median prior lines of therapy was 3 (range 1-13), and 86% pts were refractory to prior therapy. CRS (according to the criteria by Lee et al. Blood 2014) occurred in 45 patients (23% G1, 24% G2, 3% G3, 1% G4). At the highest dose cohort (25 mg) ≥G3 CRS occurred in 3/8 pts at cycle 1, thereby preventing further dose escalation. One patient in the 25 mg cohort died of upper GI bleeding after an episode of severe CRS. All other CRS events were manageable and resolved, and patients were retreated without delay at the same dose at cycle 2, where only one additional CRS event was seen (G1).

In the efficacy evaluable pts (n=84) the ORR and CR rate by investigator assessment (Lugano 2014 criteria) in aNHL (n=76) was 46% and 29%, and in FL (n=8) 63% and 50%, respectively. In the highest dose cohorts (10-25 mg) the ORR and CR rate in aNHL (n=38) was 55% and 37% indicating a dose-response relationship. CR was usually achieved at the first or second response assessments (C3 or C6) although in 4 aNHL pts late conversion from PR or SD to CR was observed at cycle 12. A patient with FL initially dosed at 15 µg who had progressed was retreated at 10 mg, achieving CR. After a median follow up of 3.8 months all but 2 CRs are still ongoing. Responses were seen across NHL subtypes and across prognostic factors such as disease burden, prior lines of therapy, and refractoriness to prior therapy. CD20-TCB exposure and receptor occupancy increased dose-dependently across the investigated dose range. No anti-drug-antibodies have been found. Mode of action was demonstrated by rapid and sustained T cell activation in peripheral blood and tumor biopsies.

**Conclusions:** CD20-TCB is a novel 2:1 format T-cell-engaging bispecific antibody which displays highly promising clinical activity in heavily-pretreated NHL.

**Keywords:** B-cell lymphoma; CD20; immune system.

**Disclosures:** Dickinson, M: Consultant Advisory Role: Roche; Honoraria: Roche. Morschhauser, F: Consultant Advisory Role: Advisory role for Celgene, Roche, BMS, Gilead, Epizyme, Verasteem; Honoraria: Novartis, Janssen, Abbvie. Iacoboni, G: Honoraria: Celgene, Novartis, Roche. Carlo-Stella, C: Consultant Advisory Role: Sanofi, ADC Therapeutics, Servier France, Roche; Honoraria: BMS, MSD, Novartis, Janssen.

**Sureda, A:** Other Remuneration: Travel Grants from Roche. Salles, G: Consultant Advisory Role: Abbvie, Celgene, Gilead, Epizyme, Janssen, Karyopharm, Kite, Merck, Morphosys, Novartis, Roche, Servier, Takeda; Honoraria: Abbvie, Amgen, BMS, Celgene, Gilead, Epizyme, Janssen, Karyopharm, Kite, Merck, Morphosys, Novartis, Roche, Servier, Takeda.

**Martinez, J:** Honoraria: Novartis, Celgene, BMS, Jansen; Research Funding: Novartis, Celgene, BMS, Jansen. Crump, M: Consultant Advisory Role: Roche Canada, Servier, Kyte/Gilead. Thomas, D: Employment Leadership Position: Roche; Stock Ownership: Roche. Morcos, P: Employment Leadership Position: Roche; Stock Ownership: Roche.

**Ferlini, C:** Employment Leadership Position: Roche; Stock Ownership: Roche. Broeske, A: Employment Leadership Position: Roche. Bacac, M: Employment Leadership Position: Roche; Stock Ownership: Roche.

**Dimier, N:** Employment Leadership Position: Roche; Stock Ownership: Roche. Umaña, P: Employment Leadership Position: Roche; Stock Ownership: Roche. Moore, T: Employment Leadership Position: Yes; Stock Ownership: Yes. Weisser, M: Employment Leadership Position:

Roche; Stock Ownership: Yes. Hutchings, M: Consultant Advisory Role: Takeda, Roche, Celgene; Honoraria: Takeda, Roche, Celgene, Janssen; Research Funding: Takeda, Roche, Novartis, Celgene.

## 054 ANALYSIS OF EFFICACY AND SAFETY OF LONCASTUXIMAB TESIRINE (ADCT-402) BY DEMOGRAPHIC AND CLINICAL CHARACTERISTICS IN RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA

J. Radford<fnref n="1" /> | B. Kahl² | M. Hamadani³ |

C. Carlo-Stella⁴ | O.A. O'Connor⁵ | K.M. Ardeshna⁶ |

J. Feingold⁷ | S. He⁷ | E. Reid⁸ | M. Solh⁹ |

K. Chung¹⁰ | L. Heffner¹¹ | D. Ungar⁷ | P. Caimi¹²

<table><caption>TABLE 1 Overall response to loncastuximab tesirine by selected demographic and clinical characteristics in patients with R/R DLBCL</caption><thead><tr><th>Factor</th><th>Group</th><th>Dose (≥120 µg/kg) % (responders/total)</th></tr></thead><tbody><tr><td rowspan="3">Age, y</td><td>&lt;65</td><td>33.3 (23/69)</td></tr><tr><td>65-74</td><td>52.8 (19/36)</td></tr><tr><td>≥75</td><td>59.1 (13/22)</td></tr><tr><td rowspan="2">Sex</td><td>Male</td><td>42.1 (32/76)</td></tr><tr><td>Female</td><td>45.1 (23/51)</td></tr><tr><td rowspan="3">Country</td><td>Italy</td><td>40.9 (9/22)</td></tr><tr><td>UK</td><td>36.7 (11/30)</td></tr><tr><td>US</td><td>46.7 (35/75)</td></tr><tr><td rowspan="2">Bulky disease</td><td>Absent</td><td>46.8 (51/109)</td></tr><tr><td>Present</td><td>22.2 (4/18)</td></tr><tr><td rowspan="2">Double-/Triple-hit</td><td>Absent</td><td>47.6 (50/105)</td></tr><tr><td>Present</td><td>22.7 (5/22)</td></tr><tr><td rowspan="2">Transformed</td><td>No</td><td>39.6 (38/96)</td></tr><tr><td>Yes</td><td>54.8 (17/31)</td></tr><tr><td rowspan="4">ECOG performance status</td><td>0</td><td>48.4 (15/31)</td></tr><tr><td>1</td><td>43.0 (34/79)</td></tr><tr><td>2</td><td>26.7 (4/15)</td></tr><tr><td>3*</td><td>100.0 (2/2)</td></tr><tr><td rowspan="2">Response to first line therapy</td><td>Relapsed</td><td>53.1 (43/81)</td></tr><tr><td>Refractory</td><td>23.1 (6/26)</td></tr><tr><td rowspan="2">Response to most recent therapy</td><td>Relapsed</td><td>59.1 (26/44)</td></tr><tr><td>Refractory</td><td>35.1 (26/74)</td></tr><tr><td rowspan="2">Number of prior therapies</td><td>≤3 lines</td><td>43.8 (35/80)</td></tr><tr><td>&gt;3 lines</td><td>42.6 (20/47)</td></tr></tbody></table>

<footnote n="1">¹Department of Medical Oncology, University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom;</footnote>

<footnote>*Patients with ECOG performance status 3 were not eligible for the study. Abbreviations: DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; R/R, relapsed/refractory; y, year.</footnote>
<figure><img src="image_29.png" /><figcaption>**Figure 1:** Duration of response to loncastuximab tesirine (≥120 µg/kg) by response to (A) first-line therapy and (B) most recent therapy in patients with DLBCL</figcaption></figure>

²Department of Medicine, Oncology Division, Washington University in St. Louis, St. Louis, MO, United States; ³Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, United States; ⁴Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas University, Milan, Italy; ⁵Center for Lymphoid Malignancies, New York-Presbyterian/Columbia University Irving Medical Center, New York, United States; ⁶Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom; ⁷Clinical Development, ADC Therapeutics, Murray Hill, NJ, United States; ⁸Division of Hematology/Oncology, University of California San Diego Health Moores Cancer Center, La Jolla, CA, United

States; ⁹Blood and Marrow Transplant Program, Northside Hospital, Atlanta, GA, United States; ¹⁰Department of Hematology and Oncology, Greenville Health System, Greenville, SC, United States; ¹¹Department of Haematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States; ¹²University Hospitals Cleveland Medical Center, Case Western Reserve University (CWRU), Cleveland, OH, United States

**Introduction:** Diffuse large B-cell lymphoma (DLBCL) accounts for approximately one-third of non-Hodgkin lymphomas (NHL) and expresses CD19, a B-cell marker. Loncastuximab tesirine (Lonca)
comprises a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin. A first-in-human study of Lonca in patients (pts) with relapsed/refractory (R/R) B-cell NHL demonstrated encouraging and durable single-agent antitumor activity and manageable toxicity at doses ≥120 µg/kg in pts with R/R DLBCL. Here we present subgroup analyses of response in R/R DLBCL.

**Methods:** Pts ≥18 years of age with R/R B-cell NHL were enrolled in this phase 1 study (NCT02669017). Analyses of treatment-emergent adverse events (TEAE), overall response rate (ORR) by demographic and clinical characteristics, and duration of response (DoR) by response to prior therapy were performed in pts with DLBCL receiving ≥120 µg/kg Lonca.

**Results:** As of data cutoff (October 16, 2018), 129 pts with DLBCL had received Lonca at ≥120 µg/kg; 129 and 127 pts were evaluable for safety and efficacy, respectively.

The most common TEAEs, regardless of relationship to Lonca, were fatigue (42.6%), peripheral edema (34.1%), and nausea (34.1%). The most common grade ≥3 TEAEs were hematological abnormalities (neutrophil count decreased [38.0%]; platelet count decreased [27.1%]; anemia [11.6%]) and increased gamma-glutamyltransferase (20.2%). The TEAE profile was comparable between age groups.

ORR in pts with DLBCL was 43.3%. Subgroup analyses of ORR are presented in Table 1. Older pts had higher ORR than younger pts (≥75 years: 59.1%; 65-74 years: 52.8%; <65 years: 33.3%). Pts with transformed disease had higher ORR than those with de novo DLBCL (54.8% vs 39.6%).

Pts who responded to first-line therapy had higher ORR than primary refractory pts (53.1% vs 23.1%), as did pts who responded to their most recent therapy (59.1% vs 35.1% for refractory pts). Median DoR was longer for primary refractory pts than relapsed pts (7.03 vs 4.11 months; Figure 1), and comparable for pts refractory to the most recent therapy vs relapsed (4.11 vs 4.80 months). Further details will be presented at the meeting.

**Conclusions:** Lonca at ≥120 µg/kg has substantial antitumor activity in patients with R/R DLBCL. In subgroup analyses, older pts and those with transformed or primary refractory disease had particularly encouraging responses.

Study sponsor: ADC Therapeutics

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

**Disclosures:** Radford, J: Research Funding: ADC Therapeutics. Kahl, B: Consultant Advisory Role: ADC Therapeutics; Research Funding: ADC Therapeutics. Hamadani, M: Consultant Advisory Role: ADC Therapeutics, MedImmune, Jansen, Celgene, Cellerant; Research Funding: Otsuka, Takeda, Sanofi Genzyme, MedImmune, Merck, ADC Therapeutics; Other Remuneration: Speaker bureau: Sanofi, Genzyme. Carlo-Stella, C: Consultant Advisory Role: ADC Therapeutics, Sanofi, Roche; Honoraria: BMS, MSD, Novartis, Janssen; Research Funding: Sanofi, ADC Therapeutics, Servier France, Roche. O'Connor, O: Research Funding: ADC Therapeutics. Ardeshna, K: Consultant Advisory Role: Celgene, Roche, Takeda, ADC Therapeutics; Research

Funding: ADC Therapeutics. Feingold, J: Employment Leadership Position: ADC Therapeutics; Stock Ownership: ADC Therapeutics. He, S: Employment Leadership Position: ADC Therapeutics; Stock Ownership: ADC Therapeutics. Reid, E: Other Remuneration: ADC Therapeutics, Millenium Pharmaceuticals, AbbVie. Solh, M: Research Funding: ADC Therapeutics; Other Remuneration: Speaker bureau: Amgen, Celgene. Chung, K: Research Funding: ADC Therapeutics. Heffner, L: Other Remuneration: Institutional research support: Pharmacyclics, Genentech, Kite, ADC Therapeutics. Ungar, D: Employment Leadership Position: ADC Therapeutics; Stock Ownership: ADC Therapeutics. Caimi, P: Consultant Advisory Role: Genentech, Kite Pharma; Research Funding: ADC Therapeutics; Other Remuneration: Speaker Bureau: Celgene.

055
# ANALYSIS OF CLINICAL DETERMINANTS DRIVING SAFETY AND EFFICACY OF CAMIDANLUMAB TESIRINE (ADCT-301, CAMI) IN RELAPSED/REFRACTORY (R/R) CLASSICAL HODGKIN LYMPHOMA (CHL)

G. Collins¹ | S. Horwitz² | M. Hamadani³ |
F. Samaniego⁴ | A. Spira⁵ | P. Caimi⁶ | A. Davies⁷ |
T. Menne⁸ | P. Fields⁹ | H. Cruz¹⁰ | S. He¹¹ |
J. Boni¹¹ | J. Feingold¹¹ | J. Wuerthner¹⁰ | J. Radford¹²

¹Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; ²Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States; ³Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, United States; ⁴Department of Lymphoma/Myeloma, MD Anderson Cancer Center, The University of Texas, Houston, TX, United States; ⁵Research Institute, Virginia Cancer Specialists, Fairfax, VA, United States; ⁶University Hospitals, Cleveland Medical Center, Case Western Reserve University (CWRU), Cleveland, OH, United States; ⁷Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom; ⁸Cancer Services and Clinical Haematology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, United Kingdom; ⁹Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; ¹⁰Clinical Research, ADC Therapeutics, Epalinges, Switzerland; ¹¹Clinical Development, ADC Therapeutics, Murray Hill, NJ, United States; ¹²Department of Medical Oncology, The University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom

**Introduction:** Cami is a humanized anti-CD25 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin with impressive activity in a phase 1 trial (NCT02432235) in heavily pretreated patients (pts) with cHL. Cami's immunological mode of action may have synergistic efficacy with checkpoint inhibitors (CHPi) and could underlie autoimmune toxicities observed in this trial, such as Guillain-Barré Syndrome (GBS)/radiculopathy. Here we report subgroup analyses to identify
<table><caption>**TABLE 1** ORR by selected demographic and clinical characteristics in 45 µg/kg dose-expansion cohort</caption><thead><tr><th rowspan="2">Characteristic</th><th rowspan="2">Subgroups</th><th colspan="2">45 µg/kg cohort (N=37)</th></tr><tr><th>ORR n/N, % (95% CI)</th><th>CR n/N, %</th></tr></thead><tbody><tr><td>Overall</td><td>-</td><td>32/37, 86.5 (71.2-95.5)</td><td>16/37, 43.2</td></tr><tr><td rowspan="2">Age, y</td><td>≤55</td><td>25/28, 89.3 (71.8-97.7)</td><td>12/28, 42.9</td></tr><tr><td>>55</td><td>7/9, 77.8 (40.0-97.2)</td><td>4/9, 44.4</td></tr><tr><td rowspan="2">Sex</td><td>Female</td><td>12/14, 85.7 (57.2-98.2)</td><td>6/14, 42.9</td></tr><tr><td>Male</td><td>20/23, 87.0 (66.4-97.2)</td><td>10/23, 43.5</td></tr><tr><td rowspan="3">Disease stage at study entry</td><td>I-II</td><td>12/14, 85.7 (57.2-98.2)</td><td>6/14, 42.9</td></tr><tr><td>III</td><td>8/8, 100.0 (63.1-100.0)</td><td>5/8, 62.5</td></tr><tr><td>IV</td><td>12/15, 80.0 (51.9-95.7)</td><td>5/15, 33.3</td></tr><tr><td rowspan="2">Number of prior therapies</td><td>&lt;4</td><td>6/6, 100.0 (ND)</td><td>3/6, 50.0</td></tr><tr><td>≥4</td><td>26/31, 83.9 (ND)</td><td>13/31, 41.9</td></tr><tr><td rowspan="2">Response to first-line systemic anticancer therapy</td><td>Refractory<sup>a</sup></td><td>11/13, 84.6 (54.6-98.1)</td><td>5/13, 38.5</td></tr><tr><td>Relapsed<sup>b</sup></td><td>21/24, 87.5 (67.6-97.3)</td><td>11/24, 45.8</td></tr><tr><td rowspan="2">Response to most recent prior systemic anticancer therapy</td><td>Refractory<sup>a</sup></td><td>22/25, 88.0 (68.8-97.5)</td><td>9/25, 36.0</td></tr><tr><td>Relapsed<sup>b</sup></td><td>8/10, 80.0 (44.4-97.5)</td><td>6/10, 60.0</td></tr><tr><td rowspan="4">Prior CHPi<sup>c</sup></td><td>≤4 months</td><td>14/15, 93.3 (68.1-99.8)</td><td>6/15, 40.0</td></tr><tr><td>>4 months</td><td>6/8, 75.0 (34.9-96.8)</td><td>3/8, 37.5</td></tr><tr><td>None</td><td>9/11, 81.8 (48.2-97.7)</td><td>6/11, 54.5</td></tr><tr><td>Timing unknown<sup>d</sup></td><td>3/3, 100.0 (29.2-100.0)</td><td>1/3, 33.3</td></tr></tbody></table>

<sup>a</sup>Stable or progressive disease to first-line/most recent therapy.

<sup>b</sup>Partial response or CR to first-line/mos recent therapy.

<sup>c</sup>Time between last CHPi and first Cami dose.

<sup>d</sup>Patients who received CHPi but timing information was missing.

Abbreviations: CHPi, checkpoint inhibitor; CI, confidence interval; CR, complete response; ND, not determined; ORR, overall response rate; y, year.

<figure><img src="image_30.png" /><figcaption>**Figure 1: Probability of objective response vs C<sub>max</sub> in patients with cHL receiving Cami**</figcaption></figure>

Graphics depict mean and 95% confidence intervals of predicted probabilities. Colored numbers denote the dose (µg/kg) groups administered; yellow diamonds and vertical dotted lines denote the median respective exposures. *P*-value is overall significance of model with predictors compared to intercept alone. Ab, antibody; cHL, classical Hodgkin lymphoma; C<sub>max</sub>, concentration maximum; PBD, pyrrolobenzodiazepine.

clinical determinants of antitumor activity, safety, and pharmacokinetic (PK) exposure-response relationships.

**Methods:** R/R cHL pts aged ≥18 years were treated with 5-300 µg/kg Cami every 3 weeks, including dose expansion at 30 and

45 µg/kg. Analyses of response and treatment-emergent adverse events (TEAE) were performed using descriptive statistics. Peak (C<sub>max</sub>) and average (C<sub>avg</sub>) concentrations of conjugated antibody in serum were determined using a population PK model and associated with objective response using logistic regression.

**Results:** Overall response rate (ORR) was 73.1% in the study population and 86.5% at 45 µg/kg (n=37; 43.2% complete response). **Table 1** presents subgroup analyses of response at 45 µg/kg. Of note, 3 pts improved from partial to complete response after permanent treatment discontinuation.

In PK modeling, a significant association of C<sub>max</sub> to objective response was observed for the typical pt (p=3.273 x 10<sup>-8</sup>; **Figure 1**); mean predicted probability of Cami response was 0.84 for pts who responded to their most recent therapy vs 0.70 for refractory pts. Autoimmune and neurologic TEAE profiles were comparable between pts with differing prior CHPi exposure. The 5 reported cases of GBS/radiculopathy did not appear related to prior CHPi (≤4 mo: 1 pt [4%]; >4 mo: 1 pt [7%]; none: 2 pts [10%]; 1 pt [20%] who received CHPi but timing information was missing).

Updated results will be presented, including response data for the ongoing 30 µg/kg cohort.

**Conclusions:** A difference in Cami response was seen between relapsed vs refractory pts in PK modeling, but response rates were
high across all subgroups, suggesting robust antitumor activity across the R/R cHL population. There was a trend for increased ORR in pts with recent prior CHPi exposure, <4 prior therapies, and Stage III cHL. Increased ORR in pts with recent prior CHPi could suggest a possible immunological interaction between Cami and prior CHPi, but it did not appear to increase autoimmune and neurologic TEAEs.

Study sponsor: ADC Therapeutics

**Keywords:** Hodgkin lymphoma (HL); immunochemotherapy; immunoconjugates.

**Disclosures:** Collins, G: Consultant Advisory Role: ADC Therapeutics; Research Funding: MSD, Celleron, Celgene, Amgen, ADS Therapeutics; Other Remuneration: Speaker: Roche, Janssen, Gilead; Paid expert testimony: Roche. Horwitz, S: Consultant Advisory Role: ADC Therapeutics, Aileron, Seattle Genetics, Takeda, Kyowa Hakka Kirin, Verastem, Portola, Corvus; Research Funding: Aileron, Celgene, Seattle Genetics, Takeda, Kyowa Hakka Kirin, Verastem, ADC Therapeutics, Spectrum, Forty-Seven; Hamadani, M: Consultant Advisory Role: MedImmune, Jansen, Celgene, Cellerant; Research Funding: Otsuka, Takeda, Sanofi Genzyme, MedImmune, Merck, ADC Therapeutics; Other Remuneration: Speaker bureau: Sanofi, Genzyme. Samaniego, F: Research Funding: ADC Therapeutics; Spira, A: Consultant Advisory Role: AbbVie, AstraZeneca, BMS, Roche; Research Funding: ADC Therapeutics; Caimi, P: Consultant Advisory Role: Genentech, Kite Pharma; Research Funding: ADC Therapeutics; Other Remuneration: Speaker Bureau: Celgene. Davies, A: Consultant Advisory Role: Roche, Acerta Pharma, Karyopharma, Takeda, Celgene; Research Funding: Roche, Acerta Pharma, Gilead, Celgene, GSK, ADC Therapeutics; Other Remuneration: Speaker: Roche, Janssen, Gilead; Paid expert testimony: Roche. Menne, T: Consultant Advisory Role: Amgen, Takeda, Gilead; Research Funding: ADC Therapeutics; Fields, P: Consultant Advisory Role: ADC Therapeutics; Honoraria: Takeda, Roche, MSD; Cruz, H: Employment Leadership Position: ADC Therapeutics; Stock Ownership: ADC Therapeutics; He, S: Employment Leadership Position: ADC Therapeutics; Stock Ownership: ADC Therapeutics; Boni, J: Employment Leadership Position: ADC Therapeutics; Stock Ownership: ADC Therapeutics; Feingold, J: Employment Leadership Position: ADC Therapeutics; Stock Ownership: ADC Therapeutics; Wuerthner, J: Employment Leadership Position: ADC Therapeutics; Stock Ownership: ADC Therapeutics; Radford, J: Research Funding: ADC Therapeutics.

## SESSION 5 – T-CELL LYMPHOMAS

### 056
RISK OF BREAST IMPLANT ASSOCIATED ANAPLASTIC LARGE CELL LYMPHOMA (BIA-ALCL) IN A COHORT OF 3546 WOMEN PROSPECTIVELY FOLLOWED AFTER RECEIVING TEXTURED BREAST IMPLANTS

P. Ghione¹ | P.G. Cordeiro² | A. Ni³ | Q. Hu² | N. Ganesan¹ | N. Galasso¹ | A. Dogan⁴ | S.M. Horwitz¹

¹Lymphoma service, Memorial Sloan Ketterin Cancer Center, New York, United States; ²Department of Surgery, Memorial Sloan Kettering Cancer Center, Plastic and Reconstructive Surgery Service, New York, United States; ³Biostatistics Department, Memorial Sloan Kettering Cancer Center, New York, United States; ⁴Hematopathology Service, Memorial Sloan Kettering Cancer Center, New York, United States

**Background:** Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare subtype of T-cell lymphoma, developing in the fluid or capsule surrounding breast implants, primarily or exclusively in those with textured surfaces. Several prior series have estimated the risk of BIA-ALCL at 1/6920 -1/3800 women in retrospectively defined cohorts (from diagnosed cases within national or pathology databases), approximating the population at risk from sales records or other estimates (Sirinvasa 2017; Loch-Wilkinson 2017; de Boer 2018).

**Methods:** A prospective cohort study was conducted in the population that underwent breast reconstruction by a single surgeon at Memorial Sloan Kettering Cancer Center (MSKCC) from April 1993 to December 2017. Patients had long-term follow-up, and events related to implants were prospectively recorded. We identified all cases of BIA-ALCL by cross-checking data from internal clinical records, pathology records, and outside reports. Incidence rate per person-years and cumulative incidence when accounting for competing risk were calculated. 134 women who received smooth-surface implants were excluded from the analysis, since these implants have not been associated with BIA-ALCL.

### Subdistribution of developing BIA-ALCL

<figure><img src="image_31.png" /></figure>

<table><thead><tr><td>Years since implant</td><td>Cumulative risk of developing BIA-ALCL</td></tr></thead><tbody><tr><td>5</td><td>0.0</td></tr><tr><td>10</td><td>1.4*10<sup>-3</sup></td></tr><tr><td>15</td><td>6.7*10<sup>-3</sup></td></tr><tr><td>20</td><td>1.2*10<sup>-2</sup></td></tr></tbody></table>
<table><caption>TABLE 1</caption><thead><tr><th></th><th>Reason for reconstruction</th><th>Years of exposure</th><th>Presentation of BIA-ALCL</th></tr></thead><tbody><tr><td>Case 1</td><td>R - DCIS<br>L - prophylactic mastectomy</td><td>11.1</td><td>Peri-prosthetic fluid collection</td></tr><tr><td>Case 2</td><td>R - DCIS<br>L - stage I Ca</td><td>12.7</td><td>Peri-prosthetic fluid collection</td></tr><tr><td>Case 3</td><td>R - invasive tubular Ca<br>L - invasive lobular Ca</td><td>8.3</td><td>Peri-prosthetic fluid collection</td></tr><tr><td>Case 4</td><td>R - ductal hyperplasia<br>L - invasive ductal Ca</td><td>14.4</td><td>Peri-prosthetic fluid collection</td></tr><tr><td>Case 5</td><td>R - prophylactic mastectomy<br>L - DCIS</td><td>15.7</td><td>Breast mass + LN</td></tr><tr><td>Case 6</td><td>R - invasive ductal Ca<br>L - prophylactic mastectomy</td><td>10.5</td><td>Internal mammarian lymphadenopathy</td></tr><tr><td>Case 7</td><td>R - infiltrating lobular Ca<br>L - prophylactic mastectomy</td><td>9.2</td><td>Peri-prosthetic fluid collection in the context of breast Ca relapse</td></tr><tr><td>Case 8</td><td>R - DCIS<br>L - prophylactic mastectomy</td><td>11.3</td><td>Peri-prosthetic fluid collection</td></tr></tbody></table>

**Results:** From 1993 to 2017, 3546 patients underwent 6023 breast reconstructions using textured surface implants. All reconstructions were performed by a single surgeon (PGC) on patients enrolled in this study. To identify BIA-ALCL occurrence, clinical and pathological data were assessed from a prospective database. Median follow-up was 7 years (range, 3 days - 24.7 years). Eight women developed ALCL after a median exposure of 11.2 years (range, 8.3-15.8 years). Overall risk of BIA-ALCL in this cohort was 0.294 cases per 1000 person-years (1/443 women).

