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Background Relapsed and refractory multiple myeloma (RRMM) remains a major challenge. With each relapse, patients (pts) experience decreased response duration leading to shortened survival. Pts with triple-class refractory disease (refractory to one class of the following: immunomodulatory agents (IMiDs), proteasome inhibitors (PI) and anti-CD38 monoclonal antibody) have a poor prognosis. Belantamab mafodotin is a first-in class B-cell maturation antigen (BCMA) antibody-drug conjugate. The aim of this study was to analyze the clinical outcomes of belantamab/dexamethasone (Bd) in triple-class RRMM. Patients & Methods Twenty-eight pts with triple-class RRMM receiving Bd were identified at University of Kansas Health System between October 2019 and June 2021 and reviewed retrospectively. These pts received belantamab 2.5 mg/kg IV every 3 weeks and dexamethasone (20-40) mg PO weekly. Descriptive analyses were performed on available data for patient characteristics. Survival curves were generated using the Kaplan-Maier method. Responses were evaluated using the International Myeloma Working Group (IMWG) criteria. Results The median age was 67 yrs (42-85). Eleven pts (39%) had IgG isotype, 14 pts (50%) had R-ISS stage III disease, 20 pts (71%) had high-risk cytogenetics, and 13 pts (46%) had extramedullary disease (EMD). Patients characteristics are summarized in Table 1. Median number of Bd cycles received was 3 (2-18). The median number of previous lines of therapy was 5 (3-15). All pts were triple-class refractory, whereas 15 pts (54%) were penta-refractory. Twenty-one pts (75%) received autologous stem cell transplant, and 8 pts (29%) had previously received BCMA-targeted therapy. The response rate for all pts was 46% with 18% achieving very good partial response and better. Median follow-up was 7.4 months. Median progression-free survival (PFS) was 4.9 months, while median overall survival (OS) was 7.4 months. The response rates are summarized in Table 2. Keratopathy was one of the most common adverse events (AEs), occurring in 23 (82%) pts, 13 (56%) pts had grade 3 or 4 keratopathy. Nineteen patients (68%) required dose reduction or delay due to keratopathy. Other common AEs included: anemia (83%), thrombocytopenia (70%), neutropenia (30%), and elevated liver function tests (53%). Eighteen patients (64%) discontinued due to progression of disease or death. No treatment-related mortality was noted in this review. Conclusion Our analysis demonstrates a reasonable efficacy of Bd in those who are heavily treated triple-class RRMM patients in the real world. Keratopathy remains a challenging AE and the main cause of dose reduction and delay. Figure 1 Figure 1. Disclosures Atrash: AMGEN: Research Funding; Jansen: Research Funding, Speakers Bureau; GSK: Research Funding. Mahmoudjafari: GSK: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. McGuirk: Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Bellicum Pharmaceuticals: Research Funding; Pluristem Therapeutics: Research Funding.

Introduction: Lenalidomide (LEN), a standard of care for newly diagnosed multiple myeloma, is routinely administered until disease progression. However, patients with disease that has relapsed after or become refractory to LEN have been poorly represented in recent trials investigating triplet regimens after ≤ 3 prior treatment (Tx) lines. Consequently, patients who have exhausted the benefits of LEN in early relapse are a clinically relevant population in need of proven Tx options. The trial that led to approval of pomalidomide (POM) + dexamethasone (DEX) + daratumumab (DARA) evaluated patients with heavily pretreated (median of 4 prior lines of therapy) relapsed refractory multiple myeloma (RRMM; Chari et al. Blood 2017). The phase 2 MM-014 trial (NCT01946477), which is composed of 3 cohorts, was specifically designed to investigate the outcomes of sequencing POM-based therapy immediately after first- or second-line LEN-based Tx failure in patients with RRMM. In an earlier report from cohort B of MM-014, POM + DEX + DARA demonstrated promising efficacy and safety results: the overall response rate (ORR) was 77.7%, and the 1-year progression-free survival (PFS) rate was 75.1% at a median follow-up of 17.2 months (Siegel et al. Leukemia 2020). Updated efficacy and safety results from cohort B are reported here. Methods: Patients with RRMM treated with 1-2 prior Tx lines, LEN-based Tx as their most recent regimen, and progressive disease during/after their last line of Tx received POM + DEX + DARA. POM 4 mg/day was given orally on days 1-21; DEX 40 mg/day (20 mg/day in patients aged > 75 years) was given orally on days 1, 8, 15, and 22; and DARA 16 mg/kg was given intravenously on days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 for cycles 3-6, and day 1 for cycles 7+. ORR was the primary endpoint; secondary endpoints included PFS and safety. Results: In the intention-to-treat (ITT) population of 112 patients, the median age was 66.5 years, all patients had prior LEN, and 77.7% had prior bortezomib. Overall, 84 patients (75%) had LEN-refractory MM and 28 (25%) had MM that relapsed after prior LEN Tx; most patients (70 [62.5%]) received 1 vs 2 (42 [37.5%]) prior Tx lines. As of March 24, 2020, 31 patients (27.7%) were still on treatment; median follow-up was 28.4 months. The most common reasons for discontinuation in 81 patients (72.3%) were progressive disease (46 patients [56.8%]), withdrawal by patient (19 patients [23.5%]), and adverse events (AEs; 7 patients [8.6%]). The efficacy-evaluable (EE) population comprised 109 patients who received ≥ 1 dose of study Tx and had ≥ 1 post-baseline assessment and was used for supportive efficacy analyses. ORR was 77.7% (≥ very good partial response [VGPR], 52.7%) and 79.8% (≥ VGPR, 54.1%) in the ITT and EE populations, respectively. ORR was similar in patients with LEN-relapsed and LEN-refractory disease (82.1% and 76.2%, respectively). The median PFS was reached: 30.8 months in both the ITT and EE populations (Figure). Overall, 97.3% of patients had ≥ 1 grade 3/4 AE, with neutropenia (64.3%; febrile 9.8%) being the most common grade 3/4 hematologic Tx-emergent AE, followed by anemia (17.9%) and thrombocytopenia (14.3%). Grade 3/4 infections were noted in 36.6% of patients, including 16.1% with grade 3/4 pneumonia. Conclusions: POM + DEX + DARA administered in early-line Tx immediately after LEN failure continues to show a high response rate and a consistent safety profile, demonstrating the benefit of maintaining continuous immunomodulation with POM following LEN. These updated results continue to demonstrate the efficacy and safety of POM-based therapy as early as second line in patients with RRMM, even immediately after LEN failure, indicating that switching from the immunomodulatory agent class is not necessary. Furthermore, these findings support the use of POM + DEX as the foundation of novel combinations in MM. Figure 1 Disclosures Siegel: Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy. Schiller:Forma: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Deciphera: Research Funding; DeltaFly: Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; FujiFilm: Research Funding; Mateon: Research Funding; Kite Pharma: Research Funding; Karyopharm: Research Funding; Celator: Research Funding; Constellation: Research Funding; Cyclacel: Research Funding; Jazz Pharmaceuticals: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Gilead: Speakers Bureau; Astellas Pharma: Honoraria, Research Funding; Ariad: Research Funding; Actinium: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Pfizer: Current equity holder in publicly-traded company, Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Daiichi Sankyo: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida: Research Funding. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Berdeja:CRISPR Therapeutics: Consultancy, Research Funding; Cellularity: Research Funding; Celgene: Consultancy, Research Funding; Servier: Consultancy; Teva: Research Funding; Prothena: Consultancy; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bioclinica: Consultancy; Bluebird: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding; Acetylon: Research Funding; Poseida: Research Funding; CURIS: Research Funding; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Glenmark: Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy; Kesios: Research Funding; Kite Pharma: Consultancy; Legend: Consultancy; Lilly: Research Funding; Novartis: Research Funding; Constellation: Research Funding. Ganguly:KITE Pharma: Speakers Bureau; Settle Genetics: Speakers Bureau; Kadmon: Other: Ad Board. Matous:Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau. Song:Celgene: Research Funding; Celgene, Janssen, Amgen, Takeda: Honoraria. Bar:Bristol-Myers Squibb Company: Consultancy. Anz:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Fonseca:Bristol-Myers Squibb Company: Speakers Bureau. Reece:Janssen, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Otsuka: Research Funding; Janssen, Bristol-Myers Squibb, Amgen, Takeda: Consultancy, Honoraria. Lee:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Agarwal:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Bahlis:BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria.

