ALBERT

Description: Abstract 2979 Background: Thalidomide and its immunomodulatory (IMiD) derivatives such as lenalidomide have shown great promise as a treatment option for multiple myeloma (MM) patients. Pomalidomide is a newer IMiD with high in vitro potency that has shown promise as an effective treatment option for relapsed/refractory (R/R) MM patients. Recent data has shown pomalidomide to be effective in combination with dexamethasone, even for patients who are refractory to bortezomib and lenalidomide. It has been demonstrated that the addition of pegylated liposomal doxorubicin (PLD) to lenalidomide and thalidomide is effective for both R/R and frontline MM patients. Our recent trial evaluating lenalidomide in combination with dexamethasone, PLD, and bortezomib (DVD-R) showed that both efficacy and tolerability may be improved by changing the dose and schedule of these drugs. These data imply that the combination of pomalidomide, dexamethasone, and PLD for R/R MM patients may be an effective regimen. We conducted a phase 1/2 trial investigating the safety and efficacy of pomalidomide in combination with IV dexamethasone and (PLD) using a modified dose and longer 28-day schedule for patients with R/R MM. The combination of PLD, dexamethasone and lenalidomide without bortezomib has not been previously evaluated. Methods: For enrollment into the phase 1 dose-escalation portion of the study, eligible pts had to have progressive MM at the time of enrollment that has relapsed following stabilization to at least one anti-myeloma regimen or is refractory defined as progressed while receiving anti-myeloma treatment. For enrollment into the planned phase 2 portion of the study, eligible pts have to be refractory to lenalidomide (singe-agent or in combination) demonstrated by progressive disease while receiving lenalidomide or relapse within 8 weeks of the last dose of lenalidomide. Patients who have received previous pomalidomide treatment were not eligible. Patients must not have received chemotherapy, corticosteroids, immunotherapy, antibody therapy, or treatment with thalidomide, lenalidomide, or bortezomib within 3 weeks of receiving study drug, nor extensive radiation therapy within 4 weeks of receiving study drug. During the phase 1 part of the trial, pomalidomide was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 patients each on days 1–21 of each 28-day cycle. Dexamethasone was administered intravenously at 40 mg over 30 min on days 1, 4, 8, and 11 of each cycle. PLD was administered at 5 mg/m2 as an IV infusion over 30–90 min on days 1, 4, 8, and 11 of each cycle. Pomalidomide doses were escalated until maximum tolerated dose (MTD) was reached. Once MTD was reached, all subsequent patients will be enrolled at that dose. Results: Ten of 40 planned patients have been enrolled to date, all during the phase 1 portion of the trial. Pts received a median of 4 prior treatments (range, 1–8) with a median of 1 prior PLD regimens (range, 0–1). Pts have completed a median of 1 cycle (range: 0–12) with a median of 1.2 months of follow up (range: 0.2–3.6). To date, the trial has enrolled all three cohorts in phase 1 (1 patient in cohort 1 chose to withdraw during Cycle 1 and was replaced). MTD has not yet been reached with no dose limiting toxicities (DLTs) in the first 2 cohorts. The 3 patients in cohort 3 are currently in Cycle 1. Seven patients are currently evaluable for efficacy and the 3 patients in cohort 3 have not yet had response assessment. Best response for evaluable patients is as follows: 3 patients have shown partial response, 2 patients have shown minor response, 1 is exhibiting stable disease (SD) but shows a decreasing monoclonal protein, and 1 has progressed. The incidence of reported adverse events (AEs) so far is low. Only 1 grade 3 or 4 (G3, G4) AE has been observed. The most common AEs were lymphopenia, which occurred in 6 pts (G1: 3; G2: 2; G3: 1), elevated urea nitrogen occurred in 4 pts (all G1), neutropenia occurred in 4 pts (all G1), and leukopenia occurred in 4 pts (all G1). Conclusions: The combination of pomalidomide with dexamethasone and PLD on a 28-day cycle may be an effective treatment option with acceptable tolerability for relapsed/refractory MM patients. Disclosures: Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. Entospletinib is an orally bioavailable, selective inhibitor of Syk. Methods: This Phase 2 trial is evaluating entospletinib 800 mg BID in a study of 204 patients with previously treated lymphoid malignancies. Tumor imaging was planned at weeks 8, 16, 24 and then every 12. Tumor response was assessed per Cheson 2007 criteria. Results: A cohort of 69 patients with iNHL (41 follicular lymphoma [FL], 11 lymphoplasmacytoid lymphoma [LPL], 17 marginal zone lymphoma [MZL]) are included in this analysis. Median age was 66 years (range 41 - 89). 58% were male. The median number of prior treatments (Rxs) regimens was 3 (range 1- 14). Prior Rxs included anti-CD20 antibodies (rituximab 99%, ofatumumab 4%), alkylating agents (90%; bendamustine 51%) and anthracyclines (35%). Baseline risk factors: Ann Arbor Stg III-IV (70%), Gr 3a FL (29%), FLIPI ≥3 (34%). Median duration of Rx was 16 weeks with 10 patients continuing on Rx. Entospletinib was generally well tolerated. The most common TEAEs (any Grade/≥Gr 3, independent of causality) were fatigue (54%/13%), nausea (49%/4%), diarrhea(36%/0%), vomiting (26%/0%), headache (23%/1%), pyrexia (23%/3%), decreased appetite (22%/0%), constipation (22%/1%) and common laboratory abnormalities were increased AST (33%/15%), increased ALT (41%/19%), increased total bilirubin (32%/16%), anemia (36%/13%) and neutropenia (38%/13%). 4 patients died while on study from progressive disease. At the time of this analysis, 66 of 69 patients have been treated through first response assessment (1 patient ongoing not reaching first response assessment, 1 patient discontinued due to AE and 1 patient withdrew consent prior to it). 38 out of 61 (62%) patients evaluable for SPD experienced reduced tumor burden, with median duration of Rx 28 weeks (range 4-92). 9/61 (15%) achieved a decrease of ≥ 50% in SPD. The ORR was 13.0% (95% CI: 6.1%, 23.3%), with 7 patients achieving a PR, one LPL patient achieving MR and one patient achieving a CR. Forty-one patients (59.4%) had stable disease. The primary end point of 24 weeks PFS was 48.9% (95% CI: 34.6%, 61.7%). Median PFS was 5.5 months (95% CI: 4.4 months, 8.2 months). There were 39 patients (56.5%) with events of disease progression. Conclusions: Entospletinib monotherapy given with this dose and schedule was well tolerated and demonstrated activity in patients with advanced relapsed iNHL, including those with poor prognostic features. Further development of entospletinib in iNHL will focus on the development of combination approaches with chemotherapy and targeted agents. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Sharman: Calistoga: Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Roche: Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Off Label Use: Management of CLL/SLL and follicular lymphoma. Kolibaba:Takeda Pharmaceuticals International Co.: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Janssen: Research Funding; GSK: Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding. Abella:Gilead: Employment. Eng:Gilead: Employment. He:Gilead Sciences: Employment. Hu:gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

Description: Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who previously received POM treatment were ineligible. POM was administered orally on days 1-21 of a 28-day cycle, while DEX (40 mg) and PLD (5mg/m2) were both infused on days 1, 4, 8, and 11. During phase 1 enrollment, three cohorts were enrolled at 2, 3 and 4 mg doses of POM, and DEX and PLD were both administered at fixed doses. Phase 2 enrollment commenced once the MTD was established from the phase 1 portion of the study. Results As of August 1, 2015, 70 pts were screened, 68 were enrolled in the trial (with the pre-planned enrollment goal reached) and had received study drug, and a total of 50 pts were evaluable for safety and efficacy. Among all enrolled pts, 60pts discontinued treatment and 8 remain active. Pts had received a median of 4 prior treatments (range 1-18). Median number of cycles for all pts was 4 (range 1-8), with a median follow-up time of 5.5 months (range 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 57 pts enrolled in phase 2, 53% percent were refractory to LEN and steroids with or without other agents and 31% had previously received PLD. A median of 4 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Fifty-five pts were evaluable for response as 2 pts are active but have not yet had any post-baseline disease assessment. Among all evaluable pts (n=55) enrolled in phase 2, the overall response rate (ORR) was 33% (CR= 5%, VGPR= 5% and PR=23%) and clinical benefit rate (CBR) was 47% with 11 pts (26%) showing stable disease and 5 pts (12%) demonstrating progressive disease. For all evaluable pts enrolled in phase 2, the median follow-up time was 3.6 months (range 0-12 months) and the median PFS was 4.2 months (range 0.3- 29.0+). ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (36% and 51%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (49 pts; 72.0%), lymphopenia (36 pts; 52.9%), leukopenia (33 pts; 48.5%), hyponatremia (27 pts; 39.7%), and hypokalemia (26pts; 38.2%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures No relevant conflicts of interest to declare.

Description: Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. GS-9973 is an orally bioavailable, selective inhibitor of Syk. Methods: This Phase 2 trial enrolled 41 patients with CLL and 15 patients with SLL treated with GS-9973 800 mg BID. Tumor imaging occurred at weeks 8, 16, 24 and then every 12. Response was independently evaluated according to Hallek 2008 as modified by Cheson 2012 for patients with CLL and Cheson 2007 for patients with SLL. Primary endpoint for the study was PFS at 24 weeks. Results: The median ages of CLL and SLL patients were 73 (range 51-89) and 70 (range 57-84), respectively. 68% of CLL subjects and 60% of SLL subjects were male. Ten patients had 17p deletions/TP53 mutations and 17 had SF3B1 or NOTCH1 mutation, or 11q22.3 deletion. The median number of prior regimens for CLL was 2 (range 1-8) and for SLL was 2 (range 1-10). Prior therapies included anti-CD20 antibodies (98%), alkylating agents (86%, [bendamustine 63%]) and fludarabine (66%). 12 CLL and 6 SLL patients are still on treatment; the median duration of treatment for all CLL and SLL patients was 36 weeks The most common treatment emergent AEs (any Grade/≥Gr 3, independent of causality) were fatigue (70%/7%), nausea (54%/2%), diarrhea(48%/0%), cough(34%/0%), dizziness (32%/2%), headache (29%/0%), pyrexia (29%/0%), decreased appetite (27%/2%), upper respiratory tract infection(27%/0%), constipation (23%/0%). Common laboratory abnormalities were increased AST (30%/5%), increased ALT (43%/4%), increased total bilirubin (41%/16%), anemia (50%/7%) and neutropenia (54%/29%). Forty-nine patients were treated for at least 8 weeks and 54 patients had ≥ 1 efficacy assessment, two patients discontinued prior to the first response assessment, one due to AE and one withdrew consent. Per investigator assessment, 51 out of 52 (98%) patients evaluable for SPD experienced reduced tumor bulk; 38 (73%) achieved a decrease of ≥ 50%. The ORR was 62.5% (95% CI: 48.6%, 75.1%), with 35 patients achieving a PR and no subject achieving a CR. Thirteen patients (23.2%) had stable disease. The primary end point of 24 weeks PFS was 72.3% (95% CI: 57.1%, 83.0%). Median PFS was 20.5 months (95% CI: 7.7 months, not reached). There were 24 patients (42.9%) with events, 22 (39%) with disease progression and two deaths (4%) attributed to septic pneumonia and pseudomonal infection which was unrelated to entospletinib by investigator assessment. Among the 35 responding patients, median DOR was 21.3 months (95% CI: 13.2 months, not reached). Results of an independent response assessment are pending and will be presented. Entospletinib was well tolerated and demonstrated substantial activity in patients with CLL, and SLL including those with poor prognostic features. Entospletinib activity seems comparable to that reported by other approved BCR pathway inhibitors with the median PFS reported for Idela of 15.8 months (Blood. 2014;123(22):3390-3397) and Ibrutinib reported 42.6% overall response rate and a PFS of 70-80% @ 12 months (ibrutinib PI) Current studies plans include studying Entospletinib in combination therapy. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Sharman: Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Research Funding; Calistoga: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Research Funding; TG Therapeutics, Inc.: Research Funding; Janssen: Research Funding. Kolibaba:Janssen: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; GSK: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Gilead: Consultancy, Research Funding. Abella:Gilead: Employment. Di Paolo:Gilead Sciences: Employment, Equity Ownership. Eng:Gilead: Employment. Hu:gilead: Employment. He:Gilead Sciences: Employment. Reddy:gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

Description: INTRODUCTION: Patients undergoing hematopoetic stem cell transplantation or myelosuppressive chemotherapy for solid and hematologic malignancies commonly develop thrombocytopenia requiring prophylactic platelet transfusions once their level falls below ten thousand. In our institution, the primary replacement product is single donor platelets. This is collected by an apheresis machine using only one donor and they also undergo processing and testing prior to transfusion which leads to higher hospital costs. Recently, there has been the advent of Acrodose platelets which are obtained from whole blood. These platelets are leuko-reduced, ABO matched, pooled and bacteria tested making them "transfusion ready" for the hospital. These platelets enhance patient safety with culture-based bacteria testing for whole blood derived platelets. Moreover, it lowers handling costs at the hospital by eliminating the need for pooling and bacterial testing at the hospital. The Acrodose system can detect 〉1 CFU/ml of bacteria at a rate of 99.3% thus reducing the risks of false positives. They also have inline filtration systems capable of producing leukocyte reduced whole blood platelets and plasma. Each unit of Acrodose platelets contains pools of 4-6 units of lueko-reduced platelet concentrates in plasma. The purpose of this study is to evaluate platelet response and time to next transfusion in both leukemic and stem cell transplant patients between single donor and Acrodose platelet transfusions. METHODS: Data was collected from October 2012 to October 2013. There were a total of 349 platelet transfusions given, 61 were Acrodose and 288 were single donor. There were seventeen bone marrow transplant patients of which sixteen were autologous (seven had multiple myeloma, eight had Non-Hodgkin’s lymphoma and one had POEMS syndrome) and one was allogeneic for chronic lymphocytic leukemia. In addition, there were twenty acute leukemia patients. The bone marrow transplant patients received a total of 45 platelet transfusions of which 37 were single donor and 8 were Acrodose. The acute leukemia patients received a total of 150 platelet transfusions of which 17 were Acrodose and 133 were single donor. RESULTS: The average increase among all patients receiving Acrodose versus single donor platelets was 28.9 versus 19.8, respectively. The median increase for Acrodose versus single donor was 28 versus 16. The median time to next transfusion for Acrodose versus single donor was 4 versus 2 days. In subgroup analysis, the average increase among bone marrow transplant patients receiving Acrodose versus single donor platelets was 21.7 versus 27.8, respectively. The median increase for Acrodose versus single donor was 18 versus 20. The median time to next transfusion for Acrodose versus single donor was the same at 3 days. Among acute leukemia patients, the average increase in patients receiving Acrodose versus single donor platelets was 28 versus 18.6, respectively. The median increase for Acrodose versus single donor was 27 versus 15. The median time to next transfusion for Acrodose versus single donor was 4 versus 2 days. CONCLUSION: In our single institutional experience, Acodose platelets induced a more robust response and increased the time to next transfusion compared to single donor platelets among all patients and acute leukemia patients. That same effect was not see with the bone marrow transplant patients. The reason for this is unclear and more studies are needed. Disclosures No relevant conflicts of interest to declare.

Description: Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

Description: Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. Entospletinib is an orally bioavailable, selective inhibitor of Syk (Kd 7.6 nM, no other kinase 〈 100 nM). Methods: This Phase 2 trial is evaluating Entospletinib 800 mg BID in a 41 subject cohort with previously treated FL in a study of 165 subjects with lymphoid malignancies. Tumor imaging was planned at weeks 8, 16, 24 and then every 12. Tumor response was assessed per Cheson 2007 criteria. Results: For the subjects with FL included in this analysis, median age was 67 years (range 41 – 89), 49% were male. The median number of prior Rx regimens was 2 (range 1-8). Prior treatments (Rxs) included anti-CD20 antibodies (rituximab 100%, ofatumumab 5%), alkylating agents (95%; bendamustine 51%) and anthracyclines (51%). Baseline risk factors: Ann Arbor Stg III-IV (66%), Gr 3a FL (27%), FLIPI ≥3 (34%). At the time of this analysis, 41 subjects with follicular lymphoma were enrolled and 38 subjects have been treated through first response assessment (1 subject ongoing prior to first response assessment, 1subject discontinued due to AE and 1 subject withdrew consent). Entospletinib was generally well tolerated. The most common TEAEs (any Grade/≥Gr 3, independent of causality) were fatigue (46%/12%), nausea (42%/2%), diarrhea(27%/0%), decreased appetite (22%/0%), vomiting (22%/0%) and common laboratory abnormalities were increased AST (37%/17%), increased ALT (34%/20%), increased total bilirubin (27%/5%), anemia (34%/10%) and neutropenia (22%/10%). Reversible Grade 3 or 4 ALT/AST elevations occurred in 8 (19.5%) FL subjects. 3 subjects died while on study: 2 from progressive disease and 1 from acute renal failure investigator reported as unrelated to study drug. Investigator response assessments are available for 29 subjects, 16/29 (55%) subjects experienced reduced tumor bulk measured by SPD; 3 (10%) achieved a decrease of ≥ 50%. CR has not been observed at this early evaluation. 14/41 subjects continue on Rx. Median duration of Rx for all patients was 15 weeks. Among all patients who experienced reduction in tumor volume, median duration of Rx was 25 weeks (range 4-51). Conclusions: Entospletinib monotherapy given with this dose and schedule was generally well tolerated and demonstrated moderate activity in subjects with advanced relapsed FL, including those with poor prognostic features. Updated data with longer follow-up duration will be presented at the meeting. Disclosures Sharman: Gilead Sciences: Research Funding. Klein:Gilead Sciences: Research Funding. Boxer:Gilead Sciences: Research Funding. Kolibaba:Gilead Sciences: Research Funding. Hawkins:Gilead Sciences: Research Funding. Abella:Gilead Sciences: Employment, Equity Ownership. Wu:Gilead Sciences: Employment, Equity Ownership. Yasenchak:Gilead Sciences: Research Funding.

Description: Introduction:The prognosis is poor for patients with follicular lymphoma (FL) who experience early relapse within 2 years of initial diagnosis and for those who are double refractory to both rituximab and chemotherapy (Casulo et al. J Clin Oncol 2015). Avadomide, a cereblon-modulating agent that promotes degradation of the hematopoietic transcription factors Aiolos and Ikaros, is being examined in this setting. Avadomide demonstrated promising clinical activity in combination with obinutuzumab or rituximab in relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and FL (Michot et al. Blood 2017; Ribrag et al. Blood 2017). Herein, we report FL subgroup analyses for the avadomide plus rituximab combination (Arm D) of the CC-122 DLBCL-001 study in both lenalidomide-naïve and treated patients. Methods: CC-122-DLBCL-001 (NCT02031419) is aphase Ib dose escalation/expansion study of avadomide, CC-223, and CC-292 given orally as doublets, and as triplets in combination with rituximab, as well as avadomide plus rituximab doublets, in patients with R/R DLBCL or FL after ≥1 prior line of therapy. In the dose expansion phase of the study, patients received avadomide once daily (QD) for 5 days/week (5/7 d), with a fixed dose of intravenous rituximab 375 mg/m2/cycle (28-day cycle). The study endpoints were safety, tolerability, pharmacokinetics, preliminary efficacy (overall response rate [ORR] and complete response [CR]), and blood pharmacodynamic markers of avadomide. Results: As of May 1, 2018, 37 patients with FL were enrolled in the Arm D expansion group, including 29 in cohort 1 (no prior lenalidomide) and 8 in cohort 2 (≥2 cycles of prior lenalidomide). Baseline patient characteristics were similar between the two cohorts. In the total FL population, the median age was 61 years (range, 41-81 years), 54% were male, and 46% had an Eastern Cooperative Oncology Group performance status of 1. The median number of prior systemic anticancer regimens was 3 (range, 1-8). At disease diagnosis, three patients (8%) had bulky disease (≥7 cm in single dimension) and 7 (19%) had high Follicular Lymphoma International Prognostic Index scores. Twenty-three patients (62%) were refractory to rituximab and 11 (30%) were double-refractory to rituximab and an alkylating agent. As of the data cutoff, 27 patients (71%) were ongoing and no evaluable patients had experienced a dose-limiting toxicity. The most common (≥10%) any-grade adverse events (AEs) were neutropenia (46%) and anemia (24%). Grade 3/4 AEs occurring in 〉1 patient were neutropenia (32%); fatigue, dizziness, and anemia (8% each); febrile neutropenia and diarrhea (5% each). Six patients (16%) experienced serious AEs related to study drugs. One patient died during the study (sepsis considered possibly related to study treatment). Avadomide dose reduction occurred in 7 (19%) patients. Among all FL patients, the ORR was 65% with 8 patients (22%) achieving a CR. Response rates appeared to be independent of prior lenalidomide treatment, with an ORR of 62% (CR=14%) in cohort 1 and an ORR of 75% (CR=50%) in cohort 2. The median follow up for progression-free survival (PFS) was 6.3 months and 49% of patients had

Description: Background: Approximately 9% to 27% of patients undergoing hematopoietic stem cell transplantation (HSCT) develop a cardiac arrhythmia (CA).[1] This complication correlates with longer length of stays, higher probability of ICU admission, and higher mortality compared to patients who do not develop CA. Moreover, post-transplant CA is associated with greater risk of death within a year of HSCT. Identification of predictive risk factors for CA in patients undergoing HSCT has been elusive. Traditional risk factors like male gender, smoking, hypertension, diabetes, hypercholesterolemia, or established coronary artery disease, have not been found to be predictive of pre or post-transplant CA in HSCT patients. Echocardiogram may help identifying patients at risk of post-surgical arrhythmias but this has not been the case in HSCT.[2] MUGA scan has not been able to identify patients at risk for developing cardiac events during HSCT either.