Achievement of CR with undetectable minimal residual disease (uMRD) may be associated with a longer survival in CLL, but BCR signaling inhibitors alone seldom allow reaching uMRD. We conducted a ...multicenter phase II trial aiming at exploring the efficacy of an induction treatment associating obinutuzumab and ibrutinib, followed by immunochemotherapy for patients who do not reach CR with uMRD. Previously untreated fit patients with active Binet stage A and B or stage C CLL, no TP53 mutation/deletion, CIRS score < 7 and ECOG 0 or 1 were eligible. Induction treatment consisted of 6 courses of obinutuzumab (1000 mg D1, D8, D15 for cycle 1 and D1 for cycles 2 to 6) along with ibrutinib 420 mg/d for 9 months. Assessment of response to induction was performed at month 9, including CT-scan, bone marrow (BM) biopsy, peripheral blood (PB) and BM MRD testing. Patients in CR with BM MRD < 0.01% (by 8-color flow cytometry) received ibrutinib alone for 6 additional months whereas all the other patients received 4 courses of fludarabine (F) + cyclophosphamide (C) and obinutuzumab along with continuous ibrutinib until month 16. Patients with stable or progressive disease were taken off study. Final evaluation of response was performed at D1 Month 16. The primary endpoint of this study was the rate of CR (according to IWCLL 2008 guidelines) with uMRD in BM at month 16 and the assumption that at least 30% of patients would achieve this goal at the end of the overall strategy.
Between November 2015 and May 2017, 135 patients (89 males/46 females) were enrolled; 7% were Binet stage A, 67% stage B and 26% stage C. Median age was 62 years (range, 35-80). Genetic alterations included 26% del(11q), 19% trisomy 12 and 56% del(13q); 15% had a complex karyotype and 56% patients had unmutated IGHV status. Median Beta 2 microglobulin was 3.6 mg/L (1.5-7.5) and median GFR (Cockroft) was 81 mL/min (42-173).
At Month 9, 92% patients had received the 8 planned infusions of obinutuzumab. Ibrutinib dosage was reduced in 4 patients and definitively discontinued in 3 of them (3.9%) due to AE (atrial fibrillation, atrial flutter and neutropenia). Fifty seven percent of the patients presented at least a grade (G) 3 toxicity during the first 9 months of treatment (neutropenia 24%, anemia 6% and thrombocytopenia 31%). One hundred and thirty patients were evaluable for response at M9 and 5 not evaluable (2 deaths: one sudden at M7 and one accidental at M8; one acute coronary syndrome; one listeria meningitidis and one acute pulmonary edema at day 1 cycle 1). In intention to treat (ITT), ORR was 100% with 41% of patients reaching CR (42% for evaluable patients) but only 12% had BM MRD < 0.01%. Therefore 88% of the patients were planned to receive FC and obinutuzumab treatment while continuing ibrutinib.
At month 16, 115 patients were evaluable for response. In ITT, the CR rate was 69% (78% for evaluable patients) and 79% of patients had BM MRD < 0.01% (90% of evaluable patients). Overall, 62% patients achieved CR with BM MRD < 0.01% (ITT) and 70% evaluable patients did so. The IGHV mutational status did not impact the quality of response.
During the trial second period (M9 to M16), 38% patients presented at least a G3 toxicity: neutropenia 24%, thrombocytopenia 15%, anemia 1.5%, febrile neutropenia 3%, gastrointestinal disorders 9.5% and cardiac events 2.4%. A total of 41 serious AEs were observed throughout the entire treatment duration: 9 cardiac events including 1 atrial flutter and 3 atrial fibrillations, 4 hemorrhagic events, 7 infections, 3 second cancers (2 basocellular carcinoma, 1 renal adenocarcinoma) and 2 deaths.