Introduction: Proteasome inhibitors-based regimens are the mainstay of initial therapy for most patients with multiple myeloma. Daratumumab is a human IgGκ monoclonal antibody that targets CD38 with direct antitumor effects and has an immunomodulatory component. Recent studies have demonstrated that addition of daratumumab to standard regimens enhance direct cytotoxicity on myeloma cells and have shown survival benefits. Yet, there are notable safety concerns. We performed a combined analysis of randomized controlled trials (RCT) to determine the risk of second primary malignancies (SPM) and peripheral sensory neuropathy (PSN) with newer daratumumab combination regimens. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with multiple myeloma that mention SPM and PSN as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,547 patients with multiple myeloma from 5 phase III RCTs were eligible. Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, DVd vs Vd and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. Daratumumab was utilized in relapsed and refractory multiple myeloma in the POLLUX study (n= 564) and the CASTOR study (n= 480) and as first-line treatment for patients with multiple myeloma in the ALCYONE study (n= 700), the CASSIOPEIA study (n= 1085) and the MAIA study (n= 737). The I2 statistic for heterogeneity was 25, suggesting some heterogeneity among RCT. The SPM incidence was 76 (4.29%) in study group vs 77 (4.34%) in control group. The RR for SPM was 1.12 (95% CI: 0.74 - 1.69; P = 0.58) and RD was 0.01 (95% CI: -0.01 to 0.02; P = 0.34). The RR for SPM was noted at 2.56 (95% CI: 0.26 - 25.46; P = 0.42) in a subset of relapsed and refractory multiple myeloma. Any-grade PSN was reported in 527 (46.84%) in daratumumab arm vs 550 (48.72%) in control arm with the RR of 0.98 (95% CI: 0.80 -1.21; P = 0.88). High-grade PSN was noted in 63 (5.6%) vs 76 (6.73%) in control group with the RR of 0.73 (95% CI: 0.42 -1.27; P = 0.27). Conclusions: Our meta-analysis depicted that there was no significant increase in the risk of second primary malignancies and peripheral sensory neuropathy in patients on daratumumab combination regimen, in newly diagnosed and relapsed refractory multiple myeloma, compared to control arm. However, long-term follow-up of these patients is required to determine the actual relation with second primary malignancies. Disclosures No relevant conflicts of interest to declare.

Introduction: Phosphatidylinositol 3-kinase (PI3K) is a kinase protein involved in downstream signaling for multiple pathways in B cells and is important for B cell survival, proliferation and metabolism. Hence, PI3K inhibitors have become an attractive therapeutic option for treatment of B cell malignancies. Two prominent PI3K inhibitors, (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), are currently being studied in relapsed and refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) and have shown to improve survival in recent trials with notable toxicities. We analyzed phase 3 trials to assess the incidence of serious adverse events, pneumonitis, infection and sepsis associated with PI3K inhibitors in this susceptible population. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL that mention serious adverse events, pneumonitis, infection and sepsis as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were included in analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCTs. The incidence of serious adverse events was 479 (73.69%) in study group vs 252 (44.92%) in control group (RR, 1.58; 95% CI: 1.37 - 1.83; P < 0.0001 and RD, 0.26; 95% CI: 0.13 - 0.40; P = 0.0002). Pneumonitis was noted in 20 (3.07%) vs 1 (0.18%) in control group with RR of 6.53 (95% CI: 1.74 -24.53; P = 0.005) and RD of 0.02 (95% CI: 0.01 - 0.04; P = 0.0004). The incidence of any-grade pneumonia was 107 (16.46%) in study group vs 54 (9.63%) in control group (RR, 1.61; 95% CI: 1.00 - 2.58; P = 0.05). High-grade pneumonia was reported in 81 (12.46%) in idelalisib arm versus 35 (6.24%) in control group with RR of 1.84 (95% CI: 0.82 - 4.13; P = 0.14). Pneumocystis jiroveci pneumonia (PJP) rate was 2.24% higher in study group compared to control arm (RR, 3.87; 95% CI: 1.22 - 12.29; P = 0.02). Any-grade upper respiratory tract infection (URTI) was 14% in study group versus 7.84% in control arm (RR, 1.65; 95% CI: 1.17 - 2.34; P = 0.005). Sepsis rate was 2.88% higher in idelalisib group compared to control arm and the pooled RR was statistically significant at 2.68 (95% CI: 1.19 - 6.04, P = 0.02). Treatment-related deaths were 64 (11.85%) in study arm vs 28 (6.17%) in control arm according to analysis of 3 trials. The pooled RR was also statistically significant at 1.87 (95% CI: 1.21 -2.88; P = 0.005). Conclusions: Our meta-analysis showed that the incidence of serious adverse events, pneumonitis, PJP pneumonia, any-grade URTI and sepsis was significantly higher in PI3K inhibitors group with RR of 1.58 for serious adverse events, RR of 6.53 for pneumonitis, RR of 3.87 for PJP pneumonia and RR of 2.68 for sepsis respectively. Moreover, patients on PI3K inhibitors experienced 5.68% higher incidence of treatment-related deaths with RR of 1.87, compared to control arm. Since treatment-related serious toxicities and deaths are higher amongst patients treated with these agents, extra caution should be observed and recommended with their use. Disclosures No relevant conflicts of interest to declare.

Introduction: Multiple myeloma is a hematologic cancer of plasma cell, a blood cell which normally produce antibodies, and accounts for approximately 13% of all hematologic malignancies. Daratumumab is a human anti CD38 IgGκ monoclonal antibody with a well characterized mechanism of action via direct antitumor effects and an immunomodulatory component and the incorporation of daratumumab to standard multiple myeloma regimen has shown to significantly improve response rates and survival, with notable toxicities. We performed a combined analysis of randomized controlled trials (RCT) to determine the risk of infection and pneumonia in patients with multiple myeloma treated with daratumumab. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with multiple myeloma that mention infection including pneumonia as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,547 patients with multiple myeloma from 5 phase III RCTs were eligible. Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, DVd vs Vd and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. Daratumumab was utilized in relapsed and refractory multiple myeloma in the POLLUX study (n= 564) and the CASTOR study (n= 480) and as first-line treatment for patients with multiple myeloma in the ALCYONE study (n= 700), the CASSIOPEIA study (n= 1085) and the MAIA study (n= 737). The I2 statistic for heterogeneity was 35, suggesting some heterogeneity among RCT. The incidence of any-grade infection was 58.01% in study group vs 48.06 % in control group (RR, 1.21; 95% CI: 1.12 - 1.31; P < 0.0001). High-grade infection rate was 5.46% higher in daratumumab group compared to control arm (RR, 1.27; 95% CI: 1.13 - 1.44; P = 0.0001). Any-grade pneumonia was reported in 12.58% in study arm versus 7.72%% in control group with RR of 1.63 (95% CI: 1.08 - 2.45; P = 0.02). High-grade pneumonia was 8.47% in study group versus 5.52% in control arm (RR, 1.51; 95% CI: 0.97 - 2.35; P = 0.07). The RR for high-grade pneumonia was statistically significant at 2.07 (95% CI: 1.50 - 2.85; P < 0.0001) in a subset of newly diagnosed multiple myeloma patients treated with daratumumab (n= 2503). Conclusions: The addition of daratumumab to standard multiple myeloma regimen contributed to higher incidence of all grades of infection and any-grade pneumonia, with RR of 1.27 for high-grade infection and RR of 1.63 for any-grade pneumonia. However, high-grade pneumonia was only found to be significant in a subset of patients with newly diagnosed multiple myeloma treated with daratumumab, with RR of 2.07. Timely intervention with proper supportive care is required. Disclosures No relevant conflicts of interest to declare.

