Pediatr Blood Cancer 2009;53:491–492
BRIEF REPORT Pediatric Acute Lymphoblastic Leukemia Complicated by Secondary Hemophagocytic Lymphohistiocytosis Omer Devecioglu, MD,1 Sema Anak, MD,1 Didem Atay, MD,2* Pinar Aktan, MD,1 Esra Devecioglu, MD,1 Beril Ozalp, MD,1 and Ebru Saribeyoglu, MD1 Hemophagocytic lymphohistiocytosis (HLH) may be familial or secondary to infections, malignancies, metabolic disorders. Infectious causes are mostly viral and EBV is the mostly frequently seen etiologic agent. In this case, we report a child with acute lymphoblastic leukemia (ALL), who had three episodes of secondary
Key words:
HLH, possibly due to two different viral etiologies, namely CMV and RSV together with her malignancy, during her induction-consolidation treatment. Pediatr Blood Cancer 2009;53: 491–492. ß 2009 Wiley-Liss, Inc.
ALL; familial or secondary HLH; viral infection
INTRODUCTION Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease of activated histiocytes and lymphocytes that commonly occurs in infancy, although it has been seen in all age groups. It may be familial (FHLH) or secondary to infections, malignancies, or metabolic disorders. Infections are mostly viral and EBV is the mostly frequently seen etiologic agent [1–3]. According to Histiocyte Society guidelines, the diagnosis of HLH requires that five out of eight criteria be fulfilled. First, there are the five initial criteria: fever, cytopenia (two of three lineages), splenomegaly, hypertriglyceridemia and/or hypofibrinogemia, hemophagocytosis. Then there are three recent criteria; low or absent NK-cell activity, hyperferritinemia, high plasma levels of soluble CD25 (Soluble 12–2 receptor) [4,5]. In addition, the diagnosis of FHLH is justified by a positive familial history and parental consanguinity is suggestive. Several genetic defects causing FHLH have recently been identified and have elucidated the pathophysiology of HLH [6,7]; such as PRF1, MUNC13-4, STX11. Twenty to fifty percent of all FHL cases, the underlying mutation is still unknown. FHLH can be sporadic with the association of immune deficiencies like Che´diak–Higashi syndrome 1 (CHS 1), Griscelli syndrome 2 (GS 2) and X-linked lymphoproliferative syndrome (XLP). We describe an 18-month-old child with ALL who experienced three episodes of secondary HLH due to two different viral etiologies, namely CMV and RSV together with her malignancy.
CASE REPORT An 18-month-old female, with no parental consanguinity, was receiving treatment for acute precursor B lymphoblastic leukemia (ALL), had her first HLH episode during consolidation therapy just following a CR after her induction period. On the 14th day of consolidation therapy, she developed a febrile neutropenic episode. The fever did not respond to various antibiotic regimens. During the third week, laboratory investigations showed the following: pancytopenia, negative cultures (aerobic, anaerobic, fungal), negative serology for common viruses (EBV, CMV, parvovirus B 19, hepatitis A and B) and Toxoplasma gondii, ferritin 3,394 ng/ml, triglycerides 473 mg/dl, cholesterol 204 mg/dl, ESR: 28 mm/hr, fibrinogen 278 mg/dl. Bone marrow aspirate revealed prominent hemophagocytosis. Intravenous immunglobulin (IVIG) therapy
ß 2009 Wiley-Liss, Inc. DOI 10.1002/pbc.22064 Published online 20 May 2009 in Wiley InterScience (www.interscience.wiley.com)
(0.4 g/kg/day, 3 days) was started but the fever persisted. Serologic tests for viruses were repeated and a high-dose-steroid regimen (30 mg/kg/day 3 days, 20 mg/kg/day 3 days, 10 mg/kg/day 3 days, 2 mg/kg/day 3 weeks) was begun. The fever normalized after 2 days steroids and the patient looked well; a second serologycal test for CMV was positive. Ganciclovir and weekly IVIG were given along with steroids. After 4 weeks, ferritin, triglycerides, cholesterol, ESR levels were normalized and bone marrow aspirate was negative for hemophagocytosis. After these, ALL treatment was restarted from where the consolidation treatment was interrupted. The child then received the interim maintenance, 31=2 months from the first HLH attack, she developed an RSV infection together with three other patients in our department. She had fever and laboratory findings including the following: ferritin 6,040 ng/ml, triglycerides 316 mg/dl, cholesterol 219 mg/dl, ESR: 93 mm/hr, fibrinogen 278 mg/dl together with hemophagocytosis in the bone marrow aspirate. She received five days of IVIG (0.4 g/kg/day) treatment and the findings resolved together with oral ribavirin therapy for RSV infection for three weeks. Ten days after the completion of RSV treatment, the patient developed ascites, weight gain and hyperbilirubinemia