Serum Albumin Levels Strongly Predict Survival Outcome of Elderly Patients with Diffuse Large B-Cell Lymphoma Treated with Rituximab-Combined Chemotherapy.

Background: In the current Japanese aging society, a high number of very elderly patients (age ranged from 80 to 93) with diffuse large B-cell lymphoma (DLBCL, most frequent hematological malignancy), who require chemotherapy are encountered. However, standard chemotherapy can result in severe adverse effects in elderly patients. Although various scoring systems are available to assess frailty, they are too complicated to immediately make a therapeutic decision, and studies on indications for chemotherapy in elderly patients are few. Materials and Methods: In the present study, we retrospectively analyzed the clinical records of 56 patients with DLBCL aged 80 or older who received R-CHOP or similar chemotherapy. Association of various clinical parameters, including performance status, stage, B symptom(s), laboratory data and relative dose intensity and survival outcomes was examined. Results: Pretreatment serum albumin level was identified as the only factor that predicts overall and progression-free survivals. Conclusion: We have concluded that very elderly DLBCL patients aged 80 or older with hypoalbuminemia may be unfit for standard chemotherapy, regardless of other factors. Alternative or palliative therapy should be considered for those patients.

A case of AL amyloidosis associated with follicular lymphoma with plasmacytic differentiation.

A 58-year-old woman underwent emergency surgical resection of the small intestine for intussusception as diagnosed at our hospital. Histopathological diagnosis of the resected specimen of the ileum was amyloid light chain (AL) amyloidosis. The colonoscopy after the surgical resection and following histopathological analysis of the biopsied specimens of the colon revealed follicular lymphoma (FL) grade 1 with plasmacytic differentiation. Histological findings of these ileal and colonic lesions were characteristic. In the ileum, CD10-positive lymphoid follicles and CD38-positive interfollicular plasma cell infiltration into villi were detected. The amyloid deposition was localized to the ileum and was adjacent to lymphoid follicles and interfollicular plasma cells. Furthermore, fluorescence in situ hybridization (FISH) for paraffin-embedded tissue sections (tissue-FISH) revealed that both the B cells in follicular lesions and the interfollicular plasma cells showed IGH/BCL2 fusion signals, which means the interfollicular plasma cells were originated from the differentiated neoplastic follicular B cells. The patient was treated with six courses of lymphoma chemotherapy and attained complete remission without any symptoms associated with amyloidosis. Further case analyses are needed to clarify the clinicopathological findings and to establish therapeutic strategy of AL amyloidosis associated with FL and FL with plasmacytic differentiation.

Combined rituximab, bendamustine, and dexamethasone chemotherapy for relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma: a multicenter phase II study.

This multicenter phase II study (UMIN000008145) aims to investigate the efficacy and safety of six cycles of combination therapy (RBD) comprising rituximab, bendamustine, and dexamethasone (DEX) for relapsed or refractory (RR) indolent B-cell non-Hodgkin lymphoma (B-NHL) and mantle cell lymphoma (MCL). Although the initial study protocol comprised 20 mg/body DEX on days 1 and 2, and 10 mg/body on days 3-5 [high-dose (HD-) DEX group], the dose of DEX was later decreased to 8 mg/body on days 1 and 2 [low-dose (LD-) DEX group] due to frequent cytomegalovirus (CMV) antigenemia and recurrent retinitis. We enrolled 33 patients, and LD-DEX and HD-DEX were administered in 15 and 18 patients, respectively. The overall response and the 3-year progression-free survival rates were 88% and 75.5%, respectively. The leading adverse event was myelosuppression. Incidence of grade 3-4 leukocytopenia, neutropenia, and lymphocytopenia was 55%, 67%, and 91%, respectively. The most frequent nonhematological adverse events were CMV antigenemia and rash (33% and 30%, respectively). Incidence of CMV antigenemia over 10/100,000 white blood cells was significantly lower with LD-DEX than that with HD-DEX (P = 0.0127). In conclusion, RBD showed significant effectiveness for RR indolent B-NHL and MCL.

Immunosuppressive therapy with rabbit antithymocyte globulin therapy for acquired aplastic anemia: a multi-institutional retrospective study in Japanese adult patients.

We retrospectively analyzed efficacy and safety of therapy with rabbit antithymocyte globulin (rATG) in combination with cyclosporine A (CsA) in 30 Japanese adult patients with acquired aplastic anemia (AA) in the Kyoto Clinical Hematology Study Group. The median observation period was 31 months and the median age of the patients was 54 years. The objective response rates (ORRs) to rATG plus CsA increased over time until 18 months after the start of treatment; the rate of achievement of better than partial response at 18 months was 66.7%. The 2-year overall survival (OS) rate was 79% in all patients. In eight patients aged ≥ 75 years old, the ORR was 62.5% and the 2-year OS rate of 50% was not significantly inferior to that in patients aged ≤ 74 years old. The overall mortality rate was 16.7% in our cohort, while the mortality rate in patients aged ≥ 75 years old was 37.5%, which was higher than that in patients aged ≤ 74 years old (9.1%), although the difference was not statistically significant. Collectively, rATG combined with CsA is an effective and feasible treatment for AA, while patients should be appropriately selected.

Elotuzumab for the Treatment of Relapsed or Refractory Multiple Myeloma, with Special Reference to its Modes of Action and SLAMF7 Signaling.

Elotuzumab, targeting signaling lymphocytic activation molecule family 7 (SLAMF7), has been approved in combination with lenalidomide and dexamethasone (ELd) for relapsed/refractory multiple myeloma (MM) based on the findings of the phase III randomized trial ELOQUENT-2 (NCT01239797). Four-year follow-up analyses of ELOQUENT-2 have demonstrated that progression-free survival was 21% in ELd versus 14% in Ld. Elotuzumab binds a unique epitope on the membrane IgC2 domain of SLAMF7, exhibiting a dual mechanism of action: natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and enhancement of NK cell activity. The ADCC is mediated through engagement between Fc portion of elotuzumab and FcgRIIIa/CD16 on NK cells. Enhanced NK cell cytotoxicity results from phosphorylation of the immunoreceptor tyrosine-based switch motif (ITSM) that is induced via elotuzumab binding and recruits the SLAM-associated adaptor protein EAT-2. The coupling of EAT-2 to the phospholipase Cg enzymes SH2 domain leads to enhanced Ca2+ influx and MAPK/Erk pathway activation, resulting in granule polarization and enhanced exocytosis in NK cells. Elotuzumab does not stimulate the proliferation of MM cells due to a lack of EAT-2. The inhibitory effects of elotuzumab on MM cell growth are not induced by the lack of CD45, even though SHP-2, SHP-1, SHIP-1, and Csk may be recruited to phosphorylated ITSM of SLAMF7. ELd improves PFS in patients with high-risk cytogenetics, i.e. t(4;14), del(17p), and 1q21 gain/amplification. Since the immune state is paralytic in advanced MM, the efficacy of ELd with minimal toxicity may bring forward for consideration of its use in the early stages of the disease.

An adult-onset case of chronic active Epstein-Barr virus infection with fulminant clinical course.

A 56-year-old Japanese male with chronic active Epstein-Barr virus (EBV) infection (CAEBV) who developed systemic gamma-delta T-cell lymphoproliferative disease (LPD) is reported. Although immune cooling therapy was effective, he died of sudden and severe hypoxia and anemia soon after the initiation of cytotoxic chemotherapy that had been previously recommended. There might remain a difficulty to control fulminant adult-onset CAEBV. Additionally, we describe three types of lymphoid cells that were observed in his peripheral blood: morphologically normal lymphocytes, large blastic cells and mature ones with rough granules. Morphological observation appeared to be useful to estimate clinical manifestations. Since CAEBV is extremely rare disease in adult population, it is important to accumulate clinical data to more understand the pathogenesis or to establish treatment strategy.

Hairy B-Cell Lymphoproliferative Disorder and its Differential Diagnosis: a Case with Long-Term Follow-Up.

Hairy B-cell lymphoproliferative disorder (HBLD) is one of chronic polyclonal B-cell lymphocytosis. We report a 47-year-old female Japanese patient diagnosed as having HBLD based on lymphocytosis with hairy cell appearance and characteristic phenotypes including CD11c+ and without B-cell monoclonality. She was a non-smoker and possessed HLA-DR4. She has been closely followed up without treatment and lymphoma development for over five years. Although this disease is quite rare and has been reported, to our knowledge, in only 13 Japanese cases, an accurate diagnosis, particularly differential diagnosis from persistent polyclonal B-cell lymphocytosis or hairy cell leukemia-Japanese variant is essential for the prevention of unnecessary treatments.

Expression of Master Regulators of T-cell, Helper T-cell and Follicular Helper T-cell Differentiation in Angioimmunoblastic T-cell Lymphoma.

Objective It has been postulated that the normal counterpart of angioimmunoblastic T-cell lymphoma (AITL) is the follicular helper T-cell (TFH). Recent immunological studies have identified several transcription factors responsible for T-cell differentiation. The master regulators associated with T-cell, helper T-cell (Th), and TFH differentiation are reportedly BCL11B, Th-POK, and BCL6, respectively. We explored the postulated normal counterpart of AITL with respect to the expression of the master regulators of T-cell differentiation. Methods We performed an immunohistochemical analysis in 15 AITL patients to determine the expression of the master regulators and several surface markers associated with T-cell differentiation. Results BCL11B was detected in 10 patients (67%), and the surface marker of T-cells (CD3) was detected in all patients. Only 2 patients (13%) expressed the marker of naïve T-cells (CD45RA), but all patients expressed the marker of effector T-cells (CD45RO). Nine patients expressed Th-POK (60%), and 7 (47%) expressed a set of surface antigens of Th (CD4-positive and CD8-negative). In addition, BCL6 and the surface markers of TFH (CXCL13, PD-1, and SAP) were detected in 11 (73%), 8 (53%), 14 (93%), and all patients, respectively. Th-POK-positive/BCL6-negative patients showed a significantly shorter overall survival (OS) than the other patients (median OS: 33.0 months vs. 74.0 months, p=0.020; log-rank test). Conclusion Many of the AITL patients analyzed in this study expressed the master regulators of T-cell differentiation. The clarification of the diagnostic significance and pathophysiology based on the expression of these master regulators in AITL is expected in the future.

Acute lymphoblastic leukemia with eosinophilia lacking peripheral blood leukemic cell: a rare entity.

We describe a 57-year-old woman who was diagnosed as precursor B-cell acute lymphoblastic leukemia with marked eosinophilia (ALL-eo). She presented with low grade fever and eosinophilia (absolute count 16.5 × 10(9)/l). Most of eosinophils had hypogranular cytoplasm. Immature cells were absent in her peripheral blood. Since her platelet count was low, bone marrow examination was carried out. 57.2 % of nucleated cells were blastic cells positive for CD10, 19, and 20. Chromosomal analysis revealed a karyotype of 46,XX,t(5;14)(q31;q32). Despite induction chemotherapy, her disease progressed and she died of sepsis a month later. ALL-eo is extremely rare and the diagnosis might be delayed unless leukemic cells are seen in peripheral blood. Therefore, bone marrow should be examined as soon as possible in cases with eosinophilia not only for the differential diagnosis of eosinophilic disorders but also not to overlook ALL-eo.