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High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is widely used as a salvage therapy for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL). To investigate the safety and efficacy of regimens including high-dose MCNU followed by ASCT for DLBCL, we analyzed the data from prospective multicenter trials. Twenty-nine patients were analyzed, and the median follow-up time for survival patients was 70 months. Fifteen patients received MCVC conditioning regimen, and fourteen patients received MEAM regimen. Major toxicities associated with these conditioning regimens included nausea (69%), anorexia (66%), febrile neutropenia (62%), diarrhea (59%), and mucositis (34%). One patient who developed severe sinusoidal obstructive syndrome and acute lung injury died without disease progression, and overall therapy-related mortality at 5 years was 3%. No patient developed therapy-related hematological malignancy. At 5 years, overall survival and progression-free survival in all patients were 82.8 and 58.2%, respectively. The 5-year OS in patients treated by the MCVC and MEAM regimens were 73.3 and 92.9%, respectively. These results suggest that regimens including high-dose MCNU followed by ASCT are feasible and effective for the treatment of relapsed or high-risk DLBCL. Further investigation is needed to evaluate of these regimens.

Aspergillus and Candida species are the main causative agents of invasive fungal infections in immunocompromised human hosts. However, saprophytic fungi are now increasingly being recognized as serious pathogens. Trichoderma longibrachiatum has recently been described as an emerging pathogen in immunocompromised patients. We herein report a case of isolated suspected invasive pulmonary infection with T. longibrachiatum in a 29-year-old man with severe aplastic anemia who underwent allogeneic stem cell transplantation. A direct microscopic examination of sputum, bronchoaspiration, and bronchoalveolar lavage fluid samples revealed the presence of fungal septate hyphae. The infection was successfully treated with 1 mg/kg/day liposomal amphotericin B.

Occult hepatitis B virus (HBV) infection is a clinical challenge, but its relationship to clinicopathologic features and the risk of progression to malignant lymphoma (ML) are poorly defined. We estimated the prevalence of HBV infection of 1,358 patients with newly diagnosed ML. HBV infection was more prevalent in ML than in control patients. The occult HBV infection group had a higher median onset age, no liver or spleen involvement, and higher prevalence of diffuse large B-cell lymphoma than the other groups, indicating that occult HBV infection is a distinct clinicopathologic entity. J. Med. Virol. 88:2206-2210, 2016. © 2016 Wiley Periodicals, Inc.

Chronic hepatitis C virus (HCV) infection conditions are proposed to be an HCV syndrome of hepatic, extrahepatic or systemic disorders with malignancies such as a malignant lymphoma (ML).[1] HCV is...

Aspergillus and Candida species are the main causative agents of invasive fungal infections in immunocompromised human hosts. However, saprophytic fungi are now increasingly being recognized as serious pathogens. Trichoderma longibrachiatum has recently been described as an emerging pathogen in immunocompromised patients. We herein report a case of isolated suspected invasive pulmonary infection with T. longibrachiatum in a 29-year-old man with severe aplastic anemia who underwent allogeneic stem cell transplantation. A direct microscopic examination of sputum, bronchoaspiration, and bronchoalveolar lavage fluid samples revealed the presence of fungal septate hyphae. The infection was successfully treated with 1 mg/kg/day liposomal amphotericin B.

Occult hepatitis B virus (HBV) infection is a clinical challenge, but its relationship to clinicopathologic features and the risk of progression to malignant lymphoma (ML) are poorly defined. We estimated the prevalence of HBV infection of 1,358 patients with newly diagnosed ML. HBV infection was more prevalent in ML than in control patients. The occult HBV infection group had a higher median onset age, no liver or spleen involvement, and higher prevalence of diffuse large B-cell lymphoma than the other groups, indicating that occult HBV infection is a distinct clinicopathologic entity. J. Med. Virol. 88:2206-2210, 2016. © 2016 Wiley Periodicals, Inc.

