Propensity-score matched analysis of the efficacy of maintenance/continuous therapy in newly diagnosed patients with multiple myeloma: a multicenter retrospective collaborative study of the Japanese Society of Myeloma.

BACKGROUND: Maintenance ± consolidation or continuous therapy is considered a standard of care for both transplant-eligible and -ineligible patients with multiple myeloma (MM). However, long-term benefits of such therapy have not yet been clarified in the context of clinical practice. PURPOSE: To clarify the efficacy of maintenance/continuous approach, we retrospectively analyzed the cohort data of newly diagnosed MM patients by propensity-score matching based on age, gender, revised International Staging System (R-ISS) stage, and implementation of transplantation to reduce the bias due to confounding variables. FINDINGS: Among 720 patients, 161 were identified for each of the maintenance and no maintenance groups. Maintenance/continuous therapy employed immunomodulatory drugs (n = 83), proteasome inhibitors (n = 48), combination of both (n = 29), or dexamethasone alone (n = 1). Progression-free survival (PFS) was significantly prolonged in the maintenance group compared with the no maintenance group (median 37.7 and 21.9 months, p = 0.0002, respectively). Prolongation of PFS was observed in both transplanted and non-transplanted patients (p = 0.017 and p = 0.0008, respectively), with standard risk (p < 0.00001), R-ISS stage I (p = 0.037) and stage II (p = 0.00094), and those without obtaining complete response (p = 0.0018). There was no significant benefit in overall survival (OS), but it tended to be better in the maintenance group in non-transplanted patients. Regarding the treatment pattern, the substitution or addition of drugs different from the induction therapy and the combination with immunomodulatory drugs and proteasome inhibitors appeared to be more beneficial for PFS but not OS. CONCLUSION: These results support the benefit of current maintenance/continuous approach in routine clinical practice in the management of MM.

IgG4-related Disease with a Cardiac Mass.

A 69-year-old man with palpitations and decreased blood pressure was referred. Echocardiography showed a mass in the right atrium and cardiac septum. The serum IgG4 level was 1,450 mg/dL. A biopsy of the cardiac mass showed fibrosis with inflammatory cells and increased IgG4-positive plasma cells and lymphocytes. Flow cytometry and polymerase chain reaction of the immunoglobulin heavy chain did not demonstrate monoclonality. He was diagnosed with IgG4-related disease (IgG4-RD). IgG4-RD with a cardiac mass is rare and it is difficult to distinguish it from malignant lymphoma by a pathological examination alone. We therefore performed a biopsy and analyzed the clonality in order to make an accurate diagnosis of IgG4-RD.

Tumor long-axis diameter and SUVmax predict long-term responders in 90Y-ibritumomab tiuxetan monotherapy.

90Y-ibritumomab tiuxetan (90Y-IT) is widely used, but the factors responsible for its optimal treatment effects are unknown. We enrolled 34 patients with relapsed indolent lymphoma treated with 90Y-IT monotherapy at Gunma University Hospital between 2003 and 2014 in the present study. Clinical data including computed tomography and 18-Fluoro-deoxyglucose positron emission tomography were retrospectively analyzed. The overall response rate and complete response rate were 91% and 82%, respectively. The median progression-free survival (PFS) and overall survival were 32 months and not reached, respectively. In univariate analysis, tumor long-axis diameter ≤ 2.5 cm, maximum standardized uptake value (SUVmax) ≤ 6.5, localized disease, normal levels of serum soluble interleukin-2 receptor, and the number of involved nodal sites ≤ 3 immediately prior to 90Y-IT were associated with median PFS greater than 6 years. However, in multivariate analysis, only tumor long-axis diameter ≤ 2.5 cm and SUVmax ≤ 6.5 affected PFS [hazard ratio (HR) 0.130, P = 0.0021 and HR 0.283, P = 0.0311, respectively]. Patients with only one prior regimen needed less granulocyte colony-stimulating factor and platelet transfusion. Thus, 90Y-IT treatment should be considered for patients with indolent lymphoma in first relapse who have tumor long-axis diameter ≤ 2.5 cm and SUVmax ≤ 6.5.

