ALBERT

Description: Background: Because infections are a major cause of morbidity and mortality after AML induction chemotherapy, patients typically remain hospitalized for monitoring and rapid antimicrobial therapy until hematopoietic recovery. With declining early mortality and improved oral antimicrobials, interest in moving post-induction care to the outpatient setting has emerged. In the 5-year period since completing a prospective phase 2 trial evaluating an Early Hospital Discharge (EHD) strategy, EHD following AML-like induction chemotherapy has become routine at our institution. In recent retrospective analyses, we found 〉80% of EHD patients required hospital readmission, primarily for neutropenic fever. Still, the EHD strategy was safe and reduced healthcare resource utilization, and EHD patients spent 〉70% of their post-chemotherapy time as outpatients. Here, we investigated differences in the pattern of infectious complications between patients managed as outpatients following induction chemotherapy and those who remain hospitalized until hematopoietic recovery. Methods: We retrospectively identified all adults ≥18 years with untreated AML/high-grade myeloid neoplasms (≥10% blasts in blood/ bone marrow) who started intensive induction chemotherapy ("7+3" or a regimen of similar/higher intensity) at our institution from 8/1/2014-7/31/2018. Patients were considered "EHD" if they were discharged from the hospital

Description: Background CD19-targeted chimeric antigen receptor-engineered (CD19 CAR)-T cell immunotherapy has shown promising efficacy in patients with relapsed or refractory (R/R) B-cell malignancies. The potential benefits of repeat infusions of CD19 CAR-T cells are unknown, and the factors associated with response, CAR-T cell in vivo expansion, and progression-free survival (PFS) after repeat infusion of CD19 CAR-T cells have not been investigated. Methods We analyzed the outcomes of patients with R/R B-cell malignancies after a second infusion of CD19 CAR-T cells (CART2) on a phase 1/2 trial (NCT01865617) at our institution. Responses after CAR-T cell therapy were evaluated around day 28 after infusion and defined according to the 2018 NCCN guidelines for acute lymphoblastic leukemia (ALL), 2018 iwCLL for chronic lymphocytic leukemia (CLL), and the Lugano criteria for non-Hodgkin lymphoma (NHL). Logistic, Cox and linear regression were used for multivariable analyses of response, progression-free survival and peak CD8+ CAR-T in blood, respectively. Bayesian model averaging was performed for variable selection. Results Forty-four patients evaluable for response (ALL, n=14; CLL, n=11; NHL, n=19) were included in this study. The median age at the time of CART2 was 58 (range, 23-73). Patients were heavily pre-treated (median prior therapies, 6; range, 2-13), and 16 patients (36%) had bulky (≥ 5cm) nodal or extramedullary disease. The median time from the first CAR-T infusion (CART1) to CART2 was 70 days (range, 28-712). Twenty-eight patients (64%) had received a CART1 dose ≥ 2x106 CAR-T cells/kg. Fifteen patients (32%) had not responded to CART1, 22 (50%) relapsed or progressed after having initially responded (complete response [CR], n=15; partial response [PR], n=7) to CART1; 7 (16%) received CART2 in PR after CART1. All characteristics are shown in the Table. We observed responses in all disease types, including 3 of 14 ALL patients (21%; all CR/CRi), 4 of 11 CLL patients (36%; CR/CRi, n=3; partial response [PR], n=1), and 9 of 19 NHL patients (47%; CR, n=2; PR, n=7). After a median follow-up of 43 months (range, 16-66) in alive and responding patients, the estimated 4-year PFS probability in responders was 23% (95% CI, 9-59%). The 4-year overall survival probability in responders was 36% (95% CI 19-71%) compared to 24% (95% CI, 12-47) in non-responders. Multivariable logistic regression modeling identified predictors of response after CART2: CART1 lymphodepletion (high-intensity cyclophosphamide and fludarabine [CyFlu] vs no CyFlu, OR=12.19, 95% CI, 1.10-1689.85, p=0.04), and peak of in vivo CAR-T cell expansion after CART2 (OR=2.31 per log10 CD8+ CAR-T cell/µL increase, 95% CI, 1.17-5.29, p=0.01). In a multivariable Cox model, a higher peak of CD8+ CAR-T cells after CART2 (HR=0.47 per log10 CD8+ CAR-T cell/µL increase, 95%CI, 0.33-0.68, p CART1 cell dose was associated with longer PFS (HR=0.36, 95% CI, 0.16-0.86, p=0.02). This suggested that CD8+ CAR-T cell peak after CART2 and factors increasing CART2 peak (e.g. prevention of immune rejection or increase in the infused cell dose) are key elements associated with outcomes of CART2. Hence, we looked at factors associated with higher CD8+ CART2 peak. In multivariable linear regression, CART1 CyFlu predicted a higher peak of CD8+ CAR-T cells after CART2 (high-intensity CyFlu vs no CyFlu, p

