The outcome of hematopoietic stem cell transplantation in Korean children with hemophagocytic lymphohistiocytosis

Yoon HS, Im HJ, Moon HN, Lee JH, Kim H‐J, Yoo KH, Sung KW, Koo HH, Kang HJ, Shin HY, Ahn HS, Cho B, Kim HK, Lyu CJ, Lee MJ, Kook H, Hwang TJ, Seo JJ. The outcome of hematopoietic stem cell transplantation in Korean children with hemophagocytic lymphohistiocytosis.
Pediatr Transplantation 2010: 14:735–740. © 2010 John Wiley & Sons A/S. Abstract: Chemoimmunotherapy‐based treatments have improved the survival of patients with HLH, but outcomes of the patients are still unsatisfactory. We report here the outcome of Korean children with HLH who underwent HSCT, which was analyzed from the data of a nation‐wide HLH registry. Retrospective nation‐wide data recruitment for the pediatric HLH patients diagnosed between 1996 and 2008 was carried out by the Histiocytosis Working Party of the Korean Society of Hematology. Nineteen patients who received HSCT among the total of 148 enrolled children with HLH were analyzed for the transplant‐related variables and events. The probability of five‐yr survival after HSCT was 73.3% with a median follow‐up of 57. Two months compared to 54.3% for the patients who were treated with chemoimmunotherapy only (p = 0.05). The reasons for HSCT were active disease after eight wk of initial treatment (n = 9), relapsed disease (n = 5), and FHL (n = 5). Fourteen patients are currently alive without disease after HSCT, four patients died of treatment‐related events (infection in two and graft failure in two) at early post‐transplant period, and one patient died of relapse at one yr post transplantation. The survival of patients who were transplanted because of active disease after eight wk of initial treatment was worse compared to those patients who had inactive state at that time (60.6% vs. 100%, respectively, p = 0.06). Of the four patients who received transplants using cord blood, three died of graft failure (n = 2) and relapse (n = 1). The five‐yr probability of survival after HSCT according to the donor type was 85.7% for the MRDs (n = 6), 87.5% for the MUDs (n = 8), and 40% for the MMUDs (n = 5) (p = 0.03). Other variables such as age, CNS involvement at the time of diagnosis, the etiology of HLH (familial or secondary), and the conditioning regimens had no influence on the five‐yr OS of the HLH patients who underwent HSCT. HSCT improved the survival of the patients who had familial, relapsed, or severe and persistent SHLH in the Korean nation‐wide HLH registry. Although numbers were small, these results are similar to other reports in the literature. The disease state after initial treatment, the stem cell source of the transplant, and the donor type were the important prognostic factors that affected the OS of the HLH patients who underwent HSCT.     

Rotavirus‐associated hemophagocytic lymphohistiocytosis (HLH) after hematopoietic stem cell transplantation for familial HLH

Hemophagocytic lymphohistiocytosis (HLH) is a life‐threatening disorder of immune regulation. HLH consists of two forms: familial and acquired, the latter which occurs in association with infection, malignancy, rheumatic disease and acquired immune deficiency. Herein, we report a case of acquired HLH in a child who had received allogeneic hematopoietic stem cell transplantation for familial HLH with UNC13D mutation. Based on microbiology, only rotavirus was identified as a possible organism triggering HLH. The patient's fulminant clinical course included acute respiratory failure, a sepsis‐like pattern, disseminated intravascular coagulopathy, and rhabdomyolysis, leading to multiorgan failure and death from septic shock.     

Allogeneic hematopoietic stem cell transplantation is associated with cure and durable remission of late‐onset primary isolated central nervous system hemophagocytic lymphohistiocytosis

Primary isolated CNS presentation of HLH is exceedingly rare and typically associated with significant morbidity and mortality. We describe an adolescent patient with late‐onset, primary isolated CNS HLH and a compound heterozygous PRF1 mutation (c50delT (p.L17 fs); c.1229G>C (p.R410P)), not previously reported with this phenotype. He was successfully treated with allogeneic HSCT following a reduced‐intensity conditioning regimen, despite a high pre‐HSCT comorbidity index. Two years after transplant, he is alive and in disease remission. While patients with systemic HLH and active CNS disease have relatively poorer outcomes, a high index of suspicion may aid with early diagnosis of primary isolated CNS HLH; prompt treatment with HSCT may be associated with improved cure and durable remission of this rare disease.     

