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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 -
Leukemia Oct 2023This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy... (Randomized Controlled Trial)
Randomized Controlled Trial
This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy (cytarabine and daunorubicin) or non-intensive chemotherapy (azacitidine) in patients with untreated acute myeloid leukemia. Overall survival (primary endpoint) was similar between the glasdegib and placebo arms in the intensive (n = 404; hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.782-1.408; two-sided p = 0.749) and non-intensive (n = 325; HR 0.99; 95% CI: 0.768-1.289; two-sided p = 0.969) studies. The proportion of patients who experienced treatment-emergent adverse events was similar for glasdegib versus placebo (intensive: 99.0% vs. 98.5%; non-intensive: 99.4% vs. 98.8%). The most common treatment-emergent adverse events were nausea, febrile neutropenia, and anemia in the intensive study and anemia, constipation, and nausea in the non-intensive study. The addition of glasdegib to either cytarabine and daunorubicin or azacitidine did not significantly improve overall survival and the primary efficacy endpoint for the BRIGHT AML 1019 phase 3 trial was not met. Clinical trial registration: ClinicalTrials.gov: NCT03416179.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute; Daunorubicin; Cytarabine; Azacitidine; Anemia; Nausea
PubMed: 37604981
DOI: 10.1038/s41375-023-02001-z -
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 -
Blood Advances Nov 2023The pivotal RATIFY study demonstrated midostaurin (50 mg twice daily) with standard chemotherapy significantly reduced mortality in adult patients (<60 years) with...
The pivotal RATIFY study demonstrated midostaurin (50 mg twice daily) with standard chemotherapy significantly reduced mortality in adult patients (<60 years) with newly diagnosed (ND) FLT3mut acute myeloid leukemia (AML). Considering that AML often present in older patients who show poor response to chemotherapy, this open-label, multicenter phase 3b trial was designed to further assess safety and efficacy of midostaurin plus chemotherapy in induction, consolidation, and maintenance monotherapy in young (≤60 years) and older (>60 years) patients with FLT3mut ND-AML. Compared with RATIFY, this study extended midostaurin treatment from 14 days to 21 days, substituted anthracyclines (idarubicin or daunorubicin), and introduced variation in standard combination chemotherapy dosing ("7+3" or "5+2" in more fragile patients). Total 301 patients (47.2% >60 years and 82.7% with FLT3-ITDmut) of median age 59 years entered induction phase. Overall, 295 patients (98.0%) had at least 1 adverse event (AE), including 254 patients (84.4%) with grade ≥3 AE. The grade ≥3 serious AEs occurred in 134 patients. No difference was seen in AE frequency between age groups, but grade ≥3AE frequency was higher in older patients. Overall, complete remission (CR) rate including incomplete hematologic recovery (CR + CRi) (80.7% [95% confidence interval, 75.74-84.98]) was comparable between age groups (≤60 years [83.5%]; >60 to ≤70 years [82.5%]; in patients >70 years [64.1%]) and the type of anthracycline used in induction. CR + CRi rate was lower in males (76.4%) than females (84.4%). Overall, the safety and efficacy of midostaurin remains consistent with previous findings, regardless of age, sex, or induction regimen. The trial is registered at www.clinicaltrials.gov as #NCT03379727.
Topics: Male; Female; Humans; Aged; Middle Aged; Daunorubicin; Idarubicin; Leukemia, Myeloid, Acute; Staurosporine; Antibiotics, Antineoplastic; Anthracyclines; fms-Like Tyrosine Kinase 3
PubMed: 37581981
DOI: 10.1182/bloodadvances.2023009847 -
Annals of Hematology Jul 2020
Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Fatal Outcome; Female; Humans; Middle Aged; Sarcoma; Uterine Neoplasms
PubMed: 32367177
DOI: 10.1007/s00277-020-04065-8 -
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