Description: Introduction Lymphodepletion chemotherapy followed by infusion of T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) has shown remarkable efficacy in patients (pts) with relapsed/refractory (R/R) CD19+ B-cell malignancies, with high response rates reported in non-Hodgkin lymphoma (NHL). Durable responses have been observed in a subset of pts, but the factors associated with these long-term remissions have not been identified. We studied adults with R/R CD19+ B-cell NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by infusion of 2 x 106 CD19 CAR-T cells/kg, and identified factors before and after CAR-T cell infusion that are associated with progression-free survival (PFS). Methods We conducted a phase 1/2 open-label clinical trial (NCT01865617) with the primary objective of evaluating the feasibility and safety of infusing a defined composition of CD4+ and CD8+ CD19 CAR-T cells after lymphodepletion chemotherapy in pts with R/R CD19+ B-cell malignancies. Best responses are reported according to the Lugano criteria (Cheson, JCO 2014). PFS was defined as the time from CAR-T cell infusion until disease progression or death, without censoring for new therapy. Logistic regression and penalized Cox regression multivariable modeling using elastic net were performed for analysis of response and PFS, respectively. Results Characteristics of the 57 pts in the study are shown in Table 1. One patient with incomplete response assessment was excluded. For the 56 remaining pts, the best overall response rate (ORR) without additional therapy was 57% (95% confidence interval [CI], 43-70%), with 48% achieving complete remission (CR; 95% CI, 35-62%). Most pts with partial response (PR) or stable disease (SD) after initial restaging at 4 weeks after CAR-T cell infusion received new therapy (11 of 15, 73%). All pts with PR/SD on initial restaging who did not receive additional therapy after CAR-T cells (n = 4) subsequently achieved CR. The duration of persistence of CAR-T cells was longer in pts who did not receive new therapy (15.7 vs. 5.3 months; P = .06). Eight of 9 pts with indolent histology achieved CR (89%; 95% CI, 51-99%). For the 47 pts with aggressive NHL, the best ORR was 51% (95% CI, 36-66%), with 40% (95% CI, 27-56%) achieving CR. Among aggressive NHL subtypes, pts with DLBCL (n = 28) had best ORR and CR rates of 50% (95% CI, 33-67%) and 43% (95% CI, 25-63%), respectively. In pts with aggressive lymphoma, multivariable analysis showed that the probability of achieving CR was independently associated with a lower pre-lymphodepletion serum LDH concentration (P = .003) and greater increase in serum MCP-1 concentration from a pre-lymphodepletion timepoint to immediately before CAR-T cell infusion (P = .01). Analysis of pts with all histologic subtypes showed that those achieving CR had better PFS and overall survival (OS) compared to those who did not achieve CR (median PFS: CR, not reached; non-CR, 1.35 month; Figure 1). In pts achieving CR, after a median follow-up of 20.2 months (range 2.5-32.4 months), the 24-month probabilities of PFS and OS were 59% (95% CI, 41-84%) and 79% (95% CI, 64-97%), respectively. No pts with indolent NHL who achieved CR (n = 8) have relapsed with a median follow-up of 14.5 months (range, 10.7-30.1 months). For pts with aggressive lymphoma who achieved CR, after a median follow-up of 26.9 months (range, 2.5-32.4 months), the median PFS was 20.0 months (95% CI, 9.2-not reached), and 24-month probabilities of PFS and OS were 46% (95% CI, 28-76%) and 72% (95% CI, 54-96%), respectively. In aggressive NHL, multivariable analysis suggested that, in addition to being associated with the probability of achieving CR, serum LDH and MCP-1 concentration also impacted the probability of longer PFS. The model found that lower pre-lymphodepletion serum LDH (P = .0004) and higher serum MCP-1 peak after CAR-T cell infusion (P = .05), along with higher serum IL-7 (P = .02) and lower serum IL-18 (P = .02) concentrations before lymphodepletion were independently associated with better PFS. Similar findings were obtained after multivariable analysis was performed only in those who had achieved CR. Conclusion CR after CD19 CAR-T cell therapy appears to be a strong predictor of PFS in adult pts with B-cell NHL. Identification of additional factors associated with better PFS might guide future management strategies for pts achieving CR after CD19 CAR-T cell therapy. Disclosures Hirayama: DAVA Oncology: Honoraria. Hay:DAVA Oncology: Honoraria. Li:Juno Therapeutics: Employment, Equity Ownership. Lynch:Incyte: Research Funding; Johnson Graffe Keay Moniz and Wick LLP: Consultancy; Juno Therapeutics: Research Funding; Rhizen Pharmaceuticals: Research Funding; Takeda: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Kiem:Homology Medicine: Consultancy; Rocket Pharmaceuticals: Consultancy; Magenta: Consultancy. Ramos:Seattle Genetics: Employment, Equity Ownership. Shadman:Gilead Sciences: Research Funding; Genentech: Consultancy; Pharmacyclics: Research Funding; Celgene: Research Funding; Mustang Biopharma: Research Funding; Genentech: Research Funding; TG Therapeutics: Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy; Verastem: Consultancy; Beigene: Research Funding; AstraZeneca: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy. Cassaday:Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Kite Pharma: Research Funding; Adaptive Biotechnologies: Consultancy; Merck: Research Funding; Pfizer: Consultancy, Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Incyte: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Riddell:Cell Medica: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; NOHLA: Consultancy; Adaptive Biotechnologies: Consultancy. Maloney:GlaxoSmithKline: Research Funding; Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria; Janssen Scientific Affairs: Honoraria. Turtle:Bluebird Bio: Consultancy; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Nektar Therapeutics: Consultancy, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Consultancy; Gilead: Consultancy; Adaptive Biotechnologies: Consultancy; Aptevo: Consultancy.

Description: Background We reported durable responses to CD19-specific chimeric antigen receptor-modified T-cell therapy (JCAR014) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients (pts) after prior failure of ibrutinib (Turtle, JCO 2017; NCT01865617). In those pts, ibrutinib was not administered during CAR-T cell immunotherapy. Continuation of ibrutinib through leukapheresis, lymphodepletion and CAR-T cell therapy may prevent tumor progression after ibrutinib withdrawal, mobilize tumor into the blood, improve CAR-T cell function, and decrease cytokine release syndrome (CRS). Methods We conducted a phase 1/2 study of CD19 CAR-T cell immunotherapy in R/R CLL pts and established a regimen of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by JCAR014 at 2 x 106 CAR-T cells/kg (Turtle, JCO 2017). We then compared outcomes of these pts (No-ibr cohort) with a subsequent cohort that received Cy/Flu with 2 x 106/kg JCAR014 CAR-T cells with concurrent ibrutinib (420 mg/d) from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion (Ibr cohort). Dose reduction was permitted for toxicity. CRS was graded by consensus criteria (Lee, Blood 2014) and neurotoxicity and other adverse events were graded by CTCAE v4.03. Response was evaluated according to 2008 IWCLL criteria. Results Seventeen and 19 pts were treated in the Ibr and No-ibr cohorts, respectively. Pt characteristics were comparable (Table 1). Progression on ibrutinib was noted in 16 (94%) and 18 pts (95%) in the Ibr and No-ibr cohorts, respectively, and prior ibrutinib intolerance was reported in 1 pt in each cohort. The time to intolerance or failure of ibrutinib prior to treatment with JCAR014 was longer, and the pre-leukapheresis LDH was lower in the Ibr compared to the No-ibr cohort. The median follow-up in responders was 98 and 764 days in the Ibr and No-ibr cohorts, respectively. Administration of ibrutinib with Cy/Flu and JCAR014 was well tolerated in most pts; ibrutinib was reduced or discontinued in 6 pts (35%) at a median of 21 days after JCAR014 infusion. In the Ibr cohort, 1 pt with grade 2 CRS developed fatal presumed cardiac arrhythmia and 1 pt developed a subdural hematoma in the setting of trauma and thrombocytopenia. No differences in the incidences of grade ≥3 cytopenias were observed. Concurrent ibrutinib administration did not appear to affect the frequency or severity of neurotoxicity. Although the proportions of pts with grade ≥1 CRS were similar between cohorts (76% vs 89%, P = 0.39), the severity of CRS (grade ≥3 CRS: Ibr, 0%; No-Ibr, 26%; P = 0.05) and serum peak IL-8 (P = 0.04), IL-15 (P = 0.003) and MCP-1 (P = 0.004) concentrations were lower in the Ibr cohort. However, we found comparable CD8+ (P = 0.29) and higher CD4+ (P = 0.06) CAR-T cell counts in blood in the Ibr cohort. Sixteen pts (94%) and 18 pts (95%) in the Ibr and No-ibr cohorts, respectively, have completed response assessment. We observed a higher proportion of responders (complete and partial remission) by IWCLL criteria in the Ibr compared to the No-ibr cohort (88% vs 56%, respectively, P = 0.06). Ten of 12 pts (83%) with lymph node disease before treatment with Cy/Flu and JCAR014 in the Ibr cohort achieved CR or PR by IWCLL imaging criteria, compared to 10/17 pts (59%) in the No-ibr cohort (P = 0.23). The proportion of pts with pretreatment bone marrow (BM) disease who had no disease by flow cytometry after CAR-T cell immunotherapy was similar in the Ibr compared to the No-ibr cohort (75% vs 65%, P = 0.71). However, among pts with no disease by BM flow cytometry after CAR-T cell immunotherapy, a higher proportion of pts in the Ibr cohort had no malignant IGH sequences at 4 weeks (83% vs 60%, respectively, P = 0.35). We performed univariate logistic regression analysis for response by IWCLL criteria and variables with P 〈 0.10 were considered for stepwise multivariable analysis (Table 2). In the multivariable analysis, the Ibr cohort and a lower pre-treatment SUVmax on PET imaging were each associated with a higher probability of response by IWCLL criteria (Ibr cohort, OR = 14.02, 95%CI [0.52-379.61], P = 0.05; SUVmax, OR = 1.31 per SUV unit decrease, 95%CI [1.05-1.67], P 〈 0.001). Conclusion Administration of ibrutinib from 2 weeks before leukapheresis until 3 months after JCAR014 was well tolerated in most pts. This approach might decrease the incidence of severe CRS and improve responses in pts with R/R CLL. Disclosures Hirayama: DAVA Oncology: Honoraria. Hay:DAVA Oncology: Honoraria. Li:Juno Therapeutics: Employment, Equity Ownership. Lymp:Juno Therapeutics: Employment, Equity Ownership. Till:Mustang Bio: Patents & Royalties, Research Funding. Kiem:Magenta: Consultancy; Homology Medicine: Consultancy; Rocket Pharmaceuticals: Consultancy. Shadman:TG Therapeutics: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; AstraZeneca: Consultancy; Verastem: Consultancy; Beigene: Research Funding; Mustang: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Abbvie: Consultancy. Cassaday:Merck: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Incyte: Research Funding; Kite Pharma: Research Funding; Adaptive Biotechnologies: Consultancy; Jazz Pharmaceuticals: Consultancy. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Riddell:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Adaptive Biotechnologies: Consultancy; NOHLA: Consultancy; Cell Medica: Membership on an entity's Board of Directors or advisory committees. Maloney:GlaxoSmithKline: Research Funding; Juno Therapeutics: Research Funding; Seattle Genetics: Honoraria; Roche/Genentech: Honoraria; Janssen Scientific Affairs: Honoraria. Turtle:Nektar Therapeutics: Consultancy, Research Funding; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Aptevo: Consultancy; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Consultancy; Adaptive Biotechnologies: Consultancy; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy; Gilead: Consultancy.

Description: BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T-cell therapy has proven to be highly effective in patients with relapsed or refractory large B-cell lymphomas, yielding early complete response (CR) rates of ~40%, which are typically sustained. Unfortunately, most patients will not experience prolonged disease control. Despite this fact, little data exist defining the outcomes and impact of subsequent therapies for such individuals. Limited data also exist on the ability for such patients to pursue further clinical trials or allogeneic hematopoietic stem-cell transplant (HSCT). This project details the specific interventions and outcomes of this population to better inform the management of patients who suffer progressive disease (PD) after CD19-specific CAR T-cell therapy. METHODS: Adults with diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), and high-grade B-cell lymphomas (HGBCL) who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance were included in this analysis. Patients who received CAR T-cell therapy in conjunction with additional protocol-specified therapy were excluded. Those who exhibited PD or persistent lymphoma after CAR T-cell therapy were the focus of this study. We defined initial PD as patients who had evidence of disease progression on the initial response assessment. Delayed PD was defined as achieving a CR, partial response (PR), or stable disease (SD) on the initial response assessment, but eventually progressed or received subsequent anti-lymphoma therapy. Baseline characteristics and all data were retrieved from the electronic medical record up until date of death or date of last contact in our system, including subsequent interventions and outcomes. Primary endpoint of this analysis was overall survival (OS). RESULTS: Between October 2013 and May 2018, we identified 51 patients with PD following CD19-specific CAR T-cell therapy. Baseline characteristics are listed in the Table 1. Histologies included DLBCL (29), HGBCL (11), tFL (8) and PMBCL (3). Median age was 60 years (range 26-75), 65% were male, median prior regimens was 3 (range 1-8). Median time from CAR T infusion to PD was 42 days (range 11-609), with 27 (53%) patients exhibiting initial PD. Median follow up after time of progression was 4.2 months. Initial PD was associated with a higher risk of death (HR 2.376, 95% CI 1.19-4.75, p=0.0143, Figure 1). The median OS for those with initial PD and delayed PD was 5.1 months (95% CI 2.0-9.3) and 13.6 months (4.1-not reached) respectively. 39 (76%) patients received ≥ 1 subsequent therapies after PD. Initial therapies included: 2nd CAR T infusion (14), targeted therapy (10), chemotherapy +/- rituximab (7), other immunotherapy (3), radiotherapy (3), intrathecal chemotherapy (1) and allogeneic HSCT (1). 12 (24%) patients received no further therapy despite PD. Those who received ≥ 1 subsequent therapies after PD had a lower risk of death (HR 0.344, 95% CI 0.149-0.793, P=0.0122) compared to those who did not. There was no difference in survival if 2nd CAR T infusion was the next line therapy compared to others (p=0.449), targeted therapy compared to others (p=0.417), or chemotherapy compared to others (p=0.565). 5 (10%) patients enrolled onto a clinical trial as next line therapy. 4 (8%) patients eventually received an allogeneic HSCT after PD, 2 of whom are still alive. We identified 8 patients who were alive for ≥ 12 months after progression without evidence of lymphoma. Last line of therapy for these patients included allogeneic HSCT (2), subsequent CD19-specific CAR-T cell infusion (2), ibrutinib (2), lenalidomide/rituximab (1), and radiotherapy (1). CONCLUSIONS: Patients with PD post anti-CD19 CAR T-cell therapy, particularly those exhibiting initial PD, have poor long-term outcomes. Patients receiving at least one anti-lymphoma therapy after PD had improved overall survival, although no single approach appeared to confer a survival benefit. Few enrolled onto a clinical trial or received an allogeneic HSCT. These data reinforce the need to both further improve the durable CR rate after CAR T-cell therapy and to develop effective strategies for those not achieving a CR. Figure 1 Figure 1. Disclosures Gopal: Spectrum: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Brim: Consultancy; Janssen: Consultancy, Research Funding; Asana: Consultancy; Gilead: Consultancy, Research Funding; Aptevo: Consultancy; Incyte: Consultancy; Teva: Research Funding. Maloney:Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; Janssen Scientific Affairs: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding. Turtle:Caribou Biosciences: Consultancy; Adaptive Biotechnologies: Consultancy; Nektar Therapeutics: Consultancy, Research Funding; Bluebird Bio: Consultancy; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptevo: Consultancy; Gilead: Consultancy. Smith:Genentech: Research Funding; Acerta Pharma BV: Research Funding; Incyte Corporation: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Shadman:TG Therapeutics: Research Funding; Mustang Biopharma: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Consultancy; Verastem: Consultancy; Gilead Sciences: Research Funding; AbbVie: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; Beigene: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Celgene: Research Funding. Cassaday:Seattle Genetics: Other: Spouse Employment, Research Funding; Incyte: Research Funding; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy, Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Lynch:Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding.

Description: PURPOSE: Autologous stem cell transplantation (ASCT) is the standard of care for patients with chemosensitive relapsed or refractory diffuse large B-cell lymphoma (DLBCL). However, even with this aggressive approach, 40-70% of patients will still relapse. Many conventional conditioning regimens employ a combination of chemotherapy +/- total body irradiation (TBI), with further dose escalation limited by non-hematological toxicities. CD20-targeted radioimmunotherapy (RIT) delivers high doses of tumor-localized radiation with relative sparing of vital organs and has been successfully utilized to improve the efficacy and reduce the normal organ toxicity of ASCT. Based on the radiosensitivity of DLBCL and the reduced cross-resistance with chemotherapy, we hypothesized that RIT-based ASCT would improve survival outcomes for patients with relapsed/refractory DLBCL. PATIENTS AND METHODS: We performed a prospective phase II trial utilizing RIT-based myeloablative conditioning with high-dose I-131 tositumomab (to deliver ≤25 Gy to critical normal organs), cyclophosphamide (100mg/kg) and etoposide (60mg/kg) followed by ASCT in patients with relapsed/refractory DLBCL. Additionally, based on retrospective chart review, we identified and evaluated 61 eligibility-matched control patients who underwent myeloablative conditioning with TBI (12Gy), cyclophosphamide (100mg/kg), and etoposide (60mg/kg) at our Center during the trial enrollment period. RESULTS: From October 1999 to May 2011, we treated 27 DLBCL patients on this phase II trial. Baseline patient characteristics included advanced disease (89%), IPI≥2 (52%), and a median age of 51.4 years (range 31.9-59.1). The vast majority of patients had received prior rituximab (89%), with 59% considered rituximab refractory (defined as less than partial remission (PR) following or relapse within 6 months of rituximab therapy) and 55% experiencing relapse within 12 months of rituximab-based immunochemotherapy (R-chemo). Fifteen percent of patients achieved complete remission (CR) with their last chemotherapy regimen, 37% achieved PR, 26% had stable disease (SD) and 22% had progressive disease (PD). Patients received a median I-131 activity of 540 mCi (range 285 to 797), with lung (n=21), liver (n=4), and kidney (n=2) as the critical normal organs receiving the highest absorbed dose. Engraftment of neutrophilsand platelets occurred at a median of 13 (range 9-17) and 11 (range 7-38) days after ASCT, respectively. The 100-day non-relapse mortality was 7% (n=2), with one death due to cardiac failure and one due to respiratory failure. With a median follow up of 6.6 years (range 0.2-15.5), median overall survival (OS) was not reached and median progression free survival (PFS) was 3.5 years. Median PFS in the highest-risk patients, as defined by recurrent disease within 12 months of R-chemo (n=15) or chemorefractory relapse (n=13), was 22.6 and 10.8 months, respectively. Serial annual bone marrow evaluations did not identify any cases of treatment-associated myelodysplastic syndrome or acute myeloid leukemia. In comparison to the RIT group, the 61 eligibility-matched, TBI-conditioned control group patients were less heavily pretreated (2 vs 3 average prior regimens [p=

Description: Background: The impact of prior salvage therapy with brentuximab vedotin (BV) for relapsed/ refractory Hodgkin lymphoma (HL) on long-term outcomes after reduced intensity conditioned (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) is unknown. Early studies (Chen et al Biol Blood Marrow Transplant 2014; 20: 1864-1868) suggested an improved 2-year progression free survival (PFS) with BV salvage given before allo-HCT compared to patients without prior BV treatment. In the current study, we analyzed the impact of prior therapy on the incidence of chronic graft-versus-host disease (cGVHD) and other major outcomes in patients, who received an RIC allo-HCT for relapsed HL. Methods: This is a retrospective study of relapsed/refractory HL patients who had RIC allo-HCT between 2005-2014 at the Fred Hutchison Cancer Research Center. Patients were grouped according to prior history of salvage therapy with or without BV pre allo-HCT. Baseline patient characteristics are shown in the Table. Results: Of the 62 consecutive allo-HCT recipients in this study, 25 had prior therapy with BV (BV group) and 37 received other chemotherapy alone (No BV group) for relapsed HL before allo-HCT. More patients in the BV group were in complete remission at allo-HCT (Table). The 100 day acute GVHD and 5 year cGVHD incidence for the BV vs. no BV group were 58% (95% confidence intervals [CI]: 39%-78%) vs. 65% (95% CI: 50%-80%), p=0.6 and 46% (95% CI: 26%-67%) vs. 51% (95% CI: 35%-68%), p=0.66, respectively. The 5 year non-relapse mortality and relapse/ progression for the BV vs. no BV group were 8% (95% CI: 1%-19%) vs. 25% (95% CI: 11%-38%), p=0.13 and 46% (95% CI: 24%-67%) vs. 38% (95% CI: 22%-53%), p0.98. The 5 year PFS and overall survival for BV vs. no BV group were 46% (95% CI: 25%-68%) vs. 38% (95% CI: 22%-53%), p=0.44 and 78% (95% CI: 60%-95%) vs. 56% (95% CI: 40%-72%), p=0.14. The major cause of death in both groups was relapsed HL. Conclusion: With longer follow-up, similar incidences of cGVHD, PFS and OS were observed in patients who received salvage therapy for relapsed/refractory HL prior to allo-HCT with or without BV. Any potential differences in cGVHD and other major outcomes need to be tested in a larger population. Table 1. Characteristics Prior treatment with Brentuximab vedotin Yes N=25 No N=37 Median age, years (range) 27 (14-47) 32 (17-64) Disease stage at diagnosis, n (%) I II III IV 2 (8)11 (44)7 (28)5 (20) 0 (0)15 (41)12 (32)10 (27) Prior history of local radiation pre allo-HCT 20 (80) 29 (78) No. of prior lines of therapies pre allo-HCT 4 (2 - 10) 3 (2 - 7 ) Prior autologous HCT, n (%) 0 1 2 (tandem auto) 1 (4) 21 (84) 3 (12) 0 (0) 35 (96) 2 (4) Disease status at allo-HCT, n (%) Complete remission Partial remission Progressive disease 9 (36) 13 (52) 3 (12) 7 (19)20 (54)10 (27) Median interval from diagnosis to allo-HCT, months (range) 33 (10.7-222) 30.7 (5-292) Graft type, n (%) Bone Marrow Peripheral blood stem cells 9 (36) 16 (64) 15 (41) 22 (59) Donor type, n (%) Haploidentical Matched related Matched unrelated Mismatch unrelated 16 (64) 5 (20) 4 (16) 0 (0) 17 (46) 14 (38) 5 (14) 1 (2) Conditioning for allo-HCT, n (%) FLU/CY/TBI (2 Gy) FLU/TBI (2 Gy) FLU/TBI (3 Gy) TBI (2 Gy) 16 (64) 6 (24) 1 (4) 2 (8) 17 (46) 15 (40) 0 (0) 5 (14) GVHD prophylaxis, n (%) CNI/MMF/post transplant CY CNI+MMF+/- other 16 (64) 9 (36) 17 (46)20 (54) Median follow-up, months (range) 34 (4 - 99) 84 (34 - 121) Abbrev: FLU fludarabine, CY cyclophosphamide, TBI total body irradiation,CNI calcineurin inhibitor, MMF mycophenolate mofetil Disclosures Maloney: Seattle Genetics: Honoraria; Roche/Genentech: Honoraria; Janssen Scientific Affairs: Honoraria; Juno Therapeutics: Research Funding. Gopal:Gilead, Spectrum, Pfizer, Janssen, Seattle Genetics: Consultancy; Spectrum, Pfizer, BioMarin, Cephalon/Teva, Emergent/Abbott. Gilead, Janssen., Merck, Milennium, Piramal, Seattle Genetics, Giogen Idec, BMS: Research Funding; Millennium, Seattle Genetics, Sanofi-Aventis: Honoraria. Cassaday:Seattle Genetics: Research Funding; Pfizer: Research Funding. Sandmaier:Gilliad: Honoraria; ArevaMed: Honoraria; Jazz Pharmaceutical: Honoraria; Seattle Genetics: Honoraria; Abmit: Research Funding; Bellicum: Research Funding.

