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Prepublished online as a Blood First Edition Paper on June 7, 2002; DOI 10.1182/blood-2002-01-0172.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Childhood Cancer Research Unit,
Karolinska Institutet, Department of Pediatric Hematology and Oncology,
Karolinska Hospital, Stockholm, Sweden; the Department of Pediatrics,
Stockholm Söder Hospital, Karolinska Institutet, Stockholm,
Sweden; the Onco Ematologia Pediatrica, Ospedale dei Bambini G di
Cristina, Palermo, Italy; the Department of Pediatrics, Leiden
University Medical Center, Leiden, The Netherlands; the Children's
Hospital Medical Center, Cincinnati, OH; the St Anna Children's
Hospital, Vienna, Austria; the Children's Research Hospital, Kyoto
Prefectural University of Medicine, Japan; the Department of
Pediatrics, Yale University School of Medicine, New Haven, CT; the
Children's Research Institute, Washington, DC; the Great Ormond Street
Hospital, London, United Kingdom; the Department of Hematology and
Oncology, Children's University Hospital, Hamburg, Germany.
Hemophagocytic lymphohistiocytosis (HLH) comprises familial
(primary) hemophagocytic lymphohistiocytosis (FHL) and secondary HLH
(SHLH), both clinically characterized by fever, hepatosplenomegaly, and
cytopenia. FHL, an autosomal recessive disease invariably fatal when
untreated, is associated with defective triggering of apoptosis and
reduced cytotoxic activity, resulting in a widespread accumulation of T
lymphocytes and activated macrophages. In 1994 the Histiocyte Society
initiated a prospective international collaborative therapeutic study
(HLH-94), aiming at improved survival. It combined chemotherapy and
immunotherapy (etoposide, corticosteroids, cyclosporin A, and, in
selected patients, intrathecal methotrexate), followed by bone
marrow transplantation (BMT) in persistent, recurring, and/or familial
disease. Between July 1, 1994, and June 30, 1998, 113 eligible patients
aged no more than 15 years from 21 countries started HLH-94. All had
either an affected sibling (n = 25) and/or fulfilled the Histiocyte
Society diagnostic criteria. At a median follow-up of 3.1 years, the
estimated 3-year probability of survival overall was 55% (95%
confidence interval ± 9%), and in the familial cases, 51%
(± 20%). Twenty enrolled children were alive and off therapy for
more than 12 months without BMT. For patients who received
transplants (n = 65), died prior to BMT (n = 25), or were
still on therapy (n = 3), the 3-year survival was 45% (± 10%).
The 3-year probability of survival after BMT was 62% (± 12%).
HLH-94 is very effective, allowing BMT in most patients. Survival of
children with HLH has been greatly improved.
(Blood. 2002;100:2367-2373) Hemophagocytic lymphohistiocytosis (HLH) represents
a spectrum of inherited and acquired conditions with disturbed immune regulation of different severity, and it encompasses 2 main conditions that have common clinical and pathobiological characteristics: familial
(primary) hemophagocytic lymphohistiocytosis (FHL) and secondary
hemophagocytic lymphohistiocytosis (SHLH). In contrast to SHLH, which
may affect any age and which may subside spontaneously, FHL is an
invariably fatal inherited disease seen mostly in infancy and early
childhood.1-3 The annual childhood incidence of FHL has
been estimated (in Sweden) at 1.2 cases per 1 000 000, corresponding to 1:50 000 births.4 Common findings include fever,
hepatosplenomegaly, pancytopenia, and reduced cytotoxic T- and natural
killer (NK)-cell activity, as well as a widespread accumulation of T
lymphocytes and macrophages, some of which may engage in
hemophagocytosis.1-5 Central nervous system (CNS)
involvement is frequent, ranging from irritability, bulging fontanel,
and neck stiffness, to convulsions, cranial nerve palsies, ataxia,
psychomotor retardation, and coma.6-9
A hypercytokinemia, mainly involving proinflammatory cytokines,
mediates the clinical and laboratory findings.10-14 A
defective triggering of apoptosis in FHL was recently suggested as the
underlying pathophysiologic mechanism.15 In 1999, genetic
studies showed linkage to the chromosome regions 9q21.3-22 and 10q21-22
for some, but not all, patients.16-18 Recent studies
revealed perforin gene defects in 10q21-22-linked
FHL-patients,19-21 supporting the hypothesis that FHL, at
least in some patients, is caused by a deficiency in the triggering of
apoptosis.15,19-23 Of differential diagnostic importance
is that a few male patients with HLH recently have been shown to harbor
germline mutations in SH2D1A/SAP, the gene causing X-linked
lymphoproliferative syndrome (XLP).24
Chemotherapy with epipodophyllotoxin derivatives, etoposide (VP-16) and
teniposide (VM-26), combined with corticosteroids and intrathecal
methotrexate (IT MTX) induce remission in FHL.25-27 Remission also can be achieved with immunotherapy, that is,
antithymocyte globulin (ATG) and steroids followed by cyclosporin A
(CSA).28 Ultimately, all FHL patients relapsed and died
until Fischer and coworkers showed that cure could be achieved through
allogeneic bone marrow transplantation (BMT),29 which was
later confirmed by others.30-32
Despite these improvements in treatment, multiple problems
remained, including death prior to or during remission.2
Prompted by these therapeutic difficulties, in 1994 the Histiocyte
Society developed a treatment strategy (HLH-94) that combines (rather than randomizes between) 2 previously reported regimens:
chemotherapy33 and immunotherapy.30 HLH-94 is
based on VP-16, corticosteroids, CSA, and, in selected patients, IT
MTX, prior to intended BMT.34 Herein we present results
for 113 patients, recruited during a 4-year period, with a major focus
on survival and outcome.
