Venetoclax combined with hypomethylating agents and the CAG regimen (DCAG) in relapsed/refractory AML: A single- center clinical trial

doi:10.21203/rs.3.rs-2996129/v1

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Research Article

Venetoclax combined with hypomethylating agents and the CAG regimen (DCAG) in relapsed/refractory AML: A single- center clinical trial

https://doi.org/10.21203/rs.3.rs-2996129/v1

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Purpose

Relapsed/refractory acute myeloid leukemia (R/R AML) has a low remission rate and poor prognosis, and the current therapeutic measures are limited and low in effectiveness. This clinical study investigated the efficacy and safety of the Bcl-2 inhibitor venetoclax (VEN) used in combination with the DCAG regimen (decitabine/azacytidine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor) in the treatment of R/R AML.

Methods

We analyzed the clinical data of R/R AML patients who received the VEN-DCAG regimen at the First Medical Center of the PLA General Hospital from 3/2021 to 1/2023. Postmedication responses were observed and analyzed, including CR/CRi (complete remission/complete remission with incomplete hematological recovery) rate, measurable residual disease (MRD) negative rate (patients achieving CR/CRi), overall survival (OS), event-free survival (EFS), and success rate of subsequent bridging allogeneic hematopoietic stem cell transplant (allo-HSCT).

Results

Twenty patients treated with VEN + DCAG for R/R AML were included. The median age was 40 (10–70) years, 11 (55%) were male and 9 (45%) were female. The ORR was 90% (18/20) after the 1st cycle of treatment, with 17 (85%) CR/CRi (10 MRD negative) patients, 1 (5%) PR, and 2 (10%) NR patients. Twelve patients (7 MRD- CR, 4 MRD + CR, 1 NR) were treated with the subsequent VEN-DCAG regimen, 3 cases MRD turned negative (1 course of MRD + CR), 1 NR patient died of disease progression after receiving the subsequent VEN-DCAG, and 13 patients eventually achieved MRD- CR (76.5%). Among them, there were 7 patients in the relapse group, 7 with CR/CRi and 6 with MRD-negative CR (85.7%); there were 13 patients in the refractory group, 10 with CR/Cri and 7 with MRD-negative CR (70%). The treatment response rates were 100% (7/7) and 84.6% (11/13) for patients in the relapse and refractory groups, respectively. All patients experienced varying degrees of adverse events (AEs), with hematologic AEs (mainly myelosuppression) and nonhematologic AEs (with fever, gastrointestinal discomfort and infection being more common). At the last follow-up, 1 (MRD + CR) of 11 patients (7 MRD- CR, 4 MRD + CR) who received allo-HSCT died; 5 (2 MRD- CR, 1 PR, 2 NR) of 9 patients (6 MRD- CR, 1 PR, 2 NR) who were not treated with allo-HSCT died. The median follow-up time was 12.7 (2.6–21.8) months for the 14 surviving patients. The median OS was 4.35 (0.7–18.1) months for the 6 patients who died.

CONCLUSION

VEN-DCAG is an effective treatment regimen for R/R AML patients, with high rates of complete remission and good tolerability in both relapsed and refractory AML patients. The rate of MRD-negative CR can be further improved by increasing the number of courses of treatment in patients with MRD-positive CR. Allo-HSCT should be bridged as soon as possible after achieving CR by VEN-DCAG, which can significantly improve patient survival.

Venetoclax

hypomethylating agents

CAG regimen

Relapsed

Refractory

Acute myeloid leukemia

Acute myeloid leukemia has a high relapse rate. The prognosis after relapse is poor, treatment measures are limited, and there is no uniform treatment protocol^{[1, 2]}. In recent years, the use of targeted drugs and hypomethylating agents (HMAs) has provided more treatment options for patients with R/R AML, and some patients are expected to achieve complete remission, thus creating conditions for subsequent bridging of allo-HSCT. The Bcl-2 inhibitor venetoclax (VEN) is capable of targeting the antiapoptotic protein Bcl-2 without relying on genetic mutations to induce apoptosis in tumor cells and has shown great advantages in the treatment of hematologic malignancies^[3–5]. Venetoclax in combination with HMAs has been approved as a first-line standard of care for elderly/unfit patients with newly diagnosed AML and has shown some efficacy in patients with R/R AML but is far from adequate^[6–8]. The DCAG regimen consisting of demethylating agents combined with cytarabine, aclarubicin, and granulocyte colony-stimulating factor (G-CSF) has been shown to be an effective treatment option for AML^{[9, 10]}. Preclinical studies have shown that venetoclax in combination with decitabine and aclarubicin has synergistic antitumor cell proliferative effects and promotes apoptosis and cell cycle arrest in AML cells^{[11, 12]}. Therefore, VEN-HMAs-CAG is likely to have a better synergistic anti-AML cellular effect, and there is still a great lack of clinical studies for the regimen. To further optimize the R/R AML treatment regimen and improve the remission and survival rates of such patients, this clinical trial retrospectively analyzed the efficacy and safety of VEN combined with DCAG in the treatment of R/R AML patients.

