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The Lancet. Haematology Nov 2023Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive... (Randomized Controlled Trial)
Randomized Controlled Trial
10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.
BACKGROUND
Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes.
METHODS
This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m) was administered over the first 3 days and cytarabine (200 mg/m) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants.
FINDINGS
Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group.
INTERPRETATION
10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics.
FUNDING
Janssen Pharmaceuticals.
Topics: Humans; Middle Aged; Aged; Decitabine; Leukemia, Myeloid, Acute; Cytarabine; Daunorubicin; Transplantation, Homologous; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37914482
DOI: 10.1016/S2352-3026(23)00273-9 -
Drugs Dec 2018VYXEOS is a liposomal-encapsulated formulation of daunorubicin and cytarabine delivering a fixed, synergistic 1:5 molar ratio (hereafter referred to as... (Review)
Review
VYXEOS is a liposomal-encapsulated formulation of daunorubicin and cytarabine delivering a fixed, synergistic 1:5 molar ratio (hereafter referred to as daunorubicin/cytarabine liposome). Daunorubicin/cytarabine liposome is approved in several countries worldwide for the treatment of adults with therapy-related acute myeloid leukaemia (tAML) and AML with myelodysplasia-related changes (MRC). Approval was based on its clinical benefit in older patients with newly diagnosed high-risk/secondary AML in a pivotal phase III trial. In this study, daunorubicin/cytarabine liposome significantly prolonged overall survival (OS) and event-free survival (EFS) relative to conventional chemotherapy with cytarabine plus daunorubicin (hereafter referred to as 7 + 3). Daunorubicin/cytarabine liposome was also associated with significantly higher rates of complete remission (CR) and CR with incomplete haematological recovery (CRi) compared with 7 + 3. Daunorubicin/cytarabine liposome had an acceptable tolerability profile in older patients with newly diagnosed high-risk/secondary AML. The safety profile of daunorubicin/cytarabine liposome, including types and severities of adverse events, was generally similar to that of 7 + 3. Therefore, daunorubicin/cytarabine liposome is an important treatment option for adults with newly diagnosed tAML or AML-MRC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Approval; Europe; Humans; Leukemia, Myeloid, Acute; Liposomes; Remission Induction; United States
PubMed: 30511323
DOI: 10.1007/s40265-018-1022-3 -
Leukemia Jun 2022By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a...
By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.
Topics: Cell Line, Tumor; Cysteine; Cystine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Nuclear Proteins; Sulfasalazine
PubMed: 35474100
DOI: 10.1038/s41375-022-01573-6 -
Hematology. American Society of... Dec 2022Acute myeloid leukemia (AML) secondary to antecedent hematologic disorder or prior therapeutics for cancer represent a diverse group of leukemias often associated with...
Acute myeloid leukemia (AML) secondary to antecedent hematologic disorder or prior therapeutics for cancer represent a diverse group of leukemias often associated with inferior outcomes. Conventional therapy with cytarabine-based chemotherapy has been the mainstay of care for the past 30 years with disappointing overall outcomes. Novel therapies, including liposomal cytarabine/daunorubicin, and venetoclax-based therapies have emerged as options in recent years based on studies showing improvement in outcomes over standard-of-care therapies. Despite these advances, mutations in TP53 are associated with inferior response to both therapies and represent an area of unmet clinical need. Novel strategies with immune-targeted therapies such as CD47 monoclonal antibodies appear active in early-phase studies, but randomized studies have yet to report outcomes leading to approval. Allogeneic transplant remains the only known curative therapy for many of these cases. Nonetheless, pretransplant high-risk molecular features of secondary AML are associated with inferior outcome despite transplantation. An optimal approach to secondary AML is yet to be determined.