Introduction: PATP in solid cancer patients remains uncertain and is not routinely recommended although thrombosis is shown to be the second leading cause of death in cancer patients. Many studies failed to demonstrate in solid cancer outpatients improvement in overall survival despite decreasing venous thromboembolism (VTE) rates by PATP. We conducted a systematic review and meta-analysis of RCTs to determine the benefit and risk of PATP with low-molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs) in patients with gastrointestinal cancers receiving chemotherapy. Methods: We performed a comprehensive literature search using MEDLINE and EMBASE databases through June 30, 2019. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE as a primary or secondary endpoint and the major bleeding (MB) as a safety outcome were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Results: A total of 1,932 patients with gastric, gastroesophageal junctional (GEJ) and colorectal cancers from a subgroup of three RCTs were included in our meta-analysis. The prophylactic doses of LMWHs and DOAC (rivaroxaban) were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I2 statistic for heterogeneity was 0, suggesting homogeneity among RCTs. The VTE incidence was 13 (1.26%) in PATP group and 23 (2.55%) in control group with a RR of 0.49 (95% CI: 0.25 to 0.96, P = 0.04). The absolute RD in VTE was -0.01 (95% CI: -0.03 to -0.00, P 0.04) with an estimate of the number needed to treat (NNT) of 78 to prevent one VTE event. In a subset of patients with gastric and GEJ cancers (n=587), the VTE incidence was 4 (1.37%) in PATP group and 10 (3.40%) in control group with a RR of 0.40 (95% CI: 0.13 to 1.24, P = 0.11). Conclusions: In our study, the relative risk reduction is 48% with a NNT of 78 to prevent one VTE in ambulatory patients with gastrointestinal cancers. Nevertheless, there is no statistically significant reduction in VTE events in a subset of gastric and GEJ cancers which are considered high risk in Khorana score. Based on the findings, PATP is not recommended in patients with gastrointestinal cancers on chemotherapy at this time. Further studies are necessary to define high risk subsets of gastrointestinal cancer patients receiving chemotherapy who may benefit from PATP. Disclosures Oo: Medical Education Speakers Network: Honoraria; Janssen and Janssen: Other: site co-investigator.

Introduction: Chronic lymphocytic leukemia is the most prevalent adult leukemia in western countries. Phosphatidylinositol 3-kinase (PI3K) is a kinase protein involved in downstream signaling for the B-cell receptor signaling pathway and has been shown to involve in the pathogenesis of chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/ SLL) by promoting B-cell survival, proliferation and metabolism. Two prominent PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), have recently shown to improve survival in patients with relapsed and refractory CLL/ SLL. We undertook a systematic review and meta-analysis of phase 3 randomized controlled trials to determine the risk of hematological toxicities associated with PI3K inhibitors. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL that mention hematological toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were included. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCTs. The RR of all-grade side effects were as follows: anemia, 1.39 (95% CI: 0.89 - 2.17; p = 0.15); neutropenia, 1.33 (95% CI: 1.06 - 1.67; p = 0.02); and thrombocytopenia, 1.23 (95% CI: 0.69 - 2.18; p = 0.48). The RR of high-grade adverse effects were as follows: anemia, 1.29 (95% CI: 0.62 - 2.67, p = 0.50); neutropenia, 1.51 (95% CI: 1.22 - 1.88; p = 0.0001); and thrombocytopenia, 1.21 (95% CI: 0.66 - 2.22; p = 0.53). The incidence of febrile neutropenia was 76 (11.69%) in study group vs 22 (3.92%) in control group with RR of 2.62 (95% CI: 1.27 -5.41, P = 0.009). Conclusions: PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), increased the risk of all grades of neutropenia and febrile neutropenia, with RR of 2.62 for febrile neutropenia, in patients with relapsed and refractory CLL/SLL. Vigilant monitoring is warranted, and proper supportive care and dose modifications should be followed. Disclosures No relevant conflicts of interest to declare.

Introduction: Management of newly diagnosed multiple myeloma (NDMM), which accounts for 1% of all cancers, is an area in dire need of therapeutic innovation. In recent years, the introduction of novel agents is one of the major advances in the management of patients with NDMM, in both transplant- eligible and transplant- ineligible candidates. Studies have combined daratumumab, a human IgGκ monoclonal antibody that targets CD38 which is highly expressed on myeloma cells, with proteasome inhibitors and immunomodulatory agents-based regimens in the first-line treatment of NDMM. The purpose of our study is to explore and consolidate the efficacy of upfront daratumumab combination regimen in patients with NDMM. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with newly diagnosed/ untreated multiple myeloma were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) for overall response rate (ORR), including stringent complete response (sCR), CR and very good partial response (VGPR). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Three phase III RCTs with a total of 2,528 patients with NDMMwere included.Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. The I2statistic for heterogeneity was 0, suggesting homogeneity among RCT. The pooled HR for PFS was statistically significant at 0.52 (95% CI: 0.44-0.61; P < 0.0001). The PFS benefit was observed in all ISS categories, types of immunoglobulin (Ig) and standard risk cytogenetic; ISS I cohort (HR, 0.55; 95% CI: 0.37- 0.82; P = 0.003), ISS II cohort (HR, 0.43; 95% CI: 0.33- 0.55; P < 0.0001), ISS III cohort (HR, 0.63; 95% CI: 0.48- 0.82; P = 0.0006), IgG cohort (HR, 0.56; 95% CI: 0.40- 0.77; P = 0.0003), non-IgG cohort (HR, 0.52; 95% CI: 0.28- 0.97; P = 0.04), and standard risk cytogenetic cohort (HR, 0.43; 95% CI: 0.35- 0.53; P < 0.0001). The pooled HR for PFS in high risk cytogenetic cohort was not statistically significant at 0.76 (95% CI: 0.53- 1.10; P = 0.15). The pooled RR for ORR was 1.13 (95% CI: 1.01-1.26; P = 0.03), sCR was 2.02 (95% CI: 1.33-3.08; P = 0.001), CR was 1.46 (95% CI: 1.20-1.79; P = 0.0002),and VGPR was 1.01 (95% CI: 0.82-1.25; P = 0.93). The pooled RR for negative minimal residual disease (MRD) was 2.54 (95% CI: 1.24-5.20; P = 0.01). Conclusions: Upfront combination regimen with daratumumab significantly improved PFS, ORR, sCR and CR along with negative MRD, compared to control arm in patients with NDMM. The improvement in PFS was noted across all subgroups except in high-risk cytogenetic group. More randomized studies are required to explore further novel agents and to formulate optimal combination regimen to improve survival in this high-risk cytogenetic subset. Disclosures No relevant conflicts of interest to declare.

Introduction: Thrombosis is the second leading cause of death in cancer patients and patients with APC are categorized as high-risk of developing venous thromboembolism (VTE). Many trials had failed to demonstrate improvement in survival with PATP. Despite decreasing VTE events, PATP in solid cancer patients is not routinely recommended. We conducted an updated meta- analysis of RCTs to determine the benefit and risk of PATP with low-molecular weight heparins (LMWH) and direct oral anticoagulants (DOAC) in patients with APC receiving chemotherapy. Methods: We performed a comprehensive literature search using MEDLINE and EMBASE databases through June 30, 2019. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE as a primary or secondary endpoint and the major bleeding (MB) as a safety outcome were incorporated in the analysis. The primary meta- analytic approach was a random effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Results: A total of 1,013 patients with APC from two RCTs and a subgroup of another three RCTs were included in our meta-analysis. The prophylactic, intermediate and therapeutic doses of LMWH and prophylactic dose of DOAC (rivaroxaban) were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I2statistic for heterogeneity was 60, suggesting some heterogeneity among RCTs. The VTE incidence was 28 (5.43%) in PATP group and 60 (12.07%) in control group with a RR of 0.44 (95% CI: 0.20 to 0.99, P = 0.05) and RD of -0.06 (95% CI: -0.11 to -0.01, P = 0.01). In fixed effects model, the pooled RR was 0.45 (95% CI: 0.29 to 0.70, P = 0.0003) and the absolute RD in VTE was -0.07 (95% CI: -0.10 to -0.03, P = 0.0002) with an estimate of the number needed to treat (NNT) of 15 to prevent one VTE event. MB events were reported in 9 (4.11%) patients in PATP group compared to 7 (3.27%) in control group according to an analysis of 2 RCTs. The pooled relative risk for MB was statistically non-significant at 1.25 (95% CI: 0.47 to 3.31, P = 0.65). Conclusions: In our study, PATP in APC may statistically significantly decrease VTE events, approximately with relative risk reduction of 55% and a NNT of 15, without increasing MB events. Proper selection of patients who are high risk for VTE in outpatient setting is important. More RCTs are required to further define high risk subsets of APC patients receiving chemotherapy who may benefit from PATP. Disclosures Oo: Medical Education Speakers Network: Honoraria; Janssen and Janssen: Other: Research: site co-investigator .