Aims Although hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological disorders, there is persistent immunosuppression in both allogeneic and autologous HSCT. Dendritic cells (DCs) play key roles in the immune system. This study investigated whether the DC progenitor cells within patients' peripheral blood after HSCT have the potential to differentiate into DCs. Main methods Twenty-eight patients were included in this study, and peripheral blood samples were basically taken before starting the conditioning regimen, on the day of transplantation (day 0), and on days + 14, + 28, + 42, + 70 and + 170 after transplantation. Immature DCs (iDCs) were induced from adherent mononuclear cells by using recombinant human granulocyte-macrophage colony-stimulating factor plus interleukin-4. Key findings The iDCs expressed cell surface antigens such as CD40 and HLA-DR, and they had phagocytotic activity, thus showing the characteristics of iDCs. The induction of iDCs was possible from day + 14 after HSCT. However, there were differences between allogeneic and autologous HSCT in the expression of CCR5 in iDCs at day + 14 after transplantation. Furthermore, the up-regulation of maturation-related antigens by maturation stimuli was higher after HSCT compared with before HSCT. Significance We demonstrated that patients' peripheral blood mononuclear cells have the potential to differentiate into DCs beginning on day + 14 after HSCT, although some differences exist between allogeneic and autologous HSCT and between before and after HSCT.

Chronic myeloid leukemia (CML) is caused by the BCR-ABL oncogene. The Philadelphia chromosome (Ph) from a reciprocal translocation, t(9;22) (q34;q11) causes a fusion gene, BCR-ABL, that encodes a constitutively active tyrosine kinase. Treatment of CML by imatinib is effective to control the tyrosyl phosphorylation of the protein related to the cell signaling. BCR-ABL mRNA is overexpressed in the minimal residual disease (MRD), known as an early sign of relapse. Between December 2005 and June 2008, we measured BCR-ABL mRNA levels in the bone marrow (BM) from patients by quantitative real-time polymerase chain reaction (RQ-PCR) in Aomori Prefectural Central Hospital. Eighty-six samples from 26 patients were collected. Among the 26 CML patients, 11 patients (42%) were in the pretreatment group. Seven (64%) of the 11 patients achieved complete molecular response (CMR). In the post-treatment group consisting of the remaining 15 patients, 9 (60%) patients achieved CMR. The patients receiving imatinib at a dose over 300 mg per day required 13 (6-77) months [median (range)] to achieve CMR. On the other hand, the patients receiving a dose below 300 mg per day required 29.5 (11-84) months [median (range)]. When BCR-ABL mRNA was detected during the treatment course of patients with CMR, careful observation of BCR-ABL mRNA was useful for tracking the clinical course of patients. In conclusion, the BCR-ABL mRNA level was useful for monitoring the clinical course in 26 patients with CML.

Background We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib-resistant or imatinib-intolerant chronic myeloid leukemia (CML). Methods From 2009 to 2011, 54 CML-chronic phase (CP) patients with resistance (n = 40) or intolerance (n = 25) to imatinib were registered to undergo dasatinib treatment. Eleven patients showed both resistance and intolerance to imatinib. Coincidentally, the resistance criteria in this study were the same as a non-optimal response to tyrosine kinase inhibitors (TKIs) as defined in the European LeukemiaNet (ELN) 2013 recommendations. Results The overall incidence rate of major molecular response (MMR) at 12 months was 62.3% (n = 47). Forty patients with resistance to imatinib who were ‘warning’ and ‘failure’ patients based on the ELN 2013 recommendations were assessed; cumulative MMR and MR4.5 rates were 62.5% (n = 39) and 21.0% (n = 40), respectively, at 12 months. Twelve patients who showed a BCR-ABL transcript level >1% on the international scale did not achieve a MMR or discontinued dasatinib treatment because of insufficient effects. With regard to safety issues, grade 3/4 non-hematologic adverse events (AEs) were infrequent. Conclusions Patients with non-optimal responses (who meet ELN 2013 warning and failure criteria) to imatinib should be switched quickly to dasatinib, which is less toxic in CML-CP patients, to improve their prognoses. A BCR-ABL1 IS of

