Sho Yamazaki

Haemophagocytic lymphohistiocytosis is a recurrent and specific complication of acute erythroid leukaemia.

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of severe hyperinflammation caused by proliferation of reactive lymphohistiocytes with marked haemophagocytosis (Janka, 2007). It comprises two different conditions: familial HLH and acquired HLH. Acquired HLH can be caused by infections, rheumatoid disorders and malignant neoplasms. Malignant neoplasm-associated HLH is mainly accompanied by malignant lymphoma and, less frequently, by other haematological malignancies and carcinomas. We present a case of HLH complicating acute erythroid leukaemia (AEL) transformed from myelodysplastic syndrome (MDS). AEL, as proposed in the 2008 World Health Organization (WHO) classification, represents a minor subtype of acute myeloid leukaemia (AML) defined by predominant proliferation of erythroid progenitors in the bone marrow (Arber et al, 2008). It is further classified into two subgroups; erythroleukaemia (erythroid/myeloid) and pure erythroid leukaemia. Erythroleukaemia (erythroid/myeloid), historically referred to as AML M6a in the FrenchAmerican-British (FAB) classification, is characterized by erythroid dominance (>50%) with myeloblasts comprising over 20% of non-erythroid cells (NEC). It can manifest de novo or evolve from MDS or from other myeloproliferative neoplasms. Pure erythroid leukaemia (FAB M6b) is another rare subtype where there is proliferation of immature erythroblasts (>80%) without evidence of myeloid components. With a literature review, we focus on a specific relationship between HLH and AEL.

Safety of high-dose micafungin for patients with hematological diseases

Abstract This study was conducted as a retrospective, observational, exploratory cohort study with the aim of elucidating the safety profile of micafungin at doses exceeding 150 mg daily. We identified adult patients with hematological diseases who had received micafungin therapy for ≥ 7 consecutive days. Twenty-six patients administered micafungin at 300 mg daily (high-dose group) were compared with 58 patients administered micafungin at 150 mg daily (standard-dose group). The most frequent adverse events (AEs) were hepatotoxicity, hypertension and diarrhea. AEs were recorded in 42 (72%) and 19 (73%) patients in the standard-dose and high-dose groups, respectively (p = 1.00). Hepatobiliary AEs were noted in 28 (48%) and 15 (58%) patients, respectively (p = 0.48). Serious AEs and resultant treatment discontinuation were infrequent. Our results suggest that micafungin was safe and well tolerated at 300 mg daily.

The significance of free light chain measurements in the diagnosis of myelomatous pleural effusion.

Dear Editor, Pleural effusion accompanies approximately 6 % of patients with multiple myeloma (MM) [1, 2]. It is usually associated with nephritic syndrome, pulmonary embolism, congestive heart failure, and infections. Myelomatous pleural effusion (MPE) is a relatively rare cause, affecting only 0.8 % of MM patients. The diagnostic criteria for MPE were originally defined as follows: (1) a monoclonal protein in pleural fluid immunoelectrophoresis, (2) atypical plasmacytes in the pleural effusion, and (3) histological confirmation by a pleural biopsy or by an autopsy [3]. In recent years, the usefulness of serum and urine free light chain (FLC) concentrations in the diagnosis and efficacy assessment of MM was demonstrated [4]. Here, we focus on the clinical significance of FLC in the diagnosis of MPE through a case report. A 47-year-old man visited our institution because of progressive pancytopenia. Urine and serum immunofixation electrophoresis (IFE) detected Bence–Jones protein (BJP) λ paraprotein. Bone marrow aspirate showed marked proliferation of plasma cells, leading to the diagnosis of MM. Induction therapy with bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen led to amelioration of proteinuria. However, he developed dyspnea after two cycles of VCD therapy. F18 fluorodeoxyglucose positron emission tomography combined with computed tomography scan revealed uptakes in a mass on the left chest wall (Fig. 1a). Because of a rapid increase in the left pleural effusion (Fig. 1b), percutaneous catheter drainage was exerted. Microscopic examination presented infiltration of plasma cells (Fig. 1c), and IFE detected BJP λ paraprotein (Fig. 1d). Thus, we speculated that the pleural effusion was produced by the adjacent plasmacytoma. Notably, concentrations of κ and λ FLCs in the effusion were 6.7 and 4,360 mg/L (free κ/λ ratio, 1/651), whereas those in the serum were 0.6 and 1,040 mg/L, respectively (free κ/λ ratio, 1/1,733). The bone marrow specimen then did not show apparent proliferation of atypical plasma cells. The response to salvage treatment was transient, and he succumbed to death 4 months after the onset of MPE. An autopsy confirmed that the chest wall plasmacytoma penetrated the pleura. Our case meets all the original diagnostic criteria for MPE. The most frequent subclass of immunoglobulins in the MPE is IgA, followed by IgD and IgG [5]. From this viewpoint, BJP-type MPE is relatively infrequent. Would both absolute FLC values and free κ/λ ratio in the pleural fluid help the diagnosis of BJP-type MPE? Oudert et al. recently supported this idea through a case of BJP κtype MPE. Compared with serum, the MPE was remarkable for a higher absolute κ FLC value (1,660 vs. 300 mg/L) and a greater free κ/λ ratio (>5,000 vs. >1,000) [6]. In our case, absolute λ FLC value was higher in the MPE than in the serum (4,360 vs. 1,040 mg/L). On the other hand, free κ/λ ratio in the MPE did not exceed that in the serum (1/651 vs. 1/1,733). Comprehensively, MPE may be characterized by an absolute FLC value which is much higher than that in the serum, although it is partly attributed to the different FLC clearance between pleural effusion and serum. A. Tsukamoto :Y. Yoshiki : S. Yamazaki :K. Kumano : F. Nakamura :M. Kurokawa (*) Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan e-mail: kurokawa-tky@umin.ac.jp

