ALBERT

Description: Abstract 4192 Background Most hospitals have clinical guidelines for the off-label use of recombinant activated Factor VII (rFVIIa, Novoseven), primarily as part of a massive transfusion protocol. Over the past years rFVIIa has increasingly been used outside the approved indications in haemophilia with inhibitors and Glanzmann's Thrombasthenia, particularly in trauma, cardiac surgery and other critical bleeding episodes. Use in these areas remains controversial. Methods Monash University established the Haemostasis Registry in 2005 (with an educational grant from NovoNordisk Pharmaceuticals) to monitor the use of rFVIIa throughout Australia and New Zealand. More than 95 hospitals are contributing data to the Registry including all major users of rFVIIa in Australia and New Zealand. As part of the process of joining the Registry project, participating hospitals are asked to supply copies of their protocols for use of rFVIIa. Results Approximately 3000 cases of rFVIIa use have been reported to the Register. Major areas of use are cardiac surgery (∼ 41%), other surgery (∼17%) and trauma (∼15%). The majority(77.3%) of hospitals have documented protocols for rFVIIa use. Many of these are similar and are centred around situations of massive transfusion. However, 64.5% of cases of rFVIIa use submitted to the Haemostasis Registry, from hospitals where protocols exist, do not conform with the numerical components of these protocols. Conclusions This is the largest dataset of rFVIIa cases published to date and can now provide greater insight into the actual rather than theoretical use of rFVIIa in Australia and New Zealand. Lack of compliance with hospital protocols for rFVIIa use indicates either that the protocols do not reflect actual and appropriate use or that clinicians need to be further educated regarding what is currently considered appropriate use. In the absence of sound clinical trial evidence, consensus regarding appropriate use has not been achieved. In these circumstances, data from the Haemostasis Registry continues to be important in elucidating the safety and efficacy of rFVIIa and providing important feedback to doctors and hospitals. The Haemostasis Registry is funded through an unrestricted Educational Grant from NovoNordisk Pharmaceuticals Pty Ltd. None of the authors have a financial interest in the outcomes of the study. Disclosures: Off Label Use: Recombinant activated Factor VII (rFVIIa, Novoseven). FVIIa is a naturally occurring initiator of haemostasis. Its recombinant form, rFVIIa, is approved for the treatment of spontaneous & surgical bleeding in patients with haemophilia A or B and with antibodies to either factor VIII or factor IX. It has been extensively used amongst haemophiliacs and appears to enhance clotting at the site of bleeding without systemic activation of the coagulation cascade At high doses rFVIIa binds to the surface of activated platelets and initiates the coagulation cascade at these sites Recently various case series and case reports have reported the efficacy of rFVIIa in patients with life-threatening bleeding in patients with coagulation disturbances but without coagulation inhibitors.

Description: Introduction: Standard treatment with intensive induction chemotherapy (IC) for pts with AML can induce remission, but responses are often short-lived, and the majority of pts will relapse (Chen Y, et al. Medicine 2016;95:e4182). Although maintenance therapy with injectable AZA has improved disease-free survival in pts with AML in complete remission (CR) or CR with incomplete hematologic recovery (CRi) after intensive chemotherapy (Huls G, et al. Blood 2019;133:1457; Oliva EN, et al. Blood 2019;134(Supp 1):117), overall survival (OS) benefits have been more difficult to achieve. In the randomized, phase 3 QUAZAR AML-001 study (NCT01757535), maintenance therapy with CC-486, a novel oral formulation of AZA, demonstrated a significant 9.9-month improvement in OS and a 31% reduction in mortality versus placebo (PBO) for pts with AML in first CR/CRi following intensive chemotherapy (Wei AH, et al. Blood 2019;134:LBA-3). In the absence of direct head-to-head clinical studies to guide treatment selection, we used an ITC to evaluate the comparative efficacy of CC-486 versus injectable AZA as maintenance therapy in pts with AML in first remission after intensive chemotherapy. Methods: Relative OS was calculated by using individual patient data (IPD) derived from published Kaplan-Meier (KM) OS curves from the QUAZAR AML-001 (NCT01757535) study of CC-486 versus PBO, and 2 studies of injectable AZA versus control (HOVON 97 [EudraCT 2008-001290-15] and QoLESS [EudraCT 2010-019710-24]) using Engauge digitization software (Guyot P, et al. BMC Med Res Methodol 2012;12:9). Unlike pts from the intervention arm (CC-486, AZA), pts in the PBO/control arm did not receive cancer therapy post-IC. For each study, time-specific relative OS benefit was calculated by dividing the difference in the KM OS estimate between each intervention arm and the respective PBO/control arm by the KM OS estimate for the PBO/control arm (Betts KA, et al. poster presented at EHA 2017:E1300). Treatment effect was measured by fitting parametric survival curves to the IPD from the intervention arm and PBO/control arms, respectively. The restricted mean survival time (RMST) was estimated as the area under the OS curve (AUC) at 1, 2, 3, 4, and 5 years. The incremental AUC (ΔAUC) was determined at selected timepoints by subtracting the RMST of the PBO/control arm from the RMST of the intervention arm for each study. A 95% confidence interval for the incremental mean survival time was estimated via simulation from the variance-covariance matrix of the fitted parametric model using ≥ 10,000 iterations. Results: Follow-up was longest for QUAZAR AML-001 (5 years) with both HOVON 97 and QoLESS limited to 30 months at time of analysis. Overall, CC-486 showed a sustained and numerically higher relative OS benefit through 60 months compared with AZA in HOVON 97 and QoLESS (Figure). The relative benefit of AZA versus control in the initial 18 months appeared to fade, reaching close to or below zero around month 21. Indeed, the relative OS benefit with CC-486 and AZA (HOVON 97, QoLESS) was 30.4%, 20.3%, and 15.5% at 12 months; 35.5%, 17.0%, and 21.8% at 18 months; and 36.4%, −7.7%, and 2.2% at 24 months, respectively. Log-normal survival curves were fitted to IPD from each intervention arm and the respective PBO/control arm. Comparing the RMST, CC-486 showed a statistically meaningful improvement in mean survival time at 1, 2, 3, 4, and 5 years and for the entire extrapolation period, while AZA was not associated with significant OS benefits at any time point in HOVON 97 or QoLESS (Table). The mean incremental survival benefit with CC-486 versus PBO and AZA (HOVON 97 and QoLESS) versus control at 3 years was 4.18 versus 1.18 and 2.35 months, respectively; at 5 years was 6.14 versus 1.11 and 0.99 months, respectively; and for the entire extrapolation period was 10.12 versus −6.58 and −18.32 months, respectively. The improvement in mean OS of 10.12 months with CC-486 was consistent with the median OS improvement (9.9 months) reported in QUAZAR AML-001. Conclusions: In this ITC, CC-486 had a longer duration of follow-up than injectable AZA and an earlier and more durable relative OS benefit, which was maintained beyond 60 months. This analysis demonstrates that CC-486 was associated with a meaningful improvement in mean survival time, and that maintenance treatment with CC-486 provides a long-term survival benefit compared with the relative short-term benefit observed with AZA. Disclosures Chen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Disher:Eversana: Current Employment. Siddiqui:Eversana: Current Employment. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Suero:Eversana: Current Employment; Bristol Myers Squibb: Consultancy. Cameron:Eversana: Current Employment. Gavanji:Eversana: Current Employment. Cameron:Eversana: Current Employment, Current equity holder in private company.

Description: The nuclear receptors (NR) retinoid X receptors (RXRs) exert immunomodulatory functions to control inflammation and metabolism via homodimers and heterodimers with several other NRs including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers but not heterodimers. Here, we show that in vivo IRX4204 was compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T cell proliferation, reducing T helper 1 differentiation and promoting regulatory T cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating pro-inflammatory pathways. In vitro, inducible Treg differentiation from naïve CD4+ T cells was enhanced by IRX4204; in vivo, IRX4204 increased the conversion of donor Foxp3- T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrate that IRX4204 supported Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be used as a novel approach to prevent acute GVHD in the clinic.

Description: CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (ALL, n=14; CLL, n=9; NHL, n=21) who received CART2 on a phase 1/2 trial at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 CRS, 9%; grade ≥3 neurotoxicity, 11%). After CART2, CR was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before CART1 and an increase in the CART2 dose compared to CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received Cy-Flu lymphodepletion before CART1 and a higher CART2 compared to CART1 cell dose. The identification of two modifiable pre-treatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.

Description: Introduction: MYC/BCL2 double hit lymphoma (DHL), defined as a large B-cell lymphoma with concurrent MYC and BCL2 translocations, is the most common type of DHL. Although multiple studies focused on DHL have been published, several issues regarding impact on prognosis remain controversial including: 1) history of low grade B cell lymphoma; 2) morphology (diffuse large B-cell lymphoma [DLBCL] versus B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma [BCLU)]; 3) Absence or low expression of MYC or BCL2; 4) MYC translocation partner gene; and especially 5) most effective therapy. The aim of this study was to attempt clarify the prognostic importance of these factors in DHL. Methods: 157 patientsdiagnosed with MYC/BCL2 DHL between 2003 and April 2015 at two institutions were included in this study. MYC and BCL2 gene rearrangement were confirmed by FISH using a MYC breakapart probe and BCL2 and IGH dual color dual fusion probes. BCL6/3q27gene status was tested either by FISH using breakapart probe or by karyotype. MYC partner gene was identified by karyotype. MYC/BCL2 DHL cases were identified if they had rearrangements of MYC and BCL2 but not BCL6. Positive for MYC or BCL2 by immunohistochemistry was defined by 〉40% and 〉50% of lymphoma cells showed positive expression, respectively. Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Fisher's exact test was used to compare the clinicopathologic features. Statistical analysis was performed using SPSS 23 software. Results: There were 103 men and 54 women with a median age of 61 years (range, 18-87). 110 patients had de novo disease and 47 patients had a history of low-grade B-cell NHL, mostly follicular lymphoma. The clinicopathologic features were similar (P〉0.05) between patients with a history of low-grade B-cell NHL and patients with de novo NHL, and therefore analysis was performed on all 157 DHL cases. Using the 2008 WHO classification, there were 91 DLBCL, 61 BCLU, and 5 composite lymphoma (4 DLBCL + follicular lymphoma and 1 DLBCL + B-lymphoblastic lymphoma). 99% of cases had a germinal center B-cell immunophenotype by the Hans algorithm. MYC expression was observed in 39/47 (83%) and BCL2 in 129/141(91%) of cases. MYC and BCL2 dual expression was present in 34/46(74%) cases. Of the 39 cases assessed, the MYC translocation partner was IGH in 13, IG light chain in 19, and a non-IG gene in 7 cases. 144 patients had complete treatment information: 61 received the R-CHOP regimen initially, 31 R-EPOCH, 29 R-HCVAD, and 23 various other chemotherapy regimens. 39 patients also received stem cell transplant (SCT) including 31 autologous and 8 allogeneic. 62 patients reached complete remission (CR) after initial chemotherapy. The median overall survival was 19 months. In a univariate analysis that evaluated 17 clinicopathologic parameters including those mentioned in introduction, extranodal sites of disease, bone marrow involvement, CNS involvement, advanced stage, and high/high-intermediate International Prognostic Index score were associated with a worse overall survival (OS, P

Description: BACKGROUND: Regulatory T cells (Tregs) are non-redundant mediators of immunity and tolerance. Adoptive transfer of CD4+Foxp3+ Tregs has emerged as a promising therapy for graft-versus-host disease (GVHD) following allogeneic HSCT (aHSCT), solid organ transplantation and autoimmune diseases (Hanash AM, Blood 2005; Copsel S, Wolf D, Haematologica 2019; Marek-Trzonkowska N, Diabetes Care 2012; Tang Q, J Mol Cell Biol 2012). Our prior work was the first to demonstrate a two-pathway in vivo strategy targeting TNFRSF25 (with TL1A-Ig fusion protein) and CD25 (with low dose IL-2, IL-2LD) receptors can elicit a rapid and strong increase in Treg numbers and function (Wolf D, BBMT 2017). In fact, very low numbers of these in vivo expanded donor Tregs exhibited effective GVHD suppression in recipients following aHSCT (Copsel S, BBMT 2018). Based on these findings and the success of IL-2LD in pre-clinical and clinical studies, we asked: are there phenotypic/functional differences between Tregs expanded via IL-2LD, TL1A-Ig or their combined application (TL1A-Ig+IL-2LD)? METHODS: Mice were administered IL-2LD, TL1A-Ig or TL1A-Ig+IL-2LD over 6 days. Splenic and lymph node (LN) Treg phenotype was determined by flow cytometry. Treg functionality was assessed with sorted populations using an in vivo MHC-mismatched aHSCT. RESULTS: Treatment of C57BL/6-FoxP3RFP mice with TL1A-Ig+IL-2 LD versus IL-2LD only treatment resulted in significantly higher levels of activation/differentiation and functional markers on Tregs including KLRG1, CD103, Nrp1, ICOS (Fig. 1A). Ki67 expression was higher in two-pathway versus IL-2LD stimulation alone (Fig.1B). These data suggested a key role for TNFRSF25 stimulation. Notably, Treg stimulation with TL1A-Ig alone drove the above phenotype indicating a pathway difference between the TNFRSF25 and IL-2 receptors. This difference was further apparent as high affinity IL-2 receptor (CD25) expression was reduced after TL1A-Ig +/- IL-2LD -mediated expansion compared with IL-2 LD alone stimulated Tregs (Fig. 1A). Results were corroborated using a second independent mouse strain, BALB/c, following use of these protocols. To begin addressing if the observed phenotypic differences between CD25 vs. TNFRSF25 + CD25 expanded Tregs could be related to a more potent Treg in vivo suppressive activity, an initial MHC-mismatched aHSCT (donor/recipient = C57BL/6-BALB/c) was performed. We employed 200,000 sorted Tregs (〉98% purity by CD4+FoxP3+ selection from C57BL/6-FoxP3RFP reporter mice) from donor unexpanded, IL-2LD, or TL1A-Ig+IL-2LD treated mice combined with 1.0 x106 T cells. As anticipated, transfer 200,000 TL1A-Ig+IL-2LD stimulated Tregs ameliorated acute GVHD (Fig. 1C). Remarkably, lower GVHD clinical scores were obtained using the same number of IL-2LD only expanded Tregs compared with TL1A-Ig+IL-2LD stimulated Tregs (Fig. 1C). Moreover, early post-transplant, higher LN and splenic CD4/CD8 ratios were detected in aHSCT recipients treated with IL-2LD expanded Tregs vs. TL1A-Ig+IL-2LD (Fig. 1D). CONCLUSION: Our donor TL1A-Ig+IL-2LD Treg expansion protocol promotes a more activated/differentiated and proliferative phenotype versus IL-2LD stimulation alone. This finding may have accounted for their initial effectiveness - but less efficient long-term GVHD amelioration compared to IL-2LD only stimulated Tregs. Multiple variables are associated with the application of Tregs for therapy including numbers, persistence, and suppressive capacity. Our findings suggest a rationale that one-pathway and / or two-pathway stimulated Tregs may be beneficial for use in aHSCT recipients dependent on whether there is a perceived need for prolonged Treg presence and the stage of GVHD. Disclosures Levy: Heat Biologics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pelican Therapeutics: Consultancy, Research Funding.

Description: CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is a novel treatment with promising results for patients with relapsed/refractory lymphoid malignancies. CAR-T cell therapy has known early toxicities of cytokine release syndrome (CRS) and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We have utilized patient-reported outcomes (PROs), including PROMIS®measures, to assess outcomes of patients with relapse/refractory chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia (ALL) who were treated with CD19-targeted CAR-T cells on a clinical trial in our institution (NCT01865617) and survived at least one year after treatment. Between October 2018 to February 2019, 52 patients (at their 1-5 year anniversary after CAR-T cell therapy) were sent a questionnaire. The questionnaire included the PROMIS Scale v1.2-Global Health and the PROMIS-29 Profile v2.1, as well as 30 additional questions, including questions pertaining to cognitive function. As of February 28, 2019, 40 questionnaires were returned (76.9% response rate) and were included in the analysis. Patients' characteristics are summarized in Table 1. Cognitive function was assessed by asking if patients had experienced difficulties with concentration, finding words, memory, or solving problems since their CAR-T cell therapy; answer "yes" to each of the questions received "1" point to determine the total cognitive difficulty score (0-4). PROMIS measures are standardized to a T-score metric, with a score of 50 representing the general US population mean. Clinically meaningful differences were defined as a 5-point difference in scores (1/2 standard deviation). The cohort's self-reported cognitive difficulties and PROMIS mean T scores are shown in Table 2. Mean T scores of PROMIS domains of Global Mental health, Global Physical Health, Social Function, anxiety, depression, fatigue, pain and sleep disturbance were not clinically meaningfully different from the mean in the general US population. However, 19 participants (47.5%) reported at least one cognitive difficulty and/or clinically meaningful depression and/or anxiety (Figure 1), and 7 participants (17.5%) scored ≤ 40 in Global Mental Health, indicating at least one standard deviation worse than the general population mean. On risk factor analysis, younger age was found to be associated with worse Global Mental Health (p=0.02), anxiety (p=0.01) and depression (p=0.01). Anxiety prior to CAR-T cell therapy was associated with increased likelihood of anxiety after CAR-T cell therapy (p=0.001). Multivariate analysis confirmed association between age and PROMIS Global Mental Health score (p=0.03). 15 participants (37.5%) reported cognitive difficulties post CAR-T cell therapy. On multivariate analysis, depression prior to CAR-T cell therapy was statistically significantly associated with higher likelihood of self-reported cognitive difficulties after CAR-T therapy (p=0.02) and there was a trend for association between acute neurotoxicity after CAR-T cell infusion and self-reported long-term cognitive difficulties (p=0.08). Having more cognitive difficulties was associated with worse Global Mental Health (p=0.0001) and worse Global Physical Health (p= 0.01). Similarly, worse scores for pain interference, sleep disturbance, fatigue, depression, anxiety, physical function, and social function were associated with more long-term self-reported cognitive difficulties (p=0.007,p=0.0003, p=0.00006, p=0.01, p=0.0007, p=0.003, p=0.0004 respectively). Our study demonstrates overall good neuropsychiatric outcomes in 40 long-term survivors after CAR-T cell therapy. However, despite good overall mean scores, nearly 50% of patients in the cohort reported at least one negative neuropsychiatric outcome (anxiety, depression or cognitive difficulty), and almost 20% scored at least one standard deviation lower than the general US population mean in Global Mental Health, indicating that there is a significant number of patients who would likely benefit from mental health services following CAR-T cell therapy. Younger age, anxiety and depression pre-CAR-T cell therapy, and acute neurotoxicity after CAR-T cell infusion may be risk factors for long-term neuropsychiatric problems in this patient population. Larger studies are needed to confirm these findings. Disclosures Shaw: Therakos: Other: Speaker Engagement. Lee:AstraZeneca: Research Funding; Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Turtle:T-CURX: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Ad hoc advisory board member. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; A2 Biotherapeutics: Honoraria, Other: Stock options ; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria.

Description: Key Points Routine staging by PET-CT identifies all clinically relevant marrow involvement by DLBCL. Cases with marrow involvement identified by PET-CT have PFS and overall survival similar to stage IV cases without marrow involvement.

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: Background: The paradigm for treatment selection in newly diagnosed (ND) multiple myeloma (MM) is largely predicated on establishment of suitability for front-line autologous stem cell transplantation. In this context, real-world evidence from multiple jurisdictions demonstrates that the most widely employed front-line (1L) therapies are bortezomib (B)-based triplets in transplant-eligible patients, and in transplant-ineligible patients, B-based triplets (or doublets) or the combination of lenalidomide and dexamethasone. While a sound hypothetical rationale for treatment stratification at diagnosis is recognised, viz alternative treatments for high-risk (HR) versus standard-risk disease, this is rarely employed in either everyday practice or clinical trials. A significant impediment to such an approach is the lack of a uniformly recognised risk stratification model that not only recognises truly HR disease (e.g. median survival from diagnosis 〈 24 months [m]) but is also accessible and affordable. Against this background we evaluated data from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) to define characteristics of 'functional' HR disease that could inform response-adaptive strategies, thus enabling the appropriate therapeutic targeting of HR patients. Methods: NDMM patients enrolled on to the MRDR since February 2013 with available data were evaluated. Patients were defined as either sub-optimal responders (SOR) to 1L if their best response was minimal response or stable disease (but not progressive disease [PD]), or early progressors (EP) if they demonstrated PD within 12m of commencing 1L therapy, irrespective of whether this occurred on or after the completion of 1L therapy. For categorical variables p-values were determined using a Pearson's chi-squared test, for continuous variables p-values were calculated using a Wilcoxon rank-sum test. Survival analysis was performed using the Kaplan-Meier method and p-values determined with the log-rank test. Results: 1320 NDMM patients were included with a median follow-up of 23m (12-37 IQR, 0-83 range). Of these, 152 were SOR (11.5%) and 118 were EP (8.9%). At diagnosis only 2 factors associated with SOR were identified: age 〉70y (p