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1.
Blood ; 138(SUPPL 1):3525, 2021.
Article in English | EMBASE | ID: covidwho-1770434

ABSTRACT

Background - The WINDOW-1 regimen introduced first-line ibrutinib with rituximab (IR) followed by 4 cycles of R-HCVAD for younger mantle cell lymphoma (MCL) patients (pts) demonstrating 90% CR on IR alone and we aimed to improve the CR rate with the addition of venetoclax. We therefore investigated the efficacy and safety of IR and venetoclax (IRV) followed by risk-stratified observation or short course R-HCVAD/MTX-ARA-C as consolidation in previously untreated young patients with mantle cell lymphoma (MCL). Our aim was to use a triplet chemotherapy-free induction to reduce the toxicity, complications and minimize chemotherapy exposure in MCL pts. Methods - We enrolled 50 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT03710772. Pts received IR induction (Part-1) for initial 4 cycles. Pts were restaged at cycle 4 and received IRV for up to eight cycles (Cycle 5 to Cycle 12) starting with ramp up venetoclax dosing in Cycle 5. All pts who achieved CR prior to cycle 12 continued to receive IRV for 4 cycles (maximum 12 cycles) and then moved to part 2. Pts were stratified into three disease risk groups: high, moderate and low risk categories from the baseline data for assignment to R-HCVAD/MTX-ARA-C as consolidation in part 2 (4 cycles, 2 cycles, or no chemotherapy for high, medium and low risk pts respectively). Briefly, low risk pts were those with Ki-67 ≤30%, largest tumor mass <3 cm, low MIPI score and no features of high risk disease (Ki-67 ≥50%, mutations in the TP53, NSD2 or in NOTCH genes, complex karyotype or del17p, MYC positive, or largest tumor diameter >5 cm or blastoid/pleomorphic histology or if they remain in PR after 12 cycles of part 1. Medium risk are pts which did not belong to low or high-risk category. Those who experienced progression on part 1 went to part 2 and get 4 cycles of part 2. Patient were taken off protocol but not off study, if they remained in PR after 4 cycles of chemotherapy, these patients were followed up for time to next treatment and progression free survival on subsequent therapies. After part 2 consolidation, all pts received 2 years of IRV maintenance. The primary objective was to assess CR rates after IRV induction. Adverse events were coded as per CTCAE version 4. Molecular studies are being performed. Results - Among the 50 pts, the median age was 57 years (range - 35-65). There were 20 pts in high-risk group, 20 pts in intermediate-risk group and 10 pts in low-risk group. High Ki-67 (≥30%) in 18/50 (36%) pts. Eighteen (36%) had high and intermediate risk simplified MIPI scores. Six (12%) pts had aggressive MCL (blastoid/pleomorphic). Among the 24 TP53 evaluable pts, eight pts (33%) had TP53 aberrations (mutated and/or TP53 deletion by FISH). Forty-eight pts received IRV. Best response to IRV was 96% and CR of 92%. After part 2, the best ORR remained unaltered, 96% (92% CR and 4% PR). The median number of cycles of triplet IRV to reach best response was 8 cycles (range 2-12). Fifteen pts (30%) did not receive part 2 chemotherapy, two pts (4%) received 1 cycle, 16 pts (32%) 2 cycles and 13 pts (26%) got 4 cycles of chemotherapy. With a median follow up of 24 months, the median PFS and OS were not reached (2 year 92% and 90% respectively). The median PFS and OS was not reached and not significantly different in pts with high and low Ki-67% or with/without TP53 aberrations or among pts with low, medium or high-risk categories. The median PFS and OS was inferior in blastoid/pleomorphic MCL pts compared to classic MCL pts (p=0.01 and 0.03 respectively). Thirteen pts (26%) came off study - 5 for adverse events, 3 for on study deaths, and 2 for patient choice, 2 patients lost to follow up and one for disease progression. Overall, 5 pts died (3 on trial and 2 pts died off study, one due to progressive disease and another due to COVID pneumonia). Grade 3-4 toxicities on part 1 were 10% myelosuppression and 10% each with fatigue, myalgia and rashes and 3% mucositis. One pt developed grade 3 atrial flutter on part 1. None had grade 3-4 bleeding/bruising. Conclusions - Chemotherapy-free induction with IRV induced durable and deep responses in young MCL pts in the frontline setting. WINDOW-2 approach suggests that pts with low risk MCL do not need chemotherapy but further follow up is warranted. This combined modality treatment approach significantly improves outcomes of young MCL pts across all risk groups. Detailed molecular analyses will be reported. (Figure Presented).

