.

1. DDX41 mutated AML

Germline DDX41 mutations account for approximately 80% of the genetic susceptibility in adult myeloid neoplasms (MNs), representing 3.8% of MDS/AML patients [24]. In patients with DDX41 mutation AML receiving intensive chemotherapy, the overall response rate is 100% [25], with a low relapse rate in the first year. However, relapse rates increase in the second and third years, and the 3-year cumulative relapse rate is similar to that of patients with wild-type DDX41 in the intermediate-to-high-risk groups [26]. In the ELN 2022 guidelines, due to the normal cytogenetics, these patients are often classified into the intermediate-risk group, or in cases with concomitant mutations in the myelodysplasia-related (MR) gene or TP53, they are classified into the high-risk group. The experience from the Mayo Clinic suggests that if patients' conditions and blood cell counts remain stable, they can be monitored with a 5-year survival rate of 100%, with treatment initiation after disease progression, where the median OS in the treatment group is 41 months [27]. Patients with DDX41 mutation AML respond well to VEN+HMA treatment, with a 2-year OS of 91.1% [10,11]. According to the ELN 2024 guidelines, they are classified as having a favorable prognosis and are not affected by TP53 mutations, even in the presence of “multiple-hit” TP53 mutations and signaling pathway mutations (FLT3-ITD and K/N-RAS) [12]. Patients with DDX41 mutated AML treated with venetoclax had an improved survival than those receiving allogenic hematopoietic stem cell transplantation (allo-HSCT), with 2-year OS was 91% and 80%, respectively [10]. Regarding donor search for allo-HSCT for AML with a germline DDX41 mutation, it is essential to ensure that the donor must be negative for this mutation when the donor is a family donor. If the related donor has a positive mutation, which can cause the development of donor-derived leukemia, allo-HSCT should performed from an unrelated donor.

2. NPM1 mutated AML

NPM1^mut AML is a subtype of AML with recurrent genetic abnormalities, with a median age of onset of 68 years, accounting for 30-35% of adult AML cases. Intensive chemotherapy is the standard treatment for young adult NPM1^mut AML patients, while VEN+HMA can extend survival for older and unfit patients for intensive chemotherapy [13]. According to the ELN 2022 guidelines based on intensive chemotherapy, NPM1^mut AML is also classified as favorable prognosis, while those with FLT3-ITD^pos are classified as intermediate risk [1]. In the ELN 2024 guidelines based on VEN+HMA treatment, NPM1^mut AML patients also have a favorable prognosis, but factors affecting prognosis include not only FLT3-ITD^pos but also K/N-RAS^mut signaling pathway mutations [12]. In the Mayo genetic risk model, NPM1^mut AML patients' survival is classified as intermediate risk [21], with IDH2^mut improving survival, while KRAS^mut worsens survival. In the Hokkaido Leukemia Network risk stratification, NPM1^mut AML is classified as a “Venetoclax-sensitive gene mutation.” Newly diagnosed NPM1^mut AML patients have a high CR/CRi rate after receiving VEN+HMA induction therapy, and high-risk gene mutations affecting efficacy include FLT3-ITD^pos, TP53^mut and RUNX1^mut.

Most studies in intensive chemotherapy regimens show that MR gene mutations do not affect the prognosis of NPM1^mut AML patients [[28], [29], [30], [31]], with only a few studies suggesting that MR gene mutations worsen the prognosis of NPM1^mut AML [32]. In studies of NPM1^mut AML patients treated with either intensive chemotherapy or low-intensity treatment (VEN+AZA or low-dose cytarabine, LDAC), MR gene mutations worsen the prognosis, showing no difference in survival compared to NPM1^mut AML with FLT3-ITD^pos, thus suggesting classification into the intermediate risk group [33]. NPM1^mut AML patients with MR gene mutations have a better OS than NPM1 wild-type AML with MR gene mutations [29].

In elderly NPM1-mutated AML patients over 65 years old, HMA+VEN treatment resulted in a 1-year OS greater than 80%, and the 2-year OS was projected to be 70% (median OS not yet reached). VEN+AZA treatment in elderly “unfit” NPM1-mutated AML patients can rapidly reduce minimal residual disease (MRD), and post-treatment MRD response is closely related to prognosis, with patients achieving MRD negativity after four cycles showing favorable outcomes [34]. In a Phase 3 clinical trial with 5 years of follow-up, a median treatment-free remission of 45.8 months was observed among patients in the discontinuation group. There was no difference in relapse risk, relapse-free duration, or OS between the continuous treatment group and the discontinuation group [35]. The clinical outcomes of NPM1-mutated AML with additional gene mutations are highly heterogeneous. Expanding the sample size for prospective studies will help achieve more accurate risk stratification for NPM1-mutated AML patients and facilitate more precise clinical treatment recommendations. Treatment decisions should be based on a combination of ELN genetic risk stratification and MRD monitoring to determine the optimal timing for allo-HSCT.

3. CH-related gene mutated AML

Clonal hematopoiesis (CH)-related gene mutations include DNMT3A^mut, IDH1/2^mut, and TET2^mut. IDH1/2 mutations account for 11%-33% of AML patients [36]. Although, in the ELN 2022 risk stratification for intensive chemotherapy AML, IDH1/2^mut AML has an intermediate prognosis, both VEN+AZA and AZA+IVO treatment regimens show favorable outcomes for IDH1/2^mut AML patients. Under the VEN+AZA treatment regimen, IDH1/2^mut AML patients have longer survival than IDH1/2^wt AML patients. High risk chromosomal abnormalities do not affect the OS of IDH1/2^mut AML patients receiving VEN+AZA treatment [6]. IDH2^mut AML patients benefit more from VEN+AZA treatment compared to IDH1^mut AML patients [6,8,17]. The median OS of IDH1^mut and IDH2^mut AML patients treated with VEN+AZA are 27.7 months and 36.9 months, respectively [3]. IDH2^mut AML patients treated with IDH2 inhibitors (enasidenib) combined with AZA have less favorable results than those treated with VEN+AZA [37], but IVO+AZA is more effective than VEN+AZA in IDH1^mut AML patients [23]. Among IDH2^mut AML patients, IDH2^mut R172K has a higher CR/CRi rate and longer survival than R140Q. In the ELN 2024 guidelines, mutations in signaling pathway genes (FLT3-ITD^pos and K/N-RAS^mut) make the prognosis of IDH2^mut AML worse but do not influence the prognosis of IDH1^mut AML [12]. In the Mayo genetic risk survival model, IDH2^mut AML is the only favorable prognosis type, and is only influenced by KRAS^mut. IDH1/2 mutated AML patients who discontinued treatment in remission with negative MRD after VEN+AZA were associated with increased OS [38]. Decision of allo-HSCT should be based on additional gene mutations and MRD monitoring.

Other CH-related gene mutations in AML: TET2^mut accounts for 7%-25% of AML patients. Although TET2 is a methylation gene, AZA treatment for TET2^mut AML does not extend OS more than chemotherapy [14]. DNMT3A^mut AML patients receiving VEN+HMA treatment have a higher CR/CRi rate (77%) compared to DNMT3A^wt AML patients. In the Japanese Hokkaido Leukemia Network, DNMT3A^mut is categorized as a “Venetoclax-sensitive mutation,” and, like NPM1^mut and IDH1/2^mut, it has a good prognosis.

4. MR gene mutated AML

According to International Consensus Classification (ICC) 2022 and the 5th edition of the WHO, AML with MR gene mutations is a new AML classification [39,40]. MR gene mutations include eight genes related to secondary AML (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2) and RUNX1 mutations which was previously classified as a subtype of recurrent genetic abnormalities in the WHO 2016. AML with MR gene mutations is classified as a poor prognosis group in the ELN 2022 guidelines [41]. However, MR gene mutations do not affect prognosis in AML patients undergoing VEN+HMA treatment in the ELN 2024 and VIALE-A four-gene prognostic model. VEN+HMA treatment improved the survival of AML patients with MR gene mutation [18].

RUNX1^mut and ASXL1^mut AML were already classified as high-risk in the ELN 2017 guidelines because of poor response to chemotherapy. Mayo gene risk model suggests RUNX1^mut AML patients show poor response to VEN+HMA induction therapy. However, the median OS for RUNX1^mut AML patients treated with VEN+AZA is 32.5 months, indicating that RUNX1^mut does not affect survival [3]. ASXL1^mut AML patients show higher CR/CRi rates after receiving VEN+AZA induction treatment, and the response of ASXL1^mut AML to VEN+AZA has been validated in in vitro experiments [42]. In relapsed/refractory AML patients, ASXL1^mut AML patients also respond well to VEN+AZA, although the MRD-positive rate and relapse rate are high [3]. In intermediate-risk cytogenetic subgroups with or without NPM1^mut, ASXL1^mut does not affect prognosis [43]. ASXL1^mut and RUNX1^mut do not predict survival when treated with VEN+AZA, so they are not included in survival prediction in the three gene risk models [44].

Splicing factor (SF) gene mutations are found in 29% of non-CBF AML patients, including SRSF2^mut, U2AF1^mut, SF3B1^mut and ZRSR2^mut. SF mutations are more common in secondary/therapy-related AML. SF^mut AML is classified as high-risk in the ELN 2022 guidelines, with poor prognosis during intensive chemotherapy. However, in patients with SF^mut AML treated with VEN+HMA, the outcomes are similar to those of SF^wt AML. Patients with SF^mut AML undergoing VEN+AZA treatment have a lower risk of relapse and death. The sensitivity of SF^mut AML to VEN has also been confirmed in in vitro experiments [19].

5. TP53 mutated AML

TP53^mut accounts for 5%-10% of AML cases. TP53^mut AML cell lines exhibit low expression of BCL-2, leading to insensitivity to VEN, which directly binds to BCL-2 protein. This resistance has also been confirmed in vitro for demethylating agents and cytarabine. The CR/CRi rate in TP53^mut AML patients after induction therapy ranges from 13%-49%, significantly lower than that in TP53^wt AML (85%). Chemotherapy (46%) and VEN+HMA (33%) are more effective than HMA (21%). Regardless of the treatment, the median OS is no longer than 7 months, with only allo-HSCT improving survival in TP53^mut AML patients. Only 8% of TP53^mut AML patients survive beyond 2 years. TP53^mut AML patients experience more severe bone marrow suppression and an early mortality rate of 26%, significantly higher than that of TP53^wt AML (4%) [45]. TP53^mut AML is classified as high-risk in all prognostic models. Long-term survival was achieved only in patients who were consolidated with allo-HSCT [[46], [47], [48]].

6. Signal pathway gene mutated AML

Mutations in signaling pathway genes, such as FLT3-ITD, K/NRAS^mut and PTPN11^mut, are associated with drug resistance and poor prognosis [7]. In patients with FLT3-ITD^pos AML, the CR/CRi rate following treatment with VEN+AZA is low, and VEN+AZA does not improve survival in these patients [21]. Single-agent VEN therapy in FLT3-ITD^pos AML leads to rapid development of resistance, with relapse and overproliferation of FLT3-mutated clones, potentially due to upregulation of the BCL-2 family protein MCL-1 [4]. In the Mayo genetic risk model, FLT3-ITD^pos affects induction therapy response rates but does not influence survival. In the Japanese Hokkaido Leukemia Network risk stratification, FLT3-ITD^pos does not affect survival, with the benefit observed from the widespread use of FLT3 inhibitors (gilteritinib and quizartinib) [22]. Other models, including the ELN 2024 guidelines, modified ELN 2024, and the VIALE-A four-gene risk stratification, report an intermediate or poor prognosis for FLT3-ITD^pos patients. In the ELN 2024 guidelines and VIALE-A four-gene risk stratification, K/NRAS^mut confers an intermediate prognosis, but in the Mayo model, only KRAS^mut affects survival in AML patients, while NRAS^mut does not have prognostic value. KRAS^mut AML patients treated with VEN+HMA have a low CR/CRi rate (47%) and a median OS of only 3.3 months, whereas NRAS^mut does not impact survival (median OS of 15.4 months). PTPN11^mut AML patients have poor survival outcomes following VEN+AZA treatment [20]. Therefore, in the refined ELN 2024 guidelines, NRAS^mut is categorized as having an intermediate prognosis, while KRAS^mut and PTPN11^mut are associated with a poor prognosis.

7. AML with adverse cytogenetic karyotype

AML-MR with chromosomal abnormalities has shorter survival compared to patients with isolated MR gene mutations [49]. After treatment with AZA alone, the OS of these patients is double that of those treated with conventional chemotherapy. High-risk chromosomal karyotype AML is resistant to conventional chemotherapy but responds to the VEN+AZA regimen [17]. The VIALE-A phase 3 trial confirmed that VEN+AZA treatment significantly improved the CR/CRi rate in patients with adverse chromosomal karyotype AML [3]. In patients with adverse chromosomal karyotype AML without TP53^mut, the median survival is 23.4 months with VEN+AZA, similar to the remission rate, duration of remission, and survival in patients with intermediate-risk chromosomal karyotype AML [8]. This suggests that VEN+AZA treatment benefits some AML patients with poor chemotherapy outcomes, with TP53^mut influencing survival in patients with adverse chromosomal karyotype AML.

In the Mayo genetic risk model, adverse prognostic chromosomal karyotype, complex karyotype, and monosomy show low response rates to VEN+AZA and poor survival [21]. The Mayo model also includes survival prediction after achieving CR/CRi. Univariate and multivariate analyses reveal that the survival risk model includes adverse chromosomal karyotype and KMT2Ar. KMT2Ar does not affect CR/CRi rates [21], but the median OS is only 0.9 years, requiring allo-HSCT to improve survival. The Mayo prognostic model confirms that AML with KMT2Ar has a poor prognosis.

8. MRD response

Among AML patients treated with VEN+AZA who survived for ≥2 years, in addition to those with favorable prognosis such as DDX41^mut, IDH1/2^mut, and NPM1^mut, there are also patients who achieved MRD response. The VIALE-A phase 3 trial confirmed that patients who were MRD-negative after VEN+AZA treatment had a longer median survival than those with persistent MRD positivity (34.2 vs 18.7 months) [17,50]. In NPM1-mutated AML, patients achieving MRD negativity after four cycles have a favorable prognosis [34]. There is no difference in survival between AML patients who achieved MRD response after one or multiple cycles of VEN+AZA treatment [50]. However, a retrospective study at Mayo Clinic found no survival difference between MRD-negative and MRD-positive patients [11].

In summary, for elderly AML patients who are not suitable for intensive chemotherapy, the risk stratification for VEN+HMA treatment differs from the intensive chemotherapy approach, with the focus on the patient’s induction treatment response rate and median OS. Similar to the intensive chemotherapy model’s risk stratification, MRD response remains a key prognostic factor. Compared with chemotherapy, the primary beneficiaries of VEN+HMA treatment are those with adverse chromosomal karyotypes, MR gene mutations, and CH-associated gene mutations in AML. Some researchers suggest that patients who show a good response to VEN and derive significant benefit may stop treatment after a limited period [20], with NPM1^mut AML [35] and IDH1/2^mut AML [38] already being confirmed. The retrospective studies showed allo-HSCT had an independent favorable impact on OS in each risk category [11,18]. We emphasize the crucial role in reaching a potential cure in patients with high-risk AML [51]. With the expansion of alternative donor options and the development of improved conditioning and Graft versus Host Disease (GvHD) prophylaxis regimens, allo-HSCT post-HMA+VEN may become more accessible, even in an older population [52].

Fund programs

National Natural Science Foundation of China (202103021224001); Taiyuan science and technology project (202239)

CRediT authorship contribution statement

Jiajia Sun: Writing – review & editing, Writing – original draft, Visualization, Resources, Investigation, Conceptualization. Zhiping Guo: Writing – review & editing, Writing – original draft, Validation, Resources, Project administration, Investigation, Formal analysis, Conceptualization.

Declaration of competing interest

All authors declare no conflicts of interest.