the highest score (6 and 8) in 35 (83%) and 33 (78%) of pts., respectively. The most frequent comorbidity was arterial hypertension (19%) and diabetes (6%). PET-2 was positive in 6/39 pts, with a Deauville score of 4 in 5 and 5 in 1 patient. 12/39 did not complete the treatment for toxicity (6), progression (5) or investigator decision (1). 125 grade 3-4 toxicities were recorded: lymphopenia (56%), neutropenia (19%), CMV reactivation (2.4%), febrile neutropenia (2.4%), rash/infusion reaction (3.2%). Five pts died of recurrent HL (2), CMV reactivation (2) and stomach cancer (1). In an intention to treat analysis 39 pts are evaluable for response: 27 (69%) were in CR. After a median FU of 16.2 (12.2-26.6) months 17 pts experienced a treatment failure: 3 for progression during treatment and 12 for progression or relapse 94-670 days after treatment end. The 2y OS and PFS rate in intention to treat were 85% (95% CI 72-100) and 47% (95% CI 31-71) and in per protocol analysis 100% and 75% (95% CI 58-97), respectively.

**Conclusion:** The present analysis, though conducted in 2/3 of enrolled patients showed that Be-BV is an effective regimen in the real life of elderly HL, when delivered according to the schedule. The toxicity of this treatment could be improved by a more strict prophylaxis of CMV infections.

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

## 238
# PET-ADAPTED NIVOLUMAB +/- ICE AS INITIAL SALVAGE THERAPY IN RELAPSED/REFRACTORY HODGKIN LYMPHOMA

A.F. Herrera<fnref n="1" /> | R. Chen<fnref n="1" /> | J. Palmer² | N. Tsai³ |

K. McBride<fnref n="1" /> | J. Song⁴ | M. Mei<fnref n="1" /> | J. Zain<fnref n="1" /> |

L. Nikolaenko<fnref n="1" /> | L. Popplewell<fnref n="1" /> | A. Nademanee<fnref n="1" /> |

S. Rosen<fnref n="1" /> | L. Kwak<fnref n="1" /> | H. Lee⁵ | S. Forman<fnref n="1" />

**Introduction:** Nivolumab (nivo) is an anti-PD-1 antibody that restores effective anti-tumor immune responses and is tolerable and effective in patients (pts) with relapsed/refractory (RR) Hodgkin lymphoma (HL). Nivo combined with brentuximab vedotin (BV) as initial salvage therapy yields high response rates and favorable progression-free survival as a bridge to autologous stem cell transplantation (ASCT) in pts with RR HL. With the frontline approval of BV, it is necessary to evaluate the role of nivo as salvage therapy separate from BV. We report the preliminary results of a phase 2 trial evaluating PET-adapted nivo +/- ICE chemotherapy as initial salvage treatment in RR HL prior to ASCT.

**Methods:** In this prospective, multicenter trial, pts with biopsy-proven RR HL after frontline therapy received 3 mg/kg nivo every 2 weeks for up to 6 cycles. PET-CT was performed after cycle 3 and cycle 6. After cycle 6, pts in CR proceeded to ASCT while pts not in CR received nivo + ICE (NICE) for 2 cycles. The primary endpoint was complete response rate according to 2014 Lugano classification.

**Results:** 28 pts were evaluable for toxicity; 26 were evaluable for response. 68% were male, median age 35 years, 46% were primary refractory; at baseline, 50% had stage III-IV, 43% had B symptoms, and 68% had bulky disease (> 5cm). 22 pts received nivo alone and 6 pts received nivo/NICE. 25 pts completed therapy, 1 pt discontinued early in CR to undergo ASCT, 2 pts discontinued nivo early due to adverse events (AE, 1 pt = Gr 4 altered mental status, 1 pt = Gr 2 pneumonitis). Nivo-related AEs were consistent with known AE profile, rash (21%, all grade 1) was the most common AE and only 1 pt had grade 3-4 AEs (1 HIV+ pt with Gr 4 altered mental status and Gr 3 tumor lysis syndrome). In pts who received NICE, the most common AEs were nausea and vomiting (50%, all Gr 1) and the only Gr 3-4 event was Gr 4 neutropenia in one pt.

25 out of 26 evaluable pts (96%) responded to nivo, with a best CR rate of 81% (21/26). 3 pts who initially responded to nivo (1 CR, 2 PR) had progressive disease at the end of 6 cycles. At the end of nivo, the CR rate was 77% (20/26) and overall response rate was 85% (22/26). 6 pts were treated with NICE and 5 achieved CR (83%). Overall, at the end of protocol therapy (nivo or nivo/NICE), 96% (25/26) of evaluable pts were in CR. 22 pts proceeded to ASCT directly after protocol therapy and 3 pts in CR refused ASCT. One pt with PR after NICE subsequently responded to additional salvage therapy and is proceeding to ASCT. In pts who proceeded to ASCT, a median of 2 stem cell collections were required, a median of 4.8x10⁶ CD34+ cells/kg (range 3.12 – 16.23) were collected, and the median time to neutrophil and platelet engraftment were 11 and 13 days, respectively. All transplanted pts remain in CR with median follow-up time of 5 months (range, 0-19mo).

**Conclusion:** PET-adapted Nivo followed by NICE is a well-tolerated and highly effective first salvage regimen in pts with RR HL that merits further exploration.

AFH and RC contributed equally

**Keywords:** Hodgkin lymphoma (HL); ICE; nivolumab.

**Disclosures:** Herrera, A: Consultant Advisory Role: Bristol-Myers Squibb, Genentech, Merck, Adaptive Biotechnologies and Kite Pharma/Gilead; Research Funding: Bristol-Myers Squibb, Genentech, Immune Design, AstraZeneca, Merck, Seattle Genetics and Kite Pharma, Gilead Sciences.

## 239
# TRANSCRIPTIONAL NETWORKS ASSOCIATED WITH TREATMENT FAILURE IN ADVANCED-STAGE HODGKIN LYMPHOMA: DATA FROM THE RATHL TRIAL (CRUK/07/033)

<footnote n="1">¹Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, United States; ²Clinical Research, City of Hope Medical Center, Duarte, United States; ³Information Sciences, City of Hope Medical Center, Duarte, United States; ⁴Pathology, City of Hope Medical Center, Duarte, United States; ⁵Lymphoma & Myeloma, MD Anderson Cancer Center, Houston, United States</footnote>
S.H. Lim¹ | C. Burton² | S. Barrans² |

A. Kirkwood³ | P. Patrick³ | L. Stevens³ |

L. Clifton-Hadley³ | P.W. Johnson¹ | S.M. Thirdborough¹

¹Centre for Cancer Immunology & CRUK Centre, University of Southampton, Southampton, United Kingdom; ²HMDS, Leeds Cancer Centre, Leeds, United Kingdom; ³CR UK & UCL Cancer Trials Centre, UCL Cancer Institute, University College London, London, United Kingdom

**Introduction:** First line treatment of advanced-stage Hodgkin lymphoma produces high response rates but fails in up to 20%, with disease progression or relapse. Interim PET imaging is used for guiding treatment adaptation. However, in the RATHL trial¹, 15% of patients with interim negative PET experienced subsequent disease relapse, indicating a need to improve upon the current approach. We performed next generation RNA sequencing on a selected cohort within the RATHL trial, to identify transcriptional networks associated with treatment failure. These analyses serve to study the mechanisms of chemotherapy resistance in Hodgkin lymphoma and yield gene sets which might improve upon the negative predictive value of interim PET.

**Methods:** Whole transcriptome profiling was performed on RNA derived from diagnostic FFPE samples. The cases selected were divided into 2 groups; group one, patients who experienced disease relapse, progression or death within 2 years of trial registration (interim PET neg (n = 21) vs PET pos (n = 11)), and group two, patients who continued to be in complete remission at 2 years (n = 38). Both cohorts were standardised in histology subtype, age, stage, bulk, performance status and B symptoms. Unsupervised consensus gene co-expression network analysis was used to identify features associated with chemotherapy response.

**Results:** After RNA sequencing data pre-processing and outlier removal, a measure of topological overlap (TO) was calculated separately for the two groups, based on pairwise correlations between 12,209 expressed genes. The TO between each gene pair was then set to parallel minimum. Within this consensus dissimilarity matrix, 57 modules were identified by unsupervised clustering. These modules were highly enriched for genes associated with immune and non-immune cells (e.g. T-helper cells, macrophages and lymphatic endothelial cells) as well as biological response pathways (e.g. endothelial-mesenchymal transition and angiogenesis). Conventional differential expression analysis indicated that treatment failure was associated with increased extracellular matrix components and myeloid lineage genes. To gain an insight into how these changes might confer chemotherapy resistance, we constructed eigengene networks between co-expressed modules for each group. This analysis indicated that aberrant lymphatic vessel growth and development were associated with treatment failure, driven by a network of paracrine signals between eosinophils, M2 macrophages and endothelial cells.

**Conclusions:** Our findings indicate that protective signals arising from the stromal microenvironment, centered on a CXCL9-CXCR3 axis,

confer chemotherapy resistance and suggest targeted therapies may be useful in this context.

**Reference**

¹Johnson P et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma. NEJM 2016;374:2419-29.

**Keywords:** classical Hodgkin lymphoma (cHL); gene expression profile (GEP); macrophages.

**Disclosures:** Lim, S: Consultant Advisory Role: Celldex Therapeutics; Honoraria: Gilead; Research Funding: Celldex Therapeutics, Bioinvent, Incyte; Other Remuneration: Takeda, BMS. Burton, C: Consultant Advisory Role: Roche, Takeda, BMS, Celgene; Honoraria: Roche, Takeda, BMS; Other Remuneration: Roche, Takeda. Barrans, S: Other Remuneration: HTG molecular. Johnson, P: Consultant Advisory Role: Janssen; Honoraria: Bristol-Myers Squibb, Takeda, Novartis, Celgene, Janssen, Epizyme, Boeringher Ingelheim, Kite, Genmab, Incyte; Research Funding: Janssen, Epizyme.

240
OUTCOME AND TREATMENT OF
RELAPSING EARLY PET NEGATIVE
PATIENTS INCLUDED IN THE
EORTC/LYSA/FIL H10 TRIAL ON STAGES
I/II HODGKIN LYMPHOMA

A. Gac¹ | L. Chartier² | T. Girinsky³ | M. Gotti⁴ |

J. Lazarovici⁵ | I. Aurer⁶ | P. Musto⁷ | G. Damaj⁸ |

M. Federico⁹ | C. Fortpied¹⁰ | J. Raemaekers¹¹ |

M. Meignan¹² | M. Hutchings¹³ | A. Versati¹⁴ |

M. Andre¹⁵ | O. Reman¹

¹Institut d'Hématologie de Basse-Normandie, Centre Hospitalier Universitaire, Caen, France; ²Pôle Biométrie-Biostatistiques, LYSARC, Pierre Bénite, France; ³Département de Radiothérapie, Institut de Cancérologie Gustave Roussy, Villejuif, France; ⁴Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; ⁵Département d'Hématologie, Institut de Cancérologie Gustave Roussy, Villejuif, France; ⁶Zavod za Hematologiju, Klinike i Zavodi za Unutarnje Bolesti, Zagreb, Croatia; ⁷Referral Cancer Center of Basilicata, IRCCS-CROB, Rionero in Vulture (Pz), Italy; ⁸Département d'hématologie, université de Basse-Normandie, Caen, France; ⁹University of Modena and Reggio Emilia, Department of Diagnostic, Clinical and Public Health Medicine, Modena, Italy; ¹⁰Department of Statistic, EORTC, Brussels, Belgium; ¹¹Department of Hematology, Radboud University Medical Center, Nijmegen, Netherlands; ¹²Département de Médecine Nucléaire, Hospital Henri Mondor, Creteil, France; ¹³Department of Hematology, University Hospital Rigshospitalet, Copenhagen, Denmark; ¹⁴Department of Nuclear Medicine, Arcispedale S. Maria Nuova, Reggio Emilia, Italy; ¹⁵Département d'Hématologie, Université Catholique de Louvain, YVOIR, Belgium

**Background:** The final results of the randomized EORTC/LYSA/FIL H10 trial showed that early PET negative patients have an excellent
<table><caption>TABLE 1. Demographic, disease and treatment characteristics in relapsing patients</caption><thead><tr><th rowspan="2"></th><th colspan="2">Initial treatment received</th><th rowspan="2">All<br>N=94</th><th rowspan="2">p-value</th></tr><tr><th>CT<br>N=66</th><th>CMT<br>N=28</th></tr></thead><tbody><tr><td>Sex, Female</td><td>25 (37.9%)</td><td>14 (50.0%)</td><td>39 (41.5%)</td><td>0.36</td></tr><tr><td>Median Age</td><td>31.2</td><td>30.4</td><td>31.2</td><td>0.85</td></tr><tr><td>Prognostic factors</td><td></td><td></td><td></td><td>0.005</td></tr><tr><td>Favourable</td><td>30 (45.5%)</td><td>4 (14.3%)</td><td>34 (36.2%)</td><td></td></tr><tr><td>Unfavourable</td><td>36 (54.5%)</td><td>24 (85.7%)</td><td>60 (63.8%)</td><td></td></tr><tr><td>Ann Arbor clinical stage</td><td></td><td></td><td></td><td>0.25</td></tr><tr><td>I</td><td>15 (22.7%)</td><td>3 (10.7%)</td><td>18 (19.1%)</td><td></td></tr><tr><td>II</td><td>51 (77.3%)</td><td>25 (89.3%)</td><td>76 (80.9%)</td><td></td></tr><tr><td>Histologically documented Hodgkins Lymphoma (HL)</td><td></td><td></td><td></td><td>0.87</td></tr><tr><td>Lym Depl</td><td>1 (1.5%)</td><td>0 (0.0%)</td><td>1 (1.1%)</td><td></td></tr><tr><td>Mix Cell</td><td>11 (16.7%)</td><td>4 (14.3%)</td><td>15 (16.0%)</td><td></td></tr><tr><td>Nod Lym Predom</td><td>2 (3.0%)</td><td>0 (0.0%)</td><td>2 (2.1%)</td><td></td></tr><tr><td>Nod Scler</td><td>48 (72.7%)</td><td>24 (85.7%)</td><td>72 (76.6%)</td><td></td></tr><tr><td>Undass</td><td>3 (4.5%)</td><td>0 (0.0%)</td><td>3 (3.2%)</td><td></td></tr><tr><td>Other</td><td>1 (1.5%)</td><td>0 (0.0%)</td><td>1 (1.1%)</td><td></td></tr><tr><td>Median number of nodal areas</td><td>2.0</td><td>2.5</td><td>2.0</td><td>0.15</td></tr><tr><td>Bulky mediastinum, Yes</td><td>23 (34.8%)</td><td>10 (35.7%)</td><td>33 (35.1%)</td><td>0.99</td></tr><tr><td>B symptoms, Yes</td><td>21 (31.8%)</td><td>13 (46.4%)</td><td>34 (36.2%)</td><td>0.24</td></tr><tr><td>WHO performance status (0-4)</td><td></td><td></td><td></td><td>0.095</td></tr><tr><td>0</td><td>57 (86.4%)</td><td>19 (67.9%)</td><td>76 (80.9%)</td><td></td></tr><tr><td>1</td><td>7 (10.6%)</td><td>8 (28.6%)</td><td>15 (16.0%)</td><td></td></tr><tr><td>2</td><td>2 (3.0%)</td><td>1 (3.6%)</td><td>3 (3.2%)</td><td></td></tr><tr><td>Median ESR</td><td>26.0</td><td>54.5</td><td>37.0</td><td>&lt;0.001</td></tr><tr><td>Number of salvage treatment lines</td><td></td><td></td><td></td><td>0.74</td></tr><tr><td>1</td><td>47 (71.2%)</td><td>22 (78.6%)</td><td>69 (73.4%)</td><td></td></tr><tr><td>2</td><td>6 (9%)</td><td>3 (10.7%)</td><td>9 (9.6%)</td><td></td></tr><tr><td>≥3</td><td>12 (18.2%)</td><td>3 (10.7%)</td><td>15 (16%)</td><td></td></tr><tr><td>Unknown</td><td>1 (1.6%)</td><td>0 (0%)</td><td>1 (1%)</td><td></td></tr><tr><td>Type of salvage treatment</td><td></td><td></td><td></td><td>0.012</td></tr><tr><td>ASCT</td><td>41 (63.1%)</td><td>25 (89.3%)</td><td>66 (71.0%)</td><td></td></tr><tr><td>CT and/or RT</td><td>24 (36.9%)</td><td>3 (10.7%)</td><td>27 (29.0%)</td><td></td></tr><tr><td>Unknown</td><td></td><td></td><td></td><td></td></tr></tbody></table>

<figure><img src="image_161.png" /><figcaption>Figure 1: PFS2 in PET2 negative patients by initial treatment: blue line represents group initially treated by CMT and red line, group initially treated by CT.</figcaption></figure>
outcome with combined modality therapy (CMT) or chemotherapy (CT) only, although relapses occurred in both treatment arms. We analyzed the type of salvage treatment and outcome of these relapsing patients.

**Methods:** In the H10 trial, previously untreated patients, 15-70 years old, with classical supradiaphragmatic stage I-II HL, both favorable (F) and unfavorable (U) according to EORTC/LYSA criteria, were eligible. The primary protocol treatment for earlyPET (after 2xABVD) negative patients consisted of: in F patients, 3xABVD+involved-node radiotherapy (INRT) or 4xABVD; in U patients 4xABVD+INRT or 6xABVD. In 2010, the H10 trial was amended since more early relapses occurred in the CT arm of the trial and from that moment on, all early PETnegative patients received CMT. All earlyPET negative patients who relapsed were included in the current analysis and grouped in the CMT or CT group, dependent of the actually delivered primary treatment. The type of salvage treatment was left to the discretion of the investigator. Second progression/relapse (PFS2) was defined as the time from randomization to objective tumor progression on next-line treatment or death from any cause.

**Results:** Ninety-four earlyPET negative patients relapsed, 28 of those after initial CMT and 66 after CT. Their demographic and disease characteristics are described in table 1. In CMT, almost all relapses occurred in the U group whereas in CT relapses both in F and in U. Regarding salvage treatment, 69 patients received 1 line of treatment, 9 received 2 lines and 15 received 3 lines or more; for one patient, this information is missing. Overall, 66 (71%) patients received autologous stem cell transplantation (ASCT) and 29% received CT and/or RT. After CMT, the first salvage treatment was ASCT in 25/28 patients, while after CT the ASCT was first line salvage in 41/66. Overall, relapsed patients had a similar number of treatment lines whether they were initially treated with CMT or CT, but the type of treatment differed significantly with more ASCT in the CMT group (89.3% vs 63.1%, p = 0.012). There was no significant difference in OS or PFS2 between relapsing patients treated initially with CMT or CT: 3y-OS of 89% (95% CI: 69.7-96.3) vs 93.9% (95% CI: 84.6-97.7 resp.) and PFS2 (3y-PFS2 of 79.6 (95% CI:57.5-91) vs 78% (95% CI:65.7-86.3, resp.). The 3y-PFS2 and OS of patients undergoing ASCT was 62.8% and 93.9% and the 3-y PFS and OS of patients treated with CT and/or RT only was 88.9% and 88.6% respectively.

**Conclusion:** The outcome of earlyPET negative patients relapsing after first line treatment is good, irrespective of initial treatment with CMT or CT. More patient received ASCT as first line salvage in the CMT group. The PFS2 and OS were comparable in patient treated with initial CMT and CT.

**Keywords:** Hodgkin lymphoma (HL).

## 241
FIRST SALVAGE TREATMENT WITH BENDAMUSTINE AND BRENTUXIMAB VEDOTIN IN HODGKIN LYMPHOMA: A PHASE 2 STUDY OF FIL ONLUS

**V. Stefoni¹** | **A. Broccoli¹** | **B. Botto²** |

**P. Corradini³** | **A. Pinto⁴** | **A. Re⁵** | **U. Vitolo²** |

**S. Fanti⁶** | **L. Argnani¹** | **P. Zinzani¹**

¹Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy; ²Hematology, Department of Oncology, University Hospital Città della Salute e della Scienza, Turin, Italy; ³IRCCS Istituto Nazionale dei Tumori, University of Milano, Milan, Italy; ⁴Hematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione Pascale, Naples, Italy; ⁵Hematology, Azienda socio-sanitaria territoriale, Ospedali Civili di Brescia, Brescia, Italy; ⁶Nuclear Medicine, Medicina Nucleare Metropolitana, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

**Introduction:** Effective salvage options inducing high complete metabolic response (CMR) rates without significant toxicity are needed for Hodgkin lymphoma (HL) patients failing induction treatment and who are candidate to autologous stem cell transplantation (ASCT). Brentuximab vedotin (BV) and bendamustine are monotherapies both active in the relapsed/refractory setting and their combination (the BBV regimen) possibly enhances their activity.

**Methods:** A single-arm multicenter phase 2 study investigating the efficacy and safety of BBV as first salvage therapy in 40 patients with relapsed/refractory HL was conducted. Intravenous bendamustine was administered at the dose of 90 mg/m² (day 1 and 2) and BV at the standard dose of 1.8 mg/kg (day 1) every 21 days, for 2-6 cycles. Patients with at least disease stability could mobilize peripheral blood stem cells (PBSC) and proceed to ASCT.

**Results:** Thirty-eight patients were evaluable for efficacy: 30 (78.9%) had a CMR and 2 (5.3%) a partial response, leading to an overall response rate (ORR) of 84.2%. The ORR in the primary refractory subset was 75.0%, among relapsed patients it was 94.4%. Thirty-five patients could mobilize PBSC and 33 underwent ASCT. At a median follow-up of 23 months, the estimated 3-year overall survival and progression-free survival are 88.1% and 67.3%. During therapy, only 3 grade IV cases of neutropenia occurred and resolved within a week. No grade 4 extra-hematologic toxicities were reported; skin reactions were however rather frequent and involved 26 patients overall.

**Conclusions:** These results suggest that the BBV regimen exhibits promising efficacy and a manageable toxicity in a challenging subpopulation of HL patients.

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

**Disclosures:** Zinzani, P: Consultant Advisory Role: Verastem, MSD, EUSAPHARMA, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, Immune Designa, Celgene, Portola, Roche, Kyowa Kirin.

## 242
PHASE 1B KEYNOTE-013 STUDY OF PEMBROLIZUMAB IN PATIENTS WITH CLASSIC HODGKIN LYMPHOMA AFTER BRENTUXIMAB VEDOTIN FAILURE: RESULTS OF >4 YEARS OF FOLLOW-UP
<table><caption>TABLE 1</caption><thead><tr><th></th><th>Total Population N=31</th><th>ASCT Unsuccessful/Received BV After ASCT n=16</th><th>ASCT-Ineligible/Received BV n=8</th><th>ASCT Unsuccessful/Received BV Before ASCT n=7</th></tr></thead><tbody><tr><td>Objective response (CR +PR), % (95% CI)</td><td>58 (39-76)</td><td>69 (41-89)</td><td>38 (9-76)</td><td>57 (18-90)</td></tr><tr><td>Complete remission (CR), %</td><td>19</td><td>19</td><td>25</td><td>14</td></tr><tr><td>Partial remission (PR), %</td><td>39</td><td>50</td><td>13</td><td>43</td></tr><tr><td>Stable disease, %</td><td>23</td><td>19</td><td>38</td><td>14</td></tr><tr><td>Progressive disease, %</td><td>19</td><td>13</td><td>25</td><td>29</td></tr></tbody></table>

P.L. Zinzani<fnref n="1" /> | P. Armand<fnref n="2" /> | V. Ribrag<fnref n="3" /> | J. Michot<fnref n="3" /> | J. Kuruvilla⁴ | Y. Zhu⁵ | M. Farooqui⁵ | A. Nahar⁵ | C.H. Moskowitz⁶

**Introduction:** Programmed death-1 (PD-1) inhibitors are an effective treatment option for patients (pts) with relapsed/refractory classic Hodgkin lymphoma (cHL). The multicohort phase 1b KEYNOTE-013 study (NCT01953692) of the PD-1 inhibitor pembrolizumab (pembro) in pts with hematologic malignancies included cHL as an independent expansion cohort. To better understand the durability of responses in this patient population, we present long-term follow-up results for the cHL cohort.

**Methods:** Pts with cHL who experienced relapse after, were ineligible for or refused autologous stem cell transplantation (ASCT) and whose

disease progressed after brentuximab vedotin (BV) therapy were enrolled. Pts received pembro IV 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points were safety and complete remission rate (CRR) per central review. Secondary end points were overall response rate (ORR) duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Data cutoff was September 28, 2018.

**Results:** Among enrolled patients (N = 31), median follow-up was 52.8 mo (range, 7.0-57.6). The median number of lines of prior therapy was 5 (range, 2-15), and in 74% of pts, prior ASCT was ineffective. At analysis, 81% of pts had discontinued, primarily because of progression (48%), and 19% of pts had completed treatment. CRR was 19% and partial remission was 39%; ORR was 58% (18/31) (Table). Median DOR was not reached (Figure). Seven patients had a response duration ≥12 mo; 2 patients had a response duration ≥36 mo. Median PFS was 11.4 mo (95% CI, 4.9-27.8); 24-mo PFS rate was 30% (Figure). Median OS was not reached; 24-mo and 36-mo OS rates were 87% and 81%, respectively. Among pts refractory to (n = 11) and not refractory to (n = 20) first treatment, CRR was 27% and 15% respectively; ORR was 55% and 60%. By transplant status and BV status at baseline, ORR was 69% among pts who received BV after ASCT failure, 57% among pts with failed ASCT and BV before ASCT and 38%

<figure><img src="image_162.png" /></figure>

<figure><img src="image_163.png" /></figure>

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

<footnote n="2">²Medical Oncology, Dana-Farber Cancer Institute, Boston, United States;</footnote>

<footnote n="3">³Medical Oncology, Institut Gustave Roussy, Villejuif, France; ⁴Medical Oncology and Hematology, Princess Margaret Cancer Centre and University of Toronto, Toronto, Canada; ⁵Medical Oncology, Merck & Co, Inc., Kenilworth, United States; ⁶Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, United States</footnote>
among pts who received BV and were ineligible for ASCT (Table). Overall, 22 pts (71%) experienced treatment-related adverse events (TRAEs), with diarrhea (23%) the most common; 6 pts (19%) experienced grade 3-5 TRAEs.