Introduction: Bruton's tyrosine kinase (BTK) is a kinase involved in cellular signaling downstream of the B cell receptor and is involved in B-cell survival and proliferation. Hence, BTK inhibitors have become an attractive therapeutic target for a multitude of B cell malignancies, mainly chronic lymphocytic leukemia. Ibrutinib is an oral potent covalent inhibitor of BTK and hence employed in many hematologic malignancies for BTK inhibition. Yet, the risk of atrial fibrillation and major bleeding remains considerable. We undertook an updated analysis of phase III trials to assess the incidence of atrial fibrillation and major bleeding associated with ibrutinib in this susceptible population. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing ibrutinib in patients with hematologic malignancies that mention atrial fibrillation and major bleeding were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,920 patients with CLL/SLL, mantle-cell lymphoma, Waldenstrom's macroglobulinemia and diffuse large b-cell lymphoma, from 10 phase III RCTs were eligible. Studies compared ibrutinib+ obinutuzumab vs chlorambucil+ obinutuzumab, ibrutinib vs chlorambucil, bendamustine+ rituximab vs ibrutinib vs ibrutinib+ rituximab, ibrutinib+ rituximab vs fludarabine+ cyclophosphamide+ rituximab, ibrutinib vs rituximab, ibrutinib vs ofatumumab, ibrutinib+ bendamustine+ rituximab vs bendamustine+ rituximab, ibrutinib vs temsirolimus, ibrutinib+ rituximab+ cyclophosphamide+ doxorubicin+ vincristine+ prednisone vs rituximab+ cyclophosphamide+ doxorubicin+ vincristine+ prednisone were included in the analysis. The randomization ratio was 2:1 in E1912 study and Huang et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 32, suggesting some heterogeneity among RCT. The atrial fibrillation incidence was 142 (6.52%) in study group vs 17 (0.97%) in control group. The RR for atrial fibrillation was 5.37 (95% CI: 2.74 - 10.54; P < 0.0001) and RD was 0.06 (95% CI: 0.04 to 0.08; P = < 0.0001). Major bleeding was reported in 50 (2.29%) in ibrutinib arm vs 21 (1.20%) in control arm with the RR of 1.73 (95% CI: 1.03 -2.91; P = 0.04). In a subset of patients with CLL/SLL treated with ibrutinib (n= 2658), atrial fibrillation rate was 6.29% higher in study group compared to control arm (RR, 6.14; 95% CI: 2.49 - 15.14; P < 0.0001) and major bleeding rate was 1.32% higher in ibrutinib arm (RR, 2.16; 95% CI: 1.02 - 4.55; P = 0.04). Conclusions: Our study again demonstrated that ibrutinib increases the risk of atrial fibrillation in patients with hematologic malignancies, significantly with a RR of 5.37. Ibrutinib also contributed to higher risk of major bleeding by 1.73. These results are concordant with our previous findings on ibrutinib and remain persistent. Hence, caution is advised with the use of ibrutinib amongst patients who are predisposed to these conditions. Disclosures No relevant conflicts of interest to declare.

Introduction: Multiple myeloma, which accounts for 1% of all cancers, is a hematologic cancer in which clonal plasma-cell proliferation leads to complications and death. Over the recent years, it has shown that the introduction of novel agents, including daratumumab and the incorporation of proteasome inhibitors and immunomodulatory drugs has improved outcomes in patients with multiple myeloma. Daratumumab is a human, CD38-targeting, IgG1κ monoclonal antibody with direct antitumor effects and an immunomodulatory component and has recently shown to improve survival in patients with multiple myeloma. However, there are considerable safety concerns. The purpose of our study is to determine the risk of TD and deaths due to treatment-related adverse events (TRAE) in patients with multiple myeloma treated with daratumumab. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with multiple myeloma were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Five phase III RCTs with a total of 3,547 patients with multiple myeloma were eligible. Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, DVd vs Vd, DVd + thalidomide (T) vs VTd and DRd vs Rd. The randomization ratio was 1:1 in all studies. Daratumumab was utilized in relapsed and refractory multiple myeloma in the POLLUX study (n= 564) and the CASTOR study (n= 480) and as first-line treatment for patients with multiple myeloma in the ALCYONE study (n= 700), the CASSIOPEIA study (n= 1085) and the MAIA study (n= 737). The I2 statistic for heterogeneity was 39, suggesting some heterogeneity among RCTs. TD due to TRAE was noted in 120 (6.77%) vs 179 (10.08%) in control group with RR of 0.68 (95% CI: 0.51 -0.91; P = 0.0009) and RD of -0.03 (95% CI: -0.06 to 0.00; P = 0.02). TD due to infection/ pneumonia was reported in 0.95% vs 0.73% in control group (RR, 1.19; 95% CI: 0.42 -3.34; P = 0.75). Treatment-related deaths were 64 (3.61%) in daratumumab arm vs 77 (4.34%) in control arm. The pooled RR was not statistically significant at 0.86 (95% CI: 0.59 -1.25; P = 0.43). Conclusions: The rate of discontinuation of trial treatment due to adverse events was significantly lower in the daratumumab group (6.77%) than in the control arm (10.08%) with RR of 0.68, favoring daratumumab combination regimen. Furthermore, there was no significant difference in the treatment discontinuation due to pneumonia or infection and treatment-related deaths due to TRAE in the daratumumab group, compared to control arm. Disclosures No relevant conflicts of interest to declare.

Introduction: The B-cell receptor signaling pathway involves in the pathogenesis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/ SLL), the most common adult lymphoproliferative disorder in western countries. Ibrutinib, a novel Bruton's tyrosine kinase (BTK) inhibitor, has shown great efficacy in the treatment of hematological malignancies via inhibition of BTK, a kinase involved in cellular signaling downstream of the B-cell receptor. However, treatment becomes more challenging upon progression after initial treatment. We performed a combined analysis of currently available randomized controlled trials (RCTs) to evaluate the efficacy of ibrutinib in relapsed or refractory CLL/SLL. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing ibrutinib in patients with previously treated, relapsed or refractory CLL/SLL were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Three phase III RCTs (HELIOS, RESONATE and Huang et al. studies) with a total of 1,129 patients with relapsed or refractory CLL/SLL were eligible. Studies compared ibrutinib vs ofatumumab, ibrutinib vs rituximab, and ibrutinib+ bendamustine+ rituximab vs bendamustine+ rituximab were included in the analysis. The randomization ratio was 2:1 in Huang et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCT. The pooled HR for PFS was statistically significant at 0.17 (95% CI: 0.12-0.22; P < 0.0001). The PFS benefit was observed in all Rai stages, either del11q or del17p status and bulky disease (≥ 5cm); Rai stage ≤ 2 cohort (HR, 0.14; 95% CI: 0.09- 0.22; P < 0.0001), Rai stage >2 cohort (HR, 0.26; 95% CI: 0.19- 0.36; P < 0.0001), del11q group (HR, 0.10; 95% CI: 0.06- 0.17; P < 0.0001), del17p group (HR, 0.24; 95% CI: 0.14- 0.39; P < 0.0001), and bulky disease cohort (HR, 0.19; 95% CI: 0.15- 0.25; P < 0.0001). Conclusions: Our study depicted that ibrutinib maintains activity in previously treated, relapsed or refractory CLL/SLL, across all Rai stages, in bulky disease and in del11q or del17p. Thus, the use of ibrutinib is likely beneficial to patients with relapsed or refractory CLL/SLL, regardless of disease stage, bulkiness or del11q/del 17p status. Disclosures No relevant conflicts of interest to declare.