Haploidentical hematopoietic stem cell transplantation with post‐transplant high‐dose cyclophosphamide in high‐risk children: A single‐center study

Recently, haploidentical transplantations have been performed with unmanipulated BM or PBSC. This approach is becoming more widely adopted with the use of PTCY. However, there is limited evidence about this approach in children. We present 15 children who received 16 haploidentical HSCT with unmanipulated BM or PBSC using PTCY for GVHD prophylaxis. Post‐transplant CY(50 mg/kg IV) was given on the third and fifth day, and CsA or tacrolimus with MMF or MP was also used for GVHD prophylaxis. All patients engrafted at a median of 16 and 18 days for neutrophil and thrombocyte recovery, respectively. Grades II–III acute GVHD developed in seven patients, and mild chronic GVHD was found in two patients. Two patients died within the first 100 days due to sepsis (TRM 12.5%). Eleven patients are currently alive, with a median follow‐up of 12 months (range 6–22 months). The 12‐month OS and DFS were 75 ± 10.8% and 68.8 ± 11.6%, respectively. Our results with these high‐risk patients are encouraging for haploidentical HSCT in pediatric patients. Future studies should continue to assess haploidentical HSCT, including comparison of other modalities, in a primary pediatric population.     

Life-threatening hemophagocytic syndromes: Current outcomes with hematopoietic stem cell transplantation

Abstract:  Life-threatening hemophagocytic syndromes represent a subset of genetic disorders of inflammation. Many are rapidly lethal and can only be definitively treated at the present time with allogeneic hematopoietic stem cell transplantation (HSCT). In this report, current results with allogeneic transplantation for Hemophagocytic Lymphohistiocytosis (HLH) are described. HLH typically presents symptomatically during infancy and early childhood and can be identified by a constellation of numerous physical findings and laboratory tests indicative of overwhelming inflammation. The majority of patients with familial HLH lack natural killer (NK) cell function; in approximately 50% of cases the specific underlying genetic cause can now be discerned. Effective treatment consists of initial combination therapy with proapoptotic chemotherapy (typically etoposide) and anti-inflammatory therapies (principally steroids) in addition to aggressive supportive care, followed by allogeneic HSCT from the best available donor. Over the past 25 yr, through collaborative worldwide efforts, survival of children with HLH and related disorders has improved from 5% at 1 yr after diagnosis to greater than 50% 3–5 yr after diagnosis.     

异基因造血干细胞移植治疗噬血细胞综合征

噬血细胞综合征又称噬血细胞性淋巴组织细胞增生症,分为原发性和继发性两大类.对于家族性噬血细胞综合征(familial hemophagocytic lymphohistiocytosis,FHL)和难治性EB病毒相关噬血细胞综合征(EBV-HLH),异基因造血干细胞移植是目前唯一有效的治疗手段,但其鉴别诊断尤为困难,移植后多种并发症以及高病死率也受到越来越多人的关注.该文总结了近年来异基因造血干细胞移植治疗FHL和难治性EBV-HLH在诊断、预处理方案、移植后并发症、死亡原因分析及预后等方面的研究进展.     

The role of allogeneic hematopoietic stem cell transplantation and Epstein‐Barr virus infection on the treatment for child primary hemophagocytic lymphohistiocytosis patients with X‐linked lymphoproliferative disease: A rare case report and family survey study

XLP‐2 is known as a rare primary immunodeficiency disease, which is characterized by the susceptibility to EBV infection and potential development into the pHLH. The existing studies believe that the dysfunction of XIAP represents one of the most significant pathogenic mechanisms of XLP‐2, and allo‐HSCT is regarded as a crucial treatment for the long‐term survival in XLP‐2 patients. In our present study, a 2‐year‐old male patient was diagnosed with XLP‐2. After receiving chemotherapy by using HLH‐2004 without allo‐HSCT, he reached a complete remission, and his EBV load was brought under control. Our family survey revealed a novel frameshift mutation in the XIAP gene in this patient, as well as in his cousin and grandfather. Until now, the patient has been followed up for 22 months with no recurrence reported yet. Based on these findings, it is believed that for child pHLH patients with XLP‐2, the treatment by controlling symptoms alone without allo‐HSCT and with regular monitoring of EBV load could be conducive to a long‐term survival.     

The yield of monitoring adenovirus in pediatric hematopoietic stem cell transplant patients

Human adenovirus (HAdV) is recognized as a serious pathogen after allogeneic hematopoietic stem cell transplantation (HSCT), causing morbidity and mortality. Currently, there is no universal agreement regarding routine HAdV surveillance after HSCT. We assessed the impact of HAdV weekly monitoring by polymerase chain reaction (PCR) on HAdV viremia rates and the risk factors that influence survival. Three-hundred and fifty-six pediatric allogeneic HSCT were done between 2007 and 2015. Until July 2011, HAdV testing was performed based on clinical suspicion (cohort 1, n?=?175) and from August 2011, weekly blood-HAdV monitoring was done (cohort 2, n?=?181) until day +100. Twenty-three patients (4 [2.3%] from cohort 1 and 19 [10.5%] from cohort 2, p?=?.001) were found with HAdV viremia and seven of them died. Both cohorts had a similar incidence of HAdV-associated mortality (3/175; 1.7% in cohort 1 and 4/181; 2.2% in cohort 2). Respiratory failure was the cause of death in all patients. Clinical symptoms appeared prior to or within 5?days of HAdV detection in cohort 2. In summary, weekly monitoring was associated with higher detection of HAdV. The study could not assess survival benefit due to small numbers of HAdV-positive cases. In many instances, symptoms occurred with the development of positive HAdV blood PCR results and hence, symptomatology could have triggered the test. Future studies are needed to provide data that help establishing a uniform approach for regular monitoring of HAdV post-transplant.     

