ALBERT

Description: Key Points Global survival rate was 74% at a median follow-up after HSCT of 57 months. Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome.

Description: Background: Invasive fungal infections (IFIs) incur significant morbidity and mortality in neutropenic patients with hematological malignancies (HEM) 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 HEM, 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 L-AMB (2.5 mg/kg once daily) as a first-line empirical antifungal treatment for 102 hospitalized FN patients with AML (MCFG, 53; L-AMB, 49). 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 L-AMB was 14.8 and 17.1 days, respectively. The efficacy rates of MCFG and L-AMB were not significantly different (58.5% vs. 44.9%, p = 0.1698*), evaluated based on: (1) successful treatment of baseline fungal infection (3/5cases (5.7%) vs. 0/1case (0%), p = 0.170*), (2) absence of breakthrough fungal infection (90.6% vs. 98.0%, p = 0.112*), (3) survival for ≥7 days after study completion (88.7% vs. 89.8%, p = 0.855*), (4) absence of premature study drug discontinuation due to poor efficacy or drug-related adverse events (67.9% vs. 75.5%, p = 0.396*), and (5) resolution of fever during neutropenia (66.0% vs. 55.1%, p = 0.258*). However, discontinuation due to drug-related adverse events occurred less frequently in the MCFG group (1.9% vs. 12.2%, p = 0.038*). In safety evaluation, adverse events of creatinine increase and hypokalemia were less often in the MCFG group than in the L-AMB group (9.4% vs. 26.5%, P=0.023*, 22.6% vs. 57.1%, P=0.0004*). *: Chi square test. Conclusions: MCFG was as effective as L-AMB, and better tolerated than L-AMB as an empirical antifungal therapy in FN patients with AML. Disclosures Ishida: Kyowa Hakko Kirin Co: Research Funding; Nippon Shinyaku Co: Research Funding; CHUGAI PHARMACEUTICAL CO: Research Funding; Astellas Pharma Inc.: Other: Astellas Pharma Inc. (Tokyo, Japan) supported this clinical study with a grant; the sponsor was not involved in the design of study, the enrollment of patients, the collection, analysis, interpretation of the data., Research Funding.

Description: Background: In vitro observations have indicated that preplatelets, which are anucleate discoid particles that can reversibly into proplatelet fragments, are one of platelet progenitos from cultured megakaryocytes (MKs) (Thon JN, et al. JBC 2010). Recently, we identified that bone marrow (BM) MKs form and release two types of platelet progenitors, using intra-vital imaging and ultra-structural analysis of mice BM (Kowata S, et al. Thrombosis and Haemostasis 2014). However, in vivo, how the platelet progenitors translate into individual platelets after leaving BM remains poorly understood. To elucidate whether platelet progenitors have an ability of conversion into individual platelets, we performed following experiments. Methods: We isolated platelet progenitors rich fraction from whole blood of enhanced green fluorescence protein (EGFP) transgenic mice by the centrifugation (100 g, 15 min) and bovine serum albumin gradient. Mature platelets were isolated from whole blood of EGFP mice by the centrrifugation (100 g, 15 min). In vivo: The freshly enriched progenitor rich fraction or mature platelets, both of which were positive for EGFP, was transfused into wild type mice. The peripheral blood was obtained and analyzed by flow cytometry continually. The EGFP positive mature platelets in platelet gate were counted. In vitro: The freshly enriched progenitor isolates were cultured in IMDM medium at 37°C. The continual change of their characteristics in the shape and size were assessed using fluorescent microscopy with high resolution. Time-lapse images of the processes were also captured. All animal procedures were approved by the Institutional Animal Care and Use Committee of Iwate Medical University. Results: The length and size of platelet progenitors were extremely varied (Fig. 1). The red, yellow, green, and dark blue segments in the bar chart indicate the platelet progenitors (5um). The frequency of platelet progenitor was 4% at normal condition (Fig. 1 graph on the left), but increased remarkably to 3-fold at recovery from acute thrombocytopenia (Fig.1 graphs in the middle). The maximum length of platelet progenitor was more than 200 µm (Fig. 1 picture in the top right). These data were consisted with the concept from our previous study of intra-vital imaging of BM MKs (Thrombosis and Haemostasis 2014). In vivo: Flow cytometric analysis showed that there was a time-dependent increase in EGFP platelet number in the gate of mature platelet, after the injection of EGFP positive platelet progenitor rich fraction. The control was carried out using EGFP positive mature platelets instead of platelet progenitors rich fraction. (mean ± SD, 0 h: 100%, 3h: 111 ± 6.8%, 6h: 105 ± 7.1% n=3, control 0 h: 100%, 3h: 101± 6.0%, 6h: 94 ± 5.2% n=3, Data were shown as % of the number of EGFP positive mature platelets at 0 h. P

Description: Lenalidomide (Len), an immunomodulatory drug, has significant clinical activity in patients with relapsed and refractory multiple myeloma (MM), and it is usually administered at a dose of 25 mg daily. For Len to exert its therapeutic effects with minimum adverse effects, it is important to determine the most suitable dosage on the basis of the physiques and body surface area (BSA) of patients. We investigated the relationship between pharmacokinetic variability of this drug and its toxicity and therapeutic efficacy. The institutional review boards and ethics committees at both participating centers approved the study protocol and all patients provided written informed consent. Thirteen Japanese patients with relapsed and refractory MM were enrolled in this study. They were treated with Len at 10-25 mg for 21 days every 4 weeks. The dose of Len administered to patients with renal dysfunction was reduced according to consensus statements on the optimal use of Len. Dexamethasone at 8-40 mg weekly was added to each drug cycle. Peripheral blood was collected three hours after Len administration in the first cycle and the plasma concentration of Len was evaluated using high performance liquid chromatography. Response and progression were assessed according to the International Myeloma Working Group criteria and the severity of adverse events was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. The median values of age (years) and estimated creatinine clearance (eCLcr, mL/min) of the 13 enrolled patients (male to female ratio=5:8) were 69 and 66.3, respectively. The number of patients in stages I, II, and III or the unknown stage of the International Staging System were 8, 1, 2, and 2, respectively. The number of the patients who achieved the best responses during three cycles of treatment were one (7.7%) in complete response, four (30.8%) in partial response, and eight (61.5%) in stable disease. The percentage of hematological adverse events (Grade 3/4) was 38.5% and no non-hematological events (Grade 3/4) were observed. The Len concentration ranged from 172.5 ng/mL to 555.6 ng/mL with a median concentration of 341.8 ng/mL. eCLcr values did not correlate with Len concentrations, but significantly correlated with C/D ratios (p

Description: BACKGROUND: Febrile neutropenia (FN) is often observed in hematological malignancy (HEM). Although most are considered to be due to bacterial infections, it is often difficult to specify the focuses and pathogens of infections in FN patients. Presepsin (Pre-SEP) is a subtype of soluble CD14, which is a receptor for lipopolysaccharide (LPS)/LPS-binding protein complexes and is expressed on the myeloid and monocytic cells' surface. Recently, Pre-SEP has been shown to be a useful biomarker for assessing the severity of sepsis. However, little is known about the biological characteristics of Pre-SEP in FN patients. Therefore, we compared the Per-CEP to the established infection markers including procalcitonin (PCT) and C-reactive protein (CRP) continually in FN patients. METHODS: We measured Pre-SEP concentration in the plasma, PCT and CRP on Day 0, 2, 4, 7 and 14 after the onset of FN and compared them to those of non-febrile neutropenic patients. Furthermore we evaluated the impact of Pre-SEP, PCT and CRP on the diagnosis and assessment of active infection status in FN, using the cut-off value by setting to 314 pg/ml, 0.50 ng/ml and 0.30 mg/ml. Correlation analysis was performed using Peason's correlation coefficient test. RESULTS: Sixty-two hospitalized FN patients with HEM (AML 14, ALL 9, MDS 14, NHL 13, MM 8, ATL 2, others 2 cases) were treated according to IDSA guideline. Figure 1 showed the each data in Pre-SEP, PCT and CRP value on day 0, 2, 4, 7 and 14. The frequency of less than the cut-off value at day 0 of FN onset were 33.8 %, 77.4 % and 37.1 % in Pre-SEP, PCT and CRP respectively, indicating that Pre-SEP showed the highest sensitivity. On day 0, a significant correlation was not observed between Pre-SEP and PCT (P=0.457, correlation coefficient: 0.096) but it was observed between Pre-SEP and CRP (P

