Citations

Abstract Background: Central nervous system (CNS) lymphoma, both primary and secondary disease, carries the worst prognosis of all Non-Hodgkin’s lymphoma with a 5 year survival of less than 30% with current therapeutic options. Recent studies have shown constitutive activation of both NF-κB and MAPK signaling pathways in the maintenance and progression of CNS lymphoma. This often coincides with mutations in MYD88. IRAK4 is a serine/threonine kinase that mediates interleukin 1 receptor (IL-1R) and Toll-like receptor (TLR) signaling downstream of MYD88, and is a novel therapeutic target for this disease. CA-4948 is an oral first-in-class small molecule inhibitor of IRAK4 that has demonstrated clinical activity in patients with systemic Non-Hodgkin’s Lymphoma. Our study goal was to evaluate CA-4948 efficacy in a syngeneic preclinical model of primary CNS B cell lymphoma (A20), supporting future clinical investigation of this agent in this difficult to treat disease. Materials and Methods: Plasma, cerebrospinal fluid (CSF), and brain tissue (both naïve and tumor bearing) were assessed for CA-4948 drug concentration following single high-dose oral administration using UPLC-MS/MS. Biomarker expression, including NF-κB and MAPK, was measured in control and CA-4948 treated brain tissue resected from tumor-bearing animals using multi-parameter immunohistochemistry and 3D modeling of cleared tissue. Dose-dependent survival responses were also measured using the A20 preclinical model of primary CNS lymphoma. Results: While brain concentrations of CA-4948 remained low with respect to plasma (~4-5%), therapeutic dose levels were attained in both CSF and brain tissue (>502 nM). No significant difference between naïve and A20 tumor bearing brain tissue was observed, indicating the blood brain barrier remained intact in this model. Biomarker analyses revealed significant downregulation of both MAPK and NF-κB signaling pathways in response to CA-4948, as evidenced by reduced protein levels of phospho-p38Thr180/Tyr182, phospho-ERK1/2Thr202/Tyr204, and phospho-p65Ser536 in both the tumor cells and the tumor microenvironment. Finally, CA-4948 treatment produced a dose-dependent survival response in syngeneic animals harboring CNS A20 tumors. Conclusions: CA-4948 is able to reach therapeutic dose levels in the CNS in a preclinical murine model of CNS lymphoma, producing significant and dose-dependent anti-tumor activity and survival advantage. These data support further evaluation of CA-4948 in clinical investigation and treatment of patients with CNS lymphoma. Citation Format: Christina A. von Roemeling, Bently P. Doonan, Lan Hoang-Minh, Han W. Tun, Elizabeth Martinez, Raul Soikes, Reinhard von Roemeling, Duane A. Mitchell. The IRAK4 inhibitor CA-4948 demonstrates antitumor activity in a preclinical model of CNS lymphoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P243.

Abstract Introduction: Novel genetic classifications of diffuse large B-cell lymphoma (DLBCL) highlight the molecular complexity beyond cell of origin and provide new therapeutic implications. Next generation trials may incorporate novel agents for different genetic subtypes based on the pathogenesis mechanisms. For example, with the LymphGen classification, the MCD, BN2, ST2, and EZB subtypes are predicted to be susceptive to PI3K/mTOR targeting (Wright 2020). However, PI3K inhibitors have not been tested in the frontline, although data on the mTOR inhibitor everolimus were encouraging (Alliance 1085). We launched a phase 1/1b trial (NCT04323956) to investigate the feasibility of combining a novel PI3K inhibitor parsaclisib with standard R-CHOP immunochemotherapy and to seek an efficacy signal. Methods: Adult patients with newly diagnosed DLBCL were eligible if any of the following was present: 1) non-GCB subtype per the Hans algorithm; 2) expression of either Myc (≥40%) or Bcl2 (≥50%) by immunohistochemistry; or 