scholarly journals Outcomes of Adult and Pediatric Patients with Hematologic Malignancies and COVID-19: A Systematic Review and Meta-Analysis of 1847 Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-41
Author(s):  
Abi Vijenthira ◽  
Inna Gong ◽  
Thomas A Fox ◽  
Stephen Booth ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Pediatric Patients ◽  
Hematologic Malignancy ◽  
Meta Analysis ◽  
Advisory Board ◽  
Hospitalized Patients ◽  
Private Company ◽  
Advisory Committees ◽  
Risk Of Death

Introduction: Clinical outcomes for patients with hematologic malignancy and COVID-19 have not been aggregated. We completed a systematic review and meta-analysis to estimate the risk of death and other important outcomes for these patients. Methods: We searched Pubmed and EMBASE up to July 25, 2020, to identify reports of patients with hematologic malignancy and COVID-19 (including papers where the patients with hematologic malignancy were a subset of the total study population). The primary outcome was a pooled mortality estimate, considering all patients and only hospitalized patients. Secondary outcomes included pooled estimates for the risk of ICU admission, mechanical ventilation, and non-invasive ventilation in hospitalized patients. Mortality data were stratified by age, treatment status, and malignancy subtype. For treatment status, "systemic anti-cancer therapy (SACT)" was defined as patients on any anti-cancer therapy. "Cytotoxic SACT" was defined as patients on cytotoxic therapy only. "Not on treatment" was defined as patients on observation or those who were at least 28 days beyond their last active treatment. Sensitivity analyses were conducted on the primary outcomes limiting to studies with low risk of bias, and to studies including both outpatients and hospitalized patients. Due to data limitations, only the primary outcome was assessed for pediatric studies. Pooled prevalence and risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effects model using MetaXL and Revman 5.4 software. Results: A total of 25 adult studies and 4 pediatric studies comprising 1847 patients from China, Europe, the United Kingdom, and North America were included (Figure 1 and Table 1). The majority of patients were hospitalized (83%). The overall risk of death amongst all patients was 36% (95% CI 31-41, N=1763), and amongst hospitalized patients was 40% (95% CI 36-45, 24 studies with 1295 patients) (Figure 2). Patients aged >60 years had a significantly higher risk of death than patients <60 years (46% vs. 26%, RR 1.56, 95%CI 1.15-2.13, N=597) (Figure 3). The pooled risk of death in pediatric patients was 4% (95% CI 1-9, N=102) (Figure 2). The risk of ICU admission among hospitalized adult patients was 23% (95% CI 17-29, N=1165); mechanical ventilation 16% (95% CI 12-21, N= 826); and non-invasive ventilation 16% (95% CI 9-26%, N=373). The estimated RR of death among patients on SACT compared to no treatment was 1.22 (95% CI 0.84-1.78; N=457, Figure 3a). The RR of death among patients on cytotoxic SACT versus no treatment was similar at 1.29 (95% CI 0.78-2.15; N=176, Figure 3b). All subgroups of hematologic malignancy had high risks of overall mortality: acquired bone marrow dysfunction syndromes 57% (95% CI 42-72, 11 studies, 42 patients); leukemias 44% (95% CI 31-58, 15 studies, 159 patients), plasma cell dyscrasias 38% (95% CI 29-47, 18 studies, 387 patients); lymphomas (including CLL) 32% (95% CI 26-38, 16 studies, 696 patients); lymphomas (excluding CLL) 32% (95% CI 18-48, 11 studies, 156 patients); CLL 31% (95% CI 24-39, 13 studies, 457 patients); myeloproliferative neoplasms 37% (95% CI 25-49, 9 studies, 62 patients). Sensitivity analysis including only studies with a low risk of bias showed a similar estimate for risk of death among all patients (37% (95% CI 31-42, 20 studies with 1412 patients)) compared to all studies. Sensitivity analysis including only studies reporting on a combination of outpatients and hospitalized patients also showed a similar estimate for risk of death among all patients (38% (95% CI 32-44), 11 studies with 1214 patients) compared to all studies. Conclusion: Adult patients with hematologic malignancy and COVID-19, especially hospitalized patients, appear to experience a high risk of dying (pooled risk estimate 36%). Older patients experience higher mortality, and pediatric patients appear to be relatively spared. Importantly, based on the observational data available to date, recent cancer treatment does not appear to significantly increase the risk of dying. These data highlight the need for robust strategies to prevent patients with hematologic malignancy from contracting COVID-19, and may help inform discussions about prevention strategies, treatment, and goals of care. Disclosures Cook: Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; IQVIA: Research Funding; Sanofi: Consultancy; Amgen: Consultancy; Roche: Consultancy; Karyopharm: Consultancy. Zwicker:Dova: Honoraria, Other: Advisory board; Portola: Honoraria, Other: Advisory board; Incyte: Research Funding; Quercegen: Research Funding; Parexel: Consultancy; Sanofi: Consultancy; CSL: Consultancy; Pfizer/BMS: Honoraria, Other: Advisory board. Scarfo:Gilead: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wood:Pfizer: Research Funding; Best Doctors/Teladoc: Consultancy; Koneksa Health: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Elektra Labs: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; ASH Research Collaborative: Honoraria; Genentech: Research Funding. Hicks:Gilead Sciences: Research Funding.