Description: BACKGROUND: The overall survival of patients with newly diagnosed chronic myeloid leukemia (CML) has improved significantly since the introduction of tyrosine kinase inhibitors (TKIs), and recently, some patients with CML who achieve stable deep molecular response (DMR) to TKI therapy could safely suspend treatment. In addition to European LeukemiaNet criteria (ELN), the European Society for Medical Oncology (ESMO) proposed that less than 0.01% of BCR-ABL1 transcript (MR4.0) on the International Scale (IS) after 18 months is optimal for patients to achieve treatment-free remission. Branford et al. indicated that major molecular response (MMR; less than or equal to 0.1% of BCR-ABL1 IS ; MR3.0) at three months predicts stable undetectable BCR-ABL1 transcript levels during imatinib treatment. However, second-generation TKIs induce more rapid and deeper responses at early time points compared to imatinib; however, whether early molecular response predicts MR4.0 by 18 months to second-generation TKI therapy, remains unclear. AIMS: We retrospectively analyzed BCR-ABL1 transcript levels in patients with CML in chronic phase (CML-CP) at 3, 6, 12, and 18 months after initiating dasatinib treatment to identify molecular milestones that would predict MR4.0 by 18 months. METHODS: Fifty-nine newly diagnosed patients with CML-CP were included in this study. The median age was 61 years (18-81 years), 72% of whom were males, and patients older than 65 years comprised 31% of the overall enrollment. Eighty-six percent of them had low and intermediate Sokal scores. Patients received 100 mg of dasatinib once daily. Dose interruption or reduction was allowed if drug-related grade 3 non-hematological toxicity or grade 3 or worse hematological toxicity occurred.BCR-ABL1/ ABL ratio IS (BCR-ABL1 IS) was performed at approximately 3-month intervals. To assess the kinetics of response, we calculated halving time (HT) of BCR-ABL1 IS. HT-BCR-ABL1 was calculated as described by Branford et al. We used a receiver-operating characteristic (ROC) curve to identify the cut-offs in transcript levels at three and six months. Mann-Whitney test was used to determine statistical significance. Categorical variables were compared using Fisher's exact test. Factors were subjected to multivariate analysis using Cox regression; differences with p

Description: ALPS is characterized by chronic lymphoproliferation in combination with autoimmunity; mutations of molecules involved in FAS-dependent pathways play causative roles in this syndrome. The hallmarks of ALPS are an elevated CD4/CD8 double-negative T (DNT) cell count and attenuated induction of apoptosis by FAS stimulation. Autoimmune thrombocytopenia and/or hemolytic anemia are common in cases of ALPS; the combination of autoimmune thrombocytopenia and hemolytic anemia is referred to as Evans syndrome. ALPS is diagnosed in 47% of patients who present with Evans syndrome. Some patients with ALPS-like syndromes harbor mutations in RAS or PRKCD. In this study, we performed whole-exome analysis of undiagnosed patients exhibiting autoimmunity in combination with lymphoproliferation. Fifteen pediatric patients presenting with autoimmunity were enrolled in this study. Although not all of them fulfilled the diagnostic criteria of ALPS, most of them exhibited an ALPS-like phenotype, an autoimmune hematological disorder such as Evans syndrome, or immune thrombocytopenia with hepatosplenomegaly. Elevated counts of DNT cells among TCRαβ-positive cells were observed in some cases. All of the subjects screened negative for mutations in FAS, FASL, KRAS, and NRAS. These patients were subjected to whole-exome analysis, which revealed several mutations with known disease associations. One patient carried a mutation in CASP10, a causative gene for ALPS-CSAP (ALPS 2). This patient exhibited a typical ALPS phenotype with an elevated DNT cell count. In addition, we identified CTLA4 mutations in two patients, one of whom was described as ALPS type V (ALPS 5) and the other as CTLA4 haploinsufficiency with autoimmune infiltration (CHAI). A mutation in STAT3 was present in one patient. Dominant-negative mutations in the STAT3 gene result in hyper-IgE syndrome. Recently, an activating mutation of STAT3 was reported in infantile-onset multisystem autoimmune disease (ADMIO). It should be noted that an activating mutation of STAT3 results in a phenotype very similar to that of ALPS. Intriguingly, two autoinflammatory associated genes, PSTPIP1 and RNASEH2B were identified. Mutations in RNASEH2B causes Aicardi-Goutière syndrome (AGS), which phenotypically overlaps with SLE. Typical AGS develops as a results of biallelic mutations in causative genes. In this case, a heterozygous frame shift mutation was identified. Further evaluation is required to confirm whether this heterozygous frame shift mutation RNASEH2B really causes SLE or ALPS like symptoms. PSTPIP1 mutation causes pyogenic Arthritis, pyoderma gangrenosum and acne (PAPA) syndrome. The identified E250K mutation was one of the typical mutation in this disease. This patient exhibited SLE like symptom with hepatosplenomegaly without typical PAPA syndrome like symptoms, such as acne or pyoderma of the skin. Sequencing of the remaining patients yielded inconclusive results. The classical ALPS diagnostic procedure is well designed and suitable for identification of FAS-dependent apoptotic dysregulation. However, the measurement of FAS-dependent apoptosis requires technical skill, and the data quality is therefore dependent on the investigator. Moreover, RAS-associated ALPS-like disease (RALD, ALPS 3) and ALPS 5 (CHAI) cannot be identified by conventional ALPS diagnostic procedures. Therefore, the methods for diagnostic classification of these diseases need to be updated. It is interesting that mutations of autoinflammatory associated genes are involved in ALPS or SLE like patients. Our results reveal that a comprehensive genomic approach is a powerful tool for the characterization of ALPS or ALPS-like diseases. Together with recent progress in genome analysis in the PID field, our analyses provide an updated list of genes for use in differential diagnosis of ALPS-like diseases. This update will facilitate convenient genomic approaches such as comprehensive targeted sequencing focusing on genes involved in ALPS or ALPS-like diseases. This approach can be directly applied in the clinic to yield diagnostic benefits. Disclosures No relevant conflicts of interest to declare.

