Rosenthal, Allison

Abstract Objectives: Primary central nervous system lymphoma (PCNSL) is a rare aggressive B-cell lymphoma, particularly in HIV-negative individuals, that represents a clinical challenge due to its location and lack of comprehensive molecular and biologic description. Histopathologic features are that of diffuse large B-cell lymphoma with expression of pan-B-cell markers as well as cell of origin (COO) germinal center B cell (GCB) and post-germinal center B cell (non-GCB) markers. Previous studies using immunohistochemistry (IHC) suggest that the majority of PCNSL cases are non-GCB. However, gene expression profiling has revealed non-GCB to be comprised of two distinct subtypes, namely activated B-cell (ABC) and unclassified (UNC) subtypes that are indistinguishable by IHC. To date COO testing using the highly accurate Lymph2Cx gene expression profiling assay has not been reported in PCNSL. Methods: IRB approval was obtained and HIV negative patients diagnosed with PCNSL, who had given informed consent and for whom archived tumor tissue was available for testing were identified. COO testing was performed using the Lymph2Cx NanoString assay on RNA extracted from formalin-fixed, paraffin embed tissues using our established laboratory protocols. Clinical data including patient demographics, lines of treatment and survival outcomes were collected and correlated with each other and Lymph2Cx COO results. Results: Thirty-two HIV-negative patients diagnosed between January 2005 and June 2015 were included. Median age was 61 years (30-82) and 53% were male. Radiographic information was available for 18/32 patients. Eleven (61%) had a single brain lesion at diagnosis, while 7 (39%) had >1 brain lesion. Lines of systemic therapy were 1 (91%) and 2 (9%). All patients received methotrexate-based induction therapy (44% received methotrexate, rituximab and temozolomide, 16% received single-agent methotrexate, 31% received methotrexate and rituximab, and 9% received the modified Bonn regimen; methotrexate and cytarabine-based induction). A total of 10 patients (31%) received high-dose chemotherapy and autologous stem cell transplant (ASCT) for consolidation. Of the 10 patients that underwent consolidation therapy, 9 underwent ASCT after first line induction, and 1 underwent ASCT after second line therapy. None of the patients received whole-brain radiation therapy. At a median follow-up of 29 months (range of 2-107) median event-free survival (EFS) was 16.3 months (95% CI, 8.8-45.7), and median overall survival (OS) was 41.2 months (95% CI, 28.5-NE). COO testing using the Lymph2Cx assay revealed that 91% (29/32) were ABC, 9% (3/32) were GCB, and none were UNC. Histopathology reports described COO using the Hans algorithm in 11 of the 32 cases. Of the 3 determined to be GCB on Lymph2Cx, 1 was denoted GCB by the Hans algorithm and 2 were not stained to determine COO. Of the 29 determined to be ABC by Lymph2Cx, 9 were denoted non-GCB and 1 was denoted GCB by the Hans algorithm, and 19 were not stained to determine COO. Conclusions: This series of HIV-negative patients with PCNSL showed median survival consistent with previous studies. In this first series using the Lymph2Cx assay, we confirmed that over 90% of PCNSLs are of ABC subtype, which concurs with previous reports that PCNSL tumors are predominately non-GCB by the Hans algorithm. These findings provide biological rationale forthat pharmacologic interventions targeting B-cell receptor signaling to be explored in clinical trials in the majority of patients with PCNSL. Figure. Figure. Disclosures Rimsza: NanoString: Other: Inventor on the patent for the Lymph2Cx assay.

