Summary Background Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this ...treatment combination provided greater survival benefit than did chlorambucil or fludarabine. Methods 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. Findings There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38% vs 15%, respectively; overall response rate 94% vs 80%, respectively; p<0·0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0·006 and 0·04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0·00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (VH ) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. Interpretation Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.
ABSTRACT
We have performed simulations of cluster formation along two regions of a spiral arm taken from a global Milky Way simulation, including photoionizing feedback. One region is characterized ...by strongly converging flows, the other represents a more typical spiral arm region. We find that more massive clusters are able to form on shorter time-scales for the region with strongly converging flows. Mergers between clusters are frequent in the case of the strongly converging flows and enable the formation of massive clusters. We compare equivalent clusters formed in simulations with and without ionization. Photoionization does not prevent massive cluster formation, but can be seen to limit the masses of the clusters. On average, the mass is reduced by around 20 per cent, but we see a large spread from ionization having minimal difference to leading to a 50 per cent reduction in mass. Photoionization is also able to clear out the gas in the vicinity of the clusters on Myr time-scales, which can produce clusters with larger radii that are surrounded by more massive stellar haloes. We find that the ionizing feedback has more impact in our second region that is less dense and has less strongly converging flows.
Abstract
We compare the properties of clouds in simulated M33 galaxies to those observed in the real M33. We apply a friends of friends algorithm and CPROPS to identify clouds, as well as a ...pixel-by-pixel analysis. We obtain very good agreement between the number of clouds, and maximum mass of clouds. Both are lower than occurs for a Milky Way-type galaxy and thus are a function of the surface density, size, and galactic potential of M33. We reproduce the observed dependence of molecular cloud properties on radius in the simulations, and find this is due to the variation in gas surface density with radius. The cloud spectra also show good agreement between the simulations and observations, but the exact slope and shape of the spectra depend on the algorithm used to find clouds, and the range of cloud masses included when fitting the slope. Properties such as cloud angular momentum, velocity dispersions, and virial relation are also in good agreement between the simulations and observations, but do not necessarily distinguish between simulations of M33 and other galaxy simulations. Our results are not strongly dependent on the level of feedback used here (10 and 20 per cent) although they suggest that 15 per cent feedback efficiency may be optimal. Overall our results suggest that the molecular cloud properties are primarily dependent on the gas and mass surface density, and less dependent on the localized physics such as the details of stellar feedback, or the numerical code used.
ABSTRACT
We present simulations of the formation and evolution of clusters in spiral arms. The simulations follow two different spiral arm regions, and the total gas mass is varied to produce a range ...of different mass clusters. We find that including photoionizing feedback produces the observed cluster mass–radius relation, increasing the radii of clusters compared to without feedback. Supernovae have little impact on cluster properties. We find that in our high-density, high gas mass simulations, star formation is less affected by feedback, as star formation occurs rapidly before feedback has much impact. In our lowest gas density simulation, the resulting clusters are completely different (e.g. the number of clusters and their masses) from the case with no feedback. The star formation rate is also significantly suppressed. The fraction of stars in clusters in this model decreases with time flattening at about 20 per cent. In our lowest gas simulation model, we see the formation of a star-forming group with properties similar to an OB association, in particular similar to Orion Ia. We suggest that low densities and stronger initial dynamics are conducive to forming associations rather than clusters. In all models, cluster formation is complex with clusters merging and splitting. The most massive clusters that form have tended to undergo more mergers.
Detection of minimal residual disease (MRD) in chronic lymphocytic leukaemia (CLL) is becoming increasingly important as treatments improve. An internationally harmonised four-colour (CLR) flow ...cytometry MRD assay is widely used but has limitations. The aim of this study was to improve MRD analysis by identifying situations where a less time-consuming CD19/CD5/κ/λ analysis would be sufficient for detecting residual CLL, and develop a six-CLR antibody panel that is more efficient for cases requiring full MRD analysis. In 784 samples from CLL patients after treatment, it was possible to determine CD19/CD5/κ/λ thresholds that identified cases with detectable MRD with 100% positive predictive value (PPV). However, CD19/CD5/κ/λ analysis was unsuitable for predicting iwCLL/NCI response status or identifying cases with no detectable MRD. For the latter cases requiring a full MRD assessment, a six-CLR assay was designed comprising CD19/CD5/CD20 with (1) CD3/CD38/CD79b and (2) CD81/CD22/CD43. There was good correlation between four-CLR and six-CLR panels in dilution studies and clinical samples, with 100% concordance for detection of residual disease at the 0.01% (10(-4)) level (n=59) and good linearity even at the 0.001-0.01% (10(-5)-10(-4)) level. A six-CLR panel therefore provides equivalent results to the four-CLR panel but it requires fewer reagents, fewer cells and a much simpler analysis approach.