Topics: Humans; Daunorubicin; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute; Cytarabine; Neoplasms, Second Primary
PubMed: 36485116
DOI: 10.1182/hematology.2022000324 -
Critical Reviews in Oncology/hematology May 2023CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine, was approved for newly diagnosed therapy-related acute myeloid leukemia (AML) and AML with... (Review)
Review
CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine, was approved for newly diagnosed therapy-related acute myeloid leukemia (AML) and AML with myelodysplasia-related changes in adults in 2017 (US; updated to patients aged ≥1 year in 2021) and 2018 (EU/UK) based on improved survival and remission and comparable safety versus 7 + 3 chemotherapy in a randomized trial in older adults. Real-world studies have since evaluated CPX-351 in routine practice across several countries and addressed important data gaps (e.g., use in younger adults, measurable residual disease negativity, outcomes by mutation). This review discusses real-world studies of CPX-351 as AML treatment, with the aim of helping prescribers make informed treatment decisions.
Topics: Humans; Aged; Daunorubicin; Leukemia, Myeloid, Acute; Cytarabine; Liposomes; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37028531
DOI: 10.1016/j.critrevonc.2023.103984 -
Best Practice & Research. Clinical... Dec 2017Induction therapy for acute myeloid leukemia has not changed much since 1973, when the 7 + 3 regimen of cytarabine and daunorubicin was born. Since then, various... (Review)
Review
Induction therapy for acute myeloid leukemia has not changed much since 1973, when the 7 + 3 regimen of cytarabine and daunorubicin was born. Since then, various strategies have been evaluated to improve patient response, including dose intensification, the incorporation of additional agents into the regimen, the development of novel agents, and modified approaches for older patients. Recently, two novel agents, CPX-351 and gemtuzumab ozogamicin, have been approved by the US Food and Drug Administration. This review discusses each of the induction strategies and their impact on patient outcomes.
Topics: Aminoglycosides; Antibodies, Monoclonal, Humanized; Cytarabine; Daunorubicin; Gemtuzumab; History, 20th Century; History, 21st Century; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute
PubMed: 29156199
DOI: 10.1016/j.beha.2017.10.001 -
The New England Journal of Medicine Aug 2021
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Hidradenitis; Humans; Leukemia, Monocytic, Acute; Staurosporine
PubMed: 34347955
DOI: 10.1056/NEJMicm2101571 -
Clinical Lymphoma, Myeloma & Leukemia Jun 2020Despite the approval of 8 new drugs for acute myeloid leukemia (AML) since 2017, the disease remains challenging, given the significant toxicity associated with... (Review)
Review
Despite the approval of 8 new drugs for acute myeloid leukemia (AML) since 2017, the disease remains challenging, given the significant toxicity associated with available treatments and relatively low cure rates, especially in older adults. Although advantageous for patients, self-congratulatory rejoicing about the new agents would be extremely premature. Questions abound about the need for a specific versus less specific FLT3 inhibitor (eg, midostautin) in the upfront setting and whether a single agent (gilteritnib), albeit better than chemotherapy, is sufficient for relapsed disease. Is the new liposomal formulation of daunorubicin/cytarabine better than '3 + 7' only in secondary AML? Should only those newly diagnosed patients with core binding factor AML routinely receive gemtuzumab ozogamicin? The isocitrate dehydrogenase inhibitors were approved based on non-randomized data; thus, one wonders whether single-agent isocitrate dehydrogenase inhibitor therapy is appropriate for relapsed patients. Glasdegib, an orally available hedgehog inhibitor, is approved in conjunction with low-dose cytarabine in unfit patients but is rarely used in favor of a combination of hypomethylating agents or low-dose cytarabine with venetoclax, which are hopeful newly approved combinations for the older and/or unfit previously untreated. Perhaps venetoclax-based combinations should be more widely used, but the data is currently lacking. Thus, a temperate approach, more clinical research, and a critical analysis of the available data remain important in this "optimistic" new era of AML therapeutics.
Topics: Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cytarabine; Daunorubicin; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds; Pyrazines
PubMed: 32151586
DOI: 10.1016/j.clml.2020.02.005 -
Nature Cancer Dec 2023Ex vivo drug response profiling is a powerful tool to study genotype-drug response associations and is being explored as a tool set for precision medicine in cancer....
