Efficacy of venetoclax and azacitidine based therapy in favorable-risk unfit acute myeloid leukemia: a real-world study

doi:10.21203/rs.3.rs-5301043/v1

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Efficacy of venetoclax and azacitidine based therapy in favorable-risk unfit acute myeloid leukemia: a real-world study

https://doi.org/10.21203/rs.3.rs-5301043/v1

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Venetoclax combined with azacitidine (VA) is a new standard of care for newly diagnosed patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. We retrospectively analyzed patients who were diagnosed with favorable-risk unfit AML and received VA-based induction regimen between October 2020 and December 2023 in our center. Among 70 patients, 14 had RUNX1::RUNX1T1, 11 had CBFb::MYH11, 14 had CEBPA bzip mutations and 31 had NPM1 mutations. The median age was 60 years (IQR 49–67) and the median follow-up was 18.0 months (IQR 10.9–26.1). The cumulative CR/CRi rate of VA-based induction regimen for all patients was 84.3% (59/70). The median induction course was 1 (range 1–2). The CR/CRi rate for RUNX1::RUNX1T1, CBFb::MYH11, CEBPA bzip and NPM1 mutations was 35.7% (5/14), 90.9% (10/11), 100% (14/14) and 96.8% (30/31), respectively. Twenty patients received long-term VA-based therapy, and 30 received chemotherapy after remission. The MRD negativity rate after two cycle of consolidation therapy was 85.0% (17/20) for VA group and 73.3% (23/30) for chemotherapy group (p = 0.33). There was no significant difference in 2-year OS (p = 0.90) and 2-year EFS (p = 0.58) between VA group (OS: 88.2%; EFS: 41.2%) and chemotherapy group (OS: 83.3%; EFS: 42.8%). The 2-year OS (p = 0.01) and 2-year EFS (p < 0.01) of patients with negative MRD (OS: 89.8%; EFS: 51.4%) were significantly better than those with positive MRD (OS: 65.6%; EFS: 0%). VA-based regimens was an superior option for induction in favorable-risk unfit AML patients who were non-RUNX1::RUNX1T1 positive. Further studies are needed to conform its long-term efficacy.

Venetoclax and azacitidine

Favorable-risk AML

Long-term efficacy

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy. The 5-year survival rate of patients with AML is less than 30%. Based on molecular biology and cytogenetic characteristics, AML can be classified into favorable-risk, intermediate-risk, and poor-risk categories. AML patients with favorable-risk benefits from cytarabine and anthracycline-based induction chemotherapy, which is the standard induction regimen for favorable-risk AML[1, 2]. Previous studies have shown that the complete remission (CR) rate of favorable-risk AML treated with cytarabine and anthracycline-based induction regimens can reach 73.1–95.0%[3–6]. In favorable-risk AML patients, consolidation therapy is mainly based on intermediate/high-dose cytarabine, with a 5-year overall survival rate of approximately 46–74%[7, 8]. In our center, the 3-year OS of patients with core binding factor (CBF) AML is 76.6%, especially those with minimal residual disease (MRD) < 0.1%[9, 10].

Venetoclax in combination with hypomethylating agents (decitabine or azacitidine) has emerged as a first-line treatment for unfit patients with newly diagnosed AML who are ineligible for intensive chemotherapy[2, 11, 12]. Venetoclax plus azacitidine (VA) is a well-tolerated regimen with high response rates. The VIALE-A study demonstrates that in unfit AML patients with intermediate to poor-risk cytogenetic category, VA can achieve a composite remission rate of 66.7% and a median survival of 14.7 months. The efficacy in NPM1 subgroup is especially remarkable[13, 14]. In relapsed or refractory AML patients (RR-AML), treatment with decitabine and venetoclax also shows an encouraging overall response rate (ORR) of 62%, but with a shorter median overall survival (OS) of 7.8 months[15]. However, the data for the use of venetoclax in combination with hypomethylating agents for treating favorable-risk unfit AML patients is still relatively lacking. In addition, the guidelines recommend that after achieving CR in unfit AML patients treated with venetoclax plus hypomethylating agents, either venetoclax plus hypomethylating agents or chemotherapy can be chosen for consolidation therapy[1, 2, 12]. There is currently still a lack of data on the long-term efficacy of venetoclax plus hypomethylating agents in AML patients with favorable-risk. Therefore, in this study, we retrospectively analyzed the efficacy of VA-based regimen in newly diagnosed favorable-risk unfit AML patients and its feasibility of long-term consolidation treatment in our cohort.