Description: Abstract 3082 Background: High-dose therapy (HDT) and autologous hematopoietic cell transplantation (auto HCT) has been shown to improve outcomes in mantle cell lymphoma (MCL) when used in first remission. In contrast, most series evaluating HDT and auto HCT when used for relapsed/refractory (rel/ref) disease suggest that the outcomes are typically poor. Such data have broadly limited the use of HDT and auto HCT in this setting, though the question of a potential benefit of this approach in a subset of these patients has never been addressed. We, thus, hypothesized that certain factors could be identified to predict which patents with rel/ref MCL would experience a favorable outcome after auto HCT. Methods: Records from consecutive pts older than 18 years with a confirmed diagnosis (dx) of MCL receiving HDT and auto HCT between April 1996 and February 2011 at our center were reviewed. Pts who received auto HCT for either second or later remission or for primary refractory disease were identified while excluding those who received a planned tandem auto-allogeneic HCT. Characteristics both at dx and at the time of pre-HCT work-up were recorded. The statistical significance of differences in event rates was evaluated with the proportional hazards regression model. Reported p-values are based on the Wald statistic, and two-sided p-values less than 0.05 were considered statistically significant. Kaplan-Meier (K-M) curves were used to estimate the probabilities of overall and progression-free survival (OS and PFS, respectively). Results: From a cohort of 165 pts, 68 (41%) met the prespecified definition of rel/ref MCL. In this subgroup, the median PFS was 14 months and the median OS was 36 months. The median age at the time of auto HCT was 58 years (range 41–70), and the median number of treatments pre-HDT was 2 (range 1–6). There were 9 pts (13%) with blastoid histology, and 18 patients (26%) had B symptoms (sx) at the time of dx. The median time from dx to auto HCT was 25 months (range 4–183). Pretransplant disease status included CR = 15 (22%), PR = 42 (62%), and chemorefractory or untested relapse = 11 (16%). Pretransplant simplified MIPI scores based on data obtained prior to HDT (sMIPI-Auto) were as follows: ≤ 2 in 26 pts (38%), 3 in 28 pts (41%), and ≥ 4 in 14 pts (21%). Three factors were identified as independent predictors of worse OS and PFS in multivariable models: 1. higher sMIPI-Auto (HR 2.0 for OS, p = 0.001; HR 3.1 for PFS, p 〈 0.001), 2. presence of B sx (HR 2.5 for OS, p = 0.009; HR 2.6 for PFS, p = 0.005), and 3. lower remission quotient (RQ), calculated by dividing the time in months from diagnosis to auto HCT by the number of prior treatments (HR 1.8 for OS, p = 0.002; HR 1.4 for PFS, p = 0.01). The estimated linear predictors from this multivariable model allowed formulation of a predictive score for OS and PFS, which defined a subset of 23 pts (34%) with relatively low risk of death and/or progression having at least 2 favorable features from the above analysis (see Figure, Score 1). Favorable groups specifically included: 1) sMIPI-Auto of ≤ 2 and no B sx, with a RQ ≥ 5, 2) sMIPI-Auto of ≤ 2, presence of B sx, and a RQ of ≥ 14, and 3) sMIPI-Auto of 3, no B sx, and a RQ of ≥ 14. Pts not meeting one of these sets of criteria, particularly those with either a sMIPI-Auto of ≥ 4 or a RQ of 〈 5 (independent of the other factors), were predicted to do poorly (see Figure, Scores 2 and 3). The K-M 3-yr estimates for PFS were 66% (95% CI 41 – 82%) for Score 1, 23% (95% CI 9 – 40%) for Score 2, and 24% (95% CI 8 – 45%) for Score 3; the K-M 3-yr estimates for OS were 80% (95% CI 54 – 92%) for Score 1, 43% (95% CI 22 – 62%) for Score 2, and 29% (95% CI 11 – 49%) for Score 3. Conclusions: These data identify 3 simple factors (sMIPI-Auto, B symptoms, and high RQ) that can be used to distinguish MCL patients who may experience prolonged OS and PFS after auto HCT used for the treatment of rel/ref disease. In contrast to studies to date, our detailed analysis of this specific population could be used to provide another effective therapeutic option for up to one third of patients with rel/ref MCL, though independent validation of these results is required. Disclosures: Holmberg: Sanofi: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Otsuka: Research Funding; Millenium: Research Funding.

Description: Background : Increasing data from single-arm studies suggest da-EPOCH-R may be optimal therapy for subsets of aggressive B-NHL, including primary mediastinal B-cell lymphoma, germinal-center DLBCL, and forms with MYC dysregulation. However, da-EPOCH-R administration is considerably more complex than R-CHOP, requiring twice-weekly laboratory monitoring and critical dose adjustments. Major studies in DLBCL (Wilson Blood 2002, Wilson JCO 2008) employ daily GCSF in particular. When daily GCSF is used, a mean overall dose intensity equivalent to dose level 2 is achieved. In younger patients with mediastinal B-cell lymphoma, more than half of patients attained dose level 4. We hypothesized that the use of da-EPOCH in general would have increased over the last decade. In a key subset of patients receiving first-line da-EPOCH-R for aggressive B-NHL, we sought to identify frequency of peg-filgrastim use, as a fundamental deviation from protocol-specified therapy, and identify maximum dose level achieved with peg-GCSF vs. daily GCSF. Given their similarity, we did not anticipate that choice of growth factor would predict likelihood of reaching dose level 4. Methods: We identified all patients receiving da-EPOCH from 2005 to 2015 at the University of Washington and Seattle Cancer Care Alliance and analyzed cases for baseline features, growth factor employed, and maximum dose level attained. Patients with DLBCL and variants (PMBCL, transformed lymphoma, DLBCL-PTLD) and BCL-unclassifiable (BCLU), who received at least 4 cycles of da-EPOCH with rituximab as first-line standard of care therapy (not in context of a clinical trial) were subject to detailed analysis regarding growth factor and dose level achieved. IRB approval was obtained. Results: 165 patients receiving da-EPOCH were initially identified, demonstrating an over 5-fold increase