Haemophagocytic lymphohistiocytosis occurred during induction chemotherapy in an acute monocytic leukemia patient with FLT3-ITD and DNMT3A mutations

Haemophagocytic lymphohistiocytosis occurred during induction chemotherapy in an acute monocytic... Background: Haemophagocytic lymphohistiocytosis (HLH) is considered to be a large challenge for clinicians due to the variable overlaps of symptoms with other severe diseases and a high rate of mortality. Prompt diagnosis and treatment are crucial to avoid a fatal outcome. However, very limited reports have focused on HLH during chemotherapy (Ch-HLH) due to a low incidence and insufficient knowledge. Case presentation: A 22-year-old male was diagnosed with acute monocytic leukemia with FLT3-ITD and DNMT3A mutations and pulmonary infection. He received IA regimen (Idarubicin, 8 mg/m2/d for 3 days and cytarabine, 100 mg/m2/d for 7 days) chemotherapy, anti-infection drugs and blood components transfusions. During the stage of 9 9 bone marrow suppression, he presented with a fever, cytopenia (WBC, 0.43 × 10 /L; Hb, 73 g/L and PLT, 1 × 10 /L), refractory coagulation dysfunction (APTT, 104.0 s; PT, 30.5 s and Fbg, 0.87 g/L), splenomegaly (3 cm below the costal margin), hyperferritinemia (SF > 3000 μg/L), increased soluble interleukin-II receptors (sIL-2R > 7500 u/mL) and haemophagocytosis in the bone marrow and was diagnosed with HLH. After he was treated with methylprednisolone at 500 mg/d for 3 days, 120 mg/d for 3 days and 80 mg/d for 3 days, followed by a gradually reduced dose combined with powerful anti-infection drugs, his symptoms subsided and his abnormal parameters recovered to normal levels. Conclusion: Patients with HLH in acute leukemia have a high rate of mortality. This case report provides helpful clinical experiences relative to the recognition and treatment of Ch-HLH for clinicians. Keywords: Haemophagocytic lymphohistiocytosis, Malignancy, Acute monocytic leukemia, FLT3-ITD, DNMT3A Background by a wide range of factors, including infections, ma- Secondary haemophagocytic lymphohistiocytosis lignancies, autoimmune diseases, metabolic diseases (HLH) is characterized by prolonged fever, hepatos- and acquired immune deficiencies. Of these, plenomegaly, cytopenia, hypertriglyceridemia, hyper- malignancy-associated HLH (M-HLH) is considered ferritinemia and haemophagocytosis in the bone to be a large challenge to clinicians due to variable marrow, liver, spleen or lymph nodes. It is caused overlaps of symptoms with other types of HLH, sep- sis and multiorgan failure, resulting in a higher inci- dence of misdiagnosis and mortality [1]. M-HLH * Correspondence: yx021021@sina.com can occur in newly diagnosed or relapsed malig- Xiaojie Zhang, Yunyun Wang and Ailin Yang contributed equally to this work. nancy (called “malignancy-triggered HLH”)and dur- Department of Hematology, The First Affiliated Hospital of Nanchang ing chemotherapy, especially in the treatment University, 17 Yongwai Zheng Street, Nanchang 330006, Jiangxi, China course of leukemia or lymphoma (called “HLH dur- Jiangxi Key Laboratory of Molecular Diagnosis and Precision Medicine, 17 Yongwai Zheng Street, Nanchang 330006, Jiangxi, China ing chemotherapy”, Ch-HLH). Prompt diagnosis and Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Li et al. BMC Cancer (2018) 18:604 Page 2 of 6 treatment are crucial to avoid a fatal outcome RUNX1-RUNX1T1, C-KIT/D816V, NPM1 or CEBPA mu- caused by multiorgan dysfunction. However, very tations. Therefore, he was clinically diagnosed with acute few reports have focused on M-HLH, especially monocytic leukemia with FLT3-ITD and DNMT3A Ch-HLH, due to a low incidence and insufficient mutations and pulmonary infection. He received IA knowledge. Therefore, in this article, we present a regimen chemotherapy (Idarubicin, 8 mg/m /d, for 3 rare case of HLH that occurred at the stage of in- days and cytarabine, 100 mg/m /d, for 7 days), duction chemotherapy in a patient with acute anti-infection drug treatments (Imipenem/cilastatin, monocytic leukemia with FLT3-ITD and DNMT3A vancomycin hydrochloride and voriconazole, time from mutations. admission to d6 during the stage of IA chemotherapy) and blood components transfusions. Case presentation In the following days, his lung infection gradually A 22-year-old male was admitted to our centre due improved and his body temperature decreased to to a fever that lasted for 5 days (37.5–38.5 °C), the normal level. SF, PCT and CRP decreased to coughing, expectoration, nose bleed and sporadic 324 μg/L, 0.75 ng/mL and 25.4 mg/L, respectively. petechiae in both lower limbs. The physical examin- Multiple high-density bilateral pulmonary paren- ation indicated moist rales in his lung and sporadic chyma plaques were obviously absorbed. However, petechiae in both lower limbs, but no enlarged due to bone marrow suppression after chemother- superficial lymph nodes, liver or spleen. The blood apy, he developed a fever again, his body cell count revealed 25.31 × 10 /L white blood cells temperature was increased to over 39 °C and his 