**Conclusions:** This study, evaluating the risk of women with textured breast implants from a prospective database with long-term follow-up, demonstrated that the incidence rate of BIA-ALCL may be higher than previously reported. These results can help inform implant choice for women undergoing breast reconstruction.

**Keywords:** anaplastic large cell lymphoma (ALCL); extranodal lymphomas; T-cell lymphoma (TCL).

PERIPHERAL T-CELL LYMPHOMA: A MULTICENTER GELTAMO/FIL STUDY

M. Lopez-Parra¹ | M. Bellei² | A. Rambaldi³ |
S. Novelli⁴ | C. Panizo⁵ | M. Martelli⁶ | I. Dhouly⁷ |
M. Bastos⁸ | A. Gutierrez⁹ | J. Sancho¹⁰ |
M. Ramirez¹¹ | J. Moraleda¹² | E. Carrillo Cruz¹³ |
A. Jimenez Ubieto¹⁴ | I. Jarque¹⁵ | U. Vittolo¹⁶ |
N. de las Heras¹⁷ | R. Arranz¹⁸ | J. Lopez-Jimenez¹⁹ |
C. Montalbán²⁰ | M. Pascual²¹ | P. Corradini²² |
S. Bobillo²³ | G. Estefania²⁴ | M. Spina²⁵ |
G. Rossi²⁶ | M. Manni²⁷ | M. Federico²⁸ |
D. Caballero¹ | A. Martín¹

¹Hematology, University Hospital of Salamanca-IBSAL, Salamanca, Spain;

²Department of Diagnostic, Clinical and Public Health Medicine,

University of Modena, Modena, Italy;

³Hematology and bone marrow transplant Unit, University of Milan, Milan, Italy;

⁴Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;

⁵Hematology, Clínica Universidad de Navarra, Pamplona, Spain;

⁶Hematology, Sapienza, University of Rome, Rome, Italy;

⁷Hematology, Hospital Clínico de Barcelona, Barcelona, Spain;

⁸Hematology, Hospital Gregorio Marañón, Madrid, Spain;

⁹Hematology, Hospital Son de Espases, Palma, Spain;

¹⁰Hematology, Hospital Germans Trias i Pujol/ ICO-IJC, Barcelona, Spain;

¹¹Hematology, Hospital de Jerez de la Frontera, Jerez de la Frontera, Spain;

¹²Hematology, Hospital Virgen de la Arrixaca, Murcia, Spain;

¹³Hematology, Hospital Virgen del Rocío, Sevilla, Spain;

¹⁴Hematology, Hospital 12 de Octubre, Madrid, Spain;

¹⁵Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain;

¹⁶Dipartimento di Oncologia e Ematologia, Città della Salute e della Scienza di Torino, Turin, Italy;

¹⁷Hematology, Complejo Asistencial Universitario de León, León, Spain;

¹⁸Hematology, Hospital La Princesa, Madrid, Spain;

¹⁹Hematology, Hospital Universitario Ramón y Cajal, Madrid, Spain;

²⁰Hematology, MD Anderson Cancer Center, Madrid, Spain;

²¹Hematology, Hospital Carlos Haya, Málaga, Spain;

²²Hematology, University of Milan, Milan, Italy;

²³Hematology, University Hospital Vall d'Hebron, Barcelona, Spain;

²⁴Hematology, Hospital Reina Sofía, Córdoba, Spain;

²⁵Division of Medical Oncology, National Cancer Institute, Aviano, Italy;

²⁶Hematology, Spedali Civili, Brescia, Italy;

²⁷Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy;

²⁸Hematology, Università degli Studi di Modena e Reggio Emilia, Modena, Italy

**Introduction:** The role of autologous stem cell transplantation (ASCT) after first-line chemotherapy in patients with peripheral T-cell lymphomas (PTCL) is controversial. The main objective of our study is to analyse the progression-free survival (PFS) and overall survival (OS) of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy, compared to a control group with similar characteristics who did not undergo ASCT as part of first-line.

**Methods:** This is a retrospective study performed in 44 hospitals from GELTAMO and FIL groups. Inclusion criteria were: i) Histological diagnosis of PTCL between 2001 and 2010; ii) patients deemed fit for
<table><caption>**TABLE 1** Patient characteristics</caption><thead><tr><th>Characteristics</th><th>Cases (transplanted patients) N (%)</th><th>Controls (non-transplanted patients) N (%)</th></tr></thead><tbody><tr><td>Age, median (range)</td><td>50 (18-70)</td><td>50 (19-67)</td></tr><tr><td>Sex, male</td><td>64 (59%)</td><td>62 (60%)</td></tr><tr><td>ECOG performance status &lt;2</td><td>24 (22%)</td><td>15 (15%)</td></tr><tr><td>B Symptoms</td><td>55 (51%)</td><td>41 (42%)</td></tr><tr><td>Ann Arbor Stage III-IV*</td><td>88 (84%)</td><td>56 (55%)</td></tr><tr><td>IPI ≥ 3*</td><td>54 (55%)</td><td>29 (30%)</td></tr><tr><td>PIT ≥ 3*</td><td>40 (39%)</td><td>23 (24%)</td></tr><tr><td>Histology*</td><td></td><td></td></tr><tr><td>Angioimmunoblastic T-cell lymphoma</td><td>32 (29%)</td><td>16 (15%)</td></tr><tr><td>Peripheral T-cell lymphoma, NOS</td><td>40 (37%)</td><td>30 (29%)</td></tr><tr><td>Peripheral T-cell lymphoma, lymphoepitelioid variant</td><td>2 (2%)</td><td>-</td></tr><tr><td>ALCL, T/null cell, ALK+, primary systemic type</td><td>4 (4%)</td><td>27 (26%)</td></tr><tr><td>ALCL, T/null cell, ALK-, primary systemic type</td><td>19 (17%)</td><td>21 (20%)</td></tr><tr><td>Enteropathy type T-cell lymphoma</td><td>5 (5%)</td><td>4 (4%)</td></tr><tr><td>Hepatocytesplenic T-cell lymphoma</td><td>4 (4%)</td><td>1 (1%)</td></tr><tr><td>NK/T-cell lymphoma, nasal type (not localized)</td><td>4 (4%)</td><td>2 (2%)</td></tr><tr><td>Primary cutaneous gamma-delta</td><td>1 (1%)</td><td>-</td></tr><tr><td>First-line treatment</td><td></td><td></td></tr><tr><td>CHOP/CHOP-like</td><td>83 (76%)</td><td>89 (86%)</td></tr><tr><td>CHOEP/CHOEP-like</td><td>25 (23%)</td><td>12 (12%)</td></tr><tr><td>Others</td><td>1 (1%)</td><td>2 (2%)</td></tr></tbody></table>

Abbreviations: ALCL, anaplastic large-cell lymphoma; ECOG, Eastern cooperative Oncology Group; IPI, International Prognostic Index; PIT, Prognostic Index for Peripheral T cell Lymphoma.

ASCT at the time of diagnosis; and iii) partial remission (PR) or CR after anthracycline-based first-line treatment. A landmark analysis was performed, with time zero defined as the time at which the assessment after the first-line was carried out.

**Results:** 286 patients were registered. For this analysis, we have only considered 212 patients who were in CR or uncertain CR after first-line chemotherapy. A total of 109 patients underwent ASCT (cases) and 103 did not (controls). The causes for not receiving

<figure><img src="image_32.png" /><figcaption>Figure 1. Overall survival of transplanted patients (continuous line) and non-transplanted patients (dashed line) after excluding ALCL ALK+ cases</figcaption></figure>

ASCT were: medical decision (N=84), poor performance status (N=10), patient decision (N=7) and other reasons (N=2). The baseline clinicopathologic characteristics of the patients are listed in table 1. The histologic subtypes were different between groups: angioimmunoblastic T-cell lymphoma and PTCL-NOS were more frequent in the transplant group, whereas anaplastic large cell lymphoma (ALCL), ALK+ was more frequent in the control group. More patients in the transplant group had adverse prognostic factors (table 1). First-line treatment was similar in both groups. With a median follow up of 73.9 months, no significant differences in survival were observed between cases and controls in the overall series. However, after excluding ALCL ALK+ cases, the PFS (65% vs 44% at 5 years, p=0,012) and OS (74% versus 65% at 5 years, p=0,046, figure 1) were significantly better in the patients who underwent ASCT. The PFS advantage in favour of ASCT was independent of IPI or type of first-line chemotherapy in the Cox multivariate analysis (HR 1.62, 95% CI 1.03-2.54, p=0.35).

**Conclusion:** Our results indicate that ASCT in 1st CR improves the survival of patients with PTCL other than ALK+ anaplastic large-cell lymphoma. These results should be confirmed in a prospective randomized study. A propensity score matching analysis is planned.

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

## 058
FIRST-LINE THERAPY OF T-CELL LYMPHOMA: ALLOGENEIC OR AUTOLOGOUS TRANSPLANTATION FOR CONSOLIDATION - FINAL RESULTS OF THE AATT STUDY

O. Tournilhac¹ | L. Truemper² | M. Ziepert³ |

K. Bouabdallah⁴ | M. Nickelsen⁵ | S. Maury⁶ |

<footnote>*p < 0.05</footnote>
P. Reimer⁷ | A. Jaccard⁸ | W. Herr⁹ |
M. Wilhelm¹⁰ | G. Cartron¹¹ | G. Wulf² |
L. Sanhes¹² | P. Dreger¹³ | T. Lamy¹⁴ |
F. Kroschinsky¹⁵ | H. Lindemann¹⁶ | M. Roussel¹⁷ |
A. Viardot¹⁸ | D. Sibon¹⁹ | A. Delmer²⁰ |
L. De Leval²¹ | G.L. Damaj²² | C. Gisselbrecht²³ |
P. Gaulard²⁴ | A. Rosenwald²⁵ | B. Friedrichs²⁶ |
B. Altmann²⁷ | N. Schmitz²⁶

¹Service d'Hematologie, EA7453 Chelter, CIC-1405, CHU de Clermont-Ferrand, Université Clermont Auvergne, Clermont-Ferrand, France;

²Hematology and Oncology, Georg August University Göttingen, Goettingen, Germany; ³Statistics and Epidemiology, Institute for Medical Informatics, Leipzig University, Leipzig, Germany; ⁴Department of Haematology, University Hospital of Bordeaux, Bordeaux Pessac, France;

⁵Onkologie Lerchenfeld, Onkologie Lerchenfeld, Hamburg, Germany;

⁶Université Paris-Est Créteil Val De Marne, AP-HP Hôpital Henri Mondor, Créteil, France; ⁷Hämatologie, Kliniken Essen-Sued, Essen, Germany;

⁸Hématologie Clinique et Thérapie Cellulaire, CHU de Limoges - Hôpital Dupuytren, Limoges, France; ⁹Department of Internal Medicine III, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; ¹⁰Med. Klinik 5, Klinikum Nuernberg, Nuernberg, Germany;

¹¹Service d'Hématologie Clinique, CHU de Montpellier, UMR CNRS 5235, Montpellier, France; ¹²Hematology, Centre Hospitalier Saint Jean, Perpignan, France; ¹³Internal Medicine V, University of Heidelberg, Heidelberg, Germany; ¹⁴Rennes University Hospital, INSERM Research Unit 1236, Rennes University, Rennes, France; ¹⁵Medical Department I, Dresden University Hospital, Dresden, Germany; ¹⁶Hematology Oncology Clinic, Saint Josefs Hospital, Hagen, Germany; ¹⁷Service d'Hématologie, IUC Oncopole, Toulouse, France; ¹⁸Internal Medicine III, University Hospital Ulm, Ulm, Germany; ¹⁹Hematology, CHU Necker, Paris, France; ²⁰Hematology, CHU Robert Debré, Reims, France; ²¹Pathologie Clinique, Institut Universitaire de Pathologie, Lausanne, Switzerland; ²²Institut d'Hématologie, CHU de Caen, Caen, France; ²³Institut Hématologie, Hôpital Saint-Louis, Paris, France; ²⁴Département de Pathologie, Groupe Hospitalier Henri Mondor, Créteil, France; ²⁵Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany; ²⁶Hämatologie, Medizinische Klinik A Hämatologie UniversitätsklinikMünster, Münster, Germany; ²⁷Statistics and Epidemiology, Institute for Medical Informatics (IMISE), Leipzig, Germany

**Background:** In patients (pts) with peripheral T-cell lymphoma (PTCL) results of first-line therapy remain poor; guidelines recommend consolidation with autologous transplantation (autoSCT) in transplant-eligible pts. AATT (Autologous or Allogeneic Transplantation in T-cell lymphoma) sought to improve first-line therapy and compared alloSCT with autoSCT.

**Methods:** This was a prospective randomized trial comparing autoSCT with alloSCT in younger pts (18-60 yrs) with newly diagnosed PTCL who had achieved CR, PR, or SD after 4 courses of CHOEP and 1 course of DHAP. Pts were to receive BEAM followed by autoSCT or myeloablative conditioning (fludarabine, busulfan, cyclophosphamide)

followed by alloSCT from a matched related or unrelated donor. Primary endpoint was 3-year event-free survival (EFS). The study was stopped prematurely after a pre-planned interim analysis (JCO 33, 2015, suppl 8507a)

**Results:** 103 pts randomized upfront to autoSCT (n = 54) or alloSCT (n = 49) formed the full analysis set. Median age was 50 years, 63% were male. 36 pts (35%) could not proceed to transplantation mostly due to early progression. Median observation time for EFS was 42 months. 3-year EFS and overall survival (OS) did not significantly differ between alloSCT and autoSCT (EFS: 43% (95% CI29-57%) vs. 38% (25-52%), p = 0.58, OS: 57% (43-71%) vs. 70% (57-82%)(p = 0.41). Comparing pts who actually received autoSCT (n = 41) or alloSCT (n = 26) EFS, PFS, and OS also showed no significant difference. No patient relapsed but eight pts (31%) died of treatment-related mortality (TRM) after alloSCT compared to 13 relapses (36%) but no TRM observed after autoSCT. Comparison of pts with aaPI 2/3 vs. 0/1 showed significant differences for all endpoints.

**Conclusions:** AlloSCT or autoSCT given to consolidate response in pts with PTCL showed no significant survival differences. While exerting a strong GvL-effect alloSCT resulted in substantial TRM. For younger pts with PTCL autoSCT remains the preferred consolidation, in particular, because pts relapsing after autoSCT can be successfully salvaged with alloSCT.

**Keywords:** allogeneic stem cell transplant (alloSCT); autologous stem cell transplantation (ASCT); T-cell lymphoma (TCL).

**Disclosures:** Tournilhac, O: Consultant Advisory Role: Roche, Abbvie, Janssen-Cilag, Takeda; Honoraria: Roche, Celgene, Roche, Abbvie, Janssen, Gilead Science; Research Funding: Amgen. Nickelsen, M: Consultant Advisory Role: Roche; Celgene; Janssen China R&D; Honoraria: Roche; Celgene; MSD Oncology; Roche; Celgene; MSD Oncology; Other Remuneration: Travel, accommodations, expenses: Roche; Celgene; Janssen China R&D. Maury, S: Consultant Advisory Role: Pfizer; Amgen; Miltenyi Biotec; Other Remuneration: Patents, Royalties, other intellectual Property: Inserm. Reimer, P: Consultant Advisory Role: Takeda; Honoraria: Pfizer; Roche; Other Remuneration: Travel, accommodations, expenses: Gilead Sciences, Takeda, Abbvie, Bristol-Myers Squibb. Jaccard, A: Honoraria: Amgen; Celgene; Janssen China R&D; Research Funding: Celgene; Janssen China R&D; Other Remuneration: travel, accommodations, expenses: Celgene, Amgen, Janssen China R&D. Cartron, G: Consultant Advisory Role: Celgene; Roche; Honoraria: Gilead Sciences; Sanofi; Roche; Celgene; Janssen China R&D. Wulf, G: Consultant Advisory Role: Kite Gilead; Novartis; Other Remuneration: Speaker's Bureau: Novartis. Sanhes, L: Consultant Advisory Role: Biogaran, Celgene, Novartis. De Leval, L: Consultant Advisory Role: Abbvie; Honoraria: Roche; Other Remuneration: Travel, accommodations, expenses: MSD. Damaj, G: Consultant Advisory Role: Roche, Takeda, Novartis; Honoraria: Roche, Takeda, Novartis; Research Funding: Takeda, Roche; Other Remuneration: Travel Roche, Pfizer. Gisselbrecht, C: Research Funding: Roche/Genentech; JHL Biotech; Other Remuneration: Speakers' Bureau: Roche/Genentech. Gaulard, P: Consultant Advisory Role: Takeda; Research Funding: Takeda; Other Remuneration: Travel, accommodations, expenses: Roche; Takeda.
**Schmitz, N:** Consultant Advisory Role: Riemser; Stock Ownership: Celgene; Honoraria: Takeda; Gilead sciences; Riemser; Janssen China R&D; Research Funding: Janssen China R&D; Other Remuneration: Travel, accommodations, expenses: Takeda; Gilead sciences; Riemser; Janssen China R&D.

059
TREATMENT BENEFIT ASSOCIATING WITH
NON-ANTHRACYCLINE CHEMOTHERAPY
IN EXTRANODAL NK/T-CELL LYMPHOMA,
NASAL TYPE

S. Qi¹ | Y. Yang¹ | W. Liu² | L. Zhang³ | H. Su⁴ |

Y. Yang⁵ | X. He⁵ | B. Qu⁶ | L. Qian⁷ |

X. Hou⁸ | H. Wang⁹ | G. Li¹⁰ | Y. Zhang¹¹ |

X. Qiao¹² | Y. Zhu¹³ | J. Cao¹⁴ | J. Wu¹⁵ |

T. Wu¹⁶ | S. Zhu¹⁷ | M. Shi¹⁸ | L. Xu¹⁹ | Y. Li¹

¹Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; ²Medical Oncology, Peking University Cancer Hospital & Institute, Beijing, China; ³Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; ⁴Oncology, 307 Hospital, Academy of Military Medical Science, Beijing, China; ⁵Radiation Oncology, Chongqing Cancer Hospital & Cancer Institute, Chongqing, China; ⁶Radiation Oncology, The General Hospital of Chinese People's Liberation Army, Beijing, China; ⁷Radiation Oncology, The Affiliated Provincial Hospital of Anhui Medical University, HEFEI, China; ⁸Radiation Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China; ⁹Radiation Oncology, Jiangxi Cancer Hospital, Nanchang, China; ¹⁰Radiation Oncology, Beijing Hospital of the Ministry of Health, Beijing, China; ¹¹Radiation Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; ¹²Radiation

<figure><img src="image_33.png" /></figure>

<table><thead><tr><th>No. at risk</th><th>Time (months)</th></tr></thead><tbody><tr><td>non-ANT 1351</td><td>996 750 518 341 200 92</td></tr><tr><td>ANT 1209</td><td>880 701 586 503 425 333</td></tr></tbody></table>

<figure><img src="image_34.png" /></figure>

<table><thead><tr><th>No. at risk</th><th>Time (months)</th></tr></thead><tbody><tr><td>non-ANT 1351</td><td>922 677 471 308 177 83</td></tr><tr><td>ANT 1209</td><td>762 584 485 417 357 279</td></tr></tbody></table>

<figure><img src="image_35.png" /></figure>

<table><thead><tr><th>No. at risk</th><th>Time (months)</th></tr></thead><tbody><tr><td>non-ANT 1096</td><td>818 633 441 291 171 80</td></tr><tr><td>ANT 1096</td><td>803 643 537 462 395 312</td></tr></tbody></table>

<figure><img src="image_36.png" /></figure>

<table><thead><tr><th>No. at risk</th><th>Time (months)</th></tr></thead><tbody><tr><td>non-ANT 1096</td><td>764 572 400 262 150 70</td></tr><tr><td>ANT 1096</td><td>705 540 446 385 335 264</td></tr></tbody></table>

Non-ANT chemotherapy associated with prolonged OS(HR, 0.69; 95%CI 0.60-0.78; P<.001; Fig. A) and PFS (HR, 0.65; 95%CI 0.57-0.73; P<.001 Fig. B) comparing to ANT chemotherapy After PSM, the OS (HR, 0.69; 95% CI, 0.60-0.80; P<.001, Fig. C) and PFS advantage (HR, 0.66; 95% CI, 0.58 -0.75; P<.001, Fig. D) still remained statistically significant.
Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China; ¹³Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China; ¹⁴Radiation Oncology, Shanxi Cancer Hospital and the Affiliated Cancer Hospital of Shanxi Medical University, Taiyuan, China;

¹⁵Radiation Oncology, Fujian Provincial Cancer Hospital, Fuzhou, China;

¹⁶Radiation Oncology, Affiliated Hospital of Guizhou Medical University, Guizhou Cancer Hospital, Guiyang, China; ¹⁷Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, China; ¹⁸Radiation Oncology, Xijing Hospital, Fourth Military Medical University, Xian, China; ¹⁹Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, China

**Introduction:** The recommended non-anthracycline (non-ANT) chemotherapy on treating Extranodal NK/T-cell lymphoma, nasal type (ENKL) is based on evidences of single-arm phase I/II studies and retrospective series with limited cases and short-term follow-ups. The current study was to investigate treatment benefit of non-ANT chemotherapy in comparison to anthracycline (ANT) chemotherapy in a large-scaled cohort.

**Methods:** Patients consecutively diagnosed with ENKL and treated with chemotherapy with/without radiotherapy between 2000 and 2015 from 20 Chinese institutes were retrospectively analyzed. Association of short-term response and long-term survival with chemotherapy categories were evaluated.

**Results:** 2560 cases were enrolled, 87% had stage I-II disease, and median age was 43. The proportion of non-ANT chemotherapy increased notably through 2005 to 2012. Demographic and disease characteristics showed great similarities across chemotherapy subgroups. Non-ANT chemotherapy associated with increased response comparing to ANT regimen (CR, 40 vs. 28%; PR, 43 vs.37 %, P<0.05). With a median follow-up of 4 years, overall survival (OS) and progression free survival (PFS) were significantly better favoring non-ANT chemotherapy in the entire cohort (5-year OS, 68.9% vs 57.5%, P < 0.001; 5-year PFS, 59.5% vs 44.5%, P < 0.001), localized disease (5-year OS, 73.3% vs 60.9%, P < 0.001; 5-year PFS, 64.0% vs 47.6%, P < 0.001), advanced disease (OS, 39.8% vs 29.9%, P = 0.013; PFS, 30.1% vs 18.8%, P = 0.003), and each risk subgroups, respectively. The survival benefit remained consistent after adjustments with multivariate analysis and propensity score matching analysis. Gemcitabine + L-Asparaginase combination showed promising treatment outcomes, especially for advanced disease.

**Conclusions:** Non-ANT chemotherapy constituted the mainstay of chemotherapy in ENKL treatment. The application of non-ANT chemotherapy associated improved response and survival comparing to ANT chemotherapy.

**Keywords:** anthracycline; L-asparaginase; T-cell lymphoma (TCL).

060
SINTILIMAB FOR RELAPSED/REFRACTORY
(R/R) EXTRANODAL NK/T CELL

LYMPHOMA (ENKTL): A MULTICENTER,
SINGLE-ARM, PHASE 2 TRIAL (ORIENT-4)

R. Tao¹ | L. Fan² | Y. Song³ | Y. Hu⁴ |

W. Zhang⁵ | Y. Wang⁶ | L. Xu⁷ | H. Zhou⁷ | J. Li²

¹Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; ²Department of Hematology, Jiangsu Province Hospital, Nanjing, China; ³Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China; ⁴Department of Hematology, Union Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, China; ⁵Department of Hematology, Peking Union Medical College Hospital, Beijing, China; ⁶Department of Hematology, Tianjin Medical University Cancer Institute and Hspital, Tianjing, China; ⁷Medical Science, Innovent Biologics (Suzhou) Co. Ltd, Suzhou, China

**Introduction:** ENKTL account for more than 20% of the peripheral T-cell lymphoma in Asia. Patients with r/r ENKTL have a poor prognosis after failing an L-asparaginase based regimen, and the median overall survival is less than 6 months. The overexpression of PD-L1 induced by EBV infection is a potential mechanism for ENKTL to avert immune surveillance, and recent studies of PD-1 antibodies in pts with r/r ENKTL have demonstrated potential efficacy. Sintilimab, a fully human anti-PD-1 monoclonal antibody, has a safety profile consistent with other approved PD-1 antibodies and was approved for r/r classical Hodgkin lymphoma in China in 2018. This multicenter, single-arm, phase 2 study aims to validate the efficacy and safety of sintilimab monotherapy in patients with r/r ENKTL in China.

**Methods:** Patients with pathologically confirmed relapsed or refractory ENKTL were enrolled. Sintilimab was given 200 mg IV Q3W, until PD, death, unacceptable toxicity, or withdrawal from the study. Treatment beyond PD is allowed. Tumor response evaluation was performed by both PET-CT and CT/MRI with contrast. The primary endpoint was objective response rate based on LUGANO 2014 criteria. Data cut-off date for this analysis was Feb 2, 2019.

**Results:** From Aug 31, 2017 to Feb 7, 2018, a total of 28 patients were enrolled: 60.7% (17/28) male and the median age was 37 (range: 19~65) yr. Sixty-eight percent (19/28) of patients were stage IV and 89.3% (25/28) were ECOG PS ≥ 1. All patients had failed an L-asparaginase based regimen, the median lines of previous therapy were 3 (range: 1~13), 78.6% (22/28) patients received prior radiotherapy and 7.1% (2/28) had failed HSCT. Median duration of therapy was 14.04 (range: 1.4~17.3) months and 19 patients are still receiving sintilimab. Sixty-eight percent (19/28, 95%CI: 47.6%~84.1%) of patients achieved response (CR+PR), including 4 pts who experienced PD prior to having a response. DCR was 85.7% (24/28), including 5 pts who experienced PD before SD or response. The 1-year OS rate was 82.1% and the median OS has not been reached. Most TRAEs were G1~2 (67.9%) and no patients discontinued treatment due to AEs. The most common TRAE was decreased lymphocyte count (46.4%, 13/28) and 84.6% were grade 1~2. SAEs occurred in 21.4%
of patients and none were related to sintilimab. No patients died from AEs.

**Conclusions:** ORIENT-4 is the first multicenter and prospective study validating efficacy of PD-1 antibody in ENKTL and with results. Sintilimab is effective and well tolerated in r/r ENKTL and could be a promising treatment option for these patients. Early disease progression observed by PET scan in this study could be pseudo-progression as it did not correlate with poor outcome, which warrants further investigation. Clinical trial information: NCT03228836

**Keywords:** monoclonal antibodies (MoAb); PD-1; peripheral T-cell lymphomas (PTCL).

**Disclosures:** Xu, L: Employment Leadership Position: Innovent Biologics (Suzhou) Co. Ltd. Zhou, H: Employment Leadership Position: Innovent Biologics (Suzhou) Co. Ltd.

## FOCUS ON... SESSION: CLL AND MORE

### 061
FIVE-YEAR FOLLOW-UP OF FIRST-LINE IBRUTINIB FOR TREATMENT OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA//SMALL LYMPHOCYTIC LYMPHOMA

A. Tedeschi¹ | J. Burger² | P.M. Barr³ | T. Robak⁴ |

C. Owen⁵ | P. Ghia⁶ | O. Bairey⁷ | P. Hillmen⁸ |

S. Coutre⁹ | S. Devereux¹⁰ | S. Grosicki¹¹ |

H. McCarthy¹² | J. Li¹³ | D. Simpson¹⁴ |

F. Offner¹⁵ | C. Moreno¹⁶ | S. Dai¹⁷ | I. Lal¹⁸ |

J.P. Dean¹⁸ | T.J. Kipps¹⁹

¹Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; ²Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States; ³Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States; ⁴Department of Hematology, Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland;

⁵Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada; ⁶Department of Experimental Oncology, Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy; ⁷Department of Hematology, Rabin Medical Center, Petah Tikva, Israel; ⁸Department of Medicine, The Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds, United Kingdom; ⁹Department of Medicine, Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA, United States; ¹⁰Department of Hematology, Kings College Hospital, NHS Foundation Trust, London, United Kingdom;

¹¹Department of Internal Medicine, School of Public Health, Silesian Medical University, Katowice, Poland; ¹²Department of Hematology, Royal Bournemouth General Hospital, Bournemouth, United Kingdom;

¹³Department of Medicine, Jiangsu Province Hospital, Nanjing, China;

¹⁴Department of Hematology, North Shore Hospital, Auckland,

New Zealand; ¹⁵Department of Clinical Hematology, Universitair Ziekenhuis Gent, Gent, Belgium; ¹⁶Department of Hematology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain; ¹⁷Department of Biostatistics, Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, United States; ¹⁸Department of Clinical Science, Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, United States; ¹⁹Department of Medicine, UCSD Moores Cancer Center, La Jolla, CA, United States

**Introduction:** Ibrutinib (ibr) is a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase (BTK) approved in the EU and other regions to treat chronic lymphocytic leukemia (CLL). The phase 3 RESONATE-2 study compares the efficacy and safety of first-line ibr vs chlorambucil (chl) in older patients (pts) with CLL/small lymphocytic lymphoma (SLL). There is a critical clinical need for long-term efficacy and safety data for ibr, which is given as continuous therapy.

**Methods:** RESONATE-2 is a phase 3, randomized, open-label, international study (PCYC-1115/1116; NCT01722487, NCT01724346). Pts with previously untreated CLL/SLL without 17p deletion and ≥65 y old (N=269) were randomized 1:1 to continuous ibr 420 mg once daily or chl 0.5–0.8 mg/kg for up to 12 cycles. Efficacy was assessed by investigator per International Workshop on Chronic Lymphocytic Leukemia 2008 criteria with modification during long-term follow-up. Prevalence rates for adverse events (AE) are reported.

**Results:** Baseline characteristics were well balanced between ibr and chl arms. After a median follow-up of 60 mo (range 0.1–66 mo), superior progression-free survival (PFS) was sustained for ibr vs chl (hazard ratio [HR] 0.15 [95% CI 0.10–0.22]). PFS estimates at 5 y were 70% for ibr vs 12% for chl. Ibr improved PFS compared to chl in pts with unmutated immunoglobulin heavy chain variable region (IGHV; HR 0.11 [95% CI 0.06–0.19]), 11q deletion (HR 0.03 [95% CI 0.01–0.11]), and the high-risk genomics subgroup (unmutated IGHV, 11q deletion, and/or TP53 mutation; HR 0.08 [95% CI 0.05–0.15]). Ibr also resulted in improved overall survival (OS) vs chl; 83% vs 68% at 5 y, even with 57% of pts crossing over from chl to ibr after progression. With ibr, overall response rate, including partial response with lymphocytosis, for ibr was 92%. The complete response (CR)/CR with incomplete marrow recovery (CRi) rate increased to 30% at 60 mo from 11% at primary analysis (18 mo). Common grade ≥3 AEs included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%), with rates of most events decreasing over time. Dose reductions due to grade ≥3 AEs decreased over time and discontinuation rates due to AEs remained stable over time. After ibr discontinuation, pts responded to subsequent CLL therapies, such as chemoimmunotherapy and alternate kinase inhibitors. Ibr maintains benefit in 58% of pts who remained on therapy.

**Conclusions:** Single-agent ibr sustained superior PFS and OS compared to chl, including for pts with high-risk genomic features, in the longest follow-up to date from a phase 3 study of first-line BTK-directed therapy. After up to 66 mo follow-up, responses to ibr improved over time with almost three-fold more pts achieving CR/CRi with long-term
O. Al-Sawaf¹ | E. Lilienweiss¹ | J. Bahlo¹ |
S. Robrecht¹ | A. Fink¹ | M. Patz¹ | M. Tandon² |
K. Humphrey² | Y. Jiang³ | W. Schary⁴ |
M. Porro Lurà⁵ | M. Ritgen⁶ | E. Tausch⁷ |
S. Stilgenbauer⁸ | B. Eichhorst¹ | K. Fischer¹ |
M. Hallek⁹ | K. Kreuzer¹

¹Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne, Germany; ²Clinical Development Oncology, Roche Products Limited, Welwyn Garden City, United Kingdom; ³Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, United States; ⁴Clinical Development, Oncology, AbbVie Inc., North Chicago, IL, United States;
⁵Pharmaceuticals Division, PDGo, F. Hoffmann-La Roche Ltd., Basel, Switzerland; ⁶Department II of Internal Medicine, Campus Kiel, University of Schleswig-Holstein, Kiel, Germany; ⁷Department III of Internal Medicine, Ulm University, Ulm, Germany; ⁸Department III of Internal Medicine, Ulm University, Ulm, Germany, and Department for Hematology, Oncology and Rheumatology, Saarland University Medical School, Homburg/Saar, Germany; ⁹Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne, CECAD (Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases), University of Cologne, Cologne, Germany

**Introduction:** CKT (≥3 chromosomal aberrations) is associated with poor prognosis in CLL. In the CLL14 trial, treatment-naïve, elderly, unfit CLL patients (pts) received chlorambucil plus obinutuzumab (ClbG, n=216) or venetoclax plus obinutuzumab (VenG, n=216) for 12 cycles. After median follow-up of 29 months (mo), longer progression-free survival (PFS), and higher overall response rate (ORR) and rate of minimal residual disease (MRD) negativity were seen with VenG vs ClbG. Here, we present a prospective evaluation of CKT in CLL pts treated with a fixed-duration, chemotherapy-free regimen of VenG.

<figure><img src="image_37.png" /><figcaption>**Figure 1:** PFS according to treatment group and presence of CKT or NCKT</figcaption></figure>

**Methods:** Metaphase spreads were produced after IL-2/CpG-stimulation and analyzed according to ISCN 2013. ORR, PFS, overall survival (OS) and MRD rates were evaluated according to presence of CKT alone and in combination with TP53aberrations. PFS and OS were estimated using the Kaplan-Meier method. Survival times were compared using non-stratified log-rank tests. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression modelling.

**Results:** Chromosome analysis was performed successfully in 397/432 (92%) randomized pts. CKT and non-CKT (NCKT) were found in 34 (17%) and 166 (83%) VenG pts, respectively, and 30 (15%) and 167 (85%) ClbG pts, respectively. Del(17p)/TP53mut was detected in 11/34 (32%) VenG CKT pts and in 9/29 (31%) ClbG CKT pts. Most pts with CKT were graded as high or very high risk according to the CLL-International Prognostic Index (CLL-IPI; 79% and 82%, respectively). In the VenG arm, ORR was 82% in CKT and 87% in NCKT pts; MRD negativity rate 3 mo after treatment completion in peripheral blood (PB) was 79% vs 77%, respectively, and in bone marrow (BM) 59% and 58%, respectively. No difference in PFS (Figure 1) or OS was seen between CKT and NCKT pts (median not reached [NR]; HR 1.909 [95% CI 0.806-4.520] and HR 1.511 [95% CI 0.496-4.600], respectively).

For ClbG, ORR was 50% in CKT and 78% in NCKT pts; MRD negativity rate was lower in CKT vs NCKT pts, in PB (20% vs 40%, respectively) and BM (0% vs 22%, respectively). Median PFS was 19 mo in ClbG CKT pts and NR in NCKT pts (HR 2.790 [95% CI 1.631-4.772], p<0.001). OS was significantly shorter in CKT vs NCKT pts (median NR; HR 3.736 [95% CI 1.357-10.287], p=0.006).

In CKT pts, presence of del(17p)/TP53mut did not significantly alter PFS compared with pts without del(17p)/TP53mut in the VenG (HR 1.419 [95% CI 0.317-6.353]) or ClbG groups (HR 2.103 [95% CI 0.795-5.567]).

**Conclusion:** CKT, which can be observed frequently in older, treatment-naïve CLL pts, correlates with CLL-IPI high/very high risk, although 2/3 of these pts do not show TP53 aberrations. CKT is associated with shorter PFS and OS in pts treated with ClbG, including pts without TP53 aberrations. VenG can overcome this adverse risk. These data support the importance of chromosome analysis before frontline therapy, and the value of VenG in CLL CKT pts.

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

This abstract has been previously submitted to EHA 2019.

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

**Disclosures:** Al-Sawaf, **O:** Other Remuneration: AbbVie, Roche, Gilead, Janssen. **Bahlo, J:** Honoraria: Roche; Other Remuneration: Expenses: Roche. **Fink, A:** Consultant Advisory Role: Janssen Pharamceutical. **Tandon, M:** Employment Leadership Position: Roche. **Humphrey, K:** Employment Leadership Position: Roche; Stock Ownership: Roche. **Jiang, Y:** Employment Leadership Position: Genentech; Stock Ownership: Genentech. **Schary, W:** Employment Leadership Position: AbbVie;
Stock Ownership: AbbVie. Porro Lurà, M: Employment Leadership Position: F. Hoffmann - La Roche Ltd; Stock Ownership: F. Hoffmann - La Roche Ltd. Ritgen, M: Consultant Advisory Role: Roche, Abbvie; Research Funding: Roche, Abbvie; Other Remuneration: Personal Fees: Roche. Tausch, E: Consultant Advisory Role: Roche; Other Remuneration: Speakers' Bureau: Roche; Expert Testimony: Abbvie; Expenses: Abbvie. Stilgenbauer, S: Research Funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Other Remuneration: Personal Fees: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis. Eichhorst, B: Consultant Advisory Role: Abbvie, Roche; Honoraria: Abbvie, Roche; Research Funding: Abbvie, Roche; Other Remuneration: Speakers' Bureau: Abbvie, Roche; Expenses: Abbvie, Roche. Fischer, K: Other Remuneration: Expenses: Roche. Hallek, M: Consultant Advisory Role: Roche, Abbvie; Honoraria: Roche, Abbvie, Gilead, Janssen, Celgene, Boehringer Ingelheim; Research Funding: Roche, Abbvie; Other Remuneration: Speakers' Bureau: Roche, Abbvie. Kreuzer, K: Consultant Advisory Role: Roche, Abbvie; Other Remuneration: Expert Testimony: Roche, Abbvie.

063
IMPACT OF MAJOR GENOMIC
ALTERATIONS ON OUTCOME OF
RELAPSED/REFRACTORY CHRONIC
LYMPHOCYTIC LEUKEMIA PATIENTS
RECEIVING VENETOCLAX PLUS
RITUXIMAB IN THE PHASE 3 MURANO
STUDY

J. Wu¹ | C. Bolen² | J.F. Seymour³ | P. Hillmen⁴ |
B. Eichhorst⁵ | E. Eldering⁶ | T.J. Kipps⁷ |
A.W. Langerak⁸ | C. Mellink⁹ |
A.F. van der Kevie-Kersemaekers⁹ | C. Owen¹⁰ |
B. Chyla¹¹ | E.A. Punnoose¹ | J. Wang¹² |
M. Boyer¹³ | K. Humphrey¹⁴ | Y. Jiang¹ | A.P. Kater⁶

¹Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, United States; ²Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA, United States; ³Peter MacCallum Cancer Centre, Royal Melbourne Hospital, and University of Melbourne, Melbourne, Australia; ⁴Department of Haematology, St. James' University Hospital, Leeds, United Kingdom; ⁵Department I for Internal Medicine, University of Cologne, Cologne, Germany; ⁶Department of Hematology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands; ⁷Moores Cancer Center, UC San Diego Health, San Diego, CA, United States; ⁸Department of Immunology, Erasmus MC University Medical Center, Rotterdam, Netherlands; ⁹Genome Diagnostic Laboratory, Amsterdam University Medical Centers, Amsterdam, Netherlands; ¹⁰Departments of Medicine and Oncology, University of Calgary, Calgary, AB, Canada; ¹¹Cancer Biomarkers, Abbvie, North Chicago, IL, United States; ¹²Product Development Biometrics, Genentech Inc., South San Francisco, CA,

United States; ¹³Clinical Science, Roche Products Limited, Welwyn Garden City, United Kingdom; ¹⁴Clinical Development Oncology, Roche Products Limited, Welwyn Garden City, United Kingdom

**Introduction:** We reported superior efficacy for venetoclax + rituximab (VenR) vs bendamustine + rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) in the MURANO study (NCT02005471), with significant progression-free survival (PFS) benefit and sustained undetectable minimal residual disease (uMRD), irrespective of historical risk factors for poor response. This analysis explores the clinical impact on outcome of major somatic mutations and cytogenetic high-risk features in patients (pts) treated with VenR and BR in MURANO.

**Methods:** Whole exome sequencing (WES) and analysis of genomic complexity (aGC; defined as having ≥3 or ≥5 genetic aberrations) by high-density array-comparative genomic hybridization were performed on baseline DNA specimens, available from 313/389 enrolled pts. Kaplan-Meier estimates and Cox proportional-hazards models were used to analyze PFS. uMRD was defined as <1 CLL cell in 10,000 leukocytes in peripheral blood (PB).

**Results:** At least one of the 9 mutated driver genes examined was identified in 234/313 (74.8%) pts from both arms; clonal mutations of ATM occurred in 30.7% of pts, TP53 in 24.9%, SF3B1 in 22.0%, NOTCH1 in 13.7%, BRAF in 8.3%, BIRC3 in 8.0%, and NRAS/KRAS/MYD88 in 1.6% each. After 36.0 months' median follow-up, a PFS benefit was observed consistently with VenR over BR across mutated (mut) and wildtype (WT) subgroups for ATM, TP53, SF3B1, NOTCH1 (Figure 1) and BIRC3. Median PFS for VenR was not reached in TP53mut or WT pts, compared with medians of 12.2 months (mo; hazard ratio [HR] 0.11, 95% confidence interval [CI] 0.055-0.24) and 21.6 mo (HR 0.16, 95% CI 0.098-0.25), respectively, for BR. Within treatment arms, inferior PFS was observed with both VenR and BR for TP53mut pts, but only with VenR for NOTCH1mut pts (interaction p=0.007). Two-year PFS with VenR was 76% for NOTCH1mut pts vs 89% for WT. Negative impact on PFS in NOTCH1mut VenR pts was confirmed by multivariate analysis (MVA) with IGHV, del(17p)/TP53, B2M, stage, and age as covariates (HR 0.54, 95% CI 0.22-1.30). Higher rates of disease progression were seen in NOTCH1mut (47.1%) vs WT (13.9%) pts treated with VenR, but not BR (69.2% vs 70.8%, respectively).

The PB uMRD rate was lower in NOTCH1mut pts (23.5% vs 49.3% in WT pts) at the end of Ven treatment visit. Prevalence of all CLL key mutated genes will be presented. Assessments of aGC are ongoing and impact on clinical outcomes will also be shown.

**Conclusions:** We assessed the mutational landscape of R/R CLL by WES and confirmed prior mutation frequency reports. Superior PFS benefit was observed for VenR vs BR in all clinical and molecular subgroups assessed, including the key CLL driver mutations reported here. NOTCH1 mutations may define a new high-risk pt subgroup for VenR. To address the biological basis of the findings, MVA, further validation in larger cohorts and deep sequencing for subclones are needed.

**Acknowledgment:** Venetoclax is being developed in collaboration between Genentech and AbbVie. Genentech and AbbVie provided
<figure><img src="image_38.png" /><figcaption>Figure 1: Kaplan-Meier plots of investigator-assessed PFS according to NOTCH1, SF3B1, ATM, and TP53 MUT vs WT subgroups</figcaption></figure>

financial support for the MURANO study. Third-party editorial assistance, under the direction of Jenny Wu, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

This abstract has been previously submitted to EHA 2019.

**Keywords:** chronic lymphocytic leukemia (CLL); cytogenetics; Notch pathway.

**Disclosures:** Wu, J: Employment Leadership Position: Genentech/Roche; Stock Ownership: Genentech/Roche; Other Remuneration: Expenses: Genentech/Roche. Bolen, C: Employment Leadership Position: Genentech/Roche; Stock Ownership: Genentech/Roche. Seymour, J: Consultant Advisory Role: Abbvie, Acerta, Celgene, Janssen, Roche, Takeda; Honoraria: AbbVie, Roche; Research Funding: AbbVie, Celgene, Janssen, Roche; Other Remuneration: Expert Testimony: Roche; Expenses: Abbvie; Review activities: Celgene. Hillmen, P: Consultant Advisory Role: Abbvie, Janssen; Honoraria: Abbvie, Janssen, Roche; Research Funding: Abbvie, Janssen, Roche (all Institution only); Other Remuneration: Travel, Accommodations, expenses: Janssen, Abbvie. Eichhorst, B: Consultant Advisory Role: AbbVie, Roche; Honoraria: AbbVie, Roche; Research Funding:

AbbVie, Roche; Other Remuneration: Travel, accommodations, expenses: AbbVie, Roche; Speakers' bureau: AbbVie, Roche. Eldering, E: Research Funding: Celgene, Roche, Gilead. Kipps, T: Employment Leadership Position: UC, San Diego Health, Moores Cancer Center; Consultant Advisory Role: AbbVie, Genentech/Roche, Gilead, Pharmacyclics, Celgene; Honoraria: Gilead, AbbVie, Pharmacyclics, Janssen, Verastem; Research Funding: AbbVie, Genentech/Roche, Pharmacyclics, Oncernal; Other Remuneration: Speakers' bureau/Advisory committee: AbbVie, Pharmacyclics, Janssen, Verastem. Langerak, A: Consultant Advisory Role: AbbVie; Research Funding: Roche-Genentech, Gilead. Mellink, C: Research Funding: The cytogenetics laboratory (AMC) receives research funding from Roche to perform the microarray analysis. van der Kevie-Kersemaekers, A: Research Funding: The cytogenetics laboratory (AMC) receives research funding from Roche to perform the microarray analysis. Owen, C: Honoraria: AbbVie, Roche, AstraZeneca, Janssen, Gilead, Teva. Chyla, B: Employment Leadership Position: AbbVie; Stock Ownership: AbbVie. Punnoose, E: Employment Leadership Position: Genentech, Member of the Roche Group; Stock Ownership: Genentech, Member of the Roche Group; Other Remuneration: Patents, Royalties, other intellectual property: Genentech,
Member of the Roche Group. **Wang, J:** Employment Leadership Position: Genentech; Stock Ownership: Hoffmann-La Roche. **Boyer, M:** Employment Leadership Position: Roche; Stock Ownership: Roche. **Humphrey, K:** Employment Leadership Position: Roche; Stock Ownership: Roche. **Jiang, Y:** Employment Leadership Position: Genentech; Stock Ownership: Genentech. **Kater, A:** Consultant Advisory Role: AbbVie; Honoraria: Abbvie; Research Funding: Genetech, Roche, AbbVie; Other Remuneration: Travel, accommodations, expenses: Roche.

064
AN UNDETECTABLE PB MRD STATUS SHOULD BE THE THERAPEUTIC GOAL WITH VENETOCLAX THERAPY IN RELAPSED/ REFRACTORY CLL

S.M. Handunnetti<fnref n="1" /> | T.E. Lew² | V.S. Lin² |
M.A. Anderson² | D. Carney<fnref n="1" /> | M. Wolf<fnref n="1" /> |
N. Came<fnref n="1" /> | S. Juneja<fnref n="1" /> | D. Westerman<fnref n="1" /> |
C.S. Tam<fnref n="1" /> | A.W. Roberts² | J.F. Seymour<fnref n="1" />

**Introduction:** BCL2 inhibitor venetoclax (Ven) is highly active in relapsed/refractory CLL. Attainment of undetectable minimal residual disease (uMRD; <10⁻⁴), especially in bone marrow (BM), strongly predicted progression free survival when analyzed after short term follow up (Seymour 2017). We aimed to determine:

1. Correlation between peripheral blood (PB) and BM uMRD assessment

2. Association between uMRD in PB and BM with MRD recrudescence and time to progression (TTP)

3. Time to uMRD attainment

4. Factors associated with uMRD attainment

**Methods:** 62 CLL patients treated with continuous Ven were serially monitored for MRD in PB and BM, using flow cytometry by ERIC methodology. Patients who came off Ven, including some in deep remission, were censored at time of cessation. Baseline factors assessed included variables in Table 1. Kaplan Meier and univariate analyses were done with significance set at P<0.05.

**Results:** Of 17 patients with PB uMRD and paired BM samples, 14 (82%) had confirmed uMRD in BM (Fig 1a).

1. Patients who achieved PB uMRD had prognosis at least as favorable as patients who achieved BM uMRD with respect to time to

A

<figure><img src="image_39.png" /></figure>

B

<figure><img src="image_40.png" /></figure>

C

<figure><img src="image_41.png" /></figure>

D

<figure><img src="image_42.png" /></figure>

**Figure 1:** A) MRD in paired BM in patients who achieved PB uMRD. B) Time to uMRD recrudescence in PB stratified by time from uMRD achievement in PB v BM. C) Time to iwCLL progression stratified by achievement of uMRD in PB v BM. Patients who progressed / came off Ven before median time to uMRD achievement (18 months for PB and BM uMRD) were excluded in landmark analysis. D) Cumulative incidence of PB uMRD v Time on Ven.

<footnote n="1">¹Department of Hematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia; ²Blood Cells and Blood Cancers, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia</footnote>
<table><caption>**TABLE 1** Baseline characteristics & association with uMRD in PB</caption><thead><tr><th>Variable</th><th></th><th>N=</th><th>PB uMRD N= (%)</th><th>Fisher's Exact P value</th></tr></thead><tbody><tr><td rowspan="2">Age ≥ 65</td><td>Y</td><td>38</td><td>11 (29%)</td><td rowspan="2">0.781</td></tr><tr><td>N</td><td>24</td><td>8 (33%)</td></tr><tr><td rowspan="2">≥ Prior Lines of Therapy</td><td>Y</td><td>25</td><td>6 (24%)</td><td rowspan="2">0.410</td></tr><tr><td>N</td><td>37</td><td>13 (35%)</td></tr><tr><td rowspan="2">Fludarabine Refractory</td><td>Y</td><td>30</td><td>7 (23%)</td><td rowspan="2">0.277</td></tr><tr><td>N</td><td>32</td><td>12 (38%)</td></tr><tr><td rowspan="2">Bulky Disease</td><td>Y</td><td>28</td><td>9 (32%)</td><td rowspan="2">1.000</td></tr><tr><td>N</td><td>34</td><td>10 (29%)</td></tr><tr><td rowspan="2">Rituximab Combination Therapy</td><td>Y</td><td>14</td><td>6 (43%)</td><td rowspan="2">0.327</td></tr><tr><td>N</td><td>48</td><td>13 (27%)</td></tr><tr><td rowspan="2">Dose ≥400mg</td><td>Y</td><td>46</td><td>17 (37%)</td><td rowspan="2">0.114</td></tr><tr><td>N</td><td>16</td><td>2 (13%)</td></tr><tr><td rowspan="2">Del(17p) and / or TP53Mutation</td><td>Y</td><td>33</td><td>6 (18%)</td><td rowspan="2">0.015</td></tr><tr><td>N</td><td>21</td><td>11 (52%)</td></tr><tr><td rowspan="2">Complex Karyotype</td><td>Y</td><td>14</td><td>1 (7%)</td><td rowspan="2">0.023</td></tr><tr><td>N</td><td>21</td><td>10 (48%)</td></tr><tr><td rowspan="2">Prior navitoclax</td><td>Y</td><td>9</td><td>0 (0%)</td><td rowspan="2">0.047</td></tr><tr><td>N</td><td>53</td><td>19 (36%)</td></tr></tbody></table>

MRD recrudescence and TTP (Fig 1b & c). Median time to MRD recrudescence after uMRD attainment in PB was 46 months (Fig 1b).

2. Of 62 patients, 19 achieved PB uMRD (31%). 2 patients had PB uMRD confirmed after 4-5 years without prior MRD tests. Excluding them, median time to PB uMRD was 18 (range 5-26) months and 90% of PB uMRD attainment occurred by 24 months (Fig 1d). Median follow up from Ven start for 43 patients who did not achieve PB uMRD was 25 (range 4-73) months.

3. Baseline TP53 dysfunction, complex karyotype and prior navitoclax were associated with lower likelihood of PB uMRD (Table 1).

**Conclusions:** PB uMRD commonly correlates with BM uMRD in CLL patients treated with Ven, and serves as an equivalent predictor of long term outcome. Patients who have not achieved PB uMRD by 24 months are unlikely to do so. This group is enriched for TP53dysfunction and complex karyotype. While patients achieving uMRD have prolonged TTP, CLL eventually recrudesces, supporting a drive to time-limited combination therapy.

**Keywords:** chronic lymphocytic leukemia (CLL); minimal residual disease (MRD); venetoclax.

**Disclosures:** Handunnetti, S: Research Funding: AbbVie. Lew, T: Employment Leadership Position: TEL is an employee of Walter and Eliza Hall Institute, potentially eligible for royalty payments related to venetoclax. Lin, V: Employment Leadership Position: VSL is an employee of Walter and Eliza Hall Institute, potentially eligible for royalty payments related to venetoclax. Anderson, M: Employment Leadership Position: MAA is an employee of Walter and Eliza Hall Institute and is eligible for royalty payments in relation to venetoclax; Honoraria: AbbVie. Tam, C: Honoraria: AbbVie, Janssen; Research Funding: AbbVie, Janssen. Roberts, A: Employment Leadership Position: AWR is an employee of Walter and Eliza Hall Institute and eligible for royalty payments in relation to venetoclax; Research Funding: AbbVie. Seymour, J: Consultant Advisory Role: JFS is advisory boards for AbbVie, Acerta, Celgene, Genentech, Janssen, Roche, Sunesis and Takeda.; Honoraria: AbbVie, Acerta, Celgene, Genentech, Janssen, Roche, Sunesis and Takeda.; Research Funding: AbbVie, Genentech, Celgene and Janssen.

## 065 TRANSCEND CLL 004: MINIMAL RESIDUAL DISEASE AFTER LISOCABTAGENE MARALEUCEL IN PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA

T. Siddiqi¹ | K.A. Dorritie² | J.D. Soumerai³ |

D.M. Stephens⁴ | J.A. Dubovsky⁵ | H.H. Gillenwater⁶ |

L. Gong⁷ | J. Thorpe⁸ | L. Yang⁹ | W.G. Wierda¹⁰

¹Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, United States; ²Division of Hematology-Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, United States; ³Department of Medicine, Center for Lymphoma, Massachusetts General Hospital, Boston, United States; ⁴Internal Medicine/Division of Hematology and Hematologic Malignancies, University of Utah, Huntsman Cancer Institute, Salt Lake City, United States; ⁵Translational Medicine, Juno Therapeutics, a Celgene Company, Seattle, United States; ⁶Clinical Research & Development, Juno Therapeutics, a Celgene Company, Seattle, United States; ⁷Global Clinical Research & Development, Juno Therapeutics, a Celgene Company, Seattle, United States; ⁸Translational Sciences, Juno Therapeutics, a Celgene Company, Seattle, United States; ⁹Biometrics, Juno Therapeutics, a Celgene Company, Seattle, United States; ¹⁰Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States

**Introduction:** Eradication of minimal residual disease (MRD) in patients with chronic lymphocytic leukemia (CLL) may be necessary for deep and durable responses. We assessed safety, pharmacokinetics, and efficacy of 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 1/2 TRANSCEND CLL 004 study.

**Methods:** Eligible patients had CLL/small lymphocytic lymphoma (SLL), received ≥2 prior lines of therapy (including Bruton's tyrosine
kinase inhibitors [BTKi] unless medically contraindicated), and had Eastern Cooperative Oncology Group performance status of ≤1. After lymphodepleting chemotherapy, patients received liso-cel infusion at either dose level 1 (50 × 10⁶ total CAR+ T cells) or dose level 2 (100 × 10⁶ total CAR+ T cells). Patients were monitored for dose-limiting toxicities (DLTs). Response was assessed by International Workshop on CLL 2008 criteria. MRD was assessed by flow cytometry in blood (sensitivity, 10⁻⁴) and by Next-Generation Sequencing in bone marrow (BM; sensitivity, 10⁻⁶).

**Results:** At the data cutoff, 16 patients had received liso-cel; 6 at dose level 1 and 10 at dose level 2. 75% of the patients had high-risk features (TP53 mutation, complex karyotype, del17p), all had received prior ibrutinib, and 50% had received prior venetoclax. Median number of prior lines of therapy was 4.5 (range, 2–11). There was 1 DLT of grade 4 hypertension, which occurred at at dose level 2. The most common grade 3/4 treatment-emergent adverse events were cytopenias (thrombocytopenia, 75%; anemia, 69%; neutropenia, 63%; leukopenia, 56%). One patient had grade 3 cytokine release syndrome (CRS); 3 patients had grade 3 neurological events (NE). Best overall response rate (ORR) in 15 evaluable patients was 87% (13/15). Seven patients (47%) achieved complete remission with/without complete blood count recovery (CR/CRi). ORR at 6 mo was 83% (5/6). Undetectable MRD in blood was achieved in 10/15 patients (67%) by day 30, and in 7/8 patients (88%) in BM. MRD-negative CRs were seen in patients who had failed both BTKi and venetoclax. Median time to peak blood CAR-T cell level was 16 days (range 4–30).

**Conclusions:** In this study of heavily pretreated patients with standard- and high-risk CLL/SLL and previous ibrutinib treatment, liso-cel-related toxicities of CRS and NE were manageable and grade 3 or higher events were limited. Patients rapidly achieved CR/CRi and undetectable MRD. The phase 2 component of the study is currently enrolling patients for treatment at dose level 2. Additional follow-up will be presented.

**Keywords:** CD19; chronic lymphocytic leukemia (CLL); T-cells.

**Disclosures:** 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. Dorritie, K: Research Funding: Juno, Kite Pharma; Other Remuneration: Travel, Accommodations, Expenses: Kite Pharma. Soumerai, J: Consultant Advisory Role: Verastem; Research Funding: Dr. Soumerai's institution received research funding from: TG Therapeutics, Genentech/Roche, BeiGene. Stephens, D: Honoraria: Genentech; Research Funding: Gilead, Karyopharm, Acerta. Dubovsky, J: Employment Leadership Position: Juno Therapeutics, a Celgene Company; Stock Ownership: Juno Therapeutics, a Celgene Company; Research Funding: Celgene; Other Remuneration: Patents, Royalties, Other Intellectual Property: Celgene; Travel, Accommodations, Expenses: Celgene. Gillenwater, H: Employment Leadership Position: Juno Therapeutics, a Celgene Company; Stock Ownership: Juno Therapeutics, a Celgene Company. Gong, L: Employment Leadership Position: Juno Therapeutics, a Celgene Company; Stock Ownership: Juno Therapeutics, a Celgene Company. Thorpe, J: Employment

Leadership Position: Juno Therapeutics, a Celgene Company; Stock Ownership: Juno Therapeutics, a Celgene Company. Yang, L: Employment Leadership Position: Juno Therapeutics, a Celgene Company; Stock Ownership: Juno Therapeutics, a Celgene Company. Wierda, W: Consultant Advisory Role: Genzyme Corporation; Honoraria: Sanofi; Research Funding: Dr. Wierda's institution received research funding from GSK/Novartis, Abbvie, Genentech, Karyopharm, Pharmacyclics LLC, Acerta Pharma, Gilead Sciences, Juno Therapeutics, KITE Pharma, Sunesis, Miragen, Oncternal Therapeutics, Inc., Cyclacel, Loxo Oncology, Inc., Janssen, Xencor.

066

THE BRAF INHIBITOR VEMURAFENIB PLUS RITUXIMAB PRODUCES A HIGH RATE OF DEEP AND DURABLE RESPONSES IN RELAPSED/REFRACTORY HAIRY CELL LEUKEMIA: UPDATED RESULTS OF A PHASE-2 TRIAL

E. Tiacci¹ | L. De Carolis¹ | E. Simonetti¹ | F. Zaja² |

M. Capponi¹ | A. Ambrosetti³ | E. Lucia⁴ |

A. Antolino⁵ | A. Pulsoni⁶ | S. Ferrari⁷ |

P. Zinzani⁸ | L. Rigacci⁹ | G. Gaidano¹⁰ |

R. Della Seta¹¹ | N. Frattarelli¹² | P. Falcucci¹³ |

G. Visani¹⁴ | R. Foà⁶ | B. Falini¹

¹Institute of Hematology and Center for Hemato-Oncology Research, University and Hospital of Perugia, Perugia, Italy; ²Hematology Unit, Azienda Sanitaria Universitaria Integrata-Ospedale Maggiore, Trieste, Italy; ³Department of Medicine, Section of Hematology, Verona, Italy; ⁴Hematology Unit, Ospedale di Cosenza, Cosenza, Italy; ⁵Hematology Unit, Department of Transfusional Medicine - SIMMT, Maria Paternò-Arezzo Hospital, Ragusa, Italy; ⁶Hematology Unit, Department of Translational and Precision Medicine, "Sapienza" University of Rome, Roma, Italy; ⁷Department of Hematology, Spedali Civili di Brescia, Brescia, Italy; ⁸Institute of Hematology, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy; ⁹Hematology and Stem Cell Transplant Unit, AO San Camillo Forlanini, Roma, Italy; ¹⁰Department of Translational Medicine, Division of Hematology, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; ¹¹Hematology Unit, Ospedale di Carrara, Carrara, Italy; ¹²Hematology Unit, Ospedale di Frosinone, Frosinone, Italy; ¹³Hematology Unit, Ospedale di Ronciglione, Viterbo, Italy; ¹⁴Hematology Unit, Ospedale di Pesaro, Pesaro, Italy

**Introduction:** Up to 50% of hairy cell leukemia (HCL) patients relapse after purine analogs. We identified the BRAF-V600E kinase mutation as the genetic cause of HCL (Tiacci et al., NEJM 2011). We documented, in 26 relapsed/refractory patients treated with the oral BRAF inhibitor vemurafenib for a median of 16 weeks, 96% of overall responses (including 35% complete remissions - CR), obtained after a median of 8 weeks (Tiacci et al., NEJM 2015). However, residual bone marrow (BM) HCL cells persisted even in CR cases (5-10% cells) and the median relapse-free survival in all responding patients was 9 months.
<figure><img src="image_43.png" /><figcaption>FIG. 1A</figcaption></figure>

B

<figure><img src="image_44.png" /></figure>

C

<figure><img src="image_45.png" /></figure>

Since HCL strongly expresses CD20, rituximab could improve the effi-
cacy of BRAF inhibition by targeting leukemic cells resistant to
vemurafenib.

**Methods:** In this academic, phase-2, single-center trial (EudraCT 2014-003046-27), relapsed/refractory HCL patients received vemurafenib (960 mg b.i.d.) for 8 weeks and concomitant rituximab (375 mg/m² i.v.) every 2 weeks. Rituximab was then given as consolidation 4 times every 2 weeks post-vemurafenib.

**Results:** We enrolled 31 patients (median age: 59 years) with a median of 3 previous therapies. Toxicity was mostly of grade 1-2, without myelosuppression, and overlapped that of either drug when used alone.

Strikingly, a CR was achieved by 26/27 (96%) evaluable cases, includ-
ing 2 with delayed platelet recovery and 2 with incomplete resolution
of splenomegaly who nonetheless remain in otherwise CR at 22.5 and
25 months post-treatment. The 26 CR cases, all previously treated
with purine analogs, also included some patients previously refractory
to rituximab (n=5) and/or who had relapsed after a prior BRAF inhibi-
tor (n=7; 5 obtained a PR and 2 a CR after the BRAF inhibitor). Nota-
bly, a CR was obtained after just 4 weeks of vemurafenib and two
doses of rituximab in 15/24 evaluable patients (63%). Measurable
residual disease (MRD) by allele-specific PCR (sensitivity: 0.05%
BRAF-V600E alleles) was absent in the BM of 17/26 (65%) patients;
in 8/17 cases (47%), MRD clearing was obtained before rituximab
consolidation.

Progression-free survival (PFS) in 29 evaluable cases was 83% at a
median of 29.5 months (range: 2-45) (Fig. 1A). Progressions (n=5)
always occurred in MRD-positive cases, including 3/5 whose immedi-
ate prior treatment was a BRAF inhibitor (leading to PR in all 3 cases).

Indeed, PFS was significantly longer in the 17 MRD-negative CR cases (100% at a median of 30.5 months) than in the 9 MRD-positive CR cases (44% at a median of 24.5 months) (p=0.001; Fig. 1B). In subsequent BM evaluations, 16/17 (94%) CR patients maintained a MRD-negative status at a median of 22.5 months (range 12.5-36.5) (Fig. 1C).

**Conclusions:** Vemurafenib plus rituximab is a brief, safe and non-myelotoxic regimen inducing MRD-negative durable responses in most relapsed/refractory HCL patients. Randomized testing against the chemotherapy-based standard of care in the frontline setting is warranted.

**Keywords:** BRAF; hairy cell leukemia; minimal residual disease (MRD).

**Disclosures:** Tiacci, E: Research Funding: Roche.

FOCUS ON... SESSION: CHEMOTHERAPY-FREE STRATEGIES

067

PREDICTIVE VALUE OF POD24
VALIDATION IN FOLLICULAR LYMPHOMA
PATIENTS INITIALLY TREATED WITH
CHEMOTHERAPY-FREE REGIMENS IN A
POOLED ANALYSIS OF THREE
RANDOMIZED TRIALS OF THE SWISS
GROUP FOR CLINICAL CANCER
RESEARCH (SAKK).
A. Moccia¹ | S. Schär² | S. Hayoz² | M. Pirosa¹ |

C. Taverna³ | U. Novak⁴ | E. Kimby⁵ |

M. Ghielmini¹ | E. Zucca⁶

¹Department of Medical Oncology, Oncology Institute of Southern Switzerland and SAKK Coordinating Center, Bellinzona, Switzerland;

²Coordinating Center, SAKK, Bern, Switzerland; ³Division of Medical Oncology, Kantonsspital Münsterlingen and SAKK Coordinating Center, Münsterlingen, Switzerland; ⁴Department of Medical Oncology, Inselspital

/ Bern University Hospital and SAKK Coordinating Center, Bern, Switzerland; ⁵Division Unit of Hematology, Karolinska Institutet, Department of Medicine at Huddinge, Stockholm, Sweden; ⁶Department of Medical Oncology, Oncology Institute of Southern Switzerland, SAKK Coordinating Center and Bern University Hospital, Bellinzona, Switzerland

**Introduction:** It is well established that follicular lymphoma (FL) patients who have progression of disease within 24 months (POD24) from frontline immunochemotherapy have worse overall survival (OS) and thus constitute a high-risk population (Casulo et al. J Clin Oncol 33:2516-2522, 2015; Jurinovic et al., Blood 128:1112-1120, 2016). Thus far, however only one report from the Nordic Lymphoma Group (NLG) has shown, without an independent validation cohort, that this endpoint can be useful also to predict the long term survival of patients receiving systemic treatment with chemotherapy-free regimens (Lockmer et al. J Clin Oncol 36:3315-3323, 2018).

In the present study, we sought to confirm that early progression after first-line treatment is affecting OS also in patients initially treated with immunotherapy only.

**Methods:** In order to determine whether POD24 is associated with inferior OS, we analyzed a pooled dataset of three randomized trials

including FL patients with advanced and symptomatic disease con-
ducted between 1998 and 2016 by the Swiss Group for Clinical Can-
cer Research (SAKK), namely the SAKK35/98 and 35/03 studies,
which evaluated different durations of rituximab therapy, and the
SAKK 35/10 study, which compared rituximab monotherapy versus
rituximab plus lenalidomide in the front-line therapy. OS was calcu-
lated from disease progression in patients with POD24 and from
24 months after the start of treatment in the reference group of those
without POD24.

**Results:** A total number of 521 FL patients were enrolled in the three SAKK studies, 333 of them had no prior systemic treatment (64 in the SAKK 35/98, 115 in the SAKK 35/03 and all 154 in the SAKK 35/10 studies, respectively) and received front-line therapy with Rituximab alone (n=256) or in combination with lenalidomide (n=77). We excluded 1 patient from the analysis who died without progression within 24 months and 14 other patients who were lost to follow-up without progression within 24 months from treatment start. Hence, the final cohort of this study comprised 318 evaluable patients. POD24 was observed in 85 of 318 (27% [95%-CI: 22, 32]) patients initially treated without chemotherapy. Patients with POD24 showed a trend towards more advanced disease at presentation than the reference group without POD 24: stage IV (55% vs 43%), B-symptoms (26% vs 17%), bulky disease (44% vs 35%), but the differences did not reach the statistical significance. In patients with early POD, median age was 59 years, 42 patients were male (49%) and 43 female (51%), and 20 had elevated LDH (24%). In the reference group of patients without POD24, median age was also 59 years, 97 patients were male (42%) and 136 female (58%), and 48 had elevated LDH (21%). Figure 1 shows the Kaplan-Meier estimates of survival according to POD24. Median survival was not reached in either of the treatment groups. The patients experiencing POD24 had 5- and 10-year OS rates of 69% and 59%, respectively, while in the reference group the 5- and 10-year OS rates were 92% and 77% (HR = 3.12 [1.73, 5.65]; log-rank P < 0.0001). In a multivariable Cox model POD24 predicted poor survival (P=0.0355) across all studies irrespectively of LDH value, presence of B-symptoms or advanced stage. FLIPI score and beta2-microglobulin values were available only in the SAKK 35/10 study and could not be included in the model.

**Conclusions:** We provided the first validation in an independent cohort of the recent observation that POD24 retains its prognostic validity in patients treated without chemotherapy and may represent a useful endpoint for the future evaluation of novel chemotherapy-free strategies.

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

**Disclosures:** Moccia, A: Consultant Advisory Role: Takeda, Roche, Janssen. Taverna, C: Consultant Advisory Role: Takeda, Celgene, Janssen, AMGEN; Research Funding: Celgene. Kimby, E: Consultant Advisory Role: Roche, Celgene; Honoraria: Roche, Celgene; Research Funding: Roche.

Kaplan-Meier survival estimates

<figure><img src="image_46.png" /></figure>
# 068 EFFICACY AND SAFETY OF OBINUTUZUMAB + LENALIDOMIDE + ATEZOLIZUMAB IN PATIENTS WITH RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA: PRIMARY ANALYSIS OF A PHASE 1B/2 TRIAL

F. Morschhauser¹ | N. Ghosh² | I. Lossos³ |
M.L. Palomba⁴ | A. Mehta⁵ | O. Casasnovas⁶ |
D. Stevens⁷ | S. Chitra⁸ | A. Knapp⁸ | T. Nielsen⁸ |
M. Oestergaard⁹ | M. Wenger⁸ | G. Salles¹⁰

¹Institute of Hematology-Transfusion, Centre Hospitalier Régional Universitaire de Lille, Lille, France; ²Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC, United States; ³Division of Hematology, Department of Medicine, University of Miami, Miami, FL, United States; ⁴Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States; ⁵Division of Hematology and Oncology, University of Alabama School of Medicine, Birmingham, Alabama, United States; ⁶Service d'Hématologie clinique, CHU Dijon Bourgogne - Hôpital François Mitterrand, Dijon, France; ⁷Norton Cancer Institute, Norton Healthcare, Louisville, KY, United States; ⁸Product Development Oncology, F. Hoffmann-La Roche Ltd, Basel, Switzerland; ⁹Oncology Biomarker Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland; ¹⁰Haematology Department, Université Claude Bernard de Lyon, Lyon University Hospital, Villeurbanne, France

**Introduction:** In the phase 2 GALEN study, induction and maintenance with obinutuzumab (GA101; G) plus lenalidomide (LEN) demonstrated favourable activity and tolerable safety in patients (pts) with

relapsed/refractory (R/R) follicular lymphoma (FL). G plus atezolizumab (atezo) has also demonstrated activity in this setting. We present primary efficacy and safety data from a phase 1b/2 study (BO29562; NCT02631577) evaluating induction and maintenance with G-LEN-atezo in pts with R/R FL.

**Methods:** BO29562 is an open-label, multicentre study. All pts had received ≥1 prior anti-CD20-containing chemoimmunotherapy regimen. An initial 3+3 dose-escalation phase to define the phase 2 LEN dose was followed by an expansion phase. Pts received induction with six 28-day cycles (C) of: G 1000 mg IV on day (D) 1, 8, and 15 of C1 and D1 of C2-6; LEN 15/20 mg (dose escalation) or 20 mg (expansion) PO on D1-21 of C1-6; and atezo 840 mg IV on D1 and 15 of C2-6. Responders received maintenance for 24 months (G 1000 mg D1 every 2 months; LEN 10 mg D1-21 months 1-12; atezo 840 mg D1-2 every month). The primary endpoint was complete response (CR) by PET-CT assessed by Independent Review Committee (IRC; modified Lugano 2014 criteria) at end of induction (EOI). Minimal residual disease (MRD) was evaluated at EOI (10⁻⁵ sensitivity) using the Adaptive ImmunoSEQ® NGS platform (v2).

**Results:** At the time of the primary analysis (23 October 2018), 38 pts (LEN 15 mg, n=4; 20 mg, n=34) had enrolled and entered induction. Baseline characteristics were: median age, 61.5 years; male, 50.0%; Ann Arbor Stage III-IV, 78.9%; FLIPI high-risk (≥3), 26.3%; bulky disease (≥7cm), 15.8%; ≥2 prior lines of therapy, 47.4%; refractory to last line of prior regimen, 44.7%; and refractory to last line of anti-CD20 treatment, 28.9%. In the primary efficacy population (LEN 20 mg, n=32), CR rate at EOI was 71.9% (double-refractory pts [n=12], 66.7%). Most pts who received maintenance had durable clinical responses (median duration of response not yet reached [n=32]; **Figure**). At baseline, 22/28 MRD-evaluable pts had a circulating clone detected. Of these, 21 were MRD-evaluable at

<figure><img src="image_47.png" /><figcaption>**Figure.** Duration of response* by investigator assessment
(n=32; median observation time 14.5 months [range 0.6-32.1 months])</figcaption></figure>

*Defined as the time from first PR or CR based on PET/CT to PD or death from any cause
CT, computerized tomography; CR, complete response; PET, positron emission tomography; PD, progressive disease; PR, partial response
EOI; 16 (76.2%) were MRD-negative (CR, n=15; partial response, n=1). The proportion of pts receiving >90% dose intensity during induction (n=34) and maintenance (n=27), respectively, was: G, 91.2% and 100%; LEN, 76.5% and 70.4%; and atezo, 71.9% and 85.2%. All treated pts had ≥1 adverse event (AE), 28 (73.6%) pts had a grade 3-4 AE, 12 (31.6%) had a serious AE, and 9 (23.7%) had an AE that led to discontinuation of any drug (induction, n=6; maintenance, n=3).

**Conclusions:** CR rate at EOI for the chemo-free regimen G-LEN-atezo is comparable with currently available treatment options in this indication and higher than with historical controls, with durable activity. The overall safety and tolerability profile is consistent with the known profiles for the individual drugs and for G-LEN.

**Acknowledgment:** Third-party medical writing assistance, under the direction of Franck Morschhauser, was provided by Zoe Toland and Helen Cathro of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

**Keywords:** follicular lymphoma (FL); lenalidomide; obinutuzumab.

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

**Ghosh, N:** Consultant Advisory Role: Seattle Genetics, Janssen, PCYC, Gilead/Kite, Spectrum, BMS, AbbVie, TG Therapeutics, Celgene/Juno; Research Funding: Genentech/Roche, Janssen, PCYC, TG Therapeutics, Seattle Genetics, Juno Therapeutics. **Lossos, I:** Consultant Advisory Role: Seattle Genetics, Janssen Scientific. **Palomba, M:** Consultant Advisory Role: Merck, Pharmacyclics; Stock Ownership: Seres; Honoraria: Flagship Ventures, Novartis, Elovo, Seres, Jazz Pharmaceuticals, Therakos, Amgen, Merck; Other Remuneration: Seres, Juno. **Mehta, A:** Consultant Advisory Role: Spectrum, Celgene, Kite, BMS; Research Funding: Incyte, Roche, Merck, BMS, Epizyme, Seattle Genetics, Kite, Forty Seven Inc, Takeda, Rhizen, Juno; Other Remuneration: Speakers' Bureau: Astra Zeneca, Kite, Spectrum, Kyowa Kirin, Seattle Genetics. **Casasnovas, O:** Consultant Advisory Role: Roche, Takeda, BMS, Merck, Gilead, Janssen; Honoraria: Roche, Takeda, BMS, Merck, Gilead, Janssen; Research Funding: Roche, Takeda, Gilead, Abbvie; Other Remuneration: Roche, Takeda, Janssen. **Stevens, D:** Employment Leadership Position: Norton Healthcare. **Chitra, S:** Employment Leadership Position: Genentech.

