G. Nowakowski¹ | W. Willenbacher² | R. Greil³ |
T.S. Larsen⁴ | K. Patel⁵ | U. Jäger⁶ | R.F. Manges⁷ |
L. Trümper⁸ | C. Haioun⁹ | H. Everaus¹⁰ |
N. Kalakonda¹¹ | J. Knoble¹² | P. de Nully Brown¹³ |
J.M. Jørgensen¹⁴ | D. Cunningham¹⁵ |
N. Domper Rubio¹⁶ | M. Casadebaig¹⁷ | O. Manzke¹⁶ |
J. Munoz¹⁸

¹Hematology, Mayo Clinic, Rochester, United States; ²Department of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria; ³Department of Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute and Cancer Cluster, Salzburg, Austria; ⁴Department of Hematology, Odense University Hospital, Odense, Denmark; ⁵Center for Blood Disorders and Stem Cell Transplant, Swedish Cancer Institute, Seattle, United States; ⁶Department of Hematology, Medical University of Vienna, Vienna, Austria; ⁷Hematology/Oncology, Parkview Health, Fort Wayne, United States; ⁸Abteilung für Hämatologie und Onkologie, Universitätsmedizin Göttingen, Göttingen, Germany; ⁹Lymphoid Malignancies Unit, Henri Mondor University Hospital, University Hospital, APHP, Créteil, France; ¹⁰Department of Hematology-Oncology, Tartu University Hospital, Tartu, Estonia; ¹¹Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom; ¹²Medical Oncology and Hematology, Mark H. Zangmeister Cancer Center, Columbus, United States; ¹³Department of Hematology, Rigshospitalet, Copenhagen University Hospital, København, Denmark; ¹⁴Departments of Clinical Medicine and Hematology, Aarhus University Hospital, Aarhus, Denmark; ¹⁵Gastrointestinal and Lymphoma Unit, The Royal Marsden Hospital, London, United Kingdom; ¹⁶Global Clinical R&D, Celgene International, Boudry, Switzerland; ¹⁷Statistics, Celgene International, Boudry, Switzerland; ¹⁸Medical Oncology, Banner MD Anderson Cancer Center, Gilbert, United States

**Introduction:** We report the results of a phase 2, open-label study (NCT03003520) of durvalumab (durva) in combination with R-CHOP or R²-CHOP (R-CHOP + lenalidomide) in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL).

**Methods:** Subjects (≥18 years; ECOG 0-2) with previously untreated, high/high-intermediate risk DLBCL (IPI ≥3/NCCN-IPI ≥4) were stratified to durva + R-CHOP (Arm A, GCB DLBCL) or R²-CHOP for 6-8 cycles (Arm B, ABC DLBCL) based on cell of origin identified by gene expression followed by durva consolidation up to month 12 from start of induction. After the US Food and Drug Administration placed clinical holds on trials that include combination therapy with checkpoint inhibitors and immunomodulatory agents, the study was revised to include both ABC and GCB in Arm A (durva + R-CHOP). The primary endpoint was complete response rate at the end of induction; secondary endpoints were rate of subjects continuing to consolidation, safety, and response in biological subgroups.

**Results:** A total of 46 subjects were treated (safety; A/B, n=43/3); median age, 62/66 y; male, 61%/67%; ECOG 2, 19%/33%; Ann Arbor

stage IV, 79%/33%; bulky disease: 49%/67%; double/triple-hit lymphoma, 30%/33%. As of Aug 2, 2018, 30/3 (A/B) had completed induction therapy, and 19 subjects (A) were ongoing. Complete response rate (95% confidence interval) at end of induction was (A) 54% (37%-71%) and (B) 67% (9%-99%); 68%/67% (A/B) continued to consolidation therapy and were progression-free at month 12. The safety profile was as expected for the components of the combination regimen with no new safety signals identified. Frequent treatment-emergent adverse events (TEAEs; ≥25%; A+B) included fatigue (61%), neutropenia (52%), peripheral sensory neuropathy (50%), nausea (46%), diarrhea (28%); constipation, decreased appetite, insomnia, pyrexia (24% each); and alopecia, dizziness, dyspnea, headache, stomatitis (22% each). Grade 3/4 TEAEs occurred in 84%/100% of subjects (A/B), and 3 subjects (2/1) died with no death related to study treatment. Follow-up for efficacy and safety is ongoing.

**Conclusions:** Durva + R-CHOP combination therapy has an acceptable safety profile and demonstrates encouraging response rates in subjects with high-risk DLBCL including double-hit lymphoma.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); PD-1L; R-CHOP.

**Disclosures:** Nowakowski, G: Consultant Advisory Role: Celgene Corporation, Genentech, MorphoSys; Research Funding: Celgene Corporation, MorphoSys, NanoString Technologies. Willenbacher, W: Consultant Advisory Role: Amgen, Bristol-Myers Squibb, Celgene Corporation, Gilead Sciences, Janssen, Merck, Novartis, Roche, Takeda; Honoraria: Amgen, Celgene Corporation, Gilead Sciences, Janssen, Novartis, Roche; Research Funding: Amgen, Celgene Corporation, Janssen, Takeda; Other Remuneration: Gilead Sciences (speakers bureau). Greil, R: Consultant Advisory Role: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene Corporation, Gilead Sciences, Janssen Biotech, Merck, MSD, Novartis, Roche, Takeda; Honoraria: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene Corporation, Gilead Sciences, Merck, MSD, Novartis, Roche, Sandoz, Takeda; Research Funding: Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene Corporation, Merck, MSD, Novartis, Roche, Sandoz, Takeda; Other Remuneration: Amgen, AstraZeneca, Celgene Corporation, Gilead Sciences, Janssen China R&D, MSD, Novartis, Roche (travel, accommodations, expenses). Larsen, T: Other Remuneration: AbbVie (travel, accommodations, expenses). Patel, K: Consultant Advisory Role: AstraZeneca, Celgene Corporation, Genentech, Juno Therapeutics, Sunesis Pharmaceuticals, Verastem; Honoraria: DAVA Oncology; Research Funding: Aptevo Therapeutics, AstraZeneca, Bristol-Myers Squibb, Celgene Corporation, Curis, MEI Pharma, Pharmacyclics, Sunesis Pharmaceuticals, Takeda, Xencor; Other Remuneration: AstraZeneca, Genentech, Pharmacyclics/Janssen (speakers bureau); MEI Pharma (travel, accommodations, expenses). Jäger, U: Consultant Advisory Role: AbbVie, Amgen, Celgene Corporation, Gilead Sciences, Roche; Honoraria: AbbVie, Amgen, AOP Orphan Pharmaceuticals, Bioverativ, Bristol-Myers Squibb, Celgene Corporation, Emergent BioSolutions, Gilead Sciences, Janssen-Cilag, Mundipharma, Novartis, Roche, Sandoz, Takeda; Research Funding: AbbVie, Bioverativ, Celgene Corporation, Gilead Sciences, Infinity Pharmaceuticals, Janssen-Cilag, MSD, Novartis, Roche, Takeda. Trümper, L: Consultant Advisory Role: Nordic Nanovector, Seattle Genetics, Takeda; Research Funding: Amgen, Roche, Spectrum Pharmaceuticals. Haioun, C: Consultant
**Advisory Role:** Celgene Corporation, Janssen China R&D, Roche, Takeda; Honoraria: Amgen, Gilead Sciences, Novartis, Servier; Other Remuneration: Amgen, Celgene Corporation, Roche (travel, accommodations, expenses). Everaus, H: Other Remuneration: Sanofi (travel, accommodations, expenses). Kalakonda, N: Research Funding: Celgene Corporation. Knoble, J: Employment Leadership Position: Ohio Oncology and Hematology, LLC; Consultant Advisory Role: Bayer, Puma Oncology. de Nully Brown, P: Consultant Advisory Role: Celgene Corporation. Jørgensen, J: Consultant Advisory Role: Gilead Sciences; Stock Ownership: Bristol-Myers Squibb, Gilead Sciences, Novo Nordisk; Research Funding: Celgene Corporation, Gilead Sciences, Roche; Other Remuneration: Gilead Sciences (travel, accommodations, expenses). Cunningham, D: Research Funding: Amgen, AstraZeneca, Bayer, Celgene Corporation, Clovis Oncology, Eli Lilly, Janssen, MedImmune, Merck, Merrimack, Sanofi, 4SC. Domper Rubio, N: Employment Leadership Position: Celgene Corporation; Stock Ownership: Celgene Corporation; Other Remuneration: Celgene Corporation (travel, accommodations, expenses, patents, royalties, other intellectual property). Casadebaig, M: Employment Leadership Position: Celgene Corporation; Stock Ownership: Celgene Corporation; Other Remuneration: Celgene Corporation (travel, accommodations, expenses, patents, royalties, other intellectual property). Manzke, O: Employment Leadership Position: Celgene Corporation; Stock Ownership: Celgene Corporation; Other Remuneration: Celgene Corporation (travel, accommodations, expenses, patents, royalties, other intellectual property). Munoz, J: Consultant Advisory Role: Alexion Pharmaceuticals, Bayer, Bristol-Myers Squibb, Celgene Corporation, Genentech, Gilead Sciences, Janssen, Juno Therapeutics, Kite Pharma, Kyowa Hakko Kirin, Pfizer, Pharmacyclics, Seattle Genetics; Other Remuneration: AstraZeneca, Bayer, Gilead Sciences, Kite Pharma, Pharmacyclics/Janssen.

088

INITIAL RESULTS OF A MULTICENTER
PHASE 2 STUDY OF VENETOCLAX IN
COMBINATION WITH DOSE-ADJUSTED R-
EPOCH FOR PATIENTS WITH RICHTER'S
SYNDROME (CRC-043)

M.S. Davids<fnref n="1" /> | P.A. Thompson<fnref n="2" /> | K.A. Rogers³ |
S. Tyekucheva⁴ | S. Pazienza<fnref n="1" /> | K. Francoeur<fnref n="1" /> |
S.K. Renner<fnref n="2" /> | J. Bazemore<fnref n="1" /> | M. Rocchio<fnref n="1" /> |
U. Ihuoma<fnref n="1" /> | C.A. Jacobson<fnref n="1" /> | D.C. Fisher<fnref n="1" /> | J.R. Brown<fnref n="1" />

**Introduction:** Despite recent advances in CLL, the outcomes for Richter's Syndrome (RS) remain dismal. Complete response (CR) is observed only in about 20% of RS patients (pts) who receive

chemoimmunotherapy such as dose-adjusted (da)-R-EPOCH, with short PFS/OS of <6 mo (Rogers et al., 2018). The oral Bcl-2 inhibitor venetoclax (ven) had a 43% response rate in RS (Davids et al., 2017). Here, we report for the first time on an ongoing study of ven + da-R-EPOCH in RS.

**Methods:** This is a single-arm, phase 2, investigator sponsored trial of ven + da-R-EPOCH for RS (NCT03054896) open in the CLL Research Consortium (CRC) at 3 US sites. We treated CLL pts with biopsy-confirmed DLBCL transformation with R-EPOCH for 1 cycle, then after count recovery with accelerated inpatient daily ven ramp-up (20/50/100/200/400 mg), then ven + da-R-EPOCH for up to 5 additional 21d cycles (ven 400 mg qd, d1-10 of each cycle). Responders then received alloHCT or daily ven 400 mg qd maintenance in 28d cycles. Response by Lugano criteria with PET/CT, toxicity by CTCAE v4.03.

<figure><img src="image_55.png" /></figure>

<footnote n="1">¹Medical Oncology, Dana-Farber Cancer Institute, Boston, United States;</footnote>

<footnote n="2">²Leukemia, The University of Texas MD Anderson Cancer Center,
Houston, United States; ³Hematology, The Ohio State University,</footnote>

<footnote>Columbus, United States; ⁴Biostatistics and Computational Biology,</footnote>

<footnote>Dana-Farber Cancer Institute, Boston, United States</footnote>
**Results:** As of 21 Feb 2019, 20 pts have been treated. Median age: 63 yrs (range 50-77), 33% del(17p), 43% complex karyotype, and 29% and 10% TP53 and NOTCH1 mutation, respectively. Median # prior CLL treatments 2 (range 0-5, prior ibrutinib (n=8), idelalisib (n=2), and ven (n=2); 5 pts no prior treatment). Median # ven + da-R-EPOCH cycles in this ongoing study is 3.5 (range 1-6), including 5 pts who recently enrolled. 4 pts had dose de-escalation of R-EPOCH and 1 pt had dose escalation. ≥Gr 3 heme toxicity included: neutropenia (45%), anemia (35%), thrombocytopenia (25%). ≥Gr 3 non-heme toxicities in ≥15% of pts: febrile neutropenia (20%), hypocalcemia and hypophosphatemia (15% each). No TLS occurred with daily ven ramp-up after 1 cycle of R-EPOCH. Infectious complications: 3 pts with sepsis during C1 of R-EPOCH (prior to starting ven) and 1 pt each with influenza A and norovirus while on combination therapy. 7 pts died, including 4 due to disease progression (2 during C1 before ven), and 1 each due to sepsis, sudden death, and GVHD post-alloHCT. 8 pts are not evaluable for efficacy of the combination (3 are still in C1, 4 had toxicity in C1 and never started ven, 1 pt withdrew in C1). Of the 12 evaluable pts who have started combination therapy, 9 responded (ORR 75%); 8/12 (67%) had CR, all of whom also had undetectable bone marrow MRD for CLL. 5 pts went to alloHCT, with pts still in CR now up to 1.5 yrs post-alloHCT. With a median follow-up of 3 mo (range 0-17.9), median PFS is 10 mo (Fig 1A), median OS is 16.3 mo (Fig 1B).

**Conclusions:** Our initial data suggest that ven + da-R-EPOCH is a feasible regimen to treat RS. Expected toxicities from intensive chemoimmunotherapy were seen, without significant additional toxicity from ven, including no TLS with daily ven ramp-up. The 67% CR and PFS/OS of 10/16.3 mo are favorable in the context of historical results. Accrual is ongoing, and updated results will be presented.

**Keywords:** DA-R-EPOCH; Richter's syndrome (RS); venetoclax.

**Disclosures:** Davids, M: Consultant Advisory Role: AbbVie, Acerta Pharma, Adaptive Biotechnologies, Astra-Zeneca, Celgene, Genentech, Gilead Sciences, Janssen, MEI Pharma, Merck, Pharmacyclics, Roche, Syros Pharmaceuticals, TG Therapeutics, Verastem; Research Funding: Acerta Pharma, Bristol-Myers Squibb, Genentech, MEI Pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem. Thompson, P: Consultant Advisory Role: Genentech, AbbVie. Rogers, K: Consultant Advisory Role: Acerta Pharma; Research Funding: Genentech, AbbVie. Francoeur, K: Consultant Advisory Role: Verastem. Brown, J: Consultant Advisory Role: AbbVie, Acerta Pharma, BeiGene, Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, Novartis, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, Verastem; Honoraria: Janssen, Teva; Research Funding: Gilead, Loxo, Sun, Verastem; Other Remuneration: Morphosys, Invectys.

089
IMPROVED OUTCOMES IN PATIENTS (PTS)
WITH BCL2-POSITIVE DIFFUSE LARGE B-
CELL LYMPHOMA (DLBCL) TREATED WITH
VENETOCLAX (VEN) PLUS R-CHOP:

RESULTS FROM THE PHASE 2 CAVALLI
STUDY

**F. Morschhauser¹** | **I.W. Flinn²** | **R. Gasiorowski³** |
**À. Illés⁴** | **P. Feugier⁵** | **R. Greil⁶** | **N.A. Johnson⁷** |
**J. Larouche⁸** | **P.J. Lugtenburg⁹** | **C. Patti¹⁰** |
**G. Salles¹¹** | **M. Trněný¹²** | **S. de Vos¹³** | **F. Mir¹⁴** |
**M. Kornacker¹⁵** | **E.A. Punnoose¹⁶** | **D. Samineni¹⁷** |
**E. Szafer-Glusman¹⁶** | **A. Petrich¹⁸** | **A. Sinha¹⁹** |
**N. Spielewoy²⁰** | **K. Humphrey²¹** | **A. Bazeos²²** |
**A.D. Zelenetz²³**

¹Institute of Hematology-Transfusion, Université de Lille, Centre Hospitalier Universitaire [CHU] Lille, Groupe de Recherche sur les Formes Injectables et les Technologies Associées, Lille, France; ²Center for Blood Cancers, Sarah Cannon Research Institute-Tennessee Oncology, Nashville, TN, United States; ³Department of Haematology, Concord Hospital, University of Sydney, Sydney, Australia; ⁴Faculty of Medicine, Department of Hematology, University of Debrecen, Debrecen, Hungary; ⁵Service d'Hématologie, CHU Régional de Nancy, Vandoeuvre lès Nancy, France; ⁶3rd Medical Department, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria; ⁷Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada; ⁸Hematology-Oncology, CHU de Québec, Hôpital de l'Enfant-Jésus, Quebec, Canada; ⁹HOVON Lunenburg Lymphoma Phase I-II Consortium, Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands; ¹⁰Department of Hematology, Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy; ¹¹Clinical Hematology, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, University of Lyon, Pierre-Benite, France; ¹²1st Department of Medicine, Charles University General Hospital, Prague, Czech Republic; ¹³Division Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; ¹⁴On assignment to PD Clinical Oncology, Roche Products Ltd, Welwyn Garden City, United Kingdom, and Royal Marsden Hospital, Sutton, United Kingdom; ¹⁵Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland; ¹⁶Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, United States; ¹⁷Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, United States; ¹⁸Oncology Early Development, AbbVie, North Chicago, IL, United States; ¹⁹Product Development, Roche Products Ltd, Welwyn Garden City, United Kingdom; ²⁰Pharmaceutical Development Clinical Science Oncology, F. Hoffmann-La Roche Ltd, Basel, Switzerland; ²¹Clinical Development Oncology, Roche Products Ltd., Welwyn Garden City, United Kingdom; ²²PD Clinical Science, Oncology, Roche Products Ltd., Welwyn Garden City, United Kingdom; ²³Lymphoma Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York City, NY, United States

**Introduction:** BCL2 and BCL2 plus MYC overexpression, and coexisting BCL2 and MYC translocation (double-hit [DH]) are associated with poor outcomes in DLBCL. Ven, a highly selective BCL2
<figure><img src="image_56.png" /><figcaption>**Figure:** PFS in the overall population and BCL2 IHC+ pts</figcaption></figure>

Median follow-up: CAVALLI, 22.3 months (data cut-off, Jul 13, 2018); GOYA, 29.6 months (data cut-off, Apr 29, 2016). *Covariates: age, sex, ECOG PS, BMI, IPI (high vs non-high), bulky disease (>7.5cm), disease stage (IV vs I-III), LDH, COO

<table><caption>**Table:** PET-CR at EOT across biomarker subgroups in CAVALLI and GOYA</caption><thead><tr><th rowspan="3">Pts</th><th colspan="4">PET-CR rate</th><th rowspan="3">Delta CR,<br>% (95% CI)</th></tr><tr><th colspan="2">CAVALLI</th><th colspan="2">GOYA</th></tr><tr><th>%</th><th>N</th><th>%</th><th>N</th></tr></thead><tbody><tr><td>All</td><td>69</td><td>208</td><td>63</td><td>564</td><td>6 (0–13)</td></tr><tr><td>BCL2 IHC+</td><td>65</td><td>105</td><td>60</td><td>151</td><td>5 (0–14)</td></tr><tr><td>DE</td><td>67</td><td>81</td><td>61</td><td>124</td><td>6 (0–18)</td></tr><tr><td>BCL2 FISH+</td><td>70</td><td>40</td><td>48</td><td>59</td><td>23 (7–39)</td></tr><tr><td>DH</td><td>71</td><td>7</td><td>25</td><td>8</td><td>46 (37–56)</td></tr></tbody></table>

DE, double-expressor

inhibitor, may enhance the current standard regimen of rituximab (R) +CHOP chemotherapy. Phase (Ph) 1b of CAVALLI (NCT02055820) established Ven 800 mg on Days (D) 1–4, Cycle (C) 1 and D1–10, C2–8 as the recommended Ph 2 dose combined with R-CHOP in first-line (1L) DLBCL. We report safety, efficacy and biomarker analyses of CAVALLI Ph2 (data cut-off, July 13 2018).

**Methods:** Eligible pts were ≥18 yrs old with 1L DLBCL, ECOG performance status ≤2 and IPI score 2–5. Oral Ven 800 mg was given on D1–4, C1 and D1–10, C2–8 combined with R (8 Cs) and CHOP (6–8 Cs); 21-day Cs. Primary endpoint was PET-complete response (CR) at end of treatment (EOT; modified Lugano criteria 2014). Secondary endpoints were PFS, OS and safety. The R-CHOP control arm of GOYA (564 pts, IPI 2–5) was used as a historical control. Factors affecting completion of 8 treatment Cs were assessed using multivariate analysis (MVA). Time-to-event endpoints were compared using adjusted Cox regression. Biomarker analyses included BCL2 and MYC immunohistochemistry (IHC), *BCL2 and MYC* translocations by fluorescence *in situ* hybridization (FISH) and cell of origin (COO) by NanoString.

**Results:** Of 211 pts enrolled in CAVALLI, 208 received any treatment and were analyzed for efficacy and safety. Baseline characteristics for CAVALLI vs GOYA were similar, but more Ann Arbor Stage IV (65% vs 47%) and BCL2 IHC+ (58% vs 49%) pts enrolled in CAVALLI. In the overall population, EOT PET-CR rates were similar (CAVALLI, 69%; GOYA, 63%), while PET-CR rates were higher in CAVALLI for BCL2 FISH+ and DH pts (Table). PFS was improved in the overall and BCL2 IHC+ populations vs GOYA (Figure); PFS benefit in BCL2 IHC+ pts was observed across ABC and GCB COO subtypes. There was also evidence of OS benefit vs GOYA; HR 0.7, 95% CI 0.43–1.1 (overall), HR 0.7, 95% CI 0.35–1.2 (BCL2 IHC+). Grade

3–4 AEs occurred in 86% of pts in CAVALLI vs 66% in GOYA, mainly cytopenia, febrile neutropenia (FN) and infection. A trend towards lower neutropenia and FN/infection incidence was seen in pts receiving G-CSF prophylaxis. On MVA, age <60 yrs was the only factor to predict completion of 8 treatment Cs (p=0.002). There were 4 fatal AEs (2%) in CAVALLI vs 30 (5%) in GOYA, but follow-up was longer in GOYA (29.6 vs 22.3 months). The high AE rate in CAVALLI led to dose interruptions/discontinuations; 61% of pts received >90% relative dose intensity (RDI) of Ven; 73% received >90% RDI for cyclophosphamide and doxorubicin. The RDI of chemotherapy was similar in GOYA.

**Conclusions:** Adding Ven to R-CHOP improved efficacy in BCL2 IHC+ 1L DLBCL pts versus matched GOYA controls. A higher rate of cytopenia, FN and infection was observed in CAVALLI vs GOYA; however, there was no increase in risk of death and the RDI of chemotherapy was similar.

**Acknowledgments:** Venetoclax is being developed in collaboration between Genentech and AbbVie. Genentech and AbbVie provided financial support for the study. Third-party editorial assistance was provided, funded by F. Hoffmann-La Roche Ltd.

This abstract has been previously submitted to EHA 2019.

**Keywords:** BCL2; diffuse large B-cell lymphoma (DLBCL); venetoclax.

**Disclosures:** Morschhauser, F: Consultant Advisory Role: Gilead; Honoraria: Celgene, Roche, Janssen, Bristol-Myers Squibb, Servier, Epizyme.

**Flinn, I:** Consultant Advisory Role: Abbvie, Seattle Genetics, TG Therapeutics, Verastem; Research Funding: Acerta, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmaceutics, Portola Pharmaceuticals, Roche, Seattle Genetics, TG Therapeutics, Trillim Therapeutics, Abbvie,
ArQule, BeiGene, Curis, FoRMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem. **Gasiorowski, R:** Honoraria: Novartis, MSD, Takeda, Abbvie. **Illés, Á:** Consultant Advisory Role: Janssen, Celgene, Novartis, Pfizer, Takeda, Roche; Honoraria: Janssen, Celgene, Novartis, Pfizer, Takeda, Roche; Research Funding: Takeda, Seattle Genetics; Other Remuneration: Expenses: Novartis, Janssen, Pfizer, Roche. **Feugier, P:** Consultant Advisory Role: Roche, Janssen, Gilead, Abbvie, Amgen; Honoraria: Roche, Janssen, Gilead, Abbvie, Amgen; Other Remuneration: Expenses: Roche, Janssen, Gilead, Abbvie, Amgen. **Greil, R:** Consultant Advisory Role: Celgene, Novartis, Roche, Bristol-Myers Squibb, Takeda, Abbvie, AstraZeneca, Janssen, MSD, Merck, Gilead; Honoraria: Celgene, Roche, Merck, Takeda, Sandoz, AstraZeneca, Novartis, Amgen, Bristol-Myers Squibb, MSD, Abbvie, Gilead; Research Funding: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol-Myers Squibb, MSD, Sandoz; Other Remuneration: Expenses: Roche, Amgen, Janssen, AstraZeneca, Novartis, MSD, Celgene, Gilead. **Johnson, N:** Consultant Advisory Role: Roche; Honoraria: Roche. **Larouche, J:** Consultant Advisory Role: AstraZeneca; Research Funding: AstraZeneca, Roche, Merck, BMS, Takeda; Other Remuneration: Expenses: AstraZeneca. **Lugtenburg, P:** Consultant Advisory Role: Roche, Takeda, Servier, Bristol-Myers Squibb, Celgene, Sandoz, Genmab; Research Funding: Roche, Servier, Takeda. **Salles, G:** Consultant Advisory Role: Roche/Genentech, Gilead, Janssen, Celgene, Novartis, Merck, Pfizer, Acerta Pharma, Kite Pharma, Servier, MorphoSys, Epizyme; Honoraria: Roche/Genentech, Amgen, Janssen, Celgene, Servier, Gilead, Novartis, Abbvie, Merck, Takeda, MorphoSys. **Trněný, M:** Consultant Advisory Role: Takeda, Bristol-Myers, Squibb, Incyte, Abbvie, Amgen, Roche, Gilead Sciences, Janssen, Celgene, MorphoSys; Honoraria: Janssen, Gilead Sciences, Takeda, Bristol-Myers Squibb, Amgen, Abbvie, Roche, MorphoSys, Incyte; Research Funding: Roche; Other Remuneration: Expenses: Gilead Sciences, Takeda, Bristol-Myers Squibb, Roche, Janssen, Abbvie. **de Vos, S:** Consultant Advisory Role: Bayer, Verastem. **Mir, F:** Employment Leadership Position: Roche. **Kornacker, M:** Employment Leadership Position: F. Hoffmann-La Roche Ltd.; Stock Ownership: F. Hoffmann-La Roche Ltd., Bayer AG, J&J. **Punnoose, E:** Employment Leadership Position: Genentech, Member of the Roche Group; Stock Ownership: Genentech, Member of the Roche Group; Other Remuneration: Patents, Royalties, other intellectual property: Genentech, Member of the Roche Group. **Samineni, D:** Employment Leadership Position: Genentech; Stock Ownership: Roche. **Szafer-Glusman, E:** Employment Leadership Position: Genentech; Stock Ownership: Roche. **Petrich, A:** Employment Leadership Position: Abbvie; Stock Ownership: Abbvie; Other Remuneration: Expenses: Abbvie. **Sinha, A:** Employment Leadership Position: Roche; Stock Ownership: Roche. **Spielewoy, N:** Employment Leadership Position: Roche; Stock Ownership: Roche. **Humphrey, K:** Employment Leadership Position: Roche; Stock Ownership: Roche. **Bazeos, A:** Employment Leadership Position: Roche; Stock Ownership: Roche. **Zelenetz, A:** Consultant Advisory Role: Genentech/Roche, Gilead, Celgene, Janssen, Amgen, Novartis, Adaptive Biotech, MorphoSys, Gilead, Abbvie, AstraZeneca; Honoraria: Genentech/Roche, Gilead, Celgene, Janssen, Amgen, Novartis, Adaptive Biotech, MorphoSys, Gilead, Abbvie, AstraZeneca; Research

Funding: MEI Pharma, Roche, Gilead, Beigene; Other Remuneration: Expenses: Genentech/Roche, Gilead, Celgene, Janssen, Amgen, Novartis, Adaptive Biotech, MorphoSys, Gilead, Abbvie, AstraZeneca; DMC chair: Beigene.