9 9 (WBC) (normal range, 4-10 × 10 /L) with 30% blasts, blood cell counts decreased to 0.43 × 10 /L WBC, 142 g/L haemoglobin (Hb) (normal range, 120– 73 g/L Hb and 1 × 10 /L PLT in the 11 days after 150 g/L), 11 × 10 /L platelets (PLT) (normal range, finishing IA chemotherapy. To our surprise, his co- 100–300 × 10 /L), 30.6 g/L albumin (ALB) (normal agulation dysfunction worsened, with APTT and PT range, 40–55 g/L), 303 U/L lactate dehydrogenase prolonged to 104.0 s and 30.5 s, respectively, and (LDH) (normal range, 0–248 U/L), 14 s prothrom- Fbg decreased to 0.87 g/L. TT and the plasma bin time (PT) (normal range, 9.8–12.1 s), 57.7 s acti- protamine paracoagulation test (3P test) were nor- vated partial prothrombin time (APTT) (normal mal. PCT and CRP increased to 3.8 ng/mL and range, 21.1–36.5 s), 18.0 s thrombin time (TT) (nor- 35.7 mg/L again, respectively. Serological tests for mal range, 14.0–21.0 s), 3.11 g/L fibrinogen (Fbg) EBV-DNA and CMV-DNA, a blood culture, the G (normal range, 1.8–3.5 g/L), 688 μg/L serum ferritin test and the GM test were still negative. The levels (SF) (normal range, 30–400 μg/L), 2.75 ng/mL procal- of ALT, AST, BIL, Scr and TG were normal. The citonin (PCT) (< 0.5 ng/mL) and 44.5 mg/L patient was originally diagnosed with severe infec- C-reactive protein (CRP) (normal range, 0–8mg/L). tion, systemic inflammatory response syndrome In addition, Epstein-Barr virus (EBV) and cytomegalo- (SIRS), and disseminated intravascular coagulation virus (CMV) DNA serological tests, blood culture (DIC) and was treated with 80 mg/d methylprednis- (veins in both upper limbs, cultures for aerobic, an- olone for 3 days (from d11 to d13 after finishing aerobic and fungal agents, three times), T-spot test, chemotherapy), fresh frozen plasma, platelets, (1–3)-Beta-D-Glucan assay (G test) and galactoman- cryoprecipitate anti-fibrinolysis drugs, and powerful nan assay (GM test) were all negative. The counts for antibiotics, including cefoperazone/sulbactam, tige- alanine aminotransferase (ALT), aspartate aminotrans- cycline and voriconazole (from d10 after finishing ferase (AST), bilirubin (BIL), serum creatinine (Scr) chemotherapy until his temperature returned to the and triglycerides (TG) were normal. The computed normal level and granulocytic deficiency resolved). tomography (CT) scan examination revealed multiple However, his coagulation dysfunction did not im- high-density bilateral pulmonary parenchyma plaques, prove and his peripheral blood cells were not re- bilateral pleural effusion and a slightly enlarged stored at 14 days after finishing IA chemotherapy spleen. The ECG showed sinus tachycardia. Echocar- following the above treatments. He was subjected to diography showed that the left ventricular ejection bone marrow aspiration. Surprisingly, cell prolifera- fraction was 65%. A bone marrow smear revealed acute tion in his bone marrow was extremely active, with monocytic leukemia with 43% blasts (Fig. 1b). Flow cy- 7% blasts and 5% haemophagocytic cells (Fig. 2a tometry revealed tumour cells that positively expressed and b). In addition, his SF was > 3000 μg/L, soluble CD38, CD13, CD64, CD11b, CD15, CD14 and HLA-DR interleukin-II receptor (sIL-2R) was > 7500 u/mL, (Fig. 1a). The chromosome karyotype was normal. and spleen was 3 cm below the left costal margin. FLT3-ITD Exon 11 and DNMT3A Exon 23 c.G2645A Table 1 shows the patient’s clinical parameters. mutations were detected (Fig. 1c and d), but no Based on the fever, hypofibrinogenemia, Li et al. BMC Cancer (2018) 18:604 Page 3 of 6 Fig. 1 (See legend on next page.) Li et al. BMC Cancer (2018) 18:604 Page 4 of 6 (See figure on previous page.) Fig. 1 The patient was diagnosed with AML with FLT3-ITD and DNMT3A mutations. a Flow cytometry indicated that the leukemia cells positively expressed CD38, CD13, CD64, CD11b, CD15, CD14 and HLA-DR. b The bone marrow smear revealed AML. c FLT3-ITD Exon 11 mutation was found using PCR amplicon analyses. d DNMT3A Exon 23 c.G2645A mutations were found by next generation sequencing analyses using IGV software splenomegaly, cytopenia, hyperferritinemia, in- recommendations for the diagnosis and management of creased sIL-2R and haemophagocytosis in bone mar- HLH-associated malignancies, M-HLH can occur in the row, he was diagnosed with HLH. Because of phase of diagnosis or chemotherapy, including induction, incomplete cytokine storms blockade, the previous consolidation, and even maintenance [2, 5]. dose of methylprednisolone presumably did not ef- So far, very few sporadic reports on M-HLH dur- fectively suppress HLH. Therefore, he was given ing the onset of acute myeloid leukemia (AML) or 500 mg/d of methylprednisolone for 3 days (d14–16 course of chemotherapy have been reported [6–10]. after finishing chemotherapy), 120 mg/d for d17–19, Excessive cytokines secreted by malignant cells and/ and80mg/dfor d20–22, followed by a gradually re- or viruses may be the cause of AML-triggered HLH, duced dose. Eventually, his temperature dropped to and viruses, invasive fungi and bacterial infections