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7012 Background: DLBCL with expression of MYC and BCL2 (double expressor lymphoma, DEL), has an adverse prognosis. Venetoclax, an inhibitor of BCL2, was previously studied in combination with R-CHOP. A051701 is a phase II/III randomized trial of chemoimmunotherapy +/- venetoclax in DEL and double hit lymphoma cohorts. Here we report initial phase II results from the DEL cohort. Methods: Patients (pts) age ≥ 18 years (y) with untreated DEL were randomized 1:1 to R-CHOP (Arm 1) or R-CHOP-venetoclax (Arm 2). DEL was defined as MYC expression ≥40% and BCL2 expression ≥50%, without double hit cytogenetics. Enrollment was based on local pathology results that were centrally confirmed. Venetoclax 800 mg was given orally days 4-8 of cycle 1 and days 1-5 of subsequent cycles for up to 6 cycles. All cycles were supported by GCSF or peg-GCSF. The primary endpoint was progression-free survival (PFS) with 84% power to detect a HR of 0.518 corresponding to 2y PFS rate of 65% in Arm 1 and 80% in Arm 2 (1-sided α=0.20). Results: 119 DEL pts were enrolled: 60 Arm 1; 59 Arm 2. Analyses were performed for the modified intent-to-treat population, defined as eligible pts with confirmed DEL histology (n=113; 56 Arm 1, 57 Arm 2). Median age was 64 y (range 22-85); baseline demographic factors were well balanced except for advanced stage (more common in Arm 1; (77% vs 60%, p=0.051). Most pts were non-germinal center B cell-like by immunohistochemistry (Arm 1 72%, Arm 2 58%), high-intermediate/high risk IPI (Arm 1 54%, Arm 2 51%) and ECOG performance status 0-1 (Arm 1 95%, Arm 2 86%). BCL2 rearrangements were detected in 25% and 33% of pts on Arm 1 and Arm 2, respectively. Most pts completed therapy per protocol (84% Arm 1, 75% Arm 2). Median follow up is 27 months (m). No difference in PFS was observed with 12-m PFS estimates of 77% in Arm 1, 76% in Arm 2 [HR = 0.98 (95% CI: 0.48 – 2.01), p=0.95]. The end of treatment (EOT) overall and complete response rates among patients with an EOT assessment were 87.5% and 70% in Arm 1, and 90% and 82% in Arm 2. Overall survival (OS) was not statistically significantly different with 12-mo OS estimates of 94% in Arm 1 and 79% in Arm 2 [HR = 1.27 (95% CI: 0.57 – 2.79), p=0.56]. Grade ≥3 adverse events (AEs) occurred more frequently in Arm 2 (42% vs 76%). The most commonly increased grade ≥3 AEs included neutropenia (20% vs 47%), anemia (4% vs 25.5%), thrombocytopenia (5.5% vs 24%), febrile neutropenia (7% vs 16%) and fatigue (0% vs 11%). No grade 5 AEs on treatment were reported on Arm 1, and 3 were reported on Arm 2 (lung infection and sudden death NOS, both possibly related; respiratory failure, unlikely related). Conclusions: Adding venetoclax to R-CHOP in DEL pts did not improve PFS and resulted in increased toxicity. The study did not meet its primary endpoint in phase II, and so did not proceed to phase III. Clinical trial information: NCT03984448 .

