Abstract: Background: Chronic lymphocytic leukemia (CLL) is associated with significant genomic heterogeneity that might explain its variable clinical course. Although there are established prognostic genomic features already detected by fluorescence in-situ hybridization (FISH), next generation sequencing (NGS) technologies have uncovered a myriad of novel mutations in CLL that may influence both prognosis and treatment decisions (Landau DA et al. 2015). Recently commercial NGS panels are actively used outside of the research spectrum. This study describes the mutational landscape of unselected consecutive CLL patients analyzed using commercial NGS platforms at a single academic institution as a part of routine clinical care. Materials and methods: Using Total Cancer Care (TCC) and Moffitt Cancer Center (MCC) CLL databases (N=1,267 patients) we retrospectively identified a subset of 148 subjects from January 2014 to May 2016 with confirmed CLL diagnosis and an available commercial NGS panel (Genoptix® and FoundationOne®). Molecular testing was done on bone marrow biopsies and/or peripheral blood samples either during the first clinic visit, or at time of disease progression. We used descriptive statistics to annotate demographic characteristics, disease prognostic features, mutation frequencies, and the class and type of molecular changes found in the cohort. We utilized standard statistical methods (Chi-square) to assess associations between known prognostic factors (age, CLL-IPI score, IGHV mutational status, B2M, ZAP-70 and CD38+ status, and FISH detected mutations) and identified mutations. Time to first treatment was estimated with the Kaplan-Meier method and curves compared with log-rank test. All statistical analyses where done using SPSS v24.0 Results: From our cohort of 148 CLL patients with an available commercial NGS panel, 110 and 38 were sequenced using Genoptix® and FoundationOne® panels, respectively. At the time of molecular sequencing 48 (32.3%) had high or very high CLL-IPI scores, 77 (52%) had unmutated IGHV, 22 (14.8%) harbored del11q, 19 (12.8%) had del17q and 10 (6.7%) had a complex karyotype. Seventy (47.2%) patients were treatment naïve and 59 (40%) had received CLL directed therapy before NGS testing. Of the previously treated patients, 56% received fludarabine-based regimens and 27% received at least one B-cell receptor inhibitor. The mean number of mutations in our patient cohort was 6.3 (3.1 per Genoptix® and 9.5 per FoundationOne®). Most common mutations types were missense (74.7%) and frameshift (14%). Most frequently mutated genes (≥7 cases) were: ATM (25.6%), TP53 (15.5%), NOTCH1 (15.5%), SF3B1 (14.1%), FAT1 (8.1%), BCOR (8.1%) and CREBBP (7.4%) (Figure 1). TP53 mutations had higher CLL-IPI scores (p 〈 0.001), del17q (p 〈 0.001), previous fludarabine based therapy (p 〈 0.009), fludarabine resistance (p=0.016) and shorter TFT in comparison to TP53wt (16.5 vs. 64.2 months, p=0.002). Interestingly, FAT1 mutation was universally correlated with mutated IGHV status (p 〈 0.001), and lower probability CLL-directed treatments (p=0.006). Table 1 shows correlation of general characteristics and other mutated genes. Conclusions: NGS, through validated commercial gene platforms, is readily available outside of clinical trials for CLL patients for genomic risk assessment and could accurately replicate findings of earlier reports. Challenges remains in regards of cost, adequate bioinformatics support and accessibility that restrict its availability to academic centers. Figure 1 Percentage of patients with the most common mutated genes Figure 1. Percentage of patients with the most common mutated genes Table 1 Table 1. Disclosures Nodzon: Novartis: Speakers Bureau. Chavez:Janssen: Speakers Bureau. Pinilla-Ibarz:Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Novartis: Consultancy; Novartis: Consultancy; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau.