scholarly journals Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients

Blood ◽  
2020 ◽  
Vol 136 (25) ◽  
pp. 2881-2892
Author(s):  
Abi Vijenthira ◽  
Inna Y. Gong ◽  
Thomas A. Fox ◽  
Stephen Booth ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Systematic Review ◽  
Pediatric Patients ◽  
Hematologic Malignancy ◽  
Meta Analysis ◽  
Hematologic Malignancies ◽  
Hospitalized Patients ◽  
Adult Patients ◽  
Risk Of Death ◽  
Dying Patients ◽  
Pooled Prevalence

Abstract Outcomes for patients with hematologic malignancy infected with COVID-19 have not been aggregated. The objective of this study was to perform a systematic review and meta-analysis to estimate the risk of death and other important outcomes for these patients. We searched PubMed and EMBASE up to 20 August 2020 to identify reports of patients with hematologic malignancy and COVID-19. The primary outcome was a pooled mortality estimate, considering all patients and only hospitalized patients. Secondary outcomes included risk of intensive care unit admission and ventilation in hospitalized patients. Subgroup analyses included mortality stratified by age, treatment status, and malignancy subtype. Pooled prevalence, risk ratios (RRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Thirty-four adult and 5 pediatric studies (3377 patients) from Asia, Europe, and North America were included (14 of 34 adult studies included only hospitalized patients). Risk of death among adult patients was 34% (95% CI, 28-39; N = 3240) in this sample of predominantly hospitalized patients. Patients aged ≥60 years had a significantly higher risk of death than patients <60 years (RR, 1.82; 95% CI, 1.45-2.27; N = 1169). The risk of death in pediatric patients was 4% (95% CI, 1-9; N = 102). RR of death comparing patients with recent systemic anticancer therapy to no treatment was 1.17 (95% CI, 0.83-1.64; N = 736). Adult patients with hematologic malignancy and COVID-19, especially hospitalized patients, have a high risk of dying. Patients ≥60 years have significantly higher mortality; pediatric patients appear to be relatively spared. Recent cancer treatment does not appear to significantly increase the risk of death.

scholarly journals The Role of Proteasome Activator PA28α in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5499-5499
Author(s):  
Yanyan Gu ◽  
Benjamin G Barwick ◽  
Mala Shanmugam ◽  
Craig C Hofmeister ◽  
Jonathan L. Kaufman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
The United States ◽  
Myeloma Cell ◽  
Advisory Board ◽  
20S Proteasome ◽  
Advisory Committees