**Conclusions:** After a median follow-up of >4 years, some heavily pretreated pts for whom BV therapy was ineffective maintained long-term response with single-agent pembro. The safety profile of pembro was tolerable and as expected.

**Keywords:** Hodgkin lymphoma (HL); PD-1; Pembrolizumab.

**Disclosures:** Zinzani, P: Consultant Advisory Role: Verastem, MSD, Eusapharma, Sanofi, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, Immune Design, Celgene, Portola, Roche, Kyowa Kirin; Other Remuneration: Speaker's Bureau: Verastem, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, Immune Design, Celgene, Portola, Roche, Eusapharma, Kyowa Kirin. Armand, P: Employment Leadership Position: Merck & Co., Inc., Bristol Myers Squibb Pharmaceuticals, Infinity Pharmaceuticals; Consultant Advisory Role: Merck & Co., Bristol Myers Squibb Pharmaceuticals, Infinity Pharmaceuticals; Research Funding: Merck & Co., Bristol Myers Squibb Pharmaceuticals, Pfizer, Inc, Affimed, Roche, Serventa, Otsuka, Sigma-Tau; Other Remuneration: Travel fees, gifts, and others: Bristol Myers Squibb Pharmaceuticals, Merck & Co.

**Ribrag, V:** Employment Leadership Position: Gilead, Infinity, Bristol Myers Squibb Pharmaceuticals, Laboratoires Servier, NanoString Technologies, Incyte Corporation; Consultant Advisory Role: Gilead, Infinity, Bristol Myers Squibb Pharmaceuticals, Laboratoires Servier, NanoString Technologies, Incyte Corporation; Research Funding: Amgen; Other Remuneration: Travel fees, gifts, and others: Roche, Bristol Myers Squibb Pharmaceuticals. Kuruvilla, J: Consultant Advisory Role: Merck; Other Remuneration: Payment for lectures including service on speaker's bureau: Merck. Zhu, Y: Employment Leadership Position: Merck.

**Farooqui, M:** Employment Leadership Position: Merck & Co., Inc.; Stock Ownership: Merck & Co., Inc. Nahar, A: Employment Leadership Position: Merck & Co., Inc. Moskowitz, C: Employment Leadership Position: Celgene, Genentech, Merck & Co., Seattle Genetics Inc.;

Consultant Advisory Role: Celgene, Genentech, Merck & Co., Seattle Genetics Inc.; Research Funding: Pharmacyclics, Genentech, Merck & Co., Seattle Genetics Inc.

## 243
CHECKPOINT INHIBITION BEFORE HAPLOIDENTICAL TRANSPLANTATION IN RELAPSED OR REFRACTORY HODGKIN LYMPHOMA PATIENTS IS ASSOCIATED WITH HIGHER PFS WITHOUT INCREASED TOXICITIES

C. de Philippis¹ | F. Legrande² | S. Bramanti¹ |

C. Montes de Oca² | R. Dulery³ | R. Bouabdallah² |

A. Granada² | R. Devillier² | J. Mariotti¹ |

B. Sarina¹ | S. Harbi² | V. Maisano² | S. Furst² |

T. Pagliardini² | P.J. Weiller² | C. Lemarie² |

B. Calmels² | C. Chabannon² | C. Carlo-Stella¹ |

A. Santoro¹ | M. Mohty³ | D. Blaise² | L. Castagna¹

¹Hematology, Humanitas Cancer Center, Rozzano, Italy; ²Hematology, Institut Paoli Calmettes, Marseille, France; ³Hematology, Hospital Saint-Antoine, Paris, France

**Background:** Immune checkpoint inhibitors (CPI) before allogeneic stem cell transplantation (SCT) could enhance allogeneic T-cell responses, increasing both the graft-versus-tumor effect and the incidence of immune complications.

**Methods:** We retrospectively analyzed the outcome of 52 consecutive HL patients undergoing haploidentical (haplo)-SCT with post-transplant cyclophosphamide as Graft Versus Host Disease (GVHD) prophylaxis between 2014 and 2018. The aim of this study was to

<table><thead><tr><th>Patient characteristics</th><th>No CPI treatment (n=24)</th><th>CPI treatment (n=28)</th><th>p</th></tr></thead><tbody><tr><td>Age at transplant</td><td>31 (9-64)</td><td>29 (20-61)</td><td></td></tr><tr><td>Prior autologous</td><td>22 (92%)</td><td>20 (71%)</td><td>0.58</td></tr><tr><td>Prior lines of therapy</td><td>4 (2-8)</td><td>6 (3-9)</td><td><strong>0.0006</strong></td></tr><tr><td>Disease status at SCT:</td><td></td><td></td><td></td></tr><tr><td>- CR</td><td>17 (71%)</td><td>18 (64%)</td><td></td></tr><tr><td>- PR</td><td>5 (21%)</td><td>8 (29%)</td><td>0.9</td></tr><tr><td>- SD</td><td>1 (4%)</td><td>-</td><td></td></tr><tr><td>- PD</td><td>1 (4%)</td><td>2 (7%)</td><td></td></tr><tr><td>Stem cells source</td><td></td><td></td><td></td></tr><tr><td>Bone marrow</td><td>5 (21%)</td><td>10 (36%)</td><td>0.35</td></tr><tr><td>Peripheral blood stem cells</td><td>19 (79%)</td><td>18 (64%)</td><td></td></tr><tr><td>Conditioning regimen</td><td></td><td></td><td></td></tr><tr><td>Non mieloablative</td><td>18 (75%)</td><td>19 (68%)</td><td>0.74</td></tr><tr><td>Reduced intensity</td><td>6 (25%)</td><td>9 (32%)</td><td></td></tr><tr><td>HCT-CI</td><td></td><td></td><td></td></tr><tr><td>0-1</td><td>4 (17%)</td><td>11 (39%)</td><td></td></tr><tr><td>2-3</td><td>17 (71%)</td><td>17 (61%)</td><td>0.40</td></tr><tr><td>4-5</td><td>3 (12%)</td><td>-</td><td></td></tr><tr><td>Median follow-up (months)</td><td>26.9 (6.5-55.1)</td><td>23.7 (10.3-43.1)</td><td>0.076</td></tr></tbody></table>
compare the outcome of 28 patients who received CPI before haplo-SCT to 24 patients who underwent haplo-SCT without prior CPI. Patients' characteristics are listed in Table 1. The two cohorts were similar in their main pre-transplant characteristics, except for the CPI group who received more line therapy.

**Results:** After a median follow-up of 26 months (range 7.5-55), taking into account all the patients, the 6-months cumulative incidence (CI) of aGVHD grade 2-4 was 33% (95% CI, 20-45), whereas the 2-year CI of moderate to severe cGVHD was 11.5% (95% CI, 4-24). The 1-year CI of NRM was 10% (95% CI, 8-31) and the 2-year CI of relapse was 13% (95% CI, 5-25). The 2-year OS and PFS were 78% (95% CI, 62-88) and 69.5% (95% CI, 52-82), respectively. In univariate analysis, prior use of CPI had no effect on either acute or chronic GVHD. The 6-month CI of grade 2-4 aGVHD was 39% (95% CI, 21-57) in the CPI group and 25% (95% CI, 10-44) in the non-CPI group (p = 0.23), while the 2-year CI of moderate to severe cGVHD was 16% (95% CI, 3-39) and 9% (95% CI, 1-26), respectively (p = 0.67). The 2-year CI of relapse in the CPI group was only 4% (95% CI, 0-16) versus 22% (95% CI, 8-41) (p = 0.08) in the non-CPI group. A significantly higher 2-year PFS was observed in the CPI group (89% (95% CI, 70-96) vs 54% (95% CI, 31-72), p = 0.029)). No differences were observed in OS and NRM between the two cohorts, the 2-year OS was 88% (95% CI, 66-96) in the CPI group vs 71% in the non-CPI group (95% CI, 47-86) (p = 0.30), and the 2-year CI of NRM was 10% (95% CI, 4-27) vs 24% (95% CI, 8-44) (p = 0.26) respectively. Based on the other pre-transplant characteristics, only a correlation between disease status at SCT and OS was found: the 2-year OS was 84% (95% CI, 61-94) in CR patients, 73% (95% CI, 35-91) in PR patients and 50% (95% CI, 6-85) in PD/SD patients (p = 0.04). In multivariate analysis, disease status other than CR had a negative impact on OS (hazard ratio (HR) 6.18 (95% CI, 1.13-33, 72) for PR and HR 14 (95% CI, 199-98.29) for PD/SD). Treatment with checkpoint inhibitors before SCT was an independent protective factor for PFS (HR 0.23 (95% CI, 0.05-0.92)).

**Conclusions:** CPI as a bridge to haplo-SCT significantly improve the PFS in relapse/refractory HL, lowering the relapse rate. Pre-treatment with CPI did not enhance the toxicity. However, the main limitation of our study lies in the small number of patients; further studies are warranted to extend our findings.

**Keywords:** allogeneic stem cell transplant (alloSCT); Hodgkin lymphoma (HL); nivolumab.

## 244
# HOW TO SELECT DONOR, STEM CELL SOURCE, AND CONDITIONING REGIMEN FOR HAPLOIDENTICAL TRANSPLANTS WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE FOR LYMPHOMA: A REPORT OF THE EBMT LWP

A. Bazarbachi¹ | A. Boumendil² | H. Finel² |

L. Castagna³ | A. Dominietto⁴ | D. Blaise⁵ |

J. Diez-Martin⁶ | J. Tischer⁷ | Z. Gülbas⁸ |
H. Labussière Wallet⁹ | L. Lopez Corral¹⁰ |
M. Mohty¹¹ | Y. Koc¹² | I. Yakoub-Agha¹³ |
C. Schmid¹⁴ | J. el Cheikh¹ | M. Arat¹⁵ |
E. Forcade¹⁶ | P. Dreger¹⁷ | V. Rocha¹⁸ |
G. Gutiérrez García¹⁹ | Y. Chalandon²⁰ | C. Ferra²¹ |
C. Orvain²² | S. Robinson²³ | S. Montoto²⁴ | A. Sureda²⁵

¹Internal medicine American University of Beirut Medical Center Beirut, Lebanon; ²Lymphoma Working Party EBMT LWP Paris Office/ Hôpital Saint-Antoine Paris, France; ³Hematology Istituto Clinico Humanitas Rozzano Milano, Italy; ⁴Hematology Second Division of Hematology and Bone Marrow Transplantation, IRCCS AOU San Martino-IST Genoa, Italy; ⁵Hematology Institut Paoli Calmettes Marseille, France; ⁶Hematology Hospital Gregorio Marañón Madrid, Spain; ⁷Hematology Klinikum Grosshadern Munich, Germany; ⁸Hematology Anadolu Medical Center Hospital Kocaeli, Turkey; ⁹HematologyCentre Hospitalier Lyon SudLyon, France; ¹⁰Hematology Hospital Clínico Salamanca, Spain; ¹¹Hematology Hôpital Saint Antoine Paris, France; ¹²HematologyMedical Park Hospitals Antalya, Turkey; ¹³Hematology Hôpital Huriez Lille, France; ¹⁴Hematology Klinikum Augsburg Augsburg, Germany; ¹⁵Hematology Florence Nightingale Sisli Hospitallstanbul, Turkey; ¹⁶Hematology CHU Bordeaux, France; ¹⁷Hematology University of Heidelberg Heidelberg, Germany; ¹⁸Hematology Hospital Sirio-Libanes Sao Paulo, Brazil; ¹⁹Hematology Hospital Clinic, Universitat de Barcelona IDIBAPS, Barcelona, Spain; ²⁰Hematology Hôpitaux Universitaires Geneva, Switzerland; ²¹Hematology ICO-Hospital Universitari Germans Trias i Pujol Barcelona, Spain; ²²Hematology CHRU Angers, France; ²³Hematology Bristol Oncology Centre Bristol, United Kingdom; ²⁴Hematology Barts Health NHS Trust London, United Kingdom; ²⁵Hematology ICO – Hospital Duran i Reynals Barcelona, Spain.

**Introduction:** Allogeneic stem cell transplantation (SCT) is potentially curative for patients with lymphoma, particularly those who progress after autologous SCT. For patients with no identical donor a haploidentical transplant (haploSCT) with post-transplant cyclophosphamide (ptCy) is becoming a major alternative. However, multiple haploidentical donors are often available and the identification of the best donor, as well as the adequate stem cell source and conditioning becomes a dilemma.

**Methods:** We used a large sample from the European Society for Blood and Marrow Transplantation registry. We identified 474 adults

<table><caption>TABLE 1</caption><thead><tr><td>Lymphoma subtype</td><td>2-year PFS</td><td>2-year OS</td></tr></thead><tbody><tr><td>Hodgkin</td><td>57%</td><td>72%</td></tr><tr><td>Follicular</td><td>56%</td><td>56%</td></tr><tr><td>Mantle cell</td><td>52%</td><td>61%</td></tr><tr><td>Diffuse large B cell</td><td>35%</td><td>35%</td></tr><tr><td>Peripheral T cell</td><td>54%</td><td>62%</td></tr></tbody></table>
(65% males; median age: 41 years) with Hodgkin lymphoma (HL; 240), peripheral T-cell lymphoma (PTCL; 88), diffuse large B-cell lymphoma (DLBCL; 77), mantle cell lymphoma (MCL; 40) or follicular lymphoma (FL; 29), who received a haploSCT with ptCy between 2010 and 2016.

**Results:** The median follow-up of alive patients was 32 months. The 2-year progression free survival (PFS) and overall survival (OS) for each lymphoma subtype are shown in Table 1. On multivariate analysis, acute GVHD (aGVHD) grade 2-4 was higher when using sibling donors (HR = 1.9 p = 0.01) whereas grade 3-4 was higher when using peripheral stem cells (HR = 4.5 p = 0.001) or CMV donor negative/recipient positive status (HR = 5.3 p = 0.04). Chronic GVHD was higher in male patients (HR = 1.7 p = 0.03) or those in partial response (PR) at SCT (HR = 1.7 p = 0.03) and lower with male donors (HR = 0.6 p = 0.02). Non-relapse mortality was lower in PTCL (HR = 0.4 p = 0.02) but higher in patients with refractory disease (HR = 2.2 p = 0.006), older patients (HR = 1.2 p = 0.02), a CMV donor positive /recipient positive status (HR = 2 p = 0.04), or the use of a reduced intensity conditioning other than "Baltimore" (HR = 1.7 p = 0.04). PFS and OS were lower for patients in PR (HR = 1.8 p = 0.001; and 1,6 p = 0.01, respectively), in refractory disease (HR = 3.3 p = 0.001; and 2.9 p = 0.001, respectively), or a CMV donor positive /recipient positive status (HR = 1.7 p = 0.01 for both), whereas a diagnosis of FL or HL positively affected PFS (HR = 04 p = 0.02; and 0.5 p = 0.001, respectively), and a diagnosis of PTCL improved PFS and OS (HR = 0.6 p = 0.02; and 0.5 p = 0.005 respectively). No other donor characteristics (age, gender, relationship to recipient, HLA mismatch, ABO incompatibility, or prior pregnancies) affected PFS or OS.

**Conclusion:** PFS and OS are mostly influenced by disease status and lymphoma subtype, supporting the use of any haploidentical family member as a donor.

**Keywords:** allogeneic stem cell transplant (alloSCT).

245
# IMPACT OF CLASS II HLA MISMATCH ON CLINICAL OUTCOMES IN HODGKIN LYMPHOMA PATIENTS RECEIVING HAPLOIDENTICAL STEM CELL TRANSPLANTATION (HAPLO-SCT) WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE (PT-CY)

L. Castagna<fnref n="1" /> | S. Bramanti<fnref n="1" /> | R. Devillier² |

T. Pagliardini² | B. Sarina<fnref n="1" /> | C. Lemarie² | S. Furst² |

J. Mariotti<fnref n="1" /> | A. Granata² | C. de Philippis<fnref n="1" /> |

S. Harbi² | F. Legrand² | V. Maisano² |

R. Bouabdallah² | C. Carlo-Stella<fnref n="1" /> | B. Calmels² |

C. Chabannon² | D. Blaise² | A. Santoro<fnref n="1" />

**Introduction:** In Hodgkin lymphoma (HL) patients unmanipulated Haplo-SCT with PT-Cy seems to induce a stronger graft versus lymphoma effect than conventional donors. Usually, HLA class II molecules are expressed infrequently on Hodgkin Reed-Sternberg cells, but their expression is a predictor of favorable outcome after immunotherapy with anti-PD-1 antibodies. This is a retrospective study aiming to evaluate the impact of class II HLA mismatch, both in graft versus host (GVH) and host versus graft (HVG) direction, between donor and recipient, after haplo-SCT in HL.

**Methods:** Donors and recipients were typed using the DNA method (sequence specific oligonucleotide and sequence based typing) for HLA-A, -B, -C, -DRB1, -DQ, at a high resolution level, as defined by European federation for immunogenetics standards. Class II HLA mismatch in the GVH direction was defined as the presence of host antigens or alleles not shared by the donor. HLA mismatch in the HVG direction was defined as the presence of donor antigens or alleles not shared by the host.

Patients were conditioned with nonmyeloablative or reduced intensity conditioning regimens, infused with bone marrow or peripheral blood stem cells, and graft versus host disease (GVHD) prophylaxis was PT-CY (at day +3 and +4), cyclosporine A/tacrolimus, and MMF (both from day +5).

**Results:** From March 2010 and March 2018, we retrospectively analyzed 85 patients in 2 institutions. 24 donor/recipient pairs had a class II mismatch: 17 in GVH direction and 7 in HVG direction. We evaluated the main clinical outcomes according to the presence of class II HLA mismatch in any direction. Comparing pairs with class II mismatch to pairs without, the CI of Grade 2-4 acute GVHD and Grade 3-4 acute GVHD was 8 % and 0% (p = 0.02) vs 33% and 5 % (p = 0.272), respectively. The CI of cGVHD was 0 % vs 9 % (p = 0.16). The 1-year relapse incidence was 13% and 26% (p = 0.176) and the 1-year NRM was 15 % and 20% (p = 0.489) The 2-year PFS was 73% vs 54 % (p = 0.081) and the 2-year OS was 80% and 67 %(p = 0.125), The 1-year graft-relapse-free survival (GRFS) was 73% vs 44 % (P = 0.012), respectively. In the multivariate analysis, the class II mismatch significantly reduce the risk of acute GVHD (HR 0.19, CI95 0.04 - 0.81, p = 0.025) and improve the GRFS (HR 0.27, CI95 0.11-0.68, p = 0.005). However, even if not statistically different probably due the low number of patients, the presence of mismatch improve the relapse incidence (HR 0.33, CI95 0.07-1.50, p = 0.15), PFS (HR 0.44, CI95 0.18-1.08, p = 0.07) and OS (HR 0.50, CI95 0.18-1.35, p = 0.17).

**Conclusions:** This study suggests that in HL patients treated with haplo-SCT with PT-Cy, a class II HLA mismatch, in GVH or HVG direction, can induce a strong anti-tumoral effect and protect from GVHD, translating in a high GRFS. These data should be analyzed in more patients, and if confirmed, this difference could be help in the donor selection.

<footnote n="1">¹Hematology, Humanitas Research Center, Rozzano, Italy; ²Hematology, Institut Paoli Calmettes, Marseille, France</footnote>
**Keywords:** allogeneic stem cell transplant (alloSCT); graft-versus-lymphoma; Hodgkin lymphoma (HL).

## IMMUNOTHERAPY

### 246
REAL-WORLD RESULTS ON CD19 CAR T-CELL FOR 60 FRENCH PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA INCLUDED IN A TEMPORARY AUTHORIZATION FOR USE PROGRAM

C. Thieblemont¹ | S. Le Gouill² | R. Di Blasi¹ |
G. Cartron³ | F. Morschhauser⁴ | E. Bachy⁵ |
J. Paillassa¹ | S. Bernard¹ | B. Tessoulin² |
T. Gastine² | N. Fegueux³ | T. Kanouni³ |
S. Manier³ | P. Sesques⁵ | R. Houot⁶ | C. Haouin⁷ |
H. Tilly⁸ | G. Salles⁵

¹Hematology, APHP, Saint-Louis Hospital, Paris, France; ²Hematology, CHU Nantes, Nantes, France; ³Hematology, CHU Montpellier, Montpellier, France; ⁴Hematology, CHU Lille, Lille, France; ⁵Hematology, CHU Lyon, Pierre-Benite, France; ⁶Hematology, CHU Rennes, Rennes, France; ⁷Hematology, APHP, Henri Mondor Hospital, Créteil, France; ⁸Hematology, Centre H. Becquerel, Rouen, France

**Background:** Autologous anti-CD19 chimeric antigen receptor (CD19 CAR) T-cell therapy demonstrated significant clinical benefit and a manageable safety profile for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), with 6-month ORR at 41-47% and CR at 32-41% in the 3 pivotal clinical trials (ZUMA1, TRANS-CEND, JUNO), leading to a rapid approval in third line R/R DLBCL in Europe and USA. Since April 2018 in France, a cohort patient program (called ATU) allowed to use the CD19 CAR T-cells, Axicabtagene and Tisagenlecleucel, for patients with DLBCL, primary mediastinal B-cell lymphomas (PMBL) and transformed FL (tFL), recurrent or refractory after ≥ 2 systemic therapy lines; CNS excluded.

**Methods:** We performed a retrospective analysis of the patients treated with Axicabtagene or Tisagenlecleucel between April 2018 and Feb 2019 in the 5 authorized centres. The eligibility criteria were confirmed based on age, comorbidities, LVEF ≥ 45%, no pericarditis or cardiogram abnormality, clearance ≥ 60 mL/min, ALT/AST ≤ 2.5 N, total bilirubin < 1.5 mg/dL, no pleural effusion, SpO2 > 92% without oxygen, lymphocytes ≥ 100/µL, no rapid progressive disease (compressive mass, PS > 2 or rapid increase of LDH), no active neurological disease, no auto-immune disease. The final decision was validated by a local multidisciplinary tumor board.

**Results:** A total of 60 patients have been selected for a treatment with Yescarta (30) or Kymriah (30). 73% of the patients were referred. Median age was 52 (range 18-77). 11 (18%) pts were over 65 years

old. 67% were male. By histology, patients presented with DLBCL (n = 42), PMBL (n = 8), trFL (n = 9), and transformed marginal zone lymphoma (n = 1). 68% were primary refractory defined as progressive or stable disease as the best response to the most recent chemotherapy regimen or disease progression or relapse within 12 months after autologous stem cell transplantation (ASCT). Median number of prior lines was 3 (range 2 to 9) and 18 (30%) pts had a prior ASCT. Only one leukapheresis was necessary, except for 4 patients who required 2-4 leukapheresis. At time of analysis, 45 patients have been reinfused. 5 patients died before reinfusion, 3 because progressive disease and 2 because of infections. The median time duration between the ATU validation and receipt of the CD19 CAR T-cells was 47.5 days (range 30-190 days). During this time, all patients except 4 (93%) received a bridging therapy. The median time between the receipt of the cells and their infusion was 6 days (range 1 to 20 days). Data regarding efficacy and tolerance will be further analysed.

**Conclusion:** The time elapsed between ATU validation and CAR T-cell reception remains substantial and a bridging therapy was necessary for almost all patients. The LYSA group and the CALYM institute (www.calym.org) are organizing a national registration program for these patients with clinical and biological data collection.

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

**Disclosures:** Thieblemont, C: Consultant Advisory Role: Gilead, Roche, Novartis, Janssen, Takeda, Bayer, Kyte.

### 247
SAFETY AND PRELIMINARY EFFICACY IN PATIENTS WITH RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA RECEIVING LISOCABTAGENE MARALEUCEL IN TRANSCEND NHL 001

M. Wang¹ | L.I. Gordon² | M.L. Palomba³ |
J.S. Abramson⁴ | C. Andreadis⁵ | N. Ghosh⁶ |
M. Lunning⁷ | D. Maloney⁸ | T. Farazi⁹ |
J. Garcia¹⁰ | B. Xie¹¹ | K. Newhall¹² | C. Dehner¹² |
T. Siddiqi¹³

¹Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States; ²Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, United States; ³Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States; ⁴Center for Lymphoma, Massachusetts General Hospital Cancer Center, Boston, United States; ⁵Department of Medicine, University of California, San Francisco, United States; ⁶Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, United States; ⁷Hematology/Oncology, University of Nebraska Medical Center, Omaha, United States; ⁸Clinical Research Division, Fred Hutchison Cancer Research Center, Seattle, United States; ⁹Clinical Research and Development, Juno Therapeutics, a Celgene Company, Seattle, United States; ¹⁰Clinical Research & Development, Juno
Therapeutics, a Celgene Company, Seattle, United States; ¹¹Biostatistics, Juno Therapeutics, a Celgene Company, Seattle, United States; ¹²Clinical Operations, Juno Therapeutics, a Celgene Company, Seattle, United States; ¹³Hematology/ Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, United States

**Introduction:** Most patients with mantle cell lymphoma (MCL) relapse after first-line immunochemotherapy, with poor responses to salvage therapy. We report initial dose-finding results from patients with relapsed/refractory MCL treated with lisocabtagene maraleucel (liso-cel; JCAR017), an investigational, anti-CD19 chimeric antigen receptor (CAR) T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the ongoing phase 1 TRANSCEND study.

**Methods:** Eligible patients had confirmed MCL (cyclin D1 expression, t[11;14]) with relapsed/refractory disease after ≥1 prior lines of therapy. After lymphodepleting chemotherapy, liso-cel was administered at 1 of 2 dose levels: dose level 1 (50 × 10⁶ total CAR+ T cells) or dose level 2 (100 × 10⁶ total CAR+ T cells).