090
CD19-DIRECTED CAR T CELL THERAPY
(CTL019) FOR RELAPSED/REFRACTORY
DIFFUSE LARGE B-CELL AND FOLLICULAR
LYMPHOMAS: FOUR YEAR OUTCOMES

E.A. Chong¹ | J. Svoboda¹ | S.D. Nasta¹ |

D.J. Landsburg¹ | N. Winchell¹ | E.R. Chong¹ |

D. Porter² | B. Levine² | C.H. June² | S.J. Schuster¹

¹Lymphoma Program, University of Pennsylvania, Philadelphia, United States; ²Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, United States

**Introduction:** Anti-CD19 chimeric antigen receptor-modified T cell therapy (CAR T) is indicated for diffuse large B-cell, high grade B-cell, transformed follicular and primary mediastinal B-cell lymphomas. To date, the longest reported median follow-up is 19 months (mo) for tisagenlecleucel (Schuster et al., Blood 2018) and 24 mo for axicabtagene ciloleucel (Locke et al., Lancet Oncol 2019). We previously reported two-year follow-up for 28 patients (pts) who received CTL019 (Schuster et al., NEJM 2017). We now report our four-year experience with CAR T (CTL019, now tisagenlecleucel).

**Methods:** We enrolled pts with relapsed/refractory CD19+ diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL) from February 2014 to September 2017 on a single institution trial of CTL019. Eligible pts had no curative treatment options, prognosis of <2 years survival, and less than complete response to last therapy. Pts underwent leukapheresis, bridging therapy at the investigator's discretion, then lymphodepleting therapy followed by a single dose of 1e8 to 5e8 CTL019 cells. Outcomes were analyzed as of February 25, 2019.

**Results:** Median follow-up is now 49 mos. 49 pts, 24 with DLBCL and 15 with FL, were enrolled. Median age at enrollment was 56 years (range: 25 - 77) and 41% were women. The median number of prior therapies was 5 (range: 2-10). Median ECOG PS was 1 (range: 0-1). 78% had advanced stage lymphoma at enrollment. 38 pts received the protocol-specified dose of CTL019. 46% of DLBCL pts and 71% of FL pts had a complete response (CR). For DLBCL, median progression free survival (PFS) is 5.8 mo (95%CI: 1.6 mo-NE), median overall survival (OS) 22.2 mo (95%CI: 10.9-45.6mo). For FL, median PFS is 32.4 mo (95%CI: 3.5 mo-NE), median OS was not reached (95%CI: 27.2mo-NE). For responding patients with DLBCL or FL, median response duration (RD) was not reached at 49 mo follow-up (DLBCL RD, 95%CI: 3.2 mo-NE; FL RD, 95%CI: 9.5 mo-NE). The patient with the longest follow-up remains in remission from DLBCL (double-hit) at 60 mo after CTL019. Of 21 pts in CR, only 6 received IVIG for recurrent or severe infections and 2 pts developed late myelodysplasia.
<figure><img src="image_57.png" /></figure>

Four patients relapsed more than 12 months from CTL019 infusion (PFS: 16.3 mo, 26.2 mo, 32.4 mo, 35.2 mo). At the time of these late relapses, CAR T cells persisted by quantitative PCR and there was no loss of CD19 expression by tumor cells.

**Conclusions:** At a median follow-up over four years, we demonstrate that a single infusion of CTL019 provides durable remissions in pts with relapsed/refractory DLBCL and FL. This is the longest follow-up for CTL019 therapy for relapsed/refractory B-cell lymphomas reported to date.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); follicular lymphoma (FL); T-cells.

**Disclosures:** **Chong, E:** Consultant Advisory Role: *Novartis. Svoboda, J:* Consultant Advisory Role: *Kite Pharma; Research Funding: Novartis. Nasta, S:* Research Funding: *Roche, Incyte, Debiopharm, Rafael, Aileron, Takeda/Millennium. Landsburg, D:* Consultant Advisory Role: *Curis, Celgene; Research Funding: Curis, Takeda, Triphase; Other Remuneration: Seattle Genetics =. Porter, D:* Employment Leadership Position: *Genentech; Consultant Advisory Role: Novartis, Kite Pharma, Incyte, Glenmark; Stock Ownership: Genentech; Research Funding: Novartis; Other Remuneration: Novartis. Levine, B:** Employment Leadership Position: *Tmunity Therapeutics; Consultant Advisory Role: CRC Oncology, Cure Genetics, Novartis, Terumo, Avectas, Brammer Bio, Incysus, Vycellix; Other Remuneration: Novartis. June, C:* Consultant Advisory Role: *Novartis, Immune Design, Viracta, Carisma; Stock Ownership: Tmunity Therapeutics; Research Funding: Novartis; Other Remuneration: Novartis. Schuster, S:* Consultant Advisory Role: *Pfizer, Nordic Nanovector, Celgene, Gilead, Merck, Novartis, Pharmacyclics, Loxo Oncology, Acerta, AstraZeneca; Research Funding: Acerta, Celgene, Genentech, Gilead, Merck, Novartis, Pharmacyclics; Other Remuneration: Novartis.*

## SESSION 6 – LYMPHOMA PATHOLOGY

### 091
DIAGNOSIS AND CLASSIFICATION
ASSISTANCE FROM LYMPHOMA
MICROSCOPIC IMAGES USING DEEP
LEARNING

**P. Brousset** | **C. Syrykh** | **A. Abreu** | **N. Amara** |

**C. Laurent**

*Pathology, IUCT-Toulouse Oncopole, Toulouse, France*

The microscopic diagnosis of lymphoma remains challenging. Recent data from our group within the French (nationwide) Lymphopath network shows that 20% of diagnoses are inaccurate, with direct impact on patient care¹. Another difficulty is the subclassification of lymphoma subtypes to predict therapeutic response and clinical behaviour. For these, molecular techniques, not affordable for all pathology departments, have become critical. Currently, automated solutions that could help with diagnostic decisions or histological grading are lacking, and it is unreasonable to expect pathologists to be experts on rare tumours if they only see a few cases per year. Digital microscopy offers unique features which are not available in conventional optical microscopy² and allows automated image analysis and quantification by using computer vision and, in particular, deep learning (DL) approaches.³ Using DL on digital slides we tried to address two questions: 1) Can we train deep neural network (CNN) to distinguish follicular lymphoma (FL) from either follicular hyperplasia or other small B-cell lymphoma subtypes on hematoxylin-eosin stained lymph node digital slides? 2) Can CNN separate germinal center from non germinal center diffuse large B-cell lymphoma (DLBCL) the same way? Patch extraction or patch coordinated extraction was carried with different architectures (Residual Net, GoogleNet, VG-GNet) of whole slides images. A home designed neural network classification was also performed on 125x125pixel non-overlapping tiles of a whole slide image extracted at very low resolution (pyramid level 5 ó 7,68µm/pixel). The latter classifier was a fairly simple CNN architecture. It stacked three blocks of Convolution-MaxPooling with respectively 32, 64 and 128 filters, followed by two 1024-unit fully connected layers. Output of the network is a 2-unit layer with softmax activation to produce class probabilities. As to the diagnosis of FL, the accuracy of our method is superior to that of non expert pathologists, with an average area under the curve (AUC) of 0.95. Furthermore, we trained CNNs to predict GC and non GC phenotype of DLBCL previously determined with Hans' algorithm with an average AUC of 0.882. Our models were validated on independent series of biopsies (training, testing and validation sets) and provide quite similar accuracy irrespective of the architecture we used. These findings strongly suggest that DL models, even on very simple CNNs, can assist pathologists in the diagnosis and subclassification of lymphoma as recently shown is subsets of lung cancers.³

### References

1) Laurent C et al. J Clin Oncol. 2017;35:2008-17.

2) Krenacs T et al. Digital microscopy - 2010. Microscopy: Science, Technology, Applications and Education. A. Méndez-Vilas and J. Díaz (Eds.).

3) Coudray N et al. Nat Med. 2018;24(10:1559-67).

**Keywords:** diffuse large B-cell lymphoma (DLBCL); follicular lymphoma (FL).
092

INTEGRATING TUMOR- AND MICROENVIRONMENT-REFLECTING GENES IN A UNIQUE AND ROUTINE-APPLICABLE ASSAY FOR ACCURATE RISK PREDICTION IN DLBCL

S.A. Pileri¹

S. Mazzara¹

E. Derenzini²

F. Melle¹

G. Motta¹

V. Tabanelli¹

U. Vitolo³

A. Chiappella³

M. Fabbri¹

C. Agostinelli⁴

C. Tarella²

A. Rambaldi⁵

A. Guarini⁶

G. Opinto⁶

M.C. Vegliante

S. De Summa⁶

S. Ciavarella

¹Unit of Diagnostic Hematopathology, European Institute of Oncology, IRCCS, Milan, Italy; ²Onco-Hematology Unit, European Institute of Oncology, IRCCS, Milan, Italy; ³Department of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy; ⁴Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy;

C

Progression Free Survival

<table><thead><tr><th>Variable p-value</th><th>N</th><th>HR</th></tr></thead><tbody><tr><td>Clusters Reference</td><td>2</td><td>40</td></tr><tr><td>Reference</td><td>1</td><td>30</td><td>6.35 (1.89, 23.35)</td></tr><tr><td>0.003</td><td>1</td><td>30</td><td>6.35 (1.89, 23.35)</td></tr><tr><td>0.026</td><td>3</td><td>57</td><td>4.06 (1.18, 13.97)</td></tr><tr><td>0.008</td><td>4</td><td>48</td><td>5.28 (1.54, 18.11)</td></tr><tr><td>IPI Reference</td><td>Intermediate-High</td><td>28</td><td></td></tr><tr><td>Reference</td><td>High</td><td>47</td><td>1.47 (0.81, 2.68)</td></tr><tr><td>0.208</td><td>High</td><td>47</td><td>1.47 (0.81, 2.68)</td></tr></tbody></table>

D

Overall Survival

<table><thead><tr><th>Variable p-value</th><th>N</th><th>HR</th></tr></thead><tbody><tr><td>Clusters Reference</td><td>2</td><td>40</td></tr><tr><td>Reference</td><td>1</td><td>30</td><td>7.37 (1.61, 33.66)</td></tr><tr><td>0.01</td><td>1</td><td>30</td><td>7.37 (1.61, 33.66)</td></tr><tr><td>0.09</td><td>3</td><td>57</td><td>3.73 (0.83, 16.89)</td></tr><tr><td>0.01</td><td>4</td><td>48</td><td>6.59 (1.50, 28.99)</td></tr><tr><td>IPI Reference</td><td>Intermediate-High</td><td>28</td><td></td></tr><tr><td>Reference</td><td>High</td><td>47</td><td>1.84 (0.94, 3.57)</td></tr><tr><td>0.07</td><td>High</td><td>47</td><td>1.84 (0.94, 3.57)</td></tr></tbody></table>

A

<figure><img src="image_58.png" /></figure>

B

<figure><img src="image_59.png" /></figure>

Legend to the Figure

Figure 1 - Prognostic subgroups of DLBCL based on integration of COO + TME gene expression. Kaplan-Meier curves of PFS (A) and OS (B) and show that patients in clusters 1 and 4 have significantly shorter OS and PFS than those in cluster 2 and 3. Tables report data of multivariate analysis for PFS (C) and OS (D), adjusted for clusters and IPI.
⁵Department of Hematology and Oncology, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo and University of Milan, School of Medicine, Milan, Italy; ⁶Hematology and Cell Therapy Unit, IRCCS-Istituto Tumori 'Giovanni Paolo II', Bari, Italy

**Introduction:** Sequencing studies identified mutational drivers in diffuse large B cell lymphoma (DLBCL), capturing outcome difference in previously unrecognized patient subsets. However, the lack of routine-applicable genomic approaches limits translation of such information to the clinic. Currently, molecular prognostication consists in cell of origin (COO) determination by the Lymph2Cx NanoString assay. We recently developed two independent prognostic signatures incorporating genes reflecting the COO, the activation of pivotal oncogenic pathways, and the composition of tumor microenvironment (TME). We aimed this study at examining the prognostic strength of a model combining the performance of each signature and developing a comprehensive NanoString assay rapidly transferable to the clinic for prognostic purposes.

**Methods:** The expression of the genes was measured by the NanoString nCounter Analysis System using customized probes for 73 genes, including 15 COO genes, 6 additional oncogenic genes (MYC, BCL-2, NFKBIA, PIK3CA, PTEN, STAT3), 47 TME genes, and 5 housekeeping genes. The analysis was performed on 175 newly diagnosed, nodal DLBCL, homogeneously selected from the RHDS0305 and DLCL04 trials. Patients had comparable clinical features and double-hit cases were excluded. Heatmaps, Kaplan-Meier survival estimator, tree-based survival model, and P values were produced by 'R' statistical software. Long-rank test was used to compare overall survival (OS) and progression-free survival (PFS) among groups. Multivariate analysis was constructed through the Cox proportional hazards regression model.

**Results:** Based on the expression of the COO and oncogenic genes, a tree-based survival model stratified patients into subgroups showing significantly different survival, with MYC, BCL-2 and NFKBIA holding additional prognostic power based on their high (H) or low (L) expression. The TME panel identified a lower gene expression cluster (C3) with significantly worse survival than those at intermediate (C2) and higher expression (C1). Integration of COO-, TME-, and MYC/BCL-2/NFKBIA-based data produced a new survival risk categorization of DLBCL. The high-risk category, showing the worst outcomes, includes ABC/H/C1-2-3, ABC/L/C3 and GCB/H/C3 cases; the intermediate-risk category comprises ABC/L/C2, GCB/H or L/C1 and UN/H or L/C1 or C3 cases; whereas the low-risk category contains GCB/H or L/C2, GCB/L/C3, UN/H/C1 or C2 and UN/L/C2 or C3 cases, with longer survival. An unsupervised clustering analysis was also performed based on the expression of the entire 74-gene panel and stratified cases into four clusters with significantly different OS (p=0.011) and PFS (p=0.009). In particular, cluster 1 and 4 showed significantly worse survival than cluster 2 and 3 (Figure 1), and a multivariate Cox analysis indicated that the prognostic performance of the panel overcomes the IPI score. Finally, such model was also validated "in silico" using a gene expression profiling dataset (GSE10846 and

GSE98588) relative to a cohort of 146 DLBCL patients uniformly selected according to R-CHOP treatment.

**Conclusions:** This study supports the idea that DLBCL heterogeneity involves both tumor and TME, resulting in diverse transcriptional subtypes with distinct outcomes and, putatively, diverse biology. Our integrative analysis prompts the development of a new survival categorization outperforming current prognostic risk-assessment. Moreover, the applicability of a unique Nanostring-based assay to routine biopsies may facilitate the stratification of patients at diagnosis and their inclusion in future trials exploring novel therapeutic approaches.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); gene expression profile (GEP); prognostic indices.

093
CONCORDANCE BETWEEN
IMMUNOHISTOCHEMISTRY AND GENE
EXPRESSION PROFILING SUBTYPING FOR
DIFFUSE LARGE B-CELL LYMPHOMA IN
THE PHASE 3 PHOENIX TRIAL

S. Balasubramanian¹ | S. Wang² | C. Major³ |

B. Hodkinson³ | M. Schaffer³ | L.H. Sehn⁴ |

P. Johnson⁵ | P.L. Zinzani⁶ | J. Carey⁷ | G. Liu² |

C. Loefgren² | M. Shreeve¹ | S. Sun² | S. Zhuang² |

J. Vermeulen⁸ | L.M. Staudt⁹ | A. Younes¹⁰ |

W. Wilson¹¹

¹Clinical Oncology, Janssen Research & Development, San Diego, CA, USA, San Diego, United States; ²Clinical Oncology, Janssen Research & Development, Raritan, NJ, USA, Raritan, United States; ³Oncology Translational Research, Janssen Research & Development, Spring House, PA, USA, Spring House, United States; ⁴BC Cancer Centre, BC Cancer Centre for Lymphoid Cancer, Vancouver, Canada; ⁵Cancer Research UK Clinical Centre, University of Southampton, Southampton, United Kingdom; ⁶Institute of Hematology, "Seràgnoli" University of Bologna, Bologna, Italy; ⁷Clinical Oncology, Janssen Research & Development, Spring House, PA, USA, Spring House, United States; ⁸Clinical Oncology, Janssen Research & Development, Leiden, Netherlands; ⁹Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States; ¹⁰Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, United States; ¹¹National Cancer Institute, National Institutes of Health, Bethesda, United States

**Introduction:** Diffuse large B-cell lymphoma (DLBCL) can be classified based on cell-of-origin (COO) into germinal center B-cell-like (GCB), activated B-cell-like (ABC), and unclassified (UNC) subtypes by gene expression profiling (GEP), and GCB and non-GCB subtypes by immunohistochemistry (IHC). In the phase 3 PHOENIX trial (NCT01855750) that enrolled untreated patients (pts) with non-GCB DLBCL by IHC, ibrutinib (ibr) + R-CHOP did not improve event-free survival (EFS) vs placebo (pbo) + R-CHOP in the intent-to-treat (ITT,
<figure><img src="image_60.png" /><figcaption>Figure. (A) Number of Calls by IHC or GEP; (B) Overall, Non-GCB, and GCB Concordance (%); (C) EFS in ABC and GCB DLBCL in Patients < 60 Years</figcaption></figure>

non-GCB by IHC) or ABC (by GEP) populations; however, an increase in EFS and overall survival with ibr was seen in pts < 60 years (yrs), but not in pts ≥ 60 yrs due to increased toxicity in elderly pts. This work aimed to determine the concordance between IHC and GEP for DLBCL subtyping and outcomes related to subtypes.

**Methods:** Baseline paraffin-embedded, formalin-fixed tissue samples were used to confirm non-GCB DLBCL by Hans-based IHC (Dako pharmDx™ kit) at a central laboratory. Available tumor samples were retrospectively analyzed for ABC subtype by GEP (HTG EdgeSeq DLBCL COO Assay). The concordance was evaluated by comparing non-GCB calls by IHC with ABC + UNC by GEP or GCB calls between IHC and GEP. Survival outcomes were compared between GEP sub-types in each arm and across study arms.

**Results:** In all screened pts, 1111/1336 (83.2%) samples also provided evaluable GEP results; the concordance between GEP and IHC was 80.2% for non-GCB and 61.3% for GCB calls, resulting in an overall concordance of 76.9% (Figure), with 73.7% of non-GCB samples (by IHC) being identified as ABC by GEP. In pts < 60 yrs (n = 506), the concordance for non-GCB, GCB, and overall was 76.1%, 67.6%, and 74.3% respectively. In 747 evaluable samples from 838 enrolled non-GCB pts, 75.9% were ABC by GEP; 17.2% were GCB and 6.8% UNC.

In both ITT and age < 60 yrs populations, EFS rate in GCB DLBCL by GEP was higher vs ABC in either arm, although the difference was not statistically significant and even smaller in the ibr arm. When comparing the two arms in the ITT population, EFS was similar between arms regardless of COO. In pts < 60 yrs, EFS was better with the addition of ibr to R-CHOP in ABC pts (HR 0.56 [95% CI, 0.33-0.98]; p = 0.0348; Figure); the difference between arms was not statistically significant in GCB (HR 0.64 [95% CI, 0.22-1.86; p = 0.4119]) or UNC (HR 1.12 [95% CI, 0.22-5.97]) subtypes as numbers were small.

**Conclusions:** The overall concordance between non-GCB by Hans-based IHC and GEP using the EdgeSeq DLBCL COO Assay was 74-77% in the ITT population and age-related subgroups, even with centralized testing. Although only 75.9% of enrolled pts were the ABC subtype, the addition of ibr improved outcomes in pts < 60 yrs in both IHC-based non-GCB or GEP-based ABC DLBCL.

**Keywords:** gene expression profile (GEP); ibrutinib; immunohisto-chemistry (IHC).

**Disclosures:** Balasubramanian, S: Employment Leadership Position: Janssen, Pharmacyclics; Stock Ownership: Pharmacyclics, Johnson & Johnson, Gilead Sciences, Celgene, Vertex, AbbVie. Wang, S: Employment Leadership Position: Janssen; Stock Ownership: Janssen. Major,
C: Employment Leadership Position: Janssen; Stock Ownership: Janssen. Hodkinson, B: Employment Leadership Position: Janssen R&D. Schaffer, M: Employment Leadership Position: Janssen; Stock Ownership: Janssen. Sehn, L: Consultant Advisory Role: Celgene, AbbVie, Seattle Genetics, TG Therapeutics, Janssen, Amgen, Roche/Genentech, Gilead Sciences, Lundbeck, Apobiologix, Karyopharm Therapeutics, Kite Pharma, Merck, Takeda Pharmaceuticals, TEVA Pharmaceuticals Industries, TG Therapeutics; Honoraria: Amgen, Apobiologix, AbbVie, Celgene, Gilead Sciences, Janssen-Ortho, Karyopharm Therapeutics, Kite Pharma, Lundbeck, Merck, Roche/Genentech, Seattle Genetics, Takeda Pharmaceuticals, TEVA Pharmaceuticals Industries, TG Therapeutics; Research Funding: Roche/Genentech (Inst). Johnson, P: Consultant Advisory Role: Janssen, Epizyme, Boehringer Ingelheim; Honoraria: Takeda Pharmaceuticals, Bristol-Myers Squibb, Novartis, Celgene, Kite Pharma, Genmab, Incyte, MorphoSys; Research Funding: Janssen, Epizyme; Other Remuneration: Combined use of Fc gamma RIIb (CD32b) and CD20-specific antibodies; WO patent, PCT/GB2011/051572; EU11760819.0. Zinzani, P: Honoraria: Servier, Bristol-Myers Squibb, Gilead, Jansen, Merck Sharp & Dohme, Celltrion, Celgene, Roche; Other Remuneration: Verastem, Servier, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme, Celltrion, Celgene, Roche. Carey, J: Employment Leadership Position: Janssen Research and Development; Stock Ownership: Johnson & Johnson. Liu, G: Employment Leadership Position: Janssen. Loefgren, C: Employment Leadership Position: Janssen; Stock Ownership: Janssen. Shreeve, M: Employment Leadership Position: Janssen; Stock Ownership: Johnson & Johnson, Pfizer. Sun, S: Employment Leadership Position: Johnson & Johnson; Stock Ownership: Johnson & Johnson. Zhuang, S: Employment Leadership Position: Janssen Research & Development; Stock Ownership: Johnson & Johnson. Vermeulen, J: Employment Leadership Position: Janssen; Stock Ownership: Janssen. Staudt, L: Other Remuneration: Patents and patents pending regarding gene expression profiling in lymphoma that have been licensed by Nanostring and for which I receive royalties. Younes, A: Consultant Advisory Role: BMS, Incyte, Janssen, Genentech and Merck; Honoraria: Merck, Roche, Takeda Pharmaceuticals, Janssen, AbbVie; Research Funding: Janssen (Inst), Curis (Inst), Pharmacyclys (Inst), Roche (Inst), AstraZeneca (Inst), Genentech (Inst).

