Jiang, Liuyan

Abstract Background: trALL is an important secondary primary malignancy (SPM) that has recently been appreciated. While patients (pts) with MM have an 8%-17% risk of developing an SPM while on lenalidomide (R) maintenance following autologous stem cell transplant (ASCT), trALL has been rarely observed. Little is known about the characteristics of trALL in pts with MM compared to pts who had other malignancies prior to the development of trALL. We define tALL as any prior exposure to cytotoxic chemotherapy and/or radiation for another malignancy, and herein, we report a comparative analysis of characteristics and outcomes of pts with trALL with and without MM from the Mayo Clinic Cancer Center (MCCC). Methods: We performed a systematic search in the 3-site MCCC registry and included all pts diagnosed and received at least 1 cycle of ALL-directed therapy and/or underwent allogeneic transplantation (AlloHCT) for ALL between 2007-2020. All cases of trALL in this series are B-ALL. Comparisons of characteristics between trALL patients with and without MM were made using a Wilcoxon rank sum test (continuous variables) or Fisher's exact test (categorical variables). Time-to-event variables were compared using unadjusted Cox proportional hazards regression models. Results: 70 trALL pts (14 MM [20%], 56 non-MM [80%]) were identified during the study period. The median age at trALL diagnosis was 63.9 (range 47-71) for MM pts and 63.1 (range 18.2-84) for non-MM pts. Median follow-up from trALL diagnosis was 1.42 years (range 0.02-10.6 years). The most common prior non-MM malignancies among tALL pts were breast (28.6%), lymphoma (17.9%), myeloid (17.9%), and GU/GYN (14.3%). Amongst the 14 MM pts, 100% (n=10) had ISS-I disease, 8 (57%) had IgG K MM, 1 (n=10) had high risk cytogenetics, 8 (57.1%) received R-based induction , 4 (28.6%) received CyBorD induction, 4(28.6%) received VRD induction, 3 (21.4%) received RD induction. 10 (71.4%) pts were actively on R when they developed trALL, 8 (57.1%) pts received prior ASCT. The median time to develop trALL following ASCT for MM was 46.3 months (m), (95% CI 20.4-67.6), 12 (85.7%) pts received R maintenance with a median duration of 53m (95% CI 16.9-121). The median time to develop trALL after initiation of R maintenance was 61.2m (95% CI 16.9-123.4). The most common trALL induction regimen received was HyperCVAD which was used in 71.4% of MM pts and 51.8% of non-MM pts. In comparison to non-MM pts, MM patients had a significantly lower WBC at diagnosis (Median: 2.0 vs. 5.8, P=0.005),no t(9;22) BCR/ABL1 cytogenetics (0.0% vs. 35.7%, P=0.008), a higher frequency of hypodiploid/near-triploid (Ho-Tri) cytogenetics (42.9% vs. 12.5%, P=0.009), and a lower frequency of prior radiation therapy (7.1% vs. 44.6%, P=0.012). MM pts had a higher frequency of AlloHCT for trALL (71.4% vs. 42.9%, P=0.075) and were more commonly in complete response (CR) at transplant (100.0% vs. 70.8%, P=0.078). No trALL in MM pts were Ph-like ALL. There was a statistically significant difference in time to development of trALL between previous malignancy locations (P=0.018), with GU/GYN (Median: 9 years) having the longest time and myeloid (Median: 3 years) having the shortest time; MM was 6 years. In the overall pt cohort, 56 (80%) pts achieved a complete response after induction and 60% (n=25) were minimal residual disease (MRD)+ after induction. Pts with MM had a significantly lower likelihood of being MRD+ after induction (OR=0.09, P=0.015). Overall, 24.3% of pts relapsed after induction therapy for trALL; 39 (55.5%) died after trALL diagnosis including 43% (n=35) who died after AlloHCT. Although pts with MM tended to have better outcomes compared to non-MM trALL pts in terms of overall survival after trALL diagnosis (Figure 1A), survival after AlloHCT (Figure 1B), relapse rate after trALL diagnosis and non-relapse mortality after AlloHCT, none of these findings were statistically significant in this small cohort (Figure 1C). Conclusion: trALL is a unique SPM that can occur in pts with MM. It is associated with Ho-Tri cytogenetics and is BCR/ABL1 negative. The majority of MM pts that developed trALL had undergone prior ASCT and were on R maintenance when they developed trALL. Despite being more likely to have adverse cytogenetics features, MM-associated trALL has similar survival compared to non-MM-associated trALL which speaks to the poor survival outcomes of this SPM. Further research on trALL in MM pts is merited. Figure 1 Figure 1. Disclosures Litzow: Amgen: Research Funding; Pluristem: Research Funding; AbbVie: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee. Bergsagel: Janssen: Consultancy. Fonseca: Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; Bayer: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; BMS: Consultancy; Mayo Clinic in Arizona: Current Employment; Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Novartis: Consultancy; Merck: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Murthy: CRISPR Therapeutics: Research Funding. Ailawadhi: GSK: Consultancy, Research Funding; Sanofi: Consultancy; Pharmacyclics: Consultancy, Research Funding; Takeda: Consultancy; Medimmune: Research Funding; Xencor: Research Funding; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectar: Research Funding; Beigene: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Ascentage: Research Funding. Foran: actinium: Research Funding; taiho: Honoraria; bms: Honoraria; servier: Honoraria; pfizer: Honoraria; novartis: Honoraria; OncLive: Honoraria; abbvie: Research Funding; boehringer ingelheim: Research Funding; takeda: Research Funding; trillium: Research Funding; aptose: Research Funding; revolution medicine: Honoraria; syros: Honoraria; sanofi aventis: Honoraria; certara: Honoraria; gamida: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