**Knapp, A:** Employment Leadership Position: F. Hoffman-La Roche Ltd. Nielsen, T: Employment Leadership Position: Roche; Stock Ownership: Roche. **Oestergaard, M:** Employment Leadership Position: Hoffmann-La Roche, Novo Nordisk. **Wenger, M:** Employment Leadership Position: F. Hoffmann-La Roche Ltd.; Stock Ownership: F. Hoffmann-La Roche Ltd. **Salles, G:** Consultant Advisory Role: Abbvie, Celgene, Gilead, Epizyme, Janssen, Karyopharm, Kite, Merck, Morphosys, Novartis, Roche, Servier, Takeda; Honoraria: Abbvie, Amgen, BMS, Celgene, Gilead, Epizyme, Janssen, Karyopharm, Kite, Merck, Morphosys, Novartis, Roche, Servier, Takeda.

069
AUGMENT PHASE III STUDY:
LENALIDOMIDE/RITUXIMAB (R²)
IMPROVED EFFICACY OVER

RITUXIMAB/PLACEBO IN
RELAPSED/REFRACTORY FOLLICULAR
PATIENTS IRRESPECTIVE OF POD24
STATUS

**J. Leonard¹** | **M. Trneny²** | **K. Izutsu³** | **N. Fowler⁴** |
**X. Hong⁵** | **H. Zhang⁶** | **F. Offner⁷** | **A. Scheliga⁸** |
**G. Nowakowski⁹** | **A. Pinto¹⁰** | **F. Re¹¹** |
**L. Fogliatto¹²** | **P. Scheinberg¹³** | **I. Flinn¹⁴** |
**C. Moreira¹⁵** | **M. Czuczman¹⁶** | **S. Kalambakas¹⁷** |
**P. Fustier¹⁸** | **C. Wu¹⁹** | **J. Gribben²⁰**

¹Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, United States; ²General Hospital, Charles University, Prague, Czech Republic; ³Hematology, National Cancer Center Hospital, Tokyo, Japan; ⁴Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States; ⁵Hematology, Fudan University Shanghai Cancer Center, Shanghai, China; ⁶Hematology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; ⁷Hematology, UZ Gent, Gent, Belgium; ⁸Hematology, INCA Instituto Nacional De Cáncer, Rio de Janeiro, Brazil; ⁹Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, United States; ¹⁰Hematology, Istituto Nazionale Tumori, Fondazione 'G. Pascale', IRCCS, Naples, Italy;
¹¹Hematology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy;
¹²Hematology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil;
¹³Hematology, Hospital A Beneficência Portuguesa de São Paulo, São Paulo, Brazil; ¹⁴Hematology, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, United States; ¹⁵Hematology, Instituto Português de Oncologia Do Porto Francisco Gentil Epe, Porto, Portugal; ¹⁶Global Clinical R&D Hematology/Oncology, Celgene Corporation, Summit, United States; ¹⁷Global Medical Affairs, Celgene Corporation, Summit, United States; ¹⁸Global Medical Affairs, Celgene International Sarl, Boudry, Switzerland; ¹⁹BioStatistics, Celgene Corporation, Summit, United States; ²⁰Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom

**Introduction:** Relapse within 2 years of initial chemoimmunotherapy (ie, POD24) in follicular lymphoma (FL) patients has been associated with less favorable prognosis and survival (Casulo et al. Blood. 2019). The objective of this analysis was to examine the potential impact of POD24 in FL patients receiving lenalidomide/rituximab (R²) vs rituximab/placebo (R/placebo) from the phase III AUGMENT study.

**Methods:** Patients with FL grade 1-3a were relapsed/refractory (R/R) after ≥ 1 prior systemic therapy, but were not refractory to rituximab. Treatment arms included R² (lenalidomide PO 20 mg/day [d], d1-21/28 X12 cycles plus rituximab IV 375 mg/m² given cycle 1, d1, 8, 15, 22 and d1, cycles 2-5) and R/placebo (treated on the same schedule). Progression-free survival (PFS) was the primary endpoint, evaluated by 2007 IWG (without PET). For the AUGMENT study, POD24 was defined post-hoc as progression or relapse within 2 years of initial antilymphoma treatment, which included immuno- and/or chemotherapy.
<table><caption>TABLE 1 Efficacy of R² vs R/placebo by POD24 Status in Patients With R/R Follicular Lymphoma</caption><thead><tr><th rowspan="2"></th><th colspan="3">R<sup>2</sup></th><th colspan="3">R/Placebo</th></tr><tr><th>All FL Patients<br>(n = 147)</th><th>POD24<br>(n = 56)</th><th>No POD24<br>(n = 89)</th><th>All FL Patients<br>(n = 148)</th><th>POD24<br>(n = 57)</th><th>No POD24<br>(n = 89)</th></tr></thead><tbody><tr><td>Median PFS, mo<br>(95% CI)</td><td>39.4<br>(23.1-NR)</td><td>30.4<br>(16.8-NR)</td><td>39.4<br>(22.9-NR)</td><td>13.9<br>(11.2-16.0)</td><td>13.8<br>(6.7-16.9)</td><td>13.9<br>(11.2-16.6)</td></tr><tr><td>ORR, %</td><td>80</td><td>80</td><td>80</td><td>55</td><td>51</td><td>58</td></tr><tr><td>CR, %</td><td>35</td><td>30</td><td>37</td><td>20</td><td>18</td><td>21</td></tr></tbody></table>

**Results:** As of 22June2018, 295 FL grade 1-3a patients had been randomized 1:1 to R² (n=147) and R/placebo (n=148). Median age was 62 years (range, 26-88), 74% of patients had Ann Arbor stage III/IV disease, 34% high FLIPI score, 84% had received prior rituximab, and 53% prior antilymphoma treatment within 2 years of enrollment. Of these FL patients, 56 (38%) R² and 57 (39%) R/placebo patients were identified as POD24 (ie, relapsing/progressing within 2 years of initial treatment). For all FL patients and subgroups based on POD24 status, median PFS was improved in the R² vs R/placebo arm (Table). For patients with POD24, HR was 0.41 (95% CI, 0.24-0.68) and for patients with no POD24, HR was 0.43 (95% CI, 0.28-0.65), both groups favoring the R² arm. Best overall response rates (ORR) and complete responses (CR) were similar within each arm in all FL patients and with or without POD24 (Table). Treatment with R² (vs R/placebo) reduced the risk of relapse/progression by 59% in patients with POD24, and improved both ORR and CR. Similar outcomes were observed for patients who relapsed within 2 years from diagnosis (data not shown).

**Conclusions:** R² demonstrated superior efficacy over R/placebo in patients with FL grade 1-3a, including those with POD24, patients who have historically been associated with worse outcomes.

**Keywords:** follicular lymphoma (FL); lenalidomide; rituximab.

**Disclosures:** Leonard, J: Consultant Advisory Role: Celgene, Biotest, Sunesis Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Epizyme, Pfizer, Bayer, Genentech/Roche, ADC Therapeutics, MEI Pharma, AstraZeneca, Novartis, Merck, Sutter Medical Group, Morphosys, Beigene, Nordic Nanovector, Bristol-Myers Squibb, United Therapeutics, Karyopharm Therapeutics, Sand; Research Funding: (all institutional): Celgene, Alliance for Clinical Trials in Oncology, Takeda, Pfizer, National Cancer Institute; Other Remuneration: Travel, Accommodation, Expenses: BeiGene. Trneny, M: Consultant Advisory Role: Takeda, BMS, Incyte, Abbvie, Amgen, Roche, Gilead, Janssen, Celgene, MorphoSys; Honoraria: Janssen, Gilead, Takesa, BMS, Amgen, Abbvie, Roche, MorphoSys, Incyte; Other Remuneration: Travel & Expenses: Gilead, Takeda, BMS, Roche, Janssen, Abbvie. Izutsu, K: Consultant Advisory Role: Eisai, MSD, Takeda, Ono, AstraZeneca, Abbvie, Bayer, Novartis, Chugai, Daiichi Sankyo, Otsuka; Honoraria: Kyowa Hakko Kirin, Eisai, MSD, Takeda, Janssen, Dainippon Sumitomo, Mundipharma, Nihon Mediphysics, Abbvie, Chugai, Zenyaku, Bristol Myers Squib, Astellas; Research Funding: HUYA bioscience, MSD, Astellas Amgen, AstraZeneca, Abbvie, Eisai, Ono, Sanofi, ARIAD, Symbio, Zenyaku, Celgene, Solaisia, Takeda, Daiichi Sankyo, Chugai, Novarsis, Bayer, Pfizer.

**Fowler, N:** Consultant Advisory Role: Roche/Genentech, TG

Therapeutics, Verastem, Bayer, Celgene, Novartis; Research Funding: Roche, Celgene, Gilead Sciences, TG Therapeutics, Novartis, Abbvie, BeiGene. Nowakowski, G: Consultant Advisory Role: (author's institution for all): Celgene, Morphosys, Genentech; Research Funding: (author's institution for all) Celgene, NanoString Technology, MorphoSys. Pinto, A: Consultant Advisory Role: Servier, Roche, MDS Pharma, BMS; Honoraria: Roche, MDS Pharma, Celgene, Servier, BMS; Other Remuneration: Speakers' Bureau: Roche; Patents, Royalties or Intellectual Property: EDO-Mundipharma; Travel: Roche, Takeda. Scheinberg, P: Consultant Advisory Role: Novartis, Abbvie, Alexion Pharmaceuticals, Janssen, Celgene; Honoraria: Novartis; Other Remuneration: Speakers' Bureau: Novartis, Pfizer. Flinn, I: Consultant Advisory Role: Abbvie, Seattle Genetics, TG Therapeutics, Verastem; Research Funding: (All institutional): Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmaceuticals, Portola Pharmaceuticals, Roche, TG Therapeutics, Trillium Therapeutics, Abbvie, ArQuile, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, Unum Therapeutics, MorphoSys AG, Abbvie. Czuczman, M: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Kalambakas, S: Employment Leadership Position: Celgene; Stock Ownership: Celgene, Novartis. Fustier, P: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Wu, C: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Gribben, J: Consultant Advisory Role: Abbvie, Acerta Pharma/Astra Zeneca, Celgene, Janssen; Honoraria: Abbvie, Acerta Pharma/Astra Zeneca, Celgene, Janssen, Gilead Sciences, Roche/Genentech, TG Therapeutics; Research Funding: Acerta Pharma/Astra Zeneca, Janssen, Celgene.

070

INTERIM ANALYSIS OF PHASE IIIB
MAGNIFY STUDY OF INDUCTION R²
FOLLOWED BY MAINTENANCE IN
PATIENTS WITH RELAPSED/REFRACTORY
INDOLENT NON-HODGKIN LYMPHOMA

J. Sharman¹ | M. Coleman² | A. Yacoub³ |

J. Melear⁴ | S. Fanning⁵ | K. Kolibaba⁶ |

F. Lansigan⁷ | C. Reynolds⁸ | K. Foon⁹ | J. Li¹⁰ |

M. Llorente⁹ | M. Rummel¹¹ | D. Andorsky¹²
<table><caption>TABLE 1 Efficacy for induction R² in R/R iNHL</caption><thead><tr><th></th><th>ORR, %</th><th>CR, %</th><th>Median TTR, mo (range)</th><th>Median DOR, mo (95% CI)*</th><th>Median PFS, mo (95% CI)*</th></tr></thead><tbody><tr><td>Overall</td><td>73</td><td>45</td><td>2.7 (1.6-12.0)</td><td>36.8 (35.8-NR)</td><td>36.0 (26.5-NR)</td></tr><tr><td>By histology</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>FL gr 1-3a</td><td>74</td><td>46</td><td>2.8 (1.6-12.0)</td><td>NR (27.7-NR)</td><td>30.2 (23.0-NR)</td></tr><tr><td>MZL</td><td>65</td><td>38</td><td>2.7 (1.9-11.1)</td><td>35.8 (NR-NR)</td><td>38.4 (26.5-38.4)</td></tr><tr><td>Rituximab-refractory status</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>63</td><td>40</td><td>2.8 (1.6-12.0)</td><td>35.8 (19.2-NR)</td><td>18.1 (15.5-26.5)</td></tr><tr><td>No</td><td>78</td><td>47</td><td>2.7 (1.6-11.6)</td><td>NR (36.8-NR)</td><td>NR (36.0-NR)</td></tr></tbody></table>

¹Willamette Valley Cancer Institute and Research Center, US Oncology Research, Eugene, United States; ²Clinical Research Alliance Inc., Weill Cornell Medicine, New York, United States; ³Hematology, University of Kansas Cancer Center, Westwood, United States; ⁴Texas Oncology - Austin, US Oncology Research, Austin, United States; ⁵Greenville Health System, US Oncology Research, Greenville, United States; ⁶Compass Oncology, US Oncology Research, Vancouver, United States; ⁷Hematology, Dartmouth-Hitchcock Medical Center, Lebanon, United States; ⁸Hematology, IHA Hematology Oncology Consultants - Ann Arbor, Ypsilanti, United States; ⁹Global Medical Affairs, Celgene Corporation, Summit, United States; ¹⁰BioStatistics, Celgene Corporation, Summit, United States; ¹¹Hematology, Justus-Liebig Universität, Giessen, Germany; ¹²Rocky Mountain Cancer Centers, US Oncology Research, Boulder, United States

**Introduction:** The lack of standard treatment approaches for relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL), along with a less than 1 y median progression-free survival (PFS) with PI3K inhibitors in this setting, indicate an unmet need in these patients. The immunomodulatory agent lenalidomide enhances the activity of rituximab when used in combination (R²). Recent phase III results reported from the AUGMENT study show a median PFS of 39.4 mo in patients with R/R iNHL patients (Leonard. ASH 2018:445).

**Methods:** MAGNIFY is a multicenter, non-registrational phase IIb trial in patients with R/R follicular lymphoma (FL) grade 1-3a and marginal zone lymphoma (MZL), and was designed to determine the optimal duration of lenalidomide (NCT01996865). R² treatment includes lenalidomide 20 mg/d, d1-21/28 plus rituximab 375 mg/m²/wk cycle 1 and q8wk cycles 3+ given for 12 cycles. This induction phase is followed by 1:1 randomization to continued R² vs rituximab maintenance in patients with stable disease or better. These analyses examine the interim primary endpoint of overall response rate (ORR; 1999 IWG) for induction R². Efficacy-evaluable patients include those receiving ≥ 1 treatment with available baseline and post-baseline assessments.

**Results:** 370 enrolled patients included 80% FL grade 1-3a and 20% MZL with a median age of 66 y, 83% stage III/IV disease, and a median of 2 prior therapies (95% prior rituximab-containing). At a median 16.7 mo follow-up, the ORR was 73% and complete response (CR) was 45% (Table). ORR and CR showed similar efficacy results by histology. The overall median time to response (TTR) was 2.7 mo,

median duration of response (DOR) was 36.8 mo, and median progression-free survival (PFS) was 36.0 mo. Based on rituximab-refractory status at baseline, patients who were rituximab-refractory and non-refractory had a respective ORR of 63% and 78%, CR of 40% and 47%, and median PFS 18.1 mo vs not reached. Of 370 randomized patients, 142 (38%) have entered the maintenance phase. The most common all-grade adverse events were 48% fatigue, 40% neutropenia, 35% diarrhea, 30% nausea, and 29% constipation. The most common grade 3/4 adverse event was neutropenia at 34%, whereas all other grade 3/4 adverse events were < 6%.

**Conclusions:** R² therapy is an active treatment regimen in patients with R/R FL grade 1-3a and MZL, including patients who were refractory to rituximab, and with a tolerable safety profile.

**Keywords:** indolent lymphoma; lenalidomide; rituximab.

**Disclosures:** Sharman, J: Employment Leadership Position: US Oncology; Consultant Advisory Role: Pharmacyclics, Celgene, TG Therapeutics, Genentech, Abbvie, Acerta Pharma/Astra Zeneca; Research Funding: (all institutional) Pharmacyclics, Genentech, Celgene, Acerta Pharma, Gilead Sciences, Seattle Genetics, TG Therapeutics, Merck, Takeda; Other Remuneration: Expert Testimony: Gilead Sciences. Coleman, M: Consultant Advisory Role: Medaptive Health; Stock Ownership: Medaptive Health; Research Funding: Medaptive Health; Other Remuneration: Speakers' Bureau: Medaptive Health. Yacoub, A: Consultant Advisory Role: Medaptive Health; Other Remuneration: Speakers' Bureau: Medaptive Health. Melear, J: Employment Leadership Position: Medaptive Health. Fanning, S: Consultant Advisory Role: Medaptive Health; Stock Ownership: Medaptive Health; Other Remuneration: Speakers' Bureau: Medaptive Health. Kolibaba, K: Employment Leadership Position: Compass Oncology; Consultant Advisory Role: Gilead Sciences; Honoraria: TG Therapeutics; Research Funding: (all institutional) Acerta, Celgene, Cell Therapeutics, Genentech/Roche, Gilead Sciences, Janssen, Pharmacyclics, Novartis, Seattle Genetics, TG Therapeutics; Other Remuneration: Travel: TG Therapeutics. Lansigan, F: Consultant Advisory Role: Spectrum; Research Funding: Spectrum. Foon, K: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Li, J: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Llorente, M: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Rummel, M: Consultant Advisory Role: Medadaptive; Honoraria: Medadaptive; Research Funding: Medadaptive; Other Remuneration: Travel: Medadaptive. Andorsky, D: Consultant Advisory Role: Medadaptive; Research Funding: Medadaptive.

<footnote>*If patients were already in maintenance at data cutoff, then response assessments also contributed to DOR and PFS.</footnote>
071
RITUXIMAB PLUS LENALIDOMIDE IS AS EFFECTIVE AS IMMUNOCHEMOTHERAPY IN THE ERADICATION OF MOLECULAR DISEASE IN UNTREATED FOLLICULAR LYMPHOMA: RELEVANCE LYSA ANCILLARY STUDY

M.H. Delfau-Larue¹ | M.L. Boulland² | P. Feugier³ |
H. Maisonneuve⁴ | O. Casasnovas⁵ | C. Haioun⁶ |
G.M. Pica⁷ | T. Lamy de la Chapelle⁸ | L. Ysebaert⁹ |
H. Tilly¹⁰ | J.C. Eisenmann¹¹ | S. Le Gouil¹² |
V. Ribrag¹³ | H. Jardel¹⁴ | S. Glaisner¹⁵ |
G. Cartron¹⁶ | G. Salles¹⁷ | L. Xerri¹⁸ | T. Fest² |
F. Morschhauser¹⁹

¹Biological Hematology and Immunology Department, U955 Eq9, APHP, Groupe Hospitalier Mondor, Creteil, France; ²Hematobiology department, CHU Pontchaillou, Rennes, France; ³Service d'Hématologie, CHRU de Nancy, Vandoeuvre les Nancy, France; ⁴Service d'Onco-Hématologie, CHD Vendée, La Roche-sur-Yon, France; ⁵Service d'Hématologie Clinique, CHU Le Bocage, Dijon, France; ⁶Unité Hémopathies Lymphoïdes, University hospital Mondor, Creteil, France; ⁷Service Hématologie, CH Métropole Savoie, Chambéry, France; ⁸Service d'Hématologie Clinique, CHU Pontchaillou, Rennes, France; ⁹Service d'Hématologie, IUCT Oncopole, Toulouse, France; ¹⁰U1245 and Département d'Hématologie, Centre Henri Becquerel, Rouen, France; ¹¹Département d'Hématologie, CH de Mulhouse, Hôp Emile Muller, Mulhouse, France; ¹²Service d'Hématologie Clinique, CHU de Nantes - Hôtel Dieu, Nantes, France; ¹³Hematology Department, Gustave Roussy Cancer Campus Grand Paris,

Villejuif, France; ¹⁴Service Hématologie, Centre Hospitalier Bretagne-Atlantique, Vannes, France; ¹⁵Service d'Hématologie, Centre René Huguenin, Saint-Cloud, France; ¹⁶Department of Hematology, CHU Montpellier, Montpellier, France; ¹⁷Département d'Hématologie, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Lyon, France; ¹⁸Departement de Bio-pathologie, Institut Paoli-Calmettes, Marseille, France; ¹⁹Département d'Hématologie, EA 7365, CHU Lille, Lille, France

**Introduction:** Molecular response (MR) after first-line immunochemotherapy in patients (pts) with follicular lymphoma (FL) is considered as a valuable surrogate endpoint of patient outcome. RELEVANCE is the first phase III trial comparing the chemo-free regimen R2 vs R-Chemo followed by R maintenance in previously untreated pts with FL. The objective of the minimal residual disease (MRD) analysis was to determine the ability of a chemo free regimen to eradicate the MRD.

**Methods:** The MRD study in RELEVANCE was performed in 45 LYSA participating centers. Diagnostic peripheral blood (PB) and bone marrow (BM) samples were screened by the t(14;18) biomed 2 PCR (Evans 2007) in the 440 included pts. In t(14;18) (+) pts, MRD was quantified by ddPCR (Delfau-Larue, 2018) (ratio tumor cells /analyzed cells, with a sensitivity of at least 10⁻⁴) in PB and BM at baseline, at week 24 (W24) (end of induction in R-chemo arm), and at W120 (end of maintenance in both arms). Factors associated (p<0.10) with (+) MRD at W24 were integrated in a backward stepwise logistic regression model. Survival was calculated using Kaplan-Meier estimates.

**Results:** A t(14;18) translocation was detectable in 222 pts before treatment. Compared to all LYSA pts enrolled in RELEVANCE, pts with MRD analyses presented more frequently with BM involvement (62% vs 48% p=.003), Ann Arbor stage III-IV (96% vs 90%, p=.004) and higher FLIPI score (FLIPI 2-5 91% versus 83%, p=.002). No

<figure><img src="image_48.png" /></figure>
significant difference was observed in term of treatment arm (55% in R-chemo vs 49% in R²). At diagnosis, 213/220 PB and 136/139 BM samples were (+) with a median of 0.0058 and 0.021 respectively. At W24, 98% and 78% of those pts have reached MR in PB and BM respectively. The MRD positivity in BM at W24 was significantly (p=.02) more frequently observed in pts receiving R-chemo (32% vs 15%), in those with beta2m ≥ 3 mg/L (55% vs 34%, p=.05), and in those with higher levels of molecular disease before treatment (median value ten times higher in pts with (+) MRD (PB=0.056 and BM=0.16) than in pts with (-) MRD (PB=0.0056 and BM=0.016), p= 0.03 and p=0.02 respectively). Multivariate analysis results showed that only R-Chemo arm (OR=3.4, p=.008) and beta2m ≥ 3 mg/L (OR=3.1, p=.014) were factors independently associated with an increased risk of MRD (+) in BM at W24. Achievement of MRD negativity at W24 in BM was significantly associated with an improved PFS (p=.011) (3-year PFS 85.3% vs 54.4% for pts with (+) MRD (figure). At W120 in pts with persisting clinical response, only 2/166 pts were MRD (+) in PB, and 11/99 in BM. Longer follow up is needed to evaluate the prognostic value of those positive samples.

**Conclusions:** In agreement with the clinical results of RELEVANCE trial, our results show that an immunomodulatory induction treatment in first line FL can achieves high rate of MR in both blood and bone marrow; Achieving a complete MR at the end of induction was predicting a more favorable PFS.

**Keywords:** follicular lymphoma (FL); lenalidomide; minimal residual disease (MRD).

**Disclosures:** Delfau-Larue, M: Research Funding: Celgene. Maisonneuve, H: Other Remuneration: personal fees from Roche and Celgene outside the submitted work. Casasnovas, O: Consultant Advisory Role: Advisory Board (Celgene, Roche, Takeda, BMS, MSD, Gilead, Janssen); Research Funding: Takeda, Gilead, Roche. Haioun, C: Other Remuneration: personal fees from Celgene and Roche during the conduct of the study. Tilly, H: Other Remuneration: personal fees from Celgene. Cartron, G: Other Remuneration: personal fees for consultancy and honoraria from Roche and Celgene. Salles, G: Other Remuneration: grants and personal fees from Celgene and Roche. Morschhauser, F: Other Remuneration: personal fees for advisory boards and scientific lectures from Celgene and Roche.

072
SAKK 35/15: A PHASE I TRIAL OF
OBINUTUZUMAB IN COMBINATION WITH
VENETOCLAX IN PREVIOUSLY
UNTREATED FOLLICULAR LYMPHOMA
PATIENTS

A. Stathis¹ | U. Mey² | S. Schär³ | F. Hitz⁴ |

C. Pott⁵ | N. Mach⁶ | F. Krasniqi⁷ | U. Novak⁸ |

C. Schmidt⁹ | K. Hohloch² | D. Kienle² | D. Hess⁴ |

A. Moccia¹ | M. Unterhalt⁹ | K. Eckhardt³ |

S. Hayoz³ | D. Rossi¹⁰ | S. Dirnhofer¹¹ |

L. Ceriani¹² | F. Bertoni¹³ | C. Buske¹⁴ | E. Zucca¹ | W. Hiddemann⁹

¹Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; ²Oncology and Hematology, Kantonsspital Graubuenden, Chur, Switzerland; ³Coordinating Center, SAKK, Bern, Switzerland; ⁴Oncology/Hematology, Kantonsspital St.Gallen, St.Gallen, Switzerland; ⁵Medizinischen Klinik II Hämatologie und Internistische Onkologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany; ⁶Service d'Oncologie, Département d'Oncologie, Hôpitaux Universitaires de Genève, Genève, Switzerland; ⁷Medical Oncology, University Hospital of Basel, Basel, Switzerland; ⁸Department of Medical Oncology, Inselspital / Bern University Hospital, Bern, Switzerland; ⁹Department of Medicine III, University of Munich, Munich, Germany; ¹⁰Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland; ¹¹Pathologie, Universitätsspital Basel, Basel, Switzerland; ¹²Nuclear Medicine and PET-CT centre, Imaging Institute of Southern Switzerland, Bellinzona, Switzerland; ¹³Lymphoma Genomics, Institute of Oncology Research, Bellinzona, Switzerland; ¹⁴CCC Ulm, University Hospital Ulm, Ulm, Germany

**Introduction:** The anti-CD20 monoclonal antibody obinutuzumab and the bcl-2 inhibitor venetoclax are both active in different lymphoma subtypes. SAKK 35/15 is an open label phase I trial, which is being conducted by the Swiss Group for Clinical Cancer Research (SAKK) and the German Low Grade Lymphoma Study Group (GLSG)/German Lymphoma Alliance (GLA) and aims to determine the recommended phase II dose (RP2D), toxicity profile and preliminary activity of obinutuzumab in combination with venetoclax in previously untreated advanced stage follicular lymphoma (FL) patients (pts).