Treatment protocol
It is often not possible to differentiate between inherited HLH and
SHLH at diagnosis, unless there is already an affected child in the
family. Most children with the inherited form of the disease will
appear as sporadic cases since the inheritance is autosomal recessive.
Moreover, an association with a viral infection cannot be used to
justify the diagnosis of SHLH, since such infections may be concomitant
with the onset of FHL and even trigger the disease.4,35,36
Because of these difficulties, children with severe or persistent
disease are recommended to start HLH therapy also if there is no
evidence of familial disease. In patients without family history but
with relapsing or nonresponding disease, an underlying inherited defect
is most likely, as in the verified familial ones. On the contrary, in
responding patients that do not relapse when treatment is stopped, a
secondary cause is likely. Genetic analyses may provide a distinct
diagnosis,16-21 but the results are rarely available at
onset of the disease. Moreover, the genetic explanation is presently
known only for a minority of the patients.20
Bone marrow transplantation
Patients
Since it may be difficult and sometimes impossible to distinguish
FHL from SHLH, and since the mortality in SHLH is also
high,35 the HLH-94 protocol, though primarily designed for
the treatment of FHL, was open for all HLH patients. Furthermore, bouts
of FHL may be triggered by infections,36 which is also
true of SHLH, the latter commonly associated with a strong macrophage
activation and often referred to as infection- (virus-) associated
hemophagocytic syndrome (IAHS/VAHS) or malignancy-associated
hemophagocytic syndrome (MAHS).35 Acknowledging these
diagnostic difficulties, the protocol recommended stopping therapy
after 8 weeks for nonfamilial cases with resolved disease, and
treatment was restarted only in cases with reactivation.
Statistical analysis
Overall survival Altogether, 63 (56%) of the 113 children were alive at latest follow-up (median follow-up, 37.5 months). Forty of these 63 patients (63%) had undergone BMT (Table 1). Fifty percent of the deceased children (25/50) had undergone BMT. The estimated 3-year probability of survival of all 113 children is 55% ± 9%, 95% confidence interval (Figure 4A), and if the 9 patients who changed therapy are excluded, the 3-year probability of survival of the remaining 104 children is 59% ± 10% (see Figure 2, bottom line). The 3-year survival in the 88 patients without an affected sibling is 56% ± 11%. If the 20 patients who are alive and off therapy without BMT are not included in the analysis, 43 of 93 (46%) were alive with a 3-year probability of survival of 45% ± 10% (n = 93).
Family history, gender, and age at onset Of the 113 children, 25 (13 M/12 F) had a positive family history, that is, an affected sibling, either at diagnosis (n = 22) or later during the study (n = 3), the oldest being 6 years at onset. The 3-year probability of survival in these 25 patients was 51% ± 20% (Figure 4B). Twenty of these children had a BMT, 13 (65%) of whom are alive. None of the patients with verified familial disease survived without BMT (Table 1), resulting in death from disease at days 2, 64, 89 (after a varicella infection), 111 (changed protocol day 29), and 294, respectively. There was no difference in the 3-year overall survival with regard to gender (data not shown).The mean age at onset was similar in the familial cases (13 months) and
in the patients who received transplants (13 months), whereas
the corresponding age was higher (47 months) in the 20 patients who are
alive and off therapy without BMT (Table
2). Overall, the 3-year probability of
survival was significantly better in children at least 1 year old at
onset (72% ± 13%), compared to children younger than 1 year old
(42% ± 12%) (P < .005). However, if the 20 patients
who are alive and off therapy without BMT are not included in the
analysis, there was no significant difference in survival comparing
these ages at onset (P = .17).
