加拿大多伦多病童医院Lillian Sung联合美国宾夕法尼亚州费城儿童医院Brian T. Fisher研究小组比较了卡泊芬净与氟康唑预防儿童和青年急性髓系白血病侵袭性真菌病的疗效。2019年11月5日出版的《美国医学会杂志》发表了这项成果。

2011年4月至2016年11月，研究组在美国和加拿大的115家医疗机构进行了一项多中心、随机、开放标签的临床试验，招募了517名年龄为3个月至30岁，最近确诊为初发、复发或继发的急性髓系白血病患者。在第一个化疗周期中，将患者随机分组，其中257名接受卡泊芬净治疗，260名接受氟康唑治疗。之后在每个化疗周期的中性粒细胞减少期进行预防性治疗。

共有508名（98%）患者完成了试验。两组中共发生23例已证实或可能的侵袭性真菌病，其中卡泊芬净组6例，氟康唑组17例，包括14例霉菌，7例酵母菌和2例不明真菌。卡泊芬净组已证实或可能的侵袭性真菌病的5个月累积发病率为3.1%，显著低于氟康唑组（7.2%）；卡泊芬净组已证实或可能的侵袭性曲霉菌病的5个月累积发病率为0.5%，显著低于氟康唑组（3.1%）。

卡泊芬净组和氟康唑组经验性抗真菌治疗率分别为71.9%和69.5%，2年总生存率分别为68.8%和70.8%，差异均无统计学意义。关于毒副反应，卡泊芬净组中发生低钾血症22例，呼吸衰竭6例，丙氨酸转氨酶升高4例，氟康唑组则分别为13例、9例和8例。

综上，对于儿童、青少年和青年急性髓系白血病，与氟康唑相比，卡泊芬净能显著降低侵袭性真菌病的发生率，可用于预防性治疗。但由于试验提前终止，该结论仍有待进一步验证。

附：英文原文

Title: Effect of Caspofungin vs Fluconazole Prophylaxis on Invasive Fungal Disease Among Children and Young Adults With Acute Myeloid Leukemia: A Randomized Clinical Trial

Author: Brian T. Fisher, Theoklis Zaoutis, Christopher C. Dvorak, Michael Nieder, Danielle Zerr, John R. Wingard, Colleen Callahan, Doojduen Villaluna, Lu Chen, Ha Dang, Adam J. Esbenshade, Sarah Alexander, Joseph M. Wiley, Lillian Sung

Issue&Volume: 2019/11/05

Abstract: 

Importance  Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds.

Objective  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).

Interventions  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.

Main Outcomes and Measures  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.

Results  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).

Conclusions and Relevance  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.

DOI: 10.1001/jama.2019.15702

Source: https://jamanetwork.com/journals/jama/article-abstract/2753898