Novel agents for acute myeloid leukemia

Acute myeloid leukemia (AML) is a complex hematological disease characterized by genetic and clinical heterogeneity. Recent advances in the understanding of AML pathogenesis have paved the way for the development of new agents targeting specific molecules or mechanisms that contribute to finally move beyond the current standard of care, which is \u201c3 + 7\u201d regimen. In particular, new therapeutic options such as targeted therapies (midostaurin and enasidenib), monoclonal antibodies (gemtuzumab ozogamicin), and a novel liposomal formulation of cytarabine and daunorubicin (CPX-351) have been recently approved, and will be soon available for the treatment of adult patients with AML. In this review, we will present and describe these recently approved drugs as well as selected novel agents against AML that are currently under investigation, and show the most promising results as monotherapy or in combination with chemotherapy. The selection of these emerging treatments is based on the authors\u2019 opinion

The most luminous blue quasars at 3.0<z<3.3. II. CIV/X-ray emission and accretion disc physics

We analyse the properties of the CIV broad emission line in connection with the X-ray emission of 30 bright SDSS quasars at z~3.0-3.3 with pointed XMM-Newton observations, which were selected to test the suitability of AGN as cosmological tools. In our previous work, we found that a large fraction (~25%) of the quasars in this sample are X-ray underluminous by factors of >3-10. As absorbing columns of >10$^{23}$ cm$^{-2}$ can be safely ruled out, their weakness is most likely intrinsic. Here we explore possible correlations between the UV and X-ray features of these sources to investigate the origin of X-ray weakness. We fit their UV SDSS spectra and analyse their CIV properties (e.g., equivalent width, EW; line peak velocity, $\upsilon_{\rm peak}$) as a function of the X-ray photon index and 2-10 keV flux. We confirm the trends of CIV $\upsilon_{\rm peak}$ and EW with UV luminosity at 2500 angstrom for both X-ray weak and X-ray normal quasars, as well as the correlation between X-ray weakness and CIV EW. In contrast to some recent work, we do not observe any clear relation between the 2-10 keV luminosity and $\upsilon_{\rm peak}$. We find a correlation between the hard X-ray flux and the integrated CIV flux for X-ray normal quasars, whilst X-ray weak quasars deviate from the main trend by more than 0.5 dex. We argue that X-ray weakness might be interpreted in a starved X-ray corona picture associated with an ongoing disc-wind phase. If the wind is ejected in the vicinity of the black hole, the extreme-UV radiation that reaches the corona will be depleted, depriving the corona of seeds photons and generating an X-ray weak quasar. Yet, at the largest UV luminosities (>10$^{47}$ erg s$^{-1}$), there will still be an ample reservoir of ionising photons that can explain the excess CIV emission observed in the X-ray weak quasars with respect to normal sources of similar X-ray luminosities.Comment: 22 pages, 15 figures (with 3 more figures in the Appendix), abstract abridged. Accepted for publication in A&

Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia.

BACKGROUND: The prophylactic use of fluoroquinolones in patients with cancer and neutropenia is controversial and is not a recommended intervention. METHODS: We randomly assigned 760 consecutive adult patients with cancer in whom chemotherapy-induced neutropenia (<1000 neutrophils per cubic millimeter) was expected to occur for more than seven days to receive either oral levofloxacin (500 mg daily) or placebo from the start of chemotherapy until the resolution of neutropenia. Patients were stratified according to their underlying disease (acute leukemia vs. solid tumor or lymphoma). RESULTS: An intention-to-treat analysis showed that fever was present for the duration of neutropenia in 65 percent of patients who received levofloxacin prophylaxis, as compared with 85 percent of those receiving placebo (243 of 375 vs. 308 of 363; relative risk, 0.76; absolute difference in risk, -20 percent; 95 percent confidence interval, -26 to -14 percent; P=0.001). The levofloxacin group had a lower rate of microbiologically documented infections (absolute difference in risk, -17 percent; 95 percent confidence interval, -24 to -10 percent; P<0.001), bacteremias (difference in risk, -16 percent; 95 percent confidence interval, -22 to -9 percent; P<0.001), and single-agent gram-negative bacteremias (difference in risk, -7 percent; 95 percent confidence interval, -10 to -2 percent; P<0.01) than did the placebo group. Mortality and tolerability were similar in the two groups. The effects of prophylaxis were also similar between patients with acute leukemia and those with solid tumors or lymphoma. CONCLUSIONS: Prophylactic treatment with levofloxacin is an effective and well-tolerated way of preventing febrile episodes and other relevant infection-related outcomes in patients with cancer and profound and protracted neutropenia. The long-term effect of this intervention on microbial resistance in the community is not known