[3] In view of the detrimental consequences associated with CA during HSCT and the lack of reliable predictive risk factors, we decided to analyze and identify potential risk factors for CA in patients transplanted at our institution. Objective: This study aims to determine risk factors for the development of CA in patients undergoing HSCT. Methodology: A retrospective analysis of 138 consecutive patients undergoing HSCT at our institution between January 1st, 2015 and December 31st, 2017 was performed. One patient was excluded due to lack of baseline EKG. Data from patients ≥ 18 y/o who underwent autologous or allogeneic HSCT was analyzed. Variables analyzed included: age, gender, ethnicity, prior HSCT, diagnosis, type of transplant (autologous vs allogeneic), prior anthracycline exposure, diabetes mellitus, chronic kidney disease, hypertension, coronary artery disease, congestive heart failure, hyperlipidemia, previous arrhythmias, amyloidosis, documented STEMI or NSTEMI, home medications continued during HSCT, prior cardiovascular procedures, left ventricular ejection fraction prior to HSCT, baseline QTc prior to HSCT, stem cell dose, conditioning regimen, graft-versus-host disease prophylaxis, number of prior acute kidney injuries using RIFLE criteria, documented infections, electrolyte abnormalities, and hemoglobin 〈 7.0 g/dL. Statistical Methods: The Statistical Analysis Software (SAS) System program V9.0 was used for analysis. To compare potential risk factors of categorized data by patients with a documented arrhythmia and patients without a documented arrhythmia, a univariate comparison was performed using chi-square or Fisher's Exact test. Variables that were collected and demonstrated, as per-patient means, were analyzed using a multivariable T Test linear regression. A difference in incidence of arrhythmias between variables with a P-value of 〈 0.05 were statistically significant. Results: 31 patients (23%) developed CA during their HSCT. The most common type was atrial fibrillation (n= 13; 42%). The incidence of CA was greater in patients with a diagnosis of Non-Hodgkin's Lymphoma (17/31; 54.8%) vs (7/106; 6.6%); (p 〈 0.001) and QTc greater than 500 msec at any time during transplantation (8/31; 25.8%) vs (6/106; 5.6%) (p= 0.0011). All other risk factors did not have an association with an increased risk of CA during HSCT. Mean length of hospital stay, incidence of ICU admission, and number of in-hospital deaths were not statistically different between groups. Conclusion: Our data suggests that a diagnosis of Non-Hodgkin's Lymphoma or QTc prolongation ≥ 500 msec at any time during HSCT may be risk factors for CA during HSCT. Our study has the limitation of being a single institution analysis however, most patients (70%) in this analysis were prospectively placed on cardiac telemetry making our assessment of the incidence of CA during HSCT reliably accurate. Prospective interventional studies are warrant. [1] Tonorezos, Emilys S; Stillwell, Elizabth E; Calloway, James J., et al., Bone Marrow Transplant. 2015 Sep; 50(9): 1212-1216. [2] Osranek M, Fatema K, Qaddoura F, et al. Left atrial volume predicts the risk of atrial fibrillation after cardiac surgery: a prospective study. J Am Coll Cardiol. 2006;48(4):779-786. [3] Garcia I., Rodriguez T.E., Davis S., et al.; The Necessity of MUGA Scans to Detect Risks for Cardiac Toxicity in Patients Considered for Bone Marrow Transplantation. Tandem IBMTR/ASBMT Meeting; Orlando, FL 2002. Disclosures No relevant conflicts of interest to declare.

Description: Introduction DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. Methods For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3-5 or age-adjusted IPI (aaIPI) scores of 2-3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. Results At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22-78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (〉20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. Conclusions 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP. Disclosures Halwani: Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding; Takeda: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Other: Travel Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Miragen: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding. Yasenchak:Seattle Genetics: Research Funding. Farber:Seattle Genetics: Research Funding. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Fayad:Seattle Genetics: Consultancy, Research Funding. Holkova:Seattle Genetics: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Acerta: Research Funding. Patel-Donnelly:Seattle Genetics: Research Funding. Yimer:Ariad Pharmaceuticals: Consultancy; Biotheranostics: Consultancy; Bluebird Bio: Equity Ownership; Kite Pharma: Equity Ownership; Clovis Oncology: Equity Ownership; Juno Therpeutics: Equity Ownership; Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding. Levy:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding. Seetharam:Seattle Genetics: Research Funding. Belada:Seattle Genetics: Research Funding. Brooks:Seattle Genetics: Research Funding. Kingsley:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Wagner-Johnston:Seattle Genetics: Research Funding. Ruffner:Forma Therapeutics: Consultancy; Sydnax: Consultancy; Seattle Genetics: Employment, Equity Ownership; Array Biopharma: Employment; Medivation: Employment. Bartlett:Gilead: Consultancy.