3) MYC rearrangement by FISH. High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, regardless of morphology, was also eligible. All patients received parsaclisib plus R-CHOP. Phase 1 followed a 3+3 design and the primary endpoint was maximum tolerated dose (MTD) of parsaclisib. Dose levels tested were level 1 (20 mg QD, d1-10; starting level) and level 2 (20 mg QD, d1-14). MTD was defined as the dose level below the lowest dose that induced dose limiting toxicity (DLT) in at least one-third of patients. The primary endpoint in phase 1b is complete response (CR) rate by PET. Results: From July 2020 to June 2021, 15 patients were enrolled, 9 in phase 1 and 6 in phase 1b. The median age at diagnosis was 56 years (range 20-79), and 7 (47%) were female. One patient (7%) had ECOG PS ≥2, 7 (47%) had elevated LDH, 7 (47%) had >1 extranodal site, 13 (87%) had stage III/IV, and 7 (47%) had high-intermediate or high risk International Prognostic Index. Pathology was DLBCL in 13 patients (2 with concurrent follicular lymphoma) and high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in 2 patients. Four (27%) had non-GCB subtype, 7 (47%) had Myc or Bcl2 single expression, 8 (53%) had Myc/Bcl2 double expression, and 5 (33%) had MYC rearrangement (2 with concurrent BCL2 and/or BCL6 rearrangements). In phase 1, 3 patients were enrolled at dose level 1 and 6 patients were enrolled at dose level 2. No DLT was observed. Therefore, MTD was not reached, and dose level 2 was selected for phase 1b dose expansion. Six patients were enrolled in phase 1b to date. At the data cutoff date of 7/22/2021, 8 patients completed all 6 cycles of treatment, 1 competed 5 cycles, 3 completed 3 cycles, 2 completed 2 cycles, and 1 completed 1 cycle. Treatment-related adverse events (AE) are summarized in Table 1. The most common hematological AE included lymphopenia (60%), anemia (53%), neutropenia (53%), and thrombocytopenia (27%), and the most common non-hematological AE included nausea (67%), alopecia (40%), constipation (33%), fatigue (33%), dyspepsia (20%), and peripheral sensory neuropathy (20%). The most common grade 3 or 4 AE included lymphopenia (47%), neutropenia (33%), and anemia (13%). One 80-year-old female required parsaclisib dose reduction in cycle 3 and subsequent parsaclisib discontinuation as well as cyclophosphamide and doxorubicin dose reductions due to febrile neutropenia (no source of infection was identified). No other patients required dose reductions. The median follow-up was 3.7 months (range 0.8-10.7). Thirteen patients were evaluable for interim response by PET. The objective response rate was 92%, with 8 (62%) CR and 4 (31%) partial response (PR). One (8%) patient progressed before cycle 2 following a transient clinical response (shrinking palpable mass). Among those who achieved an objective response at interim, 7 patients were evaluable for end of treatment response and all 7 maintained a response, with 6 (86%) CR and 1 (14%) PR. Conclusions: Parsaclisib and R-CHOP combination therapy was generally well tolerated, with no DLT observed in phase 1 and no major safety concerns in both phase 1 and the ongoing phase 1b expansion. The preliminary efficacy signal of objective response appears encouraging in a small cohort of high risk patients. Parsaclisib plus R-CHOP can be an experimental arm for future frontline DLBCL trials investigating genetic subtype-driven novel therapies. Figure 1 Figure 1. Disclosures Wang: Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genentech: Research Funding; MorphoSys: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. King: Celgene/BMS: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Tun: Gossamer Bio, Acrotech: Consultancy; Mundipharma, Celgene, BMS, Acrotech, TG therapeutics, Curis, DTRM: Research Funding. Habermann: Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Parsaclisib is an investigational agent used in this clinical trial.

