Cardiotoxicity of CPX-351 in children and adolescents with relapsed AML: a Children's Oncology Group report.

Introduction: Anthracyclines are effective in treating acute myeloid leukemia (AML) but limited by cardiotoxicity. CPX-351, a liposomal daunorubicin and cytarabine, may provide therapeutic benefit with less cardiotoxicity. Acute changes in left ventricular systolic function and cardiac biomarkers were evaluated after a cycle of CPX-351 in children with relapsed AML treated on the phase 1/2 Children's Oncology Group study, AAML1421. Methods: Subjects received 135 units/m2/dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/- 1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 left ventricular ejection fraction (LVEF) with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of ≥10%-<50%. Results: Twenty-five of 38 heavily anthracycline pre-treated (median 348 mg/m2 daunorubicin equivalents) subjects enrolled on AAML1421 were included in the cardiac analyses. At baseline, centrally quantitated LVEF was <50% in 8 of 25 subjects (32%) with a median LVEF of 53.8% [48.0, 56.9]. Following CPX-351, LVEF declined significantly (ΔLVEF -3.3% [-7.8, 0]) and 6 of 25 subjects (24%) experienced CTRCD. Amongst all subjects, hs-cTnT was modestly increased at end of cycle 1 compared to baseline [baseline hs-cTnT 7.2 (3, 10.6); ΔcTnT 1.80 (0, 6.1), p = 0.03]. NT-proBNP remained stably elevated without significant change. No significant associations were seen between NT-proBNP or cTnT levels and post-CPX-351 LVEF. Discussion: In this single arm study of anthracycline pre-treated children exposed to CPX-351, baseline abnormalities in cardiovascular function were prevalent. Following CPX-351, LVEF decreased, cTnT increased, and NT-proBNP did not change. Longer follow-up is needed to determine whether these changes result in clinically meaningful long-term decrements in cardiac function. An ongoing randomized trial of CPX-351 compared to standard anthracyclines in anthracycline naïve patients will provide further insight into the cardiac effects of CPX-351 (ClinicalTrials.gov; NCT04293562).

Rationale and design of the Children's Oncology Group study AAML1831 integrated cardiac substudies in pediatric acute myeloid leukemia therapy.

Background: Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in de novo pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of de novo pediatric AML. Methods/design: Children (age <22 years) with newly diagnosed AML were enrolled and randomized to CPX-351-containing induction 1 and 2 (Arm A) or standard daunorubicin and dexrazoxane-containing induction (Arm B). Embedded cardiac correlative studies aim to compare the efficacy of this liposomal anthracycline formulation to dexrazoxane for primary prevention of cardiotoxicity by detailed core lab analysis of standardized echocardiograms and serial cardiac biomarkers throughout AML therapy and in follow-up. In addition, AAML1831 will assess the ability of early changes in sensitive echo indices (e.g., global longitudinal strain) and cardiac biomarkers (e.g., troponin and natriuretic peptides) to predict subsequent LVSD. Finally, AAML1831 establishes expert consensus-based strategies in cardiac monitoring and anthracycline dose modification to balance the potentially competing priorities of cardiotoxicity reduction with optimal leukemia therapy. Discussion: This study will inform diagnostic, prognostic, preventative, and treatment strategies regarding cardiotoxicity during pediatric AML therapy. Together, these measures have the potential to improve leukemia-free and overall survival and long-term cardiovascular health in children with AML. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04293562.

Phase II study of liposome-encapsulated doxorubicin plus cyclophosphamide, followed by sequential trastuzumab plus docetaxel as primary systemic therapy for breast cancer patients with HER2 overexpression or amplification.

PURPOSE OF THE STUDY: Trastuzumab combined with sequential chemotherapy with taxanes and anthracyclines as primary systemic therapy achieved high rates of pathologic complete response (pCR). Non-pegylated liposome-encapsulated doxorubicin (NPLD) has shown equal efficacy but minor cardiotoxicity compared to doxorubicin. This phase II study aimed to evaluate the activity and safety of trastuzumab with sequential chemotherapy for early or locally advanced HER2 positive BC. METHODS: Preoperative treatment included NPLD (60 mg/mq iv) plus cyclophosphamide (600 mg/mq iv) every 3 weeks for 4 cycles followed by docetaxel (35 mg/mq iv) plus trastuzumab (4 mg/mq loading dose iv, then 2 mg/mq iv) weekly for 16 weeks. Primary endpoint was pCR defined as the absence of residual invasive cancer both in the breast and regional nodes. Clinical staging was exploratory evaluated by CT-PET. RESULTS: 43 pts were treated from december 2005 to September 2011, 39 of them were evaluable for the purpose of study. Median age was 53 years (range: 31-78), the majority of pts had tumour stage cT2 (63%), tumour grade 3 (86%), clinical nodes involvement N+ (77%), ER positive (56%) and Ki-67 ≥20% (77%). pCR was reported in 19 (49%) of 39 pts. There was an association between Ki-67 ≥20% at baseline and pCR (p = 0.018). No cardiac toxicity or discontinuation of trastuzumab was reported. CT-PET modified the clinical stage for 10 patients showing new loco-regional lymph nodes. CONCLUSIONS: This study confirms that integrating anti-HER2 therapy in primary treatment for HER2 positive breast cancer is active. NPLD is a safe option to minimize cardiotoxicity.