Patient population

Patients with acute myeloid leukemia treated at the First Medical Center of the PLA General Hospital from Mar. 2021 to Jan. 2023 were selected. Patients were included in the trial according to the following criteria: 1. patients who did not achieve CR status after receiving > 1 standard regimen of chemotherapy (refractory); patients who had achieved CR and then developed leukemic cells in the peripheral blood or ≥ 5% primitive cells in the bone marrow or developed extramedullary leukemic infiltration (relapsed); 2. patients treated with the VEN + DCAG regimen for at least 1 course; 3. patients with an Eastern Cooperative Oncology Group (ECOG) score of ≤ 3. All enrolled patients were diagnosed by bone marrow cytomorphology, leukemia immunophenotyping, cytogenetics, and molecular biology.

Study design

This study analyzed the efficacy and safety of the VEN-DCAG regimen in R/R AML patients and was approved by the Ethics Committee of the First Medical Center of the PLA General Hospital (S2022-740-01).

Twenty patients with R/R AML were enrolled: 17 were treated with the VEN + decitabine (DAC) + CAG regimen, and 3 were treated with the VEN + azacitidine (AZA) + CAG regimen. VEN administration: 400 mg daily orally or 100 mg daily (combined with azole antifungals) orally d1-14. DAC 20 mg/m² d1-5, IV; AZA 50–75 mg/m² d1-7, IV; CAG regimen: cytarabine 50–100 mg/m²/d d1-5 IV, aclarubicin 20 mg/d IV (6 cases d1/3/5, 14 cases d1-5), G-CSF 300 µg/d (2 cases) or polyethylene glycol long-acting colony-stimulating factor (PEG-CSF) 6 mg once a week (18 cases); G-CSF or PEG-CSF was discontinued when the white blood cell count (WBC) was ≥ 2×109/L. Symptomatic supportive treatment, such as the transfusion of blood products or anti-infection, was given according to the actual situation.

Assessments

Patients were primarily assessed for 1-course efficacy and total efficacy. The efficacy assessment mainly included the complete remission/complete remission with incomplete hematologic recovery (CR/CRi) rate, partial remission (PR), nonremission (NR), minimal residual disease (MRD) negative remission rate, overall survival (OS), event-free survival (EFS), and success rate of subsequent bridging HSCT. The safety assessment mainly analyzed the occurrence of adverse events (AEs) after VEN-DCAG treatment, which was determined mainly by clinical symptoms, laboratory tests, imaging examinations, etc. The adverse event severity grading standard was adopted from the National Cancer Institute (NCI) adverse event grading (CTC-AE) version 4.03^[13].

The main definitions are as follows: CR, disappearance of signs and symptoms of leukemia, absence of leukemic cells in the leukocyte classification, < 5% primitive cells in the bone marrow, absence of extramedullary leukemia and neutrophil count ≥ 1.0×10⁹/L, PLT ≥ 100×10⁹/L; CRi, disappearance of signs and symptoms of leukemia, absence of leukemic cells in the leukocyte classification, < 5% primitive cells in the bone marrow, absence of extramedullary leukemia, and neutrophil count < 1.0×10⁹/L or PLT < 100×10⁹/L; PR, bone marrow primitive cells decreased to 6%-20% or decreased more than 50% from pretreatment; NR, not meeting the above criteria. MRD-negative status was defined as negative leukemia immunotyping by flow cytometry (FCM). OS was defined as the time from entry into VEN combination therapy until death from any cause or last follow-up. EFS was defined as the time from entry into VEN combination therapy until disease progression, relapse, death from any cause, or last follow-up. The overall response rate (ORR) was calculated as CR + CRi + PR.

Follow-up and statistical methods

Patient status was acquired by telephone follow-up and review of outpatient or inpatient records. The follow-up cutoff date was April 1, 2023. The end point of follow-up was the follow-up cutoff or death from any cause. Data were analyzed using SPSS 26.0 software, and outcome data are expressed as the median (range) or number (percentage). Survival curves were plotted using the Kaplan‒Meier method, and survival was compared between groups using the log-rank test. P < 0.05 was considered to indicate a statistically significant difference.

