The Challenges in AML-MRC

Harry Erba, MD, PhD:The liposomal formulation is given as a 90-minute infusion. It does not have to be given through a central line. However, since it contains daunorubicin, there is the concern that it could cause a skin reaction. So, I typically use a central venous catheter for administration. But it’s a 90-minute infusion on days 1, 3, and 5. At day 14, if there’s persistent disease but there has been some cytoreduction in the study, what’s recommended is to give 2 doses of the liposomal formulation on days 1 and 3.

The dose there during induction is 44 mg/m²of the daunorubicin, 100 mg/m²of the cytarabine in each of those doses. For the consolidation, it’s days 1 and 3, 90-minute infusion at a lower dose.

Because it’s only a 90-minute infusion, this can be given in the outpatient setting. In fact, in the clinical trial, half of the patients received consolidation as an outpatient. I think my only cautionary note would be if giving liposomal formulation during an induction in the outpatient setting, the patient has to be well educated to come back to the clinic in the event of any bleeding symptoms or fevers, have transportation back to make it so that it safely can be given to patients. In the clinical trial, almost all of them received the liposomal formulation as an inpatient.

One challenge in this patient is the fact that he just had a myocardial infarction. And what is not clear from the history that’s given to us is, exactly how was the myocardial infarction handled? In my experience, it’s often very difficult for a cardiologist to consider angiography and stent placement because these patients have low platelet counts and they won’t be able to tolerate being on double antiplatelet agents for very long. And clearly, this patient has an acuity with the leukocytosis that requires him to be treated very quickly.

Giving an anthracycline shortly after a myocardial infarction is obviously a concern, but if he has preserved left ventricular function, I would go ahead and do that because otherwise his options are very limited. I don’t think the hypomethylation agents would be a good option for this patient.

In terms of saying that this liposomal formulation has less cardiac toxicity, we can’t say that from the clinical trial. In fact, in the data reported to the FDA, there was 20% incidence of nonconduction cardiac toxicity from both 7 + 3 and from liposomal formulation. Now I don’t expect a 20% decrease in LV function in my patients getting 7 +3, that’s permanent from the anthracycline. I think what we were seeing there is in a patient with sepsis, there’s a transient decrease in LV function. But it was the same in both arms, and I think the important point there is that we can’t specifically say that the liposomal formulation, just because it targets the marrow more than the free drug, will have less cardiac toxicity. And so, it’s recommended that we consider the dose of daunorubicin in the liposomal formulation equivalent in terms of its cardiotoxicity as it’s given in the freeform IV. So, you need to calculate total anthracycline exposure for your patients, especially those who may have treatment-related AML and been exposed to anthracyclines before when considering giving this drug.

This patient is a very challenging patient and the outcome was excellent. And I think this is an important message here. You know in the acuity of the situation, we need to get this patient into a remission and try to get him to the only curative option for his disease: allogeneic stem cell transplant. Having said that, even without transplant, liposomal daunorubicin/cytarabine improved survival compared to 7 + 3. So, in a patient with a proliferative acute myeloid leukemia who has myelodysplasia-related changes—in this case, by cytogenetics or treatment-related AML—I think the randomized phase II study suggested, and now the pivotal phase III study confirmed, the superiority of liposomal daunorubicin/cytarabine over 7 + 3 and the way we’ve been giving it for the past 40 years.

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