Multiple myeloma (MM) is a commonly occurring hematologic malignancy in the United States with poor prognosis. Among all treatments, proteasome inhibitor (PI) based regimens have been a major breakthrough for patients' outcomes. Available PIs all target 20S proteasome core complex, and the duration of response is limited by toxicity and resistance development. Until now, the underlying mechanism of drug resistance remains unclear. The proteasome is the major proteolytic machinery in protein homeostasis which is pivotal for myeloma cell survival. A functional proteasome consists of 20S proteasome core particle with regulatory particle on one or both ends. There are 3 types of proteasome regulators that could activate a 20S proteasome, PA700 (19S), 11S REG (PA28) and PA200. The 11S REG (PA28) protein family consists of three members, α, β, and γ. PA28 α/β are IFN-γ inducible and with higher expression in antigen presenting cells. Currently, the function of 11S subunit remains largely unknown. Our analysis of plasma cells from MM patients and healthy donors has demonstrated that expression of 11S proteasome is higher in myeloma cells than normal plasma cells and progressively upregulated with disease progression. To further identify the function of 11S proteasome especially PA28α in MM, we generate PA28α knockdown stable MM cell lines. We have found that knockdown of PA28α inhibits MM cell growth and proliferation, also induces myeloma cell resistance to PIs. The mechanism of PI resistance is different from knocking down of 19S or 20S proteasome subunits. Silencing of PA28α inhibits proteasome activity and decreases proteasome work load concurrently, resulting in a favorable proteasome load vs capacity ratio. Altogether, in this report, we describe the function of PA28α in MM cells, also provide novel insights into regulating PIs sensitivity through modulation of the 11S proteasome subunit PA28α. Disclosures Hofmeister: Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Kaufman:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; AbbVie: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy. Nooka:Amgen: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation. Boise:Genentech Inc.: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Research Funding. Lonial:Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy, Research Funding.

scholarly journals Baseline Characteristics of Patients in Peak: A Global, Longitudinal Registry of Patients with Pyruvate Kinase Deficiency

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Rachael F. Grace ◽  
Audra Boscoe ◽  
Chris Bowden ◽  
Bertil Glader ◽  
Hitoshi Kanno ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Pediatric Patients ◽  
Chelation Therapy ◽  
Treatment Patterns ◽  
Missense Mutations ◽  
Private Company ◽  
Advisory Committees ◽  
The Mean

Background: Pyruvate kinase (PK) deficiency is a rare, inherited hemolytic anemia caused by autosomal recessive mutations in the PKLR gene, whereby a glycolytic defect causes a reduction in adenosine triphosphate generation. Current treatment options are supportive and include splenectomy, blood transfusions, and iron chelation therapy. To better understand the natural history, treatment patterns, and burden of disease, the observational PK Deficiency Natural History Study (NHS) (NCT02053480) enrolled 254 adult and pediatric patients with PK deficiency at 30 sites in 6 countries between 2014 and 2017 and followed patients for 2 years. The Peak Registry (NCT03481738) was developed to continue and expand on this research. This retrospective and prospective observational registry aims to enroll 500 adult and pediatric patients at ~ 60 sites in up to 20 countries over 7 years, with 2-9 