The spliceosome: a new therapeutic target in chronic myeloid leukaemia

RNA splicing factors are frequently altered in cancer and can act as both oncoproteins and tumour suppressors. They have been found mutated or deregulated, justifying the growing interest in the targeting of splicing catalysis, splicing regulatory proteins, and/or specific, key altered splicing events. We recently showed that the DNA methylation alterations of CD34+CD15− chronic myeloid leukaemia (CML) cells affect, among others, alternative splicing genes, suggesting that spliceosome actors might be altered in chronic-phase (CP)-CML. We investigated the expression of 12 spliceosome genes known to be oncogenes or tumour suppressor genes in primary CP-CML CD34+ cells at diagnosis (n = 15). We found that CP-CML CD34+ cells had a distinct splicing signature profile as compared with healthy donor CD34+ cells or whole CP-CML cells, suggesting: (i) a spliceosome deregulation from the diagnosis time and (ii) an intraclonal heterogeneity. We could identify three profile types, but there was no relationship with a patient’s characteristics. By incubating cells with TKI and/or a spliceosome-targeted drug (TG003), we showed that CP-CML CD34+ cells are both BCR::ABL and spliceosome dependent, with the combination of the two drugs showing an additive effect while sparing healthy donors cells. Our results suggest that the spliceosome may be a new potential target for the treatment of CML

Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study

BACKGROUND We recently reported that peroxisome proliferator‐activated receptor γ agonists target chronic myeloid leukemia (CML) quiescent stem cells in vitro by decreasing transcription of STAT5. Here in the ACTIM phase 2 clinical trial, we asked whether pioglitazone add‐on therapy to imatinib would impact CML residual disease, as assessed by BCR‐ABL1 transcript quantification. METHODS CML patients were eligible if treated with imatinib for at least 2 years at a stable daily dose, having yielded major molecular response (MMR) but not having achieved molecular response 4.5 (MR4.5) defined by BCR‐ABL1/ABL1 IS RNA levels ≤ 0.0032%. After inclusion, patients started pioglitazone at a dosage of 30 to 45 mg/day in addition to imatinib. The primary objective was to evaluate the cumulative incidence of patients having progressed from MMR to MR4.5 over 12 months. RESULTS Twenty‐four patients were included (age range, 24‐79 years). No pharmacological interaction was observed between the drugs. The main adverse events were weight gain in 12 patients and a mean decrease of 0.4 g/dL in hemoglobin concentration. The cumulative incidence of MR4.5 was 56% (95% confidence interval, 37%‐76%) by 12 months, despite a wide range of therapy duration (1.9‐15.5 months), and 88% of 17 evaluable patients who were still on imatinib reached MR4.5 by 48 months. The cumulative incidence of MMR to MR4.5 spontaneous conversions over 12 months was estimated to be 23% with imatinib alone in a parallel cohort of patients. CONCLUSION Pioglitazone in combination with imatinib was well tolerated and yielded a favorable 56% rate. These results provide a proof of concept needing confirmation within a randomized clinical trial (EudraCT 2009‐011675‐79). Cancer 2017;123:1791–1799. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes

Eltrombopag for myelodysplastic syndromes or chronic myelomonocytic leukaemia with no excess blasts and thrombocytopenia: a French multicentre retrospective real-life study.

peer reviewedDespite a moderate prevalence in low-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), thrombocytopenia remains a risk of severe bleeding and therapeutic options are still limited. There are only a few studies with eltrombopag (ELT), a thrombopoietin receptor agonist, in those patients. In this retrospective multicentre study, ELT was used in 50 patients with MDS and 11 with CMML, with no excess of marrow blasts and platelet counts of <50 × 109 /l in a 'real-life' situation. Platelet response occurred in 47 (77%) patients. The median (range) duration of response was 8 (0-69) months. None of the eight still responders who discontinued ELT had relapsed, at a median (range) of 16 (6-23) months after ELT discontinuation. Although 36% of the patients were anti-coagulated or anti-aggregated only 10% of patients had Grade ≥3 bleeding events. Thrombotic events were observed in six (10%) patients, who all but one had a medical history of arterial or venous thrombosis. Progression to acute myeloid leukaemia occurred in four (7%) patients. In this first 'real-life' study, ELT was effective and generally well tolerated in patients with MDS/CMML without excess blasts

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

[Excerpt] Multiple myeloma (MM) is the third most common hematological malignancy, after Non-Hodgkin Lymphoma and Leukemia. MM is generally preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS) [1], and epidemiological studies have identified older age, male gender, family history, and MGUS as risk factors for developing MM [2]. The somatic mutational landscape of sporadic MM has been increasingly investigated, aiming to identify recurrent genetic events involved in myelomagenesis. Whole exome and whole genome sequencing studies have shown that MM is a genetically heterogeneous disease that evolves through accumulation of both clonal and subclonal driver mutations [3] and identified recurrently somatically mutated genes, including KRAS, NRAS, FAM46C, TP53, DIS3, BRAF, TRAF3, CYLD, RB1 and PRDM1 [3,4,5]. Despite the fact that family-based studies have provided data consistent with an inherited genetic susceptibility to MM compatible with Mendelian transmission [6], the molecular basis of inherited MM predisposition is only partly understood. Genome-Wide Association (GWAS) studies have identified and validated 23 loci significantly associated with an increased risk of developing MM that explain ~16% of heritability [7] and only a subset of familial cases are thought to have a polygenic background [8]. Recent studies have identified rare germline variants predisposing to MM in KDM1A [9], ARID1A and USP45 [10], and the implementation of next-generation sequencing technology will allow the characterization of more such rare variants. [...]French National Cancer Institute (INCA) and the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myélome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myélome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organizatio

