[Successful treatment of relapsed and refractory multiple myeloma by using clarithromycin-lenalidomide, low-dose dexamethasone(BiRd), and melphalan-prednisolone(MP)].

The development of novel agents has markedly improved the prognosis of multiple myeloma(MM). However, salvage therapies for patients with MM that is refractory to novel agents and conventional chemotherapies have not been established. Herein, we describe successful treatments for such patients with the combination of clarithromycin, lenalidomide, and lowdose dexamethasone(BiRd)with or without melphalan and prednisolone(MP). Although its duration was relatively short, the remission is important in terms of the salvage strategy until the second generation of novel agents becomes available.

Life-threatening hemorrhagic pneumonia caused by Stenotrophomonas maltophilia in the treatment of hematologic diseases.

Since the late 1990s, Stenotrophomonas maltophilia (S. maltophilia) has become one of the most common nonfermenting Gram-negative bacilli that cause opportunistic infection. Patients with hematologic diseases are the most risky candidate for S. maltophilia pneumonia or sepsis because of chemotherapy-induced neutropenia or immunodeficiency. Frequent exposure to broad-spectrum antibiotics and prolonged insertion of central venous catheter further enhance the risk of S. maltophilia infection. One of the most severe S. maltophilia infections is hemorrhagic pneumonia. This type of infection is mostly fatal because of pulmonary alveolar hemorrhage that leads to acute respiratory failure. Furthermore, S. maltophilia exhibits a high-level intrinsic resistance to conventional antibiotics such as ß-lactams and aminoglycosides and, more recently, the increasing acquired resistance to co-trimoxazole and quinolones. According to our experienced and previously reported cases, all of the patients with hemorrhagic pneumonia caused by S. maltophilia had a fatal course within a few days after the onset of the pneumonia. In this article, we perform a systematic review on a total 30 cases of hemorrhagic pneumonia induced by S. maltophilia from our institutions and the literature, and we describe its early diagnosis, prophylaxis, and recommended therapeutic strategy for the infection in the treatment of hematologic disease.

[Remission of lymphoma-associated pure red cell aplasia after successful chemotherapy for B-cell lymphoma].

A 49-year-old man was diagnosed with pure red cell aplasia (PRCA) based on low reticulocyte count (0.1%) and near absence of erythroblasts in the bone marrow (BM). While a small number of CD20-positive large abnormal cells was observed in the BM, Multiplex PCR confirmed B cell monoclonality. Gallium scintigraphy showed abnormality only in the BM, and we made a diagnosis of PRCA secondary to BM-derived B-cell malignant lymphoma. He was treated with rituximab-combined CHOP therapy with subsequent resolution of both disorders. He was further treated with high dose chemotherapy with auto-PBSCT, sustaining complete remission of the PRCA and lymphoma.

[Alleviation of palmoplantar pustulosis associated with adult T cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation].

A 68-year-old female with palmoplantar pustulosis was referred to our hospital in July, 2009 because of liver dysfunction, a positive test for HTLV-1, and circulating abnormal lymphocytes with irregularly shaped nuclei. A diagnosis of acute type adult T cell leukemia/lymphoma (ATLL) was made based on generalized lymph node swelling and high levels of serum LDH, in addition to the findings described above. The associated palmoplantar pustulosis responded to some extent to antibiotics, steroid ointment, and narrow band UBV light irradiation. For ATLL, she was serially treated with CHOP chemotherapy, an LSG 15 protocol, and CytaBOM protocol with consequent partial remission. These chemotherapies did not affect the palmoplantar pustulosis. For ATLL in partial remission, we performed allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from a related donor (HTLV-1-negative) with a conditioning regimen consisting of fludarabine, melphalan, and total body irradiation with 3 Gy in February, 2010. After the engraftment of donor hematopoietic cells, ATLL cells disappeared and the patient currently (as of April, 2012) remains in complete remission (CR). The residual palmoplantar pustulosis was further improved soon after allo-PBSCT and disappeared on Day 84 after transplantation. This refractory skin disease has also been in CR to date.

[Improvement of patient adherence by mixing oral itraconazole solution with a beverage (orange juice)].