the normal level, his coagulation dysfunction gradually after chemotherapy may be the major triggers of improved, with an APTT of 46.2 s, PT of 11.8 s and Fbg Ch-HLH. In the present case, the patient had a of 4.82 g/L, and his peripheral blood cells were restored to fever, hypofibrinogenemia, splenomegaly, cytopenia, 9 9 15.0 × 10 /L WBC, 78 g/L Hb and 42 × 10 /L PLT. How- hyperferritinemia, increased sIL-2R levels and hae- ever, 34% of blasts were still observed in the bone marrow mophagocytosis in the bone marrow during the in- smear at 20 days after finishing IA chemotherapy. The pa- duction of chemotherapy, fulfilling the diagnostic tient is still alive and being followed. Figure 3 shows the criteria of HLH 2004 [11]. Lehmberg et al. [10]re- treatment course of the patient. ported 21 cases of M-HLH. Among these, 8 patients had Ch-HLH, including 2 cases of AML, 5 cases of acute lymphoblastic leukemia (ALL) and 1 case of Discussion lymphoma; 6 patients occurred in the stage of re- In recent years, M-HLH with a high rate of misdiag- mission; and 2 patients occurred in the stage of in- nosis and mortality has gained increasing attention duction chemotherapy. In addition, E. coli,EBV, from clinicians because its symptoms are nonspecific HHV6,aspergillus,adenovirus and CMV were found and overlap with some severe illnesses, including sep- in the seven patients. Although we actively sought sis, SIRS and multiorgan failure. The most common infectious causes, including EBV, CMV, and herpes tumour types that trigger HLH are haematological simplex virus, and performed a blood culture, a G neoplasms (93.7%) with T-cell or natural-killer (NK) test and a GM test, the positive triggers remained lymphoma or leukemia (35.2%), followed by B-cell unclear. It is possible thatHLH was co-triggeredby lymphoma (31.8%), other non-specified hematologic excessive cytokine secretion by leukemia cells and neoplasms (14.4%) and Hodgkin lymphoma (5.8%). Of lung infection in this patient. these, leukemia-triggered HLH accounted for only Patients with M-HLH and Ch-HLH show very 6.4% of cases [2–4]. According to consensus poor survival, with a median overall survival of 0.9– ab Fig. 2 The bone marrow cell morphology of the patient at 14 days after finishing IA chemotherapy. a and b indicate haemophagocytic cells (at the arrowhead) and some promonocytes can be seen in the bone marrow smear (Wright-Giemsa staining, × 1,000) Li et al. BMC Cancer (2018) 18:604 Page 5 of 6 Table 1 The clinical parameters of the patient Parameters Before chemotherapy d6 during the IA chemotherapy d11–14 after finishing chemotherapy d20 after finishing chemotherapy WBC (×10 /L) 25.3 3.2 0.4 15.0 Hb (g/L) 142 66 73 78 PLT (×10 /L) 11.0 5 1 42 APTT (s) 57.7 72 104 46.2 PT (s) 14.0 14.6 30.5 11.8 Fbg (g/L) 3.1 2.2 0.87 4.8 TG (mmol/L) 1.5 – 0.8 0.9 SF (μg/L) 688 324 > 3000 1259 PCT (ng/mL) 2.8 0.75 3.8 0.7 CRP (mg/L) 44.5 25.4 35.7 49.1 LDH (U/L) 303 481 57 392 9 9 WBC white blood cell (normal range, 4-10 × 10 /L), Hb hemoglobin (normal range, 120–150 g/L), PLT platelet (normal range,100–300 × 10 /L), APTT activated partial prothrombin time (normal range, 21.1–36.5 s), PT prothrombin time (normal range, 9.8–12.1 s), Fbg fibrinogen (normal range, 1.8–3.5 g/L), TG triglycerides (normal range, 0–1.7 mmol/L), SF serum ferritin (normal range, 30–400 μg/L), PCT:procalcitonin (< 0.5 ng/mL), CRP C-reactive protein (normal range, 0–8 mg/L), LDH lactate 2 2 dehydrogenase (normal range, 0–248 U/L), IA regimen idarubicin, 8 mg/m /d at d1–3, Cytarabine, 100 mg/m /d at d1–7 1.2 years and 6-month survival rates of 67 and 63%, parameters did not improve or become restored. respectively [2, 10]. This patient had FLT3-ITD Due to an uncontrolled hyperinflammation response, Exon 11 and DNMT3A Exon 23 c.G2645A muta- he was then treated with methylprednisolone at tions, which predict a worse prognosis. In fact, the 500 mg/d for 3 days and 120 mg/d for 3 days, patient was refractory to chemotherapy and followed by a gradually reduced dose. His achieved no remission after a cycle of standard regi- temperature and coagulation dysfunction were then men chemotherapy. The relationship between HLH successfully controlled to normal levels, suggesting and some subtypes of leukemia such as FLT3-ITD that a sufficient dose of glucocorticosteroids may be and/or DNMT3A mutations is unclear. effective to control the hyperinflammation response The best therapeutic approach for Ch-HLH re- in Ch-HLH patients. mains elusive. Based on iatrogenic immunosuppres- sion and consecutive triggering infections, if Conclusions infections are detected in patients with Ch-HLH, In summary, Ch-HLH is a life-threatening disease the consensus is that chemotherapy should be post- with very high mortality. Early recognition, a suffi- poned and powerful anti-infection treatment should cient dose of glucocorticosteroids and regulation of be considered first [2]. In the present case, the pa- the hyperinflammation response are crucial to avoid tient was given 80 mg/d methylprednisolone for 3 a fatal outcome due to