ALBERT

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 Multiple myeloma (MM) is considered incurable but patients achieving minimal-residual disease (MRD) negative status following treatment have significantly better overall and progression-free survival. MM is highly heterogeneous both between and within patients, limiting the curative potential of novel agents targeting specific pathways. However all MM is highly sensitive to radiation. The α-emitter astatine-211 (211At) deposits a very large amount of energy (~100 keV/μm) within a few cell diameters (50-90 μm) resulting in irreparable double strand DNA breaks, making 211At, targeted to MM cells, particularly suited to eliminating MRD. CD38 is expressed on malignant plasma cells regardless of mutational status, and CD38 monoclonal antibodies (mAbs) constitute a proven targeted therapy for MM but do not alone eradicate disease. We proposed that 211At conjugated to an anti-CD38 mAb could effectively eliminate MM MRD, and tested this hypothesis in cellular and murine models. Methods We conjugated the anti-CD38 mAb OKT10 and an isotype matched control mAb, BHV1, to the amine-reactive labeling agent B10-NCS and labeled the final constructs with 211At. To assess in vitro cell binding we incubated each labeled construct with CD38+ cell lines, washed, and then measured cell pellet radioactivity in a gamma counter. To assess cytotoxicity we incubated CD38+ and CD38- cell lines with unlabeled or 211At-labeled OKT10-B10 for 60 hrs, then assayed viability. NOD.Cg-Rag1tm1MomIl2rgtm1Wjl/SzJ (NRG) mice bearing H929luc or OPM-2luc MM xenografts were generated by subcutaneous (SQ) flank injection of 107 cells 7 days prior to treatment. MRD was modeled by intravenous (IV) injection of 2.5 - 5 x 105 cells 5 days prior to treatment. Radioimmunotherapy (RIT) was administered by IV injection of 7.5 - 45 µCi of 211At-OKT10-B10 or 211At-BHV1-B10. For biodistribution studies (n = 5/group) mouse tissues were harvested 24 hrs post RIT and measured in a gamma counter. For therapy studies (n = 8-10/group), all mice received syngeneic bone marrow transplant 3 days post RIT. Disease progression was assessed by tumor dimensions, luminescence imaging and survival. Results 211At-CD38 mAb selectively bound and killed CD38+ but not CD38- MM cells in vitro. In vivo, biodistribution experiments demonstrated that 211At-CD38 RIT delivered 2.4 times more radiation to MM xenografts than did control 211At-BHV1 RIT (p = 0.007), and delivered significantly higher dose to tumor than to healthy tissues including lung (p = 0.04) and kidney (p = 0.015). In murine therapy studies, 211At-CD38 RIT at 15 - 45 µCi at least doubled median survival relative to untreated controls in each of two MM SQ xenograft models (p 〈 0.003). However, no mice in these models achieved complete remission and all eventually died of disease. In contrast, therapy studies using MRD models showed that 30 µCi 211At-CD38 RIT eliminated detectable disease in 80% of mice at day 21, compared to 20% of mice receiving nontargeted 211At RIT and 0% of untreated mice. At day 130, 50% of the 30 µCi 211At-CD38-RIT mice remained alive and disease-free, while all nontargeted and untreated mice died before day 85 (Fig. 1, survival of 30 µCi 〉 15 µCi 211At-CD38-RIT [p = 0.016] and all other groups [p 〈 0.0007]). The impact of therapy on body weight as well as hematopoietic, liver and kidney function was mild and returned to normal within 32 days of treatment. Conclusions The efficacy of CD38 targeted 211At appears to be a function of disease distribution and malignant plasma cell access, as compellingly demonstrated by our models. Bulky tumor geometry reduces mAb penetration. In contrast, the isolated cells and small tumor clusters that define MRD are readily accessible to mAbs, creating optimal conditions for α-emitter cell kill. In an era of highly potent MM therapy, preventing relapse remains frustratingly rare. Our approach is both agnostic to high-risk cytogenetic features and offers the potential to eliminate all residual MM cell clones. These encouraging findings will be explored in a clinical trial of 211At-CD38 RIT. Disclosures Orozco: Actinium Pharmaceuticals: Research Funding. Jones:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Till:Mustang Bio: Patents & Royalties, Research Funding. Gopal:Teva: Research Funding; Spectrum: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; Incyte: Consultancy; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Pfizer: Research Funding; Aptevo: Consultancy; Takeda: Research Funding; Merck: Research Funding; Asana: Consultancy. Green:Juno Therapeutics: Patents & Royalties, Research Funding.

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: Mantle Cell Lymphoma (MCL) exhibits short remission durations and a poor prognosis. To improve on these outcomes, many have advocated the use of high-dose therapy (HDT) and ASCT. The MIPI predicts overall survival (OS) from diagnosis, yet it remains unknown if the MIPI assessed at diagnosis (MIPI-Dx) or prior to transplant (MIPI-Tx) can be used to predict OS from ASCT. To address this question we retrospectively evaluated the association of the MIPI-Dx and MIPI-Tx, and other characteristics with OS following HDT and ASCT in 87 consecutive MCL patients transplanted at our center. Baseline characteristics included: median age at diagnosis=56 years (range, 35–70), median age at transplant=57 years (range, 35 – 70), stage III-IV=97%, median LDH/upper limit of normal (ULN) at diagnosis=0.91 (range, 0.46–5.65), median LDH/ULN at transplant= 0.88 (range, 0.39–3.00), median white blood cell (WBC) count at diagnosis=7.50 x 109 / liter (range, 1.40 – 54.70), mean WBC count at transplant=4.66 x 109 /liter (range, 0.07 – 17.60), median number of prior chemotherapy regimens=2 (range, 1–5). The estimated 5-year OS and PFS for the entire cohort were 56% (95% CI, 39–73%) and 45% (95% CI, 30 – 60%), respectively with a median follow up among surviving patients of 2.0 years (range 0.1 – 10.1 years). The MIPI-Dx was a better predictor of OS (p0 (hazard ratio (HR) of 3.0, p=0.03), number of prior regimens 〉2 (HR 5.2, p=0.01), lack of complete remission (CR) (HR 3.4, p=0.04), and elevated LDH (HR 4.4, p=0.01) as associated with higher risk of death after transplant. These results indicate that the MIPI-Dx is a robust prognostic tool that can even be used to predict outcomes after a later transplant, suggesting that it may continue to reflect the biology of an individual patient’s disease over time. Further assessment of survival predictions after ASCT can be made independently by examining pre-transplant factors including performance status, number of prior regimens, attainment of CR, and LDH. Though these data require prospective validation, our results can be used to counsel patients about outcomes and account for potential differences in results from clinical trials of HDT and ASCT for MCL. Figure Figure

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: Mantle cell lymphoma (MCL) has one of the worst prognoses of any subtype of non-Hodgkin’s lymphoma (NHL), with a median survival of 3–4 years in most series. High-dose therapy followed by autologous stem cell transplantation (ASCT) is an increasingly common treatment approach for MCL, and some ASCT studies suggest that less heavily pre-treated patients have a longer duration of progression-free survival (PFS), suggesting that ASCT may lead to more favorable outcomes if used earlier in the course of therapy. We analyzed the outcomes of ASCT with respect to remission status at the time of transplantation and induction regimen used in 56 consecutive transplanted patients with MCL. Twenty-one patients received induction chemotherapy with HyperCVAD with or without rituximab (±R) followed by ASCT in first complete or partial remission (CR1/PR1), 15 received CHOP (±R) followed by ASCT in CR1/PR1, and 20 received ASCT following disease progression. A variety of conditioning regimens were used for ASCT in all 3 groups. Estimates of overall (OS) and progression-free survival (PFS) at 3 years among patients transplanted in CR1/PR1 were 93% and 63%, compared with 46% and 36% for patients transplanted with relapsed or refractory disease, respectively (Figure 1). The hazard of mortality among patients transplanted with relapsed or refractory disease was 6.09 times that of patients transplanted in CR1/PR1 (P=.006). Patients in the CHOP (±R) group appeared to have a higher risk of failure for PFS compared to patients in the HyperCVAD (±R) group, though the difference did not reach statistical significance (hazard ratio [HR] 3.67, P=.11) with the small sample size available. The estimated 3-year PFS was 81% for patients in the HyperCVAD group and 44% for patients in the CHOP group. Patients who received R with induction therapy had a reduced risk of mortality (HR 0.33, P=.05) and failure for PFS (HR 0.28, P=.005) compared to those who did not. In summary, these results suggest that ASCT in first remission leads to improved survival outcomes for patients with MCL compared to ASCT with relapsed or refractory disease, and a HyperCVAD (±R) induction regimen may be associated with an improved PFS among patients transplanted in CR1/PR1. Figure 1. Kaplan-Meier estimates of overall survival from the time of ASCT, with respect to remission status at ASCT. Figure 1. Kaplan-Meier estimates of overall survival from the time of ASCT, with respect to remission status at ASCT.

