Citations

Abstract Background: Although approximately half of adult patients with acute lymphoblastic leukemia (ALL) achieve long-term survival, those who relapse have poor long-term outcomes (El Fakih et al. Hematol Oncol Stem Cell Ther. 2017; Oriol et al. Haematologica. 2010). The initial report of Phase 1 of ZUMA-3, the Phase 1/2 trial of KTE-C19 for treatment of relapsed/refractory (R/R) ALL (NCT02614066), has thus far demonstrated promising efficacy among patients infused with KTE-C19, with a 71% complete remission (CR) rate (CR or CR with incomplete hematologic recovery [CRi]), 88% undetectable minimal residual disease (MRD), and manageable toxicity across all doses (Shah et al. ASH 2017. #888). Here, we present updated safety and efficacy data from Phase 1 of ZUMA-3. Methods: Adult patients (≥ 18 y) with R/R ALL (Ph+ allowed), > 5% bone marrow blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 CAR T cells/kg after low-dose conditioning chemotherapy with fludarabine 25 mg/m2/day for 3 days and a single dose of cyclophosphamide 900 mg/m2 on the third day of conditioning. The primary endpoint for Phase 1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence and time to onset and resolution of adverse events (AEs), rate of undetectable MRD remission in the bone marrow using flow cytometry, and duration of remission. KTE-C19 expansion and persistence were also assessed. Safety analyses included all patients who received KTE-C19, and patients with ≥ 2 months of follow-up were evaluated for efficacy. Results: As of April 12, 2018, 35 patients have received KTE-C19 with a median follow-up of 11 months (range, 2 - 25 months). The median age was 40 years (range, 18 - 69 years), 51% of patients were male, 66% had ECOG 1, 13 patients (37%) had prior blinatumomab, and 60% had received ≥ 3 prior lines of treatment. The median bone marrow blast burden at screening was 70% (range, 5 - 100). Six patients received the 2 × 106 cells/kg dose, 14 received 1 × 106 cells/kg, and 15 received 0.5 × 106 cells/kg. No DLTs were observed in the DLT period. The most common Grade ≥ 3 AEs were hypotension (40%), pyrexia (34%), decreased platelet counts (34%), and anemia (31%). Grade ≥ 3 CRS occurred in 9 patients (26%), with a median time to onset of 5 days (range, 1 - 15 days). There were 2 KTE-C19-related Grade 5 events: 1 cerebral infarction at the 0.5 × 106 cells/kg dose and 1 previously reported multiorgan failure secondary to cytokine release syndrome (CRS) at the 2 × 106 cells/kg dose. Grade ≥ 3 CRS resolved in all patients (not including 2 patients with a Grade 5 event), and the median time to resolution was 11 days (range, 7 - 42 days). Grade ≥ 3 treatment-emergent neurologic events occurred in 16 patients (46%), and the median time to onset was 7 days (range, 4 - 24 days). With the exception of 2 patients with unresolved neurologic events due to death, Grade ≥ 3 neurologic events resolved in all patients (14/14), with a median time to resolution of 17 days (range, 6 - 53 days). Among the 32 patients evaluable for response, the overall rate of undetectable MRD was 78% (95% CI, 60% - 91%). CR or CRi was achieved by 23 patients (72%), and 1 patient (3%) had blast-free BM. KTE-C19 levels were examined in 23 patients as of July 31, 2017. Robust KTE-C19 expansion was observed across all dose levels assessed. Conclusion: High rates of remission were achieved by adult patients with R/R ALL, with approximately three-quarters of patients achieving CR or CRi with undetectable MRD after a single dose of KTE-C19 in ZUMA-3. The safety profile was generally manageable, and most cases of high-grade CRS and neurologic events resolved. These results demonstrate that KTE-C19 offers clinical benefit for patients with otherwise limited treatment options. Disclosures Wierda: AbbVie, Inc: Research Funding; Genentech: Research Funding. Bishop:United Healthcare: Employment; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Speakers Bureau; Juneau Therapeutics: Speakers Bureau; Novartis Pharmaceuticals Corporation: Speakers Bureau. Logan:Adaptive Biotech: Consultancy; Napajen: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Holmes:Unum: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; Novartis: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Rigel: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy. Abedi:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Research Funding; CIRM: Research Funding; BMS: Speakers Bureau; Takeda: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Research Funding. Arellano:Cephalon: Research Funding. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Mardiros:Kite, a Gilead Company: Employment; Kite, a Gilead Company: Equity Ownership; Mustang Bio: Patents & Royalties; Kite, a Gilead Company: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Shen:Zhejiang DTRM Biopharma LLC: Other: Clinical Operations Director. Vezan:Kite Pharma: Employment; Kite, Gilead, Abbv, MRK: Equity Ownership. Jain:Kite Pharma, Amgen: Equity Ownership; Kite Pharma: Employment; Kite Pharma: Patents & Royalties.

