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The 2010 and 2017 editions of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults are widely recognized among physicians and investigators. There have been major advances in our understanding of AML, including new knowledge about the molecular pathogenesis of AML, leading to an update of the disease classification, technological progress in genomic diagnostics and assessment of measurable residual disease, and the successful development of new therapeutic agents, such as FLT3, IDH1, IDH2, and BCL2 inhibitors. These advances have prompted this update that includes a revised ELN genetic risk classification, revised response criteria, and treatment recommendations.

Purpose: Most data on the prognostic impact of cytogenetic abnormalities come from the setting of newly diagnosed multiple myeloma, it remains unclear whether the dynamic changes of cytogenetic aberrations affect the prognostic evaluation in multiple myeloma. Methods: We analyzed the prognostic impact of dynamic changes of cytogenetic abnormalities with a cohort consisting of 80 paired patients with consecutive cytogenetic data both at diagnosis and recurrence among 568 patients with newly diagnosed multiple myeloma. Results : Three patterns of recurrence were established from 80 paired patients: Pattern A (40%) consisted of 32 patients without new cytogenetic abnormalities at the time of progression. Pattern B (15%) consisted of 12 patients harboring new standard risk (SR) cytogenetic aberrations. Pattern C (45%) consisted of 36 patients with new high-risk (HR) cytogenetic abnormalities. The median overall survival (mOS; P Conclusions: Dynamic cytogenetic changes significantly affected prognostic evaluation in multiple myeloma. Patients harboring new HR cytogenetic abnormalities and escalated genetic risk stratification at relapse had worse outcomes. Figure 1 Disclosures Anderson: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) occur in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib - an oral, potent inhibitor of the mutant IDH1 (mIDH1) enzyme - is FDA-approved for adults with relapsed/refractory m IDH1 AML and adults with newly diagnosed m IDH1 AML who are ≥ 75 years or have comorbidities that preclude use of intensive induction chemotherapy (IC). Data from a phase 1b study of 23 patients with newly diagnosed m IDH1 AML showed a favorable safety profile and encouraging clinical activity of ivosidenib + azacitidine (IVO+AZA; NCT02677922). Methods: In this global, double-blind, randomized, placebo-controlled, phase 3 study, patients were randomized 1:1 to IVO 500 mg once daily + AZA 75 mg/m 2 subcutaneously or intravenously for 7 days in 28-day cycles, or placebo + AZA (PBO+AZA), and stratified by region and de novo vs secondary AML. Key eligibility: untreated AML (WHO criteria), centrally confirmed m IDH1 status, not eligible for IC, ECOG 0-2. Primary endpoint: event-free survival (EFS; time from randomization until treatment failure, i.e. failure to achieve complete remission [CR] by week 24, relapse from remission, or death from any cause). Key secondary endpoints: CR rate, overall survival (OS), CR + CR with partial hematologic recovery (CRh) rate, and objective response rate (ORR). Results: From 19-Mar-2018 to 18-Mar-2021, 146 patients were randomized: 72 to IVO+AZA (median [interquartile range] age, 76.0 [70.5-79.5] years) and 74 to PBO+AZA (median [interquartile range] age, 75.5 [70.0-80.0] years). Fifty-four (75.0%) patients had de novo AML vs 18 (25.0%) with secondary AML in the IVO+AZA arm. Sixteen (22.2%) patients receiving IVO+AZA had poor-risk genetics per ELN guidelines vs 20 (27.0%) patients receiving PBO+AZA. Thirty-nine (26.7%) patients remain on treatment (27/72 patients in the IVO+AZA arm vs 12/74 patients in the PBO+AZA arm). EFS was statistically significant (HR = 0.33 [95% CI 0.16, 0.69]; P = 0.0011) in favor of the IVO+AZA arm. Median OS with IVO+AZA was 24.0 months vs 7.9 months with PBO+AZA (HR = 0.44 [95% CI 0.27, 0.73]; P = 0.0005). CR rate with IVO+AZA was 47.2% (34/72 patients; 95% CI 35.3%, 59.3%) vs 14.9% (11/74 patients; 95% CI 7.7%, 25.0%) with PBO+AZA (P < 0.0001). Median time to CR was 4.3 months with IVO+AZA vs 3.8 months with PBO+AZA. CR+CRh rate with IVO+AZA was 52.8% (38/72 patients; 95% CI 40.7%, 64.7%) vs 17.6% (13/74 patients; 95% CI 9.7%, 28.2%) with PBO+AZA (P < 0.0001). The CR rate by 24 weeks for IVO+AZA vs PBO+AZA was 37.5% and 10.8%, respectively. ORR with IVO+AZA was 62.5% (45/72 patients; 95% CI 50.3%, 73.6%) vs 18.9% (14/74 patients; 95% CI 10.7%, 29.7%) with PBO+AZA (P < 0.0001). All reported P-values are 1-sided. Common all-grade adverse events (AEs) occurring in > 20% of patients receiving IVO+AZA vs PBO+AZA were nausea (42.3% vs 38.4%), vomiting (40.8% vs 26.0%), diarrhea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), anemia (31.0% vs 28.8%), febrile neutropenia (28.2% vs 34.2%), thrombocytopenia (28.2% vs 20.5%), constipation (26.8% vs 52.1%), and pneumonia (23.9% vs 31.5%). Sixty-six (93.0%) patients receiving IVO+AZA vs 69 (94.5%) patients receiving PBO+AZA experienced a grade ≥ 3 AE. Common grade ≥ 3 AEs occurring in > 20% of patients receiving IVO+AZA vs PBO+AZA included febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), and pneumonia (22.5% vs 28.8%). Frequency of all-grade differentiation syndrome (DS) as assessed by investigators was 14.1% with IVO+AZA vs 8.2% with PBO+AZA, and that of grade ≥ 3 DS was 4.2% with IVO+AZA vs 4.1% with PBO+AZA. Based on the recommendation of the Independent Data Monitoring Committee, further enrollment into the study was prematurely discontinued due to evidence of benefit. Conclusions: IVO+AZA significantly improved EFS, OS, and clinical response (CR, CR+CRh, ORR) compared with PBO+AZA in patients with IC-ineligible, newly diagnosed m IDH1 AML. The safety profile of IVO+AZA was favorable and consistent with previous studies. These data demonstrate the clinical benefit of IVO+AZA in this difficult-to-treat AML population. Disclosures Montesinos: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Forma Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Recher: Incyte: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Takeda: 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, Research Funding. Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Heuser: Tolremo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Astellas: Research Funding; BergenBio: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Calado: AA&MDS International Foundation: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis Brasil: Honoraria; Instituto Butantan: Consultancy; Alexion Brasil: Consultancy. Schuh: Kite/Gilead: Research Funding; GlycoMimetics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees. Daigle: Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Servier: Current Employment. Hui: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Boehringer Ingelheim: Ended employment in the past 24 months. Zhang: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Pandya: Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Servier: Current Employment. Gianolio: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. de Botton: Pierre Fabre: Other; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Honoraria, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Döhner: Oxford Biomedicals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Ulm University Hospital: Current Employment. OffLabel Disclosure: 1) Ivosidenib (AG-120) is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test in: i) Adult patients with newly diagnosed AML who are 75 years of age or older or who have comorbidities that preclude use of intensive induction chemotherapy ii) Adult patients with relapsed or refractory AML. 2) It is being evaluated in a clinical trial in combination with azacitidine in adults 18 years of age or older with previously untreated acute myeloid leukemia with an IDH1 mutation.

Background: Hairy cell leukemia-variant (HCL-v) is one type of chronic lymphocytic proliferative disorders which was classified into splenic B-cell lymphoma/leukemia, unclassifiable. Both clinical and laboratory characteristics and treatment strategy remain elusive due to the rarity of the disease. Here, we firstly presented the diseases features and efficacy of a variety of treatment options in a large cohort from China. Methods: Thirty-three patients were diagnosed with HCL-v in Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College from June 1990 to February 2021. We analyzed the disease characteristics and treatment outcome, especially in terms of clinical manifestation, immunophenotypic and molecular evaluation and efficacy of multiple first-line treatment. Results: The median age of this cohort was 59 years (range, 34-79 years) at diagnosis, with 23 males and 10 females. Abdominal mass and relative signs (n=22) and abnormal complete blood count (n=9) were the most common chief complaints. Splenomegaly was present in 32 (97.0%) cases, among whom 26 (78.8%) cases were massive. Leukocytosis and leukopenia were presented in 23 (69.7%) patients and 5 (15.2%) patients, with a median white blood cell count of 21.58×10 9/L (range, 1.34-224.59×10 9/L). The median percentage of the leukemic cells in bone marrow tested by flow cytometry was 33% (range, 6.2%-96%), and immunophenotyping showed monoclonal B-cells positive for pan B-cell antigens (CD19, CD20, CD22, CD79b) in almost all patients (Table). CD11c was positive in all patients, and CD103 was positive in 20/26 (76.9%) patients. CD25 was negative in 30/33 (90.9%) patients, and CD23 was negative in 20/26 (76.9%) cases. CD200 was frequently expressed among patients (15/21, 71.4%). For the pathological pattern of bone marrow involvement, 20/27 (74.1%) patients showed a predominantly interstitial pattern. Moreover, Annexin A1 was negative in all (n=12) patients detected by immunohistochemistry. Conventional cytogenetic analysis showed abnormal karyotype in 10/24 (41.7%) patients, including 6 patients with complex karyotype. Fluorescence in situ hybridization analysis showed deletion of TP53 in 4/20 (20.0%) patients and IGH translocation in 5/16 (31.3%) patients. The BRAF V600E mutation was negative in all the patients (n=20). In 2 of 14 (16.7%) patients, TP53 mutation was detected by next-generation sequencing. Sixteen of nineteen (84.2%) patients showed monoclonal IGHV rearrangements, and the most common rearrangement fragment was VH4-34 (n=3, 18.8%). Six of seventeen (35.3%) patients presented with unmutated IGHV and patients with VH4-34 were all unmutated. 31 patients needed treatment finally. Treatment choices included interferon-α (IFN-α) in 11 patients, chlorambucil (CLB) in 5 patients, single purine nucleoside analogs (PNA) in 3 patients and PNA plus rituximab in 9 patients. Four patients who received IFN-α or CLB treatment also underwent splenectomy. The objective response rate was 100% for patients receiving PNA plus rituximab and 77% for cases receiving others. And people treated with PNA plus rituximab had a higher complete response rate compared to the other regimen (75% versus 12%, P = 0.004). During a median follow-up of 32 months (range, 3-207) for 29 patients, 14 (48.3%) patients experienced at least one relapse or progression, and 7 (24.1%) patients had 2 or more relapses. Of note, one case also underwent a diffuse large B-cell lymphoma transformation. The median PFS and OS were 31 months (95% CI 25.5-36.5) and 70 months (95% CI 50.5-89.5), respectively. PNA plus rituximab prolong PFS compared to the others (3-year PFS rate 80% [95%CI 20-97] versus 10% [95%CI 1-35], P = 0.012, Figure A). But no significant difference in 3-year OS rate was observed between two groups (100% [95%CI 100-100] versus 43% [95%CI 10-73], P = 0.128, Figure B). Conclusion: HCL-v is a rare disease with specific clinical and immunophenotypic features but may overlap with classic hairy cell leukemia or other splenic B-cell neoplasms. Overall, it is an indolent lymphoma with recurrent progression, and the use of PNA plus rituximab in first-line treatment can result in a deeper and longer remission. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