2.
Molecular Genetics and Metabolism ; 132:S40, 2021.
Article in English | EMBASE | ID: covidwho-1735090

ABSTRACT

Cytogenetic abnormalities involving chromosome 16 are found in 5– 8% of acute myeloid leukemia (AML). These are typically a pericentric inversion inv(16)(p13.1q22) or a translocation, t(16;16)(p13.1;q22), involving the MYH11 and CBFB genes localized to chromosome 16p13.1 and 16q22, respectively. In addition, less common rearrangements include deletion of the long arm of chromosome 16, del(16) (q22), and cryptic insertions involving the MYH11 and the CBFB genes with otherwise normal karyotypes. In this report, we present the first AML case with a new translocation involving the CBFB gene. The more common CBFB - MYH11 fusion product resulting from the inversion and/or translocation of chromosome(s) 16 leads to an AML with monocytic and granulocytic differentiation and abnormal eosinophil component with large, purple to violet color eosinophilic granules. This entity typically corresponds to the adult AML-M4Eo in French-American- British (FAB) Classification and now called AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH1 in the new 2017 WHO Classification. Patients may present with myeloid sarcoma at initial diagnosis or at relapse. We present a case of an 80-year-old male with a history of prostate cancer post radiotherapy who was referred for COVID-19 testing. A complete blood count with differential revealed neutropenia and a macrocytic anemia. A bone marrow biopsy and a bone marrow aspirate confirmed a diagnosis of AML with 33% blasts including myeloblasts and promonocytes. Interphase fluorescence in situ hybridization (FISH) analysis with a break-apart probe for CBFB showed an abnormal hybridization pattern consistent with rearrangement of CBFB in 66% of nuclei. Chromosome analysis revealed an abnormal karyotype with two related clones: 47,XY, t(10;16)(p13;q22),+22[4]/48,idem,+8[16]. Sequential GTG-FISH confirmed that the 3’ region of CBFB was translocated to 10p13 in the t(10;16) and the 5’ region remained on 16q. Based on the karyotype, the patient’s bone barrow exhibits clonal evolution having acquired additional chromosome abnormalities (trisomy 22 and trisomy 8). Molecular studies by next generation sequencing showed NRAS p.Gln61Lys mutation with a VAF of 11.21%. No genomic alterations were detected in KIT, KRAS or FLT3 genes. AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) is associated with a high rate of complete remission and favorable overall survival when treated with intensive consolidation therapy. However, their prognostic advantage may be affected by additional cytogenetic abnormalities and/or other gene mutations. Specifically, trisomy 22, is a frequent abnormality additional to inv(16) detected as a secondary finding which has been associated with an improved outcome when compared to the prognosis associated with inv(16) alone. Furthermore, KIT (in 30–40%), FLT3 (in 14%), NRAS (in 45%) and KRAS (in 13%) mutations are common in this AML type. The prognostic implications of KIT mutation (especially involving exon 8) do not appear to be significantly poor prognostic compared to other AML types. On the other hand FLT3-TKD mutations and trisomy 8 are associated with a worse outcome. The patient is currently receiving Vidaza 75 mg/m2, days 1–7 of a 28 days cycle with Venetoclax mg daily of a 28-day cycle and his clinical prognosis is currently unclear. Further analysis by DNA sequencing may help to characterize the molecular nature of the fusion gene product resulting from the novel t(10;16)(p13;q22). To the best of our knowledge, this is the first reported case of an AML patient with translocation t(10;16)(p13;q22) involving the CBFB gene. Given the rarity and lack of additional information regarding the effects of this abnormality, the prognosis and survival cannot be predicted.

3.
Cogent Medicine ; 8, 2021.
Article in English | EMBASE | ID: covidwho-1617059

ABSTRACT

Background: Coronavirus disease 19 (COVID-19) tends to be milder in children, but severe cases have been reported. We described a case report of a toddler admitted to our department with additional findings, highlighting the importance of assessing the patient as a whole. Case Presentation: A previously healthy, 15-month-year-old girl presented with fever and dry cough for 10 days, respiratory distress and PCR SARS-CoV-2 was positive. At admission, she presented with hypoxemia (SpO2 89-90% in room air), global retraction and bilateral bronchospasm. She was treated with bronchodilators, methylprednisolone, remdesivir and also amoxicillin/clavulanic acid. Her complete blood count revealed leucocytosis 16,160x109/L, 41% lymphocytes, C-reactive protein 57,9 mg/L, procalcitonin 0,13 ng/mL, sedimentation rate 44 mm/h, ferritin 218,4 ng/mL. Chest computed tomography (CT) scan revealed bilateral peripheral areas of ground glass, coexisting consolidation areas at inferior lobes but also revealed a 6 cm supra-renal mass. Abdominal ultrasound and CT confirmed an heterogeneous right supra-renal gland mass of 5,5cm along the greatest diameter with diffuse calcifications, evolving the inferior vena cava and the renal vascular pedicle, no signs of liver, bone, cutaneous or ganglionic metastization. These features were suggestive of neuroblastoma in stage L2. Vanillylmandelic acid, normetanephrine/creatinine ratio and metanephrine/creatinine ratio were elevated. The metaiodobenzylguanidine (Mibg) scan showed a localized disease. The total excision of the tumour mass was performed, and the histology confirmed neuroblastoma with no N-myc oncogene amplification, nor other bad prognosis chromosomal abnormalities. She is currently under oncological surveillance, with no signs of recurrence. Learning Points Discussion: Neuroblastoma is the most common extracranial solid tumour of childhood. It is known for its broad spectrum of clinical behaviour and outcome. In this case, although this toddler was admitted due to COVID-19 pneumonia, it allowed to identify a localized tumour, perform excision and due to the favourable biology tumour, she has a very good chances of being cured and free of disease.

