A 60-year-old male with a medical history for type-II diabetes mellitus was referred to the hematology department of our hospital (the First Affiliated Hospital of Zhejiang University School of Medicine [Hangzhou, China]) on January 15, 2022 with complaints of remittent fever and fatigue for more than one year-duration.
At the local hospital, blood routine examination showed white blood cell (WBC) count of 4.6 × 109/L, hemoglobin level (HGB) of 67 g/L, platelet count (PLT) of 107 × 109/L, His C-reactive protein level (CRP) was 91.6 mg/L. Empiric antiinfection and red cell transfusions were given. Positron emission tomography-computed tomography (PET-CT) scan showed multiple plump lymph nodes with increased FDG uptake in areas II-III of both neck, mediastinum, hilum of lung, retroperitoneum, splenomegaly with high FDG uptake. Multiple FDG uptake increases in right humerus head, stalk sternum, right fourth anterior rib, T2 pedicle, T8 and L5 vertebrae, right sacrum wing, left femoral neck, and right ischium. A bone marrow (BM) smear revealed hemophagocytic histiocytes and flow cytometry was negative. BM biopsy was normal. Cytogenetics showed a normal 46, XY karyotype. Right inguinal lymph node puncture showed no evidence of malignancy. HLH was highly suspected.
Subsequently, he was admitted to our hospital, labs on admission showed a WBC of 3.2 × 109/L, HGB of 58 g/L, and PLT of 32 × 109/L. The serum IL-6 and IL-10 were high at 41.29 pg/ml (reference 0.10–2.9) and 919.29 pg/ml (reference 0.10–5.00), respectively. Ferritin was 3200.4 ng/ml (reference 7.0–323.0), Triglyceride was 4.19mmol/L (reference 0.30–1.70). lactate level was 1.5 mmol/L. Epstein-Barr virus was positive with a low replication rate of 1.59×103copies/mL. The viral workup for cytomegalovirus, influenza A and B viruses, human immunodeficiency virus, and hepatitis B and hepatitis C viruses were all negative. CT scan of the abdomen showed retroperitoneal and right inguinal lymphadenopathy, as well as splenomegaly (Fig. 1A and 1B). A BM smear revealed hemophagocytic histiocytes (Fig. 1C).
At this point, this patient met 6 criteria of HLH-2004 diagnostic criteria and was diagnosed with HLH. Thus, he was administered a combined therapy of oral ruxolitinib 15mg twice a day with methylprednisolone 100mg per day on the day of admission. Soluble CD25 level and natural killer (NK) cell activity were later obtained, the former was up to 180985 pg/mL and the latter decreased to 12.86%. Moreover, NK cells stimulation test showed severe dysregulation of immune response (Fig. 2A) and NK cells killing activity decreased (Fig. 2B). The patient's temperature dropped to normal within 24 hours of starting treatment, but he developed shortness of breath 3 days later. He had a temperature of 36.4℃, a heart rate of 93 beats per minute, a blood pressure of 119/86 mmHg, and 24 breaths per minute. Artery Blood Gas showed pH 7.37, oxygen partial pressure 139 mmHg, carbon dioxide partial pressure 29.3 mmHg, bicarbonate 16.5 mmol/L, and lactic acid 11.9 mmol/L. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, creatinine and procalcitonin were normal. Combined with the clinical manifestations and the above tests, we thought that the patient developed Warburg effect. We transferred the patient to the intensive care unit and initiated continuous renal replacement therapy (CRRT) on January 18, 2022. Meanwhile, ruxolitinib in combination with methylprednisolone was continued.
Because the lactate level was still high after 6 days of CRRT (6.7 mmol/L), we stopped ruxolitinib and managed the patient with etoposide, cyclophosphamide, vincristine, and dexamethasone (ECOP) regimen as diagnostic chemotherapy. Lactate level reduced to 1.5mmol/L in the next day and CRRT was stopped. We then received the pathologic report of the patient's BM biopsy and confirmed DLBCL (Fig. 1D), immunohistochemical (IHC) showed CD20, MUM1, BCL-2 and C-MYC expression, and negative for CD30/CD3/CD5/cyclin-D1/CD56/EBER. On February 8, 2022, the patient was treated with a rituximab, cyclophosphamide, doxorubicin, vincristine, dexamethasone (R-CHOP) regimen and passed the myelosuppression phase safely.
