Burden of Illness and Outcomes in the 2nd Line Treatment of Large B-Cell Lymphoma: A Real-World Comparison of Medicare Beneficiaries with and without Stem Cell Transplants

Introduction: Standard first line therapy (LOT) for patients (pts) with large B-cell lymphoma (LBCL) involves chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or a similar regimen, e.g. R-CHOP with the addition of etoposide (R-EPOCH). While most pts respond, 30-40% of pts relapse or fail to achieve remission with 1st LOT. For those pts, the goal of curative 2nd LOT is typically platinum-based salvage chemotherapy in preparation for autologous stem cell transplant (ASCT). However, many pts (50% or more) do not qualify for intensive therapy, either due to age or comorbidities, or because they do not respond to or cannot tolerate salvage chemotherapy. For those further treatment options are limited. Objectives: In a sample of U.S. LBCL pts 65 and older, who have progressed to 2nd LOT and are eligible for ASCT, to compare the patient characteristics, treatments, costs and overall survival between pts who received SCT with those who did not. Methods: This retrospective cohort study used 100% Medicare Fee-for-Service Parts A/B claims data and Part D Prescription Drug Event data to identify pts ≥ 65 years of age, newly diagnosed with LBCL in 2012-2017, and who had ≥ 6 months continuous enrollment pre-diagnosis (baseline) and ≥ 12 months post-diagnosis, or who died after initiation of 2nd LOT. All were treated with a CHOP-like regimen 1st LOT and progressed to 2nd LOT. Eligible pts who received a 2nd LOT with a SCT-preparative regimen per NCCN guidelines were stratified into the "ASCT-intended" cohort, and the remainder into the "ASCT-not-intended" cohort. The ASCT-intended group was further subset into those who received a SCT and those who did not (Non-SCT). These 2 subsets formed the primary comparison groups. Baseline characteristics were age, gender, race, dual eligibility status (i.e. Medicare plus Medicaid), and Charlson-Deyo Comorbidity Index (CCI). Measures of utilization during follow-up (from initiation of 2nd LOT to loss to follow-up) were hospitalizations, outpatient and emergency department (ED) visits, and post-acute care. Costs during follow-up reflected standardized, inflation-adjusted, all-cause paid amounts. Utilization and cost metrics were standardized to per-patient-per-month (PPPM). Overall survival (OS) was measured from the start of 2nd LOT until death, disenrollment or the end of the study period. Results: 4,758 pts met all inclusion criteria. 3,713 (78%) did not receive a SCT-preparative regimen after 1st LOT. 1,045 pts (22%) received a SCT-preparative regimen and constituted the ASCT-intended group. Of these, 244 (23.3%) received a SCT and 801 (76.7%) did not. The remainder of this report focuses on a comparison of the SCT and non-SCT cohorts. Baseline characteristics, treatments, utilization and cost are summarized in Table 1. Both groups were predominantly white, but SCT pts were, on average, 5 years younger, slightly more likely to be male, and had slightly lower mean CCI scores. 13.1% of non-SCT pts were dual eligible vs. 4.5% of SCT (all p < .01 except Race). 93.9% of SCT procedures were autologous, and no pts had more than 1 SCT during follow-up. Non-SCT pts had higher all-cause utilization for all categories except for acute hospitalizations. The higher inpatient utilization for the SCT group may reflect the SCT procedure itself (94% of SCT were inpatient). A similar pattern was observed in the cost data, where Non-SCT pts incurred higher costs except for acute hospitalizations. Results for OS are summarized in Figure 1. Non-SCT pts had significantly lower rates of survival than SCT pts. 94.7% of SCT pts were still alive 6 months after initiation of 2nd LOT, whereas only 66.9% of non-SCT pts were. At two years post-2nd LOT, survival rates were 69.7% vs. 36.3%. Conclusions: In this study, only 23.3% of SCT-intended pts ultimately received it. The remaining 76.7% were SCT-intended but never received a transplant. Compared to the SCT pts, the non-SCT pts were older, had more comorbidities, had higher rates of healthcare utilization and costs post-2nd line therapy in all categories (except acute inpatient), and lower OS. 38.7% of non-SCT pts proceeded to additional lines of lymphoma-directed therapies beyond 2nd line, which may suggest that their clinicians felt that there was potential benefit to further treatment. These data suggest there may be unmet need for elderly pts with LBCL who are eligible for ASCT, but do not ultimately receive it. Disclosures Kilgore: Kite, A Gilead Company: Research Funding. Wong:Kite, A Gilead Company: Research Funding. Thornton Snider:Precision Medicine Group: Ended employment in the past 24 months, Research Funding; Gilead Sciences: Current equity holder in publicly-traded company, Research Funding; Kite, A Gilead Company: Current Employment. Cheng:Kite, A Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Schroeder:Kite, A Gilead Company: Research Funding. Mohammadi:Kite, A Gilead Company: Research Funding.

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Relapses after Achieving EFS24 in Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era

Blood ◽

10.1182/blood-2018-99-113213 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 454-454 ◽

Cited By ~ 1

Author(s):

Yucai Wang ◽

Umar Farooq ◽

Brian K. Link ◽

Mehrdad Hefazi ◽

Cristine Allmer ◽

...

Keyword(s):