Extranodal malignant non-Hodgkin lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma) represents a subtype of B-cell lymphoid malignancies with distinct clinicopathological features and is often associated with a favorable prognosis. Recent cytogenetic studies have revealed that t(11;18)(q21;q21) is a characteristic chromosomal aberration in low-grade B-cell MALT-type lymphoma. In the present study, we employed florescence in situ hybridization analysis using contiguous YAC clones mapped to the 18q21.1 region to identify a YAC clone, y789F3, encompassing the breakpoint of t(11;18)(q21;q21) in a MALT lymphoma. PI artificial chromosome (PAC) contigs constructed on this YAC clone were used to analyze the breakpoint region. PAC clone 264m4 was observed on normal chromosome 18 and on der(18), and PAC clone 879n 10 on normal chromosome 18 and on der(II), confirming that the breakpoint is located between these two PAC clones. We also found that a region of approximately 500 kb between the two PAC clones was deleted. These results indicate that the locus between PAC clones 264m4 and 879n 10 at 18q21.1 involved in t(11;18) translocation or associated deletion plays an important role in the development of MALT lymphoma.

The t (11; 18) (q21; q21) translocation is a characteristic chromosomal aberration in lowgrade B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type. We previously identified a YAC clone y789F3 encompassing the breakpoint at 18q21 in MALT lymphoma patient. BAC and PAC contigs were constructed on the YAC, and BAC 193f9 was found to encompass the breakpoint region. We further narrowed down the breakpoint region at 18q21 in five MALT lymphoma patients by means of FISH and Southern blot analyses using the plasmid contig constructed from the BAC 193f9. The breakpoints at 18q21 in three of the five MALT patients were found to be clustered within approximately 20kb region. By using exon amplification and cDNA library screening, we identified a novel cDNA spanning the breakpoint region that exhibited aberrant mRNA signals in four of five MALT lymphoma patients. We refer to the gene encoding this transcript as MALT1 (Mucosa-Associated Lymphoid Tissue lymphoma translocation gene 1). The alteration of MALT1 by translocation is strongly suggested to play an importance role in the development of MALT lymphoma.

A 22-year-old Japanese woman was diagnosed with hemophagocytic lymphohistiocytosis and subsequently was treated with etoposide and cyclophosphamide. On Day 22, multiple nodular lesions appeared in the bilateral lungs. Neither the administered antibiotics nor the antifungal agent were effective, and she died suddenly of respiratory failure on Day 35. An autopsy revealed disseminated zygomycosis and a pulmonary infarction due to the embolization of an angioinvasive fungus, which was later identified as Cunninghamella bertholletiae using in situ hybridization of 18S rRNA. C. bertholletiae is aggressive as well as resistant to antifungal agents. This rare species should therefore be taken into consideration as a potential causative agent of zygomycosis.

A 81-year-old woman was diagnosed as having diabetes mellitus (DM) at 58 years of age. She started insulin therapy the following year, but her blood sugar levels were poorly controlled. At the age of 75, she tested positive for the anti-GAD antibody (7.8 U/ml) and was diagnosed as having slowly progressive type 1 DM (SPIDDM), as well as vitiligo vulgaris. At 78 years of age, chronic thyroiditis was diagnosed after positive tests for anti-thyroid peroxidase antibody and anti-thyroglobulin antibody. At the age of 81, general fatigue and jaundice appeared concomitantly with severe anemia, with Hb levels at 5.2 g/dl. Low serum vitamin B12 levels and the finding of erythroblastic hyperplasia with megaloblasts in bone marrow led to the diagnosis of pernicious anemia. Anemia was alleviated by intramuscular injections of vitamin B12. The patient developed chronic thyroiditis, vitiligo vulgaris, and pernicious anemia concomitantly with SPIDDM, and was diagnosed as having polyglandular autoimmune syndrome type III. Attention should be paid to these potentially associated autoimmune diseases in daily practice during the follow-up of SPIDDM patients.

