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This study evaluated ofatumumab (Ofa), an anti-CD20 monoclonal antibody, alone or with bendamustine (Benda), in transplant-ineligible patients with mantle cell lymphoma. Low-risk patients received Ofa monotherapy. Non-responders received subsequent treatment with Benda-Ofa. Six patients received Ofa monotherapy and 3 patients crossed over to Bend-Ofa. Twenty-four high-risk patients were initially treated with Benda-Ofa. The overall response rate for patients treated with Ofa monotherapy was 1/6 (17%) and 23/25 (92%) for patients treated with Benda-Ofa. With a median follow-up of 8.6 years, all Ofa patients progressed with a median progression-free survival (PFS) of 0.6 years (95% CI 0.31-NR) and remain alive. With a median follow-up of 6.3 years, Bend-Ofa treated patients had median PFS 2.5 years (95% CI 1.8-NR) and a median overall survival of 7.4 years (95% CI 5.8-NR). Benda-Ofa had a favorable adverse event profile and efficacy similar, but not clearly superior, to those reported for Benda-Rituximab.

Purpose: 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). Patients and Methods: 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. Results: 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 R­GemOx (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; P < 0.0001), and R-GemOx (HR: 0.47; P = 0.0003). Conclusions: 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

Between 1998 and 2009, a total of 295 patients (median age 58, 53% females) with newly diagnosed early-stage follicular lymphoma (FL) were managed at Memorial Sloan Kettering Cancer Center. Approximately half of patients (137, 46%) underwent initial observation and half (158, 54%) immediate treatment: radiation alone (n = 108), systemic treatment alone (n = 29), or combined modality treatment (n = 21). Median follow-up was 8.4 years (range 0.3–17.2), and 10-year overall survival (OS) was 87.2%. OS was similar between initially-observed and immediately-treated patients (hazard ratio [HR]: 1.25, 95% CI: 0.67–2.36, p = 0.49). For patients receiving radiation alone, 5-year OS was 98.0%. Patients selected for systemic therapy alone had high-risk baseline features and had shorter OS than patients treated with radiation alone (HR 3.38, 95% CI 1.29–8.86, p = 0.01). Combined modality treatment did not yield superior survival compared with radiation alone (P > 0.05) but was associated with better progression-free survival (HR 0.36, 95% CI 0.14–0.90, p = 0.03). The rate of transformation increased steadily over time and was 4.2% at 5 years and 10.8% at 10 years. This modern-era analysis rationalized the role of initial observation in patients with early-stage FL although patients receiving radiation therapy also demonstrate excellent outcome.

Mature B cell neoplasms, previously indolent non-Hodgkin lymphomas (iNHLs), are a heterogeneous group of malignancies sharing similar disease courses and treatment paradigms. Most patients with iNHL have an excellent prognosis, and in many, treatment can be deferred for years. However, some patients will have an accelerated course and may experience transformation into aggressive lymphomas. In this review, we focus on management concepts shared across iNHLs, as well as histology-specific strategies. We address open questions in the field, including the influence of genomics and molecular pathway alterations on treatment decisions. In addition, we review the management of uncommon clinical entities including nodular lymphocyte-predominant Hodgkin lymphoma, hairy cell leukemia, splenic lymphoma and primary lymphoma of extranodal sites. Finally, we include a perspective on novel targeted therapies, antibodies, antibody–drug conjugates, bispecific T cell engagers and chimeric antigen receptor T cell therapy.

BACKGROUND Emavusertib, an oral interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, targets toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathway in B-cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of NF-κB, causing inflammation and tumor growth. Emavusertib has been reported to be well tolerated and active as monotherapy in heavily pretreated relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). In a murine PDX model of primary CNS lymphoma (PCNSL), emavusertib crossed the blood-brain barrier, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, emavusertib showed in vivo anti-cancer synergy in B-cell NHL. METHODS This is an ongoing open-label trial (NCT03328078) in patients with R/R NHL. Currently, we are in the dose escalation portion of combination therapy to evaluate safety and efficacy following treatment of emavusertib at dose levels of 200 or 300mg BID with ibrutinib at full prescribed dose. As of May 6th, 2022, 13 patients have been treated with emavusertib+ibrutinib combination therapy. RESULTS Among the 13 patients, two were diagnosed with R/R PCNSL and had several prior lines of anti-cancer therapy. Emavusertib in combination with ibrutinib (560 mg daily) appeared to be well tolerated in these two subjects. One patient experienced Gr3 treatment-related adverse events (thrombocytopenia, muscle weakness, pain). The preliminary efficacy data demonstrated one CR and one SD. The patient who achieved CR after the combination therapy was originally intolerant to high-dose methotrexate based chemoimmunotherapy and did not achieve complete remission after switching to ibrutinib, providing early clinical evidence of CNS penetration and anti-tumor activity of emavusertib. CONCLUSION In R/R PCNSL, these preliminary data suggest that combination therapy has a tolerable safety profile with promising anti-cancer activity and may overcome ibrutinib resistance.

The prognosis of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Chimeric antigen receptor (CAR) T-cell therapy has been approved for R/R DLBCL after 2 prior lines of therapy based on data from single-arm phase 2 trials, with complete responses (CRs) in 40% to 60% of patients. However, a direct comparison with other treatments is not available and, moreover, its true efficacy in real-world patients is unknown. In this single center, retrospective, observational study of 215 patients, we compared outcomes in patients treated with CAR T-cell therapy (n = 69) with a historical population treated with alternate therapies (n = 146). Patients treated with CAR T cell vs alternate therapies demonstrated a CR rate of 52% vs 22% (P < .001), median progression-free survival (PFS) of 5.2 vs 2.3 months (P = .01), and median overall survival (OS) of 19.3 vs 6.5 months (P = .006), and this advantage appeared to persist irrespective of the number of lines of prior therapy. After adjusting for unfavorable pretreatment disease characteristics, superior overall response rate in the CAR T cohort remained significant; however, differences in PFS and OS between cohorts did not. In addition, patients who responded to alternate therapies demonstrated prolonged remissions comparable to those who responded to CAR T therapy. We contend that in select clinical scenarios alternate therapies may be as efficacious as CAR T therapy; thus, additional study is warranted, ideally with randomized prospective trials.

Recent prospective clinical trial data suggest that patients with Hodgkin’s lymphoma who continue treatment with ABVD, despite failing to attain a complete metabolic response on interim PET (PET2+), may fare better than previously published. We describe the outcomes of PET2+ patients who continued ABVD and compare the performance of a quantitative measure based on the lesion-to-liver SUV ratio (LLS qPET2+) to that of the subjective Deauville criteria (dvPET2+). We analyzed all patients with newly diagnosed advanced-stage Hodgkin lymphoma treated with frontline ABVD at the Memorial Sloan Kettering Cancer Center between 2008 and 2017. Eligibility was set to correspond with the RATHL inclusion criteria. Images were reviewed by two nuclear medicine physicians and discordant cases were resolved with a third expert in consensus. qPET2+ was defined as LLS ≥ 1.3. We identified 227 patients of whom 25% (57) were qPET2+, but only 14% (31) were dvPET2+. Forty-eight patients (84%) continued ABVD with a 3-year PFS of 70% for qPET2+ and 64% for dvPET2+. In conclusion, interim PET interpretation in clinical practice may be associated with a higher rate of scans deemed positive. Irrespective of the criteria for PET2 positivity, a subset of patients may continue ABVD without a dismal outcome.

PURPOSE We conducted a phase II study evaluating pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD) as second-line therapy for relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) (ClinicalTrials.gov identifier: NCT03618550 ). METHODS Transplant eligible patients with rel/ref cHL following first-line therapy were treated with two to four cycles of pembrolizumab (200 mg intravenous [IV], day 1), gemcitabine (1,000 mg/m2 IV, days 1 and 8), vinorelbine (20 mg/m2 IV, days 1 and 8), and liposomal doxorubicin (15 mg/m2, days 1 and 8), given on 21-day cycles. The primary end point was complete response (CR) following up to four cycles of pembro-GVD. Patients who achieved CR by labeled fluorodeoxyglucose-positron emission tomography (Deauville ≤ 3) after two or four cycles proceeded to high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). HDT/AHCT was carried out according to institutional standards, and brentuximab vedotin maintenance was allowed following HDT/AHCT. RESULTS Of 39 patients enrolled, 41% had primary ref disease and 38% relapsed within 1 year of frontline treatment. 31 patients received two cycles of pembro-GVD, and eight received four cycles. Most adverse events were grade 1 or two, whereas few were grade 3 and included transaminitis (n = 4), neutropenia (n = 4), mucositis (n = 2), thyroiditis (n = 1), and rash (n = 1). Of 38 evaluable patients, overall and CR rates after pembro-GVD were 100% and 95%, respectively. Thirty-six (95%) patients proceeded to HDT/AHCT, two received pre-HDT/AHCT involved site radiation, and 13 (33%) received post-HDT/AHCT brentuximab vedotin maintenance. All 36 transplanted patients are in remission at a median post-transplant follow-up of 13.5 months (range: 2.66-27.06 months). CONCLUSION Second-line therapy with pembro-GVD is a highly effective and well-tolerated regimen that can efficiently bridge patients with rel/ref cHL to HDT/AHCT.

7560 Background: Tafasitamab (tafa) + lenalidomide (LEN) demonstrated efficacy in adult patients (pts) with R/R DLBCL ineligible for autologous stem-cell transplant in the pivotal Phase II study L-MIND (NCT02399085) and received accelerated approval in the United States in 2020 and conditional marketing authorization in Europe and Canada in 2021 in this setting. RE-MIND2 (NCT04697160), an observational, retrospective cohort study, compared pt outcomes from L-MIND with matched pt cohorts treated with other NCCN/ESMO recommended therapies. Methods: Methodology for RE-MIND2 has been presented previously. Hypothesis-generating analyses were conducted for pt subgroups of number of extranodal sites (ENS) (0–1 vs ≥2) and elevated lactate dehydrogenase (LDH) (yes vs no) in matched cohorts of pts receiving tafa + LEN vs systemic therapies pooled (STP), polatuzumab vedotin + bendamustine + rituximab (pola-BR), rituximab + LEN (R2), and CD19 CAR-T therapies (CAR-T). The primary endpoint was overall survival (OS). Results: Of 3,454 pts enrolled, 961, 106, 106, and 149 were treated with STP, pola-BR, R2, and CAR-T, resulting in 76, 24, 33, and 37 matched pairs for pts receiving tafa + LEN, respectively. Hazard ratios (HR) for OS show a trend toward favoring tafa + LEN in most pt subgroups (Table). Conclusion: These analyses suggest that tafa + LEN may be associated with improved OS vs selected systemic therapies for certain pts with high-risk disease and may further inform physicians’ treatment choices for pts with R/R DLBCL. These analyses are not powered for statistical comparison; small sample sizes in some subgroups result in wide confidence intervals (CI) and so results must be interpreted with caution. Data for other treatment cohorts, pt subgroups, and endpoints will be presented. Funding: MorphoSys AG. Clinical trial information: NCT04697160. [Table: see text]

7575 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of nuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. CA-4948 has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. CA-4948 crossed the blood-brain barrier in a murine PDX model of pCNS lymphoma, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, CA-4948 showed in vivo synergy in B-cell NHL. Here we will present an update on the preliminary efficacy data of CA-4948+ibrutinib in R/R hematologic malignancies. Methods: This is an ongoing open-label trial (NCT03328078) of CA-4948 as monotherapy and in combination with ibrutinib. Part A1 (completed) dose escalation of CA-4948 as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing. Part A2 (dose escalation in combination with ibrutinib), and Part B (a basket design of 4 expansion cohorts of CA-4948 and ibrutinib: BTK-naïve MZL, DLBCL, or PCNSL and NHL with adaptive resistance to ibrutinib). The primary endpoints of Parts A1 and A2 include safety, tolerability, and RP2D. The primary endpoints of Part B include CR or ORR, with key secondary endpoints of DOR, DCR, PFS and OS following treatment of CA-4948 at dose levels of 200 (DL1) or 300 mg BID (DL2) with ibrutinib at full prescribed dose. Results: As of December 7th, 2021, 35 heavily pretreated NHL patients have received CA-4948 monotherapy (median age 66 years, range 50-87), of which six patients have been on CA-4948 for approximately 1 year or longer, suggesting CA-4948 has a long-term acceptable safety and tolerability profile at RP2D (dose level of 300 mg BID). In Part A2, 10 patients are treated with CA-4948+ibrutinib (median age 65 years, range 56-82). Median number of prior lines of anti-cancer therapies is 3 (range 1-8). No DLTs were observed at 200 or 300 mg dose levels to date. The preliminary efficacy data of seven evaluable patients with combination therapy showed 1 CR (MCL), 2 PR (MCL and MZL), 3 SD, and 1 PD, 3 of whom had failed prior ibrutinib. The preliminary data indicate the combination therapy may overcome ibrutinib resistance. Conclusions: CA-4948 as a monotherapy and in combination with ibrutinib is well tolerated with an acceptable long term safety profile and promising efficacy. Part A2 is transitioning to Part B basket cohorts of MZL, ABC-DLBCL, PCNSL and NHL with adaptive resistance to ibrutinib. Clinical trial information: 03328078.

