Abstract: Background: While most patients (pts) with follicular lymphoma (FL) have excellent outcomes with frontline chemoimmunotherapy (CIT), a subset of pts will experience early progression, which is associated with inferior survival. Earlier identification of high-risk FL pts could allow for intervention with novel treatments to forestall early progression. Current prognostic tools are imperfect, particularly for pts receiving bendamustine-based regimens, and novel biomarkers are needed. In Hodgkin lymphoma, interim positron emission tomography (iPET) evaluated based on Deauville score (DS) is highly prognostic and is used to guide response-adapted therapy. The prognostic value of iPET using DS has not yet been assessed in a large population of FL pts receiving frontline CIT. We hypothesized that iPET would predict progression-free survival (PFS) in this population which could support PET-guided treatment approaches. Methods: We retrospectively identified pts with a diagnosis of FL (grade 1-3B) who initiated frontline CIT at Dana-Farber Cancer Institute from 1/2005-3/2019 and underwent an iPET after 2-4 cycles of CIT. Pts who received radiation (XRT) prior to CIT were included. Baseline, interim, and (when available) end-of-treatment (EOT) PET scans were reviewed by a nuclear medicine radiologist in a blinded fashion and assigned a DS of 1-5. Results: 118 pts were identified. The median age was 55 (range 26-82). 73 pts (62%) had grade 1-2 FL, 17 pts (14%) grade 3A, 15 pts (13%) grade 3B, 12 pts (10%) grade 3 NOS, and 1 pt (1%) grade not reported. FLIPI score was low for 32%, intermediate for 42% and high for 26%. In total, 5 pts (4%) received XRT before CIT. The most common CIT regimens were RCHOP (54%) and BR (42%) (Table 1). 107 pts (91%) received 6 cycles of CIT and 4 pts (3%) received 8 cycles, while 7 pts (6%) discontinued CIT after 4-5 cycles due to cytopenias (4), heart failure (1), infection (1), or pt decision (1). 88% of iPETs were performed after 3 cycles. iPET DS was 1 for 18%, 2 for 57%, 3 for 13%, 4 for 9%, and 5 for 3%. EOT PET was available for review for 112 pts (95%) and demonstrated DS of 1 for 32%, 2 for 56%, 3 for 3%, 4 for 4%, and 5 for 5%. After CIT, 29 pts (25%) received a median of 9 doses (range 1-13) of rituximab maintenance (RM) and 2 pts (2%) received consolidative XRT. With a median follow-up of 54 months (range 5-186), the 4-year (yr) PFS and overall survival (OS) for the entire cohort were 69% (95% CI 58-77%) and 94% (95% CI 87-98%), respectively. iPET was a significant predictor of PFS (p=0.0011 for 5 categories). Compared to pts with an iPET DS of 1-2, pts with a DS of 3 (HR 3.0, p=0.006) or a DS of 4-5 (HR 3.4, p=0.004) had inferior PFS (Figure 1) and were grouped together in a +iPET group (n=30) for all analyses. The 4-yr PFS for DS 1-2 and DS 3-5 pts were 77% and 46%, respectively (HR 3.2, p & lt;0.001). iPET had similar prognostic value among pts receiving BR (HR 3.3 p=0.033) or RCHOP (HR 3.6, p=0.005) and retained significance when pts with grade 3B FL were excluded (HR 2.6, p=0.007). iPET was not predictive of OS (HR 1.6, p=0.48). EOT PET was also a significant predictor of PFS (p & lt;0.0001 for 5 categories). 3 pts with a DS of 3 on EOT PET had favorable outcomes and were grouped with DS 1-2 pts. A positive EOT PET (defined as DS 4-5) was observed more frequently among pts with an iPET DS of 3-5 (9/29 pts; 31%) compared to an iPET DS of 1-2 (1/83 pts; 1%) (p & lt;0.001). To determine if iPET provides additional prognostic information beyond EOT PET, we sorted pts into 4 groups based on iPET/EOT PET status (i.e. -/-, +/-, -/+, and +/+). Compared to -/- pts, +/- pts (HR 2.4, p=0.039), -/+ pts (HR 3.6, p=0.045) and +/+ pts (HR 9.1, p= & lt;0.001) all had inferior PFS (Figure 2). A multivariable analysis confirmed that iPET (HR 2.9, p=0.017), EOT PET (HR 7.6, P & lt;0.001), high FLIPI (HR 2.5, p=0.011), and RM (HR 0.3, p=0.015) were significant predictors of PFS, while CIT regimen (p=0.94) and grade (p=0.21) were not. Conclusions: Our study suggests that iPET may be a useful prognostic marker in FL. Additionally, iPET interpretation may be different in FL compared to other lymphomas. In this cohort, pts with a DS of 3 on iPET had inferior PFS with outcomes similar to those of pts with a DS of 4-5. A DS of 3-5 on iPET appears to predict earlier progression independent of EOT PET while providing response-driven prognostic information earlier in a patient's treatment course. If validated, these results suggest that iPET could be investigated as a tool for response-adapted treatment strategies in FL. Disclosures Salles: BMS/Celgene: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; Epizyme: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; Genmab: Honoraria, Other; Karyopharm: Honoraria; Takeda: Honoraria. Zelenetz:MEI Pharma: Research Funding; Celgene: Research Funding; Sandoz: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Celgene: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Consultancy; MorphoSys: Research Funding; Gilead: Consultancy; Genentech/Roche: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Roche: Research Funding. Brown:Janssen, Teva: Speakers Bureau; Gilead, Loxo, Sun, Verastem: Research Funding; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy. Crombie:AbbVie: Research Funding; Bayer: Research Funding. Davids:Ascentage Pharma: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Merck: Consultancy; Research to Practice: Honoraria; Syros Pharmaceuticals: Consultancy; Zentalis: Consultancy; Sunesis: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Fisher:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Jacobsen:Merck: Consultancy; Acerta: Consultancy; Astra-Zeneca: Consultancy; Pharmacyclics: Research Funding; F. Hoffmann-LaRoche: Research Funding; Novartis: Research Funding; Takeda: Honoraria. LaCasce:BMS: Consultancy; Research to Practice: Speakers Bureau; UptoDate: Patents & Royalties. Armand:Sigma Tau: Research Funding; Tensha: Research Funding; Pfizer: Consultancy; Affimed: Consultancy, Research Funding; IGM: Research Funding; Adaptive: Consultancy, Research Funding; Celgene: Consultancy; Merck & Co., Inc.: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Infinity: Consultancy; ADC Therapeutics: Consultancy; Genentech: Research Funding.

Abstract: T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune “neighborhoods” in which malignant B cells are surrounded by exceptionally high numbers of PD-L1–expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.

Abstract: Introduction: Peripheral T-cell lymphomas (PTCL) are a rare subset of non-Hodgkin lymphomas with an overall response rate to CHOP-based therapy of 80% but 5-year survival ranges between 20-40%. (Ellin et al Blood 2014) While response by PET/CT is prognostic (Mehta-Shah Blood Advances 2019), the high rate of relapse after complete response suggests that more sensitive determinants of minimal residual disease may have prognostic and even therapeutic importance. T-cell receptor gene rearrangement (TCR) by next generation sequencing is able to detect a known TCR clonotype at 10-5. (Shah et al AMP 2017) Therefore, in a prospective multi-institutional study, we sought to evaluate the utility of peripheral blood TCR by next generation sequencing in quantifying minimal residual disease in peripheral T-cell lymphoma. (NCT03297697) Here we report the results of TCR evaluation at the end of CHOP-based therapy. Methods: Patients with previously untreated PTCL (PTCL-NOS: peripheral T-cell lymphoma, NOS; angioimmunoblastic T-cell lymphoma: AITL; anaplastic large cell lymphoma: ALCL;, monomorphic epitheliotropic intestinal T-cell lymphoma: MEITL) treated with anthracycline based therapy for curative intent were eligible for the study. TCR (TCR gamma, TRG, or TCR beta, TRB) clonotype was established from baseline diagnostic tumor tissue. Peripheral blood (10cc) was collected in Streck tubes for TCR clonotype at each cycle of therapy, after completion of CHOP-based therapy, every 6 months for two years, at progression and in the stem cell product (if collected). TCR clonality was assessed and tracked using the LymphoTrack® TRG/TRB Assays-MiSeq® (Invivoscribe, San Diego, CA). Results: 39 patients were enrolled in the study (16 PTCL-NOS, 10 AITL, 7 ALK- ALCL, 5 ALK+ ALCL, 1 MEITL). One patient was enrolled with PTCL-NOS but was withdrawn after confirming a diagnosis of T-ALL. One patient with ALK- ALCL withdrew consent prior to sample collection. 19 patients have completed frontline therapy and have end of treatment TCR analysis available. The remaining 18 patients either have not yet completed treatment or did not have samples analyzed at the time of submission. Patients received CHOEP (n=10), BV-CHP (n=4), CHOP (n=32), CEOP (n=1) and CHOP+azacitidine (n=1). Median age was 61 (range: 22-80). Sixteen completed 6 cycles of therapy and of these, 7 underwent consolidation with an autologous transplant. One stopped due to intolerance after 5 cycles and remains in complete remission. 2 had progression of disease prior to completion of 6 cycles of therapy. At end of treatment evaluation by PET/CT, 13/19 (68%) had complete remission, 1/19 (5%) had partial remission and 5/19 (26%) had progressive disease. Of the 19 patients, 15 (78.9%), including 1 with leukemic disease, had TCR clonotype identifiable in the baseline diagnostic tissue, and 4 (21.1%) did not have a TCR clonotype identified (3 PTCL NOS, 1 ALK+ ALCL) in tumor tissues at baseline. Two of 15 patients had undetectable TCR clonotype in the blood at end of treatment and neither of them has relapsed. Thirteen of the 15 patients had detectable TCR clonotype at end of treatment. Of the 10 patients in complete remission by PET/CT at the end of treatment with known clonotype, 8 had a detectable TCR clonotype and 2 had undetectable TCR at the end of CHOP-based therapy. Five of 6 patients with PD or PR at end of treatment had detectable TCR clonotype in the blood and 1 lacked clonotype in baseline samples. At a median follow up of 13.1 months, only one patient has relapsed and this patient had positive peripheral blood TCR at end of treatment despite PET CR. We will present the end of treatment evaluation for all patients on the study at the time of the meeting. Conclusions: Measurement of peripheral blood TCR at the end of treatment is feasible in PTCL using next generation sequencing with a known tumor clonotype. Lack of radiographic CR was highly correlated with detectable TCR, but detectable TCR was also frequently seen in complete remission by PET/CT. Longer follow up, including analysis of TCR following autologous transplant, is required to determine if TCR clonotype at the end of CHOP-based therapy predicts likelihood of relapse and to evaluate the dynamics of TCR clonotype during and after completion of treatment. This study was supported by the Lymphoma Research Foundation and T-cell Leukemia/Lymphoma Society. Disclosures Mehta-Shah: Bristol Myers-Squibb: Research Funding; Celgene: Research Funding; Kyowa Hakko Kirin: Consultancy; C4 Therapeutics: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding; Innate Pharmaceuticals: Research Funding; Genetech/Roche: Research Funding. Fehniger:Indapta: Consultancy; Nkarta: Consultancy; Kiadis: Consultancy; HCW Biologics: Research Funding; Compass Therapeutics: Research Funding; ImmunityBio: Research Funding; Orca Biosystems: Consultancy; Wugen: Consultancy. Jacobsen:Takeda: Honoraria; Acerta: Consultancy; Astra-Zeneca: Consultancy; Merck: Consultancy; F. Hoffmann-LaRoche: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Kahl:AbbVie: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Laboratories Inc: Consultancy; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bartlett:Seattle Genetics: Consultancy, Research Funding; Millennium: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Acerta: Consultancy; Affimed Therapeutics: Research Funding; BTG: Consultancy; Janssen: Research Funding; BMS/Celgene: Research Funding; Immune Design: Research Funding; Kite, a Gilead Company: Research Funding; Forty Seven: Research Funding; ADC Therapeutics: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Roche/Genentech: Consultancy, Research Funding; Autolus: Research Funding. Ghobadi:Amgen: Consultancy, Research Funding; WuGen: Consultancy; EUSA: Consultancy; Bristol Myers Squibb: Consultancy; Kite: Consultancy, Research Funding. Moskowitz:Merck: Research Funding; Seattle Genetics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Miragen Therapeutics: Consultancy; Incyte: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Consultancy. Huang:Invivoscribe: Current Employment. Hutt:Invivoscribe: Current Employment. Vigil:Invivoscribe: Current Employment. Olson:Invivoscribe: Current Employment. Jacobsen:Invivoscribe: Current Employment. Horwitz:GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; Myeloid Therapeutics: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; ASTEX: Consultancy; Affirmed: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; C4 Therapeutics: Consultancy.

Abstract: Background: Induction chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for transplant eligible (TE) patients (pts) with untreated mantle cell lymphoma (uMCL); however, there is no consensus on the optimal induction regimen. The addition of rituximab + high-dose cytarabine (RC) to an RCHOP-like regimen is associated with better outcomes. In addition, two randomized trials have demonstrated superior efficacy and tolerability for rituximab/bendamustine (RB) compared to RCHOP for uMCL. Based on this, we conducted a phase 2 trial of 3 cycles of RB followed by 3 cycles of RC in 23 TE pts with uMCL, with encouraging preliminary results (Armand, BJH 2016). Pts continued to be followed for relapse and survival. Meanwhile, RB/RC became the standard frontline regimen at Dana-Farber Cancer Institute (DFCI). Simultaneously, investigators at Washington University in St. Louis (WUSTL) initiated a similar study of alternating cycles of RB/RC for uMCL. Herein, we report the results of both phase 2 trials as well as the off-trial experience. Methods: In the DFCI trial, TE pts (age 18-69) with uMCL were treated with 3 cycles of RB (R 375 mg/m2 d1, B 90 mg/m2 d1-2) followed by 3 cycles of RC (R 375 mg/m2 d1, C 3gm/m2 BID d1-2 with dose reductions for age, renal dysfunction, or pre-existing neurotoxicity). Off-trial pts treated with RB/RC at DFCI or in consulting community practices were retrospectively identified using clinical and pharmacy databases. In the WUSTL trial, TE pts (age 18-65) received alternating cycles of RB (cycles 1, 3, 5) and RC (cycles 2, 4, 6) (same dosing as above). Response assessments were made using CT scans for the DFCI trial and PET/CT for the WUSTL trial and DFCI off-trial pts. Results: In total, 86 pts (23 DFCI trial, 49 DFCI off-trial, 14 WUSTL trial) were treated with RB/RC. The median age was 57 (range 30-72). Pts in the WUSTL cohort were more likely to be male, have a high MIPI score, and have blastoid variant (Table). 94% of pts completed 6 cycles of RB/RC therapy. Off-trial pts were more likely to receive a lower starting dose (≤ 2gm/m2) of cytarabine (76%) compared to trial pts (38%). At the EOI, the overall response rate and CRR were 98% and 92%, respectively, with similar response rates across cohorts (Table). 73 pts (85%) subsequently underwent ASCT and 4 additional pts (5%) have ASCTs planned. 9 pts did not undergo ASCT because of persistent or PD (n=3), prolonged cytopenias (n=3), an incidentally identified ASXL1 mutation without cytopenias (n=1), pt preference (n=1), and inadequate stem cell collection (n=1). Delayed platelet engraftment after ASCT was seen for pts receiving alternating cycles of RB/RC compared to sequential RB/RC at day 30 (plts 〈 50: 70% vs 16%, p=0.001) and at day 100 (plts 〈 100: 60% vs 21%, p=0.017). An initial cytarabine dose 〉 2gm/m2 was also associated with reduced 30-day platelet count (plts 〈 50: 41% vs 8%, p=0.004). There was 1 treatment-related death from respiratory failure and RSV infection (Day 56 after ASCT). Median follow-up was 32m (range 4-69m) among survivors overall (54m for DFCI trial, 28m for DFCI off-trial, 19m for WUSTL trial). The 24m and 48m PFS for the entire cohort were 88% (95CI 77-93) and 80% (95CI 66-89), respectively (Figure, panel A); the 24m and 48m OS were 96% (95CI 89-99) and 92% (95CI 81-97), respectively. PFS and OS were similar across cohorts with a trend towards inferior PFS in the higher-risk WUSTL cohort (Figure, panel B). PFS was similar among non-trial pts treated at DFCI (n=32) and in community centers (n=17). In univariate analyses, a higher cytarabine dose ( 〉 2gm/m2) was not associated with improved PFS, while blastoid or pleomorphic variant (HR 4.5, p=0.016) and high-risk MIPI score (HR 4.0, p=0.034) were both associated with inferior PFS. Conclusions: Induction therapy with RB/RC followed by ASCT achieved high rates of durable remissions in two phase 2 clinical trials. Similarly favorable outcomes were observed with off-trial use of this regimen both at an academic center and in community practices. RB/RC is therefore an excellent choice of induction therapy for TE pts with uMCL, and could be further tested in comparative prospective trials. Sequential, rather than alternating, RB/RC cycles and lower dose cytarabine may reduce the risk of prolonged thrombocytopenia post-ASCT. Figure 1. Figure 1. Disclosures Kahl: Juno: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Acerta: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy. LaCasce:Research to Practice: Speakers Bureau; Bristol-Myers Squibb: Other: Data safety and monitoring board; Seattle Genetics: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria. Jacobson:Bayer: Consultancy; Novartis: Consultancy; Precision Bioscience: Consultancy; Humanigen: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Davids:Gilead: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Merck: Consultancy; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Brown:Sun Pharmaceutical Industries: Research Funding; Roche/Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Research Funding; Genentech: Consultancy; Celgene: Consultancy; Boehringer: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Verastem: Consultancy, Research Funding; Loxo: Consultancy; TG Therapeutics: Consultancy; Sunesis: Consultancy. Bartlett:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Pharmacyclics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Novartis: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Bristol-Meyers Squibb: Research Funding; Immune Design: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Novartis: Research Funding; Millennium: Research Funding. Armand:Merck: Consultancy, Research Funding; Adaptive: Research Funding; Otsuka: Research Funding; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Jacobsen:Seattle Genetics: Consultancy; Merck: Consultancy.

Abstract: Introduction: Peripheral T-cell lymphomas (PTCL) are a rare subset of non-Hodgkin lymphomas in which approximately 80% patients will have an overall response to CHOP based therapy but 5-year survival ranges between 20-40%. (Ellin et al Blood 2014) While response by PET/CTs have been helpful in risk stratifying patients (Mehta-Shah Blood Advances 2019), the high rate of relapse after complete response (CR) suggests that more sensitive determinants of minimal residual disease (MRD) could have prognostic and even therapeutic importance. T-cell receptor gene rearrangement sequencing (TCR) is standardly performed by next generation sequencing and is able to detect a known TCR clonotype at 10 -5. (Shah et al AMP 2017) Therefore, in a prospective multi-institutional study, we sought to evaluate the utility of TCR by next generation sequencing in quantifying MRD in PTCL. (NCT03297697). Here we report the results of the TCR evaluation at the end of CHOP-based therapy. Methods: Subjects with previously untreated PTCL (PTCL-NOS: peripheral T-cell lymphoma, NOS; angioimmunoblastic T-cell lymphoma: AITL; anaplastic large cell lymphoma: ALCL; T-follicular helper phenotype peripheral T-cell lymphoma: PTCL-TFH, monomorphic epitheliotropic intestinal T-cell lymphoma: MEITL) who were being treated with anthracycline based therapy for curative intent were eligible for the study. TCR (TRG or TRB) clonotype was established from baseline formalin fixed paraffin embedded tumor tissue or peripheral blood when tissue samples are not available. TCR clonality was identified using the LymphoTrack® TRG/TRB Assays - MiSeq® (Invivoscribe, San Diego, CA) when top %reads is ≥2.5% and is at least 2x compared to the background. Results: 43 subjects were enrolled in the study and 41 were evaluable (15 PTCL-NOS, 10 AITL, 7 ALK- ALCL, 5 ALK+ ALCL, 3 PTCL-NOS with TFH phenotype, 1 MEITL). One subject was enrolled with PTCL-NOS and later found to have T-ALL and was withdrawn from the study. One subject with ALK- ALCL withdrew consent prior to sample collection. Subjects initiated treatment with CHOEP (n=16), BV-CHP (n=11), CHOP (n=5), CEOP (n=1) CHOP+azacitidine (n=6), CHOEP+lenalidomide (n=1), EPOCH (n=1). The median age was 65 (range: 22-80). Sixteen underwent a consolidative autologous transplant. Among the 41 evaluable subjects, 73% (30/41) had tissue samples and 27% (11/41) had only PB samples for TCR clonotype assessment. TCR clonotype was identified in 78% (32/41) tissue samples and not in 23% (9/40: 1 Nodal TFH, 2 AITL, 1 ALK- ALCL, 5 ALK+ ALCL) samples. Of the 32 subjects with baseline clonotype, 2 patients (1 AITL, 1 PTCL) did not have end of treatment (EOT) samples for TCR MRD evaluation. For EOT MRD evaluation, 80% (24/30) were had detectable MRD by TCR (MRD positive) and 20% (6/30) had undetectable TCR (TCR MRD negative). For the EOT evaluation by PET/CT, 63% (19/30) had CR, 10% (3/30) had partial remission (PR) and 27% (8/30) had progressive disease (PD). Among the 6 TCR MRD negative subjects, PET/CT responses were 67% (4/6) for CR and 33% (2/6) for PR, respectively. Among the 24 TCR MRD positive subjects, PET/CT responses were 63% (15/24) for CR, 33% (1/24) for PR and 33% (8/24) for PD. Of those with positive MRD 13/24 (54%) have relapsed/progressed including 8 with primary refractory disease. At the end of CHOP-based therapy, 79% (15/19) subjects with PET CR were TCR MRD positive, and 21% (4/19) were TCR MRD negative. Among the 11 subjects with either PD or PR by PET/CT, 82% (9/11) were TCR MRD positive, and 18% (2/11) were TCR MRD negative. At a median follow up of 20.7 months, progression free survival and overall survival at 18 months did not differ between those who were TCR MRD positive or negative respectively at EOT (OS 64% vs 67% p=0.63; PFS 41% vs 50% p=0.40). We plan to present additional follow up for all patients on the study including MRD post autologous transplant at the time of the meeting. Conclusions: Measurement of peripheral blood TCR at the end of treatment is feasible in peripheral T-cell lymphomas using next generation sequencing with a known tumor clonotype. Detectable TCR at the end of treatment correlates with lack of CR but the majority of patients in complete remission by PET/CT have a detectable TCR clonotype at end of treatment. Longer follow up is required to determine if consolidative transplant alters TCR dynamics. This study was supported by the Lymphoma Research Foundation and T-cell Leukemia/Lymphoma Society. Figure 1 Figure 1. Disclosures Mehta-Shah: C4 Therapeutics: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Karyopharm: Consultancy; Kiowa Hakko Kirin: Consultancy; Verastem: Research Funding. Jacobsen: Takeda: Consultancy; Syros: Consultancy; Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding. Fehniger: Wugen: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties: related to memory like NK cells, Research Funding; Affimed: Research Funding; Compass Therapeutics: Research Funding; HCW Biologics: Research Funding; Kiadis: Other; ImmunityBio: Research Funding; OrcaBio: Other; Indapta: Other. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. Bartlett: Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Ghobadi: Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Atara Biotherapeutics: Consultancy; Wugen: Consultancy; Celgene: Consultancy. Moskowitz: Seattle Genetics: Consultancy, Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Merck: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Miragen: Research Funding; Beigene: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Consultancy; Incyte: Research Funding; Janpix Ltd.: Consultancy. Jacobsen: Invivoscribe: Current Employment. Olson: Invivoscribe: Current Employment. Vigil: Invivoscribe: Current Employment. Hill: Invivoscribe: Current Employment. Elias: Invivoscribe: Current Employment. Huang: Invivoscribe: Current Employment. Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Celgene: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding.

Abstract: Background: The leading cause of death after high-dose chemotherapy and autologous stem cell transplantation (ASCT) for relapsed / refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains disease relapse. Except for specific subsets, DLBCL appears to have relatively low susceptibility to single-agent PD-1 blockade. However, administering PD-1 blockade early after ASCT could leverage the remodeling immune landscape and minimal residual disease state to increase the therapeutic effect of PD-1 blockade and decrease the relapse rate after ASCT. A prior study with pidilizumab showed encouraging results in this setting (Armand et al. JCO 2013;31:4199-206), but the specificity of that antibody is still under investigation. We therefore conducted a phase 2 multi-center single-arm study of the anti-PD-1 monoclonal antibody pembrolizumab (pembro) in patients with chemosensitive DLBCL after ASCT. Another arm of this study enrolled pts with R/R classical Hodgkin lymphoma and will be presented separately. Methods: Patients ≥ 18y with R/R DLBCL who had received no more than 3 lines of prior therapy and had undergone ASCT with chemosensitive disease were enrolled on this study. In addition to meeting standard eligibility criteria for pembro treatment, pts had to have recovered from ASCT toxicities and had to begin study treatment within 60 days of stem cell infusion, with a goal of starting treatment within 21 days of hospital discharge. All patients received pembro 200mg IV every 3 weeks for 8 cycles. PET-CT scans were obtained at post-ASCT baseline, after 3 and 7 cycles, then at 12 and 18 months post-ASCT. The primary endpoint was the progression-free survival rate (PFS) at 18 months after ASCT, assessed using the International Harmonization Project 2007 criteria, with the approach considered promising if 22 patients were alive and in remission at 18 months. Results: 31 pts were enrolled and 2 withdrew consent before starting treatment. Among the 29 eligible pts, median age was 57 (22-76). Prior to ASCT, 18 (62%) were in CR and 11 (38%) were in PR. At study baseline (post-ASCT), 25 (86%) were in CR. 18 pts (62%) completed all 8 cycles of pembro per protocol. 11 pts (38%) stopped pembro early for pt choice (n=1, after febrile neutropenia), toxicity (n=6, including 3 pts with gr3 pneumonitis, 1 with g3 hepatitis, 1 with gr4 aplastic anemia) or progressive disease (n=4). 23 pts (79%) experienced a total of 57 gr3 or higher adverse events (AEs). The most common gr4 AE was neutropenia (n=6, 21%). Concerning related AEs, 9 pts (31%) experienced 14 gr3-4 AEs at least probably related to pembro including neutropenia (4 gr3, 1 gr 4) and pneumonitis (2 gr3). 10 pts (34%) experienced at least one immune-related AE of gr2 or higher severity including pneumonitis (n=1 gr2, n=2 gr3), transaminitis (n=1 gr2, n=1 gr3) and rash (n=1 gr2, n=1 gr3). There were no treatment-related deaths. Among the 29 eligible pts, 1 patient withdrew consent after cycle 1 and 1 pt was lost to follow-up after the 12m assessment (in CR). 27 pts (93%) were evaluable for the primary endpoint. 10 patients (34%, 95% CI: 18-54%) experienced disease relapse at a median of 5 months (3-18) after ASCT, and all other evaluable patients (n=17, 59%, 95% CI: 39-76%) were in CR at the 18m timepoint. 2 pts have died, both of whom had relapse at 3m after ASCT. Correlative studies including immune reconstitution and MRD analyses are ongoing. Conclusions: Pembrolizumab administered after ASCT in patients with R/R DLBCL is feasible with toxicity similar to its use in the R/R setting for other hematological malignancies. The high rate of neutropenia on this study, which is not a common AE of pembro in other settings, may be related to the burden of prior therapy or possibly to an accentuated toxicity of pembro in this specific patient population. The 18-month progression-free rate did not meet the protocol-specified primary objective, and therefore does not support a larger confirmatory study. Future studies in this setting should likely focus on specific subsets of DLBCL, e.g. primary mediastinal BCL, EBV+ DLBCL, T cell histiocyte rich LCL, which may be especially sensitive to PD1 blockade. Disclosures Chen: REGiMMUNE: Consultancy; Magenta Therapeutics: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Armand:Pfizer: Consultancy; Adaptive: Research Funding; Merck: Consultancy, Research Funding; Infinity: Consultancy; Affimed: Consultancy, Research Funding; Otsuka: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Herrera:Seattle Genetics: Research Funding; KiTE Pharma: Consultancy, Research Funding; Gilead Sciences: Research Funding; Merck, Inc.: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; Immune Design: Research Funding. LaCasce:Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Seattle Genetics: Consultancy, Honoraria. Jacobson:Pfizer: Consultancy; Precision Bioscience: Consultancy; Kite: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Humanigen: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. Rodig:Merck & Co., Inc.: Research Funding; Affimed Inc.: Research Funding; KITE Pharma: Research Funding; Bristol-Meyers-Squibb: Research Funding. Shipp:AstraZeneca: Honoraria; Merck: Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Disease relapse remains the leading cause of failure after autologous stem cell transplantation (ASCT) for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We conducted a phase 2, multicenter, single-arm study of the anti–PD-1 monoclonal antibody pembrolizumab given after ASCT in patients with chemosensitive DLBCL, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary endpoint) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Twenty-nine patients were treated on this study; 62% completed all 8 cycles. Seventy-nine percent of patients experienced at least one grade 3 or higher adverse event, and 34% experienced at least one grade 2 or higher immune-related adverse event. Overall, 59% of patients were alive and progression free at 18 months, which did not meet the primary endpoint. The 18-month overall survival was 93%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with R/R DLBCL, but the PFS did not meet the protocol-specific primary objective and therefore does not support a larger confirmatory study. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

Abstract: Background: Autologous stem cell transplantation (ASCT) can be curative for a subset of patients (pts) with relapsed/refractory classical Hodgkin lymphoma (cHL). Post-ASCT maintenance therapy with brentuximab vedotin (BV) improves progression-free survival (PFS) among pts with high-risk clinical features, and PD-1 blockade is also being investigated in this setting. Ideally, novel biomarkers could be used to guide pt selection for these post-ASCT therapies. We hypothesized that the presence of minimal residual disease (MRD), quantified using immunoglobulin-based next generation sequencing (IgNGS), could predict post-ASCT relapse. As a preliminary test of this hypothesis, we analyzed a cohort of cHL pts who had serial peripheral blood mononuclear cell (PBMC) and plasma samples collected before or after ASCT. Methods: Samples from 2 cohorts (n=36) were analyzed. 28 pts were prospectively enrolled on a biobanking protocol and underwent ASCT at Dana-Farber Cancer Institute between 2014-2016 (biobank cohort). In addition, 8 pts underwent ASCT between 2015 and 2016 and subsequently participated in a multicenter phase II trial of post-ASCT pembrolizumab maintenance (PM) (trial cohort) (Armand, Blood 2020). Tumor tissue and serial post-ASCT plasma and PBMC samples were collected for all pts, and some pts also had pre-ASCT PB samples available for analysis. NGS of Ig receptor sequences (IgNGS) (clonoSEQ Ò, Adaptive Biotechnologies) was used to identify and track tumor clonotypes, as previously described (Ching, BMC Cancer 2020). MRD testing was not used for clinical decision making. Results: The 36 enrolled pts received a median of 2 lines of therapy, and 30 pts (83%) achieved a complete response (CR) on pre-ASCT positron emission tomography (PET). In total, 19 pts received post-ASCT treatment - PM (n=8, all on trial), radiation therapy (n=5), BV maintenance (n=4), and allogeneic stem cell transplantation as part of a planned tandem transplant (n=2). Among 36 enrolled pts, 12 (33%) had an identifiable clonotype (11/28 biobank and 1/8 trial). Higher rates of clonotype detection were seen in pts aged & lt;32 (median) (56% vs 11%, p=0.012) and pts with primary refractory disease (56% vs 16%, p=0.030). With a median follow-up of 50 (range 4-75) months, there were no significant differences in PFS or overall survival among pts with and without a detectable tumor clonotype. The 12 clonotyped pts had a median of 4 (range 1-13) post-ASCT plasma and 3 (range 1-17) post-ASCT PBMC samples. Among the 4 pts who relapsed, 3 had MRD detected within plasma samples with lead times of 0, 11, and 909 days (Figure 1). The pembrolizumab trial pt had detectable MRD early after ASCT which cleared within 9 weeks of starting pembrolizumab therapy, remained undetectable for the duration of pembrolizumab treatment, and became detectable again 5 months after completing PM in conjunction with clinical relapse. All pts with detectable MRD in a post-ASCT plasma sample subsequently relapsed (100% specificity). One pt relapsed without detectable MRD, but had a long interval (312 days) from last plasma sample to relapse. IgNGS testing from PBMC samples did not correlate with clinical outcomes; only two PBMC samples had detectable MRD and both were from a pt who did not relapse. 3 pts had pre-ASCT plasma samples collected concurrently with post-salvage PET scans. One pt achieved a partial response (PR) after 2 cycles of bendamustine and BV (Benda-BV), progressive disease after 4 cycles of Benda-BV, and a CR after pembrolizumab. MRD was detected after two cycles of Benda-BV (6.52 counts per million), was rising after 4 cycles of benda-BV (8.99 counts per million) and was undetectable after pembrolizumab. The pt remains in remission after a tandem transplant. Pre-ASCT samples were MRD negative in two other pts (1 CR, 1 PR) following salvage chemotherapy, both of whom remain in remission after ASCT. Conclusions: The clonotype detection rate among pts with cHL was considerably lower than has been reported for other B-cell lymphomas, likely due to the scarcity of Reed Sternberg cells within cHL tumor samples. Novel MRD techniques for cHL should be investigated. In this pilot study, among pts with a detectable clonotype, MRD was a dynamic marker of response to different therapies and was a specific indicator of impending relapse, suggesting that additional studies of MRD in cHL are warranted. Figure 1 Figure 1. Disclosures Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy. Crombie: Roche: Research Funding; Incyte: Consultancy; Karyopharm: Consultancy; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding. Davids: TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Takeda: Consultancy; Surface Oncology: Research Funding; AbbVie: Consultancy; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy. Jacobsen: Takeda: Consultancy; Syros: Consultancy; Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding. Jacobson: Lonza: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau; Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Humanigen: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support. LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Dahi: Kite / Gilead: Membership on an entity's Board of Directors or advisory committees. Chen: Gamida: Consultancy; Incyte: Consultancy. Herrera: ADC Therapeutics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Tubulis: Consultancy; Kite, a Gilead Company: Research Funding; Seagen: Consultancy, Research Funding; Takeda: Consultancy; Gilead Sciences: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Armand: IGM: Research Funding; Tensha: Research Funding; Roche: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; Enterome: Consultancy; Daiichi Sankyo: Consultancy; Miltenyi: Consultancy; Tessa Therapeutics: Consultancy; GenMab: Consultancy; C4: Consultancy; Kite: Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Otsuka: Research Funding; Sigma Tau: Research Funding; Morphosys: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding.

Abstract: Backgound Venetoclax (V) plus obinutuzumab (O) regimen is active as frontline CLL treatment; a little over half of patients (pts) will achieve undetectable minimal residual disease in the bone marrow (BM-uMRD) with one year of time-limited therapy (Fischer et al. NEJM 2019). Novel strategies may further augment the efficacy of VO. Ibrutinib was previously combined with VO, but relatively high rates of infusion reactions and neutropenia were observed, as were the characteristic toxicities of ibrutinib including diarrhea and bruising (Rogers et al. Blood 2018). Acalabrutinib (A), a more selective BTK inhibitor, is well-tolerated and active as monotherapy or with O, and we previously found that it sensitizes CLL cells to V (Deng et al. Leukemia 2017). We hypothesized that a time-limited triplet combination of A, V, and O (AVO) could achieve a high rate of BM-uMRD with good tolerability. For the first time we now report on the safety and preliminary efficacy data of AVO in previously untreated CLL pts. Methods This ongoing open-label, single arm, phase 2 investigator-initiated study (NCT03580928) enrolled pts with previously untreated CLL without restriction by prognostic marker status. Eligibility: requiring treatment by iwCLL criteria, ECOG PS ≤ 2, creatinine clearance ≥50ml/min, absolute neutrophil count ≥500/mm3, and platelets ≥30,000/mm3. A, V, and O are started sequentially (see figure), with one 28-day cycle lead-in with A at 100 mg bid, then 2 cycles of AO (with O at standard dosing), then V ramp-up beginning at C4, followed by 3 more cycles of triplet AVO therapy. After 6 months of O, the AV doublet continues through C15; pts with BM-uMRD-negative CR after C15 may discontinue therapy, while all others continue AV until completing C24, with the option to discontinue therapy if in BM-uMRD CR at that time. Response is assessed by 2018 iwCLL criteria, including bone marrow biopsy with MRD testing in the BM and peripheral blood (PB) by 8-color flow cytometry at a sensitivity of at least 10-4. The primary endpoint is the rate of BM-uMRD CR after 15 cycles. Non-hematologic adverse events (AEs) are assessed by CTCAE v5.0, with hematologic toxicity determined by iwCLL criteria. Results The data cut for this interim analysis was July 11, 2019. The study is fully accrued at 37 pts. Median age: 63 years (range: 41-78), 73% male. Baseline prognostic features: unmutated IGHV in 23 (62%) pts, TP53 aberrant disease (defined as either del(17p) and/or TP53 mutation) in 10 (27%) pts, del(11q) in 10 (27%) pts, and complex karyotype in 7 (19%) pts. Thirty-six pts remain on study drugs with a median time on therapy of 8 months (range: 2-11). One pt withdrew consent after 6 cycles due to gastrointestinal symptoms. The overall response rate for the 24 pts who have completed re-staging at C8 is 100%, 18 (75%) PR and 5 (25%) CR. At C8 restaging, 65% of pts were PB-uMRD, 50% of pts were BM-uMRD, and 3 pts (13%) had BM-uMRD CRs. In 8 pts with TP53-aberrant disease who have reached C8, 6 had PR and 2 had CR, with 3 pts BM-uMRD. The most frequent AEs have been fatigue (81% total, 78% gr 1+2, 3% gr ≥3) and headache (76% total, 73% gr 1+2, 3% gr ≥3). Bruising was reported by 16 pts (43%, all gr 1+2). The most frequent gr 3/4 AE has been neutropenia (68% total, 32% gr ≥3). Infusion-related reactions were seen in 8 pts (22%, 19% gr 1+2, 3% gr ≥3). Laboratory tumor lysis syndrome (TLS) occurred in 2 pts (5%), both gr 3 immediately after starting O and prior to any V; both pts continued O. Out of 32 pts, 31 (97%) were medium-to-high risk for TLS on C1D1 but only 3 (9%) were medium-to-high risk at V initiation on C4D1, with 4 medium-to-low risk pts electively admitted for V initiation. One case of gr 3 atrial fibrillation and no cases of hemorrhage or febrile neutropenia were observed. Conclusion Our preliminary data suggest that even at an early response evaluation after 8 cycles of therapy (including only 4 months of V), AVO as frontline CLL therapy leads to a high proportion of pts achieving BM-uMRD and CR, including pts with TP53-aberrant disease. The AE profile is favorable, with a low rate of infusion reactions and no significant cardiac or bleeding toxicities. Updated data will be presented at the meeting for this ongoing study. Based on our initial results we have opened an expansion cohort to further characterize the efficacy and safety of AVO. AVO will also be studied head-to-head against chemoimmunotherapy and the AV doublet in the phase 3 trial CL-311 (NCT03836261), which is currently enrolling. Figure Disclosures Montegaard: Pharmacyclics: Consultancy; Janssen: Consultancy. Jacobson:Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Pfizer: Consultancy, Research Funding; Humanigen: Consultancy, Other: Travel Expenses; Bayer: Consultancy, Other: Travel Expenses; Precision Biosciences: Consultancy, Other: Travel Expenses; Celgene: Consultancy, Other: Travel Expenses. Jacobsen:Astra-Zeneca: Consultancy; Novartis: Research Funding; F. Hoffmann-LaRoche: Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Acerta: Consultancy. LaCasce:Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy; Research to Practice: Speakers Bureau; Humanigen: Consultancy. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy; Celgene/Juno: Consultancy. Armand:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; Infinity: Consultancy; Genentech: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding. Brown:BeiGene: Consultancy; AbbVie: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Juno/Celgene: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; Research to Practice: Honoraria. OffLabel Disclosure: Acalabrutinib, venetoclax, obinutuzumab - combination therapy for previously untreated CLL