To clarify the clinical outcome of peripheral T-cell lymphomas (PTCLs), we conducted a retrospective review comparing the outcomes of patients with PTCL (nodal peripheral T-cell lymphoma, unspecified, n=34 ; angioimmunoblastic T-cell lymphoma, n=12) to those with diffuse large B-cell lymphoma (DLBCL, n=48). All patients received CHOP-based chemotherapy without rituximab. PTCL patients presented at a more advanced clinical stage (91% vs. 65%, P

The Wilms' tumor gene 1 (WT1) encodes a transcription factor that is involved in normal cellular development and cell survival. WT1 mRNA is overexpressed in the minimal residual disease (MRD) of patients with hematopoietic malignancy patients, particularly acute myeloid leukemia (AML). MRD represents the condition with the low levels of leukemia cells in the bone marrow and is known as a sign of recurrence. In hematopoietic malignancies, definition of remission is based on the lack of MRD at submicroscopic level. Between December 2005 and June 2008, we started to measure WT1 mRNA levels in the peripheral blood (PB) from patients by quantitative real-time PCR in Aomori Prefectural Central Hospital. Three hundreds and eight samples from 95 patients were evaluated. The patients included AML (55 patients), acute lymphoblastic leukemia (11), myelodysplastic syndrome (20), malignant lymphoma (5), chronic myeloid leukemia (1), prostatic carcinoma (1), and leukopenia (2). Among the 55 AML patients, 21 patients were pretreated with remission induction therapy. In the clinical course of 21 patients, timely therapeutic approaches could be started for relapse by the early detection of WT1 mRNA overexpression before the morphological findings were apparent. Monitoring WT1 mRNA is helpful to identify patients at high-risk relapse. High overall survival rate (71.2%, 15/21, median: 24.6 months, range 1.1-35.6 months) was achieved in 3 years. The overall survival rate of 34 post-treatment patients was 61.7% (median: 23.5 months, range 0.13-126.5 months after treatment start). In conclusion, the WT1 mRNA level is a sensitive biomarker for monitoring MRD.

Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, that is rapidly internalized after binding to CD33. This is followed by intracellular release of calicheamicin, which induces double-stranded DNA breaks, cell cycle arrest, and apoptosis. So GO is a more selective agent for acute myeloid leukemia (AML), because the CD33 antigen is expressed on AML, while it is not expressed on normal hematopoietic stem cells and nonhematopoietic tissues. However, some studies indicated that this agent showed resistance to refractory AML cells via various mechanisms, and that there were no potent effects. In this study, we report a 76-year-old female with recurrent AML who responded to single therapy with GO, achieving complete remission for more than 1 year after the start of administration, although additional remission induction was impossible. The response to GO can be stratified with reference to the response to conventional chemotherapy.

Background: We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan (IMIDAS PART2 study; UMIN000006358). Several groups reported that some of CML patients who achieved stable deep molecular response (DMR) level or deeper could stop Tyrosine Kinase Inhibitor (TKI) and approximately 40% of these patients could keep therapy free survival by cessation of TKI. Discontinuation of TKI has emerged as a new goal of treatment in CML. Achievement of DMR is necessary for discontinuation of TKI. The aim of the present study was to analyze the prognostic significance of (i) BCR-ABL transcript International Scale (BCR-ABL IS) levels, (ii) the halving time and (iii) velocity of BCR-ABL transcript elimination using an optimized cutoff according to receiver operating characteristic (ROC) analysis. Methods: Eighty newly diagnosed CML-CP patients were included in this study. Patients received dasatinib 100mg once daily. Treatment has continued until disease progression or unacceptable toxicity. Clinical efficacy and safety was partially reported in 55th ASH Meeting. We sought to investigate the impacts of above 3 parameters within the initial 1 or 3 months of therapy. Halving time was calculated by the method, described by Branford et al. Velocity of BCR-ABL transcript elimination at 1 or 3 months (V-BCR-ABL1m or 3m respectively) was calculated as BCR-ABL IS at 1 or 3 months (BCR-ABL IS1m or 3m respectively) divided by that at diagnosis. Results: One patient was withdrawal before administration of dasatinib. Seventy-nine patients administered dasatinib 100 mg once daily. The estimated MMR and DMR rates were 92.1 % (95%CI, 76.8-97.3 %) and 60.9% (95%CI; 42.3-73.4 %) by 12 months respectively. The patients who had already achieved DMR at 3 months were excluded from landmark analysis. The cut off values for prediction of DMR at 12 months were obtained by ROC analysis. Those of BCR-ABL IS1m and BCR-ABL IS3m were 11.7% and 0.284% respectively. Those of halving times on 0-1 month and 0-3months (halving time1m and 3m) were 17.8 and 13.6 days respectively. Those of V-BCR-ABL1m and V-BCR-ABL3m were 0.321 and 0.018 respectively. The estimated DMR at 12 months, 95% CI and probability (P), obtained by Kaplan-Myer analysis, were shown in Figure 1. Odd' ratio, obtained by Chi-square test, was shown in Table 1. The patients with less than 0.321 at V-BCR-ABL1m showed the highest DMR at 12 months (80%), the least probability (P=0.009) and the least odd' ratio (0.175). At 3 months, there were similar data in these parameters among BCR-ABL IS3m, halving time3m and V-BCR-ABL3m. Figure 1 showed the cumulative DMR rate according to the cutoff values in V-BCR-ABL1m and V-BCR-ABL3m. V-BCR-ABL1m 0.321 and V-BCR-ABL3m 0.018 separated best. Conclusion: These data strongly suggested that V-BCR-ABL1m,3m would be a significant landmark to predict DMR at 12 months as well as BCR-ABL IS1m,3m, halving time1m,3m. Among them, less than 0.321 in V-BCR-ABL1m was identified as an optimized predictive cutoff value of DMR at 12 months. Disclosures Ishida: Bristol-Myers Squibb: Honoraria.