After discharge, the patient developed a high fever and was readmitted with a confirmed pulmonary Acinetobacter baumannii infection. After treatment with polymyxin B sulfate combined with cefoperazone sodium and sulbactam sodium, the patient's infection was gradually controlled. However, the patient's serum creatinine increased (183mmol/L) during the treatment, which was considered to be caused by polymyxin B sulfate. After polymyxin B was changed to aerosol inhalation, the patient's serum creatinine gradually decreased to the normal level. Since then, the patient's hemoglobin and platelet levels decreased again, which was considered to be due to DLBCL progression. On March 22, 2022, the patient was treated with a chemo-free regimen: rituximab, orelabrutinib and lenalidomide.
Three weeks later, the patient suddenly developed anuria with a rapid rise in serum creatinine to 401 ummol/L. The patient was treated with CRRT again, however anuria did not improve. Two weeks later, the patient was transferred to the Nephrology department and placed on hemodialysis, but serum creatinine continued to rise. Then rituximab combined with orelabrutinib were administrated on May, 20, 2022. After that, the patient's serum creatinine level began to decrease gradually. However, after 1 week of chemotherapy, the patient developed headache and lethargy. Brain magnetic resonance imaging (MRI) demonstrated multiple nodules and patchy abnormal signal lesions were found in the bilateral cerebral, cerebellar hemispheres and the left cerebral peduncle. Diffusion-weighted images (DWI) showed hyperintensity and T2-flair showed hypointensity (Fig. 3). Cerebrospinal fluid (CSF) analysis showed elevated total protein 128.6 mg/dl (reference 15–45) and nucleated cell count of 260/ul (96% for neutrophils and 4% for macrophages ). Glucose and chlorine were normal. CSF metagenomic next generation sequencing (mNGS) indicated Aspergillus infection. Lymphoma infiltrating central nervous system complicated by aspergillus infection was diagnosed. Cefoperazone and sulbactam sodium, colistin sulphate as well as voriconazole were given, however, infection was still not under controlled, the patient died on June, 6, 2022. (The laboratory indicators during the hospital course are summarized in Table 1).
Table 1
The laboratory parameters during the hospital course.
Day after admission | Leukocytes (×109/L) | Neutrophils (×109/L) | Hemoglobin (g/L) | Plt (×109) | Ferritin (ng/ml) | IL-6 (pg/ml) | IL-10 (pg/ml) | Lactate (mmol/L) | Cr (umol/L) | Treatment |
1 | 3.23 | N | 58 | 32 | 3200.04 | ND | ND | 4.6 | N | Ruxolitinib |
3 | 2.31 | 1.75 | 55 | 22 | 3132.36 | 41.29 | 919.29 | ND | N | |
4 | 2.67 | 1.98 | 55 | 31 | ND | ND | ND | 14.6 | N | |
10 | N | N | 68 | 33 | 4842.79 | ND | ND | 6.7 | 54 | ECOP |
11 | 2.63 | N | 55 | 13 | 3826.05 | ND | ND | N | N | Ruxolitinib |
26 | N | N | 54 | 51 | 2263.8 | 11.5 | 274.97 | 3.2 | N | RCHOP |
68 | N | 7.77 | 57 | 35 | 1954.16 | 116.02 | 488.33 | ND | 109 | OR2 |
95 | 1.55 | 0.76 | 49 | 32 | 4799.89 | 249.22 | 27.35 | N | 401 | |
106 | 2.82 | 1.41 | 51 | 39 | 2539.59 | 71.69 | 18.4 | N | 232 | |
127 | 3.6 | 2.1 | 70 | 89 | 1481.2 | 42.89 | 13.68 | ND | 447 | rituximab and orelabrutinib |
N: normal, ND: no data |