multiorgan dysfunction and days and fresh frozen plasma, platelets, cryoprecipi- improve the overall survival of these patients. The tate, anti-fibrinolysis drugs and powerful antibiotics present case report may provide some clinical expe- to control the inflammation response and his coagu- riences regarding the recognition and treatment of lation dysfunction. However, his abnormal Ch-HLH for clinicians. Fig. 3 The treatment course of the patient (each small grid represents 1 day) Li et al. BMC Cancer (2018) 18:604 Page 6 of 6 Abbreviations 4. Machaczka M, Klimkowska M, Chiang SC, Meeths M, Muller ML, Gustafsson 3P test: plasma protamine paracoagulation test; ALB: Albumin; ALL: Acute B, et al. Development of classical Hodgkin’s lymphoma in an adult with lymphoblastic leukemia; ALT: Alanine aminotransferase; AML: Acute myeloid biallelic STXBP2 mutations. Haematologica. 2013;98(5):760–4. leukemia; APTT: Activated partial prothrombin time; AST: Aspartate 5. Machaczka M, Vaktnas J, Klimkowska M, Hagglund H. Malignancy-associated aminotransferase; BIL: Bilirubin; CMV: Cytomegalovirus; CRP: C-reactive hemophagocytic lymphohistiocytosis in adults: a retrospective population- protein; CT: Computed tomography; DIC: Disseminated intravascular based analysis from a single center. Leuk Lymphoma. 2011;52(4):613–9. coagulation; EBV: Epstein-Barr virus; Fbg: Fibrinogen; G test: (1–3)-Beta-D- 6. Yamazaki S, Nakamura F, Nasu R, Nannya Y, Ichikawa M, Kurokawa M. Glucan Assay; GM test: Galactomannan assay; Hb: Haemoglobin; Haemophagocytic lymphohistiocytosis is are recurrent and specific HLH: Secondary haemophagocytic lymphohistiocytosis; IA complication of acute erythroid leukaemia. Br J Haematol. 2011;153(5):669–72. regimen: Idarubicin and cytarabine; LDH: Lactate dehydrogenase; M- 7. Zhao D, Qian L, Shen J. Acute myelocytic leukemia in a patient with HLH: Malignancy-associated HLH; PCT: Procalcitonin; PLT: Platelets; hemophagocytic lymphohistiocytosis: a case report. Oncol Lett. 2014;8(6):2634–6. PT: Prothrombin time; Scr: Serum creatinine; SF: Serum ferritin; sIL-2R: Soluble 8. Lackner H, Seidel MG, Strenger V, Sovinz P, Schwinger W, Benesch M. interleukin-II receptor; SIRS: Systemic inflammatory response syndrome; Haemophagocytic syndrome in children with acute monoblastic leukemia- TG: Triglycerides; TT: Thrombin time; WBC: White blood cell another cause of fever of unknown origin. Support Care Cancer. 2013; 21(12):3519–23. 9. Delavigne K, Bérard E, Bertoli S, Corre J, Duchayne E, Demur C, et al. Funding Haemophagocytic syndrome in patients with acute myeloid leukemia This work is financially supported by grants from the National Natural undergoing intensive chemotherapy. Haematologica. 2014;99(3):474–80. Science Foundation of China (81360353, 81560034, 81560036), the Natural 10. Lehmberg K, Sprekels B, Nichols KE, Woessmann W, Müller I, Suttorp M, Science Foundation of Jiangxi province (20142BAB205072) and the Young et al. Malignancy- associated haemophagocytic lymphohistiocytosis in Scientist Training Program (20153BCB23040) of Jiangxi Province. children and adolescents. Br J Haematol. 2015;170(4):539–49. 11. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. Availability of data and materials HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic The raw data supporting our findings can be requested from the lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31. corresponding author. Authors’ contributions XZ, YW and AY designed and wrote the manuscript. ZZ, WT, NZ and HS contributed to the review and revision of the manuscript. FL contributed to the final review and approval of the manuscript. All authors read and approved the final version of the manuscript. Ethics approval and consent to participate The study was reviewed and approved by the First Affiliated Hospital of Nanchang University. Consent for publication Written informed consent was obtained from the patient for the publication of this case report and the accompanying images. Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details Department of Hematology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Street, Nanchang 330006, Jiangxi, China. 2 3 Medical College, Nanchang University, Nanchang 330006, China. Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. Jiangxi Key Laboratory of Molecular Diagnosis and Precision Medicine, 17 Yongwai Zheng Street, Nanchang 330006, Jiangxi, China. Received: 14 February 2017 Accepted: 21 May 2018 References 1. Li F, Yang Y, Jin F, Dehoedt C, Rao J, Zhou Y, et al. Clinical characteristics and prognostic factors of adult hemophagocytic syndrome patients: a retrospective study of increasing awareness of a disease from a single- center in China. Orphanet J Rare Dis. 2015;10:20. 2. Lehmberg K, Nichols KE, Henter JI, Girschikofsky M, Greenwood T, Jordan M, et al. Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica. 2015;100(8):997–1004. 3. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–16. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Cancer Springer Journals