**Methods:** Pts with grade 1 to 3A FL, untreated and in need of systemic therapy were eligible. Two dose levels are being evaluated in a 3+3 design with an expansion cohort at the RP2D. DL1 consists of venetoclax 600mg once daily (OD) and DL2 of venetoclax 800mg OD, continuously for six 28-day (d) cycles, starting on cycle 1 d 2. In both DLs pts receive obinutuzumab 1000mg on d 1, 8, 15 of cycle 1 and on d 1 of cycles 2-6. Following cycle 6, pts on partial or complete remission (PR or CR) continue maintenance treatment with single agent obinutuzumab 1000mg every two months for up to 2 years.

**Results:** The study completed its accrual with 25 pts enrolled (3 in DL1 and 22 in DL2). Demographics: median age 55 (range 30-78), F: M = 12:13, ECOG 0:1:2 = 21:3:1 pts, stage II:III: IV= 2:10:13 pts, FLIPI score low:intermediate:high=5:10:10 pts, reason for start of systemic therapy B symptoms:bulky disease:clinical progression:symptomatic disease=10:10:13:19 pts. Among 22 pts completing cycle 1, only one patient treated at DL2 had a dose limiting toxicity consisting of grade (G) 4 thrombocytopenia after the first obinutuzumab infusion. Three pts have not completed cycle 1 yet. Thus far, adverse events (AE) of G ≥3, of at least possible attribution to study treatment, were neutropenia (2 pts, both G4), thrombocytopenia (2 pts, 1 G3 and 1 G4), and one pt each for anemia (G3), febrile neutropenia (G3), fatigue (G3), AST increase (G3), ALT increase (G3), lymphopenia (G3) and
pneumonitis (G3). AEs were all manageable and no toxic deaths were seen. The median relative dose intensity (proportion of administered doses relative to planned doses) was 100% for both drugs. Eleven pts are currently receiving combination therapy and 10 are on maintenance, while 4 pts discontinued treatment, 3 for progressive disease (2 under combination therapy and one during maintenance) and one for AEs (thrombocytopenia G4, ALT increase G3 and pneumonitis G3). Eleven pts are evaluable for response at 6 months, 10 were evaluated by PET-CT and one by CT only. Five achieved CR (45%; 95% CI, 17-77%), 4 PR (36%; 95% CI, 11-69%) and 2 pts had progressive disease, for an overall response rate (ORR) at 6 months of 82% (95% CI, 48-98%).

**Conclusions:** This is the first study to assess obinutuzumab plus venetoclax in untreated advanced FL in need of systemic therapy. The two drugs could be safely combined and may represent a valuable chemotherapy-free regimen. The RP2D is venetoclax 800mg OD continuously for 6 cycles starting on d 2 of cycle 1 in combination with obinutuzumab 1000mg on d 1,8,15 of cycle 1 and on d 1 of cycles 2-6, followed by obinutuzumab maintenance for up to two years. Preliminary data show promising activity and updated results will be presented.

**Keywords:** follicular lymphoma (FL); obinutuzumab; venetoclax.

**Disclosures:** Stathis, A: Research Funding: Roche; Other Remuneration: Travel support Abbvie. Mey, U: Consultant Advisory Role: Roche; Honoraria: Roche. Schmidt, C: Research Funding: Roche.

Hess, D: Stock Ownership: Roche. Moccia, A: Consultant Advisory Role: Roche. Unterhalt, M: Research Funding: Roche. Rossi, D: Honoraria: Roche. Zucca, E: Consultant Advisory Role: Roche; Research Funding: Roche. Hiddemann, W: Honoraria: Roche; Research Funding: Roche.

¹CLL Program, Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, United States; ²Lymphoma Department, University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, United States; ³Department of Pathology and Laboratory Medicine, University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, United States; ⁴Department of Hematology, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; ⁵Division of Hematologic Malignancies, Duke University Medical Center, Durham, NC, United States; ⁶Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY, United States; ⁷Clinical Development, TG Therapeutics, Inc., New York, NY, United States

**Introduction:** Preclinical data suggest that PD-1 mediates immune evasion in CLL, however clinical data indicate that pembrolizumab (pembro) monotherapy is ineffective in r/r CLL patients (pts) (0% ORR; Ding, BLOOD 2017). We hypothesized synergistic activity with PD-1 + PI3K blockade. Umbralisib (Umbra), is a PI3Kδ inhibitor with unique effect on CK1ε. We conducted a Ph 1 (3+3 design) study to assess the safety and activity of Umbra with the anti-CD20 mAb ublituximab (UTX) and pembro in r/r CLL and RT - the first reported triple combination of a PD-1 inhibitor + PI3Kδi + anti-CD20 mAb.

**Methods:** Treatment for CLL: Induction: Umbra (800mg daily) + UTX (900mg 3 out of 4 wks) for two 28-day cycles (Cy). Consolidation (Cy3-6): Pembro (dose level 1=100mg, dose level 2=200mg) every 3 wks + Umbra 800mg daily + UTX (900mg in Cy4 & 6). Maintenance: Cy≥6, Umbra 800 mg daily. For RT pts, all study drugs started in Cy1: Umbra 800 mg daily + UTX 900 mg Cy1 (D1, 8, 15), D1 Cy2-4, Cy7 and q3 cycles thereafter + pembro D3 of Cy1 and D2 of Cy2-4. Primary endpoint safety; secondary efficacy. Peripheral blood and/or BM was obtained for correlates at screening, Cy2, & Cy6.

## FOCUS ON... SESSION: NON-CLINICAL AND EARLY CLINICAL DATA

### 073
PHASE I/II STUDY OF UMBRALISIB (TGR-1202) IN COMBINATION WITH UBLITUXIMAB (TG-1101) AND PEMBROLIZUMAB IN PATIENTS WITH REL/REF CLL AND RICHTER'S TRANSFORMATION

A.R. Mato¹ | J. Svoboda² | E.T. Luning Prak³ |
S.J. Schuster² | P.Y. Tsao³ | C. Dorsey¹ |
L.M. Sarmasti¹ | P.S. Becker⁴ | D.M. Brander⁵ |
S. Nasta² | D.J. Landsburg² | C.M. King² |
B. Morrigan⁴ | J. Elwell⁴ | K. Kennard² |
L. Roeker¹ | A.D. Zelenetz⁶ | M. Purdom⁷ |
D. Paskalis⁷ | P. Sportelli⁷ | H.P. Miskin⁷ |
M.S. Weiss⁷ | M. Shadman⁴

<figure><img src="image_49.png" /><figcaption>Figure 1: Time on Study</figcaption></figure>
**Results:** 18 pts treated to date: 11 CLL (5 at 100 mg pembro / 6 at 200 mg pembro) and 7 with RT (4 at 100 mg pembro / 3 at 200 mg). Demographics: M/F (12/6), med age 69.5 yrs (range 53-81), med prior tx 2 (1-9) (for RT, med prior was 5, all ibrutinib refractory), 83% refractory to immediate prior tx. 13/14 BTK exposed pts were refractory. 61% were high risk (del17p, del11q, TP53 mut, Notch1 mut or complex karyotype). AE's (all causality) were manageable. Grade 3/4 AE's included neutropenia (n=6, 33%), ALT/AST increase (n=3, 17%), and thrombocytopenia (n=3, 17%). One DLT occurred at 200 mg dose level (ALT/AST elevation). MTD not reached. No increase in expected Gr≥ 3 PI3Kδ-associated toxicities noted (1 pneumonitis, no colitis events). ORR was 91% for CLL pts, with 7/11 pts progression free at median f/u of 24.8 mos, including one CLL pt off all therapy for 32+ mos. ORR was 83% in BTK refractory pts (5/6); notably 80% of BTK refractory CLL pts achieved a response to Umbra + UTX (U2) induction alone prior to the addition of pembro. 5/7 RT pts were available for efficacy (1 ineligible, 1 too early to evaluate): 2 CR, 1 SD (40%.) and 2 PD. RT CRs were durable (20+ mos and 12 mos, each); both were ibrutinib refractory, had 7 (including SCT) and 8 prior lines respectively, and one had failed CAR-T. Fig 1 is a Swimmer Plot of time on study. Correlative studies demonstrated relative retention of Tregs.

**Conclusion:** The triple combination of umbralisib + ublituximab + pembrolizumab was well-tolerated. Responses were durable in BTK refractory, high risk pts, including two CRs in RT pts. Data suggests that time-limited therapy could be possible. Enrollment is ongoing in both the CLL and RT cohorts and an amendment is planned to evaluate the triplet combination of U2 + TG-1501 (PD-L1 mAb).

**Keywords:** chronic lymphocytic leukemia (CLL); Richter's syndrome (RS).

**Disclosures:** Mato, A: Consultant Advisory Role: TG Therapeutics, Inc., Genentech, PCYC, Loxo, Abbvie, Sunesis, Celgene, Verastem; Research Funding: TG Therapeutics, Inc., PCYC, Loxo, Abbvie, Regeneron, Sunesis. Dorsey, C: Consultant Advisory Role: TG Therapeutics, Inc. Brander, D: Consultant Advisory Role: TG Therapeutics, Inc. Purdom, M: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Paskalis, D: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Sportelli, P: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Miskin, H: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Weiss, M: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Shadman, M: Consultant Advisory Role: Abbvie, Genentech, Sound Biologics; Verastem, ADC therapeutics, Atara Biotherapeutics; Research Funding: Mustang Bio, Celgene, Pharmacycyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Acerta Pharma, Merck.

074
PEMBROLIZUMAB WITH RCHOP IN
PREVIOUSLY UNTREATED DIFFUSE LARGE
B-CELL AND GRADE 3B FOLLICULAR

LYMPHOMA: FINAL RESULTS OF A PHASE I
TRIAL

**S.D. Smith¹** | **R.C. Lynch¹** | **B.G. Till¹** | **A.J. Cowan¹** |
**Q.V. Wu²** | **J.M. Voutsinas²** | **M. Shadman¹** |
**A. Shustov¹** | **R.D. Cassaday¹** | **J.R. Fromm³** |
**A.K. Gopal¹**

¹Division of Medical Oncology, Department of Internal Medicine, UW/FHCRC, Seattle, United States; ²Department of Clinical Biostatistics, Fred Hutchinson Cancer Research Center, Seattle, United States; ³Laboratory Medicine/Hematopathology, University of Washington, Seattle, United States

**Background:** Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) is standard first-line therapy diffuse large B-cell lymphoma (DLBCL). The anti-PD-1 antibody pembrolizumab (P) shows limited efficacy in relapsed DLBCL, but the first-line setting may represent a better opportunity for PD-1 inhibition. We report final results testing the safety of P+RCHOP in aggressive B-NHL.

**Methods:** Adults with previously untreated DLBCL, transformed lymphoma and grade 3 B follicular lymphoma were eligible. P was given at 200 mg IV q 3 weeks x 6 doses, with standard RCHOP x 6 q 3 weeks. A sample size of 30 permitted estimation of the rate of clinically relevant toxicity (assumed 40% with RCHOP alone) with a 95% CI of 23-57%. Response rates (Lugano criteria), event-free survival (EFS), overall survival (OS) and progression-free survival (PFS) were secondary endpoints. End of treatment (EOT) PR with negative biopsy, or repeat PET converting to Deauville 1-3, were scored as CR. PDL1 expression was analyzed using the 22c3 antibody.

**Results:** From March 2016- August 2018, 30 pts were enrolled and treated (Table 1). Grade 3-5 clinically significant AE's occurred in

<table><caption>TABLE 1 Pt Characteristics (N=30)</caption><tr><td>Median age (range)</td><td>62 (22-78)</td></tr><tr><td>Gender female</td><td>11/30</td></tr><tr><td>Histology</td><td>DLBCL NOS: 24<br>EBV+ DLBCL: 2<br>TCHLBL: 1<br>Grade 3B FL: 3</td></tr><tr><td>Composite DLBCL/FL</td><td>5/30</td></tr><tr><td>Non-GCB by IHC</td><td>11/26 (excluding<br>TCHLBL, grade 3B FL)</td></tr><tr><td>PII: Low (0-1), Low-int (2), High-int (3),<br>High (4-5)</td><td>8, 9, 11, 2</td></tr><tr><td>NCCN PII: Low (0-1), Low-int (2-3),<br>High-int (4-5), High (≥6)</td><td>2, 12, 16, 0</td></tr><tr><td>Double expressor</td><td>6/18 tested</td></tr><tr><td>Double hit</td><td>1 (grade 3b composite<br>w/low-grade FL)</td></tr></table>
<figure><img src="image_50.png" /></figure>

14 pts (14/30, 46%) and 18 SAE's occurred in 12 pts (12/30, 40%). Four immune-related adverse events (IRAE) occurred: grade 3 rash, grade 1 hyperthyroidism, grade 2 colitis, and grade 3 pneumonitis (in a 78 y.o. with a history of tobacco use and COPD). One pt. died during cycle 1 from bleed of gastric DLBCL, despite inpatient management, and was not assessed for response or dose intensity.

Anthracycline relative dose intensity was 94.7%. 26/29 received all planned P. ORR in 29 assessable pts was 93%: 24 CR (83%), 3 PR (19%) and 2 SD/PD (7%). 19 pts had PET- CR on EOT assessment; 3 had initial PR but a negative biopsy, and 2 had PR converted to CR with repeat PET. Among 8 pts with residual FDG-avid lesions on EOT PET, only 1 relapse occurred.

At 16 months follow-up, four relapses and 2 deaths occurred, with PFS/OS of 82/97% at 18 months (Figure 1). In 22 tested pts to date, 55% had PDL-1 tumor cell ≥ 30%, and PDL H-score (a weighted average) was 0 in 3 pts, 1-99 in 9 pts, and 100 or more in 10 pts. PFS was inferior in PDL1 H score 0 pts (p<.001) and IPI 3-5 pts (p=.07), but no different in GCB vs non-GCB.

**Conclusions:** P + RCHOP did not show toxicity beyond what is expected with RCHOP, and was associated with a high CR rate in this trial. FDG avid lesions in pts with PR were commonly false positives. Significant PDL-1 tumor staining was seen in most pts tested, and appears to predict PFS; final PDL-1 results will be presented. Our data supports further comparative study of P+RCHOP in DLBCL.

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

**Disclosures:** Smith, S: Consultant Advisory Role: Merck Sharp and Dohme Corp., AstraZeneca; Research Funding: Acerta Pharma BV, AstraZeneca, Ayala (spouse), Bristol Myers Squibb (spouse), De Novo Biopharma, Genentech, Ignyta (spouse), Merck Sharp and Dohme Corp., Pharmacyclics, Portola Pharmaceutics, Seattle Genetics. Lynch, R: Research Funding: Takeda Pharmaceuticals, Rhizen Pharmaceuticals, TG

Therapeutics, Incyte Corporation. Till, B: Research Funding: Roche/Genentech, Mustang Bio. Cowan, A: Consultant Advisory Role: Celgene Corp; Research Funding: Janssen, Abbvie, Celgene/Juno Therapeutics. Shadman, M: Consultant Advisory Role: Abbvie, Genentech, Sound Biologics, Verastem, ADC therapeutics, Atara Biotherapeutics; Research Funding: Mustang Biopharma, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Acerta Pharma, Merck. Cassaday, R: Employment Leadership Position: Seattle Genetics; Consultant Advisory Role: Amgen and Pfizer; Research Funding: Amgen, Incyte, Kite/Gilead, Merck, and Pfizer. Gopal, A: Consultant Advisory Role: Janssen, Gilead, Brim Bio, Aptevo, SeagGen, InCyte, Asana; Research Funding: Merck, Teva, BMS, Pfizer, Janssen, SeaGen, Takeda, Spectrum, Gilead, Effector.

075
ZANUBRUTINIB PLUS OBINUTUZUMAB IN
PATIENTS WITH CHRONIC LYMPHOCYTIC
LEUKEMIA/SMALL LYMPHOCYTIC
LYMPHOMA (CLL/SLL) OR
RELAPSED/REFRACTORY (R/R)
FOLLICULAR LYMPHOMA (FL)

C.S. Tam¹ | H. Quach² | A. Nicol³ | X. Badoux⁴ |
H. Rose⁵ | H.M. Prince⁶ | M.F. Leahy⁷ | R. Eek⁸ |
N. Wickham⁹ | S.S. Patil¹⁰ | J. Huang¹¹ |
R. Prathikanti¹¹ | L. Wang¹¹ | W. Reed¹¹ | I.W. Flinn¹²

¹Department of Haematology, Peter MacCallum Cancer Centre, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia; ²Department of Haematology, St Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia; ³Lymphoma, Brisbane Clinic for Lymphoma, Myeloma, and Leukaemia, Brisbane, QLD, Australia; ⁴Department of Haematology, St. George Hospital, Sydney, NSW, Australia; ⁵Haematology, University Hospital, Geelong, Victoria, Australia; ⁶Haematology, Epworth Healthcare and Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia; ⁷Haematology, Royal Perth Hospital, Perth, WA, Australia; ⁸Research Unit, Border Medical Oncology, Albury, NSW, Australia; ⁹Ashford Cancer Centre Research, Adelaide Cancer Centre, Adelaide, SA, Australia; ¹⁰Haematology, The Alfred Hospital, Melbourne, Victoria, Australia; ¹¹Research and Development Center, BeiGene(Beijing) Co., Ltd, Beijing, China, BeiGene USA, Inc., San Mateo, CA, United States; ¹²Sarah Cannon Research Institute, Tennessee Oncology PLLC, Nashville, TN, United States

**Introduction:** Bruton Tyrosine Kinase (BTK) plays a critical role in B cell receptor (BCR) signaling. Zanubrutinib is a selective and irreversible BTK inhibitor that has demonstrated potent inhibition of BTK preclinically, with minimal inhibition of other kinases; it has minimal effect on interleukin-2 inducible tyrosine kinase (ITK) and does not inhibit ITK-mediated rituximab-induced antibody-mediated cytotoxicity.

**Methods:** This is a phase 1b study of the combination of zanubrutinib with obinutuzumab in patients with B-cell malignancies. Eligible
<table><caption>TABLE 1</caption><thead><tr><th></th><th>37 CLL (n=37) / SLL (n=8) (20 TN & 25 RR) n = 45</th><th>R/R FL n = 36</th></tr></thead><tbody><tr><td><strong>Demographics</strong></td><td></td><td></td></tr><tr><td>Median (range) age, y</td><td>68 (38, 82)</td><td>59 (34, 86)</td></tr><tr><td>Median (range) prior therapies</td><td>1 (0, 4)</td><td>2 (1, 9)</td></tr><tr><td><strong>Safety, n (%)</strong></td><td></td><td></td></tr><tr><td>Grade ≥3 AEs</td><td>32 (71)</td><td>18 (50)</td></tr><tr><td>Serious AEs</td><td>22 (49)</td><td>12 (33)</td></tr><tr><td>AEs leading to zanubrutinib discontinuation</td><td>2 (4)</td><td>2 (6)</td></tr><tr><td>Fatal AEs</td><td>1 (2)</td><td>0</td></tr><tr><td><strong>Efficacy (Evaluable)</strong></td><td>n = 45</td><td>n = 36</td></tr><tr><td>Median (range) follow-up, mo</td><td>25 (8, 34)</td><td>18 (2, 34)</td></tr><tr><td><strong>ORR, n/N (%)</strong></td><td>43/45 (96)<br>CLL: 15/15 TN, 20/22 RR<br>SLL: 5/5 TN, 3/3 RR</td><td>26/36 (72)</td></tr><tr><td><strong>Best response</strong></td><td></td><td></td></tr><tr><td>CR</td><td>12 (27)<br>CLL: 5/15 TN, 6/22 RR<br>SLL: 1/5 TN, 0/3 RR</td><td>13 (36)</td></tr><tr><td>PR</td><td>31 (69)</td><td>13 (36)</td></tr><tr><td>Stable disease</td><td>2 (4)</td><td>5 (14)</td></tr><tr><td>Progressive disease</td><td>0</td><td>5 (14)</td></tr></tbody></table>

patients had ECOG status of 0-2, neutrophil count >1000/µL, platelets >40,000/µL, adequate renal and hepatic function and no significant cardiac disease. Growth factors, transfusion and anticoagulation were allowed. The primary efficacy endpoint was objective response using 2007 International Working Group criteria.

**Results:** As of 16Nov2018, enrollment was complete with 45 CLL/SLL patients (20 treatment-naïve [TN] and 25 R/R) and 36 R/R FL patients. Median follow-up was 25.5 mo (range: 7.9-33.5) for CLL/SLL and 17.8 mo (range: 2.3-33.8) for R/R FL. One fatal adverse event (AE) occurred: squamous cell carcinoma in a CLL patient with prior squamous cell carcinoma. Serious AEs were reported in 22 (49%) CLL/SLL and 12 (33%) R/R FL patients. Common (>20%) any-grade AEs reported in CLL/SLL patients were upper respiratory tract infection (URTI; 49%), neutropenia (42%), contusion (33%), diarrhea (27%), cough (27%), fatigue (27%), and pyrexia (22%); and in FL patients were URTI (39%), contusion (28%), fatigue (25%), and cough (22%). AEs lead to zanubrutinib discontinuation in 2 (4%) CLL/SLL (disseminated cryptococcus and squamous cell carcinoma) and 2 (6%) R/R FL patients (lethargy, ascites). There were no AEs of atrial fibrillation. All patients completed baseline and ≥1 response assessment. Overall response rates [complete response+partial response] were 96% in CLL/SLL (100% for TN, 92% for R/R) and 72% in R/R FL. There were 6 CRs in patients with TN CLL/SLL, 6 in R/R CLL/SLL and 13 in R/R FL.

**Conclusions:** The combination of zanubrutinib plus obinutuzumab was generally well tolerated and active in patients with CLL/SLL and R/R FL. Few patients discontinued due to AEs. A Phase 2 trial comparing zanubrutinib plus obinutuzumab against obinutuzumab alone in R/R FL is ongoing.

**Keywords:** B-cell receptor inhibitors; chronic lymphocytic leukemia (CLL); follicular lymphoma (FL).

**Disclosures:** Tam, C: Honoraria: Beigene, Janssen, AbbVie, Novartis; Research Funding: Janssen and AbbVie. Quach, H: Consultant Advisory Role: Celgene, Janssen Cilag, Takeda, Karyopharm, Amgen; Research Funding: Celgene, Amgen. Nicol, A: Research Funding: Parexel, Iqvia; Other Remuneration: Travel, Accommodations, Expenses: Amgen, Janssen, Novartis. Badoux, X: Consultant Advisory Role: AbbVie; Honoraria: Roche. Prince, H: Consultant Advisory Role: Takeda, Janssen, Amgen, Allergan; Honoraria: Takeda, Janssen, Amgen, Celgene, Allergan; Research Funding: Allergan. Leahy, M: Honoraria: Vifor Pharma; Other Remuneration: Travel, Accommodations, Expenses: Amgen. Wickham, N: Stock Ownership: ICON CONSOLIDATED HOLDINGS; Other Remuneration: Travel, Accommodations, Expenses: Celgene. Huang, J: Employment Leadership Position: BeiGene; Stock Ownership: BeiGene. Prathikanti, R: Employment Leadership Position: BeiGene; Stock Ownership: BeiGene, Amgen. Wang, L: Employment Leadership Position: BeiGene; Stock Ownership: BeiGene; Other Remuneration: Patents, Royalties: BeiGene. Reed, W: Employment Leadership Position: BeiGene; Stock Ownership: BeiGene; Other Remuneration: Travel, Accommodations, Expenses: BeiGene. Flinn, I: Consultant Advisory Role: Abbvie, Seattle Genetics, TG Therapeutics, Verastem; Research Funding: Acerta, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite, Novartis, Pharmacyclics, Portola, Roche, TG Therapuetics, Trillium, Abbvie, ArQule, BeiGene, Curis, FORMA Therapuetics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead, Astra Zeneca, Juno, Unum Therapuetics, MorphoSys, AG, Abbvie.

## 076 A PHASE I/II TRIAL OF IBRUTINIB, INTRATUMORAL CPG AND LOCAL RADIATION IN PATIENTS WITH LOW-GRADE B-CELL LYMPHOMA: INTERIM CLINICAL AND CORRELATIVE RESULTS

T. Shree¹ | M.S. Khodadoust¹ | D. Czerwinski¹ | M.J. Frank¹ | W.X. Hong¹ | R. Greenstein¹ | S. Long² | B. Martin³ | R. Levy¹

¹Department of Medicine, Division of Oncology, Stanford University, Stanford, United States; ²Department of Pathology, University of California San Francisco, San Francisco, United States; ³Department of Pathology, Stanford University, Stanford, United States

**Introduction:** Local treatment with intratumoral CpG (a toll-like receptor 9 agonist) and low-dose radiation can elicit antitumor immune
<figure><img src="image_51.png" /><figcaption>**Figure 1.** Waterfall plot depicting percent change in sum of product diameters (SPD) from baseline to best overall response for each evaluable patient. Bars are colored by best overall response and shaded by inclusion (solid bars) or exclusion (hashed bars) of the injected site in the SPD. PR, partial response. SD, stable disease. PD, progressive disease. △Both patients with progressive disease as best response met criteria for progression other than a 50% increase in SPD (one had a new site of disease and the other had progression at one target lesion).</figcaption></figure>

responses and global tumor reduction in patients with low-grade lymphoma (Frank, *Cancer Discov*, 2018). Ibrutinib compromises B-cell survival by inhibiting Bruton's tyrosine kinase, but also modulates T-cells by inhibiting interleukin-2-inducible T-cell kinase. In a mouse model of lymphoma, ibrutinib plus intratumoral CpG was curative of systemic disease, an effect that was T-cell dependent (Sagiv-Barfi, *Blood*, 2015). Thus, we initiated a phase I/II clinical trial combining oral ibrutinib, intratumoral CpG and local low-dose radiation in adults with recurrent low-grade lymphoma (NCT02927964).