Initial and continuation immunochemotherapy The initial and continuation therapy was successful in altogether 88 of 113 (78%) children, in that they were either admitted for BMT (n = 65) or were still alive at last follow-up (n = 23) (Table 3). Similarly, 80% (20 of 25) of the patients with a positive family history received BMT. Of the 25 deaths during the initial and continuation therapy, 20 were reported as death from disease (at a median of 100 days after onset of therapy, range, 2-899 days), 4 died of toxicity (median, 16 days; range, 6-59), and 1 after a diagnostic biopsy. During the first 2 months of therapy (the initial therapy), 56 patients (53%) achieved a resolution (7 of whom had a reactivation), 34 (32%) improved but had no resolution, whereas 4 (4%) did not improve and 12 (11%) died (starting at day 2) (missing data in 7 patients). Eight children died during the subsequent 4 months, and 5 died more than 6 months after onset of therapy (days 221, 294, 345, 507, and 899) (Figure 1).
Results of BMT Sixty-five children (41 M/24 F) underwent BMT, 40 (62%) (24 M/16 F) of whom are alive. The 3-year probability of survival after BMT is 62% (± 12%) with a median follow-up after BMT in the survivors of 30 months (range, 10-63) (Figure 5) (estimated in 64 patients because of missing date of BMT in 1 child). The median time from onset of therapy to BMT was 187 days (range, 65-995), being 164 days (range, 65-995) in the familial and 217 days (range, 78-933) in the nonfamilial cases. There was no difference in survival when comparing the patients with BMT performed early (n = 32, 62% ± 17%, estimated 3-year-survival) versus late (n = 32, 61% ± 18%) after onset of therapy, using the median time to BMT as the cut-off time. Survival with regard to donor is presented in Table 4. Donor-cell engraftment was achieved in 51 of 57 patients, 2 of the nonengrafted died within 17 days (no data [nd] in 8 additional patients). All surviving BMT patients are free of disease. Among patients alive at BMT + 1year (n = 41), only 1 of 26 patients (nd = 15) had a mixed chimerism.
In the 25 deceased BMT patients, death occurred prior to day +100 in 20 patients, caused by BMT complications (n = 17) or reactivation of HLH (n = 3). One child died at day +121 (261 days after onset of therapy) of a surgical hemorrhage due to a disease unrelated to HLH. The remaining 4 died of reactivation at day +112, Epstein-Barr virus (EBV)-associated lymphoproliferative disease at +152, relapse and subsequent AML at +433, and unclear respiratory disease at +550. Surviving non-BMT patients Altogether, 23 children (8 M/15 F), all without a positive family history, were alive without having received BMT, 20 of whom are off therapy and without evidence of disease for more than 12 months (follow-up range, 1.1-4.2 years; mean, 2.3 years), and 3 have been on therapy for more than 1 year (1.9-2.0 years; 2 on CSA alone, 1 also receives corticosteroids). Ten of the 20 patients off therapy received only initial therapy, and for the 10 patients who started continuation therapy, the mean duration of their total treatment was 359 days. Five of the latter 10 children had a nonactive disease at 2 months, whereas 4 had not received a resolution and 1 had experienced reactivation during the initial therapy. Almost all (19 of 20) of the patients off therapy were older than 12 months at onset (including 4 of the altogether 6 children 6 years and older), and the majority (n = 12; 60%) were reported from East Asia.Neurological symptoms and intrathecal therapy Neurological alterations at onset were reported in 35 of 109 (32%) patients (missing data [md] in 4 patients). At 2 months, with 101 alive patients, neurological alterations were reported in 13 of 95 (14%) patients (md = 6). At the time of BMT, 9 of 53 patients (17%) had neurological alterations (md = 12), and at BMT +100 days 8 of 36 patients (22%) (md = 9). Of the 14 patients with neurological manifestations at onset who underwent BMT and were alive at BMT +1 year, 3 had neurological alterations at that time and 10 had not (md = 1).Patients with neurological alterations at onset (n = 35). At 2 months after onset, 21 of the surviving 31 patients did not have any neurological abnormalities. Intrathecal therapy during the first 2 months, administered to 15 of the 30 survivors (missing data on intrathecal therapy in 1 patient), was associated with normalization of symptoms at 2 months in 10 of 15 individuals. In the patients who did not receive intrathecal therapy, the neurological symptoms also normalized in 10 of 15 children. Patients without neurological alterations at onset (n = 74). Altogether, 68 of these 74 patients survived 2 months, during which time 11 had and 48 had not received intrathecal therapy (md = 9). At 2 months after onset, 3 of these 68 children had neurological alterations (md = 6), 1 of whom had received intrathecal therapy. Prognostic factors The prognostic influence of 2 factors, age at onset and the interval between onset of therapy and BMT, were analyzed, but neither of these factors was associated with significant alterations in overall survival (data not shown).