**Results:** At data cutoff, 9 patients (n = 6 at dose level 1 and n = 3 at dose level 2) had received liso-cel. The median (range) age was 66 (58–78) years; 7 patients were male. Histologies included blastoid (n = 3) and pleiomorphic (n = 1) variants. Eight patients had documented Ki67 >30% (40%–80%); 1 patient had TP53 mutation. Patients had received a median of 5 (3–7) prior therapies; 3 patients had received prior hematopoietic stem cell transplant. All 9 patients had prior ibrutinib; 4 had a best response of progressive disease on ibrutinib. Six of 9 patients (67%) received bridging chemotherapy. Four of 9 patients (44%) had serious treatment-emergent adverse events (TEAEs). Five of 9 patients (56%) had grade 3/4 TEAEs, primarily anemia, neutropenia, and hypophosphatemia (22% each). Three of 9 patients (33%) had cytokine release syndrome (CRS); all were grade 1. Median time to CRS onset was 6 (2–7) days; median time to resolution was 6 (2–6) days. One patient received tocilizumab and corticosteroids. There were no neurological events. Four patients died, all in dose level 1 (3 from disease progression; 1 after receiving a new anticancer therapy post liso-cel). Overall response rate was 78% (7/9 patients; 4/6 in dose level 1, median follow-up 12.4 [95% CI: 9.2–12.4] mo; 3/3 in dose level 2, median follow-up 1.4 [95% CI: 1.0–1.4] mo). Two patients in dose level 1 maintained a durable complete response until last follow-up (day 281 and 378, respectively). Median time to peak CAR+ T cell expansion: 9.5 (9–10) days at dose level 1 and 17.5 (10–27) days at dose level 2.

**Conclusions:** In this phase 1 study in patients with relapsed/refractory MCL, liso-cel treatment showed tolerable toxicity and had clinical activity. Updated data for dose level 2 and longer follow-up will be presented.

**Keywords:** CD19; mantle cell lymphoma (MCL); T-cells.

**Disclosures:** Wang, M: Consultant Advisory Role: BioInvent International, IO Biotech, Celgene, Juno, Janssen, Pharmacyclics, AstraZeneca, MoreHealth, Pulse Biosciences, AxImmune; Stock Ownership: MoreHealth; Honoraria: Janssen, Dava Oncology OMI, PeerView

Institute for Medical Education (PVI); Research Funding: Dr. Wang's institution is the recipient of research funding from: Janssen, AstraZeneca, Acerta Pharma, Kite Pharma, Juno, BeiGene, Novartis, Celgene, BioInvent International, Karus, Oncternal, Amgen; Other Remuneration: Travel, Accommodations, Expenses from: Janssen, AstraZeneca, Celgene, Dava Oncology, OMI. Gordon, L: Consultant Advisory Role: Juno, Bayer, Gillead; Other Remuneration: Patents: Zylem. Palomba, M: Consultant Advisory Role: Merck, Pharmacyclics; Stock Ownership: Seres Therapeutics (Immediate Family Member COI); Honoraria: Flagship Ventures (Immediate Family Member COI), Novartis (Immediate Family Member COI), Evelo (Immediate Family Member COI), Seres Therapeutics (Immediate Family Member COI), Jazz Pharmaceuticals (Immediate Family Member COI), Therakos (Immediate Family Member COI), Amgen (Immediate Family Member COI), Merck & Co. Inc (Immediate Family Member COI); Other Remuneration: Patents, Royalties, Other Intellectual Property: Seres Therapeutics (Immediate Family Member COI), Juno (Immediate Family Member COI). Abramson, J: Consultant Advisory Role: Gilead Sciences, Seattle Genetics, Celgene, Novartis, Amgen, Juno Therapeutics, Karyopharm, Verastem, Bayer, Abbvie, Janssen, Merck, Kite Pharma, Genentech, EMD Serono; Research Funding: Seattle Genetics, Celgene, Genentech, Juno Therapeutics, Al Therapeutics. Andreadis, C: Employment Leadership Position: Genentech employee (spouse); Consultant Advisory Role: Celgene, Novartis, Gilead, Seattle Genetics, Jazz, Astellas; Stock Ownership: Roche; Research Funding: Novartis, Celgene, Amgen, Merck. Ghosh, N: Consultant Advisory Role: Celgene, Juno Therapeutics. Lunning, M: Consultant Advisory Role: AbbVie, Bayer, Celgene, Genentech, Gilead Sciences, Inc, Janssen/Pharmacyclics, Juno Therapeutics, Kite, Novartis, Portola, Sanofi-Genzyme, Seattle Genetics, Spectrum, TG Therapeutics, Verastem; Research Funding: Dr. Lunning's institution is the recipient of research funding from: Celgene, Curis, Janssen Scientific Affairs, LLC, Juno Therapeutics, miRagen, Pharmacyclics, TG Therapeutics. Maloney, D: Honoraria: Kite Pharma, Gilead, Genentech, Novartis, Eureka; Research Funding: Dr. Maloney's institution is the recipient of research funding from: Kite Pharma, Juno Therapeutics, Celgene; Other Remuneration: Travel, Accommodations, Expenses from A2 Biotherapeutics; Patents pending for Methods and Compositions Related to Toxicity Associated with Cell Therapy, Methods for the Treatment of B Cell Malignancies Using Adoptive Cell Therapy, Biomarkers and Uses Thereof for Selecting Immunotherapy Intervention, Methods for Adoptive Cell Therapy Targeting ROR1. Farazi, T: Employment Leadership Position: Juno Therapeutics, a Celgene Company; Stock Ownership: Juno Therapeutics, a Celgene Company. Garcia, J: Employment Leadership Position: Juno Therapeutics, a Celgene Company; Stock Ownership: Celgene, Amgen; Other Remuneration: Patents, Royalties, Other Intellectual Property: Juno Therapeutics. Travel, Accommodations, Expenses: Celgene. Xie, B: Employment Leadership Position: Juno Therapeutics, a Celgene Company, Seattle Genetics (Immediate Family Member COI); Stock Ownership: Juno Therapeutics, a Celgene Company, Seattle Genetics (Immediate Family Member COI). Newhall, K: Employment Leadership Position: Juno Therapeutics, a Celgene Company; Stock Ownership: Juno Therapeutics, a Celgene Company. Dehner, C: Employment Leadership Position: Juno Therapeutics, a
Celgene Company; Stock Ownership: Juno Therapeutics, a Celgene Company. Siddiqi, T: Consultant Advisory Role: AstraZeneca, Juno, BeiGene; Research Funding: Dr. Siddiqi's institution received research funding from Juno, Celgene, Kite, Pharmacyclics, BeiGene, AstraZeneca, Oncternal, TG therapeutics; Other Remuneration: Speaker for Pharmacyclics, Jansen, Seattle Genetics, AstraZeneca.

248
OUTCOMES OF PATIENTS ≥ 65 YEARS OF AGE IN ZUMA-1, A PIVOTAL PHASE 1/2 STUDY OF AXICABTAGENE CILOLEUCEL (AXI-CEL) IN REFRACTORY LARGE B CELL LYMPHOMA

S.S. Neelapu¹ | C.A. Jacobson² | O.O. Oluwole³ |
J. Munoz⁴ | A. Deol⁵ | D.B. Miklos⁶ |
N.L. Bartlett⁷ | I. Braunschweig⁸ | Y. Jiang⁹ |
J.J. Kim⁹ | L. Zheng⁹ | J.M. Rossi⁹ | F.L. Locke¹⁰

¹Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States; ²Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; ³Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, United States; ⁴Cancer Immunotherapy Program, Banner MD Anderson Cancer Center, Gilbert, United States; ⁵Department of Oncology, Karmanos Cancer Center, Wayne State University, Detroit, United States; ⁶Medicine - Med/Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, United States; ⁷Department of Medicine Oncology Division Medical Oncology, Washington University School of Medicine and Siteman Cancer Center, St. Louis, United States; ⁸Department of Medicine (Oncology), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, United States; ⁹Clinical Development and Biostatistics, Kite, a Gilead Company, Santa Monica, United States; ¹⁰Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, United States

**Background:** Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved in the European Union and the United States for the treatment of patients with relapsed or refractory large B cell lymphoma with ≥ 2 prior systemic therapies. In the 2-year follow-up of ZUMA-1, the objective response rate was 83% with a complete response rate of 58%, and 39% of patients were in ongoing response (Locke et al. *Lancet Oncol.* 2019). Here, we report efficacy and safety outcomes by age.

**Methods:** Eligible patients with refractory large B cell lymphoma underwent leukapheresis and conditioning chemotherapy followed by a target dose of 2 × 10⁶ anti-CD19 CAR T cells/kg. The Phase 2 primary endpoint was investigator-assessed objective response rate. Additional key endpoints were adverse events, overall survival, and levels of CAR gene-marked cells in peripheral blood. Efficacy was evaluated for Phase 2 patients; safety was evaluated for all treated

patients (Phases 1 and 2). Patients were analyzed by age ≥ 65 years vs
< 65 years.

**Results:** As of August 11, 2018, 108 patients were treated. Patients aged ≥ 65 years (n = 27) vs < 65 years (n = 81) had a median age of 69 years vs 55 years, respectively, and were 81% vs 63% male; 70% vs 36% had an International Prognostic Index score of 3-4, 59% vs 57% had an Eastern Cooperative Oncology Group performance status of 1, 67% vs 72% had ≥ 3 prior therapies, and median tumor burdens were 3790 mm² vs 3574 mm². Median follow-up was 27.1 months for Phase 2 patients (n = 101). The objective response rate for patients ≥ 65 years (n = 24) and < 65 years (n = 77) was 92% and 81% (complete response rate, 75% and 53%), respectively, with ongoing responses in 42% and 38% of patients (ongoing complete response, 42% and 35%). The 24-month overall survival rate was 54% for patients ≥ 65 years and 49% for patients < 65 years. Most patients experienced Grade ≥ 3 adverse events (100% of patients ≥ 65 years; 98% of patients < 65 years), and 4% of each group (1/27 patients ≥ 65 years and 3/81 patients < 65 years) died due to adverse events as previously reported. Grade ≥ 3 neurologic events and cytokine release syndrome occurred in 44% vs 28% and 7% vs 12% of patients ≥ 65 years vs < 65 years, respectively. CAR T cell expansion by peak level (43 vs 35 cells/µL) or area under the curve (562 vs 448 days × cells/µL) was similar in patients ≥ 65 years vs < 65 years, respectively.

**Conclusions:** The 2-year follow-up of ZUMA-1 demonstrates that axi-cel can induce high rates of durable responses with a manageable safety profile for patients ≥ and < 65 years. Axi-cel offers substantial clinical benefit for older patients with refractory large B cell lymphoma who otherwise have limited treatment options.

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

**Disclosures:** Neelapu, S: Consultant Advisory Role: Merck Sharp & Dohme, Celgene, Kite, a Gilead Company, Novartis, Unum Therapeutics, Cell Medica, Incyte, Gilead Sciences, Pfizer, Precision Biosciences; Honoraria: Bio Ascend, Medscape, Physician Education Resource, Dava Oncology; Research Funding: Celgene, Bristol-Myers Squibb, Merck Sharp & Dohme, Kite, a Gilead Company, Pharmacyclics, Acerta Pharma, Cellectis, Poseida Therapeutics, Karus Therapeutics, Unum Therapeutics, Gilead Sciences; Other Remuneration: Travel, Accommodations, Expenses: DAVA Oncology, Medscape, Physician Education Resource, Kite, a Gilead Company, Gilead Sciences, Merck, Unum Therapeutics, Celgene, Chugai Pharma, Precision Biosciences, Novartis, Pfizer. Jacobson, C: Other Remuneration: Kite, a Gilead Company, Novartis, Precision Biosciences, Bayer, Pfizer, Humanigen. Oluwole, O: Consultant Advisory Role: Pfizer, Kite, a Gilead Company, Bayer, Spectrum. Munoz, J: Consultant Advisory Role: Kite, a Gilead Company, Pfizer, Bayer, Alexion Pharmaceuticals, Bristol-Myers Squibb, Janssen, Seattle Genetics, Gilead Sciences, Kyowa Hakko Kirin, Juno Therapeutics, Genentech, Celgene; Other Remuneration: Speakers' Bureau: Kite, a Gilead Company, Bayer, Pharmacyclics/Janssen, AstraZeneca, Gilead Sciences. Deol, A: Consultant Advisory Role: Novartis, Kite, a Gilead Company, Agios. Miklos, D: Consultant Advisory Role: Kite, a Gilead Company, Adaptive Biotechnologies, Novartis, Juno/Celgene, Pharmacyclics, Janssen; Honoraria: Sanofi; Research Funding: Pharmacyclics, Novartis, Roche/Genentech, Kite, a Gilead Company, Adaptive Biotechnologies; Other Remuneration: Travel,
Accommodations, Expenses: Kite, a Gilead Company, Pharmaceuticals/Janssen, Adaptive Biotechnologies, Sanofi, Juno Therapeutics; Patent: Patent held with Pharmacyclics supporting Ibrutinib for cGVHD (no royalty claim). Bartlett, N: Consultant Advisory Role: Pfizer; Research Funding: Affimed Therapeutic, Bristol-Myers Squibb, Celgene, Forty Seven, Genentech, Gilead Sciences; Other Remuneration: Immune Design, Kite, a Gilead Company, Merck, Millennium, Pharmacyclics, Acerta Pharma. Braunschweig, I: Other Remuneration: Speakers' Bureau: Kite, a Gilead Company. Jiang, Y: Employment Leadership Position: Kite, a Gilead Company; Stock Ownership: Gilead Biosciences. Kim, J: Employment Leadership Position: Kite, a Gilead Company. Zheng, L: Employment Leadership Position: Kite, a Gilead Company. Rossi, J: Employment Leadership Position: Kite, a Gilead Company; Stock Ownership: Gilead Biosciences. Locke, F: Consultant Advisory Role: Cellular Biomedicine Group, Kite, a Gilead Company, Novartis; Research Funding: FORMA Therapeutics.

249

SAFETY AND EFFICACY OF
AXICABTAGENE CILOLEUCEL (AXI-CEL) IN
OLDER PATIENTS: RESULTS FROM THE US
LYMPHOMA CAR-T CONSORTIUM

D. Sano¹ | L. Lekakis² | L. Feng¹ | L.J. Nastoupil¹ |

M.D. Jain³ | J.Y. Spiegel⁴ | S. Dahiya⁵ | Y. Lin⁶ |

A. Ghobadi⁷ | M. Lunning⁸ | B.T. Hill⁹ |

P. Reagan¹⁰ | O. Oluwole¹¹ | J. McGuirk¹² |

A. Sehgal¹³ | A. Deol¹⁴ | A. Charalambos¹⁵ |

A.H. Goy¹⁶ | J. Munoz¹⁷ | A. Cashen¹⁸ |

N.N. Bennani⁶ | A.P. Rapoport⁵ | J.M. Vose⁸ |

D.B. Miklos⁴ | F.L. Locke³ | S.S. Neelapu¹

¹Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, United States; ²Bone Marrow Transplant/Hematology, University Of Miami, Miami, United States; ³Blood, Bone Marrow Transplant and Cellular Therapy, Moffitt Cancer Center, Tampa, United States; ⁴Hematology, Stanford University, Stanford, United States; ⁵Hematology/Bone Marrow Transplant, University of Maryland Medical Center, Baltimore, United States; ⁶Hematology, Mayo Clinic, Rochester, United States; ⁷Bone Marrow Transplant, Washington University Medical Campus, Saint Louis, United States; ⁸Hematology/Oncology, University of Nebraska Medical Center, Omaha, United States; ⁹Hematology and Medical Oncology, Cleveland Clinic, Cleveland, United States; ¹⁰Lymphoma, University of Rochester Medical Center/Wilmot Cancer institute, Rochester, United States; ¹¹Hematology and Oncology, Vanderbilt University Medical Center, Nashville, United States; ¹²Hematological Malignancies and Cellular Therapeutic, The University of Kansas Health System, Kansas City, United States; ¹³Hematology and Oncology, UPMC Hillman Cancer Center, Pittsburgh, United States; ¹⁴Department of Oncology, Wayne State University/Karmanos Cancer Center, Detroit, United States;

¹⁵Hematology and Bone Marrow Transplant, University of California San Francisco, San Francisco, United States; ¹⁶Hematology and Oncology,

Hackensack University Medical Center, Hackensack, United States;
¹⁷Lymphoma/Myeloma, Banner MD Anderson Cancer Center, Gilbert, United States; ¹⁸Bone Marrow Transplantation & Leukemia, Washington University Medical School, St. Louis, United States

†DS and LL contributed equally.

**Introduction:** Axi-cel, an autologous anti-CD19 CAR T-cell therapy, induced an overall response rate (ORR) of 83% and complete response (CR) rate of 58% in patients with refractory large B-cell lymphoma on the pivotal ZUMA-1 study. At a median follow-up of 27.1 mo, 39% of the patients remain in remission (Neelapu et al. N Eng J Med 2017; Locke et al, Lancet Oncol 2019). Here, we present retrospective analysis of safety and efficacy outcomes in older patients treated with axi-cel in the post-approval setting from a 17-center US Lymphoma CAR-T Consortium.

**Methods:** Patients with relapsed/refractory diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, high-grade B-cell lymphoma, or transformed follicular lymphoma, received axi-cel infusion following conditioning with cyclophosphamide and fludarabine. Bridging therapy was allowed. Cytokine release syndrome (CRS) was graded by Lee criteria and neurotoxicity (CAR-related encephalopathy syndrome or CRES) was graded according to CTCAE or CARTOX system.

**Results:** Of 300 apheresed patients, 206 (69%) were <65 years (yrs) and 94 (31%) were ≥65 yrs. Baseline characteristics such as gender, ECOG performance status, stage, number of prior lines of therapy, prior autologous transplant, refractory status, and bridging therapy usage were comparable between the two groups but patients ≥65 yrs had higher IPI (IPI 3-5: 77% vs. 44%, P<0.001). Of the apheresed patients, 14 (7%) patients <65 yrs and 10 (11%) patients ≥65 yrs did not receive axi-cel. Overall, 274 patients (191 <65 vs. 83 ≥65) were evaluable for safety and 272 patients (190 <65 vs. 82 ≥65) were evaluable for efficacy. Of the axi-cel-treated patients, best ORR through day 90 was comparable between the two groups (82% for all patients; 82% <65 vs. 84% ≥65, P = 0.61) but CR rate was higher in patients ≥65 yrs (57% for all patients; 51% <65 vs. 71% ≥65, P<0.01). Median follow-up for all patients was 5.9 months. Estimated median PFS (7.4 mo <65 vs. 9.2 mo ≥65, P = 0.83) and OS (18.7 mo <65 vs. not assessable ≥65, P = 0.99) were comparable between the two groups.

Incidence and severity of CRS was comparable in both groups (all CRS grades: 91% <65 vs. 92% ≥65; grade ≥3 CRS: 7% in both groups). There was a trend towards higher incidence of CRES in older patients (all CRES grades: 65% <65 vs. 78% ≥65, P = 0.08) but grade ≥3 CRES was comparable (31% <65 vs. 35% ≥65, P = 0.53). There were two axi-cel-related deaths, one in each group. The use of tocilizumab and corticosteroids were not significantly different between the two groups. Median hospitalization period was 14 days in both groups and ICU admission rate was 32% in both groups.

These safety and efficacy results had similar pattern when patients were grouped based on age cut-off of 60 or 70 yrs.
**Conclusions:** Our results suggest that the safety and efficacy of axi-cel are largely comparable between younger and older patients with the exception of CR rate, which was higher in older patients.

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

## 250 PRELIMINARY RESULTS OF EARLIER STEROID USE WITH AXICABTAGENE CILOLEUCEL (AXI-CEL) IN PATIENTS WITH RELAPSED/REFRACTORY LARGE B CELL LYMPHOMA

M.S. Topp¹ | T. Van Meerten² | M. Wermke³ |
P.J. Lugtenburg⁴ | M.C. Minnema⁵ | K.W. Song⁶ |
C. Thieblemont⁷ | Y. Jiang⁸ | V. Plaks⁹ |
A. Kerber¹⁰ | M.J. Kersten¹¹

¹Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany; ²Department of Hematology, University Medical Center Groningen on behalf of HOVON/LLPC (Lunenburg Lymphoma Phase I/II Consortium), Groningen, Netherlands; ³Medical Department I, University Hospital Carl Gustav Carus, Dresden, Germany; ⁴Lunenburg Lymphoma Phase I/II Consortium - HOVON/LLPC, Erasmus MC, Rotterdam, Netherlands; ⁵Department of Medical Oncology, University Medical Center Utrecht on behalf of HOVON/LLPC (Lunenburg Lymphoma Phase I/II Consortium), Utrecht, Netherlands; ⁶Division of Hematology | Department of Medicine, The University of British Columbia, Vancouver, Canada; ⁷Service Onco-Hematologie, Hôpital Saint Louis, Paris, France; ⁸Biostatistics, Kite, a Gilead Company, Santa Monica, United States; ⁹Cell Biology, Kite, a Gilead Company, Santa Monica, United States; ¹⁰Clinical Development, Kite, a Gilead Company, Santa Monica, United States; ¹¹Internal Medicine, Academic Medical Center University of Amsterdam on behalf of HOVON/LLPC (Lunenburg Lymphoma Phase I/II Consortium), Amsterdam, Netherlands

**Background:** Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved in the EU and US for patients with relapsed/refractory large B cell lymphoma with ≥ 2 prior systemic therapies. In the 2-year follow-up of ZUMA-1, the objective response rate was 83% with a complete response rate of 58%. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 11% and 32% of patients, respectively; 26% of patients received steroids, and 43% received tocilizumab (Locke et al. *Lancet Oncol.* 2019). A safety expansion cohort was added to evaluate the effect of earlier steroid use on the rates of these adverse events (AEs).

**Methods:** Eligible patients with relapsed/refractory large B cell lymphoma were leukapheresed and received conditioning chemotherapy followed by a target dose of 2 × 10⁶ anti-CD19 CAR T cells/kg. Patients in this cohort received early steroid intervention starting at Grade 1 NE and at Grade 1 CRS when no improvement

was observed after 3 days of supportive care. The primary endpoint for this cohort was incidence and severity of CRS and NE.

**Results:** As of September 14, 2018, 21 of 40 planned patients received axi-cel with a minimum follow-up of 1 month (median, 2.6 months). The median age was 63 years (range, 36 - 73), 67% were male, 81% had disease stage III-IV, 76% were relapsed/refractory to ≥ second-line therapy, and 10% had relapsed post-autologous stem cell transplantation. Seventy-six percent of patients received steroids and 81% received tocilizumab. Most patients (81%) had Grade ≥ 3 AEs, most commonly neutrophil count decreased (33%), anemia (29%), and pyrexia (24%). Grade ≥ 3 NE occurred in 10% of patients; the most common symptoms were somnolence (10%) and confusional state (10%). Grade 1 and 2 NE occurred in 38% and 5% of patients, respectively. No patient had Grade ≥ 3 CRS; 33% of patients had Grade 1 CRS and 67% had Grade 2. There were no deaths due to AEs; 1 patient died due to disease progression. The objective response rate per investigator assessment was 76% with 48% of patients achieving a complete response. Pharmacokinetic data will be presented.

**Conclusions:** Early use of steroids may help in managing severe CRS and NE by potentially reducing their incidence in patients treated with CAR T cell therapy without affecting response rates. Optimizing AE management may help to further improve the benefit-risk profile of CAR T cell therapy.

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

**Disclosures:** Topp, M: Consultant Advisory Role: Kite, a Gilead Company; Amgen; Roche; Regeneron. Wermke, M: Consultant Advisory Role: Bristol-Myers Squibb, Merck, Kite, a Gilead Company, and Novartis; Honoraria: Bristol-Myers Squibb, Merck, Roche, and Novartis; Other Remuneration: travel expenses from AstraZeneca and Bristol-Myers Squibb. Lugtenburg, P: Consultant Advisory Role: Takeda, Servier, Roche, Bristol-Myers Squibb, Celgene, Sandoz, and Genmab; Research Funding: Takeda and Servier. Minnema, M: Consultant Advisory Role: Servier, Takeda, Amgen, Janssen-Cilag; Research Funding: Celgene; Other Remuneration: travel expenses from Roche and Amgen. Song, K: Honoraria: Celgene, Janssen, Amgen, Novartis, Takeda; Research Funding: Celgene. Thieblemont, C: Honoraria: Celgene, Abbvie, Bayer, Janssen, Roche, Incyte; Research Funding: Roche. Jiang, Y: Employment Leadership Position: Kite, a Gilead Company; Stock Ownership: Gilead Sciences. Plaks, V: Employment Leadership Position: Kite, a Gilead Company. Kerber, A: Employment Leadership Position: Kite, a Gilead Company. Kersten, M: Consultant Advisory Role: Kite, a Gilead Company; Honoraria: Kite, a Gilead Company; Other Remuneration: travel expenses from Kite, a Gilead Company.

## 251 PHASE 1 STUDY OF ANTICD19 CAR-T CELLS WITH TNFα TRANSMEMBRANE DOMAIN AND 41BB, CD3ζ COSTIMULATORY DOMAINS. RESPONSES IN SUBJECTS WITH RAPIDLY PROGRESSIVE LYMPHOMA
P.F. Caimi¹ | J.S. Reese-Koc¹ | F. Otegbeye¹ |
D. Schneider² | K. Chamoun¹ | K.M. Boughan¹ |
B.W. Cooper¹ | E. Galloway¹ | M.M. Gallogly¹ |
W. Kruger² | A. Worden² | M. Kadan² | E. Malek¹ |
L. Metheny² | B. Tomlinson¹ | D.N. Wald¹ |
R.P. Sekaly³ | R. Orentas² | B. Dropulic² | M. de Lima¹

¹Medicine - Hematology and Oncology, University Hospitals Seidman Cancer Center, Cleveland, United States; ²Miltenyi Biotec Company, Lentigen, Gaithersburg, United States; ³Department of Pathology, Case Western Reserve University, Cleveland, United States

**Introduction:** AntiCD19 CAR-T cells have shown encouraging anti-lymphoma activity. Decreased time from apheresis to CAR-T infusion can make this therapy available to patients (pts) with rapid disease progression. We present the interim results of a phase I clinical trial using on-site CAR-T manufacture for treatment of relapsed / refractory (r/r) B cell non Hodgkin lymphoma (NHL).

**Methods:** Adult pts with r/r CD19+ B cell lymphomas who failed ≥ 2 lines of therapy were enrolled. Autologous T cells were transduced with a lentiviral vector (Lentigen Technology, Inc, LTG1563) encoding an antiCD19 binding motif, CD8 linker, tumor necrosis receptor superfamily 19 (TNFRS19) transmembrane region, and 4-IBB/CD3ζ intracellular signaling domains. GMP-compliant manufacture was done using CliniMACS Prodigy, in a 12-day culture. Dose levels were 0.5, 1 and 2 x 10⁶ CAR-T cells/kg. Lymphodepletion was done with cyclophosphamide (60mg/kg x 1) and fludarabine (25mg/m²/d x 3).

