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Salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) is a potentially curative treatment for patients with relapsed or refractory large B-cell lymphoma (rrLBCL) with chemosensitive disease. A

Patients with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART19). However, more than half of recipients will experience treatment failure. Thus, approaches are needed to identify high-risk patients who may benefit from alternative or consolidative therapy. We evaluated low-pass whole-genome sequencing (lpWGS) of cell-free DNA (cfDNA) before CART19 as a new approach for risk stratification. We performed lpWGS on pretreatment plasma samples from 122 patients at time of leukapheresis who received standard-of-care CART19 for rrLBCL to define DNA copy number alterations (CNAs). In multivariable selection, high focal CNA score (FCS) denoting genomic instability was the most significant pretreatment variable associated with inferior 3-month complete response rates (28% vs 56%, P = .0029), progression-free survival (PFS; P = .0007; hazard ratio, 2.11), and overall survival (OS; P = .0026; hazard ratio, 2.10). We identified 34 unique focal CNAs in 108 (89%) patients; of these, deletion 10q23.3 leading to loss of FAS death receptor was the most highly associated with poor outcomes, leading to inferior PFS (P 1 extranodal site), we built a simple risk model that could reliably risk stratify patients. Thus, lpWGS of cfDNA is a minimally invasive assay that could rapidly identify high-risk patients and may guide patient selection for and targeted therapies to evaluate in future clinical trials.

Long-term follow up of prospective studies has shown that continuous Bruton's tyrosine kinase inhibitor (BTKi) therapy leads to durable remissions in previously untreated patients with TP53-altered chronic lymphocytic leukemia (CLL); however, it is unknown how variant allele frequency (VAF) of TP53 mutation (TP53-m) or percentage of cells with deletion of chromosome 17p [del(17p)] influences efficacy of firstline BTKi. We performed a retrospective analysis of 130 patients with CLL with baseline del(17p) and/or TP53-m treated with BTKi with or without the BCL2 inhibitor venetoclax (VEN) and with or without CD20 antibody in the firstline setting. A total of 104/130 (80%) patients had del(17p). TP53-m was noted in 89/110 (81%) patients tested; there were 101 unique TP53-m with an available VAF. The 4-year progression-free survival (PFS) and overall survival (OS) rates were 72.9% and 83.6%. No baseline characteristics including IGHV mutation status and number of TP53 alterations were associated with significant differences in PFS or OS, though a trend toward shorter PFS with increasing karyotypic complexity (hazard ratio 1.08, p = .066) was observed. Del(17p) was identified in25% of cells in 26/104 (25%) of patients, and 28/101 (28%) of TP53-m were low-burden with a VAF of10%; outcomes of these patients were similar to those with high-burden lesions. This study suggests that low-burden TP53 alterations should not be ignored when assessing genomic risk in CLL in the era of targeted therapy.

Diffuse large B-cell lymphoma (DLBCL) can be cured with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); however, one-third of patients experience refractory or relapsed disease. Studies comparing R-CHOP with modified regimens replacing R with obinutuzumab (O) or adding lenalidomide (L) did not result in improved outcomes; however, L and O together may enhance natural killer-cell mediated antibody-dependent cellular toxicity when paired with CHOP. Here, we report on a phase 1b/2 study of 53 patients with newly diagnosed DLBCL who received 6 cycles of LO-CHOP. The end of treatment overall and complete response rates of the 50 evaluable patients were 98% and 90%, respectively. After a median follow-up of 4.5 years, the 4-year progression free and overall survival rates were 87.4% and 91.3%, respectively. Grade 3 to 4 adverse events were experienced by 70% of patients, including neutropenia (38%), thrombocytopenia (17%), fatigue (13%), and neutropenic fever (13%). Of the 33 patients profiled with circulating tumor DNA (ctDNA) sequencing, 31 (94%) had detectable pretreatment ctDNA with cancer personalized profiling by deep sequencing, 24 (73%) were classifiable by the LymphGen classifier, and 15/20 (75%) and 12/17 (71%) patients achieved early and major molecular responses after 1 and 2 cycles, respectively. Using phased variant enrichment and detection sequencing, 16/18 evaluable patients (89%) showed no detectable ctDNA after at least 5 cycles of LO-CHOP. LO-CHOP demonstrates high efficacy and tolerability in newly diagnosed DLBCL, leading to a high rate of undetectable minimal residual disease by ctDNA. This trial has been registered at www.clinicaltrials.gov as NCT02529852.

Novel therapies largely have replaced chemoimmunotherapy as optimal first-line treatment of chronic lymphocytic leukemia (CLL). Approved novel therapies for CLL in the first-line setting include Bruton tyrosine kinase inhibitors, ibrutinib and acalabrutinib, and the BCL2 inhibitor venetoclax. Each of these novel agents has its own unique attributes and they have not been compared head to head in randomized trials. This review summarizes the pivotal trials that led to the approval of novel agents and compares the features of each agent to guide treatment decisions in treatment-naive CLL. Ongoing studies investigating combinations of novel agents in the first-line setting also are discussed.

Chronic lymphocytic leukaemia (CLL) rarely presents in adolescent and young adult (AYA) patients (patients aged 15-39 years). Disease characteristics and outcomes of AYA patients with CLL are not well understood, particularly in the era of novel oral targeted therapies. We analysed outcomes of 227 AYA patients with CLL diagnosed in the last two decades and evaluated at our institution. Median time to first treatment (TTFT) was 2·2 years, and five- and 10-year overall survival (OS) were 90% and 78%, respectively. Pre-treatment elevated beta 2-microglobulin, advanced Rai stage, del(11q) or del(17p) by FISH, unmutated IGHV and CD38 positivity were associated with both shorter TTFT and OS. Within the subgroup of patients who received oral targeted therapy at any time, del(11q) or del(17p) and complex karyotype were associated with shorter OS. First-line treatment choice was significantly associated with time to second treatment (P < 0·001). Patients harbouring del(11q) or del(17p) experienced shorter time to Richter transformation and were more likely to undergo an allogeneic stem cell transplant. There was a significant association between age and both OS and time to Richter transformation. Our study is the first analysis of AYA patients with CLL with a large number of patients treated with oral targeted therapies.

In RE-MIND2 (NCT04697160), patient-level outcomes from the L-MIND study (NCT02399085) of tafasitamab plus lenalidomide were retrospectively compared with patient-level matched observational cohorts treated with National Cancer Care Network (NCCN)/European Society for Medical Oncology (ESMO)-listed systemic therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).Data were collected from health records of eligible patients aged ≥18 years with histologically confirmed DLBCL who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients from L-MIND were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest-neighbor matching, balanced for nine covariates. The primary analysis compared tafasitamab plus lenalidomide with patients who received any systemic therapy for R/R DLBCL (pooled in one cohort) or bendamustine plus rituximab (BR) or rituximab plus gemcitabine and oxaliplatin (R-GemOx; as two distinct cohorts). The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and time-to-event outcomes.In RE-MIND2, 3,454 patients were enrolled from 200 sites in North America, Europe, and Asia-Pacific. Strictly matched pairs of patients consisted of tafasitamab plus lenalidomide versus systemic therapies pooled (n = 76 pairs), versus BR (n = 75 pairs), and versus R-GemOx (n = 74 pairs). Significantly prolonged OS was reported with tafasitamab plus lenalidomide versus systemic pooled therapies [hazard ratios (HR): 0.55; P = 0.0068], BR (HR: 0.42; P0.0001), and R-GemOx (HR: 0.47; P = 0.0003).RE-MIND2, a retrospective observational study, met its primary endpoint, demonstrating prolonged OS with tafasitamab plus lenalidomide versus BR and R-GemOx. See related commentary by Cherng and Westin, p. 3908.

Many patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) will not respond to platinum-containing salvage chemotherapy. Predicting treatment failure earlier could help clinicians minimize chemotherapy toxicities for non-responders in favor of other treatments. We conducted a pilot study where 2 early PET/CTs were obtained on days 4 (D4) and 21 (D21) of cycle 1 (C1) of salvage therapy for DLBCL. Twenty-five patients were enrolled and have evaluable data. Ten (40%) had an unplanned therapy change after C1 and before end-of-treatment (EOT) evaluation due to treatment failure on early PET/CT as interpreted by the treating physician. Early PET/CT response at D4 or D21 was not associated with EOT response in evaluable patients. Disease specific survival was longer for patients with a persistent response on both D4 and D21 (p = 0.042). Early PET/CT may predict salvage chemotherapy failure and could inform future clinical trials investigating early therapy change to non-chemotherapy treatments.

Two-thirds of newly diagnosed cases of diffuse large B-cell lymphoma (DLBCL) are cured with R-CHOP, an immunochemotherapy regimen that has been the standard of care for almost two decades. Ongoing molecular characterization of DLBCL has revealed a heterogeneous disease comprised of multiple subtypes based on putative cell of origin or somatic mutations with unique oncogenic signaling pathways. The door has been opened to the use of novel agents that target the specific molecular vulnerabilities of DLBCL, but despite this, multiple randomized studies have not identified a suitable drug 'X' to combine with R-CHOP. This report will review recent attempts to add individual novel agents to R-CHOP in the mission to improve frontline treatment for DLBCL and discuss promising ongoing studies. It will offer potential strategies to explore when designing future clinical trials, including exploiting synergy between multiple novel agents.

Key Points An incidental histologic diagnosis of DLBCL was identified during temporary interruption of ibrutinib treatment in patients with CLL. In contrast to an aggressive clinical course typical of Richter transformation, these patients responded to reinitiation of ibrutinib alone.

Introduction Patients (pts) with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART), but more than half of recipients will experience treatment failure. High pretreatment tumor burden by elevated LDH, metabolic tumor volume, or circulating tumor DNA (ctDNA) levels by clonotype sequencing are associated with inferior outcomes. Low pass whole genome sequencing (lpWGS) is a highly simplified assay capable of identifying copy number alterations (CNA) from cell free DNA (cfDNA) in blood and requires less time, cost, and sample volume to perform vs. other cfDNA sequencing methods; it may be an efficient and precise proxy for tumor burden to identify pts at high risk of progression after CART. Here, we performed lpWGS on pretreatment plasma samples from pts who received CART for rrLBCL and incorporated it into a prognostic risk model. Methods Pts with rrLBCL treated with standard-of-care CART between 5/2018 and 2/2021 at MDACC with plasma samples from time of apheresis were retrospectively identified. cfDNA was extracted from plasma, DNA libraries constructed, and lpWGS performed with a mean coverage of 1.3X. CNA segmentation was generated by CopyWriteR and CNApp (Franch-Expósito et al. Elife 2020) was used to compute scores for focal (FCS, Results A total of 135 pts had available plasma collected from the apheresis timepoint, of which 131 (97%) were successfully sequenced and included in the analysis. A total of 122 (93%) pts received their CART product and 9 (7%) died before infusion. Median follow up was 20.7 mo (range 0.5-36) with data cutoff 6/15/2021. Pt characteristics at time of apheresis are described in Table 1. A total of 83 (68%) treated pts progressed and 68 (56%) died. Median PFS and OS were 4.5 and 13.5 mo, respectively, with 1-year PFS and OS rates of 36% and 57%. ECOG PS > 1 was the only covariate associated with death before infusion (p 1 extranodal (EN) site of disease, LDH > upper limit normal (ULN), and FCS > 52 (median). FCS > 52 was associated with inferior PFS (p=0.0029, HR 1.93 95% CI 1.24-2.99, Fig. 1A), durable response rate (44 v 18%, p=0.0031), and OS (p=0.0027, HR 2.09 95% CI 1.28-3.41, Fig. 1B). Representative genome-wide CNA profiles of 2 pts with FCS of 40 (Fig. 2A) and 203 (Fig. 2B) are included. We created a risk score from 0-3 where pts received 1 point for each negative prognostic feature met (> 1 EN site, LDH > ULN, and FCS > 52), then stratified pts by low (0), intermediate (1-2), or high risk (3). PFS (p Discussion This retrospective analysis is the first to incorporate lpWGS of pretreatment cfDNA to determine CNA burden and associate it with outcomes after CART therapy. The FCS score is associated with survival and is likely a surrogate for ctDNA and tumor burden due to variability in tumor purity. Having > 1 EN site of disease and LDH > ULN were also independently associated. A simple risk model using the 3 variables can reliably risk stratify CART pts prior to therapy, should be validated in an independent/prospective dataset, and could achieve the goal of identifying high-risk pts for interventional studies. lpWGS may therefore represent a more time-, cost-, and sample-efficient method of utilizing pt plasma vs. alternative sequencing methods. Figure 1 Figure 1. Disclosures Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Parmar: Cellenkos Inc.: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Ahmed: Merck: Research Funding; Seagen: Research Funding; Xencor: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Steiner: Seattle Genetics: Research Funding; Rafael Pharmaceuticals: Research Funding; BMS: Research Funding. Samaniego: Imbrium: Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding. Nastoupil: MorphoSys: Honoraria; Pfizer: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Janssen: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; ADC Therapeutics: Honoraria; TG Therapeutics: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; IGM Biosciences: Research Funding; Caribou Biosciences: Research Funding; Novartis: Honoraria, Research Funding; Bayer: Honoraria; Epizyme: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Gilead/Kite: Honoraria, Research Funding. Neelapu: Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. Westin: Curis: Research Funding; Umoja: Consultancy; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding.

Introduction Long-term follow up of prospective studies has shown that continuous Bruton's tyrosine kinase inhibitor (BTKi) therapy leads to durable remissions in previously untreated TP53-altered CLL. Additionally, combining BTKi with the BCL2 inhibitor venetoclax (VEN) achieves deep remissions with similar rates of undetectable measurable residual disease in these high-risk patients (pts) compared to those with wildtype TP53. Without randomized data, it is unclear which pts would benefit most from combined targeted therapy over BTKi monotherapy. It is also unknown how size of the TP53-altered clone influences efficacy of BTKi therapy. We performed a retrospective analysis of pts with CLL with baseline deletion 17p [del(17p)] and/or mutated TP53 (TP53-m) treated with BTKi +/- VEN +/- CD20 mAb in the first-line setting. Methods Pts with CLL/SLL and pretreatment testing (FISH and TP53 sequencing by NGS assay in >95% of pts with 1% limit of detection) performed at our institution (MDACC) demonstrating del(17p) and/or TP53-m who received first-line BTKi-based therapy were included. Pts started treatment between March 2012 and June 2021. The primary endpoint was progression-free survival (PFS) from therapy start. Pts were categorized into those who received first-line BTKi +/- CD20 mAb versus combined BTKi and fixed-duration VEN +/- CD20 mAb. Outcomes were analyzed by baseline characteristics, including size of the TP53-altered clone (% cells with del(17p) and variant allele frequency [VAF] for TP53-m). Results A total of 140 pts with TP53 alteration who received first-line BTKi-based treatment for CLL were included. Pretreatment characteristics are summarized in Table 1. The median follow-up was 3.0 years (range, 0.1 to 9.0). Overall, a total of 38 (27%) pts experienced a progression event, 18 (13%) pts died, and 10 (7%) experienced RT. The 4-year PFS rate was 72.7% and median PFS was 6.3 years (Fig. 1A). The 4-year OS rate was 87.2% (Fig. 1B). A total of 112/140 (80%) pts had pretreatment del(17p). The median % of cells with del(17p) was 60.5% (range, 3.5-99). TP53-m was noted in 100 of the 120 (83%) tested. There were 120 unique TP53 mutations, of which 115 had an available VAF; the median VAF was 34.1% (range, 1-99.5). Among the pts tested for both del(17p) and TP53-m (n=120), 42 (35%) pts had a single alteration [del(17p) or single TP53-m] and 78 (65%) had multiple alterations [both del(17p) and TP53-m or multiple TP53-m]. By univariable analyses, no baseline characteristic was significantly associated with PFS. PFS was not different for TP53-m pts based a VAF threshold of 10% (Fig. 2A) and del(17p) pts based on a threshold of 25% cells affected (Fig. 2B). No baseline characteristic was associated with OS. A total of 101 (72%) pts received a BTKi +/- CD20 mAb without VEN; 39 (28%) received BTKi and VEN (+/- CD20 mAb) (4 pts included who did not get VEN due to early study withdrawal or data censoring). PFS was significantly longer for BTKi + VEN pts vs. BTKi only pts (p=0.009, Fig. 3A) with a HR of 0.18 (95% CI 0.04-0.77) and there was a trend for longer OS in BTKi + VEN pts (p=0.092, Fig. 3B) with a HR of 0.21 (95% CI 0.03-1.57). BTKi + VEN pts were less likely to harbor TP53-m (69% v 90%, p=0.008) or multi-alteration TP53 (44% v 75%, p Conclusions We report favorable 4-year PFS and OS rates of 72.7% and 87.2% in a large retrospective cohort of pts with TP53-altered CLL receiving first-line BTKi-based therapy. The clone size either by % FISH+ or by TP53-m VAF was not associated with PFS, which may reflect the high efficacy of BTKi. PFS appears longer for pts treated with BTK + VEN compared to BTKi only pts, and there was a trend towards improved OS. Though the BTKi + VEN group had lower rates of TP53-m and multiple TP53 alterations, neither characteristic was associated with shorter PFS. Heterogeneity in patient follow-up and response assessment schedule across this pt cohort could be a confounding factor. Whether combination fixed-duration BTKi + VEN is preferable over sequential treatment with these agents remains an unanswered question; this is especially pertinent in pts with high-risk genomics. Therefore, studies dedicated to enrolling such patients are needed to formally clarify optimal treatment for these high-risk patients. Figure 1 Figure 1. Disclosures Burger: Beigene: Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; AstraZeneca: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Thompson: Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding. Ferrajoli: Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Kantarjian: Immunogen: Research Funding; Aptitude Health: Honoraria; Daiichi-Sankyo: Research Funding; Astra Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; NOVA Research: Honoraria; Jazz: Research Funding; KAHR Medical Ltd: Honoraria; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Astellas Health: Honoraria; Ascentage: Research Funding; Novartis: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Wierda: Juno Therapeutics: Research Funding; KITE Pharma: Research Funding; Loxo Oncology, Inc.: Research Funding; Miragen: Research Funding; Cyclacel: Research Funding; Sunesis: Research Funding; Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Karyopharm: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; GSK/Novartis: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Jain: Beigene: Honoraria; Janssen: Honoraria; Servier: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; TG Therapeutics: Honoraria; AstraZeneca: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Pharmacyclics: Research Funding; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding.

Background Patients (pts) with relapsed or refractory (R/R) diffuse large b-cell lymphoma (DLBCL) can achieve cure with platinum-containing chemotherapy (PCC) and autologous stem cell transplant (autoSCT). Only half of pts respond to PCC based on a positron emission tomography/computed tomography (PET/CT) scan after 2 cycles, but most experience significant toxicity. Minimizing exposure to PCC for non-responders in favor of other treatments such as anti-CD19 CAR T-cell therapy (CART19) is important. We hypothesized that PET/CTs performed earlier during salvage therapy could predict end-of-treatment (EOT) response and survival. We conducted an investigator initiated single-institution pilot study (NCT02405078) where 2 early PET/CTs were obtained during cycle 1 (C1) of salvage PCC. Methods Adult R/R DLBCL pts eligible for PCC with a pre-therapy PET/CT were eligible for enrollment. The PCC regimen was selected by the treating physician. The primary endpoint was EOT response. PET/CTs were obtained on D4 and D21 of C1 of PCC, and at EOT after 2-3 cycles. Treating physicians were not blinded to early PET/CT results. Disease-specific survival (DSS) was defined as time from D1 of C1 of salvage PCC to death from DLBCL. Results A total of 25 pts with a median age of 61 years (range 25-82) at relapse treated with PCC between 2/5/2016 and 10/30/2018 were included in the analysis, with data cutoff as of 2/29/2020. Selected baseline pt characteristics are as follows: 68% were GCB cell-of-origin by Hans algorithm, 60% were stage III/IV, 88% had an ECOG PS < 2, 44% an international prognostic index (IPI) ≥3, and 32% double-hit lymphoma. Median time from initial diagnosis to first progression was 5.8 months. Therapies received were R-DHAP (44%), R-ICE (36%), and other regimens (20%). Ten (40%) pts had a therapy change after C1 and before EOT evaluation due to early treatment failure or progression based on early PET/CT result as interpreted by the treating physician. Twelve (48%) continued with a second cycle of the same regimen, and 3 discontinued therapy. Sixteen (64%) pts were evaluable for EOT response by PET/CT, while 7 (28%) pts were missing an EOT PET/CT due to early progression and 2 for other reasons. The only baseline characteristic different between EOT responders, non-responders, and pts missing EOT evaluation due to early progression was time from initial diagnosis to progression (8.6 vs. 5.3 vs. 4.5 months, p=0.035). Overall response (OR; complete or partial response) by Lugano criteria or decrease in maximum standardized uptake value (ΔSUVmax) ≥50% at D4 or D21 was not associated with EOT response. Median follow up was 19.7 months (range 0.7-40.9) from start of PCC. Median progression free survival was 2.7 months. Eleven pts died, 9 (36%) from progressive DLBCL and 2 from transplant complications. DSS was 61% at 24 months. DSS was worse for pts with an ECOG PS > 1 (p=0.002), IPI ≥3 (p=0.046), and who did not receive R-ICE or R-DHAP (p=0.006). There was no difference in DSS based on the D4 or D21 PET/CT individually, by OR or ΔSUVmax. DSS was better for pts who had a persistent OR on both D4 and D21 vs. pts without a persistent OR (p=0.042) and was 100 vs. 47% at 24 months (Fig). Of the 6 pts with a persistent OR, 4 had a late first relapse (range 23.1-78.9 months after diagnosis) and 2 had an early first relapse (1.9-9.0 months). A total of 28% of pts had autoSCT and 8% allogeneic SCT, and 28% eventually had CART19 if not responsive to salvage treatment. Of the 10 pts who changed therapy after C1, 2/3 of the CART19 recipients were alive at data censoring compared to 1/7 of the pts who did not receive CART19. Discussion This pilot study is the first of its kind to investigate early PET/CT during salvage therapy for R/R DLBCL. Early PET/CT result did not predict the primary endpoint of EOT response, confounded as therapy was changed for some pts before final response evaluation due to early progression. Persistent OR on early PET/CTs during C1 predicted excellent DSS, even if pts were refractory to frontline treatment. Early therapy change after C1 based on unsatisfactory early PET/CTs to spare pts from ineffective therapy was feasible, with possible benefit to switching to CART19, but numbers were low and CART19 was not uniformly available during the study period. Risk for chemotherapy failure can be predicted early during salvage therapy, which may be important to change therapy to non-chemotherapy treatments such as CART19. Figure Disclosures Nastoupil: Genentech, Inc.: Honoraria, Research Funding; Gamida Cell: Honoraria; Merck: Research Funding; TG Therapeutics: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Bayer: Honoraria; Gilead/KITE: Honoraria; LAM Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Lee:Seattle Genetics: Research Funding; Takeda: Research Funding; Oncternal Therapeutics: Research Funding; Guidepoint Blogal: Consultancy; Celgene: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau. Neelapu:Incyte: Other: personal fees; N/A: Other; Unum Therapeutics: Other, Research Funding; Calibr: Other; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Poseida: Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Cell Medica/Kuur: Other: personal fees; Celgene: Other: personal fees, Research Funding; Cellectis: Research Funding; Pfizer: Other: personal fees; Legend Biotech: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Precision Biosciences: Other: personal fees, Research Funding; Adicet Bio: Other; Takeda Pharmaceuticals: Patents & Royalties; Novartis: Other: personal fees. Flowers:Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; OptumRx: Consultancy; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Spectrum: Consultancy; Acerta: Research Funding; Millennium/Takeda: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Kite: Research Funding; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding. Chuang:Sage-Evidence=Based Medicine & Practice: Consultancy. Westin:47 Inc: Consultancy; Curis: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Genentech: Consultancy; Juno: Consultancy; Kite: Consultancy; MorphoSys: Consultancy; Unum: Consultancy.

Background Patients with a diagnosis of MYC-rearranged non–Burkitt aggressive B-cell lymphoma (MYC-R), including those with double hit lymphoma, are at high risk of developing relapsed/refractory disease, even if treated with intensive front-line immunochemotherapy. It is common in clinical practice and clinical trials to perform an interim positron emission tomography (PET)/computed tomography (CT) scan (iPET) during front-line therapy for diffuse large B-cell lymphoma. However, the utility of the iPET result for MYC-R patients for predicting outcomes is unclear. Patients and Methods We performed a single-center retrospective study with centralized pathologic review and PET/CT image acquisition and interpretation for 28 MYC-R patients. The patients received front-line therapy with R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone) or intensive immunochemotherapy. Results Eight patients had iPET-positive (iPET+) and 20 patients had iPET-negative (iPET−) results using the Deauville visual assessment criteria. At a median follow-up length of 30.4 months, progression-free survival was 65% and overall survival was 76%, neither of which differed significantly between the iPET− and iPET+ patients. The positive predictive value of iPET for progression at 30 months was 25%, and the negative predictive value was 65%. Conclusion Although patients with MYC-R lymphoma have been reported to be at high risk of primary treatment failure, this was not predicted by iPET+ results. Thus, the iPET result should not be used to guide changes in front-line or consolidative therapy for these patients.