Lugano Criteria Research Articles

Repeat Infusions of CD19 CAR-T Cells: Factors Associated with Response, CAR-T Cell In Vivo Expansion, and Progression-Free Survival

Background CD19-targeted chimeric antigen receptor-engineered (CD19 CAR)-T cell immunotherapy has shown efficacy for relapsed or refractory (R/R) B-cell malignancies, but absence of complete response or relapses are still observed in a significant portion of patients (pts). Objectives To evaluate outcomes after repeat infusion of CD19 CAR-T cells, and identify the factors associated with response, CAR-T cell in vivo expansion, and progression-free survival (PFS). Methods We analyzed data from pts with R/R B-cell malignancies who received a second infusion of CD19 CAR-T cells (CART2) on a phase 1/2 trial (NCT01865617) at our institution. Responses were evaluated 4 weeks after CAR-T cell 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). Results Forty-four pts evaluable for response were included in this study (see Table). Pts were heavily pre-treated (median prior therapies, 6), and 16 pts (36%) had bulky (e 5cm) disease. Prior to CART2, 15 pts (32%) had not responded to CART1, 22 (50%) relapsed or progressed after initial response (complete response [CR], n=15; partial response [PR], n=7) to CART1, and 7 (16%) were in ongoing PR. We observed responses to CART2 in 3 of 14 ALL pts (21%; all CR/CRi), 4 of 11 CLL pts (36%; CR/CRi, n=3; partial response [PR], n=1), and 9 of 19 NHL pts (47%; CR, n=2; PR, n=7). After a 43-month median follow-up, the estimated 4-year PFS and OS probabilities in responders were 23% (95% CI, 9-59%) and 36% (95% CI 19-71%), respectively. Multivariable logistic regression identified lymphodepletion intensity before CART1 (high-intensity cyclophosphamide and fludarabine [CyFlu] vs Other, OR=12.19, p=0.04; high intensity versus low intensity CyFlu, OR=3.83, p=0.08) and the peak blood CAR-T cell count after CART2 (OR=2.31 per log10 CD8+ CAR-T cell/µL increase, p=0.01) as predictors of response to CART2. In a multivariable Cox model, higher peak CD8+ CAR-T cell count after CART2 (HR=0.47 per log10 CD8+ CAR-T cell/µL increase, p Conclusion Outcomes after second infusions of CD19 CAR-T cells might be improved with high-intensity CyFlu lymphodepletion prior to CART1 and by increasing the CAR-T cell dose at the time of CART2.

Abstract A071: Phase I trial of the combination of bortezomib and clofarabine in adults with refractory solid tumors, lymphomas, or myelodysplastic syndromes

Abstract Background: The NCI ALMANAC study carried out a systemic in vitro drug screen with 2.8 million dose combinations to identify drug pairs with greater than additive activity. This was followed by patient-derived xenograft models, which demonstrated that the combination of the proteasome inhibitor bortezomib and the nucleoside analog clofarabine was highly active. Both agents have been approved by FDA: bortezomib for multiple myeloma & mantle cell lymphoma, and clofarabine for acute lymphoblastic leukemia. However, neither agent is approved for solid tumors or myelodysplastic syndrome (MDS). Our pre-clinical models suggest that the activity of this drug pair may be due to modulation of DNA damage and enhancement of the intrinsic apoptotic cascade. While both drugs can initiate apoptosis, bortezomib resistance occurs when the drug fails to upregulate the apoptotic promoter BAX; however, clofarabine can stabilize BAX and facilitate apoptosis via alternate pathways (unpublished data). We are conducting an ongoing phase 1 trial to evaluate the activity of bortezomib and clofarabine in refractory solid tumors, lymphomas, and MDS. Methods: The trial uses a 3+3 design, enrolling at least one solid tumor/lymphoma and one MDS patient (pt) at each dose level. The occurrence of pre-defined hematologic dose limiting toxicity (DLT) or a second instance of a grade 2 hematologic toxicity triggers expansion of the dose level into separate cohorts: (1) solid tumor/lymphoma & (2) MDS. Starting dose of clofarabine was 1 mg/m2 administered intravenously (IV) on day (D)1-5, with bortezomib 0.8 mg/m2 SQ on D1-4 of 21-day cycles. Response was measured using RECIST 1.1, Lugano criteria, and IWG, respectively. Exploratory endpoints include DNA damage and epithelial-to-mesenchymal phenotype transition in blood and malignant tissue. Results: As of July 2019, 15 pts were enrolled with advanced solid tumors (n=11), lymphoma (1) & MDS (3). Median patient age is 62 (48-80 yrs). Median lines of prior therapy is 3 (1-7). One pt had a DLT (grade 3 anemia in a solid tumor pt at dose level 3), leading to the separation into solid tumor/lymphoma and MDS cohorts. In the MDS cohort, 2 pts had stable disease (SD) as best response (1pt with >8 months duration of response [DOR] following hypomethylating agent [HMA] failure). In the solid tumor/lymphoma cohort, 2 pts achieved a best response of SD (1pt with > 7 months DOR, with colorectal adenocarcinoma). The only toxicity possibly attributed to treatment in the MDS cohort was grade 3 neutropenia. In the solid tumor/lymphoma cohort, the grade 3 toxicities were anemia (2) and lymphopenia (4); there was one grade 4 lymphopenia, and no grade 3/4 neutropenia or thrombocytopenia. Conclusions: This unique trial design demonstrates that conducting a phase 1 study with both solid tumors and hematologic malignancies is feasible and efficient, eliminating the need for a larger sample size or two separate trials. Treatment with bortezomib and clofarabine has shown early activity in a colon cancer pt and an MDS pt post HMA failure, where treatment options are critically limited. Dose escalation and pharmacodynamic studies are ongoing. Future studies include assessment of drug pair mechanism of action using a validated apoptosis multiplex assay and next-generation sequencing. Funded by NCI Contract No. HHSN261200800001E Citation Format: Sabrina S. Khan, Geraldine O'Sullivan, Larry Rubinstein, Shivaani Kummar, Lamin Juwara, Jennifer Zlott, Arjun Mittra, Murielle Hogu, Jerry Collins, Apurva Srivastava, Brandon Miller, Ralph E. Parchment, Christopher S. Hourigan, Steven Pavletic, James Doroshow, Alice P. Chen, Naoko Takebe. Phase I trial of the combination of bortezomib and clofarabine in adults with refractory solid tumors, lymphomas, or myelodysplastic syndromes [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A071. doi:10.1158/1535-7163.TARG-19-A071

Abstract A072: Preliminary results of ASTX660, a novel non-peptidomimetic cIAP1/2 and XIAP antagonist, in 107 patients with solid tumors or lymphoma

Abstract Background: ASTX660 is an oral, novel nonpeptidomimetic, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). ASTX660 is currently being evaluated in a first-in-human phase 1–2 study in patients (pts) with advanced solid tumors or lymphoma (ClinicalTrials.gov NCT02503423). In the ongoing phase 2, ASTX660 has demonstrated preliminary evidence of clinical activity in the relapsed/refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) cohorts (Mehta et al, presented at the EHA Conference 2019, abs PS1073). Here, we report overall efficacy and safety data from the solid tumors (head and neck squamous cell carcinoma [HNSCC]; cervical carcinoma and other solid tumors) and lymphoma (diffuse large B-cell lymphoma [DLBCL], PTCL, CTCL,) phase 2 cohorts. Methods: Pts received treatment with ASTX660 orally at the RP2D 180mg/day on days 1 to 7, and 15 to 22 in a 28-day cycle. In the first stage 14 evaluable pts were enrolled in each of the 6 phase 2 cohorts with the option to expand the cohort if activity was observed. The primary endpoint was response rate as assessed by the investigator according to the Lugano criteria (DLBCL and PTCL), Global Assessment (CTCL), or RECIST 1.1 (solid tumors). Adverse events (AEs) were assessed per CTCAE V4.03. Results: As of June 4, 2019, a total of 107 pts have received ASTX660 in the solid tumors and lymphoma phase 2 cohorts (HNSCC n=14; DLBCL n=16; PTCL n=26; CTCL n=23; cervical carcinoma n=14; other solid tumors n= 14). Median age (range) was 61 (23-84) years and median number (range) of prior anticancer regimens was 3 (0-12). Among all pts, the most common related AEs of any grade (≥ 10%) were rash (35%), lipase elevation (34%), amylase elevation (29%), diarrhea (14%), fatigue (14%), AST elevation (13%), nausea (13%), and anemia (11%). Related AEs ≥ Grade 3 occurring in ≥ 5% of pts were rash (18%), lipase elevation (16%) and amylase elevation (9%). As of 4 June 2019, 86 pts (80%) discontinued study treatment: 64 (60%) due to progressive disease, 13 (12%) due to AE, 4 (4%) due to death, 4 (4%) due to withdrawal by participant and 1 (1%) for investigator’s decision. At the time of analysis, the ORR was 36% in the PTCL cohort and 15% in the CTCL cohort. One PR was reported in a pt with metastatic melanoma after 12 cycles of treatment. No objective responses were reported in the HNSCC, DLBCL or cervical cohorts. Accrual in the PTCL and CTCL continues; updated efficacy and safety data will be presented at the meeting. Conclusion: In the phase 2 part of the study ASTX660 monotherapy has demonstrated a manageable safety profile and encouraging activity in PTCL and CTCL warranting cohort expansion. Future plans include evaluation of ASXT660 both as mono- or combination therapy in selected malignancies. Citation Format: Antoine Hollebecque, Sarit Assouline, Felipe Samaniego, Benoit You, Francine Foss, Anca Prica, Sarah W. Gordon, Marc Webster, Martin JS. Dyer, Dima El-Sharkawi, Geoffrey I. Shapiro, Lisa Nabell, Sarah P. Blagden, John Lister, Susanna V. Ulahannan, Yijun Sun, Danna Chan, Roberta Ferraldeschi, Monica Mita. Preliminary results of ASTX660, a novel non-peptidomimetic cIAP1/2 and XIAP antagonist, in 107 patients with solid tumors or lymphoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A072. doi:10.1158/1535-7163.TARG-19-A072

Complete Response Status According to RECIL 2017 Criteria Shows High Concordance with Lugano 2014 Criteria and Is Highly Prognostic for Outcome in Previously Untreated Patients with CD20-Positive Diffuse Large B-Cell Lymphoma (DLBCL)

Complete Response Status According to RECIL 2017 Criteria Shows High Concordance with Lugano 2014 Criteria and Is Highly Prognostic for Outcome in Previously Untreated Patients with CD20-Positive Diffuse Large B-Cell Lymphoma (DLBCL)

Prediction of High-Risk Group of Primary Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Patients Using a CT-Based Radiomics Model with Machine Learning

Introduction Approximately 15% of diffuse large B-cell lymphomas (DLBCL) do not respond to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) or equivalent regimen. These primary refractory cases (prDLBCL) have a particularly poor survival. There are currently no reliable biomarkers to a priori identify prDLBCL patients and include them in clinical trials, while avoiding needless toxicity from predictably ineffective therapy. In this study, we evaluated the potential for radiomic analysis with machine learning for predicting prDLBCL. Method This study included adult patients with prDLBCL from a single institution from 2009 to 2018, who had first-line treatment with an R-CHOP like regimen, had never received systemic treatment for indolent lymphoma, and who had a CT scan at the time of diagnosis. Refractory (R) patients were defined by progression of disease (PD) after completion of at least one cycle, or failure to achieve a complete response (CR) after at least 4 cycles, as per Lugano criteria (Cheson, JCO 2014). Non-refractory (NR) patients were matched 1:1 on sex and R-IPI for the comparison group. Enlarged lymph nodes (≥1.5 cm in greatest diameter) were eligible for evaluation. The 6 largest nodes were selected at each node site (abdomen, chest, axilla and neck) and for each node category (refractory node (RN), partial response (PR) and CR, as per Lugano criteria). 3D Slicer software was used for the delineation of the region of interest (ROI) either for subsequent 2D analysis (largest axial section) or 3D analysis (total node volume). Each node was manually contoured by two independent readers and also was reviewed by an experienced senior oncologic radiologist. A total of 788 and 1218 features were extracted from 2D and 3D regions of interest, respectively, using Pyradiomics open source software. Two independent machine learning approaches, Random Forests (RF) and Support Vector Machine (SVM), were tested for constructing the prediction models. 70% of cases were randomly assigned to the training set and 30% to the independent testing set. In the node model (NM) each independent node's response to treatment was predicted. In the patient model (PM), groups of nodes per site (abdomen, chest, axilla and neck) were used to predict the overall patient response. Results A total of 26 refractory patients were identified with a total 149 nodes (RN=55, PR=20, CR=74) and matched to 26 NR patients for comparison, with a total of 105 CR nodes. Seventeen nodes with significant artifact were excluded from the analysis (7 from NR patients and 10 from R patients). RF had consistently superior performance compared to SVM and was used for constructing the final prediction models. Furthermore, 2D radiomic analysis had superior performance compared to 3D radiomic analysis. In the independent testing (prediction) set, the mean accuracy between the 2 readers for this model for distinguishing a R from NR patient was 80% (mean sensitivity and specificity, 73% and 88%, respectively). This model was able to predict a R patient (positive predictive value (PPV)) in 100% and 71% of the case, respectively for readers 1 and 2. The area under the ROC curve (AUC) was 0.96 and 0.81 for reader 1 and 2, respectively (Figure 1A). For performance of the radiomic model for distinguishing individual refractory from responsive nodes, the independent testing set had a mean accuracy of 75% (mean sensitivity, specificity, PPV, and NPV of 80%, 69%, 78%, and 71% respectively). The AUC per reader were 0.82 and 0.85 (Figure 1B). Conclusion We demonstrate that the use of CT radiomic analysis with machine learning for identifying a priori primary refractory DLBCL patients is feasible. These models provide a relatively high prediction accuracy, which currently cannot be done in the clinical setting based on standard, largely qualitative, imaging characteristics. The main limitations of our study include small patient numbers in this pilot study and exclusion of extranodal sites. The next step for this project would be to evaluate this approach in a larger cohort that includes a second independent institution. CT-based radiomics is promising and should be further explored to achieve this unmet need for predicting prDLBCL prior to therapy initiation. Disclosures Forghani: GE Healthcare: Consultancy, Honoraria, Research Funding; 4Intel Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder. Reinhold:FRQS: Other: FRQS Grant. Assouline:Pfizer: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria.

Preliminary Safety and Anti-Tumor Activity of XmAb13676, an Anti-CD20 x Anti-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Preliminary Safety and Anti-Tumor Activity of XmAb13676, an Anti-CD20 x Anti-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Brief Pembrolizumab(PEM) Monotherapy Results in Complete and Near Complete Responses in the Majority of Untreated Patients with Classical Hodgkin Lymphoma (cHL): A Multicenter Phase 2 PET-Adapted Study of Sequential PEM and AVD

Background: Pembrolizumab (PEM), an anti-PD-1 antibody is approved for the treatment of relapsed/refractory cHL based on results of a pivotal trial demonstrating an overall response rate (ORR) of 69% and 22% complete response (CR) rate. To investigate the impact of PEM monotherapy in previously untreated patients (pts), we conducted a phase 2 clinical trial of sequential PEM followed by AVD chemotherapy for untreated cHL. Herein, we report the primary analysis of response (PET2) to single agent PEM in the frontline setting and the results of interim FDG18-FDG PET-CT (PET3) following AVD x 2. Methods: Pts > 18 years of age with newly diagnosed cHL stages I-IV, including early stage pts with at least 1 risk factor according to NCCN criteria, were eligible. Pts were treated sequentially with 3 cycles of PEM at 200 mg every 3 weeks followed by an interim PET-CT (PET2) for primary analysis. Subsequently, pts received 4-6 cycles of AVD chemotherapy based on initial stage, with PET-CT's repeated after 2 cycles of AVD and at the end of therapy. There was no consolidative radiotherapy. Response to single agent PEM was assessed by Lugano criteria and decline in total metabolic tumor volume (TMV). We hypothesized that PEM monotherapy prior to AVD would result in a CR rate of 50% and would reduce the frequency of PET-positivity on the interim PET (PET3) following 2 cycles of AVD compared to prior reports. Results: Thirty pts enrolled from September 2017- March 2019 with a data cutoff of June 14, 2019. The median age of participants was 30 (range, 21-77), and 4 pts were ages >60. Eleven were male, and the majority (83%) were Caucasian. Twelve pts had early unfavorable disease (6 each with elevated ESR, B-symptoms, and bulky mediastinal masses). Eighteen pts had advanced stage disease (5 Stage 3, 13 Stage 4; IPS score 3 -4 in 7, 1-2 in 10). Adverse risk factors for all 30 pts included bulky disease or large mediastinal mass (n=12), B-symptoms (n=14) and extranodal disease (n=16). Overall therapy was well tolerated and most adverse events were grade 1-2. Related events of any grade included hypertension (n=10), rash (n=9), anemia (n=8), infusion reactions (n=5), elevated liver function tests (n=5), arthralgias (n=4) and hypo- or hyperthyroidism (n=3). Grade 3 and 4 events (whether or not judged to be related) were as follows Gr3: lymphopenia (n=4), febrile neutropenia (n=3), neutropenia (n=3), hypertension (n=2), diarrhea (n=1), hyperglycemia (n=1), and hyponatremia (n=1); Gr 4: neutropenia (n=10); transaminitis (n=1); sepsis (n=1). The only Grade 3 or 4 immune-related adverse event was the one grade 4 transaminitis that resolved with steroid administration and a delay in therapy. Eleven of 30 pts achieved CR (37%; Deauville 1-3) following initial PEM monotherapy including three with large mediastinal masses. Four additional patients with bulky disease and four others had major reductions in disease following PEM monotherapy, but did not achieve CR by Lugano criteria (Fig 1A). To better characterize the depth of response, we quantitated the decline in total metabolic tumor volume (TMV) (Fig 1B). Eight of the 17 pts with < CR to PEM monotherapy for whom TMV could be analyzed had > 90% reduction in TMV. A single pt had an atypical response with clearance of original disease sites, but development of new sites that resolved after two cycles of AVD. Across all pts, the CR (Deauville 1-3) rate following 2 cycles of AVD, was 100%. Median follow up is 6.5 (range: 1 - 12) months among those who have completed therapy. No pt has required a change in treatment, relapsed, or progressed, with progression-free and overall survival rates both at 100%. Conclusion: Although the study did not meet its primary endpoint, our data demonstrate that 3 cycles of PEM is highly active in pts with newly diagnosed early unfavorable or advanced stage cHL. PEM monotherapy resulted in > 90% reduction in TMV in the majority of pts, and when followed by AVD x's 2, CR in 100%. No pts have experienced progression or change of therapy to date and treatment was overall very well tolerated. This radiotherapy- and bleomycin-free approach warrants further investigation in larger trials to confirm response rates and assess efficacy compared with other novel combinations in the frontline setting. Disclosures Pro: Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Karmali:Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Astrazeneca: Speakers Bureau. Gordon:Gilead: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer; Bayer: Other: Advisory Board. Winter:Merck: Consultancy, Research Funding.

Comparison of CT and PET-Based Assessments per Lugano Criteria in FDG-Avid Lymphoma- a Retrospective Analysis of Independent Review Assessments

Background: The Lugano classification criteria introduced in 2014 is widely used in clinical trials as well as in clinical practice for response assessment in Lymphoma. The criteria recommend a combination of disease morphology assessment using Computed Tomography (CT) and lesion metabolic activity assessment on Positron Emission Tomography (PET), with PET metabolic assessments being the driver for overall response assessment. In this study, we analyzed the alignment between assessments made using both modalities. The independent review assessments of 583 subjects with 1032 follow up timepoints from multiple Phase I to Phase-III multi-center clinical trials to determine the alignment between assessments made using both modalities. Methods: 583 subjects with 1032 post-baseline timepoints from multiple phases I to phase-III multi-center clinical trials on lymphoma were retrospectively analyzed using the independent review data. All clinical trials used the Lugano Classification as a response assessment criteria. The variability between the PET-based metabolic assessments [Complete Metabolic Response (CMR), Partial Metabolic Response (PMR), No Metabolic Response (NMR) and Progressive Metabolic Disease (PMD)] and CT-based morphological assessments [(Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD)] for the same timepoint was analyzed by comparing the following: Timepoints where PET-based assessment was CMR, but CT based assessment was not CR and vice versa Timepoints where PET-based assessment was PMD, but CT based assessment was not PD and vice versa Results: 280 timepoints had CMR on PET, but only 109 of these 280 timepoints (39%) had an assessment of CR on CT (147 were PR, 23 SD, and 1 PD) 138 timepoints that had CR on CT but 32 (23%) were non-CMR on PET (29 were PMR, 1 NMR, and 2 PMD). 343 timepoints had PMD on PET and 301 of these 343 timepoints (88%) had an assessment of PD on CT (2 were CR, 28 PR, 12 SD) 115 timepoints had PD on CT Scan, but 10 (8%) timepoints that had PD on CT were non-PMD on PET (1 CMR, 6 PMR, and 3 NMR) Conclusion: The results shown above suggest that PET and CT based assessments may not always be aligned. CMR on PET can be associated with residual disease on CT in about 61%, whereas a CR on CT may have associated residual metabolic activity on PET in 23% cases. This is in alignment with the Lugano criteria where PET-based metabolic activity assessment is considered a driver in lymphoma response assessment than CT. PET findings show the metabolic activity of the lesions, whereas morphological response on CT scan may be affected by underlying treatment-related effects such as fibrosis and may not always align with PET response. A PMD on PET is associated with a progression on CT scan most of the times and vice versa, but in a small number of the case, progression may not be aligned on two modalities and may need further investigation by biopsy and follow-up imaging. Disclosures No relevant conflicts of interest to declare.

A Multi-Center Dose-Finding Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Fimepinostat (CUDC-907) in Combination with Venetoclax in Patients with Relapsed/Refractory (R/R) Lymphoma

A Multi-Center Dose-Finding Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Fimepinostat (CUDC-907) in Combination with Venetoclax in Patients with Relapsed/Refractory (R/R) Lymphoma

Safety and Efficacy of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Mantle Cell Lymphoma: A Multicenter, Open-Label, Phase II Study

Mantle cell lymphoma (MCL), a subtype of aggressive B-cell non-Hodgkin lymphoma (NHL), remains challenging with unsatisfied outcomes from standard therapy. The clinical significance of Bruton's Tyrosine Kinase (BTK) inhibitors has been validated in multiple subtypes of NHL. Ibrutinib, the first BTK inhibitor, has been approved by FDA for the treatment of refractory and relapse (r/r) MCL. In spite of encouraging efficacy, clinically often referred adverse events such as diarrhea, bleeding and atrial fibrillation, respectively following ibrutinib treatment. It has been hypothesized that poor target selectivity (inhibitive effect on EGFR, TEC, BMX and others) may partially explain the occurrence of these adverse events. As such, there are focused efforts to develop new BTK inhibitor with high target selectivity aiming to improve the safety. Orelabrutinib (ICP-022) is a novel, potent irreversible BTK inhibitor with high selectivity for BTK vs other kinases including TEC- and EGFR-family members. Results from Phase I study demonstrated excellent safety/tolerability profiles as well as favorable pharmacokinetic and pharmacodynamic properties. Sustained BTK occupancy at 24 hr was achieved with once daily dosing regimen. In this presentation, we describe the clinical results of orelabrutinib in Chinese patients with r/r MCL. This is an open-label, multicenter, two stages, phase II study. The primary endpoint was objective response rate (ORR) and the duration of response (DOR) and safety were chosen as secondary endpoints. The stage I was designed for regimen selection (RP2D, N=20 for 100 mg, bid and 150 mg, qd each, respectively), while the stage II for efficacy at RP2D (N=86 150 mg, qd). Response was assessed per Lugano criteria (2014). Total of 106 pts with r/r MCL were enrolled. As of 31 May 2019, sixty-two pts had completed six cycles of treatment (28 days/cycle). The median duration of treatment was 197.5 days. Safety: A total of 106 pts were enrolled and treated at 22 centers in China. The most frequent (>15%) adverse events (AEs) of any cause were mostly hematological toxicities including thrombocytopenia and neutropenia; and respiratory system infections as well as rash. The frequently reported (>10%) grade 3 or higher AEs of any cause were thrombocytopenia (12.3%). No grade 2 or higher hemorrhage was reported. No treatment related grade 3 GI or cardio toxicity was observed. Of the 106 patients, twenty-five experienced serious AEs and 13 of them were treatment-related (primarily occurred as hematologic toxicities and / or infections). Efficacy: Forty patients, divided into two cohorts (n=20 each), were enrolled in stage I. The regimen, 150 mg, qd, was selected as RP2D based on a better ORR and the convenience of once daily dosing. All patients who were enrolled in the stage I continued their treatment. At the time of reporting (the 31 May 2019), 97 patients had response assessments. The response rate was assessed by traditional CT image technology. The ORR was 82.5% (80/97) for combining both regimens with the complete response rate (CR) 24.7% (24/97), partial responses 57.7% (56/97). Stable disease was seen in 9.3% (9/97). The total disease control rate is 91.8%. Six (6.2%) patients progressed by the first response assessment. The median duration of response rate (DOR) has not been reached. Conclusion: Orelabrutinib is safe and well tolerated with no reported treatment related grade 3 or higher GI toxicity, atrial fibrillation/flutter and severe bleeding in this study. Orelabrutinib is efficacious to treat patients with r/r MCL. The improved safety, resulting from high target selectivity, and the convenience of daily dosing regimen provides orelabrutinib as the potential of preferred therapeutic choice for B cell malignancy. Disclosures Lu: Beijing InnoCare Pharma Tech. Co., Ltd.: Employment. Zhang:Beijing InnoCare Pharma Tech Co., Ltd: Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Employment.

MSKCC Early Experience Using Radiotherapy As a Bridging Strategy for Relapsed Diffuse Large B Cell Lymphoma before CD19 CAR T Therapy

MSKCC Early Experience Using Radiotherapy As a Bridging Strategy for Relapsed Diffuse Large B Cell Lymphoma before CD19 CAR T Therapy

Ibrutinib, Venetoclax Plus Obinutuzumab in Newly Diagnosed Mantle Cell Lymphoma Patients

Ibrutinib, Venetoclax Plus Obinutuzumab in Newly Diagnosed Mantle Cell Lymphoma Patients

Detectable Circulating Tumor DNA 28 Days after the CD19 CAR T-Cell Therapy, Axicabtagene Ciloleucel, Is Associated with Poor Outcomes in Patients with Diffuse Large B-Cell Lymphoma

Detectable Circulating Tumor DNA 28 Days after the CD19 CAR T-Cell Therapy, Axicabtagene Ciloleucel, Is Associated with Poor Outcomes in Patients with Diffuse Large B-Cell Lymphoma

Bendamustine and Rituximab Plus Venetoclax in Untreated Mantle Cell Lymphoma over 60 Years of Age (PrE0405): A Phase II Study

Background: Mantle Cell Lymphoma (MCL) is an aggressive form of Non Hodgkin Lymphoma (NHL) and typically presents in patients over the age of 60 years. Bendamustine and rituximab (BR) combination is one of the standard treatments for MCL and is given to patients for whom high dose chemotherapy with autologous stem cell rescue is planned in the first remission. Progression free survival (PFS) with BR is approximately 36 months (Rummel M Lancet 2013; Flinn IW Blood 2014) and the regimen is overall well tolerated. Venetoclax (VEN) is an orally available inhibitor of BCL2, an anti-apoptotic protein highly expressed in several NHL. Single agent activity has mostly been studied in a Phase I study (in various NHL histologies) where 28 MCL patients were enrolled. Overall response rate was 75% (21 of 28) but complete response (CR) rate was only 21% (6 of 28). Tumor lysis syndrome (TLS) has been associated with VEN and initial dosing requires a ramp up period (Davids MS JCO 2018). VEN has also been combined with other agents in MCL with promising activity (Tam CS NEJM 2018) VEN has been studied as a chemotherapy sensitizer and has shown pre-clinical synergy with chemotherapy. In Follicular lymphoma, BR+VEN was studied at 800mg PO continuous daily dosing and showed an excessive Grade 3-4 adverse event (AE) rate of 78% compared to historical studies of 46% (Zinzani ASH 2016). We hypothesize that, in MCL, VEN can be safely combined with BR at a lower dose and intermittent dosing with improvements to the response rate based on historical controls and maintain a better safety profile. Study Design: This Phase II single arm, multicenter study evaluates VEN at a max dose of 400mg with BR (Bendamustine 90mg/m2 IV day 1 and 2; rituximab 375mg/m2 IV or SQ equivalent day 1) for six 28-day cycles in untreated patients with MCL over the age of 60 years (NCT03834688). Cycle 1 will include a VEN dose titration over the 4 week course (20mg D1-7, 50mg D8-14, 100mg D15-21, and 200mg D22-28). For Cycles 2-6, VEN will be given at 400mg daily x 10 days starting with day 1. Participants are followed for 6 cycles, though will be followed for progression and survival afterward. Participants may receive maintenance rituximab at investigator's discretion. Eligible participants, age 60 years or older, must have biopsy proven untreated MCL with t(11;14) or cyclin D1 expression, though a short course of steroids is allowed for symptomatic MCL. They must have adequate organ function and not require any prohibited concomitant medications. Primary outcome is CR rate as assessed by the Lugano criteria. We estimate a historical CR rate of BR after induction of about 70%. A 15% increase in this rate, to 85% CR, is considered promising for the combination. To achieve this goal, the study will enroll 56 participants (53 eligible) to achieve a 90% power to detect the difference with a 10% Type I error rate. We will also evaluate PFS and overall survival. TLS is an AE of interest and will be evaluated after 19 participants have been enrolled and treated during cycle 1. Minimal residual disease (MRD) will be assessed throughout the study. MRD from peripheral blood will be compared to bone marrow aspirates in all participants undergoing bone marrow aspirate at the end of treatment. Tumor samples at screening and progression will be collected for future study. This study is conducted through PrECOG and is funded by Genentech, a member of the Roche Group. Venetoclax is co-developed by Genentech and AbbVie. The study is slated to open in Fall of 2019 at 10 US sites. Figure Disclosures Portell: AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board. Naik:Celgene: Other: Advisory board. Parsons:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Kahl:BeiGene: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy. OffLabel Disclosure: Venetoclax is not approved for use in MCL.

Response-Adapted Therapy in HIV-Associated Diffuse Large B-Cell Lymphoma: Updated Results of a Prospective Phase II Study of Short-Course-EPOCH-RR

Background: Response-adapted therapy aims to minimize toxicity while maintaining efficacy. Patients with HIV-associated lymphomas are at increased risk for complications and minimizing treatment is advantageous. In 33 patients with HIV-associated diffuse large B-cell lymphoma (DLBCL), we previously reported a 5-year freedom from progression (FFP) and overall survival (OS) rate of 84% and 68%, respectively, with 79% of patients receiving only 3 cycles of short course EPOCH-RR (Dunleavy, 2010). In that study, treatment duration was based on an interim FDG PET-CT scan comparing global reduction of SUV to baseline. Herein, we report an updated analysis including an additional 22 patients and investigate the predictive value of interim PET scans using modern Lugano response criteria. Methods: Eligible patients had untreated HIV-associated DLBCL with adequate organ function. All performance status and stages were eligible, including CNS involvement. Pre-treatment evaluation included bone marrow biopsy, lumbar puncture, CT and PET scan, and brain MRI/CT if indicated. Infusional EPOCH was delivered every 21 days with rituximab on days 1 and 5 (SC-EPOCH-RR) without dose-adjustment for a minimum of 3 and maximum of 6 cycles. HIV antiretroviral therapy (ART) was held until completion of systemic chemotherapy. Treatment response was determined by CT and PET imaging after 2 cycles, with restaging imaging performed consecutively after each cycle. Patients that had a global PET decrease > 50% compared to pre-treatment PET, were treated with only 1 additional cycle. Patients who did not decrease > 50% on PET, continued treatment until there was < 25% reduction in bidimensional products on serial CT imaging. Active CNS disease was treated with twice weekly intrathecal (IT) methotrexate until CSF clearance followed by maintenance IT therapy. All other patients received prophylactic IT methotrexate starting on cycle 3 for 8 doses. The primary endpoint of the study was progression-free survival (PFS). Independent and blinded review of PET scans using Lugano response criteria (Deauville score 1-3 = negative, score 4-5 = positive) was performed by a nuclear medicine specialist (M.A.). Results: Fifty-five patients were enrolled between March 2001 and February 2019. Median age was 42 (range, 9-60) and 85% were male. Ann Arbor stage was III/IV in 84% and 71% had a high-intermediate or high IPI score. Six (11%) patients had CNS involvement, and 6 (11%) had bone marrow involvement. Median CD4 count was 210 cell/m3 (range 0-1192). Cell-of-origin by Hans classified 69% as GCB and 22% were EBV positive. 31 patients were tested for MYC rearrangement by FISH and 5 (16%) were positive. Patients received a median of 3 cycles of therapy; 1 (2%) patient received only 1 cycle, 2 patients (4%) received 2 cycles, 45 patients (82%) received 3 cycles, 3 (5%) patients received 4 cycles, and 4 (7%) patients received 5 cycles. After a median potential follow-up of 12.6 years, 5-year FFP, PFS and OS were 76.0%, 64.3% and 71.8%, respectively [Figures 1, 2]. Two patients progressed during therapy, while 11 patients relapsed after therapy - all within 12 months of treatment completion. Of 18 deaths on study, 6 were due to disease progression and 12 died from causes unrelated to lymphoma or treatment. Of forty-seven patients with interim (post-cycle 2) PET scans, 30 (64%) became PET negative after 2 cycles. The 5-year PFS was not different in patients who achieved interim PET negativity: 73.4% versus 62.7% (p = 0.14 for comparison of entire PFS curves) [Figure 4]. Of the 13 total patients who progressed or relapsed, 5 were negative on interim PET. Conclusion:Response-adapted SC-EPOCH-RR therapy is effective for HIV-associated DLBCL and many patients are cured with only 3 cycles of therapy. Interim PET scans after 2 cycles using Lugano criteria did not reliably predict clinical outcomes. Further studies investigating the role of circulating tumor DNA (ctDNA) for genotyping and predicting clinical outcomes are planned. This work was supported by the Intramural Research Program of NCI. Disclosures Dunleavy: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

Ibrutinib in Relapsed or Refractory Transformed Indolent B-Cell Non-Hodgkin Lymphoma: Final Results from a Prospective Phase II Study

Background : Relapsed or refractory (R/R) transformed indolent B-cell non-Hodgkin lymphoma (iB-NHL) is an uncommon clinical entity associated with poor prognosis. Unfortunately, most trials of aggressive B-NHL tend to specifically exclude transformed disease resulting in scant prospective data to guide therapy. We performed a prospective phase II trial of single agent ibrutinib in patients with previously treated transformed iB-NHL and now report the final results (NCT02207062). Methods : Eligibility included measurable, biopsy-proven transformed iB-NHL, no prior ibrutinib, ECOG 0-2, and prior receipt of ≥ 1 line of therapy for the transformed disease. Treatment consisted of oral ibrutinib 560 mg daily until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response rate (ORR, per Lugano criteria by independent radiology review), with a predefined threshold of success ≥ 30%. Secondary endpoints included clinical benefit rate (CBR, defined as ORR and/or stable disease of ≥ 6 months), progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoints included ORR according to cell-of-origin (COO) of transformed lymphoma assessed by Hans algorithm and disease burden measured by computed tomography (CT) and metabolic tumor volume (MTV). Results : From October 2014 to March 2019, 20 patients were treated (Table 1). At enrollment, patients had received a median of 4 prior therapies (range 2 to 9) and were refractory to chemotherapy in 10 (50%) cases. Histology of transformed disease was diffuse large B cell lymphoma (DLBCL) in all patients. Two patients came off study prior to response assessment and without clinical evidence of disease progression: 1 after 1.3 months for intractable mucositis and 1 who died suddenly and without known cause 1.9 months into treatment. Median time on therapy was 3.1 months range (0.6 to 48.0) with 3 (15%) patients continuing on therapy > 1 year. Eighteen patients were evaluable for response. The ORR was 39% (complete response = 17%) and CBR was 44%. Median PFS and OS were 4.1 and 22.4 months, respectively, and median duration of response was 2.3 months; estimated 12-month PFS was 18% (Figure 1). ORR was more common in cases of low tumor burden but this association did not meet statistical significance on univariate analysis (p = 0.15 for maximum tumor < 5 cm by CT and p = 0.06 for MTV < 100 cm3). ORR was superior after prior autologous hematopoietic stem cell transplantation (auto-HSCT) (p = 0.01) and was not associated with DLBCL COO (p = 0.75). Dose holds for toxicity were required on 6 occasions in 5 (25%) patients for a median duration of 17.5 days (range 8 to 21); no reductions in dose were performed. Ibrutinib was resumed after resolution of toxicity at full dose in each case with the exception of an episode of pneumonia that, despite resolution, prompted the patient to stop treatment on study. Adverse events (AEs) considered related to ibrutinib were most commonly grade 1-2 and included fatigue (55%), bruising (55%), and diarrhea (35%). Grade ≥ 3 AEs included atrial arrythmia in 2 patients and the following AEs in 1 patient each: ventricular arrythmia, neutropenia, lymphopenia, mucositis/esophagitis, nausea, pneumonia, sepsis, and death of unknown cause. Conclusions : Ibrutinib appears active in R/R transformed iB-NHL and may provide extended disease control for a subset of patients or as part of a bridging strategy prior to CAR-T or transplant. The observed toxicity profile was consistent with other trials. Efficacy may be greater in cases of lower tumor burden and in patients previously treated with auto-HSCT. Further investigation of ibrutinib and focused study of agents in transformed iB-NHL is warranted. Disclosures Graf: BeiGene: Research Funding; AstraZeneca: Research Funding; TG Therapeutics: Research Funding. Cassaday:Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests; Amgen: Consultancy, Research Funding. Lynch:Rhizen Pharmaceuticals S.A: Research Funding; Incyte Corporation: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Juno Therapeutics: Research Funding. Krakow:Bellicum Pharmaceuticals: Research Funding; Highpass Bio: Research Funding; Magnolia Innovations: Consultancy. Smith:Denovo Biopharma: Research Funding; Acerta Pharma BV: Research Funding; Portola Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; Pharmacyclics: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Seattle Genetics: Research Funding. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding. OffLabel Disclosure: Ibrutinib is not approved for previously treated transformed indolent B-cell lymphoma.

Rapid and Durable Responses with the SYK/JAK Inhibitor Cerdulatinib in a Phase 2 Study in Relapsed/Refractory Follicular Lymphoma-Alone or in Combination with Rituximab

Rapid and Durable Responses with the SYK/JAK Inhibitor Cerdulatinib in a Phase 2 Study in Relapsed/Refractory Follicular Lymphoma-Alone or in Combination with Rituximab

Patient-Level Meta-Analysis of End-of-Therapy PET-CR as a Surrogate Endpoint for PFS and OS in Patients with Previously Untreated DLBCL: Implications for Clinical Trial Design

Patient-Level Meta-Analysis of End-of-Therapy PET-CR as a Surrogate Endpoint for PFS and OS in Patients with Previously Untreated DLBCL: Implications for Clinical Trial Design

Metabolic Tumor Volume for Early Response Assessment in Early-Stage Unfavorable Hodgkin Lymphoma Treated with Nivolumab in the GHSG Nivahl Phase II Trial

Background: Metabolic tumor volume (MTV) measured by FDG-PET/CT is becoming established as an independent risk factor for treatment failure in Hodgkin lymphoma (HL). Moreover, response to treatment with novel agents including checkpoint inhibitors may be better reflected by a decrease in MTV than by currently used response criteria. Our aim was to evaluate the early response to first-line HL treatment with the PD-1 inhibitor nivolumab using MTV. Methods: The analysis set included 59 patients with newly diagnosed, early-stage unfavorable HL treated within the prospective, multicenter, open label, randomized, phase II NIVAHL trial of the German Hodgkin Study Group (GHSG). Patients in NIVAHL were randomized to receive either four double cycles of nivolumab, doxorubicin, vinblastine, and dacarbazine (4x Nivo-AVD, group A, n=31) or a sequential therapy starting with 4x nivolumab monotherapy followed by 2xNivo-AVD and 2x AVD (group B, n=28). Early response to treatment was assessed at a 1st interim restaging after either 2x Nivo-AVD or 4x nivolumab. All NIVAHL patients who underwent PET at both initial staging and early response assessment, with images available to the central review panel for quantitative analysis before April 30th 2019, were included. MTV was calculated using a fixed SUV threshold of 4 for both staging and restaging. Results: Patient characteristics of the MTV analysis subset presented here did not differ in any relevant way from the overall NIVAHL trial population. Median age of the 59 patients was 27 years (range 18-57) with a female predominance (61%). All patients presented with stage II disease (IIB 27%) and ≥3 involved areas was the most common risk factor (75%) followed by elevated erythrocyte sedimentation rate (51%), extranodal disease (17%) and large mediastinal mass (14%). Mean MTV at initial staging was 124 ml (range 4 - 578 ml) and 177 ml (11 - 581 ml) in groups A and B, respectively. In both groups a marked decrease in MTV was observed at the 1st interim restaging (Figure 1): After 2x Nivo-AVD all patients in group A showed a reduction of MTV >80% (mean percentage change in MTV -99.8%). In group B a reduction of MTV >80% was observed in 26/28 patients (93%), while in 2/28 patients an increase <10% was observed (mean percentage change in MTV -91%; Figure 1). The mean residual MTV at interim restaging after 2x Nivo-AVD was 0.4 ml (range 0 - 8) in group A and 11 ml after 4x nivolumab in group B (range 0 - 176). The reduction of MTV was observed irrespective of initial MTV with a similar mean percentage change in patients above and below the median MTV in both groups. When applying the Deauville score, however, the number of patients presenting with a Deauville score ≥4 was higher in the group with an initial MTV above the median MTV than in the group where initial MTV lay below the median value. Using the Lugano criteria and a Deauville score of 4 or higher as cut-off for PET-positivity, early interim complete remission was observed in 81% of patients after 2xNivo-AVD, as compared to 51% after 4x nivolumab monotherapy. Further analyses regarding MTV and response at the 2nd and end-of-treatment restaging as well as survival data are not yet available due to limited follow-up. These data will be available at the time of presentation and shown at the meeting. Conclusions: Marked reductions of MTV demonstrate an excellent early efficacy for both 2x Nivo-AVD and 4x nivolumab as 1st-line therapy for early-stage unfavorable HL. The unexpectedly and previously unreported high MTV reduction with nivolumab monotherapy indicates a relevant potential of anti-PD1 mono- or debulking-therapy in the 1st-line treatment of early-stage unfavorable HL. Early interim response assessment based on MTV may help to identify HL patients treated with anti-PD1 antibodies in whom a significant reduction or even omission of chemotherapy could be considered. MTV appears to have the potential to accurately measure response to immune checkpoint inhibition. However, correlation of early MTV reduction with response at the end of treatment or with survival data is pending. Disclosures Borchmann: Novartis: Honoraria, Research Funding. Bröckelmann:Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; MSD Sharpe & Dohme: Research Funding.

Pivotal Safety and Efficacy Results from Transcend NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed/Refractory (R/R) Large B Cell Lymphomas

Pivotal Safety and Efficacy Results from Transcend NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed/Refractory (R/R) Large B Cell Lymphomas