Untreated FHL is invariably fatal, with a median survival of 1 to
2 months.1 In 1993, a study of 122 patients reported an
estimated overall 5-year survival of 22%.2 Thus, the
present results with an estimated 3-year probability of survival of
51% (± 20%) for the familial cases represents a great improvement. When comparing different HLH reports with regard to therapeutic results, it is important to be aware that the percentage of patients with SHLH may vary and, importantly, our data above refer to children with verified familial disease (Table 5).
This figure also represents a reasonable estimate of the final cure
rate, since few deaths occur later than 3 years after onset of therapy.
In contrast to many reports, our study registered patients
prospectively from diagnosis, not only patients recruited for BMT. The
HLH-94 protocol was effective in a wide range of institutions
internationally, each treating very few cases, and the present report
includes patients from 21 countries.
In FHL, 2 steps are essential for survival: (1) effective initial and continuation therapy, and (2) a successful BMT. Altogether, 20 (80%) of the 25 familial cases, that is, children with an affected sibling, survived the initial and continuation therapy and were admitted for BMT, with only 5 deaths prior to BMT, indicating a high success rate of the immunochemotherapy (Table 3). In the entire study population, a total of 88 of 113 (78%) were either admitted to BMT (n = 65) or still alive without BMT, with at least 1-year follow-up since onset (n = 23). The major toxicity of the pre-BMT therapy was neutropenia, in particular during the first 2 months, but since neutropenia is common also in untreated HLH, it is sometimes difficult to determine to what extent neutropenia was due to therapy or to active disease. The 3-year probability of survival after BMT was 62% in our multi-institutional study (n = 65). It has to considered that only a minority of the BMTs were performed with matched related donors (n = 15). Recent BMT series have reported data ranging from a 3-year probability of survival of 45% (n = 20) to an overall survival of 64% with HLA-nonidentical donors (n = 14) and 100% in a single-center material with matched sibling donors and unrelated donors (n = 12).37-40 High mortality rates have previously been described also in infection-associated HLH (52% in a review of all patients reported in the literature 1979-1996), in particular in EBV-associated HLH.35 Treatment according to HLH-94, without BMT, appears beneficial also in secondary HLH.41 Lack of signs of disease activity during a prolonged period (longer than 12 months) after cessation of therapy, without previous BMT, will most likely suggest the diagnosis of SHLH. The inflammatory meningoencephalopathy in HLH, which may cause severe and permanent CNS dysfunction,6-8 deserves prompt and adequate therapy considering the low regenerative potential of nervous tissue. This was an important rationale for the intensive initial systemic dexamethasone and etoposide therapy in HLH-94. Neurological alterations were reported in 35 of 109 (32%) of the patients at registration. In these 35 affected individuals, the symptoms normalized in 21 of the 31 survivors after 2 months of HLH-94 therapy. The rate of normalization was similar whether intrathecal therapy was used (67%) or not (67%) as an additional treatment to systemic corticosteroids, etoposide, and CSA, but the value of IT MTX was not studied in a randomized fashion. Additional data will be required to better evaluate the value of intrathecal therapy. We speculate that the biology of the remarkably beneficial effects of etoposide in HLH, previously not well understood, may be explained by the recent findings that FHL is associated with a defective triggering of apoptosis,15,19,22 at least in a subset of patients, since etoposide is known to be an excellent initiator of apoptosis.42 In contrast to autoimmune lymphoproliferative syndrome (ALPS) with defective Fas-induced apoptosis, FHL is characterized by lack of (lytic granule-dependent) apoptosis induction, that is, lack of cytotoxic and NK cell-mediated apoptosis but, interestingly, in ALPS as well as in FHL, the result is a lymphoproliferation/nonmalignant accumulation of immune cells.22 Similarly, the effect of dexamethasone might be explained by its anti-inflammatory and proapoptotic properties, particularly valuable since the drug also penetrates well into the CNS, and CSA is known to reduce T-cell activity, which is increased in HLH. An increased incidence of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has been reported following the use of epipodophyllotoxin derivatives.43 Etoposide was included in the present protocol because it previously had shown to have a positive effect in FHL, a disease that without treatment is uniformly fatal. We are aware of 2 reports on AML/MDS in HLH following prolonged use of epipodophyllotoxins,44,45 and here we report a third patient, a child without sustained engraftment after BMT, who relapsed and died of AML on day 552 after onset of therapy (day +433 after BMT). An alternative pre-BMT approach based entirely on immunosuppression (ATG, corticosteroids, CSA, and IT MTX) can also be effective, but it may result in a lower rate of complete remission at the time of BMT as compared to treatment including the highly apoptosis-inducing drug etoposide.38,42 We conclude that the risk of development of MDS/AML in HLH patients following etoposide treatment is limited and acceptable considering its positive therapeutic effects but that prolonged administration of epipodophyllotoxins should be avoided if possible. Whereas HLH traditionally is separated in familial (primary) and secondary HLH, this distinction may not be possible in the initial clinical setting until improved molecular diagnosis is available, but the search for underlying gene mutations is encouraged.46 Proving an acute infection at onset does not have any major therapeutic importance, since not only SHLH but also FHL often features a triggering infectious agent.36 In less severe SHLH cases, either no treatment or a short duration of therapy might suffice, but future studies are necessary to define these subsets, possibly with additional genetic markers. If the disease is familial, relapsing, or severe and persistent even without family history, the BMT from the best available donor is strongly recommended.38-40 Finally, this report also demonstrates the value of international collaboration in conducting clinical studies of rare disorders.
