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Rituximab has markedly improved the outcomes of B cell lymphoma, and its maintenance has been shown to be beneficial in low grade B cell lymphoma (LGBCL). We conducted a multicenter, phase II trial of intensive rituximab induction and maintenance therapy for LGBCL to optimize the rituximab monotherapy. Patients with newly diagnosed or rituximab naïve relapsed LGBCL received 8 weekly rituximab as induction, then continued maintenance therapy with rituximab for 4 weeks at 6-month intervals. The primary endpoint was the overall response rate (ORR). Forty-five patients were enrolled from 2005 to 2009 and 36 were eligible. The ORR was 83.3% (30/36) with a complete response rate of 72.2% (26/36). The 3-year progression-free survival (PFS) was 76.7% with a median follow-up of 43.0 months. Five grade three toxicities were observed (no grade 4). Our findings suggest that this regimen demonstrates high activity with durable PFS and minimal toxicity in LGBCL patients.

The international staging system (ISS) is the most commonly used risk-stratification system for patients with multiple myeloma (MM) and is determined by serum albumin and β2-microglobulin levels. In the two determinants, β2-microglobulin levels are frequently observed to be elevated in patients with myeloma, particularly in those with renal impairment. In comparison with patients with intact immunoglobulin myeloma, patients with LC myeloma do not necessarily show decreased levels of serum albumin. The clinical impact of ISS in patients with LCMM, in particular the distinction between ISS I and II, may be complicated due to non-decreased levels of serum albumin in both stages. Accordingly, we have attempted to assess clinical relevance of the ISS in patients with LC myeloma. The clinical data of 1899 patients with MM diagnosed between January 2001 and December 2012 were collected from 38 affiliated hospitals of the Japanese Society of Myeloma. Significant difference was not found between stage I (n = 72) and stage II (n = 92) in LC myeloma patients (n = 307). The mean serum albumin concentration of patients with LC myeloma was within the reference range but higher than that of patients with IgG + IgA myeloma (n = 1501), which complicates the distinction between ISS stage I and II myeloma. Patients with LC myeloma had low frequencies of t(4; 14) and high frequency of elevated lactate dehydrogenase, and despite a relevant amount of missing data in our registry (R-ISS stage I; n = 11, stage II; n = 32, and stage III: n = 18), the information included in the R-ISS scoring system seems to be more accurate than ISS to obtain a reliable risk stratification approach in non-ISS stage III LC myeloma patients.

Clinical information regarding non-Hodgkin lymphoma (NHL) in adolescents and young adults (AYA) is lacking. We retrospectively analyzed 1426 consecutively registered patients with newly diagnosed NHL. Of 798 DLBCL patients, 42 (5.3%) were identified as AYA (16–39 years). The characteristics of AYA DLBCL patients showed no significant differences compared to older adult DLBCL patients (age ≥ 40 years). Progression-free survival (PFS) and overall survival (OS) in AYA were similar to those in patients aged 40–60 years. However, in older adult groups, PFS and OS were significantly different according to the age group (40–60, 61–79, and ≥ 80 years). In univariate analysis in AYA, performance status, clinical stage, International Prognostic Index (IPI), and age-adjusted IPI significantly affected both PFS and OS. In multivariate analysis, only clinical stage was identified as an independent predictor among AYA. In conclusion, disease characteristics and outcomes of DLBCL in AYA were nearly the same as those in older adults.

SummaryUpshaw–Schulman syndrome (USS) is a congenital thromboticthrombocytopenic purpura (TTP) due to mutations in the gene thatencodes for ADAMTS13 (ADAMTS13), but its clinical signs may be mild orabsent during childhood. We have identified 37 patients with USS (24females, 13 males) belonging to 32 families. The nine women from sixfamilies who were diagnosed during their first pregnancy are the focus of thisreport. Six of the nine women had episodes of thrombocytopenia duringchildhood misdiagnosed as idiopathic thrombocytopenic purpura.Thrombocytopenia occurred during the second–third trimesters in each oftheir 15 pregnancies, with 16 babies (one twin pregnancy), often followed byTTP. Of 15 pregnancies, eight babies were stillborn or died soon after birth,and the remaining seven were all premature except one, who was bornnaturally following plasma infusions to the mother that had started at8 weeks’ gestation. All nine USS women had severely deficient ADAMTS13activity. ADAMTS13 analyses demonstrated that eight women werecompound heterozygotes of Y304C/G525D (2 siblings), R125VfsX6/Q1302X (2 siblings), R193W/R349C (2 siblings), I178T/Q929X, andR193W/A606P; one woman was homozygous for R193W. Only the R193Wmutation has been previously reported. These observations emphasize theimportance of measuring ADAMTS13 activity in the evaluation ofthrombocytopenia during childhood and pregnancy.Keywords: Upshaw–Schulman syndrome, pregnancy, ADAMTS13 mutation,thrombocytopenia, haemolytic anaemia.

Many controlled clinical trials have proven that rituximab improves the clinical outcome of patients with mature B cell lymphoma. This study was conducted to assess the contribution of rituximab in the actual clinical practice. Patients with newly diagnosed mature B cell lymphoma treated at 20 National Hospital Organization hospitals from January 2000 to December 2004 were consecutively registered. Rituximab was approved in September 2002 for indolent B cell lymphoma and in September 2003 for aggressive B cell lymphoma in Japan. The patients were divided into two groups depending on whether they received induction therapy containing rituximab. The endpoint was to evaluate the rituximab benefit based on 2-year progression-free survival (PFS) and 2-year overall survival (OS). A total 1126 patients received chemotherapies. Of these, 762 were diagnosed as diffuse large B cell lymphoma (DLBCL) and 215 as follicular lymphoma (FL). PFS and OS were markedly improved in the rituximab group compared with the non-rituximab group in patients with DLBCL (both P < 0.001) and in patients with FL (P < 0.001 and P = 0.003 respectively). Rituximab, when used for remission induction therapy, significantly improved the clinical outcome of the mature B cell lymphoma patient in actual clinical practice.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive form of human leukemia/lymphoma. Although this disease is initiated by infection with human T-lymphotropic virus type 1 (HTLV-1), many HTLV-1 carriers survive for a long period without aggressive illness, suggesting that other factors may play roles in the progression of ATLL to an aggressive state. However, the mechanism involved in this progression still remains unclear. Previously, we have reported that ASY/Nogo mRNA was markedly down-regulated in human small-cell lung carcinomas, whereas it was expressed in normal tissues and other lung carcinomas, such as adenocarcinoma and squamous cell carcinoma. To understand whether or not ASY/Nogo gene is involved in the progression of ATLL, we examined the expression of ASY/Nogo mRNA in smoldering, chronic and aggressive ATLL, and found that the expression level of ASY/Nogo mRNA was markedly reduced in clinically aggressive ATLL. HTLV-1 Tax expression was not affected by the down-regulation of ASY/Nogo mRNA. These results indicate that the ASY/Nogo gene may act as a suppressor against ATLL progression, independent of Tax expression.

Mature T cell lymphoma has been noted for poor prognosis when compared with B cell lymphoma, even in the pre-rituximab era. To confirm this difference, a retrospective cohort study was conducted. One hundred-and nineteen patients with mature T cell lymphoma and 568 patients with diffuse large B cell lymphoma (DLBCL) who did not receive rituximab as first induction were studied. Overall survival (OS) was worse for patients with international prognostic index (IPI) scores indicating low-risk mature T cell lymphoma than for those with DLBCL (3-year OS 87 % vs. 58 %, P = 0.001), but not in other risk groups. Prognosis of mature T cell lymphoma was significantly poorer in the IPI low-risk group, as compared with DLBCL.

The outcome of sixty-four patients with acute leukemia in first remission who had been treated with either bone marrow transplantation (BMT) or conventional chemotherapy was retrospectively evaluated (a median follow-up of 37 months). Among them, 26 patients (age range; 14-42 years) received allogeneic BMT from HLA-identical siblings and 38 patients (age range; 13-43 years) who had no HLA-identical donors undertook the continued combination chemotherapy. Kaplan-Meier product-limit estimate of actuarial survival of acute myelogenous leukemia (AML) patients was 48.9% for the BMT group and 15.7% for the chemotherapy group (p = not significant, NS). For acute lymphoblastic leukemia (ALL) patients, the survival following BMT was 80.2% and was significantly higher than that of the chemotherapy group of 33.3% (p0.05). The disease-free survival of AML and ALL for the BMT group was 34.3% and 36.5%, respectively, which was higher than that of the chemotherapy group (16.7% and 23.4%, respectively (p = NS)). These findings in our Japanese single institution study suggested that BMT may be the treatment of choice for adult patients with acute leukemia in first remission if they had suitable donors and that more effective therapeutic regimens were necessary for patients without compatible donors in order to obtain the longer remission duration.

Although adult T-cell leukemia/lymphoma (ATLL) is initiated by infection with human T-cell leukemia virus (HTLV-1), many other factors are thought to be required for the progression from indolent ATL to aggressive ATLL. The drs gene was originally isolated as a novel suppressor gene of v-src transformation and was shown to induce apoptosis in human cancer cells. To investigate the involvement of drs downregulation in the progression of ATLL, we examined the expression of drs in smoldering, chronic and aggressive ATLL, and found that drs expression was markedly reduced in clinically aggressive ATLL. In aggressive ATLL cell lines, expression of drs mRNA was not detected, although expression of drs mRNA was detected in T-cell lines infected with HTLV-1. A correlation between drs downregulation and expression of the Tax gene was not observed in these T-cell lines. Furthermore, introduction of drs into an ATL cell line, HUT 102, by retrovirus vector suppressed the colony formation of the cells in soft agar and enhanced apoptotic cell death of the cells under low serum culture conditions. These results indicate that downregulation of drs is closely linked to the progression of ATLL, independently of Tax expression, suggesting that drs may suppress the progression of ATLL via enhancing apoptosis.

We evaluated the clinical course of acute myeloid leukemia (AML) and the levels of WT1 mRNA in 191 AML patients. Of 114 previously untreated patients with AML, 107 cases were positive for WT1 mRNA (93.9% : 107/114). WT1 mRNA expression-levels declined to below 50 copies/microg RNA ("negative") after remission was achieved in all 66 patients who achieved remission and 84.8% (47/54) cases were "negative" at the end of the follow-up periods. On the other hand, WT1 mRNA was expressed in 87.0% of non-remission cases (47/54), maintaining 50 copies/microg of RNA or higher ("positive"). In all 29 cases who relapsed during the follow-up observation period after achieving remission, WT1 mRNA levels declined transiently approximately around the time of achieving remission and then rose again when the disease relapsed. Moreover, we determined the time of elevation of WT1 mRNA in 29 relapsed cases. In 79.3% of relapsed cases (23/29), WT1 mRNA levels rose above 200 copies/microg RNA, 43 days (median) before the diagnosis of "relapse". Given the percent of the correct diagnosis, WT1 mRNA at 200 copies/microg RNA appeared to be a reasonable cut-off level for early detection of AML-relapse. The WT1 mRNA level reflected the clinical condition. Taken together, these findings indicate that WT1 mRNA levels allow us to detect the presence of so-called "minimal residual disease" (leukemic cells) that cannot be detected by morphological examination. Besides these promising data, this kit is suitable for routine monitoring of AML because this kit utilizes peripheral blood as a test specimen, reducing the patient's burden at the time of collection of clinical samples as compared with bone marrow aspirate.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by clonal blood cells that are deficient in glycosylphosphatidylinositol-anchored proteins because of somatic mutations of the PIG-A gene. Many patients with PNH have more than one PNH clone, but it is unclear whether a single PNH clone remains dominant or minor clones eventually become dominant. Furthermore, it is unknown how many hematopoietic stem cells (HSCs) sustain hematopoiesis and how long a single HSC can support hematopoiesis in humans. To understand dynamics of HSCs, we reanalyzed the PIG-A gene mutations in 9 patients 6 to 10 years after the previous analyses. The proportion of affected peripheral blood polymorphonuclear cells (PMNs) in each patient was highly variable; it increased in 2 (from 50% and 65% to 98% and 97%, respectively), was stable in 4 (changed less than 20%), and diminished in 3 (94%, 99%, and 98% to 33%, 57%, and 43%, respectively) patients. The complexity of these results reflects the high variability of the clinical course of PNH. In all patients, the previously predominant clone was still present and dominant. Therefore, one stem cell clone can sustain hematopoiesis for 6 to 10 years in patients with PNH. Two patients whose affected PMNs decreased because of a decline of the predominant PNH clone and who have been followed up for 24 and 31 years now have an aplastic condition, suggesting that aplasia is a terminal feature of PNH.