There have been some reports on the efficacy and tolerability of an oral itraconazole (ITCZ) solution as prophylaxis for fungal infection in patients with hematological malignancies. However, there are some cases where the bitter taste of oral ITCZ solution leads to an interruption of administration because the patient refuses to take this medicine. Therefore, we prospectively investigated the pharmacokinetics and promotion of treatment adherence in patients taking oral ITCZ solution mixed with a beverage. Compared with the responses of patients taking oral ITCZ solution with water, the taste of the agent was improved significantly when mixed with orange juice, although the plasma concentration of the agent did not differ between the two groups. Using this method, we can expect an improvement in treatment adherence and this method can easily be applied in clinical practice. This method is highly useful and should become common knowledge.

[A case of sarcomatoid malignant peritoneal mesothelioma responding to combination chemotherapy of cyclophosphamide, vincristine, adriamycin and dacarbazine(CYVADIC)].

A 66-year-old woman was seen at our hospital because of abdominal fullness. A computed tomography(CT)revealed massive tumors in abdominal cavity. The patient underwent surgery consisting of tumorectomy, segmental gastrectomy, partial resection of small intestin, transverse colectomy, left oophorectomy and gastrostomy. By using immunohistochemical staining, the patient was diagnosed as sarcomatoid malignant peritoneal mesothelioma. Rapidly abdominal fullness occurred as of 22 days after the operation, and an abdominal CT revealed the massive recurrent tumors. We started a combination chemotherapy of cyclophosphamide, vincristine, adriamycin and dacarbazine (CYVADIC). The recurrent tumors showed remarkable reduction after the two courses of CYVADIC chemotherapy. Although we next started carboplatin and paclitaxel combination chemotherapy, she died due to rapidly progression of the disease with disseminated intravascular coagulation after 132 days of the operation. Malignant mesothelioma, especially sarcomatoid mesothelioma, is known to have a poor prognosis. However, our case suggests that we could improve the prognosis of sarcomatoid malignant mesothelioma by aggressive chemotherapy.

Gamma-heavy chain monoclonal gammopathy with undetermined significance (MGUS).

Gamma-heavy chain disease (γ-HCD) is a rare B-cell tumor producing truncated IgG lacking the light chain. The clinical features of γ-HCD are heterogeneous, similar to lymphoplasmacytic lymphoma, and most patients have generalized and progressive disease. In some γ-HCD patients, autoimmune diseases are associated. Thus, γ-HCD as a restricted or indolent disease is exceptional. A 66-year-old male was referred to our hospital because of subungual hemorrhage at the bilateral halluces. Physical and laboratory examination results were nonspecific, and the hemorrhage was revealed to be traumatic. However, serum electrophoresis demonstrated a small M-peak, which was monoclonal IgG-Fc without the corresponding light chain on immunofixation and immunoelectrophoresis. Bone marrow aspirate demonstrated a small number of lymphoplasmacytic cells that were positive for CD19, CD38, CD138, and cyIgG, but negative for cyκ- and -λ light chains on flow cytometry. A diagnosis of γ-HCD was made. Chest and abdominal CT demonstrated neither hepatosplenomegaly, lymphadenopathy, nor bone lytic lesions. The serum concentrations of IgG and M-peak configuration have remained relatively unchanged for nearly 3 years. Therefore, this γ-HCD may correspond to a rare form of monoclonal gammopathy with undetermined significance.

IgA-producing lymphoplasmacytic lymphoma carrying the chromosomal abnormality t(8;14).

IgA-producing lymphoplasmacytic lymphoma (LPL) is rare and IgH/c-myc translocation is rare in LPL. This is the first report of a case of IgA-producing LPL carrying t(8;14). An 86-year-old woman presented inguinal and intra-abdominal lymph node swelling, and lytic bone lesions in the lumbar vertebrae. A diagnosis of IgA-producing LPL was immunohistochemically made by inguinal lymph node biopsy. The serum IgA level was 1,180 mg/dL, which was revealed to be composed of IgA-λ monoclonal protein. Bone marrow chromosomal analysis demonstrated a complex abnormal karyotype, including t(8;14)(q24;q32), which was confirmed by FISH analysis. Abnormal lymphocytes positive for CD19, CD20, cyIgA, and cyλ were detected on flow cytometry analysis of marrow cells. Best supportive care was selected because of dementia and refractory urinary tract infection. Circulating lymphoplasmacytic cells with the same phenotype and karyotype were observed, and increased in number. The aggressive clinical course, including lytic bone lesions, may have been due to IgH/c-myc translocation or the nature of IgA-producing LPL.