years of follow-up. Objective: This analysis aimed to characterize the baseline demographics and clinical characteristics of patients with PK deficiency enrolled in the Peak Registry as of 24March2020. Methods: Demographic, diagnostic, medical history, laboratory, treatment, and other relevant data were collected from participating clinicians via electronic case report forms. To be eligible for inclusion in this analysis, patients were required to have genetically confirmed PK deficiency and available demographic information. All analyses reported here are descriptive and based on data as of the date of enrollment in the registry. Continuous variables are summarized by the number of non-missing observations, mean, standard deviation (SD), median, and range. Categorical variables are summarized as counts and percentages. Results: A total of 141 patients met the inclusion criteria, across 11 countries in North America and Europe. A summary of baseline demographics and clinical characteristics is shown in the Table. Fifty patients (35.5%) had completed 2 years of follow-up in the NHS and then moved to the Peak Registry; the remainder were newly recruited to the Peak Registry. The mean age of study participants at enrollment was 25.5 years (SD 19.1); 78 patients (55.3%) were female. Mean reported age at first symptoms was 5.8 years (SD 13.2) and mean age at diagnosis was 11.7 years (SD 16.0). Fifty-seven percent of patients were classified as having missense/missense mutations, 34.4% as having missense/non-missense mutations, and 8.6% as having non-missense/non-missense mutations. The mean hemoglobin at enrollment was 8.8 g/dL (range: 5.8-12.9 g/dL). Mean reticulocyte count was 19.8% (range: 2.2-42.4%), mean lactate dehydrogenase was 382 IU/L (range: 135-849 IU/L), and mean indirect bilirubin was 4.3 mg/dL (range: 0.8-23.1 mg/dL). Among the 45.2% of patients who had been splenectomized, the mean age at splenectomy was 7.2 years. Chelation therapy had been previously prescribed to 40.3% of patients. Among the 27 patients for whom ferritin data were available, the mean was 867.9 ng/L (range: 78.1-2499.0 ng/L), and 18 patients (66.7%) had a level > 500 ng/L. Ninety-nine patients (70.2%) had received at least one transfusion in their lifetime. Among the 45 patients who were known to have received at ≥ 1 transfusion in the 12 months prior to enrollment, the mean number of transfusions during that period was 5 (SD 4.3), with 18 of those patients (40.0%) having received ≥ 6 transfusions. Conclusions: New data emerging from the Peak Registry will provide valuable insights into the patient characteristics, treatment patterns, and burden associated with PK deficiency. The population is demographically heterogenous and represents a broad geography. Patients have a wide range of hemoglobin levels, and iron overload is common. The substantial rates of splenectomy, cholecystectomy, transfusions, and chelation use are indicative of a high disease and treatment burden in patients with PK deficiency. This abstract is presented on behalf of the Peak Registry Steering Committee and Peak Registry Investigators. Disclosures Grace: Novartis: Research Funding; Pfizer: Research Funding; Agios: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees. Boscoe:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Bowden:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Glader:Agios Pharmaceuticals, Inc.: Consultancy. Layton:Cerus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. van Beers:Novartis: Research Funding; Pfizer: Research Funding; RR mechatronics: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yan:Agios Pharmaceuticals: Consultancy. Bianchi:Agios Pharmaceuticals: Other: Scientific Advisor.