A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia patients. Final results of the GIMEMA LAL1509 protocol

The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Ph+ acute lymphoblastic leukemia patients, was based on a dasatinib plus steroids induction - with central nervous system prophylaxis - followed by dasatinib alone in patients in complete molecular response or chemotherapy and/or allogeneic transplantation in patients not reaching a complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and 9 p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved a complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained a complete molecular response. Among non-complete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months, range 3-40.1), 13 during consolidation and 4 post-transplant. ABL1 mutations (5 T315I, 3 V299L, 1 E281K and 1 G254E) were found in 10/13 relapsed cases. With a median follow-up of 57.4 months (range: 4.2-75.6), overall survival and disease-free survival are 56.3% and 47.2%. A better diseasefree survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (p=0.005 and p=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemo-free induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up. EudraCT 2010-019119-39

Loss of heterozygosity in acute leukemia: evidence of frequent submicroscopic deletions

Although chromosomal abnormalities are detected by conventional cytogenetic analysis (CCA) in 40–60% of patients with acute myeloid leukemia (AML), cryptic chromosomal deletions may only be detected by molecular analysis. To determine their frequency, we studied 74 cases of AML by microsatellite allelotype assay using 35 microsatellites spanning eight chromosomal regions known to be frequently involved in AML. In 42 (57%) we found DNA imbalance at the screened loci. This was detected by CCA only in 4 cases. Our data show that cryptic deletions are a common event in AML

ERK1/2 phosphorylation is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia

Abstract Extracellular signal-regulated kinase-1/2 (ERK1/2) is frequently found constitutively activated (p-ERK1/2) in hematopoietic diseases, suggesting a role in leukemogenesis. The aim of this study was to assess the expression and clinical role of p-ERK1/2 in adult acute lymphoblastic leukemia (ALL). In 131 primary samples from adult de novo ALL patients enrolled in the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) Leucemia Acute Linfoide (LAL) 2000 protocol and evaluated by flow cytometry, constitutive ERK1/2 activation was found in 34.5% of cases; these results were significantly associated with higher white blood cell (WBC) values (P = .013). In a multivariate analysis, p-ERK1/2 expression was an independent predictor of complete remission achievement (P = .027). Effective approaches toward MEK inhibition need to be explored in order to evaluate whether this may represent a new therapeutic strategy for adult ALL patients

Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults

BACKGROUND: Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment.METHODS: We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment.RESULTS: Of the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [i.e., IKZF1 plus]). ABL1 mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%).CONCLUSIONS: A chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.)

Measuring supermassive black holes with gas kinematics: the active S0 galaxy NGC 3998

We present results from a kinematical study of the gas in the nucleus of the active S0 galaxy NGC 3998 obtained from archival HST/STIS long-slit spectra. We analyzed the emission lines profiles and derived the map of the gas velocity field. The observed velocity curves are consistent with gas in regular rotation around the galaxy's center. By modeling the surface brightness distribution and rotation curve of the H_alfa emission line we found that the observed kinematics of the circumnuclear gas can be accurately reproduced by adding to the stellar mass component a compact dark mass (black hole) of M_bh = 2.7(-2.0,+2.4) 10**8 M_sun (uncertainties at a 2 sigma level); the radius of its sphere of influence (R_sph ~ 0".16) is well resolved at the HST resolution. The BH mass estimate in NGC 3998 is in good agreement with both the M_bh vs. M_bul (with an upward scatter by a factor of ~2) and M_bh vs. sigma correlations (with a downward scatter by a factor of ~3-7, depending on the form adopted for the dependence of M_bh on sigma). Although NGC 3998 cannot be considered as an outlier, its location with respect to the M_bh-sigma relation conforms with the trend suggesting the presence of a connection between the ``residuals'' from the M_bh-sigma correlation and the galaxy's effective radius. In fact, NGC 3998 has one of the smallest values of R_e among the galaxies with measured M_bh (0.85 kpc) and it shows a negative residual. This suggests that a combination of both sigma and R_e is necessary to drive the correlations between M_bh and other bulge properties, an indication for the presence of a black holes ``fundamental plane''.Comment: Accepted for publication in A&

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL 6560 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and \u3b3-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade 653, 18.2%) and 27.3% (grade 653, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.gov as #NCT01641107