Abstract: e18546 Background: Primary goal in management of chronic myeloid leukemia (CML) is to prevent progression to BP-CML. Even with the use of induction chemotherapy with a TKI, outcome remains dismal in BP-CML. We describe our experience with the management of BP-CML. Methods: Retrospective chart review was performed on CML patients treated between 2001 and 2016. Out of 585 CML cases, 58 (10%) had a diagnosis of BP-CML. Kaplan-Meier method with log-rank test was utilized for survival calculations. All p-values calculated were two sided. Results: The overall survival (OS) of BP-CML cohort was 31.9 months (mo) from diagnosis. In the patients diagnosed in chronic or accelerated phase, median time to progression to BP-CML was 19.1 mo. The median OS from the BP-CML diagnosis was not different when progressed from an earlier phase compared toBP-CML (10.8 vs 11.0, p 0.62). Trend toward worse OS was noted in myeloid BP-CML compared to lymphoid BP-CML (9.2 vs 17.5 mo, p 0.32). The median OS in the single agent TKI cohort (n=21) was 12.8 mo vs 10.9 mo (p 0.72) in the combination cohort (n = 36). Treatment with a single agent TKI vs combination therapy did not significantly impact OS in either myeloid (9.2 vs 9.1 mo, p 0.32) or lymphoid (14.5 vs 18.3 mo, p 0.24) BP-CML. Out of 26 patients (44.8%) who received allogeneic stem cell transplant, 26% (n=6) received a single agent TKI prior to transplant and 76.9% (n=20) received combination therapy. A trend toward improved OS was noted in the single agent TKI cohort (128.5 vs 24.0 mo, p 0.23). When stratified by the presence of standard Philadelphia chromosome or with additional cytogenetic aberrations, no difference in OS was noted (10.9 vs 12.1 mo, p 0.51). Monosomy 7 was present in greater frequency in lymphoid BP-CML than myeloid BP-CML (35.7% vs 6.3%, p 0.02). Conclusions: Our data suggest no survival difference when BP-CML is treated with a single agent TKI compared to a combination therapy, regardless of histology type. Therefore, single agent TKIs should be considered as an effective frontline therapy option for BP-CML, which may prevent the potential toxicity associated with chemotherapy. These findings need further validation in a larger prospective cohort.

Abstract: e14019 Background: Axi-cel is an anti-CD19 CAR T-cell therapy that can lead to long term disease control for patients with refractory LBCL including DLBCL, PMBCL, HGBL, and tFL. Beyond day 30, grade 3 or higher cytopenias were reported in 17% of patients (Locke 2019). We sought to further characterize cytopenias after axi-cel. Methods: We evaluated patients with LBCL treated with axi-cel at Moffitt from May 2015 to May 2018. Counts at apheresis and days 30, 90 and 180 after axi-cel infusion were recorded. Data was censored at date of progression, death or last follow-up. AEs were per CTCAE v4.03. Results: 52 patients were identified. Count data at each time is presented in the table. In total, 37.8% (17/45), 17.8% (8/45), and 28.9% (13/45) of patients experienced any grade 3-4 neutropenia, anemia or thrombocytopenia beyond day 30. Beyond day 30: 24.4% (11/45) received G-CSF; one (2.2%) received a TPO-agonist; none received an EPO-agonist; 15.6% (7/45) IVIG; 11.1% (5/45) PRBC; and 8.9% (4/45) platelet transfusion. 11 patients had bone marrow biopsies to evaluate cytopenias, at a median of 50 days (range 29-434) following axi-cel infusion. Median cellularity was 16.3% (range 5-45%), and 3/11 had reticulin staining indicating fibrosis. One patient, previously reported (Locke, Mol. Ther, 2017), had therapy related MDS and evidence of prior CHIP mutation. Conclusions: Prolonged neutropenia, lymphopenia, anemia, and thrombocytopenia occurred at least 180 days following axi-cel therapy in LBCL patients, in the absence of disease progression. Transfusion burden was low, and most patients recovered without an intervention.[Table: see text]