**Methods:** Enrolled patients received intratumoral injections of CpG (SD-101, 3mg) weekly for 5 doses, starting on the second day of a 2-day course of local radiation (4Gy) to the same site. Daily oral ibrutinib (560mg) began on day 9. Treatment-emergent adverse events (AEs), ibrutinib dose modifications and adherence were recorded at every visit. Revised Lugano criteria were used to assess response to therapy, based on CT scans at 3, 6, 12, 18, and 24 months. Fine needle aspirates (FNAs) were obtained from CpG-injected and non-injected tumor sites pre- and post-treatment and analyzed by flow cytometry and single-cell RNA sequencing (scRNAseq). When available, viably preserved tumor and peripheral blood cells were used for *in vitro* immune response assays.

**Results:** As of January 2nd, 2019, 13 patients have been treated, with a median follow-up of 7.7 months. AEs are consistent with known effects of ibrutinib and of CpG with no unexpected AEs to suggest synergistic toxicity. There were no grade 4 or 5 events. AEs led to ibrutinib dose reduction or discontinuation in 3 patients. At the time of analysis, 6 of 12 evaluable patients had achieved a partial response (50% ORR) and 3 of them had achieved greater than 50% reduction in distal tumor burden (Figure 1). Eight of 12 patients had experienced at least a 30% reduction in distal tumor burden. Flow cytometry revealed decreased T follicular helper cells and increased CD4 and/or CD8 effector T-cells, CD137+ activated T-cells, and NK cells in

CpG-injected tumors. Abscalop immune effects in distant non-injected lesions included an increase in Granzyme B+ CD8 T-cells, most prominent after the addition of ibrutinib. scRNAseq data showed significant transcriptional shifts in tumor cells and in tumor-infiltrating T-cells, including signatures of interferon response. Finally, *in vitro* assays showed tumor-specific immune responses in peripheral blood T-cells of all 6 evaluable patients.

**Conclusion:** Early data suggest that the combination of oral ibrutinib, intratumoral CpG, and local low-dose radiation is safe and can generate systemic antitumor immune responses and systemic tumor shrinkage in low-grade lymphoma.

**Keywords:** ibrutinib; immunochemotherapy; indolent lymphoma.

077

EXTENDED FOLLOW-UP OF A PHASE I TRIAL OF IPILIMUMAB, NIVOLUMAB AND BRENTUXIMAB VEDOTIN IN RELAPSED HODGKIN LYMPHOMA: A TRIAL OF THE ECOG-ACRIN RESEARCH GROUP (E4412)

C.S. Diefenbach¹ | F. Hong² | R. Ambinder³ |

J. Cohen⁴ | M. Robertson⁵ | K. David⁶ |

R. Advani⁷ | T. Fenske⁸ | S. Barta⁹ |

N. Palmisano¹⁰ | J. Svoboda⁹ | D. Morgan¹¹ |

R. Karmali¹² | B. Kahl¹³ | S. Ansell¹⁴

¹Hematology-Oncology, Perlmutter Cancer Center at NYU Langone Health, New York, United States; ²ECOG-ACRIN Biostatistics Center, Dana Farber Cancer Institute, Boston, United States; ³Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, United States; ⁴Winship Cancer Institute, Emory University, Atlanta, United States; ⁵Hematology-Oncology, Indiana University School of Medicine, Indianapolis, United States; ⁶Hematology-Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, United States; ⁷Oncology, Stanford Cancer Institute, San Francisco, United States; ⁸Hematology-Oncology, Froedtert and the Medical College of Wisconsin, Milwaukee, United States; ⁹Abramson Cancer Center, University of Pennsylvania, Philadelphia, United States; ¹⁰Hematology-Oncology, Thomas Jefferson University Hospital, Philadelphia, United States; ¹¹Hematology-Oncology, Vanderbilt Ingram Henry Cancer Center, Nashville, United States; ¹²Feinberg School of Medicine, Northwestern University, Chicago, United States; ¹³Oncology, Washington University School of Medicine, St. Louis, United States; ¹⁴Hematology-Oncology, Mayo Clinic, Rochester, United States

**Background:** Relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical problem. We hypothesized that activating the immune microenvironment, and concurrently targeting tumor cells with brentuximab vedotin (B) could overcome tumor resistance. Here we report the extended follow-up for all patients treated on Phase 1 of E4412 with the combinations of B (1.2 or 1.8 mg/kg), nivolumab (N) 3mg/kg and ipilimumab (I) (1 or 3mg).
<figure><img src="image_52.png" /><figcaption>Figure 1: PFS and OS</figcaption></figure>

**Methods:** Patients with confirmed R/R HL were enrolled sequentially in cohorts of B-I (n=21), B-N (n=18), and B-N-I (n=22). Schedule was: B-N q 21 days for 16 cycles and N an additional 12 months; 1 q 3 weeks for 4 cycles and then q 3 months (B-I), or every 12 weeks for up to 24 months (B-N-I). Dose limiting toxicity (DLT) was defined within the first cycle of therapy.

**Results:** As of 3/1/2019, 64 patients were enrolled of which 61 were eligible, 3 were ineligible due to prior treatment or laboratory values. The median age was 33; median prior therapies 2 (excluding SCT) across all cohorts, range: 1-9 (B-I), 1-6 (B-N), and 1-5 (B-N-I). Twenty-five patients (40%) had prior SCT: 9 (B-I), 7 (B-N), and 9 (B-N-I). Seven patients: 3 (B-I), 4 (B-N) and 1 (B-N-I) had prior BV.

**Safety:** All enrolled patients are evaluable for safety. There were 2 grade 5 pneumonitis deaths, one each in B-N and B-N-I. There were 5 DLTs: pneumonitis and typhlitis (B-N), and one each grade 4 diabetic ketoacidosis and hyperglycemia, transient grade 3 AST elevation, and post AlloSCT grade 4 GVHD (B-N-I). Significant grade 3 AEs included rash (12%), and colitis, gastritis, pancreatitis, and arthritis each in 1 patient. Common toxicities considered at least possibly related to drug, included: fatigue (28%), transaminitis (36%), rash predominantly with B-I (25%) versus 8% combined B-N, and B-N-I, peripheral neuropathy (53%) and diarrhea (43%), primarily grade 1-2.

**Response:** Five patients: (1 each B-I, B-N, and 3 B-N-I) were unevaluable for response. For the entire cohort the ORR/CR is 76%/57% (B-I), 88%/61% (B-N), and 82%/73% (B-N-I). For patients with at least 2 cycles of therapy and one imaging time point the ORR/CR is 80%/60%, 94%/64%, and 95%/84% for B-I, B-N and B-N-I respectively. With a median follow-up of 2.98 years, 2 years, and 1.35 years the 1 year PFS is 60%, 68%, and 72% for B-I, B-N and B-N-I respectively. The median OS has not been reached for any of the arms (Figure 1).

**Conclusion:** All combinations were well tolerated, with mainly grade 1-2 immune toxicities, however deaths secondary to pneumonitis

were noted in N containing cohorts. The ORR and CR rate in the N containing cohorts is superior to that of B-I doublet; the CR of B-N-I is higher than both doublet combinations and some patients have durable responses. It remains to be seen if a higher CR rate will eventually translate into more durable response rates. The ongoing randomized phase 2 study (E4412) is comparing the B-N doublet to the B-N-I triplet (NCT01896999).

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

**Disclosures:** Diefenbach, C: Consultant Advisory Role: BMS, Merck, Seattle Genetics; Honoraria: BMS, Merck, Seattle Genetics; Research Funding: BMS, Merck, Seattle Genetics.

078

HIGH EXPRESSION OF BCL-2 AND BCL-XL IN DIFFUSE LARGE B-CELL LYMPHOMA CONFER POOR PROGNOSIS BUT MAY BE REVERSIBLE BY COMBINED INHIBITION WITH BET INHIBITORS AND BH3 MIMETICS.

T.E. Cummin¹ | K. Cox¹ | T. Murray¹ | S. Barrans² |

C. Sha³ | D. Westhead³ | C. Burton² | A. Davies⁴ |

M. Cragg¹ | P. Johnson¹ | M. Carter¹

¹Cancer Sciences, University of Southampton, Southampton, United Kingdom; ²Haematalogical Malignancies Diagnostic Service, University of Leeds, Leeds, United Kingdom; ³Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom; ⁴Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom

**Introduction:** Double-hit lymphoma (DHL) and double-expressor (DE) Diffuse Large B cell Lymphoma (DLBCL) are both characterised by dysregulation of MYC and BCL-2, and associated with worse
survival following treatment with current standard of care (R-CHOP). Novel approaches capable of improving response for these subgroups are therefore urgently needed. Surprisingly, venetoclax, a BH3-mimetic that potently inhibits BCL-2, has limited activity in this disease. We therefore sought to understand the expression and potential prognostic relevance of all anti-apoptotic BCL-2 family members, not just BCL-2, in DLBCL and how these might be overcome with new therapeutic approaches. To this end we investigated a novel BET inhibitor (BETi), PLX2853, and its combination with the BH3-mimetics, venetoclax (BCL-2) and WEHI-539 (BCL-xL).

**Methods:** We analysed the relationship between survival and expression of BCL-2 family mRNA using the Whole Genome-DASL array from 928 patients from the REMoDL-B trial. E-myc lymphoma cell lines (LCLs) and DLBCL cell lines (CL) (4 GCB, 3 ABC) were utilised to dissect potential mechanisms of cell death following exposure to BETi and BH3-mimetics. Techniques employed included qPCR, western blot, immunoprecipitation, retroviral transduction, flow cytometry and in-vivo mouse studies.

**Results:** We identified differential mRNA expression patterns of anti-apoptotic BCL-2 family members in DLBCL subtypes. These had prognostic relevance: specifically, across sub-types high BCL-2 conferred poor response to R-CHOP, whilst in GCB DLBCL high BCL-xL was associated with worse survival.

In Eμ-myc LCLs, a novel BETi developed by structure-based design, PLX2853, induced cell death at lower concentrations than other agents of its class. Cell death was mediated by upregulation of the pro-apoptotic protein, BIM, associated with downregulation of the suppressive miR-17~92.

When Eμ-myc LCLs were transduced to overexpress BCL-2 or BCL-xL, reflecting the situation in DLBCL they became resistant to PLX2853. Similar resistance to BETi was seen in human DLBCL CLs. E-myc LCLs overexpressing BCL-2 or BCL-xL could be resensitised to BETi through combination with venetoclax or WEHI-539, respectively, and this was associated with priming of anti-apoptotic proteins with BIM.

In GCB DLBCL CLs, BIM upregulation in response to PLX2853 was identified. The combination of PLX2853 and venetoclax produced synergistic increases in cell death, resulting in reduced tumour growth and enhanced survival in NSG mice bearing DLBCL xenografts.

**Conclusion:** We identified a varied landscape of expression of anti-apoptotic BCL-2 proteins in DLBCL and highlighted the contribution of high BCL-xL expression to treatment resistance in DLBCL. High expression of anti-apoptotic BCL-2 family members also provides resistance to BETi. However, this could be overcome by use of specific BH3-mimetics targeting the relevant pro-survival BCL-2 member, involving mitochondrial priming.

**Keywords:** "double-hit" lymphomas; BCL2; venetoclax.

**Disclosures:** Cummin, T: Research Funding: Plexxikon. Barrans, S: Other Remuneration: HTG. Burton, C: Consultant Advisory Role: Roche, Takeda, BMS, Celgene; Honoraria: Roche, Takeda, BMS; Other Remuneration: Roche. Davies, A: Consultant Advisory Role: Roche, Kite, Celgene, Acerta, MorphoSys, BioInvent; Honoraria: Roche, Celgene, Kite, Janssen; Research Funding: Roche, Acerta, Celgene, Gilead,

Karyopharma, GSK; Other Remuneration: Roche, Celgene. Cragg, M: Consultant Advisory Role: Bioinvent International, Roche, Boehringer Ingelheim, Baxalta and GLG; Research Funding: Bioinvent, Roche, Iteos, Gilead and GSK. Johnson, P: Consultant Advisory Role: Janssen; Honoraria: Bristol-Myers Squibb, Takeda, Novartis, Celgene, Janssen, Epizyme; Research Funding: Janssen, Epizyme.

## FOCUS ON... SESSION: NON-CLINICAL NEW DRUGS

079

### FIRST-IN-CLASS HAT ACTIVATOR HIGHLY SYNERGISTIC WITH PAN-HDAC INHIBITOR ROMIDEPSIN LEADING TO PROFOUND HISTONE ACETYLATION CYTOTOXICITY

Y. Liu<fnref n="1" /> | J. Fiorito² | Y. Gonzale<fnref n="1" /> | E. Zuccarello² |
E. Calcagno² | J.M. Camarillo<fnref n="3" /> | P.M. Thomas<fnref n="3" /> |
N. Kelleher<fnref n="3" /> | S. Deng<fnref n="4" /> | D. Landry<fnref n="4" /> |
O.A. O'Connor<fnref n="1" /> | A.J. Wolfe⁵ | B. Moyer⁵ |
O. Arancio² | J. Amengual<fnref n="1" />

**Introduction:** Inactivating mutations of the histone acetyltransferase (HAT) coding genes, EP300 and CREBBP, present in ~40% of germinal center (GC) derived lymphomas. Mutations are monoallelic, suggesting that their activity may be restored if the wildtype allele's function can be enhanced.

**Methods:** Starting from parent compound CTPB, a library of 70 HAT modulating analogues was synthesized. The cytotoxic effects were evaluated by cell TiterGlo. Functional effects on the acetylation of histone was measured by immunoblot in cell free assays. Histone acetylation was measured in cells following histone extract and immunoblot or mass spectrometry. P53 acetylation was measured by immunoblot. Binding of lead HAT compound YF2 to p300 was determined by recording ¹H-¹⁵N HSQC NMR spectra of recombinant ¹⁵N-enriched p300-bromodomain. Synergy was calculated by Excess over Bliss (EOB>10 = synergy). SCID-beige mice were xenografted with SUDHL6 and treated with either vehicle, YF2 40mg/kg, romidepsin 2mg/kg or the combination. Mice were evaluated for tumor volume by caliper. Survival was determined using the Kaplan Meier method.

**Results:** The IC50 of 29 compounds ranged from 3.6-43.2 µM in 4 DLCBL cell lines. Four compounds demonstrated significant dose

<footnote n="1">¹Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, United States; ²TAUB Institute, Columbia University Medical Center, New York, United States;</footnote>

<footnote n="3">³Departments of Chemistry and Molecular Biosciences and the Feinberg School of Medicine, Northwestern University, Chicago, United States;</footnote>

<footnote n="4">⁴Experimental Therapeutics, Department of Medicine, Columbia University Medical Center, New York, United States; ⁵Ichor Therapeutics Inc, Lafayette, United States</footnote>
dependent increase in acH3K27 (EC50 9.4 ± 3.1 - 152.7 ± 0.8 nM) and acH3K18 (EC50 83.4 ± 1.3 - 269.9 ± 0.8 nM). YF2 was chosen as the lead compound because it demonstrated functional effect on acetylation and selective cytotoxicity in EP300 mutated versus WT cell lines (medium IC50 5 µM and 19 µM respectively, p<0.0005). In cells, YF2 induced acetylation of H3K27 6-fold and p53 5-fold. YF2 induced acH3K27 in mouse lymphoma tissue 2-fold. The IC50 of YF2 ranged from 5.9 to 25 µM in DLBCL lines (N=11) and 4.4 to 14 µM in TCL lines (N=6). YF2 induced cytotoxicity in 3 primary patient samples including a FL patient (CREBBP and p53 mutated). The addition of YF2 induced numerous chemical shift perturbations throughout the ¹H-¹⁵N HSQC NMR spectrum of ¹⁵N-enriched p300-bromodomain indicating binding.

The combination of YF2 and romidepsin demonstrated strong synergism in 8 out of 11 DLBCL cell lines (6/6 EP300 mut, 2/5 wt, EOB=48) and 2 out of 4 TCL lines (EP300 wt, EOB=28). The combination led to enhanced acetylation in multiple histone marks compared to single agents. In mice, the combination of YF2 and romidepsin was well tolerated with no weight loss. Single agent treatment with YF2 or romidepsin led to equivalent tumor growth delay and the combination was superior. Mice treated with the combination demonstrated a significant prolonged survival.

**Conclusions:** YF2 induces HAT-mediated acH3K27 and Acp53. It demonstrates selective cytotoxicity in EP300-mutated DLBCL and strong synergy with romidepsin in DLBCL and TCL. The combination demonstrated significant tumor growth delay in mice suggesting a potential precision medicine opportunity for patients harboring HAT mutations.

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

**Disclosures:** Liu, Y: Research Funding: Appia Pharmaceuticals. O'Connor, O: Research Funding: Celgene; ADC Therapeutics; Seattle Genetics. Amengual, J: Research Funding: Appia Pharmaceuticals.

080
COPANLISIB AND VOLASERTIB
OVERCOME IBRUTINIB-VENETOCLAX
RESISTANCE VIA TARGETING PI3K-AKT
SIGNALING AND G2/M CELL CYCLE
TRANSITION IN MANTLE CELL
LYMPHOMA

R. Zhang | W. Lee | S. Huang | Y. Liu |
A.H. Leeming | J.M. McIntosh | K.J. Nomie |
C.V. Jiang | M. Wang

Lymphoma/Myeloma, University of Texas, MD Anderson Cancer Center,
Houston, United States

**Background:** Mantle cell lymphoma (MCL) is an aggressive and incurable non-Hodgkin lymphoma (NHL). Bruton's tyrosine kinase (BTK) and anti-apoptotic proteins, including BCL2, promote MCL survival and progression. BTK inhibitor ibrutinib and BCL2 inhibitor venetoclax alone or in combination have proven to be effective treatment options for MCL. However, mono- and dual resistance frequently develops, necessitating the development of new therapies to overcome primary and acquired ibrutinib and venetoclax resistance in MCL.

**Methods:** Cell viability, cell apoptosis and cell cycle arrest assays were conducted to investigate the *in vitro* efficacies of copanlisib and

<figure><img src="image_53.png" /></figure>

**Figure 1. Copanlisib and volasertib overcome ibrutinib-venetoclax dual-resistance in orthotopic MCL PDX models.** An orthotopic PDX model was established using a primary MCL sample from a patient with ibrutinib-venetoclax dual resistance. The PDX cells were isolated and injected intravenously into NSG mice and allowed to engraft for 4 four weeks. The mice were administrated with single agents copanlisib at 6 mg/kg/2d, idelalisib at 50 mg/kg/2d, or vehicle (A), or ibrutinib at 50 mg/kg/d, volasertib at 10 mg/kg/week, or vehicle (B) for 4 weeks. At the end of experiments, spleen weight was measured and plotted. Spleen weight of normal NSG mice was also included (A-B). ***, p<0.001; ****, P<0.0001.
volasertib alone or in combination. Western blotting was conducted to investigate the signaling pathways altered upon drug treatment. An orthotopopic PDX model was established from a MCL patient with dual resistance to ibrutinib-venetoclax. Single agent copanlisib at 6 mg/kg/2d, idelalisib at 50 mg/kg/2d, ibrutinib at 50 mg/kg/d, volasertib at 10 mg/kg/week, or vehicle control, were administrated in mice carrying the orthotopic PDX model to assess their *in vivo* efficacies.

**Results:** Our data revealed that PI3K-AKT signaling closely associated with ibrutinib resistance, venetoclax resistance and dual resistance. Constitutive PI3K-AKT-mTOR signaling overcomes the G2/M cell cycle checkpoint and promote continuous cell proliferation in tumor cells. All four isoforms of PI3K, α, β, γ and δ are expressed in all the MCL cell lines tested. Unlike idelalisib, a PI3Kδ-specific inhibitor, copanlisib is a pan-PI3K inhibitor, which targets all PI3K isoforms, and was approved by FDA to treat follicular lymphoma. Compared to idelalisib, copanlisib is more potent in targeting MCL cells *in vitro* with IC50 at a nanomolar range. Copanlisib significantly inhibited *in vivo* tumor growth of an ibrutinib-venetoclax dual-resistant PDX model (Fig. 1A). PLK1, a central player in regulating G2/M transition, acts upstream of PI3K/AKT signaling via phosphorylating PTEN to cause a tumor-promoting metabolic state. Volasertib, a specific PLK1 inhibitor, is under a phase III clinical trial for patients with Acute Myeloid Leukemia. Volasertib dramatically arrested MCL tumor cells at G2/M phase, which leads to cell apoptosis at a low nanomolar range. Volasertib at 10mg/kg/week significantly inhibited *in vivo* tumor growth of the ibrutinib-venetoclax dual -resistant PDX model (Fig. 1B). More interestingly, the combination of copanlisib and volasertib induced synergistic effect in ibrutinib-resistant, venetoclax-resistant, and ibrutinib-venetoclax dual resistant cell lines. Detailed mechanism of the observed synergy is still under investigation *in vitro* and *in vivo*.

**Conclusion:** Copanlisib and Volasertib are potent agents in targeting MCL cells *in vitro* and *in vivo*, and have great potential to overcome ibrutinib and venetoclax resistance in MCL.

**Keywords:** BCL2; mantle cell lymphoma (MCL); PI3K/AKT/mTOR.

081

THE LANDSCAPE OF DRUG PERTURBATION EFFECTS IN LEUKEMIA AND LYMPHOMA

S. Scheinost<fnref n="1" /> | J. Lu² | L. Wagner<fnref n="1" /> | J. Huellein² |

T. Walther<fnref n="1" /> | L. Sellner<fnref n="1" /> | A. Theocharides³ |

B. Bornhäuser⁴ | M. Kühn⁵ | T. Kindler⁵ |

F. Florence Nguyen-Khac⁶ | M. Crespo Maull⁷ |

F. Bosch⁷ | M. Manz³ | J. Bourquin⁴ | S. Dietrich<fnref n="1" /> |

W. Huber² | T. Zenz³

Switzerland; ⁵Haematology and Oncology, University Hospital Mainz, Mainz, Germany; ⁶Haematology, Hôpitaux Universitaires Pitié Salpêtrière, Paris, France; ⁷Haematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain

**Introduction:** As new generations of targeted therapies emerge, the functional relationships of mutations to tumor phenotypes or drug response remain largely unknown. Here, we measured ex vivo sensitivity of 710 tumor samples from 18 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We also included sequential samples from CLL over the disease course.

**Methods:** Compounds were pre-diluted in dimethylsulfoxide and cryopreserved primary cells were cultured in RPMI 1640 medium containing 10% human AB serum and seeded on top of the drugs at a final concentration of 1 x 10⁶ cells/ml in a 384 well format. After 48h (37°C, 5% CO₂), cell viability was determined by luminescence measurement (EnVision Plate Reader, PerkinElmer) using an ATP assay (CellTiter-Glo, Promega). Raw data were processed using a data analysis pipeline (R/Bioconductor package cellHTS2) which enabled visualization of data. Accuracy and reproducibility were confirmed with technical (n=9; R²>0.9) and biological replicates (R²=0.7-0.9). In total 710 blood samples were screened on this platform. 347 samples were obtained from 141 patients at different clinical time points were used for longitudinal investigation.

**Results:** To obtain a global overview of drug response, we used hierarchical clustering and T-SNE of all patients and found that disease and genotypes show differential drug response. IGHV status, trisomy 12 and individual gene mutations were associated with drug response to multiple drugs (n>10). p53 mutation was associated with decreased response to *in vitro* treatment with Cytarabine, Fludarabine and Nutlin-3a (n=321; 2µM; p<0.05). We identified drugs with disease specific response for individual lymphomas including T-PLL. The analysis of sequential samples showed stable drug response over time in most patients but also revealed that a subset of patients who underwent *in vivo* treatment with Idelalisib or Ibrutinib (n=16) showed changes in *in vitro* sensitivity to several small molecule inhibitors. BCR inhibitor therapy led to higher sensitivity to bromodomain inhibitor OTX015 and less sensitivity to heat shock protein 90 inhibitors Ganetespib and Onalespib (all 2µM; p<0.05) in line with activity of HSP inhibitors mediated through BCR targeting.

**Conclusion:** Ex-vivo high-throughput drug screening discovers entity/genotype-specific vulnerabilities. BCR inhibitors lead to alteration of drug sensitivity pattern which can be assessed and may form the basis for optimized combination treatment. Our data of drug response profiles and Omics characterization will provide a unique tool to query molecular determinants of response and thus provide hypothesis for clinical trials.

**Keywords:** B-cell receptor inhibitors; chronic lymphocytic leukemia (CLL); non-Hodgkin lymphoma (NHL).

<footnote n="1">¹Molecular Therapy n Haematology and Oncology, NCT, Heidelberg, Germany; ²Genome Biology, EMBL, Heidelberg, Germany; ³Medical Oncology and Haematology, University Hospital Zürich, Zürich, Switzerland; ⁴Pediatric Oncology, Childrens' Hospital Zürich, Zürich,</footnote>
082
DISCOVERY OF A NOVEL, POTENTIAL
FIRST-IN-CLASS MALT1 PROTEASE
INHIBITOR FOR THE TREATMENT OF B
CELL LYMPHOMAS

U. *Philippar*¹ | T. *Lu*² | N. *Vloemans*¹ |
M. *Bekkers*¹ | L. *van Nuffel*¹ | M. *Gaudiano*¹ |
K. *Wnuk-Lipinska*¹ | B. *Van Der Leede*³ |
K. *Amssoms*⁴ | K. *Kimpe*⁵ | B. *Medaer*⁶ |
T. *Greway*⁷ | Y. *Abraham*⁸ | M. *Cummings*⁹ |
E. *Trella*¹⁰ | G. *Vanhoof*¹⁰ | W. *Sun*¹¹ |
J. *Thuring*¹² | P. *Connolly*² | J. *Linders*¹³ |
J. *Gerecitano*¹⁴ | J. *Goldberg*¹⁴ | J. *P. Edwards*² |
Y. *Elsayed*¹⁵ | J. *Smit*¹⁶ | J. *Bussolari*¹⁶ | R. *Attar*¹⁵

¹Oncology Discovery, Janssen Research & Development, Beerse, Belgium;

²Discovery Chemistry, Janssen R&D, Springhouse, United States;

³Nonclinical Safety, Janssen R&D, Beerse, Belgium; ⁴PDM, Janssen R&D, Beerse, Belgium; ⁵Pharmaceutical Sciences, Janssen R&D, Beerse, Belgium; ⁶Portfolio Management, Janssen R&D, Beerse, Belgium; ⁷DMPK, Janssen R&D, Raritan, United States; ⁸Computational Biology, Janssen R&D, Beerse, Belgium; ⁹Computational Chemistry, Janssen R&D, Springhouse, United States; ¹⁰Molecular and Cellular Pharmacology, Janssen R&D, Beerse, Belgium; ¹¹Molecular and Cellular Pharmacology, Janssen R&D, Springhouse, United States; ¹²Discovery Chemistry, Janssen R&D, Beerse, Belgium; ¹³Project Management, Janssen R&D, Beerse, Belgium; ¹⁴Experimental Medicine, Janssen R&D, Raritan, United States; ¹⁵Oncology Heme DAS, Janssen R&D, Springhouse, United States; ¹⁶CDTL Oncology, Janssen R&D, Springhouse, United States

**Introduction:** Constitutive activation of the classical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) pathway is a clear driver of B-cell lymphomas, especially the aggressive activated B cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key mediator of the classical NF-κB signaling pathway downstream of B-cell and T-cell receptor. MALT1 possesses 2 functions: a scaffolding function to recruit NF-κB signaling proteins and a protease function to cleave and inactivate inhibitors of the NF-κB signaling pathway.