Using healthcare claims data to analyze the prevalence of BCR-ABL-positive chronic myeloid leukemia in France: A nationwide population-based study

International audienceBACKGROUND: Data on Chronic Myeloid Leukemia (CML) prevalence are scarce. Here we provide an estimation of the prevalence of CML in France for the year 2014 using French national health insurance data.METHODS: We selected patients claiming reimbursement for tyrosine kinase inhibitors (TKI) or with hospital discharge diagnoses for CML, BCR/ABL-positive or with full reimbursement of health care expenses for myeloid leukemia. We built an algorithm which we validated on a random sample of 100 potential CML patients by comparing the results obtained using the algorithm and the opinion of two hematologists who reviewed the patient demographics and sequence of care abstracted from claims data (internal validity). For external validity, we compared the number of incident CML patients identified using the algorithm with those recorded in French population-based cancer registries in departments covered by such a registry.RESULTS: We identified 10 789 prevalent CML patients in 2014, corresponding to a crude prevalence rate of 16.3 per 100 000 inhabitants [95% confidence interval (CI) 16.0-16.6]: 18.5 in men [18.0-19.0] and 14.2 in women [13.8-14.6]. The crude CML prevalence was less than 1.6 per 100 000 [1.2-2.0] under age 20, increasing to a maximum of 48.2 [45.4-51.2) at ages 75-79. It varied from 10.2 to 23.8 per 100 000 across French departments. The algorithm showed high internal and external validity. Concordance rate between the algorithm and the hematologists was 96%, and the numbers of incident CML patients identified using the algorithm and the registries were 162 and 150, respectively.CONCLUSION: We built and validated an algorithm to identify CML patients in administrative healthcare databases. In addition to prevalence estimation, the algorithm could be used for future economic evaluations or pharmaco-epidemiological studies in this population

Long-term excess mortality and net survival among elderly diffuse large B-cell lymphoma patients after front-line R-CHOP treatment.

In the era of immunochemotherapy, data on the long-term prognosis of elderly patients diagnosed with a diffuse large B-cell lymphoma (DLBCL) are scarce. In this population and on the longer term, other-cause mortality is an important competing risk that needs to be accounted for. Using clinical trial data and relative survival approaches, we estimated the 10-year net survival (NS) and we described the excess mortality hazard (EMH) due (directly or indirectly) to the DLBCL, over time and according to main prognosis factors using flexible regression modelling. The 10-year NS was 65% [59; 71]. Using the flexible modelling, we showed that the EMH decreases steeply after diagnosis. The variables 'performance status', 'number of extra-nodal sites' and the serum 'lactate dehydrogenase' were strongly associated with the EMH, even after adjustment on other important variables. EMH is very close to zero at 10 years for the whole population, so DLBCL patients do not experience an increased mortality compared to the general population in the long term. The number of extra-nodal sites was an important prognostic factor shortly after diagnosis, suggesting that it is correlated with an important but unmeasured prognostic factor that would lead to this selection effect over time

Second- or third-generation tyrosine kinase inhibitors in first-line treatment of chronic myeloid leukemia in general population: Is there a real benefit?

International audienceINTRODUCTION: Since 2009, multiple randomized trials have shown faster and deeper responses in CML patients treated with new-generation TKI (NG-TKI) compared to those treated with imatinib (IM). Are the same results observed in the general population?MATERIALS AND METHODS: Patients were identified from the three French hematological malignancies population-based registries. All CML patients (ICD-O-3: 9875/3) diagnosed between 2006 and 2016 and resided in registries areas were included. The TKI generation effect on achievement of MMR in first-line therapy was assessed through a multivariate competitive risk analysis. An alluvial plot described the pathways leading to death.RESULTS: In total, 507 CML patients received TKI in first-line treatment, 22% were enrolled in a clinical trial. After adjustment, NG-TKI patients were significantly more likely to achieve MMR during first-line therapy than IM patients (HR: 1.88 CI95% [1.35-2.61]). At the end of follow-up, 212 patients were still in first-line therapy (46 of them died), 203 switched to second-line (43 subsequently died), 26 were on TFR from first-line (4 subsequently died), and 20 stopped their treatment (16 subsequently died).DISCUSSION: In this comprehensive real-life setting, the results were consistent with clinical trials. The results are not sufficient to conclude that a NG-TKI treatment is superior with regard to these patients, despite indications regarding differences between the TKI generation effect on survival and tolerance

Longitudinal studies of SRC family kinases in imatinib- and dasatinib-resistant chronic myelogenous leukemia patients.

International audienceThis report aims to more accurately define the frequency of the involvement of SRC Family Kinases (SFKs) in imatinib- and dasatinib-resistant CML patients. Clinical samples were analysed during in vivo treatment. We confirmed the high frequency of SFKs involvement in Tyrosine kinase inhibitor-resistant CML (52% of the cases) and even further in progressive disease and blast crises (60% of the cases). The SFKs deregulation is also observed in patients harboring BCR-ABL mutations. In T315I and F317L mutated patients, CML-resistance appears to be promoted by SFKs kinase protein reactivation once the BCR-ABL mutated clone has decreased on Omacetaxine