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The Lancet. Haematology Jun 2022Adults with acute myeloid leukaemia have unsatisfactory clinical outcomes and rates of complete remission. Venetoclax combined with azacytidine or low-dose cytarabine...
Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial.
BACKGROUND
Adults with acute myeloid leukaemia have unsatisfactory clinical outcomes and rates of complete remission. Venetoclax combined with azacytidine or low-dose cytarabine has shown efficacy in adults aged 75 years or older (or 18-74 years with comorbidities precluding intensive chemotherapy) with acute myeloid leukaemia. We aimed to investigate the activity and safety of venetoclax plus 3+7 daunorubicin and cytarabine chemotherapy in adults with acute myeloid leukaemia.
METHODS
We conducted a two-stage, single-arm, phase 2 trial at three public hospitals in China. We enrolled patients aged 18-60 years with previously untreated de novo acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Patients received induction treatment with intravenous daunorubicin (60 mg/m on days 1-3), intravenous cytarabine (100 mg/m on days 1-7), and oral venetoclax (100 mg on day 4, 200 mg on day 5, and 400 mg on days 6-11; DAV regimen). For induction therapy, the length of the treatment was 28-35 days per cycle and the number of treatment cycles was one or two. The primary endpoint was the composite complete remission rate (complete remission plus complete remission with incomplete blood cell count recovery) after one cycle of induction treatment, assessed in the as-treated population. Secondary endpoints were bone marrow measurable residual disease by flow cytometry, event-free survival, overall survival, and adverse events. This trial is ongoing and is registered with Chinese Clinical Trial Registry, ChiCTR2000041509.
FINDINGS
Between Dec 25, 2020, and July 7, 2021, 36 patients were assessed for eligibility and 33 were enrolled. 15 (45%) patients were men and 18 (55%) were women, and all were Asian. The composite complete remission rate after one cycle of DAV regimen was 91% (95% CI 76-98; 30 of 33 patients) in the entire cohort. 29 (97%) of 30 patients who reached complete remission had undetectable measurable residual disease (ie, <0·1%). Grade 3 or worse adverse events included neutropenia in 33 (100%) of 33 patients, thrombocytopenia in 33 (100%), anaemia in 33 (100%), febrile neutropenia in 18 (55%), pneumonia in seven (21%), and sepsis in four (12%). No treatment-related deaths occurred. With a median follow-up of 11 months (IQR 9-12), estimated 1-year overall survival was 97% (95% CI 91-100) and 1-year event-free survival was 72% (56-94).
INTERPRETATION
The DAV regimen represents an effective induction therapy for newly diagnosed adults with acute myeloid leukaemia, which resulted in a high rate of complete remission. These findings are an important contribution to the field, showing a safe strategy to incorporate venetoclax into the most common induction regimen used to treat newly diagnosed acute myeloid leukaemia internationally.
FUNDING
Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang, National Natural Science Foundation of China, Key Research and Development Program of Zhejiang.
TRANSLATION
For the Chinese translation of the abstract see Supplementary Materials section.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Neoplasm, Residual; Sulfonamides
PubMed: 35512726
DOI: 10.1016/S2352-3026(22)00106-5 -
Advanced Science (Weinheim,... Mar 2024Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to...
Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML patients is evaluated. 90% of treated patients achieved complete remission, underscoring the potential of this regimen as a compelling therapeutic intervention. To elucidate underlying mechanisms governing response to DAV in AML, quantitative phosphoproteomics to discern distinct molecular signatures characterizing a subset of DAV-sensitive patients is used. Cluster analysis reveals an enrichment of phosphoproteins implicated in chromatin organization and RNA processing within DAV-susceptible and DA-resistant AML patients. Furthermore, kinase activity profiling identifies AURKB as a candidate indicator of DAV regimen efficacy in DA-resistant AML due to AURKB activation. Intriguingly, AML cells overexpressing AURKB exhibit attenuated MCL-1 expression, rendering them receptive to DAV treatment and maintaining them resistant to DA treatment. Moreover, the dataset delineates a shared kinase, AKT1, associated with DAV response. Notably, AKT1 inhibition augments the antileukemic efficacy of DAV treatment in AML. Overall, this phosphoproteomic study identifies the role of AURKB as a predictive biomarker for DA, but not DAV, resistance and proposes a promising strategy to counteract therapy resistance in AML.
Topics: Young Adult; Humans; Leukemia, Myeloid, Acute; Bridged Bicyclo Compounds, Heterocyclic; Sulfonamides
PubMed: 38161214
DOI: 10.1002/advs.202305885 -
Hematological Oncology Mar 2024Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy (DAV) has shown safety and efficacy in eligible patients with newly diagnosed acute myeloid leukemia...
Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy (DAV) has shown safety and efficacy in eligible patients with newly diagnosed acute myeloid leukemia (AML). However, there are no direct comparisons between DAV and 3 + 7 daunorubicin and cytarabine chemotherapy (DA) alone. We performed a propensity score-matched analysis to compare the outcomes of DAV group with historical DA group and identify the clinical and molecular characteristics of patients who might benefit from the DAV regimen. The DAV group had a higher Complete remission (CR) rate than the DA group (90% vs. 55%, p = 0.008). 25 (96%) patients in the DAV group had a higher MRD-negative CRc rate compared with 13 (62%) patients in the DA group (p = 0.006). After a median follow-up duration of 19.15 (IQR 17.13-21.67) months, the DAV group had an improved overall survival (p = 0.001) and event-free survival (p = 0.069), but not disease-free survival (p = 0.136). Collectively, DAV regimen induced high CR rates and deep MRD-negative CRc rates after one cycle of induction therapy, as well as prolonged the overall survival, in young adult patients with AML who were eligible for intensive chemotherapy. The addition of venetoclax to intensive chemotherapy should be considered in the future to achieve better survival advantages in eligible AML patients.
Topics: Young Adult; Humans; Propensity Score; Leukemia, Myeloid, Acute; Daunorubicin; Cytarabine; Pathologic Complete Response; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 38415873
DOI: 10.1002/hon.3260 -
Pediatric Blood & Cancer Sep 2020Approximately 40% children with acute myeloid leukemia (AML) invariably relapse, after attaining the first complete remission (CR), with dismal long-term outcome. There...
Outpatient ADE (cytarabine, daunorubicin, and etoposide) is feasible and effective for the first relapse of pediatric acute myeloid leukemia: A prospective, phase II study.
BACKGROUND
Approximately 40% children with acute myeloid leukemia (AML) invariably relapse, after attaining the first complete remission (CR), with dismal long-term outcome. There is little consensus regarding choice of optimal induction chemotherapy regimen for relapsed pediatric AML.
PROCEDURE
A prospective single arm phase II study (CTRI/2017/02/007757) was carried out at our center to evaluate the safety and efficacy of outpatient cytarabine, daunorubicin, and etoposide (ADE) regimen in pediatric AML (≤18 years) at the first relapse. Response evaluation was done by bone marrow aspiration morphology along with minimal residual disease (MRD) assessment. All adverse events including need and duration of hospitalization, transfusion support, and antimicrobial use were recorded.
RESULTS
Total 45 patients were included with median age of 12 years. The CR rate of the cohort was 66% and 54% of patients were MRD negative. The estimated 2-year event-free survival (EFS) and overall survival (OS) were 29% (±7%) and 34% (±7%), respectively. The presence of fever at relapse was associated with inferior CR rate (P = .001), positive MRD (P = .01), and inferior EFS (P = .02), while not achieving nadir absolute neutrophil count of zero during induction was associated with inferior CR rate (P = .03) and inferior OS (P = .04). Approximately all patients developed ≥Grade 3 cytopenia and febrile neutropenia. Twenty-six (59%) patients required hospitalization for management of toxicity and there were four (9%) deaths attributed to infection.
CONCLUSION
ADE is an effective induction regimen for pediatric AML patients at the first relapse with reasonable toxicity profile. Outpatient administration of the regimen is feasible in the presence of proper support structure and rigorous follow up.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Prospective Studies; Recurrence; Survival Rate
PubMed: 32672904
DOI: 10.1002/pbc.28404 -
Annals of Hematology Mar 2021Mixed phenotype acute leukemia (MPAL) is a rare type of leukemia with a limited number of studies conducted to characterize its clinical spectrum and most importantly... (Comparative Study)
Comparative Study
Acute lymphoblastic leukemia-like treatment regimen provides better response in mixed phenotype acute leukemia: a comparative study between adults and pediatric MPAL patients.
Mixed phenotype acute leukemia (MPAL) is a rare type of leukemia with a limited number of studies conducted to characterize its clinical spectrum and most importantly the best treatment modality. MPAL blasts show more than one phenotype either myeloid/monocytic with T- or B-lymphoid or extremely rare triple lineage associated phenotypic markers. This study aimed to characterize MPAL cases with special emphasis on comparing adult and pediatric age groups, exploring treatment regimens, and clinical outcome. Among 2571 acute leukemia patients, 102 MPAL cases fulfilling the 2008/2016 WHO diagnostic criteria of MPAL were recruited in the study. The incidence of MPAL was 4% of acute leukemia patients. Pediatric cases were 54 (53%) while adults were 48/102 (47%). Myeloid/B-lymphoid phenotype was found in 86/102 (84%), with BCR-ABL fusion gene transcript detected in 14/102(13.7%) patients. ALL-like treatment showed better response rates as compared with the myeloid based regimen (p = 0.001). MPAL behaves in a manner that resembles in clinical features, their lymphoid progenitor counterpart leukemias both in adults and pediatric patients with superior treatment response to ALL-like regimen, especially in adults.
Topics: Adolescent; Adult; Age of Onset; Aged; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Protocols; Child; Child, Preschool; Cohort Studies; Cytarabine; Daunorubicin; Egypt; Etoposide; Female; Humans; Incidence; Induction Chemotherapy; Infant; Leukemia, Biphenotypic, Acute; Maintenance Chemotherapy; Male; Middle Aged; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Treatment Outcome; Young Adult
PubMed: 33230570
DOI: 10.1007/s00277-020-04354-2