In conclusion, this MRD-driven strategy given for a definite period of time leads to a very high rate of uMRD CR in previously untreated CLL fit patients without TP53 aberration and displays an acceptable security profile. To our knowledge, these results are superior to standard FC + rituximab (FCR) or any chemo-free regimen. We hypothesize that this very high rate of bone marrow undetectable MRD will translate in a prolonged PFS while discontinuing treatment.
Laribi:Novartis: Other: Grant and personal fees; Takeda: Other: Grant and personal fees; Teva: Other: Grant; Gilead: Other: Personal fees; Sandoz: Other: Grant; Roche: Other: Grant; Amgen: Other: Personal fees; Hospira: Other: Grant. Salles:Novartis: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Takeda: Honoraria. Leblond:Gilead: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Honoraria; Amgen: Honoraria. Cartron:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cymbalista:Gilead: Honoraria; AbbVie, Inc: Honoraria; Janssen: Honoraria; Sunesis: Research Funding. Feugier:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Occupational exposure constitutes a common risk factor for lung cancer. We observed molecular alterations in 73% of never-smokers, 35% of men and 8% of women were exposed to at least one occupational ...carcinogen. We report herein associations between molecular patterns and occupational exposure.BioCAST was a cohort study of lung cancer in never-smokers that reported risk factor exposure and molecular patterns. Occupational exposure was assessed
a validated 71-item questionnaire. Patients were categorised into groups that were unexposed and exposed to polycyclic aromatic hydrocarbons (PAH), asbestos, silica, diesel exhaust fumes (DEF), chrome and paints. Test results were recorded for
and
mutations, and
alterations.Overall, 313 out of 384 patients included in BioCAST were analysed. Asbestos-exposed patients displayed a significantly lower rate of
mutations (20%
44%, p=0.033), and a higher rate of
mutations (18%
4%, p=0.084).
alterations were not associated with any occupational carcinogens. The DEF-exposed patients were diagnosed with a
mutation in 25% of all cases. Chrome-exposed patients exhibited enhanced
and
mutation frequency.Given its minimal effects in the subgroups, we conclude that occupational exposure slightly affects the molecular pattern of lung cancers in never-smokers. In particular, asbestos-exposed patients have a lower chance of
mutations.
The 2013-2016 West African Ebola outbreak infected 28,616 people and caused 11,310 deaths by 11 May 2016, across six countries. The outbreak has also resulted in the largest number of EVD survivors ...in history-over 17,000. Guinea was declared Ebola-free on 1 June 2016. Reports from the outbreak documented 3814 cases resulting in 2544 deaths and 1270 survivors. EVD survivors face various neuropsychological and psycho-affective alterations that have not been fully identified yet. This study aims to document the depressive symptoms among adult survivors in Guinea.
Depressive symptoms were investigated using the French version of the Center for Epidemiologic Studies-Depression Scale (CES-D) administered to all adult survivors (≥ 20 years) participating in the PostEboGui study and receiving care in Conakry. The study was combined with a clinical consultation by a psychiatrist at the Donka National Hospital in Conakry that ensured adapted care was provided when needed.
Overall, 256 adult participants receiving care in Conakry participated in this study: 55% were women, median age 31 years IQR: 26-40. The median time since the Ebola Treatment Center (ETC) discharge was 8.1 months IQR: 4.1-11.7. 15% had a score above the threshold values indicating psychological suffering (15% for men and 14% for women). 33 people (16 women and 17 men) met with the psychiatrist, which resulted in the diagnosis of 3 cases of post-traumatic stress disorder (PTSD), 3 cases of mild depression, 13 cases of moderate depression, and 11 cases of severe depression, including 1 with kinesthetic hallucinations and another with visual hallucinations, and 1 with suicidal ideation and 3 with attempted suicide. Severe depression was diagnosed between 1 and 19 months after ETC discharge. The various identified forms of depression responded favorably to conventional drug therapies and cognitive behavioral therapy.
Long-term follow-up for EVD survivors will be necessary to understand the evolution of these pathologies. In the current post-epidemic context, these cases underscore the need to strengthen mental health diagnostic systems and treatment on a national scale.