Background: The incidence of B-cell ALL follows a bimodal distribution, with the first peak occurring in childhood and a second peak occurring around the age of 50. While the prognosis for pediatric patientshas improved over the past decades, prognosis for the elderly remains very poor. Despite a high rate of response to induction chemotherapy, only 30-40% of adult patients with ALL will achieve long-term remission. Patients with primary refractory and chemo-refractory B-cell ALL have an extremely poor prognosis. A chimeric antigen receptor (CAR) specific for the CD19 B lymphocyte molecule has provide an option of treating B-cell malignancies. Although these CAR-modified T cell products target the same antigen, the designs of CD19-targeted CAR T-cells vary significantly. CNCT19 is autologous CD19-directed genetically modified T cell immunotherapy. The structure of chimeric antigen receptor (CAR) includes CD19scFv-hCD8α hinge-CD8α TM-4-1BB-CD3ζ in tandem. The patent protected CD19scFv sequence is derived from CD19 monoclonal antibody HI19a featured with high specificity and affinity to CD19. This strong binding capability to CD19 leads to killing of the CD19 positive malignant B-cells. Use of 4-1BB co-stimulatory domain is expected to reduce the severity of treatment-associated cytokine release syndrome (CRS) and neurologic toxicities (NT) while maintaining a stronger and longer-term anti-tumor effect. Methods: CNCT19 has been investigated in an open-label, phase 1/2 clinical trial for adult and pediatric patients with r/r ALL who have failed ≥ 2 lines prior therapies. Leukapheresis to obtain T cells was performed following the SOP of the local hospitals. CNCT19 was infused 2 to 14 days after lymphodepletion. All the patients were hospitalized up to 2 weeks. All the PIs have been trained for the management of CNCT19-treatment related CRS and neurotoxicities. A PI committee was involved in the management of CRS and neurologic toxicity. The primary objectives of the study were to determine the safety and the clinical outcomes, including ORR within 3 months, PFS, and overall survival (OS). Results: As of October 2020, 63 patients (adults: n=32 >18 years, children: n=31 < 18 years) have received CNCD19 treatment and all subjects have been followed at least for one year. All grade adverse events occurred in 54 patients (54/63 = 85.7%). Grade ≥3 CRS and NEs occurred in 12 (12/63 = 19%) and 13 (13/63 = 20%), respectively. Out of 63 patients, 59 (59/63= 93.6%) have had overall responder rate (ORR) defined as complete remission (CR) and complete remission with incomplete hematologic recovery (CRi). Among the 59 responded patients, the minimal residual disease (MRD) was negative in 56 patients (56/69 = 94.9%) and 23 patients (38.9%) received allogeneic-HSCT treatment. The relapse-free survival (RFS) and overall survival (OS) were summarized in adult and pediatric groups separately in the following table. Conclusions: CNCT19 treatment of patients with r/r ALL demonstrates improved ORR, PFS, and OS both in children and adults. A pivotal clinical trial is going on in China to evaluate the ORR, PFS, and OS with a clinical plan to decrease the severity of treatment-related adverse events (CRS/NE). Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the global phase 3 ALCYONE trial, the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) resulted in improved outcomes over bortezomib, melphalan, and prednisone (VMP) alone in transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). At a median follow-up of 16.5 months, the median progression-free survival (PFS) was not reached (NR) for the D-VMP group versus 18.1 months for the VMP group (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.38-0.65; P Methods: Eligible pts in OCTANS and ALCYONE were ≥18 years of age, had NDMM, and were not eligible for autologous stem cell transplant due to age (≥65 years) or comorbidities. All pts received up to 9 (42-day) cycles of bortezomib 1.3 mg/m 2 subcutaneously twice weekly on Weeks 1, 2, 4, and 5 of Cycle 1 and once weekly on Weeks 1, 2, 4, and 5 of Cycles 2-9; melphalan 9 mg/m 2 orally once daily on Days 1-4 of each cycle; and prednisone 60 mg/m 2 orally once daily on Days 1-4 of each cycle. For pts in the D-VMP group, daratumumab 16 mg/kg intravenously was administered once weekly in Cycle 1, once every 3 weeks in Cycles 2-9, and once every 4 weeks thereafter until disease progression or unacceptable toxicity. Cytogenetic risk was determined at baseline via local fluorescence in situ hybridization or karyotype analysis; pts with high cytogenetic risk had a del17p, t(4;14), or t(14;16) abnormality. Results: In total, 220 Asian pts were randomized (D-VMP, n=146; VMP, n=74) in the OCTANS study and 706 global pts were randomized (D-VMP, n=350; VMP, n=356) in the ALCYONE study. The median age was 69 (range, 57-84) years in OCTANS and 71 (range 40-93) years in ALCYONE. Among pts with available cytogenetic results, 48/219 (21.9%) pts in OCTANS and 98/616 (15.9%) pts in ALCYONE had high-risk cytogenetic abnormalities. At a median follow-up of 12.3 months in OCTANS and 16.5 months in ALCYONE, in the pooled intent-to-treat (ITT) population from OCTANS and ALCYONE, the estimated 12-month PFS rate was 86.2% in the D-VMP group (n=496) versus 74.6% in the VMP group (n=430), and the estimated 18-month PFS rate was 73.3% versus 50.3%, respectively; the median PFS was NR in the D-VMP group versus 18.1 months in the VMP group (HR, 0.48; 95% CI, 0.38-0.61; P Conclusion: In a pooled analysis of Asian pts from OCTANS and global pts from ALCYONE, D-VMP demonstrated clinical benefit versus VMP in transplant-ineligible pts with NDMM. The benefit of D-VMP versus VMP was observed across clinically relevant subgroups. These results support the use of D-VMP in transplant-ineligible pts with NDMM. Figure 1 Figure 1. Disclosures Kim: BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Li: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Chim: Janssen, Takeda & Amgen: Other: received sponsorship for overseas meetings. Rodriguez-Otero: Clínica Universidad de Navarra: Current Employment; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria. Dimopoulos: Takeda: Honoraria; BMS: Honoraria; Janssen: Honoraria; Beigene: Honoraria; Amgen: Honoraria. Wroblewski: Janssen: Current Employment, Current equity holder in publicly-traded company. Carson: Janssen: Current Employment. Qi: Janssen: Current Employment, Current equity holder in publicly-traded company. Wang: Janssen: Current Employment. Song: Janssen: Current Employment. Jia: Janssen: Current Employment. Yang: Janssen: Current Employment, Current equity holder in publicly-traded company. Liu: Janssen: Ended employment in the past 24 months. Li: Janssen: Current Employment. Zhang: Janssen: Current Employment. Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

Introduction Major resources of our current knowledge on acute leukemia epidemiology and prognosis are based on data from clinical trials. Due to the selective bias of clinical trials, data might differ from the general leukemia population in real-life setting. National Clinical Research Center for Blood Disease established a comprehensive database through the electronic health records (EHR) to facilitate research of the hematologic cancers i.e. acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and acute promyelocytic leukemia (APL). The aim of the database is to gain insight into the epidemiology of these cancers, to evaluate treatment responses, to compare results between geographical regions of China. Furthermore, with the privilege of national research center, the database expects to identify prognostic and predictive factors for outcome to improve the quality of treatment and patients care. Methods The database development was initiated in 2001. Standard data elements were established to capture the key clinical variables. For individual patients, data from EHRs were extracted, integrated and quality checked. The implement of database facilitated the clinical professions to identify eligible patients, establish research projects, conduct retrospective analysis and follow-up patient outcomes. Continued efforts were made for improving the construction and quality of the database over two decades. We performed a 10-year real-world data review in the database to evaluate the quality of the recorded data and, moreover to describe the clinical, cytogenetic characteristics and survival of acute leukemia patients. The completeness for collected variables was acceptable for statistical analysis. In total, 3,404 patients (1,895 males and 1,509 females) who were diagnosed and treated between Jan. 1, 2010 and Dec. 31, 2020 were enrolled. A substantial proportion (>60%) of patients were residents of the northern and northeast region of China. Demographic and baseline characteristics also included age, age class, baseline blood test, transplantation and research participation. Molecular mutations such as nucleophosmin-1 (NPM1), FMS-related tyrosine kinase 3 (FLT3), and CCAAT/enhancer-binding protein alpha (CEBPA) et al were included in the screening panels. We explored the treatment remission rate and prognosis of different chromosomal karyotype groups among AML patients. Results The patient numbers of the AML, ALL and APL subgroups were 2,345, 769 and 290 respectively. Blood routine results well demonstrated the clinical characteristics of each subgroup (Tbl. 1). In AML group, the frequencies of NPM1, FLT3-ITD, KIT and CEBPA double mutations were 17.9%, 13.2%, 8.7% and 10.1%, respectively (Tbl. 2). In term of ALL, 640 cases (83.2%) were B-ALL and 129 (16.8%) were T-ALL. Among B-ALL, 256 cases (33.3%) were Ph positive. 10-year analysis for overall survival shown that AML patients had better outcomes as compared with ALL group (Fig. 1). In this database, 1,780 AML cases (excluding APL) were enrolled in cytogenetic analysis. The survival rates of different cytogenetic risk groups from our real-world data were separated by the ELN2017 and MRC risk stratification respectively (Fig. 2A-B). Remarkably, we found two rare but recurrent abnormalities, 16 cases with t(7;11) (p15;p15) and 12 cases with t(16;21)(p11;q22/q24;q22). Cases showed high relapse and mortality rate. Compared with the normal karyotype group, the survival of both subentities was worse and transplantation might be recommended in CR1 phase (Fig. 2C), therefore, we recommend that these two subtypes might be regarded as the worse risk group, although neither is mentioned in the current guidelines. The incidence of t(8;21) in our database was 17.9% (Fig. 3). To explore the impact of additional chromosomal abnormalities on the prognosis of t(8;21), we found that the overall survival of patients with additional trisomy 4 was worse than those without trisomy 4 (Fig. 2D), which was rarely mentioned in previous reports. Conclusion The real-world database is of great importance for defining the comprehensive features of AML, APL and ALL in clinical setting. The results offered a remarkable contribution to our knowledge on acute leukemia and identified the prognosis of rare chromosomal karyotype in AML. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

