lymphoma, a disease with excellent outcome in younger children. It is
worrying that 7 patients have died soon after presentation, perhaps
highlighting the consequences of delayed diagnosis at this age.

**Keywords:** Burkitt lymphoma (BL); non-Hodgkin lymphoma (NHL).

024
INCLUSION OF A PEDIATRIC PERSPECTIVE
INTO RECOMMENDATIONS FOR THE
INITIAL EVALUATION AND STAGING OF
HODGKIN LYMPHOMA: A CALL TO
ACTION FROM THE INTERNATIONAL
SEARCH WORKING GROUP

J. Flerlage¹ | C. Mauz-Körholz² | K. Kelly³ |

K. McCarten⁴ | A. Punnett⁵ | S. Kaste¹ |

K. Dieckmann⁶ | L. Marks⁷ | J. Seelisch⁸ |

R. Drachtman⁹ | J. Lewis⁹ | A. Beishuzen¹⁰ |

R. Kluge¹¹ | L. Kurch¹¹ | D. Stroevesandt¹² |

M. Metzger¹

¹Oncology, St. Jude Children's Research Hospital, Memphis, United States; ²Pediatric Hematology and Oncology, Martin-Luther-University, Giessen, Germany; ³Hematology/Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, United States; ⁴Diagnostic Imaging, 13Rhode Island Hospital/Warren Alpert Medical School at Brown University, Providence, United States; ⁵Pediatrics, Sickkids Hospital, Toronto, Ontario, Canada; ⁶Radiotherapy, Medizinische Universität Wien, Vienna, Austria; ⁷Pediatric Hematology/Oncology, Stanford, Palo Alto, United States; ⁸Hematology/Oncology, Children's Hospital, London Health Sciences Centre, London, Ontario, Canada; ⁹Hematology/Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, United States; ¹⁰Radiology, Princess Maxima, Utrecht, Netherlands; ¹¹Nuclear Medicine, University of Leipzig, Leipzig, Germany; ¹²Medicine, University of Halle, Halle, Germany

**Introduction:** Initial evaluation and staging of patients with Hodgkin lymphoma (HL) provides the foundation for formulation of a risk-adapted treatment plan. The Ann Arbor staging system at first, and later the Cotswolds modifications criteria, have helped classify patients into risk groups according to the distribution and number of anatomic sites of disease. As imaging has evolved over the years fewer invasive measures (laparotomy with splenectomy or bone marrow biopsies) are required to determine involved sites. However, radiologic advances have created new challenges as they allow for volumetric measurements of disease; factors such as "bulk" disease are now prognostic and part of staging. Further refinements to the staging of patients with HL are needed to allow for improved prognostication and assignment to risk groups. While the treatment regimens for pediatric Hodgkin lymphoma have somewhat differed from that of adults with a goal to minimize late-effects and specific cumulative drug dosages for this young and surviving population, the staging is the same as for adults.

**Methods:** The International SEARCH (Staging, Evaluation and Response Criteria Harmonization) for CAYAHL (Childhood, Adolescent and Young Adult Hodgkin Lymphoma) group is comprised of representatives from the Children's Oncology Group, European Network for Pediatric HL, St. Jude-Stanford-Dana-Farber consortium, and the Asociación de Hemato-Oncología Pediátrica de Centro América to facilitate the interpretation and comparison of clinical studies worldwide. As we look ahead to potential changes in the staging of HL, we feel it is important to ensure pediatric representation from the SEARCH for CAYAHL group. Given that adolescent and young adult patients are a known peak age range for HL and shared between the adult and pediatric groups, the more unified the staging remains across all age ranges, the better patient outcomes can be compared between trials and inform decision-making. In an era where positron emission tomography scans are the standard for initial staging work up, many new strategies such as the utilization of total metabolic tumor volume, may provide an improved methodology for staging.

**Conclusion:** As the field of HL moves forward, initial staging is an evolving process. Despite differences in the treatment of pediatric and adult patients with HL there is a need to ensure consistency in the staging between the groups. The SEARCH for CAYAHL working group has representation from all major pediatric consortia and should work together with colleagues from the adult groups towards a common goal and vision for the establishment of new staging criteria.

**Keywords:** Hodgkin lymphoma (HL); positron emission tomography (PET).

025
SAFETY AND RESPONSE AFTER 2 CYCLES
OF BRENTUXIMAB VEDOTIN
SUBSTITUTING VINCRISTINE IN THE
OEPA/COPDAC REGIMEN FOR HIGH RISK
PEDIATRIC HODGKIN LYMPHOMA (HL)

M. Metzger¹ | C. Mauz-Körholz² | J. Flerlage¹ |

J. Bartelt³ | A. Billett⁴ | J.K. Choi⁵ | M. Ehrhardt¹ |

T. Georgi⁶ | D. Hasenclever⁷ | F. Wang⁸ |

H. Zhang⁸ | S.C. Kaste⁹ | R. Kluge⁶ | D. Körholz² |

L. Kurch⁶ | M. Link¹⁰ | D. Stoevesandt³ |

M.M. Hudson¹ | M. Krasin¹¹

¹Oncology, St Jude Children's Research Hospital, Memphis, United States;
²Pediatric Hematology Oncology, Justus Liebig Universität, Giessen,
Germany; ³Clinic of Radiology, Martin Luther University, Halle (Saale),
Germany; ⁴Blood Disorders Center, Dana-Farber/Boston Children's
Hospital, Boston, United States; ⁵Pathology, St Jude Children's Research
Hospital, Memphis, United States; ⁶Nuclear Medicine, University of
Leipzig, Leipzig, Germany; ⁷Institut for Medical Informatics, University of
Leipzig, Leipzig, Germany; ⁸Biostatistics, St Jude Children's Research
Hospital, Memphis, United States; ⁹Diagnostic Imaging, St Jude Children's
Research Hospital, Memphis, United States; ¹⁰Pediatric Hematology
Oncology, Stanford University Medical Center, Palo Alto, United States;
¹¹Radiation Oncology, St Jude Children's Research Hospital, Memphis, United States

**Introduction:** This study regimen is based on the GPOH-HD 2002 study that demonstrated 5-year EFS and OS of 87% and 95% respectively with 6 cycles OEPA/COPDAC and 20-30 Gy IFRT. The subsequent EuroNet-C1 study showed that 30% of high-risk patients achieved an adequate response (AR) after 2 cycles of OEPA and could forgo radiation therapy. To explore if radiation could be reduced further, this study substituted Brentuximab vedotin (Bv) for vincristine in the regimen.

**Methods:** Children ≤ 18 years of age, newly diagnosed with stage IIB, IIIB, and IV classical Hodgkin lymphoma were treated with Bv substituting vincristine (AEPA/CAPDac) and 25 Gy ISRT only to areas not in CR at early response evaluation (CR: >75% anatomic response - product of 2 perpendicular diameters of lesions by CT and Deauville Score (DS) < 4 on PET). Objectives: To evaluate the safety of AEPA/CAPDac and the efficacy, defined as the number of patients achieving AR when retrospectively applying the Euro-Net C1 criteria (AR: residual tumor volume ≤50% [CT/MRI] and DS < 3 in lesions ≥ 2 cm and DS < 2 in smaller lesions) following 2 cycles of AEPA.

**Results:** 77 patients were enrolled in this multi-institutional trial between 8/2013 and 2/2018 (table). Therapy was well-tolerated with most common adverse events being leukopenia and excessive weight gain. Peripheral neuropathy was rarely reported (mostly grade 2; 3 grade 3). Events included one cardiac death (arrhythmia associated to myocarditis) during therapy and one disease progression in an originally

<table><caption>TABLE 1 Patient characteristics</caption><thead><tr><th>Characteristic</th><th>N (%)</th></tr></thead><tbody><tr><td>Total 77 patients</td><td></td></tr><tr><td>Gender</td><td></td></tr><tr><td>Female</td><td>39 (51)</td></tr><tr><td>Male</td><td>38 (49)</td></tr><tr><td>Age at diagnosis in yrs</td><td></td></tr><tr><td>Median (range)</td><td>16.2 (6.0 -18.99)</td></tr><tr><td>Race</td><td></td></tr><tr><td>White</td><td>51 (66)</td></tr><tr><td>Black</td><td>16 (21)</td></tr><tr><td>Asian</td><td>4 (5)</td></tr><tr><td>Other</td><td>6 (8)</td></tr><tr><td>Histology</td><td></td></tr><tr><td>Nodular sclerosing</td><td>59 (77)</td></tr><tr><td>Lymphocyte rich</td><td>4 (5)</td></tr><tr><td>Mixed cellularity</td><td>3 (4)</td></tr><tr><td>Classical NOS</td><td>11 (14)</td></tr><tr><td>Stages</td><td></td></tr><tr><td>IIB</td><td>13 (17)</td></tr><tr><td>IIIB</td><td>19 (25)</td></tr><tr><td>IVA</td><td>12 (16)</td></tr><tr><td>IVB</td><td>33 (43)</td></tr></tbody></table>

involved site (now disease free > 4 years after retrieval therapy). The first 32 enrolled patients were available for post-hoc EuroNet-C1 response assessment. The proportion of patients achieving AR following AEPA (x2) using the EuroNet-C1 criteria did not differ from that observed after OEPA (x2) in EuroNet C1, TG3 28% versus 30% (90% CI [16; 44]).

**Conclusions:** AEPA/CAPDac is very well tolerated without substantial neurotoxicity. Substitution of vincristine with Bv did not reduce the proportion of individuals receiving radiation compared to EuroNet-C1 trial; however, radiating only sites of inadequate response (less than 1 out of 5 sites) rather than all sites of initial disease reduces the number of sites treated. Additional follow-up is required to determine the sustainability of disease free and overall survival. This is a PI initiated trial, sponsored by Seattle Genetics Inc.

**Keywords:** brentuximab vedotin; Hodgkin lymphoma (HL).

**Disclosures:** Metzger, M: Research Funding: Seattle Genetics.

## 026 RESPONSE-ADAPTED TREATMENT WITH NIVOLUMAB AND BRENTUXIMAB VEDOTIN IN YOUNG PATIENTS WITH RELAPSED/REFRACTORY CLASSICAL HODGKIN LYMPHOMA: CHECKMATE 744 SUBGROUP ANALYSES

K.M. Kelly<fnref n="1" /> | S. Daw² | C. Mauz-Körholz<fnref n="3" /> |

M. Mascarin⁴ | G. Michel⁵ | S. Cooper⁶ |

A. Beishuizen⁷ | K.J. Leger<fnref n="8" /> | A. Garaventa⁹ |

S. Buffardi¹⁰ | L. Brugières¹¹ | P. Harker-Murray¹² |

P.D. Cole¹³ | R.A. Drachtman¹³ | T. Manley¹⁴ |

S. Francis¹⁵ | M. Sacchi¹⁵ | T. Leblanc¹⁶

<footnote n="1">¹Department of Pediatric Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, United States; ²Paediatric and Adolescent Haematology-Oncology, University College Hospital, London, United Kingdom;</footnote>

<footnote n="3">³Department of Pediatric Hematology and Oncology, University Hospital Justus Liebig University, Giessen, Germany; ⁴AYA and Pediatric Radiotherapy Unit, IRCCS Centro di Riferimento Oncologico, Aviano, Italy; ⁵Service d'Hématologie pédiatrique, CHU de Marseille - Hôpital de la Timone, Maresille, France; ⁶Pediatric Oncology, Johns Hopkins Hospital, Baltimore, United States; ⁷Pediatric Oncology/Hematology, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands;</footnote>

<footnote n="8">⁸Hematology-Oncology, Seattle Children's Hospital, Seattle, United States; ⁹UOC Oncologia, Ematologia e Trapianto di Midollo, IRCCS Istituto Giannina Gaslini, Genoa, Italy; ¹⁰Paediatric Haemato-Oncology, Santobono-Pausilipon Hospital, Naples, Italy; ¹¹Department of Paediatrics, Institut Gustave Roussy, Villejuif, France; ¹²Pediatric Hematology-Oncology, Children's Hospital of Wisconsin, Milwaukee, United States; ¹³Division of Pediatric Hematology/Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, United States; ¹⁴Seattle Genetics, Bothell, United States; ¹⁵Bristol-Myers Squibb, Princeton, United States; ¹⁶Service d'Hématologie Pédiatrique, Hôpital Robert-Debré APHP, Paris, France</footnote>
**Introduction:** New strategies for first salvage therapy (tx) are required for young patients (pts) with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) to improve cure rates and long-term safety, particularly in pts with primary refractory cHL. In adult R/R cHL, first salvage with nivolumab + brentuximab vedotin (BV) resulted in 82% objective response rate (ORR) with 61% complete metabolic response (CMR). CheckMate 744 (NCT02927769) is an ongoing phase 2 study evaluating a risk-stratified, response-adapted approach using nivolumab, BV, and bendamustine (benda) in children, adolescents, and young adults with R/R cHL. In the standard-risk cohort, the regimen was well tolerated and resulted in high CMR rates prior to consolidation with high-dose chemotherapy (HDCT)/autologous transplantation (auto-HCT). Here, we evaluate this approach in primary refractory pts, and in pediatric pts (aged < 18 y) in CheckMate 744, focusing on the nivolumab + BV induction (IND) phase.

**Methods:** Pts aged 5-30 y, after 1 prior tx without auto-HCT were eligible. Risk stratification was based on disease stage at diagnosis, time to relapse, B symptoms or extranodal disease at relapse, extensive disease with radiation tx (RT) contraindicated at relapse, or relapse in a prior RT field. In the standard-risk (R2) cohort, pts received 4 IND cycles with nivolumab + BV. Tumors were assessed every 2 cycles by investigators and blinded independent central review (BICR) per Lugano 2014 criteria. Pts who achieved CMR any time after cycle 4 proceeded to HDCT/auto-HCT consolidation. Pts with suboptimal response after IND received 2-4 cycles of BV + benda intensification (INT). Primary endpoint was CMR rate per BICR any time before consolidation. Efficacy and safety in primary refractory pts, and in pts aged < 18 y were post hoc analyses.

**Results:** 44 pts were treated in the R2 cohort. At baseline, median age was 16 y; 31 pts (70%) were aged < 18 y and 24 (55%) had primary refractory disease. Median follow-up was 43 wk overall and 47 wk in pts aged < 18 y. Ten pts aged < 18 y entered INT; of these, only 2 received 4 INT cycles. CMR rates and ORR per BICR after IND and any time prior to consolidation for primary refractory pts and pts aged < 18 y are shown in the Table. Overall, 12/44 pts (27%) experienced a grade (G) 3-4 tx-related adverse event (TRAE). Among pts aged <

<table><caption>Table. CMR rates and ORR in primary refractory patients and in pediatric patients (aged <18 y) per BICR</caption><thead><tr><th>n (%)</th><th>Overall (n=44)</th><th>Primary refractory (n=24)</th><th>Pediatric (aged &lt;18 y) (n=31)</th></tr></thead><tbody><tr><td>After nivolumab + BV induction</td><td></td><td></td><td></td></tr><tr><td>CMR</td><td>26 (59)</td><td>15 (63)</td><td>18 (58)</td></tr><tr><td>ORR</td><td>36 (82)</td><td>19 (79)</td><td>25 (81)</td></tr><tr><td>Any time prior to consolidation</td><td></td><td></td><td></td></tr><tr><td>CMR</td><td>38 (86)</td><td>20 (83)</td><td>27 (87)</td></tr></tbody></table>

18 y, 10/31 (32%) experienced a G3-4 TRAE, most commonly neutropenia (2/31 pts; 6%); no deaths or TRAEs led to discontinuation. Tx-related immune-mediated AEs were all G1-2, and were maculopapular rash, hypersensitivity, and infusion-related reaction (1 pt each).

**Conclusions:** Response-adapted tx with nivolumab + BV achieved high CMR rates after 4 IND cycles in primary refractory pts with cHL. In pediatric pts with a standard risk of relapse, IND with nivolumab + BV, followed by BV + benda INT for suboptimal response, demonstrated high CMR rates and favorable safety prior to consolidation.

**Keywords:** brentuximab vedotin; classical Hodgkin lymphoma (cHL); nivolumab.

**Disclosures:** Kelly, K: Research Funding: Merck. Beishuizen, A: Consultant Advisory Role: Janssen. Leger, K: Honoraria: Jazz Pharmaceuticals (advisory board); Research Funding: Abbott Diagnostics. Brugières, L: Consultant Advisory Role: Takeda; Research Funding: Bristol-Myers Squibb. Harker-Murray, P: Other Remuneration: Bristol-Myers Squibb. Manley, T: Employment Leadership Position: Seattle Genetics; Stock Ownership: Seattle Genetics. Francis, S: Employment Leadership Position: Bristol-Myers Squibb; Stock Ownership: Bristol-Myers Squibb. Sacchi, M: Employment Leadership Position: Bristol-Myers Squibb.

027
IBRUTINIB + CHEMOIMMUNOTHERAPY (CIT) FOR RELAPSED/REFRACTORY MATURE B-CELL NON-HODGKIN LYMPHOMA (B-NHL) IN CHILDREN (SPARKLE TRIAL): INITIAL SAFETY, PK, AND EFFICACY

A. Burke<fnref n="1" /> | A. Beishuizen² | D. Bhojwani³ |

B. Burkhardt⁴ | V. Minard-Colin⁵ | R. Norris⁶ |

E. Kabickova⁷ | F. Pinarli⁸ | N. Tacyildiz⁹ |

J. de Jong¹⁰ | G. Liu¹¹ | A. Howes¹² |

K. Nottage¹¹ | M. Salman¹¹ | X. Woot de Trixhe¹³ |

M. Cairo¹⁴

<footnote n="1">¹Department of Paediatric Haematology, Oncology and Palliative Care, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, United Kingdom; ²Department of Hematology and Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands; ³Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles, United States; ⁴Pediatric Hematology and Oncology, University Hospital Münster, Münster, Germany; ⁵Department of Child and Adolescent Cancer, Gustave Roussy, Paris, France; ⁶Cancer & Blood Disorders Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States; ⁷Department of Pediatric Hematology and Oncology, Charles University and University Hospital Motol, Prague, Czech Republic; ⁸Department of Pediatric Oncology, Gazi University, Ankara, Turkey; ⁹Department of Pediatric Hematology and Oncology, Ankara University, Ankara, Turkey; ¹⁰Clinical Pharmacology & Pharmacometrics, Janssen Research & Development LLC, San Diego,</footnote>
<figure><img src="image_11.png" /><figcaption>**Figure. Ibrutinib Exposures With 240-440 mg/m² Doses.** Box/whisker plots of estimated AUC on PK occasions by cycle and day for each dose for (A) AUC~t~ (estimated AUC of 24-hour dosing interval) and (B) AUC~∞~ (dose*F/CL; predicted AUC at steady state). Solid line represents median, box represents 25/75%, and whiskers represent 10/90% confidence interval. (C) AUC~t~ vs age and (D) AUC~t~ vs body surface area (BSA). Lines represent individual patients, color represents dose, and symbol represents PK occasion.</figcaption></figure>

United States; ¹¹Clinical Oncology, Janssen Research & Development LLC, Raritan, United States; ¹²Clinical Oncology, Janssen Research & Development, High Wycombe, United Kingdom; ¹³Clinical Pharmacology & Pharmacometrics, Janssen Research & Development, Beerse, Belgium; ¹⁴Department of Pediatrics, New York Medical College, Valhalla, United States

**Introduction:** The survival of children with relapsed/refractory (R/R) B-NHL is < 40%. Ibrutinib (ibr), a BTK inhibitor indicated for adult B-cell malignancies, has shown significant preclinical activity in Burkitt lymphoma (BL). We report results from the run-in phase of an ongoing phase 3 trial of ibr + CIT in pediatric R/R mature B-NHL.

**Methods:** SPARKLE (NCT02703272) is a 2-part, randomized, open-label trial assessing the safety and efficacy of ibr + rituximab, ifosfamide, carboplatin, etoposide (RICE), and dexamethasone (D) or R, vincristine, idarubicin, C, I (RVICI), and D CIT vs CIT alone in pediatric R/R mature B-NHL. Part 1 is a safety/PK run-in in ~24 planned patients (pts) aged 1 to < 18 years (yrs) treated with ibr up to 440 mg/m2/day (max 560 mg/day for 28-day cycles) by oral suspension/capsule + 3 cycles of RICE or RVICI. Ibr was initiated at 240 mg/m2 and escalated if no safety concerns. Ibr exposure (area under concentration-time curve [AUC]), safety, and preliminary

efficacy were assessed. In Part 2, additional pts are randomized to ibr + CIT or CIT alone.

**Results:** As of Dec 7, 2018, 21 pts had received ≥ 1 dose of ibr (11 ibr + RICE; 10 ibr + RVICI): 13 had BL, 2 Burkitt-like lymphoma, 3 diffuse large B-cell lymphoma (DLBCL), 2 primary mediastinal BCL, and 1 high-grade BCL. Median age was 8 (range, 3-17) yrs. 33.3% of pts had > 1 prior line of therapy. In the ibr + RICE and ibr + RVICI arms, respectively, median cycle number (range) was 3 (1-4) and 2 (1-4), and median ibr relative dose intensity was 66.3% and 43.4%. AUCs (n = 20) were within target range (250-1500 ng.h/mL) in the 12-17 yr age group (n = 6), supporting the 329 mg/m2 dose. AUCs at this dose were lower than expected in younger pts (n = 14), prompting an increase to 440 mg/m2. No AUC value was > 1500 ng.h/mL (Figure). 3 pts completed treatment (tx), 1 remains on study, and 17 discontinued early (5 death; 3 progression [PD]; 1 investigator decision; 8 HSCT).

All pts had ≥ 1 tx-emergent adverse event (TEAE) grade (gr) ≥ 3 (18 tx [ibr or RICE/RVICI] related), with hematologic, gastrointestinal, and infectious events being most common (≥ 50%); 19 had a serious AE (all gr ≥ 3; 7 tx related); no TEAEs led to discontinuation. 5 pts (2 ibr + RICE, 3 ibr + RVICI) had a major hemorrhage event (all gr 3/4); 2 events were possibly related to ibr. 13 pts died: 4 from sepsis (1 ibr
+ RICE, 3 ibr + RVICI), 9 from PD (3 ibr + RICE, 6 ibr + RVICI). Overall response rate was 57.1% (12/21) in all pts (7 complete, 5 partial responses): 72.7% (8/11) with ibr + RICE and 40% (4/10) with ibr + RVICI. Median event-free survival was not reached with ibr + RICE and was 2.4 months with ibr + RVICI.

**Conclusions:** These results support continued assessment of ibr + RICE/RVICI in this poor prognosis pediatric population. Safety is consistent with known profiles of the drugs in the combination regimens. Part 2 is ongoing, assessing the efficacy of the combination with ibr at 440 mg/m2 and 329 mg/m2 in pts aged < 12 and ≥ 12 yrs, respectively.

**Keywords:** ibrutinib; immunochemotherapy; non-Hodgkin lymphoma (NHL).

**Disclosures:** Burke, A: Consultant Advisory Role: Janssen, Merck, and Roche. de Jong, J: Employment Leadership Position: Janssen; Stock Ownership: Janssen. Liu, G: Employment Leadership Position: Janssen. Howes, A: Employment Leadership Position: Janssen; Research Funding: Janssen. Nottage, K: Employment Leadership Position: Janssen; Stock Ownership: Janssen. Salman, M: Employment Leadership Position: Janssen; Stock Ownership: Janssen. Woot de Trixhe, X: Employment Leadership Position: Janssen. Cairo, M: Research Funding: Janssen.

028
CHIMERIC ANTIGEN RECEPTOR T-CELLS
(CAR-T) FOR REFRACTORY AND RELAPSED
BURKITT'S LYMPHOMA: EARLY RESPONSE
IN PEDIATRIC PATIENTS

W.Q. Zhang<fnref n="1" /> | B. Hu<fnref n="1" /> | L. Jin² | J. Yang² | J. Du<fnref n="1" /> | S. Wang<fnref n="1" /> | Y.L. Ren<fnref n="1" /> | Y. Liu<fnref n="1" /> | Y.H. Zhang<fnref n="1" />

**Introduction:** Pediatric patients with relapsed or refractory Burkitt's lymphoma (BL) present as a major challenge due to their poor outcomes despite use of high-intensity chemotherapy and anti-CD20 monoclonal antibody (mAb). CAR-T has shown efficacy in treating refractory or relapsed leukemia and Non-Hodgkin Lymphoma in adult

patients. The aim of our study is to assess the safety and efficacy of CAR-T in the treatment of refractory or relapsed BL in pediatric patients.

**Methods:** Patients with refractory/relapsed BL were enrolled to clinical trial (ChiCTR18000144) during January 2018-January 2019. The inclusion criteria were: 1) No complete remission (CR) after at least 5 courses of standard chemotherapy plus anti-CD20 mAb; or 2) No partial remission (PR) or showing progression after 2 courses of second-line chemotherapy; and 3) High expression of at least one B cells markers (CD19/CD20/CD22) examined by immunohistochemistry. The highest expressed marker was chosen for the first round CAR-T target. The therapeutic doses of CAR-T range from 1x10⁶ to 3x10⁶ per kilogram of body weight each course. The CAR-T cell numbers and cytokines were measured weekly. Tumor responses were evaluated at day 30 and day 60 post infusion and every two months thereafter.

**Results:** Five refractory or relapsed BL patients, aged 6 to 10 years with a median age of 8 years, were enrolled, 4 males (80%) and 1 female (20%) according to St Jude's staging at the initial diagnosis: 3 cases (60%) in stage III, 2 cases (40%) in stage IV, 1 case of CNS invasion (20%), 1 case of bone marrow invasion (20%). They all failed initial intense chemotherapy and anti-CD20 mAb treatment (Table 1). They were then treated with 1 to 3 rounds of CAR-T (Table 2). Patients were monitored for CAR-T side effects: fever, gastro-intestine discomfort, rash, capillary leak syndrome, Immuno-pneumonia, tremor, hypotension, immunocytopenia, abnormal coagulation, liver dysfunction. One patient (20%) was diagnosed of cytokine-release syndrome (CRS) grading I and the other four grading III(80%). All subjects recovered fully after active symptomatic and supportive treatment including application of glucocorticoids in CRS grading III, but no patient required Tombuzumab. There were no death events (Table 2). Three subjects (60%) achieved CR by one round of CD19 CAR-T cell therapy, while two subjects (40%) achieved PR with first round of CD19 CAR-T treatment and achieved CR with subsequent CD22 or CD22 and CD20 CAR-T. The overall response rate (OR) was 100% with a median follow up 249 days, range 62-382 days, last follow up date January 30, 2019. (Table 3). Currently, all patients were in event-free survival.