**Results:** As of March 15, 2019, 7 pts (4 women, 3 men) were enrolled. Median age was 60y [range 43-69]. Diagnoses include DLBCL (n = 3) PMBCL, follicular lymphoma (FL), transformed FL, and transformed lymphoplasmacytic lymphoma; with a median of 4 previous treatments. All pts were refractory to the prior line of therapy and 6 had symptomatic bulky disease at the time of lymphocyte collection.

CAR-T cell product manufacture was successful in all pts. Mean transduction rate was 44% [range 29-57]. CAR-T cell doses were 0.5 x 10⁶/kg (n = 3) and 1 x 10⁶/kg (n = 4). Median apheresis to infusion time was 13 days [range 13-20], 5 products were infused fresh. CAR-T persistence peaked in peripheral blood MNCs between days 14-21, all evaluable subjects had persistent CAR-Ts on day 30.

Cytokine release syndrome was observed in 5 pts. Grade 1 - 2 (Lee) was observed in 4 pts; whereas 1 pt died as a consequence of CRS in the context of bulky disease. Pharmacologic interventions for CRS included tocilizumab (n = 4), siltuximab (n = 2) and steroids (n = 1). One pt presented grade 4 CRES (CARTOX-10) with resolution after steroids. Among 6 pts evaluable for response, 4 have achieved complete response. One pt did not respond and died and 1 subject died secondary to CRS. After a median follow up 3.5 months all responding pts are alive and 1 relapsed 6 months after treatment.

**Conclusions:** In this ongoing phase 1 study, second generation antiCD19 CAR-T cells with TNFRS19 transmembrane domain and

4-IBB/CD3z have clinical activity against refractory lymphomas. The response rates observed so far indicate that antiCD19 CAR-T cell therapy is active in patients with rapidly progressive disease. The presence of bulky disease is associated with high risk of CRS, and debulking strategies prior to CAR-T cell therapy or lower doses should be considered. The short manufacture time achieved by local CAR-T cell manufacture with the CliniMACS Prodigy enables treatment of a very high risk NHL population.

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

**Disclosures:** Schneider, D: Employment Leadership Position: Lentigen.

Kruger, W: Employment Leadership Position: Lentigen. Worden, A: Employment Leadership Position: Lentigen. Orentas, R: Employment Leadership Position: Lentigen. Dropulic, B: Employment Leadership Position: Lentigen.

## 252
CD19/CD20-REDIRECTED BISPECIFIC CAR T CELL TREATMENT IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL NON-HODGKIN LYMPHOMA

Y. Wang | Z. Wu

Immunology Research Lab, Chinese PLA General Hospital, Beijing, China

**Background:** Patients with relapsed or refractory non-Hodgkin lymphoma (NHL) have a dismal prognosis. CART therapy targeting CD19 and CD20 achieves outstanding clinical responsiveness in B-cell malignancies, in B-NHL, the target CD19- or CD20-modified CAR-T cell therapy achieved a 41-54% complete remission rate, but the variability of single-target antigens in tumor cell leads to therapeutic resistance and relapse. We have previously constructed eight bispecific, tandem CD19/CD20 CAR structures and screened the optimal CAR structure with robust antitumor activity. Base on this, we performed aphase I trial to assess the safety and efficacy of CD19 and CD20 bispecific CAR T cells to patients with refractory or relapsed CD20 or CD19 positive B-cell lymphoma.

**Methods:** Adult (≥18 years) patients with pathologically confirmed diagnosis of CD20+ or CD19+ NHL and active relapsed or refractory disease were eligible. The patients underwent cytoreductive chemotherapy for tumor debulking and lymphocyte-depletion between days -7 to -2 before T cell infusion. Patients received bispecific CAR T cell dose from 1.5 to 8 x10⁶/kg. The level of the CAR gene was detected by Real-time PCR, and the CAR T cell in peripheral blood or in tumor site was detected by flow cytometry and RNAscope. Clinical responses were assessed according to the recommendations of the International Workshop NHL Response Criteria. Toxicity and adverse events were graded using the National Cancer Institute Common Terminology Criteria of Adverse Events version 3.0. Disease staging using computed tomography (CT) and positron emission tomography (PET) scans was performed at the time of study entry. CT was repeated during follow up
every two months (first year), every six months (years 2-3) and yearly thereafter. A FDG-PET study was performed at six weeks after treatment in all patients.

**Results:** Forty-two patients were enrolled, and 36 patients has completed a three-month assessment. The current overall objective response rate was 34 of 36 (94.4%) with 29 complete remissions (CRs) and 5 partial remissions (PRs). No severe toxicity was observed. Twenty-seven patients occurred Cytokine release syndrome (CRS). This clinical trial is ongoing (www.clinicaltrials.org as NCT03097770).

**Keywords:** B-cell lymphoma; CD19; CD20.

253
CYTOKINE RELEASE SYNDROME AND NEUROTOXICITY BY BASELINE TUMOR BURDEN IN ADULTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH TISAGENLECLEUCEL

R.T. Maziarz¹ | S.J. Schuster² | S.G. Ericson³ |

E.S. Rusch³ | J. Signorovitch⁴ | J. Li⁴ |

V.V. Romanov³ | D.G. Maloney⁵ | F.L. Locke⁶

¹Center for Hematologic Malignancies, Oregon Health & Science Knight Cancer Institute, Portland, United States; ²Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States; ³US Oncology Medical, Cell and Gene Therapy Program, Novartis Pharmaceuticals Corporation, East Hanover, United States; ⁴Health Economics and Outcomes Research, Analysis Group, Inc., Boston, United States; ⁵Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States; ⁶Blood and Marrow Transplant and Cellular Immunotherapy, H. L. Moffitt Cancer Center, Tampa, United States

**Introduction:** Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel has demonstrated efficacy with favorable benefit-risk profile in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. CAR T-cell therapy is associated with cytokine release syndrome (CRS) and neurotoxicity (NT). This post-hoc analysis described safety profiles among tisagenlecleucel-treated adults with r/r DLBCL, stratified by baseline tumor burden.

**Methods:** CRS and NT events observed in JULIET were graded with approaches common to CAR T-cell therapy (CRS: Penn, Lee; NT: Common Terminology Criteria for Adverse Events v4.03 [CTCAE], modified CAR-T Related Encephalopathy Syndrome [mCRES]). Penn grades were reported prospectively per trial protocol; Lee, mCRES and CTCAE grades were obtained via expert consensus grading (ASH 2018: #4190; #4183). JULIET patients (pts) were stratified by baseline tumor burden, defined by active tumor volume (TV; <100 vs ≥100 mL per PET scan) or presence of bulky

disease (BD; any single tumor mass >10 cm in CT-determined, longitudinal diameter). Demographics, disease characteristics, medical history, CRS and NT grades were summarized and compared between subgroups.

**Results:** Of 111 JULIET pts infused with tisagenlecleucel as of Dec 8, 2017, TV was assessed in 95 pts, divided into two subgroups: <100 mL (n = 60), ≥100 mL (n = 35). Overall, pts were similar in demographics and medical history; with one exception, BD pts (N = 9) had no prior HSCT (0.0% vs 52.9%, p<0.01). The rates of any CRS grade were similar (<100 vs ≥100 mL: 50.0% vs 68.6% per Lee; 51.7% vs 68.6% per Penn). Higher TV was associated with CRS grade≥3 (Lee: 11.7% vs 31.4%; Penn: 13.3% vs 34.3%, both p<.05). Of 64 pts with CRS, baseline TV was available for 55 (<100 mL n = 31; ≥100 mL n = 24); a higher number of pts with TV > 100 mL had CRS within 3 days post infusion (35.5% vs 87.5%, p<.001) and experienced high fever (>38.6°C) due to CRS (83.9% vs 100.0%, p<.05). CRS duration, tocilizumab administration and corticosteroid use were similar between subgroups. With CTCAE grading, NT grades were similar between subgroups; with mCRES grading; high TV pts had higher NT rates compared with low TV group (any grade: 11.7% vs 31.4%, p<.05) and grade 3 or 4 NT (8.3% vs 22.9%, p<.05). No Grade 5 CRS or NT were observed. BD pts had higher grade 3 and 4 CRS rates per Lee (13.7% vs 55.6%, p<.01).

**Conclusions:** This JULIET post-hoc analysis observed differences in CRS and NT grades among pts with low vs high baseline tumor burden according to BD or TV and indicates an association between tumor burden and higher rates of CRS grade 3 and 4 by both Penn and Lee scales. There was a correlation between BD and NT grade 3 and 4 per mCRES; but the trend was not observed with CTCAE grading. These findings may help guide clinical care of r/r DLBCL pts with BD and/or high TV receiving tisagenlecleucel.

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

**Disclosures:** Maziarz, R: Consultant Advisory Role: Incyte, Juno Therapeutics; Honoraria: Novartis Pharmaceuticals, Kite Therapeutics; Research Funding: Novartis Pharmaceutica; Other Remuneration: Athersys Inc. Schuster, S: Consultant Advisory Role: Celgene, Dava Oncology, Merck, Nordic Nanovector; Honoraria: Celgene, Dava Oncology, Genentech, Merck, Novartis Pharmaceuticals, Nordic Nanovector, OncLive, Physicians' Education Resource, LLC; Research Funding: Celgene, Genentech, Merck, Novartis Pharmaceuticals; Other Remuneration: Gilead, Novartis Pharmaceuticals, Nordic Nanovector, Pfizer. Ericson, S: Employment Leadership Position: Novartis Pharmaceuticals Corporation; Stock Ownership: Novartis Pharmaceuticals Corporation. Rusch, E: Employment Leadership Position: Novartis Pharmaceuticals Corporation. Signorovitch, J: Employment Leadership Position: Analysis Group, Inc.; Research Funding: Novartis Pharmaceuticals Corporation. Li, J: Employment Leadership Position: Analysis Group, Inc.; Research Funding: Novartis Pharmaceuticals Corporation. Romanov, V: Employment Leadership Position: Novartis Pharmaceuticals Corporation. Maloney, D: Honoraria: Janssen Scientific Affairs, Seattle Genetics, Roche/Genentech; Research Funding: Juno Therapeutics, GlaxoSmithKline.
254

CORRELATIVE ANALYSES OF CYTOKINE
RELEASE SYNDROME AND
NEUROLOGICAL EVENTS IN
TISAGENLECLEUCEL-TREATED
RELAPSED/REFRACTORY DIFFUSE LARGE
B-CELL LYMPHOMA PATIENTS

V. Bachanova¹ | J. Westin² | C. Tam³ |

P. Borchmann⁴ | U. Jaeger⁵ | J. McGuirk⁶ |

H. Holte⁷ | E. Waller⁸ | S. Jaglowski⁹ |

M. Bishop¹⁰ | C. Andreadis¹¹ | S.R. Foley¹² |

I. Fleury¹³ | T. Teshima¹⁴ | S. Mielke¹⁵ |

G. Salles¹⁶ | P.J. Ho¹⁷ | K. Izutsu¹⁸ | R. Maziarz¹⁹ |

K. Van Besien²⁰ | M.J. Kersten²¹ |

N. Wagner-Johnston²² | K. Kato²³ | P. Corradini²⁴ |

X. Han²⁵ | S. Agoulnik²⁶ | J. Chu²⁷ | L. Eldjerou²⁸ |

L. Pacaud²⁷ | S. Schuster²⁹

¹Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, United States; ²Department of Lymphoma & Meyloma, M.D. Anderson Cancer Center, Houston, United States;

³Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia; ⁴Department of Hematology/Oncology, University Hospital of Cologne, Cologne, Germany; ⁵Department of Hematology/Hemostaseology, Medical University Vienna, Vienna, Austria; ⁶Division of Hematologic Malignancies and Cellular Therapeutics, Kansas Hospital and Medical Center, Kansas City, United States;

⁷Lymphoma Section, University of Oslo, Oslo, Norway; ⁸Department of Stem Cell Transplantation and Immunology, Emory University School of Medicine, Atlanta, United States; ⁹Department of Internal Medicine, The Ohio State University, Columbus, United States; ¹⁰Section of Hematology/Oncology, University of Chicago, Chicago, United States;

¹¹Department of Hematology and Blood and Marrow Transplant, University of California San Francisco, San Francisco, United States;

¹²Division of Clinical Pathology, McMaster University, Hamilton, Canada;

¹³Department of Hematology, Hôpital Maisonneuve-Rosemont, Montreal, Canada; ¹⁴Department of Hematology, Hokkaido University Hospital, Sapporo, Japan; ¹⁵Department of Internal Medicine, University Hospital Wuerzburg, Wuerzburg, Germany; ¹⁶Hematology Department, Lyon-Sud Hospital Center, Pierre-Benite, France; ¹⁷Department of Haematology, Royal Prince Alfred Hospital, Camperdown, Australia; ¹⁸Department of Hematology, National Cancer Center Hospital, Tokyo, Japan;

¹⁹Department of Hematology and Oncology, Oregon Health and Science University, Portland, United States; ²⁰Department of Medical Oncology, Weill Cornell Medicine, New York, United States; ²¹Department of Hematology, Academic Medical Center, Amsterdam, Netherlands;

²²Department of Oncology and Hematologic Malignancies, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, United States; ²³Hematology, Oncology & Cardiovascular Medicine, Kyushu University, Fukuoka Prefecture, Japan; ²⁴Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy; ²⁵Biomarkers and Diagnostics Biometrics, Novartis Pharmaceuticals Corporation, East

Hanover, United States; ²⁶Precision Medicine, Novartis Pharmaceuticals Corporation, Cambridge, United States; ²⁷Novartis Oncology, Novartis Pharmaceuticals Corporation, East Hanover, United States; ²⁸Global Cell & Gene Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, United States; ²⁹Division of Hematology Oncology, University of Pennsylvania, Philadelphia, United States

**Background:** Tisagenlecleucel (anti-CD19 CAR-T cell therapy) has shown durable responses and a manageable safety profile in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). We report a 24 mo clinical update and correlative analyses between cytokine release syndrome (CRS)/neurological events (NE) and inflammatory/lab analyte markers.

**Methods:** JULIET (NCT02445248) is a single-arm, pivotal, phase 2 trial of tisagenlecleucel in adult pts with r/r DLBCL. The primary endpoint was overall response rate (ORR: complete [CR] + partial response). Peak (within 1 mo of infusion) serum cytokine levels/lab parameters were correlated with rate/grade (gr) of CRS (by Penn) and NE (by CTCAE v4.03) within 8 wk of infusion.

**Results:** As of 11 Dec 2018, 115 pts were infused (99 evaluable for efficacy). ORR remained 54% (95% CI: 43, 64), CR rate was 40%, and median duration of response was not reached (NR; 95% CI: 10, -) at a max follow-up of almost 24 mo from onset of response. Of 31 pts with CR at 6 mo, 3 relapsed between 6-12 mo and 1 relapsed beyond 12 mo. Median overall survival for all 115 pts was 10.3 mo (NR for pts in CR). Severe (gr 3/4) CRS and NE occurred in 23% and 11%, respectively. 83% of pts with any gr NE also had CRS; 62% of pts with severe NE had severe CRS. Median time to onset of CRS and NE was 3 and 6 d, respectively. Peak cytokine levels within 1 mo of infusion were increased in pts with CRS/NE and the trend was more noticeable in pts with severe CRS and severe NE. Higher CRP, ferritin, interferon- (IFNG), IL2, IL6, and IL10 were observed in pts with severe CRS; severe NE showed similar trends of a lesser degree, except for IFNG. In pts with CRS, cytokines peaked on d 6-9, with early increase of IL2, IL6, and IFNG in the first 2 d post-infusion with severe CRS. Low platelet count, elevated lactate dehydrogenase, and below-normal albumin levels were seen after lymphodepleting chemotherapy; these trends continued post-infusion in pts with severe CRS. As CRS progressed, hepatic and kidney dysfunction-related analytes trended toward an increase, peaking 2 wk post-infusion in pts with

<table><caption>**TABLE 1** Number of patients with coincidence of CRS and NE in the JULIET trial</caption><thead><tr><th></th><th>N = 115</th><th>Any Grade NE (n = 23/115)</th><th>Grade 3/4 NE (n = 13/115)</th></tr></thead><tbody><tr><td>No CRS</td><td>49</td><td>4</td><td>3</td></tr><tr><td>Grade 1/2 CRS</td><td>40</td><td>6</td><td>2</td></tr><tr><td>Grade 3 CRS</td><td>17</td><td>6</td><td>2</td></tr><tr><td>Grade 4 CRS</td><td>9</td><td>7</td><td>6</td></tr><tr><td>Any Grade CRS</td><td>66</td><td>19</td><td>10</td></tr></tbody></table>
<figure><img src="image_164.png" /><figcaption>Figure 1B. Peak serum cytokine levels within 1 mo of infusion by NE gr (N = 115)</figcaption></figure>

<figure><img src="image_165.png" /></figure>

severe CRS. Additional univariate/multivariate analyses using pts' disease and clinical characteristics in an attempt to predict CRS/NE severity are ongoing.

**Conclusions:** With almost 24 mo max follow-up, tisagenlecleucel continued to demonstrate durable efficacy. Severe NE appeared to correlate with severe CRS. Trends in peak levels of several markers were noted with severe CRS and – to a lesser extent – severe NE.

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

**Disclosures:** Bachanova, V: Consultant Advisory Role: Novartis; Research Funding: GAMIDA Cell, UNUM, Novartis, GT Biopharm.

Westin, J: Consultant Advisory Role: Novartis, Kite Pharma, Juno, Celgene, Janssen, Genentech. Tam, C: Honoraria: Novartis. Borchmann, P: Honoraria: Novartis. Jaeger, U: Honoraria: AbbVie, Bioverativ, Celgene, Gilead, Janssen, MSD, Novartis, Roche, Takeda Millenium, Amgen, AOP Orphan, BMS, Sandoz; Research Funding: Bioverativ, Celgene, Gilead, Janssen, MSD, Novartis, Roche; Other Remuneration: AbbVie, Celgene, Gilead, Janssen, MAD, Novartis, Roche, Takeda Millenium, Amgen, AOP Orphan, BMS, Sandoz. McGuirk, J: Honoraria: Kite Pharma; Research Funding: Novartis, Kite Pharma, Fresenius Biotech,

Astellas Pharma, Bellicum Pharmaceuticals, Gamida Cell, Pluristem Ltd.

Holte, H: Consultant Advisory Role: Novartis; Honoraria: Novartis.

Waller, E: Employment Leadership Position: Cambium Medical Technologies; Consultant Advisory Role: Kalytera, Novartis; Stock Ownership: Cerus Corporation, Chimerix; Honoraria: Cambium Medical Technologies, Kalytera, Novartis; Research Funding: Celldex, Novartis, Pharmacyclics. Jaglowski, S: Honoraria: Kite Pharma, Juno; Research Funding: Novartis. Bishop, M: Employment Leadership Position: United Healthcare; Honoraria: Celgene, Jeneau Therapeutics, Novartis.

Andreadis, C: Honoraria: Novartis, Genentech, Seattle Genetics, Gilead, Astellas; Research Funding: Novartis, Cellerant Therapeutics, Incyte, Pharmacyclics, Amgen, Genentech. Fleury, I: Honoraria: Gilead, Novartis, Roche, Seattle Genetics, Janssen, AbbVie. Teshima, T: Honoraria: Novartis; Research Funding: Novartis. Mielke, S: Consultant Advisory Role: Celgene, KIADIS Pharma, Miltenyi Biotec, DGHO, EHA. Salles, G: Consultant Advisory Role: Novartis; Honoraria: Novartis. Ho, P: Other Remuneration: Novartis, Celgene, La Jolla Pharmaceuticals. Izutsu, K: Honoraria: Novartis, Eisal, Kyowa Hakko Kirin, MSD, Takeda, Janssen, Bristol Myers Squib, Dainihon Sumitomo, Mundipharma, Nihon
Mediphysics, Chugai, AstraZeneca, AbbVie, Bayer, Ono, Celgene; Research Funding: Novartis, Eisal, MSD, Takeda, Janssen, Mundipharma, Chugai, AbbVie, Bayer, Ono, Gilead, Zenyaku, Celgene, Solasia, Symbio, Astellas, Astellas Amgen, Diichi Sankyo. Maziarz, R: Consultant Advisory Role: Novartis, Incyte, Juno Therapeutics; Honoraria: Novartis, Incyte, Juno Therapeutics, Kite Therapeutics; Research Funding: Novartis; Other Remuneration: Athersys, Inc. Van Besien, K: Research Funding: Novartis. Kersten, M: Consultant Advisory Role: Roche, Celgene, Takeda, Novartis, Kite, BMS; Honoraria: Roche, Celgene, Takeda, Novartis, Kite; Research Funding: Roche, Celgene, Takeda. Wagner-Johnston, N: Consultant Advisory Role: Juno, ADC Therapeutics, Janssen. Corradini, P: Consultant Advisory Role: Celgene, AbbVie, Amgen, Daiichi Sankyo, Gilead, Janssen, Kiowakirin, Novartis, Roche, Sanofi, Servier, Takeda. Han, X: Employment Leadership Position: Novartis. Agoulnik, S: Employment Leadership Position: Novartis. Chu, J: Employment Leadership Position: Novartis. Eldjerou, L: Employment Leadership Position: Novarits. Pacaud, L: Employment Leadership Position: Novartis. Schuster, S: Honoraria: Celgene, Genentech, Merck, Pharmacyclics, Novartis, Nordic Nanovector, Acerta, Pfizer, Gilead; Research Funding: Celgene, Genentech, Merck, Pharmacyclics, Novartis, Gilead.

255
MANAGING CYTOKINE RELEASE
SYNDROME (CRS) AND NEUROTOXICITY
WITH STEP-UP DOSING OF
MOSUNETUZUMAB IN
RELAPSED/REFRACTORY (R/R) B-CELL
NON-HODGKIN LYMPHOMA (NHL)

L.H. Sehn<fnref n="1" /> | S. Assouline² | N.L. Bartlett³ |

F. Bosch⁴ | C.M. Diefenbach⁵ | I. Flinn⁶ |

J.Y. Hong⁷ | W.S. Kim⁸ | M. Matasar⁹ |

L. Nastoupil¹⁰ | S.J. Schuster¹¹ | M. Shadman¹² |

S.S. Yoon¹³ | B. Bender¹⁴ | W. Chu¹⁵ |

G.M. Hernandez¹⁶ | A. Kwan¹⁷ | B. McCall¹⁴ |

I. Sison¹⁸ | C. Wang¹⁷ | M.C. Wei¹⁵ | S. Yin¹⁵ |

K. Yousefi¹⁹ | L.E. Budde²⁰

Center, New York, NY, United States; ¹⁰Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; ¹¹Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA, United States; ¹²Medical Oncology Division, Department of Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; ¹³Division of Hematology/Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; ¹⁴Clinical Pharmacology Development, Genentech, Inc., South San Francisco, CA, United States; ¹⁵Product Development Oncology, Genentech, Inc., South San Francisco, CA, United States; ¹⁶Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, United States; ¹⁷Safety Science Oncology, Genentech, Inc., South San Francisco, CA, United States; ¹⁸Clinical Operations, gRED, Genentech, Inc., South San Francisco, CA, United States; ¹⁹Product Development, Biometrics, Biostatistics, Genentech, Inc., South San Francisco, CA, United States; ²⁰Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA, United States

**Introduction:** T-cell directed therapies (e.g., CAR-T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/infusion-related reaction (IRR). Mosunetuzumab is a CD20/CD3 bispecific antibody that directs T-cells to engage and eliminate malignant B-cells. We report safety results from an ongoing Phase 1/1b study (NCT02500407) of mosunetuzumab in patients (pts) with R/R B-cell NHL.

**Methods:** Pts received ascending doses on Day 1, Day 8, and Day 15 of Cycle 1 (step-up dosing), then a fixed dose on Day 1 of every 21-day cycle thereafter, up to a maximum of 17 cycles. Primary outcome measures included safety and efficacy.

**Results:** As of October 23, 2018, 114 pts who received step-up dosing of mosunetuzumab were evaluable for safety (Table). The majority of adverse events (AE) occurred during Cycle 1 and 2. Neurologic AEs (NAE), defined from Nervous System or Psychiatric System Organ Classes, were mostly low grade, transient (median duration 4 days) and reversible; most common ones were headache (14%) and

<table><caption>TABLE 1 Safety</caption><thead><tr><th>Pts, n (%)</th><th>n=114 [Max dose: 20 mg]</th></tr></thead><tbody><tr><td>≥1 AE</td><td>109 (96)</td></tr><tr><td>Gr ≥3 AEs; drug-related</td><td>68 (60); 33 (29)</td></tr><tr><td>Serious AE*; drug-related</td><td>34 (30), 15 (13)</td></tr><tr><td>NAE</td><td>50 (44)</td></tr><tr><td>Gr 1–2</td><td>46 (40)</td></tr><tr><td>Gr 3</td><td>4 (4)</td></tr><tr><td>CRS/IRR</td><td>29 (25)</td></tr><tr><td>Gr 1–2</td><td>28 (25)</td></tr><tr><td>Gr 3</td><td>1 (1)</td></tr></tbody></table>

<footnote n="1">¹Medical Oncology, BC Cancer Centre for Lymphoid Cancer and University of British Columbia, Vancouver, BC, Canada; ²Division of Hematology, Jewish General Hospital, Montréal, QC, Canada; ³Sitehan Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; ⁴Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain; ⁵Department of Hematology/Oncology, New York University Medical Center, Brooklyn, NY, United States; ⁶Blood Cancer Research Program, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, United States; ⁷Department of Oncology, ASAN Medical Center, Seoul, Republic of Korea; ⁸Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul, Republic of Korea; ⁹Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer</footnote>

<footnote>*excluding progressive disease</footnote>
dizziness (8%). Gr ≥3 NAEs occurred in 4 pts (4%) with only 1 treat-
ment-related event (hepatic encephalopathy). CRS/IRR was reported
in 25% of pts, with only 1 Gr 3 event. Most common CRS symptoms
were pyrexia (86%), chills (38%), and tachycardia and headache (14%
each). There were no Gr 5 events related to CRS or NAEs. No appar-
ent dose toxicity relationship was observed with step-up dosing in
these pts, despite escalation of the Cycle 1 Day 15 dose to 20 mg,
consistent with observed peak IL-6 levels after a low Cycle 1 Day
1 dose. In these pts, objective responses were observed in 24/73
(33%; complete response [CR], 13 [18%]) aggressive NHL and 17/32
(53%; CR, 10 [31%]) indolent NHL pts.

**Conclusions:** Step-up dosing has enabled continued dose escalation of mosunetuzumab with no apparent increases in toxicity, exhibiting a promising risk-benefit profile.

**Acknowledgement:** This work was funded by F. Hoffmann-La Roche Ltd. Third-party medical writing assistance, under the direction of Laurie Sehn, was provided by Louise Profit and Russell Craddock of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

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

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

**Disclosures:** **Sehn, L:** Consultant Advisory Role: AbbVie, Amgen, Roche/Genentech, Inc., Apobiologix, AstraZeneca, Acerta, Celgene, Gilead, Janssen, Kite, Karyopharm, Lundbeck, Merck, MorphoSys, Seattle Genetics, Teva, Takeda, TG Therapeutics; Honoraria: /Genentech, Inc., Apobiologix, AstraZeneca, Acerta, Celgene, Gilead, Janssen, Kite, Karyopharm, Lundbeck, Merck, MorphoSys, Seattle Genetics, Teva, Takeda, TG Therapeutics; Research Funding: Roche/Genentech, Inc. **Assouline, S:** Employment Leadership Position: No; Consultant Advisory Role: Yes. Pfizer, Roche; Stock Ownership: No; Honoraria: No; Research Funding: No; Other Remuneration: Travel, Accommodation, Expenses: Roche; Speakers' bureau: Pfizer, Roche. **Bartlett, N:** Consultant Advisory Role: Pfizer, Seattle Genetics, ADC Therapeutics; Research Funding: Seattle Genetics, Genentech, Kite Pharma, Merck, Bristol-Myers Squibb, Celgene, Immune Design, Forty Seven, Affirmed Therapeutics, Janssen, Pharmacycyclics, Millennium, Gilead Sciences. **Bosch, F:** Consultant Advisory Role: Roche, Janssen, Celgene, Abbvie, Novartis, Gilead; Honoraria: Roche, Janssen, Celgene, Abbvie, Novartis, Gilead; Research Funding: Roche, Janssen, Celgene, Abbvie, Novartis, Gilead, Sobi, Bayer; Other Remuneration: Roche, Janssen, Celgene, Abbvie, Novartis, Gilead (speakers' bureau). **Diefenbach, C:** Consultant Advisory Role: Seattle Genetics, Bayer, Bristol-Myers Squibb, Genentech/Roche, Merck; Stock Ownership: Gilead Sciences; Research Funding: Seattle Genetics, Genentech, Incyte, LAM Therapeutics, Merck, Bristol-Myers Squibb, Millennium, MEI Pharma. **Flinn, I:** Consultant Advisory Role: AbbVie, Seattle Genetics, TG Therapeutics, Verastem; Research Funding: Acerta, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Inc., Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacycyclics, Portola Pharmaceuticals, Roche, Seattle Genetics, TG Therapeutics, Trillim Therapeutics, AbbVie, ArQule, BeiGene, Curis, FoRMA Therapeutics, Forty

Seven, Merck, Pfizer, Takeda, Teva, Verastem. **Hong, J:** Consultant Advisory Role: Takeda, Roche; Honoraria: Takeda, Roche, Janssen, Celgene, Mundipharma, Celtrion, Eisai; Research Funding: Janssen, Boryung Pharmaceutical. **Kim, W:** Research Funding: Roche, Takeda, Eisai, Mundipharma, Pfizer, Celtrion, Kyowa-Kirin, J&J. **Matasar, M:** Consultant Advisory Role: Genentech, Bayer, Merck, Juno Therapeutics, Roche, Teva, Rocket Medical, Seattle Genetics; Stock Ownership: Merck; Honoraria: Genentech, Roche, Bayer, Pharmacycyclics, Janssen, Seattle Genetics; Research Funding: Genentech, Roche, Bayer, Pharmacycyclics, Janssen, Seattle Genetics; Other Remuneration: Genentech, Roche, Seattle Genetics, Bayer (travel, accommodation and expenses). **Nastoupil, L:** Honoraria: Celgene, Genentech, Gilead, Janssen, Novartis, Spectrum, TG Therapeutics; Research Funding: Celgene, Genentech, Janssen, Merck, TG Therapeutics. **Schuster, S:** Consultant Advisory Role: Celgene, Genentech, Inc., Gilead, Pfizer, Novartis, Nordic Nanovector, Acerta; Honoraria: Celgene, Genentech, Inc., Gilead, Pfizer, Novartis, Nordic Nanovector, Acerta; Research Funding: Celgene, Genentech, Inc., Novartis, Acerta, Gilead. **Shadman, M:** Consultant Advisory Role: AbbVie, Genentech, Inc., Sound Biologics, Verastem, ADC Therapeutics, Atara Biotherapeutics; Research Funding: Mustang Biopharma, Celgene, Pharmacycyclics, Gilead, Genentech, Inc., AbbVie, TG Therapeutics, Beigene, Acerta Pharma, Merck. **Yoon, S:** Consultant Advisory Role: Novartis, AbbVie, Amgen, Celgene, Roche; Research Funding: Roche. **Bender, B:** Employment Leadership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc.; Other Remuneration: Genentech, Inc. **Chu, W:** Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. **Hernandez, G:** Employment Leadership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc. **Kwan, A:** Employment Leadership Position: Genentech, Inc./Roche; Stock Ownership: Genentech, Inc./Roche. **McCall, B:** Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. **Sison, I:** Employment Leadership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc. **Wang, C:** Employment Leadership Position: Ultragenyx Pharmaceuticals, Inc.. **Wei, M:** Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. **Yin, S:** Employment Leadership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc.; Other Remuneration: Genentech, Inc. (travel, accommodation, expenses). **Yousefi, K:** Employment Leadership Position: Roche; Other Remuneration: Roche (travel, accommodation and expenses). **Budde, L:** Consultant Advisory Role: Gilead, Genentech, AstraZeneca; Research Funding: Mustang Therapeutics, Merck & Co, Amgen; Other Remuneration: Gilead, AstraZeneca (speakers' bureau).
L. Fayad¹ | F. Samaniego¹ | S. Ahmed¹ |

A. Varma² | S. Arafat¹ | S. Johncy¹ | P. Kebriaei² |

V.E. Mulanovich³ | E. Ariza Heredia³ | S.S. Neelapu¹

¹Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, United States; ²Stem Cell Transplant, MD Anderson Cancer Center, Houston, United States; ³Infectious Disease, MD Anderson Cancer Center, Houston, United States

**Introduction:** Cytopenia lasting beyond 30 days has been observed after CAR T cell therapy. Here, we describe the hematopoietic recovery and immune reconstitution following axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma.

**Methods:** Patients with available complete blood counts 30 days after axi-cel infusion were eligible for the analysis. Significant cytopenia was defined as any grade 3 or greater hematological toxicity (absolute neutrophil count < 1 x 10⁹/L, hemoglobin < 8 g/dL, platelet count < 50 x 10⁹/L).

**Results:** Of 31 patients treated on ZUMA-1 (N = 24) and ZUMA-9 (N = 7) trials at our institution, grade ≥3 cytopenias were observed in 15 (48%) patients at day 30 (d30), represented by neutropenia in 9 (29%), anemia in 5 (16%), and thrombocytopenia in 13 (42%). Baseline (d-5) characteristics associated with d30 grade ≥3 cytopenia on univariate analysis were ECOG performance status >0 (60% vs 19%, p = 0.03) and >3 prior therapies (67% vs 25%, p = 0.03). A trend for association with previous autologous stem cell transplant (93% vs 44%, p = 0.07) and higher baseline ferritin levels (2025 ng/mL vs 450 ng/mL, p = 0.08) was observed. While on study, patients with d30 grade ≥3 cytopenia had a significantly higher need for intravenous immunoglobulins (Ig)(67% vs 25%, p = 0.03) and

platelet transfusion (73% vs 25%, p = 0.01). No significant association was observed between d30 grade ≥3 cytopenia and subsequent grade ≥3 infections (27% vs 31%, p = 1), need for growth factor support (both 100%, p = 1), red blood cell transfusions (87% vs 63%, p = 0.22) or diagnosis of myelodysplastic syndromes (20% vs 1%, p = 0.33). Fifty-nine infectious complications were observed during the study, and the etiology was viral in 16 (27%) cases, bacterial in 7 (12%), fungal in 4 (7%); no organism was isolated in 32 (54%) patients.

No significant association was observed between d30 grade ≥3 cytopenia and overall response rate (93% vs 81%, p = 0.60) or complete remission rate (53% vs 50%, p = 1).

At a median follow-up of 2.7 years, a higher 3-year progression-free survival was observed for patients with d30 grade ≥3 cytopenia (63% vs 35%, p = 0.18)(Figure 1A).

Among patients with ongoing response at most recent follow-up, resolution of grade ≥3 cytopenia was observed in 75% of patients at 1 year and 86% at 2 years; recovery in CD4, CD8, CD56, CD19, and IgG was observed in 63%, 100%, 100%, 29%, and 58% of patients at 1 year, and 86%, 100%, 100%, 25% and 50% of patients at 2 years. Among patients with d30 cytopenia, a strongly significant and positive correlation was observed between platelet count and CD56 count (r = +0.64, p<0.001) (Figure 1B).

**Conclusions.** Grade ≥3 cytopenias are common after axi-cel therapy, but resolve in most patients by 1 year. Recovery of CD4 T cells appears to be delayed beyond 1 year in 1/3 of the patients, highlighting the need for prolonged prophylaxis for opportunistic infections. The effect of CAR T cells on the bone marrow microenvironment warrants further investigation.

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

<figure><img src="image_166.png" /></figure>

<figure><img src="image_167.png" /></figure>
## 257 COMPREHENSIVE REPORT OF ANTI-CD19 CHIMERIC ANTIGEN RECEPTOR T-CELLS (CAR-T) ASSOCIATED NON RELAPSE MORTALITY (CART-NRM) FROM FAERS

K. Anand¹ | S. Pingali¹ | J. Ensor¹ | S.S. Neelapu² | S. Iyer²

¹Hematology/Oncology, Houston Methodist Cancer Center, Houston, United States; ²Lymphoma/Myeloma, UT MD Anderson Cancer Center, Houston, United States

**Background:** CAR-T cells targeting CD19 positive B-cells have improved outcomes for relapsed/refractory non-Hodgkin lymphoma

<table><caption>TABLE 1 Analysis of cases of anti-CD19 CAR-T NRM</caption><thead><tr><th></th><th>Tisangenlecleucel (n=61)</th><th>Axicabtagene ciloleucel (n=34)</th></tr></thead><tbody><tr><td>Total Deaths (n=95)</td><td></td><td></td></tr><tr><td>Median age</td><td>21 years (3-78 years; n=57)</td><td>64 years (13-71 years; n=21)</td></tr><tr><td>Number of patients ≤18 years</td><td>26 (median-age 7.5 years)</td><td>1 (13 years)</td></tr><tr><td>Number of patients >18 years</td><td>31 (median-age 48 years)</td><td>20 (median-age 64 years)</td></tr><tr><td>Unknown age of patients</td><td>4</td><td>13</td></tr><tr><td>Sex</td><td></td><td></td></tr><tr><td>Male</td><td>33</td><td>12</td></tr><tr><td>Female</td><td>25</td><td>17</td></tr><tr><td>Unknown</td><td>3</td><td>5</td></tr><tr><td>Indications</td><td></td><td></td></tr><tr><td>ALL</td><td>31</td><td>2</td></tr><tr><td>NHL</td><td>13</td><td>23</td></tr><tr><td>Chronic lymphocytic leukemia</td><td>2</td><td>0</td></tr><tr><td>Unknown</td><td>15</td><td>9</td></tr><tr><td>Non Relapse Mortality*</td><td></td><td></td></tr><tr><td>Cytokine release syndrome(CRS)</td><td>14 (23%)</td><td>18 (53%)</td></tr><tr><td>Hematological</td><td>28 (46%)</td><td>9 (26%)</td></tr><tr><td>Cardiovascular</td><td>29 (47%)</td><td>14 (41%)</td></tr><tr><td>Neurological</td><td>28 (46%)</td><td>19 (56%)</td></tr><tr><td>Renal</td><td>25 (41%)</td><td>3 (9%)</td></tr><tr><td>Gastrointestinal</td><td>17 (28%)</td><td>9 (26%)</td></tr><tr><td>Respiratory</td><td>20 (32%)</td><td>8 (23%)</td></tr><tr><td>Infectious</td><td>34 (56%)</td><td>15 (44%)</td></tr><tr><td>Hepatic</td><td>4 (6%)</td><td>3 (9%)</td></tr><tr><td>Median time to AEs</td><td>7 days</td><td>5 days</td></tr></tbody></table>

(NHL) and B-cell acute lymphoblastic leukemia (B-ALL). CAR-T emergent toxicities for FDA approved therapies leading to non-progression related death have been reported in the pivotal studies. However, they are underreported and there remains a need to obtain a comprehensive report of NRM emergent with anti-CD19 CAR-T.

**Methods:** We retrospectively searched FDA adverse events reporting system (FAERS) for all adverse events (AE) related to "Tisangenlecleucel(T)" and "Axicabtagene ciloleucel(AC)" reported from 2013-2018. FAERS contains AEs from clinical trials and standard of care patients. All cases with the outcome of death were analyzed.

**Results:** Total numbers of anti-CD19 CAR-T pts reported were 636, out of which 288 cases received "T" and 348 received "AC". Out of total 129 total deaths, 95 died due to non-disease progression. Patient characteristics are summarized in Table 1. CART-NRM for entire cohort was 15%; 21% for "T" and 10% for "AC". Major toxicities reported include CRS, hematological, cardiovascular, neurological and infectious. Difference in mortality is likely related to different patient population, diagnoses and the CAR-T construct.

**Conclusion:** CART-NRM remains considerably high at 15%. Our analysis highlights the major toxicities and informs the potential opportunities for interventions to reduce mortality. We will present updated data with comparative analysis of published clinical studies at the upcoming ICML Meeting in Lugano.

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

## 258 SAFETY OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT IN ADULTS AFTER CD19 TARGETED CHIMERIC ANTIGEN RECEPTOR-MODIFIED T-CELL (CAR-T) THERAPY

M. Shadman¹ | J. Gauthier² | K.A. Hay² |

J.M. Voutsinas² | F. Milano¹ | A. Li¹ |

A.V. Hirayama² | M.L. Sorror¹ | R.D. Cassaday³ |

B.G. Till¹ | A.K. Gopal¹ | B.M. Sandmaier¹ |

D.G. Maloney¹ | C.J. Turtle¹

¹Clinical Research Division/Medical Oncology, Fred Hutch/University of Washington, Seattle, United States; ²Clinical Research Division, Fred Hutch, Seattle, United States; ³Clinical Research Division/Hematology, Fred Hutch/University of Washington, Seattle, United States

**Introduction:** Allogeneic hematopoietic cell transplant (allo-HCT) is offered to selected patients (pts) after chimeric antigen receptor-modified T-cell (CAR-T) therapy. Lymphodepletion and CAR-T therapy have immunosuppressive and immunomodulatory effects that could alter the safety profile of subsequent allo-HCT.

**Methods:** We reviewed our institutional experience with adult pts who received an allo-HCT after prior CD19 CAR-T and focused on post allo-HCT toxicities. Cox proportional hazard models were used

<footnote>*Overlapping toxicities</footnote>
to study association between clinical factors and overall survival and non-relapse mortality (NRM).

**Results:** We identified 32 pts (ALL = 19; NHL/CLL = 13). Median age at allo-HCT was 46 years (23-74). The median time from CAR-T to allo-HCT was 72 days in ALL and 122 days in NHL/CLL pts. Nine pts (28%) had 2 CAR-T infusions. After first CAR-T, 22 pts (69%) had CRS (grade 3, 6%) and 15 (47%) developed NT (grade 3, 19%). After second CAR-T, 3 pts (33%) had CRS and 2 (22%) had NT (grade 4: 1). All ALL pts were in complete remission and all NHL/CLL patients had active disease at the time of allo-HCT. Myeloablative conditioning (MAC) was used in 59% of pts (74% of ALL; 39% of NHL/CLL). Graft sources were matched unrelated (53%), matched related (16%), umbilical cord blood (16%), haploidentical (9.5%), and mismatched-unrelated (6%). Nineteen pts (59%) had HCT-Cl ≥ 2. All pts had neutrophil recovery (median 18.5 days to 1000/mm³) and all but 3 had platelet recovery (median 14 days to 70,000/mm³). Three pts (9%) developed thrombotic microangiopathy. Grade 3-4 acute GVHD occurred in 8 (25%) pts and 5 (16%) pts developed chronic GVHD. Within 100 days after allo-HCT, 3 pts (9.4%) developed CMV disease (all gastrointestinal). Other viral infections included HSV-1 stomatitis (n = 1), parainfluenza (n = 2) and RSV pneumonia (n = 1), adenovirus hepatitis (n = 1). Six pts (18%) had invasive fungal infections (3 with documented aspergillosis). One patient had vitreous toxoplasmosis. Eleven pts (34%) had bacterial infections. Other complications included: renal (16.5%); pulmonary (12.5%), cardiac (6%), hepatic (3%), neurologic (3%). Six ALL pts (31%) died due to: disease (n = 2), aspergillosis pneumonia (n = 1), sepsis (n = 1), GVHD (n = 1), and idiopathic pulmonary syndrome (n = 1). Six NHL/CLL pts (46%) died due to: disease (n = 2), GVHD (n = 2), pulmonary emboli (n = 1) and fungal infection (n = 1). The NRM rate at 100-day and 1-year was 16% and 21% for ALL pts and 15% and 33% for NHL/CLL pts. In ALL pts, earlier (less than 80 days) utilization of allo-HCT after CAR-T was associated with improved survival [HR 4.01, 95% CI: (1.14-14.0); p = 0.03]. In NHL/CLL pts, MAC was associated with higher mortality [HR 3.83 (0.91-16.6); p = 0.06].

**Conclusions:** Toxicities did not exceed the expected incidences in this high-risk population. The data provide a platform for the design of larger studies to address the role of allo-HCT after CAR-T immunotherapy.

**Keywords:** allogeneic stem cell transplant (alloSCT); T-cells.

**Disclosures:** Shadman, M: Consultant Advisory Role: *bbvie, Genentech, Sound Biologics; Verastem, ADC therapeutics and Atara Biotherapeutics;* Research Funding: *Mustang Bio, Celgene, Pharmacycyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Acerta Pharma, Merck. Cassaday, R:* Employment Leadership Position: *Seattle genetics (spouse);* Consultant Advisory Role: *Amgen and Pfizer;* Stock Ownership: *Seattle genetics (spouse);* Research Funding: *Amgen, Incyte, Kite/Gilead, Merck and Pfizer. Till, B:* Research Funding: *Mustang Bio;* Other Remuneration: *Patent/Royalty: Mustang Bio. Gopal, A:* Research Funding: *Teva, Bristol-Myers Squibb, Merck, Takeda, TG Therapeutics, and Effector, Seattle Genetics, Pfizer, Janssen, Gilead, Spectrum, Amgen and Incyte;* Other Remuneration: *personal fee: Seattle Genetics, Pfizer, Janssen, Gilead, Spectrum, Amgen and*

Incyte, Aptevo, BRIM Bio, Seattle Genetics, Bayer, IMAB and Sanofi. Maloney, D: Honoraria: Kite Pharma, Gilead, Genentech, Novartis, Eureka; Research Funding: Kite Pharma, Juno Therapeutics, Celgene; Other Remuneration: Travel, Accommodations, Expenses: A2 Biotherapeutics Patents pending: Methods and Compositions Related to Toxicity Associated with Cell Therapy, Methods for the Treatment of B Cell Malignancies Using Adoptive Cell Therapy, Biomarkers and Uses Thereof for Selecting Immunotherapy Intervention, Methods for Adoptive Cell Therapy Targeting ROR1. Turtle, C: Consultant Advisory Role: Caribou Biosciences, Eureka Therapeutics, and Precision Biosciences, Aptevo, Juno Therapeutics, a Celgene company, Kite, a Gilead Company, Humanigen, Nektar Therapeutics, and Novartis; Stock Ownership: Caribou Biosciences, Eureka Therapeutics, and Precision Biosciences; Research Funding: Juno Therapeutics, a Celgene company, and Nektar Therapeutics; Other Remuneration: patents licensed to Juno Therapeutics, a Celgene company.

259
CLINICAL AND BIOLOGICAL EVALUATION
OF THE NOVEL CD30/CD16A
TETRAVALENT BISPECIFIC ANTIBODY
(AFM13) IN RELAPSED OR REFRACTORY
CD30-POSITIVE LYMPHOMA WITH
CUTANEOUS PRESENTATION: A
BIOMARKER PHASE IB/IIA STUDY
(NCT03192202)

A. Sawas¹ | P. Chen² | G. Vlad¹ | M. Lipschitz² |

M. Abdul-Hay³ | J. Lue¹ | C. Deng¹ |

J.E. Amengual¹ | E. Marchi¹ | J. Shulman⁴ |

H. Elgedawe¹ | M.V. Shong¹ | K. Khan¹ |

L. Geskin¹ | S.J. Rodig⁵ | O. O'Connor¹

¹Medicine, Columbia Medical Center, New York, United States; ²Dana-Farber Cancer Institute, Center for Immuno-Oncology, Boston, United States; ³Medicine, New York University Medical Center, New York, United States; ⁴Medicine, Mount Sinai Medical Center, New York, United States; ⁵Pathology, Brigham & Women's Hospital, Boston, United States

**Introduction:** Natural Killer cells (NKC) play an important role in tumor immune-surveillance. AFM13 is a CD30/CD16A targeting high affinity bispecific tetravalent antibody that engages and activates NKC. This study evaluates AFM13 clinical and immunological activity. It examines the immunologic changes in the tumor and peripheral blood (PB) as a function of the dose and method of administration of AFM13 over time.

**Methods:** Subjects with relapsed or refractory CD30 expressing lymphoma with cutaneous involvement were recruited into 3 cohorts: 1.5 mg/kg IV weekly, 7 mg/kg IV weekly and 7 mg/kg continuous intravenous infusion (CIVI) over 5 days weekly. Each cohort consisted of 3 patients. Subjects received 8 weeks of therapy each cycle. Response assessment was performed on week 11 of each cycle by mSWAT,
<table><caption>**TABLE 1** Clinical results displayed by cohort, disease, toxicity and response</caption><thead><tr><th>Cohort</th><th>Disease</th><th>Toxicity</th><th>Response</th></tr></thead><tbody><tr><td rowspan="3">1.5 mg/kg IV weekly</td><td>Systemic Anaplastic Large Cell Lymphoma-ALK negative</td><td>No AE</td><td>PR</td></tr><tr><td>Transformed Mycosis Fungoides</td><td>No AE</td><td>POD</td></tr><tr><td>Cutaneous anaplastic large cell lymphoma</td><td>Rash (G4)<br>Skin infection (G3)</td><td>CR</td></tr><tr><td rowspan="3">7 mg/kg IV weekly</td><td>Mycosis Fungoides</td><td>IRR (G1)</td><td>SD</td></tr><tr><td>Transformed Mycosis Fungoides</td><td>IRR (G1)</td><td>SD</td></tr><tr><td>Transformed Mycosis Fungoides</td><td>Skin infection (G3)<br>IRR (G1)</td><td>Not assessed</td></tr><tr><td rowspan="3">7 mg/kg CIVI over 5 days weekly</td><td>Transformed Mycosis Fungoides</td><td>No AE</td><td>PR</td></tr><tr><td>Systemic Anaplastic Large Cell Lymphoma-ALK negative</td><td>No AE</td><td>PR</td></tr><tr><td>Mycosis Fungoides</td><td>No AE</td><td>POD</td></tr></tbody></table>

photography, PET imaging and PB flow cytometry. A 2nd cycle was administered if there was no progression. Subjects underwent skin biopsies and PB immunologic studies as follows: pretreatment, day 5, week 4 and week 8 of therapy. Biopsies were analyzed and evaluated by a pathologist and IHC image analyzer. PB samples were analyzed by flow cytometry.

**Results:** Nine subjects were accrued. Age 37-79 years, 3 of 9 where white and 6 of 9 were men. The median number of prior therapies

was 4 (1-11) and 2 patients had progressed on brentuximab vedotin. The disease etiologies, treatment emergent toxicities and response by cohort are presented in table 1. An objective response rate of 44% was observed in the study.

In the PB, flow cytometry revealed a decrease in circulating NK (CD56+ CD3-, CD56+ CD16+ and NKp46+) during therapy with post therapy recovery. The activation marker CD69 on NK increased in responders (R) compared to non-responders (NR).

<caption>**Figure 1:**</caption>

a) Increase in the expression of the activation marker CD69 on NK cells from responders compared to non-responders

<figure><img src="image_168.png" /></figure>

b) Increase in % of CD56 in total cells over time in responders vs. non-responders

<figure><img src="image_169.png" /></figure>
Similarly, tumor biopsies in R showed increased infiltration and activation of CD56+ NKC as opposed to NR (Figure 1). NKC cytotoxicity through the expression of Granzyme B was seen in R vs. NR. Flow quantitation of circulating CD4+ CD25+ T cells (Tregs) shows a decrease in R vs. NR.

**Conclusions:** AFM13 demonstrated a high ORR of 44% among a population of heavily pretreated patients with a CD30 positive lymphoproliferative T-cell malignancy. AFM 13 exhibited activity post brentuximab vedotin failure. In addition, biological changes in NKC infiltration and activation in the PB and tissue biopsy correlate with response. This data is the first to demonstrate the therapeutic advantages of this bispecific, and the first to correlate changes in NKC as a function of dose and schedule.

**Keywords:** anaplastic large cell lymphoma (ALCL); CD30; cutaneous T-cell lymphoma (CTCL).

## 260
# IPILIMUMAB PLUS LENALIDOMIDE FOR TREATMENT OF RELAPSED DISEASE AFTER ALLOGENEIC STEM CELL TRANSPLANTATION (AlloSCT) IN PATIENTS (PTS) WITH LYMPHOID MALIGNANCIES

I.F. Khouri¹ | D.R. Milton² | C. Nicholas³ |

E. Jabbour⁴ | S. Singh³ | L. Vence³ | J.P. Allison³ |

A.M. Gulbis⁵ | P. Sharma⁶

¹Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, United States; ²Biostatistics, University of Texas MD Anderson Cancer Center, Houston, United States; ³Immunology, University of Texas MD Anderson Cancer Center, Houston, United States; ⁴Leukemia, University of Texas MD Anderson Cancer Center, Houston, United States; ⁵Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, United States;

⁶Immunology, Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, United States

**Purpose:** Treatment of relapsed lymphoma after alloSCT requires novel strategies. Clinical trials using ipilimumab in this setting have disappointing results. Based on its immunomodulatory properties, we hypothesized that lenalidomide can harness the immune effect of ipilimumab to combat lymphomas.

**Experimental design:** Patients with lymphoma or chronic lymphocytic leukemia (CLL) who relapsed after alloSCT, with no active graft-versus-host disease (GVHD) were eligible. Treatment consisted of 8 total cycles of lenalidomide 10 mg PO daily for 21 days (cycles 1, 3, 5 and 7) alternating with ipilimumab 3 mg/kg IV on day 1 (Cycles 2, 4, 6 and 8).

**Results:** Eleven pts were enrolled. Median age was 55 yrs (range, 44-66). Histologies included [Follicular (n = 2), CLL (n = 3), Mantle cell (n = 2), diffuse large b-cell (n = 3; 2 of whom were Double-hit), and T-cell anaplastic lymphoma (n = 1)]. The median number of therapies excluding the alloSCT was 3 (range 2-7). Two failed a prior autologous

SCT, one had 2 prior alloSCT, and three failed prior donor lymphocyte infusions. Two pts relapsed within 3 months of their alloSCT prior to enrollment on study. One pt was taken off study after cycle 1 of lenalidomide due to flare of previously diagnosed liver and skin GVHD. Another pt developed skin chronic GVHD after cycle 4 which precluded treatment with the pre-planned 8 cycles. No other cases of GVHD were noted. Overall response rate was 73%. Five (45%) pts had a complete response (four of which were durable at 14+, 32+, 33 + and 34+ months (including one CLL pt who failed prior ibrutinib, idelalisib, venetoclax and CAR-T), and 3 (27%) had partial response (PR). With a median follow-up time of 30.8 months (range, 3-45.1 months), 9 (82%) patients remain alive. One PR pt died secondary to cardiac complications after an elective surgery; and 1 died of progression.

**Immune monitoring:** We conducted multiparametric flow cytometric analyses of PBMCs before and after treatment. We previously identified an increase in the number of inducible costimulatory (ICOS) +CD4+ T cells as a pharmacodynamic biomarker for ipilimumab-based therapy. In the present trial, we observed a statistically significant increase in the number of ICOS⁺CD4⁺FoxP3⁺ T cells number with a notable increase after the first cycle of lenalidomide and a further increase after the first dose of ipilimumab, suggesting an additive effect to these 2 agents when combined together (P = 0.007). We also found a higher frequency of CD4+ICOS+PD-1+ and CD8+PD-1 T effector cells in the responders at baseline when compared to non-responding pts. In contrast, the non-responders had a higher frequency of CD4+GATA3+ T effector memory cells at baseline.

**Conclusions:** These results demonstrate promising durable responses in pts with lymphoid malignancies who relapsed after alloSCT. Future analysis in a bigger cohort would help validate these findings.

**Keywords:** immune system; non-Hodgkin lymphoma (NHL).

## 261
# DONOR LYMPHOCYTE INFUSIONS INDUCE DURABLE RESPONSES IN PATIENTS WITH FOLLICULAR, MANTLE AND T CELL LYMPHOMAS RELAPSING AFTER AN ALLOSCT. AN EBMT-LWP STUDY

S. Robinson¹ | A. Boumendil² | H. Finel² |

I. Khvedelidze² | E. Kanfer³ | K. Peggs⁴ |

S. Fuesrt⁵ | R. Ram⁶ | E. Marjit⁷ |

E. Vandenberghe⁸ | B. Afanasyev⁹ | G. Wulf¹⁰ |

J. Maertens¹¹ | A. Tsolukani¹² | N. Schapp¹³ |

D. Beelen¹⁴ | Y. Chalandon¹⁵ | G. Gurman¹⁶ |

J. Finke¹⁷ | D. Bron¹⁸ | J. Tischer¹⁹ |

P. Corradini²⁰ | D. Caballero²¹ | V. Potter²² |

N. Kroger²³ | C. Burney¹ | N. Schmitz²⁴ |

A. Sureda²⁵ | P. Dreger²⁶ | S. Montoto²⁷
¹Haematology, University Hospital Bristol, Bristol, United Kingdom;
²LWP, EBMT, Paris, France; ³Haematology, Hammersmith Hospital, London, United Kingdom; ⁴Haematology, University College London Hospital, London, United Kingdom; ⁵Haematology, Paoli Calmettes, Marseille, France; ⁶Haematology, Sourasky, Tel Aviv, Israel;
⁷Haematology, Leiden University, Leiden, Netherlands; ⁸Haematology, St James Hospital, Dublin, Republic of Ireland; ⁹Haematology, Pavlov Medical University, St Petersburg, Russian Federation; ¹⁰Haematology, University Hospital, Goettingen, Germany; ¹¹Haematology, University Hospital, Leuven, Netherlands; ¹²Haematology, City Hospital, Nottingham, United Kingdom; ¹³Haematology, St Radboud Hospital, Nijmegen, Netherlands; ¹⁴Haematology, University Hospital, Essen, Germany; ¹⁵Haematology, University Hospital, Geneva, Switzerland;
¹⁶Haematology, Ankara University, Ankara, Turkey; ¹⁷Haematology, University of Freiburg, Freiburg, Germany; ¹⁸Haematology, Institute Jules Bordet, Brussels, Belgium; ¹⁹Haematology, Med Klinik Klinikum Grosshaderm, Munich, Germany; ²⁰Haematology, Istituto Nazionale dei Tumori, Milan, Italy; ²¹Haematology, Hospital Clinic, Salamanca, Spain;
²²Haematology, Kings College hospital, London, United Kingdom;
²³Haematology, University Hospital Eppendorf, Hamburg, Germany;
²⁴Haematology, University Hospital, Muenster, Germany;
²⁵Haematology, Oncology Institute, Barcelona, Spain; ²⁶Haematology, University of Heidelberg, Heidleberg, Germany; ²⁷Haematology, St Bartholomew's Hospital, London, United Kingdom

**Introduction:** Donor lymphocyte infusions (DLI) can be employed to treat relapsed lymphoma following allogeneic stem cell transplantation (alloSCT) and provide the most direct evidence for the graft versus lymphoma effect. Given the paucity of data describing the efficacy of DLIs in NHL relapsing after alloSCT we have conducted an extensive analysis from the EBMT database.

**Methods:** 118 patients [follicular lymphoma (FL) n = 28, diffuse large B cell lymphoma (DLBCL) n = 28, T cell lymphoma (TCL) n = 52 and mantle cell lymphoma (MCL) n = 10] who received DLI as the only treatment for clinical relapse post alloSCT were identified on the EBMT database. The median age at alloSCT was 50 (18-73) years. There were 37 female and 81 male patients who underwent an alloSCT with reduced intensity (n = 90) or myeloablative conditioning (n = 28) from matched sibling (n = 63), unrelated (n = 47) or mismatched family (n = 8) donors. 85 were T cell depleted with CAMPATH or ATG. The median time from alloSCT to relapse was 3.8 months (18 days-67 months).

**Results:** Patients received a median of 1 (range 1-19) DLIs at a median starting dose of 1.5 x10⁶ CD3/kg (0.01-120x10⁶ CD3/kg) at a median of 152 days (18-2136) post alloSCT. The median time from relapse to the first DLI was 35 days (0-168). The best response achieved in 102 evaluable patients was CR in 56 and PR in 10, whereas 13 patients had stable disease and 23 progressed. The median duration of response was 36 months (range 1-168). When analysed according to histology the overall response rate (ORR=CR +PR) for FL was 88% (CR 77%), DLBCL 41% (32% CR), TCL 60% (53% CR) and MCL 86% (CR 71%). The median duration of responses for

FL, DLBCL, TCL and MCL were 30 (range 2-150), 38 (4-76), 37 (range 1-168) and 50 months (13-116), respectively. With a median follow up of 77 months after the 1st DLI, 36 (31%) patients remain in complete remission, 29 (25%) without any further therapy. 37 patients (35%) received additional antilymphoma therapy after the DLI. Of 20 patients with FL achieving a CR post DLI, 13 (65%) remain in remission without further therapy at a median of 74 months. Of 24 patients with TCL that achieved a CR with DLI, 20 (83%) remain in remission without further therapy at a median of 95 months. Following the DLI 43 (36%) patients developed aGVHD (6 grade I, 13 grade II, 11 grade III, 9 grade IV, 4 grade unknown) and 33 (28%) developed cGVHD (11 limited, 20 extensive, 2 unknown). Following the first DLI the cumulative incidence of relapse was 31% (CI 22-41) at 4 years. The 4-year PFS after 1st DLI was 39% (CI 30-50) and the OS, 44% (CI 35-54).

**Conclusions:** DLI monotherapy can induce significant ORR in patients with NHL which are most impressive in FL and MCL. Although the ORR was not so high in patients with TCL, those who achieved a CR post DLI have an excellent chance of long-term remission. In contrast, in DLBCL DLI as single treatment provides only limited benefit. Acute and chronic GVHD remains a significant complication of DLI.

**Keywords:** allogeneic stem cell transplant (alloSCT).

262

## INTRANODAL TREATMENT WITH IFNA-DENDRITIC CELLS AND RITUXIMAB INDUCES SYSTEMIC CLINICAL RESPONSE AND ENDOGENOUS VACCINATION AGAINST FOLLICULAR LYMPHOMA: FINAL RESULT OF A PHASE I STUDY

C. Cox<fnref n="1" /> | L. Castiello² | M. Mattei³ |

L. Santodonato² | G. D'agostino² | E. Muraro⁴ |

D. Martorelli⁴ | C. Lapenta⁵ | A. Di Napoli⁶ |

F. Di Landro⁷ | M. Cangemi⁴ | A. Pavan⁶ |

P. Castaldo⁸ | S. Hohaus⁷ | S. Donati⁵ |

E. Montefiore² | C. Berdini³ | S. Borgioni³ |

D. Carlei² | D. Monque² | L. Ruco⁶ | D. Prosperi⁹ |

A. Tafuri⁶ | F. Spadaro⁵ | P. Sestili⁵ | M. Spada² |

R. Dolcetti¹⁰ | S. Santini⁵ | C. Rozera² | E. Arico'² |

I. Capone² | F. Belardelli¹¹

<footnote n="1">¹Haematology, AOU Sant'Andrea, Rome, Italy & King's College Foundation Trust, London, United Kingdom; ²FaBioCell, Core Facilities, Istituto Superiore di Sanita', Rome, Italy; ³Radiology, AOU Sant'Andrea, Rome, Italy; ⁴Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; ⁵Department of Oncology and Molecular Medicine, Istituto Superiore di Sanita', Rome, Italy; ⁶Department of Clinical and Molecular Medicine, AOU Sant'Andrea, Rome, Italy; ⁷Institute of Hematology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy;</footnote>
<sup>8</sup>Surgery, AOU Sant'Andrea, Rome, Italy; <sup>9</sup>Nuclear Medicine, AOU Sant'Andrea, Rome, Italy; <sup>10</sup>Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia; <sup>11</sup>Institute of Translational Pharmacology, CNR, Rome, Italy

**Purpose:** This study was aimed at evaluating the feasibility, safety, immunological and clinical responses in patients with Follicular lymphoma (FL) treated with monocyte-derived dendritic cells generated in the presence of interferon-alpha and GM-CSF (IFN-DC) in combination with low doses of Rituximab (R).

**Experimental design:** Firstly, we analyzed *in vitro* and *in vivo* the immunological properties of IFN-DC against FL. Thus, we performed a phase I trial in 8 refractory and relapsed FL patients based on sequential intranodal injections of low-dose of R and unloaded IFN-DC and report the safety, clinical and immunological results of the enrolled patients.

**Results:** Preclinical studies indicated that IFN-DC can synergize with R leading to increased cytotoxicity and T cell tumor infiltration. The clinical evaluation showed that the combined treatment was totally safe. The overall response rate was 50%, PET-negative complete response rate 37% and remission is still ongoing in 2/4 of responding patients (median follow-up 26 months, range 11-47). Notably, following the combined therapy all patients showed induction/enhancement of T cell responses by CD107 degranulation or IFN-g ELISPOT assay against patient-specific tumor IGHV sequences.

**Conclusions:** These results represent the proof-of-principle on the effectiveness of unloaded IFN-DC in inducing durable clinical responses and promoting induction of tumor specific peripheral T cells, thus suggesting the occurrence of an effective endogenous antitumor vaccination. The overall findings indicate that some unique properties of IFN-DC can be successfully exploited to induce/enhance antitumor responses, thus representing a valuable antitumor strategy for novel and more effective combination therapies in cancer patients.

**Translational relevance:** The development of protocols of *in situ* cancer immunotherapy aimed at inducing an endogenous vaccination is currently regarded as a practical and promising antitumor strategy, with potential advantages with respect to the use of defined tumor antigens for inducing a broader antitumor immunity, potentially targeting also neoantigens emerging during tumor progression and therapies. This study represents the first evidence on the safety and clinical effectiveness of IFN-DC, a unique type of DC rapidly generated from monocytes under simple GMP conditions and endowed with special immunostimulatory properties. Combined with low doses of intranodal injection of R, IFN-DC induced clinical response in cancer patients and promoted the induction of tumor specific T cells. All this implies the occurrence of an endogenous antitumor vaccination possibly resulting in clinical response. The findings suggest that IFN-DC are a good candidate for a selective clinical use in combination therapies in cancer patients

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

NOVEL TREATMENTS

263
COPANLISIB SYNERGIES WITH
CONVENTIONAL AND TARGETED AGENTS
INCLUDING VENETOCLAX IN PRECLINICAL
MODELS OF B- AND T-CELL LYMPHOMAS

C. Tarantelli¹ | M. Lange² | E. Gaudio¹ |

L. Cascione¹ | F. Spriano¹ | I. Kwee¹ | A. Arribas¹ |

A. Rinaldi¹ | T. Jourdan² | M. Berthold² |

F. Margheriti¹ | G. Gritti³ | D. Rossi¹ | A. Stathis⁴ |

N. Liu² | E. Zucca⁴ | O. Politz² | F. Bertoni¹

¹Institute of Oncology Research, Università della Svizzera Italiana, Bellinzona, Switzerland; ²Pharmaceuticals Division - Therapeutic Research Groups Oncology, Bayer AG, Leverkusen, Germany; ³USC Ematologia, Ospedale Papa Giovanni XXIII, Bergamo, Italy; ⁴IOSI, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

**Introduction:** Copanlisib has shown activity in lymphomas, but the number of patients achieving complete remission is relatively low, a problem shared by many targeted agents. We performed a pharmacological screening to identify active combinations.

**Methods:** We tested copanlisib as single agent and in combination with other molecules in cell lines derived from mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and T cell lymphomas (T-NHLs). Synergism was evaluated with Chou-Talalay combination index, as previously done (Tarantelli et al, CCR 2018).

**Results:** Copanlisib showed an *in vitro* dose-dependent antitumor activity in the vast majority of the models with a median IC50 of 75 nM (95% C.I., 21-160 nM). The drug was active both in B- (n = 17) and T-NHLs (n = 9), but the latter were less sensitive (285 vs 22 nM, P = 0.0002). The *in vitro* activity was confirmed using the human JeKo-1 MCL xenograft model.

We evaluated 16 combination partners, including rituximab (B-NHL), crizotinib and brentuximab vedotin (T-NHLs), lenalidomide, bendamustine, agents targeting AKT1/2, BCL2, BET, BTK, CDKs (pan, CDK4/6, CDK9), HDAC, JAK1/2, MALT1, and the proteasome. In B-NHLs, copanlisib/venetoclax were the most beneficial (14 synergism, 2 additive), and the 4th best in T-NHLs (5 synergism, 1 additive). The combination led to increased apoptosis, as shown by a dose-dependent increased PARP cleavage in 3 MZL, and 1 MCL cell lines and by a reduction of cell viability in 2 MCL primary cells. In MZL (SSK41) and MCL (Jeko1) 24h exposure to copanlisib determined a dose-dependent down-regulation of pAKT and anti-apoptotic proteins (BCL-XL in the MZL and of MCL1 in the MCL). These changes were maintained in cells exposed to the combination, but not after venetoclax alone. An *in vivo* experiment using the SSK41 MZL cell line validated the beneficial effect of this combination and also of copanlisib/lenalidomide (*in vitro* beneficial in 12/17 B- and 4/9 T-NHL). In T-NHLs, benefit was observed in all ALCL-ALK+ with
copanlisib/crizotinib (3/4 synergisms). All but one of the non ALCL-ALK+ cell lines achieved a synergism with copanlisib/ruxolitinib. Copanlisib/brentuximab vedotin was synergistic in the non ALCL-ALK+ and Sezary Syndrome cell lines.

Transcriptome analysis identified the PIM1 and PIM2 kinases and the anti-apoptotic gene MCL1 as up-regulated in the MZL cell line HAIR-M exposed to copanlisib (5nM, for 4, 8 and 12h). Thus, we tested combinations with the PIM inhibitor AZD1208 and the MCL1 inhibitor MIK665 (S63845) in 3 MCL and 3 MZL cell lines. Both combinations were synergistic in the HAIR-M and beneficial in additional 5/5 and 3/5 cell lines, respectively.

**Conclusions:** Our study identified a series of active copanlisib-containing combinations and provided the rational for the design of the new SAKK 66/18 phase I study exploring copanlisib plus venetoclax in relapsed/refractory B-cell lymphomas.

**Keywords:** marginal zone lymphoma (MZL); PI3K/AKT/mTOR; venetoclax.

**Disclosures:** Lange, M: Employment Leadership Position: Bayer AG.

Jourdan, T: Employment Leadership Position: Bayer AG. Berthold, M:

Employment Leadership Position: Bayer AG. Rossi, D: Consultant
Advisory Role: Gilead, AbbVie, Janssen, AstraZeneca; Honoraria: Gilead,
AbbVie Janssen, Roche; Research Funding: Gilead, AbbVie, Janssen.

Stathis, A: Research Funding: Bayer, Merck, Pfizer, Novartis, Roche;

Other Remuneration: travel grant from AbbVie. Liu, N: Employment
Leadership Position: Bayer AG. Zucca, E: Consultant Advisory Role:
Roche, Mei Pharma, Astra Zeneca; Research Funding: Roche, Janssen;

Other Remuneration: travel grants from AbbVie and Gilead; expert statements provided to Gilead. Politz, O: Employment Leadership Position: Bayer AG. Bertoni, F: Research Funding: Acerta, Bayer AG; Other Remuneration: travel grants from Astra Zeneca, PIQUR Therapeutics AG.

## 264
MECHANISMS OF SECONDARY RESISTANCE TO IDELALISIB IN MARGINAL ZONE LYMPHOMA

A. Arribas<fnref n="1" /> | S. Napoli<fnref n="1" /> | E. Gaudio<fnref n="1" /> | L. Cascione<fnref n="1" /> |

A. Di Veroli² | C. Tarantelli<fnref n="1" /> | F. Spriano<fnref n="1" /> |

A. Zucchetto³ | F. Rossi³ | A. Rinaldi<fnref n="1" /> | A. Stathis⁴ |

G. Stussi⁴ | V. Gattei³ | G. Cruciani² | E. Zucca⁴ |

D. Rossi<fnref n="1" /> | F. Bertoni<fnref n="1" />

**Background:** PI3Kδ-inhibitor (i) idelalisib (IDEL) is currently used to treat indolent lymphomas including marginal zone lymphoma (MZL).

However, a subset of patients relapses due to acquired resistance. A better understanding of resistance mechanisms could help to design improved therapies. With this aim, we generated MZL cell lines resistant to IDEL.

**Materials and Methods:** Cells were kept under IDEL(IC90) until acquisition of resistance (RES) or with no drug (parental, PAR). Stable resistance was confirmed by MTT assay after 2-weeks of drug-free culture. Multi-drug resistance phenotype was ruled out. Cells underwent transcriptome profiling (RNA-Seq), lipidomics profiling, pharmacological screening (348 compounds), and immunophenotypic analysis.

**Results:** The RES models, with 5-10 fold times higher IC50s than PAR counterparts, derived from VL51 and Karpas1718 presented different mechanisms of resistance to IDEL, although both involved secreted molecules since conditioned media conferred resistance to IDEL in the PAR cells. Lipidomics analyses revealed increased levels of specific triacylglycerols and glycerophosphocholines with lower cardiolipins and sphingomyelins levels in RES-VL51, and up-regulated of some triacylglycerols and repressed levels for specific glycerophosphocholines in the RES-K1718.

Comparing RES vs PAR, there was an enrichment at transcriptomic level in IL6-STAT3, chemokines and PDGFRA signatures for the RES-VL51, paired with increased p-AKT and p-BTK levels. In particular, there was an over-expression of IL6, PDGFRA and CXCR4. In accordance, addition of a CXCR4-i overcame resistance. Furthermore, targeting IL6 or PDGFRA with siRNAs partially reverted the resistance, and the effect was stronger when both genes were silenced. Finally, the pharmacologic screening showed anti-proliferation activity of a PDGFR-i in the RES.

In the RES-K1718 model, there was enrichment for proliferation signatures and growth factors. HB-EGF and ERBB4 were among the most up-regulated transcripts and their involvement in the resistance mechanisms were studied. First, recombinant HB-EGF stimulation was able to induce resistance to IDEL and also to the BTK-i ibrutinib in both PAR lines. Second, RES-K1718 recovered sensitivity to IDEL upon combination with a pan ERBB-i and with ibrutinib, tested due to its reported ERBB inhibition capacity.

**Conclusions:** We created two distinct novel models derived from MZL of secondary resistance to the PI3Kδ-i idelalisib. These models, driven by different biologic processes, will help in clarifying mechanisms of resistance to the drug and to evaluate alternative therapeutic approaches. Indeed, we already identified potential active treatments that might overcome resistance to IDEL and are worth of further investigations.

**Keywords:** idelalisib; marginal zone lymphoma (MZL).

## 265
A SELECTIVE AND COVALENT INHIBITOR OF ITK BLOCKS TCR SIGNALING, INHIBITS PROLIFERATION OF HUMAN SÉZARY CELLS IN VITRO, AND INDUCES TUMOR REGRESSION IN DOGS WITH T-CELL LYMPHOMA

<footnote n="1">¹Institute of Oncology Research, Università della Svizzera Italiana, Bellinzona, Switzerland; ²Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy; ³Centro di Riferimento Oncologico di Aviano, Centro di Riferimento Oncologico di Aviano - CRO, Aviano, Italy; ⁴Oncology Institute of Southern Switzerland, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland</footnote>
J.J. Buggy¹ | P.P. Ng¹ | J.W. Janc¹ | A. Hotson¹ |

C.M. Hill¹ | D.H. Thamm² | Y.H. Kim³ |

M. Khodadoust³ | M. Mobasher¹ | R.A. Miller¹

¹Biology, Corvus Pharmaceuticals, Burlingame, United States; ²Flint
Animal Cancer Center, Colorado State University, Fort Collins, United
States; ³School of Medicine, Stanford University, Stanford, United States

**Introduction:** ITK is a tyrosine kinase involved in T-cell receptor (TCR) signaling and differentiation of naïve T cells. ITK is closely related to RLK, a kinase of redundant function that is expressed in cytotoxic T cells and Th1 but not Th2 cells. Studies in knockout mice indicate that selective inhibition of ITK will inhibit Th2 differentiation and allow normal T cell immunity. ITK is widely expressed in T cell malignancies and signaling is associated with poor survival in peripheral T cell lymphoma (PTCL). Copy number gain of the ITK gene is often seen in PTCL and ITK is frequently overexpressed in cutaneous T-cell lymphoma (CTCL). Therefore, selective inhibition of ITK may be a new treatment strategy. Here we describe CPI-818, a compound designed to bind covalently and selectively to the CYS-442 residue of ITK.

**Methods:** Human PBMC, T cell lines and Sézary cells were stimulated in vitro with anti CD3/CD28 with or without CPI-818. TCR signaling and proliferation were evaluated by flow cytometry and western blots. Mice were treated with CPI-818 and effects on immune cell subsets, humoral and cellular immune response were evaluated. Th skewing in mice was determined using an ovalbumin vaccine adoptive transfer model. Companion dogs with TCL were treated with CPI-818 at 20mg P.O. BID and evaluated for safety and tumor response.

**Results:** CPI-818 inhibits kinase activity with $IC_{50}$ values of 2.3nM, 430nM and 850nM for ITK, RLK and BTK, respectively. In a wider survey of 468 human kinases, CPI-818 (1µM) was highly selective for ITK. CPI-818 inhibited anti-CD3/28 induced phosphorylation of ERK and PLCγ1 in PBMC and inhibited IL-2 secretion in stimulated Jurkat T cells (75 nM). in vitro proliferation of human Sézary cells was inhibited with 200nM of CPI-818, a concentration that did not affect the proliferation of autologous normal T cells. Anti CD3/28-induced Th2 cytokine production in Sézary cells was also inhibited by CPI-818. in vivo studies showed no changes in blood counts or T, B, NK cell subsets in lymphoid organs of mice given CPI-818 for 28 days. Neither primary nor secondary antibody responses nor CD4 T cell responses to KLH antigen were inhibited. Spleen cells from treated mice demonstrated an increase in the ratio of $IFNγ$/IL-4 cells indicative of Th1 skewing. Three dogs with T-cell lymphoma; 1 PTCL and 2 CTCL were treated with CPI-818 for 2-20 weeks. Treatment was well tolerated with no dose limiting toxicities and no changes in lymphocyte counts. One complete (CTCL, 5 months duration) and two partial responses were observed.

**Conclusions:** CPI-818 blocks TCR signaling and T cell activation and also affects T cell differentiation with a biasing to Th1 cells. There are preferential anti-proliferative effects in Sézary cells compared to

autologous normal T cells. The demonstration of safety and clinical activity in dogs with T-cell lymphoma support recently initiated clinical trials in patients with TCL.

