CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial

Lancet, Jeffrey E.; Uy, Brian; Newell, Laura F.; Lin, Tara L.; Ritchie, Ellen K.; Stuart, Robert K.; Strickland, Stephen A.; Hogge, Donna E.; Solomon, Scott R.; Bixby, Dale; Kolitz, Jonathan E.; Schiller, Gary J.; Wieduwilt, Matthew J.; Ryan, Daniel; Faderl, Stefan; Cortes, Jorge

doi:10.1016/s2352-3026(21)00134-4

Cited by 116 publications

(67 citation statements)

References 28 publications

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“…In a phase 3 study, induction followed by consolidation with CPX-351 provided superior OS and remission rates compared with conventional 7 + 3 chemotherapy in older adults with newly diagnosed high-risk/secondary AML, with a similar safety profile [ 7 , 8 ]. Similar to other studies, insufficient quality-of-life data were collected during the phase 3 study of CPX-351 versus 7 + 3 to permit analysis.…”

Section: Discussionmentioning

confidence: 99%

“…These properties may help minimize the systemic distribution of daunorubicin and cytarabine [ 24 ]. CPX-351 additionally prolongs drug exposure and maintains the synergistic 1:5 molar ratio of daunorubicin and cytarabine within the liposome for over 24 h after administration in patients with AML [ 25 ], which could contribute to the improved efficacy reported for CPX-351 versus 7 + 3 in this study [ 7 , 8 ]. Further, post hoc subgroup analyses of the phase 3 study in patients who achieved CR or CRi found that those who achieved remission with CPX-351 versus 7 + 3 had improved OS and post-transplant outcomes, suggesting deeper remissions may be achieved with CPX-351 [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…The pivotal phase 3 study that formed the basis for the approvals evaluated older patients with newly diagnosed high-risk/secondary AML and found that, after a median follow-up of 20.7 months, overall survival (OS) was significantly improved with CPX-351 versus the conventional 7 + 3 regimen of cytarabine and daunorubicin (9.56 vs 5.95 months; hazard ratio [HR] = 0.69 [95% confidence interval (CI): 0.52, 0.90]; 1-sided P = 0.003) with a comparable safety profile [ 7 ]. After 5 years of follow-up (median: 60.65 months), the OS benefit with CPX-351 induction followed by consolidation was maintained versus 7 + 3 (HR = 0.70 [95% CI: 0.55, 0.91]) [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML

Cortes

Lin

et al. 2021

J Hematol Oncol

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Background CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality‐adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up. Methods Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses. Results The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology. Conclusions This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 (https://clinicaltrials.gov/ct2/show/NCT01696084) and is complete.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML

Cortes

Lin

et al. 2021

J Hematol Oncol

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“…The non-PEGylated liposomal formulation of daunorubicin, DaunoXome ® (DNX), is indicated as a first-line cytotoxic therapy for advanced HIV-associated Kaposi's sarcoma. CPX-351 (Vyxeos ® ) is a liposome-based nanocarrier encapsulating daunorubicin and cytarabine in 1:5 molar ratio [76]. Therapy with CPX-351 was associated with significantly prolonged survival compared to the standard of care "7 + 3" regimen (conventional cytarabine and daunorubicin) in the elderly patients with so far untreated AML, while its safety profile was comparable [77,78].…”

Section: Liposomal Formulations Of Doxorubicin-the First Nanomedicine...mentioning

confidence: 99%

Targeted Drug Delivery and Theranostic Strategies in Malignant Lymphomas

Etrych

Braunová

Zogala

et al. 2022

Cancers

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Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) 131I-tositumomab and 90Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody–drug conjugate (ADC) for the treatment of lymphomas, anti-CD30 brentuximab vedotin, paved the path for the preclinical development and clinical testing of several other ADCs, including polatuzumab vedotin and loncastuximab tesirine. Other modalities of TDD are based on new formulations of “old” cytostatic agents and their passive trapping in the lymphoma tissue by means of the enhanced permeability and retention (EPR) effect. Currently, the diagnostic and restaging procedures in aggressive lymphomas are based on nuclear imaging, namely PET. A theranostic approach that combines diagnostic or restaging lymphoma imaging with targeted treatment represents an appealing innovative strategy in personalized medicine. The future of theranostics will require not only the capability to provide suitable disease-specific molecular probes but also expertise on big data processing and evaluation. Here, we review the concept of targeted drug delivery in malignant lymphomas from RIT and ADC to a wide array of passively and actively targeted nano-sized investigational agents. We also discuss the future of molecular imaging with special focus on monoclonal antibody-based and monoclonal antibody-derived theranostic strategies.

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“…In the phase 3 study of CPX-351 versus conventional 7 + 3 chemotherapy, CPX-351 improved median OS among patients who achieved CR or CRi, as well as the likelihood of proceeding to HCT and median OS landmarked from the date of HCT [ 51 , 52 ], suggesting the potential for achievement of deeper responses with CPX-351. However, MRD is not yet assessed in the context of a large, randomized study of CPX-351 treatment, although real-world data on MRD assessment after CPX-351 treatment are encouraging.…”

Section: Promising Strategies To Achieve Mrd Negativity In High-risk Amlmentioning

confidence: 99%

Measurable Residual Disease in High-Risk Acute Myeloid Leukemia

Cluzeau

Lemoli

McCloskey

et al. 2022

Cancers

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Mounting evidence suggests measurable residual disease (MRD) assessments are prognostic in acute myeloid leukemia (AML). High-risk AML encompasses a subset of AML with poor response to therapy and prognosis, with features such as therapy-related AML, an antecedent hematologic disorder, extramedullary disease (in adults), and selected mutations and cytogenetic abnormalities. Historically, few patients with high-risk AML achieved deep and durable remission with conventional chemotherapy; however, newer agents might be more effective in achieving MRD-negative remission. CPX-351 (dual-drug liposomal encapsulation of daunorubicin/cytarabine at a synergistic ratio) demonstrated MRD-negativity rates of 36–64% across retrospective studies in adults with newly diagnosed high-risk AML and 84% in pediatric patients with first-relapse AML. Venetoclax (BCL2 inhibitor) demonstrated MRD-negativity rates of 33–53% in combination with hypomethylating agents for high-risk subgroups in studies of older adults with newly diagnosed AML who were ineligible for intensive therapy and 65% in combination with chemotherapy in pediatric patients with relapsed/refractory AML. However, there is no consensus on optimal MRD methodology in AML, and the use of different techniques, sample sources, sensitivity thresholds, and the timing of assessments limit comparisons across studies. Robust MRD analyses are needed in future clinical studies, and MRD monitoring should become a routine aspect of AML management.

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CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial

Cited by 116 publications

References 28 publications

Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML

Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML

Targeted Drug Delivery and Theranostic Strategies in Malignant Lymphomas

Measurable Residual Disease in High-Risk Acute Myeloid Leukemia

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