Patient characteristics

The median age of the 20 patients was 40 (10-70) years, 11 (55%) were male and 9 (45%) were female (Table 1). There were 17 cases of primary AML, 1 case secondary to myelodysplastic syndrome (MDS); 5 years after aplastic anemia unrelated donor transplantation secondary to AML 1 case, and treatment-related AML 1 case (anterior mediastinal germ cell tumor). Grouped according to AML disease stage, 13 patients had refractory disease and 7 patients showed relapse, including 2 cases of relapse after allo-HSCT; 4 cases in the good prognosis group, 8 cases in the moderate prognosis group, and 8 cases in the poor prognosis group according to the ELN2022 version of AML genetic risk stratification; 11 cases received 1 course of previous treatment, 9 cases received >1 course of treatment, 13 cases received HMA treatment, 3 cases received venetoclax, and 2 cases had received allo-HSCT. The median percentage of bone marrow (BM) primitive cells before treatment was 27.65 (4.0-76.8)%, the median hemoglobin (HGB) level was 78 (45-135) g/L, the median white blood cell (WBC) count was 2.46 (0.59-64.51) × 10⁹/L, and the median platelet (PLT) count was 48 (6-873) × 10⁹/L. Karyotype examination revealed a normal karyotype in 8 cases, a moderate prognosis karyotype in 8 cases and a poor prognosis karyotype in 4 cases. Reverse transcription RT‒PCR molecular biology detected the AML1-ETO fusion gene in 3 cases, the MLL-AF6 fusion gene and MLL-MLL fusion gene in 2 cases each, and the RUNX1-RUNX1T1 fusion gene, KMT2A-SEPTIN9 fusion gene and FUS-ERG fusion gene in 1 case each. Second-generation gene sequencing (NGS) detected 7 cases of IDH1/2 mutations, 6 cases each of DNMT3A and WT1 mutations, 3 cases of U2AF1 mutations, 2 cases each of NARS, ASXL1, TP53, BCOR, TET2, RUNX1, and 1 case each of BCORL1, NMP1, CEBPA, C-KIT and EP300 (nonsignificant mutations have been omitted) (Figure 1).

Efficacy

The ORR of 20 patients after 1 cycle of treatment was 90% (18/20), including 17 cases of CR/CRi (85%), 1 case of PR (5%), 2 cases of NR (10%), and 10 cases of MRD-CR (58.8%). Twelve patients (7 MRD- CR, 4 MRD+ CR, 1 NR) received the follow-up VEN-DCAG regimen, 10 patients received 2 cycles, 1 patient received 4 cycles, and 1 patient received 5 cycles. Three of the 4 patients with 1-course MRD+ CR were converted to MRD-CR after the 2nd course of VEN-DCAG, and 1 patient with NR had disease progression during the follow-up treatment. The final 20 patients had 17 cases of CR/CRi and 13 cases of MRD-CR (76.5%) (Table 2).

There were 7 patients in the relapse group, and all 7 patients achieved CR after 1 cycle, including 5 MRD-CR and 2 MRD+CR (1 MRD+CR was converted to MRD-CR with subsequent VEN-DCAG treatment). Two of the patients who relapsed after allo-HSCT (both 5 years after transplantation) also achieved MRD-CR after 1 cycle of VEN-DCAG. There were 13 patients in the refractory group; 10 patients (5 with MRD+CR, 5 with MRD-CR) achieved CR, 1 PR, and 2 NR after 1 cycle of treatment. Eight patients (4 with MRD-CR, 3 with MRD+CR, 1 with NR) received subsequent courses of treatment, among whom 3 had 2 cases of MRD+CR in the 1st cycle, which were converted to MRD-CR after the 2nd cycle of treatment. One NR patient after the 1st cycle had disease progression while receiving the 2nd cycle of treatment.

The MRD-negative remission rates after 1 cycle of VEN-DCAG treatment were 71.4% and 50% in the relapsed and refractory groups, respectively (P > 0.05). Analysis of the efficacy differences between the good prognosis group, the intermediate prognosis group and the poor prognosis group after VEN-DCAG treatment showed statistically significant differences in MRD-negative remission rates in all three groups after 1 course of treatment and after total treatment (1 course: 0% vs. 85.7% vs. 66.7%; total treatment: 25.0% vs. 100.0% vs. 83.3%, P=0.017). Previously untreated HMAs had a higher MRD-CR rate than those treated with HMAs (100% vs. 46.2%), P = 0.044, a statistically significant difference. Subgroup analysis of the effect of IDH, DNMT3A, and WT1 gene mutations on remission rates showed no significant difference between the three groups of mutations on MRD-negative remission rates. In addition, analysis of whether age (≥50 years), sex, disease type, number of prior courses (≥2) and karyotype grouping affected efficacy showed no statistically significant differences in either CR or MRD-CR rate differences (P > 0.05).