Introduction: Chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), the most common adult lymphoproliferative disorder in western countries, is a B-cell malignancy that is treated based on presenting symptoms and stage. The treatment response is highly variable depending on disease stage and mutation profile of the malignant B cells. Bruton tyrosine kinase (BTK) is a downstream B-cell signaling kinase that has been shown to play a major role in B cell survival and proliferation. Hence, BTK inhibitors have become an attractive therapeutic strategy for treatment of CLL/SLL in both newly diagnosed and relapse/refractory setting. Ibrutinib is a potent oral, covalent inhibitor of BTK that has gained wide acceptance in treatment of CLL/SLL. We analyzed phase III trials where ibrutinib was used in newly diagnosed untreated CLL/SLL to examine treatment effects based on disease staging and molecular profiling. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing ibrutinib in patients with newly diagnosed/ untreated CLL/SLL were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Four phase III RCTs (RESONATE-2, iLLUMINATE, E1912 and A041202 studies) with a total of 1,574 patients with newly diagnosed CLL/SLL were eligible. Studies compared ibrutinib+ obinutuzumab vs chlorambucil+ obinutuzumab, ibrutinib vs chlorambucil, bendamustine+ rituximab vs ibrutinib vs ibrutinib+ rituximab, ibrutinib+ rituximab vs fludarabine+ cyclophosphamide+ rituximab, were included in the analysis. The randomization ratio was 2:1 in E1912 study and 1:1 in other studies. The I2 statistic for heterogeneity was 75, suggesting moderate heterogeneity among RCT. The pooled HR for PFS was statistically significant at 0.28 (95% CI: 0.19-0.41; P < 0.0001). The PFS benefit was observed in all Rai stages, either del11q or del17p and unmutated or mutated IGHV status; Rai stage ≤ 2 cohort (HR, 0.29; 95% CI: 0.21- 0.41; P < 0.0001), Rai stage >2 cohort (HR, 0.31; 95% CI: 0.21- 0.46; P < 0.0001), either del11q or del17p cohort (HR, 0.19; 95% CI: 0.12- 0.31; P < 0.0001), unmutated IGHV cohort (HR, 0.18; 95% CI: 0.12- 0.27; P < 0.0001), and mutated IGHV cohort (HR, 0.27; 95% CI: 0.15- 0.49; P < 0.0001). Conclusions: Our meta-analysis showed that ibrutinib maintains activity in newly diagnosed untreated CLL/SLL, across all Rai stages, in del11q or del17p and in unmutated and mutated IGHV. The use of ibrutinib should be further explored considering other factors such as overall survival rates, detrimental side effects, and health-related quality of life for the patients. Ibrutinib clearly outlines an effective treatment option, ultimately increasing the quality of care. Disclosures No relevant conflicts of interest to declare.

Introduction: Idelalisib is a first-in-class potent, oral, selective small-molecule inhibitor of δ isoform of phosphatidylinositol 3-kinase (PI3Kδ), which involves in the signaling of B-cell receptor pathways via activation of downstream serine threonine kinases AKT and mammalian target of rapamycin (mTOR), and has been implicated in the pathogenesis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL). Yet, there are considerable safety concerns. We undertook a systematic review and combined analysis of phase 3 randomized controlled trials to determine the risk of serious adverse events, infection and sepsis in patients with relapsed/ refractory CLL/SLL treated with idelalisib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing idelalisib in patients with relapsed and refractory CLL/SLL that mention serious adverse events, infection and sepsis as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Three phase 3 RCTs with a total of 892 patients with relapsed and refractory CLL/SLL were eligible for analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 83, suggesting moderate heterogeneity among RCTs. The incidence of serious adverse events was 341 (69.59%) in study group vs 177 (44.03%) in control group with RR of 1.50 (95% CI: 1.28-1.75; p < 0.0001). Pneumonitis was noted in 14 (2.86%) vs 1 (0.25%) in control group (RR, 5.42; 95% CI: 1.22-24.13; p = 0.03). The incidence of any-grade pneumonia was 78 (15.92%) in study group vs 45 (11.19%) in control group (RR, 1.38; 95% CI: 0.98 - 1.96; P = 0.07). High-grade pneumonia was reported in 59 (12.04%) in idelalisib arm versus 33 (8.21%) in control group with RR of 1.36 (95% CI: 0.82 - 2.27; P = 0.23). Pneumocystis jiroveci (PJP) pneumonia rate was 2.56% higher in study group compared to control arm (RR, 4.25; 95% CI: 1.10 - 16.34; P = 0.04). Febrile neutropenia was noted in 13.47% in study group versus 4.73% in control arm (RR, 2.39; 95% CI: 0.90-6.34; p = 0.08). Sepsis rate was 3.36% higher in idelalisib group compared to control arm and the pooled RR was statistically significant at 2.64 (95% CI 1.10-6.30; p = 0.03). Treatment-related deaths were 45 (6.92%) in idelalisib arm vs 21 (3.74%) in control arm according to analysis of 2 trials. The pooled RR was not statistically significant at 1.64 (95% CI: 0.99 -2.71; P = 0.06). Conclusion: Patients on idelalisib experienced higher risk of serious adverse events, pneumonitis, PJP pneumonia, and sepsis, with RR of 1.50 for serious adverse events, RR of 5.42 for pneumonitis, RR of 4.25 for PJP pneumonia and RR of 2.64 for sepsis respectively. Nevertheless, there was no significant increase in treatment-related deaths due to TRAE in the idelalisib group, compared to control arm. Preemptive measures with proper supportive care are required to reduce those toxicities which can ultimately improve patients' quality of life and may probably affect patients' compliance. Disclosures No relevant conflicts of interest to declare.

Introduction: Ibrutinib, a Bruton's tyrosine kinase inhibitor, has been approved for the treatment of many hematological malignancies including but not limited to, chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma, and marginal zone lymphoma. Despite the efficacy of this drug in the treatment of hematologic diseases, multiple adverse effects have been well reported. This study seeks to present a combined analysis of currently available randomized controlled trials (RCTs) on the incidence of high-grade hematological toxicities and hypertension, in patients being treated with ibrutinib for hematological malignancies. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing ibrutinib in patients with hematologic malignancies that mention high-grade hematological toxicities and hypertension were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,920 patients with CLL/SLL, mantle-cell lymphoma, Waldenstrom's macroglobulinemia and diffuse large b-cell lymphoma, from 10 phase III RCTs were eligible. Studies compared ibrutinib+ obinutuzumab vs chlorambucil+ obinutuzumab, ibrutinib vs chlorambucil, bendamustine+ rituximab vs ibrutinib vs ibrutinib+ rituximab, ibrutinib+ rituximab vs fludarabine+ cyclophosphamide+ rituximab, ibrutinib vs rituximab, ibrutinib vs ofatumumab, ibrutinib+ bendamustine+ rituximab vs bendamustine+ rituximab, ibrutinib vs temsirolimus, ibrutinib+ rituximab+ cyclophosphamide+ doxorubicin+ vincristine+ prednisone vs rituximab+ cyclophosphamide+ doxorubicin+ vincristine+ prednisone were included in the analysis. The randomization ratio was 2:1 in E1912 study and Huang et al study and 1:1 in other studies. The I2 statistic for heterogeneity was 32, suggesting some heterogeneity among RCT. The RR of high-grade hematologic side effects were as follows: anemia, 0.60 (95% CI: 0.36 - 1.02; p = 0.06); neutropenia, 0.76 (95% CI: 0.55 - 1.05; p = 0.10); thrombocytopenia, 0.69 (95% CI: 0.35 - 1.37; p = 0.29); and febrile neutropenia, 0.65 (95% CI: 0.30 - 1.42; p = 0.29). The incidence of high-grade hypertension (HTN) was 187 (8.59%) in study group vs 40 (2.29%) in control group with RR of 2.51 (95% CI: 1.64 -3.85; P < 0.0001). In a subset of patients with CLL/SLL treated with ibrutinib (n= 2658), the RR of high-grade hematologic side effects were as follows: anemia, 0.51 (95% CI: 0.35 - 0.74; p = 0.0005); neutropenia, 0.73 (95% CI: 0.52 - 1.01; p = 0.06); thrombocytopenia, 0.72 (95% CI: 0.38 - 1.39; p = 0.33); and febrile neutropenia, 0.54 (95% CI: 0.22 - 1.37; p = 0.20). High-grade HTN rate was 8.11% higher in ibrutinib group compared to control arm (RR, 2.49; 95% CI: 1.47 - 4.22; P = 0.0007). Conclusions: This literature review determined that ibrutinib's efficacy must be carefully balanced against the mentioned side effects on a case by case basis. Of special consideration is the rate of HTN in the Ibrutinib group compared to the control. These findings need to be further explored to determine the efficacy of Ibrutinib in specific patient populations with varying underlying diseases. Disclosures No relevant conflicts of interest to declare.

