A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with less than or equal to 30% blasts

Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6–43.9%)) vs AZA (14.3% (5.4–28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50–80%); AZA, 70% (50–80%)) or time to progression (PAN+AZA, 70% (40–90%); AZA, 70% (40–80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen

The blind men and the AML elephant:can we feel the progress?

The pharmacological therapy of non-promyelocytic acute myeloid leukemia (AML) has remained unchanged for over 40 years with an anthracycline–cytarabine combination forming the backbone of induction treatments. Nevertheless, the survival of younger patients has increased due to improved management of the toxicity of therapies including stem cell transplantation. Older patients and those with infirmity that precludes treatment-intensification have, however, not benefited from improvements in supportive care and continue to experience poor outcomes. An increased understanding of the genomic heterogeneity of AML raises the possibility of treatment-stratification to improve prognosis. Thus, efforts to identify agents with non-conventional anti-leukemic effects have paralleled those aiming to optimize leukemia cell-kill with conventional chemotherapy, resulting in a number of randomized controlled trials (RCT). In the last 18 months, RCTs investigating the effects of vosaroxin, azacitidine and gemtuzumab ozogamycin and daunorubicin dose have been reported with some studies indicating a statistically significant survival benefit with the investigational agent compared with standard therapy and potentially, a new era in AML therapeutics. Given the increasing costs of cancer care, a review of these studies, with particular attention to the magnitude of clinical benefit with the newer agents would be useful, especially for physicians treating patients in single-payer health systems

Serological profile of torque teno sus virus species 1 (TTSuV1) in pigs and antigenic relationships between two TTSuV1 genotypes (1a and 1b), between two species (TTSuV1 and -2), and between porcine and human anelloviruses

The family Anelloviridae includes human and animal torque teno viruses (TTVs) with extensive genetic diversity. The antigenic diversity among anelloviruses has never been assessed. Using torque teno sus virus (TTSuV) as a model, we describe here the first investigation of the antigenic relationships among different anelloviruses. Using a TTSuV genotype 1a (TTSuV1a) or TTSuV1b enzyme-linked immunosorbent assay (ELISA) based on the respective putative ORF1 capsid antigen and TTSuV1-specific real-time PCR, the combined serological and virological profile of TTSuV1 infection in pigs was determined and compared with that of TTSuV2. TTSuV1 is likely not associated with porcine circovirus-associated disease (PCVAD), because both the viral loads and antibody levels were not different between affected and unaffected pigs and because there was no synergistic effect of concurrent PCV2/TTSuV1 infections. We did observe a higher correlation of IgG antibody levels between anti-TTSuV1a and -TTSuV1b than between anti-TTSuV1a or -1b and anti-TTSuV2 antibodies in these sera, implying potential antigenic cross-reactivity. To confirm this, rabbit antisera against the putative capsid proteins of TTSuV1a, TTSuV1b, or TTSuV2 were generated, and the antigenic relationships among these TTSuVs were analyzed by an ELISA and by an immunofluorescence assay (IFA) using PK-15 cells transfected with one of the three TTSuV ORF1 constructs. The results demonstrate antigenic cross-reactivity between the two genotypes TTSuV1a and TTSuV1b but not between the two species TTSuV1a or -1b and TTSuV2. Furthermore, an anti-genogroup 1 human TTV antiserum did not react with any of the three TTSuV antigens. These results have important implications for an understanding of the diversity of anelloviruses as well as for the classification and vaccine development of TTSuVs

Differentiation syndrome in patients with acute promyelocytic leukemia treated with all- trans retinoic acid and anthracycline chemotherapy: Characteristics, outcome, and prognostic factors

Differentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all- trans retinoic acid (ATRA). Detailed knowl- edge about DS has remained limited. We present an analysis of the incidence, char- acteristics, prognostic factors, and out- come of 739 APL patients treated with ATRA plus idarubicin in 2 consecutive trials (Programa Espanol de Tratamientos en Hematologíc [PETHEMA] LPA96 and LPA99). Overall, 183 patients (24.8%) ex- perienced DS, 93 with a severe form (12.6%) and 90 with a moderate form (12.2%). Severe but not moderate DS was associated with an increase in mortality. A bimodal incidence of DS was observed, with peaks occurring in the first and third weeks after the start of ATRA therapy. A multivariate analysis indicated that a WBC count greater than 5 x 109/L and an abnor- mal serum creatinine level correlated with an increased risk of developing severe DS. Patients receiving systematic pred- nisone prophylaxis (LPA99 trial) in con- trast to those receiving selective prophy- laxis with dexamethasone (LPA96 trial) had a lower incidence of severe DS. Pa- tients developing severe DS showed a reduced 7-year relapse-free survival in the LPA96 trial (60% vs 85%, P = .003), but this difference was not apparent in the LPA99 trial

Time-dependent changes in mortality and transformation risk in MDS

In myelodysplastic syndromes (MDSs), the evolution of risk for disease progression or death has not been systematically investigated despite being crucial for correct interpretation of prognostic risk scores. In a multicenter retrospective study, we described changes in risk over time, the consequences for basal prognostic scores, and their potential clinical implications. Major MDS prognostic risk scoring systems and their constituent individual predictors were analyzed in 7212 primary untreated MDS patients from the International Working Group for Prognosis in MDS database. Changes in risk of mortality and of leukemic transformation over time from diagnosis were described. Hazards regarding mortality and acute myeloid leukemia transformation diminished over time from diagnosis in higher-risk MDS patients, whereas they remained stable in lower-risk patients. After approximately 3.5 years, hazards in the separate risk groups became similar and were essentially equivalent after 5 years. This fact led to loss of prognostic power of different scoring systems considered, which was more pronounced for survival. Inclusion of age resulted in increased initial prognostic power for survival and less attenuation in hazards. If needed for practicability in clinical management, the differing development of risks suggested a reasonable division into lower- and higher-risk MDS based on the IPSS-R at a cutoff of 3.5 points. Our data regarding time-dependent performance of prognostic scores reflect the disparate change of risks in MDS subpopulations. Lower-risk patients at diagnosis remain lower risk whereas initially high-risk patients demonstrate decreasing risk over time. This change of risk should be considered in clinical decision making

Effect of type and concentration of ballasting particles on sinking rate of marine snow produced by the Appendicularian Oikopleura dioica

Ballast material (organic, opal, calcite, lithogenic) is suggested to affect sinking speed of aggregates in the ocean. Here, we tested this hypothesis by incubating appendicularians in suspensions of different algae or Saharan dust, and observing the sinking speed of the marine snow formed by their discarded houses. We show that calcite increases the sinking speeds of aggregates by ~100% and lithogenic material by ~150% while opal only has a minor effect. Furthermore the effect of ballast particle concentration was causing a 33 m d(-1) increase in sinking speed for a 5×10(5) µm(3) ml(-1) increase in particle concentration, near independent on ballast type. We finally compare our observations to the literature and stress the need to generate aggregates similar to those in nature in order to get realistic estimates of the impact of ballast particles on sinking speeds

Differing clinical features between Japanese and Caucasian patients with myelodysplastic syndromes:Analysis from the International Working Group for Prognosis of MDS

Clinical features of myelodysplastic syndromes (MDS) could be influenced by many factors, such as disease intrinsic factors (e.g., morphologic, cytogenetic, molecular), extrinsic factors (e.g, management, environment), and ethnicity. Several previous studies have suggested such differences between Asian and European/USA countries. In this study, to elucidate potential differences in primary untreated MDS between Japanese (JPN) and Caucasians (CAUC), we analyzed the data from a large international database collected by the International Working Group for Prognosis of MDS (300 and 5838 patients, respectively). JPN MDS were significantly younger with more severe cytopenias, and cytogenetic differences: less del(5q) and more +1/+1q, -1/del(1p), der(1;7), -9/del(9q), del(16q), and del(20q). Although differences in time to acute myeloid leukemia transformation did not occur, a significantly better survival in JPN was demonstrated, even after the adjustment for age and FAB subtypes, especially in lower, but not in higher prognostic risk categories. Certain clinical factors (cytopenias, blast percentage, cytogenetic risk) had different impact on survival and time to transformation to leukemia between the two groups. Although possible confounding events (e.g., environment, diet, and access to care) could not be excluded, our results indicated the existence of clinically relevant ethnic differences regarding survival in MDS between JPN and CAUC patients. The good performance of the IPSS-R in both CAUC and JP patients underlines that its common risk model is adequate for CAUC and JP

Cytopenia levels for aiding establishment of the diagnosis of Myelodysplastic Syndromes

We recommend that standard hematologic values be used to define cytopenias in MDS and believe a modification of the WHO definition of cytopenias as 1 of the criteria (in addition to definitive morphologic and/or cytogenetic findings) to diagnose MDS would be valuable and most accurate

The European Hematology Association Roadmap for European Hematology Research: a consensus document

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients

Immunogenicity and pathogenicity of chimeric infectious DNA clones of pathogenic porcine circovirus type 2 (PCV2) and nonpathogenic PCV1 in weanling pigs

Porcine circovirus type 2 (PCV2) is the primary causative agent of postweaning multisystemic wasting syndrome (PMWS), whereas the ubiquitous porcine circovirus type 1 (PCV1) is nonpathogenic for pigs. We report here the construction and characterization of two chimeric infectious DNA clones of PCV1 and PCV2. The chimeric PCV1-2 clone contains the PCV2 capsid gene cloned in the backbone of the nonpathogenic PCV1 genome. A reciprocal chimeric PCV2-1 DNA clone was also constructed by replacing the PCV2 capsid gene with that of PCV1 in the backbone of the PCV2 genome. The PCV1, PCV2, and chimeric PCV1-2 and PCV2-1 DNA clones were all shown to be infectious in PK-15 cells, and their growth characteristics in vitro were determined and compared. To evaluate the immunogenicity and pathogenicity of the chimeric infectious DNA clones, 40 specific-pathogen-free (SPF) pigs were randomly assigned into five groups of eight pigs each. Group 1 pigs received phosphate-buffered saline as the negative control. Group 2 pigs were each injected in the superficial inguinal lymph nodes with 200 μg of the PCV1 infectious DNA clone. Group 3 pigs were each similarly injected with 200 μg of the PCV2 infectious DNA clone, group 4 pigs were each injected with 200 μg of the chimeric PCV1-2 infectious DNA clone, and group 5 pigs were each injected with 200 μg of the reciprocal chimeric PCV2-1 infectious DNA clone. As expected, seroconversion to antibodies to the PCV2 capsid antigen was detected in group 3 and group 4 pigs. Group 2 and 5 pigs all seroconverted to PCV1 antibody. Gross and microscopic lesions in various tissues of animals inoculated with the PCV2 infectious DNA clone were significantly more severe than those found in pigs inoculated with PCV1, chimeric PCV1-2, and reciprocal chimeric PCV2-1 infectious DNA clones. These data indicated that the chimeric PCV1-2 virus with the immunogenic ORF2 capsid gene of pathogenic PCV2 cloned into the nonpathogenic PCV1 genomic backbone induces a specific antibody response to the pathogenic PCV2 capsid antigen but is attenuated in pigs. Future studies are warranted to evaluate the usefulness of the chimeric PCV1-2 infectious DNA clone as a genetically engineered live-attenuated vaccine against PCV2 infection and PMWS