Context Tafasitamab+LEN, a chemotherapy-free, novel treatment for R/R DLBCL, demonstrated efficacy in ASCT-ineligible patients in the single-arm Phase II L-MIND study (NCT02399085). Objective To compare outcomes in patients treated with tafasitamab+LEN in the L-MIND study with matched patient populations treated with commonly administered NCCN-/ESMO-recommended therapies for non-transplant-eligible patients with R/R DLBCL in routine clinical practice. Design RE-MIND2 (NCT04150328) is an observational, retrospective cohort study. The L-MIND tafasitamab+LEN cohort was matched with RE-MIND2 patients using estimated propensity score-based 1:1 nearest neighbor matching balanced for nine patient and disease baseline characteristics: age ( 9 /L), anemia (cut-off upper limit of normal). Setting Academic, public, and private hospitals in Europe, North America, and Asia-Pacific. Patients Age: ≥18 years old with histologically confirmed DLBCL. Prior systemic therapy for DLBCL: ≥1, including ≥1 anti-CD20 therapy. Interventions Data are presented for tafasitamab+LEN vs all (pooled) systemic therapies, tafasitamab+LEN vs bendamustine+rituximab (BR), and tafasitamab+LEN vs rituximab+gemcitabine+oxaliplatin (R-GemOx). Main Outcome Measures The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate, complete response rate, progression-free survival, event-free survival, duration of response, and time to next treatment. Results In RE-MIND2, 3,454 patients were enrolled from 200 centers. For the comparative analysis, 76 patients from the L-MIND tafasitamab+LEN study were included in the full analysis set. Strictly matched pairs of patients (standardized mean difference ≤0.2) included: tafasitamab+LEN vs pooled therapies, n=76 pairs; tafasitamab+LEN vs BR, n=75 pairs; and tafasitamab+LEN vs R-GemOx, n=74 pairs. Tafasitamab+LEN was associated with longer OS compared with pooled therapies (HR: 0.55; p=0.0076), BR (HR: 0.42; p Conclusions Results of this analysis suggest that tafasitamab+LEN has improved OS vs commonly used regimens. Funding This study was funded by MorphoSys AG.

Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1–3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.

We reviewed pre-diagnosis clinical data of 420 patients with pathologically confirmed myelodysplastic syndromes (MDSs) presenting with anemia. In 232 patients with yearly pre-diagnosis complete blood counts (CBCs), we also analyzed CBC kinetics in respects to a standardized timepoint in which all patients had similar levels of hemoglobin (Hgb). At the standardized timepoint (last documented 12 > Hgb ≥ 11 g/dL), occurring months-years before diagnosis, median CBC values were Hgb 11.4 g/dL, absolute neutrophil count (ANC) 2.7 × 103 (k)/mcl, and platelets (PLTs) 181 k/mcl. Gradual changes in CBC could be observed years prior to this timepoint, for the most part while within normal/near-normal limits. During this time, most patients had a coexisting alternative etiology for anemia. Patients with high-risk cytogenetic/blast features had a rapid and steeper decrease in counts in the last year before developing a concerning anemia (decrease in: Hgb 0.75 g/dL vs 0.55 g/dL; PLT 29.5 vs 4.5 k/mcl; ANC 0.86 vs 0.4 k/mcl, P = .03). Low-risk patients had a high rate of longstanding mild anemia (31% vs 16%, P = .05). Rate of development of cytopenia and number of involved hematopoietic lines were prognostic. In 65% of patients, with near normal CBC at the standardized timepoint, but in whom there was a decrease in multiple hematopoietic lines over the preceding year, the 5-year overall survival (5yOS) was 53% compared to 71% in patients with isolated slowly progressing anemia (20% of patients). In 15% of patients with mild cytopenia developing after both a rapid decrease and multiple involved lines, prognosis was dismal (5yOS 34%). In conclusion, kinetics of pre-MDS CBC values correlate with disease risk and survival.

Very low-dose radiotherapy (4 Gy; VLDRT) is an effective treatment for indolent lymphomas and offers the advantage of a shorter course and improved side effect profile compared to full dose RT regi...

A non-invasive myelodysplastic syndromes (MDS) diagnostic model would allow for care while avoiding invasive bone marrow examinations (BME). BME-established MDS patients were compared to non-MDS (BME-excluded) patients. Variables (gender, age, hemoglobin (Hb), mean red blood cell corpuscular volume (MCV), platelet (PLT), and white blood cell (WBC)) were combined with multivariate logistic regression; a probability score (Y) was calculated. MDS (n = 48) and non-MDS (n = 63) patients were used to establish the model. The ROC was drawn, giving an AUC of 0.748 (95% CI: 0.656-0.84). Two cutoff values were used for Y. Y ≥ 0.633: high likelihood (positive predictive value (PPV) = 85%); Y ≤ 0.288: low likelihood (negative predictive value (NPV) = 81%) of MDS. The first group is defined as probable MDS (pMDS); the second, probably not MDS (pnMDS). The model was validated with 40 additional patients (20 with and 20 without MDS). Using clinical and lab data, we could diagnose or exclude MDS in about half of the patients, avoiding BME. Future work will use larger cohorts of patients to improve and further validate the model.