Objectives: Patients with haematological malignancy who experience persistent fever and neutropenia often receive empirical antifungal therapy for the prevention and early treatment of invasive fungal infections. Micafungin (MCFG), a member of the echinocandin class of compounds, may be an effective alternative that is better tolerated than voriconazole (VRCZ). Methods: We conducted a randomised, cooperative group, open-label trial, comparing the efficacy and safety of micafungin with those of voriconazole as empirical antifungal therapy in febrile neutropenic patients with haematological malignancy. A successful outcome was defined as the fulfilment of all components of a 5-part composite endpoint. Results: Efficacy was evaluated in 100 patients (MCFG: 50, VRCZ: 50). Overall, favourable responses were observed in 52.0% of MCFG and 34.0% of VRCZ recipients (p = 0.069). There were no significant differences between the 2 groups in the rates of successful treatment of baseline fungal infection, absence of breakthrough fungal infection, survival for ≥7 days after treatment completion, or resolution of fever in the setting of neutropenia. Premature study discontinuation occurred less often in the MCFG group than in the VRCZ group (p = 0.001). Fewer patients who received MCFG experienced drug-related adverse events (p = 0.002). Conclusions: MCFG is as effective as and is generally better tolerated than VRCZ when given as empirical antifungal therapy in patients with persistent fever and neutropenia.

The t(11;18) (q21;q21) translocation is a characteristic chromosomal aberration in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type. We previously identified a YAC clone y789F3, which includes the breakpoint at 18q21 in a MALT lymphoma patient. BAC and PAC contigs were constructed on the YAC, and BAC 193f9 was found to encompass the breakpoint region. In the present study, we further narrowed down the breakpoint region at 18q21 in five MALT lymphoma patients by means of FISH and Southern blot analyses using the plasmid contig constructed from BAC 193f9. The breakpoints at 18q21 in three of the five MALT lymphoma patients were found to be clustered approximately within the 20 kb region. By using exon amplification and cDNA library screening, we identified a novel cDNA spanning the breakpoint region that exhibited aberrant mRNA signals in four of the five MALT lymphoma patients. The nucleotide sequence predicted an 813 amino acid protein that shows significant sequence similarity to the CD22beta and laminin 5 alpha3b subunit. We refer to the gene encoding this transcript as MALT1 (Mucosa-Associated Lymphoid Tissue lymphoma translocation gene 1). The alteration of MALT1 by translocation strongly suggests that this gene plays an important role in the pathogenesis of MALT lymphoma.