Abstract Introduction: Novel therapeutic agents such as immune checkpoint inhibitor (ICI) and brentuximab vedotin (BV) are active in classic Hodgkin lymphoma (cHL), including in patients that relapse after autologous stem cell transplant (ASCT). However, optimal management strategy is unclear for patients with relapsed or refractory (RR) cHL post-ASCT. The aim of the study is to determine the impact of novel agents relative to conventional therapy and allogeneic stem cell transplant (allo-SCT) on survival outcomes of patients with cHL who relapsed after ASCT. Methods: Patients with RR cHL who underwent ASCT between 06/1993 and 10/2017 at 3 Mayo Clinic sites were included. Clinical characteristics, treatment information, and outcome data were abstracted. For patients who relapsed after ASCT, the post-relapse progression free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox proportional hazards models. Statistical analyses were done in JMP v15.2.1 and EZR v1.54. Results: A total of 332 patients with RR cHL who underwent salvage therapy and ASCT were identified. After a median post-ASCT follow-up of 8.6 years (range 6.8-9.7), 136 (41%) patients had a relapse or disease progression after ASCT. Patient characteristics of the 136 cases are summarized in the Table. The median age at post-ASCT relapse was 34 years (range 20-73), and 77 (57%) were male. 59 (43%) relapsed within 6 months and 77 (57%) relapsed after 6 months following ASCT. 59 (45%) had an extranodal site involvement at relapse. 14 (10%) had therapy with ICI or BV as salvage therapy prior to ASCT or maintenance therapy post-ASCT. The median post-relapse PFS and OS was 0.8 (95% CI 0.6-1.1) and 3.2 years (95% CI 2.2-5.5) years, respectively. Compared to patients who relapse after 6 months, patients who relapsed within 6 months of ASCT had worse post-relapse PFS (median 0.5 [0.3-0.7] vs 1.3 [0.9-1.9] years, p=0.0003) and OS (median 1.3 [0.5-2.2] vs 6.4 [3.7-10.4] years, p=0.0003). Extranodal site involvement at relapse was not associated with post-relapse PFS (median 0.7 [0.5-1.2] vs 0.9 [0.6-1.3] years, p=0.28) but was associated with worse post-relapse OS (median 2.7 [1.5-4.2] vs 6.4 [2.6-NA] years, p=0.006). Prior therapy with ICI or BV was not associated with post-relapse PFS (median 0.6 [0.3-NA] vs 0.8 [0.6-1.1] year, p=0.8) and OS (median NR [1.0-NA] vs 3.2 [2.2-5.5] years, p=0.5). After post-ASCT relapse, the median lines of subsequent therapy were 2 (range 1-12). For first post-ASCT salvage therapy, novel agents (ICI or BV), compared to other therapies, were associated with superior post-relapse PFS (median 1.7 [0.7-3.6] vs 0.7 [0.5-1.0] years, p=0.004) and OS (median 7.6 [4.7-NA] vs 3.2 [2.2-5.6], p=0.02). Allo-SCT following first post-ASCT relapse (n=9) was not associated with improvement in post-relapse PFS (median 2.2 years [0.3-NA] vs 0.8 [0.6-1.1] years, p=0.1) or OS (median NR [0.5-NA] vs 5.1 [3.2-7.3] years, p=0.7). Patients who received ICI or BV at any point post-ASCT relapse had significantly better post-relapse OS (median 7.6 [4.3-16.7] vs 2.2 [1.4-3.7] years, p=0.004) compared to those who never received any novel agent (Figure 1A). In contrast, allo-SCT at any point post-ASCT relapse (n=27) did not improve post-relapse OS (median 5.6 [2.7-NA] vs 4.7 [2.7-7.3] years, p=0.3) (Figure 1B). In multivariate Cox regression models adjusted for age and sex, exposure to ICI and/or BV was associated with superior post-relapse OS (HR 0.5, 95% CI 0.3-0.8, p=0.007); however, allo-SCT was not associated with improvement in post-relapse OS (HR 0.8, 95% CI 0.4-1.5, p=0.5). Conclusions: Patients relapsing within 6 months of ASCT and those with extranodal involvement at relapse had inferior OS after post-ASCT relapse. Prior therapy with novel agents did not impact post-relapse survival outcomes. In the setting of post-ASCT relapse, novel therapeutic agents significantly improved survival outcomes while allo-SCT did not. Future multicenter studies are needed to explore the role of novel agents and allo-SCT in patients with RR cHL post-ASCT relapse. Figure 1 Figure 1. Disclosures Wang: Eli Lilly: Membership on an entity's Board of Directors or advisory committees; InnoCare: Research Funding; MorphoSys: Research Funding; Genentech: Research Funding; Novartis: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Paludo: Karyopharm: Research Funding. Tun: Gossamer Bio, Acrotech: Consultancy; Mundipharma, Celgene, BMS, Acrotech, TG therapeutics, Curis, DTRM: Research Funding. Cerhan: Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding. Habermann: Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Incyte: Other: Scientific Advisory Board; Seagen: Other: Data Monitoring Committee; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. 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. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding.

Abstract Introduction: Intravascular lymphoma (IVL) is an extra nodal non-Hodgkin lymphoma with tropism for vascular endothelium. It is characterized by growth of large cells within the lumen of small to medium sized blood vessels. Central nervous system (CNS) and skin are predominantly involved. This report represents a retrospective single-institution review of IVL. Methods: We identified patients (pts) with IVL evaluated at Mayo Clinic Cancer Center between January 2003 and December 2018. Demographic, clinical, radiologic, pathologic, and therapeutic data were extracted. Statistical analysis of overall survival (OS) and progression free survival (PFS)] was performed using Kaplan-Meier method. Results: Total number of pts was 55; 22% (12/55) had CNS-only IVL, 14.5% (8/55) had CNS and non-CNS IVL, and 63.6% (35/55) had non-CNS IVL. Eighty seven percent (47/54) pts were B cell type, 11% (6/54) were T cell type, one pt had NK cell type IVL and another was unknown. Four pts were diagnosed by autopsy. Median age at diagnosis was 68 years (range, 40-85). Sixty-four percent were males. ECOG performance status was <2 in 66%. The median follow-up time from diagnosis was 63 months [CI 95%, 9-NR], and 47% (26/55) were alive. The most common diagnostic biopsy sites were bone marrow (BM) 45% (25/55), skin 25% (14/55), and brain 29% (16/55). Twenty-nine patients had a PET scan. Seventy nine percent (23/29) had abnormal PET findings, with mean SUV of 8.6 (range 2.5-19.1). Of the 35 pts with non-CNS IVL, 76% (16/21) had abnormal PET; furthermore, the diagnosis was made with biopsies of the following sites: bone marrow 54% (19/35), skin 40% (14/35), lung 14% (5/35), liver 5.7% (2/35), spleen 2.8% (1/35), and omentum 2.8% (1/35). Forty-six percent (13/28) received CNS prophylaxis and ten percent (3/55) had relapse in CNS. Two out of the three pts who had CNS relapse had received CNS prophylaxis. The median time to CNS relapse in non-CNS IVL was 9 months. The most common first-line regimen was high-dose methotrexate+ rituximab containing regimen 62% (10/16) in IVL with CNS involvement and RCHOP (60%) (17/28) in non-CNS IVL. Seventeen percent of (8/48) pts received autologous stem cell transplant (ASCT) and 63% (5/8) pts were transplanted in first complete remission (CR1), and 3 pts after the first relapse. Median OS (mOS) for the whole cohort was 57 months, [CI 95%, 9-NR], and median PFS was 7 months [CI 95%, 2-NR]. There was no significant difference in mOS between groups; CNS-only IVL- 9 months (CI 95%, 1-NR), non-CNS IVL -62 months (CI 95%, 20-NR) vs combined CNS and non-CNS IVL- 4 months (CI 95%, 3-NR). mOS for those who received ASCT in CR1 was not reached (CI 95%, 10-NR) vs 51 months in non-transplant group (CI 95%, 3-NR) p=0.24. In pts with non-CNS IVL, there was no significant difference in mOS between CNS prophylaxis subgroup (NR: CI 95%, 57-NR) vs no-CNS prophylaxis subgroup (20 months: CI 95%, 0-NR), p=0.12. In those with CNS IVL mOS for early diagnosis (0-30 days from symptom onset to diagnosis was NR (CI 95%, 3-NR) vs mOS for late diagnosis (>30 days {31-14,440})-5months (CI 95% 1-NR), p=0.29]. Conclusion: 1. BM was most frequently involved in our patients. We suggest that BM biopsy should be part of diagnostic testing when IVL is suspected. 2. Most cases are of B-cell linage, consistent with reported literature. All non-B cell cases were in non-CNS locations. 3. PET scans were abnormal in more than 70% of cases indicating that this imaging modality is vital in the diagnosis due to odd location and small size of lesions. 4.Overall prognosis in the literature was poor with most patients surviving <1 year. Our cohort has mOS of 57 months. The reason(s) for better survival in our cohort could not be definitively determined. 5. CNS involvement had an overall trend towards poor prognosis; however, those diagnosed early had better outcomes; this did not reach statistical significance due to small sample size. 6. mOS was not reached for those transplanted CR1. There was a trend towards a better survival associated with CNS prophylaxis versus no prophylaxis in non-CNS IVL. 7. We suggest that CNS-centric therapeutic approach and intensive consolidation with ASCT should be considered in managing IVL. Figure 1 Figure 1. Disclosures Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Habermann: Incyte: Other: Scientific Advisory Board; Seagen: Other: Data Monitoring Committee; Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Tun: Mundipharma, Celgene, BMS, Acrotech, TG therapeutics, Curis, DTRM: Research Funding; Gossamer Bio, Acrotech: Consultancy.

Abstract Background Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) which targets CD20. This study evaluates the utilization and cost-effectiveness of (90)Y-IT in the first line treatment for patients with previously untreated low-grade FL (UFL) and marginal zone lymphoma (UMZL) treated at our institution with (90)Y-IT. Methods We utilized the Advanced Text Explorer (ATE) and the Lymphoma SPORE databases to identify two groups of patients with UFL, WHO grade 1-2, and UMZL who received treatment with either (90)Y-IT or bendamustine plus rituximab (BR) at Mayo Clinic Cancer Center between January 2003 and December 2019. We excluded all patients who had >25% bone marrow involvement with lymphoma for the BR group as this was a requirement for (90)Y-IT treatment. Inverse propensity weighting was utilized to balance the groups for baseline patients and disease characteristics. We use progression-free survival (PFS) as a denominator for the cost effectiveness/utilization evaluation. We identified meaningful and retrospectively measurable outcomes to compare between the groups. we extracted the following data; number of clinic visits in the first year after therapy, emergency room visits, number of hospital admissions, number of hospitalization days, numbers of days on the floor and ICU, number of infections, number of neutropenic fever hospitalizations, number of C-difficile events, number of blood products transfusions, overall use of growth factors due to therapy induced neutropenia, average number of times a growth factor was used, and the number of therapeutic use days. We defined days of therapeutic use as the number of days a treatment was administered on. We also calculated the average cost of the induction treatment when utilizing either (90)Y-IT or BR. The therapeutic cost included only the cost of the medications/therapies and their administration. Results Our cohort consists of a total of 143 patients - 64% (92/143) received BR and 36% (51/143) received (90)Y-IT (see Table-1 for clinical characteristics).The median follow-up from the time of therapeutic administration for the (90)Y-IT group was 5.3 years (95% CI; 4.2, 6.2) with one death and 4.7 years (95% CI; 3.9, 4.9) for the BR group with 6 deaths. The ORR was 100% in (90)Y-IT group with 94% achieving complete response (CR) while ORR in the BR group was 98% with 95% achieving CR. Rituximab maintenance was utilized in 33% of BR patients compared to only 6% in patients who received (90)Y-IT, p=0.002. After utilizing inverse propensity weighting (Figure-1), 5 years PFS was 76% for the (90)Y-IT group and 75% for the BR group, p=0.63 (Figure-2). We evaluated the average treatment effect of (90)Y-IT compared to BR on utilization outcomes, Table-2. (90)Y-IT required an average of 4.5 clinic visits less within the first year after treatment compared to BR group, p<0.001. (90)Y-IT patients had an average of 10 days less of therapeutic use days compared to the BR group, p<0.001. Patienta had similar admission rates to the hospital in both groups. However, when patients were admitted to the hospital in the first year after treatment, those who received (90)Y-IT spent an average of 1.5 days less in the hospital compared to the BR group, p=0.046. The overall use of growth factors was 40% less in the (90)Y-IT group as compared to the BR group, p<0.001. The therapeutic cost of induction of (90)Y-IT was 54% less than that of 6 cycles of BR. Transformation to a high grade of lymphoma was seen in 4 patients in the BR group and 2 patients in the (90)Y-IT group. There was only one case of myelodysplastic syndrome in the BR group and none in the (90)Y-IT group. Conclusion Radio-immunoconjugate therapy with (90)Y-IT is a very convenient and cost-effective treatment for low-grade UFL and UMZL. This is especially important amidst the COVID-19 pandemic as it requires less contact with the health system with decreased number of therapeutic days, clinic visits, use of growth factors and number of hospitalization days. The cost of the therapeutic agents and their administration was also significantly lower for the (90)Y-IT which could help reducing the burden on the health system. Figure 1 Figure 1. Disclosures Cerhan: Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding. Tun: Mundipharma, Celgene, BMS, Acrotech, TG therapeutics, Curis, DTRM: Research Funding; Gossamer Bio, Acrotech: Consultancy. OffLabel Disclosure: We are describing the use of Yttrium-90 ibritumomab tiuxetan in the first line setting in comparison to the bendamustine plus rituximab which is the standard of care

Abstract Background: Young doctors have made up a substantial part of healthcare forces during the Coronavirus Disease 2019 (COVID-19) pandemic. The aim of this study was to determine the rate and level of psychological distress among young doctors during the COVID-19 outbreak. Methods: This cross-sectional cohort study, dedicated to doctors, at or below the age of 40, was conducted in 62 countries as an online survey between September – November 2020. Survey questions covered the following areas: 1. demographics 2. work environment 3.the ‘Hospital Anxiety and Depression Scale (HADS)’ and the ‘Perceived Stress Scale 10 (PSS-10)’. The primary outcome was the rate and level of anxiety/depression and stress among surveyed population defined according to adopted cut off values (HADS>13, PSS-10>14). Secondary outcomes included risk factors for increased HADS and PSS-10 scores.Results: Among 1186 respondents, median aged 32 [29–36], 675 (44.5%) females, 96% reported a high level of anxiety/depression and 97% reported a high level of stress. Factors associated with significantly higher scores for anxiety/depression were increased work hours [OR 1.61 95%CI (1.12–2.34);p=0.01] and loss of pay [OR 5.53, 95% CI (1.57–19.47);p=0.008], while reduced work hours [OR 0.68 95% CI (0.48 - 0.98);p=0.03], increased salaries [OR 0.54 95% CI (0.35–0.85);p=0.003) and good training [OR 0.99 95%CI (0.99– 1.00);p=0.002] were associated with lower scores. Higher scores for stress were associated with higher professional experience [OR 1.08 95% CI (1.02–1.14);p=0.008], reduced salaries [OR 1.74 95% CI (1.01–2.92);p=0.04] and living with a partner [OR 1.53 95% CI (1.08–2.17);p=0.01]. Conclusions: A high rate of young doctors working clinically during the COVID-19 pandemic reported a persistently high level of psychological distress more than six months after the initial outbreak. Improvements in work organization, including reduced work hours and financial security are essential to prevent further psychological suffering among young doctors worldwide.

Abstract A novel genetically engineered mouse (GEM) model for pediatric kidney cancer expressing proximal tubule specific ASPSCR1 :TFE3 fusion gene has been developed. The Rosa26 knock-in ASPSCR1 :TFE3 mouse was crossed with SGLT2-Cre mouse that expresses Cre recombinase in the proximal tubules of the kidney. The ASPSCR1 :TFE3 fusion gene retains the DNA binding and activation domain of TFE3, whereas the N-terminal region of TFE3 is replaced with ASPSCR1 sequences. ASPSCR1 :TFE3 is known to up-regulate the Met receptor tyrosine kinase gene and induce oncogenic phenotypes such as uncontrolled cell proliferation, invasion, and metastasis. However, the molecular roles of ASPSCR1 :TFE3 are poorly understood and no standard of care (SOC) exists for pediatric TFE3 fusion renal cell carcinoma (RCC). Ultrasound (US) and histological analyses of the kidneys of 5, 6 and 7 month old mice revealed bilateral cysts and tumors, while 6-week-old mouse kidney appears normal. At gross inspection, 5-month-old mouse had cysts with a diameter of 1-2 mm while 7-month-old mouse had a polycystic kidney and in the end stage disease. Histopathology revealed neoplastic changes in initial stages in the 5-month-old mouse whereas the neoplasia was predominantly a papillary cystic renal carcinoma; solid tumor formations were observed in the 7-month-old mouse. Neoplastic cells seen in within the blood vessel walls of the 7-month-old mouse indicated future metastasis. This new TFE3 fusion GEM will provide an avenue to understand molecular events of tumorigenesis and progression as well as a model for testing novel therapeutics with survival benefit for a cancer with no current SOC. Citation Format: Aylin Alasonyalilar-Demirer, James L. Miller, Erin E. Miller, Justyna J. Gleba, Han W. Tun, John A. Copland. ASPSCR1-TFE3 gene fusion in transgenic mouse as a new pediatric kidney cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3041.

e19552 Background: Leukemic involvement (LI) in diffuse large B cell lymphoma (L-DLBCL) is very rare and has been sparsely reported. We report our experience with this entity in a large academic multi-center setting. Methods: Medical records of patients with DLBCL who received care at Mayo Clinic between 1/2003 and 6/2020 were reviewed. DLBCL patients with LI were identified. LI was defined as increased white blood cell counts and the presence of clonal B cells on peripheral blood flow-cytometry. Kaplan-Meier method was used for survival analysis. Results: Twenty patients with L-DLBCL were identified with a median follow-up of 32.5 months (CI95%, 32.5-NR). Median age at initial diagnosis was 62 (45-80) years. 60% (12/20) were male; 90% (18/20) were Caucasian. Pathologically, 90% (18/20) had DLBCL and 10% (2/20) had high-grade B cell lymphoma (HGBCL) with intermediate features between DLBCL and Burkitt lymphoma. By Hans criteria, 58% (11/19) had germinal center B-cell DLBCL (GCB-DLBCL) and 42% (8/19) had non-germinal center B-cell DLBCL (non-GCB-DLBCL). 40% (8/20) had transformed DLBCL (t-DLBCL); 36% (5/14) had double-hit lymphoma (DHL) by FISH analysis. LI was present in 55% (11/20) at initial diagnosis and 45% (9/20) at relapse. Median WBC was 39.5/ul (range, 4.3-121) with median absolute lymphocyte count of 25 k/ul (range, 0.7-117). Immunophenotypically, the leukemic lymphoma cells expressed CD19, CD20, and CD79a. Bone marrow involvement and pancytopenia were documented in all patients with a median bone marrow cellularity of 80%. Other extranodal sites of involvement with LI included spleen (65%;13/20), liver (20%;4/20), breast and soft tissue (20%;4/20), bladder or kidneys (10%;2/20), skeleton (10%;2/20), and myocardium (5%;1/20). 65% (13/20) had B-symptoms. All patients had LDH elevation (UNL 222 U/L) with a median of 2125 U/L (range, 308-10,760). 45% (5/11) of patients with LI at initial diagnosis had CNS involvement on relapse/progression. All patients with LI at initial diagnosis received anthracycline-based chemoimmunotherapy with or without CNS prophylaxis. Patients with LI at relapse had had a median of 2 prior treatments (range, 1-5) before LI. Median overall survival (OS) for the whole group was 9 months (CI 95%; 5.8-11.8). There were no long-term survivors. Median progression free survival after LI was 4.7 months (CI95%; 0.8-7.6) in the newly diagnosed group and 3 months (CI95%; 0.9-20) in the relapsed group. 90% (18/20) died due to their progressive disease. Cell of origin, DHL status, or newly diagnosed vs. relapsed status did not have a significant impact on OS in patients with L-DLBCL. Conclusions: Leukemic involvement at any time during the course of DLBCL is associated with poor prognosis. It also appears to be a major risk factor for CNS relapse. It is most frequently associated with DHL and t-DLBCL. Novel therapeutic approaches at the time of initial therapy need to be developed for L-DLBCL.