Abstract Background: Radioimmunotherapy (RIT) is an emerging clinical treatment option for patients with non-Hodgkin’s lymphoma (NHL). Yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) RIT was approved by the FDA in February 2002 for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients with rituximab-refractory follicular NHL. In 4 registrational trials of 90Y ibritumomab tiuxetan conducted between 1996 and 1999, 211 patients with B-cell NHL were treated. Of these 211 patients, 153 patients (73%) had follicular lymphoma (FL). With ongoing follow-up, long-term durable responses have been observed, but until now have not been more fully characterized. Methods: Responding patients with time to progression (TTP) of ≥12 months were identified and characterized as long-term responding (LTR) patients. Results: In the 4 registrational trials, 78 of the 211 patients (37%) were identified as LTR patients. Characteristics of these LTR patients were as follows: median age 58 years (range, 24 to 80), 44% >60 years old, 55% male, 76% with follicular lymphoma, and 41% with lymphomatous marrow involvement. LTR patients had a median of 2 prior regimens (range, 1–9): 59% had ≥2 prior therapies, 33% had ≥3 prior therapies, and 37% had no response to their last prior therapy. Thirty percent of LTR patients had bulky disease (tumor size >5 cm) and 83% had stage III/IV disease. At the time of this analysis, the median duration of response (DR) and TTP for LTR patients were 28 months (range 11–80) and 29 months (range 12–82), respectively, with a median follow-up of 50 months (range 13–82). The median DR to the last prior therapy for LTR patients was 12 months. The complete response rate (confirmed [CR] and unconfirmed [CRu]) among LTR patients was 65%, and the median DR and TTP were 29 and 31 months, respectively, for CR/CRu patients. In ongoing responders the median DR is 52 months (range 48–80). Among the 153 patients with FL, 59 (39%) were identified as LTR patients. Compared to the overall LTR patients, LTR patients with FL had similar disease characteristics, DR, TTP, and CR/CRu rates. Conclusions: Ongoing follow-up indicates that 90Y ibritumomab tiuxetan frequently produces durable long-term responses (TTP ≥12 months) in patients with relapsed or refractory B-cell NHL. Failure to respond to the therapy immediately prior to treatment with 90Y ibritumomab tiuxetan does not appear to affect the ability to achieve long-term responses with 90Y ibritumomab tiuxetan. Durable long-term responses were achieved in 37% of all patients and 39% of patients with FL treated in 4 registrational trials of 90Y ibritumomab tiuxetan at 30 centers in the US. Of these LTR patients, a high proportion were >60 years old and had received ≥3 prior therapies.

Abstract Abstract 2859 Background: PTLD is the most common malignancy, other than melanomatous skin cancer complicating solid organ transplantation and has been one of the most commonly observed fatal consequences. The histologies are diverse and include B-cell, T-cell and Hodgkin lymphomas. Rituximab has affected the outcome in CD20+ patients with PTLD. This single institution study sought to identity the outcomes in patients of all histologies and presentations managed in the post-rituximab era. Methods: Patients with solid organ transplantation who were diagnosed with PTLD at Mayo Clinic (Rochester, MN) between December 1970 and October 2009 were identified through the Mayo Clinic Lymphoma Data Base. The rituximab era was defined as patients diagnosed after December 26, 2000, the date of diagnosis for the first patient treated with rituximab in our series. Cox proportional hazards models were used to assess the association of clinical factors and overall survival (OS). Results: 143 patients diagnosed with PTLD between December 1970 and October 2009 were identified. The median age at the time of diagnosis of PTLD was 50 years (range 15–84) with 41 patients (29%) over the age of 60. 93 were male (65%). At a median follow-up of 84 months (range 1–295), 95 patients (65%) have died. The types of organ transplant included renal (39%), liver (31%), cardiac (11%), lung (6%), renal/pancreas (6%), pancreas (4%), and multiorgan (4%). 83% of patients presented with extranodal disease. 28% had involvement of the engrafted organ. 76% of the patients developed PTLD that was EBV+ by in situ hybridization. 