Introduction: Chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/ SLL) is the most common adult lymphoproliferative disorder in western countries and the B-cell receptor signaling pathway has been shown to be involved in the pathogenesis of CLL/ SLL. Phosphatidylinositol 3-kinase (PI3K) is a kinase protein in downstream signaling for multiple pathways in B cells, promoting B-cell survival, proliferation and metabolism. Two prominent PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), are currently being studied in the treatment of relapsed and refractory CLL/ SLL. The purpose of our study is to explore and consolidate the efficacy of PI3K inhibitors in patients with relapsed and refractory CLL/SLL. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were eligible for analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in the study by Jones et al. and 1:1 in other studies. The I2 statistic for heterogeneity was 82%, suggesting moderate heterogeneity among RCTs. The overall pooled HR for PFS was statistically significant at 0.30 (95% CI: 0.20- 0.47; P < 0.0001). The PFS benefit was observed across all ages and regardless of del 17p or TP53 status; age Conclusions: Our study showed that PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), significantly improved PFS in patients with relapsed and refractory CLL/ SLL regardless of age and poor prognostic features such as del17p or TP53 and IGHV unmutated status, compared to control arm. The efficacy of these drugs must be balanced against the possible side effects. Disclosures No relevant conflicts of interest to declare.

Introduction: Multiple myeloma is a hematologic cancer in which clonal plasma-cell proliferation leads to complications and death. Daratumumab is a humanized IgGκ monoclonal antibody that targets CD38 with direct antitumor effects along with immunomodulatory activity, resulting in depletion of immunosuppressive cells and clonal expansion of cytotoxic T cells. Addition of daratumumab to standard multiple myeloma regimens has recently shown to improve survival in patients with multiple myeloma with considerable safety profile. We undertook a meta- analysis of randomized controlled trials (RCT) to determine the risk of hematological toxicities in patients with multiple myeloma treated with daratumumab. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with multiple myeloma that mention hematological toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,547 patients with multiple myeloma from 5 phase III RCTs were eligible. Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, DVd vs Vd and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. Daratumumab was utilized in relapsed and refractory multiple myeloma in the POLLUX study (n= 564) and the CASTOR study (n= 480) and as first-line treatment for patients with multiple myeloma in the ALCYONE study (n= 700), the CASSIOPEIA study (n= 1085) and the MAIA study (n= 737). The I2 statistic for heterogeneity was 0, suggesting homogeneity among RCT. The RR of all-grade side effects were as follows: anemia, 0.85 (95% CI: 0.76 - 0.95; p = 0.005); neutropenia, 1.38 (95% CI: 1.09 - 1.74; p = 0.008); thrombocytopenia, 1.15 (95% CI: 0.90 - 1.47; p = 0.27); and leukopenia, 1.60 (95% CI: 1.16 - 2.20; p = 0.004). The RR of high-grade adverse effects were as follows: anemia, 0.72 (95% CI: 0.60 - 0.86; p = 0.0004); neutropenia, 1.48 (95% CI: 1.17 - 1.88; p = 0.001); thrombocytopenia, 1.15 (95% CI: 0.88 - 1.49; p = 0.31); and leukopenia, 1.72 (95% CI: 1.28 - 2.30; p = 0.0003). Conclusions: Our study demonstrated that patients on daratumumab combination regimens experienced higher risk of all grades of neutropenia and leukopenia, with RR of 1.48 and 1.72 for high-grade neutropenia and leukopenia. However, there was lower incidence of all grades of anemia in daratumumab containing group compared to control arm, favoring daratumumab-based regimens. Disclosures No relevant conflicts of interest to declare.

Background: Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a Phase II study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory multiple myeloma who have received a first or second line treatment of lenalidomide-based therapy. Immunomodulatory agents (IMiD® compounds) continue to be the backbone of multiple myeloma therapy especially when combined with monoclonal antibodies, more specifically pomalidomide had been shown previously to enhance T cell- and NK cell-mediated immunity. We sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. IMiD agents are the backbone of combination regimens in the treatment of patients with newly diagnosed or relapsed and/or refractory multiple myeloma. The anti-myeloma properties of these agents derive from a dual mechanism of pro-apoptotic effects on tumor cells as well as enhanced immune stimulation. An understanding of how IMiD agents interact with new monoclonal antibodies to modify patient immune profiles offers key insights into the role of such in innate and adaptive immunity in determining patient outcomes. Methods and Results: Peripheral blood samples were collected at screening, Cycle1 Days 1, 8, and 15, and Cycle 2 Days 1 and 15 to monitor pharmacodynamic changes in populations of T cells, NK cells, monocytes and MDSCs by flow cytometry. From 112 patients enrolled in Arm B, 98 patients had baseline and post-treatment specimens available for these analyses. As expected, combination treatment with POM + LoDEX + DARA led to decreased peripheral counts of CD56+CD16+ NK cells as well as CD4+CD38+ and CD8+CD38+ T cell subpopulations. Decreased counts were also noted in CD3-CD19+ B cells. In contrast, total counts of CD14+ monocytes and CD3+CD4+ or CD3+CD8+ T cells were stably maintained and pronounced increases were observed in proliferating CD4+Ki-67+ and CD8+Ki-67+ T cells. Further, when examined as a percent of total counts, increases were observed in CD14+ monocytes, CD3+CD4+ and CD3+CD8+ T-cells, with decreases in CD3-CD19+ B-cells and CD3-CD56+CD16+ NK cells. Correlation of these pharmacodynamic changes with clinical outcomes will be presented. In addition, baseline immune profiling of specific cell population subsets and associations with best overall response and progression-free survival is currently being analyzed. Conclusions: The triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed multiple myeloma patients progressed and are or refractory to lenalidomide. Immune characterization here is consistent with a model for clinical activity in which the loss of CD56+CD16+ NK cells along with a concomitant immune suppression by loss of CD38+CD4+ and CD38+CD8+ T- cells is offset by an increase in proliferating cytotoxic CD4+Ki-67+ and CD8+Ki-67+ T-cell populations. Our results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment. Pomalidomide had been shown previously to enhance T cell- and NK cell-mediated immunity; these data are consistent with a mechanism of action in which pomalidomide administration facilitates the ability to overcome immunosuppressive effects of Dara and LoDex. Potential associations of immune biomarkers with patient outcomes is ongoing and will be updated. Disclosures Pierceall: Celgene Corporation: Employment, Equity Ownership. Bahlis:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Siegel:Merck: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Berdeja:Takeda: Research Funding; Genentech: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Glenmark: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bluebird: Research Funding; Teva: Research Funding. Ganguly:Amgen: Consultancy; Daiichi Sankyo: Research Funding; Janssen: Consultancy; Seattle Genetics: Speakers Bureau. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Srinivas:VAHCSNJ: Employment. Bar:Celgene: Consultancy. Quick:CTI BioPharma: Research Funding. Fonseca:Celgene: Speakers Bureau. Reece:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria, Research Funding; Otsuka: Research Funding. Serbina:Celgene: Employment. Zafar:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership.

