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The bromodomain (BRD) and extraterminal (BET) proteins including BRD2, BRD3 and BRD4 have been identified as key targets for leukemia maintenance. A novel oral inhibitor of BRD2/3/4, the thienotriazolodiazepine compound OTX015, suitable for human use, is available. Here we report its biological effects in AML and ALL cell lines and leukemic samples. Exposure to OTX015 lead to cell growth inhibition, cell cycle arrest and apoptosis at submicromolar concentrations in acute leukemia cell lines and patient-derived leukemic cells, as described with the canonical JQ1 BET inhibitor. Treatment with JQ1 and OTX15 induces similar gene expression profiles in sensitive cell lines, including a c-MYC decrease and an HEXIM1 increase. OTX015 exposure also induced a strong decrease of BRD2, BRD4 and c-MYC and increase of HEXIM1 proteins, while BRD3 expression was unchanged. c-MYC, BRD2, BRD3, BRD4 and HEXIM1 mRNA levels did not correlate however with viability following exposure to OTX015. Sequential combinations of OTX015 with other epigenetic modifying drugs, panobinostat and azacitidine have a synergic effect on growth of the KASUMI cell line. Our results indicate that OTX015 and JQ1 have similar biological effects in leukemic cells, supporting OTX015 evaluation in a Phase Ib trial in relapsed/refractory leukemia patients.

The bromodomain and extra-C-terminal domain (BET) protein family is a class of epigenetic readers that recognize acetyl-lysine residues of histones, and their targeting with small molecules is a novel therapeutic approach [[1]]. Cell cycle and apoptosis induction were evaluated in a subset of cell lines, including two resistant models (NALM1, K562) after 48-h treatments with 500 nM OTX015 (Figure 1(A)). Similarly, OTX015 significantly down-regulated I MTHFD1L i and I BCL2 i in all leukemic cell lines after 4 or 24 h of treatment, in a similar manner as I MYC i , although the effect on I BCL2 i appeared reversible in three nonresistant cell lines (Figure S2). We then evaluated the downstream effects of OTX015 (500 nM) combined with azacitidine (3 µM) or panobinostat (20 nM) in sensitive and resistant OTX015 cell lines. [Extracted from the article]

Infections are a major complication in patients with acute myeloid leukemia undergoing intensive chemotherapy. They remain a major cause of therapy-associated morbidity and mortality, and represent a frequent cause of treatment withdrawal. An analysis of the medical charts of 459 younger adults included in the multicenter Acute Leukemia French Association (ALFA)-9802 trial showed that 1369 febrile episodes occurred among the 459 registered patients, including fever without identifiable source (23%) and clinically or microbiologically documented infections (77%). Bloodstream infections occurred in 314 episodes, including 129 documented episodes with Gram-positive and 96 with Gram-negative pathogens. Pulmonary infection was diagnosed in 144/1054 documented infectious episodes (14%). Invasive fungal infection was probable or proven in 116 patients. In all, 15 patients died of infection-associated complications, of whom seven died during early induction therapy, one during salvage therapy and seven during consolidation therapy. Better supportive care strategies may improve overall survival in patients undergoing chemotherapy for acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

Several reports of successful empirical treatment of idiopathic hypereosinophilic syndrome with imatinib led to the recent identification of the FIP1L1–PDGFRA fusion gene rearrangement, which characterizes a distinctive group of chronic eosinophilic leukemias. This fusion gene can be detected in eosinophils, neutrophils, mast cells, T cells, B cells and monocytes in FIP1L1–PDGFRA-positive hypereosinophilic patients suggesting a multilineage involvement. Furthermore, the same FIP1L1–PDGFRA rearrangement was identified in patients with hypereosinophilia and atypical mast cell proliferations, raising the question of a disease with two concomitant lines of differentiation. In addition, a recent report noted two cases with the association of FIP1L1–PDGFRA-positive chronic eosinophilic leukemia and T-cell lymphoblastic lymphoma (T-LBL). We report here the only third case of synchronous chronic eosinophilic leukemia and T-LBL, both associated with a FIP1L1–PDGFRA fusion transcript, confirming the occurrence of such disease and suggesting a clonal proliferation with two lines of differentiation probably arising from a primitive multipotent medullary stem cell. [ABSTRACT FROM AUTHOR]