B Cell ◽

Cumulative Incidence ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

Newly Diagnosed ◽

Indolent Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Introduction: The addition of Rituximab to chemotherapy has significantly improved the outcome of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients treated with immunochemotherapy for DLBCL who achieve EFS24 (event-free for 2 years after diagnosis) have an overall survival equivalent to that of the age- and sex-matched general population. Relapses after achieving EFS24 have been considered to be unusual but have been understudied. We sought to define the rate, clinical characteristics, treatment pattern, and outcomes of such relapses. Methods: 1448 patients with newly diagnosed DLBCL from March 2002 to June 2015 were included. Patients were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, treated per physician choice (predominantly R-CHOP immunochemotherapy) and followed prospectively. An event was defined as progression or relapse, unplanned re-treatment after initial therapy, or death from any cause. Cumulative incidence of relapse and non-relapse mortality after achieving EFS24 were analyzed as competing events using Gray's test in the EZR software. Post-relapse survival was defined as time from relapse to death from any cause and analyzed using Kaplan-Meier method in SPSS (V22). Results: Among the 1448 patients, 1260 (87%) had DLBCL alone at diagnosis, and 188 (13%) had concurrent indolent lymphoma (follicular lymphoma 115, marginal zone lymphoma 18, chronic lymphocytic leukemia 14, lymphoplasmacytic lymphoma 4, unspecified 37) at diagnosis. After a median follow-up of 83.9 months, 896 patients achieved EFS24. For all 896 patients who achieved EFS24, the cumulative incidence of relapse (CIR) was 5.7%, 9.3% and 13.2%, respectively, at 2, 5 and 10 years after achieving EFS24. Patients with concurrent indolent lymphoma at diagnosis had a higher CIR compared to those with DLBCL alone at diagnosis (10.2 vs 4.8% at 2 years, 15.7 vs 8.0% at 5 years, 28.8 vs 9.7% at 10 years, P<0.001; Figure 1). There were a total of 84 patients who relapsed after achieving EFS24. The median age at initial diagnosis was 66 years (range 35-92), and 48 (57%) were male. At diagnosis, 11 (13%) had ECOG PS >1, 37 (50%) had LDH elevation, 62 (74%) were stage III-IV, 14 (17%) had more than 1 extranodal site, and 26 (31%) were poor risk by R-IPI score. There were 58 patients with DLBCL alone at diagnosis who relapsed after achieving EFS24, and 38 (75%) relapsed with DLBCL, 13 (25%) relapsed with indolent lymphoma (predominantly follicular lymphoma), and pathology was unknown in 7 patients. In contrast, there were 26 patients with concurrent indolent lymphoma at diagnosis who relapsed after achieving EFS24, and 9 (41%) relapsed with DLBCL, 13 (59%) relapsed with indolent lymphoma, and pathology was unknown in 4 patients. In the 47 patients who relapsed with DLBCL after achieving EFS24, 45% received intensive salvage chemotherapy, 19% received regular intensity chemotherapy, 9% received CNS directed chemotherapy, and 36% went on to receive autologous stem cell transplant (ASCT). In the 26 patients who relapsed with indolent lymphoma after achieving EFS24, 27% were initially observed, 54% received regular intensity chemotherapy, 4% received intensive salvage chemotherapy, and 19% received ASCT after subsequent progression. The median post-relapse survival (PRS) for all patients with a relapse after achieving EFS24 was 38.0 months (95% CI 27.5-48.5). The median PRS for patients who relapsed with DLBCL and indolent lymphoma after achieving EFS24 were 29.9 (19.9-39.9) and 89.9 (NR-NR) months, respectively (P=0.002; Figure 2). Conclusions: Relapses after achieving EFS24 in patients with DLBCL were uncommon in the rituximab era. Patient with DLBCL alone at diagnosis can relapse with either DLBCL or indolent lymphoma (3:1 ratio). Patients with concurrent DLBCL and indolent lymphoma at diagnosis had a significantly higher CIR, and relapses with DLBCL and indolent lymphoma were similar (2:3 ratio). Even with high intensity salvage chemotherapy and consolidative ASCT, patients who relapsed with DLBCL had a significantly worse survival compared to those who relapsed with indolent lymphoma. Late relapses with DLBCL remain clinically challenging, with a median survival of 2.5 years after relapse. Figure 1. Figure 1. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Takeda: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding.

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Outcomes of Second-Line Chemotherapy and Autologous Stem Cell Transplantation for Primary Refractory Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood.v112.11.4445.4445 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4445-4445

Author(s):

David Telio ◽

Clement Ma ◽

Richard Tsang ◽

Armand Keating ◽

Michael Crump ◽

...

Keyword(s):

Cell Lymphoma ◽

B Cell Lymphoma ◽

Primary Treatment ◽

Salvage Chemotherapy ◽

High Dose ◽

Primary Therapy ◽

Second Line ◽

High Dose Therapy ◽

Large B Cell Lymphoma

Abstract Introduction: Patients (pts) with primary refractory Diffuse Large B Cell Lymphoma (REF DLBCL - defined as progession within 3 months of completion of primary therapy) sensitive to salvage chemotherapy are treated with high dose therapy and autologous stem cell transplantation (ASCT). The randomized Parma trial demonstrated survival benefit for patients with chemosensitive relapse undergoing ASCT but did not include primary refractory cases, thus current practice is based largely on retrospective series Methods: We conducted a retrospective review of 112 consecutive cases of REF DLBCL identified from our database between 1999–2007. All pts had evidence of stable or progressive disease (SD or PD) following primary treatment. Responses were assessed retrospectively using International Workshop Criteria (JCO 1999). Logistic regression was used to predict overall response rate (ORR) to salvage therapy; Cox Proportional-Hazards regression was used to analyze overall survival (OS) and progression-free survival (PFS). Salvage chemotherapy consisted of 2–3 cycles of platinum-based therapy; responding pts proceeded to PBSC mobilization and subsequent ASCT. High dose therapy consisted of VP16 60 mg/kg day –4 and melphalan 180 mg/m2 day –3 with PBSC infusion day 0. Pts with bulk disease (³ 5 cm) at progression received involved field radiation post-ASCT. Results: Median age was 46 (range 19–67); 77% had ECOG of 0–1 and 46% had limited stage disease at primary treatment failure. Where available (n=77), LDH was elevated in 74%. 21% had > 1 extranodal site. Primary treatment consisted of: CHOP 66%, R-CHOP 33% or ABVD 1%; radiotherapy was given in 15 pts. Response to primary therapy was: CR 9%, PR 31%, SD 20% and PD 41%. Second-line chemotherapy consisted of: DHAP 49, ESHAP 31, GDP (gemcitabine, dexamethasone, cisplatin) 24, or another platinum based-regimen 8. 5 pts received rituximab with the salvage regimen. ORR to first salvage chemotherapy was 24%. 2/35 pts receiving a second line and 0/6 pts receiving a third line of non-cross-resistant salvage therapy achieved response. 28 pts (25%) underwent ASCT. 6 pts received post-ASCT radiation as consolidation. With a median follow-up of 5.9 months (range 0.9–93.8), the median PFS and OS from primary treatment failure were 3 and 10 months respectively. OS may have been overestimated due to a high rate of loss to follow up after progression and subsequent censoring. In pts who underwent ASCT (median follow-up 18 months, range 0.3–89 months), median PFS was15 months after ASCT while median OS was not reached. ORR to salvage chemotherapy was predicted by normal LDH (OR=3.1; 95% CI=1.0–9.1; p=0.04). Proceeding to ASCT was predicted by normal LDH (OR=4.3; 95% CI=1.5–12.5; p=0.007), ECOG 0–1 (OR=5.2; 95% CI=1.1–23.6; p=0.03), and CR/PR with primary treatment (OR=3.2; 95% CI=1.5–12.3; p=0.01). Inferior PFS was found in pts with elevated LDH (HR=2.5; 95% CI=1.3–4.6; p=0.004), ECOG ≥ 2 (HR=1.8; 95% CI=1.1–2.9; p=0.01), and in pts having SD/PD with primary treatment (HR=1.7; 95% CI=1.1–2.6; p=0.02). OS was reduced in pts with elevated LDH (HR=5.3; 95% CI=1.8–15.0; p=0.002) and ECOG ≥ 2 (HR=2.7; 95% CI=1.4–5.2; p=0.004). Age, stage, number of extranodal sites and prior rituximab treatment were not significant predictors of any outcome. Conclusions: In summary, outcomes in patients with REF DLBCL are poor with an ORR of 25% to salvage chemotherapy and a median PFS of 15 months post-ASCT. Elevated LDH and poor functional status predict for inferior overall survival. Novel treatment approaches should be pursued in REF DLBCL.