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN with RS-T) complicated by hyperleukocytosis and gene analysis in relation to leukocytosis.

Myelodysplastic/myeloproliferative neoplasm (MDS/MPN) with ring sideroblasts and thrombocytosis (MDS/MPN with RS-T), which exhibits both an increased number of marrow ring sideroblasts and thrombocytosis, is a rare disorder classified as one of the newly established forms of MDS/MPN in the WHO 2016 classification. A 77-year-old female with marked thrombocytosis of 1,024×109/L was tentatively diagnosed with essential thrombocythemia in 2011, and the thrombocytosis was controlled using hydroxycarbamide and low-dose busulfan. In 2016, the leukocyte count increased to a peak value of 68.8×109/L (86.6% mature neutrophils) during platelet-reduction therapy. Bone marrow aspirate exhibited hypercellularity with ring sideroblasts comprising 41.5% erythroblasts without excess myeloblasts. Cytogenetic examination demonstrated the JAK2 V617F mutation and chromosomal abnormality of 46,XX,del(20)(q1?). Furthermore, dysplastic features of erythroid and granuloid precursors, as well as many large atypical megakaryocytes, were observed. Further genetic examinations revealed the SF3B1 K700E mutation, but not amplification of the JAK2 gene or pathogenic mutations in the 13 other genes examined. A diagnosis of MDS/MPN with RS-T was established and hyperleukocytosis was controlled using a higher dose of hydroxycarbamide. Although the patient maintained a stable disease state, she became RBC transfusion-dependent. Hyperleukocytosis, regardless of chemotherapy, is rare and may be novel in this disorder.

Gamma heavy chain disease (γ-HCD) as iatrogenic immunodeficiency- associated lymphoproliferative disorder: Possible emergent subtype of rheumatoid arthritis-associated γ-HCD.

Gamma heavy chain disease (γ-HCD) is a rare B-cell neoplasm that produces a truncated immunoglobulin γ-heavy chain lacking the light chain. The clinical features of γ-HCD are heterogeneous, resembling different types of B-cell lymphomas. Although rheumatoid arthritis (RA) is one of the common underlying diseases of γ-HCD, the therapeutic modality for RA has changed greatly in recent years; therefore, γ-HCD as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) should be taken into consideration. Here, we report such a γ-HCD case. A 69-year-old female was admitted because of fever, multiple lymph node swelling in the abdominal cavity, and peritoneal effusion. She had been treated using methotrexate for RA for 14 years, and using infliximab and adalimumab for Crohn's disease for one year. The serum concentration of IgG was 3,525 mg/dL, which was revealed to be monoclonal IgG lacking the light chain by rocket immunoselection assay. CD19+/CD20-/smκ-/smλ- large abnormal lymphocytes were observed in the peritoneal fluid, which were demonstrated to be clonal B-cells by PCR examination. Discontinuation of methotrexate did not improve her condition and she died of pneumonia. Many abnormal lymphocytes positive for IgG and EBER but negative for the light chain were found on immunohistological examination of necropsy specimens from the spleen and bone marrow.

T-cell large granular lymphocytic (LGL) leukemia consists of CD4+/CD8dim and CD4-/CD8+ LGL populations in association with immune thrombocytopenia, autoimmune neutropenia, and monoclonal B-cell lymphocytosis.