Haemophagocytic lymphohistiocytosis occurred during induction chemotherapy in an acute monocytic leukemia patient with FLT3-ITD and DNMT3A mutations

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Abstract

Background: Haemophagocytic lymphohistiocytosis (HLH) is considered to be a large challenge for clinicians due to the variable overlaps of symptoms with other severe diseases and a high rate of mortality. Prompt diagnosis and treatment are crucial to avoid a fatal outcome. However, very limited reports have focused on HLH during chemotherapy (Ch-HLH) due to a low incidence and insufficient knowledge. Case presentation: A 22-year-old male was diagnosed with acute monocytic leukemia with FLT3-ITD and DNMT3A mutations and pulmonary infection. He received IA regimen (Idarubicin, 8 mg/m2/d for 3 days and cytarabine, 100 mg/m2/d for 7 days) chemotherapy, anti-infection drugs and blood components transfusions. During the stage of 9 9 bone marrow suppression, he presented with a fever, cytopenia (WBC, 0.43 × 10 /L; Hb, 73 g/L and PLT, 1 × 10 /L), refractory coagulation dysfunction (APTT, 104.0 s; PT, 30.5 s and Fbg, 0.87 g/L), splenomegaly (3 cm below the costal margin), hyperferritinemia (SF > 3000 μg/L), increased soluble interleukin-II receptors (sIL-2R > 7500 u/mL) and haemophagocytosis in the bone marrow and was diagnosed with HLH. After he was treated with methylprednisolone at 500 mg/d for 3 days, 120 mg/d for 3 days and 80 mg/d for 3 days, followed by a gradually reduced dose combined with powerful anti-infection drugs, his symptoms subsided and his abnormal parameters recovered to normal levels. Conclusion: Patients with HLH in acute leukemia have a high rate of mortality. This case report provides helpful clinical experiences relative to the recognition and treatment of Ch-HLH for clinicians. Keywords: Haemophagocytic lymphohistiocytosis, Malignancy, Acute monocytic leukemia, FLT3-ITD, DNMT3A Background by a wide range of factors, including infections, ma- Secondary haemophagocytic lymphohistiocytosis lignancies, autoimmune diseases, metabolic diseases (HLH) is characterized by prolonged fever, hepatos- and acquired immune deficiencies. Of these, plenomegaly, cytopenia, hypertriglyceridemia, hyper- malignancy-associated HLH (M-HLH) is considered ferritinemia and haemophagocytosis in the bone to be a large challenge to clinicians due to variable marrow, liver, spleen or lymph nodes. It is caused overlaps of symptoms with other types of HLH, sep- sis and multiorgan failure, resulting in a higher inci- dence of misdiagnosis and mortality [1]. M-HLH * Correspondence: yx021021@sina.com can occur in newly diagnosed or relapsed malig- Xiaojie Zhang, Yunyun Wang and Ailin Yang contributed equally to this work. nancy (called “malignancy-triggered HLH”)and dur- Department of Hematology, The First Affiliated Hospital of Nanchang ing chemotherapy, especially in the treatment University, 17 Yongwai Zheng Street, Nanchang 330006, Jiangxi, China course of leukemia or lymphoma (called “HLH dur- Jiangxi Key Laboratory of Molecular Diagnosis and Precision Medicine, 17 Yongwai Zheng Street, Nanchang 330006, Jiangxi, China ing chemotherapy”, Ch-HLH). Prompt diagnosis and Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Li et al. BMC Cancer (2018) 18:604 Page 2 of 6 treatment are crucial to avoid a fatal outcome RUNX1-RUNX1T1, C-KIT/D816V, NPM1 or CEBPA mu- caused by multiorgan dysfunction. However, very tations. Therefore, he was clinically diagnosed with acute few reports have focused on M-HLH, especially monocytic leukemia with FLT3-ITD and DNMT3A Ch-HLH, due to a low incidence and insufficient mutations and pulmonary infection. He received IA knowledge. Therefore, in this article, we present a regimen chemotherapy (Idarubicin, 8 mg/m /d, for 3 rare case of HLH that occurred at the stage of in- days and cytarabine, 100 mg/m /d, for 7 days), duction chemotherapy in a patient with acute anti-infection drug treatments (Imipenem/cilastatin, monocytic leukemia with FLT3-ITD and DNMT3A vancomycin hydrochloride and voriconazole, time from mutations. admission to d6 during the stage of IA chemotherapy) and blood components transfusions. Case presentation In the following days, his lung infection gradually A 22-year-old male was admitted to our centre due improved and his body temperature decreased to to a fever that lasted for 5 days (37.5–38.5 °C), the normal level. SF, PCT and CRP decreased to coughing, expectoration, nose bleed and sporadic 324 μg/L, 0.75 ng/mL and 25.4 mg/L, respectively. petechiae in both lower limbs. The physical examin- Multiple high-density bilateral pulmonary paren- ation indicated moist rales in his lung and sporadic chyma plaques were obviously absorbed. However, petechiae in both lower limbs, but no enlarged due to bone marrow suppression after chemother- superficial lymph nodes, liver or spleen. The blood apy, he developed a fever again, his body cell count revealed 25.31 × 10 /L white blood cells temperature was increased to over 39 °C and his 9 9 (WBC) (normal range, 4-10 × 10 /L) with 30% blasts, blood