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Treatment Patterns and Outcomes of DLBCL after Failure of Front-Line Immunochemotherapy

Blood ◽

10.1182/blood.v126.23.2683.2683 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2683-2683 ◽

Cited By ~ 3

Author(s):

Umar Farooq ◽

Matthew J Maurer ◽

Stephen M Ansell ◽

Tasha Lin ◽

Grzegorz S. Nowakowski ◽

...

Keyword(s):

Systemic Therapy ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Treatment Patterns ◽

Front Line ◽

Factors Associated ◽

Line Therapy ◽

First Relapse

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is curable for the majority of patients treated with anthracycline based immunochemotherapy (IC). However, up to 40% of patients will relapse or require retreatment of DLBCL and outcomes are poor in this setting. Here we examine the incidence, treatment patterns and outcomes of relapsed DLBCL in the R-CHOP era. Methods: Patients were prospectively enrolled in the University of Iowa / Mayo Clinic SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis and followed for relapse, retreatment, and death. Clinical management at diagnosis and subsequent therapies were per treating physician. This analysis includes patients with DLBCL or primary mediastinal B-cell lymphoma (PMBCL) who underwent front-line anthracycline based IC; patients with primary CNS lymphoma or PTLD were excluded. All relapse and re-treatments were verified by medical record review. Response to front-line therapy was retrospectively classified per 2007 Revised Response Criteria for Malignant Lymphoma from available clinical and radiology records. Unplanned consolidative radiation (RT) without biopsy proven disease after achieving PR from IC (N=21) was not classified as a relapse. Results: 1039 patients with newly diagnosed DLBCL or PMBCL and treated with IC were enrolled in the MER from 2002-2012. Median age at diagnosis was 62 years (range 18-92) and 577 patients (56%) were male. 647 patients (63%) had stage III/IV disease and IPI at diagnosis was 0-1 in 350 patients (34%), 2 in 305 patients (29%), 3 in 250 patients (24%) and 4-5 in 134 patients (13%). At a median follow-up of 59 months (range 1-148), 258 patients had relapse or retreatment of DLBCL of which 184 (71%) died. Incidence of relapse was 21.7% (95% CI: 19.3%-24.4%) at 2 years and 25.5% (95% CI: 22.9%-28.5%) at 5 years. In addition, the incidence of lymphoma related death without documented relapse or retreatment was 4.7% (95% CI: 3.6%-6.2%) at 2 years. At first relapse, 174 patients (67% of relapsed) received platinum based salvage therapy with 90 (52%) subsequently proceeding to autologous stem cell transplant (ASCT). 22 patients received CNS directed systemic therapy at relapse with 9 (41%) proceeding to transplant, and 43 received non-platinum-based salvage systemic therapy with 7 proceeding to transplant (17%), 15 patients received RT only as 2nd line therapy, and 4 were untreated. At a median follow-up of 56 months (range 6-121) post-transplant, 39 of 107 patients who underwent transplant remain in remission with a 2-year post-transplant progression-free survival of 45% (95% CI 37%-56%). Response to front-line IC was predictive of post-relapse outcome. Survival post-relapse was superior in the 162 patients with responsive disease (CR or PR) at the end of front-line IC (median OS 21.0 months) compared to the 88 patients who had stable or progressive disease (median OS 6.8 months, HR = 2.33, 95% CI: 1.73-3.14 p<0.0001). Transient response in midst of front-line IC was similar to no response. Patients achieving a CR or PR to front-line IC were more likely to proceed to ASCT at relapse (55%) compared to patients with either SD or PD at the end of front-line IC (25% and 17% respectively, p<0.0001). Other factors associated with poor survival at first relapse were relapse within 12 months of diagnosis (HR = 2.24, 95% CI: 1.57-3.18, p<0.0001), IPI at diagnosis of 3-5 (HR=1.51, 95% CI: 1.13-2.03, p=0.0058), and age > 60 (HR =1.51, 95% CI: 1.12-2.03, p=0.0064). There was no difference in survival at first relapse by cell of origin (HR = 1.13, 95% CI: 0.74-1.72, p=0.59). Conclusions: Most patients undergo therapy after relapsed/refractory DLBCL but only one-third receive ASCT. Outcomes following all treatments for relapsed/refractory DLBCL remain poor. Factors associated with adverse outcomes include refractory to front-line therapy, early relapse, baseline IPI and advanced age. These outcomes provide relevant historical control for the many novel agents being tested in this unmet need. Figure 1. Figure 1. Disclosures Farooq: Kite Pharma: Research Funding. Maurer:Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding.

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Safety and Antitumor Activity Study Evaluating Loncastuximab Tesirine and Rituximab Versus Immunochemotherapy in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2020-136614 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Yuliya Linhares ◽

Mitul D Gandhi ◽

Michael Chung ◽

Jennifer Adeleye ◽

David Ungar ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Advisory Board ◽

Publicly Traded ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Large B Cell

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) who fail immunochemotherapy (IC) and are unsuitable for autologous stem cell transplantation (ASCT) and those who relapse shortly after ASCT have extremely poor prognosis and need additional treatment options. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 2 study (NCT03589469), Lonca demonstrated single-agent antitumor activity with manageable toxicity in patients with relapsed/refractory (R/R) DLBCL. Rituximab is a CD20-targeting monoclonal antibody used in front-line IC for DLBCL and in salvage regimens, such as rituximab/gemcitabine/oxaliplatin (R-GemOx). The addition of rituximab to a CD19-targeting pyrrolobenzodiazepine ADC appears to prolong tumor control in preclinical studies, providing the rationale for evaluating Lonca combined with rituximab (Lonca-R) as a treatment for R/R DLBCL. Study Design and Methods: This is a Phase 3, randomized, open-label, 2-part, 2-arm, multicenter study of Lonca-R versus standard IC in patients with R/R DLBCL (NCT04384484). Part 1 is a nonrandomized safety run-in with Lonca-R. The toxicity of Lonca-R will be compared with previous single-agent Lonca safety data after 20 patients have completed Cycle 1 in Part 1. Provided no significant increase in toxicity is observed, Part 2 will be initiated. Part 2 is a randomized study of Lonca-R versus R-GemOx (Figure 1). Key inclusion and exclusion criteria are reported in Table 1. The primary objective of Part 2 is to evaluate the efficacy of Lonca-R versus R-GemOx, using progression-free survival (PFS) as the primary endpoint. PFS will be defined as the time between randomization and first documentation of recurrence, disease progression or death (central review) and the primary analysis will compare PFS between treatment arms using stratified log-rank testing. Secondary objectives include evaluation of safety, pharmacokinetics, and immunogenicity of the combination, in addition to the impact of treatment on symptoms, patient-reported outcomes and patients' overall health. In Part 1 and in the Lonca-R arm of Part 2, patients will receive intravenous (iv) Lonca at 150 µg/kg on day 1 of each 21-day cycle for 2 cycles, then at 75 µg/kg on day 1 for up to 6 additional cycles. Rituximab 375 mg/m2 iv will be administered subsequent to Lonca infusion on day 1 of each cycle. Patients treated with Lonca-R will also be given dexamethasone 4 mg (oral, twice a day), where not contraindicated, on the day before, the day of, and the day after Lonca-R infusion. In the R-GemOx arm, patients will receive rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatin 100 mg/m2 iv on day 1 of each 14-day cycle up to a total of 8 cycles. Patients will receive premedication and supportive care according to the respective prescribing information for rituximab, gemcitabine, and oxaliplatin. The trial is planned to open in Q3/Q4 2020, and target enrollment is 350 patients. Funding: This study is sponsored by ADC Therapeutics SA; https://clinicaltrials.gov/ct2/show/NCT04384484. Disclosures Linhares: Jazz Pharmaceuticals: Consultancy; ADC Therapeutics, Verastem Oncology, Bristol Myers-Squibb (Juno), AstraZeneca: Research Funding; Miami Cancer Institute, Baptist Health South Florida: Current Employment. Gandhi:TG Therapeutics (Advisory board), GlaxoSmithKline (Advisory board): Membership on an entity's Board of Directors or advisory committees. Adeleye:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ungar:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hamadani:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding. OffLabel Disclosure: Rituximab is licensed for treatment of NHL but is being used in combination with an unlicensed drug (loncastuximab tesirine) in this study

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Rituximab-CHOP and Central Nervous System Prophylaxis Using Intrathecal Methotrexate in Primary Breast Diffuse Large B-Cell Lymphoma: A Prospective, Multicenter, Single-Arm Phase II Study

Blood ◽

10.1182/blood-2019-122631 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4076-4076

Author(s):

Ho-Young Yhim ◽

Cheolwon Suh ◽

Seok Jin Kim ◽

Deok-Hwan Yang ◽

Hyeon-Seok Eom ◽

...

Keyword(s):

Phase Ii ◽

Cumulative Incidence ◽

Research Funding ◽

Phase Ii Study ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Intrathecal Methotrexate ◽