BACKGROUND Lenalidomide (LEN) until progressive disease (PD) is an established treatment (Tx) in newly diagnosed and relapsed and/or refractory multiple myeloma (RRMM); thus, patients (pts) for whom the benefit of LEN has been exhausted are a clinically relevant population. However, LEN-refractory pts have typically been excluded from recent clinical trials investigating triplet regimens after ≤ 3 prior Tx lines. MM-014 (NCT01946477) is an ongoing phase 2 study that was designed to assess the safety and efficacy of pomalidomide (POM)-based Tx regimens in pts with RRMM and first- or second-line LEN Tx failure immediately before study entry. Earlier results from cohort A (POM + low-dose dexamethasone [LoDEX]) and cohort B (POM + LoDEX + daratumumab [DARA]) indicate that POM-based Tx is safe and effective in this setting. Here we report updated results from cohort B. METHODS Eligible pts had RRMM, had 1 or 2 prior lines of Tx, received LEN-based Tx as their most recent Tx regimen, and had PD during or after their last line of Tx. Pts received POM 4 mg/day on days 1 through 21 + LoDEX 40 mg/day (20 mg/day if aged > 75 years) on days 1, 8, 15, and 22 and DARA 16 mg/kg intravenously on DEX dosing days of cycles 1 and 2, days 1 and 15 of cycles 3 through 6, then day 1 of cycle 7 and beyond. Each Tx cycle lasted 28 days. Thromboprophylaxis was mandatory. The primary endpoint for cohort B is overall response rate (ORR) by modified International Myeloma Working Group criteria. Secondary endpoints include time to response (TTR), progression-free survival (PFS), time to progression (TTP), and safety. RESULTS The intention-to-treat (ITT) population comprised 112 pts (median follow-up, 8.2 mos); data cutoff was April 30, 2018. Median age was 66.5 years, 67.9% of pts were male, and 111 (99.1%) had ECOG PS ≤ 1. A total of 34 pts discontinued Tx: 19 due to PD, 9 due to study withdrawal, 2 due to adverse events (AEs), and 4 due to other reasons. All pts received prior LEN, and 87 (77.7%) received prior bortezomib; 84 pts (75.0%) were refractory to LEN, while 28 (25.0%) relapsed after LEN-based Tx. Median duration of the most recent prior LEN-based Tx was 23.9 mos, with 36 pts (32.1%) receiving LEN 25 mg/day during their last LEN-based Tx. ORR was 77.7%, with 33.9% of pts achieving ≥ very good partial response. Median TTR was 1.0 mo. The clinical benefit rate (≥ minimal response [MR]) was 85.7%. ORR was 80.6% in the efficacy-evaluable population (n = 108; defined as all pts who received ≥ 1 dose of study drug and had ≥ 1 post-baseline response assessment), 75.0% in LEN-refractory pts, and 76.2% in pts with 2 prior lines of Tx (n = 42). The 9-mo PFS rate was 86.3% (range, 76.5%-92.2%); median PFS was not estimable (NE; Figure). The 9-mo TTP rate was 88.1% (range, 78.3%-93.6%); median TTP was NE. The most common grade 3/4 hematologic treatment-emergent AE (TEAE) in the safety population (n = 112) was neutropenia (61.6%; Table); pneumonia was the most common grade 3/4 nonhematologic TEAE (7.1%). POM dose reductions occurred in 31 pts (27.7%); per protocol, DARA dose reductions were not allowed. POM dose interruptions due to AEs were reported in 69 pts (61.6%) and DARA dose interruptions due to AEs were reported in 82 pts (73.2%). POM and DARA dose interruptions due to neutropenia were reported in 39 (34.8%) and 42 (37.5%) pts, respectively; 25 pts (22.3%) had DARA dose interruptions due to infusion-related reactions. Median durations of POM and DARA Tx were 6.0 mos (range, 0.3-17.7 mos) and 6.6 mos (range, 0.3-18.6 mos), respectively; among those who achieved ≥ MR, pts remained on POM Tx for a median of 7.4 mos (range, 0.9-17.7 mos) and on DARA Tx for a median of 7.5 mos (range, 0.9-18.6 mos). CONCLUSIONS LEN-refractory pts with RRMM are in need of effective Tx options. MM-014 is the first prospective clinical trial to investigate a POM-based doublet or triplet regimen immediately after LEN-based Tx failure. In the context of a relatively short follow-up, the 9-mo PFS rate (86.3%) is promising. The ORR (77.7%) was higher than that previously reported with this triplet combination in heavily pre-treated pts with RRMM (≥ 2 prior lines [median, 4]; ORR, 60%), and the rate of grade 3/4 neutropenia in the present study was lower (61.6% vs 77%). These updated results from cohort B continue to demonstrate that POM + LoDEX + DARA is safe and effective following first- or second-line LEN-based Tx failure and further support earlier use of POM-based Tx in pts with RRMM Disclosures Siegel: Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau. Schiller:Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Berdeja:Bluebird: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Glenmark: Research Funding; Genentech: Research Funding; Amgen: Research Funding; Teva: Research Funding; Poseida Therapeutics, Inc.: Research Funding. Ganguly:Janssen: Consultancy; Seattle Genetics: Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Bar:Celgene: Consultancy. Quick:CTI BioPharma: Research Funding. Fonseca:Celgene: Speakers Bureau. Reece:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria, Research Funding; Otsuka: Research Funding. Agarwal:Celgene Corporation: Employment, Equity Ownership. Chung:Celgene Corporation: Employment, Equity Ownership. Zafar:Celgene: Employment. Bahlis:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Background: Sapacitabine is a novel oral nucleoside analogue with a unique ability to induce single-strand DNA breaks after incorporation into DNA, leading to production of double-strand DNA breaks and/or G2 cell cycle arrest. In AML cell lines, the active metabolite of sapacitabine, CNDAC, is synergistic with hypomethylating agents (HMAs) particularly when treated with HMAs first. In a pilot study, there were 6 CRs and 2 PRs in 25 patients treated with sapacitabine in alternating cycles with decitabine. This global randomized phase 3 study evaluated the survival benefit of this treatment strategy vs. decitabine monotherapy. Methods: Decitabine 20 mg/m2 was administered intravenously daily x 5 days of a 4-week cycle (for the control arm and odd cycles of the study arm) alternating with sapacitabine 300 mg p.o. b.i.d. x 3 days/week x 2 weeks of a 4-week cycle (even cycles of the study arm). The safety of these doses was further evaluated in the lead-in phase of the phase 3 study to confirm the findings from the pilot study. Eligible patients were ≥70 years with untreated AML and unsuitable for or unwilling to receive standard induction chemotherapy. Patients who had received HMAs for prior MDS or MPD were excluded. Results: For 482 patients randomized to receive decitabine/sapacitabine (n=241) vs. decitabine only (n=241), randomization was stratified by the presence of antecedent MDS or MPN, peripheral white blood cell count (WBC 40,000 in 59 patients (12%); 194 patients (40%) had unfavorable cytogenetic risk by SWOG criteria. Disease characteristics were well balanced in both arms. In total, 13.7% of patients achieved CR, more on the study arm vs. control (16.6% vs. 10.8%). A total of 37.3% treated patients received ≥5 cycles of treatment, similar on both arms, as were 30- and 60-day death rates. Median overall survival was 5.9 months on the study arm vs. 5.7 months on control arm, which did not reach a statistically significant difference. In the subgroup of patients with 10% patients were thrombocytopenia, anemia, neutropenia, pneumonia, febrile neutropenia, sepsis, and disease progression. Conclusion: The regimen of sapacitabine administered in alternating cycles with decitabine was active and well tolerated but it did not significantly improve overall survival as compared to decitabine monotherapy. Further analyses are being conducted to characterize the subgroups of patients who appeared to have benefited from this treatment regimen and the potential cost savings associated with the use of an oral drug. Disclosures Kantarjian: Amgen: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding. Goldberg: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; COTA: Employment, Equity Ownership; Pfizer: Honoraria; Ariad: Speakers Bureau; Jazz: Speakers Bureau. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees. Strickland: Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy; CTI BioPharma: Consultancy; Tolero Pharmaceuticals: Consultancy; Sunesis Pharamaceuticals: Consultancy, Research Funding; Baxalta: Consultancy; Alexion Pharmaceuticals: Consultancy; Astellas Pharma: Honoraria. Rubenstein: Alexion Pharmaceuticals: Speakers Bureau. Arellano: Cephalon Oncology: Research Funding. Schiller: bluebird bio: Research Funding; mateon therapeutics: Research Funding. Gaidano: Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Montesinos: Celgene Corporation: Honoraria, Research Funding. Rizzieri: Shire: Research Funding; Erytech: Research Funding. Subramanian: Boehringer-Ingelheim, Lilly, BMS, Astra-Zeneca, Pfizer, Biocept: Consultancy, Speakers Bureau. Buyse: IDDI: Employment, Equity Ownership. Chiao: Cyclacel LTD: Employment, Equity Ownership.