Background Several therapies are recommended by NCCN/ESMO guidelines for autologous stem cell transplant (ASCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). In the single-arm, Phase II L-MIND study (NCT02399085), the chemotherapy-free regimen tafasitamab + lenalidomide (LEN) demonstrated efficacy for this patient population. In the absence of randomized clinical trial data, RE-MIND2 (NCT04697160), an observational, retrospective cohort study, compared patient outcomes from L-MIND with matched patient populations treated with NCCN/ESMO recommended therapies for ASCT-ineligible patients with R/R DLBCL. Methods Data were retrospectively collected between 1 April and 13 November 2020 from academic and public hospitals, as well as private practices in North America, Europe and Asia Pacific. To ensure consistency with L-MIND I/E criteria, patients aged ≥18 years with histologically confirmed DLBCL and who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy) were enrolled. For the main analysis, patients from the L-MIND tafasitamab + LEN cohort were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest neighbor matching, balanced for six baseline characteristics: age ( A sensitivity analysis was performed using an inverse probability of treatment weighting method calculating the average effect of the treatment on the treated, to generate balanced cohorts based on nine baseline characteristics: age, refractoriness to last line of therapy, number of previous lines of therapy, history of primary refractoriness, prior ASCT, Ann Arbor Stage (I/II vs III/IV), elevated LDH (yes vs no), neutropenia (yes vs no), and anemia (yes vs no). Additional sensitivity analyses accounting for missing baseline characteristics using multiple imputation technique were performed. Data are presented for tafasitamab + LEN versus polatuzumab vedotin + bendamustine + rituximab (pola-BR), rituximab + LEN (R2), and CD19 CAR-T therapies (CAR-T). The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate (ORR), complete response rate, progression-free survival and duration of response. Results Of 3,454 patients enrolled from 200 sites, 106, 106, and 149 patients were treated with pola-BR, R2, and CAR-T, respectively. For the comparative analysis, matched patient pairs were created using 1:1 nearest neighbor matching with a caliper. Matched pairs consisted of: tafasitamab + LEN vs pola-BR, n=24 pairs; vs R2, n=33 pairs; and vs CAR-T, n=37 pairs. A significant OS benefit was associated with tafasitamab + LEN compared to pola-BR (HR: 0.44, 95% confidence interval [CI]: 0.20-0.96; p=0.038) and R2 (HR=0.44, 95% CI: 0.22-0.84; p=0.014) (Figure 1A-B). There was no significant difference in OS benefit between tafasitamab + LEN and CAR-T (HR=0.95, 95% CI: 0.47-1.91; p=0.891) (Figure 1C). ORR was 62.5% (15/24) for tafasitamab + LEN vs 58.3% (14/24) for pola-BR (p=1.000), 63.6% (21/33) vs 30.3% (10/33) for R2 (p=0.013), and 59.5% (22/37) vs 75.7% (28/37) for CAR-T (p=0.214). Improved outcomes were also observed with tafasitamab + LEN for other secondary endpoints (Table 1). Results are consistent with those obtained in the sensitivity analyses. Conclusions The results of this retrospective cohort analysis suggest that the novel tafasitamab + LEN combination may significantly improve health outcomes, with a prolonged survival benefit for ASCT-ineligible R/R DLBCL patients, relative to NCCN/ESMO recommended therapies. Tafasitamab + LEN improved survival outcomes compared with pola-BR and R2 in closely matched patient populations. Comparable outcomes were observed for tafasitamab + LEN vs CAR-T. Although based on limited patient numbers, these data may be clinically relevant in the context of emerging therapies for R/R DLBCL. While this study design does not replace randomized data, it remains more rigorous than inter-trial comparison. The limitations of comparing clinical trial and matched retrospective real-world data will be discussed. Funding: MorphoSys AG. Figure 1 Figure 1. Disclosures Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding. Joffe: AstraZeneca. Epizyme: Consultancy. Fleury: Abbvie, Astrazeneca, BMS, Celgene, Janssen, Kite-Gilead, Merck, Novartis, Roche, Seattle Genetics: Other: conference and advisory role. Peters: AbbVie, Incyte: Consultancy, Honoraria. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Marks: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Meeting attendance; Kite/Gilead: Honoraria; Merck: Consultancy. Kim: AstraZeneca: Research Funding. Zinzani: BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trotman: Beigene: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Roche: Research Funding; Janssen: Research Funding; PCYC Pharmacyclics: Research Funding. Sabatelli: Incyte: Current Employment, Current equity holder in publicly-traded company. Huang: MorphoSys: Current Employment. Waltl: MorphoSys: Current Employment. Winderlich: MorphoSys: Current Employment, Current equity holder in publicly-traded company. Ambarkhane: MorphoSys: Current Employment, Other: Support for attending meetings/travel. Kurukulasuriya: MorphoSys: Current Employment, Current equity holder in publicly-traded company, Other: Support for attending meetings/travel. Cordoba: Pfizer: Research Funding; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADCTherapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hess: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead/Kite: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Salles: Miltneiy: Consultancy; Novartis: Consultancy; Morphosys: Consultancy, Honoraria; Janssen: Consultancy; Genentech/Roche: Consultancy; Kite/Gilead: Consultancy; Regeneron: Consultancy, Honoraria; Velosbio: Consultancy; Takeda: Consultancy; Allogene: Consultancy; Ipsen: Consultancy; Loxo: Consultancy; Rapt: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Epizyme: Consultancy, Honoraria; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Background: Venetoclax (Ven; BH3 mimetic) and Obinutuzumab (O; CD20 antibody) is an approved, fixed-duration regimen (one year) that induces undetectable minimum residual disease (uMRD) and durable remissions in treatment naïve patients (pts) with chronic lymphocytic leukemia (CLL; Fischer NEJM 2019). In the CLARITY trial of venetoclax-ibrutinib (BTK inhibitor; BTKi) in relapsed or refractory CLL, peripheral blood (PB) MRD response kinetics predicted bone marrow (BM) uMRD and were associated with progression-free survival (Rawstron EHA 2020). We explored MRD as a biomarker to direct treatment duration in an investigator-initiated phase 2 trial of Zanubrutinib (BTKi) and O-Ven (BOVen). We hypothesize that early MRD kinetics will identify a defined cohort of pts with delayed BM MRD clearance, and early recurrent detectable MRD after discontinuation of treatment in pts attaining uMRD. Methods: In this multicenter, phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring treatment (iwCLL), ECOG PS ≤2, absolute neutrophil count (ANC) ≥1,000/ul, platelets (PLT) ≥75,000/ul (ANC ≥0/ul, PLT ≥20,000/ul if due to CLL). Informed consent was obtained from all pts. BOVen was administered in 28-day (D) cycles (C): Zanubrutinib 160 mg by mouth (PO) twice daily starting D1; Obinutuzumab 1000 mg IV D1 (split D1-2 if lymphocyte count ≥25,000/ul or lymph node ≥5cm), D8, D15 of C1, and D1 of C2-8; Venetoclax ramp up initiated C3D1 (target 400 mg PO daily). MRD was evaluated by flow cytometry (MRD-FC) and immunosequencing (MRD-IS; Adaptive ClonoSEQ) with uMRD defined as ≤10 -4 for flow and ≤10 -5 for IS. Treatment consisted of 8-24 cycles with duration determined by prespecified MRD criteria. Beginning on C7D1 then every 2 cycles, pts with PB uMRD-FC had BM within 14 days. If BM uMRD, PB MRD was repeated after two additional cycles. Pts with confirmed uMRD-FC in PB and BM discontinued therapy and entered posttreatment surveillance. Response was assessed per iwCLL. Adverse events (AE) were assessed per CTCAE v5. MRD-IS failure free survival (FFS) was calculated from end-of-treatment (EOT) to the date of detectable MRD-IS (≥10 -5) using the Kaplan-Meier method. Results: The study accrued 39 pts (03/19-10/19): median age 59 years (23-73), 3:1 male predominance, 28/39 (72%) IGHV unmutated, 5/39 (12.8%) del(17p)/TP53M. All pts were evaluable for toxicity with 37 evaluable for efficacy. At a median follow up of 26+ months (mo; 4.5-30.5+), 95% (35/37) pts achieved uMRD-FC in PB, among whom 33 (94%) also achieved uMRD-IS. BM uMRD-FC was seen in 89% (33/37) at a median time of 8 mo (6-16), all of whom met prespecified MRD criteria and discontinued therapy after a median of 10 mo (8-18). Three pts discontinued therapy with persistent detectable BM MRD after 24 cycles. The most common AEs were neutropenia (51%), thrombocytopenia (44%), diarrhea (44%), infusion related reaction (41%) and bruising (41%). The most common grade ≥3 AE was neutropenia (15%). No laboratory or clinical TLS occurred (Howard definition). A ≥400-fold reduction in PB MRD-IS after 4 cycles (ΔMRD400) was selected using the Youden Index and was highly predictive of attaining BM uMRD in ≤8mo (sensitivity 88% [21/24], specificity 100% [11/11], PPV 100% [21/21], NPV 79% [11/14]. As a result, the median duration of therapy was shorter among patients who achieved ΔMRD400 (8 vs 13 mo). Of 33 pts who met prespecified uMRD criteria and stopped therapy, 31 (94%) remain uMRD-FC following a median 15 mo (0-20) from EOT, and 2 pts had recurrent MRD (1 with PD recaptured PB uMRD with retreatment). Of 33 pts who discontinued therapy after achieving the prespecified MRD endpoint, MRD-IS was evaluated every 3 months in 31 pts for a median of 12 mo (range, 3-18) from EOT. MRD-IS FFS was longer in pts who achieved ΔMRD400 (log rank p Conclusion: BOVen achieved frequent, durable uMRD. All pts completed therapy (median 10 mo treatment), including 89% (33/37) who met the prespecified PB/BM uMRD endpoint. With a median posttreatment follow-up of 15 mo, 31 (94%) remain uMRD-FC. ΔMRD400 identified a cohort of pts (40%) with delayed BM MRD clearance and earlier MRD recurrence, despite longer treatment duration. ΔMRD400 warrants further study as a predictive biomarker for treatment duration. Figure 1 Figure 1. Disclosures Soumerai: Seattle Genetics: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; BMS: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; BostonGene: Research Funding; GlaxoSmithKline: Research Funding. Mato: Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genmab: Research Funding; AstraZeneca: Consultancy; MSKCC: Current Employment; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Nurix: Research Funding; AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; BeiGene: Consultancy, Research Funding. Dogan: Seattle Genetics: Consultancy; Peer View: Honoraria; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; EUSA Pharma: Consultancy. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Hochberg: Leuko: Consultancy; Intervention Insights: Consultancy. Abramson: Bluebird Bio: Consultancy; Morphosys: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Kymera: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; C4 Therapeutics: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Kite Pharma: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Batlevi: TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; GLG Pharma: Consultancy; Dava Oncology: Honoraria; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; ADC Therapeutics: Consultancy; Life Sciences: Consultancy; Moderna: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Seattle Genetics: Consultancy; Bayer: Research Funding; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Matasar: Rocket Medical: Consultancy, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Juno Therapeutics: Consultancy; Merck: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Teva: Consultancy; TG Therapeutics: Consultancy, Honoraria; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy. Palomba: Ceramedix: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Kite: Consultancy; PCYC: Consultancy; BeiGene: Consultancy; Lygenesis: Honoraria; Nektar: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; Rheos: Honoraria; Magenta: Honoraria; Pluto: Honoraria; WindMIL: Honoraria; Priothera: Honoraria. Kumar: Abbvie Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Seattle Genetics: Research Funding. Roeker: AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company. Thompson: VJHemOnc: Honoraria; MJH Life Sciences: Honoraria; Curio Science: Honoraria. Roshal: Physicians' Education Resource: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Celgene: Other: Provision of services. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Biondo: Roche: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Current Employment. Wu: Genentech, Inc.: Current Employment; Roche/GNE: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Jacob: Adaptive Biotechnologies: Current Employment. Abdel-Wahab: H3B Biomedicine: Consultancy, Research Funding; Foundation Medicine Inc: Consultancy; Merck: Consultancy; Prelude Therapeutics: Consultancy; LOXO Oncology: Consultancy, Research Funding; Lilly: Consultancy; AIChemy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Envisagenics Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Zelenetz: Novartis: Honoraria; Genentech/Roche: Honoraria, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; AstraZeneca: Honoraria; MethylGene: Research Funding; Pharmacyclics: Honoraria; Amgen: Honoraria; MEI Pharma: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Verastem: Honoraria; Beigene: Honoraria, Other, Research Funding; Abbvie: Honoraria, Research Funding; SecuraBio: Honoraria; Janssen: Honoraria; Gilead: Honoraria; MorphoSys: Honoraria; NCCN: Other; LFR: Other. OffLabel Disclosure: Zanubrutinib is administered off-label in combination with venetoclax and obinutuzumab for patients with CLL/SLL.

Introduction Histone deacetylase (HDAC) inhibitors have single agent activity in various types of lymphoma. They restore antigen-specific immune recognition in B-cell lymphoma cells and modulate programmed cell death (PD)-1 expression on circulating T-lymphocytes. Pembrolizumab (PEM) is highly active in Hodgkin Lymphoma (HL) and demonstrates a 12-month PFS of 46% in patients with R/R HL. Preclinical studies have shown synergism of this combination in mouse models of various tumors. We present the interim efficacy analysis from the first stage of our phase II trial investigating the combination of the HDAC inhibitor Entinostat (ENT) and the PD-1-blocking antibody PEM in patients with R/R HL. Methods Patients with R/R HL received ENT 5-7 mg orally once weekly and PEM 200 mg intravenously once every three weeks. Prior use of anti-PD-1 or HDAC inhibitor was allowed if there had been clinical benefit. Tumor assessment was evaluated using the RECIL criteria. The primary endpoint is the 12-month progression-free survival (PFS). Using a Simon two-stage minimax design to power the study, 21 patients were to be enrolled in the first stage with a 12-month PFS rate of 40% considered undesirable and 60% desirable. Results At time of data censoring on 7/24/21, 22 patients with HL have been enrolled. The median number of prior therapies was 5 (2-17). 7 (32%) were refractory to the most recent therapy, 13 (59%) had received autologous stem cell transplant (ASCT), 12 (55%) prior anti-PD1 antibody therapy, and 3 (14%) prior HDAC inhibitor therapy. Out of 22 evaluable patients, the overall response rate (ORR) was 86% and the complete response (CR) rate was 45%. Responding patients included 9 with prior anti-PD-1 antibody and 3 with prior HDAC inhibitor therapy. With median duration of follow-up among survivors of 8.4 months (2-26), the 12-month PFS was 72% (44%-87%). Reasons for treatment discontinuation included: progression (n=6), toxicities (n=5) consolidation with transplant or radiation (n=3), withdrawal of consent (n=3), and completion of study protocol (n=2). Severe toxicities resulting in study discontinuation were pleural effusions, pericarditis, pneumonitis and peripheral neuropathy. Out of the 22 total patients with HL enrolled in this study, 50% of patients had grade ≥3 (41%) and thrombocytopenia (32%). 41% exhibited grade ≥3 non-hematologic AEs, which included pericardial or pleural effusions (n=2, 9%), as well as fatigue, musculoskeletal pain, abdominal pain, pneumonitis, elevated lipase, hyperglycemia, and peripheral neuropathy. AEs that were potentially immune-related included hypothyroidism (n=2, 9%), elevated transaminases (n=4, 18%), diarrhea (n=3, 14%) and pneumonitis (n=2, 8%). Conclusions Interim results following stage I of this phase 2 trial demonstrates a 12-month PFS rate of 74%, meeting the primary endpoint of the study and justifying continued investigation of the combination of PEM and ENT. In this heavily pretreated patient population, responses were seen in the majority of patients despite prior exposure to anti-PD-1 agents. Figure 1 Figure 1. Disclosures Vardhana: Immunai: Membership on an entity's Board of Directors or advisory committees. Moskowitz: Bristol-Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Beigene: Research Funding; Miragen: Research Funding; Janpix Ltd.: Consultancy; Merck: Consultancy, Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Takeda: Consultancy; Incyte: Research Funding. Joffe: AstraZeneca. Epizyme: Consultancy. Khan: Seattle Genetics: Research Funding. Kumar: Seattle Genetics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Pharmacyclics: Research Funding; Abbvie Pharmaceuticals: Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding. Zelenetz: Gilead: Honoraria; Genentech/Roche: Honoraria, Research Funding; AstraZeneca: Honoraria; MorphoSys: Honoraria; Novartis: Honoraria; Pharmacyclics: Honoraria; Verastem: Honoraria; SecuraBio: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; MethylGene: Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; MEI Pharma: Honoraria, Research Funding; Janssen: Honoraria; Beigene: Honoraria, Other, Research Funding; Amgen: Honoraria; NCCN: Other; LFR: Other. Horwitz: Affimed: Research Funding; 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; 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; Celgene: Research Funding; 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. Noy: Janssen: Consultancy, Honoraria; Epizyme: Consultancy; Morphosys: Consultancy; Rafael Parhma: Research Funding; Medscape: Consultancy; Targeted Oncology: Consultancy; Pharmacyclics: Consultancy, Research Funding. Batlevi: Memorial Sloan Kettering Cancer Center: Current Employment; Moderna: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; BMS: Current holder of individual stocks in a privately-held company; Autolus: Research Funding; Pfizer: Current holder of individual stocks in a privately-held company; Dava Oncology: Honoraria; Bayer: Research Funding; Medscape: Honoraria; ADC Therapeutics: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; TouchIME: Honoraria; TG Therapeutics: Consultancy; Karyopharm: Consultancy; Seattle Genetics: Consultancy; Life Sciences: Consultancy; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Epizyme: Research Funding. Matasar: Pharmacyclics: Honoraria, Research Funding; Juno Therapeutics: Consultancy; TG Therapeutics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Rocket Medical: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; GlaxoSmithKline: Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; IGM Biosciences: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Teva: Consultancy; Janssen: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Palomba: Nektar: Honoraria; Notch: Honoraria, Other: Stock; PCYC: Consultancy; Kite: Consultancy; Ceramedix: Honoraria; Novartis: Consultancy; Priothera: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; Lygenesis: Honoraria; Pluto: Honoraria; Rheos: Honoraria; BeiGene: Consultancy; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; WindMIL: Honoraria; Magenta: Honoraria. Lee: Intellisphere, LLC: Consultancy. Dogan: EUSA Pharma: Consultancy; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Peer View: Honoraria; Seattle Genetics: Consultancy; Physicians' Education Resource: Honoraria. Salles: Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy; Kite/Gilead: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Morphosys: Consultancy, Honoraria; Rapt: Consultancy; Genentech/Roche: Consultancy; Epizyme: Consultancy, Honoraria; Beigene: Consultancy; Debiopharm: Consultancy; Regeneron: Consultancy, Honoraria; Loxo: Consultancy; Miltneiy: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Bayer: Honoraria; Velosbio: Consultancy; Allogene: Consultancy. Younes: AZ: Current Employment, Other: Senior Vice President, Global Head of Haematology (Early and Late Stage) Oncology R&D at AstraZeneca. von Keudell: Pharmacyclics: Consultancy, Honoraria; AbbVie: Research Funding; Janssen: Research Funding; Merck: Consultancy, Honoraria; Merck: Research Funding; Incyte: Consultancy, Honoraria; BMS: Research Funding.

Background: In untreated Hodgkin lymphoma (HL), metabolic tumor volume (MTV) significantly declined following pembrolizumab monotherapy, regardless of baseline MTV, and may serve as a better measure of treatment response to PD-1 blockade than the Lugano Classification (Allen, et al. Blood 2021). Furthermore, standard PET evaluation can fail to differentiate between malignancy, pseudoprogression and physiological background in patients (pts) receiving PD-1 blockade. The predictive power and prognostic significance of MTV in patients with relapsed or refractory (RR) HL receiving PD-1 blockade is unknown. We sought to examine the role of MTV in HL pts treated with PD-1 blockade. Methods: We identified 30 pts who received pembrolizumab or nivolumab-based therapy off-study for RR HL between July 2015 and May 2021. In the PET/CT analysis, all lesions were visually identified, and all measurable lesions were selected for the analysis. Responses were assessed by Lugano Classification. Indeterminant response (IR) was defined as evidence of progression on PET without clinical deterioration as per the Lyric Criteria. MTV was obtained by summing the metabolic volumes of all measurable lesions, using the 41% SUVmax threshold to measure each lesion MTV using Beth Israel plugin. MTV was evaluated at baseline (MTV0) and at first reassessment (MTV1) after initiation of PD-1 blockade. Δ (delta) MTV was calculated as % change in MTV from MTV0 to MTV1. Receiver operating characteristic (ROC) curve was performed for ΔMTV and best overall response rate (BOR) to determine the optimal cut-off value. Overall survival (OS) was measured from PD-1 blockade initiation to death or last follow-up. We examined the association between MTV and clinical factors, PET-1 response, and overall survival using Cox proportional hazards model and Fisher exact test, respectively. Results: 25 patients had complete clinical data and PET/CT analysis (Table 1). The median age at first relapse was 39 years (range: 18-81); 64% were male. 6 pts previously received PD-1 blockade on clinical trials and discontinued treatment due to study completion or toxicity. The median time between PET0 and PET1 was 3.4 months (range 2.0-7.3). Median MTV0 and MTV1 values were 39.8 ml and 17.1 ml, respectively. With a median follow up from initiation of PD-1 blockade among survivors of 38.7 months, 5 pts (19%) died. The median OS of the entire cohort was not reached (95%CI: 76.4-NR) (Figure 1). The best response to PD-1 blockade included 15 (60%) with complete metabolic response (CMR), 5 (20%) with partial metabolic response (PMR), and 5 (20%) with progression of disease (POD). Median ΔMTV was -70% (range -100 to +909%). MTV0 was not predictive of OS, PET1 response, or BOR. However, ΔMTV predicted for PET1 response (p=0.004) and BOR (p=0.004). 18 (72%) pts had a reduction in ΔMTV (range: -100, -22), while 7 (28%) pts had an increase in ΔMTV (range: 33-909). The optimal ΔMTV threshold for prediction of BOR was 120% (Figure 1). ΔMTV Among pts with IR on PET-1, ΔMTV Conclusions: Quantitative change in MTV from baseline to first reassessment may aid in predicting treatment response and long-term outcomes in patients with RR HL receiving PD-1 blockade, particularly those initially characterized as achieving indeterminate response. Further prospective clinical trials are needed to validate the role of ΔMTV in predicting response and long-term outcomes for RR HL pts receiving PD-1 blockade. Figure 1 Figure 1. Disclosures Moskowitz: Merck & Co., Inc.: Research Funding. Matasar: Seattle Genetics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Juno Therapeutics: Consultancy; Merck: Consultancy; Pharmacyclics: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Honoraria. Zelenetz: Amgen: Honoraria; MorphoSys: Honoraria; Novartis: Honoraria; MEI Pharma: Honoraria, Research Funding; Beigene: Honoraria, Other, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria; SecuraBio: Honoraria; Genentech/Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Verastem: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; MethylGene: Research Funding; AstraZeneca: Honoraria; Janssen: Honoraria; NCCN: Other; LFR: Other; Gilead: Honoraria. Joffe: AstraZeneca. Epizyme: Consultancy. von Keudell: Merck: Research Funding; Janssen: Research Funding; BMS: Research Funding; Incyte: Consultancy, Honoraria; AbbVie: Research Funding; Merck: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria. Batlevi: Medscape: Honoraria; Memorial Sloan Kettering Cancer Center: Current Employment; Moderna: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; ADC Therapeutics: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; TG Therapeutics: Consultancy; Kite Pharma: Consultancy; Seattle Genetics: Consultancy; TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Bayer: Research Funding; Viatris: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; Juno/Celgene: Consultancy; Life Sciences: Consultancy; Dava Oncology: Honoraria; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Caron: Astra-Zeneca: Current holder of individual stocks in a privately-held company; bristol myers: Current holder of individual stocks in a privately-held company; GlaxoSmithKlein: Current holder of individual stocks in a privately-held company; Johnson and Johnson: Current holder of individual stocks in a privately-held company; Novartis: Current holder of individual stocks in a privately-held company; pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Targeted Oncology: Consultancy; Epizyme: Consultancy; Janssen: Consultancy, Honoraria. Salles: Velosbio: Consultancy; Morphosys: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Novartis: Consultancy; Epizyme: Consultancy, Honoraria; Allogene: Consultancy; Rapt: Consultancy; Genentech/Roche: Consultancy; Takeda: Consultancy; Miltneiy: Consultancy; Loxo: Consultancy; Kite/Gilead: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Moskowitz: ADC Therapeutics: Research Funding; Takeda: Consultancy; Incyte: Research Funding; Merck: Consultancy, Research Funding; Beigene: Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Miragen: Research Funding; Janpix Ltd.: Consultancy; Imbrium Therapeutics L.P./Purdue: Consultancy.

Introduction: The prognostic significance of immunoglobulin heavy-chain variable region gene (IGHV) mutational status in chronic lymphocytic leukemia (CLL) is well established. Previous studies have shown that CLL patients with mutated IGHV (M-IGHV) have a better prognosis, manifested in a longer time-to first treatment (TTFT) and overall survival (OS). Here we present an analysis on the impact of IGHV mutational status in an Israeli cohort of patients with CLL. Methods: A total of 254 patients with CLL (diagnosed from 1991 to 2020), followed at the Tel-Aviv Sourasky Medical Center were included. The IGHV mutational status has been determined by next-generation sequencing (NGS) or cDNA Sanger. The sequences with a germline homology 98% or higher were considered unmutated, and those with a homology less than 98% as mutated CLL. IGHV subsets were analyzed using the ARResT/AssignSubsets website. All data were statistically analyzed by IBM SPSS Statistics 27 (IBM Corporation, Armonk, NY, USA), P-values were two-sided, and the significance level was determined at a Results: Out of 254 patients, 132 (52.0%) had an unmutated IGHV gene (UM-IGHV), and 122 (48.0%) were mutated (M-IGHV). At diagnosis, most patients (Table 1) were ≤65 years of age (n=157, 61.8%), males (n=160, 63.0%) and had an absolute lymphocytic count equal to or less than (≤)15.0 x10 9/L (n=115, 52.5%). Advanced Binet stage was more commonly associated with UM-IGHV (n=44, 57.9%) (P=0.033). Among 240 patients (94.1%), the most frequently used VH gene segments (Figure 1) included; VH1-69 (n=35, 14.6%), VH4-34 (n=24, 10.0%), VH1-2 (n=17, 7.1%), and VH3-23 (n=16, 6.7%). Six major B-cell receptors (BCR) subsets (Figure 2) were identified in 21/180 of patients (11.7%), which most commonly included: CLL#1 (n=6, 28.6%), CLL#4 (n=5, 23.8%), and CLL#2(n=3, 14.3%). Patients with M-IGHV had a longer time to first treatment (TTFT) (P In multivariate analyses of the entire cohort; for TTFT (Table 2A), males (P=0.002, HR=1.9, [1.3-2.9]), >65 years of age at diagnosis (P=0.008, HR=1.8, [1.2-2.7]), advanced Binet stage (P65 years of age at diagnosis (P=0.010, HR=2.6, [1.3-5.5]) and UM-IGHV mutational status (P=0.004, HR=2.9, [1.4-5.9]) were found to be significant factors for shorter OS. In multivariate analyses performed separately for each IGHV mutational status group; males (P=0.021, HR=2.1, [1.1-4.0]), age >65 years (P=0.002, HR=3.2, [1.5-6.4]) and advanced Binet stage (P65 years at diagnosis (P=0.039, HR=4.3, [1.1-17.0]) was the only independent predictor in M-IGHV patients, while no variable maintained its statistical significance in UM-IGHV cases. Conclusion: As previously studied, our cohort demonstrates that M-IGHV CLL patients have better TTFT and OS. However, the rate of BCR subsets in Israel appears to be lower than expected. A separated multivariate analysis for M-IGHV and UM-IGHV patients revealed different independent predictors for TTFT and OS to each of the IGHV mutational status groups. Further studies with larger cohorts are required to deeply study these differences and provide further clinical insight into the pathophysiology of CLL. Figure 1 Figure 1. Disclosures Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Herishanu: AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Medison: Honoraria.

Introduction Central nervous system relapse (secondary central nervous system lymphoma -SCNS) is an uncommon but devastating complication of aggressive B-cell lymphoma. Patients (Pts) with CNS-IPI 4-6 are at greatest risk (10.2% at 2 years). Intravenous high-dose methotrexate (HD-MTX) is widely used to mitigate SCNS risk but data supporting this practice are limited. Methods We performed a multicentre, retrospective study at 21 sites in Australia, Asia, North America and Europe. Chart or registry review was performed for consecutively diagnosed pts with diffuse large B-cell lymphoma (DLBCL) and CNS-IPI 4-6, high grade B-cell lymphoma (HGBL) with rearrangements of MYC+BCL2 and/or BCL6 and primary breast/testicular DLBCL irrespective of CNS-IPI. Pts were diagnosed between 2000-2020, 18-80 years at diagnosis, and treated with curative intent anti-CD20 based chemo-immunotherapy. Pts with CNS involvement at diagnosis were excluded. HD-MTX was defined as at least one cycle of intravenous MTX at any dose. Time to SCNS was calculated from date of diagnosis (all-pts), and from the end of frontline systemic lymphoma therapy, defined as 6x21 days from diagnosis (complete response (CR-pts)), until SCNS, systemic relapse, death, or censoring, whichever came first. Cumulative risk of SCNS was computed using the Aalen-Johansen estimator treating death and systemic relapses as competing events. Adjusted cumulative risks were obtained by using an inverse probability of treatment weighting approach. The average treatment effect was computed as the difference in adjusted 5-year risk of SCNS. Results - 2300 and 1455 pts were included in the all-pts and CR-pts analyses, respectively. Baseline demographics and details of therapy are summarised in Table 1. Except for a predominance of males, pts ≤60 years and pts with ECOG 0-1 in the HD-MTX vs no HD-MTX groups, the demographics and treatments were well balanced. At a median follow up of 5.9 years (range 0.0-19.1) and 5.5 years from diagnosis (range 0.0-18.7), 201/2300 and 84/1455 pts experienced CNS events in the all-pts and CR-pts analyses respectively. For all-pts(n=2300), CNS-IPI was 4-6 in 2052(89.2%), with R-CHOP-like therapy given to 93.8%. 410 pts (17.8%) received HD-MTX (265 HD-MTX alone, 145 in combination with intrathecal methotrexate (IT-MTX);435 received IT-MTX alone;1455 received neither. There were 32/410 and 169/1890 SCNS events, with median time from diagnosis to SCNS of 8.8 and 6.7 months in the HD-MTX and no HD-MTX groups respectively. 5-year OS was 70% (95% CI, 65-76%) and 55% (95% CI 53-57%) in HD-MTX and no HD-MTX groups respectively. There was no difference in the adjusted 5-year risk of SCNS between the HD-MTX and no HD-MTX groups (8.4% vs 9.1%, adjusted hazard ratio [HR] 0.71, p=0.100) (Figure 1). For CR-pts(n=1455), CNS-IPI was 4-6 in 1267(87.0%), with R-CHOP-like therapy given to 93.3%. 284 pts (19.5%) received HD-MTX (170 HD-MTX alone, 114 with IT-MTX);298 received IT-MTX alone;873 received neither. There were 16/284 and 68/1171 SCNS events, with median time from diagnosis to SCNS of 11.0 and 10.3 months in the HD-MTX and no HD-MTX groups respectively. 5-year OS was 74%(95% CI 67-81%) and 75%(95% CI 72-78%) in the HD-MTX groups and no HD-MTX groups respectively (adjusted HR 1.08, p=0.622). There was no difference in the 5-year risk of CNS relapse between the HD-MTX and no HD-MTX groups 5.0% vs 6.0% (adjusted HR 1.03, p=0.903) (Figure 2). Exploratory analysis of the impact of HD-MTX among the highest risk groups CNS IPI 5 (n=368), CNS-IPI 6 (n=59) and CNS-IPI 6 plus all pts with testicular, renal or adrenal involvement (n=349) did not reveal differences in SCNS rates in HD-MTX treated pts. Additional subgroup analyses will be presented at the meeting. Conclusions To our knowledge, this is the largest study of the efficacy of HD-MTX in reducing SCNS events focusing exclusively on high-risk pts. The overall incidence of CNS relapse observed was consistent with previous reports in similar patient cohorts at 9%. The use of HD-MTX did not lower SCNS rates overall or when analysis was confined to CR pts at completion of curative intent therapy to compensate for potential immortal bias associated with HD-MTX therapy. Despite the limitations of the non-randomized and retrospective design, it appears unlikely that HD-MTX is associated with a clinically meaningful reduction in SCNS rates in pts with high risk for SCNS. Figure 1 Figure 1. Disclosures Lewis: AstraZeneca: Consultancy, Honoraria; Novartis: Patents & Royalties: Conference attendance; Janssen: Honoraria, Patents & Royalties: Conference attendance; Roche: Consultancy, Honoraria. Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Bobillo: F. Hoffmann-La Roche Ltd: Consultancy, Speakers Bureau; Gilead: Speakers Bureau. Ekstroem Smedby: Takeda: Consultancy; Janssen Cilag: Research Funding. Savage: Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; Roche: Research Funding; Takeda: Other: Institutional clinical trial funding; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Eyre: Beigene: Honoraria, Research Funding; Incyte: Consultancy; Secura Bio: Consultancy, Honoraria; Janssen: Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Roche: Consultancy, Honoraria. Cwynarski: Incyte: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Atara: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences. Stewart: Teva: Honoraria; Sandoz: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria. Bishton: Gilead: Honoraria, Other: Travel grants; AbbVie: Honoraria, Other: Travel grants; Celgene/BMS: Honoraria, Other: travel grants; Celltrion: Honoraria, Other: Travel grants; Takeda.: Honoraria, Other: Travel grants . Fox: F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Eloranta: Janssen Pharmaceutical NV: Other: NV. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Manos: Bristol-Myers Squibb: Other: Travel and meetings. Hawkes: Specialised Therapeutics: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Antigene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Minson: Novartis: Research Funding; Hoffman La Roche: Research Funding. Dickinson: Celgene: Research Funding; Amgen: Honoraria; Takeda: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Øvlisen: Abbvie: Other: Travel expenses. Gregory: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Talaulikar: Roche: Honoraria, Research Funding; Jansenn: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; EUSA Pharma: Honoraria, Research Funding. Maurer: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genentech: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding. El-Galaly: Abbvie: Other: Speakers fee; ROCHE Ltd: Ended employment in the past 24 months. Cheah: Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Beigene: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory.

Purpose/Objective(s) Indolent non-Hodgkin lymphomas (iNHL), such as follicular lymphoma (FL) and marginal zone lymphoma (MZL) are highly radiosensitive. Previously untreated patients with localized disease are potentially curable (PC) with RT. While standard of care remains 24Gy, de-escalation to very low dose radiotherapy (VLDRT) of 4Gy reduces toxicities and treatment duration. Use of VLDRT outside of palliation remains controversial, however, we hypothesize it may be sufficient for most lesions. Materials/Methods We present the largest single institution VLDRT experience of adults with FL/MZL treated between 2005-2018 with modern principles including PET staging and involved site radiotherapy (ISRT). Outcomes include best clinical/radiographic response using Lugano criteria between 1.5-6 months post-VLDRT, and cumulative incidence of local progression (LP), distant progression and overall progression, all using death as competing risk. Outcomes were stratified by VLDRT intent; lesions considered PC were localized sites without prior treatment. All other sites were considered non-curable. Competing risk regression was used to identify potential histologic/clinical predictors of LP. Results In total, 250 patients were treated to 299 lesions including 52 potentially curative (PC) sites (Table 1). Post-VLDRT, overall response rate was 90% for all treated sites with 68% achieving complete response (CR). With median follow-up of 2.4y, the 2y cumulative incidence of LP was 25% for the entire cohort. PC patients had considerably lower 2y-LP of 9% (95% CI 3-19%) compared to 29% (95% CI 23-34%) for the non-curable. Lesion size > 6cm was associated with lower odds of CR and greater risk of LP relative to lesions 0-2cm. There was no suggestion of inferior outcomes for PC patients relative to non-curable. The probability of receiving additional RT to the same site 2y post VLDRT is 15% (95% CI 11-19%), and subsequent response after additional RT was 68% CR (n = 30/45), 18% partial response (n = 8), and 14% non-response (n = 6). Conclusion We demonstrate that modern VLDRT approaches utilizing PET staging and ISRT result in excellent ORR with nearly 70% CR. Importantly, the cumulative incidence of LP at 2 years post VLDRT is low at 25%, highlighting the possibility of durable remissions. Given clinical versatility and apparent efficacy for PC patients, we support an adaptive ISRT stepwise strategy where patients will be treated initially with VLDRT, reserving full dose treatment for those with suboptimal response. A prospective, multicenter study by ILROG has been developed to compare PC patients randomized to standard 24 Gy versus this proposed response-adapted approach.

Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis ( 1.8 vs not reached for ALC ≤ 0.7 at 9 months, P

Background: With the incorporation of positron emission tomography (PET) imaging as part of the standard staging evaluation of follicular lymphoma (FL), it is generally recommended to obtain the diagnostic biopsy from a lesion with the highest standardized uptake value (SUV) to rule out de novo histologic transformation (HT). In some cases such an approach might be impractical, while in other cases a biopsy from a diseased area with a high SUV may still demonstrate an indolent histology. To date, there is no data to guide treatment choices in patients (pts) with FL with high SUVmax but with no documented evidence of HT. Specifically, it remains unclear whether anthracycline-containing regimens, such as R-CHOP, provide a better outcome than R-Bendamustine (BR). Furthermore, it is unknown whether rituximab (R) maintenance is beneficial in this setting. Therefore, we aimed to compare the efficacy of R-CHOP vs BR in newly diagnosed FL pts with high SUVmax at baseline PET and to clarify the role of maintenance. Patients and Methods: We retrospectively identified 261 consecutive pts with newly diagnosed biopsy-proven FL1-3A and a SUVmax≥13 on baseline PET, who were treated with frontline R-CHOP (n=183) or BR (n=78) at 7 US cancer centers based on the physician's choice. Progression-free survival (PFS) was calculated from starting treatment until progression, relapse or death. Cut-offs of SUVmax ≥13≤18 and SUVmax>18 were used for sub-analysis (Haematologica;2020;105:1907-1913). Results: Median age was 59 years. The baseline characteristics of the two groups differed significantly for a younger age (58 vs 62 years, p=0.009), a higher rate of B-symptoms (26% vs 10%, p=0.005) and baseline SUVmax>18 (49% vs 36%, p=0.04) in the R-CHOP group. A diagnostic biopsy was obtained from the site at the highest SUV in 129 (71%) and 43 (55%) pts, respectively (p=0.01). These suggest a potential selection of R-CHOP in pts with adverse features. At the end of therapy (EoT), R-CHOP treated pts achieved higher PET-CT complete response rates (CR 82% vs 69%, p=0.02). This superiority held in pts with diagnostic biopsy at the highest SUV site (CR 83% vs 67%, p=0.03), but not in the others (CR 80% vs 71%, p=0.37). Progression occurred at EoT in 11 and 14 pts receiving R-CHOP and BR (6% vs 18%, p=0.02), with a higher rate of HT in the BR group (13% vs 4%, p=0.006). After a median follow-up of 76 months (range, 4-208 months), there was no significant difference in PFS between R-CHOP and BR treated pts (hazard ratio [HR] 1.22, p=0.34). PFS was strongly associated with FLIPI 2 (HR 2.32, p=0.01) and 3-5 (HR 2.69, p=0.003) in the univariate as well as in the multivariate analysis (FLIPI 2 HR 2.19, p=0.02; FLIPI 3-5 HR 2.51, p=0.01). There was a trend toward overall survival (OS) benefit in the R-CHOP group (Fig.1A). In the univariate analysis for OS, BR regimen (HR 2.12, p=0.03), age >60 (HR 2.54, p=0.006), FLIPI 3-5 (HR 5.13, p=0.03) and biopsy at the highest SUV site (HR 0.44, p=0.01) were prognostic, however none of those remained significant in the multivariate analysis (BR regimen HR 1.84, p=0.09; age >60 HR 1.92, p=0.08; FLIPI 3-5 HR 3.11, p=0.14; biopsy at the highest SUV site HR 0.60, p=0.13; SUVmax>18 HR 1.87, p=0.055). Among pts with EoT response after R-CHOP or BR (n=170 and n=64, respectively), one third in each group (36% vs 41%, respectively) received R-maintenance for a median of 8 administrations (range, 2-12). A significant PFS advantage (landmark analysis) was observed with R-maintenance (Fig.1B; HR 0.53, p=0.02); however, this did not translate in survival benefit (HR 0.67, p=0.49). In a multivariable model, R-maintenance (HR 0.53, p=0.02), FLIPI 2 (HR 2.47, p=0.03) and 3-5 (HR 2.79, p=0.01) remained independent prognosticators of PFS, while no parameters significantly affected OS. The 2-year HT rate (10% vs 17%) and cumulative incidence did not statistically differ between R-CHOP and BR groups (Fig.1C, p=0.159). Early progression (POD24) occurred in 43 and 22 pts who received R-CHOP and BR, respectively (24% vs 28%) and resulted in a significantly higher risk of death (HR 4.12, p=0.006). Conclusion: In newly diagnosed FL pts with SUVmax≥13 at baseline PET, R-CHOP was more effective in achieving CR and reducing the risk of early HT compared with BR, and it was associated with a trend toward survival advantage. Rituximab maintenance significantly prolonged PFS. A prospective evaluation with a larger population will be needed to confirm our findings. Disclosures Joffe: Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Ruella:Abclon, BMS, NanoString: Consultancy; Abclon: Consultancy, Research Funding; UPenn/Novartis: Patents & Royalties. Svoboda:Adaptive: Consultancy; Astra-Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Imbrium: Consultancy; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; TG: Research Funding; Genmab: Consultancy; Atara: Consultancy. Witzig:Immune Design: Research Funding; Spectrum: Consultancy; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; AbbVie: Consultancy; MorphSys: Consultancy; Incyte: Consultancy. Smith:TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics: Research Funding; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding. Armand:Affimed: Consultancy, Research Funding; Otsuka: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; IGM: Research Funding; Infinity: Consultancy; Genentech: Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy; Adaptive: Consultancy, Research Funding; Tensha: Research Funding; Roche: Research Funding; Merck & Co., Inc.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy. Nastoupil:Janssen: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Gilead/KITE: Honoraria; Gamida Cell: Honoraria; TG Therapeutics: Honoraria, Research Funding; Merck: Research Funding; Novartis: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Ansell:Takeda: Research Funding; Regeneron: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; AI Therapeutics: Research Funding; ADC Therapeutics: Research Funding. Zelenetz:Novartis: Consultancy; Adaptive Biotechnology: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy; Gilead: Research Funding; Celgene: Consultancy; Roche: Research Funding; Amgen: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Sandoz: Research Funding; Celgene: Research Funding; MorphoSys: Research Funding; MEI Pharma: Research Funding. Younes:BioPath, Xynomic, Epizyme, and F. Hoffmann-La Roche: Consultancy; Janssen, Curis, Merck, Bristol-Myers Squibb, Syndax Pharmaceuticals, F. Hoffmann-La Roche, Curis (Inst), Johnson & Johnson (Inst), Novartis (Inst): Research Funding; Janssen, AbbVie, Merck, Curis, Epizyme, F. Hoffmann-La Roche, Takeda, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Celgene, Incyte, Janssen Pharmaceuticals, Merck, Sanofi, Seattle Genetics, Takeda Millennium: Honoraria; AstraZeneca: Current Employment; MSKCC: Ended employment in the past 24 months.

Introduction Marginal Zone Lymphoma (MZL) includes three subtypes of indolent lymphoma: splenic MZL, extranodal MZL of mucosa-associated lymphoid tissue (MALT) and nodal MZL. The diagnosis of MZL is often made by exclusion of other lymphoma subtypes based on phenotype. One of the markers that are often involved in this discernment is CD5. The CD5 is not expressed in most of the cases of MZL, probably independently of the subtype, while it is usually expressed in different diseases such as Mantle Cell Lymphoma and Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia. A subgroup of MZL, however, unequivocally expresses CD5, and very little is known about the characteristics and outcomes of these patients compared to their CD5 negative counterparts. Methods From our pathology database, we collected all the reports of indolent lymphoma containing the words "marginal zone" and/or "MALT" diagnosed or reviewed at MSKCC. We reviewed the text of the selected pathology reports to identify all cases that were unequivocally MZL and reported positivity or negativity of the CD5 marker in the lymphoma cells. From the electronic medical records, we collected all the relevant clinical information for all CD5+ MZL cases, and for a subset of CD5- MZL cases with a 1:2 match for age at diagnosis and sex. The survival and baseline characteristics analyses only included patients that were followed by our lymphoma group. We report differences between groups with the chi-squared test. Overall survival (OS) was estimated using the cumulative incidence method, and time to treatment (TTT) was estimated using the subdistribution function to adjust for semi-competing risk of death on treatment initiation. A modified proportional hazards model was used to compare the subdistribution hazard between groups, and a standard Cox proportional hazards model was used to compare the hazard of death between groups. Results From 03/1998 to 09/2019, 64 patients were diagnosed with CD5+ MZL and followed by the Lymphoma Service at MSKCC. The control group of CD5- MZL included 137 patients that matched the CD5+ positive patients for age at diagnosis and sex. 20.3% of the CD5+ vs 14.6% of the CD5- MZL were nodal (p=0.30); Extra-nodal (EN) localizations included: GI tract - other than stomach (5.9% CD5+, 9.4% CD5-), stomach (17.7% CD5+, 17.1% CD5-), skin (7.8% CD5+, 12.0% CD5-), lung (9.8% CD5+, 12.0% CD5-), eye (9.8% CD5+, 7.7% CD5-), spleen (25.5% CD5+, 18% CD5-), multiple sites (13.7% CD5+, 10.3% CD5-), other single EN sites (9.8% CD5+, 13.7% CD5-). IPI score was low in 52% CD5+ vs 61% CD5-; low intermediate in 28% CD5+ vs 19% CD5-; high intermediate in 21% CD5+ vs 13% CD5-; no CD5+ had high IPI, while 7% of CD5- did (chi-square p=0.04). Transformation to DLBCL was similar in the 2 groups with 7% events in CD5+ and 4% in CD5- (p=0.42). Bone marrow involvement seemed to be more prevalent in the CD5+ MZL (67.5% vs 47.2% of the CD5-; p=0.04). IGHV was mutated in 80% of the CD5+ and 64% of the CD5- (p=0.24). OS analysis was performed first considering death by any cause: median OS was not reached for CD5+ MZL (95% C.I. 8.8 years - NE) and it was 27 years for CD5- (95% C.I. 14.3 years - NE). No difference was observed between CD5+ vs CD5- (p=0.9, Figure 1A). We also calculated MZL related survival, including deaths related to transformation to high grade lymphoma. No difference was observed between CD5+ vs CD5-, (p=0.3, Figure 1B). Median time to 1st treatment (including topical treatment and radiation therapy) was 1.4 years (95% C.I. 0.4 - 2.3) for CD5+ and 0.4 years (95% C.I. 0.3 - 0.9). No difference was observed between CD5+ vs CD5- (p=0.2, Figure 1C). Median time to first systemic treatment was 4.3 years (95% C.I. 1.6 - 12.9) for CD5+ and 7 years (95% C.I. 3.1 - 15.4) for CD5- MZL. No difference was observed between CD5+ vs CD5- (p=0.6, Figure 1D). Conclusions In this retrospective case-control analysis assessing the differences between CD5+ and CD5- MZL in terms of clinical presentation, survival, transformation occurrence and time to first topical or systemic treatment, we demonstrate that the two subgroups might have some differences in terms of bone marrow involvement but probably no difference in terms of outcome. Our sample size is small, and larger studies on a population with more events might clarify, with multivariate analysis, if these differences are real. Figure Disclosures Joffe: Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Palomba:Pharmacyclics: Honoraria; Celgene: Honoraria; Merck: Honoraria; Novartis: Honoraria; Regeneron: Research Funding; Juno Therapeutics, a Bristol-Meyers Squibb Company: Honoraria, Research Funding; Genentech: Research Funding. Noy:Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy; Pharmacyclics: Research Funding; NIH: Research Funding. Matasar:Daiichi Sankyo: Consultancy; Immunovaccine Technologies: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; Takeda: Consultancy, Honoraria. Hamlin:J&J Pharmaceuticals: Research Funding; Portola Pharmaceutics: Consultancy; Portola: Research Funding; Molecular Templates: Research Funding; Incyte: Research Funding; Celgene: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy. Kumar:Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Honoraria, Other: Honoraria for Advisory Board; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies,: Research Funding; AbbVie: Research Funding. Moskowitz:Seattle Genetics: Consultancy; Miragen Therapeutics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; Merck: Consultancy. Falchi:Genmab: Research Funding; Roche: Research Funding. von Keudell:Merck: Consultancy, Honoraria. Straus:Targeted Oncology: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; OncLive: Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Imedex, Inc.: Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Horwitz:Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; ASTEX: Consultancy. Dogan:Takeda: Consultancy; Roche: Consultancy, Research Funding; Physicians Education Resource: Consultancy; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; EUSA Pharma: Consultancy; AbbVie: Consultancy; National Cancer Institute: Research Funding. Zelenetz:BeiGene: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Gilead: Research Funding; Roche: Research Funding; Celgene: Research Funding; Sandoz: Research Funding; MorphoSys: Research Funding; MEI Pharma: Research Funding.

Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in immune cells including B lymphocytes. It forms the Myddosome complex with the MYD88 adaptor protein, with IRAK4 being essential for downstream signaling, maximal activation of NFkB with inflammatory and immune response and tumor promotion [Treon 2012; Rhyasen 2015]. CA-4948 is a novel small molecule, oral inhibitor of IRAK4, first-in-class and only suppressor of the TLR pathway currently tested in hematological malignancies. When combined with the BTK inhibitor ibrutinib that blocks parallel BCR signaling and NF-kB activating pathway, it has shown synergy in in-vivo B-cell NHL models, providing strong rationale for clinical evaluation [Booher 2018]. Recent preclinical studies demonstrated the role of IRAK4 activation as a driver of secondary, adaptive tumor resistance and survival mechanisms of hematological and solid tumor malignancies [Melgar 2019] that could be blocked by CA-4948 to delay or reverse resistance. Study Design and Methods: This is a multicenter, open-label trial of oral CA-4948 combined with ibrutinib in adult patients with relapsed or refractory hematologic malignancies. (NCT03328078). It has 2 parts: a dose escalation (Part A2), and expansion basket of 4 cohorts (Part B). Part A2: Is a truncated 3+3 design: CA-4948 starting is 200 mg BID with subsequent escalation to 300 mg BID. Both dose are safe and active against NHL as seen in the nearly completed monotherapy Part A1 of this trial Patients will receive CA-4948 with ibrutinib at the labeled dose for the respective NHL subtype (560 mg or 420 mg) until toxicity or progression. Primary objectives are safety/tolerance (MTD, RP2D); 2nd objectives are pharmacokinetics and preliminary efficacy; exploratory objectives include biomarker correlations (e.g., MYD88-L265P mut, IRAK4 pathway, NFκB inhibition). Part B basket has four cohorts: 1 -MZL, 2 - ABC-DLBCL, 3 - PCNSL, and 4 - NHL with adaptive ibrutinib resistance. Cohorts 1-3 must be BTK-inhibitor naïve. Cohort 4 includes ibrutinib treated NHLs after developing adaptive, secondary resistance. All will receive the combination of ibrutinib and CA-4948. Cohort 4 patients will be allowed a Samples sizes, statistical considerations: Approx. 18 patients in Part A2. In Part B, a Simon 2-Step design will be applied to each cohort. Early stopping rule for futility after approx. 20 patients in Stage 1: full accrual with Stage 2 will add about 25 patients. Successful signal efficacy identification in a cohort may support further expansion or a subsequent controlled trial. The safety population will include all patients in the study who received any test dose. The efficacy population will have a valid baseline and post-baseline disease assessment. Safety assessments include TEAEs, safety labs, vitals, physical exams, PK, and ECGs; efficacy assessments: tumor imaging, para-protein determination, and histo/cyto-morphologic examinations. Part A2 inclusion: Histopathologically confirmed B-cell NHL as per the WHO 2016 classification. Eligible NHL subtypes: FL, MZL, MCL, DLBCL (including extranodal lymphomas of leg, testicle, or other sites, excluding mediastinal lymphoma), CLL/SLL, primary or secondary CNS lymphoma, and WM/LPL. Patients with FL, MCL, MZL, WM/LPL, or CLL/SLL should meet clinical treatment criteria. Part B inclusion: Cohorts 1-3 include patients with MZL, ABC-DLBCL, or PCNSL who are BTK-inhibitor naïve. Cohort 4 will include ibrutinib pre-treated MCL, MZL, CLL/SLL, WM/LPL, ABC-DLBCL, or PCNSL with adaptive resistance. Exclusions for both Parts A2 and B: Significant acute or chronic toxicity from prior anti-cancer therapy that has not resolved to Grade ≤ 1, as determined by NCI CTCAE v 4.03 within 7 days prior to start of study or serious co-morbidities. Disclosures Nowakowski: NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees. Leslie:TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Lunning:Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; Acrotech: Consultancy; ADC Therapeutics: Consultancy; Legend: Consultancy; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Curis: Research Funding; Gilead: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Patel:Adaptive Biotechnologies: Consultancy; Kite: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Landsburg:Takeda: Research Funding; Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Fenske:Medical College of Wisconsin: Current Employment. Ramchandren:Merck, Seattle Genetics, Janssen, Genentech: Research Funding; Seattle Genetics, Sandoz-Novartis, Pharmacyclics, an AbbVie Company, Janssen, Bristol-Myers Squibb: Consultancy. Skarbnik:Alexion: Consultancy; Beigene: Speakers Bureau; Verastem: Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding.

Multiple myeloma (MM) is a multi–subclonal malignancy with relatively high heterogeneity. Patients who initially presented with both monoclonal-protein (MP) and free light chain (FLC) secretion but then relapsed with a light chain escape pattern have been shown to reflect disease clonal evolution and to bare a worse prognosis. We hypothesized that a discordant MP/FLC pattern at diagnosis may reflect a similar clonal evolution that had occurred prior to diagnosis of active myeloma, conferring a worse outcome. We analyzed 255 consecutive newly diagnosed MM patients who received first line bortezomib-based therapy between 2007 and 2014, hypothesizing that their MP/FLC fingerprint at diagnosis reflects clonal heterogeneity and, therefore, affects outcome. An involved FLC level ≥ 700 mg/L and MP ≥ 2.5 g/L were used as cutoffs for low vs high FLC and MP levels, respectively. Patients were divided into 4 subgroups according to their involved FLC and MP blood levels at diagnosis: HiLC and HiMP for patients with either a predominant FLC or a predominant MP, respectively, and HiLC-MP and LoLC-MP when both FLC and MP were increased or decreased, respectively. There were 68 (27%) patients with HiLC, which presented more often with International Staging System-3 stage (P

e19201 Background: Automated extraction of key clinical features from imaging reports, such as the site, size and FDG avidity of lesions would allow for automatic determination of disease stage, response to treatment and relapse. Since the language used in clinical notes is domain and often task-specific, generic Natural Language Processing (NLP) tools are of limited utility. We describe a strategy for a rapid construction of task-specific NLP algorithms. As a test case, we aimed to identify bone involvement with lymphoma from PET/CT reports. Methods: We use an adaptive-learning approach to facilitate the generation of task-specific lexicons by a domain expert. In the case of identifying bone lymphoma, these include words describing the primary aspect (PA: e.g., “ uptake”, “SUV”); the secondary aspect, in this case, osseous sites (SA: e.g., “skeleton”, “T5”); modifiers such as context-specific affirmation/ negation/ uncertainty (e.g., “increased”/ “likely reactive”/ “possibly disease”) and generic negation (e.g., “no evidence of”). Presented with sentences containing seed PA terms, an expert is tasked with an exhaustive identification of terms for the other lexicons. In an iterative process, unseen sentences that do not include terms previously identified are presented for lexicon expansion. The process is repeated until no further expansion is possible. An explicit rule-based algorithm is built based on the lexicons to classify sentences as supporting, negating or inconclusive (i.e., requiring manual review) for the feature of interest. We used 500 reports to develop the algorithm, evaluated performance against 516 unseen reports that were independently classified by a blinded annotator, and measured the amount of effort (number of iterations) required to complete the PA and SA lexicon expansion. Results: Of 44 reports with bone involvement identified by the algorithm, 43 had an actual involvement and 1 was a negative case (PPV: 98%). Of 380 reports flagged as negative, 379 were truly negative and 1 was positive (NPV: 99.7%). Sensitivity was 64% (43/67); specificity 84% (379/449); 18% (93) reports were flagged for manual review. It took 13 and 5 iterations to build the PA and SA lexicons, each involving the review of up to 10 sentences. Conclusions: With minimal effort, we were able to construct a high-accuracy NLP system specific for identifying bone lymphoma. This approach can be extended to other contexts (e.g., lung involvement), domains (e.g., pathology reports), or to be utilized in machine learning.

e20017 Background: FDG avidity above liver on interim PET (PET2) during frontline ABVD is considered a marker of impending treatment failure and an indication to switch to an intensified regimen. However, in clinical practice the utility of PET2 for treatment decisions is less clear. We describe outcomes of patients with positive PET2 who continued treatment with ABVD in the clinical setting. Methods: A retrospective study of all patients with newly diagnosed advanced-stage Hodgkin lymphoma treated with frontline ABVD at Memorial Sloan Kettering Cancer Center between 2008-2017. Eligibility criteria were set to correspond with the RATHL inclusion criteria (stage IIB - IV, or IIA bulky or ≥ 3 involved sites). We identified all PET2 reports indicating suspected residual uptake. All positive PET2 images were then reviewed by a single study radiologist. To increase reproducibility and avoid selection of borderline cases, we defined as PET2 positive only those cases with a lesion-to-liver (mean) SUV ratio ≥ 1.3. We also used a recently published stringent criterion of lesion-to-liver (max) ratio ≥ 1.4 (mPET2+). Progression-free and overall survival (PFS, OS) were calculated from the date of initial treatment until progression or death of any cause. Consolidative radiation was not considered a PFS event, and all progressions were verified by biopsy. Results: We identified 227 patients fitting RATHL inclusion criteria treated with ABVD. Median age was 34, with 25% (58) ≥ 45 years, 12% (26) had an IPS ≥ 4; 28% (64) stage II (5% II-X) and 38% (87) with extranodal involvement. 57 (25%) patients had a PET2 report indicating suspected residual lymphoma (PET2+), however, only 32 (14%) met the more stringent mPET2+ criterion. Most patients with PET2+ continued ABVD (84%, 48), and 9 switched to escBEACOPP (this subset of patients had substantially worse disease and are not the focus of this analysis). 21 (9%) patients received consolidative radiation. With a median follow-up of 47 months (42-54m), PET2+ patients who continued ABVD had a 3yPFS of 70% (58-85%, n = 48); mPET+ had a 3yPFS of 71% (55-92%, n = 24). Overall survival was excellent regardless of PET2 status (5yOS 97%). Conclusions: The outcome of PET2+ patients in this analysis was better than previously reported and the continuation of ABVD was appropriate for most patients. Use of a confirmatory biopsy is important for identifying true progressions. Patients with PET2+ had an excellent OS. Evaluation of the superiority of alternative regimens in PET2+ patients requires an ABVD comparator arm.

8062 Background: Immunotherapy with anti CD20 is often associated with mild easily manageable infusion reactions. In rare cases, patients experience severe drug hypersensitivity reactions (DHR) serum sickness or anaphylaxis. These in turn may lead to discontinuation of the drug. In our experience, switching to a different anti-CD20 agent is a feasible alternative to discontinuation or desensitization protocols. Methods: From our pharmacology database we identified all the patients that received rituximab and/or obinutuzumab, and/or ofatumumab, and/or all the patients who received a flat dose of less than 50 mL of the same drugs and were followed at our institution. From the medical record, we identified all the cases where the anti-CD20 antibody was changed due to allergy, serum sickness or other types of DHR, and all those who received minimal doses of anti-CD20 in the context of a desensitization protocol. DHRs were evaluated either by an allergist, or by retrospective review following the World Allergy Organization guidelines. Our primary comparison, was to assess the proportion of pts able to completed planned infusion of abs using either approach (Fisher’s exact Test). Results: Among 343 patients receiving at least two different anti-CD20 antibodies or a flat dose of < 50 mL, we identified 44 patients experiencing severe DHRs needing intervention. At the time of the reaction, 16 (36%) received the anti-CD20 as single agent, 24 (54%) in combination with chemotherapy, 4 (9%) in combination with ibrutinib or lenalidomide. In 9 (20%) patients the reaction was defined as anaphylactoid (8 rituximab; 1 obinutuzumab) and in 8 (18%) patients, all receiving rituximab, as serum sickness. Episodes of DHR were addressed with either desensitization (n = 29) or change of anti-CD20 agent (n = 25), 9 patients received both of these approaches, one patient switched anti-CD20 antibodies twice. Overall, 21 desensitizations were successful (72.4%), 8 failed; 23 changes of anti-CD20 were successful (92%) and 2 failed (p = 0.09). Conclusions: In patients with DHR use of an alternative anti-CD20 antibody is safe and is an alternative or complementary approach to anti-CD20 desensitization.

TPS8072 Background: Diffuse large B-cell lymphoma (DLBCL) escapes host immune responses via inhibition of the B2M and CD58 pathways and upregulation of PD-1 ligands. However, treatment results with PD-1 blockade have been disappointing. One potential mechanism is the recruitment of intra-tumoral regulatory T-cells (Tregs) which suppress anti-tumor immunity and inhibit NK cell cytotoxicity. Targeting regulatory T cells with the CCR4 antibody mogamulizumab (KW-0761) represents a molecularly informed strategy to overcome this resistance. Mogamulizumab has been safely administered in combination with pembrolizumab (MK-3475) in patients with solid malignancies and may promote CD8 T-cell dependent effector and NK cell-dependent cytotoxicity in lymphomas. Methods: This is a multi-center NIH-ETCTN phase Ib/randomized phase II study. The phase I will evaluate the safety and tolerability of mogamulizumab in combination with pembrolizumab in patients with R/R DLBCL and determine the recommended phase II dose (RP2D). A traditional 3+3 design with a starting dose of pembrolizumab 200mg IV on day 1 of a 21-day cycle and mogamulizumab 1mg/kg IV on days 1, 8, 15 and then 1.5 mg/kg IV every 21 days. The phase II will evaluate the efficacy of the combination by PFS (primary endpoint) ORR and CR (secondary endpoints). This will be a randomized 1:1 study with allowed crossover, comparing the combination to single agent pembrolizumab Correlative studies will evaluate the association of tumor infiltrating CD8 and NK cells with response to treatment, somatic mutations in B2M and CD58 and with MHC-I expression on DLBCL cells. Functional characterization of circulating immune cells in the peripheral blood and measurement of pro and anti-inflammatory cytokines will be used to assess the levels, activation status and effector function of Tregs and circulating T cells. Inclusion criteria include measurable disease, ≥2 prior lines of therapy including or ineligible for autologous stem cell transplant, ECOG ≤ 2 and normal organ function. Prior or planned allogeneic stem cell transplant, as well as prior treatment with an anti PD-1/PD-L1/CTLA4 antibody, preexisting autoimmune disease or CNS involvement by lymphoma are exclusion criteria. The study aims to enroll up to 12 patients on the phase I and up to 58 patients on the phase II and can be opened at any ETCTN participating site. To date it has been opened at two sites and is accruing the first patients for the phase I portion. Clinical trial information: NCT03309878 .

8006 Background: Venetoclax (Ven)-Obinutuzumab (O) is approved for chronic lymphocytic leukemia (CLL) achieving frequent undetectable minimum residual disease (uMRD; Fischer NEJM 2019). Ven-Ibrutinib is synergistic with frequent uMRD but with grade >3 neutropenia in 33-48% patients (pts; Tam ASH 2019; Jain NEJM 2019). Zanubrutinib (B) is a highly specific BTK inhibitor that demonstrated 100% occupancy in lymphoid tissues, so may be preferred to combine with OVen. We hypothesize that treatment (tx) with BOVen using an MRD driven discontinuation strategy will achieve frequent uMRD and durable responses. Methods: In this multicenter, investigator initiated phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring tx per iwCLL, ECOG PS 1, PLT >75 (ANC >0, PLT >20 if due to CLL). BOVen was administered in 28D cycles: B 160 mg PO BID starting D1; O 1000 mg IV D1 or split D1-2, 8, 15 of C1, D1 of C2-8; Ven ramp up initiated C3D1 (target 400 mg QD). Tx duration was determined by a prespecified uMRD endpoint (min 8 cycles). MRD was assessed in peripheral blood (PB; flow cytometry, sensitivity >10−4) starting C7D1 then every 2 cycles. Once PB uMRD was determined and confirmed in bone marrow (BM), tx continued 2 additional cycles. Adverse events (AE) were assessed per CTCAE v5. Median (med) time to uMRD (primary endpoint) was estimated using the Kaplan-Meier method. Results: The study accrued 39 pts (3-10/19): med age 59 years (23-73), 3:1 male, CLL IPI >4 26/39 (67%), unmutated IGHV 28/39 (72%), 17p del/ TP53 mutated 4/39 (10%), all pts were evaluable for toxicity with 37 evaluable for efficacy. At a med follow up of 8 months (mo; 3-10), 25/37 (68%) pts achieved PB uMRD. Med time to PB uMRD is 6 mo (4-8+). Another 8/37 (22%) had PB MRD < 0.1%. Of 25 with PB uMRD, 19 had BM uMRD with 10/19 completing 2 additional cycles and discontinued; 3 had BM MRD (all

We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma). Median number of GAs per case was 6, with 97% of patients harboring at least one alteration. Recurrent GAs were detected in genes with established roles in DLBCL pathogenesis (e.g. MYD88, CREBBP, CD79B, EZH2), as well as notable differences compared to prior studies such as inactivating mutations in TET2 (5%). Less common GAs identified potential targets for approved or investigational therapies, including BRAF, CD274 (PD-L1), IDH2, and JAK1/2. TP53 mutations were more frequently observed in relapsed/refractory DLBCL, and predicted for lack of response to first-line chemotherapy, identifying a subset of patients that could be prioritized for novel therapies. Overall, 90% (n = 169) of the patients harbored a GA which could be explored for therapeutic intervention, with 54% (n = 107) harboring more than one putative target., Key points This study demonstrates the applicability of CLIA-compliant targeted FFPE sequencing for large-scale clinical trials.TP53mut is the main predictor of refractoriness or early relapse.

The risk of developing non-Hodgkin lymphoma increases with age, yet elderly patients are under-represented in clinical trials. Here, we evaluate a combination regimen including ifosfamide, carboplatin and etoposide with or without rituximab (ICE ± R) in 32 fit elderly patients (median age 75.6 years) with relapsed or refractory diffuse large B-cell lymphoma. ICE ± R was generally administered in reduced doses and was well tolerated. The overall response rate (ORR) was 53.1% with a complete response (CR) rate of 40.6%. The median progression free survival (PFS) and overall survival (OS) were 3.9 and 17.0 months, respectively. Patients who responded to ICE ± R achieved median PFS of 47.2 months and OS of 78.9 months. Patients ineligible for autologous transplantation who responded to ICE ± R were treated with additional cycles, and achieved a median PFS of 18.9 months and OS of 21.7 months. Previous response to first-line therapy was the strongest predictor of response, PFS and OS to second-line treatment.

This study aimed to evaluate the efficacy and safety of the fludarabine-cyclophosphamide-rituximab regimen for young physically fit patients with chronic lymphocytic leukemia in the "real-life" setting. We specifically focused on the impact of dose reduction on patient outcomes. The patient cohort consisted of 128 patients with chronic lymphocytic leukemia (≤ 70 years) treated at 10 Israeli centers with front-line fludarabine-cyclophosphamide-rituximab. We defined reduced chemotherapy as two-thirds or less of the total indicated dose. Patients treated with rituximab were divided into two groups and compared: those who received full dosages of 375 mg/m(2) or 500 mg/m(2), and patients given less than six cycles with either dose. Overall and clinical complete response rates (92.8% and 70.4%), as well as toxicities and overall survival (median not reached at 6 years), were similar to other reported clinical trials, but progression-free survival was shorter (42.5 months). Almost 50% of patients had some dose reduction of chemotherapy, 21% receiving less than two-thirds of the indicated dose, while close to 30% did not complete six cycles of rituximab. Reduced doses of chemotherapy and rituximab were independently associated with shorter progression-free survival (hazard ratio 3.6, P0.0001 for reduced chemotherapy; hazard ratio 2.5, P=0.003 for incomplete-treatment with rituximab). Achieving a complete response was associated with longer overall survival but was not linked to the given dose of chemoimmunotherapy. In younger physically fit patients, front-line fludarabine-cyclophosphamide-rituximab therapy in the "real-life" setting achieves long remissions (albeit shorter than in clinical trials) and prolonged overall survival. However, dose reductions are commonly administered and may impact outcome.

Personalization of therapy to target specific molecular pathways has been placed in the forefront of cancer research. Initial reports from clinical trials designed to select patients for appropriate treatment on the basis of tumor characteristics not only have generated considerable excitement but also have identified several challenges. These challenges include the overcoming of regulatory and logistic difficulties, identification of the best selection biomarkers and diagnostic platforms that can be applied in the clinical setting, definition of relevant outcomes in small preselected patient populations, and the design of methods that facilitate rapid enrollment and interpretation of clinical trials by aggregating data across histologically diverse malignancies with common genetic alterations. Furthermore, because our knowledge of the functional consequences of many genetic alterations lags, investigators and sponsors struggle with choosing between ideal clinical trial designs and more practical ones. These challenges are amplified when more than one biomarker is used to select patients for a combination of targeted agents. This review summarizes the current status and challenges of clinical trials in the genomic era and proposes ways to address these challenges.

Automated morphological assessment of peripheral blood slides has become an important modality facilitating characterization and quantification of cells in a uniform, fast and robust manner. In this study, we evaluated the morphological diversity in peripheral blood films of 94 chronic lymphocytic leukemia (CLL) patients using the DM1200 CellaVision automated microscopy system. Aberrant lymphocytes and smudge cells were enumerated and correlated with CLL immunophenotype, chromosomal aberrations and prognostic parameters. Herein, we show that the percentages of aberrant and smudge cells was highly variable between patients and did not correlate with each other. Increased aberrant lymphocytes and fewer smudge cells were associated with an atypical immunophenotype including low expression of CD23, higher levels of FMC7 and bright surface levels of CD20. High fraction of aberrant lymphocytes also was associated with trisomy 12. These cells were predominantly of small/medium size, sometimes with cleft nuclei. No correlation was noted between aberrant or smudge cells and clinical stage, CD38, ZA70 or time to first treatment. Taken together, automated morphological analysis of peripheral blood leukocytes emerged as a powerful and robust tool for the quantitative morphological stratification of CLL. Integration of the automated morphological features discriminates between different CLL phenotypes and distinct chromosomal aberrations.

Introduction: Gemcitabine/oxaliplatin (GemOx), with or without rituximab, is a frequently used treatment of relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL), and is NCCN compendium-listed for both transplant-eligible and ineligible patients based upon results in small phase II clinical trials. Increasingly, GemOx is being accepted as a comparator arm for clinical trials in these populations. However, there is a paucity of observational data describing the effectiveness of R-GemOx in the treatment of r/r aggressive B-cell lymphoma. Methods: We conducted a retrospective analysis of the use of the GemOx regimen (with or without rituximab) in patients with r/r aggressive B-NHL at Memorial Sloan Kettering Cancer Center between January 2007 and January 2018, with a data cutoff of July 1, 2019. Data were extracted from the electronic medical record. Eligible diagnoses included diffuse large B-cell lymphoma and its subtypes (DLBCL); high-grade B-cell lymphomas (HGBL); transformed indolent B-cell lymphoma (tNHL) and grade 3B follicular lymphoma (FL3B). The primary objective of the study was to evaluate the activity of GemOx-based treatment in this patient population, as measured by overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). CR was defined by a qualitatively negative 18-FDG-PET scan following completion of GemOx. PFS was defined as the time from start of therapy to disease progression or death, censoring patients at the time of initiation of any consolidative treatment. Similarly, OS was defined as the time from the start of GemOx until death or loss to follow-up. Results: Data were collected for 140 consecutive patients that received GemOx with (n=81) or without (n=59) rituximab in the treatment of a qualifying diagnosis (Table 1). Those treated had a median age at initiation of therapy of 69 (range, 30-92) and were predominantly male (58%). The median number of prior lines of therapy was 1 (range, 1-7), and the majority (97%) had received prior rituximab; few had received either prior autotransplant (11%) or allotransplant (1%). Regarding treatment delivered, the median number of cycles of therapy was 2 (range 1-12) with a mode of 2 (n=44, 31%). The ORR was 26% (n=37) with a CR rate of 15% (n=21). When evaluated by diagnosis, the ORR was 22% (n=19/88) in DLBCL, 40% (n=4/10) in HGBL, 35% (n=14/40) in tNHL, and 0% (n=0/2) in FL3B. Of the patients that responded to GemOx, 11 were successfully bridged to transplant (7 auto; 4 allo); two of those who went on to allotransplant had previously undergone autotransplant. Additionally, 3 patients went on to subsequently receive CAR-T therapy. Assessing the cohort overall, with a median follow-up of 48.1 months, PFS was only 1.4 months (95% CI: 1.3, 1.8), and median OS was 7.8 months (95% CI: 5.5, 12.0) (Figure 1). OS was longest for patients with tNHL at 10.2 months followed by DLBCL (7.5), HGBL (6.8) and FL3B (4.1) (Figure 2). Patients that received GemOx without rituximab in the setting of rituximab-refractory disease had a median OS of 4.1 months, less than that of 10.7 months for those receiving rituximab (p=0.052). However, there was no difference observed in PFS by inclusion of rituximab (1.6 months vs. 1.3 months, p=0.166). Patients with disease that was primary refractory following first-line therapy had a median OS of 4.5 months from initiation of GemOx, less than that of 10.8 months for patients that had achieved complete remission with first-line therapy (p=0.024). Patients that received GemOx as second-line therapy did not have a statistically significantly higher ORR (31% vs. 19%), OS (10.8 vs. 6.0 months), or PFS (1.7 vs, 1.4 months; all p=NS). In the subset of patients with DLBCL, there was again no significant difference in ORR (21% vs. 22%, p=NS), OS (8.5 vs. 6.1 months), or PFS (1.6 vs. 1.4 months; all p=NS). Conclusion: Despite compendium listing for both transplant-eligible and ineligible patients, and despite its adoption as a comparator arm in current and planned trials in r/r DLBCL, the real-world activity of GemOx with or without rituximab in the treatment of relapsed or refractory aggressive B-cell lymphoma is poor. Ongoing analysis is being conducted to seek clinical and histopathologic features associated with improved outcomes with GemOx. Disclosures Batlevi: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Colbourn:GILD: Other: Stock; LLY: Other: Stock; JNJ: Other: Stock; SGEN: Other: Stock; MRK: Other: Stock; SNY: Other: Stock; BIIB: Other: Stock; ABBV: Other: Stock; CELG: Other: Stock. Horwitz:Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Portola: Consultancy; Celgene: Consultancy, Research Funding; Portola: Consultancy; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Kyowa Hakko Kirin: Consultancy; ADCT Therapeutics: Research Funding; Astex: Consultancy; Mundipharma: Consultancy; Miragen: Consultancy; Portola: Consultancy; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Affimed: Consultancy; Affimed: Consultancy; Innate Pharma: Consultancy; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Forty-Seven: Research Funding; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Forty-Seven: Research Funding; ADCT Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Astex: Consultancy; Aileron: Research Funding; Portola: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Trillium: Research Funding; Miragen: Consultancy; Trillium: Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Aileron: Research Funding; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Miragen: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Kura: Consultancy; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Infinity/Verastem: Consultancy, Research Funding. von Keudell:Bayer: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Bayer: Consultancy; Genentech: Consultancy. Kumar:Seattle Genetics: Research Funding. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Rodriguez-Rivera:Memorial Sloan Kettering Cancer Center: Employment. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; GSK: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy. Straus:Seattle Genetics: Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Elsevier (PracticeUpdate): Consultancy, Honoraria. Vardhana:ADC Therapeutics: Consultancy; Rheos Pharmaceuticals: Honoraria; Agios Pharmaceuticals: Honoraria. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Zelenetz:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, 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; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Matasar:GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Pharmacyclics: Consultancy, Honoraria, Research Funding.

Botezomib-based induction is highly effective for the treatment of newly diagnosed multiple myeloma (NDMM). We investigated the outcomes of NDMM patients who failed to respond to bortezomib-based induction in a 'real-life' clinical setting. In a cohort of 295 consecutive NDMM patients in 3 medical centers, 74 (25%) failed to achieve at least partial response after 4 induction cycles, and were classified as non-responsive. Compared to induction responders, they were older, more frequently anemic, had a higher incidence of del17p and ISS-3, and a worse performance status. In multivariable analysis, bortezomib-based induction failure occurred in 25% of patients and was the strongest independent factor predicting mortality with a 5-fold hazard ratio (95% CI 1.44-8.68). Three-year overall survival in responsive vs. non-responsive patients were 76% vs. 53%, respectively (p