Introduction: Daratumumab is a human IgGκ monoclonal antibody that targets CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the primary analysis (median follow-up, 16.5 months) of the global phase 3 ALCYONE trial, daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) significantly improved progression-free survival (PFS) versus VMP alone in patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for transplant (median PFS, not reached vs 18.1 months; hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.38-0.65; P Methods: Eligible patients in OCTANS and ALCYONE were ≥18 years of age, were diagnosed with NDMM, and were not eligible for autologous stem cell transplant due to age (≥65 years) or comorbidities. All patients received up to 9 cycles (42-days) of bortezomib (1.3 mg/m 2; subcutaneous) twice weekly on Weeks 1, 2, 4, and 5 of Cycle 1 and once weekly on Weeks 1, 2, 4, and 5 of Cycles 2 to 9; melphalan (9 mg/m 2; oral) once daily on Days 1 to 4 of each cycle; prednisone (60 mg/m 2; oral) once daily on Days 1 to 4 of each cycle. For patients in the D-VMP group, daratumumab (16 mg/kg, intravenous) was administered once weekly in Cycle 1, once every 3 weeks in Cycles 2 to 9, and once every 4 weeks thereafter until disease progression or unacceptable toxicity. Response over time (at 6, 12, 18, 24, 54 weeks) and disease progression were assessed by a validated computer algorithm in accordance with the IMWG criteria. Minimal residual disease (MRD) negativity (10 -5) was assessed by multi-parameter flow cytometry in OCTANS and by next-generation sequencing in ALCYONE. Results: In the OCTANS study, 220 Asian patients were randomized (D-VMP, n=146; VMP, n=74); in the ALCYONE study, 706 global patients were randomized (D-VMP, n=350; VMP, n=356). Median age in OCTANS was 69 (range, 57-84) years and 71 (range 40-93) years in ALCYONE. Patients were pooled from both studies (D-VMP, n=496; VMP, n=430). D-VMP increased the rate of complete response or better (≥CR; 10.2% vs 5.6%) and the rate of very good partial response or better (≥VGPR; 58.5% vs 38.1%) versus VMP after 18 weeks of treatment (Figure A). Responses deepened over time among patients in both the D-VMP and VMP groups, as shown by the ≥CR rate (D-VMP, 38.8%; VMP, 21.6%) and the ≥VGPR rate (D-VMP, 74.0%; VMP, 50.7%) at 54 weeks. At a median follow-up of 12.3 months for OCTANS and 16.5 months for ALCYONE, among patients who achieved a VGPR (D-VMP: n=145 [29.2%]; VMP: n=109 [25.3%]), the median PFS was not reached in the D-VMP group versus 19.9 months in the VMP group (HR, 0.61; 95% CI, 0.36-1.00; P=0.0499; Figure B). All patients who achieved ≥CR with or without MRD negativity (10 -5) demonstrated prolonged PFS, regardless of treatment (≥CR: HR, 1.54; 95% CI, 0.65-3.65; P=0.3210; ≥CR+MRD negativity: HR, 0.67; 95% CI, 0.13-3.40; P=0.6225; Figure B); however, more patients treated with D-VMP achieved this level of response (≥CR: D-VMP , n=212 [42.7%]; VMP, n=100 [23.3%]; ≥CR+MRD negativity: D-VMP, n=116 [23.4%]; VMP, n=27 [6.3%]; Figure B). Conclusion: In a pooled analysis of OCTANS and ALCYONE, more patients with transplant-ineligible NDMM achieved deeper responses with D-VMP versus VMP. More patients treated with D-VMP achieved ≥CR with or without MRD negativity compared with those treated with VMP alone, leading to prolonged PFS regardless of treatment. These results support the use of daratumumab in addition to VMP in transplant-ineligible Asian patients with NDMM. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Kim: BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Li: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Chim: Janssen, Takeda & Amgen: Other: received sponsorship for overseas meetings. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria; Clínica Universidad de Navarra: Current Employment. Liberati: abbvie, amgen, archigen, beigene, BMS, celgene, DR REDDY'S LABORATORIES SPA, fibrogen, glaxo, Janssen, Karyopharm, Morphosys, Novartis, Onconova, Oncopeptides ab, Roche, Sanophi, Secura Bio, Takeda, Verastem,: Research Funding. Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; SRL: Consultancy; Adaptive Biotechnologies, Eisai: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Dimopoulos: BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Wroblewski: Janssen: Current Employment, Current equity holder in publicly-traded company. Carson: Janssen: Current Employment. Qi: Janssen: Current Employment, Current equity holder in publicly-traded company. Wang: Janssen: Current Employment. Song: Janssen: Current Employment. Jia: Janssen: Current Employment. Yang: Janssen: Current Employment, Current equity holder in publicly-traded company. Liu: Janssen: Ended employment in the past 24 months. Li: Janssen: Current Employment. Zhang: Janssen: Current Employment.

Background: Due to poor prognosis, treatment options for patients with FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) who are refractory to therapy or have relapsed (R/R) are needed globally. Gilteritinib is approved in multiple countries, including Japan, and has recently received conditional approval in China for the treatment of R/R FLT3mut+ AML; in the phase 3 ADMIRAL trial, superior survival benefit and a favorable safety profile were shown for patients receiving gilteritinib compared to those receiving salvage chemotherapy (SC) (HR 0.64 [95% CI: 0.49, 0.83]; P Aim/Objective: To evaluate the efficacy and safety/tolerability of gilteritinib compared with SC in Asian patients with R/R FLT3mut+ AML after first-line therapy. Methods: In this phase 3, open-label, multicenter COMMODORE (NCT03182244) trial, adult patients in China, Russia, Singapore, Thailand, and Malaysia with R/R FLT3mut+ AML were randomized 1:1 to gilteritinib 120 mg orally per day or SC (low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine; or fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor) over continuous 28-day cycles. Patients must have had an ECOG performance status score ≤2; those with acute promyelocytic leukemia, BCR-ABL-positive leukemia, clinically active central nervous system disease, or secondary AML were excluded. The primary endpoint was overall survival (OS), and key secondary efficacy endpoints were event-free survival (EFS) and complete remission (CR). Additional secondary endpoints included duration of remission, composite CR (CRc), and safety/tolerability. OS and EFS were analyzed with stratified Cox proportional hazard models, and response rates were analyzed with the Cochran-Mantel-Haenszel test. Results of the interim analysis are presented here. Results: As of June 30, 2020, a total of 234 patients were randomized (gilteritinib, n=116; SC, n=118). Median age was 51.5 and 49.5 years in the gilteritinib and SC groups, respectively; most patients had not previously received FLT3 inhibitors (87.9% and 93.2%, respectively). Baseline FLT3 mutations in the gilteritinib vs SC groups were: FLT3-ITD (91.4% vs 83.1%), FLT3-TKD (6.0% vs 11.9%), and both FLT3-ITD and FLT3-TKD (2.6% vs 5.1%). Median follow-up duration for OS was 11.1 months for gilteritinib and 6.9 months for SC. Median OS was significantly longer in the gilteritinib group (9.0 months) compared with the SC group (4.7 months; HR 0.549 [95% CI: 0.379, 0.795]; P=0.00126; Figure); 1-year survival rates were 33.3% and 23.2%, respectively. Patients on gilteritinib had significantly longer EFS than those receiving SC (median EFS 2.8 vs 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; P=0.00004). A higher proportion of patients achieved CR on gilteritinib (16.4%) compared with SC (10.2%; P=0.17690); CRc rates were 50.0% and 20.3% (P Conclusions: Gilteritinib significantly prolonged OS and EFS compared with SC in patients with R/R FLT3mut+ AML in Asia. When adjusted for treatment exposure, safety/tolerability was favorable for gilteritinib compared with SC. The results of the COMMODORE trial further validate and affirm the clinical efficacy and safety data from the ADMIRAL trial, reinforcing the significant benefit of gilteritinib in R/R FLT3mut+ AML. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Jiang: Astellas Pharma, Inc.: Research Funding. Li: Astellas Pharma, Inc.: Research Funding. Liu: Astellas Pharma, Inc.: Research Funding. Du: Astellas Pharma, Inc.: Research Funding. Jiang: Astellas Pharma, Inc.: Research Funding. Hu: Astellas Pharma, Inc.: Research Funding. Yuan: Astellas Pharma, Inc.: Current Employment. Sakatani: Astellas Pharma, Inc.: Current Employment, Current equity holder in publicly-traded company. Kadokura: Astellas Pharma, Inc.: Current Employment. Takeuchi: Astellas Pharma, Inc.: Current Employment. Izuka: Astellas Pharma, Inc.: Current Employment. Girshova: Astellas Pharma, Inc.: Research Funding. Tan: Astellas Pharma, Inc.: Research Funding. Wong: Astellas Pharma, INc.: Research Funding. Khuhapinant: Astellas Pharma, Inc.: Research Funding. Martynova: Astellas Pharma, Inc.: Research Funding. Hasabou: Astellas Pharma, Inc.: Current Employment. Tiu: Astellas Pharma, Inc.: Current Employment.

Background Follicular lymphoma (FL) is an incurable indolent disease with a heterogeneous course. The Follicular Lymphoma International Prognostic Index (FLIPI) is the most commonly used prognostic system to predict survival. Rituximab-based immunochemotherapy is now the standard choice for the first-line therapy of FL, followed by rituximab maintenance (RM) in patients with response, which prolongs the progression-free survival (PFS). However, the role of RM in different FLIPI risk groups has never been studied as we know. In this study, we aimed to illustrate the effect of RM in FLIPI risk groups. Methods Newly diagnosed FL patients at our center were enrolled in this analysis. All the patients received the rituximab-based chemoimmunotherapy induction regimens. Response assessments were determined according to Lugano's 2014 criteria. Patients who didn't respond to induction were excluded. Categorical variables were compared using Fisher's exact test. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared with the log-rank test. Results From May 2003 to September 2020, 203 newly diagnosed FL were included. 192 patients (95.0%) achieved remission (complete response, CR/partial response, PR) after immunochemotherapy induction, of whom 96 patients continued rituximab maintenance therapies every 3 months for 1-2 years (RM group) (median 7 times，range 4 to 12). 96 patients received no maintenance or fewer than 4 times (control group) (median 0 times, range 0-3). There were no significant differences in baseline characteristics other than the Ann Arbor stage and pathological grade. The RM group patients were more likely to be at low grade (71.8% vs 54.9%, P = 0.042) and advanced stage (90.6% vs 78.7% , P = 0.027) (Table 1). After a median follow-up of 36.4 months (95% confidence interval [CI], 32.2 to 40.6), median OS and PFS were not reached. The 5-year OS rates and PFS rates were 95.1% (95%CI, 90.2%-100%) and 83.0% (95%CI, 75%-91%)(Fig 1). And RM significantly prolonged the PFS, with 5-year PFS rates 92.2% (95%CI, 85.1%-99.3%) and 70.3%(95%CI, 55%-85.6%) (P = 0.0003) (Fig 2). According to FLIPI risk stratification, patients were classified into low-risk, intermediate-risk, and high-risk groups. The 5-year PFS rates were 97.7% (95%CI, 93.2%-100%), 84.7% (95%CI, 70.4%-99%), and 67.8% (95%CI, 49%-86.6%), respectively (Fig 3). For low-risk patients, there was no significant difference in PFS for the RM group vs the control group. However, for both intermediate risk and high-risk patients, PFS was significantly longer in the RM group compared to the control group (P < 0.0001). The PFS rates at 5 years in intermediate-risk patients were 100% and 77.8% (95%CI, 40.8%-92.6%), for the RM group vs control group, high risk 76.4% (95%CI, 54.3%-98.5%), and 54.9% (95%CI, 21.6%-88.2%), respectively (Fig 4). Conclusion Standard rituximab maintenance significantly prolongs progression-free survival in FLIPI intermediate risk and high-risk patients with FL, but not in the FLIPI low risk group. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