Abstract: TPS7594 Background: Phosphoinositide 3-kinase (PI3K) inhibitors have shown promising activity in lymphoid malignancies such as mature T cell lymphoma, diffuse large B cell lymphoma, and mantle cell lymphoma. Duvelisib’s PI3K-δ and PI3K-γ activity in T cell lymphoma is promising as a single agent (Horwitz, Koch et al. 2018). While the safety profile can generally be managed, certain autoimmune adverse events may limit its adaptation in clinical practice. Azacitidine, a pyrimidine nucleoside analog of cytidine, is active in T cell lymphoma (Saillard, Guermouche et al. 2017) as well as in DLBCL (Martin, Bartlett et al. 2018). Hypomethylators could enhance the activity of PI3K inhibitors through increasing PTEN expression (Spangle, Roberts et al. 2017), and upregulation of tumor suppressor genes (Zuo, Liu et al. 2011). Duvelisib’s immune mediated adverse events may be related to shifts in T cell differentiation towards Th17 phenotype and decreases in T reg differentiation that found to be more pronounced in patients with higher immune related toxicity (Gadi, Kasar et al. 2019). Studies have shown that T regs can be induced from Cd4+CD25- T cells using DNA methyltransferase inhibition with azacitidine (Fagone, Mazzon et al. 2018). Thus, the intermittent administration of azacytidine can potentially restore the balance by increasing T regs to decrease the autoimmune toxicity while maintaining Th17 phenotype that enhances tumor killing as shown in myelodysplastic syndrome (Jia, Yang et al. 2020). Methods: This is a 3+3 phase I dose escalation study designed to determine the maximum tolerated dose (MTD) of CC-486 in combination with duvelisib in patients with lymphoid malignancies. The MTD is defined as the highest dose with an observed incidence of dose limiting toxicity (DLT) in no more than one out of six patients treated at a particular dose level. Secondary endpoints include best overall response, disease control rate and duration of response. Exploratory end points will be biomarker driven with focus on the composition of different T cell compartments during the administration of the combination. Efficacy biomarkers will include measuring the phosphorylation of AKT in peripheral CD3+ T cells. Oral duvelisib will be given continuously with the dose escalation maintained during the first 2 cycles while CC-486 schedule will be 14 days on/14 days off. The first cohort of patients are enrolled, and are in the DLT testing period. Clinical trial information: NCT05065866.

Abstract: Chimeric antigen receptor T‐cell therapy with axicabtagene ciloleucel (axi‐cel) has considerably improved survival in adults with relapsed/refractory large B‐cell lymphoma. This study reports patient‐reported outcomes (PROs) such as quality of life (QOL) and toxicity in the first 90 days after treatment. Hematologic cancer patients treated with axi‐cel ( N  = 103, mean age = 61, 39% female) completed SF‐36 or PROMIS‐29 QOL questionnaires prior to treatment and 90 days after. PRO‐Common Terminology Criteria for Adverse Events toxicity items were completed by patients at baseline and 14, 30, 60, and 90 days after treatment. Mixed models examined change in PROs over time. From preinfusion to 90 days later, patients reported improvements in physical functioning, pain, and fatigue ( p s  〈  0.01), but worsening of anxiety ( p  = 0.02). Patient‐reported toxicities worsened by day 14 with improvement thereafter. The five most severe symptoms at day 14 included fatigue, decreased appetite, dry mouth, diarrhea frequency, and problems with concentration. Results indicate improvement in some domains of QOL over time with transient patient‐reported toxicities.

Abstract: Background: New targeted therapies continue to show improved efficacy in various stages of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), sparing patients from chemoimmunotherapy. However, cure remains elusive. Here, we present a front-line alternative based on a combination of high-dose methylprednisolone (HDMP) and ofatumumab, followed by consolidative therapy with lenalidomide plus ofatumumab. Methods: This is a phase II, single-center study in patients with treatment-naive (TN) CLL/SLL. During the first treatment phase (cycles 1-3) patients received HDMP 1000 mg/m2 IV and ofatumumab 2000 mg (300 mg given week 1 then 2000 mg for a total of 12 doses) IV infusions weekly x 4 doses in cycle 1 of a 28 day cycle, then every 2 weeks for cycles 2 and 3. During the second treatment phase (cycles 4-12), patients received renally adjusted lenalidomide 5-10 mg daily and ofatumumab 2000mg IV once every 8 weeks. Growth factor support was permitted at the discretion of treating physician. Prophylactic medications included allopurinol for tumor lysis syndrome (TLS) 3 days before C1D1 through C1; and trimethoprim/sulfamethoxazole and fluconazole through cycle 4, and acyclovir through C12. Patients received aspirin 81 mg/day as thrombosis prophylaxis while on lenalidomide. Patients were assessed for response by iwCLL 2008 criteria (including imaging assessment) after completion of cycles 3 and 12. The study allowed continuation of lenalidomide if patients achieved complete (CR), partial (PR) response or stable disease (SD). Primary endpoints were efficacy, adverse events (AEs) profile, and time-to-treatment failure (TTF). Results: Between January 2012 and September 2015, the study enrolled a total of 45 patients. Median follow-up was 50.4 (5.6-72.8) months. The median age was 62.6 (48.2-86.1) years. Chromosomal analysis by FISH demonstrated Del17p in 8 (17.8%), Del11q (+/- others, except Del17p) in 10 (22.2%), Trisomy 12 (+/- others, except Del17p and Del11q) in 8 (17.8%), Del13q in 10 (22.2%), no mutations in 9 (20%) patients. The IGHV status was unmutated in 34 (75.6%) cases. Indications to start treatment were: symptomatic lymphadenopathy, symptomatic splenomegaly, anemia, and thrombocytopenia in 5 (11.1%), 10 (22.2%), 12 (26.7%), and 18 (40%), respectively. The median duration of treatment was 35.6 (2.7-66.9) months. Reasons for treatment discontinuation were: progressive disease (PD) in 9 (20%), AEs in 15 (33.3%), transplantation in 3 (6.7%), consent withdrawal in 1 (2.2%), and secondary malignancies in 2 (4.4%) cases. The overall response rates (PR+CR) at 3, 12, 24, 36, and 48 months were 75.6%, 77.8%, 66.7%, 44.4%, and 37.8%, respectively. The CR rates at 3, 12, 24, 36, and 48 months were 2.2%, 11.1%, 20%, 17.8%, and 13.3% respectively. Fifteen patients remain in PR/CR and on treatment at the time of this analysis. The intention-to-treat median TTF was 45.2 (2.9-69.7) months, and was not different among high risk groups such as Del17p, Del11q and/or unmutated IgHV. In patients who discontinued for reasons other than PD the median duration of response without treatment was 30.7 (9.8-69.7) months. Three (6.7%) patients underwent allogeneic hematopoietic cell transplantation after a median of 3 (3 - 4) treatment cycles. Treatment was well tolerated with grade 3/4 infusion reaction in 1 (2.2%) patient. Grade 3/4 treatment-related hematological AEs were neutropenia, thrombocytopenia, and anemia in 33 (73.3%), 5 (11.1%), and 1 (2.2%), respectively. Grade 3/4 infections occurred in 6 (13.3%) patients. No grade 3/4 tumor flares were observed, and there were no cases of TLS or thrombosis. Conclusion: The combination of ofatumumab, HDMP and lenalidomide is effective and well tolerated in treatment-naive CLL/SLL, even when poor prognostic features are present. Disclosures Komrokji: Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Locke:Novartis Pharmaceuticals: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Kite Pharma: Other: Scientific Advisor. Kharfan-Dabaja:Seattle Genetics: Speakers Bureau; Incyte Corp: Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau. Sokol:Spectrum Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Mallinckrodt Pharmaceuticals: Consultancy.

Abstract: Introduction: Patients (pts) with hematological malignancies (HMs) are at increased risk for severe COVID19 infection and death (Grivas, 2021). Currently, vaccination represents the most effective prevention approach. HM pts have been shown to have lower immune responses to COVID19 vaccine, particularly those with lymphoid malignancies (LMs) (Herishanu, 2021; Thakkar 2021; Tzarfari 2021). We conducted an observational cohort study at Moffitt Cancer Center (MCC) to evaluate the immune response following one and two doses of the mRNA1273 (Moderna) vaccine in cancer pts. Here we report the results for pts with LMs and assessed associated factors. Methods: MCC pts who presented for the first mRNA-1273 vaccine dose from 1/12/2021-1/25/2021 and who provided consent were enrolled. Blood samples were collected prior to the 1 st and 2 nd doses (Days 1 and 29) and ~28 days after the 2 nd dose (Day 57). The IgG response against the SARS-CoV-2 spike (S) protein was measured using a two-step ELISA adapted from the Krammer (Icahn School of Medicine at Mount Sinai) protocol. The total 103 LM pts who received both vaccine doses and had samples at all time points were included in analyses. The 214 pts with solid tumors (ST) were included as comparison. Associations of seroconversion (SV) rates with pt characteristics were evaluated using the Fisher exact test or Chi-square test as appropriate. Associations of antibody (Ab) titers with pt characteristics were examined using Kruskal Wallis test. Factors independently associated with SV rates were evaluated using multivariable logistic regression. All analyses were performed using SAS 9.4 and R studio. Results: Baseline characteristics, cancer treatments and SV rates by these factors are listed in Tables 1 and 2. 55 pts had B-cell non-Hodgkin lymphoma (B-NHL), 23 had chronic lymphocytic leukemia (CLL), 15 had T- or NK-cell lymphoma (T/NK lymphoma) and 10 had Hodgkin lymphoma (HL). SV rates were significantly lower for LM pts compared to ST pts (49.5% vs 86.9% after the 1st dose and 68.9% vs 98.1% after the 2 nd dose, respectively, p & lt;0.0001 for both doses). Pts with CLL and B-NHL had the lowest SV rates (21.7% and 43.6% after dose 1 and 65.2% and 58.2% after dose 2, respectively). None of the 11 pts on anti-CD20 monoclonal Ab (mAb) seroconverted after 2 doses. Pts on BTK inhibitors (BTKi) or PI3K inhibitors (PI3Ki) or venetoclax also had low SV rates [4/12 (33.3%) after 2 doses]. Only 1 out of the 8 pts post CAR-T seroconverted, despite the fact that 6 pts had CAR-T & gt;12 months ago and 6 pts were in remission and have not received any cancer treatment after CAR-T. Pts with CLL and B-NHL but not on CD20 mAb/BTKi/PI3Ki/venetoclax or post CAR-T had much higher SV rates (31.3-60.5% after dose 1 and 79.0-81.3% after dose 2, Table 3). Other factors associated with lack of SV after 2 doses included: lymphocyte & lt;1 x 10 9/L, low IgG level and on anticancer treatment within 3 months. Multivariate analyses showed that diagnosis of CLL or B-NHL compared to ST, CAR-T and CD20 mAb/BTKi/PI3Ki/venetoclax were independently associated with decreased SV after 2 doses (Table 4). In the univariate model, Ab titers after 1 and 2 doses were significantly lower in pts with diagnosis of CLL/B-NHL, low lymphocyte count, low IgG and on cancer treatment (Figures 1-3). HL and T/NK lymphoma had titers comparable to solid tumors (Figure 1). Conclusions: Pts with CLL and B-NHL had low SV rates and Ab titers after receiving the mRNA-1273 vaccine when compared with ST, HL and T/NK-lymphoma. Current or past treatments with CD20 mAb/BTKi/PI3Ki/venetoclax and CAR-T were associated with lower immune response, with pooled SV rates of 16.7% after 2 doses. In general, LM pts had lower SV rates and Ab titers after the 1 st dose vs ST, but responses improved after the 2 nd dose. Further studies are needed to improve immune responses to COVID19 vaccines in LM pts, including the potential role of a 3 rd booster dose. Figure 1 Figure 1. Disclosures Gaballa: Adaptive Biotechnologies: Research Funding; Epizyme: Consultancy, Research Funding; TG therapeutics: Consultancy, Speakers Bureau; Beigene: Consultancy; ADC Therapeutics: Consultancy. Saeed: Bristol-Myers Squibb Company: Consultancy; sano-aventis U.S.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutica Products, LP: Consultancy, Other: investigator; Celgene Corporation: Consultancy, Other: investigator; MEI Pharma Inc: Consultancy, Other: investigator; Kite Pharma: Consultancy, Other: investigator; Other-TG therapeutics: Consultancy, Other: investigator; Nektar Therapeutics: Consultancy, Other: research investigator; MorphoSys AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Other-Epizyme, Inc.: Consultancy; Other-Secura Bio, Inc.: Consultancy; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shah: Pharmacyclics/Janssen: Honoraria, Other: Expenses; Pfizer: Consultancy, Other: Expenses; BeiGene: Consultancy, Honoraria; Servier Genetics: Other; Jazz Pharmaceuticals: Research Funding; Precision Biosciences: Consultancy; Amgen: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Acrotech/Spectrum: Honoraria; Novartis: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy; Incyte: Research Funding. Locke: Janssen: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; EcoR1: Consultancy; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Calibr: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Umoja: Consultancy, Other; Cowen: Consultancy; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Wugen: Consultancy, Other; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Legend Biotech: Consultancy, Other. Chavez: Abbvie: Consultancy; AstraZeneca: Research Funding; Kite/Gilead: Consultancy; Karyopharm Therapeutics: Consultancy; MorphoSys: Speakers Bureau; Epizyme: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Merck: Research Funding; Adaptive: Research Funding; BeiGene: Speakers Bureau; Novartis: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet: AbbVie: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jazz: Consultancy. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Pinilla Ibarz: AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; Sellas: Other: ), patents/royalties/other intellectual property; MEI, Sunesis: Research Funding; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau. Giuliano: Merck & CO: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.