Two Acute Myeloblastic Leukemia Cases Concomitant with Hemophagocytic Lymphohistiocytosis and Review of the Literature

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Annals of Clinical & Laboratory Science, vol. 43, no. 1, 2013 85 Two Acute Myeloblastic Leukemia Cases Concomitant with Hemophagocytic Lymphohistiocytosis and Review of the Literature

Arzu Akyay1, Tiraje Celkan2, Gülşen İskender3, Ajlan Tükün4, Cihat Ogan3, and Lale Olcay1

1Dr. A.Y. Ankara Oncology Training and Research Hospital, Division of Pediatric Hematology, Ankara; 2İstanbul University Cerrahpaşa Medical Faculty, Division of Pediatric Hematology, İstanbul; 3Dr. A.Y. Ankara Oncology Training and Research Hospital, Division of Infectious Diseases, Ankara; 4Düzen Laboratory, Ankara, Turkey

Abstract. We present two patients with acute myeloblastic leukemia (FAB AML-M7 and AML-M2) complicated by hemophagocytic lymphohistiocytosis (HLH) and relevant literature review. To our knowledge, our first case is the first and youngest patient having AML-M7 associated with HLH reported in the literature. Our cases and cases in the literature highlight the high mortality rate of leukemia associated with HLH and the need for further investigation for the most appropriate therapy.

Key words: acute myeloid leukemia, hemophagocytic lymphohistiocytosis

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a In adults, FHLH may be associated with milder but rare disorder characterised by fever, hepatospleno- often recurrent episodes [3]. Secondary HLH is a megaly, cytopenia, less frequently lymphadenopa- well-recognized entity and is associated with infec- thy (LAP), rash, icterus and neurological symp- tions, autoimmune diseases, immune deficiencies, toms. There are two forms; familial and secondary metabolic diseases, drugs or malignancies [4]. HLH. Familial HLH (FHLH) is an autosomal re- Distinguishing between primary and secondary cessive syndrome with an estimated prevalence of HLH usually necessitates genetic testing due to 1/50,000 live births [1]. More than 70% of FHLH overlapping symptomatic presentations. cases usually present within infancy, and result in death unless treated. Patients with FHLH have mu- All symptoms of HLH can be explained by high tations in perforin (10q21), Munc 13-4 (17q25). concentration of pro-inflammatory cytokines and The rest have mutations in syntaxin-11, Munc 18-2 organ infiltration by activated lymphocytes and his- and other mutations that have not yet been identi- tiocytes [1,2]. The diagnosis of HLH associated fied. In the absence of known gene mutations, the with hematologic malignancies is usually difficult diagnosis of HLH requires that five out of eight di- because HLH findings may be masked by the ma- agnostic criteria of the Histiocyte Society be full- lignant process or because the findings of these two filled [2]. Hematopoietic stem cell transplantation processes may be indistinguishable. Rare cases of (HSCT) is the only curative therapy for these acute myeloid leukemia (AML) with hemophago- patients. cytosis (HPC) by leukemic blasts have been reported [5,6,7]. Herein, we present the cases of two chil- Address correspondence to Lale Olcay, MD; Associate Professor. Dr. A.Y. Ankara Oncology Training and Research Hospital, Division of dren with AML associated with HLH and a review Pediatric Hematology, Ankara, Turkey; phone: 0 312 336 09 09/7448 of the relevant literature. e-mail: [email protected]

duplication and clonal hyperdiploi- dy. NK cell activity, plasma levels of soluble CD25 were not avaible.