Among the 3 patients without CR, there was 1 NR patient, male, 70 years old, positive for MLL-AF6 fusion gene, 76% quantification of fusion gene, NR after 2 cycles of VEN-AZA treatment, NR after the 3rd course of VEN-DAC-HHT (homoharringtonine), and still NR after the 4th course adjusted to VEN-DCAG regimen, who finally died of disease progression. Another NR patient, male, 37 years old, M4, with TET2, ASXL1 and U2AF1 mutations, VAF values of 50.95%, 35.78% and 42.47%, respectively, and positive MLL/MLL fusion gene, PR after the 1st course of VEN-DHAG, NR after the 2nd course of VEN-AZA-CAG, and still NR after the 3rd course of adjustment to VEN-DCAG, finally exhibited disease progression, multiple organ failure and death. A PR patient, male, 20 years old, with an anterior mediastinal germ cell tumor with multiple metastases in the lung, was diagnosed with AML in the 2nd year of treatment by bone marrow (BM) examination due to thrombocytopenia. The chromosome examination revealed a complex karyotype (46-50, xx, +x[28], -4[28], del(5)(q31)[27], del(6)(q?23)[28], +9[27],?del(10)(p13)[5], +11[27], add(12)(q?24)[27],?add(15)(q22)[27], +21[20],+22[27][cp30]) and del(5q) positivity by FISH. The mutation sites detected by NGS were TP53 Exon8 c.817C>T p. R273C, TP53 Exon5 c.396G>T p. K132N, EP300 Exon6 c.1519A>G p. S507G, VAF values were 40.2%, 37.8%, 64.3%, respectively. There was NR after the 1st course of AZA-CAG and PR after the 2nd course of VEN-DCAG, but the anterior mediastinal tumor enlarged rapidly during treatment; both malignant tumors progressed, and the patient died during subsequent treatment with PD-1 inhibitor plus DLI.

Safety

Adverse events (AEs) were observed in all patients (Table 3). Grade ≥3 AEs were predominantly hematologic AEs, including leukopenia in 20 cases (100%), neutropenia in 20 cases (100%), thrombocytopenia in 19 cases (95%), and hemoglobin reduction in 19 cases (95%). The main nonhematological AEs were 17 (85%) fevers in the granulocyte deficiency phase, 7 (35%) infections, including 4 cases of pneumonia, 2 skin and soft tissue infections, and 1 positive blood culture; 12 (60%) gastrointestinal discomfort reactions, including nausea, vomiting, diarrhea, abdominal pain, and constipation; 7 (35%) electrolyte disturbances, 4 (20%) skin rashes, 3 (15%) cases of skin/mucosal or nasal bleeding, and 2 (10%) cases each of abnormal liver function and weakness. The lowest median HGB value after treatment was 59.5 (45.0-84.0) g/L, the lowest median WBC value was 0.22 (0.02-1.00) × 10⁹/L, and the lowest median PLT value was 5 (1-97) × 10⁹/L. Two NR patients did not improve after being given blood products and anti-infective treatment and died within 1 month after VEN-DCAG treatment; the remaining patients showed improvement after aggressive symptomatic treatment.

Follow-up and prognosis

The median cycle of VEN-DCAG treatment for all patients was 2 (1-5) cycles, with a median follow-up time of 10.4 (0.7-21.8) months and a median EFS of 9.2 (0.7-21.8) months. Eleven patients (7 MRD-CR, 4 MRD+CR) were subsequently bridged to allo-HSCT.

By the end of follow-up, 14 of 20 patients survived (12 disease-free and 2 relapsed), with a median follow-up of 12.7 (2.6-21.8) months in 14 surviving patients; 6 died (1 after transplantation and 5 without transplantation), with a median OS of 4.35 (0.7-18.1) months in 6 deceased patients. Seven patients in the relapse group had no death and 6 of 13 patients in the refractory group died, P=0.051; 10 of 11 patients who received allo-HSCT survived, and 4 of 9 patients who did not receive allo-HSCT survived[Editor1] (90.9% vs. 44.4%, P=0.05) (details in Table 4). Survival analysis showed no statistically significant difference (P > 0.05) in the comparison of OS and EFS between patients in the relapse and refractory groups (Figure 2) but a statistically significant difference (P = 0.048) in the comparison of OS between those who received allo-HSCT and those who did not receive allo-HSCT (Figure 3).