Prognostic impact of trisomy 21 in follicular lymphoma.

The chromosomal abnormalities associated with follicular lymphoma (FL) prognosis are not fully elucidated. Here, we evaluated the pattern of chromosomal abnormalities in FL, and clarified the correlations between the cytogenetic features and clinical outcome. Cytogenetic analysis was performed using standard methods of Giemsa-banding at diagnosis for 201 FL patients admitted to our hospitals between 2001 and 2013. The identified chromosomal abnormalities were: t(14;18)(q32;q21) (59·2%), +X (17·9%), del(6)(q)/-6 (16·9%), +7 (14·4%), abnormality of 1q12-21/1q (12·9%), del(13)(q)/-13 (11·9%), abnormality of 3q27 (10·4%), abnormality of 10q22-24 (10·0%), +12/dup(12)(q) (10·0%), abnormality of 1p21-22/1p (9·0%), +18 (9·0%), del(17)(p)/-17 (5·0%), and a complex karyotype (54·7%). Patients with trisomy 21 had a significantly shorter progression-free survival (P = 0·00171) and overall survival (OS) (P < 0·001) than those without trisomy 21; additionally, patients with trisomy 21 in the rituximab-treated cohort also had a significantly shorter OS (P = 0·000428). Multivariate analysis identified trisomy 21 as an independent risk factor in our cohorts with or without t(14;18) (P = 0·015). In conclusion, the presence of trisomy 21 was an independent risk factor for in FL. Chromosomal analysis of FL patients at diagnosis can provide useful information about their expected survival.

A Rare Case of Chronic Active Epstein-Barr Virus (EBV) Infection Accompanied by the Infiltration of EBV-infected CD8+ T Cells into the Muscle.

We describe a rare case of chronic active Epstein-Barr virus (CAEBV) infection, with infiltration of the skeletal muscle. A 19-year-old woman with swollen cervical lymph nodes and a fever was referred to our hospital. Swelling of the trapezium muscle and elevation of creatinine kinase level were observed. Biopsy results of the brachialis muscle revealed infiltration of Epstein-Barr virus (EBV)-encoded RNA-positive CD8 T lymphocytes. The EBV virus load in the peripheral blood was high, and EBV monoclonality was determined by Southern blot analysis. Owing to the rarity of CAEBV with skeletal muscle infiltration, this case alerts physicians to the potential diagnostic pitfalls of CAEBV.

Isoniazid-induced Pure Red Cell Aplasia in a Patient with Sarcoidosis: A Patient Summary and Review of the Literature.

A 41-year-old woman treated with isoniazid (INH) for latent tuberculosis infection and an oral corticosteroid for sarcoidosis developed severe anemia two months after initiating INH. A bone marrow examination showed erythroblastopenia, and a diagnosis of INH-induced pure red cell aplasia (PRCA) was made. Her reticulocyte count and hemoglobin levels improved two weeks after discontinuation of INH. A literature review of INH-induced PRCA shows that it occurs very rarely in the context of autoimmune disorders. This report describes a case of INH-induced PRCA occurring in a patient with sarcoidosis.

Long non-coding RNA MALAT1 is an inducible stress response gene associated with extramedullary spread and poor prognosis of multiple myeloma.

Extramedullary myeloma (EMM) occurs when myeloma develops outside the bone marrow; it often develops after chemotherapy and is associated with the acquisition of chemo-resistance and a fatal course. The mechanisms underlying extramedullary spread have not yet been fully elucidated. MALAT1 is a highly abundantly and ubiquitously expressed long non-coding RNA that plays important roles in cancer metastasis. The aims of this study were to clarify the association of MALAT1 with EMM and to elucidate the underlying mechanism of EMM formation under chemotherapeutic pressure. MALAT1 expression was significantly higher in multiple myeloma (MM) than in monoclonal gammopathy of undetermined significance. Furthermore, MALAT1 expression was markedly higher in EMM compared with that in corresponding intramedullary myeloma cells. A higher MALAT1 level was associated with shorter overall and progression-free survival. MALAT1 expression level was positively correlated with expression of HSP90AA1, HSP90AB1 and HSP90B1 but not with TP53 expression. MALAT1 was significantly upregulated by bortezomib and doxorubicin. Considering the known functions of MALAT1, our results suggest that it acts as a stress response gene that is upregulated by chemotherapy, thereby linking chemotherapy to EMM formation. Elucidating the biological implication of long non-coding RNA contributes to deeper understanding concerning the pathogenesis and investigation of novel therapeutic targets for MM.

Incidence and clinical background of hepatitis B virus reactivation in multiple myeloma in novel agents' era.

There are some reports regarding hepatitis B virus (HBV) reactivation in patients with myeloma who are HBV carriers or who have had a resolved HBV infection, and there is no standard prophylaxis strategy for these patients. We performed a retrospective multicenter study to determine the incidence and characteristics of HBV reactivation in patients with multiple myeloma. We identified 641 patients with multiple myeloma who had been treated using novel agents and/or autologous stem cell transplantation with high-dose chemotherapy between January 2006 and June 2014 at nine Japanese hospitals. The patients' characteristics, laboratory data, and clinical courses were retrieved and statistically analyzed. During a median follow-up of 101 weeks, one of eight (12.5 %) HBV carriers developed hepatitis and 9 of 99 (9.1 %) patients with resolved HBV infection experienced HBV reactivation; the cumulative incidences of HBV reactivation at 2 years (104 weeks) and 5 years (260 weeks) were 8 and 14 %, respectively. The nine cases of reactivation after resolved HBV infection had received entecavir as preemptive therapy or were carefully observed by monitoring their HBV DNA levels, and none of these cases developed hepatitis. Among patients with multiple myeloma, HBV reactivation was not rare. Therefore, long-term monitoring of HBV DNA levels is needed to prevent hepatitis that is related to HBV reactivation in these patients.

SF3B1 and IGHV gene mutation status predict poor prognosis in Japanese CLL patients.

The incidence of chronic lymphocytic leukemia (CLL) is low in Japan. The clinical course ranges from very indolent to rapidly progressive. Recently, several reports have indicated that mutation of the splicing factor 3b, subunit 1 (SF3B1) gene in CLL is predictive of a poor prognosis. Here, we investigated the SF3B1 mutational status of Japanese CLL patients and clarified the association between SF3B1 mutational status and prognostic factors. One hundred and two patients that were referred to our institutions between 1999 and 2013 were enrolled. Mutation analysis of SF3B1 (n = 87) and of the immunoglobulin heavy chain gene (IGHV) (n = 102) was performed at diagnosis. FISH analysis of del(11)(q22) was performed for 17 patients. Seven patients have SF3B1 mutation (8.0 %: K700E, 5/7; G742D, 1/7 and Y623C, 1/7). The median survival times for patients with mutated and non-mutated SF3B1 were 53 and 130 months, respectively. Overall survival of the mutated SF3B1 group was significantly lower than that of the non-mutated group (p = 0.0187). No relationship was observed between IGHV mutational status and SF3B1 mutation. There was no patient with SF3B1 mutation in the IGHV1-69 population (0/2). In conclusion, mutation of SF3B1 at diagnosis in Japanese CLL patients is predictive of a poor prognosis.

High percentage of regulatory T cells before and after vitamin B12 treatment in patients with pernicious anemia.

INTRODUCTION: In some previous studies, vitamin B12 treatment showed immunomodulatory effects and restored the immunological abnormalities in patients with pernicious anemia (PA). In the present study, peripheral blood T cell subsets, including regulatory T cells (T(reg)s), were examined before and after vitamin B12 treatment in PA patients. PATIENTS AND METHODS: The percentages of CD4, CD8, Th1, Th2 and T(reg)s were examined in 23 PA patients before vitamin B12 treatment, in 23 other PA patients after vitamin B12 treatment and in 28 healthy controls. RESULTS: The mean percentage of CD8+ T cells was significantly higher in the control group (23.0%; 95% CI, 20.4-25.6%) than in the pre- (16.0%; 95% CI, 12.1-20.0%) and posttreatment groups (15.2%; 95% CI, 11.8-18.6%; p < 0.05). The CD4/CD8 ratio was significantly lower in the control group (2.01; 95% CI, 1.66-2.34) than in the pre- (3.45; 95% CI, 2.55-7.80) and posttreatment groups (2.97; 95% CI, 2.22-3.72; p < 0.05). There was no significant difference in the mean Th1/Th2 ratio among these groups. There were significant increases in the mean percentage of T(reg)s in the pre- (6.29%; 95% CI, 5.04-7.54%) and posttreatment groups (7.77%; 95% CI, 6.34-9.20%) compared with the control group (4.18%; 95% CI, 3.92-4.47%; p < 0.05). CONCLUSIONS: The percentage of T(reg)s was significantly higher in PA patients than in normal subjects, and this high T(reg) percentage was not different before and after vitamin B12 treatment. Other immunological alterations also did not recover after vitamin B12 treatment, so that these immunological changes appear to be the cause of PA and are not induced by vitamin B12 deficiency.

Primary leptomeningeal B-cell lymphoma with normal pressure hydrocephalus at diagnosis.

An 80-year-old man, presenting with gait disturbance and memory loss, had findings of normal pressure hydrocephalus. Primary leptomeningeal lymphoma (PLML) was diagnosed based on cytology and flow cytometry of cerebrospinal fluid obtained by examination. Gadolinium-enhanced MRI showed enhancement of the brain and spinal cord but FDG-PET/CT revealed no lymph node swelling. With intrathecal chemotherapy, meningeal lesions disappeared and the gait disturbance and memory loss improved. However, the disease recurred three months later, manifesting as left facial nerve palsy, but the symptoms disappeared in response to intrathecal chemotherapy and systemic rituximab administration. Although a tumor lesion in the spinal canal was suggested by MRI examination, the patient has maintained a good clinical course for four years with intrathecal chemotherapy every three months. PLML is a very rare disease and its diagnosis is difficult. Repeated intrathecal chemotherapy appeared to be effective against PLML in this case.

[Diffuse large B-cell lymphoma of the testis relapsed 16 years after achieving complete response].

Testicular lymphoma is a rare disease, accounting for 1-2% of non-Hodgkin lymphoma and 5-9% of all testicular tumors, and has a high relapse rate with a poor prognosis. We report a patient with testicular diffuse large B-cell lymphoma (DLBCL) who relapsed after being in remission for 16 years. He had undergone orchiectomy of the right testis and was diagnosed as having DLBCL (stage IAE) at 49 years of age. After 3 cycles of CHOP, he achieved a complete remission. Orchiectomy was performed because of a left testicular tumor, and he was again diagnosed with DLBCL at the age of 65. VH3-21 was detected in lymphoma cells at the times of both the first diagnosis and the relapse based on analysis of the variable region of the immunoglobulin heavy chain. Accordingly, the lymphoma cells at relapse were confirmed to be the same clone as that which had been documented at the first diagnosis.

[Successful treatment with dasatinib for polycythemia vera patient emerging BCR-ABL positive clone during 13 years of treatment].

Herein, we report a patient with polycythemia vera (PV) who exhibited Philadelphia chromosome (Ph) positive CML-like clinical features after 13 years of hydroxycarbamide administration and successful treatment with a tyrosine kinase inhibitor (TKI). She was 64 years old when initially diagnosed with PV and was confirmed to be negative for BCR-ABL translocation. Thirteen years later, with increasing white blood cell and platelet counts, a BCR-ABL positive clone emerged and the JAK2V617F mutation disappeared. After TKI treatment, the BCR-ABL copy number decreased and the JAK2V617F mutation was again detected. Furthermore, MPN clinical features were observed. This case provides insights into the clonal divergence and growth advantage of the Ph positive clone over the MPN clone. Whether JAK2V617F is an MPN initiating event or a secondary mutation has been a point of discussion for the past several years. This issue is also considered in the present report.

Prognostic importance of the soluble form of IL-2 receptorα (sIL-2Rα) and its relationship with surface expression of IL-2Rα (CD25) of lymphoma cells in diffuse large B-cell lymphoma treated with CHOP-like regimen with or without rituximab: a retrospective analysis of 338 cases.

We evaluated the prognostic significance of the serum level of the soluble form of interleukin-2 receptorα (sIL-2Rα) and investigated its association with CD25 expression on tumor cells in diffuse large B-cell lymphoma (DLBCL). Three hundred and thirty-eight adult patients with newly diagnosed DLBCL were eligible for this retrospective study. 32.2% of patients were treated with CHOP-like regimen and 67.8% with R-CHOP-like regimen. CD25 expression on the surface of tumor cells was evaluated in 143 cases and its relationship with sIL-2Rα level was also investigated. Both overall survival (OS) and progression-free survival (PFS) were poorer in patients with higher sIL-2Rα, in both R-CHOP and CHOP groups. sIL-2Rα > 1,000 U/mL and performance status (PS) ≥ 2 were independently associated with poorer OS, and sIL-2Rα > 1,000 U/mL, age > 60 years, and ≥ 2 extranodal sites were independently associated with poorer PFS in the R-CHOP group. The sIL-2Rα level was higher in the CD25-positive group than in the CD25-negative group in stage 3 or 4 disease (p = 0.010). Multiple linear regression analysis showed CD25 expression to be independently correlated with sIL-2Rα levels. High sIL-2Rα is an important risk factor for survival in DLBCL treated with not only CHOP-like, but also R-CHOP-like regimens, regardless of the tumor's expression of CD25.

Characterization of CD56+ dendritic-like cells: a normal counterpart of blastic plasmacytoid dendritic cell neoplasm?

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy. Plasmacytoid DCs (pDCs), which are defined as lineage marker (Lin)(-)HLA-DR(+)CD56(-)CD123(+)CD11c(-) cells, are considered to be the normal counterpart of BPDCNs. However, BPDCN can be distinguished from pDCs by uniform expression of CD56. In this study, to identify a normal counterpart of BPDCN, we searched for a Lin(-)HLA-DR(+)CD56(+) population and focused on a minor subpopulation of Lin(-)DR(+)CD56(+)CD123(+)CD11c(-) cells that we designated as pDC-like cells (pDLCs). pDLC constituted 0.03% of peripheral blood mononuclear cells (PBMCs), and the pDLC/pDC ratio was higher in bone marrow cells than in PBMCs. pDLC clearly expressed BDCA2, BDCA4, and myeloid antigens, which are frequently expressed by BPDCN. pDLCs exhibited modest expression of Toll-like receptors and produced less interferon-α after CpG stimulation, but presented very low endocytic ability unlike mDCs. These functional differences were attributed to the expression profile of transcriptional factors. After in vitro culture with Flt3-ligand and GM-CSF, pDLCs expressed CD11c and BDCA1. These data suggested that pDLCs are a distinct subpopulation, with an immunophenotype similar to BPDCNs. Moreover, our results indicate that pDLCs might be immature DCs and might contribute to the immunophenotypical diversity of BPDCNs.

DNMT3B7 expression related to MENT expression and its promoter methylation in human lymphomas.

DNA methyltransferase (DNMT) 3B7 is the most expressed DNMT3B splice variant. It was reported that the loss of DNMT3B function led to overexpression of the MEthylated in Normal Thymocyes (MENT) and accelerated mouse lymphomagenesis. We investigated the DNMT3B7 expression and its relationship to MENT expression and promoter methylation in human lymphomas. DNMT3B7 and MENT expression were significantly (p<0.0001, p<0.01) higher in lymphomas than in non-malignant. Expression of DNMT3B7 and MENT were associated with MENT promoter hypomethylation. DNMT3B7 overexpression might interfere with the normal DNA methylation mechanism required for silencing the MENT proto-oncogene, and may accelerate human lymphomagenesis.

Development of IgG4-related disease 10 years after chemotherapy for diffuse large B cell lymphoma and longstanding bronchial asthma.

Reported is a rare case IgG4-related disease that developed 10 years after combination chemotherapy for non-Hodgkin lymphoma. A 59-year-old Japanese man with longstanding bronchial asthma was referred to our hospital for bilateral hilar lymph node enlargement. The initial diagnosis was diffuse large B cell lymphoma (DLBCL) by supraclavicular lymph node biopsy. Serum IgG was high (4550 mg/dL) at diagnosis. The patient achieved complete response following six cycles of combination chemotherapy. Ten years later, bilateral submaxillary gland swelling was observed. Serum IgG and IgG4 were 2909 and 1470 mg/dL, respectively. The patient was diagnosed with IgG4-related disease by submandibular lymph node biopsy. Due to the difficulty in distinguishing IgG4-related disease from DLBCL through imaging findings alone, pathological confirmation of such lesions by biopsy is mandatory before proceeding to treatment.

[Emergence of donor-derived anti-HLA antibody and subsequent transfusion-refractory thrombocytopenia after allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling donor in a patient with acute myeloid leukemia].

A 45-year-old woman with acute myelogenous leukemia developed platelet transfusion refractoriness (PTR) after the engraftment of an allogeneic peripheral blood stem cell transplantation (PBSCT) from her multiparous sister, which was attributed to HLA antibodies that could not be detected in the patient's serum before transplantation. She achieved neutrophil engraftment by day 18 and megakaryocytopoiesis and complete donor chimerism was confirmed in the bone marrow on day 21. IgG-class HLA antibodies were detected in her serum on day 24 after PBSCT; however, on day 15, no HLA antibodies were detected. The specificity of the antibodies that emerged in the patient closely resembled that of the antibodies found in the donor. The donor had probably been immunized during pregnancy by their partner's HLA-antigens expressed by the fetus. Consequently, transplanted donor-derived cells provoked HLA antibodies in the recipient early after PBSCT, and those HLA antibodies induced PTR. The presence of HLA antibodies should be examined at least in pregnant female donors whose recipients developed PTR attributable to HLA antibodies after SCT.

Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma.

Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is extremely rare, and the etiology of disease is not fully understood. We present herein the case of a primary hepatic MALT lymphoma with Helicobacter pylori and hepatitis C virus infection. A 71-year-old male was admitted to our institution to undergo a precise evaluation of a hepatic tumor incidentally detected during a computed tomography (CT) scan for chest examination. Dynamic CT showed faint enhancement during the arterial phase. The gadoxetate disodium-enhanced magnetic resonance imaging showed a hyper-intensity on the arterial phase and low intensity during the late and hepatocyte phases. Liver biopsy specimen showed small to intermediate size atypical lymphocytes with positive CD20 immunohistochemical staining. It was finally diagnosed as primary hepatic MALT lymphoma. FDG-PET/CT showed faintly increased uptake with a maximum standardized uptake value of 4.6, and did not show other pathological uptake. We present the rare case of primary hepatic MALT lymphoma and discussed the etiology of this disease.