We would like to acknowledge all collaborating colleagues and families. We are also grateful to our data managers Ulrika Kreicbergs, Anna-Maria Hasselgren-Häll, and Martina Löfstedt.
Submitted January 17, 2002; accepted April 23, 2002.
Prepublished online as Blood First Edition Paper, June 7, 2002; DOI 10.1182/blood-2002-01-0172.
Supported by The Children's Cancer Foundation of Sweden; the Medical Research Council of Sweden (#12440); the Cancer Foundation of Sweden; the Ronald McDonald Foundation; the Märta and Gunnar V. Philipson Foundation; The Cancer and Allergy Foundation of Sweden; Telethon Italy (#E755) (M.A.), IRCCS Policlinico San Matteo, Pavia (Ricerca Corrente 390 RCR97/01 and #80291) (M.A.); and the Histiocytosis Association of America.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Jan-Inge Henter, Childhood Cancer Research Unit Q6:05, Karolinska Hospital, S-171 76 Stockholm, Sweden; e-mail: Jan-Inge.Henter{at}kbh.ki.se.
1. Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983;140:221-230[CrossRef][Medline] [Order article via Infotrieve]. 2. Arico M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis: diagnosis, treatment and prognostic factors: report of 122 children from the international registry. Leukemia. 1996;10:197-203[Medline] [Order article via Infotrieve]. 3. Henter J-I, Arico M, Elinder G, Imashuku S, Janka G. Familial hemophagocytic lymphohistiocytosis (primary HLH). Hematol/Oncol Clin North Am. 1998;12:417-433[CrossRef][Medline] [Order article via Infotrieve]. 4. Henter J-I, Elinder G, Öst Å, and the FHL Study Group of the Histiocyte Society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol. 1991;18:29-33[Medline] [Order article via Infotrieve]. 5. Egeler RM, Shapiro RS, Loechelt B, Filipovich AH. Characteristic immune abnormalities in hemophagocytic lymphohistiocytosis. J Pediat Hematol Onc. 1996;18:340-345. 6. Henter J-I, Elinder G. Cerebromeningeal hemophagocytic lymphohistiocytosis. Lancet. 1992;339:104-107[CrossRef][Medline] [Order article via Infotrieve].
7.
Haddad E, Sulis ML, Jabado N, Blanche S, Fischer A, Tardieu M.
Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis.
Blood.
1997;89:794-800 8. Henter J-I, Nennesmo I. Neuropathological findings and neurological symptoms in 23 children with hemophagocytic lymphohistiocytosis. J Pediatr. 1997;130:358-365[CrossRef][Medline] [Order article via Infotrieve]. 9. Henter J-I, Söder O, Öst Å, Elinder G. Incidence and clinical features of familial hemophagocytic lymphohistiocytosis in Sweden. Acta Paediatr Scand. 1991;80:428-435[Medline] [Order article via Infotrieve].
10.
Komp DM, McNamara J, Buckley P.
Elevated soluble interleukin-2 receptor in childhood hemophagocytic histiocytic syndromes.
Blood.
1989;73:2128-2132 11. Howells DW, Strobel S, Smith I, Levinsky RJ, Hyland K. Central nervous system involvement in the erythrophagocytic disorders of infancy: the role of cerebrospinal fluid neopterins in their differential diagnosis and clinical management. Pediatr Res. 1990;28:116-119[Medline] [Order article via Infotrieve].
12.
Henter J-I, Söder O, Hansson M, Elinder G, Andersson B, Andersson U.
Hypercytokinemia in familial hemophagocytic lymphohistiocytosis.
Blood.
