Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: Long-term results of the HLH-94 treatment protocol

Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Blood (Impact Factor: 10.43). 09/2011; 118(17):4577-84. DOI: 10.1182/blood-2011-06-356261
Source: PubMed

ABSTRACT Hemophagocytic lymphohistiocytosis (HLH) used to have a dismal prognosis. We report the final results of HLH-94, the largest prospective diagnostic/therapeutic HLH study so far. The treatment includes immunosuppressive and cytotoxic therapy aiming at clinical remission, followed by HSCT in patients with familial, persistent, or recurrent disease. Altogether, 249 patients fulfilled inclusion criteria and started HLH-94 therapy (July 1994-December 2003); 227 (91%) were followed-up for ≥ 5 years. At 6.2 years median follow-up, estimated 5-year probability of survival was 54% ± 6%. Seventy-two patients (29%) died before HSCT, 64 within 1 year, 97% of whom had active disease. In 124 patients who underwent HSCT, 5-year survival was 66 ± 8%; tendency to increased survival (P = .064) in patients with nonactive disease at HSCT. Patients with familial disease had a 5-year survival of 50% ± 13%; none survived without HSCT. Patients deceased during the first 2 months more often had jaundice, edema, and elevated creatinine. Forty-nine patients (20%) were alive without signs of HLH activity and off-therapy > 1-year without HSCT; they presented at older age (P < .001), were more often female (P = .011), and less often had CNS disease (P < .001) or hepatomegaly (P = .007). To conclude, HLH-94 chemoimmunotherapy has considerably improved outcome in HLH. Collaborative efforts are needed to further reduce early mortality, HSCT-related mortality, and neurologic late effects.

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    • "The onset of FHL is often at a very young age and it is almost invariably fatal without treatment; some studies also suggested that younger HLH patients have poor outcome [10] [24]. In addition, Trottestam et al. [10] reported that patients who did not need the hematopoietic stem-cell transplantation were older at onset and more likely to be female . In this study, however, neither age nor sex was related to the fatal outcome. "
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    ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal hematological syndrome that causes a disturbance of the immune system. Overall mortality of HLH is greater than 50% and the majority of patients who die do so within the first 8 weeks of chemotherapy treatment. To find clinical parameters relating to high-risk HLH patients, this study examined associations between an early fatal outcome and potential prognostic clinical factors and laboratory findings on admission. Eighty-nine pediatric HLH patients were prospectively recruited in Children's Hospital No. 1, Ho-Chi-Minh City, Vietnam, during the period from January 2010 to August 2012. Associations between early fatal outcome and clinical and laboratory findings, including a cerebrospinal fluid examination and virological test on admission, were examined. During the 8-week therapy, 25 (28%) HLH patients died. Persistent fever (>2 weeks), severe thrombocytopenia (<75 × 10(9)/L), hyperbilirubinemia, and prolonged activated partial thromboplastin time (APTT) (>33 sec) were significant risk factors of early fatal outcome. Multivariate logistic regression analysis revealed that thrombocytopenia and prolonged APTT (P for trend was 0.054 and 0.013, respectively) were independently associated with the early fatal outcome. Persistent fever, severe thrombocytopenia, hyperbilirubinemia, and prolonged APTT on admission will be useful and practical predictors to determine high-risk HLH patients.
    Pediatric Hematology and Oncology 12/2013; 31(3). DOI:10.3109/08880018.2013.858198 · 0.96 Impact Factor
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    • "Only 14% of patients had a tri-lineage cytopenia, the most common feature of FHLH (Kaito et al, 1997; Trottestam et al, 2011). Neurological involvement, a prominent feature in about 50% of patients with FHLH (Trottestam et al, 2011), was found only in the 9% of our patients as seizures, somnolence or rigour nucalis. Of note, liquor examination was always negative . "
    British Journal of Haematology 06/2013; DOI:10.1111/bjh.12421 · 4.96 Impact Factor
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    • "Genetically defined, or primary, HLH is generally fatal unless treated with immune suppression and ultimately bone marrow transplant (Jordan and Filipovich, 2008; Trottestam et al., 2011). The pathophysiology of HLH has been modeled in Prf1- deficient and Unc13d deficient mice (Jordan et al., 2004; Crozat et al., 2007). "
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    ABSTRACT: Patients with hemophagocytic lymphohistiocytosis (HLH) exhibit immune hyper-activation as a consequence of genetic defects in secretory granule proteins of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. Murine models of HLH demonstrate significant activation of CTL as central to the disease pathogenesis, but evaluation of CTL and NK activation in children with HLH or inflammatory conditions is not well described. CD8 T cells only express granzyme B (GrB) following stimulation and differentiation into CTL; therefore, we reasoned that GrB expression may serve as a signature of CTL activation. It is unknown whether human NK cells are similarly activated in vivo, as marked by increased granule proteins. Perforin and GrB levels are measured in both CTL and NK cells by flow cytometry to diagnose perforin deficiency. We retrospectively compared GrB expression in blood samples from 130 children with clinically suspected and/or genetically defined HLH to age-matched controls. As predicted, CD8 expressing GrB cells were increased in HLH, regardless of genetic etiology. Remarkably, the GrB protein content also increased in NK cells in patients with HLH and decreased following immunosuppressive therapy. This suggests that in vivo activation of NK cells occurs in hyper-inflammatory conditions. We conclude that increased detection of GrB in CTL and NK are an immune signature for lymphocyte activation in HLH, irrespective of genetic subtype and may also be a useful measure of immune activation in other related conditions.
    Frontiers in Immunology 03/2013; 4:72. DOI:10.3389/fimmu.2013.00072
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