Phase III Study of CPX-351 Versus 7+3 in Patients 60-75 Years Old With Untreated High Risk (Secondary) Acute Myeloid Leukemia

• CPX-351 (Drug): First induction: 100 units/m2 by 90-minute IV infusion on Days 1, 3, 5. Second induction: 100 units/m2 by 90-minute IV infusion on Days 1 and 3. Consolidation therapy: 65 units/m2 by 90-minute IV infusion on Days 1 and 3.
• 7+3 (cytarabine and daunorubicin) (Drug), also known as cytarabine and daunorubicin: First induction: 7+3 was administered as: cytarabine at a dose of 100 mg/m2/day on Days 1 through 7 by continuous infusion, and daunorubicin at a dose of 60 mg/m2/day on Days 1, 2, and 3. Second induction: 5+2 was administered as: cytarabine at a dose of 100 mg/m2/day on Days 1 through 5 by continuous infusion and daunorubicin at a dose of 60 mg/m2/day on Days 1 and 2. Consolidation therapy: 5+2 was administered as: cytarabine at a dose of 100 mg/m2/day on Days 1 through 5 by continuous infusion, and daunorubicin at a dose of 60 mg/m2/day on Days 1 and 2.

Primary outcomes

• Overall Survival [From the date of randomization to death from any cause]: Overall survival was measured from the date of randomization to death from any cause, subjects not known to have died by the last follow-up were censored on the date they were last known to be alive.

Secondary outcomes

• Proportion of Subjects With a Response [Post Induction]: Complete Remission (CR)
• Event-free Survival [From the date of randomization to the date that persistent disease was documented or the date of relapse after CR or death, whichever came first]: All randomized subjects were assessed for event-free survival (EFS). EFS was defined as the time from study randomization to the date of induction treatment failure (persistent disease), relapse from CR or CRi or death from any cause, whichever came first. Subjects alive and not known to have any of these events were censored on thee date they were last examined on study.
• Remission Duration [From the date of achievement of a remission until the date of relapse or death from any cause]: Only subjects achieving CR or CRi were assessed for remission duration.
• Rate of Achieving Morphologic Leukemia-free State [Day 14]: All randomized subjects with at least 1 evaluable postrandomization bone marrow assessment performed on or after Day 14 after the last induction were assessed for MLFS.
• Proportion of Subjects Receiving a Stem Cell Transplant [Post Induction]: The number and percentage of subjects transferred for HSCT after induction treatment was recorded.

Sex: All, ages: 60 Years to 75 Years

Inclusion Criteria:

* Ability to understand and voluntarily give informed consent
* Age 60-75 years at the time of diagnosis of AML
* Pathological diagnosis of AML according to WHO criteria (with at least 20% blasts in the peripheral blood or bone marrow)
* Confirmation of:

  * Therapy related AML: t-AML must have a documented history of prior cytotoxic therapy or ionizing radiotherapy for an unrelated disease
  * AML with a history of myelodysplasia: MDSAML must have bone marrow documentation of prior MDS
  * AML with a history of CMMoL: CMMoLAML must have bone marrow documentation of prior CMMoL
  * De novo AML with karyotypic abnormalities characteristic of MDS: de novoAML must have cytogenetics with abnormalities per WHO.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Able to adhere to the study visit schedule and other protocol requirements
* Laboratory values fulfilling the following:

  * Serum creatinine < 2.0 mg/dL
  * Serum total bilirubin < 2.0 mg/dL, patients with Gilbert's Syndrome should contact the medical monitor
  * Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN Note: If elevated liver enzymes, above the ULN, are related to disease; contact medical monitor to discuss.
* Cardiac ejection fraction ≥ 50% by echocardiography or MUGA
* Patients with second malignancies in remission may be eligible if there is clinical evidence of disease stability for a period of greater than 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies, etc., at screening. Patients maintained on long-term non-chemotherapy treatment, e.g., hormonal therapy, are eligible.

Exclusion Criteria:

* Except for CMMoL, patients with history of myeloproliferative neoplasms (MPN) (defined as a history of essential thrombocytosis or polycythemia vera, or idiopathic myelofibrosis prior to the diagnosis of AML) or combined MDS/MPN are not eligible.
* Acute promyelocytic leukemia \[t(15;17)\] or favorable cytogenetics, including t(8;21) or inv16 if known at the time of randomization.
* Clinical evidence of active CNS leukemia
* Patients with active (uncontrolled, metastatic) second malignancies are excluded.
* Prior treatment intended for induction therapy of AML; only hydroxyurea is permitted for control of blood counts. For example, a patient with MDS that changes HMA dose and schedule after the diagnosis of AML is excluded. AML-type therapy, such as cytarabine alone (>1g/m2/day) or cytarabine plus an anthracycline as well as prior HSCT are also excluded.
* Administration of any therapy for MDS (conventional or investigational) must be completed by 2 weeks prior to of the first dose of study drug; in the event of rapidly proliferative disease use of hydroxyurea is permitted until 24 hours before the start of study treatment. Toxicities associated with prior MDS therapy must have recovered to grade 1 or less prior to start of treatment.
* Any major surgery or radiation therapy within four weeks.
* Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent).
* Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent obtaining informed consent
* Patients with myocardial impairment of any cause (e.g. cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV staging)
* Active or uncontrolled infection. Patients with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for ≥72 hrs.
* Current evidence of invasive fungal infection (blood or tissue culture); patients with recent fungal infection must have a subsequent negative cultures to be eligible; known HIV (new testing not required) or evidence of active hepatitis B or C infection (with rising transaminase values)
* Hypersensitivity to cytarabine, daunorubicin or liposomal products
* History of Wilson's disease or other copper-metabolism disorder

