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Haematologica Feb 2023A major obstacle in the treatment of acute myeloid leukemia (AML) is refractory disease or relapse after achieving remission. The latter arises from a few... (Review)
Review
A major obstacle in the treatment of acute myeloid leukemia (AML) is refractory disease or relapse after achieving remission. The latter arises from a few therapy-resistant cells within minimal residual disease (MRD). Resistant cells with long-term self-renewal capacity that drive clonal outgrowth are referred to as leukemic stem cells (LSC). The cancer stem cell concept considers LSC as relapse-initiating cells residing at the top of each genetically defined AML subclone forming epigenetically controlled downstream hierarchies. LSC display significant phenotypic and epigenetic plasticity, particularly in response to therapy stress, which results in various mechanisms mediating treatment resistance. Given the inherent chemotherapy resistance of LSC, targeted strategies must be incorporated into first-line regimens to prevent LSC-mediated AML relapse. The combination of venetoclax and azacitidine is a promising current strategy for the treatment of AML LSC. Nevertheless, the selection of patients who would benefit either from standard chemotherapy or venetoclax + azacitidine treatment in first-line therapy has yet to be established and the mechanisms of resistance still need to be discovered and overcome. Clinical trials are currently underway that investigate LSC susceptibility to first-line therapies. The era of single-cell multi-omics has begun to uncover the complex clonal and cellular architectures and associated biological networks. This should lead to a better understanding of the highly heterogeneous AML at the inter- and intra-patient level and identify resistance mechanisms by longitudinal analysis of patients' samples. This review discusses LSC biology and associated resistance mechanisms, potential therapeutic LSC vulnerabilities and current clinical trial activities.
Topics: Humans; Sulfonamides; Azacitidine; Leukemia, Myeloid, Acute; Neoplastic Stem Cells
PubMed: 36722405
DOI: 10.3324/haematol.2022.280800 -
Journal of Clinical Oncology : Official... May 2021Approximately 20% of patients with -mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a...
PURPOSE
Approximately 20% of patients with -mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 functions in -mutant cells.
METHODS
This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with -mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043).
RESULTS
Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only mutations by next-generation sequencing had higher rates of CR (69% 25%; = .006). Responding patients had significant reductions in variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6 7.5 months; = .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).
CONCLUSION
Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with -mutant MDS and oligoblastic AML.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Biomarkers, Tumor; Female; Humans; Male; Middle Aged; Mutation; Myelodysplastic Syndromes; Quinuclidines; Tumor Suppressor Protein p53
PubMed: 33449813
DOI: 10.1200/JCO.20.02341 -
Future Oncology (London, England) Aug 2022Prevention of relapse is a major therapeutic challenge and an unmet need for patients with acute myeloid leukemia (AML). Venetoclax is a highly selective, potent, oral... (Review)
Review
Prevention of relapse is a major therapeutic challenge and an unmet need for patients with acute myeloid leukemia (AML). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in AML cells. When combined with azacitidine, it leads to prolonged overall survival and rapid, durable remissions in treatment-naive AML patients ineligible for intensive chemotherapy. VIALE-M is a randomized, double-blind, two-arm study to evaluate the safety and efficacy of venetoclax in combination with oral azacitidine (CC-486) as maintenance therapy in patients in complete remission with incomplete blood count recovery after intensive induction and consolidation therapies. The primary end point is relapse-free survival. Secondary outcomes include overall survival, minimal residual disease conversion and improvement in quality-of-life. : NCT04102020 (ClinicalTrials.gov).
Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Cell Division; Clinical Trials, Phase III as Topic; Humans; Leukemia, Myeloid, Acute; Randomized Controlled Trials as Topic; Sulfonamides
PubMed: 35852098
DOI: 10.2217/fon-2022-0450 -
Journal of Hematology & Oncology Apr 2023Relapsed or refractory acute myeloid leukemia (R/R AML) has a dismal prognosis. The aim of this study was to investigate the activity and tolerability of venetoclax...
BACKGROUND
Relapsed or refractory acute myeloid leukemia (R/R AML) has a dismal prognosis. The aim of this study was to investigate the activity and tolerability of venetoclax combined with azacitidine plus homoharringtonine (VAH) regimen for R/R AML.