Introduction Rituximab has markedly improved the clinical outcomes of mature B cell lymphoma, and rituximab maintenance therapy has been shown to be beneficial, especially in low grade B cell lymphoma (LGBCL). Several studies evaluated intensified rituximab administration combined with chemotherapy. But so far, there has not been any trial of rituximab mono-therapy with intensive rituximab induction followed by maintenance. A multicenter, phase II trial was conducted to evaluate the efficacy and safety of rituximab as induction, weekly 8 doses, and maintenance therapy for 2 years for LGBCL. Patients and Methods Patients with measurable LGBCL according to the World Health Organization (WHO) classification (2001) without prior rituximab treatment and staged as II, II, or IV by Ann-Arbor, were eligible. Patients received rituximab (375 mg/m2) weekly for 8 weeks as induction therapy, and then patients who did not have progressive disease at the end of induction received maintenance therapy with 4 weeks of rituximab at six-month intervals (up to 2 years or disease progression). Duration of treatment was 2.5 years in total. The primary endpoint was the best overall response rate (ORR). The secondary endpoints were complete response rate (CRR), 3-year progression free survival (PFS), 3-year overall survival (OS), and safety. Survivals were assessed using the Kaplan-Meier method. Results Forty-one patients with a median age of 64 years (41 to 79) were enrolled at 12 institutes belonging to the Clinical Hematology Group of National Hospital Organization (CHG-NHO) of Japan from December 2005 to May 2009. The majority of disease histology was follicular lymphoma in 33 patients. Of 41 patients, 15 were diagnosed as high tumor burden based on GELF criteria, and FLIP risk grouping classified all into 12 low risk, 21 intermediate risk, and 12 high risk cases. Four relapsed cases were included, and they have all received prior systemic chemotherapy without rituximab. Of the 41 patients, 31 (75.6%) completed the planned 2.5 years therapy. The best ORR was 75.6% (31/41, 90% CI: 62.2-86.1%), with 63.4% CR. Three-year PFS at a median follow-up time of 43.0 months (5.3-72) was 79.7% (90% CI, 66.6-88.1%). Three-year OS at a median follow-up time of 49.4 months (5.3-72) was 97.4% (90% CI, 87.1-99.5%). Grade 3 toxicities were neutropenia in 2.5% (1/41), elevated ALT in 2.5% (1/41), and infection in 2.5% (1/41). There was no grade 4 toxicity. Conclusions Intensified rituximab induction and maintenance therapy was demonstrated to have high activity, with durable PFS and minimum toxicity in LGBCL patients. Although a further large-scale trial is needed, intensified rituximab induction followed by rituximab maintenance could be a good treatment in rituximab naïve LGBCL. Disclosures: No relevant conflicts of interest to declare.

Background Rituximab has dramatically improved the clinical outcomes of mature B cell lymphoma. It has been reported that women show more favorable survival than men with rituximab-containing treatment. A multicenter, retrospective study was conducted to assess the role of sex in survival with rituximab treatment. Patients and Methods Patients with newly diagnosed mature B cell lymphoma treated at 20 National Hospital Organization hospitals in Japan from January 2000 to December 2004 were consecutively registered. Rituximab was approved in September 2002 for indolent B cell lymphoma and in September 2003 for aggressive B cell lymphoma in Japan. The patients were divided into two groups depending on whether they received induction therapy containing rituximab. The target population of this study was all mature B cell lymphoma patients who received first remission induction therapy containing rituximab. The patients treated without rituximab were used as controls. The endpoint was to compare 2-year progression-free survival (PFS) and overall survival (OS) between men and women. Survivals were assessed using the Kaplan-Meier method, and the groups were compared using the log-rank test. Results A total of 1126 patients received systemic chemotherapies during this study period. Of these, 348 (men 185, women 163), including 184 diffuse large B cell lymphomas (DLBCLs) and 111 follicular lymphomas (FLs), were treated by rituximab-containing regimens as front-line therapy. The 2-year PFS was better in women than in men (75.8% vs. 64.2%, p=0.048). This difference was not seen in the control group (men 396, women 382), which was treated by chemotherapeutic regimens without rituximab (48.7% vs. 50.6%, p=0.994). The 2-year OS was not statistically different between men and women (81.9% vs. 88.6%, p=0.115). When this population was broken down into DLBCL and FL, the women’s benefit in 2 year PFS was not statistically significant in both subtypes. Multivariate analysis both with forced entry and stepwise method could not show that sex was an independent prognostic factor in mature B cell lymphoma treated by rituximab containing induction regimen. Conclusions In mature B cell lymphoma, women would have better PFS than men when treated with rituximab containing therapy. These data suggest that the sex-based rituximab dose modification might be considered. Disclosures: No relevant conflicts of interest to declare.

