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Secondary acute myeloid leukemia (sAML) poorly responds to conventional treatments and allogeneic stem cell transplantation (HSCT). We evaluated toxicity and efficacy of CPX-351 in 71 elderly patients (median age 66 years) with sAML enrolled in the Italian Named (Compassionate) Use Program. Sixty days treatment-related mortality was 7% (5/71). The response rate at the end of treatment was: CR/CRi in 50/71 patients (70.4%), PR in 6/71 (8.5%), and NR in 10/71 (19.7%). After a median follow-up of 11 months relapse was observed in 10/50 patients (20%) and 12 months cumulative incidence of relapse (CIR) was 23.6%. Median duration of response was not reached. In competing risk analysis, CIR was reduced when HSCT was performed in first CR (12 months CIR of 5% and 37.4%, respectively, for patients receiving (=20) or not (=30) HSCT, p = 0.012). Twelve-months OS was 68.6% (median not reached). In landmark analysis, HSCT in CR1 was the only significant predictor of longer survival (12 months OS of 100 and 70.5%, for patients undergoing or not HSCT in CR1, respectively, p = 0.011). In conclusion, we extend to a real-life setting, the notion that CPX is an effective regimen for high risk AML patients and may improve the results of HSCT.

Introduction: The outcome of patients with acute myeloid leukemia (AML) secondary to myelodisplastic syndrome (MDS) or therapy-related (t-AML) receiving conventional treatment and allogeneic stem cell transplantation consolidation (HSCT) is poor. CPX-351 is a new drug composed by liposomal encapsulated cytarabine and daunorubicin, at a fixed molecular ratio of 5:1. It showed superior results, compared to standard 3+7 induction, in a phase III trial (Lancet et al, JCO 2018) in patients affected by t-AML or AML with myelodisplasia-related changes and it is now commercially available for secondary AML (sAML). We recently published results from CPX-351 Italian Named (Compassionate) Use Program (CUP) which enrolled 73 elderly sAML patients (Guolo et al, Blood Cancer J. 2020) showing that CPX-351 is an effective induction regimen for high risk AML patients treated with a curative aim. With a limited follow up, our data suggested the good activity and tolerability of CPX-351. Good quality remissions with acceptable toxicity in the majority of patients was achieved and CPX-351 increased the feasibility of HSCT in a poor risk AML cohort. Scarce data are available on long term outcome of high risk patients receiving CPX-351 in the real life setting. Here we report the results from the extended follow up analysis of the Italian CUP. Results: Seventy three patients were enrolled between December 2018 and June 2019 in a compassionate use program (CUP) in 33 Italian Hematology Centers. Data collection began on July 2019 and included 71/73 patients (97.2%), enrolled in 31 Centers. As previously reported, median age was 65.5 years (52-79). Sixty-two (88%) patients had at least one relevant comorbidity upon enrollment. Six patients (9%) presented with ECOG 3-4 upon enrollment. With a median follow up of 22 months, median overall survival (OS) was 13 months (21.2 - 22.8 95% IC). Two-years OS was 28.6% in the whole cohort. In order to confirm the positive impact of HSCT in first complete remission (CR) and the correlation with the other variables, a landmark model was applied, including only patients alive and in CR at day 90. In landmark analysis, HSCT performed in first CR after CPX-351 was the only significant predictor of longer survival: median OS was not reached for patients transplanted in first CR Vs 12 months for patients who did not undergo HSCT, p < 0.05, Figure1). Two-year OS for patients who received HSCT was 57.6% vs 15.8% for patients who did not undergo HSCT. Conclusions: Results from the extended follow up of Italian CPX-351 CUP confirm the good activity CPX-351 in such a difficult cohort as sAML. Two-year OS for transplanted patients is high despite the high median age, the high frequency of severe comorbidities in this real life cohort of patients and the high frequency of high risk AML. On the contrary, non-transplanted patients show a poor outcome, thus confirming that CPX-351 induction as an optimal bridge to transplant induction therapy. Figure 1 Figure 1. Disclosures Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Marco: Insight,: Consultancy; Jazz: Consultancy; Janssen: Consultancy. Fracchiolla: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Speakers Bureau. Tafuri: Roche: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Rossi: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Pagano: Gilead Science, MSD, Pfizer, Basilea, Janssen, Novartis, Jazz Pharmaceutical, Cidara: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Gilead Sciences, MSD, Pfizer Pharmaceuticals, Astellas Pharma: Speakers Bureau.