Abstract We determined the effect of cortical amyloid load using18 F-florbetapir PET on cognitive performance and grey matter structural integrity derived from MRI in 318 cognitively normally ...performing older people with subjective memory impairment from the INSIGHT-preAD cohort using multivariate partial least square regression. Amyloid uptake was associated with reduced grey matter structural integrity in hippocampus, entorhinal and cingulate cortex, middle temporal gyrus, prefrontal cortex, and lentiform nucleus (p < 0.01, permutation test). Higher amyloid load was associated with poorer global cognitive performance, delayed recall and attention (p < 0.05), independently of its effects on grey matter connectivity. These findings agree with the assumption of a two stage effect of amyloid on cognition, (i) an early direct effect in preclinical stages of Alzheimer’s disease (AD) and (ii) a delayed effect mediated by down-stream effects of amyloid accumulation, such as grey matter connectivity decline.
Summary Objective Avocado–Soybean Unsaponifiables (ASU) represent one of the most commonly used drugs for symptomatic osteoarthritis (OA). The mechanisms of its activities are still poorly ...understood. We investigate here the effects of ASU on signaling pathways in mouse or human chondrocytes. Methods Mouse or human chondrocytes stimulated with interleukin-1β (IL1β, 10 ng/ml) and cartilage submitted to a compressive mechanical stress (MS) were studied in the presence or absence of ASU (10 μg/ml). Nuclear factor κB (NF-κB) activation was assessed by immunoblot, using an I-κBα antibody, nuclear translocation of NF-κB using p65 antibody, and extra-cellular signal-regulated kinase (ERK)1/2 activation using phospho and ERK1/2 antibodies. The binding of the p50/p65 complex on DNA was studied by electrophoretic mobility shift assay. Results ASU decrease matrix metalloproteinases-3 and -13 expressions and Prostaglandin E2 (PGE2 ) release in our model. The degradation of I-κBα is prevented in the presence of ASU as shown by the persistent expression of I-κBα protein in the cytosol when chondrocytes are stimulated by IL1β or MS. Nuclear translocation of the NF-κB complex is shown by the decrease of the p65 protein from the cytosol, whereas p65 appears in the nucleus under IL1β stimulation. This translocation is abolished in the presence of ASU. Moreover, bandshift experiments show an inhibition of the IL1β-induced binding of p50/p65 complexes to NF-κB responsive elements in response to ASU. Finally, among the different mitogen-activated protein kinases known to be induced by IL1β, ERK1/2 was the sole kinase inhibited by ASU. Conclusion These results demonstrate that ASU express a unique range of activities, which could counteract deleterious processes involved in OA, such as inflammation.
Abstract
ETMR, an aggressive disease characterised by C19MC alterations, were previously categorised as various histologic diagnoses. The clinical spectrum and impact of conventional multi-modal ...therapy on this new WHO diagnostic category remains poorly understood as a majority of ~200 cases reported to date lack molecular confirmation. We undertook comprehensive clinico-pathologic studies of a large molecularly confirmed cohort to improve disease recognition and treatment approaches. Amongst 623 CNS-PNETs patients enrolled in the RBTC registry, 159 primary ETMRs were confirmed based on a combination of FISH (125), methylation analysis (88), SNP and RNAseq (32) analyses; 91% had C19MC amplification/gains/fusions, 9% lacked C19MC alterations but had global methylation features of ETMR NOS. ETMRs arose in young patients (median age 26 months) predominantly as localized disease (M0-72%, M2-3 -18%) at multiple locations including cerebrum (60%) cerebellum (18%), midline structures (6%); notably 10% were brainstem primaries mimicking DIPG. Uni-and multivariate analyses of clinical and treatment details of curative regimens available for 110 patients identified metastatic disease (p=0.002), brainstem locations(p=0.005), extent of surgery, receipt of multi-modal therapy including high dose chemotherapy and radiation (P<0.001) as significant treatment prognosticators, while C19MC status, age and gender were non-significant risk factors. Analyses of events in all patients showed respective EFS at 3 and 12 months of 84%(95%CI:77–91) and 37%(95%CI:20–41) and 4yr OS of 27%(95%CI:18–37) indicating despite intensified therapies ETMR is a rapidly progressive and fatal disease. Our comprehensive data on the largest cohort of molecularly-confirmed ETMRs provides a critical framework to guide current clinical management and development of clinical trials.