scholarly journals Prospective Clinical Phase II Results on Treosulfan-Based Conditioning Treatment of 70 Paediatric Patients with Haematological Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3354-3354
Author(s):  
Krzysztof Kalwak ◽  
Peter Bader ◽  
Jan Styczynski ◽  
Bernd Gruhn ◽  
Katharine Patrick ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Hematological Malignancies ◽  
Pediatric Patients ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Advisory Board ◽  
Advisory Committees ◽  
Conditioning Treatment

Abstract Background Standard myeloablative conditioning treatment prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) of children is associated with a considerable risk of severe adverse events (AEs). Previous clinical studies in adults confirmed that treosulfan-based conditioning has myeloablative, immunosuppressive and anti-neoplastic effects associated with favorable non-relapse mortality (NRM). Therefore, treosulfan-based conditioning treatment was prospectively evaluated in pediatric patients with hematological malignancies within an extended clinical phase II trial. Patients and Methods In this prospective, single-arm, open-label phase II trial we evaluated a treosulfan-based preparative regimen in pediatric patients with hematological malignancies undergoing alloHSCT. The trial was designed to assess safety and efficacy of a body surface area (BSA) adapted treosulfan dosing regimen of 10, 12 or 14 g/m2/day (according to individual BSA of ≤0.5, >0.5 to 1.0, or >1.0 m2) on Days -6 to -4. Objectives of the trial included overall survival (OS) based on Kaplan-Meier estimates, cumulative incidence (CI) of NRM and disease relapse/progression (RI). NRM was defined as the probability of dying after alloHSCT in the absence of persisting disease or previous occurrence of relapse/progression or graft failure. Moreover, the CI of acute/chronic graft versus host disease (a/cGvHD), the conditional CI of engraftment, Kaplan-Meier estimates of GvHD-free and Relapse/Progression-free Survival (GRFS) and cGvHD-free and Relapse/Progression-free Survival (CRFS), the incidence of complete donor type chimerism (defined as ≥ 95% donor cells), as well as frequencies of adverse events (AEs) until 100 days after alloHSCT were evaluated. Further, treosulfan concentration in plasma was analyzed to calculate AUC and Cmax in a subset of patients. Results Seventy pediatric patients with acute lymphoblastic leukemia (ALL [38.6%]), acute myeloid leukemia (AML, [41.4%]), myelodysplastic syndrome (MDS, [14.3%]), or juvenile myelomonocytic leukemia (JMML, [14.3%]) were enrolled between Nov-2014 and Apr-2016. The median patient age was 9.5 years (range 0-17 years) and median follow up was 12.0 months (range 11.5-17.7 months). Patients received treosulfan intravenously at a dose of 10 g/m2/day (8.6%), 12 g/m2/day (37.1%), or 14 g/m2/day (54.3%). Treosulfan was combined with fludarabine only (7.1%) or fludarabine and thiotepa (92.9%) at the investigators' discretion. The maximum conditional CI of granulocyte engraftment was 100.0% (90% CI: 97.7, 100.0). The incidence of complete donor-type chimerism at visit Day +28 was 94.2% (90% CI: 87.2, 98.0). OS at 12 months was 91.4% (90% CI: 83.9, 95.5). NRM at 12 months was only 1.4% (90% CI: 0.0, 3.8) and RI was 15.7% (90% CI: 8.6, 22.9). There was no statistical significant difference between the three dose groups with regard to any of these objectives. Grade II to IV and III to IV aGvHD were 26.1% and 8.7%, respectively. At 12 months overall cGvHD was 24.8% and moderate/severe cGvHD was 18.8%. GRFS at 12 months was 64.7% (90% CI: 54.2, 73.4) and CRFS was 66.0% (90% CI: 55.5, 74.6). The three most common CTCAE terms of at least grade III were mucositis oral (41.4%), infections and infestations - other (28.6%), and nausea (17.1%). One (1.4%) patient developed hepatic sinusoidal occlusion syndrome (grade II acc. to Jones) and recovered after 22 days. Frequencies of AEs with at least CTCAE grade III apparently correlated with increasing dose group. However, median AUC was comparable between the three different dose groups (1287 mg*hr/L [10g/ m2], 1268 mg*hr/L [12g/m2] and 1461mg*hr/L [14g/m2]) as evaluated in a subset of 58 patients. Median Cmax was also comparable between the different dose groups (628µg/mL [10g/m2], 583µg/mL [12g/m2] and 656µg/mL [14g/m2]). Conclusions The 12-month follow-up data of this phase II trial confirm that treosulfan-based conditioning with BSA-adapted dosing was safe and effective in pediatric patients with hematological malignancies. The cumulative incidence of OS and NRM compared favorably to those reported for other conditioning regimens. Treosulfan/fludarabin/thiotepa is therefore considered to be a reasonable alternative for myeloablative conditioning in this pediatric patient population. (Funded by medac GmbH, MC-FludT.17/M, EudraCT no: 2013-003604-39; ClinicalTrials.gov identifier: NCT02333058). Figure. Figure. Disclosures Kalwak: medac: Other: travel grants; Sanofi: Other: travel grants. Bader:Riemser: Research Funding; Medac: Patents & Royalties, Research Funding; Neovii: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau. Gruhn:Jazz Pharmaceuticals: Honoraria. Patrick:medac: Other: Funding for EBMT conference fees and accomodation. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Corbacioglu:Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kremens:DSMC for industry driven clinical study: Consultancy; Miltenyi Biotec Germany: Consultancy. Vora:Pfizer: Other: Advisory board; Medac: Other: Advisory board; Novartis: Other: Advisory board; Amgen: Other: Advisory board; Jazz: Other: Advisory board.

scholarly journals Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study: A Perioperative Management Plan for Patients with Atrial Fibrillation Who Are Receiving a Direct Oral Anticoagulant

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. LBA-5-LBA-5 ◽  
Author(s):  
James Douketis ◽  
Alex C. Spyropoulos ◽  
Joanne M Duncan ◽  
Marc Carrier ◽  
Gregoire Le Gal ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Major Bleeding ◽  
Research Funding ◽  
Perioperative Management ◽  
Elective Surgery ◽  
Bleeding Risk ◽  
Advisory Board ◽  
Advisory Committees ◽  
Arterial Thromboembolism ◽  
High Bleeding Risk