1991;78:2918-2922 13. Imashuku S, Ikushima S, Esumi N, et al. Serum levels of interferon-gamma, cytotoxic factor and soluble interleukin-2 receptor in childhood hemophagocytic syndrome. Leukemia Lymphoma. 1991;3:287-292. 14. Henter J-I, Andersson B, Elinder G, Jakobson Å, Lübeck P-O, Söder O. Elevated circulating IL-1 receptor antagonist but not IL-1 agonists in familial hemophagocytic lymphohistiocytosis. Med Pediatr Oncol. 1996;27:21-25[CrossRef][Medline] [Order article via Infotrieve]. 15. Fadeel B, Orrenius S, Henter J-I. Induction of apoptosis and caspase activation in cells obtained from familial haemophagocytic lymphohistiocytosis patients. Brit J Haematol. 1999;106:406-415[CrossRef][Medline] [Order article via Infotrieve]. 16. Ohadi M, Lalloz MR, Sham P, et al. Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am J Hum Genet. 1999;64:165-171[CrossRef][Medline] [Order article via Infotrieve]. 17. Dufourcq-Lagelouse R, Jabado N, Le Deist F, et al. Linkage of familial hemophagocytic lymphohistiocytosis to 10q21-22 and evidence for heterogeneity. Am J Hum Genet. 1999;64:172-179[CrossRef][Medline] [Order article via Infotrieve]. 18. Graham GE, Graham LM, Bridge PJ, et al. Further evidence for genetic heterogeneity in familial hemophagocytic lymphohistiocytosis. Pediatr Res. 2000;48:227-232[Medline] [Order article via Infotrieve].
19.
Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al.
Perforin gene defects in familial hemophagocytic lymphohistiocytosis.
Science.
1999;286:1957-1959 20. Göransdotter Ericson K, Fadeel B, NilssonArdnor S, et al. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am J Hum Genet. 2001;68:590-597[CrossRef][Medline] [Order article via Infotrieve].
21.
Clementi R, zur Stadt U, Savoldi G, et al.
Six novel mutations in the PRF1 gene in children with haemophagocytic lymphohistiocytosis.
J Med Genet.
2001;38:643-646 22. Fadeel B, Orrenius S, Henter J-I. Familial hemophagocytic lymphohistiocytosis: too little cell death may seriously damage your health. Leuk Lymphoma. 2001;42:13-20[Medline] [Order article via Infotrieve]. 23. Arico M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol. 2001;114:761-769[CrossRef][Medline] [Order article via Infotrieve].
24.
Arico M, Imashuku S, Clementi R, et al.
Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene.
Blood.
2001;97:1131-1133 25. Ambruso DR, Hays T, Zwartjes WJ, Tubergen DG, Favara BE. Successful treatment of lymphohistiocytic reticulosis with phagocytosis with epipodophyllotoxin VP 16-213. Cancer. 1980;45:2516-2520[CrossRef][Medline] [Order article via Infotrieve].
26.
Fischer A, Virelizier JL, Arenzana-Seisdedos F, Perez A, Nezelof G, Griscelli C.
Treatment of four patients with erythrophagocytic lymphohistiocytosis by a combination of epipodophyllotoxin, steroids, intrathecal methotrexate and cranial irradiation.
Pediatrics.
1985;76:263-268 27. Henter J-I, Elinder G, Finkel Y, Söder O. Successful induction with chemotherapy including teniposide in familial erythrophagocytic lymphohistiocytosis. Lancet. 1986;2:1402[Medline] [Order article via Infotrieve].
28.
Stephan JL, Donadieu J, Le Deist F, Blanche S, Griscelli C, Fischer A.
Treatment of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins, steroids and cyclosporin A.
Blood.
1993;82:2319-2323 29. Fischer A, Cerf-Bensussan N, Blanche S, et al. Allogeneic bone marrow transplantation for erythrophagocytic lymphohistiocytosis. J Pediatr. 1986;108:267-270[CrossRef][Medline] [Order article via Infotrieve].
30.
Blanche S, Caniglia M, Girault D, Landman J, Griscelli C, Fischer A.
Treatment of hemophagocytic lymphohistiocytosis with chemotherapy and bone marrow transplantation: a single center study of 22 cases.
Blood.
1991;78:51-54 31. Todo S, Fujiwara F, Ikushima S, et al. Allogeneic bone marrow transplantation for familial erythrophagocytic lymphohistiocytosis with high dose VP16-containing conditioning regimen. Leukemia Lymphoma. 1990;1:361-364. 32. Nespoli L, Locatelli F, Bonetti F, et al. Familial hemophagocytic lymphohistiocytosis treated with allogeneic bone marrow transplantation. Bone Marrow Transplant. 1991;7(suppl 3):139-142[Medline] [Order article via Infotrieve]. 33. Henter J-I, Elinder G. Familial hemophagocytic lymphohistiocytosis: clinical review based on the findings in seven children. Acta Paediatr Scand. 1991;80:269-277[Medline] [Order article via Infotrieve]. 34. Henter J-I, Arico M, Egeler M, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. Med Pediatr Oncol. 1997;28:342-347[CrossRef][Medline] [Order article via Infotrieve]. 35. Janka G, Elinder G, Imashuku S, Schneider M, Henter J-I. Infection- and malignancy-associated hemophagocytic syndromes: secondary hemophagocytic lymphohistiocytosis. Hematol/Oncol Clin North Am. 1998;12:435-444[CrossRef][Medline] [Order article via Infotrieve]. 36. Henter J-I, Ehrnst A, Andersson J, Elinder G. Familial hemophagocytic lymphohistiocytosis and viral infections. Acta Paediatr. 1993;82:369-372[Medline] [Order article via Infotrieve].
