Treating AML With Myelodysplasia-Related Changes - Episode 4

AML-MRC: CPX-351 Versus 7+3 Therapy

Harry Erba, MD, PhD:So, liposomal daunorubicin/cytarabine is just not a fancy liposomal encapsulated way of giving the same chemotherapy we’ve been giving for the past 40 years. The preclinical science that led to the development of this agent begins with studies that have shown that the molar ratio of chemotherapy agents that are delivered to a cancer cell line in vitro may be very important in determining, or optimizing, cell kill. So, for example, with AML cell lines, when they’re exposed to daunorubicin and cytarabine at various ratios, it turns out that a 1:5 molar ratio of daunorubicin to cytarabine was the most effective at enhancing apoptosis and cell kill in those leukemia cell lines.

How do you then bring that to the clinic, or even to a preclinical murine model? Well, the only way to keep those 2 drugs in the 1:5 molar ratio after injection would be to have them liposomally encapsulated together in that ratio. And that’s what this agent is. It’s a liposomal encapsulation of daunorubicin and cytarabine in this fixed 1:5 molar ratio. Preclinical studies have shown that after a 90-minute injection of that agent, 24 hours later the daunorubicin/cytarabine remains in that fixed 1:5 molar ratio.

Preclinical studies and murine mouse studies have also shown that the 1:5 molar ratio is most effective at treating or controlling AML xenografts in murine models. And we’ve also seen in those preclinical studies that, for some reason, the liposomal formulation seems to be preferentially targeted to the bone marrow where the disease is. And so, this is the scientific basis of the liposomal daunorubicin/cytarabine. It turns out to be a different color than daunorubicin or cytarabine, it’s purple. Because the liposome is copper, and the blue of copper and the red of the daunorubicin makes the agent, when it’s reconstituted, this brilliant purple color. So, that’s the difference between liposomal daunorubicin and cytarabine.

There were phase I studies looking at the optimal dose of liposomal daunorubicin and cytarabine and then an earlier randomized phase II study where patients were randomized 2:1 to either the liposomal formulation or standard 7 + 3. And in that study of patients with newly diagnosed AML over the age of 60, there wasn’t any remarkable difference between the outcomes in those 2 populations. However, on multivaried analysis of that study, it was found that in these patients over the age of 60 who had a history of myelodysplastic syndrome, or who had a therapy-related acute myeloid leukemia—so had myelodysplasia-related changes—that there was an improvement in CR rate, there was an improvement in event-free survival, and improvement in overall survival. None of these were statistically significant. It was a subset analysis, but it was not at the cost of a higher mortality either during the induction or consolidation. And so, it was that subset analysis of a randomized phase II study that led to the pivotal phase III study evaluating liposomal daunorubicin/cytarabine in patients with AML with myelodysplasia-related changes or therapy-related AML.

Transcript edited for clarity.


Case: A 68-Year-Old Man With Newly-diagnosed AML

  • A 68-year-old man went to the emergency room with complaints of dizziness and chest pain
    • Myocardial infarction diagnosed and managed in hospital
    • During stay, CBC revealed decreased neutrophils but increased total white blood cell count
    • When stable from MI, he was referred for specialist consultation
  • Patient history and physical exam:
    • Reported fatigue, shortness of breath with minor exertion, and unexplained weight loss that have worsened over the past 2 months
    • Over the 6 months, has experienced three upper respiratory infections, often with mild fever, that were refractory to treatment, but which he attributed to being a former smoker
    • No history of cancer or cytotoxic treatment
  • Laboratory findings:
    • Absolute neutrophil count: 600 cells/µL; WBC: 85,000 cells/µL
    • Peripheral blood shows poorly differentiated myeloid cells
    • 25% blasts in peripheral blood
    • Cytogenetic abnormalities: chromosome 5 (del[5q])
  • Diagnosed with acute myeloid leukemia with myelodysplastic-related changes
  • Received Vyxeos (CTX-351) induction therapy, followed by consolidation
    • Experienced complete response and underwent HSCT