My Treatment Approach: Acute Myeloid Leukemia (AML) - Episode 3
Richard Stone, MD, and Eunice Wang, MD, comment on the role of CPX-351 in the treatment of secondary AML and offer practice pointers for treatment with this drug, including management of adverse events.
Richard Stone, MD: How do we treat the patient like this?
Eunice Wang, MD: In this instance, I’d look at the overall presentation of the patient. AML [acute myeloid leukemia] therapy in the current era requires that we individualize the treatment regimen for the patient and disease. This woman has undergone intensive or definitive therapy for her breast cancer. She’s still functionally active, has an excellent performance status, and doesn’t have any evidence of organ dysfunction, eg, liver, kidney, or heart. Her activity level is normal. She’s continuing to work full-time, chasing high school students around.
I’d think about offering her an intensive chemotherapy approach, potentially followed by allogeneic stem cell transplant for curative intent. Because we know that in most patients with a secondary therapy–related AML, the best outcomes are achieved by the performance of an allogeneic stem cell transplant as postconsolidation therapy. What are your thoughts on this?
Richard Stone, MD: I agree with everything you said. When I think about intensive chemotherapy, I think about whether the patient can tolerate it and whether it will benefit the patient. Because there are certain patients who can tolerate intensive chemotherapy, but I’m not sure [they] would benefit from it. It’s still an open question. In other words, patients with a TP53 mutation and complex karyotype may not benefit from intensive chemotherapy. They may not [have] better [results] with azacitidine and venetoclax, but at least they’re not going to be as sick.
Without any proof, I have a predilection to treat the patients [with high-risk disease] with less intensive chemotherapy, because it isn’t likely to be worse and will likely be better tolerated. That’s unproven at the moment. For this patient, I’d use an intensive approach because of her age, favorable mutational status, and good performance status. I have a similar view that she should get an intensive regimen. What do you think are the choices for an intensive regimen?
Eunice Wang, MD: This patient is over the age of 60, which makes it more straightforward. But based on her age and the diagnosis of a secondary therapy–related AML, my preference would be to treat her with CPX-351, or liposomal cytarabine-daunorubicin. That offers her the best opportunity to be free of disease in 3 to 5 years.
There were the results of a phase 3 randomized clinical trial where patients aged 60 to 75 [years] with secondary AML were [randomly assigned] to receive up-front induction of chemotherapy with either CPX-351—that liposomal formulation is dosed on days 1, 3, and 5—[or] the standard continuous infusion [of] cytarabine and daunorubicin, our 7+3 gold standard. In that trial, patients could get 2 cycles of the CPX-351 induction or 7+3. They could get consolidation with a CPX-351 vs a 5+2. Eligible patients could then go on to subsequent transplant.
The 5-year results were published in 2021 and substantiate the early findings that led to FDA approval, where about 18% in the CPX-351 group and 8% in the 7+3 group were alive and disease-free at 5 years. Of the patients who had gotten CPX-351 followed by transplant, most impressively, 53% were alive. The overall survival for those patients who had gone to subsequent transplant from CPX-351 hadn’t been reached yet. I was impressed with that because in the past, patients who got therapy-related AML rarely went into remission or long-term response. Very few of them—less than 10% with standard therapy—[survived for] 3 to 5 years. Based on those data, I’d be offering CPX-351 to this patient.
The only question would be—and I throw this back to you—what if she were 59 [years old]? Would you treat her similarly? Because the trial was for patients aged 60 to 75 years. If she were 55 or 45 [years old], would you do the same thing? Or would you restrict your interpretation of that trial to the [patients aged] 60 to 75?
Richard Stone, MD: That’s a great question. The FDA believes you could extend the [use] of CPX-351 to younger folks because they approved it in an age-agnostic fashion, which was surprising because, as you pointed out, the data were only [from results of] patients aged 60 to 75 [years]. It’s possible that a 7+3 regimen would have been better than CPX-351 for younger patients. They did a trial in all ages, [but] it didn’t show better results. They did a trial with older adults, and it was only the ones who had secondary AML who seemed to benefit from CPX-351 compared with 7+3. It’s a little unclear, but I believe it’s because CPX-351 seems to release ARA-C [cytosine arabinoside] and daunorubicin, a so-called favorable molar ratio, to kill the cells. That’s more theoretical, but it’s true. It also [remains] in the bone marrow a little longer, which accounts for its mild suppression. Maybe that’s another reason why it’s a little better.
The answer to your question is that I’d use it in a younger patient who had secondary AML. Curiously, in another post hoc analysis done by R. Coleman Lindsley, [MD, PhD], of the CPX-351 vs 7+3 trial that you mentioned, [patients] with TP53 mutations didn’t benefit from CPX-351 compared with 7+3. That’s another situation where you throw up your hands. [These] were [patients aged] 60 to 75, but I’d use it in the right patient under 60 [years of age]. In fact, there’s an ongoing trial in Europe for patients regardless of their history of MDS [myelodysplastic syndrome] or prior treatment that will compare 7+3 with CPX-351. Maybe it will turn out to be a better induction regimen than 7+3 alone. We need to wait and see.
We talked about CPX-351 compared with azacitidine-venetoclax in the retrospective studies that were published at the American Society of Hematology meeting. CPX-351 is similar to 7+3 chemotherapy, but different in that it’s given episodically on days 1, 3, and 5. As you mentioned, it’s possible to give this [treatment] outpatient if the patient isn’t ill, and we do that too. It saves hospitalization. It’s also financially toxic to the inpatient service to pay for CPX-351, which is very expensive compared with 7+3. But you may save money by not admitting the patient for as many days. We bring them in on day 10 at the start of their expected nadir, because almost all of them will [have] some fever and neutropenia, and it’s easier to have them in the hospital when that happens than outpatient [service].
We find CPX-351 to be well tolerated in general, with no hair loss, minimal GI [gastrointestinal] toxicity, and as you mentioned, prolonged myelosuppression. Those are the main considerations with CPX-351. It’s cardiotoxic. It’s hard to know how it compares with standard daunorubicin, or even doxorubicin, for those who have secondary AML. [For] your patient, it’s important to consider the prior doxorubicin if they were treated for breast cancer or another cancer. We get echocardiograms frequently for our CPX-351 patients. Any other thoughts about that, Eunice?
Eunice Wang, MD: As you mentioned, there are a lot of things to recommend in terms of the toxicity profile. Our patients are excited about the fact that they don’t lose their hair and [won’t] be inpatient for 40, 50, or 60 days. In general, there are still the complications from infection, but the ability to do part of the regimen outpatient and then do all the regimen outpatient in the consolidation setting while waiting for possible transplant improves quality of life. [It] has been demonstrated in other studies that, as compared with 7+3 and standard consolidation, patients have almost 50% improved quality-of-life scores on various questionnaires when asked about the comparison between the 2. That’s an important thing to keep in mind as we’re tailoring therapy for the patient and the disease.
Transcript edited for clarity.