**Keywords:** T-cell lymphoma (TCL); T-cell receptor (TCR).

**Disclosures:** Buggy, J: Employment Leadership Position: Corvus Pharmaceuticals; Stock Ownership: Corvus Pharmaceuticals. Ng, P: Employment Leadership Position: Corvus Pharmaceuticals; Stock Ownership: Corvus Pharmaceuticals. Janc, J: Employment Leadership Position: Corvus Pharmaceuticals; Stock Ownership: Corvus Pharmaceuticals. Hotson, A: Employment Leadership Position: Corvus Pharmaceuticals; Stock Ownership: Corvus Pharmaceuticals. Hill, C: Employment Leadership Position: Corvus Pharmaceuticals; Stock Ownership: Corvus Pharmaceuticals. Thamm, D: Consultant Advisory Role: Corvus Pharmaceuticals. Kim, Y: Consultant Advisory Role: Corvus Pharmaceuticals. Khodadoust, M: Consultant Advisory Role: Corvus Pharmaceuticals. Mobasher, M: Employment Leadership Position: Corvus Pharmaceuticals; Stock Ownership: Corvus Pharmaceuticals. Miller, R: Employment Leadership Position: Corvus Pharmaceuticals; Stock Ownership: Corvus Pharmaceuticals.

A.S. Azmi¹ | E. Seymour¹ | I. Muqbil² |

A. Aboukameel¹ | D. Bhutani³ | J. Zonder¹ |

R. Ramchandran⁴ | J. Yang¹

¹Oncology, Wayne State University, Detroit, United States; ²Chemistry,
University of Detroit Mercy, Detroit, United States; ³Oncology, University
of Columbia, New York, United States; ⁴Medicine, University of
Tennessee Medical Center, Knoxville, United States

**Introduction:** The nuclear exporter protein exportin-1 (XPO1) regulates the activity of tumor suppressor proteins (TSPs) via compartmentalization within the nucleus. XPO1 over-expression in cancer including Non-Hodgkin's Lymphoma (NHL) leads to increased nuclear export of TSPs and their functional inactivation and often correlates with poor prognosis. Single agent oral selinexor has demonstrated an ORR of 29.6% in patients with RR DLBCL with durable responses > 8 months. R-CHOP is highly active in NHL, however fails to sufficiently activate TSPs due to high XPO1 activity. This makes the enhancement of R-CHOP sensitivity through XPO1 inhibition and nuclear retention of TSPs a viable therapeutic strategy for NHL. Earlier, we had demonstrated that targeting XPO1 by Selective Inhibitor of Nuclear Export (SINE) compounds (selinexor and analogs) resulted in anti-tumor activity in patient-derived lymphoma cell lines and NHL xenograft models.

**Methods:** Using several assays for cytotoxicity and apoptosis analysis, molecular assays and CRISPR/Cas9 genome editing for specificity, we evaluate the anti-tumor activity of SINE compounds with R-CHOP
in vitro, in vivo and in a Phase Ib/II clinical trial (NCT03147885) in NHL patients. Eight NHL patients were administered R-CHOP every 3 weeks (Rituximab 375 mg/m² IV day 1; Cyclophosphamide 750 mg/m² IV day 1; Doxorubicin 50 mg/m² IV day 1; Vincristine 2 mg IVP day 1 and Prednisone 100 mg days 1-5) along with selinexor 60 mg PO weekly. Peripheral blood from patients treated with the combination was obtained for RNA-Seq, RT-PCR and protein analyses.

**Results:** SINE compounds synergized with CHOP in vitro (CI<1). Selinexor-R-CHOP and next generation analog altanexor-R-CHOP combination treatment resulted in statistically significant enhancement of survival of a systemic (disseminated) NHL model. The superior cytotoxicity was consistent with enhanced nuclear retention of different TSPs consistent with the suppression of pro-survival markers and activation of pro-apoptotic molecules in the combination treatment. Using CRISPR/Cas9 genome editing we discovered an R-CHOP priming mechanism in which XPO1 inhibition leads to the enhancement of CD20 through cancer cell selective activation of p-ERK. In blood biopsies from the selinexor-R-CHOP trial patients a statistically significant down-regulation of XPO1 and 9 pro-survival markers were uniformly captured in RNA-seq, mRNA and protein analysis and corroborated the in vitro and in vivo data. Immunostaining of the NHL patient biopsies were in line with the molecular results and showed nuclear retention of TSPs.

**Conclusion:** Selinexor plus R-CHOP demonstrates strong anti-tumor activity in established and patient derived NHL models. We are broadening the characterization of this combination regimen in patient biopsies from our ongoing trial. We anticipate that our results will bring forward a novel and effective treatment regimen for NHL.

**Keywords:** B-cell lymphoma; non-Hodgkin lymphoma (NHL); R-CHOP.

**Disclosures:** Seymour, E: Research Funding: Karyopharm Therapeutics.

267

REVERSAL OF IMMUNE TOLERANCE AND
INCREASED SURVIVAL AFTER XPO1 AND
BTK INHIBITION IN MOUSE MODELS OF
PRIMARY CNS LYMPHOMA (PCNSL)

I. Jiménez<fnref n="1" /> | J. Carabia<fnref n="1" /> | S. Bobillo<fnref n="1" /> | C. Palacio<fnref n="1" /> |
P. Abrisqueta<fnref n="1" /> | J.C. Nieto<fnref n="1" /> | J. Castellví² |
F. Martínez-Ricarte³ | L. Escoda⁴ | C. Perla⁵ |
D.H. Cespedes⁵ | J. Boix<fnref n="1" /> | N. Purroy<fnref n="1" /> |
L. Puigdefàbregas<fnref n="1" /> | J. Seoane⁶ | F. Bosch<fnref n="1" /> | M. Crespo<fnref n="1" />

**Introduction:** On the grounds of frequent deregulated chronic BCR signaling in PCNSLs, targeting the BCR pathway is emerging as a promising therapeutic avenue for these poor-prognostic patients. Unfortunately, responses to the inhibition of BCR signaling with ibrutinib are scarce and short-lasting. Of note, inhibition of the XPO-1 activity with selinexor has been shown to impede BCR and NF-kB signaling, while having excellent brain penetrance. Herein, we studied the activity of selinexor alone or in combination with ibrutinib in preclinical mouse models of PCNSL.

**Methods:** Proliferation and survival analysis in DLBCL cell lines were performed by MTS and Annexin V-propidium iodide assays. Orthotopic xenograft models were established by the injection of ABC-DLBCL cells transfected with luciferase or patient-derived PCNSL cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Immunohistochemical (IHC) detection was performed using human anti-CD20, human anti-Ki-67 and mouse anti-F4/80 antibodies. Changes in the proportion of M1/M2 macrophages and in the expression of immune checkpoints were studied by flow cytometry.

**Results:** Firstly, we observed that in vitro sensitivity to selinexor was independent of the cell of origin, but that a strong synergy with ibrutinib occurred mainly in ABC-DLBCL cells. Accordingly, after treating the OCI-Ly10 (ABC origin) bearing mice with 5mg/kg selinexor or vehicle three times a week, it was found that selinexor significantly blocked tumoral growth prolonging mice survival (median: 48 days vs. 34 days). Next, for the purpose of evaluating potential synergy between ibrutinib and selinexor, PCNSL mice were distributed in four groups: selinexor (5mg/kg twice a week), ibrutinib (25mg/kg daily), combination of both or vehicle. Although tumoral growth was blocked by all treatments, the combination of both drugs significantly increased survival compared to monotherapies. Further analysis of the innate immune microenvironment by flow cytometry and IHC showed that PCNSLs were infiltrated by macrophages, particularly by pro-tumoral M2 expressing PD1 and SIRPα. Notably, the treatment with the combination of drugs increased the proportion of inflammatory M1 macrophages, while the remaining M2 macrophages expressed lower levels of the immune checkpoints PD1 and SIRPα.

**Conclusions:** Our results show that selinexor blocks PCNSL tumor growth and prolongs survival, while its combination with ibrutinib further increases survival. Additionally, we show that PCNSL in mice is infiltrated by tumor-promoting PD1⁺ and SIRPα⁺ M2 macrophages. Treatment with both drugs favors an anti-tumoral immune response by shifting polarization toward anti-tumoral M1. These observations provide pre-clinical evidence for the development of selinexor as a new therapeutic option for PCNSL.

<footnote n="1">¹Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital (HUVH), Barcelona, Spain; ²Department of Pathology, Vall d'Hebron University Hospital (HUVH), Universitat Autònoma de Barcelona, Barcelona, Spain; ³Department of Neurosurgery, Vall d'Hebron University Hospital (HUVH), Universitat Autònoma de Barcelona, Barcelona, Spain; ⁴Department of Hematology, Hospital Universitari Joan XIII, Tarragona, Spain; ⁵Department of Neurosurgery, Hospital Universitari Joan XIII, Tarragona, Spain; ⁶Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital (HUVH), Universitat Autònoma de Barcelona, CIBERONC, Barcelona, Spain</footnote>
**Keywords:** B-cell receptor (BCR); macrophages; primary CNS lymphoma (PCNSL).

**Disclosures:** Abrisqueta, P: Honoraria: Roche, Janssen and AbbVie. Bosch, F: Honoraria: Roche, Celgene, Takeda, Astra-Zeneca, Novartis, AbbVie, Janssen; Research Funding: Roche, Celgene, Takeda, Astra-Zeneca, Novartis, AbbVie, Janssen.

## 268
THE FIRST-IN-CLASS ETS INHIBITOR TK-216 INTERFERES WITH ETS TRANSCRIPTION FACTORS AND SYNERGIZE WITH LENALIDOMIDE IN LYMPHOMA

F. Spriano<fnref n="1" /> | E. Chung<fnref n="1" /> | S. Napoli<fnref n="1" /> | C. Tarantelli<fnref n="1" /> |
E. Gaudio<fnref n="1" /> | L. Cascione<fnref n="1" /> | A. Cavalli<fnref n="2" /> | A. Rinaldi<fnref n="1" /> |
I. Kwee<fnref n="1" /> | H. Ye³ | D. Rossi<fnref n="1" /> | E. Zucca⁴ |
A. Stathis⁴ | K. Jessen⁵ | B. Lannutti⁵ |
J. Toretsky⁶ | F. Bertoni<fnref n="1" />

**Background:** Altered expression levels of members of the ETS-transcription factors are often observed in lymphomas. TK-216, clinical derivative of YK-4-279, is the first-in-class inhibitor of the Ets family of transcription factors. Here, we characterized TK-216 and YK-4-279 for their anti-lymphoma activity and mechanism of action in lymphomas.

**Methods:** Cells were exposed to YK-4-279 or TK-216 alone or combined with other compounds; cell proliferation was measured with MTT; synergy calculated with the Chou-Talalay combination index. *in vivo* studies were done in NOD-SCID mice. RNA and proteins changes were analyzed using standard techniques.

**Results:** YK-4-279 and TK-216 demonstrated an anti-tumor activity across over 50 lymphoma cell lines. The anti-tumor activity was confirmed in a DLBCL xenograft model (TMD8). Compared with control group, mice treated with TK-216 or YK-4-279 clearly presented a reduction in tumor growth (P<0.01). We then combined YK-4-279 or TK-216 *in vitro* with 5 anti-lymphoma agents (ibrutinib, idelalisib, birabresib, venetoclax and lenalidomide) in 2 ABC (OCI-LY-10, TMD8) and 2 GCB (Karpas422, SU-DHL-4) DLBCL cell lines. The biggest benefits were achieved in the combination with venetoclax and lenalidomide. Since lenalidomide is known to act in ABC DLBCL via the IRF4-SPIB axis, we firstly

confirmed the synergism also in vivo in the OCI-LY-10 xenograft model and then we evaluated the contribution of SPIB in the synergism between TK-216 and lenalidomide. Reduction in SPIB protein level was observed with both compounds as single agents but with a more pronounced effect in the combination. Co-IP experiments also demonstrated that TK-216 decreased the binding of SPIB to RHA and DDX5 in ABC-DLBCLs and of SPI1 to the same helicases in GCB-DLBCLs, as reported for EWS-FLI1 fusion protein and the two helicases in Ewing Sarcoma.

Finally, we investigated the effect of TK-216 treatment on transcriptome changes. Gene expression profiling on U2932 ABC DLBCL cell lines exposed 8 hrs to the TK-216 demonstrated that transcripts upregulated by TK-216 were enriched of genes repressed by IRF4 and SPIB, while genes downregulated by lenalidomide or positively regulated by IRF4 and SPIB were present in the transcripts downregulated by the compound. After 18 hrs of treatment with TK-216, the transcriptome changes were more similar to what reported for RNA helicase A knockdown, indicating the interference with SPIB as an early event.

**Conclusions:** In ABC DLBCL, YK-4-279 and its clinical derivative TK-216 synergize with lenalidomide, both in vitro and in vivo, interfering with SPIB. TK-216 shows a promiscuous activity on ETS factors interfering between helicases and two different ETS factors: SPIB and SPI1. A clinical trial for DLBCL patients is being designed.

Work was supported by funding from Oncosuisse KLS-3580-02-2015, Leukemia & Lymphoma Society #6521-17.

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

**Disclosures:** Jessen, K: Employment Leadership Position: Oncternal Therapeutics. Lannutti, B: Employment Leadership Position: Oncternal Therapeutics. Toretsky, J: Consultant Advisory Role: Oncternal Therapeutics; Stock Ownership: Oncternal Therapeutics.

## 269
THE NOVEL BISPECIFIC CD47-CD19 ANTIBODY TG-1801 POTENTIATES THE ACTIVITY OF UBLITUXIMAB-UMBRALISIB (U2) DRUG COMBINATION IN PRECLINICAL MODELS OF B-NHL

E. Normant<fnref n="1" /> | M.L. Ribeiro<fnref n="2" /> | D. Reyes<fnref n="2" /> |
H.P. Miskin<fnref n="1" /> | P. Sportelli<fnref n="1" /> | M.S. Weiss<fnref n="1" /> |
F. Bosch<fnref n="2" /> | G. Roue<fnref n="2" />

Umbralisib is an orally available PI3Kδ inhibitor that has demonstrated activity in preclinical models and primary B-cell non-Hodgkin lymphoma (B-NHL) cells, and in patients with B-cell malignancies. The doublet of umbralisib used in combination with the

<footnote n="1">¹Institute of Oncology Research, Università della Svizzera Italiana, Bellinzona, Switzerland; ²Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland; ³Department of Cell Biology, Albert Einstein College of Medicine and Montefiore Medical Center, New York, United States; ⁴Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; ⁵Oncternal Therapeutics, San Diego, United States; ⁶Departments of Oncology and Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C., United States</footnote>

<footnote n="1">¹Preclinical Sciences, TG Therapeutics, New York, United States;</footnote>

<footnote n="2">²Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain</footnote>
glycoengineered anti-CD20 mAb ublituximab ("U2" regimen), provides a non-chemotherapy backbone regimen on which novel multidrug combinations are being explored. TG-1801 is a novel, bispecific antibody currently in Phase 1 that selectively targets CD47 on CD19+ B-cells, sparing red blood cells or platelets, and blocking the CD47-SIRPα macrophage checkpoint on mature B cells. Here we show that activity of the U2 combination in B-NHL cell lines co-cultured with bone marrow-derived stromal cells, M2-polarized primary macrophages, and primary circulating PBMCs, is mainly associated with a decrease of anti-inflammatory cytokines genes (IL-6, IL-10, IL-1RA). In addition, upregulation of pro-inflammatory IL-2, accompanied by a 2-fold increase of M2-dependent antibody-dependent cell phagocytosis (ADCP), is also observed. Notably, when U2 is combined with TG-1801, this 2-fold increase in ADCP is doubled up to 4-fold increase. Moreover, the activated antibody-dependent cell death (ADCC) observed with TG-1801 alone (4.1-fold above control) becomes increased (7.2-fold above control) when combined with ublituximab, whereas umbralisib alone does not affect ADCC. RNA-seq analysis further reveals that U2 treatment is mainly associated with modulation of redox processes in B-NHL co-cultures (NES = -0.57, p = 0.016). Although TG-1801 single agent does not significantly affect B cell transcriptome, combination with U2 provokes the down-regulation of genes associated with cell architecture homeostasis, including cellular membranes (NES = -0.57, p = 0.006), cytoskeleton (NES = -0.51, p = 0.046), and cell proliferation (NES = -0.44, p = 0.018). *In vivo*, treatment with ublituximab alone (5mg/kg, qw) displays a tumor growth inhibition (TGI) of 88%, with 3/8 mice harboring a barely palpable tumor, while treatment with umbralisib alone (150mg/kg, bid) shows a TGI of 50%, with 2/8 mice lacking detectable tumors. TG-1801 (5mg/kg, qw) exhibits a 76% TGI with 1/8 tumor free-mouse. Most importantly, the combination of TG-1801 with umbralisib alone, ublituximab alone, and U2 achieves TGI of 85%, 93% and 93% respectively, and 35 days after the last dose 3/8 mice remain tumor-free in the triple combo groups, versus only 1/8 mouse in the TG-1801 group. Interestingly, this superior anti-tumor effect of the TG-1801-based combinations is associated with a higher infiltration of mouse macrophages within the tumors, as assessed by F4/80 IHC labeling. In conclusion, the results presented herein set the preclinical rationale for a combination strategy of the novel CD47-CD19 antibody TG-1801 with other B-cell targeted drugs, particularly umbralisib and ublituximab, in B-NHL.

**Keywords:** antibody-dependent cytotoxicity (ADC); non-Hodgkin lymphoma (NHL); PI3K/AKT/mTOR.

**Disclosures:** **Normant, E:** Employment Leadership Position: TG Therapeutics; Stock Ownership: TG Therapeutics. **Miskin, H:** Employment Leadership Position: TG Therapeutics; Stock Ownership: TG Therapeutics. **Sportelli, P:** Employment Leadership Position: TG Therapeutics; Stock Ownership: TG Therapeutics. **Weiss, M:** Employment Leadership Position: TG Therapeutics; Stock Ownership: TG Therapeutics. **Bosch, F:** Consultant Advisory Role: Roche; Honoraria: Roche; Research Funding: TG Therapeutics. **Roue, G:** Research Funding: TG Therapeutics.

270
THE ANTI-CD25 ANTIBODY-DRUG CONJUGATE CAMIDANLUMAB TESIRINE (ADCT-301) PRESENTS A STRONG PRECLINICAL ACTIVITY BOTH AS SINGLE AGENT AND IN COMBINATION IN LYMPHOMA CELL LINES

F. Spriano¹ | C. Tarantelli¹ | G. Golino¹ |

E. Gaudio¹ | L. Scalise¹ | L. Cascione¹ | E. Zucca² |

P. Van Berkel³ | A. Stathis² | F. Zammarchi³ |

F. Bertoni¹

¹Institute of Oncology Research, Università della Svizzera italiana, Bellinzona, Switzerland; ²Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; ³Pharmacology, ADC Therapeutics, London, United Kingdom

**Introduction:** Camidanlumab tesirine (ADCT-301) is an anti-CD25 antibody-drug conjugate (ADC) conjugated via a protease cleavable linker to SG3199, a highly cytotoxic DNA minor groove cross-linking pyrrolobenzodiazepine dimer (Flynn et al. *Mol Cancer Ther* 2016). ADCT-301 is currently in phase I as single agent in relapsed/refractory lymphomas (NCT02432235), advanced solid tumors (NCT03621982) and just concluded in acute myeloid leukemia (NCT02588092). We assessed its preclinical activity as single agent in 57 lymphoma cell lines and in combination with selected drugs in T cell lymphomas-derived cell lines.

**Methods:** Cell lines were exposed to increasing concentrations of ADCT-301 for 96h followed by MTT proliferation assay. CD25 expression was measured both at cell surface level via fluorescence quantitation (Quantum Simply Cellular microspheres) and at RNA level (Illumina HT-12 arrays and HTG EdgeSeq Oncology Biomarker Panel). Combination studies of increasing doses of ADCT-301 and increasing doses of additional drugs were assessed by MTT proliferation assay over 96h in FE-PD, Karpas-299, KI-JK and MAC1 cell lines. Chou-Talalay method was used to calculate median combination index (CI) (synergism CI<0.9, additive CI = 0.9-1.1, antagonism/no benefit CI> 1.1).

**Results:** ADCT-301 presented much stronger activity in T (n = 9, median IC50 = 4 pM; 95% C.I., 1.6pM-0.9nM) than B cell lymphomas (n = 48, 0.7 nM; 95% C.I., 0.4-2.6 nM) (P = 0.047). *In vitro* activity was highly correlated with CD25 expression both at cell surface level (n = 53, Pearson r = -0.50, P = 0.0001) and RNA level (n = 53, Pearson r = -0.52, P<0.0001). CD25 was also more highly expressed in T than B cell lymphoma (P<0.0001), in agreement with the IC50s differences, and the correlation was still maintained within the subgroups (T cell lymphomas, Pearson r = -0.90, P = 0.0021; B cell lymphomas; Pearson r = -0.3, P = 0.05).

Based on the higher activity in T-cell lymphomas, ADCT-301-containing combinations were evaluated in 4 cell lines derived from peripheral T cell lymphoma not otherwise specified (n = 1), ALK-pos (n = 2) or ALK-neg (n = 1) anaplastic large cell lymphoma (ALCL).
ADCT-301 plus the mTOR inhibitor everolimus showed synergism in 4/4 cell lines. Combinations with the PI3K inhibitor copanlisib, the BCL2 inhibitor venetoclax and the HDAC inhibitor vorinostat were synergistic in all but one cell line. The combination with pralatrexate was synergistic in 2/2 ALK-pos ALCL cell lines. The addition of bortezomib or romidepsin led to synergism in 2/4 cell lines. Finally, the combinations with bendamustine and with 5-azacytidine achieved synergism in 1 out 4 cell lines (ALK+ALCL Karpas-299).

**Conclusion:** The strong single agent anti-lymphoma activity and the observed *in vitro* synergisms with targeted agents support the current ADCT-301 clinical development and identify potential combination partners for future clinical studies.

**Keywords:** histone deacetylase inhibitors; pralatrexate; venetoclax.

**Disclosures:** Cascione, L: Other Remuneration: travel grant from HTG. Zucca, E: Consultant Advisory Role: Roche, Mei Pharma, Astra Zeneca; Honoraria: Gilead; Research Funding: Roche and Janssen; Other Remuneration: travel grants from Abbvie and Gilead. Van Berkel, P: Employment Leadership Position: ADC Therapeutics. Stathis, A: Research Funding: Bayer, Roche; Other Remuneration: travel grant from AbbVie. Zammarchi, F: Employment Leadership Position: ADC therapeutics. Bertoni, F: Research Funding: ADC Therapeutics, Acerta, Bayer AG, Immungen, Menarini; Other Remuneration: expert statements provided to HTG; travel grants from HTG, Astra Zeneca.

## 271
PRELIMINARY RESULTS OF A PHASE 1 DOSE ESCALATION STUDY OF THE FIRST-IN-CLASS ANTI-CD74 ANTIBODY DRUG CONJUGATE (ADC), STRO-001, IN ADVANCED B-CELL MALIGNANCIES

A. Molina<fnref n="1" /> | N. Shah<fnref n="2" /> | A.Y. Krishnan³ |

N.D. Shah⁴ | J.M. Burke⁵ | J.M. Melear⁶ |

A.I. Spira⁷ | L.L. Popplewell³ | C.B. Andreadis⁴ |

S. Chhabra<fnref n="2" /> | J.P. Sharman⁸ | J.L. Kaufman⁹ |

J.B. Cohen⁹ | R. Niesvizky¹⁰ | T.G. Martin⁴ |

C. DiLea¹¹ | J. Kuriakose<fnref n="1" /> | S.L. Matheny<fnref n="1" /> |

J.P. Leonard¹⁰

**Background:** CD74 is expressed on B cells throughout differentiation and is an attractive target for treatment of MM and NHL. Sutro's cell-free protein synthesis and site-specific conjugation platform technologies were used to generate STRO-001, a novel CD74-targeting ADC. STRO-001 contains a potent maytansinoid warhead conjugated to two specific sites (DAR of 2) using a stable non-cleavable linker. This first-in-human Phase 1, open-label, multicenter, dose escalation study was designed to evaluate the safety, tolerability, and preliminary antitumor activity of STRO-001 in adults with B-cell malignancies.

**Methods:** Patients with advanced, relapsed/refractory MM and NHL are eligible for enrollment. STRO-001 is administered as a 60-minute IV infusion on Days 1 and 15 of a 28-day cycle until disease progression or dose-limiting toxicity (DLT). Two cohorts, one for MM and one for NHL patients, with an initial accelerated dose titration design (N of 1) are being enrolled and analyzed independently with 3+3 dose escalation being triggered by pre-specified safety events.

**Results:** 14 patients (7 MM and 7 NHL), have been treated at 7 dose levels: .05, .075, .15, .27, .43, .65 and .91 mg/kg. 4 females and 10 males have been treated to date. Median age is 67 (r 21-82). Median ECOG performance - 1 (r 0-2). Median number of prior systemic therapies is 5 (range 2-12). Based on a related, grade 2 non-hematologic adverse event (fever, chills, vomiting), the 3+3 dose escalation design was triggered at the 0.91 mg/kg dose level in the NHL cohort. Median number of STRO-001 doses administered is 4 (r 1-12). 11 patients have completed at least one cycle (two doses) of STRO-001 and are evaluable for safety and for dose escalation recommendation. The most common grade 1-2 TRAEs are fatigue, nausea, chills and infusion reaction occurring in 2 out of 11 patients. One patient with localized recurrence of DLBCL achieved a complete response (CR) after 2 cycles and progressed with new sites of disease after 12 doses (6 cycles). 3 patients remain on treatment and dose escalation is ongoing. Preliminary PK analysis showed maximum serum concentrations of ADC (0.39-8.2 µg/mL) and total antibody (0.41-9.1 µg/mL) increased after single IV doses of STRO-001 (0.05-0.65 mg/kg). The terminal phase half-life estimated for total antibody in 3 patients ranged 37-47 hours. There is no evidence of anti-STRO-001 antibodies.

