Two new mutations in the HIF2A gene associated with erythrocytosis

Congenital or familial erythrocytosis/polycythemia can have many causes, and an emerging cause is genetic disruption of the oxygen-sensing pathway that regulates the ERYTHROPOIETIN (EPO) gene. More specifically, recent studies have identified erythrocytosis-associated mutations in the HIF2A gene, which encodes for Hypoxia Inducible Factor-2α (HIF-2α), as well as in two genes that encode for proteins that regulate it, Prolyl Hydroxylase Domain protein 2 (PHD2) and the von Hippel Lindau tumor suppressor protein (VHL). We report here the identification of two new heterozygous HIF2A missense mutations, M535T and F540L, both associated with erythrocytosis. Met-535 has previously been identified as a residue mutated in other patients with erythrocytosis, although the mutation of this particular residue to Thr has not been reported. In contrast, Phe-540 has not been reported as a residue mutated in erythrocytosis, and we present evidence here that this mutation impairs interaction of HIF-2α with both VHL and PHD2

Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial.

BACKGROUND:Front-line therapy for elderly or unfit patients with acute myeloid leukaemia (AML) remains unsatisfactory with poor outcomes and excessive toxicity. We studied a new low-intensity regimen of cladribine combined with low-dose cytarabine alternating with decitabine, aimed at improving outcomes in this population. Based on our previous experience, we hypothesised that this combination would be safe and more effective than current approaches with hypomethylating agents. METHODS:In this single-arm, open-label, single-centre phase 2 study, we enrolled patients aged 60 years or older with previously untreated AML or high-risk myelodysplastic syndrome who had adequate organ function and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were treated with cladribine plus low-dose cytarabine for two 28-day cycles alternating with decitabine for two 28-day cycles, for up to 18 cycles. Induction therapy (cycle 1) consisted of cladribine 5 mg/m2 intravenously over 1-2 h on days 1-5 and cytarabine 20 mg subcutaneously twice daily on days 1-10. Patients who had remission during this induction regimen moved on to consolidation therapy (cladribine 5 mg/m2 intravenously over 1-2 h on days 1-3 and cytarabine 20 mg twice daily on days 1-10, alternating with decitabine 20 mg/m2 intravenously on days 1-5). The primary outcome measure was disease-free survival. Secondary outcomes were overall survival, proportion of patients achieving complete response, proportion of patients achieving response, toxicity, and induction mortality. All treated patients were included in the analyses. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01515527. FINDINGS:Between Feb 17, 2012, and July 6, 2017, 118 patients were enrolled and treated, among whom 48 (41%) had an adverse karyotype, 20 (17%) had therapy-related AML, 18 (15%) had treated secondary AML, and 20 (17%) had TP53 mutations. Median disease-free survival was 10·8 months (IQR 5·4-25·9). 80 (68%) patients achieved objective response: 69 (58%) achieved a complete response and 11 (9%) patients had complete response with incomplete count recovery. The median overall survival was 13·8 months (6·9-28·6). The regimen was well tolerated, with one (1%) death within the first 4 weeks and eight (7%) deaths within the first 8 weeks. The most common non-haematological adverse events of grade 3 or worse were infection (88 [75%] patients), elevated total bilirubin (26 [22%] patients), rash (13 [11%] patients), and nausea (13 [11%] patients). INTERPRETATION:The combination of cladribine and low-dose cytarabine alternating with decitabine appears to be a safe and highly effective regimen for the treatment of elderly or unfit patients with newly diagnosed AML. Further testing of this regimen is warranted, and could help to provide a new, effective option for reduced-intensity therapy in this population. FUNDING:Part supported by the National Institutes of Health

Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial

BACKGROUND:Front-line therapy for elderly or unfit patients with acute myeloid leukaemia (AML) remains unsatisfactory with poor outcomes and excessive toxicity. We studied a new low-intensity regimen of cladribine combined with low-dose cytarabine alternating with decitabine, aimed at improving outcomes in this population. Based on our previous experience, we hypothesised that this combination would be safe and more effective than current approaches with hypomethylating agents. METHODS:In this single-arm, open-label, single-centre phase 2 study, we enrolled patients aged 60 years or older with previously untreated AML or high-risk myelodysplastic syndrome who had adequate organ function and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were treated with cladribine plus low-dose cytarabine for two 28-day cycles alternating with decitabine for two 28-day cycles, for up to 18 cycles. Induction therapy (cycle 1) consisted of cladribine 5 mg/m2 intravenously over 1-2 h on days 1-5 and cytarabine 20 mg subcutaneously twice daily on days 1-10. Patients who had remission during this induction regimen moved on to consolidation therapy (cladribine 5 mg/m2 intravenously over 1-2 h on days 1-3 and cytarabine 20 mg twice daily on days 1-10, alternating with decitabine 20 mg/m2 intravenously on days 1-5). The primary outcome measure was disease-free survival. Secondary outcomes were overall survival, proportion of patients achieving complete response, proportion of patients achieving response, toxicity, and induction mortality. All treated patients were included in the analyses. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01515527. FINDINGS:Between Feb 17, 2012, and July 6, 2017, 118 patients were enrolled and treated, among whom 48 (41%) had an adverse karyotype, 20 (17%) had therapy-related AML, 18 (15%) had treated secondary AML, and 20 (17%) had TP53 mutations. Median disease-free survival was 10·8 months (IQR 5·4-25·9). 80 (68%) patients achieved objective response: 69 (58%) achieved a complete response and 11 (9%) patients had complete response with incomplete count recovery. The median overall survival was 13·8 months (6·9-28·6). The regimen was well tolerated, with one (1%) death within the first 4 weeks and eight (7%) deaths within the first 8 weeks. The most common non-haematological adverse events of grade 3 or worse were infection (88 [75%] patients), elevated total bilirubin (26 [22%] patients), rash (13 [11%] patients), and nausea (13 [11%] patients). INTERPRETATION:The combination of cladribine and low-dose cytarabine alternating with decitabine appears to be a safe and highly effective regimen for the treatment of elderly or unfit patients with newly diagnosed AML. Further testing of this regimen is warranted, and could help to provide a new, effective option for reduced-intensity therapy in this population. FUNDING:Part supported by the National Institutes of Health

Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial

Front-line therapy for elderly or unfit patients with acute myeloid leukaemia (AML) remains unsatisfactory with poor outcomes and excessive toxicity. We studied a new low-intensity regimen of cladribine combined with low-dose cytarabine alternating with decitabine, aimed at improving outcomes in this population. Based on our previous experience, we hypothesised that this combination would be safe and more effective than current approaches with hypomethylating agents. In this single-arm, open-label, single-centre phase 2 study, we enrolled patients aged 60 years or older with previously untreated AML or high-risk myelodysplastic syndrome who had adequate organ function and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were treated with cladribine plus low-dose cytarabine for two 28-day cycles alternating with decitabine for two 28-day cycles, for up to 18 cycles. Induction therapy (cycle 1) consisted of cladribine 5 mg/m2 intravenously over 1–2 h on days 1–5 and cytarabine 20 mg subcutaneously twice daily on days 1–10. Patients who had remission during this induction regimen moved on to consolidation therapy (cladribine 5 mg/m2 intravenously over 1–2 h on days 1–3 and cytarabine 20 mg twice daily on days 1–10, alternating with decitabine 20 mg/m2 intravenously on days 1–5). The primary outcome measure was disease-free survival. Secondary outcomes were overall survival, proportion of patients achieving complete response, proportion of patients achieving response, toxicity, and induction mortality. All treated patients were included in the analyses. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01515527. Between Feb 17, 2012, and July 6, 2017, 118 patients were enrolled and treated, among whom 48 (41%) had an adverse karyotype, 20 (17%) had therapy-related AML, 18 (15%) had treated secondary AML, and 20 (17%) had TP53 mutations. Median disease-free survival was 10·8 months (IQR 5·4–25·9). 80 (68%) patients achieved objective response: 69 (58%) achieved a complete response and 11 (9%) patients had complete response with incomplete count recovery. The median overall survival was 13·8 months (6·9–28·6). The regimen was well tolerated, with one (1%) death within the first 4 weeks and eight (7%) deaths within the first 8 weeks. The most common non-haematological adverse events of grade 3 or worse were infection (88 [75%] patients), elevated total bilirubin (26 [22%] patients), rash (13 [11%] patients), and nausea (13 [11%] patients). The combination of cladribine and low-dose cytarabine alternating with decitabine appears to be a safe and highly effective regimen for the treatment of elderly or unfit patients with newly diagnosed AML. Further testing of this regimen is warranted, and could help to provide a new, effective option for reduced-intensity therapy in this population. Part supported by the National Institutes of Health

Clonal hematopoiesis in sickle cell disease.

BACKGROUNDCurative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. The occurrence of myeloid malignancies in these trials has prompted safety concerns. Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined. Clonal hematopoiesis (CH) is a premalignant condition that also confers significant predisposition to myeloid cancers. While it has been speculated that CH may play a role in SCD-associated cancer predisposition, limited data addressing this issue have been reported.METHODSHere, we leveraged 74,190 whole-genome sequences to robustly study CH in SCD. Somatic mutation calling methods were used to assess CH in all samples and comparisons between individuals with and without SCD were performed.RESULTSWhile we had sufficient power to detect a greater than 2-fold increased rate of CH, we found no detectable variation in rate or clone properties between individuals affected by SCD and controls. The rate of CH in individuals with SCD was unaltered by hydroxyurea use.CONCLUSIONSWe did not observe an increased risk for acquiring detectable CH in SCD, at least as measured by whole-genome sequencing. These results should help guide ongoing efforts and further studies that seek to better define the risk factors underlying myeloid malignancy predisposition in SCD and help ensure that curative therapies can be more safely applied.FUNDINGNew York Stem Cell Foundation and the NIH

Rare genetic variants explain missing heritability in smoking.

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking

Search for evidence of the type-III seesaw mechanism in multilepton final states in proton-proton collisions at s=13\sqrt{s} = 13 TeV

A search for a signal consistent with the type-III seesaw mechanism in events with three or more electrons or muons is presented. The data sample consists of proton-proton collisions at $\sqrt{s} = 13$ TeV collected by the CMS experiment at the LHC in 2016 and corresponds to an integrated luminosity of 35.9 inverse femtobarns. Selection criteria based on the number of leptons and the invariant mass of opposite-sign lepton pairs are used to distinguish the signal from the standard model background. The observations are consistent with the expectations from standard model processes. The results are used to place limits on the production of heavy fermions of the type-III seesaw model as a function of the branching ratio to each lepton flavor. In the scenario of equal branching fractions to each lepton flavor, heavy fermions with masses below 840 GeV are excluded. This is the most sensitive probe to date of the type-III seesaw mechanism