Upshaw-Schulman syndrome (USS) is a congenital deficiency of the activity of von Willebrand factor (VWF)-cleaving protease or ADAMTS13 due to its gene mutations. USS is a complex thrombo-hemorrhagic disease, but its hallmark is severe neonatal jaundice soon after birth that often requires for exchange blood transfusion, and subsequently during childhood they have repeated episodes of chronic thrombocytopenia and hemolytic anemia that are reversed by infusions of fresh frozen plasma. However, after a discovery of ADAMTS13, the presence of two phenotype expression on USS-patients was described; one is the early-onset type as abovementioned, and the other is the late-onset type which is asymptomatic during childhood and the first bout develops after adolescent or during adulthood, in association with infections or pregnancy. During the past 8 years, we diagnosed 33 patients with USS. Through analyzing the natural history and the phenotype-genotype expression in these patients, and more specifically to 9 USS-patients who had their first bout at pregnancy, we found that two clinical phenotypes of USS are mostly attributable to misdiagnosis or overlook of thrombocytopenia during childhood, and excluded a possibility of the concern on a trace amount of ADAMTS13 activity which has not been evaluated by the previous methods. Further, in vitro studies we have clearly shown that platelet aggregation or thrombi formation under high shear stress is tremendously up-regulated in the absence of ADAMTS13, that occurs proportionally to the amount of high VWF multimers, that in part is assumed to be an in vitro reflection of the circulation in USS-gravida. Download : Download high-res image (215KB) Download : Download full-size image Figure

Upshaw-Schulman syndrome (USS) is a congenital thrombotic thrombocytopenic purpura (TTP) characterized by a deficiency of ADAMTS13 activity due to its mutations. More than half of USS patients have an episode of severe jaundice during the newborn period and require exchange blood transfusions. Beyond this period, however, the clinical manifestations of USS vary significantly from patient to patient, and do not usually include Moschowitz’s pentad, a hallmark of TTP. However, a consistent clinical sign in these patients is an occasional or chronic thrombocytopenia that is enhanced by precipitating factors such as viral infections. Therefore, USS patients are often incorrectly diagnosed with idiopathic thrombocytopenic purpura (ITP) or Evans syndrome during childhood, and the underlying ADAMTS13 gene defects are overlooked. Here, we report on 7 female USS patients belonging to 4 different families, including 3 pairs of siblings who were uniformly diagnosed by episodes of thrombocytopenia or prevalence of TTP at 5~6 months of pregnancy. Plasma ADAMTS13 activity was measured with a highly sensitive ELISA using a monoclonal antibody directed against the VWF-A2 domain developed in our laboratory. The ADAMTS13 activity and gene mutations in these patients are described: Family K: an elder sister K1 (activity 0.69%; gene mutation Y304C/G525D) and a younger sister K2 (activity Fig. Family pedigree of Upshaw-Schulman syndrome Fig. Family pedigree of Upshaw-Schulman syndrome

In a part of the prospective multicenter study of the Japan Adult Leukemia Study Group (JALSG-ALL97), we studied the amount and function of three important multidrug resistant (MDR) proteins: P-glycoprotein (P-gp), multidrug resistance associated protein (MRP) and lung resistance related protein (LRP), in the leukemia cells of adult acute lymphobastic leukemia (ALL) at the diagnosis. We related the results with patients’ biological and clinical features and their treatment outcome. From May 1997 to December 2001, newly diagnosed patients with de novo ALL except B-ALL were registered and received an induction therapy including cyclophosphamide (1200 mg/m2, d1), daunorubicin (45 mg/m2, d1-3), vincristine (1.3 mg/m2, d1, 8, 15, 22), L-asparaginase (3000 U/m2, d1, 9, 11, 13, 16, 18, 20) and predonisolone (60mg/m2, d1-14). Patients achieving complete remission (CR) received 8 courses of consolidation/intensification therapy followed by maintenance therapy. Median age was 38 years old. Out of 175 patients tested, 169 were evaluable. The amount and function of the MDR proteins were analyzed in CD45-gated leukemia cells by flow cytometry. After incubating with biotinylated MRK16 (IgG2a (Fab’)), anti-MRP or anti-LRP antibodies, cells were post-stained with SA-RED670. The function of P-gp and MRP was determined by Rhodamin-123 (Rh-123) accumulation with PSC833 and carcein-AM efflux with probenecid, respectively. Factors to predict CR were age, performance status (PS), chromosome, pretreatment WBC count, CD25 expression and the function of P-gp in univariative analyses. Logistic regression analysis shows that favorable prognostic factors for the achievement of CR were PS (Ps=0) and the lower ( The clinical importance of MDR proteins has been discussed in the treatment acute leukemias. We prospectively analyzed them in patients receiving the same treatment. Our study demonstrates that the function of P-gp in de novo ALL is one of the independent unfavorable factors for CR. However, it did not change the survival rates in the treatment of ALL with combination chemotherapy. Other MDR proteins relate to neither CR rate nor survival. We have also investigated these proteins in AML (Blood 102, 605a). The MDR proteins in the treatment of ALL are possibly less important as compared to those of AML.