CD3+/CD57+ T-cell large granular lymphocyte leukemia (T-LGLL) is an indolent neoplasm, exhibiting mostly CD8+, less frequently CD4+ phenotypes, and T-LGLL consisting of 2 populations with CD8+ and CD4+ phenotypes is markedly rare. An 87-year-old female was admitted under a diagnosis of immune thrombocytopenia (ITP) with a platelet count of 5.0×109/L and increased number of LGL with unknown etiology. Her neutrophil count also decreased to 0.27×109/L and she was positive for antineutrophil antibody. The WBC count was 2.7×109/L with 34.7% LGL and flow cytometry (FCM) analysis revealed 16% CD3+/CD4+/CD8dim/CD57+ and 20.9% CD3+/CD8+/CD57+ populations. These populations also expressed granzyme B and perforin. Circulating mononuclear cells were found to be clonal by PCR analysis of T-cell receptor ß-chain gene. Serum immunofixation and bone marrow FCM analyses demonstrated 2 clonal B-cells producing IgG-λ and IgA-λ. Deep amplicon sequencing of STAT3 and STAT5B genes revealed a STAT3 R302G mutation with an allele burden of 2.6%. The thrombocytopenia and neutropenia were successfully treated by prednisolone and romiplostim with negative conversion of antineutrophil antibody. This is the first reported case of T-LGLL with dual components of CD4+/CD8dim and CD4-/CD8+ populations in terms of multiple comorbidities related to the respective CD8+ and CD4+ T-LGLLs.

Colonal monomorphic epitheliotropic intestinal T-cell lymphoma with novel phenotype of cytoplasmic CD3 expression.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a new clinical entity that was reclassified from enteropathy-associated T-cell lymphoma in the 2016 WHO classification. An 83-year-old man with fever and diarrhea was referred to our hospital because of free air in the abdominal cavity and wall thickening of the large intestine on CT. Colonofiberscopic examination revealed mucosal edema and multiple ulcers at the sigmoid colon, splenic flexure, and transverse colon. Histopathological examination of the mucosal biopsy specimen demonstrated dense infiltration of small lymphocytes with nuclear atypia, some of which exhibited intraepithelial invasion. Immunohistologically, these lymphocytes were positive for CD3, CD56, and perforin. Regarding CD3 expression, the antigen was found to only be expressed in the cytoplasm and not on the surface membrane on flow cytometric analysis. PCR examination of the T-cell receptor (TCR) gene revealed monoclonal gene rearrangements of TCR-γ and TCR-ß. Based on these findings, a diagnosis of colonal MEITL with cyCD3 expression at Lugano clinical stage 1 was made. After conservative management of the peritonitis, we treated the patient with CHOP and DeVIC regimens, but he developed progressive disease and died. The cyCD3 expression in MEITL may be novel, suggesting a thymocyte origin of the tumor cells.

Marked rebound thrombocytosis in response to glucocorticoids in a patient with acquired amegakaryocytic thrombocytopenia.

Acquired amegakaryocytic thrombocytopenia (AATP) is a rare disease characterized by thrombocytopenia and the disappearance of marrow megakaryocytes. A 43-year-old man was admitted because of thrombocytopenia of 1.0×109/L. Bone marrow aspirate demonstrated normal hematopoiesis lacking megakaryocytes, and AATP was diagnosed. The serum concentration of thrombopoietin (TPO) was high (7.72 fmol/mL). Prednisolone (PSL) at 60 mg/day was started and the platelet count recovered to 1,335×109/L; however, excessive megakaryocytopoiesis and subsequent decline in platelet count were noted 14 days later. At the peak platelet count, the TPO remained at 3.79 fmol/mL and returned to a normal level of 0.40 fmol/mL during the period of normal platelet count after PSL tapering. The marked thrombocytosis in response to prednisolone may have been caused by the high TPO after the resolution of suppressed megakaryopoiesis. Marked rebound thrombocytosis beyond 1,000×109/L after successful PSL treatment for AATP has not been previously reported.

Composite Lymphoma as Co-occurrence of Advanced Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Carrying Trisomy 12 and t(14;18) and Peripheral T-cell Lymphoma.