Patients

A retrospective study was carried out of AML patients with favorable risk who were unfit for intensive chemotherapy and received VA-based induction therapy between October 2020 and December 2023 in Peking University People’s Hospital. All patients were diagnosed with AML according to the WHO diagnostic criteria and classified according to the 2017 ELN risk classification by genetics. The unfit factors included age ≥ 75 years or 18–74 years and at least one of the following conditions: Eastern Cooperative Oncology Group (ECOG) performance status score of 2–3; severe heart, lung, liver, or kidney disease; presence of any comorbidity unsuitable for receiving intensive chemotherapy by a physician[16].The study in accordance with the principles of the Helsinki Declaration and approved by the Ethics Committee of Peking University People’s Hospital.

Induction therapy

The venetoclax was administered orally in the first cycle, with 100 mg on day 1, followed by a gradual increase to the target dose of 400 mg within 3 days (100, 200, 400 mg). The medication was continued at a daily dose of 400 mg until day 28. When co-administered with a CYP3A inhibitor (mainly voriconazole in this study), the dose was adjusted to 100 mg orally per day. The concomitant use of the hypomethylating agent AZA (75 mg/m2) was administered subcutaneously once daily from day 1 to day 7. Patients combined with KIT mutations received homoharringtonine (1mg/m² per day) intravenously injected from day 1 to 7 in first cycle. The FLT3 inhibitors were administered orally in patients combined with FLT3-ITD mutations .

Consolidation therapy

For patients who received long-term VA-based regimens, the venetoclax was administered orally with 400 mg starting from the second cycle. Aza (75 mg/m2) was administered subcutaneously once daily from day 1 to day 7 of each cycle. The FLT3 inhibitors still administered orally in patients combined with FLT3-ITD mutations. For patients who received standard chemotherapy consolidation, medium dose cytarabine (2 g/m2 every l2 h for 3 days) was given for four to six cycles. If relapse or consistent positive MRD, allo-HSCT was recommended for patients who were acheived CR/CRi after induction and unfit factors were removed[1, 17].

Efficacy and safety assessment

The primary endpoint of the study was the rate of complete remission (CR) or complete remission with incomplete blood count recovery (CRi). Secondary endpoints included minimal residual disease (MRD) negativity rate, overall survival (OS) and event-free survival (EFS). CR was defined as the disappearance of symptoms and signs of leukemia, absence of leukemia cells in the blood, less than 5% blasts in the bone marrow, no extramedullary leukemia, and a neutrophil count of ≥ 1.0×10^9/L, and platelets (PLT) of ≥ 100×10^9/L. CRi was defined as the disappearance of symptoms and signs of leukemia, absence of leukemia cells in the blood, less than 5% blasts in the bone marrow, no extramedullary leukemia, and a neutrophil count of < 1.0×10^9/L or PLT of < 100×10^9/L. Relapse was defined as the reappearance of leukemia cells in the peripheral blood, or ≥ 5% blasts in the bone marrow, or the appearance of new pathological hematopoiesis or extramedullary leukemia cell infiltration. Molecular relapse was defined as FCM ≥ 0.01% in CEBPA bzip mutations or the gene levels of RUNX1::RUNX1T1, CBFb::MYH11, NPM1 increase > 1 log units over two consecutive measurements. MRD negativity was defined as FCM < 0.01% in patients with CEBPA bzip mutations; RUNX1::RUNX1T1, CBFb::MYH11, NPM1 gene levels reduction of > 3 log units compared to baseline. OS was defined as time from diagnosis to death of any cause. EFS was defined as time from diagnosis to the first occurrence of any of the following events, including molecular relapse, relapse, transplantation, and death.