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: Introduction: An estimated 19,970 Americans died of non-Hodgkin lymphoma (NHL) in 2015, with diffuse large B-cell lymphoma (DLBCL) accounting for roughly 30% of newly diagnosed NHL. Our study focuses on three NHL subtypes: germinal center (GCB)-DLBCL, the most common DLBCL subtype; activated (ABC)-DLBCL, a particularly aggressive and high-risk subtype; and mantle cell lymphoma (MCL), considered incurable. Constitutive B-cell receptor signaling is implicated in the pathogenesis of ABC-DLBCL and MCL and may couple with aberrant apoptotic BCL-2 pathway proteins. The BCL-2 inhibitor venetoclax is a promising targeted agent that promotes apoptosis in a variety of NHL subtypes, but is almost never curative as a single agent. Radiotherapy promotes apoptosis by creating DNA strand breaks, and we hypothesized that the combination of radiotherapy and venetoclax would act synergistically in NHL to increase the probability of cures. Methods: We tested in vitro killing efficacy of sublethal 137Cesium irradiation combined with venetoclax in 15 cell lines, representing a diversity of NHL subtypes. Cells were treated with 137Cesium and venetoclax in 8 x 8 dose combination matrices, incubated 72-120 hrs, then assayed for viability with Celltiter-Glo (Promega). The degree of treatment antagonism, additivity, or synergism was determined using isobolographic analyses. For in vivo studies, we tested combinations of venetoclax with either 137Cesium total body irradiation (TBI), or CD20 pre-targeted radioimmunotherapy (PRIT), in threetumor models chosen for divergent single agent sensitivities. Tumor xenografts of Rec-1 (MCL), U2932 (ABC-DLBCL), and SU-DHL-6 (GCB-DLBCL) were produced by subcutaneous flank injection of 10 x 106 cells in male and female NOD.Cg-Rag1tm1Mom Il2rgtm1Wjl/SzJ (NRG) mice. When tumor volumes were 50 mm3, mice (n = 8-12/group) were treated with either venetoclax (100-200mg/kg daily for 10-30 days), diluent control, TBI (single dose, 6-10 Gy 137Cesium), or a combination of venetoclax and TBI. In PRIT studies, mice were coinjected with 300µg unlabeled streptavidin-conjugated anti-CD20 antibody (murine IgG2a) and 400µg HB8181 (IgG2a isotype control to block non-specific binding) in place of TBI. Twenty-one hours later, 5.8 nmol biotin-galactose "clearing agent" was administered, followed in 3 hours by 1.2 nmol DOTA-biotin labeled with 400, 800, or 1200 µCi of 90Y (14.8, 29.6, or 44.4 MBq, respectively). Results: In vitro, 10 of 15 lymphoma cell lines responded synergistically to combined radiotherapy and venetoclax, including GCB-DLBCL, ABC-DLBCL and MCL lines (p 〈 .04 in 10 cell lines). In vivo, each of 3 lymphoma models responded synergistically to combination therapy. In mice bearing Rec-1 xenografts, venetoclax alone did not affect mean survival time (p = .32), 8 Gy TBI lengthened survival by 44% compared to controls (p 〈 .0001), but TBI combined with venetoclax tripled survival time compared to controls (p 〈 .0001, combination group 〉 TBI alone). The SU-DHL-6 model produced similar results. In the U2932 model, tumors disappeared during venetoclax monotherapy, but recurred in all mice, such that mean survival time doubled compared to controls (p = .0001). Six Gy TBI had no effect (p = .73), but combining TBI with venetoclax tripled survival time compared to controls (p = .0003, combination group 〉 venetoclax alone). Using PRIT in place of TBI produced yet greater efficacy. In Rec-1 bearing mice, venetoclax had no effect alone (p = .12), 800µCi PRIT lengthened survival time 111% beyond controls (p = .0001), while the combination extended survival 483% beyond controls and cured 40% (p = .001, combination group 〉 PRIT alone). In the U2932 xenograft model, venetoclax alone doubled survival time compared to controls (p 〈 .0001) and 800µCi PRIT alone doubled survival and cured 30% (Fig. 1, p 〈 .0001). Combination treatments cured 100% (Fig. 1). Conclusion: In vitro and in vivo results support our hypothesis that radiotherapy combines effectively with venetoclax to treat NHL. Despite differences in single agent sensitivity, xenograft models of GCB-DLBCL, ABC-DLBCL and MCL all responded synergistically to combinations of either TBI or PRIT with venetoclax. PRIT combinations with venetoclax produced cures (Fig. 1) without detectable toxicity, and merit clinical preference. Ongoing studies examine predictive biomarkers and optimal treatment protocols for therapeutic efficacy. Disclosures Gopal: Paid Consultancy- Gilead, Janssen, Seattle Genetics, Spectrum, Research funding- Gilead, Janssen, Pfizer, BMS, Merck, Teva, Takeda, Spectrum, Seattle Genetics: Consultancy, Honoraria, Research Funding.

