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PURPOSE To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). METHODS Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 107) or high (5 × 108) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months). RESULTS At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups ( P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not ( P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR ( P < .0001). Toxicity was comparable in both dose groups. CONCLUSION In patients with advanced CLL, a 5 × 108 dose of CART-19 may be more effective than 5 × 107 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.

PURPOSE The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy. METHODS Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity. RESULTS Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%). CONCLUSION Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.

Purpose To characterize the impact of graft T-cell composition on outcomes of reduced-intensity conditioned (RIC) allogeneic hematopoietic stem-cell transplantation (alloHSCT) in adults with hematologic malignancies. Patients and Methods We evaluated associations between graft T-cell doses and outcomes in 200 patients who underwent RIC alloHSCT with a peripheral blood stem-cell graft. We then studied 21 alloHSCT donors to identify predictors of optimal graft T-cell content. Results Higher CD8 cell doses were associated with a lower risk for relapse (adjusted hazard ratio [aHR], 0.43; P = .009) and improved relapse-free survival (aHR, 0.50; P = .006) and overall survival (aHR, 0.57; P = .04) without a significant increase in graft-versus-host disease or nonrelapse mortality. A cutoff level of 0.72 × 108 CD8 cells per kilogram optimally segregated patients receiving CD8hi and CD8lo grafts with differing overall survival (P = .007). Donor age inversely correlated with graft CD8 dose. Consequently, older donors were unlikely to provide a CD8hi graft, whereas approximately half of younger donors provided CD8hi grafts. Compared with recipients of older sibling donor grafts (consistently containing CD8lo doses), survival was significantly better for recipients of younger unrelated donor grafts with CD8hi doses (P = .03), but not for recipients of younger unrelated donor CD8lo grafts (P = .28). In addition, graft CD8 content could be predicted by measuring the proportion of CD8 cells in a screening blood sample from stem-cell donors. Conclusion Higher graft CD8 dose, which was restricted to young donors, predicted better survival in patients undergoing RIC alloHSCT.

7509 Background: Immunotherapy with anti-CD19 CART cells induces complete remission (CR) in the minority of patients with CLL, but where CRs occur they tend to be durable. Based on preclinical evidence of synergy, we combined anti-CD19 CAR T cells with ibrutinib to test the hypothesis that pre- and concurrent treatment would enhance the CR rate. Methods: This is a pilot trial of anti-CD19 CAR T cells in adults with CLL/SLL who were not in CR despite at least 6 months of ibrutinib. Pts must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation. T cells were lentivirally transduced to express a CAR comprising CD3z, 4-1BB, and humanized anti-CD19 scFv (CTL119). Pts were lymphodepleted 1 week before infusion. Ibrutinib was continued throughout the trial. Results: Manufacturing was successful in all pts. Ten pts (9M, 1F; ages 47-77; 0-12 regimens prior to ibrutinib) have been infused. All had abnormalities of TP53 or ATM and two pts had increasing BTK C481S clones. Median marrow CLL burden was 10% (range 10-50%). The median follow-up is 6 months (range 0.5-9). Cytokine release syndrome (CRS) developed in 9 pts; gr1 in 2, gr2 in 6 and gr3 in 1 pt. One pt developed gr4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required. At 3 months, 8 evaluable pts had achieved an MRD-ve marrow CR (89%) by 9-color flow, and all remain in marrow CR at last F/U. There was modest residual splenomegaly in 3/5 patients, and adenopathy resolved in 4/6 subjects with progression in 1/6. MRD assessment by deep sequencing will be presented. Conclusions: We observed 89% MRD-ve marrow CR in pts with high-risk CLL using a well-tolerated combination of CART cells and ibrutinib. Longer follow-up will reveal the durability of these results and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy. Clinical trial information: NCT02640209.

103 Background: CD19-targeted CAR T cells show CR rates of 70-95% in B-ALL. Yet a subset of patients do not respond or relapse due to poor CAR T cell expansion and persistence. We hypothesized that PD-1 checkpoint pathway inhibition may improve CAR T cell expansion, function and persistence. Methods: Four children with relapsed B-ALL treated with murine (CTL019) or humanized (CTL119) anti-CD19 CAR T cells received 1-3 doses of the PD-1 inhibitor pembrolizumab (PEM) for partial/no response or prior history of poor CAR T cell persistence starting 14d-2mo post CAR T cell infusion. Results: PEM increased and/or prolonged detection of circulating CAR T cells in all 4 children, with objective responses in 2/4. It was well tolerated, with fever in 2 pts and no autoimmune toxicity. Pts 1-3 received CTL119 for CD19+ relapse after prior murine CD19 CAR T cells. Pt 1 had 1.2% CD19+ residual disease despite expansion with detectable CTL119 by D28 and received PEM at 2mo for progressive disease with decreasing circulating CTL119. CTL119 became detectable at 0.2% of CD3+ cells by flow cytometry, but disease progressed. Pt 2 had no response after initial CTL119 expansion with a rapid disappearance by D28. After CTL119 reinfusion with PEM added 14d later, circulating CAR T cells remained detectable at 4.4% by D28, but disease progressed with decreased CD19 expression. In Pt 3, prior treatment with both CTL019 and CTL119 produced CR with poor CAR T cell persistence followed by CD19+ relapse. CTL119 reinfusion combined with PEM at D14 resulted in CR with prolonged CTL119 persistence (detectable at D50 compared to loss by D36 after 1st CTL119 infusion). Pt 4 received PEM for widespread extramedullary (EM) involvement at D28 post CTL019 infusion despite marrow remission. Initial CTL019 expansion peaked at 63% at D10 and fell to 20% at D28. Resurgence of CTL019 expansion, with a 2nd peak of 70% 11d after PEM, was associated with dramatic reduction in PET-avid disease by 3mo post CTL019. Conclusions: PEM was safely combined with CAR T cells and increased or prolonged CAR T cell detection, with objective responses seen. Immune checkpoint pathways may impact response to CAR T cell treatments and warrant further investigation. Clinical trial information: NCT02374333, NCT02906371.

137 Background: The adoptive transfer of autologous T cells genetically modified to express a CD19-specific, 4-1BB/CD3ζ-signaling CAR (CTL019) has shown remarkable activity and induces long-term remissions in a subset of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). In ALL, CTL019 induces a complete response (CR) in over 90% of patients while in CLL 25% of patients obtain a CR. It is not fully understood why only certain patients respond to therapy. Methods: We employed next generation sequencing of RNA (RNAseq) to identify predictive indicators of response to CTL019. We performed RNAseq on leukapheresis and manufactured product T cells prior to re-infusion from 35 CLL and 7 pediatric ALL patients with heavily pre-treated and high-risk disease. To characterize potency, we performed RNAseq on the infusion product after stimulation with the CAR. Results: We find that durable remission in CLL is associated with gene expression signatures of early memory and T-effector cells, while T cells from non-responding patients are enriched in signatures of T-regulatory cells, terminal differentiation, and exhaustion. In following the results from CLL, we find that pediatric ALL manufactured T cells are significantly enriched for an early memory, naïve T cell state and all achieved a CR. In parallel in vitro experiments, stimulation of the infusion product further demonstrated that CTL019 cells from CRs have an increased capacity for activation upon stimulation. We tested if we could extend these observations to identify a phenotype of T cells that is predictive of response prior to CTL019 manufacturing and find that the signatures predictive of response at the pre-infusion stage are also observed at the earlier leukapheresis time point. Conclusions: These findings suggest that intrinsic T cell fitness dictates response to CAR T cells. These gene expression signatures, along with additional immunological biomarkers, may be used to identify which patients are most likely to respond to adoptive transfer strategies and suggest manufacturing modifications that might potentiate the generation of maximally efficacious infusion products. Clinical trial information: NCT01029366, NCT01747486, NCT01626495.

3009Background: Autologous T cells genetically modified to express a CD19-targeting CAR (CTL019) can mediate potent anti-tumor effects in CLL and other CD19+ malignancies. Since CTL019 are self-rep...

