ALBERT

Description: In epithelial cells β-catenin plays a critical role as a component of the cell-cell adhesion apparatus and as a coactivator of the TCF/LEF (T-cell transcription factor/lymphoid enhancer binding factor) family of transcription factors. Deregulation of β-catenin has been implicated in the malignant transformation of cells of epithelial origin. However, a function for β-catenin in hematologic malignancies has not been reported. β-Catenin is not detectable in normal peripheral blood T cells but is expressed in T–acute lymphoblastic leukemia cells and other tumor lines of hematopoietic origin and in primary lymphoid and myeloid leukemia cells. β-Catenin function was examined in Jurkat T–acute lymphoblastic leukemia cells. Overexpression of dominant-negative β-catenin or dominant-negative TCF reduced β-catenin nuclear signaling and inhibited Jurkat proliferation and clonogenicity. Similarly, these constructs inhibited proliferation of K562 and HUT-102 cells. Reduction of β-catenin expression with β-catenin antisense down-regulated adhesion of Jurkat cells in response to phytohemagglutinin. Incubation of Jurkat cells with anti-Fas induced caspase-dependent limited proteolysis of β-catenin N- and C-terminal regions and rapid redistribution of β-catenin to the detergent-insoluble cytoskeleton, concomitant with a marked decline in nuclear β-catenin signaling. Fas-mediated apoptosis was potentiated by inhibition of β-catenin nuclear signaling. The data suggest that β-catenin can play a significant role in promoting leukemic cell proliferation, adhesion, and survival.

Description: 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.

Description: 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.

Description: 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.

Description: Introduction: There are limited treatment options for patients with relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) who are not candidates for high-dose therapy and stem-cell transplant (SCT). Reasons for ineligibility for intensive treatment include advanced age and overall condition, comorbidities, failure to respond to standard salvage treatment regimens, progressive disease following previous SCT, and presence of other adverse risk factors. The PIX306 study evaluated the efficacy of pixantrone + rituximab (PIX+R) compared with gemcitabine + rituximab (GEM+R) in patients with relapsed aggressive B-cell NHL in this particular clinical setting. We present the primary results of the core analysis of the PIX306 trial. Methods: PIX306 was a phase 3, multicentre, open-label, randomized trial in patients aged ≥18 years diagnosed with de novo diffuse large B-cell lymphoma (DLBCL), DLBCL transformed from indolent lymphoma, or grade 3 follicular lymphoma (FL) who relapsed after at least one standard rituximab-containing multi-agent regimen. Primary refractory de novo DLBCL and grade 3 FL, defined as progression within 12 weeks of the last cycle of the first-line treatment regimen, was an exclusion criterion. Patients were randomly allocated 1:1 to receive PIX 50 mg/m2 or GEM 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle, each in combination with R 375 mg/m2 on day 1, for up to 6 cycles, with follow-up for progression up to 96 weeks. The primary endpoint was progression-free survival (PFS) as determined by the Independent Radiology Committee (IRC). Disease response was assessed according to the Modified IWG 2007 Revised Response Criteria. The current analysis is based on 197 PFS events (IRC). Overall survival (OS), complete response (CR), overall response rate (ORR), and safety were secondary endpoints. Results: The ITT population included 312 patients; 155 and 157 patients were randomly allocated to receive PIX+R and GEM+R, respectively. Groups were well balanced; no statistically significant differences in baseline demographics were shown (Table). Median age was 73 years (range: 26-91 years). Overall, 193 (61.9%) patients had received only one line of prior chemotherapy. Most patients (n=242; 77.6%) had de novo DLBCL, 43 (13.8%) had DLBCL transformed from indolent NHL and 27 (8.7%) had grade 3 FL. The majority of patients had Ann Arbor stage III/IV (n=230; 73.7%) disease, 166 (53.2%) patients had an IPI score of ≥3, and in 195 (62.5%) patients extranodal disease was diagnosed at baseline. In total, 116 (37.2%) patients had their first disease relapse within 1 year following the initiation of the front-line therapy for DLBCL or FL. Thirty-three (10.6%) patients had undergone a previous SCT. The study did not meet its primary objective of efficacy, as measured by PFS, of PIX+R vs GEM+R [P= 0.28; HR=0.85 (95% CI: 0.64, 1.14)]. The median PFS (95% CI) in the PIX+R and the GEM+R groups were 7.3 months (5.2; 8.4) and 6.3 months (4.4; 8.1), respectively. Median OS was 13.3 vs 19.6 months [HR=1.13 (95% CI: 0.83, 1.53), P=0.43], CR was observed in 35.5% vs 21.7% of patients, and ORR was 61.9% vs 43.9% in the PIX-R and GEM-R groups, respectively. Both regimens were reasonably tolerated and no new safety signals were reported. Cardiac failure was reported as a serious adverse event in 3 and 2 patients (2.0% and 1.3%) receiving PIX-R and GEM-R, respectively. Conclusions: This is the first study to investigate the efficacy of PIX+R vs GEM+R as second-line or later therapy in patients with relapsed aggressive B-cell NHL who are not eligible for SCT and who have few therapeutic options. Even though the present study did not meet its primary endpoint, the PFS observed in both the PIX+R and GEM+R groups were longer than the study outcomes previously reported in similar patient populations. Disclosures Salles: Merck: Honoraria; Servier: Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Acerta: Honoraria; AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Morphosys: Honoraria. Jurczak:Epizyme: Research Funding; Celgene: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Afimed: Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Acerta: Consultancy, Research Funding; AstraZeneca: Consultancy; European Medicines Agency: Consultancy; Servier: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; TG therapeutics: Research Funding. Andorsky:AstraZeneca: Consultancy; CTI BioPharma: Consultancy, Research Funding; Celgene: Research Funding; Genentech: Consultancy. Quick:CTI BioPharma: Research Funding. Singer:CTI BioPharma: Employment, Other: Stock options. Bedi Singh:CTI BioPharma: Employment, Other: Stock options. Wang:CTI BioPharma: Employment, Equity Ownership. Egorov:Servier: Employment. Gabarroca:Servier: Employment. Pettengell:CTI: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Servier: Honoraria; Takeda: Honoraria.

