Real-world use of blinatumomab in adult patients with B-cell acute lymphoblastic leukemia in clinical practice : results from the NEUF study

Altres ajuts: Amgen (Europe) GmbHThis retrospective observational study (NEUF) included adult patients with B-cell acute lymphoblastic leukemia (B-cell ALL) who had received blinatumomab for the treatment of minimal residual disease-positive (MRD+) or relapsed/refractory (R/R) B-cell ALL via an expanded access program (EAP). Patients were eligible if blinatumomab was initiated via the EAP between January 2014 and June 2017. Patients were followed from blinatumomab initiation until death, entry into a clinical trial, the end of follow-up, or the end of the study period (December 31, 2017), whichever occurred first. Of the 249 adult patients included, 109 were MRD+ (83 Philadelphia chromosome-negative [Ph−] and 26 Philadelphia chromosome-positive [Ph+]) and 140 had a diagnosis of R/R B-cell ALL (106 Ph− and 34 Ph+). In the MRD+ group, within the first cycle of blinatumomab treatment, 93% (n = 49/53) of Ph− and 64% (n = 7/11) of Ph+ patients with evaluable MRD achieved an MRD response (MRD <0.01%). Median overall survival (OS) was not reached over a median follow-up time of 18.5 months (Ph−, 18.8 [range: 5.1-34.8] months; Ph+, 16.5 [range: 1.8-31.6] months). In the R/R group, within two cycles of blinatumomab, 51% of Ph− and 41% of Ph+ patients achieved complete hematologic remission (CR/CRh/CRi), and 83% of Ph− and 67% of Ph+ MRD-evaluable patients in CR/CRh/CRi achieved an MRD response. Median (95% confidence interval) OS was 12.2 (7.3-24.2) months in the R/R Ph− subgroup and 16.3 (5.3-not estimated) months in the R/R Ph+ subgroup. This large, real-world data set of adults with B-cell ALL treated with blinatumomab confirms efficacy outcomes from published studies

Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia

Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, PPeer reviewe

EHA evaluation of the ESMO-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) for haematological malignancies

Objective Value frameworks in oncology have not been validated for the assessment of treatments in haematological malignancies, but to avoid overlaps and duplications it appears reasonable to build up experience on existing value frameworks, such as the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Methods Here we present the results of the first feasibility testing of the ESMO-MCBS v1.1 for haematological malignancies based on the grading of 80 contemporary studies for acute leukaemia, chronic leukaemia, lymphoma, myeloma and myelodysplastic syndromes. The aims were (1) to evaluate the scorability of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version and (3) to identify shortcomings in the ESMO-MCBS v1.1 that require amendments to improve the efficacy and validity of the scale in grading new treatments in the management of haematological malignancies. Results In general, the ESMO-MCBS v1.1 was found to be widely applicable to studies in haematological malignancies, generating scores that were judged as reasonable by European Hematology Association (EHA) experts. A small number of studies could either not be graded or were not appropriately graded. The reasons, related to the differences between haematological and solid tumour malignancies, are identified and described. Conclusions Based on the findings of this study, ESMO and EHA are committed to develop a version of the ESMO-MCBS that is validated for haematological malignancies. This development process will incorporate all of the usual stringencies for accountability of reasonableness that have characterised the development of the ESMO-MCBS including field testing, statistical modelling, evaluation for reasonableness and openness to appeal and revision. Applying such a scale will support future public policy decision-making regarding the value of new treatments for haematological malignancies and will provide insights that could be helpful in the design of future clinical trials

EHA evaluation of the ESMO—Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) for haematological malignancies

Objective: Value frameworks in oncology have not been validated for the assessment of treatments in haematological malignancies, but to avoid overlaps and duplications it appears reasonable to build up experience on existing value frameworks, such as the European Society for Medical Oncology—Magnitude of Clinical Benefit Scale (ESMO-MCBS). Methods: Here we present the results of the first feasibility testing of the ESMO-MCBS v1.1 for haematological malignancies based on the grading of 80 contemporary studies for acute leukaemia, chronic leukaemia, lymphoma, myeloma and myelodysplastic syndromes. The aims were (1) to evaluate the scorability of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version and (3) to identify shortcomings in the ESMO-MCBS v1.1 that require amendments to improve the efficacy and validity of the scale in grading new treatments in the management of haematological malignancies. Results: In general, the ESMO-MCBS v1.1 was found to be widely applicable to studies in haematological malignancies, generating scores that were judged as reasonable by European Hematology Association (EHA) experts. A small number of studies could either not be graded or were not appropriately graded. The reasons, related to the differences between haematological and solid tumour malignancies, are identified and described. Conclusions: Based on the findings of this study, ESMO and EHA are committed to develop a version of the ESMO-MCBS that is validated for haematological malignancies. This development process will incorporate all of the usual stringencies for accountability of reasonableness that have characterised the development of the ESMO-MCBS including field testing, statistical modelling, evaluation for reasonableness and openness to appeal and revision. Applying such a scale will support future public policy decision-making regarding the value of new treatments for haematological malignancies and will provide insights that could be helpful in the design of future clinical trials

Rates of inclusion of teenagers and young adults in England into National Cancer Research Network clinical trials: Report from the National Cancer Research Institute (NCRI) Teenage and Young Adult Clinical Studies Development Group