37.
Baker KS, DeLaat CA, Steinbuch M, et al.
Successful correction of hemophagocytic lymphohistiocytosis with related or unrelated bone marrow transplantation.
Blood.
1997;89:3857-3863
38.
Jabado N, de Graeff-Meeder ER, Cavazzana-Calvo M, et al.
Treatment of familial hemophagocytic lymphohistiocytosis with bone marrow transplantation from HLA genetically nonidentical donors.
Blood.
1997;90:4743-4748 39. Imashuku S, Hibi S, Todo S, et al. Allogeneic hematopoietic stem cell transplantation for patients with hemophagocytic syndrome (HPS) in Japan. Bone Marrow Transplant. 1999;23:569-572[CrossRef][Medline] [Order article via Infotrieve]. 40. Dürken M, Horstmann M, Bieling P, et al. Improved outcome in haemophagocytic lymphohistiocytosis after bone marrow transplantation from related and unrelated donors: a single-centre experience of 12 patients. Br J Haematol. 1999;106:1052-1058[CrossRef][Medline] [Order article via Infotrieve].
41.
Imashuku S, Hibi S, Ohara T, et al.
Effective control of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy.
Blood.
1999;93:1869-1874 42. Martinsson P, Liminga G, Nygren P, Larsson R. Characteristics of etoposide-induced apoptotic cell death in the U-937 human lymphoma cell line. Anticancer Drugs. 2001;12:699-705[CrossRef][Medline] [Order article via Infotrieve]. 43. Pui C-H, Ribeiro RC, Hancock ML, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. New Engl J Med. 1991;325:1632-1687. 44. Henter J-I, Elinder G, Lübeck P-O, Öst Å. Myelodysplastic syndrome following epipodophyllotoxin therapy in familial hemophagocytic lymphohistiocytosis. Pediatr Hematol Oncol. 1993;10:163-168[Medline] [Order article via Infotrieve]. 45. Kitazawa J, Ito E, Arai K, Yokoyama M, Fukayama M, Imashuku S. Secondary acute myelocytic leukemia after successful chemotherapy with etoposide for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Med Pediatr Oncol. 2001;37:153-154[CrossRef][Medline] [Order article via Infotrieve]. 46. Henter J-I. Biology and treatment of familial hemophagocytic lymphohistiocytosis: importance of perforin in lymphocyte-mediated cytotoxicity and triggering of apoptosis. Med Pediatr Oncol. 2002;38:305-309[CrossRef][Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
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  D. Ng, N. Ghosh, and L. K Hicks Hemophagocytic lymphohistiocytosis--late diagnosis in an adult patient BMJ Case Reports, August 17, 2009; 2009(aug17_1): bcr0520091858 - bcr0520091858. [Abstract] [Full Text]
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 S. Cesaro, F. Locatelli, E. Lanino, F. Porta, L. Di Maio, C. Messina, A. Prete, M. Ripaldi, N. Maximova, G. Giorgiani, et al. Hematopoietic stem cell transplantation for hemophagocytic lymphohistiocytosis: a retrospective analysis of data from the Italian Association of Pediatric Hematology Oncology (AIEOP) Haematologica, November 1, 2008; 93(11): 1694 - 1701. [Abstract] [Full Text] [PDF]
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A. Santoro, S. Cannella, A. Trizzino, G. Bruno, C. De Fusco, L. D. Notarangelo, D. Pende, G. M. Griffiths, and M. Arico Mutations affecting mRNA splicing are the most common molecular defect in patients with familial hemophagocytic lymphohistiocytosis type 3 Haematologica, July 1, 2008; 93(7): 1086 - 1090. [Abstract] [Full Text] [PDF]
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 A Trizzino, U z. Stadt, I Ueda, K Risma, G Janka, E Ishii, K Beutel, J Sumegi, S Cannella, D Pende, et al. Genotype phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations J. Med. Genet., January 1, 2008; 45(1): 15 - 21. [Abstract] [Full Text] [PDF]
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 Y. T. Bryceson, E. Rudd, C. Zheng, J. Edner, D. Ma, S. M. Wood, A. G. Bechensteen, J. J. Boelens, T. Celkan, R. A. Farah, et al. Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients Blood, September 15, 2007; 110(6): 1906 - 1915. [Abstract] [Full Text] [PDF]
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 N. Mahlaoui, M. Ouachee-Chardin, G. de Saint Basile, B. Neven, C. Picard, S. Blanche, and A. Fischer Immunotherapy of Familial Hemophagocytic Lymphohistiocytosis With Antithymocyte Globulins: A Single-Center Retrospective Report of 38 Patients Pediatrics, September 1, 2007; 120(3): e622 - e628. [Abstract] [Full Text] [PDF]