62% were stage 3–4. The IPI was intermediate-high in 39% of patients. Initial approaches to management included reduction in immunosuppression (45%), chemotherapy (12%), reduction in immunosuppression with rituximab (12%), rituximab (8%), and radiation therapy (6%). The overall response to therapeutic approaches was 46% in the pre-rituximab era and 56% in the post-rituximab era (chi-squared p=0.25). Patients treated with rituximab had an improved overall survival (HR = 1.66, 95% CI: 0.99–2.79). Patients treated in the rituximab era had improved 1 year survival (76%) compared to patients in the pre-rituximab era (59%) (chi-squared p=0.03). However, the survival advantage in the rituximab era was not maintained in longer follow-up. The median overall survival in the pre-rituximab era was 31 months compared to 56 months in the post-rituximab era (logrank p=0.63). Conclusion: The overall response rates and overall survival are improved with rituximab treatment in CD20+ PTLD, however, the natural history of all PTLD has not improved significantly in the post-rituximab era. New approaches are needed for the prevention and management of all the histologies of PTLD. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1892 Background: Primary or light chain amyloidosis (AL) is a clonal plasma cell disorder characterized by a relatively low plasma cell burden and multi-organ deposition of immunoglobulin light chain derived amyloid fibrils. The survival of patients with amyloidosis is quite variable with median survival of 12–18 months in different series, and largely dependent on the number and severity of organs involved. In addition to new drugs, the combination of melphalan and dexamethasone is an effective regimen for AL and risk adapted approaches to SCT has decreased treatment related mortality. It is not clear if the recent progress in risk stratification and treatment approaches have translated into improved survival for these patients. Methods: We studied two separate cohorts of patients; the first cohort consisting of 2118 patients with AL seen at Mayo Clinic over a 40-year period between November 1967 and August 2006 was used to examine the trends in overall survival from diagnosis during this time period. The second cohort of 443 patients seen between September 2006 and August 2009 were examined only for the changes in early mortality and for validation of a model for predicting early mortality developed using the first cohort of patients. Results: The estimated median follow up for the entire group was 7.8 years (95% CI; 7.1, 8.5). The patients were divided into 4 cohorts based on date of diagnosis; 1966–1976 (n=121), 1977–1986 (n=343), 1987–1996 (n=636) and 1997–2006 (n=1017). The median OS from diagnosis for the four cohorts were 0.9, 1.2, 1.2 and 1.5 years respectively, P < 0.001 (Figure 1). More importantly there was steady improvement in the long-term survival among these patients with 4-year survival estimates of 16%, 21%, 24% and 33% respectively. Next, we specifically looked at the survival trends within the last cohort (1996-2006), dividing the patients into three time periods; 1996–1999 (n=263), 2000–2003 (n=291) and 2003–2006 (n=463). While the OS from diagnosis was relatively unchanged between the first and second time periods (28 vs. 30% 4 year survival), there was significant improvement in the last three year period (42% survival at 4 years); P =0.02. Given the high early mortality in this disease, we specifically examined the one-year mortality among the entire patient cohort and found no clear improvement in terms of one-year mortality. Using logistic regression analysis, we identified cTnT > 0.01, NT-ProBNP > 4200 and Uric Acid > 8.0 mg/dL to be the best predictors of death within one year of diagnosis. The probability of death within one year for those with none, 1, 2, and 3 risk factors was 19, 38, 61, and 78% respectively, P < 0.01 (Figure 2). This model was further validated among patients seen during the most recent three years, September 2006 and August 2009. Conclusion: Survival in AL amyloidosis has improved over time, particularly in the recent years and likely reflects the recent improvements in therapy. However, early mortality remains a problem and baseline factors can be used to identify patients at risk for early mortality, who then can be targeted for risk adapted therapy approaches in clinical trials. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Abstract 5-azacitidine (5-AZA) is standard of care in the first-line setting for higher-risk patients with Myelodysplastic Syndrome (MDS). However, 40-50% of patients are refractory to 5-AZA and most responders ultimately demonstrate disease progression within 2 years, often progressing to AML. For patients refractory to 5-AZA, 2-year survival probability is low (15%). Thus, there is a need for more effective initial and second-line therapies for patients with higher-risk MDS. The Inhibitors of Apoptosis (IAP) Proteins are a family of molecules that suppress apoptotic cell death. Expression of IAPs is dysregulated in MDS, suggesting a potential path for therapeutic intervention. SMAC (second mitochondrial activator of caspases) is an IAP antagonist, resulting in caspase activation, inhibition of NF-kB and increased apoptosis. Birinapant is a potent bivalent SMAC mimetic with improved tolerability