Poor inclusion rates into clinical trials for teenagers and young adults (TYA; aged 13–24 years) have been assumed but not systematically investigated in England. We analysed accrual rates (AR) from 1 April 2005 up to 31 March 2007 to National Cancer Research Network (NCRN) Phase III trials for the commonest tumour types occurring in TYA and children: leukaemia, lymphoma, brain and central nervous system, bone sarcomas and male germ cell tumours. AR for 2005–2007 were 43.2% for patients aged 10–14 years, 25.2% for patients aged 15–19 years, and 13.1% for patients aged 20–24 years in the tumour types analysed. Compared with accrual from 1 April 2005 to 31 March 2006, AR between 1 April 2006 and 31 March 2007 increased for those aged 10–14 and 15–19 years, but fell for those aged 20–24 years. AR varied considerably among cancer types. Despite four trials being available, patients over 16 years with central nervous system tumours were not recruited. Rates of participation in clinical trials in England from 2005 to 2007 were much lower for TYA older than 15 years compared with children and younger teenagers. The variations in open trials, trial age eligibility criteria and extent of trial activation in treatment centres in part explain this observation. Other possible influences, such as difficulties associated with the consent of TYA require further evaluation. Closer dialogue between those involved in planning and running trials for children and for adults is necessary to improve trial availability and recruitment. Further research is required to identify trends in trial availability and accrual for those tumours constituting the remaining 26% of TYA cancers

Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia

Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in core-binding factor (CBF) acute myeloid leukemias (AMLs), but their prognostic relevance is debated. A subset of CBF AML patients harbors several signaling gene mutations. Genotyping of colonies and of relapse samples indicates that these arise in independent clones, thus defining a process of clonal interference (or parallel evolution). Clonal interference is pervasive in cancers, but the mechanisms underlying this process remain unclear, and its prognostic impact remains unknown. We analyzed a cohort of 445 adult and pediatric patients with CBF AML treated with intensive chemotherapy and with deep sequencing of 6 signaling genes (, , , , , ). A total of 152 (34%), 167 (38%), and 126 (28%) patients harbored no, a single, and multiple signaling clones (clonal interference), respectively. Clonal interference of signaling mutations was associated with older age ( = .004) and inv(16) subtype ( = .025) but not with white blood cell count or mutations in chromatin or cohesin genes. The median allele frequency of signaling mutations was 31% in patients with a single clone or clonal interference ( = .14). The repertoire of , , and / variants differed between groups. Clonal interference did not affect complete remission rate or minimal residual disease after 1-2 courses, but it did convey inferior event-free survival ( &lt; 10), whereas the presence of a single signaling clone did not ( = .44). This inferior outcome was independent of clinical parameters and of the presence of specific signaling clones. Our results suggest that specific clonal architectures can herald distinct prognoses in AML

Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia

BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849.

FTO influences adipogenesis by regulating mitotic clonal expansion

The fat mass and obesity-associated (FTO) gene plays a pivotal role in regulating body weight and fat mass; however, the underlying mechanisms are poorly understood. Here we show that primary adipocytes and mouse embryonic fibroblasts (MEFs) derived from FTO overexpression (FTO-4) mice exhibit increased potential for adipogenic differentiation, while MEFs derived from FTO knockout (FTO-KO) mice show reduced adipogenesis. As predicted from these findings, fat pads from FTO-4 mice fed a high-fat diet show more numerous adipocytes. FTO influences adipogenesis by regulating events early in adipogenesis, during the process of mitotic clonal expansion. The effect of FTO on adipogenesis appears to be mediated via enhanced expression of the pro-adipogenic short isoform of RUNX1T1, which enhanced adipocyte proliferation, and is increased in FTO-4 MEFs and reduced in FTO-KO MEFs. Our findings provide novel mechanistic insight into how upregulation of FTO leads to obesity

Constraints on Charon's Orbital Elements from the Double Stellar Occultation of 2008 June 22

The original publication is available at http://iopscience.iop.org/1538-3881/International audiencePluto and its main satellite, Charon, occulted the same star on 2008 June 22. This event was observed from Australia and La Réunion Island, providing the east and north Charon Plutocentric offset in the sky plane (J2000): X= + 12,070.5 ± 4 km (+ 546.2 ± 0.2 mas), Y= + 4,576.3 ± 24 km (+ 207.1 ± 1.1 mas) at 19:20:33.82 UT on Earth, corresponding to JD 2454640.129964 at Pluto. This yields Charon's true longitude L= 153.483 ± 0fdg071 in the satellite orbital plane (counted from the ascending node on J2000 mean equator) and orbital radius r= 19,564 ± 14 km at that time. We compare this position to that predicted by (1) the orbital solution of Tholen & Buie (the "TB97" solution), (2) the PLU017 Charon ephemeris, and (3) the solution of Tholen et al. (the "T08" solution). We conclude that (1) our result rules out solution TB97, (2) our position agrees with PLU017, with differences of ΔL= + 0.073 ± 0fdg071 in longitude, and Δr= + 0.6 ± 14 km in radius, and (3) while the difference with the T08 ephemeris amounts to only ΔL= 0.033 ± 0fdg071 in longitude, it exhibits a significant radial discrepancy of Δr= 61.3 ± 14 km. We discuss this difference in terms of a possible image scale relative error of 3.35 × 10-3in the 2002-2003 Hubble Space Telescope images upon which the T08 solution is mostly based. Rescaling the T08 Charon semi-major axis, a = 19, 570.45 km, to the TB97 value, a = 19636 km, all other orbital elements remaining the same ("T08/TB97" solution), we reconcile our position with the re-scaled solution by better than 12 km (or 0.55 mas) for Charon's position in its orbital plane, thus making T08/TB97 our preferred solution