The breakpoint of the 18q21 translocation of B-cellnon-Hodgkin's lymphoma (NHL) cell line Karpas1106P was delineated by fluorescence in situ hybridization (FISH). Karpas1106P was derived from mediastinal lymphoblastic B-cell lymphoma and exhibited the immunophenotype characteristic of marginal-zone B-cell lymphoma (MZL): smIg+, pan-B antigen+, CD5−, CD10− and CD23−. The original G-banded karyotype showed a complex translocation containing t(X;18;13)(q28;q21;q12.1). Double-color FISH (DCFISH) with whole-chromosome-painting (WCP) probes for chromosomes X, 13 and 18, and 18q-specific yeast artificial chromosome (YAC) clones defined t(X;18;13) as ider(X)t(X;18;13)(q28;q12.3q21.1;q12.1). The immunoglobulin-heavy-chain (IgH) gene was not involved in the chromosomal translocation as detected by DCFISH with VH and Cγ probes. By using contiguous YAC clones mapped from 18q12.3 to q21.1, we identified a YAC clone y852H2 with its breakpoint at 18q21.1. In Karpas1106P, the distal part of chromosome 18 from the breakpoint (18q21.1-qter) was deleted, showing loss of heterozygosity of this region. In addition, the chromosomal segment 18q21.1 was duplicated and inserted to ider(X)t(X;18;13) between Xq28 and 13q12.1 with maintaining its original orientation. The DNA sequence of the breakpoint region contained in y852H2 can serve as a candidate locus for further molecular dissection to identify the causative gene of MZL. Int. J. Cancer 78:100–105, 1998.© 1998 Wiley-Liss, Inc.

SummaryWe have developed a new computerized system for measurement of quantitative bleeding time (QBT) to detect subtle abnormalities of primary hemostasis that are difficult to detect with the standard bleeding time determination. This new apparatus can simultaneously measure the bleeding time (BT; sec), amount of total blood loss (Tv; μl), maximum bleeding rate (Rmax; μl/sec) and bleeding pattern from the bleeding time incision. We have also developed a new holder for the Simplate that enables more consistent incisions and thus improves the reproducibility of the BT test.In this study, the newly developed QBT test was performed in 137 normal healthy volunteers and 10 patients having defined abnormalities of either primary or secondary hemostasis. Comparisons of the standard BT test and our QBT were made in 5 normal subjects and 7 thrombocytopenic patients. Additionally, 6 normal subjects were examined with both tests before and after administration of aspirin. Those results show that our QBT appears to be a more sensitive indicator of primary hemostasis than the standard BT method.

Background Dasatinib is a second-generation BCR-ABL inhibitor that has a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. The previous report from the global DASISION trial showed dasatinib resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan. Methods Eighty newly diagnosed CML-CP patients were include in this study. Patients received dasatinib 100mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Primary end point was the rate of major molecular response (MMR) by 12 months. MMR defined as a BCR-ABL transcript level of 0.1% or lower on the International scale by means of a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. Secondary end points were the rate of complete cytogenetic response (CCyR) by 12 months, the rate of MR4.5 (either (i) detectable disease with 32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) by 12 months and adverse events of dasatinib (UMIN #000006358). Results Eighty newly diagnosed CML-CP patients were included in this study. All except one patient administered dasatinib 100 mg once daily. One patient was withdrawal before administration of dasatinib. So far, there were 71 patients with 6 months follow-up and 51 patients with 12 months follow-up. The estimated MMR rates were 69.5 % (95%CI, 58.7-80.3 %) by 6 months and 82.7% (95%CI, 73.0-92.4 %) by 12 months. The estimated MR4.5 rates were 27.1 % (95%CI, 16.7-37.5 %) by 6 months and 48.9% (95%CI, 36.0-61.7 %) by 12 months. Only 6 patients were withdrawal because of adverse event (5 patients) and ineffectiveness (1 patient). Conclusion Dasatinib treatment results in higher rates of molecular responses in newly diagnosed CML-CP patients in Japan. Dasatinib as the first-line agent might be acceptable for CML-CP patients because of better clinical efficacy and less toxicity. Disclosures: No relevant conflicts of interest to declare.