Antibiotics were started due to fever, but her fever persisted. Cultures revealed no microor- ganisms. She was diagnosed with AML-M7 concomitant with HLH (persistent fever (1), splenomegaly (2), cytopenia in two cell lines (3), hypertriglyceridemia Figure 1. Megakaryoblasts (a,b) and hemophagocytic histiocytes (c-f) from the bone (492 mg/dl) (4), marrow of case 1 are seen (X100). hyperferritinemia (538 ng/ml) (5), HPC in BM (6), Case Reports supportive evidence of elevated transaminases and LDH). Because the treatment of the malignancy is Case 1. A 10-month-old girl, with parental consan- crucial for resolution of HLH symptoms, AML guinity, was referred because of a seven-day history BFM-98 chemotherapy protocol was started. After of fever, petechia, echymosis, hepatosplenomegaly, the first induction the liver and spleen size dimin- anemia and thrombocytopenia. Physical examina- ished, and BM aspirate revealed remission in leuke- tion revealed pallor, petechia, ecchymosis, and hep- mia with persistent hemophagocytic histiocytes. atosplenomegaly. Investigations showed hemoglo- Thereafter, the patient developed bacterial sepsis. bin (Hb) 68 g/L, hematocrit (Htc) 19.3%, platelet Despite broad-spectrum antibiotics, fever contin- (plt) 31x 109/L, white blood cell count (WBC) ued, and BM aspirate revealed 35% megakaryo- 15x109/L (20% atypical mononuclear cells), abso- blasts with histiocytes HPC. The patient did not lute neutrophil count (ANC) 4.8x109/L, ferritin respond to AML treatment, so the HLH-2004 pro- 538 ng/ml, triglyceride 492 mg/dl, VLDL 163 mg/ tocol [2] was started just as in a few reports in the dl, AST 308 U/L, uric acid 10.6 mg/dl, LDH:14348 literature [5,6]. After the seventh day of therapy U/L, fibrinogen 238 mg/dl. Viral markers were fever subsided completely, so the HLH-2004 pro- negative, including that of Epstein Barr virus tocol was discontinued and the AML HAM block (EBV). BM aspiration revealed 70% megakaryo- was resumed. The patient achieved BM remission blast, and abundant hemophagocytic histiocytes with diminished hemophagocytotic activity after (Figure 1). The blast population was positive for the second induction of therapy. Because there was CD 34, CD41, CD45 and HLA-DR confirming no HLA matched family donor, chemotherapy AML-M7. Cerebrospinal fluid (CSF) was normal, continued. During consolidation therapy she de- cytogenetics revealed 46 XX,+7,+17,t(1;22),1q veloped a catheter infection and disseminated Acute myeloblastic leukemia cases with HLH 87 intravascular coagulation with leukemic relapse in the hemophagocytotic cells. However on the sec- both BM and central nervous system. Despite in- ond month of HLH therapy, BM aspiration re- tensive treatment, the patient expired due to sub- vealed 31% of AML FAB-M2 myeloblasts with arachnoid bleeding 3 months after the diagnosis of persistent HPC. Flow cytometric examination of AML. BM was positive for CD13, CD33, MPO, CD11, HLA-DR. Cytogenetic evaluation revealed 46 XX Case 2. A 6-year-old girl was referred because of and -7. CSF was normal. HLH therapy was stopped fever and cough which had recurred intermittently and AML-BFM 98 treatment was started under an- for three years. It was learned that HPC, pancyto- tibiotic therapy. Because there was no HLA matched penia, and hepatosplenomegaly had been detected family donor, chemotherapy continued. Bone mar- when she was hospitalized due to pneumonia two row remission of AML was achieved after consoli- years ago, but follow-up details could not be dis- dation therapy, but hemophagocytic histiocytes covered. There was first-degree consanguinity be- persisted. The patient subsequently developed a fe- tween her parents. Physical examination revealed brile neutropenia attack and intractable gastrointes- fever, pallor, petechia, multiple cervical, axillary, tinal tract hemorrhage, and expired six months af- inguinal LAP, crepitant rales in the lungs and hepa- ter diagnosis of AML. tosplenomegaly. Hb was 115 g/L, Htc 35.2%, platelets 4 x 109/L, WBC 7.8x109/L, ferritin 147 Discussion ng/ml, triglyceride 177 mg/dl, LDH 386 U/L, fibrinogen 420 mg/dl. EBV was negative. Chest Malignancy-related HLH has been most common- X-ray revealed bilateral pneumonic infiltration. ly reported with lymphomas and leukemias in the CSF was normal. NK cell activity, plasma levels of literature. Lymphoma-associated HLH is more soluble CD25 were not avaible. common in adults than in children [8]. A nationwide survey of 567 patients in Japan showed that The patient had recieved antibiotic treatment for the incidence of HLH associated with leukemia is pneumonia. After pneumonia treatment, thrombo- 0.5% for acute lymphoblastic leukemia (ALL) and cytopenia, fever, hepatosplenomegaly and LAP per- 1.5% for AML [9]. Malignancy-related HLH can sisted with additional leukopenia. One month after occur before, during, or after the onset of malig- first admission, abdominal ultrasonography and nancies. Presumably, high concentrations of in- cervical, thoracal, abdominal CT showed multiple flammatory cytokines (interleukin-1, interleukin-6, LAP. The biopsy of abdominal lymph nodes and tumor necrosis factor α and interferon γ) secreted liver displayed infiltration of histiocytes and seldom by malignant cells play an important role in the HPC. BM aspiration revealed hemophagocytic his- pathogenesis [4,8]. HLH is a poor prognostic fac- tiocytes with erythroid hyperplasia. At that time, tor for patients with hematologic cancers [9,10,11]. her WBC was 1.6x109/L, Hb 92 g/L, plt 8 x 109/L, It is questionable whether chemotherapeutic drugs ANC 0.4x109/L, ferritin 450 ng/ml, triglyceride also trigger HLH [12,13]. It is possible that the 286 mg/dl, LDH 567 U/L, AST 129 U/L, ALT development of leukemia in patients with genetic 231 U/L, fibrinogen 89 mg/dl. Because of persis- HLH mutations might trigger overt HLH, particu- tent fever (1), splenomegaly (2), cytopenia in three larly when combined with infections. Patients with cell lines (3), hypertriglyceridemia (286 mg/dl) (4), abnormalities in FHLH genes may have defective hypofibrinogenemia (89 mg/dl) (5), HPC in BM, immune surveillance of abnormal clones, and as a lymph nodes and liver (6) and supportive evidence result they might have a predisposition to leukemia of elevated transaminases (AST 129 U/L, ALT 231 [11], as is likely in our second case. Santoro et al. U/L ), the HLH-2004 protocol was started. suggest that single amino acid change in perforin Subsequently, liver size decreased with clinical im- A91V gene is significantly associated with the risk provement. BM aspiration, taken on the 15th day of developing childhood ALL [14]. In contrast, of HLH therapy, revealed significant reduction in Mehta et al. conclude that A91V polymorphism is 88 Annals of Clinical & Laboratory Science, vol. 43, no. 1, 2013