Introduction Allogeneic Chimeric Antigen Receptor (CAR) T cells engineered with non-viral methods offer a modality to reduce costs and logistical complexity of the viral process and allow lymphodepleted patients to access CAR T cell treatment. We recently proposed the use of Sleeping Beauty (SB) transposon to engineer donor-derived T cells differentiated according to the cytokine-induced killer (CIK) cell protocol (Magnani CF et al. J Clin Invest. 2021). We report here outcomes on B-cell acute lymphoblastic leukemia (B-ALL) patients, relapsing after transplantation, treated with donor-derived anti-CD19 CAR T cells (CARCIK-CD19). Methods We conducted an academic, multi-center, phase I/II dose-escalation trial in patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT). The infusion product was manufactured in-house starting from 50 mL of peripheral blood from the HSCT donor by electroporation with GMP-grade plasmids. All patients underwent lymphodepletion with Fludarabine (30 mg/m 2/day x 4 days) and Cyclophosphamide (500 mg/m 2/day x 2 days), before proceeding to CARCIK-CD19 infusion. We used the Bayesian Optimal Interval (BOIN) design to define a four-dose escalation scheme. Primary objectives were to define the Maximum Tolerated Dose (MTD), safety, and feasibility. Secondary objectives included the assessment of complete hematologic response (CR), duration of response (DOR), progression-free (PFS), event-free (EFS), and overall survival (OS). This study was registered at ClinicalTrials.gov, NCT03389035. Results From January 2018 to June 2021, a total of 32 patients were screened, 26 enrolled (6 children and 20 adults) and 21 infused (4 children and 17 adults). Reasons for not receiving infusion included consent withdrawal (N=1), disease progression not controlled by bridging therapy (N=3), acquisition of myeloid phenotype (N=1). The median number of prior therapies was 4 (range, 1-7) with a median time interval from HSCT to relapse of 9 months. The median BM blasts was 60% (range, 5-100%) at enrollment and 7% (range, 0-96%) post lymphodepletion. Of the 21 patients infused, CARCIK-CD19 were obtained by HLA-identical sibling (n=6, 29%), matched unrelated (n= 7, 33%), and haploidentical donors (n=8, 38%). Three patients (14%) received the first dose level of 1x10 6 CARCIK-CD19 cells/Kg, three (14%) the second of 3x10 6, and three (14%) the third of 7.5x10 6 whereas 12 patients (57%) received the fourth and last planned dose level of 15x10 6 cells/Kg, as no dose limiting toxicity (DLT) was observed. CRS was observed in six patients (three grade I and three grade II) and immune effector cell-associated neurotoxicity in two patients at the highest dose. Although 9 out of 21 had experienced acute or chronic graft-versus-host disease (GvHD) after the previous HSCT, secondary GvHD was never induced by CARCIK-CD19. Complete response was achieved by 13 out of 21 patients (61.9%, 95%CI=38-82%) and by 11 out of 15 patients treated with the 2 highest doses (73.3%, 95%CI=45-92%). Eleven of these responders were MRD-negative. Notably, the type of donor did not influence the achievement of CR 28 days post-infusion. At a median follow up of 21.6 months (range, 1.0-38.4 months), 10 patients (47.6%) are alive in CR (9 in the 2 highest dose levels). Overall, the median OS and EFS were 9.7 and 3.2 months, respectively, with a median DOR of 4.0 months (range, 1.0-23.5 months). Patients in CR at 28-days had a 6-months relapse-free survival of 48.4% (SE=14.9). EFS at 6 months was 26.5% (SE=9.9) and OS was 67.6% (SE=11.1). Among the 13 patients who achieved CR, two children underwent consolidation with a second allo-HSCT in complete remission. Adult patients did not receive any additional anti-leukemic therapies unless a relapse occurred, and four of them remained in remission and alive (+24, +9, +6, and +4 months). Robust CARCIK-CD19 cell expansion was achieved in most patients and CARCIK-CD19 cells were measurable for up to 22 months. Conclusions SB-engineered CAR T cells induce sustained responses in B-ALL patients relapsed after HSCT irrespective of the donor type and without severe toxicities. Disclosures Lussana: Incyte: Honoraria; Pfizer: Honoraria; Astellas Pharma: Honoraria; Amgen: Honoraria. Gritti: Takeda: Consultancy; Roche: Consultancy; Kite Gilead: Consultancy; IQvia: Consultancy; Italfarmaco: Consultancy; Clinigen: Consultancy. Biondi: Incyte: Consultancy, Other: Advisory Board; Bluebird: Other: Advisory Board; Novartis: Honoraria; Amgen: Honoraria; Colmmune: Honoraria.