Abstract Background DNMT3A and TET2 are epigenetic regulator genes commonly mutated in age-related clonal hematopoiesis (CH). Despite having opposing epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematological neoplasms. While individual impacts on the epigenome have been described using different model systems, the phenotypic complexity in humans remains to be elucidated. Results Here we make use of a natural inflammatory response occurring during coronavirus disease 2019 (COVID-19), to understand the association of these mutations with inflammatory morbidity and mortality. We demonstrate the age-independent, negative impact of DNMT3A mutant CH on COVID-19-related cytokine release severity and mortality. Using single cell proteogenomics we show that DNMT3A mutations involve myeloid and lymphoid cells. Using single cell multiomics sequencing, we identify cell-specific gene expression changes associated with DNMT3A mutations, along with significant epigenomic deregulation affecting enhancer accessibility, resulting in overexpression of IL32, a proinflammatory cytokine that can result in inflammasome activation in monocytes and macrophages. Finally, we show with single cell resolution that the loss of function of DNMT3A is directly associated with increased chromatin accessibility in mutant cells. Conclusions We demonstrate the negative prognostic impact of DNMT3Amt CH on COVID-19 related inflammatory morbidity and mortality. DNMT3Amt CH involves myeloid and lymphoid cells and in the context of COVID-19, was associated with inflammatory transcriptional priming, resulting in overexpression of IL32. This overexpression was secondary to increased chromatic accessibility, specific to DNMT3Amt CH cells. DNMT3Amt CH can serve as a potential biomarker for adverse inflammatory outcomes.

2001 Background: Systemic treatments are limited for patients with meningiomas that have progressed after surgery and/or radiation. Loss of NF2and CDKN2A/Bare common in higher grade meningiomas and promote meningioma progression in preclinical models. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance umbrella trial A071401, a genomically driven phase II study in recurrent or progressive meningiomas. Methods: Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily until progressive disease. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha =0.02). The threshold for promising results for PFS6 was 8+/24 pts. For RR, 24 evaluable pts provided >89% power to detect RR >20% (vs. null 2.5%; alpha = 0.021). The threshold for promising results for RR was 3+/24 pts. Results: Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received treatment. The mean number of treatment cycles administered was 7 and median follow-up since start of treatment was 11 months. The first 24 pts that met eligibility criteria and began treatment were considered evaluable for the primary endpoint analysis. Of the 24 pts evaluated, 58% were female and the median age was 62 years. The observed PFS6 rate was 54% (13/24 pts, 95% confidence interval 33-75%), thus the study met PFS6 endpoint. No objective responses were observed. Of the 36 pts who started treatment, eight had a grade 3 and two had a grade 4 adverse event at least possibly related to treatment. Grade 3 toxicities included anemia (2), neutropenia (2), leukopenia (1), blurry vision (1), diarrhea (2), fatigue (2), ALT elevation (1), dehydration (1), hyperkalemia (1), hyponatremia (1), dizziness (1), acute kidney injury (1), and thromboembolic event (1). Grade 4 toxicities included ALT elevation (1), AST elevation (1) and vomiting (1). Conclusions: Abemaciclib was well tolerated and resulted in an improved PFS6. The overall trial endpoint was met. Abemaciclib warrants further investigation for the treatment of patients with progressive grade 2/3 meningiomas. Support: U10CA180821, U10CA180882; UG1CA189867 (NRG Oncology); Eli Lilly; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02523014 .

Abstract The survival of patients achieving a cardiac complete response in light chain amyloidosis, defined as N-terminal pro B-type natriuretic peptide ≤350 pg/mL or B-type natriuretic peptide ≤80 pg/mL, was similar to that of a matched general population, with estimated 5-year survival rates of 93% and 95%, respectively.

Abstract Although it is evident that standard-dose whole-brain radiotherapy as consolidation is associated with significant neurotoxicity, the optimal consolidative strategy for primary central nervous system lymphoma (PCNSL) is not defined. We performed a randomized phase 2 clinical trial via the US Alliance cancer cooperative group to compare myeloablative consolidation supported by autologous stem cell transplantation with nonmyeloablative consolidation after induction therapy for PCNSL. To our knowledge, this is the first randomized trial to be initiated that eliminates whole-brain radiotherapy as a consolidative approach in newly diagnosed PCNSL. Patients aged 18 to 75 years were randomly assigned in a 1:1 manner to induction therapy (methotrexate, temozolomide, rituximab, and cytarabine) followed by consolidation with either thiotepa plus carmustine and autologous stem cell rescue vs induction followed by nonmyeloablative, infusional etoposide plus cytarabine. The primary end point was progression-free survival (PFS). A total of 113 patients were randomized, and 108 (54 in each arm) were evaluable. More patients in the nonmyeloablative arm experienced progressive disease or death during induction (28% vs 11%; P = .05). Thirty-six patients received autologous stem cell transplant, and 34 received nonmyeloablative consolidation. The estimated 2-year PFS was higher in the myeloablative vs nonmyeloablative arm (73% vs 51%; P = .02). However, a planned secondary analysis, landmarked at start of the consolidation, revealed that the estimated 2-year PFS in those who completed consolidation therapy was not significantly different between the arms (86% vs 71%; P = .21). Both consolidative strategies yielded encouraging efficacy and similar toxicity profiles. This trial was registered at www.clininicals.gov as #NCT01511562.

Abstract Sorafenib blocks nonstructural protein 5A (NS5A)-recruited c-Raf–mediated hepatitis C virus (HCV) replication and gene expression. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via sorafenib putatively differ in the presence or absence of doxorubicin. Cancer and Leukemia Group B (CALGB) 80802 (Alliance) randomized phase III trial of doxorubicin plus sorafenib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC), showed no improvement in median overall survival (OS). Whether HCV viral load impacts therapy and whether any correlation between HCV titers and outcome based on HCV was studied. In patients with HCV, HCV titer levels were evaluated at baseline and at multiple postbaseline timepoints until disease progression or treatment discontinuation. HCV titer levels were evaluated in relation to OS and progression-free survival (PFS). Among 53 patients with baseline HCV data, 12 patients had undetectable HCV (HCV-UN). Postbaseline HCV titer levels did not significantly differ between treatment arms. One patient in each arm went from detectable to HCV-UN with greater than 2 log-fold titer levels reduction. Aside from these 2 HCV-UN patients, HCV titers remained stable on treatment. Patients who had HCV-UN at baseline were 3.5 times more likely to progress and/or die from HCC compared with HCV detectable (HR = 3.51; 95% confidence interval: 1.58–7.78; P = 0.002). HCV titer levels remained unchanged, negating any sorafenib impact onto HCV titer levels. Although an overall negative phase III study, patients treated with doxorubicin plus sorafenib and sorafenib only, on CALGB 80802 had worse PFS if HCV-UN. Higher levels of HCV titers at baseline were associated with significantly improved PFS. Significance: Sorafenib therapy for HCC may impact HCV replication and viral gene expression. In HCV-positive patients accrued to CLAGB 80802 phase III study evaluating the addition of doxorubicin to sorafenib, HCV titer levels were evaluated at baseline and different timepoints. Sorafenib did not impact HCV titer levels. Despite an improved PFS in patients with detectable higher level HCV titers at baseline, no difference in OS was noted.

Introduction: Telomere biology disorders (TBD) are multisystem diseases often associated with bone marrow failure (BMF) and pulmonary fibrosis. TBD are clinically diagnosed when mean telomere lengths (TL) in blood cells measured by clinical flowFISH assays fall <1 st percentile, in comparison to age-matched reference controls. This information has limitations, e.g. TL in blood cells may not represent TL in other organs (e.g. lung, liver) and moreover, individuals with high clinical suspicion of TBD can show borderline average TL which complicates their diagnosis. The likely reason for this is that cell senescence can be triggered by shortening of a subset, or even a single chromosome arm telomere, a situation that may be missed when measuring average TL. Previous approaches to measure individual chromosome-arm telomere length (CA-TL) are only available for a small number of chromosome arms or can only estimate the number of shortened telomeres without matching them to specific chromosome arms. Taking advantage of recent developments in long-read next generation sequencing (NGS) and the availability of the recently published telomere-to-telomere (T2T) reference human genome, our group developed Telogator, (Stephens Z. et al, 2022) a bioinformatic tool that estimates CA-TL for most chromosome arms using long-read NGS data. Here we use Telogator to describe for the first time the CA-TL pattern in TBD patients in comparison with a control non-TBD cohort. Methods: TBD patients were identified through the Pre-Myeloid and Bone Marrow Failure Specialty Clinic at Mayo Clinic. All patients underwent flowFISH and genetic testing. Age-matched non-TBD patients identified at the Center for Individualized Medicine (Mayo Clinic) were used as reference controls. Informed consent was obtained from all individuals with approval from the Mayo Clinic Institutional Review Board. DNA from peripheral blood mononuclear cells was sequenced using PacBio Sequel II following the manufacturer indications for HiFi sequencing. BAM files were aligned to the T2T reference and CA-TL was calculated using Telogator as described in Stephens Z. et al. 2022. Average TL, CA-TL, and percent of short telomeres (both defined as <5 kb and <3.2 kb) were calculated. Comparisons of average TL and percent of short telomeres were performed using t-test, while Wilcoxon rank-sum test was used to compare CA-TL. Results: Four TBD patients [median age = 58.5 (52-60), 50% female] and 6 non-TBD controls [Median age = 56 (50-63), 33% female] were included in the analysis. All TBD patients presented average TL below the 1 st centile in both lymphocytes and granulocytes, and TBD-related phenotype (100% with pulmonary fibrosis, 50% with BMF, 25% with liver fibrosis). Three had a pathogenic variant in a TBD related genes [2 in TERT (NM_198253.3: c.2030G>A, p.(Gly677Asp) and c.2515_2533del, p.(Thr839Alafs*29)) and 1 in NHP2 (NM_017838.3: c.459_460delAT; p.(X154Argext29))]. The average TL calculated by Telogator showed high correlation with flowFISH values (r 2 = 0.9883, p = 0.0059) and was lower in TBD patients than controls (p = 0.0012). Next, when comparing individual CA-TL between groups, only half of CA-TL was statistically different in the TBD group compared to controls (1p, 3q, 4p, 5p, 5q, 6q, 7p, 7q, 8q, 9p, 9q, 10q, 11p, 12q, 12q, 16p, 16q, 18q, 19p, 19q, 20p, 20q, 21q - Figure 1). The percentage of telomeres <5kb and <3 kb was significantly increased in TBD patients compared to controls (p= 0.014 and 0.0333, respectively). Discussion: Using a novel informatic tool, we replicate previous results obtained using classic approaches and were able to expand on these studies by measuring specific CA-TL in TBD patients. We identified statistically significant differences at the CA-TL level in these patients when compared to age-matched controls, while other CA-TL were not statistically different. Future studies and the inclusion of additional TBD patients will help define the clinical relevance of the differential CA-TL shortening and its prevalence among TBD patients. While limited by the small number of samples in the study, we show the feasibility of using this approach to study TL with unprecedented resolution and show that Telogator offers important advantages compared to classic methods to study telomere biology that can be used in other relevant fields like aging and/or cancer. Our results pave the way to advance the mechanistic understanding of TBD.

Background: Oncolytic virotherapy, an innovative immunomodulatory therapeutic approach, is currently being investigated for its potential in treating relapsed refractory (R/R) hematologic malignancies. This study focuses on the use of an engineered Vesicular Stomatitis Virus called VSV-IFNβ-NIS, a bullet-shaped rhabdovirus which encodes both interferon beta (IFNβ) and sodium iodine symporter (NIS) with particular tumor cell tropism. Viral IFNβ serves as an indicator of viral proliferation and boosts the host's anti-tumor immune response. This is a phase 1 clinical trial with the identifier NCT03017820, wherein patients (pts) with R/R multiple myeloma (MM), and non-Hodgkin lymphoma (NHL) are treated with a single systemic administration of VSV-IFNβ-NIS. Study Design and Methods: Patient Eligibility Criteria: The Mayo Clinic Institutional Review Board approved the protocol. The study includes adult patients with relapsed or refractory multiple myeloma (MM), or T-cell lymphoma (TCL). For MM or plasmacytoma, patients should have <15% plasma cells and a largest diameter of <5 cm. TCL patients should have a mass <5 cm. Study Design: This is a single-center phase 1 trial aiming to determine the maximum tolerated dose of VSV-IFNβ-NIS in patients with R/R MM, and TCL. Secondary objectives included assessing the safety profile and estimating the clinical response rate of VSV-IFNβ-NIS. Correlative objectives involved monitoring viral replication through plasma IFN-β transgene levels and using SPECT/CT imaging with the NIS gene. Viral genomes were measured through quantitative reverse transcription (qRT) polymerase chain reaction (PCR) of VSV RNA, and any virus shedding was examined in body fluids. The tested doses were 5 × 109 TCID50, 1.7 × 1010, 5 × 1010, and 1.7 × 1011 TCID50. The virus was administered via IV infusion over 30 minutes, and patients received 650 mg acetaminophen and 50 mg diphenhydramine hydrochloride before infusion and every 6 hours for 24 hours to manage fever and hypotension. Two expansion cohorts at DL4 have been added (20 additional PTCL, 10 B-cell lymphoma and histiocytic neoplasms) to obtain additional data on tolerability and efficacy and biomarkers of response in these histologies. Safety and Response Assessments: All patients undergo toxicity evaluation, and adverse events (AEs) assessment using the Common Terminology Criteria for Adverse Events (CTCAE) version 4 criteria, except for cytokine release syndrome (CRS) grading, which follows the 2014 Lee criteria. Dose escalation and tolerability are based on the standard 3+3 phase 1 trial design. Ruxolitinib is added from days 2-5 or day -1 to day 9 depending on the arm to mitigate IFNβ toxicity. Response assessment followed the International Myeloma Working Group criteria for MM and the Lugano Classification for NHL and histiocytic neoplasms. Pharmacodynamic and Pharmacokinetic Analyses: For viremia and viral shedding assessment, RNA is isolated from whole blood, mouth rinse, buccal swabs, and urine samples. Quantitative RT-PCR determined VSV-nucleocapsid (N) RNA copy number, and virus shedding is assessed through coculturing samples on Vero cells. Anti-VSV antibodies are evaluated using the standard plaque reduction neutralization assay. Plasma cytokine levels are measured with a 30-plex human cytokine kit, and human IFN-β levels is quantified using an enzyme-linked immunosorbent assay (ELISA) kit. Statistical Analysis: Incidence of dose-limiting toxicities and AEs are tabulated by dose level (DL). AEs are summarized by type, maximum grade, and duration across patients in each DL. Spearman rank correlation tests are used evaluated correlations between laboratory-based measures, and Wilcoxon rank sum tests compared continuous measures between response groups. Response rates will be summarized by DL and disease group, with estimated response rates and corresponding 95% binomial confidence intervals calculated.

Introduction: AutoHCT is an effective therapy for patients (pts) with DLBCL who are refractory or relapse following first-line chemotherapy, but long term outcomes remain suboptimal. The BTK inhibitor ibrutinib has shown promising activity in pts with ABC-DLBCL (Wilson et al, Nat Med 2015). In 2016 we launched a randomized phase III clinical trial to evaluate the addition of ibrutinib to AutoHCT as part of conditioning and as consolidation therapy for pts with relapsed/refractory ABC-DLBCL. Patients and Methods: Following assessment of open-label treatment in a safety cohort of 6 pts, we randomly assigned pts with chemotherapy-sensitive persistent or relapsed ABC-DLBCL to receive ibrutinib 560 mg [Arm A] or placebo [Arm B] concurrently with conditioning on days -6 to -1 of AutoHCT (Cycle 1). Following count recovery and resolution of acute toxicities, pts continued ibrutinib 560 mg in Arm A or placebo in Arm B for 12 additional 28-day cycles. Crossover to Arm A using single agent ibrutinib was allowed for pts progressing on Arm B. Central pathology review was performed for disease confirmation and subtype assignment. Initially, ABC subtype assignment was performed using the Nanostring Lymphoma Subtyping Test (LST) but the study was amended to use the IHC-based Hans classifier for non-GCB on 8/15/19. Other key eligibility criteria included receipt of no more than 3 prior regimens, no active CNS involvement, no need for long-term anticoagulation, and no prior progression on Ibrutinib. Pts were stratified by time to relapse (<=12 mos vs >12 mos), type of conditioning (BEAM or CBV) and prior ibrutinib use. The original design required 296 patients with 82% power to detect a difference in 2-year progression-free survival (PFS) rates of 67% vs. 50% with a two-sided alpha of 0.05. A revised statistical design allowed an interim futility analysis to be conducted after 40 pts were enrolled and followed for 2 years. Even though the study met criteria to continue accrual to a target of 160 pts, we decided to close it early due to declining accrual on 12/20/2022. We hereby present the primary analysis of the evaluable patients enrolled (data as of 07/17/2023). Results: Between 2/6/17 and 8/24/18, we screened 255 pts but enrolled only 34 (13%) largely due to long assay turnaround times and performance characteristics with the LST. Following the switch to the IHC-based Hans classifier (after 8/15/19), 60 out of 110 pts screened were enrolled (54%) in line with our a priori expectation. In total, 45 pts were randomized to Arm A vs. 43 to Arm B, with 39 and 38, respectively, being evaluable for the primary endpoint at this time. Median age was 61 years (range 20-75 years), median number of prior lines of therapy was 2, 46% of the pts were female, 21% were refractory or had early relapse, 94% were planned to receive BEAM conditioning. Overall, 87% of pts in Arm A and 88% in Arm B underwent conditioning while 70% and 67% respectively, started maintenance therapy. The median number of cycles received was 6 in Arm A vs. 5 in Arm B. The primary endpoint of 2-year PFS was 57.6% (95% CI: 42.1%, 78.8%) in Arm A vs. 40.8% (95% CI: 26.5, 62.8%) in Arm B (HR=0.54; 95% CI: 0.26, 1.10; log-rank p = 0.087). Median PFS was 26.5 months (95% CI: 10.2, not reached [NR]) in Arm A vs. 8.1 months (95% CI: 5.4, NR) in Arm B. Only one pt crossed over to Arm A after progression on Arm B. The most common grade 3-4 AEs in each of the arms were: neutropenia (A: 14%, B: 14%), febrile neutropenia (A: 11%, B: 9%), and thrombocytopenia (A: 11%, B: 7%). Rates of any grade atrial fibrillation were similar between arms (12.8% in Arm A vs. 10.5% in Arm B); one patient had grade 3 and one patient had grade 4 atrial fibrillation, both in Arm B. Six pts had reported grade 5 events (Arm A: 2 sepsis, 1 COVID-19, 1 respiratory failure and 1 disease progression and Arm B: 1 disease progression) but only one grade 5 event (sepsis, Arm A) was deemed probably related to treatment. Conclusions: Despite an early high rate of screen failures and declining accruals due to competition with CAR-T cell therapy, the primary analysis suggests that ibrutinib with and following AutoHCT in relapsed/refractory ABC-DLBCL is well-tolerated and may improve PFS in this high-risk patient population. This trial was supported by: U10CA180821, U10CA180882, U24CA196171; U10CA180820, UG1CA233234 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG) ClinicalTrials.gov Identifier: NCT02443077 https://acknowledgments.alliancefound.org

Introduction: Single arm studies incorporating PD-1 blockade and/or brentuximab vedotin (BV) to salvage regimen have produced encouraging results in transplant-eligible relapsed/refractory classic Hodgkin lymphoma (R/R cHL) and are increasingly used in practice. As prospective randomized studies comparing PD1 based salvage to other salvage regimens are lacking, we conducted a retrospective study comparing post-transplant outcomes of R/R cHL patients who received PD1-based regimen and other novel and conventional regimen. Methods: Consecutive adult patients with R/R cHL who received salvage therapy and underwent autologous stem cell transplant (ASCT) between 2010 and 2021 at 5 United States academic institutions were included. Demographics and clinical variables were recorded at relapse by electronic health records review. Study Objectives were post-ASCT progression free survival (PFS) and overall survival (OS). Results: 981 pts of R/R cHL were identified. At relapse, median age was 31 (IQR: 21-43) years, 504 (52%) were male, 323 (49%) had advanced stage, 353 (41%) had extranodal disease (END), 185 (22%) had B symptoms, 345 (45%) were refractory to frontline therapy and 317 (32%) relapsed within a year of frontline therapy.308 (31%) received >1 line of salvage before ASCT. Patients were divided into 3 groups based on salvage therapy received: 1) 195 (20%) patients received a PD-1 agent with or without BV at any point before ASCT (PD-1 group), 2) 312 (32%) patients received BV at any point before ASCT without PD-1 (BV group), and 3) 474 (48%) patients received no novel agent before ASCT (chemo group). PFS was significantly higher in PD1 group (2-yr PFS 93.1 (CI 95: 89.4-96.9)%); compared to BV (2 yr PFS 73.9 (CI 95: 69.1-79.1)% , p <0.0001) or chemo groups (2 yr PFS 71.6 (CI 95: 67.6-75.9)% , p<0.0001). PFS was not different between the BV and chemo groups (p=0.88) (Figure 1). OS was not significantly different between PD-1 group (2 yr OS 96.2 % (CI 95: 93.2-99.2), p=0.06), BV group (2 yr OS 94.3% (CI 95: 91.7-97.0), p=0.2) and chemo group (2 yr OS 91.8% (CI 95: 89.3-94.4)). Amongst pts who were transplanted in complete metabolic response (CMR), we assessed post-ASCT PFS and OS based on salvage therapy received immediately before ASCT. Pts who received PD-1 as last salvage therapy had improved PFS compared to chemo (HR: 0.15 (CI 95: 0.07-0.3), p= <0.0001) and BV (HR: 0.2 (CI 95: 0.08-0.5), p= <0.001). Pts receiving PD-1 immediately before ASCT also had higher OS compared to those receiving chemo (HR: 0.2 (CI 95: 0.05-0.8), p= 0.02) but not BV (HR: 0.8 (CI 95: 0.4-1.3), p=0.1). There was no difference between BV and chemo group in regards to PFS and OS. In multivariable analysis that included time to relapse, B symptoms, END, pre-ASCT response, number of salvage therapy lines before ASCT, year of transplant and BV consolidation, PD-1 salvage therapy had significantly higher PFS compared to chemotherapy (HR: 0.3 (CI 95: 0.2-0.5), p= <0.001). BV group had significantly lower PFS (HR: 3.34 (CI 95: 1.8-6.0), group=0.002) compared to PD1 group. PFS was not different between BV and chemo group (p= 0.7). OS was similar between all 3 groups. Similar PFS and OS were seen among patients receiving PD-1 + BV (n=83) and PD-1 with or without chemo (n =112) (p=0.96 for PFS; p= 0.72 for OS); as well as for patients receiving PD-1 as part of their first salvage therapy (n=151) or later salvage treatments (n=44) (p=0.45 for PFS, p= 0.3 for OS). Patients who received PD1 based regimen as last salvage therapy pre-ASCT had significantly better PFS (HR: 6.8 (CI 95: 2.4-19.2), p= <0.0001) and OS (HR: 10.6 (CI 95: 2.5-44.8), p= 0.0001) compared to patients who received PD1 prior to their last line of salvage therapy per-ASCT. Conclusion: Receipt of PD-1 based salvage therapy at any point before ASCT is associated with significantly improved PFS compared to either BV or chemotherapy-based salvage treatments. In the subgroup of patients transplanted in CMR, PD1 based last salvage regimen were associated with higher PFS compared to chemotherapy and BV and higher OS compared to chemotherapy. PD1 based last salvage therapy pre-ASCT was associated with better survival compared to PD1 prior to last salvage therapy. Results of this study strongly support the use of PD-1 based salvage therapy for patients with R/R cHL. S.D., R.M., H.S contributed equally. R.S., M.M. contributed equally.