Background Dasatinib is a highly potent BCR-ABL inhibitor, with a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. Across a series of phase II and III trials with more than 2 years of follow-up, dasatinib has demonstrated durable efficacy in patients with CML following resistance or intolerance to imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib resistance or intolerance CML. Methods Fifty- five CML-CP patients from 2009 to 2011 with resistance (n=40) or intolerance (n=26) to imatinib were registered to dasatinib administration (100mg once daily). Eleven among 26 patients with intolerance also showed resistance to imatinib at the registration. Imatinib resistance was defined as a lack of partial cytogenetical response at 3 months, a lack of complete cytogenetic response at 6 months or a lack of a major molecular response at 12 months of imatinib treatment. This criteria was identical to the criteria in ELN 2013 recommendation for first line. In another words, the resistance in this study means non-optimal criteria (warning and failure) of definition of the response to TKIs, first line, in ELN 2013 recommendation. Efficacy and safety were assessed using rates of major molecular response (MMR)/ MR4.5 (either (i) detectable disease with32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) at 12 months and drug-related adverse events (AEs) respectively. All analyses were based on the modified to intension-to treat. Results One patient was withdrawal before dasatinib administration. The median duration of imatinib therapy was 545 days. The overall incidence of MMR (primary endopoint) and MR4.5 at 12 months was 67.2% (95% confidence interval, 53.3-81.1%), and 20.2 % (95% CI, 8.4–32.0 %), respectively. Forty patients with resistance to imatinib, who were warning and failure patients judged by ELN 2013 criteria, were reassessed. Cumulative MMR and MR4.5 rate were 63.4% (95% CI: 46.3-80.6) and 18.0% (95% CI: 4.9-31.1) respectively at 12 months. Eleven patients, who showed more than 1% IS at 3 months of dasatinib treatment, did not reach to MMR at 12 months or discontinued dasatinib due to insufficient efficacy in this resistance cohort. However, progression to the accelerated or blastic phase had not been observed. When imatinib were changed to dasatinib, 5 patients showed the mutations, which were effective in dasatinib therapy. New mutations have not been observed during the treatment of dasatinib. Among 54 patients, most non-hematological AEs were in grade 1/2. including diarrhea (12.7%), rash (7.3%), myalgia (5.5%) and vomiting (3.6%). Grade 3/4 non-hematological AEs were infrequent, including decreased potassium (3.6%), and increased creatinine (3.6%). Grade 1/2 fluid retention AEs were shown in 9.1% of patients, including edema (3.6%). Pleural effusion, which was only in Grade 1/2, was shown in 32.7% of patients. Grade 3/4 hematological toxicities included anemia (7.3%) and thrombocytopenia (3.6 %). Only 3 patients have permanently discontinued dasatinib treatment due to AEs. Conclusions The patients with non-optimal responses (warning and failure) judged by ELN 2013 criteria should have early intervention to dasatinib, which is less toxicity in CML-CP patients. This intervention might induce good prognosis. The BCR-ABL1 IS less than 1% at 3 months of dasatinib administration will be the valuable landmark for outcome. Disclosures: No relevant conflicts of interest to declare.

This study attempted to determine the efficacy oflansoprazole plus clarithromycin therapy in the eradication of Helicobacter pylori in gastric ulcer patients. The influence of H. pylori eradication on healing and relapse of ulcers was also studied. Thirty-nine patients received either lansoprazole 30 mg daily for 8 weeks (group 1) or clarithromycin 200 mg twice daily for 2 weeks and lansoprazole 30 mg daily for 8 weeks (group 2). Before treatment, H. pylori status was evaluated by a rapid urease test and histologic examination. H. pylori clearance and eradication were evaluated by a rapid urease test, polymerase chain reaction, and a [ 13 C]urea breath test. Clearance of H. pylori was 0% in group 1 and was 33% in group 2. Eradication of H. pylori was 0% in group 1 and 21% in group 2. Although all five ulcers were healed in patients with H. pylori eradication, ulcers were not healed in the five patients without eradication. Relapse of ulcer was observed in three patients in whom eradication had failed. In this study, for H. pylori-positive gastric ulcer patients, better results were obtained when lansoprazole plus clarithromycin therapy was used, and H. pylori eradication was achieved.