Composite lymphoma is defined as the co-occurrence of two types of lymphoma, comprising 1-4% of lymphomas, and the association of B-cell-type chronic lymphocytic leukemia (B-CLL)/small lymphocytic lymphoma and peripheral T-cell lymphoma (PTCL) is rare. Here, we report a case (77-year-old woman) of advanced B-CLL complicated by newly appearing PTCL. Two years after the onset of B-CLL, CLL cells acquired CD38 antigen expression and the disease entity became CLL/prolymphocytic leukemia. Trisomy 12 and t(14;18) karyotypes were observed. Five years after the onset of B-CLL, large abnormal cells with convoluted nuclei appeared in the peripheral blood and rapidly increased in number. These cells were positive for CD3, CD4, CD5, CD30 (partially), CD56, and αß-type T-cell receptor (TCR), in which PCR demonstrated monoclonal TCR-γ gene rearrangement. An additional diagnosis of PTCL, not otherwise specified was made. We treated her with an R-CHOP regimen, resulting in the marked reduction of B-CLL cells but progressive PTCL. Brentuximab vedotin had a transient effect, but the patient died of sepsis due to residual PTCL and pancytopenia. This case is highly informative for tumor biology of B-CLL in terms of emergence of both chromosomal abnormalities and PTCL with progression of this leukemia.

Analysis of gastrointestinal virus infection in immunocompromised hosts by multiplex virus PCR assay.

Regarding viral infection of intestinal mucosa, there have been only a few studies on limited diseases, targeting a few herpes family viruses. In this study, we analyzed 12 kinds of DNA viruses including 8 species of herpes family viruses in the gastrointestinal mucosa of patients with hematologic malignancies, inflammatory bowel diseases, collagen diseases, or other miscellaneous forms of gastroenteritis using the multiplex virus PCR assay, which we recently developed. The virus PCR assay yielded positive results in 63 of 102 patients; Epstein-Barr virus (EBV) was the most frequently detected, followed by cytomegalovirus (CMV), human herpes virus 6 (HHV-6), HHV-7, parvovirus B19, and herpes simplex virus type 1. The frequencies of viral detection in the 4 diseases were similar involving these 6 viruses. Regarding CMV colitis, the multiplex virus PCR assay was superior to the immunohistopathologic method in detecting CMV. All viruses were more efficiently detected in the mucosa than in the blood in individual patients. These results suggest that CMV, EBV, and HHV-6 were commonly detected in the gastrointestinal mucosa of patients with these 4 diseases, and our multiplex virus PCR assay was useful for the early diagnosis of gastrointestinal virus infection, especially CMV colitis.

Acute monocytic leukemia diagnosed by flow cytometry includes acute myeloid leukemias with weakly or faintly positive non-specific esterase staining.

A diagnosis of acute monocytic leukemia (AML-M5) based on α-naphthyl butyrate esterase (α-NB) staining has some problems, because AML-M5 leukemic cells often show weak or faint positivity on α-NB staining. In these situations, some cases of AML-M5 tend to be misdiagnosed as AML-M0. Therefore, we evaluated the significance of weak or faint α-NB staining in AML-M5 diagnosed by flow cytometry (FCM). Nineteen AML cases in which leukemic cells were negative for naphthol AS-D chloroacetate esterase staining were studied. For FCM, we defined leukemic cells as having a monocytic nature when more than 10% of the leukemic cells were positive for at least one of the following antigens: CD4, CD11c, CD14, and CD64. The monocytic nature determined by FCM was consistent with positive or weak positivity on α-NB staining. Five of 6 cases in which leukemic cells exhibited faint positivity for α-NB staining could be diagnosed as AML-M5 by FCM, while negative α-NB staining was consistent with a diagnosis of AML-M0. These results suggest that AML-M5 should be taken into consideration even when leukemic cells are faintly positive for α-NB staining.

Acute Myeloid Leukemia Complicated by Giant Cell Arteritis.

Giant cell arteritis (GCA), a type of systemic arteritis, is rare in Japan. We herein report a case of acute myeloid leukemia (AML) complicated by GCA that manifested during chemotherapy for AML. A 77-year-old woman with severe back pain was diagnosed with AML. She achieved complete remission with the resolution of her back pain following induction chemotherapy. However, she developed a headache and fever after consolidation chemotherapy. A diagnosis of GCA was made based on a biopsy of the temporal artery and arterial imaging. GCA should therefore be included in the differential diagnosis in AML patients complicated with a headache and fever of unknown origin.