while receiving late consolidation treatment. Defibrotide was started for venoocclusive disease, but the next day high fever and pancytopenia recurred. On the sixth day of her febrile neutropenia episode, laboratory parameters were ferritin 10,400 ng/ ml, triglycerides: 98 mg/dl, cholesterol: 140 mg/dl, ESR: 41 mm/hr, fibrinogen: 218 mg/dl. Bone marrow aspirate revealed prominent hemophagocytosis. Steroids (30 mg/kg/day Methylprednisolone 3 days, 20 mg/kg/day 3 days, 10 mg/kg/day 3 days, 2 mg/kg/day 3 weeks) were started together with defibrotide. Her temperature was normal on the second day and after 28 days all parameters and bone marrow examination normalized (Table I). During her followup, hemophagocytosis was positive in her monthly bone marrow aspirates. To protect her from the side-effects of steroids, cyclosporine-A was started and steroids were stopped. She is in a stable — ————— 1
Department of Pediatric Hematology/Oncology/BMT, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey; 2 Department of Pediatric Hematology, Okmeydani Education and Research Hospital, Istanbul, Turkey *Correspondence to: Didem Atay, Kartaltepe mah. Dost sok. Motif apt. No: 5 D:11 Bakirkoy-Istanbul 34144, Turkey. E-mail:
[email protected] Received 10 November 2008; Accepted 20 March 2009
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TABLE I. Laboratory Findings During Hemophagocytic Episodes Ferritin (ng/ml)
ESR (mm/hr)
Cholesterol (mg/dl)
Triglycerides (mg/dl)
Fibrinogen (mg/dl)
First episode (CMV)
3,394
28
204
473
278
Second episode (RSV)
6,040
93
219
316
278
Third episode (VOD)
10,400
41
140
98
218
condition and under close follow-up. Testing for mutations of the PRF1, STX11, or MUNC13-4 genes were negative. She is still receiving cyclosporine-A and IVIG.
DISCUSSION We present a case of HLH, most probably secondary to malignancy (ALL) and/or infections, that was responsive to therapy with IVIG and steroids, but relapsed after various infections. Her NK activity was almost absent and is still low but this could be attributed to her HLH and/or immunosupressive treatment. The expression of CD107 could not be analyzed, but she carries no known mutations in the PRF1, STX11, or MUNC13-4 gene. Zur Stadt et al. demonstrated the mutation of genes known to cause FHL in a Turkish cohort [8]. They found PRF1 mutations in 43%, MUNC 13-4 mutations in 19% and STX11 gene mutations in 19% of the cohort. Although no mutation could be found in our patient, this result does no exclude the diagnosis of FHLH. Over the past two decades, the underlying pathophysiology of HLH has been characterized, although the processes are not entirely understood. A current accepted theory involves an inappropriate immune reaction caused by proliferating and activated T cells associated with macrophage activation and inadequate apoptosis of immunogenic cells [9]. Perforin or pore-forming protein (PFP) maps to 10q22 and is one of the major cytolytic proteins of granules contained in cytotoxic lymphocytes [10]. Patients with perforin deficiency may have impaired defenses against intracellular pathogens and cancers, as has been demonstrated in animal models. As NK cell function or activity is decreased in up to 90% of patients, it is one of the most useful laboratory tests. NK cell number is usually not diagnostic. Secondary HLH, presumably due to two viral agents in combination with a malignancy, is a rare clinical entity, but a primary HLH should also be suspected. 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. Proving an acute infection at onset has a therapeutic importance, when infection is treatable.
Pediatr Blood Cancer DOI 10.1002/pbc
Therapy IVIG therapy (0.4 g/kg/day, 3 days) high-dose-steroid regimen (30 mg/kg/day 3 days, 20 mg/kg/day 3 days, 10 mg/kg/day 3 days, 2 mg/ kg/day 3 weeks) IVIG therapy (0.4 g/kg/day) with oral ribavirin therapy for RSV infection for 3 weeks High-dose-steroid regimen (30 mg/kg/ day 3 days, 20 mg/kg/day 3 days, 10 mg/kg/day 3 days, 2 mg/kg/day 3 weeks) with defibrotide
In our case, although responsive to immune suppressive agents such as IVIG, steroids, cyclosporine-A, this therapeutic effect was transient and a relapsing pattern was still observed. During her follow-up, hemophagocytosis was positive in her monthly bone marrow aspirates at a low level, so to potentially protect her from the side-effects of steroids, cyclosporine-A was started and steroids were stopped. This case raises the question of whether sporadic cases of harbor a cryptic genetic predisposition to HLH. Future studies are necessary to define additional genetic markers.
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