ALBERT

Description: Chimeric antigen receptor (CAR)-T-cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). The treatment is currently also being studied in other B-cell neoplasms, including multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). CD19 and B-cell maturation antigen (BCMA) have been the most popular target antigens for CAR-T-cell immunotherapy of these malignancies. This review will discuss the efficacy and toxicity data from the pivotal clinical studies of CD19- and BCMA-targeted CAR-T-cell therapies in relapsed/refractory B-cell malignancies (NHL, ALL, CLL) and MM, respectively.

Description: COVID-19 greatly affected Europe between March and May 2020. Initial reports suggest cancer and haematological malignancies as risk factors for severity and mortality, but the role of allogeneic stem cell transplantation (alloHSCT) remains unclear. The Société Francophone de Greffe de Moelle et Thérapie Cellulaire conducted a multicentre retrospective study of alloHSCT recipients diagnosed with COVID-19. We described the COVID-19 disease characteristics in this population and examined risk factors for severity and mortality. Data were collected retrospectively from the patients' charts and the ProMISe database. Diagnosis was retained only if a reverse transcription polymerase chain reaction assay test from a nose swab was positive for SARS-CoV-2. Patients were classified as severe if they were transferred to an intensive care unit (ICU) due to COVID-19 or died of COVID-19, and non-severe in other cases. Comparisons of characteristics were performed using student's t-tests and Mann-Whitney U tests for normally and abnormally distributed data, respectively, for continuous variables and χ2 or Fisher's exact tests, when appropriate for categorical variables. Risk factors associated with a severe form of COVID-19 were assessed using both univariate and multivariate logistic regressions. All analyses were performed using SAS version 9.4.6 (SAS Institute Inc., Cary, NC, USA. A two-tailed significance level p

Description: Background T-cells engineered to express a chimeric antigen receptor (CAR) based on the NKG2D receptor (NKG2D CAR) targeting the 8 NKG2D ligands (MICA/B, ULBP1-6) over-expressed by a large variety of malignancies have been developped to treat patients, including patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Previously, CYAD-01, the first generation of NKG2D CAR T-cell products, was evaluated in several Phase I clinical trials and showed initial signals of objective clinical responses in patients with r/r AML and MDS, albeit with short durability. Preclinical data have shown that NKG2D ligands MICA and MICB are transiently upregulated on activated CAR T-cells, and target-dependent killing of CAR T-cells post-infusion can potentially occur, leading to short in vivo persistence. In an effort to increase the persistence and potency of the NKG2D CAR T-cells, CYAD-02 was developed as a next-generation product using a non-gene editing approach to silence the expression of MICA and MICB. Aim MICA and MICB were down-regulated by inserting a single optimized short hairpin RNA (shRNA) targeting both MICA and MICB within the NKG2D CAR construct. This next-generation NKG2D CAR T-cell product is manufactured with the OptimAb process, resulting in CAR T-cells with a higher frequency of early memory T-cells secreting high levels of cytokines upon activation, and is referred to as CYAD-02. Results As compared to CYAD-01, CYAD-02 cell expansion in vitro was 3-fold increased. In an in vivo AML model, CYAD-02 showed 10-fold higher engraftment 1 week after injection and improved anti-tumor activity as compared to CYAD-01 manufactured with the initial mAb process. This led to a 2.6-fold increase of mouse survival as compared to CYAD-01 in a stress-test aggressive AML model where the dose of CYAD-01 was titrated down for minimal activity (figure). The first-in-human study evaluating CYAD-02, the CYCLE-1 study (NCT04167696), has been initiated in early 2020 in patients with r/r AML/MDS. The study evaluates three dose-levels of CYAD-02 (1x108, 3x108 and 1x109 cells/infusion), administered as a single infusion after non-myeloablative preconditioning chemotherapy (cyclophosphamide 300 mg/m²/day and fludarabine 30 mg/m²/day, daily for 3 days, CyFlu) according to a classical Fibonacci 3+3 design. As of August 2020, 6 patients have been treated with CYAD-02 at the dose of 1x108 or 3x108 cells/infusion. To date, the results demonstrate the safety and tolerability for CYAD-02 in patients with r/r AML and MDS with no dose-limiting toxicity observed. The study is currently enrolling at 1x109 cells/infusion. The CYAD-02 safety profile and preliminary clinical activity data together with the pharmacokinetics evaluation from the complete dose escalation segment will be provided at the time of presentation. Conclusion/summary The CYAD-02 is the first autologous CAR T-cell product based on the non-gene edited shRNA technology used to treat patients. This next generation NKG2D CAR T-cell product is currently investigated in the CYCLE-1 Phase I study in r/r AML/MDS patient population, a difficult to target disease due in part to the absence of truly AML-specific surface antigens, its rapid clinical progression and the absence of disease control by the CyFlu preconditioning. Both the anti-MICA and MICB shRNA hairpin and the OptimAb manufacturing process for CYAD-02 aim to improve CAR T-cell persistence and clinical responses. Figure Disclosures Lin: Mateon Therapeutics: Research Funding; Aptevo: Research Funding; Abbvie: Research Funding; Ono Pharmaceutical: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Jazz: Research Funding; Astellas Pharma: Research Funding; Bio-Path Holdings: Research Funding; Celgene: Research Funding; Celyad: Research Funding; Genetech-Roche: Research Funding; Seattle Genetics: Research Funding; Tolero Pharmaceuticals: Research Funding; Trovagene: Research Funding; Prescient Therapeutics: Research Funding; Pfizer: Research Funding. Demoulin:Celyad Oncology: Current Employment. Fontaine:Celyad Oncology: Current Employment. Sotiropoulou:Celyad Oncology: Current Employment. Alcantar-Orozco:Celyad Oncology: Current Employment. Breman:Celyad Oncology: Current Employment. Dheur:Celyad Oncology: Current Employment. Braun:Celyad Oncology: Current Employment. Lonez:Celyad Oncology: Current Employment. Gilham:Celyad Oncology: Current Employment. Flament:Celyad Oncology: Current Employment. Lehmann:Celyad Oncology: Current Employment.