Description: Key Points Inhibition of RNA Pol I by CX-5461 treats aggressive AML and outperforms standard chemotherapy regimens. CX-5461 induces p53-dependent apoptosis, p53-independent cell-cycle defects and differentiation, and reduces LICs.

Description: A method has been devised for the measurement of uroporphyrinogen I synthetase ih red cells. By using trichloroacetic acid as a protein precipitant, heme is removed from the final solution, allowing accurate measurement of porphyrins. The method is highly reproducible and adaptable to varying incubation volumes and enzyme preparations. It is of great value as an enzyme diagnostic method for acute intermittent porphyria and appears capable of detecting patients with the latent disease who have normal urinary δ-aminolevulinic acid and porphobilinogen excretion. It also appears to distinguish other types of porphyria from acute intermittent porphyria. The mean value of the enzyme in red cells of patients with acute intermittent porphyria was approximately 50% that of normals, indicating that the mutation causes complete lack of catalytic activity in the mutant enzyme.

Description: 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.

Description: DI-Leu16-IL2 immunocytokine is a recombinant fusion protein composed of interleukin 2 (IL2) and a CD20 targeting monoclonal antibody. Pre-clinical studies have shown it 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. In a SCID mouse model,DI-Leu16-IL2 is more effective than the individual components (IL-2 and CD20) given either alone or in combination (Gillies SD; 2005). DI-Leu16-IL2 administered intravenously to 8 relapsed/refractory Non-Hodgkin's Lymphoma (NHL) patients at a maximum dose of dose of 0.5 mg/m2 resulted in 1 complete, 1 possible partial response and 4 patients with stable disease (Nakamura R; 2013). In this multicenter open label, dose escalation trial the safety, efficacy and tolerability of subcutaneously (SC) administered DI-Leu16-IL2 was evaluated as well as the maximum tolerated dose (MTD) and optimal biological dose in patients with relapsed or refractory B cell CD20 positive lymphoma (NCT01874288). DI-Leu16-IL2 was administered on three consecutive days every 21 days up to 6 cycles. Peripheral B cell depletion was achieved with low-dose rituximab (50mg/m2) on day 1 if needed to keep rituximab levels 〉10µg/mL. The starting dose was 0.5 mg/m2 and followed a modified accelerated titration until dose limited toxicity (DLT) occurred. To be evaluable for response patients had to receive at least 2 cycles of DI-Leu16-IL2 and were then evaluated by PET/CT imaging. To date, 13 patients in 3 cohorts have been enrolled. The median age is 63 years (range, 48-83 years). Ten patients had diffuse large B cell lymphoma, 2 follicular and 1 marginal zone NHL. All were previously treated with rituximab-containing chemotherapy - median of 3 (range 1-6) prior regimens, including radiation therapy (n=5) and autologous transplantation (n=3). All patients had relapsed or refractory disease with biopsy-confirmed tumor cells expressing CD20. DI-Leu16-IL2 dose levels were 0.5 mg/m2 (n=3), 1 mg/m2 (n=3), 2 mg/m2 (n=7). DI-Leu16-IL2 was detectable in the serum at the lowest dose level. Median number of cycles were 4 (range 1-11). No DLTs have been observed. The most common drug-related adverse events (AEs) were grade 1-2 transient skin reactions with erythema, painless induration of injection site, pruritus, edema and mild constitutional symptoms (grade 1-2 chills, low-grade fever, fatigue, low appetite) suggesting an immune stimulatory response. Lymphocyte margination occurred with nadir of 0.3x103 /mL for median 2.7 days (range 1-5). Two grade 3 non-DLT toxicities (diarrhea and QTc prolongation with pre-existing RBBB) resulted in DI-Leu16-IL2 dose reduction. Transiently prolonged QTc (grade 1-2) occurred in 3 additional patients. Routine laboratory monitoring revealed grade 1-2 transient eosinophilia, anemia and thrombocytopenia in most subjects, grade 1-2 neutropenia (n=3) without neutropenic fever, grade 1 elevation of alkaline phosphatase or bilirubin. All AEs resolved completely within one week. Twelve patients are evaluable for response. After 2 cycles, tumor regression or stabilization was noted in 10 of 12 patients with mean tumor reduction of 30% (range 0%-80%). Six had sustained disease control after 4 cycles. One patient with small tumor bulk marginal zone lymphoma achieved a complete response by PET criteria, 3 patients had a partial response (55%, 55% and 80% tumor size reduction) and continue on therapy. Stable disease (SD) response was observed in all dose cohorts; best responses occurred at the highest dose level (2mg/m2) administered thus far. Three patients have had SD for up to 1 year. In conclusion, we have observed promising clinical efficacy of the novel immunocytokine DI-Leu16-IL2 in relapsed/refractory B cell NHL. SC administration has permitted higher doses than could be achieved with IV treatment and the MTD has yet to be reached. DI-Leu16-IL2 is biologically active in doses up to 2mg/m2. Repetitive SC dosing elicits clinical immune activation associated with clinical activity. Further dose escalation of DI-Leu16-IL2 is in progress. Prior DI-Leu16-IL2 therapy After 2 cycles at dose 2mg/m2 Figure 1. 65 year old female with diffuse large B cell lymphoma treated at dose level 2mg/m2 received 2 cycles of DI-Leu16-IL2. Treatment resulted in partial regression of multiple lymph node sites. Figure 1. 65 year old female with diffuse large B cell lymphoma treated at dose level 2mg/m2 received 2 cycles of DI-Leu16-IL2. Treatment resulted in partial regression of multiple lymph node sites. Disclosures Bachanova: Seattle Genetics Inc.: Consultancy, Research Funding.

Description: 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.