Adverse events (AEs) were assessment according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.

Statistics

The data were statistically analyzed and graphed using SPSS Statistics version 26.0.0 (IBM SPSS Statistics) and GraphPad Prism 9.0 software. The outcome data were presented as median (IQR) or number (percentage). The t-test and chi-square test/Fisher’s exact test were used for comparison between groups. OS and EFS were estimated using the Kaplan-Meier method and compared using the log-rank test. A p value < 0.05 was indicated statistical significance.

Patients characteristics

A total of 70 patients were enrolled in this study. The patients baseline characteristics were showed in Table 1. The median age of the patients was 60 years (IQR 49–67). Thirty-three (47.1%) patients were men and 37 (52.9%) were women. The reason for unfit for intensive therapy were age ≥ 75 year (2 patients), active infection (28 patients) and organ dysfunction (40 patients). The median follow-up time was 18.0 months (IQR 10.9–26.1). Fourteen patients had RUNX1::RUNX1T1, 11 patients had CBFb::MYH11, 14 patients had CEBPA bzip mutations and 31 patients had NPM1 mutations. The most common concomitant mutations were KIT mutations (7 patients with KIT D816 mutaiton, 4 patients with KIT non-D816 mutation), FLT3 mutation (9 patients), DNMT3A mutation (8 patients), RAS mutations (8 patients) and IDH mutations (8 patients). Fifty-seven (81.4%) patients received VA, 6 (8.6%) patients received VA + HHT and 7 (10.0%) patients received VA + FLT3 inhibitors. The median duration of venetoclax was 28 days (IQR 21–28) during the induction phase.

Table 1

Clinical characteristics of favorable-risk unfit AML patients treated with VA-based induction regimen
Variables	Total (n = 70)	CBFb::MYH11 (n = 11)	RUNX1::RUNX1T1 (n = 14)	CEBPA bzip (n = 14)	NPM1 (n = 31)
Age (years), median (IQR)	60 (49–67)	59 (44–67)	52 (48–62)	53 (44–68)	62 (60–68)
Sex, n (%)
Male	33 (47.1)	4 (36.4)	7 (50.0)	6 (42.9)	16 (51.6)
Female	37 (52.9)	7 (63.6)	7 (50.0)	8 (57.1)	15 (48.4)
Unfit factors, n (%)
Age ≥ 75y	2 (2.9)	0	0	0	2 (6.5)
Active infection	28 (40.0)	7 (63.6)	7 (50.0)	8 (57.1)	13 (41.9)
Organ dysfunction	40 (57.1)	4 (36.4)	7 (50.0)	6 (42.9)	16 (51.6)
Molecular marker, n (%)
C-kit D816	7 (10.0)	2 (18.2)	4 (28.6)	1 (7.1)	0
C-kit non-D816	4 (5.7)	3 (27.3)	1 (7.1)	0	0
FLT3-ITD^*	9 (12.9)	0	1 (7.1)	0	8 (25.8)
ASXL1	5 (7.1)	0	2 (14.3)	2 (14.3)	1 (3.2)
CSF3R	4 (5.7)	0	1 (7.1)	3 (21.4)	0
DNMT3A	9 (12.9)	0	0	0	9 (29.0)
KRAS/NRAS	8 (11.4)	6 (54.5)	0	0	2 (6.5)
IDH1/2	8 (11.4)	0	1 (7.1)	1 (7.1)	6 (19.4)
Others^#	10 (14.3)	0	4 (28.6)	2 (14.3)	4 (12.9)
Additional Kayrotypes, n (%)
-X/-Y	9 (12.9)	1 (9.1)	7 (50.0)	1 (7.1)	0
del(9q)/-9	10 (14.3)	5 (45.5)	3 (21.4)	1 (7.1)	1 (3.2)
Others^&	6 (8.6)	2 (18.2)	1 (7.1)	0	3 (9.7)
Induction regimen, n (%)
Ven + Aza	57 (81.4)	8 (72.7)	12 (85.7)	13 (92.9)	24 (77.4)
Ven + Aza + HHT	6 (8.6)	3 (27.3)	2 (14.3)	1 (7.1)	0
Ven + Aza + FLT3 inhibitors	7 (10.0)	0	0	0	7 (22.6)
Duration of venetoclax, n (%)
14 days	6 (8.6)	0	1 (7.1)	1 (7.1)	4 (12.9)
21 days	27 (38.6)	7 (63.6)	2 (14.3)	5 (35.7)	13 (41.9)
28 days	37 (52.8)	4 (36.4)	11 (78.6)	8 (57.1)	14 (45.2)
Allo-O()HSCT, n (%)	13 (18.6)	1 (9.1)	5 (35.7)	3 (21.4)	4 (12.9)
Follow-up time (months), median (IQR)	18.0 (10.9–26.1)	10.7 (9.7–20.8)	19.8 (13.5–30.0)	18.4 (15.7–29.2)	16.6 (11.4–25.6)
^*FLT3-ITD low allelic ratio (< 0.05). ^#Other additional molecular markers include: WT1, JAK1, BRC1, JAK3, SBDS, SETD2, ZBTB7A, KNMT2A, SMCIA, JAK2, PTPN11, TPMT, SRSF1. ^& Other additional karyotypes include: del(11q), + 8, +9, + 4, -2, -22, + 13.