Ex vivo drug response profiling is a powerful tool to study genotype-drug response associations and is being explored as a tool set for precision medicine in cancer. Here we conducted a prospective non-interventional trial to investigate feasibility of ex vivo drug response profiling for treatment guidance in hematologic malignancies (SMARTrial, NCT03488641 ). The primary endpoint to provide drug response profiling reports within 7 d was met in 91% of all study participants (N = 80). Secondary endpoint analysis revealed that ex vivo resistance to chemotherapeutic drugs predicted chemotherapy treatment failure in vivo. We confirmed the predictive value of ex vivo response to chemotherapy in a validation cohort of 95 individuals with acute myeloid leukemia treated with daunorubicin and cytarabine. Ex vivo drug response profiles improved ELN-22 risk stratification in individuals with adverse risk. We conclude that ex vivo drug response profiling is clinically feasible and has the potential to predict chemotherapy response in individuals with hematologic malignancies beyond clinically established genetic markers.
Topics: Humans; Cytarabine; Daunorubicin; Hematologic Neoplasms; Leukemia, Myeloid, Acute; Prospective Studies; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Treatment Outcome
PubMed: 37783805
DOI: 10.1038/s43018-023-00645-5 -
The Lancet. Haematology Jul 2023CPX-351, an encapsulated form of cytarabine and daunorubicin, has shown greater efficacy than the classic 3 + 7 treatment administration in secondary acute myeloid...
BACKGROUND
CPX-351, an encapsulated form of cytarabine and daunorubicin, has shown greater efficacy than the classic 3 + 7 treatment administration in secondary acute myeloid leukaemia. Given that higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia share similarities with secondary acute myeloid leukaemia, we aimed to investigate the safety and efficacy of CPX-351 in this context.
METHODS
This investigator-initiated two-cohort phase 2 trial was conducted by the Groupe Francophone des Myélodysplasies, with 12 participating centres in France. It comprised cohort A (reported here and completed), which included patients in first-line treatment, and cohort B, which was stopped for lack of inclusion (ie, not enough patients met the inclusion criteria), for patients with hypomethylating agent failure that is not reported here. Cohort A enrolled patients with newly diagnosed higher-risk myelodysplastic syndrome or chronic myelomonocytic leukaemia (aged 18-70 years old) with an Eastern Cooperative Oncology Group performance status of 0-1. Intravenous CPX-351 (100 mg/m cytarabine and 44 mg/m daunorubicin) was given on days 1, 3, and 5, with a second induction cycle given (same daily dose on days 1 and 3) if at least a partial response was not reached. Patients who responded could receive up to four monthly consolidation cycles (same daily dose on day 1) or allogeneic haematopoietic stem-cell transplantation (HSCT). Overall response rate after one or two induction courses according to European LeukemiaNet 2017 acute myeloid leukaemia was the primary endpoint after CPX-351 induction, whether patients received one or two induction cycles. Safety was assessed in all patients enrolled (in cohort A). This trial is registered with ClinicalTrials.gov, NCT04273802.
FINDINGS
Between April 29, 2020, and Feb 10, 2021, 21 (68%) male and ten (32%) female patients were enrolled. 27 (87%) of 31 patients responded (95% CI 70-96). 16 (52%) of the 31 patients received at least one consolidation cycle. 30 (97%) of the 31 patients included were initially considered eligible for allogeneic HSCT and 29 (94%) of the 31 patients had the procedure. Median follow-up was 16·1 months (IQR 8·3-18·1). The most common grade 3-4 adverse events were pulmonary (eight [26%] of 31 patients) and cardiovascular (six [19%] of 31 patients). There were 14 serious adverse events (mainly hospitalisation for infection [n=5] and only one was treatment-related) and no treatment-related death.
INTERPRETATION
CPX-351 appears to be active and safe in patients with higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia, allowing bridging to allogenic HSCT in most patients.
FUNDING
Jazz Pharmaceuticals.
Topics: Humans; Male; Female; Adolescent; Young Adult; Adult; Middle Aged; Aged; Leukemia, Myelomonocytic, Chronic; Cytarabine; Daunorubicin; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37245522
DOI: 10.1016/S2352-3026(23)00090-X