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CPX-351 in AML
How Newly Approved CPX-351 Will Change AML Treatment

Released: September 28, 2017

Expiration: September 27, 2018

Jeffrey E. Lancet
Jeffrey E. Lancet, MD
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The management of acute myeloid leukemia (AML) has remained largely unchanged for decades. High-risk patients represent a subgroup with poor outcomes with current therapies. CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a synergistic 5:1 molar ratio, which is maintained in the plasma and taken up in liposomal form by leukemic cells. It was approved by the FDA in August 2017 based on phase III data showing significantly improved OS vs the standard-of-care treatment, the “3+7” regimen of cytarabine plus daunorubicin. In this study, median OS was 9.56 months for CPX-351 vs 5.95 months for 3+7 (HR: 0.69; P = .005). In addition, median event-free survival was 2.53 months vs 1.31 months, respectively (HR: 0.74).

With the recent approval comes the question: How does CPX-351 fit into current treatment paradigms?

Who Should Receive CPX-351?
CPX-351 is approved for the treatment of 2 types of newly diagnosed AML: therapy-related AML (eg, following chemotherapy for another cancer) and AML with myelodysplasia-related changes (eg, antecedent myelodysplastic syndromes MDS, chronic myelomonocytic leukemia, or MDS-related cytogenetics). Given the results of the phase III study, it should be considered standard of care for fit newly diagnosed patients with these AML subtypes. Given the high frequency of these subtypes of AML in the older population (in the range of 40%), it is anticipated that CPX-351 will replace traditional 3+7 as primary for a large subset of AML patients.

Another one of the key takeaways from the trial is that more patients who received CPX-351 were able to undergo a successful allogeneic stem cell transplantation (ASCT): median OS after ASCT was not reached for CPX-351 treated patients (n = 52) vs 10.25 months for patients who had received 3+7 (n = 39) (HR: 0.46; P = .0046). These results suggest that CPX-351 may provide a more effective bridge to ASCT than 3+7, thereby lending strong consideration of CPX-351 as primary induction therapy in transplant-eligible patients with secondary or high-risk AML.

Toxicity: CPX-351 vs 3+7
Initially, there were valid concerns about potentially increased toxicity with this formulation of the 2 drugs, as its pharmacokinetic profile and liposomal formulation ensure more prolonged drug exposure. However, it now appears that CPX-351 has a very comparable and acceptable safety profile in comparison to 3+7. In the phase III study, there was a lower rate of 60-day mortality (13.7% for CPX-351 vs 21.2% for 3+7). However, there are a couple of important points to make with respect to the toxicity of CPX-351. The first is that CPX-351 causes a more prolonged neutrophil and platelet recovery time, typically 7-10 days beyond that of 3+7. Secondly, there was a higher rate of hemorrhagic and infectious adverse effects attributable to the CPX-351 arm of the study. Fortunately, these toxicities have not translated into increased risk of early death or death from other causes and do not mitigate the overall beneficial effects on survival and remission rates vs 3+7.

It should be understood that close monitoring is required with any patient undergoing intensive chemotherapy for acute leukemia, and the same certainly holds true for CPX-351. Although the experience with CPX-351 has been positive, I would emphasize that this is not a low-dose or low-intensity therapy. It is not suitable for frail patients who are considered unfit for induction therapy. CPX-351 is clearly intensive therapy that should be used only for patients who are felt to be able to tolerate a more challenging regimen.

Another point worth making is that dosing is more convenient than with 3+7, with a single infusion on Days 1, 3, and 5 compared with 3+7, which requires a continuous infusion of cytarabine for 7 days. As experience with CPX-351 increases, it may lend itself to outpatient administration in the future, but I must be clear in emphasizing that the experience with CPX-351 as induction therapy in the phase II and phase III trials has primarily used inpatient administration.

Future Considerations
Future clinical trials will likely combine other drugs with CPX-351, including drugs currently matched with 3+7, with the knowledge that it will be important to document safety and tolerability with any combination, due to potential toxicity risks. But once safety and tolerability are established with various combinations, randomized trials can begin to study the efficacy of combining CPX-351 with novel agents.

Since its recent approval, clinicians have been slowly integrating CPX-351 into practice. It takes time for a newly approved drug to be included in hospital formularies and to gain payer approval because of factors such as higher cost, lack of familiarity with the drug, and concerns for toxicity. Perhaps in the future, after careful study, outpatient administration could allow for increased patient convenience and satisfaction, along with easier reimbursement. That said, I believe that in the very near future, CPX-351 will be the go-to standard of care for older, fit patients with previously untreated high-risk AML.

Do you plan to prescribe CPX-351 for your patients with high-risk AML? Let me know your thoughts below.

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