Background: DI-Leu16-IL2 is a recombinant fusion immunocytokine composed of interleukin-2 and a CD20-targeting monoclonal antibody that maintains the activities of both antibody and cytokine components but is also involved in tumor targeting, engagement of the immune system, and induction of an anti-cancer vaccine effect. Methods: In this multicenter open label, dose escalation trial to determine the maximum tolerated dose (MTD), optimal biological dose (OBD), and recommended phase 2 dose (RP2D), we evaluated the safety, tolerability, and efficacy of subcutaneously (SC) administered DI-Leu16-IL2 in patients (pts) with relapsed or refractory CD20+ B-cell lymphoma (NCT01874288). Following peripheral B-cell depletion with low-dose rituximab (50mg/m2), DI-Leu16-IL2 was administered SC for 3 consecutive days every 21 days for 6 cycles. A 3+3 dose escalation trial design began at 0.5 mg/m2. Responses were evaluated by PET in pts who had received at least 2 cycles of therapy. Immunologic correlates were done including peripheral blood flow cytometry and serum cytokine levels. Responding (complete or partial response, CR or PR) and stable disease (SD) pts were permitted to continue treatment for an additional year. Results: Twenty-two pts in 5 dose cohorts have been enrolled, 3 at 0.5 and 1mg/m2, 7 at 2mg/m2 and 4mg/m2, and 2 at 6mg/m2. The median age is 64 years (40-84), median prior therapies is 4 (range 1-21), with 100% having received prior rituximab and chemotherapy, and 41% with prior autologous stem cell transplant. Dose limiting toxicities (DLT) occurred in 2 pts at 6 mg/m2, both with delayed (8-10 days) grade 3 cytokine release syndrome (CRS), suggesting effector cell expansion as the cause. None of the CRS required treatment with tocilizumab, however one required dose reduction, and the other discontinued therapy. The Gr 3-4 drug-related adverse events (AEs) that required dose reduction were: QTC prolongation (Gr 3) in one patient at 4 mg/m2, tumor lysis syndrome (Gr 3) at 4mg/m2, and diarrhea (Gr 3) at 1mg/m2. Hematologic AEs were eosinophilia (Gr 1-2 = 22.7%), anemia (Gr 1-2 = 45%, Gr 3-4 = 9%), thrombocytopenia (Gr 1-2 = 36%, Gr 3-4 = 4.5%), neutropenia (Gr 1-2 = 14%, Gr 3-4 = 14%) in the 22 pts evaluable for toxicity. Other AEs were local injection site reactions (Gr 1-2 = 82%), pruritus (Gr 1-2 = 82%), edema (Gr 1-2 = 23% Gr 3-4 = 5%), fever (Gr 1-2 = 41%, Gr 3-4 = 5%), and chills (Gr 1-2 = 59%). Six pts have been enrolled at 4mg/m2 and no DLTs have been encountered. The MTD was determined to be 4mg/m2. Patients with CR or PR had higher pre-treatment absolute lymphocyte counts (>700/mcL) than pts with progressive disease (P < 0.05). Repetitive SC dosing elicited lymphocyte expansion at all dose levels. Although T-regulatory cell expansion was observed in the blood, it was not associated with a worse response. Pts achieving CR showed a trend towards lower % of granulocyte-like myeloid derived suppressor cells. Pts showed reproducible increases in cytokine levels of IL-10, MCP-1, IFNgamma, and TNFalpha. Pharmacokinetic data showed consistent drug levels between cycle 1 and 2.Therefore, the OBD and RP2D was determined to be 2mg/m2 which produced 3 CR and 3 SD. Durable tumor regression or stabilization was noted in 14 of 16 (88%) evaluable pts. There were 4 CR: 1 diffuse large B-cell lymphoma (DLBCL), 2 follicular lymphoma and 1 marginal zone lymphoma; 1 PR (DLBCL) and 9 SD, and objective response rate of 31% [Figure 1]. The median duration of disease stabilization was 8 months (4-14). Of the responders, the median duration of response was 13 months (10-15). One CR continues 11 months after stopping therapy at cycle 6. Conclusions: Promising clinical efficacy of DI-Leu16-IL2 has been observed with long-term responses in relapsed/refractory B-cell NHL pts. SC administration has permitted higher doses than could be achieved with IV treatment, however, at the higher dose range, CRS was observed. Even though the MTD was 4mg/m2, given the responses, AEs, and biologic activity in the Phase I study, the RP2D was determined to be 2mg/m2. Responses were associated with a higher starting ALC, and lymphocyte expansion was dose dependent, with reproducible serum cytokine profiles. The protocol continues to enroll pts in the expansion cohorts of this phase I/II study. DI-Leu16-IL2 given subcutaneously is safe and effective, and induces durable responses even after discontinuation of therapy, suggesting an anti-tumor vaccination effect. Disclosures Lansigan: Celgene: Consultancy; Teva: Research Funding; Pharmacyclics: Consultancy; Spectrum: Consultancy, Research Funding. Vlock:Alopexx Oncology, LLC: Employment. Gillies:Provenance Bioparmaceuticals Corp: Employment.

Multiple myeloma (MM) is an incurable hematologic malignancy of transformed plasma cells. New targeted biological therapeutics are needed to increase the stringency and durability of remissions. In this study we describe SGN-CD48A, a potent CD48-targeting antibody-drug conjugate (ADC) utilizing a novel glucuronide-monomethylauristatin E (MMAE) linker, under development for the treatment of MM. CD48, or SLAMF2 (Signaling Lymphocyte Activation Molecule family member 2), is a GPI-anchored membrane protein in the SLAM family of immunoreceptors. CD48 is expressed on B and T lymphocytes, natural killer (NK) cells, and other immune cell types where it functions to modulate immune cell activation, proliferation, and differentiation. CD48 is also a tumor antigen broadly expressed in MM. We observed CD48 expression on the surface of malignant plasma cells in 90% (90/100) of human multiple myeloma patient samples examined by flow cytometry. Monoclonal antibodies (mAbs) specific for human CD48 were evaluated and a lead antibody was selected based on binding characteristics and cytotoxic activity against myeloma cells as an auristatin ADC. SGN-CD48A is a humanized anti-CD48 mAb to which eight molecules of MMAE, a potent microtubule disrupting cytotoxic drug, have been conjugated via a β-glucuronidase-cleavable linker. This novel glucuronide-MMAE drug-linker incorporates a PEG side chain and self-stabilizing maleimide to achieve homogenous drug-to-antibody ratio (DAR) 8 conjugates with decreased plasma clearance and increased preclinical antitumor activity. Following binding of CD48 at the myeloma cell surface, SGN-CD48A internalizes and traffics to lysosomal vesicles. Intracellular MMAE drug released from SGN-CD48A in myeloma cells induced cell cycle arrest at G2/M phase, phospho-histone H3 (Ser-10) phosphorylation, and caspase 3/7 dependent apoptotic cell death. SGN-CD48A demonstrated potent cytotoxic activity (EC50 values 1.0 - 11 ng/mL) against a panel of human MM cell lines, with CD48 expression levels of 135,000 - 480,000 receptors per cell. In contrast, SGN-CD48A had negligible cytotoxic activity against normal resting human B, NK, and T lymphocytes. We evaluated the in vivo antitumor activity of SGN-CD48A in disseminated MM cell line mouse xenograft models. In the NCI-H929 and EJM xenograft models, a single intraperitoneal dose of 0.3 mg/kg SGN-CD48A produced durable complete remissions in 8/8 and 6/8 mice, respectively. Similarly, in the U-266 xenograft model, a single dose of 1.0 mg/kg SGN-CD48A produced durable complete remissions in 7/8 mice. Neither unconjugated mAb nor a non-binding control MMAE ADC were active in these MM xenograft models, demonstrating that targeted delivery of MMAE drug through CD48 binding is required for activity. In summary, CD48 is a highly expressed new multiple myeloma target and the novel glucuronide-MMAE ADC SGN-CD48A shows potent antitumor activity against cell line models of MM. Disclosures Lewis: Seattle Genetics, Inc.: Employment, Equity Ownership. Olson:Seattle Genetics, Inc.: Employment, Equity Ownership. Gordon:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandall:Seattle Genetics, Inc.: Employment, Equity Ownership. Quick:Seattle Genetics, Inc.: Employment, Equity Ownership. Finn:Seattle Genetics, Inc.: Employment, Equity Ownership. Westendorf:Seattle Genetics, Inc.: Employment, Equity Ownership. Linares:Seattle Genetics, Inc.: Employment, Equity Ownership. Leiske:Seattle Genetics, Inc.: Employment, Equity Ownership. Nesterova:Seattle Genetics, Inc.: Employment, Equity Ownership. Law:Seattle Genetics, Inc.: Employment, Equity Ownership.