Achievement of CR with undetectable residual disease (uMRD) may be associated with a longer survival in CLL. New therapeutic agents have recently emerged, including new anti-CD20 antibodies and ...agents targeting BCR signaling. We conducted a multicenter phase II trial aimed to explore the efficacy of an induction treatment associating obinutuzumab and ibrutinib, followed by immunochemotherapy only in case of PR or detectable MRD. FIT treatment-naïve patients with active Binet stage A to C CLL and no TP53 mutation/deletion were eligible if CIRS score was < 7 and ECOG 0 or 1. Induction treatment consisted of 6 courses of obinutuzumab (1000 mg D1, D8, D15 for cycle 1 and D1 for cycles 2 to 6) along with ibrutinib 420 mg daily for 9 months. A first assessment of response was performed at month 9, including CT-scan, bone marrow (BM) biopsy and peripheral blood (PB) and BM MRD testing. Patients in CR with uMRD (<10-4, by 8-color cytometry) received ibrutinib alone for 6 additional months whereas the others received 4 courses of fludarabine + cyclophosphamide and obinutuzumab while continuing ibrutinib. Patients with stable or progressive disease were taken off study. Final evaluation of response was performed at Day 1 Month 16. The primary objective of this study was to obtain 30% of CR (according to IWCLL 2008 guidelines) with uMRD in BM at month 16. We report the preliminary results of the induction phase of this trial, including toxicities and response rates.
Between November 2015 and May 2017, 135 planned patients were enrolled (Table 1) including 89 males and 46 females; 8.2% were Binet stage A, 67.2% stage B and 24.6% stage C. The median age was 62.5 years (range, 35-80 years). Patients with del11q, del13q and trisomy 12 were 20.8% (25/120), 52% (51/98) and 21.6% (21/97) respectively; 9% (10/109) 12.5 % had a complex karyotype (>3 abnormalities). The median concentration of Beta 2 microglobulin was 3.6 mg/L (1.5-7). The median of creatinine clearance (Cockroft) was 81 ml/min (42-155).
A total of 37 serious AEs were observed with 24 related to the treatment, including 3 tumor lysis syndrome (grade 3), 5 cardiac events (1 hypertension (grade 3) and 2 atrial flutter (grade 2 and 3) and 2 atrial fibrillation (grade 3)), 1 diabetes mellitus (grade 2), 3 febrile neutropenia (grade 4), 2 neutropenia (grade 3), 1 pneumonia (grade 4), 1 hepatocellular injury (grade 3), 1 severe pain (grade 3), 1 hemoptysis (grade 3), 1 infection of listeria meningitidis complicated with disseminated intravascular coagulation (grade 3), 1 thrombocytopenia (grade 4), 1 hemorragic renal cyst (grade 3), 1 brain hemorrhage (grade 4), 1 diarrhea (grade 3) and 1 vomiting (grade 3). Two patients died during the study at the cut-off date, one of unknown cause and one of brain hemorrhage due to fall on the stairs not reliable to therapy.
Among the other AE, Infusion Related Reaction (IRR) only occurred during cycle 1 at day 1 for 69,5% of the patients (34.8% grade 1, 57.6% grade 2 and 7.6% grade 3), 14.5% at day 2 (only grade 1 and 2) and none at day 8 and 15, respectively. Grade 3-4 neutropenia were observed in 24.3%, 7.7%, 10.2%, 12.2%, 11.8%, 11,1%, 13.6%, 16.7% and 2.7% of cases during cycles 1 to 9, respectively. Grade 3-4 thrombocytopenia and anemia were mainly observed during cycle 1 (30.8% and 6%, respectively). Other significant toxicity was digestive (nausea, vomiting and diarrhea) occurring in 33,6% of the patients (grade 1 and 2) but only during cycle 1.