094
LONGITUDINAL ANALYSES OF
DIAGNOSTIC-RELAPSE BIOPSIES OF
DIFFUSE LARGE B CELL LYMPHOMA
SUGGEST THAT RELAPSE IS MEDIATED BY
DISTINCT MECHANISMS IN ABC AND GCB
LYMPHOMA

K. Korfi¹ | S. Araf¹ | F. Bewicke-Copley² |
E. Kumar¹ | T. Cummin³ | M. Ashton-Key⁴ |

S. Barrans⁵ | S. Van Hoppe⁵ | C. Burton⁵ |

M. Elshiekh⁶ | S. Rule⁷ | N. Crosbie⁸ | A. Clear¹ |

M. Calaminici¹ | G. Menon⁹ | C. Sha¹⁰ |

M. Bentley¹⁰ | A. Nagano² | A. Davies³ |

D. Painter¹¹ | A. Smith¹¹ | J. Okosun¹ |

J. Gribben¹ | K.N. Naresh⁶ | D. Westhead¹⁰ |

J. Wang² | P. Johnson³ | J. Fitzgibbon¹

¹Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom; ²Centre for Molecular Oncology, Barts Cancer Institute, London, United Kingdom; ³Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom; ⁴Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; ⁵HMDS, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; ⁶Cellular & Molecular Pathology, Imperial College NHS Trust & Imperial College London, London, United Kingdom; ⁷Department of Haematology, Derriford Hospital, University of Plymouth, Plymouth, United Kingdom; ⁸Department of Haematology, University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom; ⁹Haemato-Oncology Diagnostic Service, Liverpool Clinical Laboratories, Liverpool, United Kingdom; ¹⁰School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom; ¹¹Epidemiology and Cancer Statistics Group, University of York, York, United Kingdom

**Introduction:** Although diffuse large B cell lymphoma (DLBCL) can be cured using immuno-chemotherapy, 40% of patients experience relapse or refractory disease. Large-scale profiling studies have mainly focused on DLBCL at diagnosis with a limited number of longitudinal studies and no compelling biomarkers linked to relapse identified. To address this, we utilized a multifaceted approach integrating transcriptomic and intratumoral T-cell repertoire analyses in paired diagnostic/relapse tumors to enable identification of signaling pathways and microenvironmental changes underlying disease relapse.

**Methods:** We retrospectively collected archival paired diagnostic/relapse tumor biopsies from 38 de novo DLBCL patients (stage I-IV, 38-89 years old) treated with rituximab-based immuno-therapy. We performed gene expression profiling (GEP) and T-cell repertoire analysis using the Ion AmpliSeq Transcriptome Kit and TCR-β sequencing (immunoSEQ), respectively. Cell-of-origin (COO) classification was performed by the Lymph2Cx assay on NanoString to distinguish activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtypes.

**Results:** COO remained stable from diagnosis to relapse in >90% of pairs. In examples where we observed a switch in COO between diagnosis/relapse, targeted-seq analysis revealed some shared mutations suggesting that relapse tumors originated from a common ancestral clone. Our global GEP of 17 ABC-ABC and 11 GCB-GCB pairs identified 163 and 136 genes that were differentially expressed in ABC and GCB relapse tumors relative to their matched diagnostic biopsies respectively, with minimal overlap. Gene set enrichment analysis showed that ABC and GCB relapses are potentially mediated via different mechanisms, with tumor growth and proliferation signatures enriched in ABC relapse, compared with adaptive immunity-related signatures accompanying GCB progression. In parallel, we assessed the dynamics of the T-cell repertoire in paired biopsies observing a
reduction in T-cell fraction upon relapse that was most pronounced in ABC pairs and was positively correlated with changes in CD8⁺ T cells. Furthermore, we noted a decrease in T-cell clonal diversity that was independent of COO at relapse with evidence for significant T-cell specific clonal expansion.

**Conclusions:** The nature of the biological mechanisms responsible for DLBCL relapse has remained fairly elusive that may be inherent to the diagnostic tumor or acquired/enriched at disease relapse. Gene expression profiling of a series of DLBCL tumor pairs, resolved changes in gene expression that support distinct mechanisms of lymphoma relapse, based on a patient's COO, that parallel changes in the overall T-cell composition of the tumor microenvironment.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); gene expression profile (GEP); T-cells.

**Disclosures:** Korfi, K: Consultant Advisory Role: Roche. Rule, S: Consultant Advisory Role: Celgene, Sunesis, Astrazeneca, Napp, Pharmacyclics, TG Therapeutics, Kite, Gilead, Roche, Janssen; Honoraria: Celgene, Sunesis, Astrazeneca, Pharmacyclics, TG Therapeutics, Gilead, Roche, Janssen; Research Funding: Roche, Janssen; Other Remuneration: Roche, Janssen. Davies, A: Consultant Advisory Role: Roche, Kite, Celgene, Acerta Pharma, MorphoSys, Biolnvent; Honoraria: Roche, Celgene, Kite, Janssen; Research Funding: Roche, Acerta Pharma, Celgene, Gilead, Karyopharm, GSK; Other Remuneration: Roche, Celgene. Gribben, J: Honoraria: Janssen, Acerta, Celgene; Research Funding: Janssen, Acerta, Celgene. Johnson, P: Consultant Advisory Role: Janssen; Honoraria: Bristol-Myers Squibb, Takeda, Novartis, Celgene, Janssen, Epizyme, Boeringher Ingelheim, Kite, Genmab, Incyte; Research Funding: Janssen, Epizyme. Fitzgibbon, J: Consultant Advisory Role: Epizyme; Honoraria: Gilead; Research Funding: Epizyme.

095

DEFINING BURKITT-LIKE LYMPHOMA WITH 11Q ABERRATION IN A SPECIALISED UK HAEMATOPATHOLOGY DIAGNOSTIC SERVICE

S. Barrans<fnref n="1" /> | D. Painter² | S. van Hoppe<fnref n="1" /> |
A. Smith² | C. Sha³ | F. Cucco⁴ | M. Du⁴ |
D. Westhead³ | A. Davies⁵ | P. Johnson⁵ |
E. Roman² | C. Burton<fnref n="1" />

**Introduction:** A subset of aggressive lymphomas that have similar clinicopathological features to sporadic Burkitt lymphoma (BL), lack the hallmark MYC gene rearrangement that typifies BL, and are characterised by deregulation of genes on 11q<fnref n="1" />. Burkitt-like

lymphoma with 11q aberration (BLL-11q) is a provisional entity in the 2016 WHO classification of lymphoid malignancies², but its demonstration in routine practice has been limited because copy number variation using SNPa, the technique originally used to describe the abnormality, is not widely implemented for FFPE, and FISH probes to detect the simultaneous gain/loss of 11q23/11q24 are not widely available. Furthermore, there is little consensus how to treat these patients, although good outcomes based on BL-directed therapies have been reported³.

**Methods:** We retrospectively identified potential patients with 11q aberration from the HMRN population⁴ and REMoDL-B trial (ISRCTN51837425) based on their reported gene expression profile (GEP)<fnref n="1" /> using existing Illumina WG-DASL data. FISH probes were designed to cover the minimally gained and deleted regions on 11q using Cytocell MyProbes®, and these were validated against known positive cases². Of cases identified by GEP, 7/14 had an 11q aberration using FISH. In 2017 we incorporated this FISH assay into routine practice; testing samples with morphologic and immunophenotypic features that were similar to BL, but where MYC rearrangement was lacking, we identified a further 5/36 patients.

**Results:** In line with previous reports³,⁵, BLL-11q was found to be molecularly and phenotypically distinct from BL; all cases investigated to date using targeted Sanger sequencing lacked ID3/TCF3 mutations (6/6) that are associated with BL⁶, and the majority had molecular high grade (MHG)⁷ GEP (5/7) and most expressed LMO2 (3/5). This is in contrast to BL (n=138), which had high levels of ID3 (50/126) and TCF3 mutations (14/124), mostly lacked LMO2 (20/27), but also showed MHG GEP (51/65). Double hit lymphomas (DHL) had low incidence of TCF3/ID3 mutations (5/45), were mostly MHG (12/19) and mostly expressed LMO2 (6/7).

All patients treated with BL directed therapies (3/3) are alive with a median follow-up of 5 (0.4-7.6) years. Of those who received R-CHOP (n=4) or RB-CHOP (n=3), one relapsed after 8 months, one elderly patient died (10 months), and 5 remain in complete remission with a median follow-up of 2.7 (1.1-7.5) years.

**Conclusions:** These findings suggest that not all BLL-11q patients require high dose therapy, supporting the hypothesis that their biological features are more similar to DLBCL than BL. Further investigation into the molecular landscape of these patients is underway. Taken with data from the other molecular subgroups (DHL/MHG) this will direct standardised treatment decision making in routine practice, and help define when alternative therapies are warranted.

References

1. Salaverria et al 2014

2. Serdlow et al 2016

3. Rymkiewicz et al 2018

4. Smith et al 2018

5. Wagener et al 2019

6. Schmitz et al 2012

7. Sha et al 2018

<footnote n="1">¹HMDS, Leeds Cancer Centre, Leeds, United Kingdom; ²ECSG, Health Sciences, University of York, York, United Kingdom; ³School of Molecular and Cellular Biology (Faculty of Biological Sciences), University of Leeds, Leeds, United Kingdom; ⁴Department of Pathology, University of Cambridge, Cambridge, United Kingdom; ⁵Faculty of Medicine, University of Southampton, Southampton, United Kingdom</footnote>
**Keywords:** Burkitt lymphoma (BL); gene expression profile (GEP); molecular genetics.

**Disclosures:** Barrans, S: Other Remuneration: HTG molecular - travel sponsorship. Davies, A: Consultant Advisory Role: Roche, Kite, Celgene, Acerta Pharma, MorphoSys, BioInvent; Honoraria: Roche, Celgene, Kite, Janssen; Research Funding: Roche, Acerta Pharma, Celgene, Gilead, Karyopharma, GSK; Other Remuneration: Roche, Celgene. Johnson, P: Consultant Advisory Role: Janssen; Honoraria: Bristol-Myers Squibb, Takeda, Novartis, Celgene, Janssen, Epizyme, Boeringer Ingelheim, Kite, Genmab, Incyte; Research Funding: Janssen, Epizyme. Burton, C: Consultant Advisory Role: Roche, Takeda, BMS, Celgene; Honoraria: Roche, Takeda, BMS; Other Remuneration: Roche.

096
GENOME WIDE-ANALYSIS OF T(14;18)-
NEGATIVE FOLLICULAR LYMPHOMA

I. Müller<fnref n="1" /> | J. Ramis-Zaldívar² | J. Schmidt<fnref n="1" /> |

C. Egan<fnref n="3" /> | B. Gonzalez-Farre² |

J. Salmeron-Villalobos² | S. Mattern<fnref n="1" /> | V. Szablewski<fnref n="4" /> |

S. Dojcinov⁵ | A. Chott<fnref n="6" /> | C. Copie-Bergman⁷ |

I. Bonzheim<fnref n="1" /> | E. Campo² | F. Fend<fnref n="1" /> | E.S. Jaffe<fnref n="3" /> |

I. Salaverria² | **L. Quintanilla de Fend**<fnref n="1" />

**Introduction:** Follicular lymphoma (FL) represents about 20% of adult non-Hodgkin lymphomas (NHL) in Western countries. About 90% of FL carries the t(14;18)(q32;q21) translocation resulting in BCL2 over-expression. FL lacking the t(14;18) translocation and BCL2 protein expression are less well characterized and their pathogenesis remains largely unknown. The aim of this study was to genetically characterize a group of bona-fide t(14;18)-negative FL.

**Methods:** We analyzed 44 t(14;18)-negative, BCL2 protein negative, nodal FL cases grade 1-3A. PCR IGH clonality and FISH analysis for BCL2, BCL6 and IGH breaks were performed. The NGS analysis was based on a custom AmpliSeq panel (TNFRSF14, KMT2D, EP300, MEF2B, FOXO1, GNA13, HIST1H1B-E, CREBBP, EZH2, TNFAIP3, STAT6, SOCS1, XPO1, NOTCH2, MYD88, MAP2K1 and NOTCH2 [3'UTR]). The Ion Torrent sequencing platform was used. Copy number analyses were performed using the Oncoscan FFPE assay. Gains and losses and copy number neutral loss of heterozygosity (CNN-LOH) regions were evaluated and visually inspected using Nexus Bio-discovery version 9.0 software.

**Results:** All cases were IGH monoclonal and lacked a BCL2 translocation by FISH analysis. BCL6 translocation was identified in 7 cases (7/41; 17%). The genome-wide analysis showed that the 44 cases could be divided into 3 clusters based on their genetic changes. In the

<figure><img src="image_61.png" /></figure>

<footnote n="1">¹Institute of Pathology, University Hospital Tübingen, Eberhard-Karls-University of Tübingen, Tübingen, Germany; ²Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Universitat de Barcelona, Barcelona, Spain;</footnote>

<footnote n="3">³Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Maryland, United States;</footnote>

<footnote n="4">⁴Département de Biopatholog Cellulaire et Tissulaire des Tumeurs, CHU Montpellier, Hôpital Gui De Chauliac, Montpellier, France; ⁵Department of Pathology, University Hospital of Wales, Cardiff, United Kingdom;</footnote>

<footnote n="6">⁶Institute of Pathology and Microbiology, Wilhelminenspital, Vienna, Austria; ⁷Department of Pathology, Henri Mondor Hospital, APHP, INSERM U955, Université Paris-Est, Créteil, France</footnote>
first cluster there were 15 cases characterized by 1p and/or 16p CNN-LOH (100%). CREBBP and STAT6 were the most frequently mutated genes (67%), followed by TNFRSF14 (62%). Clinically, there was a female predominance (12/15; 80%), and inguinal presentation (10/15; 67%) with a frequent diffuse growth pattern (6/15; 40%). The second cluster comprised 14 cases without 1p or 16p CNN-LOH but 5 cases showed 1p deletion. CREBBP was the most frequently mutated gene (77%) followed by STAT6 (57%), KMT2D (50%), TNFRSF14 (43%) and EZH2 (36%) mutations. Clinically, there was a female predominance (9/14; 64%), some inguinal presentation (6/13; 46%) but diffuse growth pattern was rare (3 cases). In the third cluster there were 15 cases characterized by low number of genetic alterations. CREBBP was not mutated and CNN-LOH was not identified. Clinically, no sex predilection and rare inguinal presentation was observed. The BCL6 translocated cases were equally distributed among the three groups.

**Conclusions:** BCL2-negative FLs are genetically and clinically a heterogeneous disease. Three different genetic profiles were identified that correlated with some clinical features. Groups 1 and 2 had in common the frequent occurrence of STAT6 and CREBBP mutations; however, they differed in the extent of 1p and 16p CNN-LOH and deletions. Group 3 showed low mutational level and different clinical features. MAP2K1 mutations were not identified in any of the cases indicating that BCL2-negative FL and pediatric-type FL are two different entities.

**Keywords:** follicular lymphoma (FL).

## SESSION 7 – HODGKIN LYMPHOMA

### 097
STAGE I-II NODULAR LYMPHOCYTE-PREDOMINANT HODGKIN LYMPHOMA IN THE MODERN ERA: A MULTI-INSTITUTIONAL EXPERIENCE OF ADULT PATIENTS BY ILROG

M.S. Binkley<fnref n="1" /> | M. Rauf² | S.A. Milgrom³ |
C.C. Pinnix³ | R. Tsang<fnref n="4" /> | A. Ng⁵ | K.B. Roberts⁶ |
S. Gao⁶ | U. Ricardi⁷ | M. Levis⁷ | C. Casulo⁸ |
M. Stolten⁹ | C.R. Kelsey¹⁰ | J.L. Brady¹¹ |
N. Mikhaeel¹¹ | B.S. Hoppe¹² | S.A. Terezakis¹³ |
Y. Kirova¹⁴ | S. Akhtar² | I. Maghfoor² |
J.L. Koenig<fnref n="1" /> | C. Jackson⁶ | E. Song¹⁰ | S. Segal¹³ |
R.H. Advani¹⁵ | Y. Natkunam¹⁶ | L.S. Constine⁹ |
H. Eich¹⁷ | A. Wirth¹⁸ | R.T. Hoppe<fnref n="1" />

⁵Radiation Oncology, Dana Farber and Harvard University School of Medicine, Boston, United States; ⁶Radiation Oncology, Yale University, New Haven, United States; ⁷Oncology, University of Turin, Torino, Italy; ⁸Medical Oncology, University of Rochester, Rochester, United States; ⁹Radiation Oncology, University of Rochester, Rochester, United States; ¹⁰Radiation Oncology, Duke University School of Medicine, Durham, United States; ¹¹Radiation Oncology, Guy's Cancer Centre, Guy's and St Thomas' NHS Hospital, London, United Kingdom; ¹²Radiation Oncology, University of Florida, Jacksonville, United States; ¹³Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, United States; ¹⁴Radiation Oncology, Institut Curie, Paris, France; ¹⁵Medical Oncology, Stanford University School of Medicine, Stanford, United States; ¹⁶Pathology, Stanford University School of Medicine, Stanford, United States; ¹⁷Radiation Oncology, Munster University, Munster, Germany; ¹⁸Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

**Introduction:** Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon subtype of HL; the optimal management of stage I-II remains undefined.

**Methods:** We conducted a multi-center retrospective study including patients (pts) ≥16 years (yr) with CD20+ stage I-II NLPHL diagnosed from 1995-2018. Management included observation after excision, single agent rituximab (R), chemotherapy (CT), radiation therapy (RT), and combined modality therapy (CMT=RT+systemic therapy). Primary outcomes were progression-free survival (PFS, by clinical, radiographic or pathologic progression) and overall survival (OS). Outcomes were measured with the Kaplan-Meier method with uni- and multivariable analyses (MVA) conducted with Cox regression.

**Results:** We identified 437 pts with stage I-II NLPHL with median age 38 yr (range, 16-90) and median follow up of 5 yr (interquartile range=2.0-8.2). The majority were male (n=307 [70%]), had stage I (n=241 [55%]), ECOG 0-1 (n=366 [84%]), and were staged by PET-CT (n=295 [68%]). The 5-yr PFS and OS were 86.7% and 97.6%, respectively. 5-yr PFS by treatment were: 89.7% for RT (n=199 [46%], median dose 36 Gy), 92.5% for CMT (n=160 [37%]), 69.9% for CT

<figure><img src="image_62.png" /></figure>

<footnote n="1">¹Radiation Oncology, Stanford University School of Medicine, Stanford, United States; ²Medical Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; ³Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, United States;</footnote>

<footnote n="4">⁴Radiation Oncology, Princess Margaret Cancer Center, Toronto, Canada;</footnote>
(n=37 [8%]), 92.9% for observation (n=29 [7%]), and 33.3% for R (n=12 [3%]). CT only regimens were ABVD (n=27, 3 with R), R-CHOP (n=9), and R-COMP (n=1). CMT systemic therapies were ABVD (n=116, 19 with R), R-CHOP (n=24), R (n=15), MOPP (n=3), BEACOPPesc (n=1), and CVP (n=1). On univariable analysis, stage II (p=0.008), age (continuous, p=0.004), R alone (p=0.0005), and omission of RT (p=0.0001) were associated with worse PFS. There was no difference in PFS for pts with stage II NLPHL who received RT vs CMT (p=0.88). For RT alone group, RT volume (extended-field n=28 [14%], involved-field n=114 [57%], involved-site n=51 [26%], unknown n=6 [3%]) was not associated with PFS (p=0.77). On MVA, age (p=0.02) and omission of RT (p=0.002) remained associated with worse PFS. After adjusting for age and stage, treatment type was not associated with OS. A subset had immunoarchitectural pattern (IAP) available (n=206, 47.1%), and those with variant pattern (C-F n=43) had significantly worse PFS (p=0.03). 5-yr PFS for pts with IAP C-F receiving CMT (n=18) vs. RT (n=14), was 100% vs 78.6%, respectively (p=0.18). 14 pts (3.2%) experienced large cell transformation. 16 pts (3.7%) had a second cancer: n=14 outside RT field, n=2 within RT field (5 and 10-yr post-RT), n=2 no RT.

**Conclusions:** OS for pts with stage I-II NLPHL is excellent and did not differ based on treatment after adjusting for age and stage. There was no PFS benefit for pts with stage II NLPHL receiving CMT over RT alone although there was a suggestion that pts with IAP C-F may benefit from CMT. PFS was superior among pts who received RT as a component of initial therapy.

**Keywords:** nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).

098

NIVOLUMAB PLUS DOXORUBICIN, VINBLASTINE AND DACARBAZINE FOR NEWLY DIAGNOSED ADVANCED-STAGE CLASSICAL HODGKIN LYMPHOMA: CHECKMATE 205 COHORT D 2-YEAR FOLLOW-UP

S. Ansell<fnref n="1" /> | R. Ramchandren² |

E. Domingo-Domènech³ | A. Rueda⁴ | M. Trněný⁵ |

T. Feldman⁶ | H. Lee⁷ | M. Provencio⁸ |

C. Sillaber⁹ | J. Cohen¹⁰ | K. Savage¹¹ |

W. Willenbacher¹² | A. Sumbul¹³ | M. Sacchi¹³ |

P. Armand¹⁴

Medicine, University of Texas MD Anderson Cancer Center, Houston, United States; ⁸Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain; ⁹Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria; ¹⁰Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, United States; ¹¹Department of Pathology and Laboratory Medicine, British Columbia Cancer Center for Lymphoid Cancer, Vancouver, Canada; ¹²Department of Internal Medicine, Innsbruck University Hospital & OncoTyrol - Center for Personalized Cancer Medicine, Innsbruck, Austria; ¹³Bristol-Myers Squibb, Princeton, United States; ¹⁴Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States

**Introduction:** Up to 30% of patients (pts) with advanced-stage (AS) classical Hodgkin lymphoma (cHL) are not cured by current front-line therapies (Tx). High expression of programmed death-1 (PD-1) ligands in these pts, associated with frequent genetic alterations at chromosome 9p24.1 in Hodgkin Reed-Sternberg cells, supports the investigation of front-line PD-1 blockade in cHL. Promising activity and acceptable safety were reported in newly diagnosed pts with AS cHL treated with nivolumab, an anti-PD-1 immune checkpoint inhibitor monoclonal antibody, followed by nivolumab plus doxorubicin, vinblastine and dacarbazine (N-AVD) at a 9-mo follow-up of CheckMate 205 Cohort D (NCT02181738). Here, we report the efficacy and safety of this cohort in a 2-y extended follow-up, including Deauville assessment of tumor response.

**Methods:** Pts ≥ 18 y of age with newly diagnosed AS cHL (stage IIB with unfavorable risk factors, III, or IV) received 4 doses of nivolumab monotherapy (240 mg IV every 2 weeks) followed by N-AVD combination Tx for 6 cycles (12 doses). Primary endpoint was safety; secondary endpoints included complete remission (CR) rate per independent review committee (IRC) at end of study Tx (EOT) using 2007 International Working Group criteria. Complete metabolic response (CMR) was defined as a Deauville score of ≤ 3 (PET negative) in a post hoc analysis

<figure><img src="image_63.png" /></figure>

<footnote n="1">¹Division of Hematology, Mayo Clinic, Rochester, United States; ²Division of Hematology and Oncology, University of Tennessee, Knoxville, United States; ³Hematology Department, Institut Català d'Oncologia, Barcelona, Spain; ⁴Servicio de Oncología, Hospital Costa del Sol, Marbella, Spain; ⁵Department of Haematology, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic; ⁶Hematology & Oncology, Hackensack University Medical Center, Hackensack, United States; ⁷Department of Lymphoma and Myeloma, Division of Cancer</footnote>
by IRC. Overall survival (OS) and modified progression-free survival (mPFS; time to progression, death, or subsequent Tx) were exploratory endpoints. PFS was a post hoc analysis.

**Results:** Fifty-one pts were treated (median age 37 y); minimum follow-up was 24.4 mo at data cut-off. Other baseline characteristics have been previously described (Ramchandren R et al. EHA 2018). Monotherapy was completed by 49/51 (96%) pts, combination Tx by 45/50 (90%); 48 pts entered follow-up. After 2 combination cycles, CR rate was 51% per IRC (71% CMR) and 71% per investigator; at EOT, CR rate was 69% (75% CMR) per IRC and 80% per investigator. At 21 mo, mPFS rate per investigator was 80% (95% CI, 66–89) and PFS rate per investigator was 83% (95% CI, 69–91; **Figure**). Overall, 30 (59%) pts experienced grade (G) 3–4 TRAEs, most commonly neutropenia in 21 (41%). The most common G 3–4 immune-mediated AE was hepatitis (2 pts, 4%). No G 5 TRAEs occurred ≤ 30 d from last dose; 2 deaths were reported during the extended follow-up: 1 pt (aged 68 y) died 38 d after last dose due to study drug toxicity; another (aged 85 y) died 451 d after last dose due to disease progression.

**Conclusions:** With extended follow-up, nivolumab followed by N-AVD demonstrated a 21-mo PFS rate of 83% per investigator, a high metabolic response rate with 75% CMR at EOT per IRC, with no new safety signals. Incorporation of Deauville assessment improved the concordance of CR between IRC- and investigator-assessed responses. Nivolumab followed by N-AVD provides a promising alternative Tx option in newly diagnosed AS cHL.

**Keywords:** classical Hodgkin lymphoma (cHL); nivolumab; PD-1.

**Disclosures:** Ansell, S: Honoraria: WebMD, Research to Practice; Research Funding: Affimed Therapeutics (Inst), Bristol-Myers Squibb (Inst), Merck (Inst), Regeneron (Inst), Seattle Genetics (Inst), Trillium Therapeutics (Inst), Pfizer (Inst). Ramchandren, R: Consultant Advisory Role: Bristol-Myers Squibb, Seattle Genetics; Research Funding: Merck, Pharmacyclics, Janssen. Domingo-Domènech, E: Honoraria: Bristol-Myers Squibb, Takeda; Other Remuneration: Travel, Accommodations, Expenses: Bristol-Myers Squibb, Roche, Takeda. Rueda, A: Consultant Advisory Role: Bristol-Myers Squibb, Merck, MSD, Novartis, Roche, Takeda; Honoraria: Bristol-Myers Squibb, Merck, MSD, Roche. Trněný, M: Consultant Advisory Role: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Gilead Sciences, Incyte, Janssen, MorphoSys, Roche, Takeda; Honoraria: AbbVie, Amgen, Bristol-Myers Squibb, Gilead Sciences, Incyte, Janssen, MorphoSys, Roche, Takeda; Other Remuneration: Travel, Accommodations, Expenses: AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Roche, Takeda. Feldman, T: Consultant Advisory Role: Bristol-Myers Squibb, Seattle Genetics; Honoraria: Takeda; Research Funding: Portola (Inst), Seattle Genetics (Inst); Other Remuneration: Celgene, Pharmacyclics, Seattle Genetics, KITE, Johnson and Johnson, Janssen. Lee, H: Employment Leadership Position: MD Anderson Cancer Center; Consultant Advisory Role: Bristol-Myers Squibb; Honoraria: Bristol-Myers Squibb; Research Funding: Bristol-Myers Squibb, Celgene, Oncternal. Provencio, M: Consultant Advisory Role: AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Takeda, Roche, Novartis, Pfizer; Honoraria: Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Boerhinger; Research Funding: Roche, Boerhinger, Bristol-Myers Squibb. Cohen, J: Consultant Advisory Role: AbbVie, Celgene, Genentech, Pharmacyclics, Seattle Genetics; Research Funding: American Society of

Hematology, Bristol-Myers Squibb, Lam Therapeutics, Lymphoma Research Foundation, Novartis, Seattle Genetics, Takeda, Unum Therapeutics. **Sav- age, K:** Consultant Advisory Role: AbbVie, Bristol-Myers Squibb, Merck, Seattle Genetics, Servier, Verastem; Honoraria: Bristol-Myers Squibb, Merck, Seattle Genetics, Takeda; Research Funding: Roche (Inst). **Willenbacher, W:** Consultant Advisory Role: Bristol-Myers Squibb, Takeda; Honoraria: Bristol-Myers Squibb, Takeda; Research Funding: Bristol-Myers Squibb, Takeda. **Sumbul, A:** Employment Leadership Position: Bristol-Myers Squibb. **Sacchi, M:** Employment Leadership Position: Bristol-Myers Squibb. **Armand, P:** Consultant Advisory Role: Affimed Therapeutics, Bristol-Myers Squibb, Infinity Pharmaceuticals, Merck, Pfizer, Adaptive; Research Funding: Affimed Therapeutics (Inst), Bristol-Myers Squibb (Inst), Merck (Inst), Otsuka (Inst), Pfizer (Inst), Roche (Inst), Sequenta (Inst), Sigma Tau (Inst), Tensha Therapeutics (Inst), Adaptive (inst); Other Remuneration: Travel, Accommodations, Expenses: Genmab.

099

CONSOLIDATION RADIOTHERAPY COULD BE OMITTED IN ADVANCED HODGKIN LYMPHOMA WITH LARGE NODAL MASS IN COMPLETE METABOLIC RESPONSE AFTER ABVD. FINAL ANALYSIS OF THE RANDOMIZED HD0607 TRIAL

A. Gallamini<fnref n="1" /> | A. Rossi² | C. Patti<fnref n="3" /> | M. Picardi⁴ |

A. Romano⁵ | M. Cantonetti⁶ | S. Oppi⁷ |

S. Viviani⁸ | S. Bolis<fnref n="9" /> | L. Trentin¹⁰ | G. Gini¹¹ |

R. Battistini¹² | S. Chauvie¹³ | L. Bertolotti<fnref n="14" /> |

C. Pavoni² | G. Parvis¹⁵ | R. Zanotti¹⁶ |

P. Gavarotti¹⁷ | M. Cimminiello¹⁸ | C. Schiavotto<fnref n="19" /> |

P. Viero²⁰ | A. Avigdor²¹ | C. Tarella²² | A. Rambaldi²

<footnote n="1">¹Research & Clinical Innovation, Antoine Lacassagne Cancer Centre, Nice, France; ²Department of Oncology-Hematology, University of Milan and Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy;</footnote>

<footnote n="3">³Hematology, V. Cervello Hospital, Palermo, Italy; ⁴Hematology,</footnote>

<footnote>Policlinico Federico II, Naples, Italy; ⁵Hematology, Policlinico Vittorio</footnote>

<footnote>Emanuele Hospital, Catania, Italy; ⁶Hematology, Policlinico Hospital Tor</footnote>

<footnote>Vergata, Rome, Italy; ⁷Hematology, Businco Oncology Hospital, Cagliari,</footnote>

<footnote>Italy; ⁸Hematology, National Institute of tumors, Milan, Italy;</footnote>

<footnote n="9">⁹Hematology, S. Gerardo University Hospital, Monza, Italy; ¹⁰Medicine,</footnote>

<footnote>Padua University, Padua, Italy; ¹¹Hematology, Ospedali Riuniti Le</footnote>

<footnote>Torrette, Ancona, Italy; ¹²Hematology, S. Camillo Forlanini Hospital,</footnote>

<footnote>Rome, Italy; ¹³Medical Physics, S. Croce Hospital, Cuneo, Italy;</footnote>

<footnote n="14">¹⁴Hematology, S. Croce Hospital, Cuneo, Italy; ¹⁵Hematology, Mauriziano</footnote>

<footnote>Hospital, Turin, Italy; ¹⁶Hematology, Azienda Ospedaliera Universitaria</footnote>

<footnote>Integrata, Verona, Italy; ¹⁷Hematology, University Hospital Città della</footnote>

<footnote>salute, Turin, Italy; ¹⁸Hematology, S. Carlo Hospital, Potenza, Italy;</footnote>

<footnote n="19">¹⁹Hematology, S. Bortolo Hospital, Vicenza, Italy; ²⁰Hematology,</footnote>

<footnote>Dell'Angelo Hospital, Venice, Italy; ²¹Hematology and Bone Marrow</footnote>

<footnote>Transplantation, Sheba Medical Center, Tel-Aviv, Israel; ²²Hematology,</footnote>

<footnote>European Institute of Oncology, Milan, Italy</footnote>
<figure><img src="image_64.png" /></figure>

**Introduction:** Consolidation Radiotherapy (cRT) was originally proposed for ABVD-treated advanced stage Hodgkin Lymphoma (aHL) presenting with bulky or a residual mass (RM) after ABVD. However, very few published data exist on the role of cRT on RM in patients (pts) with a negative end-of treatment PET (EoT-PET) after ABVD.

**Methods:** In the HD0607 clinical trial (Gallamini JCO 2018) aHL pts (stage IIB-IVB) were treated with 2 ABVD courses, followed by an interim PET (PET-2). PET-2 positive pts were randomized to 4 BEACOPP escalated + 4 BEACOPP baseline cycles ± rituximab before each cycle. PET-2 negative pts were treated with 4 more ABVD and a EoT-PET was performed afterwards. PET-2 and EoT-PET negative pts were randomized to either cRT on the sites where a large nodal mass (LNM) was detected at baseline, or no further therapy (NFT). LNM was defined as single or a conglomerated nodal mass with the largest diameter ≥ 5 cm in baseline CT.

**Results:** After ABVD, 47/630 (7%) PET2 negative pts with a positive EoT-PET, 27/630 off study pts for disease progression or consent withdrawal and 260 pts without LNM were not suitable for the random, while 296 were randomized to cRT (148) or NFT (148). In this pts cohort the largest diameter of LNM was 5-7 cm in101 (34%) 8-10 cm in 96 (32%), while a classical bulky (diameter >10 cm) was detected in 99 (33%) pts. Prognostic factors, age, sex, stage, IPS, Performance status, extra-nodal sites, bulky disease were well balanced between the two cohorts. In pts presenting with one (265) or more (31) LNM, the most common nodal region was mediastinum (82%), followed by cervical (14%), abdominal (6%) or axillary (3%) regions. A post-ABVD RM was detected in 260 (88%) of 296 pts presenting with a LNM and in 92/99 pts with classical bulky. The median dose of RT was 30.6 (24.0-113.6) Gy, by involved field (88%) involved node (1%) or involved site (11%) technique. After a median follow-up of 5.9 (0.5-10) years the 6-year PFS for RT versus NFT in an intention to treat analysis was 92% (95% CI, 88-97%) versus 90% (95% CI, 85-95%) p = .48 (Figure) and a 6-year OS 99% (95% CI, 97-100%) versus 98% (95% CI, 96-100%), respectively. When the analysis was limited to patients with a classical bulky lesion, the 6-year PFS was 89% (95% CI, 81-99%) for consolidation RT and 86% (95% CI, 77-96%) for NFT (p = .53). The 6-year PFS of the 260 non-randomized pts without

LNM at baseline, was 92% (95% CI, 88-95%). When the analysis was limited to those with RM, the relapse rate of patients treated or not with cRT was 7% versus 9%, with a 6-year PFS of 93% (95% CI, 88% to 97%) versus 89% (95% CI, 84% to 95%) (P = .41).

**Conclusions:** cRT could be safely omitted in aHL pts presenting with a LNM and both a negative PET-2 and EoT-PET, irrespective from the LNM size. As in more than 80% of the pts the site of LNM at baseline was in mediastinum, this could translate in a significant reduction of late-onset treatment related mortality for secondary tumours and coronary arterial disease.

**Keywords:** ABVD; classical Hodgkin lymphoma (cHL); positron emission tomography (PET).

## 100 COST-EFFECTIVENESS AND COST-UTILITY ANALYSIS OF MULTIPLE TREATMENT STRATEGIES USING ABVD AND/OR BEACOPP IN THE TREATMENT OF ADVANCED-STAGE HODGKIN LYMPHOMA

A. Prica¹ | A. Vijenthira² | K. Chan³ | M. Cheung³

¹Department of Hematology/Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada; ²Postgraduate Medicine, University of Toronto, Toronto, Canada; ³Department of Hematology/Medical Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada

**Background:** There remains clinical equipoise over the best initial treatment strategy for advanced-stage Hodgkin lymphoma. Recent PET-adapted trials (RATHL, HD18, AHL2011) have tried to balance the trade-off that occurs with an inferior progression-free survival in the ABVD strategy, but higher rates of hematologic toxicity, infertility, and second malignancy in the BEACOPP strategy. The overall lifetime cost of each strategy remains unknown, especially costs which incorporate therapies for relapsed disease including brentuximab consolidation after autologous stem cell transplant and palliative therapy with nivolumab, and associated health state utilities.

**Methods:** We developed a Markov decision analytic model to compare the life expectancy, quality-adjusted life expectancy (QALYs), and direct costs with varying upfront treatment regimens for a

<table><caption>**TABLE 1** 20-year life expectancy, quality adjusted life years (QALYs) and direct costs for multiple initial treatment strategies for advanced-stage Hodgkin lymphoma</caption><thead><tr><td>Regimen</td><td>Life expectancy</td><td>QALYs</td><td>Direct costs</td></tr></thead><tbody><tr><td>ABVD</td><td>12.5 years</td><td>12.1 years</td><td>$94,152</td></tr><tr><td>BEACOPP (including HD18)</td><td>14.2 years</td><td>12.8 years</td><td>$72,203</td></tr><tr><td>RATHL</td><td>14.5 years</td><td>13.2 years</td><td>$59,247</td></tr><tr><td>Echelon-1 (A-AVD)</td><td>13.8 years</td><td>12.7 years</td><td>$165,294</td></tr><tr><td>AHL2011</td><td>14.9 years</td><td>13.4 years</td><td>$58,136</td></tr></tbody></table>
<figure><img src="image_65.png" /></figure>

hypothetical cohort of transplant-eligible patients with newly-
diagnosed advanced-stage Hodgkin lymphoma. A 20-year time hori-
zon was used. Baseline probability estimates and utilities were derived
from a systematic review of published studies (i.e. HD2000, Viviani,
EORTC, HD15, HD18, RATHL, AHL2011, Echelon-1). A Canadian
public health payer's perspective was considered and costs are pres-
ented in 2018 Canadian dollars. All costs and benefits were
discounted by 1.5%. Sensitivity analyses were performed for key
variables.

**Results:** See Table 1 for results of the 20-year model. In the base-case analysis, the AHL2011 protocol was associated with both cost-savings and improved quality-adjusted outcomes over all other treatment strategies (Figure 1A). Sensitivity analyses demonstrated that the model was robust to key variables including probability of treatment-related mortality, probability of death from secondary malignancy, and probability of infertility secondary to BEACOPP. The threshold utility of infertility was found to be 0.71 (Figure 1B). Probabilistic sensitivity analyses (10,000 simulations) were performed (Figure 1C). For the WTP threshold of $100,000, AHL2011 was the dominant strategy 73% of the time (Figure 1D).

**Conclusions:** The preferred treatment strategy for patients with newly diagnosed advanced-stage Hodgkin lymphoma is the AHL2011 PET-adapted regimen. This strategy maximizes life expectancy, quality-adjusted life years, and is the most cost-effective strategy, accounting for increased rates of hematologic toxicity, secondary malignancy, and infertility caused by exposure to at least 2 cycles of BEACOPP.

Keywords: ABVD; BEACOPP; Hodgkin lymphoma (HL).

SESSION 8 – FOLLICULAR LYMPHOMA

101
PROGNOSTIC IMPLICATIONS OF THE
MICROENVIRONMENT IN FOLLICULAR
LYMPHOMA UNDER RITUXIMAB AND
RITUXIMAB+LENALIDOMIDE THERAPY.
A TRANSLATIONAL STUDY OF THE
SAKK35/10 TRIAL

T. Menter<sup>1</sup> | A. Tzankov<sup>1</sup> | E. Zucca<sup>2</sup> | E. Kimby<sup>3</sup> |

A. Vanazzi⁴ | B. Østenstad⁵ | U.J. Mey⁶ |

D. Rauch<sup>7</sup> | B. Wahlin<sup>3</sup> | F. Hitz<sup>8</sup> | M. Hernberg<sup>9</sup> |

A. Johansson¹⁰ | P. de Nully Brown¹¹ | H. Hagberg¹² |

H. Hawle¹³ | S. Hayoz¹³ | S. Dirnhofer¹

¹Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland; ²Division of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; ³Division of Hematology, Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden; ⁴Clinical Haemato-Oncology, Istituto Europeo di Oncologia, Milan, Italy; ⁵Department of Oncology, Oslo University Hospital, Oslo, Norway; ⁶Medical Oncology and Hematology, Kantonsspital Graubünden, Chur, Switzerland; ⁷Division of Oncology,
<figure><img src="image_66.png" /></figure>

Spital Thun Simmenthal, Thun, Switzerland; ⁸Oncology/Hematology, Kantonsspital St.Gallen, St. Gallen, Switzerland; ⁹Department of Oncology, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; ¹⁰Department of Oncology, Norrlands Universitetssjukhus, Umea, Sweden; ¹¹Department of Hematology, Rigshospitalet, København, Denmark; ¹²Oncology, Uppsala University Hospital, Uppsala, Sweden; ¹³Coordinating Center, SAKK, Bern, Switzerland

**Introduction:** Follicular lymphoma (FL) constitutes a significant disease proportion of lymphomas and is prone to relapsing after therapy. Lately, new therapeutic approaches beyond conventional chemotherapy have emerged focusing on the interplay between lymphoma cells and the surrounding reactive cells of the microenvironment.

**Methods:** Here we report the immunophenotypic investigation of the microenvironment of a clinically well characterized cohort (study SAKK35/10) including 135 evaluable treatment naïve FL patients in need of treatment, who have been treated with either rituximab (R) only or a combination of rituximab and the immunomodulatory drug lenalidomide (R/R).

**Results:** After initial large-scale phenotypic (BCL2, CD3, CD4, CD5, CD8, CD21, CD68, CD163, Cereblon, c-MYC, FoxP3, GATA3, Granzyme B, PD1, PDL1, Perforin, pSTAT5, t-BET, TIA1) analysis of 34 tissue-microarrayed biopsies focusing on prognostic impact, several promising markers for T-cell subgroups were selected for further evaluation of the whole cohort of 135 patients. High ratio of CD4- to CD8-positive T cells (p=0.009) and an increased amount of PD1-positive T-cells (p=0.007) were associated with inferior progression free survival (PFS) in the whole cohort. These findings remained significant in the multivariate statistical analysis taking into consideration FLIPI and stage of the disease. Interestingly, the prognostic impact of PD1-positive T-cells and the CD4/CD8 ratio was lost in the subgroup treated with lenalidomide. In the latter group, high amounts of GATA3-positive TH2-equivalents was associated with better PFS (p<0.001) and also overall survival (p=0.030), see also the attached figure for survival curves related to PD1- and GATA3 positive T-cells of the two treatment groups.

**Conclusions:** Based on data from this prospective clinical trial on FL, we identified tumor microenvironmental characteristics which may allow prognostic stratification with respect to immuno- and combined
immuno- and immunomodulatory therapy. Our analysis implicates that lenalidomide might help to overcome the adverse prognostic implication of higher amounts of regulatory T cells in the microenvironment of follicular lymphoma and that it may have particularly favorable effects in cases with higher amounts of TH2-equivalents as demonstrated by GATA3-positive T-cells. Additional analysis by gene expression profiling of the microenvironment may further contribute to a better understanding of this so far still underestimated component of follicular lymphoma.

**Keywords:** follicular lymphoma (FL); immunohistochemistry (IHC); lenalidomide.

102
DECIPHERING THE CONTRIBUTION OF
MACROPHAGES TO FOLLICULAR
LYMPHOMA PATHOGENESIS: NEW
INSIGHTS INTO THERAPY

P. Perez Galan¹

J.G. Valero¹

A. Matas-Cespedes²

V. Rodriguez³

F. Arenas¹

J. Carreras⁴

N. Serrat¹

M. Guerrero-Hernandez¹

M. Corbera⁵

A. Yahiaoui⁶

S. Martin¹

A. Rivas-Delgado¹

S. Tannheimer⁶

M. Cid⁵

E. Campo¹

A. López-Guillermo⁷

D. Colomer¹

¹Hemato-Oncology, IDIBAPS, Barcelona, Spain; ²Clinical pharmacology and Safety Sciences, Astra Zeneca, Cambridge, United Kingdom; ³Tumor Progression, Garvan Institute of Medical Research, Sydney, Australia;

⁴Pathology, Tokai University, School of Medicine, Kanagawa, Japan;

⁵Internal Medicine, IDIBAPS, Barcelona, Spain; ⁶Oncology, Gilead Sciences, Seattle, United States; ⁷Hematology, Hospital Clinic, Barcelona, Spain

**Introduction:** Follicular Lymphoma (FL) represents the paradigm of a lymphoid neoplasia depending on microenvironment. Early studies by gene expression profiling (GEP) in FL tumor biopsies found that those cases enriched in certain genes expressed mainly in macrophages and Follicular Dendritic Cells (FDC) showed an inferior outcome (Dave et al, NEJM 2004). In the current study we have analyzed the three-way crosstalk of FL-FDC-M2, the correlation of CSF1-R expression, the M-CSF receptor essential for macrophage differentiation, with FL clinical data, and explored the potential antitumor effect of FL-M2 disruption using a specific CSF1-R inhibitor in combination with anti-B cell therapies.

<figure><img src="image_67.png" /><figcaption>Figure 2</figcaption></figure>

<figure><img src="image_68.png" /><figcaption>Figure 3</figcaption></figure>

<figure><img src="image_69.png" /><figcaption>Figure 4</figcaption></figure>

<figure><img src="image_70.png" /></figure>
**Methods:** Primary FL cells (n=5) were co-culture (48h) with M2 macrophages at 4:1 ratio, generated from peripheral blood monocytes of healthy donors (100ng/mL M-CSF). Purified B cells (CD20 beads, Miltenyi) were subjected to GEP using HG-U219 microarray (Affymetrix). Data mining analysis was done with GSEA software. IHC analysis of CSF1-R and CD163 expression were performed in FFPE of FL patients (grade 0-2 (n=59) grade 3a-3b (n=28)). *In vivo* FL-FDC mouse model was generated by sc inoculation of the FL cell lines RL or WSUFSCC L w/wo the FDC non-immortalized cell line HK in SCID mice.

**Results:** *In vivo*, FDC significantly increased FL cell lines tumorigenicity (p<0.001), being these FL-FDC co-xenografts highly infiltrated with mouse M2 macrophages (CD206+). Remarkably, macrophage depletion (liposomal clodronate) significantly (p< 0.001) decreased tumor growth, supporting the contribution of macrophages to FL progression. Cell culture supernatants from FL-FDC co-cultures were enriched in pro-angiogenic factors and in the macrophage-attractant CCL2, favoring *in vitro* monocyte recruitment to the tumor. Moreover, primary cultures of FL cells induce monocyte differentiation towards M2-like macrophages (Fig.1). FL viability was significantly increased in FL-M2 co-cultures, and gene sets related to migration, adhesion and invasion were enriched in FL cells (Fig.2). Interestingly, in FL tumor biopsies, while the well-established M2 maker CD163 did not correlate with FL clinical parameters, CSF1-R expression correlated with the histological grade. The CSF1-R inhibitor Pexidartinib (PLX3397) changed M2 integrin profile decreasing their adhesion, and switching the M2 macrophage polarization towards a M1 phenotype (Fig.3). PLX3397 hampers the *in vitro* pro-survival effect provided by M2 to FL primary cells. *In vivo*, the simultaneous targeting of FL tumor cells with anti-CD20 Rituximab and Macrophages with PLX3397, led to a cooperative and significant reduction of tumor growth (Fig.4).

**Conclusions:** In summary, these results support the role of M2 macrophages in FL pathogenesis and suggest that therapies manipulating FL-M2 crosstalk may be a new strategy, especially in combination with anti-B cell therapies.

**Keywords:** dendritic cells; follicular lymphoma (FL); macrophages.

103
# IMPACT OF PET IMAGING AND HISTOLOGIC TRANSFORMATION ON THE PROGNOSIS OF EARLY DISEASE PROGRESSION IN FOLLICULAR LYMPHOMA

C.L. Batlevi¹ | F. Sha¹ | A. Alperovich¹ | A. Ni¹ |
K. Smith¹ | Z. Ying¹ | P. Hamlin¹ | S.M. Horwitz¹ |

A. Kumar¹ | M. Matasar¹ | A.J. Moskowitz¹ |

C.H. Moskowitz² | A. Noy¹ | M.L. Palomba¹ |

C. Portlock¹ | D. Straus¹ | C. Bocomini³ |

A. Tucci⁴ | A.D. Zelenetz¹ | V.E. Seshan⁵ |

S. Luminari⁶ | L. Marcheselli⁷ | M. Federico⁶ |

A. Younes¹

¹Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, United States; ²Department of Medicine, University of Miami, Sylvester Cancer Center, Miami, United States; ³ASO Città della Salute e della Scienza di Torino, Ematologia, Turin, Italy;

⁴Department of Hematology, Spedali Civili di Brescia, Brescia, Italy;

⁵Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States; ⁶Department of Surgical, Medical, Dental and Morphological Sciences related to Transplant, Oncology and Regenerative medicine, Department of Surgical, Medical, Dental and Morphological Sciences related to Transplant, Oncology and Regenerative medicine, University of Modena and Reggio Emilia, Modena, Italy; ⁷Department of Medical and Surgical Sciences, and FIL Trial Office, University of Modena and Reggio Emilia, Modena, Italy

**Introduction:** The ability of progression-free survival status within the first 24 months (PFS24) to predict adverse overall survival (OS) in follicular lymphoma (FL) patients were reported in patients whose pretreatment imaging modality was unknown. Since 2-[¹⁸F] Flouro-2-deoxyglucose positron emission tomography (PET) based staging more accurately identifies disease sites and de novo transformation, we investigated the impact of pre-treatment PET staging on the prognostic value of PFS24.

**Methods:** We retrospectively evaluated treatment outcomes in 1,053 patients with grade 1-3A FL diagnosed and managed at Memorial Sloan Kettering Cancer Center from 1998 to 2009. We identified 238 patients with stage II-IV grade 1-3A FL initially treated with R-CHOP chemotherapy to analyze the impact of PFS24 on OS, 84 patients with pretreatment CT, 154 patients with pretreatment PET. Histological transformations to DLBCL at time of relapse were biopsy confirmed. An independent cohort of 161 FL patients, 114 patients with pretreatment CT, and 47 patients with pretreatment PET, treated with R-CHOP between 2006-2010 in the FOLL05 clinical trial was used for validation. We applied both event defining and landmark analyses to risk stratify patients based on early progression status. We used a competing risk analysis to understand the association between early progression and transformation.

**Results:** For patients not achieving PFS24 in an event defining analysis, the 10-year OS was 67.1% for PET-based pretreatment imaging and 43.2% for CT-based imaging (Figure A). In the validation cohort, the 5-year OS of patients not achieving PFS24 was 54% in CT-imaged patients and 100% in PET-imaged patients (Figure B). Using a landmark analysis at 24 months, the 10-year OS for patients not achieving PFS24 was 76% for PET-imaged and 47% for CT-imaged patients, with similar results in the validation cohort. In a competing risk model, we compared the risk of transformation and the risk of death attributed to transformation. Patients who achieve PFS24 with no progression have a 3.4% risk of transformation at 3 years (Figure C). The risk of death from transformation for patients who achieve PFS24 is <1% at 3 years. The risk of transformation in patients with early progression within 1 year is 42.4% at 3 years with risk of death from transformation being 18.6% at 3 years.
A MSKCC (R-CHOP)

<figure><img src="image_71.png" /></figure>

<figure><img src="image_72.png" /></figure>

<figure><img src="image_73.png" /></figure>

B FOLL05 (R-CHOP)

<figure><img src="image_74.png" /></figure>

<figure><img src="image_75.png" /></figure>

<figure><img src="image_76.png" /></figure>

C

<figure><img src="image_77.png" /></figure>

**Conclusion:** Our study provides evidence that in the modern era of PET-based staging, PFS24 may not be a robust surrogate endpoint for OS. The improved outcomes in PET-staged patients with early progression may be associated with identification and exclusion of patients with transformed disease at time of therapy. Patients with early progression are at risk for early death. In contrast, patients with early progression and no evidence of transformation have an extended OS, suggesting aggressive upfront therapies may not be warranted in these patients.

**Keywords:** follicular lymphoma (FL).

104
RESPONSE ORIENTED MAINTENANCE
THERAPY IN ADVANCED FOLLICULAR
LYMPHOMA. RESULTS OF THE INTERIM
ANALYSIS OF THE FOLL12 TRIAL
CONDUCTED BY THE FONDAZIONE
ITALIANA LINFOMI.

M. Federico<fnref n="1" /> | D. Mannina<fnref n="2" /> | A. Versari<fnref n="3" /> |

S. Ferrero⁴ | L. Marcheselli⁵ | C. Bocomini⁶ |

A. Dondi⁵ | A. Tucci⁷ | L. Guerra⁸ | S. Galimberti⁹ |

F. Cavallo¹⁰ | J. Olivieri¹¹ | P. Corradini¹² |

L. Arcaini¹³ | S. Chauvie¹⁴ | I. Del Giudice¹⁵ |

C. Rusconi¹⁶ | A. Pinto¹⁷ | A. Molinari¹⁸ |

A. Pulsoni¹⁵ | M. Merli¹⁹ | S. Kovalchuk²⁰ |

L. Nassi²¹ | S. Bolis²² | V. Gattei²³ | M. Manni<fnref n="1" /> |

S. Pileri²⁴ | M. Brugiatelli<fnref n="2" /> | S. Luminari²⁵ |

<footnote n="1">¹Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche, University of Modena and Reggio Emilia, Modena, Italy;</footnote>

<footnote n="2">²UOC di Ematologia, Azienda Ospedaliera Papardo, Messina, Italy;</footnote>

<footnote n="3">³Nuclear Medicine Unit, AUSL-IRCCS of Reggio Emilia, Reggio Emilia, Italy; ⁴Department of Molecular Biotechnologies and Health Sciences, Division of Hematology, University of Torino, Torino, Italy; ⁵Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto, Fondazione Italiana Linfomi, Modena, Italy; ⁶SC Ematologia, AOU Città della Salute e della Scienza di Torino, Torino, Italy; ⁷SC Ematologia, ASST-Spedali Civili, Brescia, Italy; ⁸Nuclear Medicine Unit, San Gerardo Hospital, Monza, Italy; ⁹Division of Hematology, Department of Oncology, Santa Chiara Hospital, Pisa, Italy; ¹⁰Division of Hematology, University of Torino, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy; ¹¹Clinica Ematologica, Centro</footnote>
Trapianti e Terapie Cellulari "C. Melzi", DAME, ASUI, Udine, Italy;

<sup>12</sup>Department of Oncology and Hematology, Fondazione Istituto Nazionale dei Tumori Milano University of Milano, Milano, Italy;

<sup>13</sup>Department of Molecular Medicine, University of Pavia, Division of Hematology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy;

<sup>14</sup>Medical Physics Unit, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy; <sup>15</sup>Hematology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Roma, Italy; <sup>16</sup>Division of Hematology, ASST Grande ospedale Metropolitano Niguarda, Milano, Italy; <sup>17</sup>Department of Hematology and Developmental Therapeutics, Istituto Nazionale Tumori, Fondazione 'G. Pascale' IRCCS, Napoli, Italy;

<sup>18</sup>UO Ematologia, OC Rimini AUSL Romagna, Rimini, Italy;

<sup>19</sup>Hematology, University Hospital "Ospedale di Circolo e Fondazione Macchi" - ASST Sette Laghi, University of Insubria, Varese, Italy;

<sup>20</sup>Ematologia, Università degli Studi di Firenze, Firenze, Italy;

<sup>21</sup>Hematology, AOU Maggiore della Carità, Novara, Italy; <sup>22</sup>Hematology Unit, ASST-Monza, Monza, Italy; <sup>23</sup>Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy; <sup>24</sup>Divisione di Diagnosi Ematopatologica, Istituto Europeo di Oncologia, Milano, Italy; <sup>25</sup>S.C. Ematologia, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy

**Introduction:** Rituximab maintenance after frontline R+chemo prolongs remissions and is a widely adopted treatment option for patients with follicular lymphoma (FL). Moreover, metabolic and molecular response assessed with FDG-PET and MRD have been confirmed as strong predictors of patients' survival thus suggesting the benefit of a response adapted maintenance strategy as post induction therapy.

**Methods:** FOLL12 is a multicenter, randomized, phase III, non inferiority study comparing standard vs response adapted maintenance in patients with stage II-IV, previously untreated, intermediate-high risk FL according to FLIPI2, requiring therapeutic intervention. All patients received induction immunochemotherapy (ICT) with 6 cycles of R-CHOP or 6 cycles of R-bendamustine both followed by 2 additional doses of rituximab. After induction ICT, patients in the standard arm were treated with bimonthly rituximab doses for up to two years. Patients in the experimental arm were managed according to centrally reviewed metabolic and molecular response (i.e. Complete metabolic and molecular response: no therapy; Complete metabolic response without molecular response: 4 weekly rituximab doses; Lack of metabolic response (Deauville score 4-5): radiommunotherapy with ibritumomab tiuxetan followed by standard rituximab maintenance). Primary study endpoint was 3 years progression free survival (PFS) by intention to treat. A sample size of 770 evaluable patients was planned assuming a reference of 3yr PFS at 70% with a non inferiority margin of 7% between arms.

**Results:** A total of 790 eligible patients were randomized to standard (394 patients) or experimental (396 patients) arm. Groups were well balanced according to patient characteristics and response rates. At the end of induction therapy 88% of cases resulted PET- and 91% MRD-. After a median follow-up of 37 months (range 1-71), the 3-year overall survival (OS) and PFS were 96% and 76%, respectively.

An interim analysis, planned at the occurrence of 70% events, was anticipated at the occurrence of 50% of events and submitted to the external data safety monitoring committee (DSMC). The analysis showed that response oriented experimental arm resulted significantly inferior to the standard maintenance arm in terms of PFS (estimated 3-year PFS, 68% vs. 84%; hazard ratio for PFS, 2.05 [95% CI 1.50-2.81; P < 0.0001]). The DSMC considered unlikely that longer follow-up could modify the results and was favorable in publishing these data.

**Conclusions:** In patients with intermediate-high risk FL according to FLIPI2 and requiring systemic therapy, omission of R-maintenance resulted in a significantly lower 3-year PFS, despite the attainment of a post-induction complete metabolic response.

**Keywords:** follicular lymphoma (FL); minimal residual disease (MRD); positron emission tomography (PET).

**Disclosures:** Federico, M: Honoraria: Janssen, Gilead, MedImmune.

Mannina, D: Consultant Advisory Role: Janssen, AbbVie. Ferrero, S: Consultant Advisory Role: Janssen; Honoraria: Janssen, Gilead, Servier.

Galimberti, S: Other Remuneration: Speaker for Roche, Takeda, Celgene, Janssen. Cavallo, F: Consultant Advisory Role: Takeda, Janssen. Arcaini, L: Consultant Advisory Role: CELGENE, SANDOZ, Janssen-Cilag, VERASTEM; Research Funding: Gilead. Chauvie, S: Honoraria: IAEA, CONSIP and Sirtex; Research Funding: Roche, Takeda, Fondazione Cassa di Risparmio di Cuneo and AIRC; Other Remuneration: Travel/accommodation from GE Healthcare, Philips Medical System, Sirtex, BTG, Terumo. He is co-founder of Dixit srl, spin-off of University of Torino and INFN. Rusconi, C: Consultant Advisory Role: Roche. Pinto, A: Consultant Advisory Role: Servier, Roche, Merck Sharp & Dohme; Honoraria: Roche/Genetech, Merck Sharp & Dohme, Bristol Myers Squibb, Celgene, Servier; Other Remuneration: EDO-Mundipharma (patenting process). Kovalchuk, S: Other Remuneration: Roche. Nassi, L: Consultant Advisory Role: Takeda, Janssen, MSD. Luminari, S: Consultant Advisory Role: Roche, Celgene, Sandoz, Gilead.

105
INTERIM UPDATE FROM A PHASE
2 MULTICENTER STUDY OF
TAZEMETOSTAT, AN EZH2 INHIBITOR, IN
PATIENTS WITH RELAPSED OR
REFRACTORY FOLLICULAR LYMPHOMA

F. Morschhauser<fnref n="1" /> | H. Tilly<fnref n="2" /> | A. Chaidos³ |

T. Phillips⁴ | V. Ribrag⁵ | P. Campbell⁶ |

D. Ghandi Laurent⁷ | W. Jurczak⁸ | P. McKay⁹ |

S. Opat¹⁰ | J. Radford¹¹ | A. Rajarethinam¹² |

J. Yang¹³ | H. Howell¹⁴ | K.J. Newberry¹⁵ |

D. Adib¹⁶ | G. Salles¹⁷

<footnote n="1">¹Hematology-Transfusion, Centre Hospitalier Universitaire, Lille, France;</footnote>

<footnote n="2">²Hematology, Centre de Lutte Contre le Cancer Henri Becquerel, Rouen, France; ³Medicine, Centre for Haematology, Department of Medicine, Imperial College London, Imperial College Healthcare NHS Trust,</footnote>
Hammersmith Hospital, London, United Kingdom; ⁴Hematology and Oncology, University of Michigan, Ann Arbor, United States; ⁵DITEP, Gustave Roussy, Villejuif, France; ⁶Hematology, Barwon Health, Geelong, Australia; ⁷Hematology, Hematology Institute University Hospital School of Medicine, Caen, France; ⁸Hematology, UJCM, Kraków, Poland; ⁹Hematology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; ¹⁰Hematology, Monash University, Clayton, Australia; ¹¹Medical Oncology, University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom; ¹²Data Management, Epizyme, Cambridge, United States; ¹³Biostatistics, Epizyme, Cambridge, United States; ¹⁴Clinical Operations, Epizyme, Cambridge, United States; ¹⁵Clinical Research, Epizyme, Cambridge, United States; ¹⁶Clinical Development, Epizyme, Cambridge, United States; ¹⁷Hematology, Lyon-Sud Hospital Centre, Pierre-Bénite, France

**Introduction:** Relapsed or refractory (R/R) follicular lymphoma (FL) remains an area of unmet medical need and treatments with novel mechanisms of action are desirable. The histone methyltransferase EZH2 is an important regulator of the germinal center (GC) reaction that is involved in preventing terminal differentiation of GC B-cells. EZH2 activating mutations are present in ~20% of FL patients (pts) and are postulated to be oncogenic drivers. Tazemetostat, a selective, oral EZH2 inhibitor has shown antitumor activity in a phase 1/2 study that included non-Hodgkin lymphoma pts with mutant (MT) or wild-type (WT) EZH2 tumors, providing rationale for further investigation.

**Methods:** This open-label, multicenter, phase 2 study of tazemetostat enrolled pts with either MT or WT EZH2 R/R diffuse large B-cell lymphoma or FL (Grade 1-3b). Key inclusion criteria included: age ≥18 years, ≥2 prior treatment regimens, and measurable disease. Tumor tissue was analyzed for EZH2 hot spot activating mutations (Y646X, A682G, A692V) using a cobas® EZH2 Mutation Test (Roche Molecular Systems, investigational use only). Tazemetostat 800 mg was administered orally, twice daily. Response was assessed every 8 weeks using 2007 IWG-NHL criteria. The primary endpoint was ORR (CR + PR). Secondary endpoints included PFS and safety/tolerability. Efficacy and safety were analyzed for the EZH2 MT and EZH2 WT groups.

**Results:** As of February 1, 2019, interim data were summarized from 95 FL pts (41 EZH2 MT and 54 EZH2 WT). The overall median age was 61 years, and median prior lines of therapy was 2 (range: 0-11) in

the EZH2 MT group and 3 (range: 1-8) in the EZH2 WT group. Median follow-up times, ORR, median duration of response for 92 response evaluable patients in both EZH2 MT and WT groups are highlighted in the table. Response duration was greater than 24 weeks in 83% of pts, and 50% of pts had a response duration greater than 1 year. Treatment-emergent adverse events (TEAEs) leading to dose reductions occurred in 8% of pts and study drug discontinuation due to TEAEs occurred in 9% of FL pts. The overall safety profile was similar to what has been previously reported. Grade ≥3 treatment-related TEAEs were reported in 18% of pts; no Grade 5 AEs were reported.

**Conclusion:** Tazemetostat 800 mg BID appears to be generally well tolerated with observed meaningful clinical activity and durability of response in pts with R/R FL. ORR was pronounced in pts with EZH2 activating mutations. Late onset responses have been reported on tazemetostat. Given the consistently favorable safety and low rates of discontinuation due to TEAEs, these encouraging phase 2 data demonstrate that EZH2 inhibition may be an important and effective therapeutic target in FL.

**Keywords:** follicular lymphoma (FL); germinal center B cell-like (GCB).

**Disclosures:** Morschhauser, F: Consultant Advisory Role: Gilead, Servier, Roche/Genentech; Honoraria: Celgene, BMS, Janssen. Tilly, H: Consultant Advisory Role: Celgene, Astra-Zeneca, Karyopharm, Roche; Honoraria: BMS, Janssen, Gilead; Research Funding: Celgene. Phillips, T: Consultant Advisory Role: Genentech, Gilead, Bayer, Seattle Genetics, Pharmac cyclics; Research Funding: Pharmac cyclics, Abbvie. Ribrag, V: Consultant Advisory Role: Epizyme, Servier, Nanostring, Gilead, Pharmanar, BMS, MSD, Incyte, Roche, Infinity; Honoraria: ESAI; Research Funding: Epizyme, ArgenX. Jurczak, W: Consultant Advisory Role: AstraZeneca/Acerta, European Medicines Agency, Sandoz-Nowartis, Janssen, Gilead; Research Funding: Afimed, BeiGene, Celgene, Epizyme, AstraZeneca/Acerta. McKay, P: Consultant Advisory Role: Epizyme; Honoraria: Epizyme. Opat, S: Consultant Advisory Role: Roche, Celgene, Mundipharma, Janssen; Honoraria: Roche, Celgene, Mundipharma, Janssen. Radford, J: Consultant Advisory Role: Takeda, Bristol-Myers Squibb, Seattle Genetics, Novartis; Stock Ownership: GSK, AstraZeneca; Honoraria: Takeda; Research Funding: Takeda, Pfizer, ADC Therapeutics, Celgene, AstraZeneca. Rajarethinam, A: Employment Leadership Position: Epizyme, Inc; Stock Ownership: Epizyme, Inc. Yang, J: Employment Leadership Position: Epizyme, Inc; Stock Ownership: Epizyme, Inc. Howell, H: Employment Leadership Position: Epizyme, Inc; Stock Ownership: Epizyme, Inc. Newberry, K: Employment Leadership Position: Epizyme, Inc; Stock Ownership: Epizyme,

<figure><img src="image_78.png" /></figure>

<table><thead><tr><th></th><th>EZH2 MT group (n=39 evaluable)</th><th>EZH2 WT group (n=53 evaluable)</th></tr></thead><tbody><tr><td>Objective response rate, % (95% CI)</td><td>74 (57.9, 87.0)</td><td>34 (21.5, 48.3)</td></tr><tr><td>Complete response, %</td><td>10</td><td>6</td></tr><tr><td>Partial response, %</td><td>64</td><td>28</td></tr><tr><td>Stable disease, %</td><td>26</td><td>30</td></tr><tr><td>Progressive disease, %</td><td>0</td><td>28</td></tr><tr><td>Progression-free survival, weeks (95% CI)</td><td>60.0 (46.7, 83.9)</td><td>24.6 (15.1, 47.9)</td></tr><tr><td>Median duration of response, weeks (95% CI)</td><td>40 (22.3, NE)</td><td>56 (31.7, NE)</td></tr><tr><td>Median follow-up, weeks (min, max)</td><td>64 (5-161 weeks)</td><td>107 (1-178 weeks)</td></tr></tbody></table>

CI, confidence interval; MT, mutant; NE, not estimable; WT, wild type

<figure><img src="image_79.png" /></figure>
**Inc. Adib, D:** Employment Leadership Position: *Epizyme, Inc*; Stock Ownership: *Epizyme, Inc*. **Salles, G:** Honoraria: Roche, Jannsen, Gilead, Celgene, Novartis, Amgen, BMS, Merck, Servier.

## SESSION 9 – EXTRANODAL LYMPHOMAS

### 106
**INTEGRATIVE GENOMIC ANALYSIS IDENTIFIES KEY PATHOGENIC CONCEPTS IN PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA**

A. Mottok<fnref n="1" /> | S.S. Hung² | E.A. Chavez² |

B. Woolcock² | A. Telenius² | L.C. Chong² |

B. Meissner³ | H. Nakamura³ | R.D. Gascoyne³ |

J.M. Connors³ | S. Ben Neriah² | A.J. Mungall⁴ |

M.A. Marra⁴ | R. Siebert<fnref n="1" /> | D.W. Scott³ |

K.J. Savage³ | C. Steidl²

**Introduction:** Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the current WHO classification, accounting for 2-3% of non-Hodgkin lymphomas. Molecular studies have provided evidence that PMBCL can be distinguished from diffuse large B-cell lymphoma (DLBCL) and highlighted a strong relationship between PMBCL and classical Hodgkin lymphoma (cHL). There is cumulative evidence to support that correct classification is important for patient risk stratification and therapeutic decision making. We aimed to comprehensively describe genetic alterations and perturbed pathways in molecularly defined PMBCL, as targeted sequencing studies in the past have focused on a limited number of genetic lesions involved in disease pathogenesis.

**Methods:** We performed whole-exome sequencing of 95 centrally reviewed PMBCL cases, using the SureSelect Human All Exon V6 +UTR baits (Agilent) followed by massively parallel sequencing. For 21 cases paired germline DNA was available. Somatic SNV/indel variants were identified using the intersection of predictions by VarScan, Strelka and MuTect, and annotated with SnpEff. We inform on oncogenic driver genes as identified by MutSigCV and recurrent copy number alterations utilizing CNVkit and GISTIC. For 69 patients global gene expression profiling performed on the DASL platform (Illumina) was available and 90 cases have been molecularly classified using the Lymph3Cx assay. The impact of somatic mutations on gene expression was assessed using xseq.

**Results:** Tumor and normal samples were sequenced to an average coverage of 115X. Analysis of somatic alterations in tumor-normal pairs yielded 50 putative driver genes recurrently mutated in PMBCL. Besides mutations in the JAK-STAT (SOCS1, STAT6, IL4R, PTPN1) and NFkB-pathway (TNFAIP3, NFKBIE, TRAF3), we provide additional evidence of the importance of immune evasion in this disease (CIITA, CD58, B2M) and identified the IRF-pathway as a putative novel hallmark. As expected, the most significant regions of copy number gain predicted by GISTIC were located on 9p (72%). The most frequent regions of loss were mapped to 10q, 8p, 1p, and 7p. PMBCL driver genes, with the exception of EZH2, were significantly more frequently mutated in comparison to DLBCL, whereas only three genes were significantly different between PMBCL and cHL.

**Conclusions:** Here we identified candidate driver genes with clear evidence of somatic mutations in PMBCL, the majority being distinct from DLBCL. We observed an enrichment of somatic mutations affecting genes involved in the JAK-STAT- and NFkB-pathway, and propose that the IRF-pathway is critically involved in PMBCL pathogenesis.

**Keywords:** molecular genetics; primary mediastinal large B-cell lymphoma (PMLBCL).

### 107
**OUTCOME OF PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA IN THE RITUXIMAB ERA: IMPACT OF A PET-GUIDED APPROACH**

A. Hayden<fnref n="1" /> | P. Tonseth² | D. Villa<fnref n="1" /> | A.S. Gerrie<fnref n="1" /> |

D.W. Scott<fnref n="1" /> | C.L. Freeman<fnref n="1" /> | G.W. Slack³ |

C. Parsons⁴ | T. Pickles⁴ | D. Wilson² |

J.M. Connors<fnref n="1" /> | L.H. Sehn<fnref n="1" /> | K.J. Savage<fnref n="1" />

**Background:** Primary mediastinal large B-cell lymphoma (PMBCL) is a rare subtype of lymphoma which typically presents in females with a bulky anterior mediastinal mass. Patients (pts) are treated with chemotherapy ± consolidative radiotherapy (CRT). Herein, we reviewed outcomes of PMBCL pts treated at BC Cancer in the rituximab era and the impact of a PET-adapted approach.

**Methods:** The BC Cancer Lymphoid Cancer Database was used to identify pts >16 years (y) of age with newly diagnosed PMBCL based on the WHO classification who were treated with chemotherapy + rituximab. Prior to the availability of FDG-PET scan at end of treatment (EOT) in July 2005, all pts were recommended to receive R-

<footnote n="1">¹Institute of Human Genetics, Ulm University and University Medical Centre, Ulm, Germany; ²Department of Lymphoid Cancer Research, BC Cancer, Vancouver, Canada; ³Centre for Lymphoid Cancer, BC Cancer, Vancouver, Canada; ⁴Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, Canada</footnote>

<footnote n="1">¹Centre for Lymphoid Cancer and Division of Medical Oncology, BC Cancer, Vancouver, Canada; ²Division of Radiology, BC Cancer, Vancouver, Canada; ³Centre for Lymphoid Cancer and Division of Pathology, BC Cancer, Vancouver, Canada; ⁴Division of Radiation Oncology, BC Cancer, Vancouver, Canada</footnote>
<figure><img src="image_80.png" /><figcaption>**Figure 1**

OS and TTP by Deauville</figcaption></figure>

CHOP and CRT (RT era, n=50). Since the availability of an EOT PET (PET era, n=109), only pts with a positive EOT PET (PETpos) were recommended to have CRT. Before 2014, PET scans were interpreted based on the International Harmonization Project (IHP) and after 2014 the Deauville (D) criteria (D1-3, DX = PETneg). IHP era PET scans were retrospectively reclassified using D criteria.

**Results:** 159 pts with PMBCL were identified with a median follow up of 7.9 y (range 0.7 – 16.7 y) and the following characteristics: median age 36 y (range 19-84); 57% female; 70% bulky ≥10cm; 40% pleural/pericardial effusion; 37% extranodal sites >1; 43% B symptoms; 72% elevated LDH; 63% stage I/II. Pts received R-CHOP (n=149), R-CHOP/R-ICE (n=8) or DAEPOCH-R (n=2). 70 pts (44%) received CRT, 78% (n=39) in the RT era (2001-2005) and 28% (n=31) in the PET era (>2005). The 5y time to progression (TTP) and overall survival (OS) for the entire cohort were 80% and 89%, respectively. In a treatment era comparison, there was no difference in TTP (78% vs 81%, P=0.74) and OS (86% vs 91%, P=0.26) for pts treated in the RT vs PET era, respectively, with only one pt in the PET era not having a PET scan due to disease progression. 113 pts had an EOT PET which included 10 pts who had a self-pay PET: PETneg n= 71 (63%), of which 1% (n=1) received CRT; PETpos n=42(37%), of which 79% (n=33) received CRT. For all 113 pts treated with a PET guided approach, the 5 y TTP and OS were 83% and 94% respectively. For PETneg and PETpos cases, the 5 y TTP were 88% vs 74% (P=0.03) and 5 y OS were 97% vs 88% (P=0.78), respectively.

All centrally performed PET scans pre-2014 (n=59) were reassigned by D criteria for a total of 103 D assigned cases; 71% PETneg; 29% PETpos. The 5 y TTP and OS for PETneg by D were 90% and 97%, respectively. For PETpos cases, outcomes were inferior for D5 (n=12) vs D4 (n=18): 5y TTP 33% vs 94% (P<0.0001); 5 y OS 67% vs 100% (P=0.002).

**Conclusions:** Overall outcomes of PMBCL pts primarily treated with R-CHOP are favourable with a 5 y OS of 89%. Changing to a PET-adapted approached has reduced the use of CRT by over 60% without compromising cure rates. EOT PETneg scan is associated with excellent outcomes with 90% cure rate using modern D criteria. In contrast, D5 have a very poor outcome and may benefit from alternate treatment approaches.

**Keywords:** positron emission tomography (PET); primary mediastinal large B-cell lymphoma (PMLBCL); R-CHOP.

**Disclosures:** Villa, D: Consultant Advisory Role: Roche, Lundbeck, Celgene, Abbvie, Seattle Genetics, Janssen, AstraZeneca, Gilead, Nanostring. Gerrie, A: Consultant Advisory Role: Janssen, AbbVie, Novartis; Research Funding: Roche, Lundbeck, Janssen. Scott, D: Consultant Advisory Role: Celgene and Janssen; Research Funding: Janssen, Roche/Genentech and NanoString. Freeman, C: Consultant Advisory Role: Celgene, Janssen, Amgen, Seattle genetics, Abbvie; Research Funding: Roche/Genentech. Pickles, T: Consultant Advisory Role: Sanofi, Astellas, Servier, Abbvie, Bayer, Ferring. Connors, J: Research Funding: Amgen, Bayer, Bristol-Myers Squibb (Inst), Cephalon (Inst), Genentech/Roche (Inst), Janssen Oncology (Inst), Lilly (Inst), Merck (Inst), NanoString Technologies (Inst), Roche, Seattle Genetics, Takeda. Sehn, L: Consultant Advisory Role: Roche/Genentech, Abbvie, Amgen, Apobiologix, Astra Zeneca, Acerta, Celgene, Gilead, Janssen, Kite, Karyopharm, Lundbeck, Merck, Morphosys, Seattle Genetics, Teva, Takeda, TG Therapeutics; Research Funding: Roche/Genentech. Savage, K: Consultant Advisory Role: BMS, Merck, SeaGen, Verastem; Honoraria: Takeda; Research Funding: Roche.

<footnote n="1">¹Institute of Hematology, "Seràgnoli" Bologna University, Bologna, Italy;</footnote>

<footnote n="2">²Oncologia medica, Istituto Clinico Humanitas, Rozzano-Milano, Italy;</footnote>

<footnote n="3">³Hematology and Bone Marrow Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy; ⁴Service d'Hémato-Oncologie, Hôpital Saint-Louis, Paris, France; ⁵Dept. of Hematology/Oncology, University of Rochester, Rochester, United States; ⁶Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada;</footnote>

<footnote n="7">⁷Gastrointestinal and Lymphoma Unit, Royal Marsden Hospital, London, United Kingdom; ⁸Hematology & Oncology (Cancer), University of</footnote>
Chicago, Chicago, United States; ⁹Division of Hematology, Jewish General Hospital, Montréal, Canada; ¹⁰Department of Oncology, Washington University School of Medicine, St Louis, United States; ¹¹Seattle Genetics, Bothell, United States; ¹²Bristol-Myers Squibb, Princeton, United States; ¹³Lymphoma Inpatient Unit, Memorial Sloan Kettering Cancer Center, New York, United States

**Introduction:** Primary mediastinal B-cell lymphoma (PMBL) is a rare but aggressive non-Hodgkin lymphoma (NHL) with poor outcomes in relapsed/refractory (R/R) patients. Increased programmed death-1 (PD-1) ligand and weak CD30 expression are characteristics of PMBL. PD-1 blockade and CD30-targeted therapy alone have demonstrated overall response rates (ORRs) of 41% and 13%, respectively, in R/R PMBL. Nivolumab, a fully human IgG4 anti-PD-1 immune checkpoint inhibitor monoclonal antibody, and brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, may have synergistic activities in R/R PMBL.

