Division of Pediatrics Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Division of Pediatric Allergy, Immunology and Bone Marrow Transplant, University of California San Francisco.
JAMA. 2019 Nov 5;322(17):1673-1681. doi: 10.1001/jama.2019.15702.
Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds.
To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018).
Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle.
The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival.
The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole).
Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility.
ClinicalTrials.gov Identifier: NCT01307579.
患有急性髓细胞白血病的儿童、青少年和年轻人存在由酵母和霉菌引起的危及生命的侵袭性真菌感染的高风险。
比较卡泊芬净与氟康唑预防急性髓细胞白血病化疗后中性粒细胞减少期间确诊或可能的侵袭性真菌感染和侵袭性曲霉菌病。
设计、地点和参与者：这项多中心、随机、开放性临床试验纳入了 115 家美国和加拿大机构（2011 年 4 月至 2016 年 11 月；最后一次随访 2018 年 6 月 30 日）新诊断为初发性、复发性或继发性急性髓细胞白血病的 3 个月至 30 岁的患者。
参与者在第一个化疗周期中随机分配至卡泊芬净（n=257）或氟康唑（n=260）预防。预防在每个化疗周期后的中性粒细胞减少期间进行。
主要结局是由盲法中心审查判定的确诊或可能的侵袭性真菌感染。次要结局是侵袭性曲霉菌病、经验性抗真菌治疗和总生存率。
第二次中期疗效分析和基于 394 名患者的非计划无效性分析似乎表明无效性，因此研究停止入组。在随机分组的 517 名参与者中（中位年龄 9 岁[范围 0-26 岁]；44%为女性），有 508 名（98%）完成了试验。23 例确诊或可能的侵袭性真菌感染事件（卡泊芬净 6 例，氟康唑 17 例）包括 14 例霉菌、7 例酵母和 2 例未进一步分类的真菌。卡泊芬净组 5 个月的确诊或可能的侵袭性真菌感染累积发生率为 3.1%（95%CI，1.3%-7.0%），氟康唑组为 7.2%（95%CI，4.4%-11.8%）（总体 P=0.03，对数秩检验），卡泊芬净组确诊或可能的侵袭性曲霉菌病累积发生率为 0.5%（95%CI，0.1%-3.5%），氟康唑组为 3.1%（95%CI，1.4%-6.9%）（总体 P=0.046，对数秩检验）。经验性抗真菌治疗（卡泊芬净 71.9%，氟康唑 69.5%，总体 P=0.78，对数秩检验）或 2 年总生存率（卡泊芬净 68.8%，氟康唑 70.8%，总体 P=0.66，对数秩检验）无统计学显著差异。最常见的毒性反应是低钾血症（卡泊芬净 22 例，氟康唑 13 例）、呼吸衰竭（卡泊芬净 6 例，氟康唑 9 例）和丙氨酸氨基转移酶升高（卡泊芬净 4 例，氟康唑 8 例）。
在患有急性髓细胞白血病的儿童、青少年和年轻人中，与氟康唑相比，卡泊芬净预防侵袭性真菌感染的发生率显著降低。这些发现表明，卡泊芬净可能被考虑用于预防侵袭性真菌感染，尽管由于早期终止研究而限制了研究结果的解释，因为非计划的中期分析似乎表明无效性。
ClinicalTrials.gov 标识符：NCT01307579。