Comparison of garenoxacin with levofloxacin as antimicrobial prophylaxis in acute myeloid leukemia

OBJECTIVE Levofloxacin is widely used as antimicrobial prophylaxis against high-risk chemotherapy-induced neutropenia. Garenoxacin, a fluoroquinolone developed in Japan, shows a stronger in vitro antimicrobial activity against Gram-positive bacteria than levofloxacin. METHODS We retrospectively analyzed high-risk patients with acute myeloid leukemia who were administered garenoxacin (n = 36) or levofloxacin (n = 120) during chemotherapy. We compared the profiles of infections between these fluoroquinolones. RESULTS Febrile events occurred in 31 (86%) and 93 (78%) cases in the garenoxacin and levofloxacin group, respectively (P = 0.35). Bloodstream infections by Gram-positive bacteria were recorded in one (3%) case in the garenoxacin group and 25 (21%) cases in the levofloxacin group (P < 0.01). In contrast, bloodstream infections by Gram-negative microorganisms were identified in five (4%) cases in the levofloxacin group and eight (22%) cases in the garenoxacin group (P < 0.01). CONCLUSIONS These results indicate that there may be substantial differences in the antimicrobial spectrum between different fluoroquinolones. Although there are several biases due to rather small sample size and the retrospective nature, we should take the differences into consideration when we administer a prophylactic fluoroquinolone to a patient with hematological disease.

ADAM8 Is an Antigen of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia Cells Identified by Patient-Derived Induced Pluripotent Stem Cells

Summary Properties of cancer stem cells involved in drug resistance and relapse have significant effects on clinical outcome. Although tyrosine kinase inhibitors (TKIs) have dramatically improved survival of patients with chronic myeloid leukemia (CML), TKIs have not fully cured CML due to TKI-resistant CML stem cells. Moreover, relapse after discontinuation of TKIs has not been predicted in CML patients with the best TKI response. In our study, a model of CML stem cells derived from CML induced pluripotent stem cells identified ADAM8 as an antigen of TKI-resistant CML cells. The inhibition of expression or metalloproteinase activity of ADAM8 restored TKI sensitivity in primary samples. In addition, residual CML cells in patients with optimal TKI response were concentrated in the ADAM8+ population. Our study demonstrates that ADAM8 is a marker of residual CML cells even in patients with optimal TKI response and would be a predictor of relapse and a therapeutic target of TKI-resistant CML cells.

Composite diffuse large B-cell lymphoma and CD20-positive peripheral T-cell lymphoma

Composite lymphoma is defined as two or more distinct types of lymphoma in a single anatomical site. Among various combinations, composite B‐cell and T‐cell non‐Hodgkins lymphomas (CBTL) are very infrequent. Herein we describe a 66‐year‐old female with CBTL presenting with lymphadenopathy, multiple bone lesions and an epidural tumor. Light microscopic examination of a biopsied cervical node revealed a dual population of lymphoid cells: sheets of large cells admixed with medium‐sized cells. The large cells expressed B‐cell markers and showed immunoglobulin light chain restriction, consistent with diffuse large B‐cell lymphoma (DLBCL). The medium‐sized cells were positive for CD20 as well as T‐cell markers. Because polymerase chain reaction amplification showed monoclonal rearrangement of the T‐cell receptor β chain gene, this population was compatible with peripheral T‐cell lymphoma not otherwise specified (PTCL‐NOS). We therefore made a diagnosis of composite DLBCL and CD20‐positive PTCL‐NOS. Complete remission was achieved after six cycles of R‐CHOP regimen (rituximab, doxorubicin, vincristine, cyclophosphamide and prednisolone). This is the first report of CD20‐positive PTCL‐NOS associated with composite lymphoma. Moreover, a literature review of composite DLBCL and PTCL‐NOS indicates that this rare clinical entity may be featured by efficacy of systemic chemotherapy in spite of prevalent extranodal lesions.

Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate

Chronic myelomonocytic leukemia (CMML) is an entity of myelodysplastic syndrome/myeloproliferative neoplasm. Although CMML can be cured with allogeneic stem cell transplantation, its prognosis is generally very poor due to the limited efficacy of chemotherapy and to the patient’s age, which is usually not eligible for transplantation. Comprehensive analysis of CMML pathophysiology and the development of therapeutic agents have been limited partly due to the lack of cell lines in CMML and the limited developments of mouse models. After successfully establishing patient’s derived disease-specific induced pluripotent stem cells (iPSCs) derived from a patient with CMML, we utilized these CMML-iPSCs to achieve hematopoietic re-differentiation in vitro, created a humanized CMML mouse model via teratomas, and developed a drug-testing system. The clinical characteristics of CMML were recapitulated following hematopoietic re-differentiation in vitro and a humanized CMML mouse model in vivo. The drug-testing system using CMML-iPSCs identified a MEK inhibitor, a Ras inhibitor, and liposomal clodronate as potential drugs for treating CMML. Clodronate is a drug commonly used as a bisphosphonate for osteoporosis. In this study, the liposomalization of clodronate enhanced its effectiveness in these assays, suggesting that this variation of clodronate may be adopted as a repositioned drug for CMML therapy.