**Methods:** CheckMate 436 (NCT02581631) is an open-label, phase 1/2 study of nivolumab + BV to treat CD30+ NHLs. This expansion cohort enrolled patients with confirmed PMBL and R/R disease after either high-dose conditioning chemotherapy and autologous hematopoietic cell transplantation (auto-HCT) or ≥ 2 prior multi-agent chemotherapy regimens if ineligible for auto-HCT. Patients received nivolumab (240 mg IV) and BV (1.8 mg/kg IV, pre-specified dose modifications allowed) every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were investigator-assessed ORR per the Lugano 2014 criteria, and safety.

**Results:** 30 patients were treated with nivolumab + BV and included in this primary analysis. At baseline, median (min, max) age was 35.5 (19, 83) years; patients had received a median (min, max) of 2 (2, 5) prior systemic therapies and 4 (13%) had received prior auto-HCT. With a median follow-up of 11.1 months, ORR (95% CI) was 73% (54–88), with 11 patients (37%) achieving complete remission (CR);

13 (52%) of the 25 evaluable patients had a best reduction in target lesion of > 50% (Figure). At data cutoff, 3 of the 22 responders had progressed or died before starting subsequent therapy; median duration of response has not been reached. Treatment-related AEs (TRAEs) were reported in 25 (83%) patients. The most frequently reported TRAEs were neutropenia (30%), peripheral neuropathy (27%), peripheral sensory neuropathy, thrombocytopenia, rash, and hyperthyroidism (13% each). Grade 3-4 TRAEs were reported in 16 (53%) patients, including 9 (30%) with neutropenia, 3 (10%) each with thrombocytopenia or peripheral neuropathy, 2 (7%) with decreased neutrophil count, and 1 (3%) each with hypersensitivity, colitis, rash, maculopapular rash, or immune-mediated hepatitis. Four patients (13%) had treatment-related serious AEs; 2 of them had grade 3-4 colitis, maculopapular rash, or immune-mediated hepatitis.

**Conclusions:** In patients with R/R PMBL, nivolumab + BV demonstrated a high investigator-assessed ORR of 73%, with 37% CR. TRAEs were consistent with the safety profiles of nivolumab and BV treatment alone. The combination of nivolumab + BV may be synergistic and is active in patients with R/R PMBL.

**Keywords:** brentuximab vedotin; nivolumab; primary mediastinal large B-cell lymphoma (PMLBCL).

**Disclosures:** Zinzani, P: Consultant Advisory Role: Advisory board: Verastem, Celltrion, Gilead, Janssen-Cilag, Bristol-Myers Squibb, Servier, Sandoz, MSD, Immune Design, Celgene, Portola, Roche, Eusapharma, Kyowa Kirin. Consultant: Verastem, MSD, Eusapharma, Sanofi; Other Remuneration: Speaker's bureau: Verastem, Celltrion, Gilead, Janssen-cilag, Bristol-Myers Squibb, Servier, Msd, Immune design, Celgene, Portola, Roche, Eusapharma, Kyowa kirin. Gritti, G: Consultant Advisory Role: Autolus Ltd. Brice, P: Consultant Advisory Role: Millennium/Takeda; Honoraria: Bristol-Myers Squibb, Millennium/Takeda; Research Funding: Millennium/Takeda, Seattle Genetics. Kuruvilla, J: Consultant Advisory Role: Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Karyopharm, Merck, Roche, Seattle Genetics; Honoraria: Amgen, Bristol-Myers Squibb, Celgene, Gilead, Janssen, Karyopharm, Lundbeck, Merck, Novartis, Roche, Seattle Genetics; Research Funding: Canadian Cancer Society, Leukemia and Lymphoma Society Canada, Princess Margaret Cancer Foundation, Roche, Janssen. Cunningham, D: Research Funding: Roche. Kline, J: Honoraria: Merck; Research Funding: iTeos, Merck. Johnson, N: Consultant Advisory Role: AbbVie, Bristol-Myers Squibb, Lundbeck, Merck, Roche; Honoraria: AbbVie, Bristol-Myers Squibb, Lundbeck, Merck, Roche, Seattle Genetics; Research Funding: AbbVie, Lundbeck, Roche; Other Remuneration: (Travel) Lundbeck, Roche. Mehta-Shah, N: Consultant Advisory Role: Spectrum; Research Funding: Bristol-Myers Squibb, Celgene, Geneteck, Verastem. Manley, T: Employment Leadership Position: Seattle Genetics; Stock Ownership: Seattle Genetics. Francis, S: Employment Leadership Position: Bristol-Myers Squibb; Stock Ownership: Bristol-Myers Squibb. Sharma, M: Employment Leadership Position: Bristol-Myers Squibb. Moskowitz, A: Consultant Advisory Role: Bristol-Myers Squibb, Seattle Genetics; Honoraria: Seattle Genetics, Takeda; Research Funding: ADC Therapeutics, Bristol-Myers Squibb, Incyte, Merck, Seattle Genetics.

<figure><img src="image_81.png" /><figcaption>Figure. Best change from baseline in target lesion by best overall responseª</figcaption></figure>

<footnote>ªPer Lugano 2014 criteria incorporating FDG-PET scan.</footnote>

<footnote>ᵇSum of the product of the diameters, based on CT scan.</footnote>
109

# R-CHOP PRECEDED BY ENGINEERED TUMOR NECROSIS FACTOR (TNF) IN RELAPSED OR REFRACTORY PRIMARY DIFFUSE LARGE B-CELL LYMPHOMA OF THE CNS (rPCNSL): FINAL RESULTS OF THE INGRID TRIAL

A. J. Ferreri¹ | T. Calimeri¹ | G. Conte² |

M. Ponzoni³ | F. Fallanca⁴ | D. Cattaneo⁵ |

E. Scarano¹ | C. Flavio⁶ | M. Sassone¹ |

M. Foppoli¹ | S. Perrone¹ | C. Cecchetti¹ |

P. Lopedote¹ | G. Gritti⁷ | C. Castellino⁸ |

L. Verga⁹ | F. Olcese¹⁰ | R. Mazza¹¹ | F. Ciceri¹² |

C. Bordignon¹³ | N. Anzalone² | A. Corti⁶

¹Lymphoma Unit, IRCCS Ospedale San Raffaele, Milano, Italy;

²Neuroradiology Unit, IRCCS Ospedale San Raffaele, Milano, Italy;

³Pathology Unit, IRCCS Ospedale San Raffaele, Milano, Italy; ⁴Nuclear Medicine, IRCCS Ospedale San Raffaele, Milano, Italy; ⁵Unit of Clinical Pharmacology, ASTT Fatebenefratelli Sacco University Hospital, Milano, Italy; ⁶Tumor Biology and Vascular Targeting Unit, DIBIT-1, 3A1, Lab. 6, IRCCS Ospedale San Raffaele, Milano, Italy; ⁷Hematology Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy; ⁸Unit of Hematology, Ospedale Santa Croce E Carle, Cuneo, Italy; ⁹Division of Hematology, "S Gerardo" Hospital University of Milano-Bicocca, Monza, Italy; ¹⁰S.c.Oncologia-Ematologia, ASL5 Liguria, La Spezia, Italy; ¹¹Operative Unit of Medical Oncology and Hematology, Humanitas Cancer Center, Milano, Italy;

¹²Hematology and BMT Unit, Department of Onco-Hematology, IRCCS Ospedale San Raffaele, Milano, Italy; ¹³MolMed SpA, Milano, Italy

**Background:** Patients (pts) with PCNSL are usually treated with high-dose methotrexate-based combinations that are not currently used in other DLBCL and require hospitalization and extensive expertise to manage toxicity. The use of R-CHOP could overcome these difficulties, but CNS availability of related drugs is poor. TNF induces blood-brain barrier (BBB) permeabilization and enhances CNS access of anticancer drugs. Coupling TNF with NGR, a peptide that targets CD13⁺ tumor vessels, improves its biological effects. Thus, we tested the hypothesis that this conjugate (NGR-hTNF) can break the BBB, thereby improving CNS access and activity of R-CHOP in pts with rPCNSL enrolled in a phase II trial (NCT03536039). Herein, we report results of activity, safety and BBB permeabilization.

**Methods:** HIV-neg adults with PCNSL failed after methotrexate-based chemo and measurable disease were enrolled and treated with 6 courses of R-CHOP21 preceded by NGR-hTNF (0.8 µg/m²). Overall response rate (ORR) was the primary endpoint. The two-stage Simon Minimax design was used; sample size estimated to demonstrate an improvement from 30% ORR to 50% was 28 pts. NGR-hTNF/RCHOP would be declared active if ≥12 responses were recorded. Secondary endpoints regarded changes induced by NGR-hTNF in vessel permeability, assessed by Dynamic Contrast Enhanced MRI (DCE-MRI) and

⁹⁹mTc-DTPA-SPECT, and in anticancer drug levels in CSF and plasma, and CD13 expression on diagnostic tumor samples.

**Results:** 28 pts (median age 58 yo, range 26-78; 14 males) were enrolled; 21 (75%) pts had intermediate-high IELSG score. Pts were heavily pretreated: 25 had received ASCT, WBRT or both; 15 had refractory disease.

NGR-hTNF/RCHOP was active: the predetermined activity threshold (≥12 responses) was achieved, with confirmed tumor response in 21 pts (75%; 95%CI= 59-91), which was complete in 11. At a median follow-up of 12 (4-20) months, 8 pts remain relapse free and 9 are alive. Treatment was well tolerated; toxicities were quickly solved without dose reductions or interruptions. G4 toxicities were neutropenia (44% of courses), thrombocytopenia (20%), anemia (2%), and FN (1%). 15 SAE were recorded in 13 pts: seizures (3), DVT (2), infections (5), syncope (2), constipation, FN, and LVEF reduction. There were 7 g1-2 TNF infusion reactions.

DCE-MRI and SPECT studies showed an increase of vascular permeability after NGR-hTNF infusion in tumor and perilesional areas. Specificity of this effect was suggested also by CD13 expression in all tumor samples, and by absence of changes in CSF/plasma drug levels after NGR-hTNF infusion.

**Conclusions:** NGR-hTNF/RCHOP is active and safe in pts with rPCNSL. CD13, the target of TNF, was expressed in tumor tissue and, consistently, NGR-hTNF enhanced vascular permeability specifically in tumor and perilesional areas. This innovative approach deserves to be addressed as first-line treatment in PCNSL pts.

**Keywords:** primary CNS lymphoma (PCNSL) R-CHOP

110

# POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD) AFTER SOLID ORGAN TRANSPLANT (SOT): SURVIVAL AND PROGNOSTICATION AMONG 570 PATIENTS (PTS) TREATED IN THE MODERN ERA

D. Jagadeesh¹ | D. Tsai² | W. Wei¹ |

N. Wagner-Johnston³ | E. Xie³ | S. Berg⁴ |

S.E. Smith⁴ | J.L. Koff⁵ | S. Barot¹ | D. Hwang⁴ |

S. Kim⁶ | P. Venugopal⁶ | T. Fenske⁷ | D. Sriram⁷ |

K. David⁸ | P. Santapuram⁹ | N. Reddy⁹ |

V. Dharnidharka¹⁰ | A.M. Evens⁸

¹Hematology and Medical Oncology, Cleveland Clinic, Cleveland, United States; ²Hematology/Oncology, University of Pennsylvania, Philadelphia, United States; ³Hematology and Oncology, Johns Hopkins Medical Institution, Baltimore, United States; ⁴Hematology and Oncology, Loyola University Medical Center, Melrose Park, United States; ⁵Hematology and Medical Oncology, Emory University, Atlanta, United States; ⁶Hematology and Oncology, Rush University Medical Center, Chicago, United States; ⁷Hematology and Oncology, Medical College of Wisconsin, Milwaukee, United States; ⁸Hematology and Oncology, Rutgers Cancer
Institute of New Jersey, New Brunswick, United States; ⁹Department of Medicine, Vanderbilt University Medical Center, Nashville, United States; ¹⁰Pediatric Nephrology, Hypertension and Pheresis, Washington University School of Medicine & St. Louis Children's Hospital, St. Louis, United States

**Background:** PTLDs are rare, aggressive and clinically heterogeneous diseases that may arise in the setting of immunosuppression following SOT. There remains an absence of a standard frontline treatment approach in the real world setting. We conducted a comprehensive multicenter retrospective study to analyze disease characteristics and outcomes of post-SOT PTLD in the modern era.

**Methods:** Data on newly diagnosed pts age ≥18 years (yrs) with SOT-related PTLD from 2000-2017 were analyzed from 10 academic institutions under IRB approval. Detailed patient and disease characteristics were summarized. Survival endpoints estimated by Kaplan-Meier method and compared by log rank test.

**Results:** We identified 570 PTLD pts with median age of 54 yrs (range, 18-82 yrs) at diagnosis. The majority of pts were male (67%), caucasian (79%), and had stage III-IV disease (67%) at diagnosis. Median time from SOT to PTLD was 61 months (range 0.23-1318). SOT type was renal (35%), liver (19%), lung (18%), heart (13%), intestine & pancreas (1% each), other/missing (1%) and 66 pts (12%) had multiple SOT (11% having 2 organs transplanted, 1% 3 organs). 53% had EBV positive tumor. A minority had graft involvement or rejection (19% each) at the time of diagnosis. For therapy, most pts (85%) underwent reduction in immunosuppression (RIS). For 1st line treatment, rituximab (R)-based therapy was given in 65% (R monotherapy 35% and R+chemotherapy 30%); 8% received chemotherapy without R and 27% received RIS alone. Response to 1st line therapy was: complete response (CR) 59% and partial response (PR) 12% yielding an overall response rate of 71% with 8% stable disease and 21% of pts had primary refractory disease. With 41-month median follow-up, the estimated 5 yr relapse free survival (RFS) and overall survival (OS) rates for all pts were 65% and 71%, respectively. The median OS and RFS were 185 and 181 months respectively. 23% relapsed after 1st line therapy. Outcomes varied significantly by SOT type, with cardiac and lung pts having the worst 5-yr RFS [95% CI] (49% [34, 71] and 58% [44, 77], respectively; P=0.09) and 5 yr OS [95% CI] (63% [51, 79] and 59% [48, 72], respectively, P< 0.0001. Achievement of CR vs PR to 1st line therapy by month 3 after diagnosis was strongly associated with RFS (5 yr RFS 69% [95% CI 63, 76] vs 44% [95% CI 31, 64], P< 0.0001). Furthermore, CR vs non-CR to 1st line therapy was associated with significantly improved OS (5 yr OS 85% [80, 90] vs 70% [62, 80], respectively, P< 0.0001).

**Conclusions:** These data represent the largest cohort of SOT-related PTLD pts reported to date. Collectively, pts with lung and heart SOT-related PTLD had significantly inferior OS and depth of response to 1st line therapy was a critical determinant for long-term RFS and OS. Our data demonstrates improved outcomes in pts with newly diagnosed PTLD treated in the era of novel agents.

**Keywords:** post-transplant lymphoproliferative disorders (PTLDs); PTLD.

**Disclosures:** Venugopal, P: Consultant Advisory Role: AbbVie and Bayer. Fenske, T: Consultant Advisory Role: Genentech.

# UCLI-ICML JOINT SESSION – NEW DATA ON T-CELL AND OTHER LYMPHOMAS

## 111 20-YEAR SURVIVAL DATA ANALYSIS OF PTCL PATIENTS IN PEKING UNIVERSITY CANCER HOSPITAL

Y. Song

Lymphoma Department, Peking University Cancer Hospital, Beijing, China

**Introduction:** During the past 20 years, nearly 3500 NHL patients were treated in Peking University Cancer Hospital (PUCH). Among of them, the 5-y OS of B-NHL cases improved significantly, from 50% (before 2000) to 66% (after 2010), but unfortunately the 5-y OS of PTCLs patients was never satisfied. Several frontline regimens were tried, and HDT/ASCT was given to selected newly diagnosed or R/R PTCLs patients. We evaluated the regimens and HDT/ASCT in patients who had complete medical records in PUCH.

**Methods:** 116 newly diagnosed PTCL patients received CHOP (n=46), CHOPE (n=46) or CHOPE/G (n=24, CHOPE alternating with gemcitabine-based regimen) at PUCH from 2009 to 2017 were analyzed. 83 cases (71.6%) were male. The median age was 57.5 years old. The subtypes included AITL (49.1%), ALK–ALCL (21.6%), PTCL NOS (21.6%), 6 cases of EATL, 2 of hepatosplenic γδT-cell lymphoma and 1 of SPTCL. 77.6% patients were at stage III/IV, 35.3% were with IPI 3-5.

79 patients received HDT/ASCT. The subtypes included ALCL (40.5%), advanced-stage or R/R NKTCL (26.6%), AITL (n=14), PTCL-NOS (n=10), SPTCL-αβ (n=1), SPTCL-γδ (n=1). 47 patients received HDT/ASCT as first-line consolidation (38 cases in CR1, 9 in PR1); 32 cases received HDT/ASCT after salvage chemotherapy (10 cases in CR2, 12 in PR2, 10 in SD/PD). The conditioning regimens included 47 cases with CBV, 10 with BEAC, 20 with BEAM. 2 NKTCL cases received TBI plus HD-CTX.

**Results:** For 116 newly diagnosed PTCL patients, the ORRs of CHOP, CHOPE and CHOPE/G regimens were 82.6%, 76.1% and 75.0%, with CR rates of 32.6%, 56.5% and 45.7%, respectively. With a median follow-up time of 35.5 months, the 3-y PFS of CHOP, CHOPE and CHOPE/G were 19.9%, 29.9% and 5.3%; the 3-y OS were 37.0%, 47.0% and 56.3%, respectively. CHOPE regimen showed a significantly higher CR rate (p = 0.021) and more favorable OS (p = 0.046). CHOPE/G regimen did not improve the ORR, CR or OS as compared with either CHOP or CHOPE regimen, with a significantly poorer PFS compared with CHOPE regimen (p = 0.029). Anemia and thrombocytopenia occurred most frequently in CHOPE/G regimen.

As for 79 patients who received HDT/ASCT in PUCH, at a median follow-up time of 23.6 months, the 2-y PFS and 2-y OS were 75.2%
and 83.6%, respectively. Patients in CR1 (2-y PFS 85.8%, 2-y OS 94.2%) were superior to others in survival. Patients with CR2 had no advantage in survival as compared with those with PR1 (2-y PFS: 43.8% vs. 76.2%; 2-y OS: 72.9% vs. 77.1%). Response status and LDH level before HDT/ASCT were highly predictive for PFS. Subgroup analysis revealed that patients with AITL benefited mostly from HDT/ASCT in survival, the survival rates (2-y PFS 74.3%, 2-y OS 94.9%) were superior to any other subtypes. NKTCL patients who received HDT/ASCT in CR1 also benefited from HDT/ASCT.

**Conclusions:** According to our experiences, CHOPE regimen improved the efficacy and survival of PTCLs in front-line; addition of gemcitabine resulted in more adverse events without benefit of survival. Patients with AITL and advanced-stage NKTCL who achieved CR after first-line therapy should be recommended to receive HDT/ASCT.

**Keywords:** autologous stem cell transplantation (ASCT); chemotherapy; peripheral T-cell lymphomas (PTCL).

## 112
DEVELOPING IMMUNOEPIGENETIC PLATFORMS FOR PERIPHERAL T-CELL LYMPHOMA: LEVERAGING A LOGIC FOR PD1/PDL-1 INHIBITORS

O.A. O'Connor

Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, NY, United States

The peripheral T-cell malignancies represent a group of rare and highly heterogonous diseases, widely regarded as being marginally sensitive to conventional cytotoxic chemotherapy. Over the last several years, gene expression profiling has revealed the ability to classify discrete sub-types of PTCL with greater precision, though has not produced any tangible leads regarding unique pathogenetic targets that might form the basis for a new rational therapeutic approach. What has emerged over the past decade is the growing sense the PTCL may represent the prototypical 'epigenetic' disease.

This is based on the following:

1. the PTCL are the only disease for which there are 4 histone deacetylase (HDAC) inhibitors approved as single agents;

2. recent genetic analyses have confirmed recurring mutations in TET2, IDH2 and DNMT3, mutations that collectively conspire to produce global genome wide methylation;

3. genetically manipulated murine models have consistently demonstrated that RhoG17V mutations in combination with TET2 mutations can produce spontaneous PTCL closely resembling angioimmunoblastic T-cell lymphoma (AITL); and finally

4. recent preclinical and clinical data have demonstrated potent synergy between drugs targeting the PTCL epigenome, with combinations of HDAC inhibitors plus hypomethylating agents, PI3K

inhibitors and pralatrexate producing compelling activity in patients with heavily treated disease. For example, combinations of pralatrexate and romidepsin have demonstrated overall response rates (ORR) in B-cell lymphoma and T-cell lymphoma patients of 33% and 71% respectively, with all complete remissions (CR) being seen among the patients with PTCL. A second doublet of romidepsin and oral 5-azacytidine has produced an ORR of 11% and 75% in patients with B- and T-cell lymphoma respectively, with all CR being seen among patients with PTCL. Additionally, among the patients with AITL, all have attained a complete remission. Importantly, progression free survival (PFS) is statistically superior among patients with PTCL compared to those with B-cell disease.

No obvious correlation with underlying TET2, IDH2, DNMT3 or RHOA mutations has been found thus far.

These data confirm the findings in the preclinical studies, suggesting these unique, non - chemotherapy based combinations exhibit a selectivity in one lineage of lymphoma over another.

These novel : novel doublet experiences have created an opportunity to potentially 'redesign' treatment platforms for PTCL not predicated on conventional cytotoxic therapy. Biologically, it is clear that combinations of HDAC inhibitors and hypomethylating agents appear to modulate a host of genes involved in immunomodulatory signaling pathways, including cancer testes antigens, PD-1/PDL-1, gamma-interferon, TBET, as well as expression of endretroviral elements. These immunological sequelae following exposure to a host a various epigenetic targeted drugs creates a natural logical for considering integration of rationally targeted biologicals such as the checkpoint inhibitors durvalumab (PDL-1) or pemborlizumab (PD-1). Albeit early, these studies are demonstrating that these novel immunoepigenetic based platforms have the potential to produce lineage selective activity, perhaps independent of the TET2 status, with time to event metrics that appear superior to what is being seen with the B-cell malignancies. We will share the evolving biological rational and early preclinical and clinical experience which warrants further study of these potentially paradigm changing approaches.

## 113
CLINICAL OUTCOME OF AN PROSPECTIVE, MULTICENTRE, RANDOMIZED, PHASE III NON-INFERIORITY CLINICAL TRIAL FOR PATIENTS WITH EXTRANODAL NK/T CELL LYMPHOMA TREATED BY P-GEMOX OR AspaMetDex

H. Huang<sup>1,2</sup> | Y. Gao<sup>1,2</sup> | H. Su<sup>3</sup> | Y. Huang<sup>4</sup> |
Y. Gao<sup>5</sup> | X. Wang<sup>1,2</sup> | B. Bai<sup>1,2</sup> | Y. Zhang<sup>6</sup> |
L. Su<sup>7</sup> | X. Chu<sup>8</sup> | W. Li<sup>9</sup> | J. Zhang<sup>10</sup> |
Q. Zhang<sup>11</sup> | L. Zhang<sup>12</sup> | X. Hu<sup>13</sup> | L. Zou<sup>14</sup> |
Z. Li<sup>1,2</sup> | W. Jiang<sup>1,2</sup>
¹Department of Medical Oncology, Cancer Center of Sun Yat-sen University, Guangzhou, China; ²State Key Laboratory of Oncology in South China, Guangzhou, China; ³Department of Lymphoma of Head and Neck Medical Oncology, the 307th Hospital of Chinese People's Liberation Army, the Affiliated Hospital of Military Medical Science, Beijing, China; ⁴Department of Lymphoma, Cancer Hospital of Guizhou Province, Cancer Hospital of Guizhou Medical University, Guiyang, China; ⁵Department of Haematological Oncology, Tumor Hospital of Hebei Province, Shijiazhuang, China; ⁶Department of Radiation Oncology, Cancer Center of Sun Yat-sen University, State Key Laboratory of Oncology in Southern China, Guangzhou, China; ⁷Department of Haematological Oncology, Cancer Hospital of Shanxi Province, Taiyuan, China; ⁸Department of Haematological Oncology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China; ⁹Department of Lymphoma, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; ¹⁰Department of Haematological Oncology, TCM-integrated Cancer Center of Southern Medical University, Guangzhou, China; ¹¹Department of Lymphoma, Shanxi Dayi Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China; ¹²Department of Haematological Oncology, Lanzhou University Second Hospital, Lanzhou, China; ¹³Department of Medical Oncology, the First Affiliated Hospital of

Guangxi Medical University, Nanning, China; ¹⁴Department of Medical Oncology, West China School of Medicine, West China Hospital of Sichuan University, Chengdu, China

**Introduction:** Extranodal natural killer/T-cell lymphoma (ENKTL) is an uncommon, aggressive form of non-Hodgkin's lymphoma. Optimal therapeutic strategies have not been fully defined yet. Nasal NK/T-cell lymphomas present mostly with stage I/II disease. For stage I/II nasal lymphoma, a combination of chemotherapy and radiotherapy yields good results. Concomitant chemoradiotherapy and sequential chemotherapy and radiotherapy have similar response rates and survivals. For stage III/IV nasal, nonnasal, and disseminated ENKTL, systemic chemotherapy is indicated. Conventional anthracycline-based regimens are ineffective. Regimens containing L-asparaginase are most effective. Both AspaMetDex and P-Gemox is recommended as major effective combined chemotherapy regimen by NCCN guideline. Therefore, we try to evaluate the efficacy and toxicity for P-Gemox plus thalidomide and AspaMetDex followed by extensive involved field radiotherapy (EIFRT) as first-line treatment for newly diagnosed stage I/II patients and as salvage regimen for newly diagnosed stage III/IV or relapsed/refractory ENKTL in this clinical study.