Efficacy

Hematologic efficacy

After one course of induction therapy, a total of 58 patients achieved CR/CRi with a rate of 82.9% (58/70). For 14 patients with RUNX1::RUNX1T1, CR/CRi was achieved in 5 patients (35.7%). For 11 patients with CBFb::MYH11, CR/CRi rate was 90.9% (10/11). For patients with CEBPA bzip and NPM1 mutations, CR/CRi rate was 100% (14/14) and 93.5% (29/31), respectively. One patient with NPM1 mutation received a second course of VA and achieved CR. The cumulative CR/CRi rate for 31 patients with NPM1 mutations was 96.8% (30/31). Therefore, the cumulative CR/CRi rate for all patients was 84.3% (59/70). The CR/CRi rate for patients with RUNX1::RUNX1T1 was significantly lower than that for other three groups (p < 0.01, Fig. 1).

Molecular efficacy

For 56 non-RUNX1::RUNX1T1 positive patients, 54 achieved CR/CRi (96.4%) with a VA-based induction therapy. After achieving remission, 4 patients discontinued treatment due to disease progression or various reasons. Twenty patients received a long-term VA-based therapy as consolidation, and 30 patients received standard chemotherapy after the removal of unfit factors (Fig. 2). The median age of patients who received long-term VA-based consolidation therapy was 67 years (IQR 60–69). The median course of consolidation therapy for the VA group was 6 (IQR 5–8) with a median follow-up time of 19.8 months (IQR 15.4–26.8). The median age of patients who received chemotherapy consolidation was 57 years (IQR 40–62). The median course of consolidation therapy for the chemotherapy group was 4 (IQR 4–6), and the median follow-up time was 17.1 months (IQR 11.5–25.5). The MRD negativity rate after two cycle consolidation therapy was 85.0% (17/20) for VA group and 73.3% (22/30) for chemotherapy group, which was not significant difference (p = 0.33). The relapse rate was 25.0% for VA group (5/20) and 23.3% (7/30) for chemotherapy group (p = 0.89). One patients received allo-HSCT in VA group due to relapse. Seven patients received allo-HSCT in chemotherapy groups due to relapse or persistent MRD.