Introduction Immunoglobulin heavy-chain variable genes (IGHV) is critical for the defining epitope binding affinityand B cell differentiation. Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) is a heterogeneous diseasewhose role of IGHV usage remains unknown. Besides, the clinical relevance of IGHV repertoire for LPL/WM remain largely unexplored. The aim of our study is to explore the IGH repertoire of LPL/WM in by far the largest series, and to evaluate the correlation between IGH rearrangements and genetic aberrations and clinical characteristics of LPL/WM patients. Methods A total of 162 patients with a diagnosis of LPL/WM were included in this study. Polymerase chain reaction (PCR)amplification of IGHV-IGHD-IGHJ was performed on genomic DNA or cDNA samples using the IGH Somatic Hypermutation Assay v2.0 (Invivoscribe, Technologies, San Diego, US). Sequences were aligned to IMGT (http://www.imgt.org/IMGT_vquest/vquest) and IGBLAST (https://www.ncbi.nlm.nih.gov/igblast/) databases. IGH gene repertoires, mutation status, IGHV CDR3 characteristics, genetic aberrations, MYD88 mutation status and clinical characteristics were collected to evaluate the relevance. Results Productive IGHV-D-J rearrangements were obtained in 136 out of 162 patients (84.0%). The IGHV gene repertoire was remarkably biased in LPL/WM. IGHV3-23 (15.4%), IGHV4-34 (10.3%), IGHV3-7 (8.1%), IGHV3-30 (7.4%) and IGHV3-74 (7.4%) were significantly overrepresented in LPL/WM(Figure 1). Among the 134 IGHD data, the most frequent segment was IGHD3-10 (21/134, 15.7%), followed by IGHD6-13 (18/134, 13.4%) (Figure 2). Among the 134 IGHJ data, IGHJ4 segment was selected in more than half of these rearrangements (70/136; 51.5%), followed by IGHJ6 (23/136; 16.9%) and IGHJ5 (21/136; 15.4%) (Figure 3). Most of the cases were mutated (97.0%) using a 98% IGHV germline homology cutoff. IGHV3-30 was associated with long heavy chain CDR3, indicating the specific antigen selection in LPL/WM. Patients with IGHV3-7 were significantly more likely to harbor 6q deletion (p Conclusion LPL/WM appears to be composed ofdifferent subgroups based on the IGHV repertoire. The mutational status and the IGHV CDR3 length indicated the role for antigenselection in LPL/WM development. The presence of IGHV4 genes proved to be a potential risk factor associated with outcome which deserved further study.These results showed for the first time that IGHV repertoire had clinical relevance in LPL/WM. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

Background Lemzoparlimab (also known as TJC4 or TJ011133), a novel, RBC-sparing CD47 antibody with a unique epitope, is in early phase clinical development in both the U.S. and China. Like other anti-CD47 antibodies, lemzoparlimab blocks the interaction of CD47 and SIRPα, leading to phagocytosis of various CD47+ tumor cell lines and primary AML cells. Mono-treatment of lemzoparlimab inhibited tumor growth completely and extended the overall survival of treated mice in a patient-derived AML xenograft model. Here we report initial findings in the ongoing phase I trial which is to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lemzoparlimab in relapsed and/or refractory (r/r) AML and MDS patients. Methods The trial (NCT04202003) adopted a modified 3+3 dose escalation design with weekly lemzoparlimab at dose levels of 1, 3, 10, 20 and 30 mg/kg. The initial two lower dose cohorts (1 mg/kg and 3 mg/kg) was designed to enroll one patient each, and the study would escalate to the next level (10 mg/kg) if no DLT and no predefined toxicity events (e.g. grade 2 or above drug-related non hematologic toxicity, except for isolated lab abnormality with no clinical manifestation) were observed. If the first DLT or predefined toxicity event was observed, the cohort size would be expanded at the current dose level and the study would revert to the standard 3+3 design. Safety, PK/PD parameters, and preliminary efficacy were evaluated. Results As of 24 July 2020, 5 r/r AML patients (pts) including 1 relapsed, 1 relapsed/refractory and 3 primary refractory, were enrolled across 3 dose cohorts (1 at 1 mg/kg, 1 at 3 mg/kg and 3 at 10 mg/kg). Patients had 2-4 prior therapies. Median age was 45 years (range 25-66). Four of 5 pts developed treatment emergent AEs. Most of the AEs were grade 1 or 2. Treatment-related AEs that occurred in > 1 patient included thrombocytopenia (2/5 pts, 1 with grade 1 and 1 with grade 3) and positive anti-erythrocyte antibody (2/5 pts). No dose dependent hematologic toxicities have been observed so far. There was no treatment-related dose interruption or dose discontinuation. No patient developed treatment-related SAE or death. The maximum tolerated dose (MTD) has not yet been reached and the drug was well tolerated in r/r AML pts in the background of significantly impaired hematopoietic function with or without supportive blood transfusion. The anti-CD47 interferences on the blood bank testing were mitigated before blood transfusion. With doses from 1 mg/kg to 10 mg/kg, lemzoparlimab exhibited a supraproportional increase in exposure, which can be attributed to target (CD47) mediated drug disposition at low doses. CD47 receptor occupancy (RO) was evaluated as a PD marker. The mean RO on peripheral T cells at Cmax was 74.0%, 82.0% and 84.9% for 1, 3 and 10 mg/kg, respectively. The mean RO on CD33+ tumor cells at Cmax was 45.9%, 75.8% and 82.2% for 1, 3 and 10 mg/kg, respectively. Of note, one patient with primary refractory AML achieved morphologic leukemia-free state (MLFS) after 2 cycles of lemzoparlimab treatment at 1 mg/kg. Conclusion Lemzoparlimab was well tolerated in r/r AML pts in the doses tested and importantly, consistent with preclinical data, there were no serious hematological AEs so far. No DLTs or MTD was observed up to 10 mg/kg weekly dosing so far. The PK/PD profile of lemzoparlimab is also consistent with preclinical findings. The preliminary efficacy observed was encouraging. Dose escalation will continue until MTD or RP2D is reached. Disclosures No relevant conflicts of interest to declare.

Introduction Mantle cell lymphoma (MCL) is a rare subtype of aggressive non-Hodgkin's lymphoma in which the genomic factors determining the clinical behavior are not fully understood. The genetic heterogeneity in MCL motivates us to characterize the genetic landscape, to define pattern of clonal evolution, and to determine molecular subgroups. Methods We performed whole-exome sequencing on 152 DNA samples derived from 134 MCL patients, which includes 123 untreated and 11 relapsed patients, and 16 with longitudinal samples. 95 patients received high dose cytarabine-based immunochemotherapy from BDH-MCL01 clinical trial (NCT02858804). 48 samples have matched RNA sequencing data for which 42 from untreated and 6 from relapsed patients. We used GATK, MutSig2CV, and GISTIC2.0 to identify driver genetic lesions, applied MutationalPatterns to define mutational signatures, and utilized ABSOLUTE and PhylogicNDT to determine pattern of clonal evolution. We applied NNMF consensus clustering to identify subgroups and evaluated association between genomic features and clinical outcomes. Results The median non-silent mutational burden was 29 per sample (range 8-72). 34 recurrently mutated genes were identified, containing previously reported driver mutations (TP53, ATM, CCND1, KMT2D, NSD2, SMARCA4, ARID1A, NOTCH1, NOTCH2, BIRC3, TRAF2, UBR5) and novel mutations (SP140, SVEP1, LRP1B, LRP2, PCDH10). 7 copy number gain and 13 loss regions were detected as recurrent somatic copy number alterations (frequency>10%, q We defined the clonal status of genetic lesions and pattern of clonal evolution. Del(11q22) and del(9p) tend to be clonal while mutations in NSD2, LRP1B, CTNNA2 were more likely to be subclonal (q 0.5), 4 with modest evolution (0.2 ≤ CCF change ≤ 0.5), 1 without evolution (CCF change < 0.2). Patients with extreme evolution had inferior survival than with those with modest and no evolution (median survival from first sampling was 47.5 months vs not reached, p=0.041, second sampling was 17.1 months vs not reached, p=0.023). We classified MCL into four subsets based on genetic lesions, each with distinct gene expression profile and clinical behavior (Fig C, D). Cluster 1 (C1) and cluster 2-4 (C2-4) were associated with indolent and aggressive types of MCL. Consistent with different cellular origins for two types of MCL, C1 and C2-4 were enriched for gene expression signatures of memory and CCR6 negative light zone B cells, respectively. C1 featured mutated IGHV, CCND1 mutation, amp(11q13) and active BCR signaling. C2 was enriched with del (11q22), del (1p21), ATM mutation and had upregulation of genes involved in the NF-kB and DNA repair pathways while C3 was characterized by mutations in SP140, NOTCH1 and NSD2 and downregulation of gene expression in the NF-kB, BCR signaling, MYC and inflammatory pathways. Interestingly, C4 had the highest incidence of blastoid or pleomorphic MCL (23.7%, p=0.016) and harbored del(17p), del(13q), del(9p) and mutations in TP53 and TRAF2. This cluster carried enrichment of MYC pathway activation and hyperproliferation signatures. These unique gene expression signatures indicated that coordinate genomic factors captured biologic heterogeneity. Importantly, patients in these four clusters had distinct outcomes with median PFS of not reached for C1, 41.2 months for C2, 30.7 months for C3, and 16.1 months for C4 (log rank, p Conclusion Our study provides a portrait of the MCL genetic landscape, uncovers pattern of clonal evolution in MCL, classifies patients with genetic features, links the cluster with gene expression and clinical outcome. The outcome-associated genetic signatures will guide the development of therapies in patients with the greatest need. Figure Disclosures No relevant conflicts of interest to declare.

Background: Large granular lymphocyte leukemia (LGLL) is one type of chronic lymphocytic proliferative disorders, which commonly manifests as infiltration of large granular lymphocytes in both peripheral blood and bone marrow. LGLL now includes two entities with similar clinical course, treatment strategy and outcomes: T-cell large granular lymphocytic leukemia and chronic lymphoproliferative disorder of NK cells. The standard therapy for LGLL is still elusive. Here, we presented the efficacy and safety of combinatorial oral immunoregulatory regimen thalidomide, prednisone, and methotrexate (TPM regimen) in a prospective phase 2 clinical trial. Methods: We designed this phase 2 investigator-initiated clinical trial (NCT04453345) to evaluate the clinical response and safety of the combination of thalidomide, prednisone, and methotrexate in symptomatic treatment naïve LGLL patients. The TPM regimen includes thalidomide 50-100mg per night, prednisone 0.5-1.0mg/kg qod and methotrexate 10mg/m2 per week. This regimen will be administrated for up to 12 months until disease progression or intolerable. Then, thalidomide maintenance will continue for another year or until intolerance. Meanwhile, we set Cyclosporin A (CsA) alone or plus steroids as control. Treatment dosage for CsA was 3-5mg/Kg/day with or without steroids (prednisone) 0.5-1 mg/Kg/day. The primary endpoint of this study was the complete response rate. Results: From Aug 2013, to Jan 2020, twenty-eight patients were enrolled in this study. The median follow-up time was 26 months (range: 7-96). Twenty-five patients (89%) achieved hematologic and symptomatic response. Among them, 21 patients (75%) achieved complete response (CR) and four patients achieved partial response. The median time to best clinical response was 6 months (2-18). The 3-years progression-free-survival (PFS) rate was 90%, and 3-years overall survival (OS) rate was 92%. The median PFS time was not reached in TPM group. The curative effect was better for TPM treatment group, both for overall response (OR) (TPM 89% (25/28) vs CsA 49% (49/99), P=0.000) and CR (TPM 75% (21/28) vs CsA 20% (20/99), P=0.000). Adverse events were uncommon, two patients had grade 1-2 nausea and one had grade 3 nausea. Two patients had grade 1-2 constipation and one patient experienced grade 1-2 peripheral neuritis. Conclusion: The efficacy of this TPM regimen is higher than the history reports with limited adverse events. The multiple-center clinical trial has been initiated to validate this conclusion. Disclosures No relevant conflicts of interest to declare.

Background: Current definition of multi-hit multiple myeloma (MM) is based upon the number of high-risk cytogenetic abnormalities (CA). But we may overlook the influence of standard-risk CA and different concurrent patterns. In fact, standard-risk t(11;14) and del(13q) may bring extra danger when concurrent with other CA. And the concurrency of two secondary CA may do more harm to patients than that of one secondary CA with one primary CA. This study is to answer whether CA number or pattern exert an impact on outcomes of MM patients. Methods: This study was carried out based on the prospective, non-randomized clinical trial BDH 2008/02. 537 MM patients with complete cytogenetic data were enrolled, of whom 64% (341/537) patients were treated with bortezomib-based three-drug induction therapy, and the remaining patients with thalidomide-based therapy. Autologous stem cell transplantation (ASCT) was recommended post induction therapy in transplant-eligible patients, and all patients received maintenance therapy for two years. CA were divided into primary CA [pCA: any type of IgH breakage], and secondary CA [sCA: del(17p), del(13q), gain(1q) (≥3 copies)] Results: In the era of novel agents, patients with pCA only did not have outcomes different from those patients without any FISH abnormality. Patients with s1 CA or s1+p CA had hazard ratio for PFS or OS of 1.5-2.0. Patients with s2 CA or s2+p CA had hazard ratio for PFS or OS of 2.0-3.0. Patients with concurrent del(13q), del(17p) and gain(1q) (s3 CA) had hazard ratio for PFS of 3.11 and for OS of 3.00. Patients with s3+p CA had hazard ratio for PFS of 4.65 and for OS of 6.16. Based on these results, we divided patients into four subgroups: no CA or only pCA, s1 CA in the presence or absence of pCA, s2 CA in the presence or absence of pCA, and s3 CA in the presence or absence of pCA. Both the PFS and OS decreased in a stepwise fashion with the accumulation of CA (Figure 1). Therefore, we defined double-hit MM as any one sCA in the presence or absence of pCA. Triple-hit MM referred to two sCA plus pCA or not, and quadra-hit MM referred to three sCA plus pCA or not. Furthermore, we confirmed the prognostic independence of CA pattern in the multivariant analysis with International Staging System (ISS) and LDH (Table 1). Conclusion: In this study, we found that the primary CA as a whole lost its adverse effect when treated by bortezomib-based regimens. CA subtype conferred a prognostic value. In details, secondary CA imposed an accumulative risk to patients. For the first time, we indicated that double-hit or triple-hit MM should be defined upon the number of secondary CA. This definition coincides with the "Two-Hit" theory of cancer causation and fits well with MM evolution model. The prognostic significance of CA pattern needs validation in further prospective trials. Disclosures No relevant conflicts of interest to declare.

Background: Patients with B cell acute lymphoblastic leukemia (B-ALL) relapsed after allogenic hematopoietic stem cell transplantation(alloHSCT) have poor prognosis and the median survival after relapse was 4 - 5.5 months, estimated 2-year post-relapse survival rates were 10 - 16%. Donor lymphocyte infusion (DLI) have shown limited success in the setting of relapse by a mere increase in median survival by 6 months and a significant risk of acute and chronic graft-versus-host disease (GVHD) and additional risk of marrow aplasia. The donor chimeric antigen receptor-T cell (CAR-T) for CD19 is a promising treatment for relapsed and refractory B-ALL, but the effectiveness and safety of donor-derived CD19 CAR-T cell infusion for relapsed B-ALL after alloHSCT have not been determined. Methods: Between July 2017 and Nov 2018, 10 adult patients with B-ALL relapsed (4 patients were hematologic relapsed, 3 patients were extramedullary relapse, the other 3 patients were bone marrow MRD-positive, Table) after alloHSCT were enrolled, including 9 sibling-matched stem cell transplantation and 1 haploidentical transplantation. About 100 - 200 ml venous blood form each donor was obtained and the T cells were separated. Then donor's T cells were infected with lentivirus carrying CD19 CAR plasmid which containing CD19 scfv (HI-19 clone) and 4-1BB-CD3ζ signaling domains to generate CAR-T cells. ALL the 10 Patients received FAC (fludarabine: 25-30mg/m2/d*3, cyclophosphamide:350mg/m2/d*2, cytosine arabinoside:100mg/m2/d*4) pretreatment and then a total of 5.01 × 106/kg (range, 3.39 - 6.53 × 106/kg) donor T cells including donor-derived anti-CD19 CAR-T cell (1.82 × 106/kg, (range, 1.26 - 4.67 × 106/kg)) was infused on 2 or 3 consecutive days for each patient. The levels of cytokines including IL-1,IL-2R,IL-6,IL-8,IL-10 and the percentage of the donor anti-CD19 CAR-T cells were monitored serially . Clinical manifest and the severity of cytokine release syndrome (CRS) were recorded and evaluated. The bone marrow examination was performed every 2 weeks after CAR T-cell infusion to assess the response for the first 2 months and then was performed every 1-3 months including bone marrow smear, MRD detection by flow cytometry, fusion gene detection by quantitative real-time polymerase chain reaction (qPCR), donor chimera rate by short tandem repeat(STR). Results: The median transduction efficiency of the final donor-derived CD19 CAR-T cells was 35.8%(range 25 - 70.6%). The peak of donor-derived anti-CD19 CAR-T cell expansion in the recipients was about 7 - 14days after infusion and then decreased rapidly. The serum cytokines levels varied differently: the serum IL-6 and IL-2R levels increased overtly and reached the peak during day 5 - day 7 in most of the patients, whereas the serum levels of IL-1, IL-8 and IL-10 did not vary obviously. one patient experienced Grade 3 CRS, 4 patients experienced Grade 2 CRS and the other 5 patients only experienced Grade 1 CRS. Four patients showed encephalopathy and 2 patients received glucocorticoid treatment. All the 10 patients achieved MRD negative remission and complete donor chimerism within 14days to 42days after donor's CAR-T cells infusion. No patients developed acute or chronic graft-versus-host disease (GVHD). After a median follow-up of 20.6 months (range, 13.4-30.3), 5 patients (including all the 3 patients with extramedullary relapse) relapsed with leukemia cells CD19-dim and 4 of them died due to disease progression. Only one patient received a successful secondary alloHSCT from a haplo-identical donor. The other 5 patients showed persistent complete donor chimerism with MRD negative remission(Figure). The estimated 2-year overall survival and leukemia-free survival were 68.6% and 48.0%, 2.5-year OS and LFS were 51.4% and 48.0%. Conclusion: Donor-derived CD19 CAR-T cell infusion seems to be an effective and safe treatment for B-ALL relapsed after alloHSCT, especially for those without extramedullary disease, which may be confirmed with more clinical studies. Disclosures No relevant conflicts of interest to declare.

Background: Acute myeloid leukemia (AML) is a heterogeneous disease in which 20-50% patients are resistant to chemotherapy. Relapsed/refractory (R/R) AML has a poor long-term prognosis resulting from chemotherapeutic drug resistance. However, the specific gene-drug pairs have been rarely reported. The purpose of our study was to explore an accurate algorithm for screening gene profiles classifier associated with chemotherapy drug sensitivity. Method: 43 AML patients from the Institute of Hematology and Blood Diseases Hospital were enrolled, including newly diagnosis (n=23) and R/R (n=20) AML between March 2019 to January 2020. We separated bone marrow cells (BMCs) of the 43 patients. Additionally, 24 therapeutic drugs panel (Figure 1) were selected and 7-concentration gradient were used to test drug sensitivity in vitro by HDS (High-throuphput Drug Sensitivity Analysis Strategy). Paired molecular data of RNA-seq and DNA methylation 850K CHIP implemented simultaneously. K-Means, an unsupervised algorithm, was applied to cluster all samples into two groups (Resistance/Sensitive group) according to IC50 and 100% PPC inhibition rate of each drug. We used a combination of different algorithms to build a proper gene classifier. The whole process was shown as Figure 2. The major objectives of the evaluating algorithm included F1 score, precision rate, recall rate and AUC. "pRRophetic", a R package, was modified to specify target type as "AML" in aim to estimate IC50 of samples based on GDSC database. Furthermore, we cultured Ara-C resistant cell line of HL-60 in purpose of comparing relative gene expression with wide type (wt) by quantitative Real-time PCR (qPCR) to prove the selected gene signature. Result: The HDS data suggested that sensitivities of newly diagnosis AML to chemotherapeutic-drugs were highly variable. However, Newly Diagnosis Group was more sensitive to majority chemotherapeutic drugs in contrast to R/R AML (P As heterogeneous drug response in vitro, we found K-means (k=2) was more reasonable algorithm, as compared to K-means (k=3) for grouping all samples. SVM of transcription data for each drug showed a significantly advantage over other algorithms (P Compared to newly diagnosis AML, R/R Group possessed 2134 upregulated genes and 1210 down-regulated genes in the aspect of RNA-seq data. Crosslinking analysis of RNA-seq and methylation data of the two group, 1 gene were described as up-regulated expression with hypo-methylation, and 39 genes was down-regulated expression with hyper-methylation. 8/39 genes are corresponded with SVM algorithm. Moreover, 4-gene-drug pairs, including FOXC1 for anthracyclines drug, IGFBP5 for Ara-C, VTRNA1-1 and TKTL1 for pan-drug, were investigated by overlapping TOP 5 genes for each drug of SVM algorithm and DEGs between R/R and newly diagnosis AML. High expression of four genes was identified as a risk factor for AML prognosis. The result of qPCR revealed that IGFBP5 is overexpression in Ara-C-resistant HL-60 than wt. Conclusion: We construct a model of K-Means and RFE-DEG/DMP-SVM, a validated and precise computational approach, for predicting drug sensitivity related genes in AML patients. Up-regulated expression with hypo-methylation genes may be signature genes for drug resistance. 4-gene-based classifier may make contributions to chemotherapeutic-drug resistance prediction and AML treatment decision-making. Disclosures No relevant conflicts of interest to declare.

Background: Anti-CD19 chimeric antigen receptor (CAR) T-cell is a promising therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma. 29~37% of patients can achieve sustained complete remission (CR) after anti-CD19 CAR T-cell infusion, which means that approximately two-thirds of patients will eventually progress and have extremely poor survival. We conducted a pilot study to explore the safety and efficacy of CNCT19 (a second-generation anti-CD19 CAR T-cell) cellular immunotherapy in conjunction with high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT). The preliminary results of the first 6 patients had been reported at the 61st ASH Meeting (Liu et al., 784a). Here we reported the updated enrollment, safety, efficacy, and follow-up of this study. This trial was registered at www.chictr.org.cn as ChiCTR1900025419. Methods: Patients with large B-cell lymphoma refractory to primary or salvage therapy were eligible for this study. All patients must have received rituximab and anthracycline-containing treatment during their prior therapy. Conditioning regimen included GBC/M (gemcitabine, busulfan, and cyclophosphamide/melphalan) and BEAM (carmustine, etoposide, cytarabine, and melphalan, administered in one patient), and CNCT19 was infused on day +2, +3 or +4 following autologous stem-cell infusion. Results: Between January 2018 and May 2020, 13 patients were enrolled. The median age was 48 years (range, 29~ 64 years), and there were 7 males. Diagnosis of lymphoma subtypes included diffuse large B-cell lymphoma (n=10), high-grade B-cell lymphoma with MYC, BCL2, and BCL6 rearrangement (n=1), primary mediastinal large B-cell lymphoma (n=1) and transformed follicular lymphoma (n=1). The patients received a median of 3 (range, 2~4) lines of prior therapy and 76.9% had disease that was resistant to last-line therapy. The median dose of infused stem cells was 2.54×106 per kilogram of body weight (range, 1.77~8.7×106) and the median dose of infused CNCT19 cells was 2×106 per kilogram of body weight (range, 1.7~4×106). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT criteria. After CNCT19 infusion, 92.3% of patients experienced grade 1 CRS, and no one experienced grade 2 or higher CRS. The median time after CNCT19 infusion until the onset of CRS was 1.5 days (range, 0~3), and the median time until resolution was 8 days (range, 6~10). Seven patients (53.8%) received tocilizumab and two patients (15.3%) received glucocorticoids for the management of CRS. ICANS occurred in two patients on day 5 and day 6 after CNCT19 infusion, respectively. Both of the ICANS were grade 4 and resolved after glucocorticoids treatment. The median times to neutrophil and platelet engraftment were 11 days (range, 8~32) and 17 days (range, 8~265), respectively. Ten patients were followed up for 3 or more months and evaluable for response. Eight of 10 patients achieved complete remission (CR), and the best overall response rate (ORR) and CR rate were both 80%. With a median follow-up of 11 months (range, 3~31) after CNCT19 infusion, the CR rate at 3 months and 6 months were 70% and 62.5%, respectively. Median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated proportion of PFS and OS at 12 months was 66.7% and 77.1%, respectively. Conclusion: CNCT19 infusion following HDT/ASCT could be safely administered in R/R large B-cell lymphoma patients. More patients achieved sustained remission compared with those who received anti-CD19 CAR T-cell therapy alone. The preliminary results of this pilot study support further investigation of the combination of CAR T cellular immunotherapy with HDT/ASCT. Disclosures Lv: Juventas Cell Therapy Ltd.: Current Employment.

Purpose: Splenic marginal lymphoma (SMZL) is a rare indolent B-cell lymphoma with long survival. The minimal residual disease (MRD) detection in indolent B-cell lymphomas has shown power in predicting survival and even in guiding treatment duration in chronic lymphocytic leukemia. As almost all SMZL patients have bone marrow involvement (BMI) at diagnosis, we prospectively designed the MRD detection during treatment to study its prognostic value in SMZL. Methods: SMZL patients who needed chemotherapy would regularly monitor the MRD status until undetectable MRD by multiparameter flow cytometry (MFC). Patients with MRD under 0.01% were defined as uMRD. Other clinical factors were also analysed as prognostic factors. Results: In total, 71 patients with frontline therapy were enrolled in this study. There were 284 evaluable BM MRD samples. At end of treatment, 55 patients (77.4%) got uMRD, 10 patients had a MRD level of 0.01-1%, and 6 patients had a MRD level of ≥ 1%. The uMRD rate increased at the end of treatment. With a median follow-up of 50 (24-157) months, uMRD patients showed superior outcomes compared with MRD-positive patients. Patients with uMRD had a significant better progression free survival (PFS) compared to those with MRD. PR with positive-MRD after induction therapy was a significantly poor predictor for PFS and overall survival (OS). Multivariate prognostic analysis showed it was a powerful independent prognostic factor for PFS [HR=0.357 (95%CI 0.131-0.972), P=0.044]. Conclusion: uMRD in BM was an independent prognostic factor in SMZL patients, especially for the patients only achieving PR at the end of therapy. Figure Disclosures No relevant conflicts of interest to declare.

Background BCOR gene is a transcription repressor that may influence normal hematopoiesis and is associated with poor prognosis in acute myeloid leukemia (AML) with normal karyotype. However, due to the rare mutation frequency in AML (3.8%-5%), clinical characteristics and prognosis of AML patients with BCOR mutation including abnormal karyotype are still unknown. In addition, the clonal evolution of AML patients with BCOR mutation has not been fully investigated. Methods By means of next generation of sequencing, we performed sequencing of 114 genes related to hematological diseases including BCOR on 509 newly diagnosed AML patients (except for acute promyelocytic leukemia) from March 2017 to April 2019. The 2017 European Leukemia Net (ELN) genetic risk stratification was used to evaluate prognosis. Overall survival (OS) was defined as the time from diagnosis to death or last follow-up. Relapse-free survival (RFS) was measured from remission to relapse or death. Clonal evolution was investigated through analyzing bone marrow samples at diagnosis, complete remission (CR) and relapse from the same patient. Result Among 509 AML patients, we found BCOR mutations in 23 patients (4.5%). BCOR mutations were enriched in patients with mutations of RUNX1 (p = 0.008) and BCORL1 (p = 0.0003). Patients with BCOR mutation were more at adverse ELN risk category compared to patients without BCOR mutation (p = 0.007). Besides, there was a larger proportion of patients with normal karyotype in BCOR mutation group but it had not reached statistical difference (62.5% vs 45.5%, p = 0.064). The abnormal karyotype in patients with BCOR mutations included trisomy 8, t(9;11), inv(3), -7 and complex karyotype.There were no significant differences in age, sex, white blood cell count, hemoglobin or platelet count between the two groups. More patients died during induction (13.0% vs 3.5%, p = 0.56) and fewer patients achieved CR after 2 cycles of chemotherapy when patients had BCOR mutations (69.6% vs 82.5%, p = 0.115) but the difference had not reached statistical difference . Patients with BCOR mutations had inferior 2-year OS (52.1% vs 70.7%, p = 0.0094) and 2-year RFS (29.8% vs 61.1%, p = 0.0090). After adjustment for ELN risk stratification, BCOR mutation was still remain a poor prognostic factor. However, the adverse prognostic impact of BCOR mutation is overcome by hematopoietic stem cell transplantation (HSCT), in which there was no difference between BCOR mutation group and wild type group (p = 0.474) (Figure 1). Through analysis of paired bone marrow sample at diagnosis, remission and relapse, we revealed the clonal evolution that BCOR mutation was only detected at diagnosis sample as a subclone and diminished at CR and relapse while TP53 mutation was only detected at relapse with a variant allele frequency (VAF) of 25.5%. We also found BCOR mutation at another patient's diagnosis and relapse sample while TP53 mutation was detected at relapse with VAF of 11.8%. Conclusion BCOR is associated with RUNX1 mutation and higher ELN risk. AML patients with BCOR mutation including normal and abnormal karyotype conferred a worse impact on OS that can be overcome by HSCT. BCOR mutation is a subclone at diagnosis or relapse in some patients, in which TP53 mutation clone occurred at relapse. Disclosures No relevant conflicts of interest to declare.

The majority of acute promyelocytic leukemia (APL) cases are characterized by the PML-RARα fusion gene. Although the PML-RARα fusion gene can be detected in >98% of APL cases, RARα is also found to be fused with other partner genes, which are also related to all-trans retinoic acid (ATRA)-dependent transcriptional activity and cell differentiation. In this study, we identified a novel RARα fusion gene, TBLR1-RARα (GenBank KF589333), in a rare case of APL with a t(3;17)(q26;q21),t(7;17)(q11.2;q21) complex chromosomal rearrangement. To our knowledge, TBLR1-RARα is the 10th RARα chimeric gene that has been reported up to now. TBLR1-RARα contained the B-F domains of RARα and exhibited a distinct subcellular localization. It could form homodimers and also heterodimers with retinoid X receptor α. As a result, TBLR1-RARα exhibited diminished transcriptional activity by recruitment of more transcriptional corepressors compared with RARα. In the presence of pharmacologic doses of ATRA, TBLR1-RARα could be degraded, and its homodimerization was abrogated. Moreover, when treated with ATRA, TBLR1-RARα could mediate the dissociation and degradation of transcriptional corepressors, consequent transactivation of RARα target genes, and cell differentiation induction in a dose- and time-dependent manner.

Background: Somatic heterozygous mutations in isocitrate dehydrogenase 1 (IDH1) occur in 6-10% of acute myeloid leukemia (AML) cases. Ivosidenib (AG-120) is a first-in-class, oral, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, and is FDA-approved for the treatment of mIDH1 newly diagnosed AML in patients ≥75 years of age or who have comorbidities precluding the use of intensive induction chemotherapy, and for the treatment of mIDH1 relapsed/refractory AML. In vitro, combination treatment of leukemic cell lines with ivosidenib and the hypomethylating agent azacitidine enhanced cellular differentiation and apoptosis compared with either agent alone. In an ongoing phase 1b study (NCT02677922), 23 treatment-naïve patients with mIDH1 AML were treated with ivosidenib 500 mg once daily (QD) in combination with subcutaneous azacitidine 75 mg/m2 for 7 days (in a 28-day schedule). Patients had a median age of 76 years (range 61-88), 12 patients (52%) were ≥75 years of age, and 12 of 23 were female. De novo and secondary AML was present in 15 (65.2%) and 8 (34.8%) patients, respectively. As of February 19, 2019, 10 patients (43.5%) remained on study treatment. Patients have been treated for a median of 15 cycles (range 1-30), and the spectrum of adverse events has been consistent with monotherapy experiences with ivosidenib or azacitidine. Investigators reported 4 cases of IDH differentiation syndrome. Of those, 3 were deemed to be serious adverse events, but all 4 cases resolved. The overall response rate (ORR) was 78.3% (18 of 23 patients), including 60.9% (14 of 23 patients) who achieved a complete remission (CR). Median time to response was 1.8 months (range 0.7-3.8) and to CR was 3.7 months (range 0.8-15.7); median response duration has not been reached. Preliminary mIDH1 clearance in bone marrow mononuclear cells was observed in 69% of patients (11 of 16) with CR or CR with partial hematologic recovery (CRh), including 71% (10 of 14) with CR. Methods: AGILE is a global, double-blind, randomized, placebo-controlled, phase 3 trial in patients with previously untreated mIDH1 AML who are not candidates for intensive therapy (NCT03173248). Currently, a total of 172 study centers in North America, South America, Asia, and Europe are participating in the study. Patients are being randomized 1:1 to receive either ivosidenib 500 mg QD + azacitidine 75 mg/m2 subcutaneously or intravenously for 7 days in 28-day cycles, or matched placebo + azacitidine. Randomization is stratified by region and by de novo versus secondary AML. Key eligibility criteria include patients with previously untreated mIDH1 AML (according to WHO criteria) who are not candidates for or not willing to receive intensive chemotherapy, who have an ECOG performance status 0-2, and who have received no prior treatment with a hypomethylating agent or mIDH1 inhibitor. Patients with an antecedent hematological disorder, such as myelodysplastic syndrome or myeloproliferative neoplasms, can be included if not pretreated with an mIDH1 inhibitor or hypomethylating agent. The primary outcome measure is overall survival, and key secondary outcome measures include event-free survival, CR rate, CR+CRh rate, and ORR. AGILE is currently open for enrollment globally. Disclosures Fernandez: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Recher:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Celgene: Research Funding; chugai: Research Funding; Daiichi-Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Gianolio:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Daigle:Agios: Employment, Equity Ownership. Winkler:Agios: Employment. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Paschka:Abbvie: Other: Travel expenses; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Other: Travel expenses, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Janssen: Other: Travel expenses; Amgen: Other: Travel expenses; Sunesis: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Takeda: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Ivosidenib (AG-120) is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test in: 1)Adult patients with newly-diagnosed AML who are more than 75 years old, or who have comorbidities that preclude use of intensive induction chemotherapy 2)Adult patients with relapsed or refractory AML. It is being investigated in clinical trials in combination with azacitidine in patients with DH1-mutant newly diagnosed AML.

Aplastic anemia (AA) is an immune-mediated bone marrow failure, resulting in reduced number of hematopoietic stem and progenitor cells and pancytopenia. The presence of paroxysmal nocturnal hemoglobinuria (PNH) clone in AA usually suggests an immunopathogenesis in patients. However, when and how PNH clone emerge in AA is still unclear. Hepatitis associated aplastic anemia (HAAA) is a special variant of AA with a clear disease course and relatively explicit immune pathogenesis, thus serves as a good model to explore the emergence and expansion of PNH clone. To evaluate the frequency and clonal evolution of PNH clones in AA, we retrospectively analyzed the clinical data of 90 HAAA patients that were consecutively diagnosed between August 2006 and March 2018 in Blood Diseases Hospital, and we included 403 idiopathic AA (IAA) patients as control. PNH clones were detected in 8 HAAA patients (8.9%,8/90) at the time of diagnosis, compared to 18.1% (73/403) in IAA. Eight HAAA patients had PNH clone in granulocytes with a median clone size of 3.90% (1.09-12.33%), and 3 patients had PNH clone in erythrocytes (median 4.29%, range 2.99-10.8%). Only one HAAA patients (1/8, 12.5%) had a PNH clone larger than 10%, while 24 out of 73 IAA patients (32.9%) had larger PNH clones. Taken together, we observed a less frequent PNH clone with smaller clone size in HAAA patients, compared to that in IAAs. We next attempted to find out factors that associated with PNH clones. We first split patients with HAAA into two groups based on the length of disease history (≥3 mo and < 3mo). There were more patients carried PNH clone in HAAA with longer history (21.4%, 3/14) than patients with shorter history (6.6%, 5/76), in line with higher incidence of PNH clone in IAA patients who had longer disease history. Then we compared the PNH clone incidence between HAAA patients with higher absolute neutrophil counts (ANC, ≥0.2*109/L) and lower ANC (< 0.2*109/L). Interestingly, very few VSAA patients developed PNH clone (5%, 3/60), while 16.7% (5/30) of non-VSAA patients had PNH clone at diagnosis. We monitored the evolution of PNH clones after immunosuppressive therapy, and found increased incidence of PNH clone over time. The overall frequency of PNH clone in HAAA was 20.8% (15/72), which was comparable to that in IAA (27.8%, 112/403). Two thirds of those new PNH clones occurred in non-responders in HAAA. In conclusion, PNH clones are infrequent in HAAA compared to IAA at the time of diagnosis, but the overall frequency over time are comparable between the two groups of patients. In SAA/VSAA patients who are under the activated abnormal immunity, longer clinical course and relatively adequate residual hematopoietic cells serve as two important extrinsic factors for HSCs with PIGA-mutation to escape from immune attack and to expand. Disclosures No relevant conflicts of interest to declare.

Data from systemic clinical trials about chimeric antigen receptor-modified T cell therapy against CD19 (CD19 CAR) differ in CAR design, T-cell activation and transduction methods at different institutions. However, according to these clinical trials, the single-chain fragment variable (scFv) sequence specific for tumor antigen were mostly derived from the FMC63 or SJ25C1 clones. Our previous study showed that the CD19 CAR constructed in our laboratory derived from clone HI19α (HI19α-4-1BB-ζ CAR) was highly effective in preclinical models. Herein, we conducted a single-arm, phase I clinical trial to evaluate the safety and efficacy of HI19α-4-1BB-ζ CAR (CNCT19) in patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL). From November 2016 through December 2018, 20 R/R B-ALL patients were enrolled into this clinical trial. Complete remission (CR) or complete remission with incomplete count recovery (CRi) was achieved in 100% (18/18) of patients that could be evaluated on day 28 after infusion, which accounted for 90% of all 20 enrolled patients. After a median follow-up of 17.0 months (range, 0.2 - 19.8), the median overall survival (OS) for the entire cohort of patients was 9.6 months (95% CI 4.2 - 15.0), and was not reached for 14 patients bridge to allogeneic transplantation. The median relapse free survival (RFS) of all patients was 9.0 months (95% CI, 6.7 - 11.2). Two patients died within 28 days due to cytokine release syndrome (CRS), while other patients experienced controllable cytokine-release syndrome and neurotoxicity. In order to better understand the correlation between T cell subsets and long-term response, we consistently evaluated the T cell phenotype and expansion kinetics in peripheral blood after CART infusion. The results revealed that the percentage of CD8+ naïve T cells (TN) collected from peripheral blood 20min after CAR infusion, were significantly lower in patients who relapsed from CART therapy than patients with continues CR (p=0.003), while central memory T cells (TCM), effective memory T cells (TEM) and effector T cells (TE) had similar proliferation kinetics between these two groups. In addition, multivariate analysis indicated that low percentage of CD8+TN cells was an independent factor associated with shorter RFS (p=0.033, 95% CI 0.031-0.861). This report is the first trial to provide evidence that CNCT19, a CD19 CAR constructed of a new anti-CD19 chimeric antigen receptor HI19α, has potent antileukemia activities in patients with R/R B-ALL. Furthermore, our results indicate the phenotype and kinetics of T cells are possible biomarkers to predict the long-term prognosis of CART treatment. Disclosures Lv: Juventas Cell Therapy Ltd.: Employment.

Immunosuppressive therapy (IST) based on antithymoglobin (ATG) and cyclosporin (CsA) is the first-line treatment for severe aplastic anemia (SAA) patients who are unfit for transplantation,and the overall response rate (ORR) is about 70%.The utility of eltrombopag (EPAG),a TPO receptor agonist, achieved robust hematologic response in refractory and treatment-naïve SAA patients in clinical trials and some other studies. However, only a few data came from Asia countries where higher incidence of AA has been reported. A retrospective study on the use of EPAG in AA was conducted in mainland China. Aplastic anemia (transfusion dependent non-severe, severe, and very severe) patients who started eltrombopag before Feb 2019 and continued for at least 3 months either as first-line treatment or as rescue treatment, were enrolled. The maximum daily dosage of EPAG used continuously for at least 2 weeks is defined as the stable dosage. Response criteria were referred to that used in previous reports (Townsley DM, NEJM 2017; BCSH, BJH 2016). Fifty-six patients from eleven centers were enrolled in this study, including 26 males and 30 females at the median age of 39 (7-80) years. All patients were transfusion-dependent by the time of EPAG administration, and there were 14 VSAA, 24 SAA and 18 transfusion dependent non-severe aplastic anemia (TD-NSAA). Nineteen treatment-naïve patients received EPAG and IST (ATG+CsA, n=10; CsA/CsA+androgen, n=9) as first-line treatment. Thirty-seven patients were refractory to IST. Eltrombopag was administered at a median dose of 75 (25-150) mg per day for 7 (3-31) month. The median follow-up time was 9 (3-40) months. The overall response rate in patients receiving EPAG as first-line therapy was 78.9% (15/19), and most patients achieved complete response (CR) (10/15). Among the 10 patients receiving ATG+CsA, 6 patients achieved hematologic response (HR) at 3 months post-treatment, including 3 CR. Six patients were diagnosed as VSAA and three achieved HR. For the 9 patients treated with CsA/CsA+androgen, 8 achieved HR (88.9%) and 4 were CR (44.4%) at 3 months. By last follow-up, the cumulative HR rate was 70% in ATG+CsA group and 89% in CsA/CsA+ androgen group. Among the 14 responders, 11 patients receiving EPAG at a stable dosage ≤75mg/d and achieved HR at 3 months. The overall response rate in IST-refractory patients was 46% (17/37), with trilineage response in 27% patients at 3 months. For the 18 ATG+CsA refractory SAA patients,trilineage HR occurred in 4 patients (22.2%, 4/18), bi-lineage HR in one patient and single lineage HR in one patient. Thus, the total HR was 33.3% (6/18) at 3 months and increased to 44% (8/18) by last follow-up. Among the 19 CsA/CsA+ androgen refractory patients, 6 (31.5%, 6/19) achieved trilineage HR, one achieved bi-lineage HR and 4 achieved single lineage response. Total HR rate was 57.9% (11/19) at 3 months after EPAG initiation and 68% (13/19) by last follow-up, including 9 patients with trilineage HR. Among 17 responders, 13 received a stable EPAG dose of≤75mg/d. Most patients tolerated EPAG well. Adverse events occurred in 29 patients (52%) and most were mild to moderate, including gastrointestinal symptom (n=15, e.g. abdominal pain, nausea), impaired liver function (n=5), skin changes (n=7, e.g. skin pruritus and rash) and musculoskeletal pain (n=6), and venous thrombus (n=2). Eltrombopag dosage was reduced in 2 patients due to severe digestive symptoms at 100 mg/d and discontinued in one patient who suffered from upper limb venous thrombus. In conclusion, EPAG is effective and safe in treating Chinese AA patients at a daily dose of 75mg and less. The real-world result of EPAG in Chinese patients is similar to those reported in Western countries. Disclosures No relevant conflicts of interest to declare.

Background: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a rare subtype of acute lymphoblastic leukemia with a poor long-term prognosis. Recent studies suggested that the addition of tyrosine kinase inhibitor (TKI) to the traditional chemotherapy treatment has significantly improved Ph+ ALL patients response rates, disease-free survival, and overall survival (OS). Dasatinib, a second-generation tyrosine kinase inhibitor, can pass the blood-brain barrier and possesses a stronger inhibitory effect on both SRC kinase and BCR-ABL. In theory, it might be beneficial in Ph+ ALL treatment. This prospective, single-arm study assesses the efficacy of a combination of dasatinib and pediatric-inspired regimens in Ph+ ALL patients. Methods: 30 patients from the Institute of Hematology and Blood Diseases Hospital were enrolled in this study from January 2016 to April 2018. Eligible subjects were newly diagnosed Ph+ ALL adult patients. Chemotherapy regimens were initiated after the pediatric-inspired regimens, and standard induction chemotherapy was given for four weeks. Seven courses of consolidation or hematopoietic cell transplantation (HCT) were given to those who have achieved hematological complete remission (HCR). The primary objectives of this study were the HCR and molecular complete response (MCR), the major molecular response (MMR), the overall survival (OS), and the hematologic relapse-free survival (HRFS). The median follow-up time was 28 months. The trial registration number is NCT02523976. Results : 30 subjects were enrolled in this study with a median age of 37.5 years (range 19-50 years). All patients achieved HCR after four weeks of induction therapy with a cumulative MCR rate of 87.5%(21/24). The median HRFS and median OS were 19.5 (range 2-40 months) and 21 (range 7-41 months), respectively. The molecular response, assessed through monitoring of BCR-ABL transcript expression, revealed that 61.3% of the patients reached MMR and MCR after three months of treatment. Additionally, the results indicated that patients who achieved MCR in the first three months had a better HRFS (p=0.038). Fifteen of the patients (50%) proceeded to stem cell transplantation (SCT) within the first HCR period (SCT in HCR1). Only 13.3% (2/15) of the SCT cohort relapsed, and 20% (3/15) died. It is worth mentioning that the SCT in HCR1 cohort had better HRFS (P=0.03). Most adverse events were reversible, and none of the subjects had pulmonary hypertension. Conclusion: These findings indicate that an early MCR (3 months) has a positive impact on patients survival and that Dasatinib, combined with pediatric-inspired regimens, is effective and leads to a high MCR in patients with newly diagnosed Ph+ALL. Disclosures No relevant conflicts of interest to declare.

Acute myeloid leukemia (AML) with t(6;9)(p22;q34) is listed as a distinct entity in the 2016 WHO Classification of Tumors of Heamatopoetic and Lymphoid Tissues, but the clinical features and prognostic impact are still not well established. We retrospectively reviewed 1620 AML patients diagnosed from the year 2013 to 2019 and 15 patients with t(6;9)(p22;q34) were identified. Their morphology, immunophenotype, cytogenetics, molecular findings, treatment and prognosis were analyzed. The incidence of AML with t(6;9)(p22;q34) is 0.9% (15/1620). There was 10 women and 5 men (ratio, 2:1) with a median age of 39 years (range:16-64). The median WBC count at diagnosis was 9.72×109/L(range: 1.78-45.4). According to French-American- British classification, 10 (66.7%) were M5 and 5 were M4. At cytogenetic level, t(6;9)(p22;q34) was the sole cytogenetic abnormality in 12 patients (80%) while 2 had one additional aberration and 1 presented with a complex karyotype. Molecular studies using next generation sequencing showed a unique mutation profile characterized by a high frequency of FLT3 mutations (10/13, 77%) including 9 cases with ITD and 1 case with TKD. Other mutations included RAS (3 NRAS and 2 KRAS) (5/13), FAT1 (4/13), NOTCH1 and PRDM1 (2/13 respectively). However, the common mutations of AML, such DNMT3A and NPM1, were rare in this subtype. The median number of mutated genes was 3 (range:1-6). Among the 9 patients with FLT3-ITD, FLT3-ITD ratio was measured in 5 patients and all showed a high ratio (median: 0.62, range: 0.59-1.11). All patients received induction chemotherapy; 12 (80%) patients achieved complete remission (CR) after one or two cycles of induction. Among these 15 patients, 7 underwent allogenic stem cell transplant (SCT) and all were alive in CR status at the last follow-up (median OS: 32.9 mon). In contrast, among the 8 patients who did not receive SCT, 5 died of disease relapse and the remaining 3 patients were newly diagnosed with a relatively short follow-up time (median OS: 10.4mon). In conclusion, t(6;9)/DEK-NUP214 AML represents a unique subtype of AML, with unique gene expression profiling (a high frequency of FLT3-ITD). Most patients can achieve CR after chemotherapy, allo-SCT can improve long term survival. Figure Disclosures No relevant conflicts of interest to declare.

Background: Among patients with non-Hodgkin lymphoma (NHL) and concomitant chronic or resolved hepatitis B virus (HBV) infection, HBV reactivation is an identified risk associated with chemotherapy, especially after rituximab-based immunochemotherapy. Chimeric antigen receptor (CAR) T-cell targeting CD19 can also cause B-cell aplasia as seen in patients receiving rituximab, and the risk of HBV reactivation during CAR T-cell therapy is still unknown. We performed a retrospective study to explore the risk of HBV reactivation in patients with concomitant HBV infection who had received anti-CD19 CAR T therapy at our hospital. Methods: Patients with relapse or refractory B-cell lymphoma who were treated with CNCT19 (second-generation anti-CD19 CAR T-cell provided by Juventas) at Blood Disease Hospital were retrospectively analyzed. All patients were screened for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb) at the time of evaluation for CNCT19 therapy, and those with positive HBsAg or positive HBcAb were eligible for this retrospective study. This study was approved by Blood Diseases Hospital Internal Review Board. Results: Between June 2017 and May 2019, 17 patients with relapsed or refractory B-cell lymphoma and concomitant HBV infection who were treated with CNCT19 therapy alone (n=14) or CNCT19 therapy following high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT, n=3) were included in this study. The median age was 53 years (range: 31-71years), with 53% were male. 6 patients (35%) had chronic HBV infection, defined as positive HBsAg, 11 patients (65%) had resolved HBV infection, defined as negative HBsAg and positive HBcAb. At the time of CNCT19 infusion, HBV DNA levels of all patients were lower than the normal limit ( Conclusions: Our results showed that CAR T therapy could be safely administered in patients with chronic or resolved HBV infection. Considering the small sample size and the retrospectively analysis, the risk of HBV reactivation and the recommendation for prophylactic anti-HBV NAT during CAR T therapy should be further evaluated in large and prospective studies. Disclosures Lv: Juventas Cell Therapy Ltd.: Employment.

Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with dasatinib. Overall, dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247.

Background: Patients with B cell acute lymphoblastic leukemia (B-ALL) relapsed after allogenic hematopoietic stem cell transplantation have poor prognosis. Donor lymphocyte infusion (DLI) have shown limited success in the setting of relapse by a mere increase in median survival by 6 months and a significant risk of acute and chronic graft-versus-host disease (GVHD) and additional risk of marrow aplasia. The second generation chimeric antigen receptor-T cell (CAR-T) for CD19 is a promising treatment for relapsed and refractory B-ALL, but the effectiveness and safety of donor-derived second generation of CD19 CAR-T cell infusion for relapsed B-ALL after allogenic stem cell transplantation have not been determined. Methods: Between July 2017 and June 2018, 6 adult patients with B-ALL relapsed (2 patients were hematologic relapsed; 4 patients were minimal residual disease(MRD)-positive) after allogenic stem cell transplantation were enrolled, including 5 sibling-matched stem cell transplantation and 1 haploidentical transplantation . Donor's T cells were infected with lentivirus carrying CD19 CAR plasmid which containing CD19 scfv (HI-19 clone) and 4-1BB-CD3ζ signaling domains to generate CAR-T cells. Patients received FAC (fludarabine:25-30mg/m2/d*3, cyclophosphamide:350mg/m2/d*2, cytosine arabinoside:100mg/m2/d*4) pretreatment and then total (1.25-3.5)*106/kg donor-derived 4-1BB CAR-T cell were infused in consecutive 2 or 3 days . Results: All the patients achieved MRD negative remission and complete donor chimerism. Three patients experienced grade 2 cytokine release syndrome (CRS) and received 6-8mg/kg interleukin-6 receptor blocker (tocilizumab) treatment ; the other 3 just experienced grade 1 CRS. None of these patients needed glucocorticoid treatment. No patients developed acute or chronic graft-versus-host disease (GVHD). Now all the 6 patients are alive and show complete donor chimerism with MRD negative remission. The median follow-up time are 243.5days. Conclusion: Donor-derived second generation of CD19 CAR-T cell treatment for relapsed B-ALL after allogenic stem cell transplantation were effective and safe, which may be confirmed with more clinical studies. Key words: donor-derived CD19 CAR-T cell therapy, allogenic stem cell transplantation, B cell acute lymphoblastic leukemia, relapse Disclosures No relevant conflicts of interest to declare.

Introduction: Treatment with dasatinib, a second-generation tyrosine kinase inhibitor (TKI), has resulted in high rates of cytogenetic and molecular responses for pts with CML-CP, both as initial therapy and after failure of other therapies. A reduction in BCR-ABL1 transcript levels to ≤ 10% on the International Scale (IS) at 3 mo is associated with an improved probability of deep molecular responses and superior progression-free and overall survival (PFS and OS). In DASISION, considerably more pts treated with dasatinib achieved BCR-ABL1 ≤ 10% IS compared to imatinib. BCR-ABL1 ≤ 10% IS at 3 mo is considered an optimal response by international guidelines; however, approximately one-third of pts with CML-CP on first-line (1L) imatinib will not achieve this threshold. Clinical studies exploring the potential benefit of early switching to dasatinib in pts with less than optimal responses on initial imatinib treatment have not been reported. Methods: DASCERN (NCT01593254) is a randomized, open-label, international phase 2b trial in adult pts with CML-CP who had achieved complete hematologic response (CHR) but who had BCR-ABL1 > 10% IS at 3 mo after initial treatment with 400 mg imatinib once daily (QD). Imatinib must have been started within 6 mo of the initial CML-CP diagnosis. Pts were randomized 2:1 to receive 100 mg dasatinib QD or continue imatinib at ≥ 400 mg daily with the option for dose escalation. Pts initially randomized in the imatinib cohort who met European LeukemiaNet 2013 failure criteria after randomization and without dasatinib-resistant mutations were crossed over to the dasatinib arm. The primary endpoint in DASCERN is the rate of MMR (BCR-ABL1 < 0.1% IS) at 12 mo after day 1 initiation of 1L imatinib (9 mo after randomization). Secondary endpoints include time to MMR, OS, and PFS (progression was defined as transformation to accelerated/blast phase or death). Tertiary endpoints include safety and tolerability profile of both treatment arms and cytogenetic response over time. Results: All 260 randomized pts (dasatinib: n = 174; imatinib: n = 86) had a minimum follow-up of ≥ 12 mo from the last pts 1st visit (Sokal scores: 28% low, 30% intermediate, 24% high, 18% unknown; median age 37 y [range 18-82, 95% were < 65 y]; 78% male; 73% Asian). All pts had e13a2 or e14a2 transcript types. At the time of analysis, 84% of pts were continuing in the study. Median daily dose was 100 mg QD (range 26-142) for dasatinib and 400 mg QD (range 129-825) for imatinib. Median treatment duration was 111 wk (774 d) in the dasatinib arm and 68 wk (477 d) in the imatinib arm; 42 (49%) imatinib-randomized pts crossed over to dasatinib. Rate of MMR at 12 mo in the intent-to-treat population was 29% (95% confidence interval [CI] 22, 36) for dasatinib and 13% (95% CI 7, 22) for imatinib (P = 0.005); median time to MMR was 14 mo (range 12-18) for dasatinib vs 20 mo (range 14-26) for imatinib (P = 0.053). No differences in the rate of progression or OS were observed between treatment arms. No new safety signals were observed for either treatment arm and the early switch to dasatinib did not increase the toxicity rate. Treatment-emergent pleural effusion (PE; any grade) occurred in 11 (6%) pts randomized to dasatinib and 3 (7%) imatinib-randomized pts who crossed over to dasatinib; treatment-emergent PE grade 3/4 occurred in 1 (1%) pt randomized to dasatinib and 2 (5%) pts randomized to imatinib who crossed over to dasatinib. Hematologic toxicity was similar between treatment arms: neutropenia grade 3/4 occurred in 18 (11%) pts randomized to dasatinib and 12 (29%) pts randomized to imatinib who crossed over to dasatinib; thrombocytopenia grade 3/4 occurred in 18 (11%) pts randomized to dasatinib and in 7 (17%) pts randomized to imatinib who crossed over to dasatinib. Two dasatinib-treated pts discontinued due to hematologic toxicity (1 neutropenia, 1 thrombocytopenia). Conclusions: Early results from DASCERN show that pts with suboptimal responses to imatinib at 3 mo who switched to dasatinib had a significantly increased rate of MMR at 12 mo compared to pts who remained on imatinib. Longer follow-up is required to assess the impact of early switching on PFS and OS, and achievement of deep molecular responses. Disclosures Cortes: Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Takeda: Research Funding. Kim:BMS: Research Funding; Ilyang: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Martin Regueira:Bristol-Myers Squibb: Employment, Equity Ownership. Sy:Bristol-Myers Squibb: Employment. Gurnani:Bristol-Myers Squibb: Employment.