Abstract TMB is used to guide PD-1-directed immunotherapy in solid tumor Oncology. However, it has not been systematically studied in AML, where the focus has been on cytogenetic risk and individual driver gene mutations (GM's). TMB contribution to AML epidemiology is also uncertain. We therefore studied its association with epidemiologic risk factors; driver GM's and somatic mutations (SM's) in AML risk genes which we recently demonstrated (ABCB1; CYP1A1; CYP2B6; EPHX1; ERCC1,2,& 5; MEFV; MTRR; and TERT); clinical and cytogenetic features; and outcome after therapy in the MCAEC, a highly annotated clinical epidemiology cohort of consecutive AML pts [Finn, Cancer Epidemiol 39:1084, 2015]. Methods: We obtained somatic leukemia DNA from remnant diagnostic cytogenetic pellets in 98 MCAEC patients (pts), as previously described [Foran, Blood (2017) 130:570a]. Whole exome sequencing (WES) was performed at depth of ~100 million paired end 100bp reads using Agilent SureSelectXT Human All Exon V5 + UTRs target enrichment kit. Reads were mapped to human genome build hg19 using BWA-MEM. Single nucleotide variants (SNVs) and small INDELs were identified using Mayo Clinic (MC) analytic pipeline GenomeGPS 4.0.1 following Broad GATK variant discovery best practices of alignment, realignment and recalibration, and multi-sample joint genotyping; and filtered using both germline whole exome and genome sequencing of ~1200 MC Biobank samples and public germline variant databases of 1000 genome project, 6500 individuals in exome sequencing project, and HapMap phase 3. Remaining variants were annotated using ANNOVAR, and functional variants of non-synonymous, truncating, frame-shift, and splice-sites were used in the statistical association analyses. TMB was defined as the number of functional mutations per Mb of coding region, heterozygous or homozygous. TMB associations with epidemiologic risk, clinical characteristics, and SM's in AML risk genes (listed above) or driver GM's (occurring in 5 or more pts: ASXL1, BCOR, CEBPA, DNMT3A, FLT3, IDH2, KRAS, MLL2-5, NF1, NPM1, NRAS, PHF6, RUNX1, SF3B1, STAG2, TET2, TP53, U2AF1) were evaluated using linear regression models; a rank transformation of TMB was utilized due to its skewed distribution. Multivariable analysis (MVA) models were adjusted for variables with p-value <0.05 in unadjusted analysis. Regression coefficients ("β") were estimated, interpreted as change in mean TMB rank for specified variables or characteristic. Associations with outcomes were examined using logistic regression or Cox proportional hazards regression models. All statistical tests were two-sided (version 3.6.2; R Foundation for Statistical Computing, Vienna, Austria). Results Median age at AML diagnosis was 70 yrs (Range: 19-94 yrs), and 67 pts were male. Cytogenetic risk group was favorable (7%), intermediate-normal (46%) or abnormal (20%), and poor risk (27%). 40/61 pts (66%) achieved complete remission (CR). With a median follow-up of 8.0 months (Range: 0.1 - 186), 80 pts (82%) died and 20 (20%) underwent allogeneic transplantation (AlloBMT). Median TMB was 18.2 (Range: 15.0-70.1). In MVA, significant associations with increased TMB were observed in pts with history of prior immunosuppressive therapy or solid organ transplantation (β=19.48, P=0.015), and with FLT3 (β=21.12, P=0.015), MLL2 (β=20.91, P=0.001), and MLL3 (β=11.31, P=0.031) GM's. A borderline association was observed for U2AF1 (β=16.14, P=0.057). TMB was also associated with SM's in TERT (β=25.13, P=0.028); a borderline association with SM's in ABCB1 was not confirmed in MVA (β=-17.98, P=0.069). Additionally, cytogenetic risk group was associated with TMB in MVA (P=0.005), being highest in intermediate-normal and lowest in poor risk groups. Body Mass Index was inversely associated with TMB (unadjusted β=-16.99, P=0.005), but unconfirmed in MVA (β=-8.29, P=0.12). There was no association with CR (OR=0.93, P=0.46), use of (HR=0.96, P=0.64) or relapse risk (HR=1.00, P=0.98) following AlloBMT, or survival (HR=0.97, P=0.56) (Figure). Conclusions Measurement of TMB is feasible in this AML epidemiologic cohort, and we observed important associations with AML risk factors, risk gene SM's, cytogenetic risk group, and driver GM's. We acknowledge the relatively small sample size and possibility of type II error, and therefore these observations require validation in a large prospective cohort which is planned. Figure 1 Figure 1. Disclosures Foran: OncLive: Honoraria; certara: Honoraria; actinium: Research Funding; boehringer ingelheim: Research Funding; novartis: Honoraria; abbvie: Research Funding; servier: Honoraria; taiho: Honoraria; pfizer: Honoraria; revolution medicine: Honoraria; gamida: Honoraria; takeda: Research Funding; sanofi aventis: Honoraria; trillium: Research Funding; syros: Honoraria; aptose: Research Funding; bms: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Murthy: CRISPR Therapeutics: Research Funding. Finn: Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Speakers Bureau. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Cerhan: Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Genentech: Research Funding; NanoString: Research Funding; Regeneron Genetics Center: Other: Research Collaboration.

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

Waldenström Macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is often differentiated from myeloma based on the presence of lytic bone lesions (LBL). However, WM/LPL can present with LBL and management is poorly understood. We describe a case of an 81-year-old woman with LPL who presented with LBL and was successfully treated with chemoimmunotherapy.

We report a male patient who developed eight different cancers between ages 57 and 64. BRAF p.V600E mutation was detected in Langerhans cell histiocytosis, chronic lymphocytic leukemia, histiocytic sarcoma, melanoma, and adenocarcinoma of the lung. It was not detected in multiple myeloma, basal cell carcinoma, and papillary thyroid cancer. BRAF p.V600E was not detected in normal skin tissue biopsy indicating that BRAF V600E was a somatic mutation affecting cancer cells. The presence of eight different cancers with five of them positive for BRAF p.V600E in a single patient is unprecedented. This type of BRAF p.V600E-associated poly-neoplastic syndrome has never been reported in the medical literature.

AbstractEBV‐positive HHV8‐negative EBL is part of the spectrum of EBV‐positive diffuse large B‐cell lymphoma NOS. This entity can be labeled as primary age‐related EBV‐associated EBL and appears to respond well to rituximab and thoracentesis.

AbstractIgG4‐related disease (IgG4RD) with intracranial involvement is rare. We report a 56‐year‐old male who had an excellent response to rituximab and dexamethasone after going undiagnosed for 5 years. After 3 years of rituximab maintenance, he has no evidence of disease on brain MRI.