Participant flow

Outcome results

• Overall Survival (Primary), Median, months: Arm A (CPX-351) 9.56 (6.60 to 11.86); Arm B (7+3) 5.95 (4.99 to 7.75)
• Proportion of Subjects With a Response (Secondary), Count of participants, Participants: Arm A (CPX-351) 57; Arm B (7+3) 40
• Event-free Survival (Secondary), Median, months: Arm A (CPX-351) 2.53 (2.07 to 4.99); Arm B (7+3) 1.31 (1.08 to 1.64)
• Remission Duration (Secondary), Median, months: Arm A (CPX-351) 6.93 (4.60 to 9.23); Arm B (7+3) 6.11 (3.45 to 8.71)
• Rate of Achieving Morphologic Leukemia-free State (Secondary), Count of participants, Participants: Arm A (CPX-351) 87; Arm B (7+3) 66
• Proportion of Subjects Receiving a Stem Cell Transplant (Secondary), Count of participants, Participants: Arm A (CPX-351) 52; Arm B (7+3) 39

Adverse events

Time frame: Adverse events (AE) recorded from the start of the infusion on Day 1 to the last day of the treatment period. SAE recorded from the start of the infusion on Day 1 to 30 days after completion of the treatment period.

Serious adverse events by term

68 more terms not shown.

Other adverse events by term

37 more terms not shown.

• Results publication: Shimony S, Murdock HM, Keating J, Tsai HK, Sasi A, Gibson CJ, Faderl S, Wagner A, Dronamraju N, Lin TL, Prebet T, Cortes JE, Uy GL, Lancet JE, Reilly CR, Neuberg D, Stone RM, Lindsley RC. CPX-351 selectively benefits patients with AML and myelodysplasia-related mutations in the pivotal randomized trial. Blood Adv. 2026 Apr 28;10(8):2854-2864. doi: 10.1182/bloodadvances.2025019378. PMID 41628350
• Results publication: Guolo F, Fianchi L, Martelli MP, Lussana F, Grimaldi F, Pilo F, Rondoni M, Fili C, Minetto P, Capelli D, Chiusolo P, Breccia M, Mastaglio S, Bernardi M, Bocchia M, Fumagalli M, Galimberti S, Mancini V, Piccioni AL, Maurillo L, Fracchiolla NS, Palmieri R, Vetro C, Papayannidis C, Brunetti L, Sperotto A, Gigli F, Zappasodi P, Mule A, Patti C, Borlenghi E, Dargenio M, Lessi F, Cerrano M, Cilloni D, Isidori A, Lunghi M, Alati C, Gurrieri C, Riva C, Marconi G, Lotesoriere I, Gatani S, Scattolin AM, Caizzi M, Perrone S, Billio A, Gherlinzoni F, Mannelli F, Gottardi M, Cairoli R, Candoni A, Ferrara F, Pagano L, Lemoli RM, Venditti A, Todisco E. Real World Study on the Best CPX-351 Treatment Duration and Timing for Allogeneic Stem Cell Transplantation. Am J Hematol. 2025 Dec;100(12):2293-2304. doi: 10.1002/ajh.70083. Epub 2025 Sep 24. PMID 40990091
• Results publication: Cortes JE, Lin TL, Asubonteng K, Faderl S, Lancet JE, Prebet T. Efficacy and safety of CPX-351 versus 7 + 3 chemotherapy by European LeukemiaNet 2017 risk subgroups in older adults with newly diagnosed, high-risk/secondary AML: post hoc analysis of a randomized, phase 3 trial. J Hematol Oncol. 2022 Oct 26;15(1):155. doi: 10.1186/s13045-022-01361-w. PMID 36289532
• Results publication: Cortes JE, Lin TL, Uy GL, Ryan RJ, Faderl S, Lancet JE. 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. J Hematol Oncol. 2021 Jul 13;14(1):110. doi: 10.1186/s13045-021-01119-w. PMID 34256819
• Results publication: Lancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Faderl S, Cortes JE. 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 Haematol. 2021 Jul;8(7):e481-e491. doi: 10.1016/S2352-3026(21)00134-4. PMID 34171279
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• Results publication: Kolitz JE, Strickland SA, Cortes JE, Hogge D, Lancet JE, Goldberg SL, Villa KF, Ryan RJ, Chiarella M, Louie AC, Ritchie EK, Stuart RK. Consolidation outcomes in CPX-351 versus cytarabine/daunorubicin-treated older patients with high-risk/secondary acute myeloid leukemia. Leuk Lymphoma. 2020 Mar;61(3):631-640. doi: 10.1080/10428194.2019.1688320. Epub 2019 Nov 25. PMID 31760835
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