4.
Blood ; 138:3566, 2021.
Article in English | EMBASE | ID: covidwho-1582443

ABSTRACT

Background: DLBCL is highly heterogeneous in underlying biology and clinical behavior. Several high-risk disease features and poor prognostic factors are associated with a higher propensity for refractory disease or relapse after standard R-CHOP therapy;these subset patients require novel strategies to improve upon outcomes. Single-agent TAK-659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pre-treated DLBCL (Gordon et al., Clin Cancer Res, 2020). We report results of a phase I single institution, single arm dose escalation study that assessed safety of 1 st line treatment with R-CHOP and adjunctive TAK-659 for treatment naïve high-risk DLBCL. Methods: Patients aged ≥18 years, ECOG 0-2 with untreated stage I-IV DLBCL with high-risk features defined as, ABC/non-GCB subtype, high-intermediate or high-risk NCCN-IPI (score ≥4), MYC gene rearranged by FISH including double hit lymphoma (DHL), double expressing DLBCL (DEL;overexpression of MYC ≥40% AND BCL2 ≥50% by IHC respectively), or previously treated transformed low-grade lymphoma without prior exposure to anthracycline, were eligible. Patients were treated with R-CHOP for 1 cycle on or off study followed by combined treatment with R-CHOP and TAK-659 for an additional 5 cycles on study. TAK-659 was dosed daily with dosing escalated from 60mg (dose level 1), to 80mg (dose level 2) to 100mg (dose level 3) based on a 3+3 design. The primary objective was to determine the safety and establish the maximum tolerated dose of TAK-659 when combined with R-CHOP in the front-line treatment of high-risk DLBCL. Secondary objectives were to assess preliminary efficacy of this combination as determined by overall response rate (ORR) by PET-CT (Lugano 2014 criteria), progression free survival (PFS), overall survival (OS) and establish the pharmacokinetics of TAK-659 according to dose. Results: 12 pts were enrolled from Dec 2019 to Nov 2021. The median age was 64 yrs (range 25-75);8 (67%) had stage III/IV disease, 4 (33%) with high risk NCCN-IPI ≥ 4. Histology included 7 (58%) with de novo DLBCL (4 GCB, 3 non-GCB subtype DLBCL) including 7 (58%) with DEL, 3 (25%) with transformed FL, 1 (8%) with Richter's and 1 (8%) with DHL. Dose level 3 (100 mg) was established as the MTD. PKs were measured pre- and post-dose D1 and D15 of cycle 2;Cuzick's test signaled an increase in AUC by dose level on D1 (p = 0.01) but not on D15 (Fig 1). ORR was 100% (CR 92%;Fig 2). With a median follow-up of 14.2 months, 1 pt had primary refractory disease (ABC and DEL), 2 pts with CR subsequently progressed (1 non-GC DLBCL, 1 Richter's) and 1 died of cardiogenic shock unrelated to study drug. The 12-month PFS and OS rates were 82% and 90% respectively with estimated 18-month PFS and OS rates of 68% and 90% respectively. The most common treatment related adverse events (TRAEs) attributed to TAK-659 were lymphopenia (n=12, 100%), infection (6=, 50%), AST elevation (n = 12, 100%) and ALT elevation (n = 10, 83%) (Table). Incidence and severity of transaminitis was consistent with prior reports for this agent. Most common grade 3/4 toxicities were hematologic. Median number of cycles of TAK-659 delivered was 5 (range 3-5). TRAEs led to TAK-659 dose modifications in 8 (67%) pts, though none at dose level 1: 2 (17%) required permanent dose reductions (both for lung infections), while 5 (42%) required discontinuation (4 for infection, and 1 for febrile neutropenia). R-CHOP administration was delayed in 2 pts because of TAK-659 related TRAEs. Aside from dose modifications of vincristine for peripheral neuropathy, no additional dose modifications for R-CHOP were needed. Infections encountered included bacterial and opportunistic infections (1 each for PJP, CMV and aspergillosis) and 1 case of COVID. Growth factor prophylaxis and anti-fungal therapy were not mandated;PJP prophylaxis was advised for CD4 counts < 200 at initial diagnosis. Conclusion: TAK-659, a novel SYK inhibitor combined with R-CHOP in pts with newly diagnosed high-risk DLBCL including DLBCL transformed from follic lar lymphoma and DEL produces high CR rates;survival at 12 months appears promising. A dose of 60 mg was well tolerated, did not require dose modifications and maintained a similar AUC to the MTD of 100 mg with ongoing treatment. Opportunistic infections were noted with this treatment combination suggesting that patients should receive aggressive anti-microbial prophylaxis with future evaluation of this combination. [Formula presented] Disclosures: Karmali: BeiGene: Consultancy, Speakers Bureau;Morphosys: Consultancy, Speakers Bureau;Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau;Takeda: Research Funding;Karyopharm: Consultancy;EUSA: Consultancy;Janssen/Pharmacyclics: Consultancy;AstraZeneca: Speakers Bureau;BMS/Celgene/Juno: Consultancy, Research Funding;Genentech: Consultancy;Epizyme: Consultancy;Roche: Consultancy. Ma: Beigene: Research Funding, Speakers Bureau;Juno: Research Funding;AstraZeneca: Honoraria, Research Funding, Speakers Bureau;Loxo: Research Funding;Janssen: Research Funding, Speakers Bureau;Abbvie: Honoraria, Research Funding;TG Therapeutics: Research Funding;Pharmacyclics: Research Funding, Speakers Bureau. Winter: BMS: Other: Husband: Data and Safety Monitoring Board;Agios: Other: Husband: Consultancy;Actinium Pharma: Consultancy;Janssen: Other: Husband: Consultancy;Epizyme: Other: Husband: Data and Safety Monitoring Board;Gilead: Other: Husband: Consultancy;Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board;Karyopharm (Curio Science): Honoraria;Merck: Consultancy, Honoraria, Research Funding;Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties;Bristol Myers Squibb: Honoraria, Research Funding. OffLabel Disclosure: TAK-659 will be discussed for the treatment of DLBCL (not FDA approved for this indication)