3011Background: Targeted immunotherapy with chimeric antigen receptor (CAR)-modified T cells can produce potent anti-tumor responses. We previously reported complete remissions (CR) and prolonged persistence in children and adults with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL) treated with CD19-specific CART cells (CTL019). We now report on outcomes and longer follow-up of 59 children with r/r ALL. Methods: T cells collected from the patient were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3z, and 4-1BB domains, activated/expanded ex vivo with anti-CD3/CD28 beads, and then infused at a dose of 107 to 108cells/kg with a transduction efficiency of 2.3-45%. 54/59 patients received lymphodepleting chemotherapy the week prior to cell infusion. Results: Of 59 patients aged 20mo-24y with CD19+ ALL, 44 had detectable disease prior to CTL019 cell infusion, while 15 were MRD-. 39 were treated for relapse after prior stem cell transplant (SCT). 15 patients had ...

7002Background: Genetically modified T cells expressing an anti-CD19 CAR result in response rates of 90% in children with r/r CD19+ ALL. Cytokine release syndrome (CRS) is the most significant trea...

3022 Background: Molecular imaging with FDG-PET/CT (PET/CT) is an established modality for response assessment in lymphoma patients (pts) undergoing treatment (Tx). However, pts treated with novel ...

7028 Background: Donor lymphocyte infusion (DLI) after allogeneic stem cell transplant is an established therapy for disease relapse. Long-term survival after DLI remains poor, and identification o...

7043 Background: Relapse is the most common reason for failure of allogeneic stem cell transplant (SCT). Identifying patients at increased relapse risk is crucial for improving outcomes. Prognostic somatic mutations have been identified in AML but their prognostic value after SCT is unknown. We hypothesize that next generation sequencing (NGS) can predict SCT outcome in AML. Methods: We performed NGS for 33 hematologic malignancy associated genes in 62 adult patients treated with SCT for de novo AML (2003-2013). Relapse free survival (RFS) was compared by Cox regression with adjustment for cytogenetic risk, conditioning intensity, donor type and graft source. Results: At least 1 mutation was identified in 56 (90%) patients (median 2, range 0-6) including 35 of 36 (97%) patients with intermediate cytogenetics (median 3, range 0-6). Among patients with intermediate cytogenetics transplanted in CR, poor prognostic mutations were found in 9 of 15 FLT3ITD negative patients (2 DNMT3A; 3 DNMT3A + IDH; 1 DNMT3A +...

TPS7132 Background: The poor prognosis and lack of effective treatment options for patients with r/r CLL highlight the need for novel therapies in this setting. CD19 is a promising anticancer target because it is broadly expressed on normal and malignant B cells through several stages of maturation but absent on pluripotent stem cells. CART-19 (CTL019) therapy involves adoptive transfer of autologous T cells genetically modified via lentiviral transduction to express chimeric antigen receptors (CAR) designed to target CD19+ cells. CART-19 cells express a CD19 antigen recognition domain combined with intracellular signaling domains, CD137 (4-1BB) and CD3-zeta, which mediate cytolytic T-cell activity. In patients with r/r CLL, CART-19 therapy showed potent antileukemic activity with long-term persistence of transduced cells at doses from 1.4 × 107 to 1.1 × 109 CART-19 cells. As of August 2012, 3 of 8 evaluable CLL patients achieved CR (two > 24 months and one > 5 months) and remain in CR with detectable CART-19 cells. Two patients had PR lasting 3 and 5 months, and 3 patients did not respond (Porter et al. NEJM. 2011; Kalos et al. Sci Transl Med. 2011; Porter et al. ASH 2012). Here, we describe a study to determine the optimal dose of CART-19 cells (NCT01747486). Methods: Adults with relapsed or persistent CLL or SLL after ≥ 2 previous therapies will undergo leukapheresis to obtain T cells, which will be stimulated, expanded, and lentivirus transduced ex vivo to express the CD19/4-1BB/CD3-zeta CAR. Patients will undergo lymphodepletion chemotherapy prior to infusion of CART-19 cells. In stage I of the II-stage trial, 30 patients will be randomized 1:1 and receive either 1-5 × 108 or 1-5 × 107 CART-19 T cells. The optimal dose in stage I will be selected based on clinical responses, feasibility, and tolerability. In stage II, 8 additional patients will be enrolled into the selected dose cohort. Study objectives are to determine the efficacy (CR rate within 3 months) and safety (CTCAE v 4.0) of each dose, in vivo CART-19 expansion, and manufacturing feasibility. Three patients have been enrolled as of January 2013. Clinical trial information: NCT01747486.