PFS by group

<figure><img src="image_82.png" /></figure>

PFS of untreated stage II by group

<figure><img src="image_83.png" /></figure>

PFS of untreated stage III/IV, relapsed/refractory by group

<figure><img src="image_84.png" /></figure>

OS by group

<figure><img src="image_85.png" /></figure>

OS of untreated stage II by group

<figure><img src="image_86.png" /></figure>

OS of untreated stage III/IV, relapsed/refractory by group

<figure><img src="image_87.png" /></figure>
**Methods:** We initiated the prospective, multicentre, randomized, phase III, non-inferiority clinical trial at 12 centers in China at March 2014. Patients were randomly assigned to receive either P-Gemox+thalidomide regimen (Group A: Pegaspargase 2000U/m²; im d1, Gemcitabine 1000mg/m²; iv drip, d1, d8. Oxaliplatin 130mg/m²; ivdrip, d1, thalidomide 100mg/d po, for one year.) or AspaMetDex regimen (Group B: Pegaspargase 2000U/m²; im, d1, Methotrexate 3000mg/ m²; civ 6-hour d1, calcium folinate 30mg iv, q6h, until reach safe serum MTX concentration, Dexamethasone 40mg/d ivdrip, d1-4.). For newly diagnosed stage I/II patients, both regimens were repeated every three weeks for a maximum four cycles as induction chemotherapy and followed by EIFRT at the dosage of 56Gy in 28 fractions over 4 weeks. Primary EIFRT was delivered using 6-MeV linear accelerator using 3-dimensional conformal treatment planning. For newly diagnosed stage III/IV or relapsed/refractory ENKTL, the regimens were repeated every three weeks for a maximum six cycles. Patients underwent autologous hematopoietic stem cell transplantation (ASCT) as consolidation if they achieved response (CR or PR). The primary endpoint was progression-free survival (PFS), with a non-inferiority margin of 15%.

**Results:** Between March 2014 and March 2018, 165 patients were randomly assigned. 85 patients to Group A, 80 patients to Group B. 156 patients were evaluable for response. Investigator-assessed overall response at the end of induction was 88.2% in the Group A and 75.0% in the Group B. Complete remission (CR) rate were 60.0% and 55.0%. Among 107 newly diagnosed stage I/II patients, 54 patients were assigned to Group A (52 assessed), and 53 to Group B (47 assessed). Overall response during induction in Group A and B was similar in both groups, were 64.8% and 64.2%. 58 newly diagnosed stage III/IV or relapsed refractory patients were enrolled. 31 patients were assigned to Group A (30 assessed), and 27 to Group B. The efficacy rate of Group A was higher than that of Group B. Overall response rate were 87.1% and 66.6%, respectively. At median follow-up of 24.6 (1.0-60.9) months, 3-year progression-free survival (PFS) and overall survival (OS) of whole cohort were 61.4% and 63.4%. PFS and OS rate of Group A were similar to Group B (Figure 1). Group B was better tolerated than Group A, with lower rates of agranulocytosis, thrombocytopenia and infections. While anemia, hyperbilirubinemia, edema, and increased BUN/Cr were more common in Group B. Three patients died of treatment related toxicity only in Group B. Two patients died of severe acute renal failure and sepsis at the first cycle, and one patient died of sepsis at the third cycle.

**Conclusion:** Induction chemotherapy of both P-Gemox+Thalidomide and AspaMetDex regimen followed by EIFRT yielded promising efficacy for patients with stage I/II ENKTL. There is little difference in response and survival between the two regimens. For advanced or relapsed patients, both regimen showed unsatisfied survival outcome. Meanwhile, P-Gemox+ Thalidomide was less toxic with more convenient administration in outpatients' clinics in comparison to AspaMetDex. (ClinicalTrials.gov, NCT 2085655).

**Disclosures:** No relevant conflicts of interest to declare.

**Figure 1.** OS and PFS in ENKTCL treated with P-Gemox+Thalidomide or AspaMetDex

**Keywords:** chemotherapy; extranodal lymphomas.

L. de Leval

Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland

Peripheral T-cell lymphomas (PTCL) represent diverse and aggressive malignancies. Findings derived from high-throughput transcriptomic and genomic studies have shed light onto the complex molecular features of these rare diseases, and provided the grounds to a better understanding of their pathogenesis and a more comprehensive classification, already in part reflected in the 2017 WHO classification of lymphoid tumors.

The genetic alterations in PTCL target multiple pathways. Highly recurrent mutations occur in different classes of epigenetic modifiers mostly involved in DNA or histone methylation, in T-cell receptor and co-receptors signaling pathways, and in components or regulators of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. There is established or presumed evidence that the resulting functional deregulations represent pathogenic mechanisms contributing to induce or maintain some attributes of the malignant phenotype. Although a few variants are characteristic of certain entities, for example RHOA<sup>G17V</sup> highly prevalent in angioimmunoblastic T-cell lymphoma, no novel disease-defining mutation has been found, there is major overlap in the mutational landscapes of different entities, and ALK-positive anaplastic large-cell lymphoma (ALCL) essentially remains the only PTCL defined by a specific genomic rearrangement.

Immune evasion has also emerged as another oncogenic mechanism in PTCLs. Increasing interest has developed regarding the PD-1/PDL-1 axis in lymphoid malignancies. PD-L1 is expressed at variable frequencies in different PTCLs, suggesting that PD-1 blockade may represent an efficient an efficient therapy in some patients; however, because PD-1 has been demonstrated to act as a tumor suppressor which is inactivated in a fraction of T-cell lymphomas, PD-1 checkpoint inhibition may also potentially lead to unwanted effects.

Nodal lymphomas of follicular helper T cell derivation represent the largest group of PTCL; pathological and experimental evidence suggest a multistep oncogenic process starting with epigenetic deregulation acquired in hematopoietic cells, and secondary mutations targeting T cells. In group of anaplastic large cell lymphomas, breast implant-associated cases represent a new indolent ALK-negative entity characterized by recurrent mutations in STAT3 and JAK1, without evidence of DUSP22 rearrangements. The GATA3 (TH2) and TBX2 (TH1) subgroups of PTCL-not otherwise specified defined by specific molecular signatures, are associated with different copy abnormalities and oncogenic pathways, indicating distinct oncogenic evolution.
# 115 DIFFUSE LARGE B-CELL LYMPHOMA: USING IMMUNE BIOMARKERS TO DEFINE NOVEL THERAPIES

W. Zhao

State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous type of non-Hodgkin's lymphoma varied from clinical, pathological, immunophenotypic, molecular and prognostic features. According to gene expression profiling, DLBCL can be distinguished to three sub-types, germinal center B-like (GCB), activated B-cell like (ABC) and primary mediastinal B-cell lymphoma (PMBL) subtypes, the latter two referred as non-GCB subtype. As a more practical method, classification of GCB and non-GCB subtype is mostly detected by immunohistochemistry study of CD10, BCL6, MUM1. Nowadays, growing studies have applied system biology techniques to determine multi-omic heterogeneity and to accomplish molecular classification in DLBCL.

The immunotherapy of cancer has also made significant progress in the past decade. Improved understanding of cancer immunology increases insights into the mechanism of tumor response to immune cells, elucidating the therapeutic role of immunity in cancer and fueling an expanding array of new therapeutic agents. Evaluation of the effectiveness of immunotherapy involves various immune cells within peripheral blood or tumor, including monocytes, lymphocytes, myeloid-derived suppressor cells (MDSC), as well as inflammatory factors and cytokines, etc. In DLBCL, lymphocyte-monocyte ratio (LMR) and cytokines like sIL-2R, IL-6, IL-8, IL-10, and TNF-a are significantly associated with clinical outcome. From 1114 patients with non-Hodgkin's lymphoma, we develop a nomogram for OS prediction, including lactate dehydrogenase (LDH), LMR, sIL-2R, and TNF-a. Moreover, MDSC is a group of immune cells from the myeloid lineage, including granulocyte-like (G-MDSC) and monocytic (M-MDSC). MDSC has negative correlation with T cells and increased M-MDSC is related to poor disease outcome in DLBCL.

Addition of immunoregulatory agents to R-CHOP proves efficient in treating high-risk DLBCL patients. Lenalidomide, an oral immunomodulatory agent, has shown activity in DLBCL. A phase III randomized study revealed that lenalidomide maintenance for 24 months after obtaining a CR or PR to R-CHOP significantly prolonged PFS in elderly patients with DLBCL. Atezolizumab is a humanized anti-programmed death-ligand 1 (PD-L1) antibody. Another phase I/II open-label study enrolled advanced DLBCL patients. Among 40 evaluable patients for response, 31 patients (77.5%) had a CR and 4 patients (10%) had a PR. Together, immune dysregulation plays an important role on disease progression and may become potential therapeutic targets. Further mechanism study is helpful for the identification of biological subsets

sensitive to immunotherapy and eventually to realize precision treatment in DLBCL.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); immune system.

# 116 THE T CELL PROJECT 2.0: THE MORE WE REGISTER, THE MORE WE LEARN

M. Federico¹ | M. Manni² | M. Civallero² | T. Skrypets²

¹Medical Oncology, CHIMOMO Department, University of Modena and Reggio Emilia, Modena, Italy; ²CHIMOMO Department, University of Modena and Reggio Emilia, Modena, Italy

Peripheral T-cell lymphomas (PTCLs) encompass a biologically and clinically heterogeneous group of rare neoplasms arising from mature T cells of post-thymic origin at different stage of differentiation. PTCLs account for 10-15% of all lymphoproliferative disorders in Western countries and usually exhibit a poor prognosis, with a 5-year-survival <50%.

Due to its rarity and the heterogeneity of subtypes, large, prospective, and randomized trials comparing different treatment approaches are still lacking. First-line therapy usually consists of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) +/- Etoposide. In recent years, early consolidation with high dose chemotherapy and stem cell rescue has been adopted in many Institutions, with promising results.

In any case, the risk of relapse remains quite high and relapsed or refractory patients have been shown to have a very dismal outcome. For those patients in need of salvage therapy, current data confirm the unmet need for better treatment. However, a trend towards greater response and survival in those treated with single agents, while maintaining the ability to bridge to transplantation, is emerging. In 2006 we started the T-cell Project (TCP), a prospective registry of patients with PTCL. Many lessons come from this project: 1) the risk of incorrect diagnostic classification is high, with the consequence need to find reliable tools, specific markers and objective criteria to improve accuracy in the routinely diagnostic work-up for these entities; 2) the outcome of PTCL continues to be dismal in the majority of cases and no improvement was found in OS in the majority of sub-types, compared to older series; 3) treatment remains challenging and new therapies are welcome. Moreover, this project allowed to build a new prognostic model for patients with PCTL-NOS, based on advanced stage, poor ECOG-PS, low serum albumin level and elevated absolute neutrophil counts.

Recently, several new findings have contributed to further understanding of biological, clinical, and therapeutic aspects of PTCLs. Thus, the International T-cell non-Hodgkin's Lymphoma Study Group recently launched the T-cell Project 2.0, being again a prospective, longitudinal, international, observational study of patients with PTCLs. This study adapts to changes made in diagnosis, classification, staging and response evaluation, in order to have a contemporary, real-time
understanding of the evolving landscape of T-cell lymphoma biology and treatment, together with the application of contemporary technologies to further identify of new therapeutic targets. A final accrual of 1,000 cases has been planned. At present, 60 Institutions from 18 different countries already joined the project. So far, 151 patients have been registered by 25 active sites, 34% of whom with diagnosis of PTCL-NOS.

**Keywords:** T-cell lymphoma (TCL).

**Disclosures:** Federico, M: Research Funding: Roche, Abbvie, Gador, Roemmers/Iclos, Libra, Innate, Nolver, Pfizer, Scienza Novartis, Thomas Jefferson University, Seattle Genetics Innate Pharma.

# SESSION 10 – ADVANCES IN CAR T-CELL TREATMENT

117

## Novel BAFF-R CAR T-cell Therapy for CD19 Antigen-loss Relapsed B Cell Tumors

L.W. Kwak¹ | H. Qin¹ | Z. Dong¹ | X. Wang² |

W.A. Cheng¹ | D. Smith¹ | J.Y. Song³ | I. Aldoss⁴ |

M. Muschen⁵ | S.J. Forman²

¹Toni Stephenson Lymphoma Center, City of Hope, Duarte, United States; ²Center for CAR T Cell Therapy, City of Hope, Duarte, United States; ³Department of Pathology, City of Hope, Duarte, United States; ⁴Gehr Family Center for Leukemia Research, City of Hope, Duarte, United States; ⁵Department of Systems Biology, City of Hope, Duarte, United States

**Introduction:** Chimeric antigen receptor (CAR) T cells against CD19 have shown great potential in treatment of B cell malignancies. However, tumor relapse from antigen loss can limit efficacy. B-cell activating factor-receptor (BAFF-R), a tumor necrosis factor receptor superfamily protein (TNFRSF13C), is another potential B-cell specific target of B cell malignancies. BAFF-R is an especially interesting alternative to CD19 as BAFF-R signaling is a driver of B-cell survival, which may limit the capacity of clonal B-cell tumors to escape therapy by down-regulation of antigen expression. However, while the BAFF/BAFF-R axis has been successfully targeted for autoimmune diseases, the promise for cancer therapy has not yet been fulfilled.

**Methods and Results:** A humanized, single-chain variable fragment (scFv) derivative of an anti-human BAFF-R antibody (Qin et al. Clin Can Res 2018;24:1114-1123) was engineered onto a second generation CAR construct containing 4-1BB costimulatory and CD3ζ intracellular signaling domains. BAFF-R-CAR T cells demonstrated cytotoxicity against human lymphoma and acute lymphocytic leukemia (ALL) lines. Adoptively transferred BAFF-R-CAR T cells eradicated 10-day pre-established tumor xenografts after a single treatment and were superior to CD19-CAR T cells (not shown) and

retained efficacy against xenografts deficient in CD19 expression, including one primary patient-derived xenograft (PDX). Specifically, we modeled disease relapse due to the loss of CD19 by generating CRISPR CD19 gene knock-out of the ALL (Nalm-6) cell line and a gRNA-silenced CD19 gene knock-down of an ALL PDX. We confirmed the absence of CD19 and presence BAFF-R expression, which was unaffected, on the resulting cell lines by surface staining (Fig. 1A). Using transduced CD8 T~N~ cells, we found that CD19-CAR T cells demonstrated cytotoxicity only against wild-type tumor cells, while BAFF-R-CAR T cells maintained significant cytotoxicity against both wild-type and CD19-negative tumors in vitro (Fig. 1B). The therapeutic efficacy of BAFF-R-CAR T cells was tested against human ALL Nalm-6-CD19 deficient xenografts established in NSG mice following IV tumor challenge on day 0 with luciferase-expressing cells. A single dose of 2.5 x 10⁶ CD4 T~N~ + 10⁶ CD8 T~N~ BAFF-R- or CD19-CAR T cells/mouse infused IV on day 11 post tumor implantation completely eliminated established Nalm-6-CD19KO ALL tumors and conferred long-term survival. In contrast, treatment with PBS or identical mixtures of CD19-CAR T cells or non-transduced T cells from the same donor were associated with progressive tumor growth and 100% mortality by Day 60 (Fig. 1C).

Finally, four relapsed, antigen loss primary ALLs obtained after CD19-directed therapy retained BAFF-R expression and activated BAFF-R-, but not CD19-CAR T cells. Specifically, cell surface staining demonstrated CD19 and BAFF-R expression in tumors obtained prior to CD19-targeted therapy. However, post-treatment samples exhibited clear down-regulation of CD19, while retaining positive BAFF-R expression (Fig. 1D, samples from a single representative patient shown). The ability of the primary tumor samples to activate either CD19- or BAFF-R-CAR T cells was determined by expression of the degranulation marker CD107a on the CAR T cells. Cryopreserved ALL samples were co-cultured with BAFF-R or CD19 CAR-T cells derived from the same healthy donor in the presence of anti-CD107a antibody for 6 h. Non-transduced T cells (non-CAR) from the same donor were used as a negative control. Activation of CD19-CAR T cells by all four CD19-negative post-blinatumomab therapy tumors was significantly reduced, compared with BAFF-R-CAR T cells and with corresponding available CD19-positive pre-therapy tumors, while BAFF-R-CAR T cells were equally activated by pre- and post-CD19-targeted therapy tumors (Fig.1E-F). We observed similar trends for both CD19- and BAFF-R-CAR T cell activation by pre- and post-CD19-targeted therapy tumors, as measured by specific intracellular CAR T-cell TNF-α and IFN-γ production (not shown).

**Conclusion:** Taken together, our data suggest that BAFF-R is amenable to CAR T-cell therapy and that targeting it may add to existing alternative strategies to overcome relapse from CD19 antigen loss, such as CD22 CAR T cells. Future strategies combining dual targeting of CD19 and BAFF-R may also be effective.

**Keywords:** B-cell lymphoma; CD19.

**Disclosures:** Kwak, L: Consultant Advisory Role: Pepromene Bio, InnoLifes, Enzychem, Celltrion; Stock Ownership: Pepromene Bio, InnoLifes, Xeme BioPharma; Research Funding: Pepromene Bio.
<figure><img src="image_88.png" /><figcaption>**Figure 1.** Activity of BAFF-R CAR Ts against CD19-negative human ALL lines and primary CD19 antigen-loss human ALL escape variants. A) FACS histograms of CD19 and BAFF-R expression on wildtype (WT) and corresponding KO/KD tumors. B) Cytotoxicity of corresponding tumor targets shown as the mean ± s.d. of triplicate samples. C) Bioluminescence images of groups of NSG mice as indicated and Kaplan-Meier plots of overall survival at 80 days. **P<0.001 compared with controls. D) Expression of CD19 and BAFF-R in tumor samples from a representative ALL patient pre- or post-relapse following CD19 bi-specific antibody treatment. E) Representative and F) combined degranulation data from all patients for CAR T cells following coculture of patient ALL samples with BAFF-R- or CD19-CAR T cells, mean ± SEM (*P<0.05 with Mann-Whitney analysis).</figcaption></figure>

118
PHASE I CLINICAL TRIAL OF
CD19-TARGETED 19-28Z/4-1BBL

"ARMORED" CAR T CELLS IN PATIENTS
WITH RELAPSED OR REFRACTORY NHL
AND CLL INCLUDING RICHTER
TRANSFORMATION

C.L. Batlevi<fnref n="1" />* | M.L. Palomba<fnref n="1" />* | J. Park<fnref n="1" />* |

E. Mead<fnref n="1" /> | B. Santomasso<fnref n="1" /> | I. Riviere² |

X. Wang² | B. Senechal² | R. Furman³ | J. Yang<fnref n="1" /> |

P. Kane<fnref n="1" /> | M. Hall<fnref n="1" /> | Y. Bernal<fnref n="1" /> | N. Lund<fnref n="1" /> |

C. Diamonte<fnref n="1" /> | J. Pineda<fnref n="1" /> | E. Halton<fnref n="1" /> |

C. Moskowitz⁴ | A. Younes<fnref n="1" /> | M. Sadelain⁵ |

R. Brentjens<fnref n="1" />

Engineering Facility, New York, NY, United States; ³Department of
Medicine, Weill Cornell Medical Center, New York, United States;

⁴Department of Medicine, University of Miami Sylvester Cancer Center,
Miami, United States; ⁵Center for Cell Engineering, New York, NY, United
States

* Authors contributed equally to this work.

**Introduction:** CD19-specific second generation chimeric antigen receptor (CAR) T cell therapy with either CD28 or 41BB co-stimulatory domain demonstrate complete remission (CR) rates of 30-50% in relapsed/refractory (R/R) NHL and 20-30% in CLL. Concurrent expression of 4-1BBL in a CD19 CAR T cell enhances T cell proliferation, IL-2 secretion, and cytolytic activity of CAR T cells in the inhibitory tumor microenvironment (Zhao Z et al. Cancer Cell 2015). We report the outcomes of adult patients (pts) with NHL and CLL treated with escalating doses of autologous 19-28z/4-1BBL⁺ CAR T cells (NCT03085173).

<footnote n="1">¹Department of Medicine, Memorial Sloan Kettering Cancer Center,
New York, United States; ²Michael G. Harris Cell Therapy and Cell</footnote>
<figure><img src="image_89.png" /></figure>

**Methods:** Pts with R/R NHL (DLBCL, follicular lymphoma (FL), transformed FL (tFL), Waldenström's macroglobulinemia (WM)) and CLL including Richter's transformation were eligible. Pts received conditioning chemotherapy with cyclophosphamide (Cy) alone or combined with fludarabine (Flu) followed by escalating doses of CAR T cells. For DLBCL pts, R-GemOx was the preferred bridging chemotherapy. CAR T cells were administered at dose level (DL) 1 (1x10⁵ cells/kg), DL2 (3x10⁵ cells/kg), DL3 (1x10⁶ cells/kg), and DL4 (3x10⁶ cells/kg). The primary and secondary objectives of the study was to evaluate safety of autologous 19-28z/4-1BBL CAR T cells and assess overall response rate.

**Results:** 28 pts were enrolled with R/R CLL (n=9), de novo R/R DLBCL (n=6), tFL (n=3), FL and WM (n=5), Richter's transformation (n=4), and B-ALL (n=1). Median age of the pts was 70 (range, 53-81), and median number of prior treatments was 5 (range, 2-17). No dose-limiting toxicity (DLT) was observed. All 28 pts are at least 2 weeks from T cell infusion and evaluable for toxicity. Cytokine release syndrome (CRS) was observed in 11 pt (39.3%), one patient with a grade 3 event. Neurotoxicity was observed in 11 pts (39.3%), grade 1-2 in 8 pts and grade 3 in 3 pts. Twenty-seven patients were evaluable for response; one patient was not evaluable because of progressive multifocal leukoencephalopathy attributed to prior therapy, which

developed within 1 month after CAR T cell therapy. Responses were observed at all DL. Three patients received multiple infusion of CAR T cells with response from first infusion considered evaluable. Sixteen of 27 pts (59%) achieved a CR, including 7/9 (78%) pts with DLBCL, 3/4 (75%) pts with FL, 3/9 (33%) pts with CLL, 2/3 (67%) pts with Richter's transformation, and one pt with B-ALL. The pt with WM achieved a VGPR. With a median follow-up of 169 days (24-534 days), 8 pts (29%) remain in CR. Peak CAR T cell expansion occurred at a median of 9 days after CAR T cell infusion (range, 2-82). CAR T cell detection beyond 160 days noted.

**Conclusions:** Treatment with 19-28z/4-1BBL armored CAR T cells is safe with no severe CRS. Grade 3 neurotoxicity was noted in 3 pt (11%) with no case of cerebral edema. The overall CR rate is 57% with 8 patients remaining in CR at the time of this report. Future studies are warranted to develop and improve on existing CAR T cell therapies.

**Keywords:** CD19; non-Hodgkin lymphoma (NHL); T-cells.

**Disclosures:** **Batlevi, C:** Consultant Advisory Role: GLG, Lifesci Consulting; Honoraria: Dava Oncology; Research Funding: Janssen, Novartis, Epizyme, Xynomics, Mediimmune. **Palomba, M:** Research Funding: Juno. **Park, J:** Research Funding: Juno. **Brentjens, R:** Stock Ownership: Juno; Research Funding: Juno.
# 119 CD30-CHIMERIC ANTIGEN RECEPTOR (CAR) T CELLS FOR THERAPY OF HODGKIN LYMPHOMA (HL)

C.A. Ramos | V. Torrano | M. Bilgi | C. Gerken |

O. Dakhova | Z. Mei | M. Wu | B. Grilley |

A.P. Gee | C.M. Rooney | G. Dotti | B. Savoldo |

H.E. Heslop | M.K. Brenner

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital & Houston Methodist Hospital, Houston, United States

Almost all HL and some NHL express the CD30 antigen, and monoclonal antibodies (mAb) targeting CD30 (e.g. brentuximab) produce objective antitumor responses. However, mAb have limited bio-distribution and their benefits may be short-lived. We therefore expressed the antigen binding domain of a CD30 mAb as part of a chimeric antigen receptor (CAR) on T cells, coupled to the CD28 and ζ chain endodomains. We have previously published results of a phase 1 study of autologous CD30.CAR-T cells (CD30.CARTs) infused in patients with relapsed/refractory CD30⁺ HL or NHL without preceding cytoreductive chemotherapy (Ramos et al., J Clin Invest 2017). Of 6 patients with relapsed active HL, 1 entered complete remission (CR) that has lasted more than 3 years, and 3 had transient stable disease. We have now incorporated cytoreductive chemotherapy (cyclophosphamide and fludarabine) prior to CD30.CAR T infusion to discover if we can enhance the in vivo expansion and anti-tumor activity of these CD30.CARTs (RELY-30, NCT02917083). Our preliminary results suggest a substantial improvement in efficacy.

We have manufactured CD30.CARTs for 23 patients using retroviral transduction. Cell products comprise >98% T cells with a final transduction efficiency of 97.6%±1.8%. Fourteen HL patients, all of whom had disease relapse or progression after a median of 5 treatment regimens (which included brentuximab in 11 and a PD-1 mAb in 13 patients), have received a single infusion of these CD30.CARTs under the RELY-30 trial. Three patients have been treated on dose level (DL) 1 (2×10⁷ CD30.CAR⁺ T cells/m²), 6 on DL2 (1×10⁸) and 5 on DL3 (2×10⁸). All patients received preceding lymphodepleting chemotherapy (cyclophosphamide 500 mg/m² and fludarabine 30 mg/m² daily for 3 days). CART infusions were associated with grade 1 cytokine release syndrome in 6 of the patients, and a transient maculopapular rash in 10 of the patients, starting approximately one week after administration. The molecular signal from CARTs, assessed by Q-PCR in peripheral blood, peaked at 1-2 weeks following infusion, but dropped progressively after 4 weeks and decreased to the limit of detection by 6 months. The signal level was dose dependent, with a peak average of 7,132, 14,326, and 34,433 copies/mg DNA in patients treated on DL1, DL2 and DL3, respectively; expansion was 523, 77 and 41-fold higher, respectively, than patients receiving the same CD30.CART dose without prior cytoreduction in our previous trial.

Twelve patients have been evaluated at 6 weeks after infusion. Seven have had a CR lasting up to >15 months, 1 had a partial response, and 4 had disease progression. In 2 patients who relapsed after CR and were re-biopsied, immunohistochemistry evidenced persistent tumor expression of CD30. Hence, infusion of CD30.CARTs after cytoreductive chemotherapy is well tolerated at the doses used. Inclusion of cytoreduction pre-infusion substantially improves CD30.CART expansion and appears associated with superior anti-tumor activity in relapsed patients.

**Keywords:** CD30; classical Hodgkin lymphoma (cHL); immunochemotherapy.

**Disclosures:** Ramos, C: Consultant Advisory Role: Novartis, Celgene; Research Funding: Tessa Therapeutics.

# 120 Durable responses after CD19-targeted CAR-T cell immunotherapy with concurrent ibrutinib for CLL after prior ibrutinib failure

J. Gauthier¹ | A.V. Hirayama¹ | K.A. Hay¹ |

J. Lymp² | D. Li² | A. Sheih¹ | J. Purushe¹ |

B.S. Pender¹ | R.M. Hawkins¹ | A. Vakil¹ | T. Phi¹ |

R.N. Steinmetz¹ | S.R. Riddell¹ | D.G. Maloney¹ |

C.J. Turtle¹

¹Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States; ²Statistics, Juno Therapeutics (a Celgene Company), Seattle, United States

**Introduction:** We previously reported that CD19-targeted chimeric antigen receptor-engineered T (CD19 CAR-T) cells could lead to durable responses in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients (pts) who had previously failed ibrutinib therapy. Since pre-clinical studies showed that ibrutinib might improve CAR-T cell anti-tumor efficacy and reduce cytokine release syndrome (CRS), we carried out a pilot study to evaluate the safety and efficacy of CD19 CAR-T cells with concurrent ibrutinib administration.

**Methods:** We treated pts in a pilot cohort of a phase I/II trial (NCT01865617) to evaluate the concurrent administration of ibrutinib with infusion of a defined composition of 2x10⁵ or 2x10⁶/kg CD4⁺ and CD8⁺ CD19 CAR-T cells after lymphodepletion chemotherapy in pts with R/R CLL. Ibrutinib (420mg/day) was scheduled from at least 2 weeks before leukapheresis through at least 3 months (m) after CAR-T cell infusion.

**Results:** Nineteen high risk CLL pts were included in this study. The median number of prior therapies was 5 (range: 1-10), and 17 pts (89%) had high risk cytogenetics (17p deletion and/or complex karyotype and/or 11q abnormalities). All pts had failed treatment with ibrutinib prior to study entry. Fourteen pts (74%) developed CRS (grade 1, n=6, 32%; grade 2, n=8, 42%). Despite robust expansion of CAR-T cells in blood (median peak: 159,157 transgene copies/µg DNA), we did not observe grade ≥ 3 CRS (Lee 2014 criteria). Five pts
A

iwCLL response at day 28 CR/PR Other

<figure><img src="image_90.png" /></figure>

Number at risk

<figure><img src="image_91.png" /></figure>

B

iwCLL response at day 28 CR/PR Other

<figure><img src="image_92.png" /></figure>

Number at risk

<figure><img src="image_93.png" /></figure>

C

Marrow MRD by IGH sequencing Negative Positive

<figure><img src="image_94.png" /></figure>

Number at risk

<figure><img src="image_95.png" /></figure>

D

Marrow MRD by IGH sequencing Negative Positive

<figure><img src="image_96.png" /></figure>

Number at risk

<figure><img src="image_97.png" /></figure>

Abbreviations: CAR, chimeric antigen receptor; CR, complete response; PR, partial response; iwCLL, international workshop chronic lymphocytic leukemia; MRD, minimal residual disease. P values per logrank test.

developed neurotoxicity (grade 3, n=5, 26%, CTCAE 4.03 criteria). Eighteen pts were evaluable for response at restaging 4 weeks after CAR-T cell infusion (one patient died from a presumed ibrutinib-induced cardiac arrhythmia during grade 2 CRS). Fifteen pts (83%) responded (CRi or PR) by iwCLL criteria (CRi, n=4, 22%; PR, n=11, 61%). Ten of 14 pts (71%) with nodal disease by CT achieved CR or PR by iwCLL CT criteria. We observed elimination of marrow disease by multi-parameter flow cytometry in 13 pts (72%) and 11 (61%) had no residual malignant clone by IGH sequencing. In responders by iwCLL criteria (n=15) the 1-year probabilities of OS and PFS were

80% (95% CI: 57-100) and 49% (95% CI: 23-100), respectively (median follow-up: 11m; Figure A-B). In pts who achieved MRD-negative marrow response by IGH sequencing (n=11), the 1-year probabilities of OS and PFS were 100% (95% CI: 12-100) and 62% (95% CI: 32-100), respectively (Figure C-D); 9 of 11 pts (82%) without MRD by IGH sequencing were free of disease at last follow-up (median follow-up: 9.5m). Bayesian comparisons showed the concurrent administration of ibrutinib was associated with higher probabilities of IGH-negative marrow response and lower probabilities of grade ≥ 3 CRS, compared to pts treated with CD19 CAR-T cells alone.
**Conclusions:** In conclusion, CD19 CAR-T cell therapy with concurrent ibrutinib for R/R CLL was feasible and led to high rates of durable responses, without ≥ grade 3 CRS.

**Keywords:** chronic lymphocytic leukemia (CLL); ibrutinib; immune system.

**Disclosures:** Lymp, J: Employment Leadership Position: Juno Therapeutics, A Celgene Company; Stock Ownership: Juno Therapeutics, A Celgene Company. Li, D: Employment Leadership Position: Juno Therapeutics, A Celgene Company; Stock Ownership: Juno Therapeutics, A Celgene Company. Riddell, S: Consultant Advisory Role: Cell Medica, Adaptive Biotechnologies, NOHLA; Research Funding: Juno Therapeutics. Maloney, D: Honoraria: Janssen Scientific Affairs, Seattle Genetics, Roche/Genentech; Research Funding: Juno Therapeutics, GlaxoSmithKline. Turtle, C: Consultant Advisory Role: Juno Therapeutics, Nektar Therapeutics, Eureka Therapeutics, Precision Biosciences, Caribou Biosciences.

121
HIGH RATE OF DURABLE COMPLETE REMISSION IN FOLLICULAR LYMPHOMA AFTER CD19 CAR-T CELL IMMUNOTHERAPY

<figure><img src="image_98.png" /><figcaption>Figure 1</figcaption></figure>

**Figure 1.** Progression-free (PFS) and overall survival (OS) in patients with follicular lymphoma after CD19 CAR-T cell immunotherapy. Kaplan-Meier estimates of PFS (A-B) and OS (C-D) in patients with follicular lymphoma (A-C) and transformed follicular lymphoma (B-D) who achieved complete remission (black) and in all patients (red). The numbers of patients at risk at 6-month intervals are indicated.

**A.V. Hirayama¹** | **J. Gauthier¹** | **K.A. Hay²** |
**J.M. Voutsinas¹** | **Q. Wu¹** | **A. Sheih¹** | **J. Purushe¹** |
**B.S. Pender¹** | **R.M. Hawkins¹** | **A. Vakil¹** | **T. Phi¹** |
**R.N. Steinmetz¹** | **S.R. Riddell¹** | **D.G. Maloney¹** |
**C.J. Turtle¹**

¹Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States; ²Department of Medicine, University of British Columbia, Vancouver, Canada

**Introduction:** Patients (pts) with follicular lymphoma with early relapse after initial chemoimmunotherapy have limited survival, as do those who fail multiple regimens or develop histologic transformation to large cell non-Hodgkin lymphoma (NHL). Initial responses after CD19-directed chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy in pts with follicular lymphoma have been reported; however, the incidence and durability of responses in pts with follicular lymphoma without transformation (FL) or with histologic transformation (tFL) have not been established.

**Methods:** We conducted a phase 1/2 clinical trial (NCT01865617) of CD19 CAR-T cell immunotherapy in adults with relapsed/refractory (R/R) CD19⁺ B-cell malignancies. Best responses were reported
according to the Lugano criteria. Fisher's exact and Wilcoxon rank-sum tests were used to compare categorical and non-categorical variables, respectively.

**Results:** Twenty-one pts who received cyclophosphamide and fludarabine lymphodepletion followed by 2x10⁶ CD19 CAR-T cells/kg are included in this study. Eight pts (38%) had FL and 13 (62%) had tFL. The FL pts had received a median of 4 prior therapies (range, 2-7); all had failed chemoimmunotherapy with an anti-CD20 antibody and alkylating agents; 75% had progressive disease after the last therapy; and 50% had failed prior autologous (n=3) or allogeneic (n=1) hematopoietic cell transplantation. Before lymphodepletion, 75% had stage III or IV disease; 62% had extranodal involvement; and 75% had intermediate or high FLIPI score. Seven of 8 pts with FL achieved complete remission (CR, 88%; 95% CI, 47-99) after CAR-T cells. The median time to CR was 29 days (range, 27-42), and all who achieved CR remained in remission without additional therapy (median follow-up, 24 months). Despite high-risk disease, durable CR was observed in most FL pts, indicating this therapy should be further investigated in larger studies.

For the 13 pts with tFL, the best overall response without additional therapy was 46% (95% CI, 20-74), with all responding pts achieving CR. For tFL pts who achieved CR, the median progression-free survival (PFS) was 11.2 months (95% CI, 3.3-NR; median follow-up 38 months). The median PFS for all pts with tFL was 1.4 months (95% CI, 1.2-NR) [Figure 1]. Pts with FL and tFL had comparable baseline and treatment characteristics; however, more tFL pts had elevated lactate dehydrogenase (LDH; FL vs tFL, 13% vs 69%, P = .02) and fewer had bone marrow involvement (50% vs 15%, P = .15). No significant differences were observed between FL and tFL pts in peak CAR-T cell counts in blood, or the incidence and severity of cytokine release syndrome (CRS) or neurotoxicity (NT). No severe (grade ≥3) CRS or NT were observed.

**Conclusions:** CD19 CAR-T cell immunotherapy is highly effective in adults with clinically aggressive R/R FL, with durable CR in a high proportion of FL pts.

**Keywords:** CD19; follicular lymphoma (FL); T-cells.

**Disclosures:** Hirayama, A: Honoraria: DAVA Oncology. Hay, K: Consultant Advisory Role: Celgene. Vakil, A: Stock Ownership: Nektar Therapeutics. Riddell, S: Consultant Advisory Role: Adaptive Biotechnologies, Cell Medica, Juno Therapeutics, a Celgene/Bristol-Myers Squibb company, and NOHLA; Stock Ownership: Celgene; Research Funding: Juno Therapeutics, a Celgene/Bristol-Myers Squibb company. Maloney, D: Honoraria: Janssen Scientific Affairs, Seattle Genetics, and Roche/Genentech; Research Funding: GlaxoSmithKline, and Juno Therapeutics, a Celgene/Bristol-Myers Squibb company. Turtle, C: Consultant Advisory Role: Caribou Biosciences, Eureka Therapeutics, Precision Biosciences, Aptevo, Humanigen, Juno Therapeutics, a Celgene/Bristol-Myers Squibb company, Kite, a Gilead Company, Nektar Therapeutics, and Novartis; Stock Ownership: Caribou Biosciences, Eureka Therapeutics, and Precision Biosciences; Research Funding: Juno Therapeutics, a Celgene/Bristol-Myers Squibb company, and Nektar Therapeutics.

## 122
# SAFETY OF LISOCABTAGENE MARALEUCEL GIVEN WITH DURVALUMAB IN PATIENTS WITH RELAPSED/REFRACTORY AGGRESSIVE B-CELL NON HODGKIN LYMPHOMA: FIRST RESULTS FROM THE PLATFORM STUDY

T. Siddiqi¹ | J.S. Abramson² | H.J. Lee³ |

S. Schuster⁴ | J. Hasskarl⁵ | S. Montheard⁵ |

J. Dell Aringa⁶ | E. Thompson⁷ | R. Ananthakrishnan⁸ |

M. Lunning⁹

¹Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, United States; ²Center for Lymphoma, Massachusetts General Hospital, Boston, United States; ³Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States; ⁴Department of Medicine, Abramson Cancer Center, Philadelphia, United States; ⁵Global Clinical Research & Development, Celgene International, Boudry, Switzerland; ⁶Translational Medicine, Immuno Oncology and Cellular Therapy, Juno Therapeutics, a Celgene Company, Seattle, United States; ⁷Informatics and Predictive Sciences, Juno Therapeutics, a Celgene Company, Seattle, United States; ⁸Biostatistics, Celgene Corporation, Summit, United States; ⁹Hematology/Oncology, University of Nebraska Medical Center, Omaha, United States

**Introduction:** In the ongoing TRANSCEND NHL 001 study (NCT02631044), lisocabtagene maraleucel (liso-cel; JCAR017), an investigational, anti-CD19 chimeric antigen receptor (CAR) T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, has shown high response rates and a low incidence of severe cytokine release syndrome (CRS) and neurological events (NE) in patients (pts) with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) (Abramson et al, ASCO 2018). Immune system modifiers may further enhance the response and response durability seen with anti-CD19 CAR T cell therapy. The ongoing multiarm, parallel cohort, phase 1/2 PLATFORM study evaluates liso-cel in combination with immune system modifiers in pts with R/R non-Hodgkin lymphoma (NHL). We report preliminary data from the dose escalation part of Arm A, combining liso-cel with the anti-PD-L1 antibody, durvalumab.

**Methods:** Eligible pts had R/R B-cell NHL, ≥2 prior lines of therapy, and ECOG PS ≤1. Pts received lymphodepletion with fludarabine and cyclophosphamide for 3 days before liso-cel was given at 1 of 2 dose levels (DL): DL1 = 50 × 10⁶ or DL2 = 100 × 10⁶ CAR+ T cells. Durvalumab was given as an IV infusion from day 29 at a total dose of 1500 mg/4 weeks for up to 12 months. Efficacy was assessed per the Lugano Classification.

**Results:** At data cutoff, 18 pts were enrolled (DL1 n=9; DL2 n=9). 15 pts (DL1 n=8; DL2 n=7) received liso-cel; 11 pts (DL1 n=8; DL2 n=3) completed at least one durvalumab total dose of 1500
mg/4 weeks (2 pts are awaiting treatment; 1 pt no longer met the eligibility criteria; 1 pt died of sepsis). Among the 11 pts, 7 were male; the age ranged from 53 to 78 years. Ten pts had DLBCL; 1 patient had follicular lymphoma grade 3B. Treatment-emergent adverse events included fever, CRS, and NEs (all grade ≤2), cytopenia, and fatigue related to liso-cel (n=7 pts); and hemolytic anemia, fatigue, and rash related to durvalumab (n=3 pts). Two pts had grade ≥3 related events (neutropenic fever and cytopenia) after durvalumab treatment. No CRS occurred after durvalumab infusion. One pt died of acute respiratory failure after disease progression. No dose-limiting toxicities were observed. The best overall response rate was 91% (10/11); 64% of pts (7/11) achieved a complete response (CR). Among the first 6 pts who received durvalumab, 3 pts showed increased CAR T cells at day 85 compared with pre-durvalumab levels on day 29. One pt maintained CAR T cells near peak expansion levels until day 85 and achieved CR at month 6.

**Conclusions:** Based on preliminary results, the combination of liso-cel with durvalumab has an acceptable safety profile. No CRS was observed after initiation of durvalumab. Preliminary data suggest CAR T cells persist and/or increase with combination treatment, warranting further clinical evaluation. Updated data will be presented.

**Keywords:** CD19; diffuse large B-cell lymphoma (DLBCL); PD-1L.

**Disclosures:** Siddiqi, T: Consultant Advisory Role: AstraZeneca, Juno, Pharmacyclics, BeiGene; Research Funding: Dr. Siddiqi's institution received research funding from Juno, Celgene, Kite, BeiGene, Oncternal Therapeutics, TG therapeutics, Acerta Pharma, Pharmacyclics; Other Remuneration: Speaker for Pharmacyclics, Janssen, Seattle Genetics. Travel, Accommodations, Expenses: Juno. Abramson, J: Consultant Advisory Role: Gilead Sciences, Seattle Genetics, Celgene Novartis, Amgen, Juno Therapeutics, Karyopharm, Verastem, Bayer, Abbvie, Janssen, Merck, Kite Pharma Genentech, EMD Serono; Research Funding: Seattle Genetics, Celgene, Genentech, Juno therapeutics, Al therapeutics. Lee, H: Research Funding: Celgene. Schuster, S: Consultant Advisory Role: Celgene, Novartis, Merck, Genentech, Nordic Nanovector, Gilead; Research Funding: Dr. Schuster's institution received research funding from Novartis, Celgene, Merck, Genentech. Hasskarl, J: Employment Leadership Position: Celgene International; Stock Ownership: Celgene. Montheard, S: Employment Leadership Position: Celgene. Dell Aringa, J: Employment Leadership Position: Celgene. Thompson, E: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Ananthakrishnan, R: Employment Leadership Position: Celgene. Lunning, M: Consultant Advisory Role: AbbVie, Bayer, Celgene, Genentech, Gilead Sciences, Inc, Janssen/Pharmacyclics, Juno Therapeutics, Kite, Novartis, Portola, Sanofi-Genzyme, Seattle Genetics, Spectrum, TG Therapeutics, Verastem; Research Funding: Dr. Lunning's institution received research funding from Celgene, Curis, Janssen Scientific Affairs, LLC, Juno Therapeutics, miRagen, Pharmacyclics, TG Therapeutics.

SPECIAL LECTURE

123
THE HIGH COST OF CANCER DRUGS:
WHAT CAN WE DO?

S.V. Rajkumar

Division of Hematology, Mayo Clinic, Rochester, MN, United States

The cost of cancer drugs is a major problem for patients around the world. Globally, over $110 billion is spent on the cost of cancer drugs. Each cancer drug introduced in 2017 in the United States was priced at $100,000 per year or more. The average price was in excess of $150,000 per year. More aggravating is that despite high launch prices, prices of new drugs continue to increase with time in the United States at a rate much higher than inflation. This is not sustainable.

Pharmaceutical companies usually argue that the high costs are related to cost of drug development, the value provided by new drugs, market forces, and the need to sustain future innovation. But, there are many problems with these assertions. The ability to command a high price for a drug with borderline benefit, encourages the development of closely related low risk drugs rather than truly novel drugs that can have major impact.

The high cost of cancer drugs worldwide is likely related to many factors including: a vulnerable population that is willing to pay high amounts for access to live-saving drugs, monopoly, patent ever-greening, cumbersome processes for biosimilar and generic approval, and the influence of pharmaceutical company lobbying on elected officials. In addition, there are problems unique to the United States that impact prices worldwide. High among them is the inability of the largest purchaser, Medicare, to negotiate directly for low prices with pharmaceutical companies.

Potential solutions include, patent reform, value based pricing, reciprocal approval of generics and bio-similars among countries, legalization of personal importation of prescription drugs, and compulsory licensing. In addition, physician groups should create strong national and international practice guidelines that take price into account. Physicians should also discuss affordability with their patients when prescribing drugs, and choose the most cost-effective option. Finally, oncologists should advocate for policy changes individually and collectively.

**Acknowledgements:** Supported in part by grants CA 107476, CA 168762, and CA186781 from the National Cancer Institute, Rockville, MD, USA.

**Keywords:** Hodgkin lymphoma (HL).
# SESSION 11 - NEW DRUGS COMBINATIONS

## 124
PRIMARY ANALYSIS RESULTS OF THE SINGLE-ARM PHASE II STUDY OF MOR208 PLUS LENALIDOMIDE IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (L-MIND)

G. Salles¹ | J. Duell² | E. González Barca³ |

W. Jurczak⁴ | A.M. Liberati⁵ | Z. Nagy⁶ | A. Obr⁷ |

G. Gaidano⁸ | M. Andre⁹ | N. Kalakonda¹⁰ |

M. Dreyling¹¹ | P.L. Zinzani¹² |

M. Dirnberger-Hertweck¹³ | J. Weirather¹⁴ |

S. Ambarkhane¹⁵ | K. Maddocks¹⁶

¹Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d'Hématologie, Pierre-Bénite, France; ²Medizinische Klinik und Poliklinik II, University Hospital of Würzburg, Würzburg, Germany; ³Department of Hematology, Institut Catalá d'Oncologia, Hospital Duran i Reynals, IDIBELL, Barcelona, Spain; ⁴Department of Hematology, Jagiellonian University, Kraków, Poland; ⁵SC Oncoematologia, Azienda Ospedaliera Santa Maria, Terni, Italy; ⁶First Department of Internal Medicine, Semmelweis University, Budapest, Hungary; ⁷Department of Hematology-Oncology, Palacký University Olomouc and the University Hospital Olomouc, Olomouc, Czech Republic; ⁸Division of Haematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy; ⁹Department of Hematology, Université catholique de Louvain, CHU UCL Namur, Yvoir, Belgium; ¹⁰Department of Haematology-oncology, Clatterbridge Cancer Centre and University of Liverpool, Wirral, United Kingdom; ¹¹Department of Medicine III, University Hospital of Ludwig-Maximilians-Universität, Munich, Germany; ¹²Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy; ¹³Department of Drug Safety and Pharmacovigilance, MorphoSys AG, Planegg, Germany; ¹⁴Department of Biostatistics and Data Management, MorphoSys AG, Planneg, Germany; ¹⁵Department of Clinical Development, MorphoSys AG, Planegg, Germany; ¹⁶Department of Internal Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States

**Introduction:** CD19 is an important target for the treatment of B-cell malignancies, including relapsed or refractory diffuse large B-cell lymphoma (R-R DLBCL). MOR208, an Fc-enhanced, humanized, anti-CD19 monoclonal antibody, has shown single agent activity in patients (pts) with R-R B-cell lymphoma (Jurczak et al, 2018). MOR208 combined with lenalidomide (LEN) demonstrated synergistic activity in preclinical models, which formed the basis for the single-arm phase II L-MIND study (Salles et al, ASH 2018).

**Methods:** Patients with R/R DLBCL, ineligible for autologous stem cell transplantation, who had received up to 3 prior lines of therapy,

including at least one anti-CD20 therapy, and had adequate organ function were eligible. Treatment comprised up to 12, 28-day (d) cycles (C) of MOR208, 12 mg/kg IV, q1w C1-3 (loading dose on d4 of C1), and q2w C4-12 plus LEN 25 mg PO d1-21, C1-12. Pts progression-free after C12 received MOR208 q2w until progression. The primary endpoint was independent review committee (IRC)-assessed overall response rate (ORR) as per Cheson 2007 criteria. Secondary endpoints included investigator (INV)-assessed ORR, as well as overall survival (OS), progression-free survival (PFS), duration of response (DoR), and safety.

**Results:** As of June 5, 2018, recruitment was complete (n=81 pts). At baseline, median age was 72 years (range 41-87), median number of prior therapies was 2 (range 1-4), 23% of pts had early relapse (≤12 months from initial diagnosis), 40% were rituximab-refractory (no response or progression during or within 6 months of a prior rituximab therapy), 42% were refractory to their last therapy, and 52% had an International Prognostic Index (IPI) of 3-5. MOR208 plus LEN therapy was well tolerated, and 58 (72%) pts stayed on a LEN dose of ≥20 mg/day. The most common grade ≥3 treatment-emergent adverse events were neutropenia in 43% of pts, thrombocytopenia in 17%, febrile neutropenia in 12%, anemia in 9%, leukopenia in 7%, and hypokalemia in 6% of pts. Investigator (INV)-assessed complete response (CR) and partial response rates were 33% and 25%, respectively; as a result, ORR was 58% (n=81). IRC-assessed ORR and CR rates were 54% and 32%, respectively (n=76). At a median follow-up of 12 months, the INV-assessed median PFS, OS and DoR (intention-to-treat analysis) were 16.2 months (95% CI: 6.3 months-NR), not reached (95% CI: 18.6 months-NR), and not reached (95% CI: NR-NR), respectively. Thirty-seven (46%) pts were ongoing in the study.

**Conclusions:** The combination of MOR208 and LEN was well tolerated and has shown encouraging activity and long lasting responses in pts with R-R DLBCL, who have poor prognosis and urgently need effective therapies. Primary analysis results of the study with a recent cut-off (November 30, 2018) and a longer follow-up will be presented at this conference.

**Keywords:** CD19; diffuse large B-cell lymphoma (DLBCL); lenalidomide.

**Disclosures:** Salles, G: Consultant Advisory Role: Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, Merck, Pfizer, Acerta Pharma, Kite Pharma, SERVIER, MorphoSys, and Epizyme; Honoraria: Roche/Genentech, Amgen, Janssen, Celgene, SERVIER, Gilead Sciences, Novartis, Abbvie, Merck, Takeda, and MorphoSys. González Barca, E: Consultant Advisory Role: Celltrion, Janssen, Gilead Sciences, Sandoz, and Kowa; Other Remuneration: Fees for participation in a speakers' bureau from Janssen, Abbvie, Takeda, and Roche; travel, accommodations and expenses from Abbvie, Janssen, and Roche. Jurczak, W: Consultant Advisory Role: AstraZeneca, Gilead Sciences, Sandoz-Novartis, Roche, and MorphoSys; Research Funding: MorphoSys, Roche, Sandoz-Novartis, Celltrion, Celgene, and Janssen. Gaidano, G: Consultant Advisory Role: Abbvie, Janssen, MorphoSys, and Sunesis Pharmaceuticals; Honoraria: Abbvie, Janssen, MorphoSys, and Sunesis Pharmaceuticals; Other Remuneration: Fees for participation in a speakers' bureau from