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The treatment and long-term survival of childhood acute myeloid leukemia (AML) is often complicated by the cardiotoxicity of anthracycline use. CPX-351 is a liposomal preparation of daunorubicin and cytarabine maintained at a 1:5 molar ratio that has demonstrated safety and superior efficacy in adult patients with newly diagnosed, secondary AML, and has already been approved by the U.S. Food and Drug Administration (FDA) and the European Commission in these patients or those with myelodysplasia-related changes.1
In a phase I/II study, AAML1421 (NCT02642965), Todd Cooper and colleagues investigated the use of CPX-351 followed by FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) in children with relapsed/refractory AML (R/R AML). They aimed to determine the recommended phase II dose (RP2D) of CPX-351 and estimate the response rate after two cycles of treatment in children with AML in first relapse.1
Table 1. Baseline patient characteristics1
CNS, central nervous system; CR1, complete response 1; HSCT, hematopoietic stem cell transplant |
|
Characteristic |
% of patients (n = 38) |
---|---|
CNS status |
|
CNS 1 |
81.6 |
CNS 2 |
10.5 |
Unknown |
7.9 |
Cytogenetics |
|
Normal |
13.2 |
Inv (16); t(8;21) |
15.8 |
Monosomy 7 |
5.3 |
11q23 |
15.8 |
Del(7q) |
5.3 |
3q and 13q |
2.6 |
13q only |
2.6 |
Other |
15.8 |
Unknown |
23.7 |
Disease status (length of CR1), days |
|
< 180 |
13.2 |
180–365 |
50.0 |
> 365 |
36.8 |
Prior HSCT |
|
Yes |
26.3 |
No |
73.7 |
Dose-finding phase
Efficacy phase
Table 2. Adverse events by treatment cycle1
CTCAEv4, Common Terminology Criteria for Adverse Events, Version 4 |
||
CTCAEv4 adverse event, % |
Cycle 1 (n = 38) |
Cycle 2 (n = 27) |
---|---|---|
Febrile neutropenia |
44.7 |
22.2 |
Oral mucositis |
2.6 |
— |
Fever |
5.3 |
— |
≥ 1 infections and infestations |
44.7 |
18.5 |
Decreased ejection fraction |
2.6 |
— |
Prolonged QT electrocardiogram |
18.4 |
25.9 |
Rash maculopapular |
39.5 |
3.7 |
None |
10.5 |
48.1 |
Table 3. Treatment response by cycle1
CR, complete remission; CRi, CR with incomplete blood count recovery; CRp, CR with partial recovery of platelet count; ORR, overall response rate; PR, partial response; TF, treatment failure; UE, unevaluable |
|||
Response, % |
Cycle 1 (n = 38) |
Cycle 2 (n = 27) |
Best response (n = 38) |
---|---|---|---|
CR |
37.8 |
48.1 |
54.1 |
CRp |
5.4 |
25.9 |
13.5 |
CRi |
32.4 |
7.4 |
13.5 |
PR |
18.9 |
0.0 |
13.5 |
TF |
5.4 |
18.5 |
5.4 |
UE |
2.6 |
0.0 |
2.6 |
ORR |
75.6 |
81.4 |
81.1 |
The RP2D of CPX-351 in children with R/R AML is 135 units/m2 on Days 1, 3, and 5, as this protocol was effective and demonstrated a manageable toxicity profile. Although there was some cardiac toxicity in terms of Grade 2/3 reduced ejection fraction, all patients recovered during follow-up, which further demonstrates the enhanced safety of this lysosomal preparation. Furthermore, the response rates were superior to those published by the North American Cooperative Group clinical trials for children with AML in first relapse. Taken together, these encouraging results provide the rationale for a randomized study of CPX-351 in children with de novo AML.
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