Although multiple combination regimens have been effective in improving the remission rate of AML patients, nearly 50% of patients still fail to respond to treatment or relapse. R/R AML has a low remission rate and poor prognosis, with CR/CRi rates under conventional combination chemotherapy regimens of less than 40%, a 3-year overall survival of less than 10%, and a median survival of only 6 months^[14–18]. At present, allo-HSCT is still the only treatment modality with curative potential; however, the majority of R/R AML patients have no chance of transplantation due to the inability to obtain a CR, and forcing transplantation with no CR severely weakens the transplantation outcome. ELN2022 AML guidelines clearly state that preallo-HSCT MRD + is an independent poor outcome factor after allo-HSCT; thus, it is important to improve the CR rate and depth of remission in R/R AML patients and successfully bridge to allogeneic allo-HSCT^[19].

Currently, there is no uniform protocol available for the treatment of R/R AML, and there is an urgent need for effective treatment options to increase remission rates and improve prognosis^[20–22]. Venetoclax is rapidly occupying an important position in the treatment of hematologic malignancies due to its unique antitumor mechanism and excellent antitumor effect^{[23, 24]}, of which the VEN-HMA regimen has been recommended as the first-line treatment option for elderly/unfit patients with newly diagnosed AML patients, but its efficacy remains limited in the R/R AML patient population^{[6, 8, 25, 26]}. Studies have shown that the CR/CRi rate of venetoclax monotherapy in R/R AML is approximately 20%, while in combination with HMAs, the CR/CRi rate is 11.6–46%, and the ORR is 40–70%^{[3, 6, 26–29]}. To further improve remission and long-term survival in this challenging patient population, several domestic and international teams have explored the venetoclax combination regimen. The DiNardo team published a study of VEN + FLAG-IDA in R/R AML and showed that this regimen resulted in an ORR of 72% and an MRD-negative rate of 69% in R/R AML, with a significant survival benefit and an incidence of grade ≥ 3 AEs of approximately 10%^[1]. The Daver team reported in "BLOOD" a clinical study of venetoclax-idasanutlin in R/R AML patients, showing that 55 R/R AML patients treated with the regimen had a CRc rate of 26.0%, a morphologic leukemia-free status (MLFS) rate of 12%, an MRD-negative rate (< 0.1%) of 42.9%, and a median OS of 5.1 months, and AEs were dominated by controlled myelosuppression and gastrointestinal reactions^[30]. Another study of VEN-HMAs-HHT in R/R AML published by the Liu team showed that the combination regimen had ORR rates of 78.1% in 96 patients, median OS of 22.1 months, and 1-year OS of 61.5%, with the highest incidence of grade ≥ 3 AEs being febrile granulocyte deficiency (37.4%)^[31].

Previous studies at our center have shown that the DCAG regimen consisting of HMAs combined with a modified CAG regimen is effective in treating AML patients^[32–34]. A further multicenter clinical trial (NCT 02886559) of the chidamide-DCAG regimen in R/R AML showed that the regimen achieved a CR/CRi rate of 43.1% and ORR of 55.2% in R/R AML, with AEs mainly manifesting as myelosuppression. Both the DCAG regimen and venetoclax have been confirmed to be effective against tumor cells, and preclinical studies have demonstrated synergistic antitumor cell effects of venetoclax with decitabine and aclarubicin, providing a basis for further clinical trials. There is a paucity of relevant studies on VEN-DCAG in R/R AML^[11]. Therefore, our center will conduct further clinical trials of VEN-DCAG in R/R AML based on previous research.

In our study, 17 of 20 (85%) R/R AML patients treated with VEN-DCAG achieved CR/CRi, with an ORR of 90% and an MRD-negative CR rate of 76.5%. In the investigation with a median follow-up of 10.4 months, 14 patients have survived to date, and 12 of them are in disease-free survival status. It should be noted that 5 of the 6 patients who died did not receive allo-HSCT, 1 patient who died after transplantation was MRD-positive before transplantation, and 1 of the 2 patients who survived relapse was MRD-positive before transplantation. In addition, all 6 patients who died were from the refractory group, 3 of whom achieved CR after receiving VEN-DCAG and later died of disease relapse, and 3 of whom did not achieve CR after receiving VEN-DCAG and died of disease progression. It should be mentioned that 2 of the 3 patients who did not achieve CR had previously received VEN-AZA and did not achieve CR, which may indicate that patients who did not achieve CR with the VEN-AZA regimen had limited benefit from the VEN-DCAG regimen. Our study also showed that patients with relapsed AML may benefit more from the VEN-DCAG regimen; that the MRD-negative remission rate may be improved by increasing the number of regimen cycles; and that bridging allo-HSCT after achieving CR is a favorable factor for the long-term survival of patients.

According to our study, the incidence of AEs was generally consistent with previous reports, but there was a significant improvement in the rate of complete disease remission, MRD-negative rate and ORR^{[30, 35–40]}. This indicates that the VEN-DCAG regimen may be an effective treatment option in R/R AML patients and recommends the use of bridging allo-HSCT as soon as possible after patients receive the VEN-DCAG regimen reach CR, which may significantly improve patient survival. The limitations of our study are the limited number of cases included and the relatively insufficient follow-up time. We will continue to follow up with patients for a long period and conduct further prospective, multicenter clinical trials to further evaluate the efficacy and safety of the VEN-DCAG regimen.

AML acute myeloid leukemia

R/R refractory/relapsed

VEN-DCAG venetoclax combined with decitabine/azacytidine plus cytarabine, aclarubicin and granulocyte colony-stimulating factor

CR complete remission

CRi CR with incomplete hematological recovery

PR partial remission

NR non-remission

ORR overall response rate

OS overall survival

EFS event-free survival

Allo-HSCT allogeneic hematopoietic stem cell transplant

AEs adverse events

MRD measurable residual disease

HMAs hypomethylating agents

BCL-2 B-cell lymphoma 2

HHT homoharringtonine

BM bone marrow

DAC decitabine

AZA azacitidine

FCM flow cytometry

MDS myelodysplastic syndrome

WBC white blood cell

PLT platelets

HGB hemoglobin

FLAG-IDA fludarabine combined with cytarabine, idarubicin and granulocyte colony-stimulating factor

Acknowledgements

We thank the patients, and their caregivers; co-investigators, collaborators, and members of the study team involved in the trial.

Author contributions

JY designed the clinical trial. LYF (LIU) and LYF (LI) recruited patients, analyzed data, and wrote the manuscript. LYF(LI), ZR, YZR and JY treated and took care of patients on the trial. All authors interpreted the data, drafted and reviewed the manuscript, and approved the final version of the manuscript.

Funding

All funds for this study are self-financing.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

Ethics approval and consent to participate

This study was conducted in compliance with Declaration of Helsinki principles. All procedures were approved by the Ethics Committee of the First Medical Center of the PLA General Hospital (S2022-740-01).

Competing interests

The authors declare that they have no competing interests.

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Table 1 Baseline characteristics of R/R AML patients treated with VEN-DCAG
	VEN-DCAG (n=20)
	Refractory group (n=13)	Relapse group (n=7)	All patients (n=20)
Median age, y (range)	41.0（10-70）	39.0(25-50)	40.0(10-70)
Male sex, n (%)	8(62)	3(43)	11(55)
Status before VEN-DCAG
BM blast%, median (range)	28.5（14.8-76.8）	26.8(4-50.4)	27.7（4-76.8）
WBC, 10⁹/L, median (range)	2.1(0.6-64.5)	3.2(1.4-3.5)	2.5(0.6-64.5)
PLT, 10⁹/L, median (range)	28(6-873)	113(36-130)	48(6-873)
AML type, n (%)
M2	2(15)	3(43)	5(25)
M4	3(23)	1(14)	4(20)
M5 Other AML	3(23) 5(38)	2(29) 1(14)	5(25) 6(30)
Median prior therapies, n (range)	1(1-3)	8(1-9)	1(1-9)
ELN 2022 risk group, n (%)
Favorable	2(15.4)	2(28.6)	4(20)
Intermediate	5(38.5)	3(42.9)	8(40)
Adverse	6(46.2)	2(28.6)	8(40)
Cytogenetic group, n (%)
Normal karyotype	5(38)	3(43)	8(40)
t (8;21）	2(15)	1(14)	3(15)
Adverse-risk or complex	3(23)	1(14)	4(20)
Other intermediate-risk	3(23)	2(29)	5(25)