5.
Blood ; 138:739, 2021.
Article in English | EMBASE | ID: covidwho-1582364

ABSTRACT

Background: High-risk LBCL is associated with poor prognosis after first-line anti-CD20 mAb-containing regimens, highlighting the need for novel treatments. Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, is approved for treatment of relapsed/refractory (R/R) LBCL after ≥2 lines of systemic therapy. Here we report the primary analysis of ZUMA-12, a Phase 2, multicenter, single-arm study of axi-cel as part of first-line therapy in patients with high-risk LBCL. Methods: Eligible adults had high-risk LBCL, defined by histology (double- or triple-hit status [MYC and BCL2 and/or BCL6 translocations] per investigator) or an IPI score ≥3, plus a positive interim PET per Lugano Classification (Deauville score [DS] 4/5) after 2 cycles of an anti-CD20 mAb and anthracycline-containing regimen. Patients underwent leukapheresis and received conditioning chemotherapy (cyclophosphamide and fludarabine) followed by a single axi-cel infusion at 2×10 6 CAR T cells/kg. Non-chemotherapy bridging could be administered before conditioning per investigator discretion. The primary endpoint was investigator-assessed complete response (CR) rate per Lugano. Secondary endpoints included objective response rate (ORR;CR + partial response), duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and levels of CAR T cells in blood and cytokines in serum. The primary analysis occurred after all treated patients had ≥6 months of follow-up. Results: As of May 17, 2021, 42 patients were enrolled and 40 were treated with axi-cel. Median age was 61 years (range, 23-86);68% of patients were male, 63% had ECOG 1, 95% had stage III/IV disease, 48% had DS4, 53% had DS5, 25% had double- or triple-hit status per central assessment, and 78% had IPI score ≥3. A total of 37 patients had centrally confirmed double- or triple-hit histology or an IPI score ≥3 and were evaluable for response, with 15.9 months of median follow-up (range, 6.0-26.7). The CR rate was 78% (n=29;95% CI, 62-90);89% of patients had an objective response, and median time to initial response was 1 month. Among all 40 treated patients, 90% had an objective response (80% CR rate). At data cutoff, 73% of response-evaluable patients had ongoing responses. Medians for DOR, EFS, and PFS were not reached;12-month estimates were 81%, 73%, and 75%, respectively. The estimated OS at 12 months was 91%. All 40 treated patients had AEs of any grade;85% of patients had Grade ≥3 AEs, most commonly cytopenias (68%). Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 3 patients (8%) and 9 patients (23%), respectively. Median times to onset of CRS and NEs were 4 days (range, 1-10) and 9 days (range, 2-44), with median durations of 6 days and 7 days, respectively. All CRS and most NEs (28/29) of any grade resolved by data cutoff (1 ongoing Grade 1 tremor);39/40 CRS events resolved by 14 days post-infusion and 19/29 NEs resolved by 21 days post-infusion. Tocilizumab was administered to 63% and 3% of patients for management of CRS or NEs, respectively;corticosteroids were administered to 35% and 33% of patients for CRS and NE management. One Grade 5 event of COVID-19 occurred (Day 350). Median peak CAR T-cell level in all treated patients was 36 cells/µL (range, 7-560), and median expansion by AUC 0-28 was 495 cells/µL × days (range, 74-4288). CAR T-cell levels peaked at a median of 8 days post-infusion (range, 8-37). Higher frequency of CCR7+CD45RA+ T cells in axi-cel product, previously associated with greater expansion of CAR T cells (Locke et al. Blood Adv. 2020), was observed in ZUMA-12, compared with the ZUMA-1 study in R/R LBCL (Neelapu et al. New Engl J Med. 2017). Conclusion: In the primary analysis of ZUMA-12, axi-cel demonstrated a high rate of rapid and complete responses in patients with high-risk LBCL, a population with high unmet need. With 15.9 months of median follow-up, responses were durable as medians for DOR, EFS, nd PFS were not yet reached and over 70% of patients remained in response at data cutoff. No new safety signals were reported with axi-cel in an earlier line. Overall, axi-cel may benefit patients exposed to fewer prior therapies, and further trials in first-line high-risk LBCL are warranted to assess axi-cel in this setting. [Formula presented] Disclosures: Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees;Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding;Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties;Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria. Dickinson: Janssen: Consultancy, Honoraria;Takeda: Research Funding;Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau;Amgen: Honoraria;Celgene: Research Funding;Bristol-Myers Squibb: Consultancy, Honoraria;MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau;Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau;Gilead Sciences: Consultancy, Honoraria, Speakers Bureau. Munoz: Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics/Janssen, Seagen, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau;Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium: Research Funding;Pharmacyclics/Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa Kirin, Alexion, Fosun Kite, Innovent, Seagen, BeiGene, Debiopharm, Epizyme, Karyopharm, ADC Therapeutics, Servier, and Genmab: Consultancy, Other: advisory role;Alexion, AstraZeneca Rare Disease: Other: Study investigator;Targeted Oncology, OncView, Kyowa Kirin, Physicians' Education Resource, and Seagen: Honoraria. Thieblemont: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding;Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Hospira: Research Funding;Bayer: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Oluwole: Pfizer: Consultancy;Curio Science: Consultancy;Janssen: Consultancy;Kite, a Gilead Company: Consultancy, Research Funding. Herrera: Takeda: Consultancy;Genentech: Consultancy, Research Funding;Merck: Consultancy, Research Funding;Seagen: Consultancy, Research Fundi g;AstraZeneca: Consultancy, Research Funding;Kite, a Gilead Company: Research Funding;Gilead Sciences: Research Funding;Tubulis: Consultancy;ADC Therapeutics: Consultancy, Research Funding;Bristol Myers Squibb: Consultancy, Research Funding;Karyopharm: Consultancy. Ujjani: Loxo: Research Funding;AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy;TG Therapeutics: Honoraria;Gilead: Honoraria;ACDT: Honoraria;Kite, a Gilead Company: Honoraria;Adaptive Biotechnologies: Research Funding;Atara Bio: Consultancy;AbbVie: Consultancy, Research Funding;Pharmacyclics: Consultancy, Research Funding. Lin: Sorrento: Consultancy;Legend: Consultancy;Novartis: Consultancy;Bluebird Bio: Consultancy, Research Funding;Gamida Cell: Consultancy;Janssen: Consultancy, Research Funding;Celgene: Consultancy, Research Funding;Juno: Consultancy;Vineti: Consultancy;Takeda: Research Funding;Merck: Research Funding;Kite, a Gilead Company: Consultancy, Research Funding. Riedell: Bayer: Honoraria;Karyopharm Therapeutics: Consultancy, Honoraria;Morphosys: Research Funding;Celgene/Bristol-Myers Squibb Company: Consultancy, Honoraria, Research Funding;Verastem Oncology: Honoraria;Kite, a Gilead Company: Honoraria, Research Funding, Speakers Bureau;Novartis: Consultancy, Honoraria, Research Funding;Takeda: Consultancy;BeiGene: Consultancy;Calibr: Research Funding;Xencor: Research Funding;Tessa Therapeutics: Research Funding. Kekre: Gilead: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Celgene: Consultancy, Honoraria. Lui: Gilead Sciences: Other: stock or other ownership;Kite, a Gilead Company: Current Employment, Other: travel support. Milletti: Kite, aGilead company: Current Employment;Gilead Sciences: Other: stock or other ownership. Dong: Kite, a Gilead Company: Current Employment;Gilead Sciences: Other: stock or other ownership;GliaCure/Tufts: Consultancy, Other: advisory role, Patents & Royalties. Xu: Kite, A Gilead Company: Current Employment;Gilead Sciences: Other: stock or other ownership. Chavez: MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy;ADC Therapeutics: Consultancy, Research Funding;Merk: Research Funding;AstraZeneca: Research Funding;MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau;BMS: Speakers Bureau.

6.
Blood ; 138:2249, 2021.
Article in English | EMBASE | ID: covidwho-1582362

ABSTRACT

Background: De novo nucleotide synthesis is necessary to meet the enormous demand for nucleotides, other macromolecules associated with acute myeloid leukemia (AML) progression 1, 2, 34. Hence, we hypothesized that targeting de novo nucleotide synthesis would lead to the depletion of the nucleotide pool, pyrimidine starvation and increase oxidative stress preferentially in leukemic cells compared to their non-malignant counterparts, impacting proliferative and differentiation pathways. Emvododstat (PTC299) is an inhibitor of dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis that is currently in a clinical trial for the treatment of AML. Objectives: The goals of these studies were to understand the emvododstat-mediated effects on leukemia growth, differentiation and impact on Leukemia Stem Cells(LSCs). Comprehensive analyses of mitochondrial function, metabolic signaling in PI3K/AKT pathways, apoptotic signatures, and DNA damage responses were carried out. The rationale for clinical testing emvododstat was confirmed in an AML-PDX model. Results: Emvododstat treatment in cytarabine-resistant AML cells and primary AML blasts induced apoptosis, differentiation, and reduced proliferation, with corresponding decreased in cell number and increases in annexin V- and CD14-positive cells. Indeed, the inhibition of de novo nucleotide synthesis compromises the dynamic metabolic landscape and mitochondrial function, as indicated by alterations in the oxygen consumption rate (OCR) and mitochondrial ROS/membrane potential and corresponding differentiation, apoptosis, and/or inhibition of proliferation of LSCs. These effects can be reversed by the addition of exogenous uridine and orotate. Further immunoblotting and mass cytometry (CyTOF) analyses demonstrated changes in apoptotic and cell signaling proteins (cleaved PARP, cleaved caspase-3) and DNA damage responses (TP53, γH2AX) and PI3/AKT pathway downregulation in response to emvododstat. Importantly, emvododstat treatment reduced leukemic cell burden in a mouse model of AML PDX ( Complex karyotype, mutation in ASXL1, IDH2, NRAS), decreased levels of leukemia stem cells frequency (1 in 522,460 Vs 1 in 3,623,599 in vehicle vs emvododstat treated mice), and improved survival. The median survival 40 days vs. 30 days, P=0.0002 in primary transplantation and 36 days vs 53.5 days, P=0.005 in secondary transpantation in a PDX mouse model of human AML. This corresponded with a reduction in the bone marrow burden of leukemia and increased expression of differentiation markers in mice treated with emvododstat (Fig. 1). These data demonstrate effect of emvododstat on mitochondrial functions. Conclusion: Inhibition of de novo pyrimidine synthesis triggers differentiation, apoptosis, and depletes LSCs in AML models. Emvododstat is a novel dihydroorotate dehydrogenase inhibitor being tested in a clinical trial for the treatment of myeloid malignancies and COVID-19. Keywords: AML, emvododstat, DHODH, apoptosis, differentiation References: 1 Thomas, D. & Majeti, R. Biology and relevance of human acute myeloid leukemia stem cells. Blood 129, 1577-1585, doi:10.1182/blood-2016-10-696054 (2017). 2 Quek, L. et al. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. The Journal of experimental medicine 213, 1513-1535, doi:10.1084/jem.20151775 (2016). 3 Villa, E., Ali, E. S., Sahu, U. & Ben-Sahra, I. Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides. Cancers (Basel) 11, doi:10.3390/cancers11050688 (2019). 4 DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci Adv 2, e1600200, doi:10.1126/sciadv.1600200 (2016). [Formula presented] Disclosures: Weetall: PTC therapeutics: Current Employment. Sheedy: PTC therapeutics: Current Employment. Ray: PTC therapeutics: Current Employment. Andreeff: Karyopharm: Research Funding;AstraZeneca: Research Funding;Oxford Biomedica UK: Research Funding;Aptose: Consultancy;Daiich -Sankyo: Consultancy, Research Funding;Syndax: Consultancy;Breast Cancer Research Foundation: Research Funding;Reata, Aptose, Eutropics, SentiBio;Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company;Novartis, Cancer UK;Leukemia & Lymphoma Society (LLS), German Research Council;NCI-RDCRN (Rare Disease Clin Network), CLL Foundation;Novartis: Membership on an entity's Board of Directors or advisory committees;Senti-Bio: Consultancy;Medicxi: Consultancy;ONO Pharmaceuticals: Research Funding;Amgen: Research Funding;Glycomimetics: Consultancy. Borthakur: ArgenX: Membership on an entity's Board of Directors or advisory committees;Protagonist: Consultancy;Astex: Research Funding;University of Texas MD Anderson Cancer Center: Current Employment;Ryvu: Research Funding;Takeda: Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy.

7.
Blood ; 138:868, 2021.
Article in English | EMBASE | ID: covidwho-1582312

ABSTRACT

Background: Within seconds of antigen-encounter, B-cell receptor (BCR) signaling induces dramatic changes of cell membrane lipid composition, including >40-fold increases of local PIP3-concentrations within lipid rafts. While several structural elements, including pleckstrin homology (PH) domains have been identified as PIP3-binding proteins, the underlying mechanisms that amplify BCR-signaling to assemble large signaling complexes within lipid rafts within 15 to 30 seconds, remained elusive. To understand the mechanistic and biophysical requirements for PIP3 accumulation during normal B-cell activation and acute oncogenic transformation, we identified PIP3-interacting proteins by cell-surface proteomic analyses. Results: In addition to proteins known to bind PIP3 with their PH-domains, we identified the short 133 aa protein IFITM3 (interferon-inducible transmembrane protein 3) as a top-ranking PIP3 scaffold. This was unexpected because IFITM3 was previously identified as endosomal protein that blocks viral infection by stiffening endosomal membranes to firmly contain viral cargo. Previous studies revealed that polymorphisms that lead to the expression of truncated IFITM3 are associated with increased susceptibility to viral infections, including SARS-CoV2. Among known cell membrane lipids, PIP3 has the highest negative charge. Instead of a PH-domain, IFITM3 laterally sequestered PIP3 through electrostatic interactions with two basic lysine residues (K83 and K104) located at the membrane-solution interface. Together with three other basic lysine and arginine residues K83 and K104 form a conserved intracellular loop (CIL), which enable IFITM3 to efficiently capture two PIP3 molecules. Bivalent PIP3-binding of the IFITM3-CIL enables a crosslinking mechanism that results in dramatic amplification of B-cell activation signals and clustering of large signaling complexes within lipid rafts. In normal resting B-cells, Ifitm3 was minimally expressed and mainly localized in endosomes. However, B-cell activation and oncogenic kinases induced phosphorylation at IFITM3-Y20, resulting in translocation of IFITM3 from endosomes and massive accumulation at the cell surface. Ifitm3ˉ /ˉ naïve B-cells developed at normal numbers, however, activation by antigen encounter was compromised. In Ifitm3ˉ /ˉ B-cells, lipid rafts were depleted of PIP3, resulting in defective expression of >60 lipid raft-associated surface receptors and impaired PI3K-signaling. Ifitm3ˉ /ˉ B-cells were unable to undergo affinity maturation and di not contribute to germinal center formation upon immunization. Analyses of gene expression and clinical outcome data from patients in six clinical cohorts for pediatric and adult B-ALL, mantle cell lymphoma, CLL and DLBCL, we consistently identified IFITM3 as a top-ranking predictor of poor clinical outcome. Inducible activation of BCR-ABL1 and NRAS G12D rapidly induced development of B-ALL but failed to transform and initiate B-ALL from Ifitm3ˉ /ˉ B-cell precursors. Conversely, the phospho-mimetic IFITM3-Y20E mutation, mimicking phosphorylation of the IFITM3 N-terminus at Y20 induced constitutive membrane localization of IFITM3, spontaneous aggregation of large oncogenic signaling complexes and readily initiated transformation in a genetic model of pre-malignant B-cells. Conclusions: We conclude that phosphorylation of IFITM3 upon B-cell activation induces a dynamic switch from antiviral effector functions in endosomes to oncogenic signal-amplification at the cell-surface. IFITM3-dependent amplification of PI3K-signaling is critical to enable rapid expansion of activated B-cells. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signaling complexes and amplify PI3K-signaling for malignant transformation and initiation of B-lymphoid leukemia and lymphoma. [Formula presented] Disclosures: Weinstock: SecuraBio: Consultancy;ASELL: Consultancy;Bantam: Consultancy;Abcuro: Research Funding;Verastem: Research Funding;Daiichi Sankyo: Consultancy, Research Funding;AstraZeneca: Consultanc ;Travera: Other: Founder/Equity;Ajax: Other: Founder/Equity.

8.
Meta Gene ; 31: 100990, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1482826

ABSTRACT

Background: Coronavirus disease 2019 is characterized by the elevation of a broad spectrum of inflammatory mediators associated with poor disease outcomes. We aimed at an in-silico analysis of regulatory microRNA and their transcription factors (TF) for these inflammatory genes that may help to devise potential therapeutic strategies in the future. Methods: The cytokine regulating immune-expressed genes (CRIEG) were sorted from literature and the GEO microarray dataset. Their co-differentially expressed miRNA and transcription factors were predicted from publicly available databases. Enrichment analysis was done through mienturnet, MiEAA, Gene Ontology, and pathways predicted by KEGG and Reactome pathways. Finally, the functional and regulatory features were analyzed and visualized through Cytoscape. Results: Sixteen CRIEG were observed to have a significant protein-protein interaction network. The ontological analysis revealed significantly enriched pathways for biological processes, molecular functions, and cellular components. The search performed in the miRNA database yielded ten miRNAs that are significantly involved in regulating these genes and their transcription factors. Conclusion: An in-silico representation of a network involving miRNAs, CRIEGs, and TF, which take part in the inflammatory response in COVID-19, has been elucidated. Thus, these regulatory factors may have potentially critical roles in the inflammatory response in COVID-19 and may be explored further to develop targeted therapeutic strategies and mechanistic validation.

9.
J Pathol ; 254(4): 303-306, 2021 07.
Article in English | MEDLINE | ID: covidwho-1258101

ABSTRACT

The 2021 Annual Review Issue of The Journal of Pathology contains 14 invited reviews on current research areas of particular importance in pathology. The subjects included here reflect the broad range of interests covered by the journal, including both basic and applied research fields but always with the aim of improving our understanding of human disease. This year, our reviews encompass the huge impact of the COVID-19 pandemic, the development and application of biomarkers for immune checkpoint inhibitors, recent advances in multiplexing antigen/nucleic acid detection in situ, the use of genomics to aid drug discovery, organoid methodologies in research, the microbiome in cancer, the role of macrophage-stroma interactions in fibrosis, and TGF-ß as a driver of fibrosis in multiple pathologies. Other reviews revisit the p53 field and its lack of clinical impact to date, dissect the genetics of mitochondrial diseases, summarise the cells of origin and genetics of sarcomagenesis, provide new data on the role of TRIM28 in tumour predisposition, review our current understanding of cancer stem cell niches, and the function and regulation of p63. The reviews are authored by experts in their field from academia and industry, and provide comprehensive updates of the chosen areas, in which there has been considerable recent progress. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Subject(s)
COVID-19/genetics , COVID-19/virology , Neoplasms/pathology , SARS-CoV-2/pathogenicity , COVID-19/pathology , Genomics/methods , Humans , Neoplasms/complications , Neoplasms/genetics , Organoids/pathology , United Kingdom
10.
Gene Rep ; 21: 100956, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1023579

ABSTRACT

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection is a leading cause of pneumonia and death. The aim of this investigation is to identify the key genes in SARS-CoV-2 infection and uncover their potential functions. We downloaded the expression profiling by high throughput sequencing of GSE152075 from the Gene Expression Omnibus database. Normalization of the data from primary SARS-CoV-2 infected samples and negative control samples in the database was conducted using R software. Then, joint analysis of the data was performed. Pathway and Gene ontology (GO) enrichment analyses were performed, and the protein-protein interaction (PPI) network, target gene - miRNA regulatory network, target gene - TF regulatory network of the differentially expressed genes (DEGs) were constructed using Cytoscape software. Identification of diagnostic biomarkers was conducted using receiver operating characteristic (ROC) curve analysis. 994 DEGs (496 up regulated and 498 down regulated genes) were identified. Pathway and GO enrichment analysis showed up and down regulated genes mainly enriched in the NOD-like receptor signaling pathway, Ribosome, response to external biotic stimulus and viral transcription in SARS-CoV-2 infection. Down and up regulated genes were selected to establish the PPI network, modules, target gene - miRNA regulatory network, target gene - TF regulatory network revealed that these genes were involved in adaptive immune system, fluid shear stress and atherosclerosis, influenza A and protein processing in endoplasmic reticulum. In total, ten genes (CBL, ISG15, NEDD4, PML, REL, CTNNB1, ERBB2, JUN, RPS8 and STUB1) were identified as good diagnostic biomarkers. In conclusion, the identified DEGs, hub genes and target genes contribute to the understanding of the molecular mechanisms underlying the advancement of SARS-CoV-2 infection and they may be used as diagnostic and molecular targets for the treatment of patients with SARS-CoV-2 infection in the future.

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