Survival

The probability of OS at 2 year was 88.2% (95% CI 60.6–96.9%) and 83.3% (95% CI 52.0%-95.0%) respectively in VA group (n = 20) and chemotherapy group (n = 30), which was not significant difference (p = 0.90, Fig. 3a). There was also no statistic difference in the probability of 2-year EFS between VA group (41.2%, 95% CI 15.9%-75.2%) and chemotherapy group (42.8%, 95% CI 20.4%-63.6%) (p = 0.58, Fig. 3b). The 2-year OS of patients with negative MRD (n = 39) after the second consolidation therapy (89.8%, 95% CI 62.3%-97.6%) was significantly higher than that of patients with positive MRD (n = 11) (65.6%, 95% CI 26%-87.6%) (p = 0.01, Fig. 3c). The 2-year EFS of patients with negative MRD was also significantly better than that of patients with positive MRD (51.4%, 95% CI 30.4%-68.9% vs 0%, p < 0.01, Fig. 3d). In patients who achieved MRD negativity, there was no difference in 2-year OS (p = 0.88, Fig. 3e) and 2-year EFS (p = 0.83, Fig. 3f) between those who received VA consolidation (n = 17) (OS: 92.9%, 95% CI 58.1%-98.2%; EFS: 49.5%, 95% CI 18.7%-74.5%) and those who received chemotherapy consolidation (n = 22) (OS: 87.5%, 95% CI 38.7%-98.1%; EFS: 52.8%, 95% CI 24.4%-74.9%).

Safety

During the induction therapy, all patients experienced at least one AE. The most frequently reported AE was Grade 3 or higher hematologic AE, including thrombocytopenia (84.2%), neutropenia (87.1%), febrile neutropenia (45.7%) and anemia (37.1%). The most common non-hematological AE is infection (28.5%) followed by gastrointestinal reaction (17.1%). Tumor lysis syndrome occurred in 3 patients. No patients died due to adverse events. During the consolidation therapy, the incidence of grade 3 or higher hematologic AEs in the VA group was 25.0% (5/20), while in the chemotherapy group, it was 100.0% (30/30). The incidence of infection was 15.0% (3/20) in the VA group and 46.6% (14/30) in the chemotherapy group. The platelet transfusion requirement per cycle of consolidation was 0–1 unit in the VA group and 0–5 units in the chemotherapy group.

Subgroup analysis

NPM1

Among patients with NPM1 mutations, except one who developed secondary FLT3-ITD and FLT3-TKD mutations never achieved remission after three induction therapy and died, all patients obtained remission with the VA-based induction regimen. Three patients gave up treatment after remission. Fourteen patients received long-term VA-based therapy with a median course of 6 (IQR 4–7). The MRD negativity rate after the second consolidation therapy was 85.7% (12/14). A total of 3 patients relapsed. Among 14 patients, 3 had concomitant FLT3-ITD mutations and received VA + FLT3 inhibitors for consolidation. One patient relapsed and 1 received allo-HSCT due to persistent MRD. Thirteen patients received chemotherapy for consolidation. The MRD negativity rate after the second consolidation therapy was 92.3% (12/13). Four patients relapsed and 4 patients underwent allo-HSCT. There was also no significant difference in 2-year OS (p = 0.98, Fig. 4a) and 2-year EFS (p = 0.74, Fig. 4b) between patients with VA consolidation (n = 14) (OS: 81.8%, 95% CI 44.7%-95.1%; EFS: 41.0%, 95% CI 12.7%-68.0%) and those with chemotherapy consolidation (n = 13) (OS: 73.8%, 95% CI 24.4%-93.6%; EFS: 36.6%, 95% CI 10.1%-64.3%) in NPM1 subgroup.

AML typically affects elder patients, with a median age of diagnosis at 67 years. Elderly patients (≥ 65 years) usually have a poorer response to induction chemotherapy[18, 19]. The low-intensity regimen is the standard treatment option recommended in previous guidelines for patients who are not fit for intensive chemotherapy. It mainly consists of low-intensity therapies such as HMAs (azacitidine or decitabine), or low-dose cytarabine. The efficacy of single-agent treatment with azacitidine or decitabine is less than 30%, taking 3.5–4.3 months to achieve optimal response, and it is not curative, with a median OS of less than 1 year[20, 21]. For younger, newly diagnosed unfit AML patients, such as those with active infections, active infection control is required before they can receive intensive induction therapy. Therefore, some patients may miss the opportunity for chemotherapy or have a high early treatment-related mortality rate.

Venetoclax is a targeted protein inhibitor that induces apoptosis in leukemia cells by inhibiting the anti-apoptotic protein Bcl-2[22]. In recent years, the combination of venetoclax with hopomethylating agents has been proven to be a significant advancement in the treatment of AML. This combination therapy is recommended as a first-line treatment option for elderly patients or those unfit for intensive chemotherapy, contributing significantly to improving the treatment outcomes and survival of AML patients. The pivotal VIALE-A randomized trial showed that the overall response rate (66.4% versus 28.3%; p < 0.001) and CR rate (29.7% versus 17.9%; p < 0.001) were significantly higher among patients who received azacitidine plus venetoclax than those who received azacitidine alone. The median OS was 14.7 months of patients in the azacitidine plus venetoclax group, while the median overall survival in the azacitidine alone group was 9.6 months[13, 14]. However, the patients included in the VIALE-A study were all classified as intermediate to poor-risk cytogenetic AML patients. There were limited data of efficacy for venetoclax plus HMAs in favorable-risk AML. In this study, for the first time, we analyzed the efficacy of VA-based induction regimen in 70 newly diagnosed favorable-risk unfit AML patients in our center. The results showed that the overall response rate (CR + CRi) after one cycle was 82.9%, and after two cycles, the overall response rate was 84.3%. Analysis of the four subgroups within the favorable-risk category showed that the overall response rate induced by the VA-based regimen in RUNX1::RUNX1T1-positive patients was only 35.7%, which was significantly lower than the other three subgroups. To our knowledge, this is the largest study of the efficacy of VA-based regimen in favorable-risk AML and further elucidated the inferior efficacy of VA in RUNX1::RUNX1T1-positive patients. Yu et al analyzed the short-term efficacy of VEN + azacitidine in 7 patients with t(8;21) (4 ND and 3 R/R), only 2 ND patients attained remission[23]. In a recent analysis from Zhang and colleagues showed that in 13 newly diagnosed patients with RUNX1::RUNX1T1 who received Ven + HMA, CR/CRi was achieved in 4 patients (31%). While, for 17 inv(16)/t(16;16) patients, all patients achieved CR/CRi[24]. These results were consistent with our findings. Previous study suggested that the aberrant transcription factor RUNX1::RUNX1T1 epigenetically silenced the function of the Bcl-2[25], which may partially explained the inferior efficacy of VA for RUNX1::RUNX1T1. Therefore, VA-based induction regimens can achieve a high rate of remission in favorable-risk unfit AML patients who are non-RUNX1::RUNX1T1 positive. However, the application of VA should be approached with caution in RUNX1::RUNX1T1-positive patients.

In addition to demonstrating the high efficacy of the VA regimen in intermediate to poor-risk unfit AML patients, the VIALE-A study also showed long-term benefits of prolonged use of the VA regimen in patients. The median duration of continuous CR/CRi with the VA regimen for a median of 11 cycles was 17.5 months (range: 12.9–21.0 months), with a median event-free survival (EFS) of 16.3 months (range: 12.1–19.3 months), and with a 2-year OS of 53.6%[14]. A study investigated the outcomes of patients in the VIALE-A trial who achieved CR/CRi and MRD < 10^− 3 after receiving VA treatment. The results showed that MRD < 10^− 3 was achieved by 67 of 164 (41%) and who achieved MRD < 10^− 3 with VA had longer EFS and OS[26]. A single-center retrospective study included 635 newly diagnosed AML patients who responded to insentive chemotherapy with cytarabine + anthracycline-based regimens (IA) or low-intensity treatment regimens based on venetoclax investigated the correlation between treatment intensity and OS. The results showed that regardless of treatment intensity, MRD-negative patients had superior OS and lower relapse rates[27]. Another real-world study also suggested that patients who achieved remission with the VA regimen had a MRD negativity rate of approximately 38%, and the majority of patients achieved MRD negativity within the first 6 cycles. Patients who achieved MRD negativity had a lower relapse rate and superior progression-free survival (PFS) and OS[28]. In this study, we compared for the first time the impact of prolonged VA-based treatment and chemotherapy on MRD and survival in non-RUNX1::RUNX1T1 positive favorable-risk AML patients. The results showed that compared to standard chemotherapy, long-term VA-based treatment did not significantly affect the rate of MRD negativity, OS and EFS. However, not achieving MRD negativity after consolidation therapy significantly influenced OS and EFS, which was consistent with the above results. Therefore, low-intensity long-term VA-based treatment did not affect the rate of MRD negativity in non-RUNX1::RUNX1T1 positive favorable-risk AML patients, and achieving MRD negativity implies better survival. Furthermore, a study by Chua et al. explored discontinuation of Ven + HMAs in patients who had been on treatment for more than 12 months. It was showed that among 29 patients, 13 patients discontinued treatment. The median time to treatment-free remission (TFR) after discontinuation exceeded 45.8 months. There was no significant difference in overall relapse-free survival (RFS) and OS between the discontinuation and non-discontinuation groups. In the cohort, factors supporting sustained TFR include NPM1 and/or IDH2 mutations at diagnosis, complete remission, absence of measurable residual disease, and receipt of at least 12 months of venetoclax-based combination therapy before treatment cessation[29]. There are currently no patients who have discontinued treatment in our study. Further follow-up and research are needed to validate the above results.

The safety of the VA-based regimen was also evaluated in our study. Consistent with previous studies[13], the main AEs were grade 3 or higher hematologic toxicities, primarily occurring during the induction phase. However, in patients who achieved remission and underwent prolonged VA treatment, the incidence of hematologic AEs and infections were significantly lower than in patients who received chemotherapy consolidation, which also implied a better quality of life in patients with VA consolidation.

In conclusion, the VA-based induction regimen could achieve a high proportion of CR/CRi in non-RUNX1::RUNX1T1-positive favorable-risk unfit AML patients. However, the VA-based regimen showed inferior efficacy in RUNX1::RUNX1T1-positive unfit AML patients. There were comparable MRD negativity rate, OS and EFS in non-RUNX1::RUNX1T1-positive favorable-risk unfit AML patients who received long-term VA-based treatment and chemotherapy consolidation after achieving remission. Patients who obtained MRD negativity after consolidation have superior OS and EFS. In summary, the VA-based long-term regimen achieved similar efficacy and safety as standard chemotherapy in non-RUNX1::RUNX1T1-positive favorable-risk unfit AML patients, but the cases are limited, and further investigation is needed by expanding the cases.

Ethical Approval and Consent to Participate

This study was approved by the Ethics Committee of Peking University People’s Hospital and was conducted according to the principles of the Helsinki Declaration. Informed consent was obtained from all individual participants included in the study.

Funding

This work was support by the National Key Research and Development Program of China (2021YFC2500300), Peking University People’s Hospital Research and Development Funds (RDL2022-13), and Project (RDL2023-08) supported by Peking University People's Hospital scientific research development funds.

Competing Interests

The authors declare no competing interests.

Data Availability

No datasets were generated or analyzed during the study.

Authorship

Hao Jiang and Xiaojun Huang designed the study. Qi Chen, Ying Wu, Wenjing Yu，Xiaolu Zhu, Xuying Pei, Wenbing Duan, Jinsong Jia and Jing Wang collected the data. Qi Chen and Ying Wu analyzed the data. Xiaosu Zhao, Guorui Ruan, Yingjun Chang and Hongxia Shi detected the laboratory indicators. Qi Chen prepared the typescript. All authors approved the final typescript, take responsibility for the content, and agreed to submit for publication.

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No competing interests reported.

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Efficacy of venetoclax and azacitidine based therapy in favorable-risk unfit acute myeloid leukemia: a real-world study

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Abstract

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INTRODUCTION

METHODS

Patients

Induction therapy

Consolidation therapy

Efficacy and safety assessment

Statistics

RESULTS

Patients characteristics

Efficacy

Hematologic efficacy

Molecular efficacy

Survival

Safety

Subgroup analysis

NPM1

DISCUSSION

Declarations

References

Additional Declarations

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