[12] [12] [16] [17] [18] [19] [20] [20] [20] Current report 1 Current report 2 [21] [20] [20] [21] [20]

EBV+ EBV+ Aspergillosis Adeno virus Precedent/ Reference concomitant number infection - none EBV NS NS NS NS Diarrhea Parvo virus B19 NS none NS NS Febrile neutropenia

Post Post Post (17 months) (17 Post Pre days (24 Concurrent NS NS Concurrent Timing of HLH pre/ post AML Concurrent Post (After induction) Pre Concurrent NS NS NS Concurrent ) HSCT after Concurrent

- No remissionNo remissionNo - - - - HLH outcome at death remissionNo remissionNo NS CR NS relapse NS remissionNo -

------

AML AML outcome at death AML relapse No remission NS AML relapse NS

Died Died Died in HLH daysDied 47 NS after Died in the AML month3rd relapse Died in 6th GIS month CR months Alive 40th Alive, 15 at Alive and in CR for month Lost to follow up Result days few after Died months within a hemorrhage Died diagnosis after 6 month month16th relapse Died in day 15th Died the on NS 13th AML AML of of diagnosis month diagnosis Alive Alive in 32nd

No Pulse Ig G, HLH- Ig G, Pulse none HLH ment Vin blastine- treated plt. therapy induction none none steroid Vin, cristine Etoposide Pulse steroid Dexa, Etoposide days) months HLH- 2004 therapy (7 2 AML 2004 therapy x before diagnosis Ribavirine, Dexa Dexa, Etoposid none steroid none treat

Chemo Chemo Chemo Chemo Chemo Chemo none AML treat ment Chemo none Chemo Chemo none Chemo Allo HSCT Chemo Chemo Chemo Auto PBSCT

FAB AML AML-M2 AML-M5 AML-M6 AML-M1 AML-M4 AML-M6 AML-M2 AML-M7 AML-M2 AML-M2 AML-M3 AML-M3 AML-M5b AML- M5a AML-M2

Age (year)/ Sex Review the of AML cases with hemophagocytic lymphohistiocytosis the in literature

F 52, M 73, M 76, 64, M M 51, M 59, M 67, F 16, 0.8,F 6, F M F 9.5, F 19, 15, 50, F M 13, M 9,

Table 1. 1. Table No 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 NS: Not stated; Chemo: Chemotherapy; Dexa: dexamethasone; IgG:immunoglobuline G; plt: plateletes; Epstein-Barr EBV: virus; transplantation cell stem HSCT:hematopoietic stem cell transplantation; PBSCT:peripheral blood Acute myeloblastic leukemia cases with HLH 89 not associated with increased risk of childhood markers normalize [22]. Different treatment op- ALL, but it may play a potential role in BCR-ABL tions used for HLH associated with AML were positive leukemia [15]. Genetic markers of HLH summarized in Table 1. were not available for either of our patients or their families. Patient 1 probably had secondary malig- In conclusion, we report two cases of AML associ- nancy-associated HLH triggered by an acute infec- ated with HLH. To the best of our knowledge, the tion, and Patient 2 might have had primary HLH first case we present is the first and youngest patient prior to AML. Cytogenetic abnormalities – t(1;22) with AML-M7 concurrent with HLH in the for our first patient and monosomy 7 for our sec- English literature. These cases highlight the impor- ond one – also contributed to the poor prognosis. tance of clinical consideration of HLH for patients Literature review revealed 14 (9 adults and 5 chil- who have prolonged unexplained fever during on- dren) cases of HLH in the setting of AML. Clinical set or progress of AML, since earlier detection of features of these cases [12,16-21] are summarized HLH in malignancy patients may decrease the high in Table 1. mortality rate with additional therapeutic or supportive measures. Future studies are necessary to Infections also trigger strong immunologic activa- define appropriate treatment modalities for patients tion leading to the manifestation of HLH symp- with HLH-associated AML. toms in patients with hematologic malignancies. 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