in use of this regimen over the 10-year period (Figure 1). Of these, 73 patients with DLBCL and BCLU met the above criteria, receiving da-EPOCH-R as first-line therapy. Median age was 60 (range 24-78) and patients received a median of 6 cycles (range 4-8; 75% of pts received 6 cycles) of da-EPOCH-R. Most patients (44/73, or 60%) received peg-GCSF rather than daily GCSF with da-EPOCH-R. Overall, the median, highest dose level during first-line therapy was 2 without a difference in groups receiving peg-GCSF or daily GCSF. 61% of patients attained dose level of 2, 41% achieved level 3, and 15% achieved level 4. The proportion of patients who achieved dose level 4 was comparable in the peg-GCSF group (11%) and daily GCSF (21%, p=.24, chi-2). Conclusions: Infusional da-EPOCH is being increasingly used, despite limited single arm data supporting its benefit. For first-line therapy of aggressive B-NHL, da-EPOCH-R is being broadly applied to older subgroups of patients. In that subgroup, peg-GCSF is used more than half of the time. In our population, only 15% achieved a dose level of 4 or higher, compared to over half of patients with PMBCL and a median age of 30 (Dunleavy NEJM 2013). Age is well known as a predictor of da-EPOCH dose intensity (Wilson 2002). Variations from the published protocol due to clinical judgment, as well as patient factors, are also possible factors influencing our dosing findings. Peg-GCSF vs. GCSF did not appear to impact the ability to attain dose level 4, although our study design cannot answer this definitely. Since peg-GCSF is cost effective compared to daily GCSF in lymphoma treated with CHOP (Lyman Curr Med Res Opin 2009) and more convenient, our data suggests that peg-GCSF may be a reasonable strategy to support the da-EPOCH-R regimen. Disclosures Gopal: Seattle Genetics: Research Funding. Shadman:Gilead: Honoraria, Research Funding; Acerta: Research Funding; Pharmacyclics: Honoraria, Research Funding; Emergent: Research Funding.

Description: Introduction: CD19-specific chimeric antigen receptor (CAR) T-cell therapy is FDA approved in patients with relapsed or refractory large B-cell lymphomas. While 35-40% of patients may achieve a durable complete response (CR), the toxicity incurred with CAR-T therapy could impact the ability to receive subsequent treatment in those who progress after CAR-T infusion. Our prior data suggested that patients who experienced early progression had inferior overall survival. We now update our results and evaluate the impact of laboratory abnormalities and comorbidities at the time of progression on overall survival. Methods: Adults with large B-cell lymphomas who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance were included. Patients who received CAR T-cell therapy with additional concurrent protocol-specified therapy were excluded. Those who exhibited progressive disease (PD) or persistent lymphoma after CAR T-cell therapy were the focus of this study. We defined patients who progressed or received additional lymphoma directed therapy after last CAR-T cell infusion as early PD, with all other patients defined as late PD. We collected laboratory data closest to the date of progression. We defined an absolute neutrophil count 〈 1000, platelet count 〈 75K, Creatinine 〉 upper limit of normal (ULN), INR 〉 ULN, AST/ALT 〉 2.5x ULN, total bilirubin 〉 ULN, and LDH 〉 ULN as abnormal. Primary endpoint of this analysis was overall survival (OS) landmarked to date of progression. Secondary endpoints include sub-group analyses based on early PD as well as lab abnormalities at the time of progression. A multi-variate analysis with select baseline and progression variables was also performed. Results: We identified 66 patients who met the above criteria. Median follow up for the entire cohort is 30.4 months (range 0.1-64 months) by reverse KM method. Median time from last planned CAR infusion to progression was 43.5 days (range 11-658). Median OS of the entire cohort was 5.43 months (95% CI 3.75-12.2). 25 (38%) patients experienced early PD, which was associated with inferior OS (median 3.75 vs. 10.4 months, P=0.02). LDH 〉 ULN at the time of progression defined a group with inferior outcomes (median OS 3.16 vs. 17.5 months, P ULN at progression (7.01, 95% CI 2.89-17.013), and abnormal creatinine at progression (5.32, 95% CI 1.71-16.53), as factors associated with increased risk of death. Conclusions: Patients with PD post CD19-specific CAR T-cell therapy, particularly those with early PD, elevated LDH, or renal failure experience extremely poor outcomes. These data can inform discussion of prognosis for patients who progress after CAR T-cell therapy and may predict which patients may benefit from additional anti-lymphoma therapy. Figure Disclosures Lynch: Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Juno Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Incyte Corporation: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding. Maloney:A2 Biotherapeutics: Honoraria, Other: Stock options ; Celgene,Kite Pharma: Honoraria, Research Funding; Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria. Turtle:Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Ad hoc advisory board member; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Kite/Gilead: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member. Smith:Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Ignyta (spouse): Research Funding; Genentech: Research Funding; Denovo Biopharma: Research Funding; Ayala (spouse): Research Funding; Bristol-Myers Squibb (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding. Shadman:TG Therapeutic: Research Funding; Mustang Bio: Research Funding; Atara Biotherapeutics: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Research Funding; Verastem: Consultancy; Astra Zeneca: Consultancy; ADC Therapeutics: Consultancy; Sound Biologics: Consultancy; Celgene: Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Research Funding; Acerta Pharma: Research Funding. Ujjani:Pharmacyclics: Honoraria; Atara: Consultancy; Gilead: Consultancy; Genentech: Honoraria; Astrazeneca: Consultancy; AbbVie: Honoraria, Research Funding; PCYC: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding.