King, Rebecca L.

Abstract Background Waldenström macroglobulinemia (WM) is a rare, indolent immunoglobulin M- associated lymphoplasmacytic lymphoma characterized by the alternation in the MYD88 locus in 90-95% of the cases. MYD88L265P is the most common alteration in WM patients and is considered a key molecular signature with a pathophysiological role in WM. Because of extremely low prevalence of WM with MYD88 wild type (WT) genotype there is a paucity of clinical and outcome data in this unique patient population. A recent study (Treon et al, Blood May, 2014), in an analysis based on the patients' MYD88 status, reported on the clinical features including older age at presentation and an unexpectedly higher mortality (38%) in the MYD88WTcohort compared to MYD88L265P patients (mortality 6%, P < .0001). However, the sample size of the MYD88WT WM cohort was small (n=15), with a few events during the short follow-up (median 4.84 years). Herein, we report on larger cohort of WM patients with this rare genotype. Methods This study included patients evaluated at Mayo Clinic, Rochester in whom the diagnosis of WM was established based on their clinicopathologic features and the MYD88 mutation status was determined through AS-PCR (assay sensitivity 1% mutant allele) performed on archived bone marrow samples obtained between 2007-2014. Patients with MYD88WT status were the focus of this study. Clinical data were collected from the patients' medical records. The Kaplan-Meir method was utilized for the survival analysis calculated from the time of diagnosis of WM. Outcomes of MYD88WT patients were compared with those harboring the MYD88L265Pmutation. Results Our cohort of 171 patients with an established diagnosis of WM and known MYD88 mutation status was found to be enriched for MYD88WT (n=40) patients. All patients required therapy. At diagnosis, the median age of the patients with MYD88 WT was 63 years (range 37.5-83.5 years; comparable to that of the MYD88L265P cohort, median 65 years, range: 32-92 years, p=0.16). Familial WM was identified in 10% of patients. Sixty four percent of patients presented with constitutional symptoms at diagnosis. These symptoms included fatigue (45%), weight loss (17%), night sweats (8%) dizziness (10%), dyspnea (23%), bleeding (10%), headache (10%) and hyper viscosity syndrome (5%). Splenomegaly and lymphadenopathy was observed in 20% and 27% of patients, respectively. Thirteen percent of patients had concomitant AL amyloidosis. Additional baseline characteristics are reported in Table 1. Transformation to a higher grade lymphoma was noted in 9 (23%) of patients, four of whom had received a purine analog and /or chlorambucil previously. The estimated median follow of MYD88WT patients was 8.1years (95% CI: 6.4-8.9) and their median overall survival (OS) was 8.5 years (95% CI: 6.4-29.4). No OS difference was evident between this cohort and the remainder of the patients with the MYD88L265Pmutation (n=131, median OS 11.7 years, 95% CI: 10-18, p=0.7; median follow-up 7.7 years 95% CI: 6.4-9.1, Figure 1). Conclusion In this relatively large cohort of WM MYD88WT patients with a prolonged follow-up, the MYD88mutation status was not found to be a determinant of patients' outcomes. Our findings contradict the results of a seminal previous study and require external validation, preferably through prospective studies. Disclosures Kapoor: Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Millennium: Consultancy, Research Funding; AbbVie: Research Funding; Kesios: Consultancy.

Abstract Background WM remains an incurable cancer despite recent advances. While a phase II trial has demonstrated efficacy of dexamethasone, rituximab and cyclophosphamide (DRC) in the treatment-naïve (TN) patients, this regimen has not been studied systematically in the relapsed/refractory (R/R) setting. Recent data has suggested the MYD88mutation status in WM patients can serve as a predictive marker with therapies such as ibrutinib. We examined the efficacy and tolerability of up to 6 cycles of DRC, with focus on R/R population and activity of this regimen with respect to the patients' MYD88L265Pstatus. Methods Records of WM patients seen consecutively at Mayo Clinic campuses in Rochester, Arizona and Florida from 01/2007 to 12/2014 were reviewed. MYD88L265P status, as assessed by AS-PCR, was recorded when available. Data obtained from symptomatic patients treated with DRC (dexamethasone 20 mg intravenously followed by rituximab 375 mg/m2 intravenously on day 1 and cyclophosphamide 100 mg/m2 orally bid on days 1 to 5) were analyzed. Time-to-event analyses were performed from DRC therapy using the Kaplan-Meier method. We used the Consensus response criteria (6th International Workshop). Results Of 100 symptomatic patients who received DRC, 50 had R/R WM (40% refractory) and 50 were TN. Table 1 shows the patients' baseline characteristics. In the R/R population, DRC was 2nd line (range 2-8) therapy in 58% of patients. The median IgM levels declined from 3,870 mg/dL to 1,846 mg/dL (p=0.0001) at best response. Median follow-up from DRC was 51 months (95% CI: 38-55). The median time-to-best response was 6.8 (0.5-28) months. Overall response rate (ORR) was 87% [VGPR 4%, PR 64%, MR 19%]. Four patients (9%) achieved SD and 2 patients (4%) had PD. Of the sixteen deaths (32%) noted at time of analysis, 11 were related to progressive disease. The median disease-specific survival (DSS) from DRC was not reached (NR) (95% CI: NR-NR). The median progression-free survival (PFS) and time-to-next-therapy (TTNT) were 32 months (95% CI: 15-51) and 50 months (95% CI: 35-60), respectively. In contrast, in the TN patients the median IgM levels declined from 4,130 mg/dL to 1,250 mg/dL (p=0.0001) at best response; median time to best response was 11 (0.6-47) months; median follow-up from DRC was 30 months (95% CI: 21-36). ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. Of the 7 deaths (14%) at time of analysis, 4 were related to WM progression. Median DSS from DRC was NR (95% CI: NR-NR); median PFS and TTNT were 34 months (95% CI: 23-NR) and NR (95% CI: 37-NR), respectively. Among 29 genotyped patients in whom MYD88 mutation status was available, MYD88L265P was present in 25 patients (8 of 10 TN and 17 of 19 R/R patients). The response rates and the time-to-event outcomes were similar in the MYD88L265P and wild-type patients. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Conclusions Similar to the frontline setting, DRC is an active and well-tolerated salvage regimen. In contrast to ibrutinib, DRC offers a less expensive, limited-duration treatment option, with preliminary data suggesting activity independent of patients' MYD88 mutation status. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Kumar:Glycomimetics: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Kesios: Consultancy; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Celgene: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding.

Abstract Background: We previously reported that Lenalidomide combined with R-CHOP (R2CHOP) has significant activity in non-GCB (non-germinal center B-cell) subtype of DLBCL as defined by immunohistochemistry (IHC) using Hans algorithm (J Clin Oncol. 2015 Jan 20;33(3):251-7). However, defining non-GCB subtype of DLBCL by IHC as opposed to the "gold standard" gene expression profiling (GEP) is subject to technical limitations and its prognostic value has not reproduced in some recently published studies. In addition, recent reports questioned prognostic value of GEP in prospective clinical trials as opposed to initial reports from retrospective case series. To address these concerns, we assessed outcomes by cell of origin (COO) as determined via GEP using NanoString Lymphoma Subtyping Test (LST) on formalin-fixed paraffin-embedded (FFPE) tissue on patients enrolled in a phase 2 study of R2CHOP and an independent comparison cohort of patients treated with RCHOP alone. Methods: Eligible patients for R2CHOP phase 2 study MC078E were adults with newly diagnosed, untreated, stages II-IV CD20 positive DLBCL. Patients received oral lenalidomide 25 mg days 1-10 with standard dose R-CHOP every 21 days for 6 cycles. All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis. DLBCL molecular subtype was determined by GEP using NanoString LST, a multiplexed digital gene expression assay performed on the nCounter® Dx Analysis System and reported as GCB vs ABC vs unclassified. A comparison cohort of RCHOP treated DLBCL patients was generated from the prospectively enrolled Mayo Clinic component of the Lymphoma SPORE Molecular Epidemiology Resource (MER). MER patients meeting the same inclusion criteria as MC078E with available tissue were selected based via matching on age, stage, and IPI to the MC078E patients. Event-free survival was defined as time from diagnosis (MER) or study registration (MC078E) to progression, re-treatment, or death. EFS24 was defined as being event-free at 24 months. Associations between COO and outcome were assessed via log-rank tests due to censoring for EFS24. Results: 50 MC078E R2CHOP patients enrolled between 2008 and 2013,124 matched MER RCHOP patients diagnosed between 2003 and 2012 were assessed for COO. Median follow up in 70 patients still alive was 7.9 years (1.9-13.0) in RCHOP treated patients and 4.4 years (1.9-5.5) for 24 in R2CHOP treated patients still alive. Median age was 65 years (range 35-89) in RCHOP treated patients and 69 years (22-87) in R2CHOP patients (p=0.485). 53 RCHOP treated patients (43%) and 31 R2CHOP treated patients (62%) had intermediate-high or high IPI (p=0.021). COO was GCB, ABC, and unclassified DLBCL subtype in 80, 31 and 13 patients in the 124 RCHOP cohort and 33, 13 and 4 patients in the R2CHOP treated patients, respectively (see table). EFS24 was inferior for ABC (48%) compared to GCB DLBCL 71% in MER RCHOP treated patients (p=0.013). In contrast, in R2CHOP treated pts, EFS24 was not different between ABC vs GCB DLBCL 69% vs 67% (p= 0.674). Conclusion: Cell of origin classification of DLBCL determined by NanoString LST remains prognostic in a series of prospectively enrolled DLBCL patients treated with RCHOP. R2CHOP shows promising efficacy in ABC DLBCL as defined by NanoString LST, where the addition of lenalidomide to RCHOP appears to mitigate the negative impact of an ABC molecular subtype on the outcome. Table Table. Disclosures Nowakowski: Morphosys: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Research Funding. Maurer:Kite Pharma: Research Funding; Celgene: Research Funding. Storhoff:NanoString Technologies, Inc.: Employment, Other: Stock option. Dennis:NanoString Technologies, Inc.: Employment, Other: Stock option. Gandhi:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership. Hagner:Celgene Corporation: Employment, Equity Ownership. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL..

Abstract Background Bendamustine/rituximab (BR) and dexamethasone/rituximab/cyclophosphamide (DRC) combination therapy are acceptable options for the treatment of WM, both in the frontline or salvage setting. Prospective data, however, are only available in treatment-naïve (TN) WM patients, and no direct comparison between BR and DRC has been reported. We compared outcomes of BR and DRC in relapsed/refractory (R/R) and TN WM patients seen at a single institution. Methods Records of WM patients seen consecutively at Mayo Clinic from 01/2007 to 12/2014 were reviewed. The MYD88L265P status, as assessed by AS-PCR, was recorded when available. The data obtained from symptomatic patients treated with DRC or BR were analyzed. The time-to-event analyses were performed from DRC or BR therapy using the Kaplan-Meier method. We used the Consensus criteria (6th International Workshop) for response assessment. Results Of 160 WM patients, 60 patients received BR (73% in R/R setting) and 100 patients received DRC (50% in R/R setting). In the R/R population, BR was the 2nd line (range 2-11) therapy in 47% of patients, while DRC was 2nd line (range 2-8) in 58% of patients. Rituximab monotherapy was the only prior line of therapy in 8 (20%) patients in the BR group and 20 (40%) in the DRC group (p=0.66). Baseline characteristics were similar in patients treated with BR or DRC (Table 1). Six patients received both BR and DRC during their disease course and overlapped between the 2 cohorts. Among the previous untreated patients, the median IgM levels decreased from 3,785 mg/dL to 724 mg/dL (p=0.0001) at best response with BR, while it decreased from 4,130 mg/dL to 1,250 mg/dL (p=0.001) with DRC. The median time to best response was 6.1 (1-25) months in the BR group and 11 (0.5-47) months in the DRC group (p=0.13). For patients treated with BR, the overall response rate (ORR) was 93% [VGPR 29% (n=4), PR 57% (n=8), MR 7% (n=1)]. One patient (7%) had progressive disease. For patients treated with DRC, ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. One patient (4%) achieved SD. Median follow up in the BR and DRC groups were similar (30 months). The 2-year progression-free survival (PFS) was 88% and 61% in the BR and DRC groups, respectively (p=0.08). The 2-year time-to-next therapy (TTNT) was 88% and 76% in the BR and DRC groups, respectively (p=0.35). Median PFS, TTNT and disease specific survival (DSS) were not reached with either regimen. In the R/R setting, the median IgM levels decreased from 3,880 mg/dL to 659 mg/dL (p=0.0001) at best response with BR, and from 3,870 mg/dL to 1,846 mg/dL (p=0.001) with DRC. The median time to best response was similar [7 (1-39) months with BR and 7 (0.5-28) months with DRC (p=0.77)]. For patients treated with BR, ORR was 95% [CR 3% (n=1), VGPR 38% (n=14), PR 41% (n=15), MR 13% (n=5)]. Two patients (5%) had progressive disease. With DRC, the ORR was 87% [VGPR 4% (n=2), PR 64% (n=30), MR 19% (n=9)]. Four patients (9%) achieved SD and 2 patients (4%) had progressive disease. Median follow up from BR was 32 months and 51 months from DRC (p=0.24). The 2-year PFS was 66% and 53% in the BR and DRC groups, respectively (p=0.08). The 2-year TTNT was 75% and 68% in the BR and DRC groups, respectively (p=0.24). The median DSS in the BR group was 69 months (95% CI: 65-69) and NR (95% CI: NR-NR) in the DRC group (p=0.57). The proportion of patients with R/R disease was significantly higher in the BR cohort (Table 1). In a bivariate analysis of the entire cohort for PFS, incorporating the setting (TN vs. RR) and the regimen involved (BR vs. DRC), the latter emerged as a significant factor (hazard ratio 0.52, p=0.019) in favor of BR. Time-to-event outcomes and response rates were similar in the MYD88L265P and MYD88WT patients. Grade ≥ 3 adverse events were neutropenia (12%), infections (7%) and nausea/vomiting (2%) with BR, and neutropenia (20%), thrombocytopenia (7%) and infections (3%) with DRC. Conclusions Although both DRC and BR regimens show activity and comparable toxicities, BR regimen shows a trend for superior PFS in WM patients, both in the TN and R/R setting. No difference was seen in TTNT. MYD88 L265P mutation status does not appear to impact activity of BR or DRC. Randomized controlled trial(s) are needed to confirm our findings. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Reeder:Millennium: Research Funding; BMS: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Glycomimetics: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

Abstract INTRODUCTION: Among patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the indications for liver biopsy are not known. Additionally, the histopathologic findings of CLL infiltration in the liver along with its clinical implications have not been thoroughly described in the literature. METHODS: We identified all pts with a diagnosis of CLL/SLL from the CLL Clinical Database at Mayo Clinic, Rochester, MN who underwent a liver biopsy. We also cross referenced the Mayo Clinic Hematopathology Database for all pts who underwent a liver biopsy. The indications for biopsy, description of the pathologic findings in the liver biopsy, CLL therapy and outcomes were abstracted from the clinical records. Retrospective pathology review was performed on cases with CLL involvement in which slides were available for review. RESULTS: Fifty-two CLL/SLL pts who underwent a liver biopsy were identified. The indications for liver biopsy were as follows: liver lesion identified on radiographic imaging in 21 (41%) pts, abnormal liver function tests (LFTs) in 17 (33%) pts, hepatosplenomegaly in 11 (21%) pts, and unknown in 3 (6%) pts. Among all 52 pts, there was concern for Richter transformation at time of biopsy in 7 (13%) pts. Types of biopsy were as follows: percutaneous in 20 (39%) pts, intraoperative in 17 (33%) pts, transjugular in 3 (6%) pts, and unknown in 12 (23%) pts. CLL/SLL involvement was identified in 38/52 (73%) pts undergoing liver biopsy. Among these, the diagnosis of CLL/SLL was made on liver biopsy in 8 pts, and 7 pts had additional findings on their liver biopsy including metastatic colon cancer (n=3), hemochromatosis (n=2), steatohepatitis (n=1), and cirrhosis (n=1). Liver biopsy revealed Richter transformation in 4 (8%) pts (3 pts with diffuse large B cell lymphoma (DLBCL) and 1 patient with Hodgkin lymphoma), other malignancy in the absence of CLL in 7 (15%) pts (2 metastatic colorectal, 2 metastatic esophageal, 1 hepatocellular carcinoma, 1 metastatic lung, and 1 neuroendocrine), and 1 patient with steatohepatitis. Two (4%) pts had normal findings on liver biopsy. Among the 38 pts with liver involvement by CLL, 27 had slides available for retrospective pathology review. CLL involvement ranged from 2-100% of the liver parenchyma. Seven pts (26%) underwent excisional biopsies or resections and 20 (74%) underwent core biopsies. The portal tracts were the most common region of the liver involved (22/26 pts, 85%). Of these, 8/22 (36%) pts had extension into the lobules or sinusoids, as well. Of the 4 cases without portal involvement, 2 showed extensive involvement such that it effaced the liver parenchyma in the region of involvement. One patient (4%) had a predominantly sinusoidal involvement. One patient (4%) showed small nodular infiltrates that were difficult to localize due to their size. Proliferation centers were noted in only 3 pts (11%). Most pts (29/38; 76%) whose liver biopsy demonstrated involvement by CLL did not receive immediate CLL-specific treatment. Nine of the 38 pts (24%) with CLL involvement on liver biopsy received therapy (Table): purine analog based therapy (n=4), rituximab and steroids (n=2), steroids only (n=1), alkylator and rituximab (n=1), and ibrutinib (n=1). Pts with extensive involvement of the liver by CLL were more likely to receive purine nucleoside analog based therapy compared to pts with portal infiltration by CLL (2/2 pts [100%] vs. 1/6 pts [17%]). The remaining pts were offered no therapy due to incidental finding of CLL in the liver biopsy (n=11), chemotherapy for other cancer (n=5), palliative care (n=3), or unknown (n=10). Pts with Richter's transformation received R-CHOP (n=2) and CHOP (n=1) for DLBCL, and ABVD (n=1) for Hodgkin lymphoma. Pts with other cancers without CLL received appropriate therapy for their underlying malignancy. CONCLUSION: Abnormal LFTs and radiographic abnormalities were the most common indications for a biopsy in this large cohort of CLL pts. Infiltration of the portal tracts by CLL/SLL was the most common histopathological finding. Proliferation centers were not commonly seen, which may make the diagnosis challenging for the pathologist if there is not a prior history of CLL/SLL. The mere presence of CLL/SLL infiltration did not mandate treatment and many pts were able to continue observation. Table Table. Disclosures Ding: Merck: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding. Shanafelt:GlaxoSmithkKine: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding. Parikh:Pharmacyclics: Honoraria, Research Funding.

SummaryIbrutinib‐related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment‐naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off‐study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major‐response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2–4] and 5·7 (95% CI: 4–12) months, respectively. The median follow‐up was 19 (95% CI: 14–21) months; 18‐month progression‐free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3–16·7) months, and the median duration‐of‐response was 32 (range: 23–32) months. Twenty‐five patients (31%) had discontinued therapy at last follow‐up (68% due to treatment‐related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial‐fibrillation (11%) were common non‐haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

Abstract In this month's CME article, an analysis of over 1300 patients with diffuse large B-cell lymphoma (DLBCL), Wang et al demonstrate that the approximately 13% of patients with concurrent indolent lymphoma at diagnosis had the same prognosis as those patients with isolated DLBCL.

The 2017 World Health Organization update introduced a new category of nodal peripheral T-cell lymphoma with T-follicular helper phenotype (PTCL-TFH) defined by expression of at least 2 or 3 TFH markers. Our study assesses the utility of an immunohistochemical panel of 5 TFH markers (CD10, BCL6, PD-1, CXCL13, and ICOS) for identification of TFH phenotype in angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (NOS). Immunohistochemical for the 5 markers was performed on 22 cases of AITL and 29 cases of PTCL-NOS. Cases were reviewed for morphologic features characteristic of AITL. All AITL cases showed expression of ≥2 TFH markers. This panel resulted in reclassification of 41% PTCL-NOS cases to PTCL-TFH. Positive percent agreement for the TFH phenotype is 97% for PD1, 94% for ICOS, 44% for CD10 and CXCL13, and 29% for BCL6. Negative percent agreement for TFH phenotype is 100% for CD10, BCL6, and CXCL13, 82% for ICOS and 71% for PD1. AITL cases were more likely than PTCL-TFH cases to contain expanded CD21-positive follicular dendritic cell meshworks, clear cell cytology and polymorphous inflammatory background; however, there was a significant (P<0.005) Kruskal-Wallis trend in all morphologic variables between the 3 groups suggesting a continuum from PTCL-NOS to PTCL-TFH to AITL. The median number of morphologic features of AITL also correlated significantly with number of TFH markers positive (Spearman coefficient ρ=0.759). In summary, the stain panel chosen will have an impact on cases classified as PTCL-TFH. This entity may exist along a spectrum between PTCL-NOS and AITL.

AbstractObjectivesThe 2017 Workshop of the Society for Hematopathology/European Association for Haematopathology reviewed the role of molecular genetics in the diagnosis and biology of lymphoid neoplasms.MethodsThe Workshop Panel reviewed 82 cases.ResultsMolecular genetic testing reveals alterations that expand the spectrum of diseases such as DUSP22 rearrangement in ALK-negative anaplastic large cell lymphoma, large B-cell lymphoma with IRF4 rearrangement, MYD88 mutations in B-cell lymphomas, Burkitt-like lymphoma with 11q aberrations, and diagnostic criteria for high-grade B-cell lymphomas. Therapeutic agents and natural tumor progression may be associated with transcriptional reprogramming that lead to transdifferentiation and lineage switch.ConclusionsApplication of emerging technical advances has revealed the complexity of genetic events in lymphomagenesis, progression, and acquired resistance to therapies. They also contribute to enhanced understanding of the biology of indolent vs aggressive behavior, clonal evolution, tumor progression, and transcriptional reprogramming associated with transdifferentiation events that may occur subsequent to therapy.

Background:Diffuse Large B Cell Lymphoma (DLBCL) is characterized by both biologic and genetic heterogeneity. While significant therapeutic advances have been made, nearly 30% of cases fail frontline treatment. Recent data suggest that 5–10% of DLBCL can be categorized as double/triple hit lymphoma (DH/TH), defined as having concurrent MYC, BCL2 and/or BCL6 gene rearrangements, identified by fluorescence in‐situ hybridization (FISH) probes. According to the 2017 revision of the World Health Organization classification of lymphoid neoplasms, DH/TH DLBCL is now considered a high grade B‐cell lymphoma (HGBL). While gene rearrangements represent significant genetic events in cancer, copy number alterations (CNAs) also play an important role, often through genomic amplification of oncogenes or loss of tumor suppressors. Despite their similarities, the contributions of CNAs in MYC, BCL2, and BCL6, alone, or in combination with gene rearrangements, are largely unknown in DLBCL and could identify a group of previously uncharacterized patients that may have high expression of MYC, BCL2 and/or BCL6 driven by alternative mechanisms.Aims:The goal of the study is to define the landscape and prognostic significance of gene rearrangements and copy gains in MYC, BCL2, and BCL6 in a cohort of newly diagnosed DLBCL.Methods:A total of 176 cases of DLBCL with both FISH and CNA data were available for the study. FISH was performed on formalin‐fixed paraffin‐embedded sections using break‐apart probes to MYC, BCL2, and BCL6 in the Mayo Clinic Department of Lab Medicine and Pathology. Somatic copy number alterations were identified using whole exome sequencing and the Affymetrix OncoScan® FFPE assay on patient tumor FFPE tissue, and were interrogated using Nexus Copy Number 9.0 software. All patients were treated with immunochemotherapy and prospectively followed for event‐free and overall survival.Results:FISH identified 3 groups of previously described patients, DH/TH or HGBL (n = 11), translocation positive (single MYC, BCL2, BLC6, or double BCL2/BLC6, n = 86), and translocation negative (n = 79). Expanding upon the translocation positive subgroup, copy number analysis identified patients (19 of 86, 22%) with copy number gains in a second or third gene resulting in genomic hits at both MYC and BCL2/6; we classified these as alternative‐double/triple‐hit (A‐DH/TH). An example of this would be a MYC translocation plus a BCL2 and/or BCL6 gain (n = 5), or a BCL2 and/or BCL6 translocation plus a copy gain in MYC (n = 14). Similar interrogation of a publically available dataset (n = 250), revealed similar proportions of these patient groups in an independent cohort of DLBCL, validating our findings. Cell of origin classification of the A‐DH/TH cases revealed that they were 53% GCB. A‐DH/TH patients, in comparison to the translocation‐positive/copy‐gain‐negative cases, were at greater risk of an event (Cox HR = 1.5, 95% CI = 0.71–3.0) and the cases trended towards a worse overall survival (log‐rank P = 0.065; Cox HR = 2.0, 95% CI = 0.94–4.3). Patients with copy‐gains alone had similar outcomes as those with no copy‐gain or translocations, suggesting a central role for at least one translocation event in predicting outcome.Summary/Conclusion:Our data suggest that use of CNA data in combination with traditional FISH can identify a unique subset of DLBCL, A‐DH/TH, that are missed by standard clinical practice. More importantly, we find that these patients do poorly and may benefit from more aggressive treatment, although we do acknowledge that our population size was small and further validation is needed.image