Abstract Introduction: The perioperative management of patients who are taking a direct oral anticoagulant (DOAC) for atrial fibrillation (AF) and require an elective surgery/procedure is uncertain. No studies have addressed the timing of perioperative DOAC interruption and resumption, and if perioperative heparin bridging and coagulation function testing are needed. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study hypothesized that a simple, standardized perioperative management strategy, based on DOAC-specific interruption and resumption intervals, that foregoes perioperative heparin bridging and coagulation function testing, is safe for patient care, with associated low rates of major bleeding (1%) and arterial thromboembolism (0.5%). We postulated that this management yields a high proportion of patients (>90%) with a minimal to no DOAC level at surgery/procedure. Methods: PAUSE is a prospective study with 3 parallel DOAC cohorts of patients with AF taking apixaban, dabigatran or rivaroxaban and requiring anticoagulant interruption for an elective surgery/procedure. Patients were managed using a standardized protocol based on DOAC pharmacokinetic properties, procedure-associated bleeding risk (Appendix 1) and creatinine clearance (CrCl). DOACs were interrupted for 1 day before and after surgery for a low bleed risk surgery and 2 days before and after a high bleed surgery; longer interruption was done in patients on dabigatran with a CrCl<50 mL/min (Figure 1). A blood sample was obtained just before the procedure to measure residual DOAC levels (Appendix 2). Heparin bridging and preoperative coagulation testing were not used to manage patients. Patient follow-up occurred weekly for 30 days post-procedure for the primary clinical outcomes of major bleeding and arterial thromboembolism (Appendix 3). The incidence (95% confidence interval [CI]) of clinical outcomes was determined for each DOAC cohort using an intention-to-treat (ITT) analysis (interrupted at least 1 DOAC dose) and per-protocol analysis (adhering to DOAC interruption and resumption protocol). Results: We enrolled 3007 patients from 23 sites in Canada, the U.S. and Europe (Appendix 4). The patient characteristics were (Figure 2): mean age 72.5 years; 66.1% male; 33.5% high bleeding risk surgery/procedure, with 1257 patients in the apixaban cohort, 668 in the dabigatran cohort and 1082 in the rivaroxaban cohort (Table 1). DOAC interruption and resumption intervals are shown in Table 2. The 30-day postoperative rate (95% CI) of major bleeding was 1.35% (0-2.00) in the apixaban cohort, 0.90% (0-1.73) in the dabigatran cohort and 1.85% (0-2.65) in the rivaroxaban cohort; the rate (95% CI) of arterial thromboembolism was 0.16% (0-0.48) in the apixaban cohort, 0.6% (0-1.33) in the dabigatran cohort and 0.37% (0-0.82) in the rivaroxaban cohort (Table 3). There were 2541 (84.5%) patients with preoperative DOAC levels measured: a level <50 ng/ml occurred in 90.5% of patients in the apixaban cohort, in 95.1% of the dabigatran cohort and in 96.8% of the rivaroxaban cohort. Of 1007 patients having a high bleeding risk procedure, 832 (82.6%) had DOAC levels measured: 98.8% had a level <50 ng/mL (Table 4). Rates of major bleeding and arterial thromboembolism in the per protocol analysis were comparable to those of the ITT analysis (Table 5). Conclusions: In patients with AF who were taking a DOAC (apixaban, dabigatran, rivaroxaban) and required anticoagulant interruption for an elective surgery/procedure, using a standardized DOAC-specific perioperative management strategy was safe for patient care, with associated low rates of perioperative MB (<2%) and ATE (<1%). Further, a high proportion of patients (>90% overall; 98.8% at high bleeding risk) had a minimal or no residual DOAC level at the time of the surgery/procedure. PAUSE is the largest study, to date, that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care. Study Funding: CIHR (313156) and the H&S Foundation of Canada (G-14-0006136). Aniara-Hyphen Biomed (assays). Acknowledgments: We thank Drs. Walter Ageno, David Garcia, Lehana Thabane, Wendt Lim, Lori Linkins, William Ristevski, and Demetrios J. Sahlas. Also, Kayla Lucier, Grace Wang, Tara McDougall, and HRLMP and CRLB. Supported by CanVector and REDCap. Disclosures Douketis: Bayer: Other: Advisory Board; Janssen: Consultancy; BMS: Other: Advisory Board; Biotie: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; The Medicines Company: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Portola: Other: Advisory Board; Pfizer: Other: Advisory Board. Spyropoulos:Janssen Scientific Affairs, LLC: Consultancy. Carrier:Bayer: Honoraria; Leo Pharma: Research Funding; Pfizer: Honoraria; BMS: Honoraria, Research Funding. Vanassche:Bayer: Consultancy; Boehringer Ingelheim: Consultancy; BMS/Pfizer: Consultancy. Verhamme:Bayer: Honoraria, Research Funding; Medtronic: Honoraria; Portola: Honoraria; Boehringer Ingelheim: Honoraria; Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Shivakumar:Pfizer: Honoraria; Servier: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria. Gross:Pfizer: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria; Servier: Honoraria. Lee:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Servier: Honoraria; LEO Pharma: Consultancy, Research Funding; Bayer: Consultancy, Honoraria. Le Templier:BMS-pfizer: Honoraria. Wu:Leo Pharma: Honoraria; Pfizer: Honoraria; BMS-Pfizer: Honoraria. Coppens:Bayer: Honoraria, Other: Non-financial support, Research Funding; CSL Behring: Honoraria, Other: non-financial support, Research Funding; Uniqure BV: Research Funding. Arnold:Bristol Myers Squibb: Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding. Caprini:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Recovery Force: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizor: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Membership on an entity's Board of Directors or advisory committees. Summer:Octapharma: Honoraria. Schulman:Daiichi-Sankyo: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Boehringer-Ingelheim: Honoraria, Research Funding.

scholarly journals Preclinical Evaluation of Gilteritinib on NPM1-ALK Driven Anaplastic Large Cell Lymphoma Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2865-2865
Author(s):  
Sudhakiranmayi Kuravi ◽  
Janice Cheng ◽  
Kishore Polireddy ◽  
Gabrielle Fangman ◽  
Roy A Jensen ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Advisory Board ◽  
Advisory Committees ◽  
Apoptotic Protein ◽  
Large Cell Lymphoma ◽  
Alk Positive

Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin's lymphoma (NHL) comprising 2-8% of adult and 10-20% of pediatric and adolescent NHL. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL express (nucleophosmin1) NPM1-ALK fusion gene as a result of t(2;5) chromosomal translocation. The self-dimerization of fusion kinase NPM1-ALK mediates constitutive activation of the chimeric tyrosine kinase activity leading to downstream signaling pathways responsible for lymphoma cell proliferation and survival. The current standard treatment regimen for ALK+ ALCL is CHOP (cyclophosphamide, hydroxy doxorubicin, vincristine, prednisone) chemotherapy. Oftentimes, resistance and failure of remission occur with CHOP therapy, making it a suboptimal treatment regimen for many patients. Therefore, an alternative therapeutic approach is warranted to better address the needs of the ALK+ ALCL population. Gilteritinib is a recently FDA approved tyrosine kinase inhibitor for the treatment of FMS-like tyrosine kinase (FLT3) mutation-positive acute myeloid leukemia. Along with inhibition of FLT3, gilteritinib also inhibits other tyrosine kinases such as AXL and ALK. In this study, for the first time, we demonstrated gilteritinib mediated growth inhibitory effects on NPM1-ALK driven ALCL cells. We have used a total of five cell lines in our study: NPM1-ALK endogenously expressing human ALCL cell lines (SUDHL-1, SUP-M2, SR-786, and DEL), and our laboratory generated ectopically overexpressing Ba/F3-FG-NPM1-ALK, a murine cell line. Gilteritinib treatment (5-20 nM) inhibited NPM1-ALK fusion kinase phosphorylation, which resulted in downregulation of downstream survival signaling pathways including AKT, ERK1/2, and STAT3 leading to induced apoptosis and decreased clonogenic survival. Gilteritinib mediated apoptosis was associated with caspase 3/9 and poly (ADP-ribose) polymerase cleavage with increased pro-apoptotic protein BAD and decreased anti-apoptotic protein MCL-1. Increased expression of c-Myc is associated with ALK-positive ALCL and gilteritinib treatment decreased c-Myc levels in a dose dependent manner. Cell cycle analysis demonstrated gilteritinib treatment induced cell cycle arrest at the G0/G1 phase with a concomitant decrease in G2/M and S phases. In summary, our preclinical results suggest gilteritinib has therapeutic potential for the treatment of ALCL cells expressing NPM1-ALK and other ALK /ALK-fusion driven hematologic or solid malignancies. Disclosures Lin: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ganguly:Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Honoraria, Other: Advisory Board; Kite Pharma: Honoraria, Other: Advisory Board. McGuirk:ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 797-797
Author(s):  
Talha Badar ◽  
Mark R. Litzow ◽  
Rory M. Shallis ◽  
Jan Philipp Bewersdorf ◽  
Antoine Saliba ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Research Funding ◽  
Univariate Analysis ◽  
Advisory Board ◽  
Novel Therapies ◽  
Advisory Committees ◽  
Tp53 Mutations

