CPX-351 As First Intensive Therapy for Elderly Patients with AML

Abstract

Background Acute myeloid leukemia (AML) in elderly patients is a poor prognosis disease due to many factors that include disease biology, high risk of treatment-related mortality, co-morbid illnesses, geriatric syndromes, and psychosocial factors such as cognitive decline and social isolation. Such factors make it difficult to administer intensive chemotherapy regimens needed to achieve a durable response in older patients with AML. CPX-351, Vyxeos®, is a fixed combination of the antineoplastic drugs cytarabine and daunorubicin, encased together inside the liposome in a 5:1 molar ratio. CPX-351 preferentially targets leukemic cells to a greater degree than non-leukemic cells in the bone marrow, leading to decreased cytotoxicity against normal hematopoietic cells. Methods Thirty newly-diagnosed AML patients aged ≥65yrs, without upper age limit restriction, were treated with CPX-351 as a first intensive therapy (Table 1). The primary efficacy endpoint was overall survival (OS) and the primary safety endpoint was 30-day mortality. Secondary efficacy endpoints included response rate and duration of response and assessment of the relationship between cognitive function, quality of life, and treatment outcome. Cognitive function was measured using the Montreal Cognitive Assessment (MOCA) and the Blessed Orientation-Memory-Concentration (BOMC) tests. Quality of life was assessed using the Functional Assessment of Cancer Treatment- Leukemia (FACT-Leu) questionnaire. Results Eleven patients (36.6%) achieved complete remission (CR) and 5 patients (16.6%) achieved complete remission with incomplete platelet recovery (CRi). Of these patients, 8 (26.6%) received stem cell transplants. 2 patients (6.6%) died within 30-days. Of the patients who achieved CR/CRi, 5 (16.6%) relapsed after a median remission duration of 120 days. OS at Day-30 was 93.3% and at Day-60 was 86.6%. Median OS for all patients was 14.5 months (Figure 1). Median event-free survival for all patients (defined as the time from Day 1 of treatment to persistent disease (PD) or death) has not been met at 20 months. Patients who had received prior low intensity therapy (n=16) versus those who were treatment naïve (n=14) had a significantly decreased OS (p= 0.027) (Figure 2). Median OS for previously treated patients was 5.6 months, in contrast to treatment naïve patients, who have not met median OS at 20 months. Patients who had received prior low intensity therapy also had a lower CR+CRi rate of 31.5%, in comparison to treatment naïve patients who had a CR+CRi rate of 78.5%. The most common adverse events attributable to CPX-351 were Grade 1-2 rash (20 patients, 66.7%) and Grade 2-3 decrease in left ventricular ejection fraction (LVEF) (6 patients, 20%) (Table 2). Of patients who experienced a decrease in LVEF, 5 recovered to baseline after a median of 59 days. There was a significant increase in BOMC score from baseline (BL) to the end of the first induction (EOI) (p=0.029) (Figure 3) for 29 patients. There was also a non-significant increase in the total MOCA score from BL to EOI (p=0.056) (Figure 3) for 29 patients. In addition, there was an expected overall upward trend in total FACT-Leu score from BL to EOI (n=19). There was also an upward trend in total FACT-Leu score from BL to EOI in patients who achieved CR/CRi (n=12). In contrast, there was a downward trend in total FACT-Leu score from BL to EOI in patients with PD (n=7) (Figure 4). Conclusion: Elderly AML patients can be treated safely with CPX-351 with a low 30-day mortality, a CR+CRi rate of 53.3%, and a prolonged duration of treatment response with median EFS not met at 20m. Although sample sizes for questionnaire data were small, the observed trends toward improved BOMC, MOCA, and FACT-Leu scores suggest that there may be functional cognitive improvement and improved quality of life for elderly patients treated with CPX-351. Disclosures Ritchie: Genentech: Other: Advisory board; Tolero: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board; Celgene: Other: Advisory board; Jazz Pharmaceuticals: Research Funding; Celgene, Novartis: Other: travel support; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Celgene, Incyte, Novartis, Pfizer: Consultancy. Lee:Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Desai:Cellerant: Consultancy; Astex: Research Funding; Astellas: Honoraria; Sanofi: Consultancy; Celgene: Consultancy. Roboz:Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML

“…Furthermore, in a study of "time trade-off " interviews completed by 200 patients to assess adverse effects on health associated with treatment for AML, CPX-351 induction and consolidation were associated with fewer adverse effects when compared to 7 + 3/5 + 2 [10]. Additionally, in a study of older, newly diagnosed patients with AML treated with CPX-351 (n = 19), FACT-Leukemia scores improved after the first CPX-351 induction compared to baseline in the overall population and in patients achieving CR or CRi [11].…”

“…Furthermore, survival prolongation may result from the receipt of additional therapy, which could also be associated with toxicities and negative impacts on patient qualityof-life. Several prior studies have suggested CPX-351 treatment may provide a quality-of-life benefit over conventional chemotherapy [9][10][11]. However, as data on patient-reported quality-of-life are unavailable in the phase 3 study of CPX-351 versus 7 + 3, it was previously unknown whether the survival benefit conferred with CPX-351 treatment consisted of quality time without toxicities or relapse.…”

CPX-351: An Old Scheme with a New Formulation in the Treatment of High-Risk AML

“…Several studies indicated that the treatment with CPX-351 has the ability to produce quality-of-life benefits compared to conventional chemotherapy [ 42 , 44 , 45 , 46 ].…”

Treatment of AML in Older Patients

“…With the liposomal encapsulation both drugs can be delivered in a fixed ratio with the highest proportion of synergy to enhance treatment efficacy [67]. CPX-351 preferentially targets leukaemic cells to a greater degree than non-leukaemic cells in the bone marrow, leading to decreased cytotoxicity against normal haematopoietic cells [68]. A small study of CPX-351 as firstline therapy in 30 newly-diagnosed AML patients ≥65 years showed a promising remission rate of 53.2% with a median OS 14.5 months [68].…”

“…CPX-351 preferentially targets leukaemic cells to a greater degree than non-leukaemic cells in the bone marrow, leading to decreased cytotoxicity against normal haematopoietic cells [68]. A small study of CPX-351 as firstline therapy in 30 newly-diagnosed AML patients ≥65 years showed a promising remission rate of 53.2% with a median OS 14.5 months [68]. In a randomised phase II trial in older adults with untreated AML comparing CPX-351 and conventional '3 + 7' treatment a trend towards increased response rates was observed in the CPX-351 group, 66.7% vs. 51.2%.…”