Table 2 Final response outcomes for VEN-DCAG
	Refractory group (n=13)	Relapse group (n=7)	All patients (n=20)
ORR, n (%)	11(84.6)	7(100.0)	18(90.0)
CR/CRi	10(76.9)	7(100.0)	17(85.0)
CR	7(53.8)	5(71.4)	12(60.0)
CRi	3(23.1)	2(28.6)	5(25.0)
MRD-CR	7(70.0)	6(85.7)	13(76.5)
PR	1(7.7)	0(0.0)	1(5.0)
NR	2(15.4)	0(0.0)	2(10.0)
Risk group, CR rate, n (%)
Favorable	2(100.0)	2(100.0)	4(100.0)
Intermediate	4(80.0)	3(100.0)	7(87.5)
Adverse	4(66.7)	2(100.0)	6(75.0)
Bridging Allo-HSCT, n (%)	6(46.2)	5(71.4)	11(55.0)
Median follow-up, median (range)	9.7(0.7-21.8)	11.0(2.6-20.9)	10.4(0.7-21.8)

Table 3 Adverse events after treatment with VEN-DCAG
All AEs, n (%)	All-grade (n=20)	≥3 Grade
Anemia	20 (100.0)	19 (100.0)
Thrombocytopenia	20 (100.0)	19 (95.0)
Neutropenia	20 (100.0)	20 (100.0)
Fever	17 (85.0)	9 (45.0)
Pneumonia	4 (20.0)	2 (10.0)
Skin/soft tissue infections	2 (10.0)	0 (0.0)
Bloodstream infections	1 (5.0)	0 (0.0)
Gastrointestinal symptoms	12 (60.0)	2 (10.0)
Electrolyte disorders	7 (35.0)	1 (5.0)
Mucosal/nasal bleeding	3 (15.0)	0 (0.0)
Rash	4 (20.0)	0 (0.0)
Liver function abnormalities	2 (10.0)	0 (0.0)
Fatigue	2 (10.0)	0 (0.0)