At Month 9, 92% of the patients had received the 8 planned infusions of obinutuzumab; Ibrutinib dosage was reduced for 5 patients (5/77; 6,8%) and definitively stopped in 3 out of them (3,9%) due to AE (atrial fibrillation, atrial flutter and neutropenia).
Seventy-three patients are evaluable so far for the response at M9. The ORR was 100% with 37% in CR (IWCLL criteria) and 63% in PR. Among the 63 (86%) patients with positive BM MRD, 22 were in CR and 41 in PR; 8 patients had uMRD in PB and BM including 4 patients in CR.
These preliminary results indicated that this 9 month « chemo-free » induction is associated with a high CR rate (37%) without excess of toxicity. However, the majority of the patients required subsequent immuno-chemotherapy because of detectable BM MRD.
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Dilhuydy:Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Laribi:MUNDIPHARMA: Research Funding; NOVARTIS: Honoraria, Research Funding; ROCHE: Research Funding; TEVA: Research Funding; HOSPIRA: Research Funding; AMGEN: Honoraria; TAKEDA: Honoraria, Research Funding. Salles:morphosys: Consultancy, Honoraria; BMS: Consultancy; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding. Tournilhac:AMGEN: Other: Travel funding, Research Funding; ROCHE: Honoraria, Other: Travel funding, Research Funding; GILEAD: Honoraria, Other: Travel Funding, Research Funding; Janssen: Honoraria, Other: travel funding; Abbvie: Honoraria, Other: Travel funding. Delmer:Abbvie: Consultancy, Honoraria; Janssen: Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Pegourie:Takeda, Novartis, Janssen, BMS: Consultancy. Leblond:SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria; ABBVIE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cartron:Sanofi, BMS, Jansen, celgene, Roche, Gilead: Equity Ownership; Celgene: Consultancy, Employment; Roche: Consultancy, Equity Ownership, Honoraria, Research Funding. Fornecker:Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Ysebaert:Janssen: Consultancy, Research Funding, Speakers Bureau. Dartigeas:Gilead: Other: travel grant; Mundipharma: Other: travel grant; Janssen: Consultancy; Roche: Consultancy. Cymbalista:Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Mundipharma: Honoraria; AbbVie: Consultancy, Honoraria; Roche: Other: Travel, Accommodations, Expenses. Letestu:Alexion: Consultancy, Honoraria. Feugier:Roche: Consultancy, Honoraria, Research Funding.
In patients with chronic lymphocytic leukaemia, achievement of a complete response with minimal residual disease of less than 0·01% (ie, <1 chronic lymphocytic leukaemia cell per 10 000 leukocytes) ...in bone marrow has been associated with improved progression-free survival. We aimed to explore the activity of induction therapy for 9 months with obinutuzumab and ibrutinib, followed up with a minimal residual disease-driven therapeutic strategy for 6 additional months, in previously untreated patients.
We did a single-arm, phase 2 trial in 27 university hospitals, general hospitals, and specialist cancer centres in France. Eligible patients were at least 18 years old and previously untreated, and had immunophenotypically confirmed B-cell chronic lymphocytic leukaemia; an Eastern Cooperative Oncology Group (ECOG) performance status score of less than 2; a Binet stage C according to IWCLL 2008 criteria or Binet stage A and B with active disease; no 17p deletion or absence of p53 mutation; and were considered medically fit. In the first part of the study (induction phase), all participants received eight intravenous infusions of obinutuzumab 1000 mg over six 4-weekly cycles and oral ibrutinib 420 mg once per day for 9 months. In part 2, after assessment on day 1 of month 9, patients with a complete response and bone marrow minimal residual disease of less than 0·01% received only oral ibrutinib 420 mg once per day for 6 additional months. Patients with a partial response, or with a complete response and bone marrow minimal residual disease of 0·01% or more, received 6 months of four 4-weekly cycles of intravenous fludarabine, cyclophosphamide, and obinutuzumab 1000 mg, alongside continuing ibrutinib 420 mg once per day. The primary endpoint was the proportion of patients achieving a complete response with bone marrow minimal residual disease less than 0·01% on day 1 of month 16 assessed by intention to treat (ITT). This trial is registered with ClinicalTrials.gov (number NCT02666898) and is still open for follow-up.