ABSTRACT
Far-ultraviolet (FUV) radiation greatly exceeds UV, supernovae (SNe), and winds in the energy budget of young star clusters but is poorly modelled in galaxy simulations. We present results ...of the first isolated galaxy disc simulations to include photoelectric heating of gas via dust grains from FUV radiation self-consistently, using a ray-tracing approach that calculates optical depths along the source–receiver sightline. This is the first science application of the TREVR radiative transfer algorithm. We find that FUV radiation alone cannot regulate star formation. However, FUV radiation produces warm neutral gas and is able to produce regulated galaxies with realistic scale heights. FUV is also a long-range feedback and is more important in the outer discs of galaxies. We also use the superbubble feedback model, which depends only on the SN energy per stellar mass, is more physically realistic than common, parameter-driven alternatives and thus better constrains SN feedback impacts. FUV and SNe together can regulate star formation without producing too much hot ionized medium and with less disruption to the interstellar medium compared to SNe alone.
ABSTRACT
The SEDIGISM (Structure, Excitation and Dynamics of the Inner Galactic Interstellar Medium) survey used the APEX telescope to map 84 deg2 of the Galactic plane between ℓ = −60° and +31° in ...several molecular transitions, including 13CO (2 – 1) and C18O (2 – 1), thus probing the moderately dense (∼103 cm−3) component of the interstellar medium. With an angular resolution of 30 arcsec and a typical 1σ sensitivity of 0.8–1.0 K at 0.25 km s−1 velocity resolution, it gives access to a wide range of structures, from individual star-forming clumps to giant molecular clouds and complexes. The coverage includes a good fraction of the first and fourth Galactic quadrants, allowing us to constrain the large-scale distribution of cold molecular gas in the inner Galaxy. In this paper, we provide an updated overview of the full survey and the data reduction procedures used. We also assess the quality of these data and describe the data products that are being made publicly available as part of this First Data Release (DR1). We present integrated maps and position–velocity maps of the molecular gas and use these to investigate the correlation between the molecular gas and the large-scale structural features of the Milky Way such as the spiral arms, Galactic bar and Galactic Centre. We find that approximately 60 per cent of the molecular gas is associated with the spiral arms and these appear as strong intensity peaks in the derived Galactocentric distribution. We also find strong peaks in intensity at specific longitudes that correspond to the Galactic Centre and well-known star-forming complexes, revealing that the 13CO emission is concentrated in a small number of complexes rather than evenly distributed along spiral arms.
We study the evolution of galactic magnetic fields using 3D smoothed particle magnetohydrodynamics (SPMHD) simulations of galaxies with an imposed spiral potential. We consider the appearance of ...reversals of the field, and amplification of the field. We find that magnetic field reversals occur when the velocity jump across the spiral shock is above ≈20 km s−1, occurring where the velocity change is highest, typically at the inner Lindblad resonance in our models. Reversals also occur at corotation, where the direction of the velocity field reverses in the corotating frame of a spiral arm. They occur earlier with a stronger amplitude spiral potential, and later or not at all with weaker or no spiral arms. The presence of a reversal at radii of around 4–6 kpc in our fiducial model is consistent with a reversal identified in the Milky Way, though we caution that alternative Galaxy models could give a similar reversal. We find that relatively high resolution, a few million particles in SPMHD, is required to produce consistent behaviour of the magnetic field. Amplification of the magnetic field occurs in the models, and while some may be genuinely attributable to differential rotation or spiral arms, some may be a numerical artefact. We check our results using athena, finding reversals but less amplification of the field, suggesting that some of the amplification of the field with SPMHD is numerical.
Summary Background Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not ...suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options. Methods We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m2 ) on days 1–7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov , number NCT00748189. Findings We enrolled 447 patients, median age 69 years (range 35–92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0–25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6–13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45–0·72; p<0·0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 50% patients; vs 98 43% given chlorambucil alone), with neutropenia being the most common event (56 26% vs 32 14%). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group. Interpretation Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy. Funding GlaxoSmithKline, Genmab A/S.
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