Abstract 4444 Background: Dasatinib is highly potent BCR-ABL inhibitor, with 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. Across a series of phase II and III trials with more than 2 years of follow-up, dasatinib has demonstrated durable efficacy in patients with CML following resistance or intolerance to imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with imatinib resistance or intolerance in the Japanese population. Methods: 54 CML- CP patients (median age 63.5 years) with resistance, intolerance or a suboptimal response to imatinib were submitted to dasatinib 100mg once daily. Efficacy and safety were assessed using rates of major molecular response (MMR)/ complete molecular response (CMR) or drug-related adverse events (AEs) respectively. All analyses were based on the intension-treat principle. Results: Until now, the results of 32 patients, who passed more than 12 months, have been analysed. The median time since of prior imatinib therapy was 19.2 months with 57.4 % being imatinib-resistant and 42.6 % imatinib-intolerant. The incidence of MMR (primary endopoint) and complete molecular response at 12 months was 59.3 % (95% confidence interval, 45.0 – 72.4 %), and 24.1 % patients, respectively. Progression to the accelerated or blastic phase had not been observed. All patients with baseline samples tested for mutations, and different mutations were not observed. Non-hematological AEs were mostly grade 1/2. Grade 3/4 non-hematological AEs were infrequent, including increased AST (1.9%), and increased creatinine (1.9%), respectively. Grade 1/2 fluid retention adverse events were shown in 10 patients, including 2 patients with edema, and 9 patients with pleural effusion. Grade 3/4 hematological toxicities including anemia (1.9%), neutropenia (14.8%), and thrombocytopenia (9.3 %) were shown, and 13 patients have permanently discontinued treatment due to adverse effects. Conclusions: Dasatinib treatment results in high rate of molecular response in CML-CP patients with resistance or intolerance to imatinib, and approximately 60% of evaluated patients who switched to dasatinib achieved MMR at 12 months. Importantly, among all patients who achieved molecular response, 24.1 % patients achieved CMR. Dasatinib at a dose of 100 mg once daily was generally well-tolerated, and had better efficacy for patients with CML-CP post imatinib failure. Disclosures: No relevant conflicts of interest to declare.

Abstract 1062 Background: Invasive fungal infections (IFIs) incur significant morbidity and mortality among neutropenic patients after chemotherapy. The risk for these infections is related to the intensity and duration of neutropenia, and varies from 2% to 40%. Mortality rates associated with documented IFIs are considerable, reportedly ranging from 30% to 60%. Empirical antifungal therapy is the standard care for neutropenic patients with hematological malignancies who remain febrile despite broad-spectrum antibacterial treatment. Several antifungal agents including voriconazole (VRCZ) or liposomal amphotericin B (L-AMB) have been studied as empirical therapy for febrile neutropenia (FN). However, limited data are available concerning the efficacy of micafungin (MCFG) in FN patients with acute myeloid leukemia (AML). Methods: We conducted a randomized, cooperative group, open-label trial comparing MCFG (150 mg once daily) with VRCZ (6 mg/kg twice on day 1 followed by 4 mg/kg twice daily) as first-line empirical antifungal treatment for 95 hospitalized FN patients with AML during induction or consolidation chemotherapy (MCFG, 49; VRCZ, 46). The efficacy end point was a favorable overall response, as determined by a five-component end point according to the criteria of Walsh et al (N Engl J Med 2004; 351: 1391). Results: At the time of enrolment, there were no significant differences in the demographics or baseline characteristics between the two groups. The mean treatment duration for MCFG and VRCZ was 10 and 9 days, respectively. The efficacy rates of MCFG and VRCZ were not significantly different (37.8% vs. 32.4%). The rates of breakthrough fungal infections (proven, probable and possible IFIs), successful treatment of baseline fungal infections, survival 7 days after end of therapy, and resolution of fever during neutropenia were similar in the two groups. However, premature discontinuation of therapy occurred less often in the MCFG group than in the VRCZ group (32.4% vs. 55.9%, P=0.0457*). In safety evaluation, there were fewer adverse events in the MCFG group than in the VRCZ group (27.0% vs. 64.7%, P=0.0013*). *: Chi square test Conclusions: MCFG was as effective as VRCZ, and better tolerated than VRCZ as empirical antifungal therapy in FN patients with AML. Disclosures: No relevant conflicts of interest to declare.

To the Editor: Dierlamm et al[1][1] reported in the June 1 issue of Blood that an apoptosis inhibitor gene, API2 at 11q21, and a novel gene, MLT at 18q21, are involved in t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue (MALT) lymphoma.[1][1] We recently reported the results of a