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 Y. Kitazawa, F. Saito, S. Nomura, K. Ishii, and E. Kadota A Case of Hemophagocytic Lymphohistiocytosis After the Primary Epstein-Barr Virus Infection Clinical and Applied Thrombosis/Hemostasis, July 1, 2007; 13(3): 323 - 328. [Abstract] [PDF]
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A Santoro, S Cannella, G Bossi, F Gallo, A Trizzino, D Pende, F Dieli, G Bruno, J C Stinchcombe, C Micalizzi, et al. Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis J. Med. Genet., December 1, 2006; 43(12): 953 - 960. [Abstract] [Full Text] [PDF]
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S. Marcenaro, F. Gallo, S. Martini, A. Santoro, G. M. Griffiths, M. Arico, L. Moretta, and D. Pende Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease Blood, October 1, 2006; 108(7): 2316 - 2323. [Abstract] [Full Text] [PDF]
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 H. J. van der Woude, T. S. van der Werf, E. A. M. Verschuuren, R. Y. J. Tamminga, S. Rosati, J. H. J. M. Meertens, and J. G. Zijlstra An 18-year-old man with rapidly progressive multiorgan failure after a positive mononucleosis spot test result. Chest, July 1, 2006; 130(1): 291 - 295. [Full Text] [PDF]
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S. S. Mou, T. A. Nakagawa, E. C. Riemer, T. W. McLean, M. H. Hines, and A. K. Shetty Hemophagocytic Lymphohistiocytosis Complicating Influenza A Infection Pediatrics, July 1, 2006; 118(1): e216 - e219. [Abstract] [Full Text] [PDF]
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E Rudd, K Goransdotter Ericson, C Zheng, Z Uysal, A Ozkan, A Gurgey, B Fadeel, M Nordenskjold, and J-I Henter Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies. J. Med. Genet., April 1, 2006; 43(4): e14 - e14. [Abstract] [Full Text] [PDF]
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M. Ouachee-Chardin, C. Elie, G. de Saint Basile, F. Le Deist, N. Mahlaoui, C. Picard, B. Neven, J.-L. Casanova, M. Tardieu, M. Cavazzana-Calvo, et al. Hematopoietic Stem Cell Transplantation in Hemophagocytic Lymphohistiocytosis: A Single-Center Report of 48 Patients Pediatrics, April 1, 2006; 117(4): e743 - e750. [Abstract] [Full Text] [PDF]
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C. Trambas, F. Gallo, D. Pende, S. Marcenaro, L. Moretta, C. De Fusco, A. Santoro, L. Notarangelo, M. Arico, and G. M. Griffiths A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin Blood, August 1, 2005; 106(3): 932 - 937. [Abstract] [Full Text] [PDF]
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 U. zur Stadt, S. Schmidt, B. Kasper, K. Beutel, A. S. Diler, J.-I. Henter, H. Kabisch, R. Schneppenheim, P. Nurnberg, G. Janka, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11 Hum. Mol. Genet., March 15, 2005; 14(6): 827 - 834. [Abstract] [Full Text] [PDF]
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 G. Janka and U. zur Stadt Familial and Acquired Hemophagocytic Lymphohistiocytosis Hematology, January 1, 2005; 2005(1): 82 - 88. [Abstract] [Full Text] [PDF]
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S Molleran Lee, J Villanueva, J Sumegi, K Zhang, K Kogawa, J Davis, and A H Filipovich Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis J. Med. Genet., February 1, 2004; 41(2): 137 - 144. [Full Text] [PDF]
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 A. S. M. Jawad Systemic juvenile idiopathic arthritis, Kikuchi's disease and haemophagocytic lymphohistiocytosis Rheumatology, February 1, 2004; 43(2): 254 - 254. [Full Text] [PDF]
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 B. Spivack The Differential Diagnosis of Abusive Head Trauma Widens AAP Grand Rounds, September 1, 2003; 10(3): 33 - 34. [Full Text] [PDF]
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L. Rooms, N. Fitzgerald, and K. L. McClain Hemophagocytic Lymphohistiocytosis Masquerading as Child Abuse: Presentation of Three Cases and Review of Central Nervous System Findings in Hemophagocytic Lymphohistiocytosis Pediatrics, May 1, 2003; 111(5): e636 - 640. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
9, 