**Conclusion:** CD19/CD20/CD22-CAR-T therapy showed a robust efficacy in pediatric patients with refractory and relapsed BL and the toxicity profiles were moderate and could be well controlled.

**Keywords:** Burkitt lymphoma (BL); CD19; CD22.

<table><caption>TABLE 1 Clinical characteristics of enrolled patients</caption><thead><tr><td>NO.</td><td>Onset age (Y)</td><td>Relapsed/ refractory</td><td>Stage</td><td>Risk group</td><td>Chemotherapy (courses)</td><td>Rituximab (courses)</td><td>Radiotherapy</td></tr></thead><tbody><tr><td>01</td><td>6</td><td>refractory</td><td>III</td><td>C1</td><td>7</td><td>6</td><td>no</td></tr><tr><td>02</td><td>8</td><td>refractory</td><td>III</td><td>C1</td><td>5</td><td>5</td><td>no</td></tr><tr><td>03</td><td>9</td><td>refractory</td><td>IV</td><td>C1</td><td>6</td><td>6</td><td>no</td></tr><tr><td>04</td><td>9</td><td>relapsed</td><td>III</td><td>C1</td><td>9</td><td>5</td><td>yes</td></tr><tr><td>05</td><td>10</td><td>relapsed</td><td>IV</td><td>C2</td><td>8</td><td>7</td><td>no</td></tr></tbody></table>

<footnote n="1">¹Department of Pediatric Lymphoma, Beijing Boren Hospital, Beijing, China; ²Department of Hematology Oncology, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China</footnote>
<table><caption>TABLE 2 CRS in enrolled patients</caption><thead><tr><th>CRS</th><th>01</th><th>02</th><th>03</th><th>04</th><th>05</th></tr></thead><tbody><tr><td>High fever</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Fatigue, myalgia, joint pain, loss of appetite, etc.</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Cough</td><td>+</td><td>+</td><td>-</td><td>+</td><td>+</td></tr><tr><td>Dyspnea</td><td>+</td><td>+</td><td>-</td><td>-</td><td>-</td></tr><tr><td>pulmonary exudative changes</td><td>+</td><td>+</td><td>+</td><td>-</td><td>+</td></tr><tr><td>Nausea, vomiting, diarrhea, abdominal pain, etc.</td><td>-</td><td>-</td><td>+</td><td>-</td><td>-</td></tr><tr><td>Stomatitis</td><td>-</td><td>-</td><td>-</td><td>-</td><td>+</td></tr><tr><td>Rash, itching</td><td>+</td><td>+</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Hypotension</td><td>-</td><td>-</td><td>+</td><td>-</td><td>-</td></tr><tr><td>Arrhythmia, bradycardia, tachycardia</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Oliguria, gross hematuria, foamy urine</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Creatinine and urea nitrogen increase</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Liver damage</td><td>+</td><td>+</td><td>+</td><td>-</td><td>+</td></tr><tr><td>Coagulopathy</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Capillary leak syndrome</td><td>-</td><td>-</td><td>-</td><td>-</td><td>+</td></tr><tr><td>Tremor</td><td>-</td><td>-</td><td>+</td><td>-</td><td>-</td></tr><tr><td>Application of glucocorticoid</td><td>+</td><td>+</td><td>+</td><td>-</td><td>+</td></tr><tr><td>Application of tombuzumab</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>CRS grading</td><td>III</td><td>III</td><td>III</td><td>I</td><td>III</td></tr></tbody></table>

<table><caption>TABLE 3 Efficacy evaluation</caption><thead><tr><th>NO.</th><th>Tumor site before CAR-T</th><th>Tumor size before CAR-T(cm³)</th><th>Pathological reexamination</th><th>CAR-T (courses)</th><th>CAR-T target</th><th>efficacy</th><th>Time to CR (days)</th><th>Current state</th><th>Continuous remission time (days)</th></tr></thead><tbody><tr><td rowspan="2">01</td><td rowspan="2">abdominal</td><td rowspan="2">10.5×7.5×5.7<br>7.2×5.9×6.0</td><td rowspan="2">No</td><td rowspan="2">2</td><td>CD19</td><td>PR</td><td rowspan="2">76</td><td rowspan="2">EFS</td><td rowspan="2">306</td></tr><tr><td>CD22</td><td>CR</td></tr><tr><td>02</td><td>abdominal</td><td>7.1*6.0*11</td><td>yes</td><td>1</td><td>CD19</td><td>CR</td><td>30</td><td>EFS</td><td>214</td></tr><tr><td rowspan="3">03</td><td rowspan="3">neck</td><td>3.5*3.5</td><td>no</td><td rowspan="3">3</td><td>CD19</td><td>PR</td><td rowspan="3">186</td><td rowspan="3">EFS</td><td rowspan="3">128</td></tr><tr><td>5.0*3.5</td><td>yes</td><td>CD22</td><td>PR</td></tr><tr><td>2.0×1.0</td><td>yes</td><td>CD20</td><td>CR</td></tr><tr><td>04</td><td>abdominal</td><td>7.2*2.3*6.3</td><td>yes</td><td>1</td><td>CD19</td><td>CR</td><td>30</td><td>EFS</td><td>96</td></tr><tr><td>05</td><td>Gums</td><td>7.0*3.4*3.5</td><td>no</td><td>1</td><td>CD19</td><td>CR</td><td>to be evaluated</td><td>EFS</td><td>to be evaluated</td></tr></tbody></table>

FOCUS ON... SESSION: RESULTS FROM SINGLE AGENT TRIALS

029

PHASE 2 STUDY OF ACALABRUTINIB IN IBRUTINIB-INTOLERANT PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA

K.A. Rogers¹

P.A. Thompson²

J.N. Allan³

M. Coleman³

J.P. Sharman⁴

B.D. Cheson⁵

R. Izumi⁶

M.M. Frigault⁷

C. Quah⁸

R.K. Raman⁹

M.H. Wang⁸

T.J. Kipps¹⁰

¹Division of Hematology, The Ohio State University, Columbus, United States; ²Department of Leukemia, MD Anderson Cancer Center, Houston, United States; ³Hematology/Oncology, Weill Cornell Medicine, New York, United States; ⁴Hematology Research, Willamette Valley Cancer Institute, Eugene, United States

⁵Division of Hematology/Oncology, Georgetown University Hospital, Washington, DC, United States; ⁶Early Research and Development, Acerta Pharma, South San Francisco, United States;

⁷Translational Science, Acerta Pharma, South San Francisco, United States; ⁸Clinical Development, Acerta Pharma, South San Francisco, United States; ⁹Medical Safety Science, Acerta Pharma, South San Francisco, United States; ¹⁰Research Operations, UC San Diego Moores Cancer Center, La Jolla, United States
<table><caption>TABLE 1</caption><thead><tr><th></th><th>N=60</th></tr></thead><tbody><tr><td>Overall response rate (≥ PRL), n (%)</td><td>46 (77)</td></tr><tr><td>95% CI</td><td>64, 87</td></tr><tr><td>CR</td><td>1 (2)</td></tr><tr><td>PR</td><td>42 (70)</td></tr><tr><td>PRL</td><td>3 (5)</td></tr><tr><td>Median PFS</td><td>Not reached</td></tr><tr><td>21-month PFS rate, % (95% CI)</td><td>76 (61, 86)</td></tr></tbody></table>

Abbreviations: CR, complete response; PFS, progression-free survival; PR, partial response; PRL, partial response with lymphocytosis.

**Background:** In patients with chronic lymphocytic leukemia (CLL) treated with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, intolerance was the most common reason for discontinuation (50% to 63%; Mato AR, et al. Haematologica. 2018). This Phase 2 trial evaluated acalabrutinib, a highly selective, potent, covalent BTK inhibitor, in ibrutinib-intolerant patients with relapsed/refractory CLL.

**Methods:** Patients with relapsed/refractory CLL (≥1 prior therapy) who discontinued ibrutinib due to Grade 3/4 adverse events or persistent/recurrent Grade 2 adverse events and had progressive disease after ibrutinib discontinuation were eligible. Acalabrutinib was given orally at 100 mg twice daily in 28-day cycles until progressive disease or unacceptable toxicity. The primary endpoint was overall response rate.

**Results:** Sixty patients were treated. The median age was 70 years (range, 43 to 88). Patient characteristics included bulky disease ≥5 cm (33%), Rai stage III/IV (47%), del17p (28%), del11q (23%), and unmutated IGHV (79%). Fifty-two of 55 patients (95%) with available baseline samples were wild type for BTK and PLCG2. The median number of prior therapies was 2 (range, 1 to 10). The median duration of prior ibrutinib therapy was 6 months (range, <1 to 55); common adverse events that led to ibrutinib discontinuation were atrial fibrillation/ flutter (25%), diarrhea (12%), arthralgia (10%), and rash (12%). At a median follow-up of 19 months (range, 1 to 31), 67% of patients remain on acalabrutinib; discontinuations were mostly due to progressive disease (13%) and adverse events (10%; pneumonia [n=2], diarrhea, headache, ascites, arthralgia, subdural hematoma [all n=1]). Efficacy outcomes are in the Table. Common adverse events (any grade) were diarrhea (48%), headache (40%), contusion (35%), and dizziness (32%). Serious adverse events (≥2 patients) were pneumonia (10%), anemia (3%), and syncope (3%). Atrial fibrillation occurred in 3 patients (5%; all Grade 1/2) and major hemorrhage in 2 (3%; Grade 3 hematuria and Grade 2 subdural hematoma). Grade 5 adverse events were pneumonia (n=2), bronchopulmonary aspergillosis (n=1), and ventricular fibrillation (n=1); all were considered not related to treatment.

**Conclusions:** Acalabrutinib is tolerable and effective in ibrutinib-intolerant patients, providing a viable strategy for continuing BTK inhibitor therapy.

**Keywords:** BTK inhibitors.

**Disclosures:** Rogers, K: Consultant Advisory Role: Acerta Pharma; Research Funding: Genentech and AbbVie. Thompson, P: Consultant Advisory Role: Genentech, AbbVie, Pharmacyclics, Gilead; Research Funding: Amgen, Acerta Pharma, Pharmacyclics, AbbVie; Other Remuneration: Amgen, Acerta Pharma, Pharmacyclics, AbbVie. Allan, J: Other Remuneration: AbbVie, Genentech, Sunesis, Versatem, Bayer, Pharmacyclics. Coleman, M: Consultant Advisory Role: Celgene, Gilead, Pharmacyclics; Stock Ownership: Immunomedics; Gilead; Research Funding: Celgene, GSK, Pharmacyclics, BMS, Merck, Millennium. Sharman, J: Consultant Advisory Role: Celgene, Pfizer, Genentech, TG therapeutics, AbbVie, pharmacyclics GILEAD; Research Funding: Celgene, Pfizer, Genentech, TG therapeutics, AbbVie, pharmacyclics GILEAD. Cheson, B: Consultant Advisory Role: AbbVie, AstraZeneca, Bayer, Celgene, Roche Genentech, TG Therapeutics, Epizyme, Gilead, Karyopharm, Morphosys, Pharmacyclics; Research Funding: AbbVie, AstraZeneca, Roche Genentech, TG Therapeutics, Epizyme, Gilead, Trilium. Izumi, R: Employment Leadership Position: Acerta Pharma. Frigault, M: Employment Leadership Position: Acerta/Astra Zeneca; Stock Ownership: Acerta/Astra Zeneca. Quah, C: Employment Leadership Position: Acerta Pharma/AstraZeneca. Wang, M: Employment Leadership Position: Acerta Pharma. Kipps, T: Honoraria: Pharmacyclics/ AbbVie; Genentech/Roche; Janssen; Gilead; National Cancer Institute/ NIH; Celgene; Indy Heme Review; University of Nebraska Medical Center/ Research To Practice; Society of Hematologic Oncology; Shenzhen Cancer Center; European Research Initiative on CLL (ERIC); Dava Oncology; Patient Power, LLC; Breast Cancer Research Foundation; German CLL Study Group (GCLLSG); iwNHL; NCCN CLL/ SLL Hairy Cell Leukemia Panel Meetinh; TG Therapeutics; Verastem; Bionest Partners; OncLive; Research Funding: Pharmacyclics/ AbbVie; Breast Cancer Research Foundation; Md Anderson Cancer Center; Oncternal Therapeutics, Inc.; Specialized Center of Research (SCOR)- The Leukemia and Lymphoma Society (LLS); California Institute for Regenerative Medicine (CIRM); National Cancer Institute/ NIH; Research Agreement - VelosBio, Inc.; Celgene.

030
RAPID AND DURABLE RESPONSES WITH
THE SYK/JAK INHIBITOR CERDULATINIB
IN A PHASE 2 STUDY IN
RELAPSED/REFRACTORY FOLLICULAR
LYMPHOMA-ALONE OR IN
COMBINATION WITH RITUXIMAB

S.D. Smith<fnref n="1" /> | J. Munoz² | D.A. Stevens³ |
S.M. Smith⁴ | T.A. Feldman⁵ | J.C. Ye⁶ | S. de Vos⁷ |
B.T. Hess⁸ | C.B. Miller⁹ | J.L. Khatcheressian¹⁰ |
M.R. Birrell¹¹ | J.M. Leeds¹¹ | G.P. Coffey¹¹ |
P.B. Conley¹¹ | G.C. Michelson¹¹ | J.T. Curnutte¹¹ |
P.A. Hamlin¹²

<footnote n="1">¹Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA,</footnote>
United States; ²Cancer Immunotherapy Program, Banner MD Anderson Cancer Center, Gilbert, AZ, United States; ³Norton Cancer Institute, Louisville, KY, United States; ⁴Lymphoma Program, The University of Chicago Medicine, Chicago, IL, United States; ⁵John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, United States; ⁶Rogel Cancer Center, University of Michigan Cancer Center, Ann Arbor, MI, United States; ⁷David Geffen School of Medicine, UCLA, Los Angeles, CA, United States; ⁸Hollings Medical Cancer Center, Medical University of South Carolina, Charleston, SC, United States; ⁹Cancer Institute, St. Agnes Hospital, Baltimore, MD, United States; ¹⁰Virginia Cancer Institute, Richmond, VA, United States; ¹¹R&D, Portola Pharmaceuticals, South San Francisco, CA, United States; ¹²Department of Medical Oncology, Memorial Sloan-Kettering Cancer Ctr., New York, NY, United States

**Background:** Despite recent advances, follicular lymphoma (FL) remains incurable for most patients (pts). Relapsed/refractory (r/r) FL is associated with decremental treatment responses, accumulating toxicity, and poor survival among early failures of 1st line chemo-immunotherapy. Underscored by the recent approvals of idelalisib, copanlisib, and duvelisib, targeting B-cell receptor (BCR) signaling produces ORR of ~50% in r/r pts; however, new agents with a better therapeutic index over long-term administration are needed.

SYK is a key regulator of BCR signaling (upstream of BTK and PI3K), and its inhibition results in clinical activity in FL. Compared with unaffected nodes, lymph nodes from FL pts have greater numbers of follicular helper T cells that express high levels of IL-4, which may support the tumor via the JAK1/3 pathway.

Cerdulatinib, an oral, reversible inhibitor of SYK and JAK kinases (JAK1, JAK3, TYK2), previously reported a ~45% ORR in r/r FL as a single agent. Xenograft studies suggest cerdulatinib may combine with rituximab to enhance antitumor activity. We report updated results from a Ph2a study of single-agent cerdulatinib and initial results in combination with rituximab in r/r FL.

**Methods:** This Ph2a study confirmed the safety and efficacy of cerdulatinib 30 mg BID in r/r B- and T-cell lymphoma pts. Dose reductions were permitted to 15 mg BID. Response was assessed by Lugano criteria.

**Results:** As of Jan 2019, enrollment was 40 pts in the single-agent cohort and 11 in the rituximab combination cohort. Median (range) age was 64 (42-81) and median prior therapies was 3 (1-8). Fifty (98%) pts had prior anti-CD20 therapy, and 8 (16%) had prior PI3K or BTK inhibitors. The most common AEs of any grade were diarrhea (47%), nausea (37%), lipase increase (29%), and amylase increase (22%). Grade 3+ AEs in ≥5% pts were lipase increase (24%), diarrhea (12%), amylase increase (10%), nausea (8%), hypertension (8%), and neutropenia (6%). Grade 3+ infections occurred in 6 (12%) pts. One pt had grade 5 multi-organ failure potentially related to study drug. Amylase and lipase increases generally were not associated with abdominal pain or pancreatitis. The safety profile appeared similar in both cohorts.

The ORR was 46% as a single agent (5 CRs, 13 PRs in 40 pts) and 67% in the combination cohort (4/6 PRs; 2 pts with SD had a >40%

reduction in tumor volume at 1st re-scan). Responses typically occurred after 2 cycles and were durable in the single-agent cohort, with 10 pts on drug for >1 year. Enrollment in the combination cohort is ongoing. Updated safety and efficacy will be presented.

**Conclusion:** The recommended cerdulatinib Ph2 dose of 30 mg BID was tolerable and efficacious in heavily pretreated r/r FL. The cerdulatinib + rituximab combination appears to be well tolerated, with tumor reductions in all evaluable pts. The safety profile and unique MOA of cerdulatinib support further combination studies in FL.

**Keywords:** follicular lymphoma (FL); JAK/STAT; SYK.

**Disclosures:** Smith, S: Consultant Advisory Role: Merck Sharp and Dohme Corp., AstraZeneca; Research Funding: Acerta Pharma BV, AstraZeneca, Ayala (spouse), Bristol-Myers Squibb (spouse), De Novo Biopharma, Genentech, Ignyta (spouse), Incyte Corporation, Merck Sharp and Dohme Corp., Pharmacyclics, Portola Pharmaceuticals, Seattle Genetics. Munoz, J: Consultant Advisory Role: Kite Pharma, Gilead, Pfizer, Pharmacyclics, Bayer, Bristol-Myers Squibb, Janssen, Seattle Genetics, Kyowa Hakko Kirin, Juno Therapeutics, Genentech, Celgene; Honoraria: Kite Pharma, Bayer, Pharmacyclics/Janssen, AstraZeneca, AbbVie/Genentech. Smith, S: Research Funding: Portola. Feldman, T: Consultant Advisory Role: Seattle Genetics/BMS; Honoraria: Takeda, Celgene, Seattle Genetics, AbbVie, Pharmacyclics, Janssen, KITE, BMS; Other Remuneration: Speakers Bureau: Takeda, Celgene, Seattle Genetics, AbbVie, Pharmacyclics, Janssen, KITE, BMS. Ye, J: Employment Leadership Position: Internal Medicine, University of Michigan, Rogel Cancer Center; Research Funding: Abbvie, Takeda, Celgene, Onyx, Sanofi, Karyopharm, Janssen, MingSight, Portola. de Vos, S: Consultant Advisory Role: Portola (participation in advisory board); Honoraria: Portola (participation in advisory board). Hess, B: Employment Leadership Position: MD, Assistant Professor at MUSC. Miller, C: Consultant Advisory Role: Consultant Verastem, Incyte; Honoraria: Verastem, Incyte, Takeda; Research Funding: Verastem, Incyte, Portola, Takeda. Khatcheressian, J: Employment Leadership Position: partners Virginia Cancer Institute. Birrell, M: Employment Leadership Position: Portola. Leeds, J: Employment Leadership Position: Portola; Stock Ownership: Portola. Coffey, G: Employment Leadership Position: Portola; Stock Ownership: Portola; Research Funding: Portola. Conley, P: Employment Leadership Position: Portola; Stock Ownership: Portola. Michelson, G: Employment Leadership Position: Portola; Stock Ownership: Portola. Curnutte, J: Employment Leadership Position: Executive Vice President, Research and Development, Portola Pharmaceuticals; Stock Ownership: Portola. Hamlin, P: Consultant Advisory Role: Sandoz, Karyopharm, Celgene, AstraZeneca, Juno; Research Funding: Portola, Molecular templates, Incyte, Seattle Genetics, Novartis, Janssen; Other Remuneration: Janssen DSMC.
N. Kalakonda¹ | F. Cavallo² | G. Follows³ |

A. Goy⁴ | J. Vermaat⁵ | O. Casasnovas⁶ |

O. Lavee⁷ | M. Maerevoet⁸ | J. Zijlstra⁹ |

S. Bakshi¹⁰ | R. Bouabdallah¹¹ | S. Choquet¹² |

R. Gurion¹³ | B. Hill¹⁴ | U. Jaeger¹⁵ | J. Sancho¹⁶ |

M. Schuster¹⁷ | C. Thieblemont¹⁸ | F. De la Cruz¹⁹ |

M. Egyed²⁰ | S. Mishra²¹ | F. Offner²² |

T. Vassilakopoulos²³ | K. Warzocha²⁴ | A. Oluyadi²⁵ |

D. McCarthy²⁶ | X. Ma²⁷ | K. Corona²⁸ | J. Shah²⁵ |

E. Van Den Neste²⁹ | M. Canales³⁰

¹Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom; ²Molecular Biotechnology and Health Sciences, Aziena Ospedaliero - Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; ³Haematology, Cambridge University Hospitals NHS Foundation Trust Addenbrooke's Hospital, Cambridge, United Kingdom; ⁴Oncology, Hackensack University Medical Center, Hackensack, United States; ⁵Hematology, Leiden University Medical Center, Leiden, Netherlands; ⁶Hematology, Hématologie Clinique, Dijon, France; ⁷Hematology, St. Vincent's Hospital Sydney, Darlinghurst, Australia; ⁸Hematology, Service Hématologie, Institut Bordet, Bruxelles, Belgium; ⁹Hematology, Amsterdam UMC, Amsterdam, Netherlands;

¹⁰Medical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, New Delhi, India; ¹¹Oncology/Hematology, Institut Paoli-Calmettes, Marseille, France; ¹²Hematology, Hospital Pitie Salpetriere, Paris, France;

¹³Hematology, Rabin MC, Petah Tiqwa, Israel; ¹⁴Hematology and Medical Oncology, Cleveland Clinic Main Campus, Cleveland, United States; ¹⁵Medicine I, Medical University of Vienna, Vienna, Austria;

¹⁶Clinical Hematology, Hospital Germans Trias i Pujol, Barcelona, Spain; ¹⁷Medicine, Stony Brook University, Stony Brook, United States;

¹⁸Hemato-Oncology, Hôpital Saint-Louis, Paris, France; ¹⁹Hematology, Hospital Universitario Virgen del Rocío, Sevilla, Spain; ²⁰Hematology, Teaching Hospital Mór Kaposi, Kaposvár, Hungary; ²¹Medical Oncology, Institute of Medical Sciences & SUM Hospital, Bhubaneswar, India;

²²Hematology, UZ Gent, Gent, Belgium; ²³Hematology, Laikon General Hospital of Athens, Athens, Greece; ²⁴Hematology, Instytut Hematologii i Transfuzjologii, Warszawa, Poland; ²⁵Clinical Development, Karyopharm Therapeutics Inc., Newton, United States; ²⁶Clinical Operations, Karyopharm Therapeutics Inc., Newton, United States; ²⁷Biostatistics, Karyopharm Therapeutics Inc., Newton, United States; ²⁸Medical Affairs, Karyopharm Therapeutics Inc., Newton, United States; ²⁹Hematology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; ³⁰Medicine, Hospital Universitario La Paz, Madrid, Spain

**Introduction:** Patients (pts) with R/R DLBCL who have received at least 2 lines of therapy, including pts who have progressed post stem cell transplantation (SCT) or who are not candidates for SCT, have limited treatment options. Active novel therapies with different mechanisms of actions are needed to improve the survival of these pts. Selinexor, a selective oral XPO1 inhibitor, leads to nuclear accumulation and activation of tumor suppressor proteins (e.g., p53, p21, and IkB), and reductions in c-Myc and Bcl-2 oncogenes. Single agent

<figure><img src="image_12.png" /></figure>

selinexor in heavily treated DLBCL demonstrated an overall response rate (ORR) of 25.6% with complete response (CR) in 9.3%, in a phase 1 study. To confirm these findings, a phase 2b study of selinexor was initiated.

**Methods:** This is a multicenter, open-label study in pts with R/R DLBCL who have received 2-5 lines of prior therapy. Pts may have progressed post SCT or are not candidates for SCT. Pts were stratified by subtype (germinal center B-cell [GCB] or non-GCB) and treated with 60 mg selinexor twice weekly per 28-day cycle. The primary endpoint was ORR. Secondary endpoints included duration of response (DOR) and assessment of safety. Disease response was assessed by an Independent Central Radiological Review (ICRR), using the Lugano Classification.

**Results:** 129 pts were enrolled (76 M, 53 F). Median age was 67 years (54% of pts >65 years). Median number of prior therapies was 2 (range 1-6), 34% of pts received ≥3 prior therapies, and 31% of pts had prior SCT. Two pts did not meet eligibility requirements and were excluded from the analysis. Treatment-related serious adverse events (SAEs) were reported in 21% of pts. The most frequently reported treatment-related AEs (Grades 3, 4) included: nausea (6%, 0%), thrombocytopenia (24%, 13%), fatigue (9%, 0%), anorexia (3%, 0%), and anemia (13%, 1%). Of the 85.8% pts who discontinued treatment, the majority were due to progressive disease and 9.3% were due to AEs. The ICRR determined ORR was 27.6% (14 CRs and 21 partial responses). The ORR was 32.2% for GCB and 20.6% for non-GCB subtypes. Median time to response was 57 days (range 47-115 days) and the median DOR was 8.4 months; pts with a CR had a median DOR of 13.4 months. Median progression free survival was 3.6 months. The median overall survival (OS) was 9.1 months. Median OS in pts ≥partial response was 29.7 months which was significantly longer than the 5.0 months observed in pts ≤stable disease (p<0.0001) [Figure 1].
**Conclusion:** Single agent, oral selinexor demonstrated deep and durable responses in R/R DLBCL (ORR of 27.6% and DOR of 8.4 months). No new safety signals were identified; AEs were managed with dose modification and/or supportive care. Clinical benefit was observed across both GCB and non-GCB subtypes. These results underscore the potential of selinexor as a novel therapy for R/R DLBCL.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); non-Hodgkin lymphoma (NHL).