METHODS
This phase 2 trial was done at ten hospitals in China. Eligible patients were R/R AML (aged 18-65 years) with an Eastern Cooperative Oncology Group performance status of 0-2. Patients received venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-14) and azacitidine (75 mg/m on days 1-7) and homoharringtonine (1 mg/m on days 1-7). The primary endpoint was composite complete remission rate [CRc, complete response (CR) plus complete response with incomplete blood count recovery (CRi)] after 2 cycles of treatment. The secondary endpoints include safety and survival.
RESULTS
Between May 27, 2020, and June 16, 2021, we enrolled 96 patients with R/R AML, including 37 primary refractory AML and 59 relapsed AML (16 relapsed after chemotherapy and 43 after allo-HSCT). The CRc rate was 70.8% (95% CI 60.8-79.2). In the patients with CRc, measurable residual disease (MRD)-negative was attained in 58.8% of CRc patients. Accordingly, overall response rate (ORR, CRc plus partial remission (PR)) was 78.1% (95% CI 68.6-85.4). At a median follow-up of 14.7 months (95% CI 6.6-22.8) for all patients, median overall survival (OS) was 22.1 months (95% CI 12.7-Not estimated), and event-free survival (EFS) was 14.3 months (95% CI 7.0-Not estimated). The 1-year OS was 61.5% (95% CI 51.0-70.4), and EFS was 51.0% (95% CI 40.7-60.5). The most common grade 3-4 adverse events were febrile neutropenia (37.4%), sepsis (11.4%), and pneumonia (21.9%).
CONCLUSIONS
VAH is a promising and well-tolerated regimen in R/R AML, with high CRc and encouraging survival. Further randomized studies are needed to be explored. Trial registration clinicaltrials.gov identifier: NCT04424147.
Topics: Humans; Azacitidine; Homoharringtonine; Leukemia, Myeloid, Acute; Bridged Bicyclo Compounds, Heterocyclic; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37120593
DOI: 10.1186/s13045-023-01437-1 -
Blood Apr 2022Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor...
Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor survival. Postremission maintenance therapy that prolongs MRD negativity or converts MRD+ patients to MRD- status may delay or prevent relapse and improve overall survival (OS). In the phase 3 QUAZAR AML-001 trial, oral azacitidine (oral-AZA; formerly CC-486), a hypomethylating agent, significantly prolonged OS and relapse-free survival (RFS) compared with placebo in patients aged ≥55 years with AML in first remission after intensive chemotherapy who were not candidates for hematopoietic stem cell transplantation. In this trial, MRD (≥0.1% leukemic cells in bone marrow) was assessed by multiparameter flow cytometry in serial samples collected at baseline and on day 1 of every 3 cycles. As expected, baseline MRD status was significantly associated with both OS and RFS. Multivariate analyses showed oral-AZA significantly improved OS and RFS vs placebo independent of baseline MRD status. Oral-AZA treatment also extended the duration of MRD negativity by 6 months vs placebo and resulted in a higher rate of conversion from MRD+ at baseline to MRD- during treatment: 37% vs 19%, respectively. In the oral-AZA arm, 24% of MRD responders achieved MRD negativity >6 months after treatment initiation. Although presence or absence of MRD was a strong prognostic indicator of OS and RFS, there were added survival benefits with oral-AZA maintenance therapy compared with placebo, independent of patients' MRD status at baseline. Registered at clinicaltrials.gov as #NCT01757535.