Cns Prophylaxis ◽

Large B Cell Lymphoma

Background: Primary breast diffuse large B-cell lymphoma (DLBCL) has poor outcomes with frequent extranodal failures, particularly in the central nervous system (CNS). To prevent CNS recurrence, we designed this phase II trial that addressed feasibility and activity of conventional immunochemotherapy and CNS prophylaxis. Methods: This prospective, multicenter, single-arm phase II study was conducted to evaluate efficacy and safety of 6 cycles of conventional rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days (R-CHOP) with the addition of 4 doses of intrathecal methotrexate (IT MTX; 12mg) during the first 4 cycles of R-CHOP in patients with primary breast DLBCL. Primary breast lymphoma was defined as lymphoma involving one or both breasts as a sole extranodal site regardless of specific nodal involvement status. The primary end-point was 2-year progression-free survival (PFS). Secondary end-points included cumulative incidence of CNS recurrence, overall survival (OS), and safety. All patients provided written informed consents and the study was registered at www.clinicaltrials.gov as #NCT01448096. Results: Thirty-three patients with primary breast DLBCL were enrolled between Jan 2012 and Jul 2017 in the Consortium for Improving Survival of Lymphoma (CISL) member institutions. The median age was 50 years at diagnosis (range, 29-75) and all were female. Right breast involvement was more common than left (18 [55%] vs 14 [42%]) and bilateral breast involvement was found in one patient (3%). Nodal involvement was present in 16 patients (49%), primarily in regional nodes (14 patients). Thus, the Ann Arbor stage was IE in 17 (52%), IIE in 13 (39%), IIIE in 2 (6.1%), and IV in 1 (3.0%). ECOG performance status was ≥2 in 1 patient (3%) and serum LDH level was elevated in 9 (27%). Therefore, the IPI and the CNS-IPI risk were mainly low (28 patients, 85%; respectively). No patients had CNS involvement at diagnosis. 32 (97%) of the 33 patients completed R-CHOP as planned, and the remaining patient withdraw a consent after four cycles of R-CHOP because of poor tolerance. CNS prophylaxis using IT MTX was completed as planned in 31 patients (94%), but it was discontinued in 2 patients because of patient's refusal. These 2 patients received two and three IT MTX doses, respectively. 32 patients (97%) were evaluable for treatment response and all these patients achieved a complete response. At the cutoff date of this analysis (10 Jul 2019), all patients who entered a follow-up phase had at least 24.0 months of follow-up. With a median follow-up duration of 46.1 months (IQR 31.1-66.8), 6 patients had experienced treatment failure and 3 of these died. The 2-year PFS and OS were 81.3% (95% CI, 67.7-94.8) and 93.5% (95% CI, 84.9-100.0), respectively (fig 1A and B). Of the 6 patients with treatment failure, diseases involved CNS with or without lymph nodes in 4 patients and breasts in 2 patients (1 ipsilateral and 1 contralateral breast recurrence). 3 of the four patients with CNS recurrence had isolated CNS recurrences (2 brain parenchymal and 1 meningeal disease) and one had a concurrent meningeal and lymph nodal recurrence. All 4 patients with CNS recurrence had received prophylactic IT MTX as planned by protocol. The 2-year cumulative incidence of CNS recurrence, taking into account the competing risk of death, was 12.5% (95% CI, 0.3-23.2, fig 1C). Although the number of patients with intermediate CNS-IPI risk was small (5 patients, 15%), the cumulative incidence of CNS recurrence did not differ significantly according to the CNS-IPI risk group. All CNS recurrences occurred within the first 2 years after enrolment. Toxicities were generally manageable during the R-CHOP and IT MTX treatment. No deaths as a result of toxicity occurred during treatment. Conclusion: Our study shows that conventional R-CHOP with prophylactic IT MTX is feasible in patients with primary breast DLBCL. However, given a substantially high rate of CNS recurrence, further studies to properly define the best strategy for CNS prophylaxis should be needed in patients with primary breast DLBCL. Figure 1 Disclosures Yoon: F. Hoffmann-La Roche Ltd: Research Funding. Kim:Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

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Lymphocyte-to-Monocyte Ratio at Diagnosis and Survival in De Novo Double/Triple Hit Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.3885.3885 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3885-3885

Author(s):

Luis Porrata ◽

Kay Ristow ◽

Ellen D. McPhail ◽

William Macon ◽

Matthew J Maurer ◽

...

Keyword(s):

Prognostic Factor ◽

B Cell ◽

Research Funding ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphocyte To Monocyte Ratio ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract The lymphocyte-to-monocyte ratio at diagnosis (LMR-D) has been reported to be a prognostic factor for clinical outcomes in both T-cell and B-cell lymphomas. However, there are no reports testing the prognostic ability of LMR-D in patients diagnosed with de novo double/triple hit diffuse large B cell lymphoma (DLBCL). Thus, we set out to investigate if the LMR-D is a prognostic factor for survival in de novo double/triple hit lymphomas. From 10/5/1998 until 1/16/2015, thirty-four patients with de novo double/triple hit DLBCL were identified for this study. Double and triple hit were defined by interphase FISH evaluating three fusion signals to identify the BCL2 translocation and IGK/MYC D-FISH probe to identify whether the partner is IG or non-IG. Interphase fluorescence in situ hybridization (FISH) was performed on paraffin sections using probes that included 8q24 (5'MYC, 3'MYC); t (2;8), IGK/MYC; t(8,14), MYC/IGH; t(8;22), MYC/IGL; 3q27 (3'BCL6, 5'BCL'6); and 18q21 (3'BCL2, 5'BCL2). The cohort included 14 females and 20 males. The median follow-up for the cohort was 9.0 months (range: 0.4-72.6 months). Using the median for the LMR-D as the cut-off value, patients with a LMR-D ≥ 1.2 experienced superior overall survival (OS) [Hazard ratio (HR) of 0.127, 95% confidence interval (CI) of 0.019-0.530, p < 0.004] and progression-free survival (PFS) [HR of 0.107, 95 CI of 0.024-0.335, p < 0.0001]. The median follow up for OS for patients with a LMR-D ≥ 1.2 was not reached with a 5-year OS rate of 82% (95% CI of 49%-95%) compared with a median follow-up of 10 months for patients with a LMR-D < 1.2 with a 0% 5 year OS rate, p < 0.003 (Figure 1A). The median PFS for patients with a LMR-D ≥ 2 was not reached with a 5 years PFS of 74% (95%CI, of 43%-91%) compared with a median follow-up of 4.7 months for patients with a LMR-D < 1.2 and 0% 5 year PFS rate, p < 0.0001 (Figure 1B). After adjusting for the International Prognostic Index, multivariate analysis showed that the LMR-D remained an independent prognostic factor for OS [HR = 0.180, 95% CI of 0.254-0.784, p < 0.02] and for PFS [HR of 0.127, 95%CI of 0.029-0.409, p < 0.0003]. In spite of the small cohort of de novo double/triple hit DLBCL, the LMR-D was identified as a prognostic factor for clinical outcomes for this specific set of aggressive lymphomas. Further studies are warranted to confirm our findings. Table.LMR-D ≥ 1.2, N = 18Events = 2LMR-D < 1.2, N = 16Events = 8P < 0.003LMR-D ≥ 1.2, N = 18Events = 3LMR-D < 1.2, N = 16Events = 14P < 0.0001Figure 1AB Figure 1. Figure 1. Disclosures Maurer: Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Off Label Use: New agent in a combination regimen..

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Durable Remissions Achieved with R-CHOP Chemotherapy without Radiotherapy in Patients with Primary Mediastinal B-Cell Lymphoma - the Royal Marsden Experience

Blood ◽

10.1182/blood-2018-99-119560 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4240-4240

Author(s):

Vasiliki Michalarea ◽

Dima El-Sharkawi ◽

Siraj Yusuf ◽

Mary Gleeson ◽

Laura Hickmott ◽

...

Keyword(s):

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

Advisory Board ◽

The Other ◽

Chop Chemotherapy ◽

Consolidation Radiotherapy ◽

Pet Scans

Abstract Introduction: Primary mediastinal B Cell Lymphoma (PMBL) is a high-grade non-hodgkin lymphoma with distinct clinical and biological features. Optimal chemotherapy for this lymphoma is not established but some centres favour more intensive regimes such as DA EPOCH-R over R-CHOP. The role of consolidation radiotherapy is yet to be clarified and whether it can be omitted in those patients with a negative end-of-treatment PET scan (EOT PET) regardless of induction chemotherapy. Furthermore, the occurrence of false positive EOT PET scans may lead to overtreatment. The aim of this study was to establish the outcomes of patients (pts) with PMBL who had been treated in a single centre. Methods: Pts diagnosed with PMBL between 2003 and 2015 in Royal Marsden Hospital were included. Data was collected from electronic patient records and PET CT images review. Survival was defined from date of diagnosis until date of death or date of last follow up. Results: Thirty-four pts were identified with characteristics as shown in the table. Median diameter of the mediastinal mass was 12cm (range 5.5 - 24cm); 25 (74%) pts had a mass of ≥ 10cm. The majority of pts received R-CHOP chemotherapy (2 had 14 day cycles, 30 had 21 day cycles), 1 R-GCVP and another R-PACEBOM. Median number of cycles of chemotherapy was 6 (range 1-8). Seven out of 32 (22%) pts received involved field radiotherapy (IFRT). EOT PET was available for 30 pts. Median time to obtaining EOT PET from completion of chemotherapy was 31 days (20-81). Twenty-three out of 30 pts had EOT PET negative disease with a Deauville score (DS) of 1-3. Twenty-one of these 23 pts did not receive IFRT. Two of these 21 pts relapsed in the mediastinum and were treated with salvage chemotherapy followed by autologous stem cell transplant (ASCT) of whom 1 died due to their lymphoma. The 2 patients who received consolidation radiotherapy remain in remission. Seven out of 30 pts had a positive EOT PET (DS 4-5); of whom 5 received IFRT. Two out of 5 patients relapsed and proceeded with further chemotherapy of whom 1 died due to treatment-related causes while the other 4 patients were alive at time of last follow-up. Two pts with a positive EOT PET did not have IFRT, 1 proceeded with salvage chemotherapy but died due to lymphoma and the other patient was followed up with serial PET scans and ultimately the residual avidity was considered to be due to thymic hyperplasia. Conclusion: Our analysis demonstrates that for the 23 patients who achieved a complete metabolic response on EOT PET the risk of relapse was low (9%) (despite that only 2 patients received consolidation radiotherapy) and only one patient (4%) died of lymphoma. Thus the majority of patients with a negative EOT PET scan following R-CHOP chemotherapy may not need consolidation radiotherapy. This finding should be taken into account when considering the risk/benefit of adding radiotherapy treatment to patients who are already in metabolic CR after chemotherapy. Consolidation radiotherapy is currently being investigated in a prospective IELSG37 trial, NCT01599559. Table. Table. Disclosures Chau: Eli-Lilly: Honoraria, Other: Advisory Board, Research Funding; Bristol Meyers Squibb: Other: Advisory Board; MSD: Other: Advisory Board; Bayer: Other: Advisory Board; Roche: Other: Advisory Board; Merck Serono: Other: Advisory Board, Research Funding; Five Prime Therapeutics: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Janssen-Cilag: Research Funding; Sanofi Oncology: Research Funding. Cunningham:Roche pharmaceuticals: Research Funding.

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Real-World Outcomes of Patients with Diffuse Large B-Cell Lymphoma Receiving Second Line Therapy in the United States

Blood ◽

10.1182/blood-2020-141274 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 29-30

Author(s):

Ahmed Sawas ◽

Constance Lau ◽

Michael Thomson ◽

Kathleen Maignan

Keyword(s):

Real World ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Publicly Traded ◽

Second Line Therapy ◽

Entire Cohort ◽

Large B Cell Lymphoma ◽

Line Therapy ◽

Baseline Covariates ◽

Large B Cell

Background: In the rituximab era, outcome data from patients (pts) receiving second-line therapy (2L) for diffuse large B-cell lymphoma (DLBCL) are derived mostly from randomized controlled trials or selected cohorts from specialized care centers. As new salvage strategies emerge, there is a need to reevaluate the landscape of 2L DLBCL (treatments and outcomes) in real-world (rw) patient cohorts. We investigated the timing of 2L in a cohort of US pts with DLBCL, the utilization of autologous stem cell transplantation (ASCT) as consolidation, and the overall survival (OS) in these pts. Methods We included patients from the Flatiron Health electronic health record (EHR) derived, de-identified database, with a first incident DLBCL diagnosed after January 2011, and with documented 2L therapy receipt (n=524). All pts received ≥4 doses of an anthracycline-based immune-chemotherapy in the frontline therapy (1L) setting and initiated 2L active immune-chemotherapy (anti-CD20 monoclonal antibody monotherapy was excluded) prior to December 2019 to allow for at least 6 m of potential follow-up through May 31 2020. Patients with central nervous system disease at diagnosis were excluded. Real-world overall survival (rwOS) probabilities, indexed to the start of 2L, were estimated in the entire cohort using the Kaplan-Meier method. Hazard ratios (HR) comparing rwOS were estimated using Cox regression models. Baseline covariates included demographic information, DLBCL histologic subtypes, cell of origin (COO) classified by the Hans' algorithm, cytogenetics, and the time interval in months (m) from end of 1L therapy to initiation of 2L therapy. Analyses were also re-indexed to 1 and 3 years post-2L, comparing unadjusted rwOS in pts who had received ASCT on or prior to these timepoints versus those who did not. Results In the study sample of 524 pts (57% men), median age at 2L initiation was 68 years (range 59 to 76) and 63% had stage III or IV disease at diagnosis. Initiation of 2L happened within 6 m of 1L completion for a majority of pts, 276/524 (53%), and within 2 months for one quarter, 137/524 (26%); for the rest, 92 pts (18%) initiated between 6-<12 m after 1L completion, 72 pts (14%) between ⩾12-24 m and 84 pts (16%) after 24 m. Consolidation with ASCT was documented for 115 pts (22%) and 17 pts (3%) received chimeric antigen receptor T-cells therapy. Unadjusted median rwOS in the entire cohort was 22 m [95% CI: 17, 38] (Figure 1A). This varied by interval between 1L completion and 2L initiation; for pts with shorter interval (<12 m) from 1L, median rwOS was 17 m [95% CI: 12, 30], while it was 43 m [95% CI: 22, 54] for those with a ⩾12 m interval (Figure 1B). The presence of MYC translocation alone or in combination with other cytogenetic abnormalities was associated with a shorter unadjusted median rwOS vs. absence of MYC: 9.3 m [95% CI: 8.2, 32, n=33] vs. 26 m [95% CI: 18, 43, n=491] (Figure 1C). In the adjusted model controlling for baseline covariates, older age (⩾ 70) appears to be associated with increased hazard of death (HR: 1.48 [95% CI: 1.14, 1.91]). Unadjusted rwOS analyses at 1 year following start of 2L showed better survival for patients receiving ASCT versus those who did not (HR: 0.40 [0.21, 0.76]). This association was sustained at 3 years (HR: 0.17 [0.04, 0.75]. Conclusion In a contemporary cohort of rw pts with DLBCL receiving 2L immune-chemotherapy, the majority did not receive ASCT. In this setting, age ⩾70, shorter intervals between 1L completion and 2L initiation, presence of MYC translocations, and no ASCT were factors associated with shorter survival. It may be important to address the implications of these clinical features in the investigation of 2L therapy options for pts with DLBCL. Disclosures Sawas: Daiichi Sankyo: Speakers Bureau; Affimed: Research Funding; Roche: Current equity holder in publicly-traded company; Flatiron Health: Current Employment; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau. Lau:Flatiron Health, Inc: Current Employment; Roche: Current equity holder in publicly-traded company. Thomson:Flatiron Health, Inc: Current Employment; Roche: Current equity holder in publicly-traded company. Maignan:Flatiron Health, Inc: Current Employment, Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company.

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Single Institution Experience of Gastrointestinal Involvement of Diffuse Large B- Cell Lymphoma: Presentation, Outcomes and Patterns of Treatment Failure

Blood ◽

10.1182/blood-2018-99-117651 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2982-2982

Author(s):

Puja C. Arora ◽

Victor M. Orellana-Noia ◽

Abeer Alfaraj ◽

Wenzinger Christopher ◽

Sandra Monson ◽

...

Keyword(s):

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Response To Treatment ◽

Gi Tract ◽

Cns Involvement ◽

Single Institution ◽

Large B Cell Lymphoma ◽

Duration Of Response

Abstract Introduction Extranodal (EN) involvement of the gastrointestinal (GI) tract in diffuse large B-cell lymphoma (DLBCL) presents heterogeneously across different anatomic sites and often occurs at initial diagnosis. Rituximab, anthracycline-based combination chemotherapy, radiation, and surgery have all been studied separately and in various combinations. However, given the variability in how patients may present in these contexts, there remains no consistent standard of care or pattern of treatment failure. We hypothesized these patients have different outcomes than those lacking this EN site of involvement. Methods We conducted a single-institution, retrospective analysis of consecutive cases who presented at initial diagnosis with DLBCL involving the GI tract including the esophagus, stomach, small intestine, or portion of large intestine. We performed a search in the University of Virginia Pathology database to identify all patients age >/= 18 years with DLBCL involving the GI tract and excluded those without additional clinical information available for review. A total of 51 patients were identified and we retrospectively collected data on demographics, date of diagnosis, involvement of extranodal sites, stage, International Prognostic Index (IPI) score, treatment, response to treatment, relapse, and survival at last follow-up. Results Of the 51 DLBCL patients, 65% of patients were male and 82% were Caucasian. Median age was 65 years (range 22-92). Three patients had HIV infection and no patients had active hepatitis B or C. Sites included gastric (51%), colon (27%), small bowel (12%), esophagus (4%), and rectum (2%); 4% had multiple GI sites involved. Forty-nine percent of patients presented with abdominal pain. Other common presentations included gastric/bowel perforation (12%), GI bleed (12%), gastric/small bowel obstruction (12%). Three cases (6%) were discovered on a screening colonoscopy. Forty-three percent of patients presented as stages I-IIIE versus 57% presented as stage IVE. Fifty-five percent were IPI 0-2 while 45% were IPI 3-5. Six patients (12%) had CNS involvement at presentation. Median follow-up was 20 months (range 26 days to 17 years). Six patients were lost to follow-up prior to assessment of response, and 4 had treatment discontinued early (3 due to grade 5 infection, 1 for GI perforation leading to death). One patient was still undergoing treatment. Forty patients were available to assess for response to treatment. The majority were treated with R-CHOP (57%) or DA-R-EPOCH (29%). Sixty-eight percent (n=27) had a complete response (CR), 22.5% (n=9) a partial response (PR), and 10% (n=4) were primary refractory. Of the 27 CRs, 13 (48%) had presented as stage 1-3 and 14 (52%) had presented as stage 4; 16 (59%) had an IPI score of 0-2 and 11 (41%) had an IPI score of 3-5. Of the four patients who had primary refractory disease, 3 had multiple EN sites involved at diagnosis, including 2 with CNS involvement. Of those who had a response (including CR or PR), median duration of response was 1 year (range 4 months to 13 years). Eleven patients (28%) had a relapse: 3 in the CNS, 5 in the GI tract (3 at the same site of initial involvement, 1 with a different GI site involved, and 1 with a different GI site in addition to systemic disease), and 3 in lymph nodes alone. Time to relapse ranged 1 month to 13 years with a median of 8.4 months. Fifty-seven percent of patients were alive at time of last follow-up. Median Overall survival (OS) was 5.7 years and Median Progression Free Survival (PFS) was 5.6 years (Figure 1). Conclusion There is limited data on how patients with DLBCL involving the GI tract initially present and respond to therapy. This study encompassing almost twenty years of experience at a single institution, suggests that though patients present at all stages and as low risk vs high risk IPI, outcomes are poor compared to prior studies, especially when additional extranodal sites are involved. Duration of response can be substantial, however relapses are common and may present years later indicating ongoing follow-up is imperative. Figure 1. Figure 1. Disclosures Portell: AbbVie: Research Funding; Amgen: Consultancy; Kite: Research Funding; TG therapeutics: Research Funding; BeiGene: Research Funding; Genentech/Roche: Consultancy, Research Funding; Acerta: Research Funding; Infinity: Research Funding. Williams:Sandoz: Consultancy; Pharmacyclics: Research Funding; Verastem: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; Abbvie: Consultancy; Novartis: Research Funding; Gilead: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Juno: Consultancy.

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Phase I Study of Oral Azacitidine (CC-486) Plus Salvage Chemotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2021-145493 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3567-3567

Author(s):

Brian T. Hess ◽

Leandro Cerchietti ◽

Lindsey Hendrickson ◽

Elizabeth Hill ◽

Anshu Giri ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

Global Methylation ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Methylation Patterns ◽

Large B Cell

Abstract Background A significant portion of diffuse large B-cell lymphoma (DLBCL) patients (35-40%) relapse or are refractory to frontline chemotherapy. The standard of care for relapsed/refractory (R/R) DLBCL patients has been salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) in eligible patients. Epigenetic alterations, such as aberrant DNA methylation patterns, have been linked to chemotherapy resistance in DLBCL. CC-486 is an oral hypomethylating inhibitor that inhibits DNA methyltransferase, and has provided evidence for chemotherapy sensitization in DLBCL (Clozel T, et al. Cancer Discovery, 2013). This provides rationale for addition of CC-486 to standard cytotoxic chemotherapy rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in R/R DLBCL patients who are candidates for ASCT. Here we report the results of the phase 1 trial investigating this combination. Methods Eligibility included age ≥ 18, a diagnosis of R/R DLBCL, follicular lymphoma grade 3B, or DLBCL transformed from indolent lymphoma who were candidates for salvage chemotherapy and ASCT consolidation. The study was conducted via standard 3+3 dose escalation of CC-486 at 200 mg (dose level (DL) 1), 300 mg (DL 2), and 150 mg (DL -1). A Dose limiting toxicity (DLT) was defined as grade ≥ 3 adverse event (AE) as defined by CTCAE v5 leading to ≥ 7 day delay in cycle (C) 1 or 2 of R-ICE chemotherapy as well as grade ≥ 2 vomiting/diarrhea, persisting 48 hours despite best supportive care. Patients received up to three 21-day cycles. CC-486 was given as a 7 day lead in prior to C1 and then on days 8-21 of C1 and C2 with doses held based on cytopenias/AE's per protocol. G-CSF was mandated with each cycle. The primary objective was to determine the recommended phase 2 dose (RP2D) of CC-486 in combination with R-ICE chemotherapy. Secondary objectives included overall response rate (ORR)/complete remission (CR) per 2014 IWG criteria, peripheral blood stem cell (PBSC) collection feasibility, and proportion of patients receiving ASCT consolidation. Biomarker objectives included assessment of locus specific and global methylation patterns in ctDNA at set time points. Results The study has completed accrual with enrollment of nine patients from two institutions, all of which completed planned therapy. Eight (89%) of the patients had relapsed < 1 year from completion of frontline chemotherapy. Six patients were treated at the DL1 (200 mg), three patients were treated at DL2 (300 mg), and zero patients were treated at DL-1 (150 mg) with baseline characteristics described in table 1. The most common AE's (figure 1) included nausea (78%), thrombocytopenia (78%), anemia (56%), neutropenia (55.6%), fatigue (44%), and constipation (44%). Compared with DL1, DL2 was associated with greater incidence of grade ≥ 3 hematologic AE's/cycle including neutropenia (42% v 6%), anemia (29% v 11%), and thrombocytopenia (42% v 6%); higher incidence of neutropenic fever/cycle (28.5% vs 0%); more frequent delays in day 1 of C2 or C3 of R-ICE chemotherapy (80% vs 0%); and higher rate of CC-486 doses missed in C2 and C3 due to cytopenias (40% and 4%) respectively. One DLT occurred at DL2 in a patient with grade 5 neutropenic sepsis. A planned safety review of the three patients at DL2 established that no further patients would be enrolled at this dose. No DLTs were noted in the six patients enrolled at DL1. The ORR(CR) of the 8 evaluable patients was 50%(50%) and 4/9 patients proceeded to ASCT. With a median follow up of 9.5 months (range 1.2-25.1) the median PFS and OS were 4.0 months (95% CI 2.1-NR) and 10.7 months (95% CI 9.5-NR) respectively. All 4 patients successfully collected PBSCs (defined as ≥ 3.0 x 10^6 CD34 cells/kg) with median of 4.08 x 10^6 cells/kg. Biomarker studies are pending. Discussion Patients enrolled at DL1 (200 mg) tolerated this combination well with expected hematologic AE's, no episodes of neutropenic fever, few missed doses of CC-486, no delays in R-ICE chemotherapy, and no DLTs. The CR rate was 50% and a high proportion of patients (89%) enrolled after relapsing < 1 year from completion of frontline therapy. Biomarker studies may provide information regarding DLBCL populations likely to benefit from combinations of chemotherapy and epigenetic priming. Biomarker studies related to locus specific and global methylation patterns in ctDNA will be presented at the ASH conference. Figure 1 Figure 1. Disclosures Hess: BMS: Speakers Bureau; ADC Therapeutics: Consultancy. Cerchietti: Celgene: Research Funding; Bristol Myers Squibb: Research Funding. Hill: Eli Lilly and Company: Ended employment in the past 24 months.

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