**Disclosures:** Schuster, M: Honoraria: Karyopharm Therapeutics Inc. Vassilakopoulos, T: Honoraria: Amgen, Roche, Novartis, Servier and Winmedica. Oluyadi, A: Employment Leadership Position: Karyopharm Therapeutics Inc; Stock Ownership: Karyopharm Therapeutics Inc. McCarthy, D: Employment Leadership Position: Karyopharm Therapeutics Inc; Stock Ownership: Karyopharm Therapeutics Inc. Ma, X: Employment Leadership Position: Karyopharm Therapeutics Inc; Stock Ownership: Karyopharm Therapeutics Inc. Corona, K: Employment Leadership Position: Karyopharm Therapeutics Inc; Stock Ownership: Karyopharm Therapeutics Inc. Shah, J: Employment Leadership Position: Karyopharm Therapeutics Inc; Stock Ownership: Karyopharm Therapeutics Inc.

032
TIPIFARNIB IN RELAPSED OR REFRACTORY ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA (AITL) AND CXCL12+ PERIPHERAL T-CELL LYMPHOMA (PTCL): PRELIMINARY RESULTS FROM A PHASE 2 STUDY

T. Witzig<fnref n="1" /> | L. Sokol² | W. Kim³ | F. Foss⁴ |

E. Jacobsen⁵ | F. de la Cruz Vincente⁶ | D. Caballero<fnref n="7" /> |

R. Advani⁸ | J.M. Roncero Vidal⁹ | A. Marin-Niebla¹⁰ |

A. Rodriguez Izquierdo¹¹ | R. de Ona Navarrete¹² |

M.J. Terol¹³ | E. Domingo-Domenech¹⁴ |

M. Rodriguez¹⁵ | M.A. Piris¹⁵ | J. Bolognese¹⁶ |

M.R. Janes¹⁷ | F. Burrows¹⁸ | L. Kessler¹⁹ |

V. Mishra¹⁹ | R. Curry²⁰ | M. Kurman²⁰ |

C. Scholz²⁰ | A. Gualberto²⁰

Universitario de Valencia, València, Spain; ¹⁴Hematology, Institut Catala d'Oncologia, Barcelona, Spain; ¹⁵Pathology, Fundación Jiménez Díaz, Madrid, Spain; ¹⁶Biostatistics, Cytel, Cambridge, United States; ¹⁷Biology, Wellspring Biosciences, Inc., San Diego, United States; ¹⁸Research, Kura Oncology, Inc., San Diego, United States; ¹⁹Development, Kura Oncology, Inc., San Diego, United States; ²⁰Development, Kura Oncology, Inc., Cambridge, United States

**Introduction:** Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. Tipifarnib has previously been shown to modulate the CXCL12 pathway and to drive clinical activity in CXCL12-expressing T cell lymphomas.

**Methods:** This Phase 2 study (NCT02464228) is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) study to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg orally twice daily on days 1-21 of 28-day treatment cycles. The primary endpoint is overall response rate (ORR). Ancillary studies are ongoing to investigate the prognostic value of CXCL12 expression in pts who received standard of care treatment.

**Results:** As of 20 February 2019, 43 PTCL pts (20 AITL, 21 PTCL-NOS, 1 ALK- ALCL, 1 gamma-delta TCL) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 24 pts in the ongoing AITL histology and CXCL12 cohort. Median number of prior treatment regimens was 3; 19 pts had a prior stem cell transplant. All pts had at least 1 treatment-emergent adverse event (TEAE); 39 (90%) had at least 1 drug-related TEAE and 12 (28%) at least 1 drug related SAE. The most frequently observed drug-related TEAEs of Grade >3 occurring in >10% of pts were blood and lymphatic system disorders, including neutropenia (44%), thrombocytopenia (37%), leukopenia (28%), anaemia (21%) and febrile neutropenia (21%). There have been 14 deaths on study; none were related to study drug. Of 18 evaluable pts enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. In the AITL cohort (11 evaluable pts), a 45% ORR and 73% clinical benefit rate (CBR; 3 CR, 2 PR and 3 SD) was observed. In the CXCL12+ cohort (n=3 evaluable pts), 1 PR and 2 SD have been observed, with 4 pts pending cycle 2 response evaluation. CXCL12 expression correlated with favorable outcome to tipifarnib treatment. Pre-treatment high CXCL12 expression had 90% sensitivity and 93% specificity to identify pts who experienced CR/PR/SD on study in a preliminary analysis of 24 pts. The prognosis of CXCL12 was retrospectively investigated in 73 pts who received standard of care therapy (AITL N=50, PTCL NOS=23). A trend for poor prognosis (22 vs 40 months median OS from diagnosis, HR=1.8, p=0.09) was observed in the high CXCL12 subset using the cut-off point that predicted clinical benefit under tipifarnib therapy.

<footnote n="1">¹Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States; ²Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States; ³Hematology - Oncology, Samsung Medical Center, Seoul, Republic of Korea; ⁴Medical Oncology, Yale University School of Medicine, New Haven, United States; ⁵Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; ⁶Hematology - Oncology, Hospital Universitario Virgen del Rocío, Sevilla, Spain;</footnote>

<footnote n="7">⁷Hematology - Oncology, Hospital Universitario de Salamanca, Salamanca, Spain; ⁸Medicine - Med/Oncology, Stanford University Medical Center, Palo Alto, United States; ⁹Hematology - Oncology, Institut Català d'Oncologia, Girona, Spain; ¹⁰Hematology - Oncology, Vall D'Hebron Institute of Oncology, Barcelona, Spain; ¹¹Hematology, Hospital Universitario 12 de Octubre, Madrid, Spain; ¹²Hematology, MD Anderson Cancer Center, Madrid, Spain; ¹³Hematology, Hospital Clínico</footnote>
**Conclusion:** Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment in the CXCL12+ cohort continues.

**Keywords:** angioimmunoblastic T-cell lymphoma (AITL); peripheral T-cell lymphomas (PTCL).

**Disclosures:** Witzig, T: Research Funding: Study Investigator for KO-TIP-002 (Kura Oncology). Sokol, L: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Kim, W: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Foss, F: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Jacobsen, E: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). de la Cruz Vincente, F: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Caballero, D: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Advani, R: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Roncero Vidal, J: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study).

Marin-Niebla, A: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Rodriguez Izquierdo, A: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). de Ona Navarrete, R: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Terol, M: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Domingo-Domenech, E: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Rodriguez, M: Research Funding: Kura Oncology. Piris, M: Research Funding: Kura Oncology. Bolognese, J: Consultant Advisory Role: Kura Oncology.

Janes, M: Consultant Advisory Role: Kura Oncology. Burrows, F: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Kessler, L: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Mishra, V: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Curry, R: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Kurman, M: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Scholz, C: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology.

Gualberto, A: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology.

033
Duvelisib, an oral dual PI3K-δ,γ inhibitor,
efficacy and safety in patients with relapsed
or refractory (RR) peripheral T-cell
lymphoma: rationale for the phase 2 PRIMO
trial

S.M. Horwitz¹ | F.M. Foss² | P. Porcu³ |

A. Moskowitz¹ | N. Mehta-Shah⁴ | E. Jacobsen⁵ |

M.S. Khodadoust⁵ | Y.H. Kim⁵ | D. Weinstock⁶ |

S. Lustgarten⁷ | M. Baglio⁷ | H. Youssoufian⁷ |

J. Brammer⁸

¹Memorial Sloan Kettering Cancer Center, New York, NY, United States;

²Yale Cancer Center, New Haven, CT, United States; ³Sidney Kimmel

Cancer Center, Thomas Jefferson University, Philadelphia, PA, United

States; ⁴Washington University Medical School, St. Louis, MO, United

States; ⁵Stanford Cancer Institute/School of Medicine, Stanford, CA,

United States; ⁶Dana-Farber Cancer Institute, Boston, MA, United States;

⁷Verastem Oncology, Inc, Needham, MA, United States; ⁸Ohio State

University, Columbus, OH, United States

**Background:** RR PTCL is associated with a poor prognosis, with most therapies inducing responses in <30% of pts and median progression-free survival (PFS) <4 mo. Phosphoinositide-3-kinase (PI3K) pathway has a role in survival and proliferation of malignant T cells, as well as T-cell receptor and cytokine signaling in nonmalignant T cells. Duvelisib (DUV), an oral dual PI3K-δ-γ inhibitor, exhibited potent activity against T-cell lymphoma (TCL) cell lines in vitro and rep-programmed tumor-associated macrophages from the immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype (Horwitz, *Blood* 2018). DUV monotherapy 25 mg BID is FDA approved for the treatment of RR CLL/SLL in pts who have received ≥2 lines of prior therapy and RR follicular lymphoma in pts who have received ≥2 lines of prior systemic therapy. The optimal dose of DUV in TCL is undefined. Here we summarize the safety and activity of DUV in pts with RR PTCL from 2 phase 1 studies that support the rationale for the ongoing phase 2 PRIMO study (NCT03372057).

**Methods:** In the initial phase 1 study (NCT 01476657), pts with RR PTCL received DUV until progression or intolerance, as part of a dose-escalation phase. In a separate phase 1 study (NCT02783625), pts with RR PTCL received DUV 25 mg or 75 mg BID as monotherapy for 1 mo as a lead-in to a combination regimen with either romidepsin (R) or bortezomib (B).

**Results:** A total of 29 pts with RR PTCL received DUV in the phase 1 studies. Among pts who received the DUV 75-mg dose as monotherapy or lead-in therapy before R, the ORR was 54% and 44%, with CR rates of 15% to 22%, respectively (Table). Notably, ORR was 57% among pts receiving lower dose of DUV (25 mg BID) as lead-in therapy before B. Pts receiving DUV as lead-in had a response at the end of cycle 1. In the phase 1 escalation study, response to DUV typically occurred by the first assessment (cycle 2) and was observed across a spectrum of PTCL subtypes. Two pts who attained a CR and PR, respectively, in the phase 1 escalation study completed >1 year of DUV treatment (Horwitz, *Blood* 2018). The preliminary safety profile of DUV in pts with PTCL was considered reasonable and consistent with previous reports.

**Conclusions:** DUV 25 or 75 mg BID demonstrated encouraging clinical activity and an acceptable safety profile in RR PTCL, a population in need of new and effective therapies. The ongoing phase 2 PRIMO study dose optimization phase will identify the optimal regimen of DUV monotherapy in RR PTCL and characterize the efficacy and tolerability of DUV in ≈100 pts.

**Disclosures:** Horwitz, S: Consultant or Advisory Role: ADCT Therapeutics, Aileron, Forty-Seven, Infinity/Verastem, Kyowa-Hakka-Kirin,
<table><caption>TABLE 1 DUV Efficacy in RR PTCL in Phase 1 Studies</caption><thead><tr><th rowspan="2"></th><th>Phase 1 study DUV<br>monotherapy (NCT 01476657)</th><th colspan="2">Phase 1 study DUV monotherapy lead-in before a combination<br>regimen (NCT02783625)</th></tr><tr><th>DUV 75 mg (n=13)</th><th>DUV 75 mg BID monotherapy<br>1 month lead-in before R (n=9)</th><th>DUV 25 mg BID monotherapy<br>1 month lead-in before B (n=7)</th></tr></thead><tbody><tr><td>ORR (CR + PR), n (%)</td><td>7 (54)</td><td>4 (44)</td><td>4 (57)</td></tr><tr><td>Best overall response, n (%)</td><td></td><td></td><td></td></tr><tr><td>CR</td><td>2 (15)</td><td>2 (22)</td><td>2 (29)</td></tr><tr><td>PR</td><td>5 (38)</td><td>2 (22)</td><td>2 (29)</td></tr></tbody></table>

Millennium /Takeda, Seattle Genetics, Affimed, Angimmune, Beigene, Corvus, Innate Pharma, Kura, Merck, Miragen, Mundipharma, Portola, Syros Pharmaceutical; Research Funding: ADCT Therapeutics, Aileron, Forty-Seven, Infinity/Verastem, Kyowa-Hakka-Kirin, Millennium/Takeda, Seattle Genetics, Celgene, Trillium. Porcu, P: Consultant or Advisory Role: Innate Pharma, Miragen, Kiowa, Viracta, Seattle Genetics, Beigene; Honoraria: Innate Pharma, Miragen, Kiowa, Viracta; Research Funding: Kura Pharmaceuticals. Moskowitz, A: Honoraria: Kyowa Hakko Kirin Pharma, Miragen Therapeutics, Takeda Pharmaceuticals, ADC Therapeutics, Seattle Genetics, Cell Medica, Bristol-Myers Squibb, Erytech Pharma; Research Funding: Seattle Genetics, Merck, Bristol-Myers Squibb, Incyte. Mehta-Shah N: Consultant or Advisory Role: Kyowa-Hakka-Kirin; Research Funding: Celgene, Verastem, Bristol Myers Squibb, Genentech/ Roche. Jacobsen E: Consultant or Advisory Role: Bayer; Honoraria: Seattle Genetics, Merck, Takeda, Astra-Zeneca; Research Funding: Novartis, Hoffman-LaRoche, Pharmacyclics, Merck, Celgene, Seattle Genetics. Khodadoust M: Consultant or Advisory Role: Kyowa Kirin, Inc.; Seattle Genetics. Weinstock D: Research Funding: Verastem. Lustgarten S: Employment or leadership position: Verastem; Stock ownership: Verastem. Baglio M: Employment or leadership position: Verastem; Stock ownership: Verastem. Youssoufian H: Employment or leadership position: Verastem (Head, Medical Strategy); Stock ownership: Verastem.

034

EFFICACY OF MOGAMULIZUMAB IN PREVIOUSLY TREATED PATIENTS WITH LESS ADVANCED MYCOSIS FUNGOIDES: RESULTS FROM THE MAJORIC STUDY

J. Scarisbrick<fnref n="1" /> | L.J. Geskin² | M. Bagot³ |
D.C. Fisher⁴ | C. Elmets⁵ | M. Duvic⁶ |
M. Beylot-Barry⁷ | E.J. Kim⁸ | J. Moriya⁹ |
M. Leoni¹⁰ | P.L. Zinzani¹¹

Center, Houston, United States; ⁷Service de Dermatologie, CHU de Bordeaux - Hôpital Saint-André, Bordeaux, France; ⁸Dermatology, University of Pennsylvania, Philadelphia, United States; ⁹Biostatistics, Kyowa Kirin Pharmaceutical Development, Inc., Princeton, United States; ¹⁰Medical Sciences, Kyowa Kirin Pharmaceutical Development, Inc., Princeton, United States; ¹¹Istituto di Ematologia, Università di Bologna, Bologna, Italy

**Introduction:** In the MAJORIC Phase 3 study, patients (pts) with previously treated mycosis fungoides (MF)/Sezary syndrome (SS) stage IB-IVB who received mogamulizumab (MOGA; Poteligeo®) had significantly prolonged progression-free survival (7.7 vs 3.1 months; P<0.0001) and greater overall response rates (ORR) compared to pts on vorinostat (VORI) (Kim YH, et al. Lancet Oncol 2018). Less advanced MF (stage IB/IIA) is a chronic skin malignancy that can involve blood and nodes and may require many lines of systemic therapy over the disease course with a reduced quality of life. This post-hoc analysis specifically examined efficacy and safety of the recently approved MOGA in stage IB/IIA MF pts.

**Methods:** In MAJORIC, stage IB-IVB MF/SS pts (n=372) who were treated with ≥1 prior systemic therapy were randomized to MOGA or oral VORI. In the post-hoc analysis, time to next treatment (TTNT) was defined as time to any therapy excluding topical steroids or focal radiation treatment. ORR was based on global composite response in 4 disease compartments – skin, blood, lymph nodes, and viscera – achieved at 2 consecutive visits at least 8 weeks apart. Individual compartment responses were also assessed.

**Results:** A total of 85 pts with stage IB/IIA MF were included (MOGA, IB n=15, IIA n=21; VORI, IB n=27, IIA n=22). Overall, 79% (33/42) of IB pts and 84% (36/43) of IIA pts had received ≥2 prior systemic therapies, and 24% (10/42) of IB pts and 28% (12/43) of IIA pts had received ≥6 prior systemic therapies. Median TTNT with MOGA in IB pts was 11.5 months (mo) (95% CI, 1.4,16.0) compared to 3.1 mo (95% CI, 2.7, 5.3) with VORI; in IIA pts, median TTNT was 10.1 mo (95% CI, 5.5, 12.6) and 4.9 mo (95% CI, 2.4, 8.0), respectively. ORR in IB pts receiving MOGA and VORI was 20% (3/15) and 18.5% (5/27), respectively; ORR in IIA was 19% (4/21) and 0% (0/22), respectively. With respect to stage IB and IIA, compartmental response rates with MOGA were: skin (20% [3/15], 38% [8/21]), blood (0% [0/2], 75% [6/8]), and lymph node (0% [0/0], 15% [3/20]), respectively. Adverse events were generally manageable and consistent with the ITT population.

<footnote n="1">¹Lymphoma Service, University Hospital Birmingham, Birmingham, United Kingdom; ²Dermatology, Columbia University Medical Center, New York, United States; ³Service de Dermatologie, Hôpital Saint Louis, APHP, Inserm U976, Université Paris 7, Paris, France; ⁴Hematologic Oncology, Dana-Farber Cancer Institute, Boston, United States;
⁵Dermatology, University of Alabama at Birmingham, Birmingham, United States; ⁶Dermatology, University of Texas MD Anderson Cancer</footnote>
**Conclusions:** This post-hoc analysis of TTNT, ORR, and compartmental response in stage IB/IIA demonstrates meaningful clinical benefit with MOGA in early stage MF pts previously treated with systemic therapies despite MAVORIC not being powered to determine treatment effect by disease stage.

**Sponsor:** Kyowa Kirin.

**Keywords:** cutaneous T-cell lymphoma (CTCL); monoclonal antibodies (MoAb); mycosis fungoides (MF).

**Disclosures:** Scarisbrick, J: Consultant Advisory Role: 4SC, Innate, Kyowa Kirin, Mallinckrodt, Takeda; Honoraria: 4SC, Kyowa Kirin, Mallinckrodt, Takeda; Research Funding: Kyowa Kirin, Takeda. Geskin, L: Consultant Advisory Role: Actelion, Kyowa Kirin, Mallinckrodt, Soligenix; Research Funding: Helsinn, Kyowa Kirin, Mallinckrodt, Merck; Other Remuneration: Travel, Kyowa Kirin. Bagot, M: Consultant Advisory Role: Innate, Kyowa Kirin, miRagen; Stock Ownership: Innate; Other Remuneration: Patent, Innate. Fisher, D: Consultant Advisory Role: Genetech, Gilead Sciences. Elmets, C: Consultant Advisory Role: Leo; Stock Ownership: Aevi Genomic; Research Funding: Elorac, Kyowa Kirin, Soligenix; Other Remuneration: Travel, Soligenix. Duvic, M: Consultant Advisory Role: Kyowa Kirin; Research Funding: Seattle Genetics; Other Remuneration: Travel, Kyowa Kirin. Beylot-Barry, M: Consultant Advisory Role: Takeda; Honoraria: Celgene, Takeda; Research Funding: Roche. Kim, E: Consultant Advisory Role: Actelion, Galderma, Seattle Genetics; Research Funding: Actelion, Galderma, Kyowa Kirin, Medimmune, Soligenix; Other Remuneration: Travel, Actelion, Galderma, Soligenix. Moriya, J: Employment Leadership Position: Kyowa Kirin. Leoni, M: Employment Leadership Position: Kyowa Kirin. Zinzani, P: Consultant Advisory Role: EusaPharma, Merck Sharp & Dohme, Sanofi, Verastem; Honoraria: Bristol-Myers Squibb, Celgene, Celltrion, Gilead, Jansen, Merck Sharp & Dohme, Roche, Servier; Other Remuneration: Speaker. Bristol-Myers Squibb, Celgene, Celltrion, Gilead, Jansen, Merck Sharp & Dohme, Roche, Servier, Verastem.

## FOCUS ON... SESSION: ONGOING TRIALS

### OT01
NCRI PETREA TRIAL: A PHASE 3 EVALUATION OF PET-GUIDED, RESPONSE-ADAPTED THERAPY IN PATIENTS WITH PREVIOUSLY UNTREATED, ADVANCED-STAGE, HIGH-TUMOUR-BURDEN FOLLICULAR LYMPHOMA

A.R. Pettitt<fnref n="1" /> | S. Barrington² | N. Kalakonda³ |
U.T. Khan³ | R. Jackson⁴ | S. Carruthers⁴ |
M. Oates³ | K. Lin⁵ | K. Ardeshna⁶ | T. Eyre⁷ |
C.P. Fox⁸ | B. Kennedy⁹ | K. Linton¹⁰ |
R. Malladi¹¹ | T. Menne¹² | J. Okosun¹³ |
S. Paneesha¹⁴ | S. Rule¹⁵ | A. Johnston¹⁶ | J. Trotman¹⁷

**Introduction:** Frontline treatment for advanced stage, high tumour burden follicular lymphoma (FL) usually consists of 6-8 cycles of chemotherapy combined with the CD20 antibody rituximab (R) or GA101/obinutuzumab (G). The PRIMA trial showed that R maintenance following R+chemo induction improves PFS but also increases toxicity with no OS advantage. The separation of PFS curves suggests that its main effect is to delay relapse in the minority of patients destined to progress within the first 2-3 years. The GALLIUM trial showed that replacing R with G further improves PFS but also increases toxicity and likewise has no OS advantage.

FDG PET-CT (PET) imaging has emerged as a powerful predictor of both PFS and OS following frontline R/G+chemo induction in FL. Most patients who achieve a complete metabolic response (CMR, Deauville 1-3) experience prolonged remissions irrespective of anti-CD20 maintenance whereas those who remain PET +ve (Deauville 4-5) have an increased probability of early disease progression. We therefore hypothesised that the PFS benefit of maintenance is largely confined to anatomical responders who remain PET +ve and is of limited magnitude in those who achieve a CMR. The PETReA trial was developed to test this hypothesis and also to investigate treatment intensification in the PET +ve population by adding lenalidomide to anti-CD20 maintenance. The combination of lenalidomide plus R is highly effective in FL, being superior to R in the relapsed/refractory setting and non-inferior to R+chemo in the frontline setting. Encouraging phase II data have also been obtained with lenalidomide plus G.

**Methods:** PETReA is a non-blinded, phase 3 randomised controlled trial for patients with previously untreated (excepting local

<footnote n="1">¹Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool Health Partners, Liverpool, United Kingdom; ²School of Biomedical Engineering and Imaging Sciences, St Thomas' Hospital, Kings College London, London, United Kingdom; ³Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom; ⁴CR-UK Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, United Kingdom; ⁵Haemato-Oncology Diagnostic Service, Liverpool Clinical Laboratories, Liverpool, United Kingdom; ⁶Department of Haematology, University College London, London, United Kingdom; ⁷Department of Haematology, Churchill Hospital, Oxford, United Kingdom; ⁸Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; ⁹Department of Haematology, University Hospital Leicester NHS Trust, Leicester, United Kingdom; ¹⁰Department of Haemato-oncology, Manchester Cancer Research Centre, Manchester, United Kingdom; ¹¹Department of Haematology, Queen Elizabeth Medical Centre, Birmingham, United Kingdom; ¹²Department of Haematology, Royal Freeman Hospital, Newcastle Upon Tyne, United Kingdom; ¹³Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; ¹⁴Department of Haematology, Heartlands Hospital, Birmingham, United Kingdom; ¹⁵Department of Haematology, Derriford Hospital, Plymouth, United Kingdom; ¹⁶School of Medicine & Department of Haematology, University of Tasmania & Royal Hobart Hospital, Hobart, Australia; ¹⁷University of Sydney, Concord Repatriation General Hospital, Concord, New South Wales, Australia</footnote>
<figure><img src="image_13.png" /></figure>

radiotherapy), advanced-stage FL (grade 1, 2, 3a) meeting the GELF criteria for starting treatment. Patients receive R+chemo with the option of CVP, CHOP or bendamustine. Anatomical responders are grouped based on post-induction PET status: those who achieve a CMR (Deauville 1-3) are randomised 1:1 to R maintenance (8 weekly for 12 doses) versus no further treatment, whereas those who remain PET +ve (Deauville 4-5) are randomised 1:1 to R maintenance with or without lenalidomide. The primary endpoint is PFS with secondary endpoints including OS, toxicity, quality of life, conversion to PET negativity (PET +ve group only) and response to induction therapy. The study opened in the UK in May 2018 and Australia in February 2019 and is recruiting at the expected rate.

A protocol amended is being planned to allow G as an alternative to R. In the revised design, which aims to recruit ~1000 patients from ~100 centres over 4.5 years, R- and G-treated patients will be analysed initially as a single cohort and as separate cohorts once sufficient events have accumulated. PETReA is the first trial in FL to stratify patients for separate questions based on post-induction PET status.

**Keywords:** follicular lymphoma (FL); positron emission tomography (PET).

**Disclosures:** Pettitt, A: Research Funding: Celgene, Chugai, Gilead, GSK/Novartis, Roche, Verastem; Other Remuneration: Celgene, Gilead.

Barrington, S: Consultant Advisory Role: Hofman la Roche; Honoraria: Hofman la Roche; Research Funding: Bristol Myers Squibb, Amgen, Celgene, Hofman la Roche. Kalakonda, N: Research Funding: Celgene.

Khan, U: Research Funding: UK is an MRC Clinical Training Fellow based at the University of Liverpool supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (Award Ref. MR/N025989/1), Roche Pharma, Eli Lilly and Company Limited, UCB Pharma, Novartis, the University of Liverpool and the University of

Manchester. Ardeshna, K: Other Remuneration: Advisory boards and assistance to attend conferences (travel registration and accommodation) from Roche, Takeda, Celgene, ADC Therapeutics. Eyre, T: Honoraria: Roche, Gilead, Janssen, Abbvie; Other Remuneration: Research support; Travel to scientific conferences from Gilead; travel to scientific conference from Abbvie. Fox, C: Consultant Advisory Role: Abbvie, Adienne, Celgene, Gilead, Janssen, Roche, Takeda, Sunesis, Atarabio; Honoraria: Abbvie, Adienne, Celgene, Gilead, Janssen, Roche, Takeda, Sunesis, Atarabio; Research Funding: Abbvie, Adienne, Gilead, Roche. Linton, K: Consultant Advisory Role: Celgene; Roche; Janssen; Takeda; Honoraria: Janssen; Hartley-Taylor; Roche; Other Remuneration: Janssen; Celgene; Takeda (sponsorship to attend conferences). Malladi, R: Honoraria: Roche; Research Funding: Celgene; Other Remuneration: Travel Support/Meeting attendance from Celgene. Menne, T: Honoraria: Pfizer, Amgen, Novartis, Roche, Daiichi, Kite, Celgene, Takeda; Research Funding: Janssen, Astra Zeneca. Okosun, J: Honoraria: Gilead; Research Funding: Gilead, Epizyme. Rule, S: Consultant Advisory Role: Celgene, Roche, Astra Zeneca, Janssen, Sunesis; Honoraria: Celgene, Roche, Astra Zeneca, Janssen, Sunesis; Research Funding: Janssen. Johnston, A: Consultant Advisory Role: Yes; Other Remuneration: Support to attend meeting. Trotman, J: Research Funding: Janssen, PCYC, Roche, Celgene, Beigene.

## OT02

### POLARIX: A PHASE 3 STUDY OF POLATUZUMAB VEDOTIN (POLA) PLUS R-CHP VERSUS R-CHOP IN PATIENTS (PTS) WITH UNTREATED DLBCL

H. Tilly¹ | C. Flowers² | J.W. Friedberg³ |

C. Herbaux⁴ | F. Morschhauser⁴ | L.H. Sehn⁵ |

J. Sharman⁶ | M. Trněný⁷ | C. Lee⁸ | G. Salles⁹
<figure><img src="image_14.png" /></figure>

**Background:** Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) remains the standard of care in pts with previously untreated diffuse large B-cell lymphoma (DLBCL) but outcomes remain poor in pts with high-risk disease. Pola is an antibody-drug conjugate targeting CD79b; it delivers the antimitotic agent monomethyl auristatin E. Addition of pola to bendamustine and R in pts with transplant-ineligible DLBCL resulted in improved OS (Sehn et al, 2018). In front-line treatment of DLBCL, pola is being evaluated as a replacement for vincristine within the R-CHOP regimen. In a phase Ib/II study in pts with higher risk DLBCL, pola + R-CHP demonstrated promising efficacy and a safety profile similar to that observed in the R-CHOP arm of the GOYA study (Tilly et al, 2017; Vitolo et al, 2017). The phase 3 POLARIX study investigates pola + R-CHP in untreated DLBCL.

**Methods:** POLARIX (NCT03274492) is an ongoing, international, randomised, double-blind, active-placebo-controlled, phase 3 study in pts with previously untreated DLBCL. Pts aged 18-80 years with CD20-positive DLBCL (including DLBCL not otherwise specified, GCB, and ABC subtypes), ECOG performance status 0-2, and IPI score 2-5, are stratified by IPI score (2 vs 3-5), bulky disease and geographical region and randomised (1:1). Pts receive 6 cycles of either: pola 1.8 mg/kg on Day 1 plus R-CHP (standard dosing schedule) plus vincristine placebo; or pola placebo plus R-CHOP (standard

dosing schedule). R monotherapy is administered in cycles 7 and 8 (both arms). PET-CT and CT scans are obtained at screening, after 4 cycles (planned interim assessment), and 6-8 weeks after end of study treatment. Follow-up will continue for 5 years after treatment.

**Primary endpoint:** investigator-assessed progression-free survival (PFS; Lugano classification).

**Secondary endpoints:** independent review committee-assessed PET-CT complete response rate at end of treatment, event-free survival, 2-year PFS rate, and overall survival.

Enrolment began Nov 2017. This trial is currently recruiting, and plans to enrol 875 patients in 24 countries.

© 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO Annual Meeting. All rights reserved.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); non-Hodgkin lymphoma (NHL); polatuzumab.

**Disclosures:** **Tilly, H:** Consultant Advisory Role: Karyopharm, Janssen, Roche; Honoraria: BMS, Servier; Other Remuneration: Roche (travel, accommodation and expenses). **Flowers, C:** Consultant Advisory Role: AbbVie, AstraZeneca, Bayer, BeiGene, Celgene (unpaid), Denovo Biopharma, Genentech, Inc./Roche (unpaid), Gilead, OptumRx, Karyopharm, Pharmacyclics/Janssen, Spectrum; Research Funding: AbbVie, Acerta, BeiGene, Celgene, Gilead, Genentech, Inc./Roche, Janssen Pharmaceutical, Millennium/Takeda, Pharmacyclics, TG Therapeutics. **Friedberg, J:** Consultant Advisory Role: Bayer, Astellas Pharma; Research Funding: Seattle Genetics, Kite Pharma; Other Remuneration: Roche (travel, accommodation and expenses); patent on bone marrow microenvironment signals. **Herbaux, C:** Honoraria: Roche, Janssen-Cilag, AbbVie; Research Funding: Takeda; Other Remuneration: Janssen-Cilag, AbbVie, Roche (travel, accommodation and expenses). **Morchhauser, F:** Consultant Advisory Role: Gilead; Honoraria: Celgene, Roche, Janssen, Bristol-Myers Squibb, Servier, Epizyme. **Sehn, L:** Consultant Advisory Role: Celgene, AbbVie, Seattle Genetics, TG Therapeutics, Janssen, Amgen, Roche/Genentech, Inc., Gilead Sciences, Lundbeck, Amgen, Apobiologix, Karyopharm Therapeutics, Kite Pharma, Merck, Takeda, Teva, AstraZeneca, Acerta Pharma, MorphoSys; Honoraria:

<footnote n="1">¹Centre Henri Becquerel, University of Rouen, Rouen, France;</footnote>

<footnote n="2">²Hematology and Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States; ³School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY, United States; ⁴Institute of Hematology-Transfusion, University of Lille, CHU Lille, Lille Cedex, France; ⁵Department of Medical Oncology, BC Cancer Agency, Vancouver, BC, Canada; ⁶Hematology Oncology, US Oncology and Willamette Valley Cancer Institute, Springfield, OR, United States; ⁷1st Department of Medicine - Department of Haematology, Charles University, Prague, Czech Republic; ⁸Product Development Clinical Oncology, Genentech, Inc., South San Francisco, CA, United States; ⁹Clinical Haematology, Hospices Civils de Lyon, Université Lyon-1, Lyon, France</footnote>
Amgen, Apobiologix, AbbVie, Celgene, Gilead Sciences, Janssen-Ortho, Karyopharm Therapeutics, Kite Pharma, Lundbeck, Merck, Roche/Genentech, Inc., Seattle Genetics, Takeda, Teva, TG Therapeutics; Research Funding: Roche/Genentech, Inc. Sharman, J: Consultant Advisory Role: Pharmacyclics, Celgene, TG Therapeutics, Genentech, Inc., AbbVie, Acerta Pharma/AstraZeneca; Research Funding: Pharmacyclics, Genentech, Inc., Celgene, Acerta Pharma, Gilead Sciences, Seattle Genetics, TG Therapeutics, Merck, Takeda; Other Remuneration: US Oncology (leadership), Gilead Sciences (expert testimony). 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; Other Remuneration: Gilead Sciences, Takeda, Bristol-Myers Squibb, Roche, Janssen, AbbVie (travel, accommodation and expenses). Lee, C: Employment Leadership Position: Roche; Stock Ownership: Roche. Salles, G: Consultant Advisory Role: Roche/Genentech, Inc., Gilead Sciences, Janssen, Celgene, Novartis, Merck, Pfizer, Acerta Pharma, Kite Pharma, Servier, MorphoSys, Epizyme; Honoraria: Roche/Genentech, Inc., Amgen, Janssen, Celgene, Servier, Gilead Sciences, Novartis, AbbVie, Merck, Takeda, MorphoSys.

## OT03
### PHASE III RANDOMIZED STUDY OF ENZASTAURIN/R-CHOP VS PLACEBO/R-CHOP IN FRONTLINE HIGH RISK DIFFUSE LARGE B CELL LYMPHOMA PATIENTS WITH GENOMIC BIOMARKER DGM1 (ENGINE STUDY)

J. Zhu<fnref n="1" /> | Y. Song<fnref n="1" /> | S.D. Smith² | O.A. O'Connor³ |

W. Luo⁴ | R.L. Shazer⁴ | L. Zhang⁴ | I. Han⁴ |

M.A. Jivani⁴ | Y. Liu⁴ | G.S. Nowakowski⁵

**Introduction:** Progress in genome technology allows analysis of previously completed trials to identify patient subgroups potentially benefiting from therapy. Enzastaurin is a potent inhibitor of protein kinase C beta (PKC-β) and suppresses the phosphoinositide 3-kinase (PI3K)/AKT pathway. The safety and efficacy of enzastaurin has been tested in more than 60 clinical trials including 2 major studies in DLBCL: (1) PRELUDE (A phase III maintenance trial of enzastaurin vs Placebo, N=758) (Crump, 2016), and (2) S028 (A randomized phase II study of enzastaurin/R-CHOP vs R-CHOP in frontline intermediate/high-risk DLBCL, N=101) (Hainsworth, 2016). DNA samples extracted from blood of patients from PRELUDE were retrospectively genotyped using whole genome SNP arrays. From the genome wide

screening a novel genetic biomarker, DGM1, was identified showing high correlation with response to enzastaurin treatment (Luo, ASH 2018). Importantly, these findings were replicated in the phase II S028 study. In the S028 study the hazard ratio (HR) for OS in high-risk (IPI ≥ 3) DGM1 positive (+) patients who received Enzastaurin/R-CHOP was 0.28 (0.1-0.81) when compared to subjects who received R-CHOP, a benefit favoring enzastaurin (p=0.018). These data suggest that addition of enzastaurin to R-CHOP may significantly improve outcome in frontline high-risk DGM1 (+) DLBCL. The ENGINE study was initiated to validate this finding in a prospective study.

**Methods:** This is a randomized, double-blind, placebo-controlled phase III Trial. Adult patients must have untreated historically confirmed CD20+ DLBCL and IPI ≥ 3. Patients are randomized 1:1 to enzastaurin/R-CHOP or placebo/R-CHOP for six 21-day cycles during combination phase. Randomization is stratified by IPI score: 3 vs. 4, 5, and by region. Each subject's treatment assignment will be unblinded after response assessment at the end of the combination phase. Subjects randomized to the investigational arm who have a complete or partial response will have the option to continue in the single agent phase to receive enzastaurin at 500 mg/day for up to 2 additional years. The study intends to enroll approximately 235 patients with primary endpoint of OS in DGM1 (+) patients. Secondary endpoint includes CR, ORR and safety. The study is ongoing with 53 sites open in the US and China. As of 22 Feb 2019, 78 patients have been randomized. Clinical trial information: NCT03263026.

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

**Disclosures:** Smith, S: Consultant Advisory Role: Merck Sharp & Dohme; AstraZeneca; Research Funding: Acerta Pharma BV; AstraZeneca; Ayala Pharmaceuticals; Bristol-Myers Squibb; Denovo Biopharma; Genentech; Ignyta, Incyte, Marck Sharp and Dohme Corp; Pharmacyclics; Portola Pharmaceuticals; Seattle Genetics. Luo, W: Employment Leadership Position: Denovo Biopharma; Stock Ownership: Denovo Biopharma; Research Funding: Denovo Biopharma. Shazer, R: Employment Leadership Position: Inspyr Therapeutics; Denovo Biopharma; Stock Ownership: Bristol-Myers Squibb; Pfizer. Zhang, L: Employment Leadership Position: Celgene; Denovo Biopharma; Stock Ownership: Celgene; Denovo Biopharma. Han, I: Employment Leadership Position: Denovo Biopharma. Jivani, M: Employment Leadership Position: Denovo Biopharma; Stock Ownership: TRACON Pharmaceuticals, Inc. Liu, Y: Employment Leadership Position: Denovo Biopharma. Nowakowski, G: Consultant Advisory Role: Celgene; MorphoSys; Genentech; Research Funding: Celgene; NanoString Technologies; MorphoSys.

## OT04
### THE DIAL STUDY (DUAL IMMUNOMODULATION IN AGGRESSIVE LYMPHOMA): RANDOMIZED PHASE 2 TRIAL OF VARLILUMAB PLUS NIVOLUMAB IN RELAPSED/REFRACTORY AGGRESSIVE B-CELL LYMPHOMAS

<footnote n="1">¹Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China; ²Division of Medical Oncology, University of Washington, Seattle, United States; ³Division of Hematology/Oncology, Columbia University Medical Center, New York, United States; ⁴Denovo Biopharma LLC, Denovo Biopharma LLC, San Diego, United States; ⁵Hematology, Mayo Clinic, Rochester, United States</footnote>
J.C. Villasboas¹ | C.B. Reeder² | H.W. Tun³ |
N.L. Bartlett⁴ | E. Sharon⁵ | B. LaPlant¹ | A. Adjei⁶ |
S.M. Ansell¹

¹Division of Hematology, Mayo Clinic, Rochester, United States; ²Division of Hematology, Mayo Clinic, Scottsdale, United States; ³Division of Hematology, Mayo Clinic, Jacksonville, United States; ⁴Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, United States; ⁵Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, United States; ⁶Division of Medical Oncology, Mayo Clinic, Rochester, United States

**Introduction:** The DIAL study is testing the efficacy of dual immunod modulation in patients with advanced B cell non-Hodgkin lymphoma (B-NHL). Developed by the Cancer Therapy Evaluation Program (CTEP), the trial combines the use of a programmed cell death protein 1 (PD-1) inhibitor (nivolumab) with an agonist of the CD27 receptor (varlilumab) in a randomized phase 2 design. CD27, a co-stimulatory receptor, regulates T cell activation through interaction with CD70. T cell exhaustion plays a major role in immune evasion in B-NHL. Combining varlilumab and PD-1 inhibition is highly effective in a murine model of lymphoma, and varlilumab also demonstrates direct anti-tumoral activity in xenograft models of human lymphoma cell lines via antibody-dependent cell-mediated cytotoxicity. Phase 1 data supports the safety and tolerability of single-agent varlilumab in advanced hematologic malignancies. We hypothesize that CD27 activation synergizes with PD-1 inhibition resulting in a superior anti-lymphoma effect compared to PD-1 blockade alone. The study will also evaluate the effect of these agents on tumor and immune cells using IHC, mass cytometry (CyTOF), imaging mass cytometry (IMC), multiplex ELISA, and whole exome sequencing (WES).

**Methods:** The trial is open to participation for patients with a diagnosis of an aggressive B-cell non-Hodgkin lymphoma (B-NHL) that is recurrent or refractory to standard therapy. Standard inclusion criteria and prior treatment with at least 2 lines of standard therapy are required. Prior autologous stem cell transplant and/or chimeric anti-gen receptor (CAR) T cell therapy is allowed. Patients with active CNS disease are excluded. Eligible patients will be randomized to treatment with single-agent nivolumab (group 1) or dual immunotherapy with nivolumab and varlilumab. Group 1 is allowed to cross-over at the time of progression. Nivolumab will be administered intravenously (IV) every 2 weeks (240 mg) for 4 months followed by monthly dosing (480 mg) thereafter. Varlilumab will be given IV every 4 weeks (3 mg/kg). Response assessment will be done by PET-CT scan every 12 weeks. Primary outcome is overall response rate (ORR) according to the LYRIC criteria. The trial will enroll 48 patients per arm, allowing 80% power to detect at least 20% increase in ORR in the experimental arm (group 2) assuming a 25% ORR in the control arm (group 1). The trial is registered (NCT03038672) and open to participation to members of the Experimental Therapeutics Clinical Trials Network (ETCTN) and Early Drug Development Opportunity Program (EDDOP).

**Keywords:** B-cell lymphoma; immune system; PD-1.

**Disclosures:** Tun, H: Research Funding: BMS.

OT05
ACCEPT: A PHASE IB/II COMBINATION OF ACALABRUTINIB WITH RITUXIMAB, CYCLOPHOSPHAMIDE, DOXORUBICIN, VINCRISTINE AND PREDNISOLONE (R-CHOP) FOR PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

T.E. Cummin¹ | J. Caddy¹ | K. Mercer¹ |
T. Maishman¹ | A. Schuh² | L. Lopez Pascua² |
G. Collins³ | A. McMillan⁴ | K. Ardeshna⁵ |
A. Galanopoulous¹ | C. Burton⁶ | S. Barrans⁶ |
G. Griffiths¹ | P. Johnson¹ | A.J. Davies¹

¹Southampton Cancer Research UK (CRUK) Centre/CRUK Southampton Clinical Trials Unit/CRUK Experimental Cancer Medicines Centre UK/ Southampton CRUK Clinical Trials Unit, University of Southampton, Southampton, United Kingdom; ²Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, United Kingdom; ³Lymphoma Service, Oxford University Hospitals, Oxford, United Kingdom; ⁴Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; ⁵Department of Haematology, University College Hospitals London, London, United Kingdom; ⁶Haematological Malignancies Diagnostic Service, Leeds Cancer Centre, Leeds, United Kingdom

**Background:** R-CHOP remains the standard of care in DLBCL yet many patients (pts.) either fail to respond or relapse after having achieved an initial remission. Dysregulation of B Cell receptor (BCR) signalling is well recognised in non-germinal centre (non-GC) DLBCL. In the phase III PHOENIX study, the addition of the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib (I) to R-CHOP (R-CHOP-I) did not improve the outcome of the study population with non-GC DLBCL although R-CHOP-I treated pts. aged less than 60 years had a significantly improved progression free survival (PFS) and overall survival (OS) compared to those receiving R-CHOP. In pts. aged over 60 years, the addition of I increased toxicity and compromised the delivery of R-CHOP. Acalabrutinib (A) is a second generation BTKi, with enhanced kinase selectivity and potential for better efficacy and tolerability over first-generation inhibitors. There is a strong rationale to combine this targeted agent with R-CHOP in untreated de novo DLBCL to understand its safety profile and efficacy.

**Method:** Eligible patients are treatment naive with histologically confirmed DLBCL. During cycle 1 whole transcriptome analysis will be performed to determine cell of origin (COO). All will receive 6 cycles of R-CHOP therapy on a standard 21-day schedule, with the addition of A in cycles 2-6. Subsequently a continuation phase of A only, for 2 cycles of 28 days will be administered. The primary objective of the phase Ib is to establish a recommended phase II dose of A in
combination with R-CHOP (modified classical 6+6 design). Phase II is to assess overall response rate activity of the combination and ascertain additional safety information. Secondary endpoints include duration of response, PFS and OS and their relation to the COO, and BTK receptor occupancy in PBMCs and tumour measured by a drug analogue ELISA. The effect of acalabrutinib on antibody-directed cellular cytotoxicity mediated by rituximab will be measured in vitro during treatment. To date 22 (12 in dose escalation) of a planned 28 pts. have been recruited. In the phase Ib the maximal administered dose of A (100mg bd) with R-CHOP demonstrated no safety concerns beyond those seen with R-CHOP alone. In dose expansion, regardless of age, there has been no compromise in the delivery of full dose R-CHOP when given in combination with A. With anticipated full recruitment before 06/19, safety data, with ctDNA dynamics will be presented.
The trial is coordinated by the CRUK Southampton Clinical Trials Unit. This is an investigator initiated study that has been granted free access to investigational medicinal product, trial management and translational study support through a grant from Acerta Pharma B.V. (IST-LY-801) and has endorsement from Cancer Research UK (CRUKDE/16/006). Trial registration: ISRCTN11965217 NCT03571308

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

**Disclosures:** McMillan, A: Consultant Advisory Role: Roche, Celgene, BMS, MSD; Honoraria: Roche, Celgene, BMS, MSD; Research Funding: Pfizer; Other Remuneration: Travel: Roche, Celgene, Takeda. Burton, C: Consultant Advisory Role: Roche, Takeda, BMS, Celgene; Honoraria: Roche, Takeda, BMS; Other Remuneration: Travel: Roche, Takeda. Barrans, S: Consultant Advisory Role: HTG Diagnostics; Other Remuneration: Travel: HTG Diagnostics. Griffiths, G: Research Funding: Hold educational trial grants from numerous companies including AcertaPharma. Johnson, P: Honoraria: Bristol-Myers Squibb, Takeda, Novartis, Celgene, Janssen, Epizyme, Boeringher Ingelheim, Kite, Genmab, Incyte; Research Funding: Janssen, Epizyme. 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: Travel to conferences: Roche, Celgene. Expert testimony: Roche.

OT06
TELLOMAK: T-CELL LYMPHOMA ANTI-KIR3DL2 THERAPY: AN OPEN LABEL, MULTI-COHORT, MULTI-CENTER, INTERNATIONAL PHASE II STUDY EVALUATING THE EFFICACY AND SAFETY OF IPH4102 ALONE OR IN COMBINATION WITH CHEMOTHERAPY IN PATIENTS WITH ADVANCED T-CELL LYMPHOMA

P. Porcu¹ | Y. Kim² | P. Zinzani³ | H. Sicard⁴ |
H.A. Azim Jr⁴ | M. Bagot⁵

¹Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, United States; ²Dermatology, Stanford Cancer Institute, San Francisco, United States; ³Hematology/Oncology, University of Bologna, Bologna, Italy; ⁴Research and Development, Innate Pharma, Marseille, France; ⁵Dermatology, Hôpital Saint Louis, Paris, France

**Background:** KIR3DL2 is a killer immunoglobulin-like receptor that is expressed by tumor cells across different subtypes of T-cell lymphomas (> 85% of Sézary Syndrome (SS), ~50% of mycosis fungoides (MF), and ~50% in peripheral T-cell lymphomas (PTCL)). IPH4102 is a humanized first-in-class anti-KIR3DL2 monoclonal antibody designed to deplete KIR3DL2-expressing cells via antibody-dependent cell-cytotoxicity (ADCC) and phagocytosis. A first-in-human study including 44 patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL) showed that the drug is safe and has very robust clinical activity. The majority of the patients enrolled had relapsed/refractory SS (n=35). In this population, IPH4102 produced an overall response rate (ORR) of 42.9%, and median progression free survival (PFS) of ~1 year leading to FDA fast track designation in January 2019. IPH4102 has not been previously investigated in PTCL. Preclinical studies have shown that gemcitabine and oxaliplatin can upregulate KIR3DL2 expression on T-cell lymphoma cell lines. Furthermore, IPH4102 anti-tumor activity was enhanced in-vitro by each of these chemotherapy agents, and even more by the combination.

**Methods:** This is an open-label, multi-cohort, multi-center, international phase II trial. Patients will be allocated to one of five cohorts: Cohort 1: SS, Cohorts 2&3: MF stratified according to KIR3DL2 expression, Cohorts 4&5: PTCL stratified according to KIR3DL2 expression. In the SS and MF cohorts, patients should have received ≥2 prior systemic therapies and have no evidence of large cell transformation as detected centrally. In the SS cohort, prior treatment with mogamulizumab is required. In the PTCL cohorts, only patients with PTCL-NOS, AITL and ALCL who have received ≥ 1 line of prior systemic therapy are eligible. All patients will undergo KIR3DL2 testing at baseline in a central laboratory. In the SS and MF cohorts, IPH4102 will be administered as single agent at a flat dose of 750mg weekly x 4 weeks, every 2 weeks x 20 weeks (10 doses), then every 4 weeks. In the PTCL cohorts, IPH4102 will be administered using the same schedule in combination with gemcitabine and oxaliplatin (GEMOX), which will be administered every 2 weeks for a maximum of 8 cycles. In all cohorts, IPH4102 treatment will continue until progression or unacceptable toxicity. The primary endpoint is overall response, evaluated using the International Consensus Criteria for MF/SS and the Lugano Criteria for PTCL. Secondary endpoints include safety, other efficacy endpoints, and biomarker analyses. Each cohort has a separate design and dedicated statistical analysis plan. A biomarker-stratified design is applied in cohorts 2-5 using a Simon 2-stage design to inform on the activity of assigned treatment according to KIR3DL2 expression. In total, approximately 140-260 patients will be recruited across 30-40 sites in the US and Europe.
**Keywords:** mycosis fungoides (MF); peripheral T-cell lymphomas (PTCL); Sezary syndrome.

**Disclosures:** Porcu, P: Consultant Advisory Role: Innate Pharma; Research Funding: Kyowa Kirin, Viracta. Kim, Y: Honoraria: kyowa Kirin, Eisai, Millennium/Takeda, Seattly Genetics, miRagen, Innate Pharma; Research Funding: Kyowa Kirin, Merck, Soligenix, Forty-Seven, Neomedicines, Portola Pharma, and Horizon. Zinzani, P: Honoraria: SERVIER, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, MSD, Celltrion, Celgene, Roche; Other Remuneration: Speaker bureau: Verastem, SERVIER, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, MSD, Celltrion, Celgene, Roche. Sicard, H: Employment Leadership Position: Innate Pharma; Stock Ownership: Innate Pharma. Azim Jr, H: Employment Leadership Position: Innate Pharma; Stock Ownership: Innate Pharma. Bagot, M: Consultant Advisory Role: Innate Pharma; Other Remuneration: Travel fees: Innate Pharma, Kyowa Kirin. Speaker Bureau: Acetlion. Patency: IPH4102.

## SESSION 1 - DLBCL: BIOLOGY

### 035 AN AUTOCHTHONOUS MOUSE MODEL OF MyD88 p.L265P- AND BCL2-DRIVEN DIFFUSE LARGE B CELL LYMPHOMA

G. Knittel¹ | R. Flümann¹ | P. Nieper¹ |

T. Rehkämper¹ | P. Pfeiffer¹ | A. Holzem¹ |

C. Fritz¹ | A. Klatt² | H. Kashkar³ | T. Persigehl⁴ |

M. Peifer⁵ | R. Büttner⁶ | C. Reinhardt¹

¹Dept. I of Internal Medicine, University Hospital Cologne, Cologne, Germany; ²Institute for Clinical Chemistry, University Hospital of Cologne, Cologne, Germany; ³Institute for Microbiology and Hygiene, University Hospital of Cologne, Cologne, Germany; ⁴Department of Radiology, University Hospital Cologne, Cologne, Germany; ⁵Department of Translational Genomics, University of Cologne, Cologne, Germany; ⁶Institute of Pathology, University Hospital of Cologne, Cologne, Germany

**Background:** There are several recurrent mutations in DLBCL leading to the constitutive activation of NF-kB, frequently by activating the BCR and TLR pathways (mostly via mutations in CD79B and MyD88, respectively), or by the loss of a negative feedback loop mediated by the loss of TNFAIP3.

**Methods:** Here, we aimed to investigate the role of the p.L265P mutation in lymphomagenesis. We generated a novel mouse model in which Cre-mediated recombination leads to the conditional expression of Myd88 p.L252P (the orthologue of the human MyD88 p.L265P mutation) from the endogenous locus. We combined this Myd88 allele (abbr. M) with a BCL2 overexpression allele (abbr. B) and both alleles were activated with CD19:Cre (abbr. C). The effects of these mutations were carefully characterised in vivo. Additionally, we have generated a

conditional Cd79bp.Y195H allele and model the loss of Tnfaip3 by using a previously published floxed allele.

**Results:** MBC animals showed elevated levels of self-reactive antibodies. Immunization experiments revealed that Myd88 p.L252P and BCL2 overexpression cooperate in generating exaggerated antibody responses to exogenous antigen. Ultimately, these animals develop clonal tumors which resemble features of ABC DLBCL histologically and transcriptionally. They were exquisitely sensitive to inhibition of BCL2 in vitro and in vivo. MBC tumors expressed PD-L1 at elevated levels compared to Eμ:Myc driven lesions. Anti-PD1 antibody treatment had a stabilizing effect on tumor growth and resulted in a survival benefit. We are currently investigating the effects of Cd79b p. Y195H expression and loss of Tnfaip3 and initial comparative results will be shown.

**Conclusion:** Taken together, we established a Myd88 p.L252P driven mouse model for B cell lymphoma which shares many features with human ABC DLBCL. These tumors are sensitive to inhibition of BCL2 by ABT-199 and respond to immune checkpoint blockade by anti-PD1 treatment, suggesting these treatments as potential new strategies in the therapy of a subset of DLBCL patients. Additionally, we are extending our spectrum of modelled genetic alterations recurrent in DLBCL by the use of a novel conditional Cd79b p.Y195H and a previously published Tnfaip3 flox allele.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); mouse models; MYD88.

### 036 CRYPTIC MYC AND BCL2 REARRANGEMENTS ARE AMONG A RANGE OF GENETIC MECHANISMS UNDERLYING THE DOUBLE HIT SIGNATURE IN NON-DOUBLE HIT DIFFUSE LARGE B-CELL LYMPHOMA

L.K. Hilton¹ | M. Alcaide¹ | S. Ben-Neriah² |

A. Jiang² | B.M. Grande¹ | C.K. Rushton¹ |

M. Boyle² | B. Meissner² | D.W. Scott² | R.D. Morin¹

¹Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; ²Centre for Lymphoid Cancer, BC Cancer, Vancouver, Canada

**Introduction:** High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has poor outcome after standard therapy. We recently described a gene expression signature (DHITsig) that was characteristic for HGBL-DH/TH with BCL2 rearrangement (Ennishi et al. J Clin Oncol 2019). Interestingly, while this signature identified 27% of GCB diffuse large B-cell lymphoma (DLBCL) as DHITsig positive, only half of these tumors harbored both MYC and BCL2 rearrangements detected by FISH. Here, through whole genome sequencing (WGS), we sought to identify potential mechanisms for expression of DHITsig, including aberrant MYC and BCL2 expression, in non-HGBL-DH/TH-BCL2 tumors.
<figure><img src="image_15.png" /></figure>

**Methods:** We performed WGS on 20 DHITsig-pos tumors from Ennishi *et al* that lack rearrangements of MYC, BCL2, or both. Of these, 18 cases lack a matched normal and were analyzed for somatic SNVs and indels using a combination of Strelka2 and Mutect2, using the GnomAD database to filter germline variants based on population allele fraction. Structural variants and copy number alterations were identified using Manta and Control-FREEC, respectively.

**Results:** Our analysis identified MYC or BCL2 rearrangements that were cryptic to breakapart FISH assays, revealing that 40% of these apparently non-HGBL-DH/TH-BCL2 tumors had, in fact, a "genetic double hit" (Figure 1). These MYC rearrangements involved recurrent non-IG partner loci ZCCHC7, RFTN1, or CD96. Although the breakpoints for two of these translocations were outside of the locus interrogated by FISH, the remainder involved small insertions of either the MYC gene or enhancer regions. Three tumors had focal copy number gains of MYC, including one with a double minute, and six tumors harbored gains of MIR-17-HG, a regulator of MYC expression. Similarly, rearrangements involving BCL2 that were cryptic to breakapart FISH were identified in three tumors, including the insertion of an IGK enhancer element into the BCL2 locus. In the only case lacking both BCL2 and MYC translocations, the 11q alteration associated with MYC-negative high-grade lymphomas was found. Finally, several focal deletions were found affecting the promoter region around TSS1 of the IncRNA PVT1 gene, telomeric of MYC. This locus has recently been found to contain a boundary element that insulates MYC from the actions of downstream enhancers.

**Conclusions:** Genetic mechanisms for the membership of apparently non-HGBL-DH/TH-BCL2 tumors to the DHITsig-pos subtype of DLBCL were revealed in 90% of tumors. These mechanisms included MYC and BCL2 rearrangements cryptic to FISH assays, copy number aberrations, and focal deletion of PVT1. This study further supports the notion that DHITsig identifies a new biological entity within DLBCL and highlights the limitations of FISH assays in the detection of genetic mechanisms of aberrant MYC and BCL2 expression.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); gene expression profile (GEP); high-grade B-cell lymphoma with or without rearrangement of MYC and BCL2 and/or BCL6.

**Disclosures:** Scott, D: Research Funding: Receives research funds from NanoString Technologies; Other Remuneration: Named inventor on a patent for identifying novel sub-types of DLBCL. Morin, R: Other

Remuneration: Named inventor on a patent for identifying novel sub-types of DLBCL.

037

FUNCTIONAL CHARACTERIZATION OF NFKBIZ 3' UTR MUTATIONS IN DIFFUSE LARGE B-CELL LYMPHOMA

S.E. Arthur<fnref n="1" /> | A. Mottok² | R. Cojocaru<fnref n="1" /> |

A. Jiang<fnref n="1" /> | B.M. Grande<fnref n="1" /> | M. Alcaide<fnref n="1" /> |

C. Rushton<fnref n="1" /> | D. Ennishi² | P. Kumar Lat<fnref n="1" /> |

J. Davidson<fnref n="1" /> | K.R. Bushell<fnref n="1" /> | T. Audas<fnref n="1" /> |

P. Unrau<fnref n="1" /> | D. Sen<fnref n="1" /> | R.D. Gascoyne² |

M.A. Marra<fnref n="3" /> | J.M. Connors² | G.B. Morin<fnref n="3" /> |

D.W. Scott² | C. Steidl² | R.D. Morin<fnref n="1" /> |

**Introduction:** The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) is characterized by activation of NF-kB signaling and an increased risk of mortality. Recurrent somatic mutations affecting genes such as MYD88, CD79A/B and TNFAIP3 have been shown to constitutively activate the NF-kB pathway through B-cell receptor signaling in ABC DLBCL; however, there still remain cases with no known genetic basis for this pathway activation (Arthur *et al.* *Nat Com* 2018). We recently published a meta-analysis of DLBCL genome and targeted sequencing data identifying non-coding mutations. We described novel mutations affection the 3' untranslated region (UTR) of NFKBIZ in 18% of ABC DLBCLs. Overall, NFKBIZ is mutated (amplifications and UTR mutations) in 34% of ABC DLBCLs. These NFKBIZ mutations are mutually exclusive with MYD88 mutations, implicating them in activation of the NF-kB signaling pathway. NFKBIZ encodes the IkB-ζ protein, which interacts with NF-kB transcription factors and is thought to regulate canonical NF-kB signaling. We hypothesized that these mutations affect the ability of regulatory mechanisms to target this transcript for degradation through disruption of UTR secondary structures. This leads to enhanced mRNA stability and elevated protein levels and represents a novel mechanism of promoting NF-kB signaling in ABC DLBCL.

<footnote n="1">¹Molecular Biology & Biochemistry, Simon Fraser University, Burnaby, Canada; ²Centre for Lymphoid Cancer, BC Cancer, Vancouver, Canada;</footnote>

<footnote n="3">³Genome Sciences Centre, BC Cancer, Vancouver, Canada</footnote>
**Methods:** NFKBIZ 3' UTR mutations were introduced in a DLBCL cell line using CRISPR-Cas9. NFKBIZ mRNA and protein levels were evaluated using custom designed droplet digital PCR assays and western blot. RNA-sequencing was performed on mutant and wild-type (WT) cell lines to identify genes up-regulated by IκB-ζ. A competitive growth assay with WT and CRISPR mutant lines was set up to assess whether UTR mutations provide a growth advantage in culture. The pool composition was determined by DNA sequencing and comparison of WT and mutant DNA sequences.

**Results:** Introduction of NFKBIZ mutations into DLBCL cell lines confirmed that UTR deletions lead to increased levels of mRNA and protein. Stimulation with LPS revealed that mRNA levels stay elevated for longer in mutant lines. NFKBIZ UTR deletions also give DLBCL cells a selective growth advantage over WT when grown together in culture. RNA-sequencing of mutant and WT lines revealed possible transcriptional targets of IκB-ζ, including TNFRSF14B, HCK, GNAZ, BATF and CD274. These targets are either involved in activation of NF-κB signaling, associated with decreased survival in other lymphomas or potential new drug targets in NFKBIZ mutant DLBCL.

**Conclusions:** This work highlights the role of NFKBIZ and 3' UTR mutations in driving ABC DLBCL. We demonstrate that these UTR mutations can lead to over-expression of NFKBIZ and activate potentially novel drug targets in ABC DLBCL. These findings contribute to a better understanding of the genetic basis of DLBCL, which is necessary to guide personalized therapeutic strategies.

**Keywords:** activated B-cell-like (ABC); molecular genetics; NF-κB.

## 038
# THE TRANSCRIPTION FACTOR FLI1 SUSTAINS RELEVANT BIOLOGICAL PATHWAYS AND DRIVES ONCOGENES THAT PROMOTE CELL GROWTH IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

G. Sartori | S. Napoli | L. Cascione | V. Priebe |

A. Arribas | A. Rinaldi | F. Bertoni

Institute of Oncology Research, Università della Svizzera Italiana,
Bellinzona, Switzerland

**Introduction:** Gains affecting chromosome 11, often in its integrity, are recurrent events in lymphomas. Our group identified and functionally characterized an 11q24.3 gain occurring in 25% of diffuse large B-cell lymphoma (DLBCL) cases and associated with the overexpression of two ETS transcription factors, ETS1 and FLI1 (Blood 2013). Here, we have focused on the latter to identify the network of FLI1 regulated genes in DLBCL.

**Methods:** We interrogated the specific transcriptome orchestrated by FLI1 using ChIP-Seq paired with transcriptome analysis (RNA-Seq) after FLI1 silencing (siRNA). Sequencing was performed using the NextSeq 500 (Illumina). Detection of peaks was carried out using

HOMER (v2.6), differential expressed genes were identified using a moderated t-test (limma R-package) and functional annotation was done by Gene Set Enrichment Analysis (GSEA, Broad Institute).

**Results:** ChIP-Seq on four DLBCL cell lines, two derived from activated B cell-like (ABC) subtype (HBL1 and U2932) and two from germinal center B-cell (GCB) subtype (OCI-Ly1 and VAL), identified 17.574 FLI1 binding sites. The majority of peaks mapped in promoter regions of annotated genes (37%), followed by distal intergenic regions (22%), intronic regions other than first intron (21%) and others regions like first intron, 5' or 3' UTR and exons (20%). Integration of the identified binding sites with RNA-Seq from FLI1 genetically silenced DLBCL cell lines allowed the identification of putative FLI1 direct targets. The FLI1 negatively regulated genes included tumor suppressors genes involved in negative regulation of cell cycle and p53 cascade. Among the FLI1 positively regulated targets we found genes annotated for immune response, MYC targets and B cell receptor, TNF-alpha and IL2 signaling pathways. Of note, direct targets of FLI1 overlapped with those genes regulated by ETS1, the other transcription factor including co-gained in DLBCL (Priebe et al, ICML 2017), suggesting a functional convergence within the ETS family. FLI1 positively regulated targets included MYC, CXCR5, CD40, LCK, ICAM1, CD79A, CD19, BTK, PIK3CD, PRKACD, NFBK1/2, FAIM3, BTG2, TRAF1/4/5 and IL2RA/G. Conversely, BCOR, SAP30, EZR, CDKN1B, E2F7, TFDP2 and BARD1 were among the negatively regulated. Importantly, the majority of the FLI1 positively regulated targets overlapped with those genes positively correlated with FLI1 in DLBCL clinical specimens (GSE10846, n=414). Finally, we took advantage of genome-wide CRISPR-CAS9 screening of DLBCL cell lines performed by Reddy et al. 2017 (EGAS00001002606) to identify PRKX, RASGRP1, ATG9a, ASB2, DDX21, TAF1 and AATF as FLI1-regulated driver genes in DLBCL.

**Conclusions:** We reported that FLI1 directly regulates a network of biologically crucial genes and processes in DLBCL. Further studies based on FLI1 itself or some of its targets might provide the rational for novel therapeutic approaches.

**Keywords:** B-cell receptor (BCR); diffuse large B-cell lymphoma (DLBCL); MYC.

## 039
# TRANSCRIPTIONAL AND GENOMIC INTRA-TUMOR HETEROGENEITY DRIVES SUBCLONE SPECIFIC DRUG RESPONSES IN DIFFUSE LARGE B CELL LYMPHOMA

T. Roider¹ | F. Frauhammer² | J. Seufert³ |

M. Bordas⁴ | M. Stolarczyk¹ | S. Rabe¹ | J. Malm⁵ |

P. Bruch¹ | M. Hundemer¹ | K. Rippe⁵ |

B. Goeppert⁶ | M. Seiffert⁴ | B. Brors³ |

G. Mechtersheimer⁶ | C. Müller-Tidow¹ | S. Fröhling⁷ |

M. Schlesner³ | W. Huber⁸ | S. Anders² | S. Dietrich¹
<figure><img src="image_16.png" /><figcaption>Figure 1. Study outline</figcaption></figure>

¹Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany; ²Centre for Molecular Biology, University of Heidelberg, Heidelberg, Germany; ³Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany; ⁴Department of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany; ⁵Division of Chromatin Networks, German Cancer Research Center (DKFZ) and Bioquant, Heidelberg, Germany; ⁶Institute of Pathology, University of Heidelberg, Heidelberg, Germany; ⁷Translational Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany; ⁸Genome Biology, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany

**Introduction:** Little is known about intra-tumor heterogeneity of lymphoma and their complex disease-specific lymph node (LN) microenvironment.

**Methods:** To address this gap of knowledge we characterized follicular lymphoma, diffuse large B cell lymphoma (DLBCL) and reactive LN biopsies by comprehensive immunophenotyping (29 markers, n=40) and single cell RNA sequencing (scRNA-Seq, n=7). We used state-of-the-art clustering algorithms to identify malignant subclones and separated them by fluorescence-activated cell sorting (FACS). We further characterized these subclones by whole-genome sequencing (WGS) and extensive drug response profiling (64 drugs at 5 concentrations, Figure 1).

**Results:** We sequenced a total of 17,210 malignant B cells and 7,165 non-malignant bystander cells. Non-malignant cell subsets were

distinguished based on expression profiles of established marker genes, and malignant B cells were identified based on exclusive expression of either κ or λ light chain genes. Frequencies of B and T cells calculated based on scRNA-Seq highly correlated with frequencies of B and T cells calculated based on FACS analysis (r=0.97) or immunohistochemistry analysis of corresponding paraffin sections (r=0.95). These results suggested that our approach portrays a representative picture of each tumor and its microenvironment.

We further characterized non-malignant cell populations and identified, apart from well-described T cell subsets, a distinct T helper cell population with an exhaustion gene expression profile. Unsupervised clustering of all non-malignant cells from 7 LN biopsies grouped non-malignant cells by cell subtype rather than by sample origin. In contrast, frequencies of each T cell subset were highly variable across LN biopsies. These results suggested that expression profiles and functional states of T cell subsets were comparable across multiple LN, while each lymphoma conditions its own LN microenvironment by the abundance of different infiltrating T cells.

Next, we characterized malignant B cells of individual DLBCL patients and identified distinct subclones with unique gene expression profiles. We took advantage of differentially expressed surface markers (such as CD48, CD32, CD62L) and successfully sorted viable tumor cell subclones by FACS. We could demonstrate that lymphoma subclones of the same LN exhibited a strikingly different drug response profile. To understand differential drug responses, we performed WGS of each
subclone separately. A detailed comparison of gene mutation and copy number profiles between subclones of the same LN will be presented.

**Conclusions:** Together, our results uncover the complex cellular and clonal substructure of malignant B cell lymphomas. For the first time, our research links scRNA expression profiles of aggressive lymphoma subclones with distinct drug response, gene mutation and copy number profiles.

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

## 040
THE NONCODING RNA GECPAR IS INVOLVED IN WNT SIGNALING AND HAS TUMOR-SUPPRESSOR ACTIVITY IN DIFFUSE LARGE B CELL LYMPHOMA

S. Napoli<fnref n="1" /> | L. Cascione<fnref n="1" /> | A. Rinaldi<fnref n="1" /> | G. Sartori<fnref n="1" /> |

M. Forcato² | S. Bicciato² | A. Chiappella<fnref n="3" /> |

P. Ghione<fnref n="4" /> | O. Elemento<fnref n="4" /> | G. Inghirami<fnref n="4" /> | F. Bertoni<fnref n="1" />

**Introduction:** Enhancers are cell-type specific regulatory DNA regions which play a key role in differentiation and development. Most active enhancers are transcribed in enhancer RNAs that can regulate transcription of relevant target genes by means of *in cis* but also *in trans* action. They stabilize contact between distal genomic regions and mediate interaction between DNA and master transcription factors. Here, we characterized an enhancer RNA that we called GECPAR (GERminal Center Proliferative Adapter RNA) in diffuse large B cell lymphoma (DLBCL).

**Methods:** GECPAR expression was characterized in 22 DLBCL cell lines and in a dataset of DLBCL clinical specimens and normal samples from different development stages of B cell. Direct genomic target sequences of GECPAR were determined by CHART-seq experiment and then validated at RNA level after GECPAR silencing in DLBCL cell lines. GECPAR associated signature was identified by gene set enrichment analysis and then confirmed by RNA expression correlation in RNA-seq performed on DLBCL patients. Antiproliferative activity of GECPAR was shown by proliferation assay after GECPAR silencing.

**Results:** Transcribed in the super-enhancer of POU2AF1, a key gene for the regulation of germinal center reaction, GECPAR is an enhancer RNA that we found typically expressed in normal centroblasts but less abundant in GCB-DLBCL and even lower in ABC-DLBCL. This molecule is able to regulate transcription of other genes by *in trans* activity as demonstrated performing CHART-seq experiments. In two DLBCL

cell lines, we identified a list of direct target genes of GECPAR, which we confirmed to be correlated to GECPAR expression also in a RNA-seq dataset of 32 DLBCL patients. Gene set enrichment analysis performed on GECPAR direct targets highlighted its function as transcriptional modulator of genes involved in proliferation and differentiation, including negative regulators of Wnt pathway. Accordingly to this observation, we showed that GECPAR silencing enhanced the proliferation rate of two DLBCL cell lines. Even if the exact mechanism of action of GECPAR is still to be fully elucidated, it appeared to exert its regulatory role through the antagonism with FOXJ2, a transcription factor that we showed to co-localize at the same DNA binding sites with GECPAR. GECPAR and FOXJ2 seem to counteract favoring transcription transactivation by LEF1, the main mediator of Wnt pathway activation. As final evidence of GECPAR role in Wnt pathway inhibition, in ABC-DLBCL cell lines (n=4) the response to treatment with the tankyrase inhibitor AZ6102 resulting in Wnt pathway blockade, correlated to GECPAR expression (p=0.03 R=0.97).

**Conclusions:** GECPAR is an enhancer RNA regulating proliferation in germinal center B cells and has a tumor suppressor activity in DLBCL.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); epigenetics; Wnt.

## SESSION 2 – DLBCL: CLINICAL DATA

### 041
INTEGRATION BETWEEN METABOLIC TUMOUR VOLUME AND METABOLIC HETEROGENEITY PREDICTS OUTCOME OF DLBCL LYMPHOMA PATIENTS IN THE SAKK 38/07 STUDY COHORT

L. Ceriani<fnref n="1" /> | M. Pirosa² | A. Stathis² | G. Gritti<fnref n="3" /> |

T. Ruberto<fnref n="1" /> | A. Bruno<fnref n="4" /> | A. Moccia² |

A. Rambaldi<fnref n="3" /> | S. Ferrari<fnref n="3" /> | L. Giovannella<fnref n="1" /> |

S. Hayoz⁵ | L. Mazzucchelli⁶ | S. Dirhofer⁷ |

C. Mamot⁸ | E. Zucca²

**Introduction:** Recent studies suggest that the metabolic tumor volume (MTV) assessed in baseline (18) F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) images may predict the prognosis of patients with DLBCL. The present study was aimed at assessing the ability of the baseline functional PET parameters

<footnote n="1">¹Institute of Oncology Research, Università della Svizzera Italiana, Bellinzona, Switzerland; ²Center for Genome Research, Dept. of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy;</footnote>

<footnote n="3">³Dipartimento di Oncologia ed Ematologia, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy; ⁴Weill Cornell Medicine, New York, United States</footnote>

<footnote n="1">¹Nuclear Medicine and PET-CT centre, Imaging Institute of Southern Switzerland, Bellinzona, Switzerland; ²Division of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;</footnote>

<footnote n="3">³Hematology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy;</footnote>

<footnote n="4">⁴Department of Nuclear Medicine, ASST Papa Giovanni XXIII, Bergamo, Italy; ⁵Coordinating Center, SAKK, Bern, Switzerland; ⁶Cantonal Institute of Pathology, Locarno, Switzerland; ⁷Institute of Medical Genetics and Pathology, University Hospital, Basel, Switzerland; ⁸Medical Oncology, Cantonal Hospital, Aarau, Switzerland</footnote>
<figure><img src="image_17.png" /></figure>

considered alone or in association in predicting the efficacy of conven-
tional immunochemotherapy treatment administered every 14 (R-
CHOP14) or 21 days (R-CHOP21) in two cohorts (testing and validation
sets) of DLBCL patients. Here, we report results of the testing set.

**Methods:** The testing set included 141 DLBCL patients treated with R-CHOP14 in the prospective SAKK38/07 study with available baseline PET/CT data. The lymphoma lesions were segmented by a fixed threshold algorithm, with a 2.5 SUVmax value as cut-off to estimate the metabolic tumor volume (MTV). Maximum standardized uptake value (SUVmax), and total lesion glycolysis (TLG) were estimated. MH was also measured using the area under the curve of cumulative SUV-volume histogram (AUC-CSH). The optimal MTV cut off values to discriminate subgroups with different progression free (PFS) and overall survival (OS) have been defined by ROC curves analysis. Cell of origin was determined by immunohistochemistry (Hans algorithm).

**Results:** After a median follow-up of 63 months, 30 progressions and 23 deaths were recorded. Among quantitative PET parameters baseline MTV was the most powerful predictor of outcome (Cox model p< 0.001 for PFS and OS). At 5 years, PFS was 83% for patients with low MTV vs. 59% for those with high MTV (log-rank test, p=0.0005). OS was 91% vs. 64%, respectively (log-rank test, p=0.0001). High MTV values predicted shorter PFS only in patients with non-germinal center B (GCB) subtype (n = 84) but not in patients with GCB subtype (n = 29) (log-rank test p = 0.006 vs. 0.7). In patients with high MTV, the presence of high MH increased the prognostic discrimination and the combined analysis of MTV and MH demonstrated that increased values of these two parameters might be used to identify patients with different risk of progression (Figure 1). Patients with both high MTV and high MH had a 5-years PFS of 42%, while those with both low MTV and low MH had a 5-year PFS of 83% (log-rank p< 0.0001).

**Conclusions:** Baseline MTV is a powerful predictor of clinical outcomes in patients with DLBCL treated with R-CHOP. High MTV values predict a worse response to treatment especially in patients with non-GCB subtype. A prognostic model based on the combination of MTV and MH may allow the early identification of patients at high risk of disease progression following conventional treatment. The validation of these results in an independent retrospective cohort of patients treated with R-CHOP21 is ongoing and full data will be presented.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); positron emission tomography (PET); R-CHOP.

042

SMART START: RITUXIMAB,
LENALIDOMIDE, AND IBRUTINIB ALONE
PRIOR TO COMBINATION WITH
CHEMOTHERAPY FOR PATIENTS WITH
NEWLY DIAGNOSED DIFFUSE LARGE
B-CELL LYMPHOMA

J.R. Westin

<figure><img src="image_18.png" /></figure>

L. Nastoupil

<figure><img src="image_19.png" /></figure>

F. Hagemeister

L. Fayad

K. Young

T. McDonnell

H. Chuang

S. Ahmed

R. Nair

R. Steiner

H. Lee

M. Rodriguez

S. Parmar

M. Green

S. Neelapu

R. Davis

Lymphoma & Myeloma, MD Anderson Cancer Center, Houston,
United States

**Background:** The non-germinal center (non-GCB) subtype of Diffuse Large B-cell Lymphoma (DLBCL) is associated with inferior outcomes with standard therapies. The BTK inhibitor ibrutinib (I) and
immunomodulatory agent lenalidomide (L) have promising activity in non-GCB DLBCL as single agents, and result in synthetic lethality in non-GCB DLBCL models when combined. In relapsed non-GCB DLBCL, rituximab (R), L and I result in overall response rate (ORR) of 55% (Ramchandren, ASH 2018). We conducted an investigator initiated, single-arm, open-label, phase 2 study (NCT02636322) of RLI alone and then with chemotherapy in newly diagnosed non-GCB DLBCL patients, and report the final results of the RLI lead in.

**Methods:** Adult patients with newly diagnosed non-GCB DLBCL, determined by the Hans method, with adequate organ function and performance status were eligible. The primary objectives were to determine (1A) the ORR of two cycles of RLI as initial therapy, and (1B) the complete response rate (CRR) after 6 cycles of chemotherapy combined with RLI. All patients were treated with rituximab 375 mg/m2 IV day 1, ibrutinib 560 mg po daily, and lenalidomide 25 mg po days 1-10 of 21 day cycles for 2 cycles, followed by 6 additional cycles of RLI with chemotherapy (CHOP or EPOCH per treating MD choice). Responses were assessed with PET/CT as per the Lugano criteria. Growth factors, venous thromboembolism prophylaxis, and pneumocystis pneumonia prophylaxis were required for all patients.

**Results:** The protocol accrued 60 patients from May 2016 – February 2019, with 52 patients evaluable for disease response (2 withdrew consent prior to restaging, 6 pending restaging prior to abstract deadline). The median age was 64 years (range: 30-83), 28% were >= 70 years, and 50% were female. Half the patients had poor risk IPI, 61% had advanced stage, and 71% had a Ki-67 of >= 80%. One patient had a fatal fungal infection (CNS aspergillosis) attributed to high dose corticosteroids for symptom control during screening and with RLI, leading to prohibition of corticosteroids during the RLI only cycles with no further fungal infections identified. The ORR for 2 cycles of RLI alone was 84.6% (n = 44), and the CRR was 38.5% (n = 20). One patient refused to proceed with the pre-planned chemotherapy after achieving a CR with 2 cycles of RLI, and remains relapse free with no additional therapy 18 months later. Preliminary results demonstrate a CRR of 100% for the full therapy (RLI for 2 cycles, RLI-chemo for 6 cycles), with updates to be presented at the meeting.

**Conclusions:** The Smart Start trial demonstrates the chemotherapy-free combination of rituximab 375 mg/m2, ibrutinib 560 mg, and lenalidomide 25 mg is highly effective in patients with newly diagnosed non-GCB DLBCL. Further studies are planned with other novel agents and with fewer cycles of chemotherapy consolidation for patients achieving a CR with RLI alone.

**Keywords:** activated B-cell-like (ABC); BTK inhibitors; IMiDs.

**Disclosures:** Westin, J: Consultant Advisory Role: Celgene, Janssen, Novartis, Kite, Juno, Genentech.

043
RITUXIMAB MAINTENANCE FOR PATIENTS
WITH DIFFUSE LARGE B-CELL LYMPHOMA
IN FIRST COMPLETE REMISSION: RESULTS
FROM A RANDOMIZED HOVON-NORDIC
LYMPHOMA GROUP PHASE III STUDY

P. Lugtenburg¹ | P. de Nully Brown² | B. van der Holt³ |

F. d'Amore⁴ | H. Koene⁵ | E. de Jongh⁶ |

R. Fijnheer⁷ | O. Loosveld⁸ | L. Böhmer⁹ |

H. Pruijt¹⁰ | G. Verhoef¹¹ | M. Hoogendoorn¹² |

Y. Bilgin¹³ | M. Nijland¹⁴ | K. Lam¹⁵ |

B. de Keizer¹⁶ | D. de Jong¹⁷ | J. Zijlstra¹⁸

¹Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands;

²Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; ³Hematology, HOVON Data Center, Erasmus MC Cancer Institute, Rotterdam, Netherlands; ⁴Hematology, Aarhus University Hospital, Aarhus, Denmark; ⁵Internal Medicine, St. Antonius Hospital, Nieuwegein, Netherlands; ⁶Internal Medicine, Albert Schweitzer Hospital, Dordrecht, Netherlands; ⁷Hematology, Meander MC, Amersfoort, Netherlands; ⁸Hematology, Amphia Hospital, Breda, Netherlands; ⁹Hematology, Haga Teaching Hospital, The Hague, Netherlands; ¹⁰Internal Medicine, Jeroen Bosch Hospital's-Hertogenbosch, Netherlands; ¹¹Hematology, University Hospitals Leuven, Leuven, Belgium; ¹²Internal Medicine, Medical Center Leeuwarden, Leeuwarden, Netherlands; ¹³Internal Medicine, Admiraal de Ruyter Hospital, Goes, Netherlands; ¹⁴Hematology, University Medical Center Groningen, Groningen, Netherlands; ¹⁵Pathology, HOVON Pathology Facility and Biobank, Erasmus MC, Rotterdam, Netherlands; ¹⁶Nuclear Medicine, UMC Utrecht, Utrecht, Netherlands; ¹⁷Pathology, HOVON Pathology Facility and Biobank, Amsterdam UMC, Location VUmc, Amsterdam, Netherlands; ¹⁸Hematology, Amsterdam UMC, Vrije Universiteit Cancer Center, Amsterdam, Netherlands

**Introduction:** This randomized phase III trial assessed whether intensification of rituximab (R) during the first 4 cycles of R-CHOP can improve outcome of diffuse large B-cell lymphoma (DLBCL) patients compared with standard R-CHOP. Patients in complete remission (CR) after induction treatment were randomized between rituximab maintenance and observation. Intensification of rituximab was not more effective than standard R-CHOP, showing same CR-rates and progression free survival after induction (ASCO 2016 # 7504). Here, we report the results of the second randomization for rituximab maintenance therapy.

**Methods:** Patients in CR after R-CHOP were randomized between 24 months of rituximab maintenance 375 mg/m² intravenous every 8 weeks (n = 199) or observation (n = 199). CT scans were performed at 6, 12, 18 and 24 months in both arms. The primary endpoint was disease free survival (DFS) from maintenance randomization. Secondary endpoints were overall survival (OS) and adverse events (AEs). (www.trialregister.nl NTR1014)

**Results:** Median age was 65 years (range 31-80), 48% were 66 years or older and 49% were male. The majority of patients (54%) had a high-intermediate or high aa-IPI score. After a median follow-up of 79.9 months (maximum 125.7 months), the 5-year DFS rate was 79% for rituximab maintenance versus 74% for observation. This difference was not statistically significant, with a hazard ratio of 0.83 (95% confidence interval 0.57-1.19, p=0.31, adjusted for age and aa-IPI).
The secondary endpoint OS was also not significantly different (85% versus 83% at 5 years). No clinical subgroup benefited from rituximab maintenance. Toxicity was mild. Among patients who received rituximab maintenance CTCAE grade 3 and 4 AEs were reported in 17% and 6% of patients, respectively. Infection was the most frequent AE, a grade 3 infection occurred in 6% of patients. Neutropenia was seen in 1% (grade 3) and 3% (grade 4) of patients.

**Conclusions:** Rituximab maintenance therapy provides no additional benefit for DLBCL patients in first CR after R-CHOP.

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

**Disclosures:** Lugtenburg, P: Consultant Advisory Role: Roche, Takeda, Servier, Bristol-Myers Squibb, Celgene, Sandoz, Genmab; Research Funding: Roche, Servier, Takeda. de Nully Brown, P: Consultant Advisory Role: Celgene. d'Amore, F: Consultant Advisory Role: Takeda, Servier, Kyowa Hakko Kirin, Nordic Nanovector; Research Funding: Amgen, Roche, Takeda, Sanofi. Böhmer, L: Research Funding: Celgene.

Hoogendoorn, M: Consultant Advisory Role: Novartis. Nijland, M: Other Remuneration: Roche, Abbvie. de Jong, D: Honoraria: Celgene, Takeda, Bristol-Myers Squibb; Research Funding: Genmab.

044

IMPAIRED IMMUNE HEALTH IN
SURVIVORS OF DIFFUSE LARGE B-CELL

LYMPHOMA (DLBCL): A LARGE
POPULATION-BASED STUDY

T. Shree¹ | Q. Li² | A.M. Brunson² | S. Glaser³ |
H.T. Maecker⁴ | R. Haile⁵ | R. Levy¹ | T.H. Keegan²

¹Department of Medicine, Division of Oncology, Stanford University, Stanford, United States; ²School of Medicine, University of California Davis, Sacramento, United States; ³CPIC, Cancer Prevention Institute of California, Fremont, United States; ⁴Microbiology & Immunology, Stanford University, Stanford, United States; ⁵Population Health Sciences, Cedars-Sinai, Los Angeles, United States

**Introduction:** Improved outcomes in Diffuse Large B-cell Lymphoma (DLBCL) have led to a growing number of survivors. Treatments for DLBCL and the disease itself affect the immune system, yet little is known about the immune health of survivors. We investigated whether DLBCL survivors have altered risk of developing autoimmune or infectious conditions during survivorship.

**Methods:** This retrospective cohort study compared 21,690 DLBCL survivors to survivor cohorts of breast, prostate, head and neck cancer, and melanoma in the California Cancer Registry (CCR). We linked records from the CCR to a statewide database recording diagnoses from inpatient and certain outpatient encounters to investigate the incidence of 43 pre-specified autoimmune conditions, immune

<figure><img src="image_20.png" /></figure>

**Figure 1.** Incidence rate ratios for 18 categories of immune-related conditions (autoimmune diseases, immune deficiencies, and infectious diseases) for Diffuse Large B-cell Lymphoma (DLBCL) survivors compared to survivors of either breast, prostate, head and neck cancer, or melanoma. Only results reaching significance (confidence intervals not crossing 1) are shown. Color scale is logarithmic (log10) with green shading for categories of diagnoses found more commonly in DLBCL survivors and pink and red shading for categories of diagnoses found more commonly in the comparator cohort. “vs.”, versus. CNS, central nervous system. AID, autoimmune disease.
deficiencies and infections, occurring between 1-10 years after cancer diagnosis. If an observed condition had also been recorded prior to or within 1 year of cancer diagnosis, it was excluded. We used multivariable Poisson regression models adjusted for age, sex, race/ethnicity and year of diagnosis, to estimate incidence rate ratios (IRRs) for each condition comparing DLBCL survivors to each of the other cohorts. We also estimated the cumulative incidence of selected conditions over 10 years, accounting for death as a competing risk. We performed sensitivity analyses excluding patients with stem cell transplant (SCT), limiting comparison to a cohort that had uniformly received systemic chemotherapy, and restricting the analysis to a later survivorship period (years 5-10). Finally, we expanded the analysis to encompass 595 diagnosis codes for infections, autoimmune disease and immunodeficiencies, grouped into 18 clinical categories.

**Results:** Survivor cohorts were similar with regard to frequency of healthcare encounters and median follow-up time [5.7-8.3 years]. DLBCL survivors had a significantly higher incidence of many immune-related conditions, including humoral deficiency [IRRs 13.5-18.3], autoimmune anemia [IRRs 7.4-13.4], and Sicca syndrome [IRRs 2.8-8.6]), which have been associated with DLBCL previously but here were observed with new onset during survivorship. DLBCL survivors also had elevated rates of infections, notably fungal pneumonias [IRRs 3.9-11.3], viral pneumonias [IRRs 3.9-6.6], and meningitis [IRRs 3.0-5.0]. Sensitivity analyses produced similar results. Finally, a broader assessment of infections, autoimmune diseases and immunodeficiencies grouped by clinical category found widely increased risk among DLBCL survivors (Figure 1).

**Conclusion:** These findings, from a large, population-based cohort, show that immune-related conditions in DLBCL survivors are wide-ranging, and increased risk for these conditions is long-lasting. These data highlight a need to understand the mechanisms of immune dysfunction and to define predictors of clinical risk among DLBCL survivors.

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

## SESSION 3 - CLL

### 045
INTERNATIONAL PROGNOSTIC SCORE FOR EARLY STAGE CHRONIC LYMPHOCYTIC LEUKEMIA (IPS-A)

A. Condoluci¹ | L. Terzi di Bergamo² | P. Langerbeins³ |
M. Hoechstetter³ | C. Herling³ | L. De Paoli⁴ |
J. Delgado⁵ | M. Gentile⁶ | M. Doubek⁷ |
F.R. Mauro⁸ | G. Chiodin⁹ | M. Mattsson¹⁰ |
J. Bahlo³ | G. Cutrona¹¹ | J. Kotaskova⁷ |
C. Deambrogi⁴ | R. Moia⁴ | B. Gerber¹² |
E. Zucca¹² | M. Ghielmini¹² | F. Cavalli¹² |
G. Stüssi¹² | A. Neri¹³ | M. Ferrarini¹⁴ |

R. Rosenquist¹⁰ | F. Forconi⁹ | R. Foà⁸ |
S. Pospisilova⁷ | F. Morabito¹⁵ | W.G. Wierda¹⁶ |
E. Montserrat⁵ | G. Gaidano⁴ | M. Hallek³ | D. Rossi¹

¹Experimental Hematology, Institute of Oncology Research; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; ²Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland; ³University of Cologne, Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, Köln, Germany; ⁴Translational Medicine, University of Eastern Piedmont, Novara, Italy; ⁵Hematology, Hospital Clínic de Barcelona, Barcelona, Spain; ⁶Hematology, Azienda Ospedaliera (AO) of Cosenza, Cosenza, Italy; ⁷Hematology and Oncology, University Hospital of Brno, Brno, Czech Republic; ⁸Hematology, Sapienza University, Rome, Italy; ⁹Hematology, Southampton University, Southampton, United Kingdom; ¹⁰Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; ¹¹Hematology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; ¹²Onco-hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; ¹³Hematology, University of Milan, Milan, Italy; ¹⁴Hematology, University of Genoa, Genoa, Italy; ¹⁵Hematology, Augusta Victoria Hospital, Jerusalem, Israel; ¹⁶MD Anderson Cancer Center, University of Texas, Houston, United States

**Introduction:** Most patients with chronic lymphocytic leukemia (CLL) are diagnosed in early, Binet stage A disease. Although as a whole stage A patients have good prognosis, the individual outcome is heterogeneous and can be estimated only after a period of observation. Upfront definition of the risk of treatment can be used to plan a risk-tailored active surveillance, counsel patients about their likely outcome, and design clinical trials. We aimed at developing an IPS-A for time-to-first-treatment (TTFT) prognostication in stage A CLL patients.

**Methods:** We performed an analysis using individual patient data from 10 Binet A CLL cohorts initially managed with observation, for a total of 4106 patients. The adjusted association between variables and TTFT was estimated by Cox regression. Backward elimination was used to derive the final model, and variables resulting non-significant in more than half of the validation cohorts were excluded from the model. We assigned a weighted risk score to each factor of the final model based on the regression parameters. The prognostic score was then defined as the sum of single-risk parameters. We identified different risk groups based on recursive partitioning. Discrimination capacity of the model was assessed through c-index.

**Results:** By multivariate analysis in the stage A training cohort (University of Eastern Piedmont cohort, n=358) 3 out of 19 variables independently associated with TTFT, namely: lymphocyte count >15 G/L (HR=2.6), palpable lymph nodes (HR=2.7), and unmutated IGHV genes (HR=3.1). Using weighted grading, a score of 1 was assigned to each variable. By recursive partitioning, patients were segregated into three risk categories according: low- (score 0), intermediate- (score 1), and high-risk (score 2-3) with significantly different probability of need of therapy (c-index 0.74). The trained IPS-A was consistently
<figure><img src="image_21.png" /><figcaption>Fig.1</figcaption></figure>

validated and the 3 risk groups were reproduced in 9 stage A series, including clinical trials (CLL1, n=547, c-index 0.71; CLL7, n=339, c-index 0.73; O-CLL1, n=312, c-index 0.67), institutional (MDACC, n=1225, c-index 0.66; Barcelona, n=355, c-index 0.75; Brno, n=269, c-index 0.69; Sapienza University, n=250, c-index 0.70; Southampton, n=227, c-index 0.75), and population based-series (SCAN, n=224, c-index 0.70). By compiling the training and validation series to narrow the confidence interval of the estimates, among low risk patients median TTFT was not reached and at 10 years 77% of patients were treatment free. Among intermediate-risk patients, median TTFT was 10.69 years (95% CI 9.31-13.60). Among high-risk patients, median TTFT was 3.89 years (95% CI 3.56-4.30) (Fig. 1).

**Conclusions:** Among stage A CLL initially managed with active surveillance, the IPS-A allows to inform upfront patients, physicians and researchers about the likelihood of disease progression.

**Keywords:** chronic lymphocytic leukemia (CLL); prognostic indices.

**Disclosures:** Langerbeins, P: Honoraria: AbbVie and Janssen Cilag; Research Funding: Janssen-Cilag.

046
FIXED-DURATION VENETOCLAX PLUS
OBINUTUZUMAB IMPROVES PFS AND
MINIMAL RESIDUAL DISEASE NEGATIVITY
IN PATIENTS WITH PREVIOUSLY
UNTREATED CLL AND COMORBIDITIES

K. Fischer¹ | M. Porro Lurà² | O. Al-Sawaf¹ |
J. Bahlo¹ | A. Fink¹ | M. Tandon³ | M. Dixon⁴ |
S. Robrecht¹ | S. Warburton⁵ | K. Humphrey³ |

O. Samoylova⁶ | A.M. Liberati⁷ | J. Pinilla-Ibarz⁸ |
S. Opat⁹ | L. Sivcheva¹⁰ | K. Le Dû¹¹ |
L.M. Fogliatto¹² | C. Utoft Niemann¹³ |
R. Weinkove¹⁴ | S. Robinson¹⁵ | T.J. Kipps¹⁶ |
S. Boettcher¹⁷ | E. Tausch¹⁸ | W.L. Schary¹⁹ |
B. Eichhorst¹ | C. Wendtner²⁰ | A.W. Langerak²¹ |
K. Kreuzer¹ | V. Goede²² | S. Stilgenbauer²³ |
M. Mobasher²⁴ | M. Ritgen²⁵ | M. Hallek²⁶

¹Department I of Internal Medicine and Center of Integrated Oncology
Cologne Bonn, University Hospital, Cologne, Germany; ²Pharmaceuticals
Division, PDGo, F. Hoffmann-La Roche Ltd, Basel, Switzerland; ³Clinical
Development Oncology, Roche Products Limited, Welwyn Garden City,
United Kingdom; ⁴Biostatistics, Roche Products Limited, Welwyn Garden
City, United Kingdom; ⁵Product Development - Oncology, Roche
Products Limited, Welwyn Garden City, United Kingdom; ⁶Hematology
Department, Regional Clinical Hospital N.A. Semashko, Nizhny Novgorod,
Russian Federation; ⁷Division of Onco-Hematology, Santa Maria Terni

<table><caption>TABLE 1 MRD levels in PB by NGS 3 months after treatment completion</caption><thead><tr><th>All pts (ITT) N</th><th>ClbG 216</th><th>VenG 216</th></tr><tr><th>MRD level, n (%)</th><th></th><th></th></tr></thead><tbody><tr><td>&lt;10<sup>-6</sup></td><td>9 (4.2)</td><td>67 (31.0)</td></tr><tr><td>≥10<sup>-6</sup> and &lt;10<sup>-5</sup></td><td>33 (15.3)</td><td>75 (34.7)</td></tr><tr><td>≥10<sup>-5</sup> and &lt;10<sup>-4</sup></td><td>32 (14.8)</td><td>26 (12.0)</td></tr><tr><td>≥10<sup>-4</sup> and &lt;10<sup>-2</sup></td><td>50 (23.1)</td><td>13 (6.0)</td></tr><tr><td>≥10<sup>-2</sup></td><td>62 (28.7)</td><td>10 (4.6)</td></tr><tr><td>No sample/not evaluable</td><td>30 (13.9)</td><td>25 (11.6)</td></tr></tbody></table>
<figure><img src="image_22.png" /><figcaption>**Figure 1b: Duration of MRD negativity after treatment completion**</figcaption></figure>

<figure><img src="image_23.png" /></figure>

Hospital, University of Perugia, Perugia, Italy; ⁸Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States; ⁹Haematology Department, School of Clinical Sciences at Monash Health, Monash University, Victoria, Australia; ¹⁰First Internal Department, MHAT Hristo Botev, AD, Vratsa, Bulgaria; ¹¹Hematology Department, Clinique Victor Hugo, Le Mans, France; ¹²Department of Hematology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; ¹³Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; ¹⁴Wellington Blood & Cancer Centre, Capital & Coast District Health Board, Wellington, New Zealand and Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand; ¹⁵Department of Medicine, Division of Hematology, QEII Health Sciences Center, Halifax, NS, Canada; ¹⁶Moores Cancer Center, UC San Diego Health, San Diego, CA, United States; ¹⁷Department III of Internal Medicine, University Hospital Rostock, Rostock, Germany; ¹⁸Department III of Internal Medicine, Ulm University, Ulm, Germany; ¹⁹Clinical Development Oncology, AbbVie Inc., North Chicago, IL, United States; ²⁰Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Klinikum Schwabing, Munich, Germany; ²¹Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, Netherlands; ²²Oncogeriatric Unit, Dept. of Geriatric Medicine, St. Marien Hospital, Cologne, Germany; ²³Department III of Internal Medicine, Ulm University, Ulm, Germany and Department for

Hematology, Oncology and Rheumatology, Saarland University Medical School, Homburg/Saar, Germany; ²⁴Product Development Oncology, Genentech, Inc., South San Francisco, CA, United States; ²⁵Department II of Internal Medicine, Campus Kiel, University of Schleswig-Holstein, Kiel, Germany; ²⁶Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne, CECAD (Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases), University of Cologne, Cologne, Germany

**Introduction:** The multinational, open-label, phase 3 CLL14 trial (NCT02242942) compared fixed-duration targeted venetoclax plus obinutuzumab (VenG) treatment with chlorambucil-obinutuzumab (ClbG) treatment in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. We present endpoint analyses with particular emphasis on progression-free survival (PFS) and minimal residual disease (MRD)-negativity.

**Methods:** Pts with a CIRS score >6 and/or an estimated creatinine clearance <70 mL/min were randomized 1:1 to receive equal duration treatment with 12 cycles of standard Clb or Ven 400 mg daily in combination with G for the first 6 cycles. The primary endpoint was PFS. MRD-negativity in peripheral blood (PB) or bone marrow (BM) 3 months after treatment completion was a key secondary endpoint. MRD was analyzed serially from Cycle 4 every 3 months by an allele-specific oligonucleotide polymerase chain reaction assay (ASO-
PCR; cut-off, $10^{-4}$) and by next generation sequencing (NGS; cut-offs, $10^{-4}$, $10^{-5}$, $10^{-6}$).

**Results:** 432 pts were enrolled (216 in each treatment group; intent-to-treat population). Median age, total CIRS score, and CrCl at baseline were 72 years, 8, and 66.4 mL/min respectively. After 29 months' median follow-up, superior PFS was observed with VenG vs ClbG (Figure 1a). Median PFS was not reached in either group: at Month 24, PFS rates were 88% with VenG and 64% with ClbG (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.23-0.53; P<0.0001). MRD-negativity by ASO-PCR was significantly higher with VenG vs ClbG in both PB (76% vs 35% [P<0.0001]) and BM (57% vs 17% [P<0.0001]) 3 months after treatment completion. Overall, 75% of VenG MRD-negative pts in PB were also MRD-negative in BM vs 49% in the ClbG group. Landmark analysis for this timepoint by PB MRD status showed that MRD-negativity was associated with longer PFS. MRD-negativity rates were more sustainable with VenG: 81% (VenG) vs 27% (ClbG) of pts were MRD-negative 12 months after treatment completion (Figure 1b). MRD-negativity rates by NGS confirmed these results; 78% (VenG) vs 34% (ClbG) of pts had MRD-negative status at $<10^{-4}$, 35% vs 15% at $≥10^{-6}-<10^{-5}$ and 31% vs 4% at $<10^{-6}$, respectively.

**Conclusions:** Fixed-duration VenG induced deep, high ($<10^{-4}$ in 3/4 of pts and $<10^{-6}$ in 1/3 of pts), and long lasting MRD-negativity rates (with a low rate of conversion to MRD-positive status 1 year after treatment) in previously untreated pts with CLL and comorbidities, translating into improved PFS.

**Funding:** This study was funded by F. Hoffmann-La Roche Ltd and Abbvie Inc. Third-party editing and administrative support was provided by Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

This abstract has been previously submitted in part to ASCO 2019 and EHA 2019.

**Keywords:** chronic lymphocytic leukemia (CLL); obinutuzumab; venetoclax.

**Disclosures:** Fischer, K: Other Remuneration: Expenses: Roche. Porro Lurà, M: Employment Leadership Position: Roche; Stock Ownership: Roche. Al-Sawaf, O: Other Remuneration: Other relationship: AbbVie, Roche, Gilead, Janssen. Bahlo, J: Honoraria: Roche; Other Remuneration: Expenses: Roche. Fink, A: Consultant Advisory Role: Janssen. Tandon, M: Employment Leadership Position: Roche. Dixon, M: Employment Leadership Position: Roche; Stock Ownership: Roche. Warburton, S: Employment Leadership Position: Roche. Humphrey, K: Employment Leadership Position: Roche; Stock Ownership: Roche. Liberati, A: Other Remuneration: Personal Fees: Abbvie. Pinilla-Ibarz, J: Consultant Advisory Role: Janssen, Gilead, Abbvie, Pharmacyclics, Millenium Pharmaceuticals/Takeda, TEVA, TG Therapeutics; Research Funding: TG Therapeutics; Other Remuneration: Speakers' Bureau: Janssen, Gilead, Abbvie, Pharmacyclics, Millenium Pharmaceuticals/Takeda, TEVA, Bayer. Opat, S: Consultant Advisory Role: Roche, Abbvie; Honoraria: Roche, Abbvie; Research Funding: Roche; Other Remuneration: Speakers' Bureau: Roche. Utoft Niemann, C: Consultant Advisory Role: Abbvie, Janssen, Gilead, AstraZeneca, Sunesis, Acerta, CSL Behring, Roche; Research Funding: Abbvie, Janssen; Other Remuneration: Expenses: Novartis, Gilead, Roche;

Other relationship: Roche - Payment for trial enrollment/patient management of the trial, indirectly through GCLLSG. Weinkove, R: Consultant Advisory Role: Abbvie; Honoraria: Abbvie; Other Remuneration: Other relationship: Capital & Coast District Health Board - Institution received reimbursement of the costs of conducting trial-related clinical procedures. Robinson, S: Consultant Advisory Role: Roche, AbbVie. Kipps, T: Employment Leadership Position: UC, San Diego Health, Moores Cancer Center; Consultant Advisory Role: AbbVie, Genentech-Roche, Gilead, Pharmacyclics, Celgene; Honoraria: Gilead, AbbVie, Pharmacyclics, Janssen, Verastem; Research Funding: AbbVie, Genentech-Roche, Pharmacyclics, Oncernal; Other Remuneration: Membership on an entity's board of directors, speaker's bureau, or its advisory committees: AbbVie, Pharmacyclics, Janssen, Verastem. Boettcher, S: Honoraria: Roche, AbbVie, Janssen; Research Funding: Celgene, Roche, AbbVie, Janssen; Other Remuneration: Personal Fees: Janssen, Abbvie. Tausch, E: Consultant Advisory Role: Roche; Other Remuneration: Speakers' Bureau: Roche; Expert testimony: Abbvie; Expenses: Abbvie. Schary, W: Employment Leadership Position: AbbVie; Stock Ownership: AbbVie. Eichhorst, B: Consultant Advisory Role: Abbvie, Roche; Honoraria: Abbvie, Roche; Research Funding: Abbvie, Roche; Other Remuneration: Speakers' Bureau and expenses: Abbvie, Roche. Wendtner, C: Honoraria: F. Hoffmann La-Roche Ltd, Abbvie, Janssen-Cilag, Gilead, MorphoSys, Mundipharma, Novartis; Research Funding: F. Hoffmann La-Roche Ltd, Abbvie, Janssen-Cilag, Gilead, MorphoSys, Mundipharma, Novartis. Langerak, A: Consultant Advisory Role: AbbVie; Research Funding: Roche-Genentech, Gilead. Kreuzer, K: Consultant Advisory Role: Roche, Abbvie; Other Remuneration: Expert Testimony: Roche, Abbvie. Goede, V: Consultant Advisory Role: Roche, Janssen, Gilead, AbbVie; Other Remuneration: Speakers' Bureau: Roche, Janssen, Gilead. Stilgenbauer, S: Research Funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Other Remuneration: Personal Fees: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis. Mobasher, M: Employment Leadership Position: Genentech/F. Hoffmann-La Roche Ltd, Corvus; Stock Ownership: Genentech/F. Hoffmann-La Roche Ltd, Corvus; Other Remuneration: Expenses: Genentech/F. Hoffmann-La Roche Ltd, Corvus. Ritgen, M: Consultant Advisory Role: Roche, Abbvie; Research Funding: Roche, Abbvie; Other Remuneration: Personal Fees - Roche. Hallek, M: Consultant Advisory Role: Roche, Abbvie; Honoraria: Roche, Abbvie, Gilead, Janssen, Celgene, Boehringer Ingelheim; Research Funding: Roche, Abbvie; Other Remuneration: Speakers' Bureau: Roche, Abbvie.
E. Tausch<fnref n="1" /> | J. Bahlo<fnref n="2" /> | S. Robrecht<fnref n="2" /> |
C. Schneider<fnref n="1" /> | J. Bloehdorn<fnref n="1" /> | S. Schrell<fnref n="1" /> |
C. Galler<fnref n="1" /> | O. Al-Sawaf<fnref n="2" /> | A. Fink<fnref n="2" /> | B. Eichhorst<fnref n="2" /> |
K. Kreuzer<fnref n="2" /> | M. Tandon³ | K. Humphrey³ |
Y. Jiang<fnref n="4" /> | W. Schary⁵ | M. Porro Lurà<fnref n="6" /> |
H. Döhner<fnref n="1" /> | K. Fischer<fnref n="2" /> | M. Hallek<fnref n="2" /> | S. Stilgenbauer<fnref n="1" />

**Introduction:** Genomic aberrations, IGHV mutation status and muta-
tions in genes such as TP53 are established prognostic factors in CLL
in the context of chemoimmunotherapy. Their role is less-well
established when using chemo-free regimens such as obinutuzumab
(GA-101) plus venetoclax (Ven-G).

**Methods:** We assessed the incidence and impact of genomic aberrations via FISH, mutations in 13 genes via NGS and IGHV status in the phase 3 CLL14 trial comparing G-Clb vs. Ven-G in patients with CIRS>6 or creatinine clearance < 70 ml/min. Of the intention to treat population (n=432) FISH/IGHV/NGS was assessable in 418/408/421 cases.

**Results:** The incidence of genomic aberrations considering the hierar-
chical model were del(17p) 7%, del(11q) 18%, +(12q) 18% and del
(13q) 35%. IGHV was unmutated in 61% of patients. The incidence of
gene mutations was NOTCH1 23%, SF3B1 16%, ATM 13%, TP53 10%,
XPO1 6%, RPS15 5%, POT1 5%, BRAF 4%, BIRC3 4%, NFKBIE 4%,
EGR2 4%, MYD88 2% and FBXW7 1%. High coincidence was found
for del(17p) and TP53mut. Overall response rate (ORR) to G-Clb was

lower with del(17p), del(11q) TP53<sup>mut</sup>, ATM<sup>mut</sup> and BIRC3<sup>mut</sup>. None of
the parameters impaired ORR to Ven-G.

At a median follow-up of 29 months, there were 107 events for PFS and 37 for OS in the intention to treat population. Del(17p) was the only genomic abnormality with impact on PFS in G-Clb (HR 4.6, p<0.001) and Ven-G (HR 4.4, p=0.001; Fig 1a). Similarly, TP53 mutations affected PFS in both treatment arms (G-Clb HR 2.7, p=0.001; Ven-G HR 3.1, p=0.01). None of the other evaluated factors affected Ven-G efficacy, while for G-Clb del(11q) (HR 2.3, p=0.002), BIRC3 (HR 4.0, p=0.001), NOTCH1 (HR 1.8, p=0.03) and IGHV<sup>unmut</sup> (HR 3.4, p<0.001) were adverse factors.

Ven-G was superior to G-Clb regarding PFS in most genetic sub-
groups including del(17p), del(11q), TP53<sup>mut</sup>, NOTCH1<sup>mut</sup>, SF3B1<sup>mut</sup>
and ATM<sup>mut</sup>. Regarding IGHV, only patients with unmutated status
had a significant PFS benefit from Ven-G in comparison to G-Clb
(IGHV<sup>unmut</sup> HR 0.2, p<0.001; IGHV<sup>mut</sup> HR 0.6, p=0.29; Fig 1b). Multi-
variable testing for interaction between treatment and IGHV status
was significant (p=0.03) indicating IGHV<sup>unmut</sup> as a predictive factor for
increased benefit from Ven-G. OS was lower with del(17p) in both
treatment arms (G-Clb: HR 11.0, p<0.001; Ven-G: HR 3.4, p=0.03)
and with TP53<sup>mut</sup>, BRAF<sup>mut</sup> and IGHV<sup>unmut</sup> in the G-Clb arm (HR 5.5,
p=0.002; HR 6.6, p<0.01; HR 5.4, p=0.03), while none of the other
factors were significantly associated with OS.

**Conclusion:** Prognostic value of genomic aberrations, IGHV and gene mutations were confirmed for G-Clb, while with Ven-G only del(17p) and TP53<sup>mut</sup> were associated with short PFS and only del(17p) with short OS. IGHV<sup>unmut</sup> was identified as a predictive factor identifying a group of patients with particular benefit from Ven-G.

**Keywords:** chronic lymphocytic leukemia (CLL); prognostic indices; venetoclax.

**Disclosures:** Tausch, E: Consultant Advisory Role: Roche, Abbvie; Other Remuneration: Roche, Abbvie. Bahlo, J: Honoraria: Roche. Eichhorst, B: Consultant Advisory Role: Roche, Abbvie, Janssen, Gilead, Novartis,

<figure><img src="image_24.png" /></figure>

<figure><img src="image_25.png" /></figure>

<footnote n="1">¹Department of Internal Medicine 3, Ulm University, Ulm, Germany;</footnote>

<footnote n="2">²Department I of Internal Medicine and Center of Integrated Oncology
Cologne Bonn, University Hospital Cologne, Cologne, Germany; ³Clinical
Development Oncology, Roche, Welwyn Garden City, United Kingdom;</footnote>

<footnote n="4">⁴Oncology Biomarker Development, Genentech, South San Francisco,
United States; ⁵Oncology, Abbvie Inc, North Chicago, United States;</footnote>

<footnote n="6">⁶Pharmaceuticals Division, F. Hoffmann - La Roche Ltd, Basel,
Switzerland</footnote>
Celgene; Research Funding: Roche, Abbvie, Janssen, Gilead; Other Remuneration: Speakers' Bureau: Roche, Abbvie, Janssen, Gilead, Novartis, Celgene. Kreuzer, K: Consultant Advisory Role: Abbvie, Alexion, Amgen, Ariad, Baxalta, Bayer, Biotest, Bristol-Myers Squibb, Celgene, Daiichi, Chugai, Gilead, Grifols, Hexal, Janssen-Cilag, Jazz, Novartis, Otsuka, Pfizer, Roche; Honoraria: Abbvie, Alexion, Amgen, Ariad, Baxalta, Bayer, Biotest, Bristol-Myers Squibb, Celgene, Daiichi, Chugai, Gilead, Grifols, Hexal, Janssen-Cilag, Jazz, Novartis, Otsuka, Pfizer, Roche; Research Funding: Abbvie, Alexion, Amgen, Ariad, Baxalta, Bayer, Biotest, Bristol-Myers Squibb, Celgene, Daiichi, Chugai, Gilead, Grifols, Hexal, Janssen-Cilag, Jazz, Novartis, Otsuka, Pfizer, Roche. Tandon, M: Employment Leadership Position: Roche. Humphrey, K: Employment Leadership Position: Roche; Stock Ownership: Roche. Jiang, Y: Employment Leadership Position: Genentech; Stock Ownership: Genentech. Schary, W: Employment Leadership Position: Abbvie; Stock Ownership: Abbvie. Porro Lurà, M: Employment Leadership Position: F. Hoffmann - La Roche Ltd; Stock Ownership: Yes. Fischer, K: Other Remuneration: Roche (Travel, Accommodations). Hallek, M: Consultant Advisory Role: Roche, Abbvie; Honoraria: Roche, Abbvie, Gilead, Janssen, Celgene, Boehringer Ingelheim; Research Funding: Roche, Abbvie; Other Remuneration: Speakers' Bureau: Roche, Abbvie. Stilgenbauer, S: Research Funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Other Remuneration: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis (Personal Fees).

048
Acalabrutinib vs Rituximab Plus Idelalisib (IdR) or Bendamustine (BR) by Investigator Choice in Relapsed/Refractory (RR) Chronic Lymphocytic Leukemia: Phase 3 ASCEND Study

P. Ghia<fnref n="1" /> | A. Pluta² | M. Wach³ | D. Lysak⁴ |

T. Kozak⁵ | M. Simkovic⁶ | P. Kaplan⁷ |

I. Kraychok⁸ | A. Illes⁹ | J. De La Serna<fnref n="10" /> |

S. Dolan¹¹ | P. Campbell¹² | G. Musuraca¹³ |

A. Jacob¹⁴ | E.J. Avery¹⁵ | J.H. Lee¹⁶ | T. Chen¹⁷ |

W. Liang¹⁷ | P. Patel¹⁷ | W. Jurczak¹⁸

**Background:** Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor that has shown clinical benefit in patients (pts) with RR CLL. In this randomized, global, multicenter, open-label Phase 3 study, the efficacy and safety of acalabrutinib monotherapy were evaluated vs the investigator's choice of IdR or BR in RR CLL (NCT02970318).

**Methods:** Eligible pts with RR CLL were randomized 1:1 to 100 mg oral acalabrutinib BID until progression vs IdR (150 mg oral Id BID combined with ≤8 IV infusions of R [375 or 500 mg/m²]), or BR (70 mg/m² IV B on Day 1 and 2 of each cycle combined with R [375 or 500 mg/m² IV] on Day 1 of each 28-d cycle for ≤6 cycles). Stratification was by del(17p) status (y vs n), ECOG status (0-1 vs 2), and prior therapy lines (1-3 vs ≥4). The primary endpoint was progression-free survival (PFS) assessed by independent review committee (IRC). Secondary endpoints included overall survival (OS), overall response rate (ORR; by IRC), and safety. Pts with confirmed progression on IdR/BR could cross over to receive acalabrutinib monotherapy.

**Results:** 310 pts were randomized to acalabrutinib (n=155) or IdR/BR (n=155 [IdR, n=119; BR, n=36]); median age was 67 y (range, 32-90); 16% had del(17p); 27% had del(11q); 42% had Rai stage III/IV CLL. Median (range) no. of prior therapies was 1 (1-8) for acalabrutinib and 2 (1-10) for IdR/BR. Discontinuation due to AEs occurred in 11% of pts on acalabrutinib vs 49% Id, 12% R in IdR, 11% B and 17% R in BR. At a median follow-up of 16.1 mo, acalabrutinib significantly prolonged IRC-assessed PFS vs IdR/BR (median NR vs 16.5 mo; HR 0.31, 95% CI 0.20-0.49, P<.0001; **Figure**). PFS rates at 12 mo were 88% with acalabrutinib and 68% with IdR/BR; improvement was seen across subgroups, including del(17p), TP53 mutation and Rai stage.

ORR by IRC was similar with acalabrutinib vs IdR/BR (81% vs 75%; p<.22). 12-mo OS rates were 94% and 91% (with 15 and 18 deaths) for acalabrutinib and IdR/BR, respectively. 23% of IdR/BR pts crossed over to acalabrutinib monotherapy.

All-grade AEs (≥15%) with acalabrutinib were headache (22%), neutropenia (19%), diarrhea (18%), anemia and cough (15% each); with IdR, diarrhea (47%), neutropenia (45%), pyrexia (18%) and cough (15%); with BR, neutropenia (34%), infusion-related reaction and fatigue (23% each), nausea (20%) and pyrexia (17%). Grade ≥3 AEs (≥5%) with acalabrutinib were neutropenia (16%), anemia (12%) and pneumonia (5%); with IdR (≥15%), neutropenia (40%) and diarrhea (24%); with BR (≥5%), neutropenia (31%), anemia (9%) and constipation (6%).

AEs of interest were atrial fibrillation (5.2% of pts on acalabrutinib vs 3.3% on IdR/BR), bleeding AEs (26% vs 7.2%; including major

<footnote n="1">¹Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, Italy; ²Department of Hematological Oncology, Oncology Specialist Hospital, Brzozow, Poland; ³Department of Hemato-Oncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland; ⁴Fakultní Nemocnice Plzeň, Pilsen, Czech Republic; ⁵Fakultní Nemocnice Královské Vinohrady, Prague, Czech Republic; ⁶University Hospital Hradec Kralove, Charles University, Hradec Kralove, Czech Republic; ⁷Dnipropetrovsk City Clinical Hospital No. 4, Dnipropetrovsk, Ukraine; ⁸National Cancer Institute, Kiev, Ukraine; ⁹University of Debrecen, Faculty of Medicine, Department of Hematology, Hungary;</footnote>

<footnote n="10">¹⁰Hospital Universitario 12 de Octubre, Madrid, Spain; ¹¹Saint John Regional Hospital, University of New Brunswick, New Brunswick, Canada; ¹²Barwon Health, University Hospital Geelong, Geelong, Victoria, Australia; ¹³Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; ¹⁴The Royal Wolverhampton NHS Trust, Wolverhampton, United Kingdom; ¹⁵Nebraska Hematology Oncology, Lincoln, NE; ¹⁶Gachon University Gil Medical Center, Incheon, South Korea; ¹⁷Acerta Pharma, South San Francisco, CA, USA; ¹⁸Department of Hematology, Jagiellonian University Medical College, Krakow, Poland</footnote>
<figure><img src="image_26.png" /></figure>

hemorrhage [1.9% vs 2.6%]), Grade ≥3 infections (15% vs 24%) and 2nd primary malignancies (excluding NMSC; 6.5% vs 2.6%).

**Conclusion:** Acalabrutinib monotherapy significantly improved PFS with a more tolerable safety profile vs IdR/BR in pts with RR CLL.

049
ZANUBRUTINIB FOR PATIENTS WITH RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA

W. Xu<fnref n="1" /> | S. Yang<fnref n="2" /> | K. Zhou³ | L. Pan⁴ | Z. Li⁵ |

J. Zhou⁶ | S. Gao⁷ | D. Zhou<fnref n="8" /> | J. Hu⁹ |

R. Feng¹⁰ | H. Huang<fnref n="11" /> | M. Ji¹² | H. Guo¹² |

J. Huang¹³ | W. Novotny¹³ | S. Feng¹³ | J. Li<fnref n="1" />

**Introduction:** Zanubrutinib is a selective and irreversible BTK inhibitor that has demonstrated potent inhibition of BTK preclinically, with minimal, off-target inhibition of other kinases. Complete and sustained BTK occupancy in both blood and lymph node biopsies from patients treated with zanubrutinib at 160 mg twice daily (BID) was observed in a phase 1 clinical trial.

**Methods:** In this single-arm, multicenter phase 2 study (ClinicalTrials.gov NCT03206918), zanubrutinib was given by mouth, 160 mg BID to patients with relapsed or refractory CLL/SLL until disease progression (PD) or unacceptable toxicity. Efficacy endpoints were assessed by independent review (IRC) in accordance with IWCLL guidelines (IWCLL, 2008) or the Lugano Classification (Cheson, 2014) for CLL and SLL, respectively.

**Results:** As of 14 December 2018, 91 pts (82 with CLL; 9 with SLL) were enrolled and treated at 11 centers in China. Baseline disease characteristics are summarized in the table. Median follow-up was 15.1 mo (range, 0.8-21.2 mo) with treatment discontinuation in 16 (17.6%) pts (8 due to AEs, 7 due to PD, and 1 due to pt withdrawal). A total of 83 pts (91.2%, 95% CI: 83.4, 91.6) achieved a best response of partial response with lymphocytosis (PR-L) or better according to investigators' assessment. Patients with del(17p) or TP53 mutation achieved a high

<footnote n="1">¹Hematology Department, Jiangsu Province Hospital, Nanjing, China;</footnote>

<footnote n="2">²Hematology Department, Peking University Peoples Hospital, Peking University Institute of Hematology, Beijing, China; ³Hematology Department, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China; ⁴Hematology Department, West China Hospital of Sichuan University, Chengdu, China; ⁵Hematology Department, Tianjin Hematonosis Hospital, Tianjin, China; ⁶Hematology Department, Wuhan Tongji Hospital, Wuhan, China; ⁷Hematology Department, The 1st Hospital of Jilin University, Changchun, China;</footnote>

<footnote n="8">⁸Hematology Department, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; ⁹Hematology Department, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical</footnote>

<footnote>University Union Hospital, Fuzhou, China; ¹⁰Hematology Department, Nanfang Hospital of Southern Medical University, Guangzhou, China;</footnote>

<footnote n="11">¹¹Hematology Department, The 1st Hospital of Soochow University, Suzhou, China; ¹²Clinical Development, BeiGene (Beijing) Co., Ltd., Beijing, China; ¹³Clinical Development, BeiGene USA, Inc., San Mateo, United States</footnote>
<table><thead><tr><th>Baseline Disease Characteristics</th><th>N=91</th></tr></thead><tbody><tr><td>Median age, y (range)</td><td>61.0 (35-87)</td></tr><tr><td>Male, n (%)</td><td>52 (57.1)</td></tr><tr><td>Binet stage B or C (CLL pts), n (%)</td><td>77 (93.9)</td></tr><tr><td>Stage IV (SLL pts), n (%)</td><td>7 (77.8)</td></tr><tr><td>Del(17p), n (%)</td><td>17 (18.7)</td></tr><tr><td>TP53 mutation, n (%)</td><td>20 (22.0)</td></tr><tr><td>Del(17p) or TP53 mutation, n (%)</td><td>22 (24.2)</td></tr><tr><td>Del(13q), n (%)</td><td>41 (45.1)</td></tr><tr><td>Del(11q), n (%)</td><td>20 (22)</td></tr><tr><td>Trisomy 12, n (%)</td><td>21 (23.1)</td></tr><tr><td>IGHV unmutated, n (%)</td><td>51 (56.0)</td></tr><tr><td>Lines of prior therapy, median (range)</td><td>1 (1-9)</td></tr><tr><td><strong>Efficacy*</strong></td><td></td></tr><tr><td>Complete response (CR), n (%)</td><td>4 (4.4)</td></tr><tr><td>Nodular partial response (nPR), n (%)</td><td>2 (2.2)</td></tr><tr><td>Partial response (PR), n (%)</td><td>60 (65.9)</td></tr><tr><td>Partial response with lymphocytosis (PR-L), n (%)</td><td>17 (18.7)</td></tr><tr><td>Stable disease (SD), n (%)</td><td>4 (4.4)</td></tr><tr><td>Progressive disease (PD), n (%)</td><td>1 (1.1)</td></tr><tr><td>Discontinued prior to 1st assessment, n (%)</td><td>3 (3.3)</td></tr><tr><td><strong>Safety</strong></td><td></td></tr><tr><td>Any TEAE, n (%)</td><td>91 (100)</td></tr><tr><td>Serious AE, n (%)</td><td>30 (33.0)</td></tr><tr><td>AE leading to treatment discontinuation, n (%)</td><td>8 (8.8)</td></tr><tr><td>AE leading to death<sup>b</sup>, n (%)</td><td>3 (3.3)</td></tr><tr><td><strong>Common Adverse Event</strong></td><td><strong>Any Grade</strong></td><td><strong>Grade ≥3</strong></td></tr><tr><td>Neutrophil count decreased, n (%)</td><td>62 (68.1)</td><td>40 (44.0)</td></tr><tr><td>Upper respiratory tract infection, n (%)</td><td>41 (45.1)</td><td>9(9.9)</td></tr><tr><td>Purpura, n (%)</td><td>31 (34.1)</td><td>0 (0)</td></tr><tr><td>Platelet count decreased, n (%)</td><td>30 (33.0)</td><td>8 (8.8)</td></tr><tr><td>Haematuria, n (%)</td><td>27 (29.7)</td><td>0 (0)</td></tr><tr><td>Anaemia, n (%)</td><td>25 (27.5)</td><td>8 (8.8)</td></tr><tr><td>Hypokalaemia, n (%)</td><td>23 (25.3)</td><td>6 (6.6)</td></tr></tbody></table>

ORR (95.5%). Median time for achieving first response was 2.79 mo (range, 2.6-5.6 mo) among responders. Estimated PFS rate at 12 months was 80.9% (95% CI: 67, 89). The most frequently reported AEs are summarized in the table below. Major hemorrhage was reported in 2 patients (Gr 3, gastrointestinal hemorrhage and Gr 2 intracranial hemorrhage), which led to discontinuation of zanubrutinib. Four (4.4%) pts died within 30 days of their last dose of study drug, 2 due to PD and 2 due to AEs (pulmonary infection; cardiopulmonary failure).

**Conclusions:** Zanubrutinib was generally well-tolerated and resulted in a high response rate, including in patients with del(17p) or TP53 mutation.

**Keywords:** BTK inhibitors; chronic lymphocytic leukemia (CLL); zanubrutinib.

**Disclosures:** Ji, M: Employment Leadership Position: Bei Gene, Associate Director of Clinical Development; Stock Ownership: Own BeiGene Stock. Guo, H: Employment Leadership Position: Executive Director of BeiGene; Stock Ownership: Own BeiGene Stock. Huang, J: Employment Leadership Position: CMO Hematology of BeiGene. Novotny, W: Employment Leadership Position: BeiGene Employee; Stock Ownership: Own BeiGene Stock. Feng, S: Employment Leadership Position: BeiGene USA Employee; Stock Ownership: Own BeiGene Stock.

050
A PHASE 2 STUDY TO ASSESS THE SAFETY AND EFFICACY OF UMBRALISIB IN

PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WHO ARE INTOLERANT TO PRIOR BTK OR PI3K DELTA INHIBITOR THERAPY

A.R. Mato¹ | S.J. Schuster² | N. Lamanna³ |
J.M. Pagel⁴ | I.W. Flinn⁵ | J. Barrientos⁶ |
J.A. Reeves⁷ | B.D. Cheson⁸ | P.M. Barr⁹ |
S. Kambhampati¹⁰ | F. Lansigan¹¹ | J.J. Pu¹² |
A. Skarbnik¹³ | G. Fonseca¹⁴ | C. Dorsey¹ |
N.M. LaRatta² | H. Weissbrot³ | J. Svoboda² |
E.T. Luning Prak¹⁵ | P. Tsao¹⁵ | A. Sitlinger¹⁶ |
D. Paskalis¹⁷ | P. Sportelli¹⁷ | H.P. Miskin¹⁷ |
M.S. Weiss¹⁷ | D.M. Brander¹⁶

¹CLL Program, Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, United States; ²Lymphoma Department, University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, United States; ³Columbia University Medical Center, New York-Presbyterian, New York, United States; ⁴Department of Hematology, Swedish Cancer Institute, Seattle, WA, United States; ⁵TN Oncology, Sarah Cannon Research Institute, Nashville, TN, United States; ⁶CLL Research and Treatment Program, Northwell Health, New Hyde Park, NY, United States; ⁷Florida Cancer Specialists, Sarah Cannon Research Institute, Fort Myers, FL, United States; ⁸Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, United States; ⁹Wilmot Cancer Institute, University of Rochester, Rochester, NY, United States; ¹⁰Research Medical Center, Sarah Cannon Research Institute, Kansas City, MO, United States; ¹¹Department of Hematology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States; ¹²Department of Hematology, Penn State Health, Hershey, PA, United States; ¹³Department of Hematology, John Theurer Cancer Center, Hackensack, NJ, United States; ¹⁴Florida Cancer Specialists North, Sarah Cannon Research Institute, St. Petersburg, FL, United States; ¹⁵Clinical Immunology Laboratory, University of Pennsylvania, Philadelphia, PA, United States; ¹⁶Department of Hematology, Duke University Medical Center, Durham, NC, United States; ¹⁷Clinical Development, TG Therapeutics, Inc., New York, NY, United States

**Introduction:** Although kinase inhibitor (KI) therapies are generally well tolerated, intolerance is the most common reason for discontinuation (~50% discontinuations; Mato et al 2017). Therefore, patients (pts) who discontinue a KI due to intolerance represent an unmet medical need. Umbralisib (TGR-1202, Umbra) is a novel, highly-specific PI3Kδ inhibitor which is active and well tolerated in pts with CLL. This phase 2 trial evaluates the safety/efficacy of Umbra in CLL pts who are intolerant to prior BTK or PI3Kδ inhibitor therapy.

**Methods:** KI intolerant is defined as: ≥ 1 GR 3 or ≥ 2 GR 2 non-heme tox, ≥ 1 GR 3 neutropenia with infection or fever, and/or ≥ 1 GR 4 heme tox leading to KI discontinuation. Prior KI must be discontinued for ≥ 14 days without CLL progression. Pts must start Umbra within 12 mos of prior KI. All pts treated with Umbra (800 mg oral daily) until progression, toxicity, or study conclusion. Primary endpoint is progression-free

<footnote><sup>a</sup>Best response as assessed by the investigator. IRC-assessed efficacy outcomes are on-going and will be presented.</footnote>

<footnote><sup>b</sup>One of the patients with primary reason of death due to PD also reported a fatal AE of multiple organ dysfunction syndrome.</footnote>
<figure><img src="image_27.png" /><figcaption>**Figure 1:** PFS</figcaption></figure>

survival (PFS). Secondary endpoints include time to treatment failure as compared to prior KI therapy and characterization of Umbra safety profile. Peripheral blood samples are being collected for correlative analyses to identify markers associated with KI intolerance.

**Results:** 51 pts were enrolled (44 BTK & 7 PI3Kα intolerant). Baseline demographics include: med age 70 yrs (range 48-96), med prior therapies 2 (1-7), del17p and/or TP53 (24%), del11q (18%), IGHV unmutated (57%), BTK mut or PLCg2 mut (8%). 76% required tx within 6 mos of prior KI discontinuation. Most common AEs leading to prior KI discontinuation were: rash (14 events), arthralgia, A-Fib/Cardiac, (9 events each), diarrhea/colitis, bleeding/hemorrhage (6 events each). 50 pts were evaluable for efficacy. Median PFS is 23.5 mos (95% CI 16.6-not estimable, Fig 1). As of the cut-off date, 58% of pts have been on Umbra for a longer duration than their prior KI. Most common (≥ 5%) GR ≥3 AEs while on Umbra (all causality) were: neutropenia (14%), thrombocytopenia (10%), diarrhea (8%), hypophosphatemia, pneumonia (6% each). Six pts (12%) discontinued Umbra due to an AE (pneumonitis (2), pneumonia, rash, dermatitis, pancreatitis). Four pts had recurrence of an AE that led to prior KI intolerance, however 3/4 recurrences did not result in dose-modification. No prior PI3K treated patients (n = 7) had a recurrence of AE that led to PI3K discontinuation including the 3 pts with colitis. Four pts (8%) had dose reductions (headache, hematology, AST/ALT and colitis) and were successfully re-challenged.

**Conclusion:** Umbralisib is safe and effective in a KI intolerant CLL population. These are the first prospective data to confirm that switching from KI to Umbra can result in durable, well tolerated responses. From a therapy sequencing perspective, these data suggest use of an alternate KI is a reasonable strategy prior to class switch to a BCL-2 inhibitor. Pre-umbralisib dosing samples are being analyzed for CYP-3A4 polymorphisms.

**Keywords:** BTK inhibitors; chronic lymphocytic leukemia (CLL); PI3K/AKT/mTOR.

**Disclosures:** Mato, A: Consultant Advisory Role: Genentech, TG Therapeutics, PCYC, Loxo, Abbvie, Sunesis, Celgene, Verastem, Astra-Zeneca; Research Funding: TG Therapeutics, PCYC, Loxo, Abbvie, Sunesis, Regeneron, J and J. Pagel, J: Consultant Advisory Role: TG

Therapeutics, Inc.; Research Funding: TG Therapeutics, Inc. Barr, P: Consultant Advisory Role: TG Therapeutics, Inc.; Research Funding: TG Therapeutics, Inc. Skarbnik, A: Consultant Advisory Role: Abbvie, Pharmacyclics, Janssen, Genentech; Honoraria: Verastem, Abbvie, Pharmacyclics, Janssen, Jazz, Gilead, Seattle Genetics, Genentech; Research Funding: BMS. Svoboda, J: Consultant Advisory Role: Seattle Genetics, BMS, Kite, Kyowa, Astra-Zeneca; Research Funding: Seattle Genetics, BMS, Merck, Celgene, Pharmacyclics, TG Therapeutics, Novartis. Paskalis, D: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Sportelli, P: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Miskin, H: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Weiss, M: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Brander, D: Consultant Advisory Role: TG Therapeutics, Inc.

## SESSION 4 – TREATMENT WITH NOVEL ANTIBODIES

### 051 THE FIRST-IN-CLASS ANTI-CD47 ANTIBODY HU5F9-G4 + RITUXIMAB INDUCES DURABLE RESPONSES IN RELAPSED/REFRACTORY DLBCL AND INDOLENT LYMPHOMA: INTERIM PHASE 1B/2 RESULTS

R. Advani¹ | N.L. Bartlett² | S.M. Smith³ |

M. Roschewski⁴ | L. Popplewell⁵ | I. Flinn⁶ |

G. Collins⁷ | N. Ghosh⁸ | A. LaCasce⁹ | A. Asch¹⁰ |

J. Kline³ | M. Kesevan⁷ | T. Tran¹ | J. Lynn¹¹ |

J. Huang¹¹ | B. Agoram¹¹ | J. Volkmer¹¹ |

C.H. Takimoto¹¹ | M.P. Chao¹¹ | A. Mehta¹²

¹Medicine, Stanford University, Stanford, United States; ²Medicine, Washington University St. Louis, St, Louis, United States; ³Medicine, University of Chicago, Chicago, United States; ⁴Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, United States;

⁵Hematology/Oncology, City of Hope, Duarte, United States; ⁶Medicine, Sarah Cannon Research Institute, Nashville, United States; ⁷Clinical Haematology, Oxford University, Oxford, United Kingdom; ⁸Medicine, Atrium Health, Charlotte, United States; ⁹Medicine, Dana Farber Cancer Institute, Boston, United States; ¹⁰Hematology/Oncology, University of Oklahoma, Oklahoma City, United States; ¹¹Clinical Development, Forty Seven, Inc., Menlo Park, United States; ¹²Medicine, University of Alabama Birmingham, Birmingham, United States

**Introduction:** Hu5F9-G4 (5F9) is a first-in-class IgG4 antibody targeting CD47, a macrophage immune checkpoint and “don’t eat me” signal on cancers leading to phagocytosis of tumor cells. Pre-clinically,
5F9 synergizes with rituximab to eliminate lymphoma by enhancing antibody-dependent cellular phagocytosis. 5F9+rituximab had encouraging safety/efficacy in a Phase (Ph)1b dose escalation cohort in relapsed/refractory (r/r) DLBCL and FL patients that were rituximab-refractory (Advani et al., NEJM 2018). We report on extended follow up of this Ph1b cohort and preliminary Ph2 data.

**Methods:** The Ph2 enrolled: 1) DLBCL: primary refractory or r/r to ≥ 2 prior therapies, ineligible for CAR-T therapy; and 2) indolent lymphoma (FL/MZL) r/r to ≥ 2 prior therapies. A 5F9 priming dose was used to mitigate on-target anemia; followed by weekly or Q2 week maintenance doses. Based on a potential dose-response seen in Ph1b, 5F9 maintenance doses of 30 and 45 mg/kg were tested with rituximab.

**Results:** 100 patients (63 DLBCL, 35 FL, 2 MZL) have been treated in both Ph1b+2 cohorts. Median age (range) was 66 years (21-88) with 3 median prior therapies (range 1-10). 84% were rituximab-refractory and 72% refractory to their last therapy. 5F9+rituximab was well-tolerated at 5F9 doses up to 45 mg/kg with no maximum tolerated dose reached or significant dose-dependent toxicities. Treatment-related AEs (TRAEs) in >10% of patients included infusion reactions (38%), headache (34%), chills (30%), fatigue (30%), anemia (27%), nausea (24%), pyrexia (23%) vomiting (13%), and back pain (11%). The majority were G1/2 with 7% or lower being G3/4, except G3 anemia (15%) which was an expected transient first-dose effect. Treatment discontinuation from TRAEs occurred in only 4% of patients. As of Feb 2019, for Ph1b patients dosed from 10-30 mg/kg (n=22), at a median follow up of 12 months (DLBCL) and 18 months (FL), the median duration of response had not been reached (DLBCL range: 2.4 - 20+ months; FL range: 6.2 - 22.6+ months), including some durable CRs for > 20 months. Of 100 patients enrolled, 75 patients were efficacy evaluable, 8 were not, and 17 had first assessment pending. Pooled data from Ph1b+2 efficacy evaluable patients (n=75) show an objective response rate (ORR) and CR rate of 49% and 21%, respectively. In indolent lymphoma (n=28 FL, 1 MZL), the ORR and CR rate was 66% and 24%, respectively. In DLBCL (n=46), the ORR/CR rate was 39/20%. Median time to response for responding patients was rapid at 1.8 months. The ORR for patients treated with 30 mg/kg 5F9 (n=59) was 47% and at 45 mg/kg was 71% in a limited number (n=7). Accrual is ongoing and additional data at the 45 mg/kg dose will be presented.

**Conclusions:** 5F9+rituximab is a novel immunotherapy blocking a key macrophage/cancer checkpoint. It is well tolerated with rapid and durable responses observed in heavily pre-treated DLBCL and indolent lymphoma patients. Ph2 enrollment is ongoing (NCT02953509). Funded by Forty Seven and the Leukemia and Lymphoma Society.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); indolent lymphoma; macrophages.

**Disclosures:**
**Advani, R:** Consultant Advisory Role: AstraZeneca, Autolous, Bayer Healthcare Pharmaceuticals, Cell Medica, Genentech, Gilead, Kite Pharma, Kyowa, Pharmacyclics, Seattle Genetics, Takeda; Research Funding: Agensys, Celgene, Forty Seven Inc., Genentech/Roche, Infinity, Janssen Pharmaceuticals, Kura, Merck, Millennium, Pharmacyclics, Regeneron, Seattle Genetics.
**Lynn, J:** Employment

Leadership Position: Forty Seven, Inc.; Stock Ownership: Forty Seven, Inc. Huang, J: Employment Leadership Position: Forty Seven, Inc.; Stock Ownership: Forty Seven, Inc. Agoram, B: Employment Leadership Position: Forty Seven, Inc.; Stock Ownership: Forty Seven, Inc. Volkmer, J: Employment Leadership Position: Forty Seven, Inc.; Stock Ownership: Forty Seven, Inc.; Other Remuneration: Intellectual property licensed to Forty Seven, Inc. Takimoto, C: Employment Leadership Position: Forty Seven, Inc.; Stock Ownership: Forty Seven, Inc. Chao, M: Employment Leadership Position: Forty Seven, Inc.; Stock Ownership: Forty Seven, Inc.; Other Remuneration: Intellectual property licensed to Forty Seven, Inc. Mehta, A: Consultant Advisory Role: Spectrum, Celgene, Kite, BMS; Research Funding: Incyte, Roche, Merck, BMS, Epizyme, Seattle Genetics, Kite, Forty Seven Inc, Takeda, Rhizen, Juno; Other Remuneration: Speaker's Bureau: Astra Zeneca, Kite, Spectrum, Kyowa Kirin, Seattle Genetics.

052

CLINICAL ACTIVITY OF REGN1979, AN ANTI-CD20 X ANTI-CD3 BISPECIFIC ANTIBODY (AB) IN PATIENTS (PTS) WITH (W/) RELAPSED/REFRACTORY (R/R) B-CELL NON-HODGKIN LYMPHOMA (B-NHL)

M.S. Topp¹ | J. Arnason² | R. Advani³ |

J.R. Brown⁴ | J. Allan⁵ | S. Ansell⁶ | S. O'Brien⁷ |

J. Chavez⁸ | J. Duell¹ | A. Rosenwald⁹ |

R. Charnas¹⁰ | S.R. Ambati¹⁰ | L. Adriaens¹¹ |

M. Ufkin¹⁰ | M. Zhu¹⁰ | J. Li¹¹ | P. Gasparini¹⁰ |

V. Jankovic¹⁰ | N. Fiaschi¹⁰ | W. Zhang¹⁰ |

S. Hamon¹⁰ | G. Thurston¹⁰ | A.J. Murphy¹⁰ |

G.D. Yancopoulos¹⁰ | I. Lowy¹⁰ | D. Sternberg¹⁰ |

R. Bannerji¹²

¹Department of Internal Medicine, Universitätsklinikum Würzburg, Würzburg, Germany; ²Hematology/Oncology Division, Beth Israel Deaconess Medical Center, Boston, United States; ³Department of Medicine, Stanford University, Stanford, United States; ⁴Center for Hematologic Oncology, Dana-Farber Cancer Institute, Boston, United States; ⁵Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, United States; ⁶Department of Internal Medicine, Mayo Clinic, Rochester, United States; ⁷Division of Hematology/Oncology, University of California, Irvine, United States; ⁸Department of Oncologic Sciences, Moffitt Cancer Center, Tampa, United States; ⁹Institute of Pathology, University of Würzburg, Würzburg, Germany; ¹⁰Hematology/Oncology, Regeneron Pharmaceuticals, Inc., Tarrytown, United States; ¹¹Hematology/Oncology, Regeneron Pharmaceuticals, Inc., Basking Ridge, United States; ¹²Section of Hematologic Malignancies, Rutgers Cancer Institute of New Jersey, New Brunswick, United States

**Introduction:** REGN1979 (R1979) is an anti-CD20 x anti-CD3 bispecific IgG4 Ab. We report updated results of a Phase 1 trial of R1979 in pts
<table><caption>Table. Best overall response according to Cheson 2007 criteria<fnref n="1" /></caption><thead><tr><th rowspan="2"></th><th colspan="3">R/R FL Gr 1-3a*</th><th colspan="4">R/R DLBCL</th><th colspan="4">Other R/R B-NHL (MCL, MZL, FL Gr 3b, FL unknown/ungraded, WM)</th></tr><tr><th>&lt;5 mg (n=7)</th><th>≥5-≤12 mg (n=5)</th><th>≥18-≤40 mg (n=5)</th><th>&lt;5 mg (n=15)</th><th>≥5-≤12 mg (n=11)</th><th>≥18-≤40 mg (n=11)</th><th>80 mg (n=2)</th><th>&lt;5 mg (n=5)</th><th>≥5-≤12 mg (n=3)</th><th>≥18-≤40 mg (n=4)</th><th>80 mg (n=3)</th></tr></thead><tbody><tr><td>Overall response rate (ORR), n (%)</td><td>1 (14.3)</td><td>5 (100)</td><td>5 (100)</td><td>3 (20.0)</td><td>2 (18.2)</td><td>6 (54.5)</td><td>2 (100)</td><td>2 (40.0)</td><td>1 (33.3)</td><td>3 (75.0)</td><td>2 (66.7)</td></tr><tr><td>Complete response (CR), n (%)</td><td>1 (14.3)</td><td>4 (80.0)</td><td>4 (80.0)</td><td>0</td><td>1 (9.1)</td><td>2 (18.2)</td><td>2 (100)</td><td>0</td><td>0</td><td>2 (50.0)</td><td>1 (33.3)</td></tr><tr><td>Partial response (PR), n (%)</td><td>0</td><td>1 (20.0)</td><td>1 (20.0)</td><td>3 (20.0)</td><td>1 (9.1)</td><td>4 (36.4)</td><td>0</td><td>2 (40.0)</td><td>1 (33.3)</td><td>1 (25.0)</td><td>1 (33.3)</td></tr><tr><td>Duration of follow-up, median (range) weeks</td><td>22.1 (8.1-51.3)</td><td>59.1 (31.3-63.4)</td><td>29.0 (11.1-52.6)</td><td>6.9 (3.1-52.3)</td><td>10.7 (3.1-59.3)</td><td>17.1 (2.4-59.6)</td><td>9.4 (5.4-13.3)</td><td>5.3 (5.0-44.1)</td><td>8.1 (4.3-58.6)</td><td>30.1 (4.1-39.3)</td><td>10.9 (4.3-15.3)</td></tr></tbody></table>

<figure><img src="image_28.png" /><figcaption>Figure. Best response per Cheson 2007 criteria<fnref n="1" /> in target lesions from baseline in patients with R/R FL Gr 1-3a and DLBCL treated with REGN1979 ≥5 mg</figcaption></figure>

w/ R/R B-NHL previously treated w/ anti-CD20 Ab therapy. Primary objectives are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives are to assess antitumor activity, pharmacokinetics (PK), and pharmacodynamics.

**Methods:** Eligible pts w/ R/R B-NHL must have received ≥1 prior CD20-directed Ab therapy. Treatment (tx) consists of 12 weekly intravenous doses of R1979 followed by every 2-week dosing for 12 doses (total of 36 weeks).

**Results:** As of Dec 6, 2018, 71 pts (diffuse large cell B-cell lymphoma [DLBCL] [n=39], follicular lymphoma [FL] grade [Gr] 1-3a [n=17], other [mantle cell lymphoma {MCL}, marginal zone lymphoma {MZL}, FL grade 3b, FL unknown/ungraded, or Waldenstrom macroglobulinemia {WM} [n=15]) were treated w/ R1979 0.03-80 mg and received a median of 9 doses (range 1-24). Ten pts remain on tx; 15 completed tx; 46 discontinued early (29 due to progressive disease [PD]).

No pts w/ B-NHL experienced a DLT. Most common tx-emergent adverse events (AEs) were pyrexia (n=56), chills (n=38), cytokine release syndrome (CRS; n=37, w/4 experiencing Gr ≥3). The severity of CRS symptoms declined through optimized pre-medication even w/ R1979 dose escalation. Most common Gr ≥3 AEs were decreased neutrophils/neutropenia (n=14), decreased lymphocytes/lymphopenia (n=14), anemia (n=12). No seizure and/or encephalopathy was reported. No neurological event required tx termination. Four pts discontinued due to AEs: Gr 3 hemolysis; Gr 3 fatigue; Gr 3 pneumonia; and Gr 3 neck abscess (1 each). Nine pts died on study: PD (n=6), gastric perforation (n=1), cardiac arrest (n=1), lung infection (n=1).

Tx w/ R1979 at doses ≥5 mg has shown marked efficacy in R/R FL Gr 1-3a (ORR: 100% [10/10 OR; 8/10 CR; 2/10 PR]), while increasing efficacy is observed in pts w/ R/R DLBCL (and other B-NHL subtypes) as the dose is further increased (Table and Figure); of note, in patients

<footnote>* Patients were not treated with 80 mg dose in this subtype.</footnote>

<footnote>*Two patients discontinued prior to the first on-treatment disease assessment. CR, complete response; PR, partial response.</footnote>

<footnote n="1">¹Cheson BD. Hematol Oncol Clin North Am. 2007;21:841-854.</footnote>
with R/R DLBCL, 2/11 (18%) had responses at doses between 5-12 mg, 6/11 (55%) had responses at doses between 18-40 mg, and 2/2 (100%) had responses at the 80 mg dose, with both of these latter being CRs. Elevated levels of serum cytokines were observed w/ dosing; however, no correlation was observed w/ clinical efficacy. Immunohistological analysis of malignant lymph node tissue demonstrated that pts w/ high and low CD20 achieved clinical response. Relapse among responders was seen w/ either maintenance or loss of CD20 expression, suggesting antigen-dependent and independent disease escape mechanisms.

**Conclusions:** R1979 was well tolerated in pts w/ R/R B-NHL. No DLTs and no significant neurological toxicity were observed. Tx w/ R1979 showed impressive efficacy w/ 100% ORR in R/R FL starting at doses ≥5 mg. More resistant tumors such as R/R DLBCL are showing benefit w/ increasing doses. Based on these efficacy findings, a Phase 2 study in R/R FL Gr 1-3a, R/R DLBCL, and other R/R B-NHL subtypes is planned.

**Keywords:** CD20; CD3; non-Hodgkin lymphoma (NHL).

**Disclosures:** Topp, M: Research Funding: Regeneron Pharmaceuticals, Inc. Arnason, J: Research Funding: Regeneron Pharmaceuticals, Inc. Advani, R: Research Funding: Regeneron Pharmaceuticals, Inc. Brown, J: Research Funding: Regeneron Pharmaceuticals, Inc. Allan, J: Research Funding: Regeneron Pharmaceuticals, Inc. Ansell, S: Research Funding: Regeneron Pharmaceuticals, Inc. O'Brien, S: Research Funding: Regeneron Pharmaceuticals, Inc. Chavez, J: Research Funding: Regeneron Pharmaceuticals, Inc. Duell, J: Research Funding: Regeneron Pharmaceuticals, Inc. Rosenwald, A: Research Funding: Regeneron Pharmaceuticals, Inc. Charnas, R: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Ambati, S: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Adriaens, L: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Ufkin, M: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Zhu, M: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Li, J: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Gasparini, P: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Jankovic, V: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Fiaschi, N: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Zhang, W: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Hamon, S: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Thurston, G: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Murphy, A: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Yancopoulos, G: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Lowy, I: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Sternberg, D: Employment Leadership Position: Regeneron Pharmaceuticals, Inc. Bannerji, R: Research Funding: Regeneron Pharmaceuticals, Inc.

053
CD20-TCB (RG6026), A NOVEL "2:1"
FORMAT T-CELL-ENGAGING BISPECIFIC
ANTIBODY, INDUCES COMPLETE

REMISSIONS IN RELAPSED/REFRACTORY
B-CELL NON-HODGKIN'S LYMPHOMA

M.J. Dickinson¹ | F. Morschhauser² | G. Iacoboni³ |
C. Carlo-Stella⁴ | F.C. Offner⁵ | A. Sureda⁶ |
G. Salles⁷ | J. Martinez⁸ | M. Crump⁹ |
D.N. Thomas¹⁰ | P.N. Morcos¹⁰ | C. Ferlini¹¹ |
A. Broeske¹² | M. Bacac¹³ | N.J. Dimier¹⁴ |
P. Umaña¹³ | T. Moore¹¹ | M. Weisser¹² |
M. Hutchings¹⁵

¹Peter MacCallum Cancer Centre, Royal Melbourne Hospital, The University of Melbourne, East Melbourne, Australia; ²Department of Hematology, Univ. Lille, CHU Lille, EA 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France; ³Department of Hematology, Vall d'Hebron Hospital, Barcelona, Spain; ⁴Department of Oncology and Hematology, Humanitas Clinical and Research Center, Humanitas University, Milan, Italy; ⁵Universitair Ziekenhuis Gent, Gent, Belgium; ⁶Hematology Department, Institut Català d'Oncologia Hospitalet, Barcelona, Spain; ⁷Service d'Hématologie Clinique, Université Claude Bernard de Lyon, Lyon University Hospital, Pierre-Bénite, France; ⁸Servicio de Hematología, Hospital 12 de Octubre, Madrid, Spain; ⁹Medical Oncology & Haematology, Princess Margaret Hospital, Toronto, Canada; ¹⁰Roche Innovation Center New York, Roche Pharma Research and Early Development (pRED), New York City, United States; ¹¹Roche Innovation Center Basel, Roche Pharma Research and Early Development (pRED), Basel, Switzerland; ¹²Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany; ¹³Roche Innovation Center Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, Switzerland; ¹⁴Roche Pharma, Roche Ltd, Welwyn, United Kingdom; ¹⁵Department of Haematology and Phase 1 Unit, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

**Introduction:** CD20-TCB (RG6026) is a T-cell-engaging bispecific antibody with a novel "2:1" molecular format which preclinically showed greater avidity for CD20 antigen, combinability with other anti-CD20 antibodies, and greater efficacy as compared to other CD20-CD3 bispecific formats. NP30179 is an ongoing multicenter phase I dose escalation trial investigating the safety, tolerability, pharmacokinetics (PK), biomarkers and antitumor activity of CD20-TCB.

**Methods:** Patients receive escalating doses of CD20-TCB as intravenous infusions guided by a model implementing a Bayesian CRM method with overdose control. To reduce the risk of cytokine release syndrome (CRS), a single dose of obinutuzumab as pretreatment (Gpt) is administered seven days prior to CD20-TCB to debulk B cells in peripheral blood and normal tissues (Bacac et al Clin Canc Res 2018). Updated data at clinically-relevant doses of 600 µg and above are reported.

**Results:** As of February 13th 2019 a total of 87 pts with r/r aggressive (a)NHL (DLBCL/PMBCL/trFL/Richter's transformation; n=79) and r/r FL (n=8) received CD20-TCB doses ranging from 600 µg to 25mg in a Q2W or Q3W schedule. Median age was 61 years (range 22-84),