Persistent Hypoplastic Acute Promyelocytic Leukemia with a Novel Chromosomal Abnormality of 46, XY, t(15;17), t(9;11)(q13;p13).

A diagnosis of acute promyelocytic leukemia (APL) is usually made when normal hematopoietic cells are substituted by APL cells. We encountered a unique APL patient who presented with persistent hypoplastic features of APL. An 84-year-old man presented with leukopenia (2.2 × 10(9)/L) and anemia (Hb 12.5 g/dL). Five months later, the bone marrow (BM) was hypoplastic with a normal proportion of blasts and promyelocytes (5.2%), although the latter cells were hypergranular. The karyotype of BM cells was 46, XY, t(15;17)(q22;q12), t(9;11)(q13;p13). Two months later, the BM remained hypoplastic with 8.5% hypergranular promyelocytes, some of which contained faggot of Auer rods. RT-PCR examination yielded the PML-RARα transcript, and its sequencing revealed the breakpoint of PML to be bcr2. The patient was treated with all-trans retinoic acid under a diagnosis of APL with improvement of the bicytopenia. FISH analysis of BM cells yielded a negative result regarding t(15;17), although RT-PCR was positive for PML-RARα mRNA. Six months later, APL recurred with the same karyotypic abnormalities and therapeutic resistance, and the patient died of pneumonia. A persistent hypoplastic state of APL may be a rare event, and the association of t(15;17) and t(9;11) is novel.

Marked Thrombocytosis in Chronic Eosinophilic Pneumonia and Analysis of Cytokine Mechanism.

A 47-year-old woman with marked thrombocytosis of 1,650 × 10(9)/L was diagnosed with chronic eosinophilic pneumonia (CEP) based on imaging of the lung and abundant eosinophils in bronchoalveolar lavage fluid. Known gene abnormalities that cause eosinophilia were not detected in bone marrow cells. Treatment with oral prednisolone at 20 mg/day relieved the CEP and resolved the laboratory abnormalities, including eosinophilia and thrombocytosis. Serum concentrations of interleukin (IL)-5 and IL-6 were elevated to 9.6 and 14.0 pg/mL, respectively. The megakaryocyte-potentiating activity of IL-6 and possibly, that of IL-1ß, which is known to be secreted by activated eosinophils, may have caused the marked thrombocytosis in this patient.

T-Cell Prolymphocytic Leukemia, Small Cell Variant, Possibly at the Stage of Intracytoplasmic Expression of CD3 in T-Cell Ontogenesis.

T-cell prolymphocytic leukemia, small cell variant (T-PLL-s), is a rare lymphoid neoplasm associated with a poor prognosis. We encountered a case of T-PLL-s with a characteristic phenotype. A 67-year-old female was referred to our hospital because of lymphocytosis in August 2013. Hepatosplenomegaly, lymphadenopathy, and skin lesions were absent. Hematologic examination revealed a white blood cell count of 17.9 × 10(9)/L with 81.2% mature lymphocytes, which were small with a high nuclear/cytoplasmic ratio, lacking a nucleolus and cytoplasmic granules. Anemia and thrombocytopenia were not observed. Flow cytometric analysis showed that these lymphocytes were positive for CD2, cyCD3, CD4, CD5, CD7, CD21, and CD38 (partially), but negative for smCD3, smTCR-αß and -γδ, cyTCR-ß, CD1a, CD8, CD25, HLA-DR, and terminal deoxynucleotidyl transferase. Polymerase-chain reaction analysis of cells from both the peripheral blood and the bone marrow demonstrated monoclonal rearrangement of TCR-γ. A possible rearranged band of the TCR-ß gene was observed by Southern blot analysis. The karyotype of the marrow cells was 46, XX. A diagnosis of T-PLL-s, possibly at the stage of cytoplasmic CD3 expression in the ontogenesis of T-cells, was made. The patient has been asymptomatic, and the white blood cell count has gradually increased during one-year observation, being 69.0 × 10(9)/L with 89.7% lymphocytes in August 2014.