乌鸦传媒

Expert Critique

FROM THE ASCO Reading Room

Amit Reddy, MBBS Postdoctoral Fellow Mitchell Cancer Institute, University of South Alabama

Acute myeloid leukemia (AML) is a cancer of the white blood cells that progresses very rapidly. The remission rate is much less for patients older than age 60, who also have more morbidities. Treatment for AML in older patients is a major therapeutic challenge. A new subgroup with a very poor prognosis has emerged called secondary AML, defined as AML occurring after an antecedent myeloid disease such as myelodysplastic syndromes.

A new liposomal drug formulation of cytarabine and daunorubicin (CPX-351; Vyxeos) was found to be significantly superior to standard 鈥�7+3鈥� therapy with cytarabine/daunorubicin in older adults with high-risk AML. In a phase III study the median overall survival with CPX-351 was 9.56 months compared with 5.95 months for patients receiving 7+3 therapy. Another study was done with patients who underwent allogeneic stem cell transplantation and showed that adults with high-risk AML treated with CPX-351 had only half the rate of death by 100 days post-ASCT compared with those treated with the normal 7+3 therapy. As a result, the findings suggest that CPX-531 provides a valuable link in poor-risk AML patients who undergo transplantation.

In summary, CPX-531 provides further disease control and lowers the mortality and morbidity in AML patients compared with 7+3 therapy.

Full Critique

As the saying goes, most often attributed to baseball legend Leroy "Satchel" Paige, "Age is a question of mind over matter. If you don't mind, it doesn't matter."

But when it comes to acute myeloid leukemia (AML), age seems to matter very much. According to the , the estimated remission rate for AML patients younger than age 60 is greater than 65%. Adults older than 60, however, are less likely to achieve complete remissions, and the remissions are often shorter in duration than those for younger patients. Older patients are also more likely to have significant morbidities or to die during induction therapy.

As , of the Moffitt Cancer Center in Tampa, Fla., noted at the 2016 annual meeting of the American Society of Clinical Oncology, "AML in older adults represents a major therapeutic challenge. In addition to the worse outcomes associated with aging, we also recognize that secondary AML has emerged as an important subgroup with a very poor prognosis."

Data from a published in 2015 indicate that secondary AML -- defined as AML occurring after an antecedent myeloid disease such as myelodysplastic syndromes (MDS) -- comprises 19.8% of all AML cases, and that therapy-related AML -- defined as a late complication of cytotoxic chemotherapy and/or radiotherapy -- makes up an additional 6.6% of cases.

The authors of that study found that de novo, secondary, and therapy-related AML are biologically and prognostically distinct subtypes of AML, and that "patients with non-MDS secondary AML have dismal outcomes, independent of age and cytogenetics."

Same Drugs, New Package

But as Lancet and colleagues reported at ASCO 2016, and in a subsequent analysis of data reported later that year at the American Society of Hematology (ASH) annual meeting, a liposomal formulation of cytarabine and daunorubicin (CPX-351; Vyxeos) was found to be superior to standard "7+ 3" therapy with cytarabine/daunorubicin in older patients with high-risk AML.

CPX-351 consists of 100 nm bilamellar liposomes that encapsulate a 5:1 molar ratio of cytarabine to daunorubicin. A unit dose delivers 1 mg of cytarabine and 0.44 mg daunorubicin.

In the of CPX-351 versus standard 7 + 3 induction in patients age 60 and older with newly diagnosed high-risk AML, participants were stratified by age and then randomized to receive either CPX-351 at 100 units/m² on days 1, 3, and 5 for first induction, the same dose on days 1 and 3 of re-induction, and 65 units/m² on days 1 and 3 of the consolidation phase, or to standard chemotherapy with cytarabine at 100 mg/m² and daunorubicin at 60 mg/m², for 7 and 3 days, respectively, and for 5 and 2 days each for the re-induction and consolidation phases.

The median overall survival was 9.56 months for patients treated with CPX-351, compared with 5.95 months for those receiving 7 + 3. The hazard ratio (HR) for CPX-351 was 0.69 (P = .005).

Event-free survival was also higher among patients in the CPX-351 arm, at a median 2.53 versus 1.31 months (HR 0.74, P = .021). There were also significantly more complete responses (CRs) among patients who received the liposomal formulation, at 37.3% versus 25.6% (P = .040), and the combined CR and CRi (complete response with incomplete recovery of blood counts) was also significantly better with CPX-351, at 47.7% versus 33.3% (P = .016).

The 30-day mortality rate was 5.9% among patients on CPX-351 versus 10.6% for patients on 7 + 3; the respective 60-day mortality rates were 13.7% and 21.2%.

The rates of grade 3 or greater adverse events were generally similar between the groups, except for a higher incidence of pneumonia, hypertension, and bacteremia among patients on the liposomal formulation.

Better Post-transplant Survival

At ASH 2016, Lancet presented data from a subsequent analysis of a subset of patients in the trial who went on to undergo allogeneic stem cell transplantation (ASCT). The exploratory analysis showed that those with high-risk AML treated with CPX-351 had half the rate of death within 100 days of ASCT compared with patients treated with 7 + 3. The median overall survival was not reached in the CPX-351 arm, versus 10.25 months for patients treated with 7 + 3 (HR favoring CPX-351 of 0.46, P = .0046).

In a Cox proportional model including transplant as a time-dependent variable, the HR for CPX-351 was 0.51 (P = .0007).

The finding suggests that "CPX-351 may provide a bridge to successful transplant in a poor-risk subgroup of AML patients," Lancet said.

He noted that the although the analysis should be interpreted with caution because it was an exploratory assessment of a non-randomized subgroup, the findings suggest that the lower induction-related morbidity and mortality and more effective disease control with CPX-351 may allow patients to reach transplant in better condition than if they had been treated with standard 7 + 3.