Abstract Background: Lymphoma survivors are at risk for long term and late effects which may negatively impact quality of life (QOL). Few studies have assessed the impact of change in health behaviors (physical activity (PA), alcohol and smoking) on QOL, specifically in lymphoma survivors. Methods: Patients were prospectively enrolled <9 months of diagnosis into the Lymphoma SPORE Molecular Epidemiology Resource cohort. At baseline and 3-year follow-up (FU3), patients self-reported QOL, smoking, alcohol use and PA. At FU3, survivors reported change in health behaviors since diagnosis. The Godin Leisure Score Index (LSI) was calculated as a measure of PA (Pophali et al. ASH 2017); modeled by tertile. QOL was measured via FACT-G; the total and sub-scales [emotional (EWB), functional (FWB), physical (PWB), and social/family well-being (SFWB)] scores were transformed to a 0-100 scale. Patients who completed <80% of QOL questions were excluded. The association of QOL with health behaviors was evaluated using Kruskal-Wallis test (categorical) and Spearman's rank correlation (continuous). Results: At baseline, 2805 participants were evaluable for QOL of which 2025 were evaluable at FU3. The median age at diagnosis was 62 (IQR 52-69) years. Majority were males (N=1148, 56.8%), with advanced stage III-IV disease (N=941, 62%) and ECOG performance status <2 (N=1935, 96%). At baseline, smoking status was current (N=237), former (N=802), never (N=1310) or not available (NA, N= 456). Current smokers had a significantly lower median QOL scores compared to former and never smokers for EWB (75 vs 79 vs 79, p<0.01), FWB (71 vs 79 vs 79, p<0.01), PWB (86 vs 89 vs 89, p=0.02), SFWB (86 vs 90 vs 89, p=0.02) and total FACT-G (67 vs 82 vs 82, p<0.01). The median number of pack years smoked among current &former smokers was 15.6 (range 0.5-126). There was a significant negative correlation of pack years smoked with FWB (p=0.05), and total FACT-G (p=0.04). At FU3, current smokers had significantly lower median scores compared to former and never smokers for FWB (80 vs 86 vs 86, p=0.01), PWB (89 vs 93 vs 93, p<0.01) and total FACT-G (82 vs 86 vs 87, p<0.01). EWB (83 vs 88 vs 88, p=0.12) and SFWB (83 vs 86 vs 86, p=0.12) were also lower than never and former smokers but not statistically significant. Smoking status was decreased (N=30), increased (N=0) and unchanged (N=1439) at FU3. There was no association of change in smoking with change in QOL. At baseline, alcohol use status was current (N=1189), former (N=506), never (N=518) and NA (N=592). Current alcohol users had the highest FWB (79 vs 75 vs 75, p<0.01) vs former and never users. Former users vs current and never users had the lowest PWB (86 vs 89 vs 89, p<0.01), SFWB (88 vs 89 vs 92, p<0.01) and total FACT-G (80 vs 83 vs 82, p<0.01). EWB was similar in all 3 groups. Among current & former alcohol users, the average number of drinks/week was 3.4. There was no association of the number of drinks/week with QOL except positive correlation with PWB (p=0.01). At FU3, alcohol use was reported as increased (N=40), decreased (N=312) and no change (N=875). There was no association between change in alcohol use and change in QOL. At baseline, participants with PA in the high vs low LSI tertile had significantly better median scores for FWB (79 vs 75, p=0.01), SFWB (93 vs 89, p<0.01) and total FACT-G (83 vs 82, p<0.01). At FU3, participants in the high vs low LSI tertile had significantly better scores on all subscales and total FACT-G with a significant positive correlation between the continuous LSI and QOL (FACT-G total and subscales). PA was reported as increased (N=107), decreased (N=394) and no change (N=495). There was a significant association of increase in PA with change in PWB (p<0.01), EWB (p=0.01), FWB (p<0.01) and total FACT-G (p<0.01) from baseline to FU3, but not with change in SFWB (p=0.06). In a sensitivity analysis, QOL was modeled for health behaviors in the subset of patients with QOL assessed prior to treatment; results were consistent with the QOL in all patients. Conclusions: Health behaviors in lymphoma survivors are significantly associated with QOL: better QOL is associated with not smoking, more PA, and moderate alcohol use. Current alcohol consumption, as opposed to former alcohol use, may be related to overall health status. An increase in PA after lymphoma diagnosis is associated with an increase in the QOL. Thus, modification of health behaviors has the potential to impact QOL in lymphoma survivors. Figure. Figure. Disclosures Cerhan: Celgene: Research Funding; Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board.

Abstract Background: In Phase II trials, carfilzomib (Cfz) was associated with dyspnea (34%), hypertension (14%), renal insufficiency (24%), and peripheral edema (24%) with cardiac events reported in 7% of patients (pts). In order to better understand these toxicities, we prospectively instituted detailed cardiac evaluation in 62 Cfz treated multiple myeloma (MM) pts. Methods: Pts received Cfz between 8/11-5/14. Parameters recorded included Cfz dose, concurrent chemotherapy, hydration, blood pressure, day 1 and 2 creatinine, troponin and NT-proBNP, baseline and cycle 4 echocardiograms with EF, strain and compliance. Notable cardiac events were examined for attribution. Results: Median age was 65 years, with 60% male. 20 pts had no prior therapies, 42 were relapsed; mean 4 prior therapies (range 1-10). 20 received induction chemotherapy (Cfz, dex, thalidomide, cyclophosphamide). At relapse, Cfz was given alone in 21 pts, with added cyclophosphamide in 10, and with an IMiD in 10. Cfz dose was 20mg/m2 days 1,2 and ranged from 27-45mg/m2in subsequent treatment days. Dex was given at 20-40mg weekly in 77% pts. Hydration (250-500ml) was delivered in 89% of patients pre and 63% post treatment. Baseline hypertension (>140mmHg) was present in 20% of pts and rose ≥10mmHg in 26% on day 2, but dropped ≥10mmHg in 36%. On day 8, more pts (32%) had hypertension pre-treatment. Baseline creatinine was elevated in 25% pts. 7 of 55 (13%) pts had a creatinine rise (≥0.3 mg/dL) on day 2, 5 of whom had elevation at baseline. Thus, with normal baseline creatinine and pre-treatment hydration 2/45 (4%) pts had a creatinine rise. Troponin levels on day 1 were normal in all 16 tested patients. 2/25 pts had an elevated troponin on day 2, one with associated MI on day 4. In these 2 pts, symptomatic pre-existing ischemic heart disease and severe cardiac amyloid were confounding factors. Mean baseline NT-proBNP (n=22) was elevated at 565 pg/mL (range <50-3666; normal <77) with normal baseline values in only 41%. On day 2 (n=25), the mean was significantly higher at 1580 pg/mL. Between day 1 and 2, 72% of pts had a rise ≥50 pg/mL; mean change 1387 (range 0 to +6187). On day 2, 52% had a NT-proBNP ≥500 pg/mL, while 36% were ≥1000 pg/mL. 30 pts had baseline and post-C4 treatment echocardiograms, all with normal pre-treatment EFs. Three pts (10%) developed impaired systolic function (EF<50%), however, 2 had plausible concurrent alternative etiologies (VTE/PE, hospitalized multilobar pneumonia) while one patient (during C2) had an asymptomatic unexplained decline in EF (56 to 42%) detected pre-op while hospitalized for hip fracture. Thus, 1/30 (3%) had an EF change in absence of concurrent acute illness. A fourth patient had normal echo at C4 but was hospitalized at C10 with severe sepsis and a diminished EF was documented. All 4 pts with low EF were pre-treated (≥2 therapies plus SCT). Changes in cardiac strain often precede an EF fall. Only 14/25 pts had normal baseline cardiac strain (≥ -18%). Post treatment strain measurement significantly improved in 4 pts and worsened in 4 pts, the latter accompanied by EF decline within the normal range in 2 pts (68/60%, 65/58%). 28 pts had E/e’ ratio (LVEDP) reviewed as a marker of ventricular compliance. 46% had abnormal ratios (≥ 15), prior to Cfz treatment. 20% of patients experienced worsening parameters post treatment, however, an equal number of pts demonstrated improvement. There was no consistent correlation with change in EF. Conclusions: MM pts frequently have baseline elevated cardiac peptides (59%) and abnormal cardiac strain (15% of newly diagnosed and 36% at relapse). A frequent, and sometimes dramatic, rise in the NT-proBNP occurs immediately following Cfz based chemotherapy. Acute structural cardiac events were however uncommon (3%) in the absence of confounding illness. Overall 5/62 (8%) patients had serious cardiac events during treatment with Cfz (4 EF decline, 1 MI). These toxicities were considered probably attributable to Cfz in 3/62 (5%) patients. Prospective controlled studies with longer term follow up and bortezomib treated controls are necessary to accurately document the cardiovascular impact of Cfz and the role of proteasome inhibition. Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Stewart:Celgene Novartis Array BioPharma BMS, research funding Millenium: Consultancy, Research Funding.

Abstract Introduction Non-Hodgkin lymphoma responds to single agents such as cyclophosphamide, combination therapy such as CVP and immunotherapy with monoclonal antibodies such as rituximab. There is no consensus on the optimal treatment for relapsed low grade or mantle cell lymphoma. Based on the success and tolerability of combining alkylating agents with proteasome inhibitors in multiple myeloma, a phase II clinical trial of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBor-D) was designed to explore the efficacy and safety of this combination in relapsed low grade and mantle cell lymphoma (MCL). Methods This trial enrolled relapsed patients at Mayo Clinic from October 2008 to March 2014. Eligibility required age≥18; biopsy proven follicular grades 1 or 2 lymphoma (FL), MCL, small lymphocytic lymphoma/chronic lymphocytic leukemia, marginal zone B-cell lymphoma, or Waldenström’s macroglobulinemia (WM); life expectancy >3 months; ECOG PS 0, 1 or 2; measurable disease; Hb ≥8g/dl, ANC ≥1200/uL, platelet ≥75,000/uL, creatinine ≤1.5xULN, total bilirubin ≤1.5xULN, alkaline phosphatase ≤3xULN, AST ≤3xULN; and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Treatment included rituximab 375 mg/m2 IV on day 1 and oral cyclophosphamide 300 mg/m2, IV bortezomib 1.3 mg/m2, and oral dexamethasone 40 mg on days 1, 8, 15, and 22 in a 28-day cycle. Treatment was continued two cycles beyond best response or a maximum of 12 cycles. Allopurinol 300 mg on days 0-14 for the first cycle was strongly recommended. Results 21 patients were enrolled prior to study closure due to slow accrual. Bortezomib was initially given on days 1, 4, 8, and 11 in the first 16 patients, but was subsequently modified to days 1, 8, 15, and 22 due to significant peripheral neuropathy (PN). Median age was 69 years (range 51-80) and 13 (62%) were male. 62% had stage IV disease and 17 (81%) had 2 or more prior treatments with 3 (14%) having prior autologous stem cell transplantation. Histologies included FL-I (n=6), FL-II (n=2), MCL (n=8), and WM (n=5). Patients completed a median of 4 cycles of treatment (range 1-12), discontinuing due to 9 (43%) completion per protocol, 4 (19%) progression, 5 (24%) adverse events, 1 (5%) patient refusal, and 2 (10%) other reasons. Median follow-up is 32.8 months (0.9-54.8). CR or PR as best response was observed in 13 (62%, 95% CI 38-82%; 4 CR [19%], 9 PR [43%]) patients. By histology, CR or PR was observed in 7 (88%) FL patients (4 CR, 3 PR); 2 (25%) MCL patients (both PR), and 4 (80%) WM patients (all PR). CR or PR was observed in 10/16 (62%; 4 CR, 6 PR) before and 3/5 (60%; all PR) after the change in bortezomib schedule. Among 13 patients with CR or PR, median duration of response was 25.9 months (95% CI 8.0-not reached). Median PFS and OS were 11.6 months (95% CI 3.8-not reached) and 54.8 months (95% CI 24.6-54.8), respectively. At least one Gr≥3 adverse event at least possible related was observed in 14 (67%) patients, the most common being leucopenia (7, 33%), neutropenia (7, 33%), thrombocytopenia (6, 29%), anemia (5, 24%), PN (5, 24%), and fatigue (3, 14%). Peripheral sensory neuropathy at least possibly related was Gr1, Gr2, and Gr3 in 5 (24%) patients each, with a lower rate observed for patients after the change in bortezomib schedule (before 13/16 [81%] Gr≥1, after 2/5 [40%] Gr≥1). Among 14 patients who completed a baseline and at least one post-baseline FACT/GOG-NTX additional concerns questionnaire, 10 (71%) reported clinically meaningful (≥3-point) worsening in patient-reported neurotoxicity (8/11 [73%] before and 2/3 [67%] after the change in bortezomib schedule). Conclusions Our results suggest R-CyBor-D is a safe and effective combination in patients with relapsed low grade and mantle cell lymphomas. High response rates were seen in FL and WM. The majority of significant AE’s were hematologic. However, sensory neuropathy was common with twice weekly dosing of bortezomib and lessened with weekly dosing. Determination of optimal treatment regimens in this population remains an unmet need. Additional clinical trials including larger patient numbers are necessary to confirm these observations. This trial was sponsored by Millennium Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Tiedemann:Janssen: Honoraria. Reeder:Millennium, Celgene, Novartis: Research Funding.

Abstract The growing body of genomic information collected and applied to mature aggressive B-cell lymphoma diagnosis and management has exploded over the last few years due to improved technologies with high-throughput capacity, suitable for use on routine formalin-fixed, paraffin-embedded tissue biopsies, and decreasing costs. These techniques have made evaluation of complete DNA sequences, RNA-expression patterns, translocations, copy-number alterations, loss of heterozygosity, and DNA-methylation patterns possible on a genome-wide level. This chapter will present a case of aggressive B-cell lymphoma and discuss the most important genomic abnormalities that characterize this group of entities in the recent update to the fourth edition of the World Health Organization (WHO) lymphoma classification system. Genomic abnormalities discussed will include those necessary for certain diagnoses such as translocations of MYC, BCL2, or BCL6; gene-expression-profiling categorization; the newly defined Burkitt-like lymphoma with 11q abnormalities; prognostic and predictive mutations, as well as tumor heterogeneity. Finally, our current practices for clinical triage of specimens with a potential diagnosis of aggressive B-cell lymphomas are also described. Options for treatment at relapse, in light of these genomic features, will be discussed in the third presentation from this session.

AbstractThe impact of physical activity (PA) on lymphoma survival is not known. The association of PA and change in PA with overall (OS), lymphoma‐specific (LSS) and event‐free (EFS) survival was evaluated in a prospective cohort of newly diagnosed lymphoma patients (2002‐2012). We calculated Leisure Score Indexes (mLSI) from the self‐reported usual adult PA (baseline) and at 3‐years post‐diagnosis (FU3), grouping patients by active vs insufficiently active by the American Cancer Society PA guidelines. Associations of PA with survival were assessed using hazard ratios (HRs) and 95% confidence intervals (CI) from Cox models stratified by lymphoma subtype, adjusted for age, sex, baseline BMI, and comorbidity score with change scores further adjusted for baseline PA. Three thousand sixty participants were evaluable at baseline and 1371 at FU3. Active patients had superior survival from baseline [HR (CI): OS 0.82 (0.72‐0.94); LSS 0.74 (0.61‐0.90); EFS 0.92 (0.82‐1.02)] and FU3 [HR (CI): OS 0.64 (0.46‐0.88); LSS 0.32 (0.18‐0.59); EFS 0.82 (0.61‐1.10)] compared to insufficiently active. An increase in mLSI from baseline to FU3 (vs stable mLSI) was associated with superior OS (HR = 0.70, CI 0.49‐1.00) and LSS (HR = 0.49, CI 0.26‐0.94).The continuous change in mLSI at FU3 was significantly associated with OS, LSS and EFS; maintained across subgroups and appeared linear. Higher PA among lymphoma patients at diagnosis and 3 years is significantly associated with OS, LSS, and EFS. Increasing PA after diagnosis is significantly associated with improved OS and LSS supporting an important role for PA in lymphoma survivorship and the need for intervention trials.