e18540 Background: Mantle cell lymphoma (MCL) is a small B cell lymphoma, incurable with standard chemo-immunotherapy. There is no standard upfront therapy, although Phase II trials have shown a survival benefit to dose-intensified regimens in selected patients. However, many patients are not candidates for these regimens secondary to age or comorbidites. These patients are often treated with R-CHOP with consideration for consolidation with ASCT. Methods: We conducted a retrospective cohort analysis to describe and compare the survival experiences of MCL patients at the University of Pennsylvania treated in the first-line setting with R-CHOP (N=32) with or without autologous stem cell transplant (ASCT). The primary study endpoint was PFS as assessed by chart review and confirmed by SSDI database. Results: Median follow up for all pts was 2.5 years. The median age was 62.5, and 80% (n=30) were stage IV at diagnosis. 16 patients underwent consolidative ASCT. Comparing patients treated with R-CHOP vs R-CHOP +ASCT, there were no statistical differences in terms of age, ECOG PS, LDH, WBC, beta-2microglobulin, BM or GI involvement, bulky disease or blastoid variant at baseline. The response rate for all patients was 96.9% and 87.5% of patients achieved CR. Median PFS for all patients was 2.8 years: R-CHOP alone 1.9 years vs. R-CHOP+ ASCT 3.9 years (P=0.02, HR 3.44, 95%CI: 1.2-9.5). Conclusions: Outcomes are poor for MCL patients treated with R-CHOP with continuous recurrence despite excellent initial response. Our data suggest an improved PFS in patients with advanced MCL when R-CHOP is consolidated with ASCT in first remission as compared to R-CHOP alone. Prospective RCTs are needed to determine the optimum treatment for patients who are not candidates for dose-intensive therapy.

6579 Background: Increased risks of solid and lymphoid malignancies are described in patients with autoimmune (AI) disease. The association between AI disease, AI treatment (particularly anti-TNF therapy), and AML is less established. Moreover, the pathologic characteristics of AML in this population have not been evaluated. Here we describe our AML experience in patients with prior AI disease. Methods: Patients with AML from 1992 to 2011 were identified from our database, and AI disorder was verified through chart review. Patients were included if they had an AI disorder that required systemic treatment, and diagnosed > 1 year prior to AML. Patients were excluded if details including the year of AI diagnosis or treatment(s) received were not documented. A total of 22 patients were included for analysis. Results: Median age at AML diagnosis was 59 years (range 32 – 78), 4 (18%) were men. 10 (48%) had received an anti-TNF agent, for a median duration of 30 months (range 2 – 120). Median latency from AI diagnosis to AML was 9.4 yrs. All FAB subtypes were represented except M0 and M6, 9 (41%) had M4 or M5 disease. 10/21 patients (45%) had normal cytogenetics, and 5 had favorable cytogenetics (2 with acute promyelocytic leukemia (APML)). Standard induction was given to 19 patients, and APML-directed therapy for those with APML. One patient received an autologous transplant in CR1, and 5 an allogeneic transplant (1 in CR1, 4 in CR2). 9 patients are alive in CR1. 13 relapsed, and 4 (31%) are alive in CR2 or CR3 (3 following allogeneic transplant in later CR). Median OS was 68.1 months. In univariate analysis, factors associated with OS were cytogenetics, FAB subtype, and gender. Anti-TNF therapy may be associated with poorer prognosis; this was not statistically significant. Median OS was 14.1 months for poor, 68.1 months for intermediate, and not reached for favorable risk cytogenetics. Conclusions: Median OS was higher (> 5 years) than expected. Younger age and an increased incidence of favorable risk AML may account for this finding: whether this is a meaningful biologic association or stochastic event can only be verified with larger studies. Our observations do not support a label of “secondary leukemia” or therapy-related neoplasm in this population.