Abstract Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p &lt;0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p&lt;0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p&lt;0.001) and alloHCT in CR1 (p&lt;0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p&lt;0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. &lt; 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

scholarly journals Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 901-901
Author(s):  
Sara Bringhen ◽  
Massimo Offidani ◽  
Pellegrino Musto ◽  
Anna Marina Liberati ◽  
Giulia Benevolo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Community Based ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Grade 3 ◽  
To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those &gt;75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in &gt;75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in &gt;75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p&lt;0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

scholarly journals Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1589-1589
Author(s):  
Fabian Frontzek ◽  
Marita Ziepert ◽  
Maike Nickelsen ◽  
Bettina Altmann ◽  
Bertram Glass ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
High Dose ◽  
Advisory Committees ◽  
Scientific Advisory Board ◽  
Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

scholarly journals Identification of Two CAR T-Cell Populations Associated with Complete Response or Progressive Disease in Adult Lymphoma Patients Treated with Axi-Cel

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 779-779 ◽  
Author(s):  
Zinaida Good ◽  
Jay Y. Spiegel ◽  
Bita Sahaf ◽  
Meena B. Malipatlolla ◽  
Matthew J. Frank ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Advisory Committees ◽  
Car T Cells ◽  
Scientific Advisory Board ◽  
Car T ◽  
Scientific Advisory

Axicabtagene ciloleucel (Axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). Long-term analysis of the ZUMA-1 phase 1-2 clinical trial showed that ~40% of Axi-cel patients remained progression-free at 2 years (Locke et al., Lancet Oncology 2019). Those patients who achieved a complete response (CR) at 6 months generally remained progression-free long-term. The biological basis for achieving a durable CR in patients receiving Axi-cel remains poorly understood. Here, we sought to identify CAR T-cell intrinsic features associated with CR at 6 months in DLBCL patients receiving commercial Axi-cel at our institution. Using mass cytometry, we assessed expression of 33 surface or intracellular proteins relevant to T-cell function on blood collected before CAR T cell infusion, on day 7 (peak expansion), and on day 21 (late expansion) post-infusion. To identify cell features that distinguish patients with durable CR (n = 11) from those who developed progressive disease (PD, n = 14) by 6 months following Axi-cel infusion, we performed differential abundance analysis of multiparametric protein expression on CAR T cells. This unsupervised analysis identified populations on day 7 associated with persistent CR or PD at 6 months. Using 10-fold cross-validation, we next fitted a least absolute shrinkage and selection operator (lasso) model that identified two clusters of CD4+ CAR T cells on day 7 as potentially predictive of clinical outcome. The first cluster identified by our model was associated with CR at 6 months and had high expression of CD45RO, CD57, PD1, and T-bet transcription factor. Analysis of protein co-expression in this cluster enabled us to define a simple gating scheme based on high expression of CD57 and T-bet, which captured a population of CD4+ CAR T cells on day 7 with greater expansion in patients experiencing a durable CR (mean±s.e.m. CR: 26.13%±2.59%, PD: 10.99%±2.53%, P = 0.0014). In contrast, the second cluster was associated with PD at 6 months and had high expression of CD25, TIGIT, and Helios transcription factor with no CD57. A CD57-negative Helios-positive gate captured a population of CD4+ CAR T cells was enriched on day 7 in patients who experienced progression (CR: 9.75%±2.70%, PD: 20.93%±3.70%, P = 0.016). Co-expression of CD4, CD25, and Helios on these CAR T cells highlights their similarity to regulatory T cells, which could provide a basis for their detrimental effects. In this exploratory analysis of 25 patients treated with Axi-cel, we identified two populations of CD4+ CAR T cells on day 7 that were highly associated with clinical outcome at 6 months. Ongoing analyses are underway to fully characterize this dataset, to explore the biological activity of the populations identified, and to assess the presence of other populations that may be associated with CAR-T expansion or neurotoxicity. This work demonstrates how multidimensional correlative studies can enhance our understanding of CAR T-cell biology and uncover populations associated with clinical outcome in CAR T cell therapies. This work was supported by the Parker Institute for Cancer Immunotherapy. Figure Disclosures Muffly: Pfizer: Consultancy; Adaptive: Research Funding; KITE: Consultancy. Miklos:Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees. Mackall:Vor: Other: Scientific Advisory Board; Roche: Other: Scientific Advisory Board; Adaptimmune LLC: Other: Scientific Advisory Board; Glaxo-Smith-Kline: Other: Scientific Advisory Board; Allogene: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Obsidian: Research Funding; Lyell: Consultancy, Equity Ownership, Other: Founder, Research Funding; Nektar: Other: Scientific Advisory Board; PACT: Other: Scientific Advisory Board; Bryologyx: Other: Scientific Advisory Board.

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