**Conclusions:** STRO-001 is the first ADC generated with novel cell-free protein synthesis technology and site-specific conjugation to be tested in the clinic. STRO-001 has been well-tolerated, and the absence of immunogenicity is encouraging. No ocular toxicity or DLTs have been observed and MTD has not been reached. Preliminary antitumor activity (CR) has been observed in a patient with recurrent DLBCL. The study continues to enroll patients in dose escalation. with single patient MM cohorts and 3+3 NHL cohorts. This study is registered with clinicaltrials.gov identifier NCT03424603.

**Keywords:** B-cell lymphoma; multiple myeloma (MM); non-Hodgkin lymphoma (NHL).

<footnote n="1">¹Clinical Science, Sutro Biopharma, South San Francisco, United States;</footnote>

<footnote n="2">²Oncology / Hematology, Medical College of Wisconsin, Milwaukee, United States; ³Oncology / Hematology, City of Hope, Duarte, United States; ⁴Oncology / Hematology, University of California, San Francisco, San Francisco, United States; ⁵Oncology / Hematology, Rocky Mountain Cancer Centers, Aurora, United States; ⁶Oncology / Hematology, Texas Oncology, Austin, United States; ⁷Oncology / Hematology, Virginia Cancer Specialists, Fairfax, United States; ⁸Oncology / Hematology, Willamette Valley Cancer Institute and Research Center, Eugene, United States; ⁹Oncology / Hematology, Winship Cancer Institute of Emory University, Atlanta, United States; ¹⁰Oncology / Hematology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, United States; ²Clinical Pharmacology, Aclairo Pharmaceutical Development Group, Vienna, United States</footnote>
**Disclosures:** Molina, A: Employment Leadership Position: Sutro Biopharma; Stock Ownership: Sutro Biopharma. Shah, N: Consultant Advisory Role: Juno, Kite Pharma, Cellectar; Stock Ownership: Onsec, Geron, Exelixis; Research Funding: Lentigen Technology. Krishnan, A: Employment Leadership Position: City of Hope; Consultant Advisory Role: Celgene, Onyx, Janssen Oncology, Takeda, Kite Pharma, Seattle Genetics, Sutter Medical Group, Teuda; Research Funding: Celgene, Takeda. Shah, N: Employment Leadership Position: University of California, San Francisco; Consultant Advisory Role: Takeda, Celgene, Indapta Therapeutics, TeneoBio, Brystol-Myers Squibb, Sanofi, Seattle Genetics; Stock Ownership: Indapta Therapeutics; Research Funding: Celgene, Bluebird Bio, Janssen. Burke, J: Employment Leadership Position: Rocky Mountain Cancer Center; Consultant Advisory Role: Celgene, Genentech, Gilead, Abbvie, Seattle Genetics, Tempus Labs, Kite, Juno; Research Funding: Janssen. Melear, J: Employment Leadership Position: Texas Oncology. Spira, A: Employment Leadership Position: Virginia Cancer Specialists; Research Funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, Abbvie. Popplewell, L: Employment Leadership Position: City of Hope; Honoraria: AstraZeneca, Cardinal Health. Andreadis, C: Employment Leadership Position: University of California, San Francisco. Chhabra, S: Employment Leadership Position: Medical College of Wisconsin. Sharman, J: Employment Leadership Position: Willamette Valley Cancer Institute and Research Center; Consultant Advisory Role: Abbvie, Genentech, TG Therapeutics, Pharmacyclics, Acerta, Gilead, Seattle Genetics; Research Funding: Abbvie, Genentech, TG Therapeutics, Pharmacyclics, Acerta, Gilead, Seattle Genetics. Kaufman, J: Employment Leadership Position: Winship Cancer Institute of Emory University; Consultant Advisory Role: Pharmacyclics, Janssen, Abbvie, Roche, Takeda; Honoraria: Janssen; Research Funding: Novartis, Merck, Celgene. Cohen, J: Employment Leadership Position: Winship Cancer Institute of Emory University; Consultant Advisory Role: Genentech, Seattle Genetics, Janssen; Research Funding: American Society of Hematology, Lymphoma Research Foundation, BMS, Bioinvent, Takeda, Novartis, Genentech, Seattle Genetics. Niesvizky, R: Employment Leadership Position: Weill Cornell Medical College, New York-Presbyterian Hospital. Martin, T: Employment Leadership Position: University of California, San Francisco; Consultant Advisory Role: TeneoBio; Research Funding: Sanofi, Amgen, Genentech/Roche. DiLea, C: Employment Leadership Position: Aclairo Pharmaceutical Development Group. Kuriakose, J: Employment Leadership Position: Sutro Biopharma. Matheny, S: Employment Leadership Position: Sutro Biopharma; Stock Ownership: Sutro Biopharma. Leonard, J: Employment Leadership Position: Weill Cornell Medical College, New York-Presbyterian Hospital; Consultant Advisory Role: Celgene, Abbvie, Sutter Medical Group.

V. Dufner<fnref n="1" />

C. Sayheli<fnref n="2" />

G. Gelbrich³

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

M. Goebeler<fnref n="2" />

**Introduction:** Treatment of relapsed/refractory (rr) Non-Hodgkin's lymphoma of B-cell type (B-NHL) is still challenging and new and more effective therapies are urgently warranted. Blinatumomab, a first-in-class bispecific T-cell engager (BiTE®) antibody construct, engages CD3+ cytotoxic T cells, resulting in T-cell expansion and lysis of CD19+ B cells. In a prior phase I study, blinatumomab treatment resulted in an overall response rate (ORR) of 69% and 55% in diffuse large B-cell lymphoma (DLBCL), respectively for patients treated at MTD 60 µg/m<fnref n="2" />/d. The clinically most relevant side effects are neurological symptoms and cytokine release syndrome. Based on this study we here present first single-center, long-term follow-up data on 38 patients with r/r B-NHL after treatment with blinatumomab.

**Methods:** Patients with rr B-NHL who participated in the phase I MT103-104 trial (NCT00274742) and were treated with blinatumomab at the trial site Wuerzburg were eligible for long-term follow-up analysis. Kaplan-Meier estimates for progression free survival (PFS) probability were calculated from first infusion to relapse or death. Patients without an event were censored at last follow-up. This study was conducted in accordance with the Declaration of Helsinki.

**Results:** Median OS after for all 38 patients was 4.2 years, median OS of patients treated at target dose of 60 µg/m<fnref n="2" />/day was 5.4 years, whereas patients, who did not receive the target dose, achieved a median OS of 1.0 year. Median PFS in the responders' group was 3.2 years (95% CI: 0.0-6.7 years), in the non-responders' group 32.1 days (95% CI: 23.0-41.0 days). Patients at target dose had a median PFS of 1.5 years (95% CI: 7.2 months-2.3years), in contrast to

<figure><img src="image_170.png" /></figure>

<footnote n="1">¹CCC Mainfranken, University of Wuerzburg, Wuerzburg, Germany;</footnote>

<footnote n="2">²Department Internal Medicine II, University Hospital Würzburg, Wuerzburg, Germany; ³Institute of Clinical Epidemiology and Biometry, University of Wuerzburg, Wuerzburg, Germany</footnote>
patients treated below target dose who had a PFS of 1.1 months (95% CI: 5.0 days-1.9 months; Fig. 1). At a median follow up of 4.15 years 6 patients treated at target dose were still alive and treatment-free, whereas the 13 patients treated at lower dose levels have progressed.

**Conclusion:** Here we provide first evidence that blinatumomab has the potential to induce sustained long-term remissions in patients with rr B-NHL. Prerequisite for durable remission is treatment at the effective dose of 60 µg/m<fnref n="2" />/day. Treatment with Blinatumomab in rr B-NHL is efficient.

**Keywords:** B-cell lymphoma; CD19; CD3.

273
A FIRST-IN-HUMAN TRIAL OF THE NOVEL
MULTI-ACTION THERAPY
TINOSTAMUSTINE (EDO-S101) IN
PATIENTS WITH RELAPSED/REFRACTORY
(R/R) HODGKIN LYMPHOMA (HL)

A. Pinto<fnref n="1" /> | R. De Filippi<fnref n="2" /> | P. Zinzani³ |

C. Driessen⁴ | H.W. Tun<fnref n="5" /> | K. Hilgier⁶ |

D. Remmy⁶ | T. Mehrling⁶ | O.A. O'Connor⁷

**Introduction:** Although 70-80% of patients with advanced HL are cured by first-line therapy, the management of primary refractory disease and post-transplant recurrence remains an area of high unmet medical need, even in the era of brentuximab vedotin (BV) and immune checkpoint inhibitors (CPI). The alkylating histone deacetylase inhibitor tinostamustine is a novel multi-action therapy that improves drug access to DNA strands, breaks them and counteracts damage repair. Preclinical data have shown antitumour efficacy of tinostamustine in HL cells, including some alkylator-resistant cell lines.

**Methods:** Here we report findings from the dose-escalation stage of a Phase I first-in-human study to evaluate the safety and pharmacokinetics, and to determine the maximum tolerated dose (MTD), optimal infusion time and recommended Phase II dose (RP2D) of tinostamustine in patients with R/R haematological malignancies, including HL (NCT02576496). A standard 3+3 design was used; the first cohort receiving 40mg/m<fnref n="2" /> iv tinostamustine over 1 hour. Four ascending cohorts to a maximum dose of 120mg/m<fnref n="2" />, and shorter infusion times were also explored. Dose-limiting toxicities (DLT) were defined as: any Grade (G) 3 or 4 non-haematological toxicity; nausea,

vomiting or diarrhoea ≥10 days; G4 neutropenia or thrombocytopenia ≥7 days; any ≥G2 toxicity for >3 weeks; and any toxicity resulting in a delay of the next dose administration (Cycle 2 Day 1 ≥14).

**Results:** Ten heavily pre-treated (3-7 previous lines) HL patients were enrolled and received 40-120mg/m<fnref n="2" /> tinostamustine over 60 minutes. The MTD was determined to be 100mg/m<fnref n="2" />, and recommended infusion time confirmed as 60 minutes. The principal G3/4 toxicities observed were haematological, including thrombocytopenia, neutropenia, and lymphopenia with incidence increasing with increasing dose. Efficacy signals were observed, with only 2/10 patients experiencing disease progression (PD); 1 complete (CR) and 5 partial responses (PR) were recorded plus 2 patients with stable disease. Notably, a patient with primary refractory disease who had never achieved a response despite previous chemoradiotherapy, BV and CPIs, and had never been auto-transplanted due to PD, obtained a CR of 8 months. This patient was consolidated by haplo-transplant, is GvHD-free >20 months after last tinostamustine and remains in CR as of March 2019.

**Conclusions:** Administration of tinostamustine on Day 1 in a 21-day cycle was well tolerated with signals of efficacy in patients with HL. The RP2D for tinostamustine in HL, depending on patient platelet count at treatment initiation, was determined as 80mg/m<fnref n="2" /> for those with >100 x 10⁹/l platelets, and 100mg/m<fnref n="2" /> for those with ≥200 x 10⁹/l platelets. This will be applied in the second phase of this study, where patients will be recruited into one of five different cohorts, including HL.

Funding: Mundipharma EDO GmbH

**Keywords:** Hodgkin lymphoma (HL).

**Disclosures:** Zinzani, P: Consultant Advisory Role: Verastem, MSD, Eusapharma, Sanofi; Honoraria: Verastem, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, MSD, Immune Design, Celgene, Portola, Roche, Eusapharma, Kyowa Kirin. Hilgier, K: Consultant Advisory Role: Mundipharma EDO. Remmy, D: Employment Leadership Position: Mundipharma EDO. Mehrling, T: Employment Leadership Position: Mundipharma EDO.

274
PHASE 2 STUDY OF PARSACLISIB
(INCB050465) FOR RELAPSED OR
REFRACTORY DIFFUSE LARGE B-CELL
LYMPHOMA (DLBCL) (CITADEL-202)

D. Belada<fnref n="1" /> | K. Fay<fnref n="2" /> | R. Casasnovas³ |

R. Gressin⁴ | H. Lee<fnref n="5" /> | A. Mehta⁶ | J. Munoz⁷ |

G. Verhoef⁸ | C. Corrado⁹ | D. DeMarini⁹ |

W. Zhao¹⁰ | X. Chen¹¹ | M. Coleman¹²

<footnote n="1">¹Department of Hematology, University Federico II, Naples, Italy;</footnote>

<footnote n="2">²Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy; ³Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; ⁴Interdisziplinäre Medizinische Dienste, Kantonsspital St Gallen, St Gallen, Switzerland;</footnote>

<footnote n="5">⁵Department of Hematology/Oncology, Mayo Clinic Cancer Center, Jacksonville, United States; ⁶Clinical Development, Mundipharma EDO, Basel, Switzerland; ⁷Department of Medicine, Colombia University Medical Center, New York, United States</footnote>

<footnote n="1">¹4th Department of Internal Medicine - Hematology, University Hospital Hradec Kralove, Czech Republic and Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Králové, Czech Republic;</footnote>

<footnote n="2">²Department of Haematology, St Vincent's Hospital, Darlinghurst, NSW, Australia; ³Departement d'Hématologie, University Hospital F. Mitterrand</footnote>
and Inserm UMR 1231, Dijon, France; ⁴Département d'Hématologie Clinique, Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France; Centre Hospitalier et Universitaire de Grenoble-Alpes, Grenoble, France; ⁵SA Pathology, Flinders Medical Centre, Bedford Park, SA, Australia; ⁶Department of Medicine, UAB School of Medicine, Birmingham, United States; ⁷Medical Oncology, Banner MD Anderson Cancer Center, Gilbert, United States; ⁸Department of Hematology, University Hospitals Leuven, Leuven, Belgium; ⁹Clinical Development, Incyte Corporation, Wilmington, DE, United States; ¹⁰Biostatistics, Incyte Corporation, Wilmington, DE, United States; ¹¹Drug Metabolism and Biopharmaceutics, Incyte Corporation, Wilmington, DE, United States; ¹²Medical Oncology, Clinical Research Alliance/Weill Cornell Medicine, New York, United States

**Introduction:** Parsaclisib, a potent, highly selective, next-generation PI3Kδ inhibitor, showed preliminary efficacy as monotherapy for relapsed or refractory non-Hodgkin lymphoma, including DLBCL (Abstract 410, ASH 2017), in a phase 1/2 study. This phase 2 study further assessed parsaclisib in patients with relapsed or refractory DLBCL (NCT02998476).

**Methods:** Patients enrolled into 2 groups (A, Bruton tyrosine kinase [BTK] inhibitor naïve; B, BTK inhibitor experienced) and received oral parsaclisib 20 mg once daily (QD) for 8 weeks, then 20 mg once weekly (QW). In a planned interim futility analysis conducted in the first 40 patients treated in Group A, if ≤13 (≤32.5%) responded by an independent review committee assessment, Group A was to be terminated.

**Results:** At data cutoff (22 Jun 2018), 60 patients (Group A, n = 55; Group B, n = 5) were treated (median age, 71 years [range, 36–94]; men, 63.3%; ≥3 prior systemic therapies, 60%).

At the planned interim analysis in Group A, the objective response rate (ORR; by positron emission tomography) was 25% (10/40 patients; 5 complete metabolic response [CMR], 5 partial metabolic response [PMR]); the futility boundary was crossed. At data cutoff, ORR in Group A was 25.5% (14/55 patients; 8 CMR, 6 PMR); median progression-free survival was 2.2 mo (95% CI: 2.0–4.1); median duration of response was 4.5 mo (95% CI: 2.1–5.1). Objective responses were observed in germinal center B-cell (GCB) and non-GCB sub-types. ORR in Group B was 20% (1/5 patients; 1 CMR).

The most common non-hematologic treatment-emergent adverse events (TEAEs) occurring in >10% of all patients (all grade [Gr]; Gr 3/4) were rash events (21.7%; 1.7%), colitis/diarrhea events (16.7%; 5.0%), nausea (16.7%; 0%), cough (15%; 0%), and pyrexia (15%; 8.3%). Gr 3/4 aspartate aminotransferase and alanine aminotransferase elevations occurred in 5.0% and 1.7% of patients, respectively; Gr 3/4 neutropenia and anemia occurred in 5.0% of patients each. The most frequent (>5%) serious TEAEs were pyrexia (8.3%), general physical health deterioration (6.7%), and hypercalcemia (6.7%). TEAEs led to therapy discontinuation in 7 patients (2 treatment-related), dose interruption in 20 patients (10 treatment-related), and dose reduction in 3 patients (all treatment-related). Median duration of therapy was 57.5 days (range, 11–318).

**Conclusion:** Parsaclisib monotherapy using a QD followed by QW dosing regimen was well tolerated with no new safety signals reported. Further evaluation of parsaclisib in all subtypes of DLBCL is ongoing in a combination study (NCT03424122).

**Keywords:** diffuse large B-cell lymphoma (DLBCL); non-Hodgkin lymphoma (NHL); PI3K/AKT/mTOR.

**Disclosures:** Belada, D: Research Funding: Celgene. Fay, K: Research Funding: Incyte. Casasnovas, R: Consultant Advisory Role: Roche, Takeda, Gilead, AbbVie, Bristol-Myers Squibb, Merck, Karyopharm; Research Funding: Roche, Gilead, and Takeda. Lee, H: Consultant Advisory Role: MSD and Janssen. Mehta, A: Consultant Advisory Role: Spectrum, Celgene, Kite, BMS; Research Funding: Incyte, Roche, Merck, BMS, Epizyme, Seattle Genetics; Other Remuneration: Gilead, Astra Zeneca, Kite, Spectrum, Kyowa Kirin. Munoz, J: Consultant Advisory Role: Pharmacyclics/Janssen, Bayer, Gilead/Kite, Pfizer, Juno/Celgene, and Bristol-Myers Squibb; Other Remuneration: Gilead/Kite, Bayer, Pharmacyclics/Janssen, and AstraZeneca. Corrado, C: Employment Leadership Position: Incyte Corporation; Stock Ownership: Incyte Corporation. DeMarini, D: Employment Leadership Position: Incyte Corporation; Stock Ownership: Incyte Corporation. Zhao, W: Employment Leadership Position: Incyte Corporation; Stock Ownership: Incyte Corporation. Chen, X: Employment Leadership Position: Incyte Corporation; Stock Ownership: Incyte Corporation. Coleman, M: Consultant Advisory Role: Gilead, Bayer, Celgene; Stock Ownership: Kite Pharmaceuticals; Research Funding: Incyte, Gilead, Merck, Bayer, Celgene; Other Remuneration: Gilead, Bayer, Celgene, Pharmacyclics.

## 275
ACALABRUTINIB PLUS PEMBROLIZUMAB IN RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA: A PHASE 1/2 STUDY

**T.E. Witzig<fnref n="1" />** | **K. Maddocks<fnref n="2" />** | **S. de Vos<fnref n="3" />** |
--- | --- | ---
**R. Lyons<fnref n="4" />** | **W. Edenfield⁵** | **J. Sharman<fnref n="6" />** | **J. Vose⁷** |
**H. Yimer⁸** | **H. Wei⁹** | **E. Chan¹⁰** | **P. Patel¹⁰** |
**C. Di Simone¹¹** | **M. Gandhi¹²** | **J. Vaughn¹³** |
**K. Kolibaba¹⁴** | **B. Cheson¹⁵** | **F. Samaniego¹⁶**

<footnote n="1">¹Division of Hematology, Mayo Clinic, Rochester, MN, United States;</footnote>

<footnote n="2">²Internal Medicine, Ohio State University, Columbus, United States;</footnote>

<footnote n="3">³Assistant Professor, Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, United States;</footnote>

<footnote n="4">⁴Hematology, Texas Oncology-San Antonio Medical Center, US Oncology Research, San Antonio, United States; ⁵Hematology and Oncology, Greenville Health System Cancer Institute, Greenville, United States;</footnote>

<footnote n="6">⁶Hematology, Willamette Valley Cancer Institute and Research Center, US Oncology Research, Eugene, United States; ⁷Internal Medicine, Nebraska Medical Center, Omaha, United States; ⁸Hematology, Texas Oncology-Tyler, US Oncology Research, Tyler, United States; ⁹Bio statistics, Acerta Pharma, South San Francisco, United States; ¹⁰Clinical Director, Acerta Pharma, South San Francisco, United States; ¹¹Medical</footnote>
<table><caption>TABLE 1</caption><thead><tr><th></th><th>All (N=61)</th></tr></thead><tbody><tr><td>Overall response rate, n (%) [95% CI]</td><td>16 (26) [19, 39]</td></tr><tr><td>Best response, n (%)</td><td></td></tr><tr><td>Complete response</td><td>4 (7)</td></tr><tr><td>Partial response</td><td>12 (20)</td></tr><tr><td>Stable disease</td><td>18 (30)</td></tr><tr><td>Progressive disease</td><td>22 (36)</td></tr><tr><td>Other<sup>a</sup></td><td>5 (8)</td></tr><tr><td>Duration of response, median (95% CI), mo</td><td>6.9 (2.3, not estimable)</td></tr><tr><td>Progression-free survival, median (95% CI), mo</td><td>1.9 (1.6, 3.7)</td></tr></tbody></table>

<sup>a</sup>Due to death (progressive disease, abdominal abscess [n=1 each]), clinical progressive disease (n=1), and withdrawal due to adverse events (thrombocytopenia, altered mental status [n=1 each]).

Oncology & Hematology, Arizona Oncology, US Oncology Research, Tucson, United States; <sup>12</sup>Medical Oncologist, Virginia Cancer Specialists, US Oncology Research, Woodbridge, United States; <sup>13</sup>Hematology, Fred Hutchinson Cancer Research Center, Seattle, United States; <sup>14</sup>Medical Oncology & Hematology, Northwest Cancer Specialists, US Oncology Research, Vancouver, United States; <sup>15</sup>Division of Hematology and Oncology, Georgetown University Hospital, Washington, DC, United States; <sup>16</sup>Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States

**Background:** Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase inhibitor, has a 24% overall response rate as a single agent in relapsed/refractory diffuse large B-cell lymphomas (DLBCL). Pembrolizumab targets PD-1, an immune checkpoint that limits anti-cancer responses. Pembrolizumab showed responses in patients with Richter transformation who failed ibrutinib and can augment acalabrutinib activity in vitro. This study assessed acalabrutinib plus pembrolizumab in relapsed/refractory DLBCL.

**Methods:** Patients with DLBCL, ≥1 prior chemoimmunotherapy and no prior allogeneic transplant received oral acalabrutinib 100 mg twice daily until progressive disease plus pembrolizumab 200 mg/kg intravenously every 3 weeks for up to 2 years. Germinal center B-cell (GCB) vs non-GCB subtype was assessed by immunohistochemistry. Primary endpoint was safety.

**Results:** Sixty-one patients (30 GCB; 31 non-GCB) were accrued, with a median age of 67 years (range, 30 to 85) and a median of 3 (range, 1 to 8) prior therapies; 1 patient had prior autologous transplant. The most common grade 3/4 adverse events were neutropenia (15%) and anemia (11%). Grade 5 adverse events were respiratory failure (n = 3), sepsis, septic shock, and abdominal abscess (n = 1 each). All-grade atrial fibrillation was 5% (n = 3), and major hemorrhage (≥ Grade 3) was 11% (4 gastrointestinal, 1 pulmonary, 1 epistaxis, 1 hematuria). Grade 3/4 immune-mediated events were elevated alanine aminotransferase (n = 4), pneumonitis (n = 2), and colitis (n = 1). The overall

response rate was 26% (Table) and was similar in GCB (27%) and non-GCB (26%) tumors. The median time on study was 5.2 months (0.4 to 30.4+). Acalabrutinib/pembrolizumab discontinuations were due to progressive disease (62%/56%) and adverse events (15%/26%). As of June 2018, 10 patients remain on study; 6 on active therapy and 7 without progressive disease.

**Conclusions:** Acalabrutinib plus pembrolizumab was well tolerated, with meaningful activity and some exceptional responders (>24 months) in these relapsed/refractory DLBCL patients. Randomized trials of the combination vs single agent are needed.

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

**Disclosures:** Witzig, T: Honoraria: Sandoz; Immune Design; Research Funding: Acerta; Celgene; Novartis; Spectrum. Maddocks, K: Consultant Advisory Role: AstraZeneca, Pharmacyclics, Bayer, Teva, Sandoz; Honoraria: AstraZeneca, Pharmacyclics, Bayer, Teva, Sandoz; Research Funding: Pharmacyclics, BMS, Novartis, Merck. Lyons, R: Employment Leadership Position: Texas Oncology; Stock Ownership: Texas Oncology; Research Funding: avvie, Celgene, Gilead, GenetechIncye, Rigel, Takeda. Sharman, J: Consultant Advisory Role: Celgene, Pfizer, Genentech, TG therapeutics, AbbVie, pharmacyclics GILEAD; Research Funding: Celgene, Pfizer, Genentech, TG therapeutics, AbbVie, pharmacyclics GILEAD. Yimer, H: Consultant Advisory Role: Seattle Genetics, AstraZeneca, Jenssen. Wei, H: Employment Leadership Position: Acerta Pharma. Chan, E: Employment Leadership Position: Acerta Pharma, Genentech/Roche; Stock Ownership: Acerta Pharma, Genentech/Roche, Eli Lilly & Company. Patel, P: Employment Leadership Position: Acerta/AstraZeneca; Stock Ownership: Acerta/AstraZeneca. Kolibaba, K: Employment Leadership Position: Compass Oncology; Consultant Advisory Role: Gilead; Honoraria: TG Therapeutics; Research Funding: Acerta; Celgene; CTI; Genentech; Gilead; Pharmacyclics; Novartis; Seattle Genetics; TG Therapeutics; Other Remuneration: TG Therapeutics. 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, Trillium.

276

ANTITUMOR ACTIVITY OF PEMBROLIZUMAB PLUS DINACICLIB IN PATIENTS WITH DIFFUSE LARGE B CELL LYMPHOMA: THE PHASE 1B KEYNOTE-155 STUDY

G. Gregory¹ | P. Walker² | D. Mahadevan³ |
D. Wang⁴ | J. Chang⁵ | F. Hernandez-Ilizaliturri⁶ |
A. Klein⁷ | W. Rybka⁸ | N. Wagner-Johnston⁹ |
C. Escobar¹⁰ | J.M. Pagel¹¹ | A. Mohrbacher¹² |
S. Opat¹ | J. Shortt¹ | H. Ma¹³ | J. Gwo¹³ |
M. Farooqui¹⁴ | H. Quach¹⁵