Background This non-interventional retrospective study, is intended to analyze toxicity and effectiveness of venetoclax of a large cohort of R/R and de novo AML patients treated in Italy since 2015 outside clinical trials with the ultimate goal of improving the knowledge related to venetoclax treatment in the real-life setting. Interim analysis on first 59 patients enrolled is presented here. Aims The aim of this study is to collect data on safety and efficacy of venetoclax in a large cohort of AML patients treated in Italy from 2015 to 2020 in a real-life setting (out of clinical trials). Methods This is a multicenter, retrospective, observational study. All patients with AML treated outside clinical trials with venetoclax as single agent or in combination with other drugs from 1 January 2015 to 1 April 2020 in 40 Italian Hematology Units will be considered for enrollment. Data are collected in accordance with GCP and Helsinky declaration. For this interim analysis data registered into eCRF at 30 June 2020 have been considered. Adverse events (AEs) are graded according to CTCAE v4.03. Survival is estimated with Kaplan-Meyer method. Results The study started on August 2019 and will be completed on August 2021. Up to 30 June 2020 (first data cut off) 30 sites have been activated and 59 AML patients have been registered, 27 males (46%) and 32 females (54%), with a median age of 64 years (range 35 - 83). At the time of venetoclax initiation, 14/59 (24%) patients had a refractory disease, 31 (52.5%) had relapsed disease (14 first relapse and 17 a second or further relapse), eight patients (15%) were newly diagnosed and received venetoclax as first line therapy while in six patients disease status was missing at the time of data cut off. At diagnosis, 52 patients (88%) had bone marrow involvement, of which four (7%) had extramedullary involvement (skin or subcutaneous and deep muscular localization) and one had CNS involvement. 35/59 (59%) patients were classified as fit for intensive chemotherapy, 16 (27%) unfit and two (3%) frail according to SIE, SIES and GITMO group. For six patients fitness status was missing at the time of data cut off. 45/59 (76%) patients had received previous therapy for AML, eight patients were treatment naïve at the time of venetoclax initiation. while for six patients data regarding previous AML therapy were missing at the time of data cut off. In the R/R setting (n=45), the median number of previous therapy lines were 2 (range 1-7). Nine patients had relapse after stem cell transplantation (SCT) and one of them had received double transplant. For 42/45 R/R AML patients the data regarding treatment with venetoclax were available at the time of data cut off. Three out of 42(7%) patients received venetoclax as single agents, 32 (76%) in combination with HMAs (31 Azacitidine and 1 Decitabine), and six with high or intermediate dose ARA-C. In the cohort of R/R patients treated with combination of venetoclax and HMA, in 29/32 patients venetoclax was started as a ramp up phase. The median number of venetoclax cycles was 2 (range 1-13) and the median dose administered was 400 mg daily (range 100-600). Regarding toxicity, 72 adverse events (AEs) were recorded of which 49 were grade III-IV (39 hematologic toxicities, 4 pneumonia, 2 sepsis and 4 other) and 2 fatal (sepsis). For 25 out of 32 patients treated with venetoclax and HMAs combination, a response evaluation was available at the time of data cut off. 15 patients had an evaluable response within 2 months, 7 within 4-months and for 3 the date was missing. 14 (56%) patients obtained composite complete remission (CR=9; 5 =CRi), three patients had a partial response (PR), one stable disease (SD) while seven patients were refractory. Overall, six out of 32 (19%) patients underwent allogenic transplantation after venetoclax-HMAs combination. Median OS of R/R patients treated with venetoclax plus HMA was 182 days (95% C.I 85-421.). Conclusions These preliminary data show that venetoclax in combination with HMAs has an acceptable toxicity profile and is effective in this setting of R/R patients with unfavorable prognosis. Data from more than 100 patients treated in real life setting with venetoclax in Italy since 2015 is expected by the end of 2020, and further analysis on RR patients is ongoing. Data on newly diagnosed patients treated with venetoclax alone or in combination with HMA or chemotherapy will be analyzed. *G.M. and C.C. contributed equally as last author Disclosures Todisco: Jannsen, Abbvie, Jazz:Membership on an entity's Board of Directors or advisory committees.Fracchiolla:Amgen:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau;ABBVIE:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses;Gilead:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau;Pfizer:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau.Papayannidis:Abbvie, Janssen, Novartis, Amgen, Pfizer:Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.Martelli:Pfizer:Membership on an entity's Board of Directors or advisory committees;Novartis:Membership on an entity's Board of Directors or advisory committees;Celgene:Membership on an entity's Board of Directors or advisory committees;Janssen:Membership on an entity's Board of Directors or advisory committees;AbbVie:Membership on an entity's Board of Directors or advisory committees;Amgen:Membership on an entity's Board of Directors or advisory committees;Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees.Di Renzo:BerGenBio ASA:Research Funding.Tarella:ADC Therapeutics:Membership on an entity's Board of Directors or advisory committees, Research Funding;ImmunoGen:Research Funding;TG-therapeutics:Research Funding.Rossi:Jazz:Membership on an entity's Board of Directors or advisory committees;Abbvie:Membership on an entity's Board of Directors or advisory committees;Astellas:Membership on an entity's Board of Directors or advisory committees;Novartis:Other: Advisory board;Amgen:Honoraria;Pfizer:Membership on an entity's Board of Directors or advisory committees;Janssen:Membership on an entity's Board of Directors or advisory committees;Daiichi Sankyo:Consultancy, Honoraria;Takeda:Honoraria, Membership on an entity's Board of Directors or advisory committees;Alexion:Membership on an entity's Board of Directors or advisory committees;Celgene:Membership on an entity's Board of Directors or advisory committees;Sanofi:Honoraria.

Background Significant efforts over the past few years led Chimeric Antigen Receptor (CAR) T cell therapy to success in relapsed and refractory (r/r) B-cell malignancies. Still logistical complexity, high costs and toxicities are currently the main barriers to the use of CAR T cell therapy. We therefore propose non-viral engineering of an allogeneic T cell population according to cytokine induced killer (CIK) cell protocol of differentiation. Methods We reported the updated results of our phase I/II trial in B-cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into CIK (CARCIK-CD19) according to the method enclosed in the filed patent EP20140192371. After lymphodepletion with Fludarabine (30 mg/m2/day) x 4 days and Cyclophosphamide (500 mg/m2/day) x 2 days, CARCIK-CD19 were infused following a four-dose escalation scheme (1x106, 3x106, 7.5x106 and 15x106 transduced CAR+ T cells/kg) according to the Bayesian Optimal Interval Design (BOIN). During the cell manufacturing period, bridging anti leukemic therapy from patient registration to the beginning of the lymphodepletion, was allowed. The primary endpoint was to define the Maximum Tolerated Dose (MTD) and the safety assessment. Key secondary endpoints included the assessment of complete hematologic response (CR), defined as < 5% bone marrow (BM) blasts, circulating blasts < 1%, no clinical evidence of extramedullary disease, as well as the characterization of CARCIK-CD19 persistence in PB and BM (NCT03389035). Results The cellular product was produced successfully for all patients starting from the donor-derived peripheral blood (PB) and consisted mostly of CD3+ lymphocytes (mean 98.85% ±SD 1.19%) with a mean of 38.6% CAR expression (range 15.10%-73.17%). From January 2018 to July 2020, a total of 24 patients were screened, and 15 were enrolled (4 children and 11 adults) and infused with a single dose of CARCIK-CD19 (n=3 HLA identical sibling, n=4 MUD, n=8 haploidentical donor). The leukemic burden in the BM post lymphodepletion/pre-infusion ranged from 0% to 96%. Robust expansion was achieved in the majority of the patients. The maximal expansion reached about 1x106 transgene copies per μg DNA and 70% of CAR+ T cells in PB. CD8+ T cells represented the predominant circulating CAR+ T cell subset. Persistence of central memory CAR+ T cells was observed after infusion and CAR T cells were measurable up to 9 months. CARCIK-CD19 were characterized by a high profile of safety in all treated patients. Toxicities reported were two grade I and two grade II cytokine release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GvHD), neurotoxicity, or