Topics: Antimetabolites; Azacitidine; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Neoplasm, Residual; Prognosis; Recurrence; Remission Induction
PubMed: 34995344
DOI: 10.1182/blood.2021013404 -
Blood Advances Nov 2020This study investigated the efficacy and safety of azacitidine maintenance in the posttransplant setting based on the encouraging phase 1/2 reports for azacitidine... (Randomized Controlled Trial)
Randomized Controlled Trial
This study investigated the efficacy and safety of azacitidine maintenance in the posttransplant setting based on the encouraging phase 1/2 reports for azacitidine maintenance in patients with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). Between 2009 and 2017, a total of 187 patients aged 18 to 75 years were entered into a randomized controlled study of posttransplant azacitidine if they were in complete remission. Patients randomized to the treatment arm (n = 93) were scheduled to receive azacitidine, given as 32 mg/m2 per day subcutaneously for 5 days every 28 days for 12 cycles. The control arm (n = 94) had no intervention. Eighty-seven of the 93 patients started azacitidine maintenance. The median number of cycles received was 4; a total of 29 patients relapsed on study, and 23 patients withdrew from the study due to toxicity, patient's preference, or logistical reasons. Median relapse-free survival (RFS) was 2.07 years in the azacitidine group vs 1.28 years in the control group (P = .43). There was also no significant difference for overall survival, with a median of 2.52 years vs 2.56 years in the azacitidine and control groups (P = .85), respectively. Multivariate Cox regression analysis revealed no improvement in RFS or overall survival with the use of azacitidine as maintenance compared with the control group (hazard ratios of 0.73 [95% confidence interval, 0.49-1.1; P = .14] and 0.84 [95% confidence interval, 0.55-1.29; P = .43]) [corrected]. This randomized trial with azacitidine maintenance showed that a prospective trial in the posttransplant setting was feasible and safe but challenging. Although RFS was comparable between the 2 arms, we believe the strategy of maintenance therapy merits further study with a goal to reduce the risk of relapse in patients with AML/MDS. This trial was registered at www.clinicaltrials.gov as #NCT00887068.
Topics: Adolescent; Adult; Aged; Azacitidine; Humans; Leukemia, Myeloid, Acute; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Remission Induction; Young Adult
PubMed: 33170934
DOI: 10.1182/bloodadvances.2020002544 -
American Journal of Hematology Nov 2022
Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Sulfonamides
PubMed: 36054316
DOI: 10.1002/ajh.26692 -
Nature Cancer Oct 2021DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such...
DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions. These agents induce notable toxicity to normal blood cells thus limiting their clinical doses. Herein we report the discovery of GSK3685032, a potent first-in-class DNMT1-selective inhibitor that was shown via crystallographic studies to compete with the active-site loop of DNMT1 for penetration into hemi-methylated DNA between two CpG base pairs. GSK3685032 induces robust loss of DNA methylation, transcriptional activation and cancer cell growth inhibition in vitro. Due to improved in vivo tolerability compared with decitabine, GSK3685032 yields superior tumor regression and survival mouse models of acute myeloid leukemia.
Topics: Animals; Azacitidine; DNA; DNA Methylation; DNA Modification Methylases; Decitabine; Leukemia, Myeloid, Acute; Mice
PubMed: 34790902
DOI: No ID Found -
The New England Journal of Medicine Nov 2016The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. (Clinical Trial)
Clinical Trial
BACKGROUND
The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.
METHODS
We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols.
RESULTS
Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles.
CONCLUSIONS
Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).
Topics: 5-Methylcytosine; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Azacitidine; Biomarkers, Tumor; Bone Marrow; Decitabine; Exome; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Myelodysplastic Syndromes; Prospective Studies; Risk Factors; Survival Rate; Tumor Suppressor Protein p53
PubMed: 27959731
DOI: 10.1056/NEJMoa1605949 -
Cancer Discovery Jun 2023The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of...
UNLABELLED
The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based "Mediators of apoptosis combinatorial score" (MAC-Score) linking the ratio of protein expression of BCL2, BCL-xL, and MCL1 in LSCs. MAC scoring predicts initial response with a positive predictive value of more than 97% associated with increased event-free survival. In summary, combinatorial levels of BCL2 family members in AML-LSCs are a key denominator of response, and MAC scoring reliably predicts patient response to 5-AZA/VEN.
SIGNIFICANCE
Venetoclax/azacitidine treatment has become an alternative to standard chemotherapy for patients with AML. However, prediction of response to treatment is hampered by the lack of clinically useful biomarkers. Here, we present easy-to-implement MAC scoring in LSCs as a novel strategy to predict treatment response and facilitate clinical decision-making. This article is highlighted in the In This Issue feature, p. 1275.
Topics: Humans; Proteomics; Proto-Oncogene Proteins c-bcl-2; Leukemia, Myeloid, Acute; Bridged Bicyclo Compounds, Heterocyclic; Azacitidine; Stem Cells; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36892565
DOI: 10.1158/2159-8290.CD-22-0939