and therapeutic index compared to other SMAC mimetics. This Phase Ib/2a study was designed primarily to determine the MTD and recommended Phase 2 dose and schedule of birinapant in combination with 5-AZA in patients with higher-risk MDS who are naïve or have relapsed or are refractory to 5-AZA. To date, 11 patients have been enrolled in the Phase 1b portion of the study, including 7 with IPSS classification high-risk MDS (5 male, 2 female; median age 75, range 64-82) and 4 with intermediate-risk MDS (2 male, 2 female; median age 72.5, range 65-84). All patients received standard 5-AZA, administered via either intravenous (IV) or subcutaneous (SC) routes, at 75 mg/m2 for 7 days of a 28-day cycle in combination with birinapant. Birinapant was administered IV twice weekly (Days 1 and 4) for either 3 of 4 weeks or 4 of 4 weeks per 28-day cycle at a dose of 13 mg/m2. No cycle 1 dose-limiting toxicities have been observed. Adverse events ≥ Grade 2 observed in two or more patients and judged to be related to treatment were rash/pruritis (Grade 2, 2 patients), thrombocytopenia (Grade 4, 2 patients) and neutropenia (Grade 4, 1 patient; Grade 3, 1 patient). Two SAEs, Grade 3 abdominal soft tissue necrosis with abdominal pain in the area of subcutaneous injections of 5-AZA, and Grade 3 cellulitis were judged to be related to treatment. These local injection site reactions/cellulitis were more severe than usually expected with SC 5-AZA, suggesting an on target pharmacodynamic (TNF mediated) localized synergistic effect in skin, but were not observed with IV administration. Both occurred after cycle 1 and were not considered DLTs. Data showing inhibition of NF-kB, a downstream pro-survival molecule activated by IAPs, in circulating blast cells from patients treated with birinapant at a dose of 13 mg/m2 twice weekly for 3 weeks out of 4, suggests that birinapant is pharmacologically active at this dosing schedule. Based on these and other pharmacodynamic data, despite not determining the formal MTD, the Phase 2 dosing regimen has been established as birinapant administered at 13 mg/m2 IV twice weekly for 3 weeks of a 28-day cycle in combination with 5-AZA at 75 mg/m2 by IV infusion for 7 days of a 28-day cycle. Although not a primary endpoint, evidence of clinical activity in 5-AZA resistant/refractory patients was observed in 2 of 11 patients to date, with an additional good clinical response in a 5-AZA naive high-risk MDS/CMML patient. One patient with prior 5-AZA-refractory MDS (cytogenetics: hypodiploid and +11q) showed bone marrow (BM) blast count reduction from 25% to 2% after 1 cycle of 5-AZA/birinapant treatment. Another patient with MDS (cytogenetics: +X; +19; +21) refractory to single-agent 5-AZA showed BM blast count reduction from 21% to 7% after 2 cycles. A third patient with treatment-naïve MDS/CMML-2 (cytogenetics: 46, XY, inv(6)(p11.2q15), t(6;21)(q21;q22) ) who had received prior hydroxyurea demonstrated BM blast count reduction from 17% to 2% after 3 cycles and underwent hematopoietic stem cell transplant. Several patients remain on study and are in active follow-up. This Phase 1b trial provide data for an acceptable safety profile of the first combination of a SMAC mimetic (birinapant) administered with IV 5-AZA. Early signs of clinical activity including in 5-AZA naïve and refractory patients were observed. These results provide rationale for a randomized Phase 2 study comparing birinapant in combination with 5-AZA against 5-AZA alone in the first-line setting for patients with higher-risk MDS. Disclosures Borthakur: Tetralogic Pharmaceuticals: Research Funding. Foran:TetraLogic Pharmaceuticals: Research Funding. Wang:Tetralogic Pharmaceuticals: Research Funding. Rakkar:Tetralogic Pharmaceuticals: Research Funding. Hager:Tetralogic Pharmaceuticals: Research Funding. Frey:Tetralogic Pharmaceuticals: Research Funding. Andreeff:TetraLogic Pharmaceuticals: Research Funding. Carter:Tetralogic Pharmaceuticals: Research Funding. Minderman:Tetralogic Pharmaceuticals: Research Funding. Russell:Tetralogic Pharmaceuticals: Employment. Tibes:Tetralogic Pharmaceuticals: Research Funding.

Abstract Background We aim to assess the impact of a multidisciplinary inflammatory bowel disease (IBD) conference on the management of patients with complex IBD. Methods Data were collected during each conference from February 2017 through October 2018 with chart review performed at 6 months to determine if conference recommendations were successfully implemented. Results Eighty-five patients were discussed. The presenting diagnosis was changed by 11.8%. Recommendations for further testing, medical therapy, and surgery were successfully implemented in 77.1%, 98.1%, and 88.4%, respectively. Conclusions This study supports the role of IBD multidisciplinary conferences in the management of patients with complex IBD.