dose-limiting toxicities. Seven out of 9 patients, receiving the highest doses, achieved CR and CRi at day 28. MRD-negative status for all responders was achieved by 6 out of 9 patients (1 currently in evaluation). The two patients in CR but with MRD+ relapsed with a CD19+ disease at +2.3 and +1.9 months post infusion, respectively. Among the 6 patients who achieved MRD-negative CR, two children underwent consolidation with a second allo-HSCT and are still alive and disease free (+17 and +13 months), two adult patients died of subsequent CD19+ disease relapse and two adult patients are still alive and disease free (+14 and +12 months) without additional therapies. The distribution profile of integration sites (IS) showed no preference for gene dense or promoter regions, and no particular differences between pre- and post- infusion sample IS. Samples harvested at early time points after infusion showed a highly polyclonal repertoire. At later time points (≥ 28 days after infusion) the repertoire of IS showed a marked reduction towards oligoclonality, in absence of specific dominant clones. Conclusions We can conclude that SB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Sustained response was achieved without severe toxicities. All analyzed samples appear to have a highly polyclonal IS repertoire and no signs of genotoxicity by transposon insertions could be observed. Disclosures Gritti: IQVIA: Consultancy; Amgen: Honoraria; Autolus: Consultancy; Italfarmaco: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria; Jannsen: Other: Travel Support; Takeda: Honoraria; Kite: Consultancy. Rambaldi:Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; University of Milan: Current Employment; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).

The neutrophil/lymphocyte ratio (N/L) at diagnosis has been shown to be a prognostic factor for survival in solid tumors. An increase in the neutrophil count is a marker of inflammation which is an essential part of the neoplastic process. Conversely, a decrease of the peripheral lymphocyte count might reflect an impairment of the host defense mechanism associated with advanced and aggressive cancers. Since There are only few reports on the N/L ratio in non-Hodgkin lymphomas. We studied the prognostic role of the N/L ratio at diagnosis in 286 patients with diffuse-large-B-cell lymphoma (DLBCL) enrolled in a multicenter prospective registry of the Lazio region in Italy The median age at diagnosis was 69 years (27-91) and the female/male ratio was:141/145.First, we analyzed for associations between N/L ratio and patient characteristics. The optimal cut-off value for the N/L was obtained using the Receiver Operating Curve (ROC) and according to the published data in solid tumor. N/L ≥ 4 was significantly associated with presence of B-symptoms (p=0.01) and elevated LDH levels (p=0.007) at diagnosis. Most patients were treated with R-CHOP (rituximab, cyclophosphamide, Adriamycin, vincristine, and prednisone) or R-CHOP-like (90%). Complete Remission (CR) + Partial Remission (PR) were obtained in 210/286 (73%). The median follow up period was 15 months (range: 1-33 months): 27 patients died for lymphoma relapse/progression and 16 for other causes. Patients with N/L ≥ 4 experienced a higher rate of relapse, while N/L< 4 was associated to a significantly better Overall (OS, P < 0.05) and Event Free Survival (EFS, P< 0.01). (Figure 1, panel a and b).Furthermore, considering only patients with IPI score ≤ 3, those with N/L Conclusion: The N/L ratio may be a useful and unexpensive prognostic marker in patients with DLBCL. The inferior outcome observed in patients with N/L ≥ 4 might reflect an immune and inflammatory imbalance induced by a more aggressive tumor, releasing directly or indirectly inflammatory cytokines and/or inducing immune suppression or exhaustion. A link with inflammation is suggested by the correlation of N/L ratio ≥ 4 with high LDH levels and the presence of B symptoms. Figure 1. Panel A. Overall Survival (OS) and Panel B. Event Free Survival (EFS) by N/L ratio. Panel C. Overall Survival (OS) by N/L in patients with IPI score ≤ 3. Table 1.Baseline patients characteristics (N = 268) and compared by N/L < 4 or ≥ 4 by using Chi-Square Test for categorical variables. Abbreviations not included in the text: IPI = International Prognostic Index; LDH = lactate dehydrogenase, PD: Progression Disease, NA: Not Applicable. Disclosures Cimino: Celgene: Honoraria; Bristol-Mayer: Honoraria.