**Methods:** Using a high-throughput screen followed by iterative structure-activity relationship (SAR) analyses, a lead MALT1 inhibitor was identified. The lead compound was evaluated using biochemical, in vitro cellular, in vivo tumor efficacy and safety models.

**Results:** The lead compound is a potent, selective, allosteric inhibitor of MALT1 protease activity as measured by biochemical assays, downstream cellular cytokine readouts (IL 6/10) or direct MALT1 substrate cleavage (RelB, BCL10). The compound inhibits proliferation of activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell lines bearing CD79b or CARD11 mutations as well as models mimicking resistance to covalent Bruton's Tyrosine Kinase (BTK) inhibitors.

Furthermore, combination effects were observed in CD79b-mutant cellular ABC-DLBCL models when the lead MALT1 inhibitor was combined with a BTK inhibitor. The lead MALT1 inhibitor leads to potent in vivo pharmacodynamic shutdown in CD79b- as well as CARD11-mutant ABC-DLBCL models as measured by serum IL10 or uncleaved BCL10 levels in tumors. The lead MALT1 inhibitor exhibits potent tumor growth inhibition in two human DLBCL xenograft models, OCI-Ly3 and OCI-Ly10.

To address the role of MALT1 inhibition in T cells, primary human T cells derived from normal healthy volunteers were treated with the lead MALT1 inhibitor in vitro. Dose dependent inhibition of the generation of T<sub>regs</sub> (CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup>) following CD3/28 stimulation was observed upon treatment with the lead MALT1 inhibitor suggesting a potential immune modulatory role of MALT1 inhibition.

**Conclusions:** Phase 1 clinical trials assessing the safety and efficacy of the lead MALT1 inhibitor are planned to initiate in 2019. This MALT1 inhibitor is a combination partner for BTK inhibitors and a promising treatment option for BTKi-resistant tumors with demonstrated pre-clinical activity in CARD11 mutant tumors. In addition to ABC-DLBCL, a MALT1 inhibitor is a promising treatment option for patients with CLL, MCL, WM and FL whose tumors have been shown to be sensitive to inhibition of BTK. MALT lymphomas, characterized by MALT1 and BCL10 translocations, represent another attractive target for MALT1 inhibition.

**Keywords:** BTK inhibitors; diffuse large B-cell lymphoma (DLBCL); MALT1.

**Disclosures:**
**Philippar, U:** Employment Leadership Position: Janssen R&D. **Lu, T:** Employment Leadership Position: Janssen R&D. **Vloemans, N:** Employment Leadership Position: Janssen R&D. **Bekkers, M:** Employment Leadership Position: Janssen R&D. **van Nuffel, L:** Employment Leadership Position: Janssen R&D. **Gaudiano, M:** Employment Leadership Position: Janssen R&D. **Wnuk-Lipinska, K:** Employment Leadership Position: Janssen R&D. **Van Der Leede, B:** Employment Leadership Position: Janssen R&D. **Amssoms, K:** Employment Leadership Position: Janssen R&D. **Kimpe, K:** Employment Leadership Position: Janssen R&D. **Medaer, B:** Employment Leadership Position: Janssen R&D. **Greway, T:** Employment Leadership Position: Janssen R&D. **Abraham, Y:** Employment Leadership Position: Janssen R&D. **Cummings, M:** Employment Leadership Position: Janssen R&D. **Trella, E:** Employment Leadership Position: Janssen R&D. **Vanhoof, G:** Employment Leadership Position: Janssen R&D. **Sun, W:** Employment Leadership Position: Janssen R&D. **Thuring, J:** Employment Leadership Position: Janssen R&D. **Connolly, P:** Employment Leadership Position: Janssen R&D. **Linders, J:** Employment Leadership Position: Janssen R&D. **Gerecitano, J:** Employment Leadership Position: Janssen R&D. **Goldberg, J:** Employment Leadership Position: Janssen R&D. **Edwards, J:** Employment Leadership Position: Janssen R&D. **Elsayed, Y:** Employment Leadership Position: Janssen R&D. **Smit, J:** Employment Leadership Position: Janssen R&D. **Bussolari, J:** Employment Leadership Position: Janssen R&D. **Attar, R:** Employment Leadership Position: Janssen R&D.
083

KYM-001, A FIRST-IN-CLASS ORAL IRAK4
PROTEIN DEGRADER, INDUCES TUMOR
REGRESSION IN XENOGRAFT MODELS OF
MYD88-MUTANT ABC DLBCL ALONE AND
IN COMBINATION WITH BTK INHIBITION

J. Kelleher | V. Campbell | J. Chen | J. Gollob |
N. Ji | H. Kamadurai | C. Klaus | H. Li | C. Loh |
A. McDonald | H. Rong | S. Rusin | K. Sharma |
D. Vigil | D. Walker | M. Weiss | K. Yuan |
Y. Zhang | N. Mainolfi

Discovery, *Kymera Therapeutics*, Cambridge, United States

**Introduction:** ABC DLBCL comprises approximately 45% of DLBCL and has a worse outcome with R-CHOP chemotherapy compared to GCB DLBCL. Activating mutations in MYD88 occur in 30-40% of ABC DLBCL; L265P, the most prevalent MYD88 mutation, causes constitutive assembly and activation of the Myddosome. IRAK4 kinase and scaffolding functions are essential for full signaling through the Myddosome to NFκB and MAPK pathways. Kymera Therapeutics is using a chemical knockdown strategy to develop heterobifunctional small molecule IRAK4 degraders, exemplified by KYM-001, for the treatment of MYD88-driven B cell malignancies.

**Methods:** IRAK4 in human PBMC, ABC DLBCL cell lines and tumor xenografts was quantified by immunoassays or targeted mass spectrometry. Cell viability and cell cycle were monitored by flow cytometry. Tumor xenograft studies were conducted by implanting human ABC DLBCL lines into immunocompromised mouse strains.

**Results:** KYM-001 led to potent E3 ligase-dependent degradation of IRAK4. Notably, KYM-001 more effectively inhibited TLR-activated Myddosome signaling compared to IRAK4 kinase inhibitors in human whole blood. Degradation was highly selective for IRAK4 vs >10,000 other detected proteins in the MYD88 L265P mutant ABC DLBCL line OCI-LY10. IRAK4 degradation by KYM-001 resulted in cell cycle inhibition and apoptosis within 72 h in MYD88-mutant ABC DLBCL. Since mutations in MYD88 frequently co-occur with CD79 mutations in B-cell malignancies, we investigated the potential for combined activity of IRAK4 degradation with BTK or PI3Kδ inhibition. In the OCI-LY10 and TMD8 cell lines, which have activating mutations in both MYD88 and CD79B, BTK inhibition with ibrutinib or PI3Kδ inhibition with umbralisib both synergized with KYM-001 to induce cell death in vitro.

Oral dosing of KYM-001 showed dose-dependent antitumor activity in several mouse xenograft models of human MYD88-mutant ABC DLBCL at tolerated doses and schedules. In the OCI-LY10 model, tumor regression was associated with >80% degradation of IRAK4, establishing the pharmacodynamic effect required for maximal efficacy. Combination of KYM-001 with ibrutinib drove tumor regression in both OCI-LY10 and TMD8 at suboptimal doses of each agent. Hypothesis-driven combination studies with

umbralisib and other drugs with activity in DLBCL, including lenalidomide, are in progress in MYD88-mutant DLBCL xenograft models.

**Conclusions:** KYM-001 is a first-in-class, potent, selective and orally active IRAK4 degrader that causes tumor regression in MYD88-mutant ABC-DLBCL models. Degradation of IRAK4 removes both the kinase and scaffolding functions of IRAK4, and may be superior to kinase inhibition alone. These data support clinical development of IRAK4 degraders as a promising new therapeutic opportunity for MYD88-driven lymphoma, both alone and in combination with inhibitors of complementary pathways.

**Keywords:** B-cell lymphoma; MYD88.

**Disclosures:** Kelleher, J: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Campbell, V: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Chen, J: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Gollob, J: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Ji, N: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Kamadurai, H: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Klaus, C: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Vigil, D: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Rong, H: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Loh, C: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. McDonald, A: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Sharma, K: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Weisss, M: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Yuan, K: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Zhang, Y: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Mainolfi, N: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics.

084

THE ANTIBODY-DRUG CONJUGATE (ADC)
LONCASTUXIMAB TESIRINE (ADCT-402)
TARGETING CD19 SHOWS STRONG IN
VITRO ANTI-LYMPHOMA ACTIVITY BOTH
AS SINGLE AGENTS AND IN
COMBINATION
C. Tarantelli¹ | F. Spriano¹ | G. Golino¹ |
E. Gaudio¹ | L. Scalise¹ | L. Cascione¹ | E. Zucca² |
P. van Berkel³ | A. Stathis² | F. Zammarchi³ | F. Bertoni¹

¹Lymphoma Genomics, Università della Svizzera Italiana, Institute of
Oncology Research, Bellinzona, Switzerland; ²OSI, Oncology Institute of
Southern Switzerland, Bellinzona, Switzerland; ³Pharmacology, ADC
Therapeutics, London, United Kingdom

**Introduction:** Loncastuximab tesirine (ADCT-402) is an anti-CD19 antibody-drug conjugate (ADC) conjugated via a protease cleavable linker to SG3199, a highly cytotoxic DNA minor groove cross-linking pyrrolobenzodiazepine dimer (PMID 29298756). ADCT-402 is in phase 2 as single agent for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) (NCT03589469) and in phase 1 in different combinations (NCT03684694 and NCT03685344). Here, we further assessed its preclinical activity as single agent and in combination with approved drugs in lymphoma cell lines.

**Methods:** MTT proliferation assay and IC50 calculation on cell lines exposed (96h) to increasing ADCT-402 concentrations. Pearson correlation (r): calculated for IC50s vs cell surface CD19 expression levels (absolute fluorescence quantitation with Quantum Simply Cellular microspheres; non-absolute, data from PMID 29298756) and vs RNA levels (Illumina HT-12 arrays and HTG EdgeSeq Oncology Biomarker Panel data from PMID 29066507). Synergy at 96h was assessed by Chou-Talalay combination index (CI) (synergism CI<0.9, additive CI=0.9-1.1, antagonism/no benefit CI> 1.1) on 2 activated B cell like (ABC) DLBCL (OCI-LY-3, TMD8) and 2 germinal center (GCB) DLBCL (VAL, WSU-DLCL2).

**Results:** Median ADCT-402 IC50 was 4 pM (95%CI, 2-10 pM) in 48 B-cell lymphoma lines, and, as expected based on CD19 expression pattern, over 800 times higher in 9 T-cell lymphoma lines (3.5 nM; 95%CI, 0.8-11 nM).

Focusing on B-cell lymphomas, ADCT-402 *in vitro* activity was correlated with its target expression measured both at cell surface protein level [(absolute quantitation, n=40, r -0.37 P 0.02; non-absolute quantitation, n=42, -0.48, P 0.001] and RNA level [(arrays, n=39, -0.69 P <0.001; HTG, n=31, -0.73 P 0.001]. In DLBCL, the presence of BCL2 and MYC translocations or TP53inactivation did not affect the sensitivity to ADCT-402.

ADCT-402 was then combined in GCB- and ABC- DLBCL cell lines with the BCL2 inhibitor venetoclax, the PIK3delta inhibitor idelalisib, the PIK3 inhibitor copanlisib, the proteasome inhibitor bortezomib (ABC only), the BTK inhibitor ibrutinib (ABC only), the chemotherapy agent bendamustine and with the PARP inhibitor olaparib. Synergism in all cell lines was achieved combining ADCT-402 with venetoclax and with idelalisib and in all but OCI-LY-3 with bendamustine. Synergism was observed in half of the cell lines tested with copanlisib (OCI-LY-3, VAL), ibrutinib, and olaparib (VAL, WSU-DLCL2). No advantage was seen adding bortezomib and lenalidomide to the ADCT-402 in the two ABC DLBCL (TMD8, OCI-LY-3).

**Conclusion:** The strong single agent *in vitro* anti-lymphoma activity of ADCT-402 correlated with its target expression and supports the currently on-going clinical studies in relapsed/refractory DLBCL. The novel combination data provide rational for further clinical development.

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

**Disclosures:** Cascione, L: Other Remuneration: travel grant from HTG.

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. van Berkel, P: Employment Leadership Position: ADC Therapeutics. Stathis, A: Research Funding: Bayer, Roche, ADC Therapeutics; Other Remuneration: travel grant from AbbVie. Zammarchi, F: Employment Leadership Position: ADC Therapeutics. Bertoni, F: Consultant Advisory Role: Helsinn, Menarini; Research Funding: Acerta, ADC Therapeutics, Bayer AG, Immunogen, Menarini; Other Remuneration: expert statements provided to HTG; travel grants from HTG, Astra Zeneca.

FOCUS ON... SESSION: HIGH RISK LARGE B-CELL LYMPHOMAS

085

EBV+ CNS LYMPHOMAS HAVE A
DISTINCTIVE TUMOR

MICROENVIRONMENT AND GENETIC
PROFILE, WHICH IS AMENABLE TO
COMBINATION 3RD PARTY EBV-SPECIFIC
CTL AND IBRUTINIB THERAPY

M.K. Gandhi¹,⁸ | T. Hoang² | J.W. Tobin¹ |
S.C. Law¹ | D. Talaulikar³ | S. Jain⁴ | F. Vari² |
V. Murigneux² | L. Fink² | J. Gunawardana¹ |
C. Gould¹ | H. Oey¹ | S. Delecluse⁵ | R.U. Trappe⁶ |
L. Merida de Long¹ | M.B. Sabdia¹ | G. Bhagat⁷ |
G. Hapgood⁸ | E. Blyth⁹ | L. Clancy¹⁰ | J. Casey¹¹ |
J. Wight¹² | E. Hawkes¹² | C. Keane¹,⁸

¹Mater Research UQ, Brisbane, Australia; ²Blood Cancer Research, Diamantina Institute UQ, Brisbane, Australia; ³Haematology, ANU, Canberra, Australia; ⁴Pathology, Canberra Hospital, Canberra, Australia; ⁵DKFZ, German Cancer Research Centre, Heidelberg, Germany; ⁶Hematology, DIAKO, Bremen, Germany; ⁷Pathology and Cell Biology, Institute for Cancer Genetics, New York, United States; ⁸Haematology, Princess Alexandra Hospital, Brisbane, Australia; ⁹Westmead Institute for Medical Research, University of Sydney, Westmead, Australia; ¹⁰Cellular Therapies, NSW Government Health Pathology, Westmead, Australia; ¹¹Haematology, Townsville Hospital, Townsville, Australia; ¹²Olivia Newton-John Cancer Research Institute, Heidelberg, Australia

**Introduction:** Primary CNS Lymphomas (PCNSL) with DLBCL histology in the immunosuppressed, e.g. after HIV (HIV+ PCNSL) or organ
<figure><img src="image_54.png" /><figcaption>**Fig 1.** (A) NFκB signalling is significantly upregulated in a PCNSL line (brain TK) infected with EBV compared to the non-EBV infected brain TK (p<0.05). Data represent 3 independent experiments. (B) CD8 T cells specific to the EBV antigens present in the PCNSL tissue (LMP2-FLY, BMLF1-GLC and BZLF1-RAK) were detected in CD3+ CD8+ T cells in PBMC taken 1-2 hours post CTL infusion. Shown are representative FACS plots from a patient receiving 3rd Party CTL (matched for A2 and B8) for which the latent antigen LMP2-FLY and lytic antigens BMLF1-GLC and BZLF1-RAK were present at 3.7%, 11.7% and 12.9% of IFNγ+ CD3+ T cells, respectively, in the CTL product. (C) EBV antigen specific CD8 T cells were enriched in an effector memory phenotype (CCR7-ve CD45RA-ve) compared to the non-antigen specific CD8 T cells.</figcaption></figure>

transplant (EBV+ PCNSL-PTLD: where anti-PD-1 is contraindicated), are characterized by dismal outcome and almost universal EBV positivity. However, incidence is low, biopsy material limited and immunogenetic characterization minimal. We provide detailed data (308 patients) comparing the genetic landscape and tumor microenvironment (TME) of EBV+ PCNSL-PTLD (22); HIV+ PCNSL (24); EBV-PCNSL (41); EBV- systemic (sy) DLBCL (199) and EBV+ syPTLD (22), which led to implementation of a rationally designed combination therapy.

**Methods:** Targeted sequencing, CNV analysis, nanoString (for immune checkpoints and effectors, and macrophage gene expression) and *in vitro* assays were used. Based on the findings, a novel regimen was administered to patients' refractory to or unsuitable for frontline therapy. Sequential imaging, pharmacokinetic (PK) and T cell assays were performed.

**Results:** Mutational burden was much lower in EBV+ lymphomas than EBV- lymphomas (p<0.0001). Notably, genetic aberrations in BCR-NFB were rarely observed in EBV+ PCNSL-PTLD and HIV+ PCNSL, and (unlike EBV- PCNSL) in these patients, *HLAI/II copy number loss was largely absent*. Mutations in CARD11 (which confers ibrutinib resistance) were also rare in EBV+ PCNSL-PTLD and HIV+ PCNSL. By nanoString analysis, EBV+ PCNSL-PTLD expressed higher levels of the immunosuppressive 'M2' macrophage marker

CD163 and LAG3 and PD-L1/L2 (p<0.001), and high levels of EBV protein LMP1 (known to upregulate PD-L1/L2 and NFB). *In vitro* co-incubation experiments showed a PCNSL line upregulated CD163⁺ PD-L1/L2⁺ M2 polarized monocyte/macrophages relative to a systemic DLBCL line (≥7-fold, p<0.001), and EBV infection of a PCNSL line enhanced NFB activity (Fig 1A). Three immunosuppressed patients (2 frontline, 1 refractory, ages 30-70yrs) with EBV+ lymphoma (2 PCNSL, 1 CNS + systemic) were treated with ibrutinib (starting dose 560mg) and 3rd party partially HLA matched EBV specific CTL. PK confirmed therapeutic CSF levels, including a patient on haemodialysis. CD8 T cells specific for EBV antigens present in PCNSL were detectable post infusion and had an effector memory phenotype (Fig 1B-C). Microchimerism post infusion was confirmed by ultra-sensitive ddPCR. Toxicity was manageable and all 3 are alive (2CR, 1PR).

**Conclusion:** EBV+ CNSL in the immunosuppressed, have a tolerogenic TME with intact antigen presentation and expression of viral antigens, upregulated NFB signalling and absent CARD11 mutations. Results support combination strategies that cross the Blood Brain Barrier, to block NFB driven oncogenesis (ibrutinib), reconstitute EBV specific T cell immunity (3rd Party EBV specific CTL) and expand the TCR repertoire (ibrutinib). Findings led to an ALLG phase 1 clinical trial (ACTRN12618001541291).
**Keywords:** Epstein-Barr virus (EBV); post-transplant lympho-proliferative disorders (PTLDs); primary CNS lymphoma (PCNSL).

**Disclosures:** **Gandhi, M:** Consultant Advisory Role: Celgene, Merck Sharpe & Dohme, Janssen-Cilag, Gilead, Bristol Myers Squibb; Honoraria: Amgen, Janssen-Cilag, Gilead, Roche, Merck Sharpe & Dohme, Takeda; Research Funding: Celgene, Bristol Myers Squibb, Janssen-Cilag, Gilead; Other Remuneration: Roche. **Tobin, J:** Honoraria: Amgen, Janssen - conference attendance 2017. **Trappe, R:** Consultant Advisory Role: Abbvie, Atara; Research Funding: Hoffmann-La Roche; Other Remuneration: Travel support from Celgene, Janssen, Gildead, Abbvie. **Blyth, E:** Consultant Advisory Role: Abbvie, MSD, Novartis. **Wight, J:** Honoraria: Janssen, Alexion. **Keane, C:** Consultant Advisory Role: Celgene, Gilead, MSD; Other Remuneration: Roche (Conference Travel).

086

YOUNG HIGH RISK PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA INCLUDING BCL-2/MYC DOUBLE HIT LYMPHOMAS BENEFIT FROM DOSE-DENSE IMMUNOCHEMOTHERAPY WITH EARLY CNS PROPHYLAXIS

S. Leppä<fnref n="1" /> | J. Jørgensen² | A. Tierens³ |
L. Meriranta<fnref n="1" /> | I. Østlie⁴ | P. Brown⁵ | U. Fagerli⁶ |
T.S. Larsen⁷ | S. Mannisto<fnref n="1" /> | L. Munksgaard⁸ |
M. Maisenhølder⁹ | K. Vasala¹⁰ | P. Meyer¹¹ |
M. Jerkeman¹² | M. Björkholm¹³ | Ø. Fluge¹⁴ |
S. Jyrkkiö¹⁵ | E. Ralfkiaer¹⁶ | S. Spetalen⁴ |
M. Karjalainen-Lindsberg¹⁷ | H. Holte¹⁸

**Introduction:** Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We aimed to assess, whether a dose-dense immunochemotherapy approach with early systemic CNS prophylaxis improves outcome and reduces the incidence of CNS events.

**Methods:** We conducted a Nordic Lymphoma Group phase II (NLGLBC-05) trial during 2011-2014 in patients aged 18-64 years with untreated DLBCL including BCL-2/MYC double hit lymphomas, and an age-adjusted international prognostic index (aalPI) 2-3 or site specific risk factors for CNS recurrence. Treatment consisted of two courses of high-dose methotrexate (HD-Mtx) in combination with biweekly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP-14), followed by four courses of R-CHOP-14 with etoposide (R-CHOEP-14) and one course of high dose cytarabine with R (R-HD-AraC). In addition, liposomal AraC was administered intrathecally at courses 1, 3 and 5. Our co-primary endpoints were failure free survival and CNS progression rates.

**Results:** Of 143 enrolled patients, 139 patients were eligible with a median age of 56 (range 20-64). The majority of the patients had advanced stage (92%), elevated LDH (91%), more than one extranodal site, (67%) and B-symptoms (63%). Four (2.9%) patients developed AML/MDS. Treatment related death occurred in five (3.6%) patients. Of the 119 patients who underwent PET-CT, 91 (77%) achieved a metabolic CR, and 19 of 35 patients (21%) with CT-based CRu/PR were in metabolic CR according to PET-CT. Only one out of 15 biopsies (9%) from the PET+ lesions contained vital lymphoma.

At five years of median follow-up, failure free survival (FFS), overall survival (OS) and CNS progression rates were 74%, 84% and 2.3%, respectively. Deauville score 5, but not 4 at the end of treatment was associated with increased risk of progression and death. Treatment reduced the risk of progression compared to our previous NLG-LBC-04 trial, where systemic CNS prophylaxis was given after six courses of biweekly R-CHOEP (HR=0.493; 95% CI 0.312-0.780, p=0.003), and overcame the adverse impact of aalPI3 and BCL-2/MYC double hit lymphomas on survival.

**Conclusion:** The results are encouraging with favorable survival rates, low toxic death rate and low number of CNS events.

**Keywords:** "double-hit" lymphomas; CNS prophylaxis; diffuse large B-cell lymphoma (DLBCL).

**Disclosures:** Leppä, S: Research Funding: Mundipharma, Amgen.

087

SAFETY AND EFFICACY OF THE PD-L1 INHIBITOR DURVALUMAB WITH R-CHOP OR R²-CHOP IN SUBJECTS WITH PREVIOUSLY UNTREATED, HIGH-RISK DLBCL

<footnote n="1">¹Department of Oncology, Helsinki University Hospital Comprehensive Cancer Centre, Helsinki, Finland; ²Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; ³Department of Pathology, University Health Network, Toronto, Canada; ⁴Department of Pathology, Oslo University Hospital, Oslo, Norway; ⁵Department of Hematology, Rigshospitalet, Copengahen, Denmark; ⁶Department of Oncology, St. Olavs Hospital, Trondheim, Norway; ⁷Department of Hematology, Odense University Hospital, Odense, Denmark; ⁸Department of Hematology, Roskilde Hospital, Roskilde, Denmark; ⁹Department of Oncology, University Hospital of North Norway, Tromsø, Norway; ¹⁰Department of Oncology, Central Finland Central Hospital, Jyväskylä, Finland; ¹¹Department of Oncology, Stavanger University Hospital, Stavanger, Norway; ¹²Department of Oncology, Skåne University Hospital, Lund, Sweden; ¹³Department of Hematology, Karolinska University Hospital, Stockholm, Sweden; ¹⁴Department of Oncology, Haukeland University Hospital, Bergen, Norway; ¹⁵Department of Oncology, Turku University Hospital, Turku, Finland; ¹⁶Department of Pathology, Rigshospitalet, Copenhagen, Denmark; ¹⁷Department of Pathology, Helsinki University Hospital, Helsinki, Finland; ¹⁸Department of Oncology, Oslo University Hospital, Oslo, Norway</footnote>