Bergsten Elisabet, Horne AnnaCarin, Hed Myrberg Ida, Aricó Maurizio, Astigarraga Itziar, Ishii Eiichi, Janka Gritta, Ladisch Stephan, Lehmberg Kai, McClain Kenneth L, Minkov Milen, Nanduri Vasanta, Rosso Diego A, Sieni Elena, Winiarski Jacek, Henter Jan-Inge
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden.
Blood Adv. 2020 Aug 11;4(15):3754-3766. doi: 10.1182/bloodadvances.2020002101.
We report the largest prospective study thus far on hematopoietic stem cell transplantation (HSCT) in hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. Although all patients with HLH typically need intensive anti-inflammatory therapy, patients with FHL also need HSCT to be cured. In the international HLH-2004 study, 187 children aged <18 years fulfilling the study inclusion criteria (5 of 8 diagnostic criteria, affected sibling, or molecular diagnosis in FHL-causative genes) underwent 209 transplants (2004-2012), defined as indicated in patients with familial/genetic, relapsing, or severe/persistent disease. Five-year overall survival (OS) post-HSCT was 66% (95% confidence interval [CI], 59-72); event-free survival (EFS) was 60% (95% CI, 52-67). Five-year OS was 81% (95% CI, 65-90) for children with a complete response and 59% (95% CI, 48-69) for those with a partial response (hazard ratio [HR], 2.12; 95% CI, 1.06-4.27; P = .035). For children with verified FHL (family history/genetically verified, n = 134), 5-year OS was 71% (95% CI, 62-78) and EFS was 62% (95% CI, 54-70); 5-year OS for children without verified FHL (n = 53) was significantly lower (52%; 95% CI, 38-65) (P = .040; HR, 1.69; 95% CI, 1.03-2.77); they were also significantly older. Notably, 20 (38%) of 53 patients without verified FHL had natural killer cell activity reported as normal at diagnosis, after 2 months, or at HSCT, suggestive of secondary HLH; and in addition 14 (26%) of these 53 children had no evidence of biallelic mutations despite having 3 or 4 FHL genes analyzed (natural killer cell activity not analyzed after 2 months or at HSCT). We conclude that post-HSCT survival in FHL remains suboptimal, and that the FHL diagnosis should be carefully investigated before HSCT. Pretransplant complete remission is beneficial but not mandatory to achieve post-HSCT survival. This trial was registered at www.clinicaltrials.gov as #NCT00426101.
我们报告了迄今为止关于噬血细胞性淋巴组织细胞增生症（HLH）患者造血干细胞移植（HSCT）的最大规模前瞻性研究。HLH是一种危及生命的高炎症综合征，包括家族性/遗传性HLH（FHL）和继发性HLH。虽然所有HLH患者通常都需要强化抗炎治疗，但FHL患者还需要进行HSCT才能治愈。在国际HLH - 2004研究中，187名年龄＜18岁且符合研究纳入标准（8项诊断标准中的5项、有患病同胞或FHL致病基因的分子诊断）的儿童接受了209次移植（2004 - 2012年），这些移植适用于家族性/遗传性、复发或严重/持续性疾病患者。HSCT后5年总生存率（OS）为66%（95%置信区间[CI]，59 - 72）；无事件生存率（EFS）为60%（95% CI，52 - 67）。完全缓解的儿童5年OS为81%（95% CI，65 - 90），部分缓解的儿童为59%（95% CI，48 - 69）（风险比[HR]，2.12；95% CI，1.06 - 4.27；P = 0.035）。对于经证实为FHL的儿童（家族史/基因验证，n = 134），5年OS为71%（95% CI，62 - 78），EFS为62%（95% CI，54 - 70）；未经验证为FHL的儿童（n = 53）5年OS显著较低（52%；95% CI，38 - 65）（P = 0.040；HR，1.69；95% CI，1.03 - 2.77）；他们的年龄也显著更大。值得注意的是,53名未经验证为FHL的患者中有20名（38%）在诊断时、2个月后或HSCT时报告自然杀伤细胞活性正常，提示为继发性HLH；此外，这53名儿童中有14名（26%）尽管分析了3个或4个FHL基因，但没有双等位基因突变的证据（2个月后或HSCT时未分析自然杀伤细胞活性）。我们得出结论，FHL患者HSCT后的生存率仍不理想，在HSCT前应仔细调查FHL诊断。移植前完全缓解有利于实现HSCT后的生存，但并非必需条件。该试验已在www.clinicaltrials.gov上注册，注册号为#NCT00426101。