cell counts decreased to 0.43 × 10 /L WBC, 142 g/L haemoglobin (Hb) (normal range, 120– 73 g/L Hb and 1 × 10 /L PLT in the 11 days after 150 g/L), 11 × 10 /L platelets (PLT) (normal range, finishing IA chemotherapy. To our surprise, his co- 100–300 × 10 /L), 30.6 g/L albumin (ALB) (normal agulation dysfunction worsened, with APTT and PT range, 40–55 g/L), 303 U/L lactate dehydrogenase prolonged to 104.0 s and 30.5 s, respectively, and (LDH) (normal range, 0–248 U/L), 14 s prothrom- Fbg decreased to 0.87 g/L. TT and the plasma bin time (PT) (normal range, 9.8–12.1 s), 57.7 s acti- protamine paracoagulation test (3P test) were nor- vated partial prothrombin time (APTT) (normal mal. PCT and CRP increased to 3.8 ng/mL and range, 21.1–36.5 s), 18.0 s thrombin time (TT) (nor- 35.7 mg/L again, respectively. Serological tests for mal range, 14.0–21.0 s), 3.11 g/L fibrinogen (Fbg) EBV-DNA and CMV-DNA, a blood culture, the G (normal range, 1.8–3.5 g/L), 688 μg/L serum ferritin test and the GM test were still negative. The levels (SF) (normal range, 30–400 μg/L), 2.75 ng/mL procal- of ALT, AST, BIL, Scr and TG were normal. The citonin (PCT) (< 0.5 ng/mL) and 44.5 mg/L patient was originally diagnosed with severe infec- C-reactive protein (CRP) (normal range, 0–8mg/L). tion, systemic inflammatory response syndrome In addition, Epstein-Barr virus (EBV) and cytomegalo- (SIRS), and disseminated intravascular coagulation virus (CMV) DNA serological tests, blood culture (DIC) and was treated with 80 mg/d methylprednis- (veins in both upper limbs, cultures for aerobic, an- olone for 3 days (from d11 to d13 after finishing aerobic and fungal agents, three times), T-spot test, chemotherapy), fresh frozen plasma, platelets, (1–3)-Beta-D-Glucan assay (G test) and galactoman- cryoprecipitate anti-fibrinolysis drugs, and powerful nan assay (GM test) were all negative. The counts for antibiotics, including cefoperazone/sulbactam, tige- alanine aminotransferase (ALT), aspartate aminotrans- cycline and voriconazole (from d10 after finishing ferase (AST), bilirubin (BIL), serum creatinine (Scr) chemotherapy until his temperature returned to the and triglycerides (TG) were normal. The computed normal level and granulocytic deficiency resolved). tomography (CT) scan examination revealed multiple However, his coagulation dysfunction did not im- high-density bilateral pulmonary parenchyma plaques, prove and his peripheral blood cells were not re- bilateral pleural effusion and a slightly enlarged stored at 14 days after finishing IA chemotherapy spleen. The ECG showed sinus tachycardia. Echocar- following the above treatments. He was subjected to diography showed that the left ventricular ejection bone marrow aspiration. Surprisingly, cell prolifera- fraction was 65%. A bone marrow smear revealed acute tion in his bone marrow was extremely active, with monocytic leukemia with 43% blasts (Fig. 1b). Flow cy- 7% blasts and 5% haemophagocytic cells (Fig. 2a tometry revealed tumour cells that positively expressed and b). In addition, his SF was > 3000 μg/L, soluble CD38, CD13, CD64, CD11b, CD15, CD14 and HLA-DR interleukin-II receptor (sIL-2R) was > 7500 u/mL, (Fig. 1a). The chromosome karyotype was normal. and spleen was 3 cm below the left costal margin. FLT3-ITD Exon 11 and DNMT3A Exon 23 c.G2645A Table 1 shows the patient’s clinical parameters. mutations were detected (Fig. 1c and d), but no Based on the fever, hypofibrinogenemia, Li et al. BMC Cancer (2018) 18:604 Page 3 of 6 Fig. 1 (See legend on next page.) Li et al. BMC Cancer (2018) 18:604 Page 4 of 6 (See figure on previous page.) Fig. 1 The patient was diagnosed with AML with FLT3-ITD and DNMT3A mutations. a Flow cytometry indicated that the leukemia cells positively expressed CD38, CD13, CD64, CD11b, CD15, CD14 and HLA-DR. b The bone marrow smear revealed AML. c FLT3-ITD Exon 11 mutation was found using PCR amplicon analyses. d DNMT3A Exon 23 c.G2645A mutations were found by next generation sequencing analyses using IGV software splenomegaly, cytopenia, hyperferritinemia, in- recommendations for the diagnosis and management of creased sIL-2R and haemophagocytosis in bone mar- HLH-associated malignancies, M-HLH can occur in the row, he was diagnosed with HLH. Because of phase of diagnosis or chemotherapy, including induction, incomplete cytokine storms blockade, the previous consolidation, and even maintenance [2, 5]. dose of methylprednisolone presumably did not ef- So far, very few sporadic reports on M-HLH dur- fectively suppress HLH. Therefore, he was given ing the onset of acute myeloid leukemia (AML) or 500 mg/d of methylprednisolone for 3 days (d14–16 course of chemotherapy have been reported [6–10]. after finishing chemotherapy), 120 mg/d for d17–19, Excessive cytokines secreted by malignant cells and/ and80mg/dfor d20–22, followed by a gradually re- or viruses may be the cause of AML-triggered HLH, duced dose. Eventually, his temperature dropped to and viruses, invasive fungi and bacterial infections the normal level, his coagulation dysfunction gradually after chemotherapy may be the major triggers of improved, with an APTT of 46.2 s, PT of 11.8 s and Fbg Ch-HLH. In the present case, the patient had a of 4.82 g/L, and his peripheral blood cells were restored to fever, hypofibrinogenemia, splenomegaly, cytopenia, 9 9 15.0 × 10 /L WBC, 78 g/L Hb and 42 × 10 /L PLT. How- hyperferritinemia, increased sIL-2R levels and hae- ever, 34% of blasts were still observed in the bone marrow mophagocytosis in the bone marrow during the in- smear at 20 days after finishing IA chemotherapy. The pa- duction of chemotherapy, fulfilling the diagnostic tient is still alive and being followed. Figure 3 shows the criteria of HLH 2004 [11]. Lehmberg et al. [10]re- treatment course of the patient. ported 21 cases of M-HLH. Among these, 8 patients had Ch-HLH, including 2 cases of AML, 5 cases of acute lymphoblastic leukemia (ALL) and 1 case of Discussion lymphoma; 6 patients occurred in the stage of re- In recent years, M-HLH with a high rate of misdiag- mission; and 2 patients occurred in the stage of in- nosis and mortality has gained increasing attention duction chemotherapy. In addition, E. coli,EBV, from clinicians because its symptoms are nonspecific HHV6,aspergillus,adenovirus and CMV were found and overlap with some severe illnesses, including sep- in the seven patients. Although we actively sought sis, SIRS and multiorgan failure. The most common infectious causes, including EBV, CMV, and herpes tumour types that trigger HLH are haematological simplex virus, and performed a blood culture, a G neoplasms (93.7%) with T-cell or natural-killer (NK) test and a GM test, the positive triggers remained lymphoma or leukemia (35.2%), followed by B-cell unclear. It is possible thatHLH was co-triggeredby lymphoma (31.8%), other non-specified hematologic excessive cytokine secretion by leukemia cells and neoplasms (14.4%) and Hodgkin lymphoma (5.8%). Of lung infection in this patient. these, leukemia-triggered HLH accounted for only Patients with M-HLH and Ch-HLH show very 6.4% of cases [2–4]. According to consensus poor survival, with a median overall survival of 0.9– ab Fig. 2 The bone marrow cell morphology of the patient at 14 days after finishing IA chemotherapy. a and b indicate haemophagocytic cells (at the arrowhead) and some promonocytes can be seen in the bone marrow smear (Wright-Giemsa staining, × 1,000) Li et al. BMC Cancer (2018) 18:604 Page 5 of 6 Table 1 The clinical parameters of the patient Parameters Before chemotherapy d6 during the IA chemotherapy d11–14 after finishing chemotherapy d20 after finishing chemotherapy WBC (×10 /L) 25.3 3.2 0.4 15.0 Hb (g/L) 142 66 73 78 PLT (×10 /L) 11.0 5 1 42 APTT (s) 57.7 72 104 46.2 PT (s) 14.0 14.6 30.5 11.8 Fbg (g/L) 3.1 2.2 0.87 4.8 TG (mmol/L) 1.5 – 0.8 0.9 SF (μg/L) 688 324 > 3000 1259 PCT (ng/mL) 2.8 0.75 3.8 0.7 CRP (mg/L) 44.5 25.4 35.7 49.1 LDH (U/L) 303 481 57 392 9 9 WBC white blood cell (normal range, 4-10 × 10 /L), Hb hemoglobin (normal range, 120–150 g/L), PLT platelet (normal range,100–300 × 10 /L), APTT activated partial prothrombin time (normal range, 21.1–36.5 s), PT prothrombin time (normal range, 9.8–12.1 s), Fbg fibrinogen (normal range, 1.8–3.5 g/L), TG triglycerides (normal range, 0–1.7 mmol/L), SF serum ferritin (normal range, 30–400 μg/L), PCT:procalcitonin (< 0.5 ng/mL), CRP C-reactive protein (normal range, 0–8 mg/L), LDH lactate 2 2 dehydrogenase (normal range, 0–248 U/L), IA regimen idarubicin, 8 mg/m /d at d1–3, Cytarabine, 100 mg/m /d at d1–7 1.2 years and 6-month survival rates of 67 and 63%, parameters did not improve or become restored. respectively [2, 10]. This patient had FLT3-ITD Due to an uncontrolled hyperinflammation response, Exon 11 and DNMT3A Exon 23 c.G2645A muta- he was then treated with methylprednisolone at tions, which predict a worse prognosis. In fact, the 500 mg/d for 3 days and 120 mg/d for 3 days, patient was refractory to chemotherapy and followed by a gradually reduced dose. His achieved no remission after a cycle of standard regi- temperature and coagulation dysfunction were then men chemotherapy. The relationship between HLH successfully controlled to normal levels, suggesting and some subtypes of leukemia such as FLT3-ITD that a sufficient dose of glucocorticosteroids may be and/or DNMT3A mutations is unclear. effective to control the hyperinflammation response The best therapeutic approach for Ch-HLH re- in Ch-HLH patients. mains elusive. Based on iatrogenic immunosuppres- sion and consecutive triggering infections, if Conclusions infections are detected in patients with Ch-HLH, In summary, Ch-HLH is a life-threatening disease the consensus is that chemotherapy should be post- with very high mortality. Early recognition, a suffi- poned and powerful anti-infection treatment should cient dose of glucocorticosteroids and regulation of be considered first [2]. In the present case, the pa- the hyperinflammation response are crucial to avoid tient was given 80 mg/d methylprednisolone for 3 a fatal outcome due to multiorgan dysfunction and days and fresh frozen plasma, platelets, cryoprecipi- improve the overall survival of these patients. The tate, anti-fibrinolysis drugs and powerful antibiotics present case report may provide some clinical expe- to control the inflammation response and his coagu- riences regarding the recognition and treatment of lation dysfunction. However, his abnormal Ch-HLH for clinicians. Fig. 3 The treatment course of the patient (each small grid represents 1 day) Li et al. BMC Cancer (2018) 18:604 Page 6 of 6 Abbreviations 4. Machaczka M, Klimkowska M, Chiang SC, Meeths M, Muller ML, Gustafsson 3P test: plasma protamine paracoagulation test; ALB: Albumin; ALL: Acute B, et al. Development of classical Hodgkin’s lymphoma in an adult with lymphoblastic leukemia; ALT: Alanine aminotransferase; AML: Acute myeloid biallelic STXBP2 mutations. Haematologica. 2013;98(5):760–4. leukemia; APTT: Activated partial prothrombin time; AST: Aspartate 5. Machaczka M, Vaktnas J, Klimkowska M, Hagglund H. Malignancy-associated aminotransferase; BIL: Bilirubin; CMV: Cytomegalovirus; CRP: C-reactive hemophagocytic lymphohistiocytosis in adults: a retrospective population- protein; CT: Computed tomography; DIC: Disseminated intravascular based analysis from a single center. Leuk Lymphoma. 2011;52(4):613–9. coagulation; EBV: Epstein-Barr virus; Fbg: Fibrinogen; G test: (1–3)-Beta-D- 6. Yamazaki S, Nakamura F, Nasu R, Nannya Y, Ichikawa M, Kurokawa M. Glucan Assay; GM test: Galactomannan assay; Hb: Haemoglobin; Haemophagocytic lymphohistiocytosis is are recurrent and specific HLH: Secondary haemophagocytic lymphohistiocytosis; IA complication of acute erythroid leukaemia. Br J Haematol. 2011;153(5):669–72. regimen: Idarubicin and cytarabine; LDH: Lactate dehydrogenase; M- 7. Zhao D, Qian L, Shen J. Acute myelocytic leukemia in a patient with HLH: Malignancy-associated HLH; PCT: Procalcitonin; PLT: Platelets; hemophagocytic lymphohistiocytosis: a case report. Oncol Lett. 2014;8(6):2634–6. PT: Prothrombin time; Scr: Serum creatinine; SF: Serum ferritin; sIL-2R: Soluble 8. Lackner H, Seidel MG, Strenger V, Sovinz P, Schwinger W, Benesch M. interleukin-II receptor; SIRS: Systemic inflammatory response syndrome; Haemophagocytic syndrome in children with acute monoblastic leukemia- TG: Triglycerides; TT: Thrombin time; WBC: White blood cell another cause of fever of unknown origin. Support Care Cancer. 2013; 21(12):3519–23. 9. Delavigne K, Bérard E, Bertoli S, Corre J, Duchayne E, Demur C, et al. Funding Haemophagocytic syndrome in patients with acute myeloid leukemia This work is financially supported by grants from the National Natural undergoing intensive chemotherapy. Haematologica. 2014;99(3):474–80. Science Foundation of China (81360353, 81560034, 81560036), the Natural 10. Lehmberg K, Sprekels B, Nichols KE, Woessmann W, Müller I, Suttorp M, Science Foundation of Jiangxi province (20142BAB205072) and the Young et al. Malignancy- associated haemophagocytic lymphohistiocytosis in Scientist Training Program (20153BCB23040) of Jiangxi Province. children and adolescents. Br J Haematol. 2015;170(4):539–49. 11. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. Availability of data and materials HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic The raw data supporting our findings can be requested from the lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31. corresponding author. Authors’ contributions XZ, YW and AY designed and wrote the manuscript. ZZ, WT, NZ and HS contributed to the review and revision of the manuscript. FL contributed to the final review and approval of the manuscript. All authors read and approved the final version of the manuscript. Ethics approval and consent to participate The study was reviewed and approved by the First Affiliated Hospital of Nanchang University. Consent for publication Written informed consent was obtained from the patient for the publication of this case report and the accompanying images. Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details Department of Hematology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Street, Nanchang 330006, Jiangxi, China. 2 3 Medical College, Nanchang University, Nanchang 330006, China. Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. Jiangxi Key Laboratory of Molecular Diagnosis and Precision Medicine, 17 Yongwai Zheng Street, Nanchang 330006, Jiangxi, China. Received: 14 February 2017 Accepted: 21 May 2018 References 1. Li F, Yang Y, Jin F, Dehoedt C, Rao J, Zhou Y, et al. Clinical characteristics and prognostic factors of adult hemophagocytic syndrome patients: a retrospective study of increasing awareness of a disease from a single- center in China. Orphanet J Rare Dis. 2015;10:20. 2. Lehmberg K, Nichols KE, Henter JI, Girschikofsky M, Greenwood T, Jordan M, et al. Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica. 2015;100(8):997–1004. 3. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–16.

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BMC CancerSpringer Journals

Published: May 29, 2018

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