Introduction

The WHO 2016 AML-MRC designation applies to AML patients (pts) with a history of myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm, a MDS-related cytogenetic abnormality, or multilineage dysplasia in >50% of ≥2 cell lineages in the absence of NPM1 or biallelic CEBPA mutations. AML-MRC pts typically have a poor prognosis after induction chemotherapy. CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of cytarabine [C] and daunorubicin [D] at a synergistic ratio, is approved by the FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML-MRC. A phase 3 study (NCT01696084) in older pts (60-75 y) with newly diagnosed high-risk/secondary AML found that CPX-351 significantly improved median overall survival (OS) vs conventional 7+3, with a comparable safety profile.

Objectives

An exploratory subgroup analysis of the phase 3 study compared outcomes in pts with AML-MRC who achieved complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi).

Methods

Pts were randomized 1:1 to receive 1-2 induction cycles with CPX-351 (100 units/m² [C 100 mg/m² + D 44 mg/m²] as a 90-min infusion on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m²/d continuously for 7 d [2nd induction: 5 d] + D 60 mg/m² on Days 1-3 [2nd induction: Days 1-2]). Pts achieving CR or CRi could receive up to 2 consolidation cycles with CPX-351 (65 units/m² [C 65 mg/m² + D 29 mg/m²] on Days 1 and 3) or 5+2 (as in 2nd induction). Pts could receive hematopoietic cell transplantation (HCT) at the physician's discretion.

Results

AML-MRC was diagnosed in 246/309 (80%) enrolled pts (123 pts/arm). More AML-MRC pts achieved CR+CRi with CPX-351 (59/123 [48%] vs 40/123 [33%]; odds ratio = 1.83 [95% CI: 1.09-3.09]). Median OS in pts with AML-MRC who achieved CR+CRi was longer with CPX-351 vs 7+3 (Figure 1). The HCT rate in AML-MRC pts with CR+CRi was 54% with CPX-351 vs 43% with 7+3 (relative risk = 1.18 [95% CI: 0.79-1.76]), and OS landmarked from the HCT date was longer with CPX-351 (Figure 2). The safety profile was similar between arms (Table 1), except CPX-351 was associated with longer recovery of neutrophils to ≥500/μL (35 vs 29 d) and platelets to ≥50,000/μL (37 vs 28 d) vs 7+3 in pts who received 1 induction.

Conclusions

CPX-351 improved median OS overall and OS landmarked from the HCT date vs 7+3 chemotherapy in AML-MRC pts who achieved CR+CRi. The CPX-351 safety profile in this subgroup was consistent with the overall study population and known profile of 7+3.

中文翻译：

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CPX-351与7 + 3相比获得缓解的急性髓样白血病伴骨髓增生异常相关变化（AML-MRC）的患者的结果：3期探索性分析

介绍

WHO 2016 AML-MRC名称适用于具有骨髓增生异常综合征（MDS）或MDS /骨髓增生性肿瘤病史，MDS相关的细胞遗传学异常或多谱系发育异常，且≥2个细胞系中≥50％细胞谱系的AML患者（pts）缺乏NPM1或双等位基因CEBPA突变。AML-MRC患者在诱导化疗后通常预后较差。CPX-351（Vyxeos®；柔红霉素和阿糖胞苷注射用脂质体），阿糖胞苷[C]和柔红霉素[D]的双重药物脂质体封装，具有协同作用，已获得FDA和EMA的批准，可用于治疗成人新诊断与治疗有关的AML或AML-MRC。一项对较新的高风险/继发性AML患者（60-75岁）进行的3期研究（NCT01696084）发现，CPX-351与常规7 + 3相比，显着提高了中位总体生存率（OS），并且具有可比的安全性。

目标

3期研究的探索性亚组分析比较了获得完全缓解（CR）或中性粒细胞或血小板恢复不完全（CRi）完全缓解的AML-MRC患者的结局。

方法

将Pt以1：1的比例随机分配，以在第1天，第3天，第90天输注90分钟时用CPX-351（100单位/ m ² [C 100 mg / m ²  + D 44 mg / m ² ]接受1-2个诱导周期）和5 [第二次诱导：第1和3天]）或7 + 3（C 100 mg / m ² / d连续7 d [第二次诱导：5 d] + D 60 mg / m ²在第1-3天[第二次]诱导：1-2天]）。达到CR或CRi的点可以使用CPX-351（在第1天和第3天为65单位/ m ² [C 65 mg / m ²  + D 29 mg / m ² ]）接受最多2个巩固周期或5 + 2（与第二次感应）。Pts可以根据医师的判断接受造血细胞移植（HCT）。

结果

在246/309（80％）入组患者中诊断为AML-MRC（每组123分）。使用CPX-351获得更多AML-MRC分数的CR + CRi（59/123 [48％]对40/123 [33％]；优势比= 1.83 [95％CI：1.09-3.09]）。CPX-351与7 + 3相比，达到CR + CRi的AML-MRC患者的OS中位数更长（图1）。带有CR + CRi的AML-MRC pts中的HCT率在CPX-351中为54％，而在7 + 3中为43％（相对风险= 1.18 [95％CI：0.79-1.76]），从HCT日期开始的OS为里程碑CPX-351的使用寿命更长（图2）。两组之间的安全性特征相似（表1），除了CPX-351与中性粒细胞恢复至≥500 /μL（35 vs 29 d）和血小板恢复至≥50,000/μL（37 vs 28 d）vs 7+有更长的恢复时间相关。接受1次入职培训的pt中有3分。

结论

与获得CR + CRi的AML-MRC患者进行7 + 3化疗相比，CPX-351改善了从HCT至今的总体OS中位数和OS标志性的OS。该亚组中的CPX-351安全性与总体研究人群和已知的7 + 3安全性一致。