Table 4 Clinical characteristics and efficacy of 20 R/R AML patients treated with VEN-DCAG
NO.	Sex	Age	Type	Genetic feature	Method and efficacy	VEN-DCAG cycle	Efficacy (1st)	Efficacy (total)	Follow-up time (months)	Whether or not bridged to HSCT	End of follow-up status
Refractory group
1	Male	10	M2	AML1-ETO	CDCG(PR)→DAE(NR)→VEN-DCAG(MRD+CR)	1	MRD+CR	-	21.8	Yes	Disease-free survival
2	Female	31	AML	MLL-AF6	IA(NR)→VEN-AZA-CAG(MRD+CR)→VEN-AZA-CAG(MRD-CR)→VEN-AZA-CAG(MRD-CR)→VEN-AZA-CAG(MRD-CR)→VEN-AZA-CAG(MRD-CR)	5	MRD+CR	MRD-CR	18.1	No	Death
3	Male	15	AML	AML1-ETO、RUNX1-RUNX1T1、IDH2	DAE(NR)→DCAG(PR)→VEN-DCAG(MRD+CR)	1	MRD+CR	-	14.5	Yes	Disease-free survival
4	Female	41	M2	KMT2A-SEPTIN9、NRAS	DIA(NR)→VEN-DCAG(MRD-CR)→VEN-DCAG(MRD-CR)	2	MRD-CR	MRD-CR	13.8	Yes	Relapse survival
5	Male	56	M5	IDH2、DNMT3A、WT1	DCAG(NR)→VEN-DCAG(MRD-CR)→VEN-DCAG(MRD-CR)	2	MRD-CR	MRD-CR	9.7	Yes	Disease-free survival
6	Male	28	AML	IDH2、ASXL1、U2AF1	A-AZA(NR)→VEN-DCAG(MRD-CR)	1	MRD-CR	-	8.8	Yes	Disease-free survival
7	Female	51	M5	WT1、TP53	IA(PR)→VEN-DCAG(MRD-CR)→VEN-DCAG(MRD-CR)	2	MRD-CR	MRD-CR	11.2	No	Death
8	Female	58	M4	MLL-MLL	IA(NR)→VEN-DCAG(MRD-CR)→VEN-DCAG(MRD-CR)	2	MRD-CR	MRD-CR	6.8	No	Disease-free survival
9	Male	59	M4	WT1、U2AF1	DIA(NR)→VEN-DCAG(MRD+CR)→VEN-DCAG(MRD+CR)	2	MRD+CR	MRD+CR	5.0	Yes	Death
10	Female	56	M5	IDH2、DNMT3A	DCAG(NR)→VEN-AZA-CAG(MRD+CR)→VEN-DCAG(MRD-CR)	2	MRD+CR	MRD-CR	21.0	No	Disease-free survival
11	Male	37	M4	MLL-MLL、WT1、ASXL1、U2AF1、TET2、RUNX1	VEN-DHAG(PR)→VEN-AZA-CAG(NR)→VEN-DCAG(NR)	2	NR	NR	3.7	No	Death
12	Male	20	AML	TP53、EP300	AZA-CAG(NR)→VEN-DCAG(PR)	1	PR	-	0.9	No	Death
13	Male	70	AML	MLL-AF6	VEN-AZA(NR)→VEN-AZA(NR)→VEN-DAC-HHT(NR)→VEN-DCAG(NR)	1	NR	-	0.7	No	Death
Relapse group
14	Female	50	M2	NMP1	DIA(MRD-CR)→DA(MRD-CR)→DA(MRD-CR)→A-AZA(MRD-CR)→VEN-AZA(MED-CR)→A-DAC(MRD-CR)→VEN-DCAG(MRD-CR)	1	MRD-CR	-	2.6	Yes	Disease-free survival
15	Female	39	M4	FUS-ERG、DNMT3A	IAG(PR)→IA(CR)→MAE(MRD+CR)→allo-HSCT(MRD-CR)→VEN-DCAG(MRD-CR)→VEN-DCAG(MRD-CR)	2	MRD-CR	MRD-CR	7.1	Yes	Disease-free survival
16	Female	64	M5	IDH2、NRAS、DNMT3A、BCORL1、BCOR	IA(NR)→DIAG(MRD+CR)→DIAG(MRD-CR)→DA(CR)→DCAG(MRD+CR)→VEN-DCAG(MRD-CR)	1	MRD-CR	-	8.7	No	Disease-free survival
17	Male	29	M2	AML1-ETO、C-KIT	DA(MRD+CR)→IA(MRD+CR)→Ara-C(MRD+CR)→Ara-C(MRD+CR)→HEA(MRD+CR)→Ara-C(MRD+CR)→IA(MRD+CR)→Ara-C(MRD+CR)→HAA(MRD+CR)→VEN-DCAG(MRD+CR)	1	MRD+CR	-	11.0	Yes	Relapse survival
18	Male	25	AA^a→AML	IDH1、WT1、RUNX1	allo-HSCT(CR)→VEN-DCAG(MRD-CR)→VEN-DCAG(MRD-CR)	2	MRD-CR	MRD-CR	12.7	Yes	Disease-free survival
19	Female	65	M5	IDH2、DNMT3A、BCOR、TET2	DCAG(MRD+CR)→DCAG(MRD+CR)→DCAG(MRD-CR)→DCAG(MRD-CR)→DCAG(MRD-CR)→DCAG(MRD-CR)→DHAG(MRD-CR)→DHAG(MRD-CR)→VEN-DCAG(MRD-CR)→VEN-DCAG(MRD-CR)→VEN-DCAG(MRD-CR)→VEN-DCAG(MRD-CR)	4	MRD-CR	MRD-CR	13.8	No	Disease-free survival
20	Male	25	M2	WT1、CEBPA、DNMT3A	IA(MRD+CR)→IA(MRD-CR)→HAA(MRD-CR)→HAA(MRD-CR)→IA(MRD-CR)→HAA(MRD-CR)→IA(MRD-CR)→IA(MRD-CR)→VEN-DCAG(MRD+CR)→VEN-DCAG(MRD-CR)	2	MRD+CR	MRD-CR	20.9	Yes	Disease-free survival
CDCG: chidamide+decitabine+cytarabine+G-CSF; DAE: daunorubicin+cytarabine+etoposide; IA: idarubicin+cytarabine; DIA: decitabine+idarubicin+cytarabine; A-AZA: cytarabine+azacytidine; VEN-AZA: venetoclax+azacytidine; A-DAC: cytarabine+decitabine; IAG: idarubicin+cytarabine+G-CSF; MAE: mitoxantrone+cytarabine +etoposide; DIAG: decitabine+idarubicin+cytarabine+G-CSF; DCAG: decitabine+aclacinomycin+cytarabine+G-CSF; HEA: homoharringtonine+etoposide+cytarabine; HAA: homoharringtonine+cytarabine+aclarubicin; DHAG: decitabine+homoharringtonine+cytarabine+G-CSF; AA^a: Aplastic anemia

No competing interests reported.

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Venetoclax combined with hypomethylating agents and the CAG regimen (DCAG) in relapsed/refractory AML: A single- center clinical trial

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