Description: BACKGROUND: Febrile neutropenia (FN) is often observed in patients with hematological malignancies (HEM), especially in those with acute leukemia (AL). Monotherapy with antipseudomonal beta-lactams, such as cefepime, carbapenem, or piperacillin-tazobactam, is recommended as first-line empiric antibacterial therapy in FN patients. The efficacy of meropenem (MEPM) as empiric monotherapy for FN patients with cancer has been assessed in randomized comparative trial against cefepime, imipenem/cilastain, ceftazidime with or without amikacin, and piperacillin-tazobactom. Because of those studies, MEPM is considered a standard antibiotic for the empiric treatment of FN patients with HEM.In contrast, doripenem (DRPM) is a relatively new carbapenem, and the clinical study about efficacy and safety of DRPM in FN patients with HEM is limited. Therefore, we conducted a randomized, cooperative group, open-label trial comparing DRPM (1.0 g every 8 hours) with MEPM (1.0 g every 8 hours) as the first-line empirical antibacterial therapy for high-risk FN patients with AL and myelodysplastic syndrome (MDS). METHODS: One hundred and thirty-three hospitalized patients with acute leukemia or high-risk myelodysplastic syndrome, who developed high-risk FN during or after chemotherapy (AML 77, ALL 43, APL 9, ATL 1, MDS (RAEB-2) 3cases) were randomized to each drug group (DRPM, 65; MEPM, 68). The study drug was started to administer as a mono-therapy and continued at least for 5 days without drug toxicity, and the efficacy and safety were evaluated. RESULTS: The success rate (Resolution of fever within 3 to 5 days without treatment modification: the primary endpoint) was higher in the DRPM group than in the MEPM group (60.0% vs. 45.6%), although the difference was not significant (P = 0.136). However, resolution of fever within 7 days of treatment was significantly higher in the DRPM group than in the MEPM group (78.4% vs. 60.2%, respectively, P = 0.037). Otherwise, the cumulative number of afebrile cases by day14 was 87.7% and 83.8% in the DRPM and MEPM group, respectively (P = 0.523). The success rate did not depend on neutrophil recovery: success rates for the DRPM group were 58.3% and 60.9%, with and without neutrophil recovery, respectively; success rates for the MEPM group were 33.3% and 40.9%, with and without neutrophil recovery, respectively (P = 0.233, P = 0.346). In all, 40.0% of the DRPM group and 32.3% of the MEPM group received anti-MRSA agent, as empiric or targeted antibacterial therapy of persistent or recurrent fever considering of infections by gram-positive bacteria, including methicillin-resistant species. Antifungal medications were added to 21.5% of the DRPM group and 13.2% of the MEPM group, as empiric or preemptive therapy of persistent or recurrent fevers believed to be caused by fungal infections. Survival rates at 30 days after the start of administration were 98.5% and 100% in the DRPM and MEPM group, respectively (P = 0.304). The rates of adverse events did not significantly differ between the DRPM and MEPM group (38.5% vs. 41.2%, respectively, P = 0.749), and these adverse events were clinically acceptable in the two groups, and most of patients could continue the treatment by both study drugs. CONCLUSIONS: Our clinical study suggested that DRPM had the non-inferiority of efficacy in comparison with MEPM as the first-line therapy in high-risk FN patients with AL and MDS, and both drugs could be well tolerated clinically. Disclosures Oyake: Kyowa-Hakko Kirin: Honoraria; Celgene: Honoraria; Chugai: Honoraria; Astellas: Speakers Bureau. Hanamura:Sanofi: Research Funding; Taiho: Research Funding; MSD: Research Funding; Chugai: Research Funding; Eli Lilly: Research Funding; Fujimoto: Research Funding; Zenyaku: Research Funding; Yamada Yohojo: Research Funding; Chugai: Research Funding; Astellas: Research Funding; Shionogi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria; Mundi: Honoraria; Nihon Shinyaku: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Ito:Bristol-Myers Squibb: Honoraria; Ono: Honoraria; Celgene: Honoraria.