Secondary hemophagocytic syndrome after autologous hematopoietic cell transplant and immune therapy for neuroblastoma

Secondary hemophagocytic syndrome (HPS) has been described after autologous hematopoietic cell transplant (AutoHCT). We report two cases of secondary HPS after novel consolidation therapy for high‐risk neuroblastoma as part of an institutional phase 2 trial incorporating immunotherapy into a “standard” AutoHCT regimen. Both patients developed liver dysfunction beyond expected course of hepatic veno‐occlusive disease, coagulopathy, hyperferritinemia, and when evaluated, elevated soluble interleukin‐2 receptor and hemophagocytosis. These cases highlight the need for clinicians to have a high index of suspicion for immune‐related complications in patients receiving immune therapies.     

Autoimmune hemolytic anemia and immune thrombocytopenia following hematopoietic stem cell transplant: A critical review of the literature

Autoimmune cytopenias (AIC) post‐hematopoietic stem cell transplant (HSCT) are rare but exceptionally challenging complication. We conducted a comprehensive literature review and identified a pooled incidence of post‐HSCT autoimmune hemolytic anemia and/or immune thrombocytopenia of 2.66% (SE = 0.27) in pediatric patients. Nonmalignant disease, unrelated donor transplant, peripheral or cord blood stem cell source, conditioning regimen without total body irradiation, and presence of chronic graft‐versus‐host disease were prominent risk factors. Treatment was highly variable, and cytopenias were commonly refractory. AIC represent a significant post‐HSCT complication. We report here the incidence, risk factors, and possible biology behind the development of AIC in pediatric post‐HSCT patients.     

噬血细胞综合征治疗后继发急性白血病2例报告并文献复习

目的探讨噬血细胞综合征(HLH)治疗后继发急性白血病的临床特征及预后。方法收集2例EB病毒相关HLH(EBV-HLH)患儿在接受化疗后继发急性白血病的临床资料,并复习相关文献。结果 2例患儿均为男性,分别为4岁、7岁,均接受HLH-2004方案化疗,依托泊苷(VP 16)的累积量分别为1 500 mg/m2及3 900 mg/m2;例1于首次化疗18个月后继发急性早幼粒细胞白血病(M3),予维甲酸加柔红霉素诱导化疗后达完全缓解(CR),此后规则化疗,随访30个月,持续CR;例2于首次化疗50个月后继发急性单核细胞白血病(M5),予化疗后达CR,但于诊断急性白血病15个月后复发,继予造血干细胞移植后再次达CR,此后随访1年,持续CR。2例患儿加文献报道13例HLH接受化疗后继发急性白血病患儿,共15例患儿,男10例、女5例,中位年龄2岁6个月(4个月～19岁),VP16的累积剂量中位数3 900 mg/m2(400～20 975 mg/m2),HLH与继发白血病的间隔中位时间24个月(6～72个月)。15例患儿中,5例M3,只接受化疗,均无病存活;10例其他类型急性白血病,3例接受化疗(1例死亡、2例不明),6例造血干细胞移植(3例存活、3例死亡);1例放弃治疗。结论 HLH治疗后继发的急性白血病多为急性髓系白血病,其中急性早幼粒细胞白血病接受维甲酸为基础的联合化疗,预后良好;而其他类型急性白血病预后差,造血干细胞移植或可改善预后。     

Sensorineural hearing loss in a case of familial hemophagocytic lymphohistiocytosis

Severe sensorineural hearing loss (bilateral >80 dB) was diagnosed in a case of familial hemophagocytic lymphohistiocytosis (FHL). The female patient developed HLH at 3 months of age and underwent allogeneic cord blood transplantation at 11 months of age following 7 months of immuno-chemotherapy. The type 2 FHL patient had a homozygous perforin gene mutation of 1090-1091delCT, and was noted to have hearing loss at 3.5 years of age. Retrospective evaluation did not clarify the exact causes of hearing loss. Reports on Kawasaki disease, suggesting a correlation between severe inflammatory status in infancy and the development of sensorineural hearing loss, may shed some light on this rare complication in this case of FHL. Considering the markedly improved prognosis of FHL due to recent advances made in the molecular diagnosis and in the management including allogeneic hematopoietic stem cell transplantation, auditor by screening might be warranted for surviving FHL patients.     

Pre- and post-natal treatment of hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare autosomal recessive disorder of infancy and childhood that is invariably fatal if not treated. We report on the first patient to receive post-natal HSCT for HLH after receiving in utero chemotherapy for disease stabilization.