Search

Progressively transformed germinal centers is a benign condition of unknown pathogenesis characterized by a distinctive variant form of reactive follicular hyperplasia in lymph nodes. We recently reported Ig G4-related disease in progressively transformed germinal centers. However, no large case series has been reported and clinicopathologic findings remain unclear. Here, we report 40 Japanese patients (28 men, 12 women; median age, 56 years) with progressively transformed germinal centers of the lymph nodes who fulfilled the histological diagnostic criteria for IgG4-related disease (IgG4+progressively transformed germinal centers), with asymptomatic localized lymphadenopathy involving the submandibular nodes in 24, submandibular and cervical nodes in 14, cervical nodes only in 1, and cervical and supraclavicular nodes in 1. In all, 16 (52%) of 31 examined patients had allergic disease. Histologically, the lymph nodes demonstrated uniform histological findings, namely marked follicular hyperplasia with progressively transformed germinal centers, and localization of the majority of IgG4+plasma cells in the germinal centers. Serum IgG4, serum IgE and peripheral blood eosinophils were elevated in 87%, 92% and 53% of examined patients, respectively. Eighteen patients subsequently developed extranodal lesions (including five who developed systemic disease), which on histological examination were consistent with IgG4-related disease. IgG4+progressively transformed germinal centers presents with uniform clinicopathological features of asymptomatic localized submandibular lymphadenopathy, which persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease. Nine patients were administered steroid therapy when the lesions progressed, to which all responded well. We suggest that IgG4+progressively transformed germinal centers should be included in the IgG4-related disease spectrum.

Progressively transformed germinal centers is a benign condition of unknown pathogenesis characterized by a distinctive variant form of reactive follicular hyperplasia in lymph nodes. We recently reported Ig G4-related disease in progressively transformed germinal centers. However, no large case series has been reported and clinicopathologic findings remain unclear. Here, we report 40 Japanese patients (28 men, 12 women; median age, 56 years) with progressively transformed germinal centers of the lymph nodes who fulfilled the histological diagnostic criteria for IgG4-related disease (IgG4+progressively transformed germinal centers), with asymptomatic localized lymphadenopathy involving the submandibular nodes in 24, submandibular and cervical nodes in 14, cervical nodes only in 1, and cervical and supraclavicular nodes in 1. In all, 16 (52%) of 31 examined patients had allergic disease. Histologically, the lymph nodes demonstrated uniform histological findings, namely marked follicular hyperplasia with progressively transformed germinal centers, and localization of the majority of IgG4+plasma cells in the germinal centers. Serum IgG4, serum IgE and peripheral blood eosinophils were elevated in 87%, 92% and 53% of examined patients, respectively. Eighteen patients subsequently developed extranodal lesions (including five who developed systemic disease), which on histological examination were consistent with IgG4-related disease. IgG4+progressively transformed germinal centers presents with uniform clinicopathological features of asymptomatic localized submandibular lymphadenopathy, which persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease. Nine patients were administered steroid therapy when the lesions progressed, to which all responded well. We suggest that IgG4+progressively transformed germinal centers should be included in the IgG4-related disease spectrum.

IgG4-related disease sometimes involves regional and/or systemic lymph nodes, and often clinically and/or histologically mimics multicentric Castleman's disease or malignant lymphoma. In this study, we examined clinical and pathologic findings of nine patients with systemic IgG4-related lymphadenopathy. None of these cases were associated with human herpes virus-8 or human immunodeficiency virus infection, and there was no T-cell receptor or immunoglobulin gene rearrangement. Histologically, systemic IgG4-related lymphadenopathy was classified into two types by the infiltration pattern of IgG4-positive cells: interfollicular plasmacytosis type and intra-germinal center plasmacytosis type. The interfollicular plasmacytosis type showed either Castleman's disease-like features or atypical lymphoplasmacytic and immunoblastic proliferation-like features. By contrast, the intra-germinal center plasmacytosis type showed marked follicular hyperplasia, and infiltration of IgG4-positive cells mainly into the germinal centers, and some cases exhibited features of progressively transformed germinal centers. Interestingly, eight of our nine (89%) cases showed eosinophil infiltration in the affected lymph nodes, and examined patients showed high elevation of serum IgE. Laboratory examinations revealed elevation of serum IgG4 and soluble interleukin-2 receptors. However, the levels of interleukin-6, C-reactive protein, and lactate dehydrogenase were within normal limits or only slightly elevated in almost all patients. One patient showed a high interleukin-6 level whereas C-reactive protein was within the normal limit. Autoantibodies were examined in five patients and detected in four. Compared with the previously reported cases of multicentric Castleman's disease, our patients with systemic IgG4-related lymphadenopathy were significantly older and had significantly lower C-reactive protein and interleukin-6 levels. In conclusion, in our systemic IgG4-related lymphadenopathy showed pathologic features only partially overlapping those of multicentric Castleman's disease, and serum data (especially C-reactive protein and interleukin-6) are useful for differentiating the two. Our findings of eosinophil infiltration in the affected tissue and elevation of serum IgE may suggest an allergic mechanism in the pathogenesis of systemic IgG4-related lymphadenopathy.