From 1968 to 1993, 179 newly diagnosed patients with polycythemia vera (PV) were enrolled in a prospective study using pipobroman as first chemotherapy. Among them, 140 fulfilled the Polycythemia Vera Study Group criteria for PV, and 39 patients (22%) can be considered as idiopathic erythrocytosis (IE). Vascular events occurred in 10% of IE and 20% of PV patients and solid tumors in 7.7% of IE and 12.8% of PV patients. There were no differences between PV and IE patients with regard to progression to myelofibrosis (MF), leukemic events and overall survival. Overall, 98.3% of patients initially responded to pipobroman, with very mild toxicity. A total of 164 PV patients who received more than 1 year of pipobroman were analyzed for long-term evolution. The actuarial risk of thrombosis was 15.6 and 23.8% at 10 and 18 years, respectively. In all, 21 patients developed a solid tumor during follow-up, added and/or switched drugs being a risk factor. Actuarial risk of MF was as low as 4.9 and 9.4% at 10 and 15 years, respectively. Actuarial risk of leukemia was 14.4 and 18.7% at 10 and 15 years, respectively. Hyperleukocytosis at diagnosis was the only variable significantly associated with higher risk of leukemia. The median survival was 15.5 years, with two initial adverse prognostic factors: age above 60 years and hyperleukocytosis. Despite an increasing risk of leukemia with time, survival was not lower when compared to the French matched population. Only age and hyperleukocytosis at diagnosis were found to have a prognostic value in PV. [ABSTRACT FROM AUTHOR]

In spite of the recent improvement in the outcome of acute promyelocytic leukaemia (APL) with treatment combining all trans retinoic acid (ATRA) and chemotherapy (CT), some patients with this disease still have a poor outcome. The prognostic significance of chromosomal abnormalities in addition to t(15;17) in APL is uncertain. We examined the prognostic significance of secondary chromosomal changes in 292 patients included in a European trial who were treated with ATRA and CT. The incidence of chromosomal abnormalities in addition to t(15;17) was 26% and trisomy 8 was the most frequent secondary change (46% of the cases with secondary changes). No significant differences were seen with regard to age, sex, initial white blood cell count, % of circulating blasts, platelet count, fibrinogen level and incidence of microgranular variants between patients with or without additional rearrangements. Outcome was also similar between patients with t(15;17) alone and patients with t(15;17) and other clonal abnormalities for complete remission (92% vs. 93% respectively), event-free survival at 2 years (76·1% vs. 78·1% respectively), relapse at 2 years (16·7% vs. 11·6% respectively) and overall survival at 2 years (79·9% vs. 79·5% respectively). Analysis according to the type of induction treatment (ATRA followed by CT or ATRA plus CT) or the type of maintenance treatment (with ATRA, low-dose CT or both) also failed to show any difference between the two groups. Thus, in a large cohort of APL patients treated with ATRA and CT, additional chromosomal abnormalities had no impact on prognosis. [ABSTRACT FROM AUTHOR]

The article presents information on a study which showed that the outcome of high risk myelodysplastic syndrome (MDS) after azacitidine (AZA) failure. The study the outcome of 74 patients with secondary acute myeloid leukaemia (AML) after AZA treatment failure, collected from two Johns Hopkins University trials and the French AZA compassionate programme.

To assess the value of administering timed-sequential chemotherapy (TSC; 2 therapeutic sequences separated by a 4-day interval-free chemotherapy) or high-dose cytarabine (HDAraC) cycles in consolidation therapy for acute myeloid leukemia (AML), 459 patients 15 to 50 years of age were enrolled in the prospective randomized Acute Leukemia French Association-9802 trial. Complete remission was achieved in 89%. A total of 237 patients were then randomized to either TSC consolidation (120 patients) or HDAraC consolidation cycles (117 patients). Overall, there was no significant difference between the 2 consolidation arms (5-year event-free survival [EFS]: 41% for HDAraC vs 35% for TSC), or cumulative incidence of relapse, or treatment-related mortality. Cytogenetically normal AML NPM1+ or CEBPA+ and FLT3-ITD- had the same outcome as those with favorable cytogenetics. When considering favorable and unfavorable risk groups, the trend was in favor of HDAraC. However, the difference became significant when considering intermediate cytogenetics (5-year EFS: 49% vs 29%; P = .02), especially cytogenetically normal AML (5-year EFS: 48% vs 31%; P = .04), which was related to lower relapse rate and less toxicity. This study demonstrates that TSC did not produce any benefit when used as consolidation therapy in younger adults compared with HDAraC. This trial was registered at www.clinicaltrials.gov as #NCT00880243. [ABSTRACT FROM AUTHOR]

Bromodomain and Extra-Terminal inhibitors (BETi) such as OTX015 are active in Acute Myeloid Leukaemias (AML). Their activity on Leukemic Stem Cells (LSCs) is less documented. We interrogated the anti-LSC activity of OTX015 in a niche-like long-term culture in 26 primary AML samples and validated our findings in vivo. OTX015 impaired LSCs in AMLs harbouring Core Binding Factor or KMT2A gene fusions, NPM1 or chromatin/spliceosome genes mutations, but not in those with aneuploidy/TP53 mutations. In four patients, we dissected the transcriptomic footprint of Bet inhibition on LSCs versus blasts. Our results can instruct future clinical trials of BETi in AML. [ABSTRACT FROM AUTHOR]