Description: BACKGROUND: Peripheral T-cell lymphomas (PTCL) encompass a heterogeneous group of neoplasms accounting for 10 to 15% of non-Hodgkin lymphomas worldwide. Prognosis for PTCL patients is poor and consolidation in first remission with autologous stem cell transplantation (ASCT) is widely used. Most patients though still relapse after transplant. We hypothesized that pre-ASCT bone marrow (BM) involvement detected by multi-parameter flow cytometry (FC) would identify patients with inferior outcome after ASCT. METHODS: We retrospectively analyzed the outcome of 29 consecutive PTCL patients who underwent ASCT at the Fred Hutchinson Cancer Research Center from April 2004 through July 2014. Pre-ASCT BM involvement by flow cytometry (FC) was defined as the presence of an abnormal T-cell population detected by multi-parameter FC analysis in a BM aspirate obtained within 30 days prior to ASCT. An abnormal T-cell population accounting for a percentage equal or greater than 0.01% of total leukocytes after red blood cell lysis was considered significant. RESULTS: Ten patients (34%) with angioimmunoblastic T cell lymphoma (AITCL), 8 (27%) with ALK-negative anaplastic large cell lymphoma (ALCL), 8 (27%) with peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) and 3 (12%) with other PTCL sub-types were included. Median age at transplant was 54 (range: 29-71). Twenty patients (76%) presented at ASCT in complete remission (CR) per 1999 Cheson criteria and 9 (31%) were in first CR (CR1). Fifteen patients (50%) underwent ASCT upfront. Pre-ASCT BM involvement was detected by FC analysis in 7 patients (24%, 3 patients with AITCL, 1 patient with ALCL and 3 patients with PTCL-NOS) and by morphology in 2 patients (7%, 2 patients with AITCL). The 7 patients with pre-ASCT BM involvement detected by FC experienced a significantly higher 4-year cumulative incidence of relapse (CIR) (85% versus 36%, p 〈 0.001) and lower overall survival (OS) (19% versus 89%, p 〈 0.001) with a median follow-up of 51 months. These findings were confirmed in multivariable analysis for CIR (HR = 7.37, CI = 1.14 - 47.61, p = 0.03) and OS (HR = 7.04, CI = 1.29 - 38, p = 0.024). The IPI score, absence or presence of CR1 and the number of prior therapies were included in a multivariable model for CIR, while age and the IPI score at diagnosis were taken into account for OS. ASCT performed in CR1 was associated with lower CIR (HR = 0.11, CI = 0.03-0.041, p 〈 0.001). Histologic subtypes did not impact CIR (p = 0.97) nor OS (p = 0.91) and they did not significantly differ between the groups with and without pre-ASCT BM involvement detected by FC (p = 0.60) after applying Fisher's exact test. Further analysis of the 22 patients presenting in CR at ASCT revealed that in this subgroup, pre-ASCT BM involvement by FC (n = 4) was also associated with higher CIR (75% versus 32%, p = 0.002) and lower OS (25 versus 94%, p