Multicentric Castleman disease (MCD) is an atypical lymphoproliferative disorder characterized by systemic lymphadenopathy and constitutional inflammatory symptoms. Dysregulated overproduction of interleukin-6 is responsible for the clinical abnormalities. This multicenter prospective study was undertaken to evaluate the safety and efficacy of a humanized anti–human interleukin-6 (IL-6) receptor monoclonal antibody (MRA) in patients with MCD. We report here results of the first 60 weeks of the study enrolling 28 patients. The initial dosing period consisted of 8 infusions of 8 mg/kg MRA administered biweekly. Adjustments in the dose and treatment interval were allowed for each patient in an extension phase after 16 weeks. Within 16 weeks, treatment with MRA consistently alleviated lymphadenopathy and all the inflammatory parameters. Hemoglobin, albumin, and total cholesterol levels, high-density lipoprotein cholesterol values, and body mass index all increased significantly. In addition, fatigue diminished. Chronic inflammatory symptoms were successfully managed over 60 weeks. In 8 (28.6%) patients, the MRA dose was decreased or the treatment interval was extended without exacerbation. Eleven (73.3%) of 15 patients who had received oral corticosteroids before study entry were able to do well on a reduced corticosteroid dose. Most adverse events were mild to moderate in severity. MRA was tolerated well and significantly alleviated chronic inflammatory symptoms and wasting in patients with MCD.

Multicentric Castleman disease (MCD) is an atypical lymphoproliferative disorder characterized by systemic lymphadenopathy and constitutional inflammatory symptoms. Dysregulated overproduction of interleukin-6 is responsible for the clinical abnormalities. This multicenter prospective study was undertaken to evaluate the safety and efficacy of a humanized anti–human interleukin-6 (IL-6) receptor monoclonal antibody (MRA) in patients with MCD. We report here results of the first 60 weeks of the study enrolling 28 patients. The initial dosing period consisted of 8 infusions of 8 mg/kg MRA administered biweekly. Adjustments in the dose and treatment interval were allowed for each patient in an extension phase after 16 weeks. Within 16 weeks, treatment with MRA consistently alleviated lymphadenopathy and all the inflammatory parameters. Hemoglobin, albumin, and total cholesterol levels, high-density lipoprotein cholesterol values, and body mass index all increased significantly. In addition, fatigue diminished. Chronic inflammatory symptoms were successfully managed over 60 weeks. In 8 (28.6%) patients, the MRA dose was decreased or the treatment interval was extended without exacerbation. Eleven (73.3%) of 15 patients who had received oral corticosteroids before study entry were able to do well on a reduced corticosteroid dose. Most adverse events were mild to moderate in severity. MRA was tolerated well and significantly alleviated chronic inflammatory symptoms and wasting in patients with MCD.

The protein p27Kp1is one of the cyclin‐dependent kinase inhibitors that are known to play important roles in the regulation of cell‐cycle progression. Low levels of p27 expression in malignant cells are associated with poor prognosis in patients with breast, lung, colorectal and gastric cancers. To determine the relation of cyclin‐dependent kinase inhibitors to histopathological grades of B‐cell non‐Hodgkin's lymphomas, the expression of p27, cyclin D1 and cyclin E in lymph node tissues was investigated in 56 patients with B‐cell non‐Hodgkin's lymphomas by western blotting and immunohistochemical techniques. High levels of p27 expression were observed in most lymph node tissue samples (93%) obtained from patients with low grade B‐cell non‐Hodgkin's lymphomas, while expression was low in lymph node tissue taken from all patients with intermediate and high grade B‐cell non‐Hodgkin's lymphomas. The difference in p27 expression in lymphoma tissues was significant among the different histopathological grades of B‐cell non‐Hodgkin's lymphomas (P<0.01). The analysis of the survival time of patients showed that the reduction of p27 expression correlated with poor prognosis. Cyclin D1, showed a high level of expression in mantle cell lymphomas and high grade B‐cell non‐Hodgkin's lymphomas. Cyclin E showed limited expression in 18 of 31 lymphoma tissues. Both cyclin D1 and E protein expression were not significantly different among the grades of B‐cell non‐Hodgkin's lymphomas. These results demonstrate that the level of p27 expression in lymphoma tissue is an important parameter in the classification of B‐cell non‐Hodgkin's lymphomas and in the prediction of prognosis.

Regulatory effects of glucocorticoids (dexamethasone) on myeloma cells as well as bone resorption in multiple myeloma were investigated. Glucocorticoids significantly inhibited proliferation of myeloma cells, and decreased the messenger RNA (mRNA) expressions of interleukin-6 (IL-6) and secretory type immunoglobulin G (IgG). The inhibitory effects of glucocorticoids on myeloma cell proliferation could be due to the decreased expression of IL-6 mRNA, decreased IL-6 production, and thus suppression of autocrine growth by IL-6, which is an autocrine growth factor for myeloma cells as reported previously (Nature332:83, 1988). Glucocorticoids also inhibited M-protein secretion by decreasing the levels of secretory type Ig mRNA. On the other hand, because IL-1β rather than lymphotoxin is considered to be a major osteoclast activating factor (OAF) produced by myeloma cells, and glucocorticoids decreased the expression of IL-1β mRNA and markedly suppressed the bone resorbing activity induced by IL-1β OAF in 45Ca-release bone resorption assay, it is suggestive that glucocorticoids could inhibit bone resorption induced by IL-1β OAF in multiple myeloma. Therefore, from these data it is concluded that glucocorticoids could be more effective chemotherapeutic agents in multiple myeloma than we expected, especially with regards to the inhibitory effects on proliferation and M-protein secretion from myeloma cells, as well as bone resorption by myeloma cells.

Survival of immunophenotyped non-Hodgkin's lymphomas (NHLs) diagnosed as diffuse mixed, diffuse large and large cell immunoblastic by the working formulation was evaluated based on phenotypic categories. These subtypes were grouped as diffuse aggressive NHLs due to their similarities, and categorized into T- and B-phenotype NHLs.There were 45 (57.7%) cases of T-NHL and 33 (42.3%) B-NHL. Major clinical factors such as sex, age, stage, B-symptoms and site of disease, as well as performance status (PS), LDH, primary site and number of extra-nodal sites involved showed equal distributions between T- and B-NHLs. Combination chemotherapeutic regimens based on doxorubicin were used in 84% of these cases. Complete remission was achieved in 73.6% of T-NHL and 74.1% of B-NHL. Median survival for the T- and B-NHL was the same over 30 months. Projected survival at 5 years was also similar, T-NHL (35%) and B-NHL (38%). Unilaterally, survival was adversely affected in stage III/IV of T-NHL and for age over 65 years for B-NHL. Survival was unfavorable for the B-NHL without B-symptoms when compared to T-NHLs. Multivariately, only sex, B-symptoms and PS significantly (P < 0.05) affected the survival of T-NHL.Although the overall results indicate that the response and survival of T- and B-NHL are similar, the differences observed on the effect of sex, age, stage, B-symptoms and PS on survival of T- and B-NHLs imply that, their influence on T-NHLs was different from that for B-NHLs. Therefore we suggest that separate prognostic models are needed for the T- and B-phenotype NHLs.

Human myeloma cells were purified from bone marrow aspirates from four patients having advanced myeloma, including one with common acute lymphoblastic leukemia antigen-positive myeloma. All of these myelomas had marked bone lytic lesions. From the culture supernatants of these purified myeloma cells, bone-resorbing activities were significantly revealed by 45Ca-release bone resorption assay, and IL-1 activities were also detected by IL-1 bioas-say (mouse thymocyte comitogenic assay). Sandwich enzyme immunoassay for IL-1αor IL-1βrevealed that IL-1βwas responsible for IL-1 activity of these culture supernatants. Furthermore, the bone resorbing activities of these culture supernatants were completely neutralized by pre-treatment of anti-IL-1β, but not anti-IL-1αantibody. By Northern blot analysis, IL-1βmRNA was identified from these myeloma cells. Therefore, it is concluded that myeloma cells produce IL-1β, which acts as bone-resorbing activity in multiple myeloma.

We have recently shown that two-color analysis with fluorescein isothiocyanate (FITC)–anti-CD38 antibody could clearly distinguish myeloma cells (plasma cells) from other hematopoietic cells in the bone marrow. Myeloma cells (plasma cells) alone were located at CD38strong positive (+ +)fractions. To further distinguish normal plasma cells from mature myeloma cells phenotypically, we examined immunophenotypes of normal plasma cells and myeloma cells by two-color flow cytometry with FITC-anti-CD38 antibody and phycoerythrin staining with antibody to VLA-4, MPC-1, CD44, CD56, CD19, CD20, CD24, or CD10. Normal plasma cells were all VLA-4+VLA-5+MPC-1+CD44+CD19+CD56−in the bone marrows from seven healthy donors, tonsils from four patients with chronic tonsillitis, a spleen from one patient with idiopathic thrombocytopenic purpura, and lymph nodes from two patients with chronic lymphadenitis, respectively. On the other hand, mature myeloma cells (12 of 20 cases), VLA-4+VLA-5+MPC-1+, were all CD19−and most of them CD56+, and there were no myeloma cells with the CD19+CD56−phenotype in the 20 cases of myelomas we tested. Thus, as for the expression of CD19 and CD56, normal plasma cells from various tissues are all CD19+CD56−, whereas no myeloma cells havetheCD19+CD56−phenotype. According to this finding, we investigated the expression of CD19 and CD56 on plasma cells (CD38+ +fractions) in monoclonal gammopathy of undetermined significance (MGUS). Both CD19+CD56−and CD19−CD56+plasma cells were found in all five cases of MGUS we tested, suggesting that MGUS consists of phenotypically normal plasma cells and myeloma cells. Therefore, it is reasoned that phenotypic analysis of plasma cells with anti-CDI 9 and anti-CD56 antibodies can distinguish normal plasma cells from malignant plasma cells (myeloma cells), and can detect malignant plasma cells even in MGUS or premyeloma states.

Recombinant interleukin 1α (rlL-1α) augmented proliferation of freshly isolated myeloma cells as well as B-cell stimulatory factor 2 (BSF-2)/interleukin-6 (IL-6). Recombinant IL-1α-induced proliferation was partially inhibited by anti-IL-6 antibody. In the culture supernatants of rlL-1 α-stimulated myeloma cells, IL-6 activities, which were measured by using an IL-6-dependent murine hybridoma clone, MH60.BSF2, were increased, when compared with those in the culture supernatants of nonstimulated myeloma cells. Furthermore, IL-6 messenger RNA (mRNA) expression was also augmented in IL-1 α-stimulated myeloma cells. Therefore rlL-1α stimulates myeloma cells to produce IL-6, which consequently augments proliferation of myeloma cells. Thus, IL-1 can accelerate autocrine growth of myeloma cells through IL-6.

The effects of interferon-alpha (IFNα) on in vitro proliferation and M-protein secretion in human myeloma cells were investigated. Human myeloma cells were purified from bone marrow aspirates in 12 multiple myeloma patients. Purified myeloma cells were cultured for 48 hours with IFNα at its lower concentrations (0.1 to 100 U/mL). The cells were then pulsed with 3H-TdR for the last 12 hours and 3H-TdR uptake was measured (in vitro proliferation). After 48-hour culture, supernatants were harvested and the amount of M-protein in these fluids were measured by enzyme-linked immunosorbent assay (ELISA) (in vitro M-protein secretion). In vitro M-protein secretions of myeloma cells were significantly suppressed even at 0.1 U/mL of IFNα, while 3H-TdR uptakes were not so suppressed until 10 or 100 U/mL of IFNα were added. The expressions of secretory immunoglobulin (Ig) mRNA of these myeloma cells were also selectively suppressed by IFNα. Furthermore, after IFNα had been administered intramuscularly, 3 to 6 × 106U/d for at least 1 month, in vitro M-protein secretions of these myeloma cells were decreased compared with those before IFNα administration. Therefore, these results suggest that IFNα has more sensitive inhibitory effect on M-protein secretion of human myeloma cells rather than on myeloma cell proliferation.

Human myeloma cells were purified from bone marrow aspirates from patients with multiple myeloma (MM) by Percoll discontinuous density-gradient centrifugation, E rosette formation and treatment with antimyelomonocytic antibody (Leu M1) plus complement. Thus, the purified cell fraction consisted of >90% myeloma cells, even when as little as 15% myeloma cells were contained in bone marrow mononuclear cell fraction, determined by morphological and immunologic examinations. With highly purified myeloma cells from 29 patients with IgG type MM, biologic characteristics such as spontaneous proliferation (3H-TdR uptake) and M-protein secretion rate in vitro were evaluated. Both activities varied among patients within stage I and III, and a 3H-TdR uptake of 255-24, 132 cpm/4 × 104cells, and an M-protein secretion rate of 9 to 72 pg/ cell/day, respectively, were recorded. However, in each patient, there was no correlation between 3H-TdR uptake and M-protein secretion rate. These results thus suggest that 3H-TdR uptake and M-protein secretion rate of highly purified myeloma cells are independent biologic parameters, not associated with the clinical stages, and the purification of myeloma cells we describe can contribute to further studies on the biologic characteristics and to understanding of the pathophysiology involved in MM. © 1988 by Grune & Stratton, Inc.

Human myeloma cells freshly isolated from 40 patients with IgG multiple myeloma (MM, 10 in stage I and 30 in stage III), were cultured for 48 hours with recombinant B cell stimulatory factor 2 (rBSF-2)/interleukin-6 (IL-6), which is considered a major growth factor for myeloma cells. Uptake of 3H-thymidine by these purified myeloma cells was measured, and BSF-2 response was evaluated by stimulation index and Acpm induced by rBSF-2. Myeloma cells from cases in stage I responded to rBSF-2 better than those in stage III. Moreover rBSF-2 responders also showed better response to chemotherapy. Therefore, these results suggest that in vitro response of myeloma cells to BSF-2 correlates with disease progression and clinical response in patients of MM.

Human B cell stimulatory factor 2 (BSF-2) was originally charac-terized and isolated as a T cell-derived factor that caused the terminal maturation of activated B cells to immunoglobulin-producing cells1,2. Molecular cloning of the complementary DNA predicts that BSF-2 is a protein of relative molecular mass (Mr) 26,000 similar or identical to interferon β2, hybridoma plasmacytoma growth factor and hepatocyte stimulating factor3–7. IL-6 has been proposed as a name for this molecule8,9. It is now known that BSF-2 has a wide variety of biological functions and that its target cells are not restricted to normal B cells1,10. Responses are also seen in T cells11,12, plasmacytomas6, hepatocytes7,13, haematopoietic stem cells14, fibroblasts15and rat phoeochromocytoma, PC 12 (Satoh, T. et al., manuscript in preparation). Of particular interest to this report is that human BSF-2 is a potent growth factor for murine plasmacytomas and hybridomas6,8,10. This observation suggested to us that constitutive expression of BSF-2 or its receptor could be responsible for the generation of human myelomas. In this study we report that myeloma cells freshly isolated from patients produce BSF-2 and express its receptors. Moreover, anti-BSF-2 antibody inhibits the in vitro growth of myeloma cells. This is direct evidence that an autocrine loop is operating in oncogenesis of human myelomas.

No relevant conflicts of interest to declare.

Background: Indications for allogeneic hematopoietic stem cell transplantation (allo-HCT) with reduced-intensity conditioning (RIC) have expanded widely for elderly patients and those with comorbidities. However, the optimal RIC regimen remains uncertain. A combination of fludarabine phosphate (Flu) and melphalan (Mel) is widely used in RIC regimen with comparable results to that of fludarabine phosphate and busulfan. In our hospital, Flu/Mel and low-dose total body irradiation (Flu/Mel/TBI) is mainly used in RIC regimen. We analyzed safety and efficacy in allo-HCT patients with Flu/Mel/TBI.

No relevant conflicts of interest to declare.

Background: Follicular lymphoma (FL) shows indolent clinical course and the optimal management strategy includes watchful waiting (WW). To define prognostic models for WW in clinical practice, we focused on serum soluble interleukin-2 receptor (sIL-2R) in the era of rituximab (R).

Sunami: Celgene Co. Ltd.: Research Funding; Research funding from Ono Pharmaceutical Co. Ltd., Novartis Pharmaceutical Co. Ltd.: Research Funding; Takeda Pharmaceutical Co. Ltd.: Research Funding; Ono Pharmaceutical Co. Ltd.: Research Funding.

Multiple myeloma (MM) is a heterogeneous disease in the survival outcome due to the differences in disease-, patient-, and treatment-related prognostic factors. Recently, a Revised International Staging System (R-ISS) incorporating the original ISS stage, high serum LDH, and adverse cytogenetic abnormalities (CA) such as [t(4;14), t(14;16), or del(17p)] by FISH, which is expected to predict treatment outcome more accurately in the era of novel agents and autologous stem cell transplantation (ASCT), has been proposed. However, it has been noted that more than 60% of myeloma patients are doomed to be classified as R-ISS stage II, which may encompass heterogeneous population in terms of risk factors. In the present study, we have evaluated the clinical relevance of R-ISS in Japanese patients with MM and invented a new prognostic scoring system to minimize the heterogeneity of the R-ISS stage II. Clinical features of the patients diagnosed and treated between 2001 and 2012 by the members of the Japanese Society of Myeloma were collected and assessed for the treatment outcome. Among the individual data obtained from 4138 patients from 38 centers, only those of 718 patients were complete and were further analyzed. A total of 498 patients (69.4%) were treated with conventional chemotherapy with or without novel agents without ASCT, and the remaining 220 patients (30.6%) were treated with ASCT after induction with chemotherapy with or without novel agents. The patient distribution according to R-ISS stages (I/II/III) was 154 (21.4%), 438 (61.1%), and 126 patients (17.5%), respectively, with corresponding median overall survival (OS) being 152.8, 65.2, and 45.3 months, respectively (p=8.98e-15). Although the R-ISS model could discriminate the difference between each stage distinctly in transplant-ineligible patients (median OS: stage I, 90.7; stage II, 57.5; and stage III, 33.1 months, respectively, p=2.37e-12), discrimination of the difference between the stages II and III was ambiguous in transplant-eligible patients (median OS: stage I, not reached; stage II, 71.2; and stage III, 73.8 months, respectively, p=0.0325). In addition, median OS of R-ISS stage II were quite heterogeneous according to the presence or absence of risk factors (high LDH and adverse CA): 74.2 months for ISS stage I with 1 risk factor of either LDH or CA, 34.0 months for ISS stage I with both risk factors, 130.8 months for ISS stage II without risk factors, 53.8 months for ISS stage II with 1 risk factor, 46.9 months for ISS stage II with both risk factors, and 61.8 months for ISS stage III without risk factors. These results would implicate that high LDH and/or adverse CA might exert stronger impact on OS. Accordingly, we performed a multivariate analysis to disclose more important factors that were independently associated with poor prognosis, and identified the following factors: serum albumin (<3.5 g/dl, p=0.014), b2-microglobulin (≥3.5 mg/l, p=0.0044), high LDH (>normal upper limit, p<0.00001), adverse CA by FISH (p=0.0006), and abnormal karyotype by G-banding (p=0.023). As a result, high b2-microglobulin (n=367, 51.1%), high LDH (n=139, 19.4%), and adverse CA by FISH (n=198, 27.6%) were determined to be significant important factors to be incorporated into the design of more realistic prognostic scoring system. By using these newly identified 3 risk factors (high b2-microglobulin, high LDH, and adverse CA), we have established a brand new scoring system as the Japanese Prognostic Scoring System (JPSS). By applying this scoring system, 232 (32.3%), 297 (41.4%), 160 (22.3%), and 29 patients (4.0%) were assigned to score 0, 1, 2, and 3, respectively. Median OS according to this scoring system (0/1/2/3) were 130.8, 62.4, 49.5, and 37.5 months, respectively (p=2.1e-20, Figure 1). Importantly, this scoring system is able to clearly discriminate the difference in OS between the stages both in transplant-eligible and -ineligible patients (p=2.81e-14 and p=0.000153, respectively). When the same patients were assigned to score 0, 1, and ≥2 by combining the data of scores 2 and 3, median OS of each group became 130.8, 62.4, and 47.7 months, respectively (p=1.29e-19). Thus, we hereby propose a JPSS comprising three prognostic factors as a simple and useful model for the risk assessment of Japanese patients with MM in routine practice that warrants further validation in larger studies.

Sunami: Takeda pharmaceutical Compani Limited: Research Funding; ONO PHAMACEUTICAL CO.,LTD: Research Funding.

No relevant conflicts of interest to declare.

Introduction

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Background

Introduction

IntroductionA significant progress in the management of multiple myeloma (MM) has been made in recent years by the introduction of novel treatment modalities including high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) and novel drugs such as proteasome inhibitors and immunomodulatory drugs (IMiDs). Nevertheless, MM is still an incurable disease with various complications, and it is not clear whether these approaches contribute to the improvement of patient outcomes in routine practice. Previously, the Japanese Society of Myeloma surveyed the clinical features of 1383 patients with MM diagnosed and treated between January 1990 and December 2000. In the present study, we conducted a multicenter retrospective study to evaluate the treatment outcome and prognostic factors in the era of novel agents in Japan involving 2593 new patients diagnosed and treated after December 2000.

No relevant conflicts of interest to declare.

Azacitidine (AZA) has emerged as the standard of care for treatment of higher risk myelodysplastic syndromes (MDS) based upon results of several studies. However, the rate and duration of response are insufficient and the focus of research will shift towards further optimization of clinical outcome. Studies for a dosing schedule and a combination therapy with other drugs are important. In general, there are some difficulties to fix the dosing schedule of AZA due to its side effects (infection etc.) and complications. We had carried out the strict managements for protection of infection and bleeding to keep a fixed dosing schedule of 75mg/m2/day for 5 days, followed by 21 days drug-off.Data from consecutive 62 patients with higher risk MDS treated with AZA at our institute between May 2011 and April 2013 were reviewed. AZA was strictly administered at a dosage of 75mg/m2/day intravenously for 5 days, followed by 21 days drug-off, every 26 days. Patients, whose neutropenia (≤500/mm3) were sustained, were hospitalized in clean rooms. Prophylaxis of antibiotics and the administration of G-CSF were carried out if necessary. When patients in poor risk cytogenetics achieved complete remission (CR) by AZA alone, they were subsequently received a sequential combination therapy with 5-day AZA, followed by 21 days drug-off and chemotherapy (including idarubicine or aclarubicine), followed by 35 days drug-off to maintain CR.A total of 62 patients were classified as RA 2, RAEB-1 14, RAEB-2 32, and RAEB-T 14. There were 40 male patients and 22 female. Median age was 73 years (range, 40-90). At the time of AZA treatment, 40 patients were stratified as Int-2 and 22 as High by IPSS. Sixteen patients had good risk cytogenetics, 17 intermediate, and 29 poor. Fourteen patients had 20-29% of bone marrow blasts, 32 10-19% , and 16 2-9%. Forty-seven patients were de novo MDS and 15 therapy-ralated MDS (t-MDS). Forty-five patients had the time from MDS diagnosis to AZA treatment within two month, 4 2-12 months, and 13 13-102 months.The median time of follow up was 11 months (3-27) and the median cycle of a 5-day AZA treatment was 8 (2-29). Totally, 537 cycles had been done. Days of drug-off within 21 days/cycle were 435 cycles(81%), 22-28 days/cycle 82 cycles (15%), and over 29 days/cycle 20 cycles (4%).The IWG2006 responses to AZA included 29 CR (47%), 10 marrow CR (16%), 9 stable disease (SD) with hematological improvement (HI) (15%), 6 SD without HI (10%), 3 progressive disease (PD) (5%), and 1 failure (2%). The overall response rate (ORR) was 78%. HI includes 35 HI-E (57%), 37 HI-P (59%), and 26 HI-N (42%).The CR/mCR rate in Int-2 was 23/40 (58%), High 16/22 (73%), good risk cytogenetics 11/16 (69%), intermediate 9/17 (53%), poor 19/29 (66%), 20-29% bone marrow blasts at initial diagnosis 9/14 (64%), 10-19% 21/32 (66%), and ≤9% 9/16 (56%). About the time to AZA from MDS diagnosis, the CR/mCR rates were 29/45 (64%) in 0-2 months and 10/17 (59%) in 3-102 months. Among t- MDS, 8/15 (53%) achieved to CR/mCR and among de novo MDS, 31/47 (66%) achieved to CR/mCR. Cytogenetic responses, excluding 9 normal karyotype patients, were 15/28 (54%) CR and 12/28 (42%) PR.Among 62 patients, 10 patients died and 12 received bone marrow transplantation (BTM) including 7 CR, 2 SD, and 3 PD. The median time to death from the initiation of AZA treatment was 11 months (3-23). The causes of death were 3 BMT-related, 3 PD, and 4 infection. Eight patients, including 4 CR and 4 SD, progressed to AML. They were immediately treated with chemotherapy, and 7 are still alive. Ten patients in poor risk cytogenetics, who achieved CR by AZA alone, subsequently switched to a sequential combination therapy with AZA and chemotherapy from March 2013. No relapse have been seen at present and they have been followed up.The AZA regimen fixed dosing schedule of 75mg/m2 for 5 days, followed by 21 days drug-off showed promising efficacy for higher risk MDS (ORR; 78%). Based upon our results, the response rates of AZA against Int-2 vs High and de novo MDS vs t-MDS were almost the same. When patients with poor risk cytogenetics achieved CR by AZA treatment alone, the following sequential combination therapy with AZA and chemotherapy was effective to maintain CR.No relevant conflicts of interest to declare.

There is little evidence to support the efficacy of dosage exceeding conventional high dose chemotherapy (HDC), referred to as super-HDC (SHDC) for Acute Leukemia (AL). However our hospital has been successfully conducting an original SHDC and has realized the highest complete remission rate and 10 years event free survival ratio for all generations with no selection bias. For example, de novo AML except M3 results are 91%, 59% for under 70 years old and 75%, 32% for over 70 years old respectively (51stASH #1052, until 2010). The treatment of complications is the key to SHDC success, with fungal infection one of the major complications. With our unique preemptive approach, we have successfully eliminated fungal mortalities on all AML patients with no selection bias (53stASH #1544). In this group using ITCZ as prophylaxis, pulmonary invasive aspergillosis (PIA) morbidity rate was still high, so we had to switch from ITCZ to VRCZ. Thus we theorized that VRCZ is more effective as prophylaxis. As there is little supporting data, we scheduled this prospective randomized study commencing 2011/4/23. This is the interim analysis of the first 100 of 200 patients as of 2012/9/26.

Abstract 5030

With the introduction of imatinib (IM) and subsequent TKIs such as nilotinib (NI) and dasatinib (DA), deaths due to progression of chronic myeloid leukemia (CML) have decreased dramatically. In such circumstances, the new occurrence of other malignant diseases in patients with CML on treatment with TKIs always causes distress. With the increase in long term surviving patients with CML, there is concern over whether these malignancies are related to treatment with TKIs or not. We investigated the improved prognosis in patients with CML on long-term treatment with TKIs and the occurrence of complicating malignancies.We evaluated 173 patients (101 males, 72 females) in the chronic phase of CML, all of whom had CML diagnosed at our hospital between January 1990 and June 2011 and received treatment with TKIs for at least 1 year. The median age at the start of treatment with TKIs was 57 (19 – 92) years. Patients aged 60 years and older accounted for 72 (42%). The median follow-up period after the start of treatment with TKIs was 68 (12 – 128) months. Before the onset of CML, 11 patients had prior malignancies. Treatments for CML administered before use of TKIs were hydroxyurea (HU) alone 3, HU + interferon-α (IFN-α) 47, IFN-α alone 7, chemotherapy for AML + IFN-α 2 and chemotherapy for ML + IFN-α 1. TKIs were used as frontline therapy in 113.TKI treatment of all patients initially consisted of IM at the dose of 100 mg per 12 kg body weight. We switched the drug to NI when complete molecular response (CMR) was not achieved after long-term treatment with IM. In addition, a switch to DA was used to consolidate CMR. Treatments that contained TKIs consisted of IM alone in 42, IM → NI in 46, and IM →NI → DA in 85. Two patients with a complete cytogenetic response (CCR) underwent bone marrow transplantation.Among 173 patients, the best response to treatment in patients treated with TKIs was CMR in 72, a major molecular response (MMR) in 84, CCR in 15, and refractory CML in 2. Currently, 22 have maintained CMR for 6 to 111 months after discontinuation of TKIs, and 19 (11%; 17 males, 2 females) have developed new onset of a malignancy. In these 19, the median age at the onset of cancer was 70 (31 – 85) years. Patients aged 60 years and older accounted for 15 (79%). The median period from the start of TKIs to the onset of cancer was 38 (10 – 117) months. Affected organs were bladder 5; stomach 3; rectum 3; large intestine 2; lung 2; and esophagus, appendix, prostate, and pancreas each in 1. The TKIs given to the patients with malignant diseases were IM alone in 13, IM → NI in 4, and IM → NI → DA in 2. Prior treatments included HU + IFN-α in 8 and IFN-α alone in 1. The observed number of patients who were diagnosed as malignant neoplasm was compared with the expected number. The expected number was obtained through integration of age specific incidence rate of malignant neoplasm from the start age taking medicine to the age at which the diagnosis as malignancy was made or the follow up was finished for censoring. The age specific incidence rates were estimated by interpolating five year old specific incidence rates from of the 2007's survey that was conducted by Center for Cancer Control and Information Services, National Cancer Center, Japan. The observed number/expected number (O/E) ratio for the occurrence of all malignant diseases was 1.00 (19/18.97), and the O/E for gastrointestinal cancer was 1.118 (11/9.84). Therefore, no increase in the incidence of malignant diseases was observed in patients treated with TKIs. However, the O/E for bladder cancer was 4.525 (5/1.11) with a 95% confidence interval of 1.42 – 9.32 (P = 0.0002), which means that the incidence of bladder cancer in patients treated with TKIs was higher than that in the general Japanese population. So far 19 patients have died and the median age at death was 79 (59 – 94) years. In these patients, 8 deaths were related to cancer and the others were caused by diseases associated with old age that were unrelated to the worsening of CML.The introduction of TKIs has undoubtedly improved the prognosis of patients with CML. Based on the results of this investigation, the apparent increase in malignant diseases observed during the long-term follow-up of patients treated with TKIs was generally considered to be attributable to the aging of patients. We should however further investigate whether the higher incidence of bladder cancer seen in patients treated with TKIs is incidental or not.No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Abstract 3767

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Abstract 1503

Abstract 885

Abstract 2934

Since MDS is more prevalent in the elderly, use of intensive chemotherapy is considered to be difficult. However, granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF), use of clean room and development of promising antifungal agents have resulted in dramatically enhanced safety of post-chemotherapy control of elderly patients. Thus, we attempted to use intensive chemotherapy in HR-MDS and MDS-AML patients.To evaluate, in HR-MDS and MDS-AML patients, the efficacy and safety of remission induction therapy and post-remission therapy that are standard treatment for de-novo AML in our department.This study enrolled 213 consecutive patients initially treated at our department between 2000 and 2010 who suffered MDS-related disease and whose survival was expected to be less than several months with supportive therapy alone. Almost all of the patients had ≥20% myeloblasts. The age of the patients ranged from 16 to 93 years (median: 70 years). They comprised 2 with good prognosis, 107 with intermediate prognosis and 104 with poor prognosis based on chromosomal findings.Remission induction therapy consisted of behenoyl-ara-C (BHAC) 350 mg/m2 (300 mg/m2 for patients aged ≥70 years) over 10 days and idarubicin (IDA) 12 mg/m2 (10 mg/m2 for patients aged ≥70 years) over 4 days. Additional etoposide 100 mg/m2 over 4 days was given if bone-marrow examination on Day 15 revealed residual myeloblasts of ≥5%. The efficacy of the therapy was evaluated after the first course. Patients showing maintained remission received 8 courses of post-remission therapy over 11 months. This post-remission therapy included high-dose cytarabine (2 g/m2, or 1g/m2 for patients aged ≥60 years) (HDAC) × 10 and mitoxantrone (MIT) 7mg/m2 × 3 given initially after remission. Maintenance/intensification therapy mainly consisted of BHAC 350 mg/m2 × 4 plus aclarubicin (ACR) 20 mg/body × 6 or IDA 10 mg × 1 alternately every 5 weeks. Outpatient maintenance therapy consisted of M-CSF over 7 days after the end of chemotherapy, followed by administration of G-CSF until neutrophil recovery. Patients were admitted to a clean room if WBC became <1000/mm3. As post-remission therapy, 90 patients received HDAC-MIT, while 50 did not. A total of 28 patients received bone-marrow transplantation during chemotherapy.CR and PR were achieved in 146/213 (68%) and 43/213 (20%) patients, while 14/213 (7%) showed no response (NR) and 10/213 (5%) died during chemotherapy (CD). CR rate was comparable between patients aged ≥70 years (76/110, 69%) and those aged <70 years (70/103, 68%). Chemotherapy death (CD) occurred in 9/110 (8%) patients aged ≥70 years compared to 1/103 (1%) patients aged <70 years. In terms of prognosis by chromosomal type, CR was achieved in 2/2 (100%), 79/107 (74%) and 65/104 (63%) patients with good, intermediate and poor prognosis, respectively. NR was shown in 3/107 (3%) patients with good prognosis compared to 11/1074 (11%) patients with poor prognosis. The overall survival (OS) in the whole patients ranged 1 to 122 months (median: 11 months), and the event free survival (EFS) in patients achieving CR ranged 1 to 109 months (median: 8 months). Six patients received no treatment after remission because of refusal of post-remission therapy or poor P. S. Among patients receiving post-remission therapy, EFS and OS in 75 patients with intermediate prognosis were 12 and 15 months, respectively, while those in 65 patients with poor prognosis were 6 and 10 months, respectively. EFS in those with and without HDAC-MIT were 8 and 7 months, respectively, showing no difference. OS in 28 patients receiving bone-marrow transplantation ranged 6 to 122 months (median: 17 months). A total of 22 patients (16 with chemotherapy alone and 6 with chemotherapy and bone-marrow transplantation) survived for more than 5 years. There was only one chemotherapy death during post-remission therapy.The results of this single-center clinical study indicate that major improvement of supportive therapy may allow introduction of remission safely and at a high probability in elderly patients with HR-MDS or MDS-AML. There remains a challenge since the median OS in patients with remission was still as short as around 1 year. One of the future challenges is how to use intensive chemotherapy in combination with distinctive new antileukemics such as lenalidomide.No relevant conflicts of interest to declare.

Until recently, intensive chemotherapy for acute myeloid leukemia (AML) did not necessarily lead to high success rates, partly because of deaths from infections due to the associated long-term neutropenic phase. However, the advent of effective antifungal agents or the use of granulocyte colony-stimulating factor (G-CSF) or macrophage colony-stimulating factor (M-CSF) has definitely reduced deaths from chemotherapy and has improved the results of treatment with intensive chemotherapy also in elderly patients.The complete remission rate after remission induction therapy and the event-free survival (EFS) after postremission therapy were investigated in 165 patients (99 men and 66 women) with untreated de novo AML (excluding subtype M3) who were consecutively registered in a single institution between March 2001 and March 2009. The patients' ages ranged from 16 to 94 years (median: 59 years). There were 3 patients with M0, 18 patients with M1, 25 patients with M2, 25 patients with t(8;21), 35 patients with M4, 12 patients with M4Eo, 35 patients with M5, 10 patients with M6, and 2 patients with M7.Remission induction therapy consisted of 10 days of behenoyl-ara-C (BHAC) at 350 mg/m2 (300 mg/m2 for patients 70 years or older) and 4 days of idarubicin (IDA) at 12 mg/m2 (10 mg/m2 for 70 years or older). Further, if bone marrow examination revealed 5% or more residual blast cells on day 15, etoposide was additionally administered at a dose of 100 mg/m2 for 4 days. The efficacy of the remission induction therapy was evaluated after 1 course of treatment. The patients who had achieved remission underwent 9 courses of postremission therapy, which lasted 11 months. The details are omitted, but therapy with high-dose (2 g/m2 [1 g/m2 for patients 60 years or older]) cytarabine (HDAC)×10 plus 7 mg/m2 of mitoxantrone (MIT) ×3 was performed during the 1st and 9th courses. No HDAC was performed on the elderly aged above 75 years old. The intensive therapy with Aclarubicin (ACR) of 20 mg/body for 14 days and the maintenance therapy with a combination of BHAC 350 mg/m2×4 with ACR or IDA were repeated alternately every 6 weeks. Chemotherapies other than remission induction therapy and HDAC were performed in an outpatient clinic, and if the patients with the WBC decreasing to 1000/mm3 were hospitalized in the biological clean room. M-CS was administered for 7 days after the day following the end of chemotherapy, and subsequently G-CSF was administered until the WBC becomes to be 1000/mm3.Complete remission (CR) was achieved in 143 of the 165 patients overall (86.7%), 113 of the 123 patients 69 years or younger (92.7%), and 29 of the 42 patients 70 years or older (69.1%). During the remission induction therapy, death occurred in 6 of the 165 patients overall (3.6%), 2 of the 123 patients 69 years or younger (1.6%), and 4 of the 42 patients 70 years or older (9.5%). The EFS in patients with CR was 61.5% at 8 years in patients 69 years or younger, while it was 26.9% at 5 years in patients 70 years or older. There was only a case of death due to chemotherapy during postremission therapy. Seven patients underwent bone marrow transplantation during the first remission, and 6 of these patients have been enjoying EFS.Improvement in supportive care has enabled safe intensive chemotherapy. The patients with good or intermediate prognosis were clearly improved by the present preliminary treatment at a single institution, but the patients with poor prognosis still highly require bone marrow transplantation in the future.No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Abstract 2927