Between Oct 27, 2015, and May 16, 2017, 135 patients were enrolled. After induction treatment (day 1 of month 9), 130 patients were evaluable, of which ten (8%) achieved a complete response with bone marrow minimal residual disease of less than 0·01% and were assigned to ibrutinib, and 120 (92%) were assigned to ibrutinib plus fludarabine, cyclophosphamide, and obinutuzumab. After minimal residual disease-guided treatment (day 1 of month 16), 84 (62%, 90% CI 55-69) of 135 patients (ITT population) achieved a complete response with bone marrow minimal residual disease of less than 0·01%. The most common haematological adverse event was thrombocytopenia (in 45 34% of 133 patients at grade 1-2 in months 1-9 and in 43 33% of 130 patients at grade 1-2 in months 9-15). The most common non-haematological adverse events were infusion-related reactions (in 83 62% patients at grade 1-2 in months 1-9) and gastrointestinal disorders (in 62 48% patients at grades 1 and 2 in months 9-15). 49 serious adverse events occurred, most frequently infections (ten), cardiac events (eight), and haematological events (eight). No treatment-related deaths occurred.
Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease driven strategy is safe and active in patients with previously untreated chronic lymphocytic leukaemia. With longer follow-up, including assessing the evolution of minimal residual disease, if response is maintained, this strategy could be an option in the first-line setting in patients with chronic lymphocytic leukaemia, although randomised evidence is needed.
Roche, Janssen.
Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce ...clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease.
Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors.
159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18-36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 73% of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47-68) at 6 months and 31% (21-42) at 2 years; overall survival was 29% (20-38) at 2 years and 27% (18-37) at 4 years. Overall survival was associated with non-metastatic disease (HR 0·48, 95% CI 0·28-0·80; p=0·0057) and non-brainstem location (0·42 0·22-0·81; p=0·013) on univariate analysis, as well as with gross total resection (0·30, 0·16-0·58; p=0·0014), high-dose chemotherapy (0·35, 0·19-0·67; p=0·0020), and radiotherapy (0·21, 0·10-0·41; p<0·0001) on multivariable analysis. 2-year event-free and overall survival was 0% at 2 years in patients treated with conventional chemotherapy without radiotherapy (regardless of surgery extent), and 21% (95% CI 1-41) and 30% (6-54), respectively, in patients treated with high-dose chemotherapy, and gross total resection without radiotherapy. 2-year event-free survival in patients treated with high-dose chemotherapy and radiotherapy was 66% (95% CI 39-93) for patients with gross total resection and 44% (7-81) for patients with sub-total resection. 2-5-year overall survival was 66% (95% CI 33-99, p=0·038) for patients with gross total resection and 67% (36-98, p=0·0020) for patients with sub-total resection.
Prompt molecular diagnosis and post-surgical treatment with intensive multi-modal therapy tailored to patient-specific risk features could improve ETMR survival.
Canadian Institute of Health Research, Canada Research Chair Awards, Australian Lions Childhood Cancer Research Foundation, Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía, Miracle Marnie, Phoebe Rose Rocks, Tali's Funds, Garron Cancer Centre, Grace's Walk, Meagan's Hug, Brainchild, Nelina's Hope, and Jean Martel Foundation.
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