Description: Introduction: Therapy-related myeloid neoplasms (t-MNs) account for about 10 to 20% of all cases of AML and MDS. Allogenic hematopoietic cell transplantation (allo-HCT) is considered as the only curative treatment in this high-risk setting. Given the rise of long-term cancer survivors, an increasing number of patients are expected to become transplant candidates. Physicians are concerned about the frailty and the risk of recurrence of primary cancer. In this retrospective registry-based study, we focused on patients with t-MN secondary to breast cancer radio- and/or chemotherapy, and collected information about the outcomes and complications after allo-HCT. Methods and results: In the EBMT registry we identified 252 female adult patients who underwent an allo-HCT between 2006 and 2016 for t-MN secondary to breast cancer treatment. Median age at transplantation was 57 years, and the median time from the breast cancer diagnosis to t-MN diagnosis and subsequent allo-HCT were 3.7 and 4.6 years, respectively. The indication for allo-HCT was AML and MDS in 77% and 23% of cases, respectively. Sixty-seven% of patients were in complete remission (CR) of their t-MN at the time of transplant. Abnormal karyotype was recorded in 40% of cases. A reduced Karnofsky performance status (KPS

Description: COVID-19 is a severe infectious complication in patients with underlying medical conditions such as having undergone hematopoietic stem cell transplantation (HCT). This prospective survey reports outcome on 272 COVID-19 patients from 19 countries having undergone allogeneic (n = 175) or autologous (n = 97) HCT reported to the EBMT registry or to the GETH. All patients had the diagnosis of SARS-CoV-2 documented by PCR. Patients were included in this analysis if COVID-19 diagnosis was before April 10, 2020. The overall survival was estimate by using the Kaplan Meier methods, considering the death due to any cause as an event and the time from COVID-19 infection to the latest follow-up as survival time; difference between groups were tested by the log-rank test. Univariate and multivariate risk factor analysis for overall survival were performed with the Cox regression model. The median age was 54.4 years (1.0 - 80.3) for allogeneic and 60.9 years (7.7 - 73.4) for autologous HCT patients. 20 patients were children (〈 18 years of age; median age 11.3 (1.0 - 16.9)). The median time from HCT to diagnosis of COVID-19 was 13.7 months (0.2 - 254.3) in allogeneic and 25.0 months (-0.9 - 350.3) in autologous recipients. Lower respiratory tract disease (LRTD) developed in 84.8% and 21.5% were admitted to an intensive care unit (ICU). At the time of analysis, 68/238 (28.6%) patients had died (47/155 allogeneic patients; 21/83 autologous patients). No follow-up had been received on 34 patients. The median time from infection to death was 19 days (0-102). Five patients were reported to have other primary causes of death than COVID-19. Of the patients reported to be alive, the median follow-up was 44 days. 144 (84.7%) patients (93 allogeneic; 51 autologous) had virologic resolution of the COVID-19 infection having at least one negative PCR. 26 patients were alive and known to be still COVID-19 positive (15 allogeneic; 11 autologous). For 34 patients the resolution status was unknown. Factors influencing the likelihood of resolution in multivariate analysis were underlying diagnosis (p=.01) and longer time from transplant to diagnosis of COVID-19 (p=.035). Overall survival at 6 weeks from COVID-19 diagnosis was 76.8% and 83.8% in allogeneic and autologous HCT recipients (p =ns), respectively (figure 1). Children (n=20) tended to do better with a 6-week survival of 95.0% although the difference was not significantly different (p =.12). In multivariate analysis of the total population older age (HR 1.26; 95% CI 1.05 - 1.51; p = .01) increased the risk and better performance status decreased the risk for fatal outcome (HR 0.79; 95% CI 0.69 - 0.90; p = .0003). The same factors had significant impact on overall survival in allogeneic HCT recipients (age HR 1.28; 95% CI 1.05 - 1.55; p=.01; performance status HR 0.79; 95% CI 0.68 - 0.92); p=.002) while only age impacted survival among autologous HCT patients (data not shown). Other transplant factors such as underlying diagnosis, time from HCT to diagnosis of COVID-19, graft-vs-host disease, or ongoing immunosuppression did not have a significant impact on overall survival. We conclude that HCT patients are at an increased risk compared to the general population to develop LRTD, require admission to ICU, and have increased mortality in COVID-19. Figure 1 Disclosures Duarte: Incyte Corporation: Other: Has received speaker and advisor fees. Kwon:Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Mielke:Novartis: Honoraria, Other: received via my institution, Speakers Bureau; Celgene/BMS: Honoraria, Other: received via my institution , Speakers Bureau; Bellicum: Honoraria, Other: received via my institution, Speakers Bureau; Kite/Gilead: Honoraria, Other: received via my institution , Speakers Bureau; Miltenyi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: received via my institution , Speakers Bureau; KIADIS Pharma: Honoraria, Other: received via my institution , Speakers Bureau; DNA Prime: Honoraria, Other: received via my institution , Speakers Bureau. López Jiménez:MSD: Speakers Bureau; Roche: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Abbvie: Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau.