**Employment Leadership Position:** Full-time salaried employee of Research Triangle Institute d/b/a RTI Health Solutions, an independent research institute, which was retained by Genentech to conduct the study that is the subject of this abstract. There is no connection between an RTI employee's compensation and the projects on which they work. Information about projects with other clients is confidential.; Research Funding: Full-time salaried employee of Research Triangle Institute d/b/a RTI Health Solutions, an independent research institute, which was retained by Genentech to conduct the study that is the subject of this abstract. There is no connection between an RTI employee's compensation and the projects on which they work. Information about projects with other clients is confidential. Comenencia-Ortiz, E: Employment Leadership Position: Roche, Genentech; Stock Ownership: Roche, Genentech; Other Remuneration: Employment by a for-profit health care company that funded any part of this research: Genentech. Masaquel, A: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. Ravelo, A: Employment Leadership Position: Genentech; Stock Ownership: Genentech.

## 516
REAL-WORLD ASSESSMENT OF PRACTICE EFFICIENCY WITH THE INTRODUCTION OF SUBCUTANEOUS RITUXIMAB

M.J. Matasar¹ | A. Qiu¹ | S. Shapouri² | E.N. Drill³ |

J. Schade¹ | A. Ravelo² | A. Ni³ | T.M. To² |

K.L. Dawson²

¹Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States; ²US Medical Affairs, Genentech, Inc., South San Francisco, CA, United States; ³Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States

**Introduction:** Rituximab (R), available as an intravenous (IV; R-IV) infusion or subcutaneous (SC; R-SC) injection, is used in the treatment of follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukaemia (CLL). This study evaluated real-world practice efficiency changes associated with the adoption of R-SC by studying differences in chair time by route of administration.

**Methods:** We conducted a retrospective analysis of practice care delivery measures before and after adoption of R-SC at Memorial Sloan Kettering Cancer Center (MSKCC). Data for patients (pts) with FL, DLBCL or CLL receiving R-based therapy from September 2016 to September 2018 were extracted from the electronic medical record. A linear mixed effect multivariate model with random intercept was used to analyse the association between treatment type (R-IV vs R-SC) and chair time (defined as the difference in pt room-in and room-out times) in the year prior to and following R-SC adoption at MSKCC. Model covariates included treatment time and location, therapy type (monotherapy vs combination) and pt demographics. Given the prolonged infusion time, pts' first dose of R-IV was excluded from the analysis.

**Results:** Data were collected during 6744 visits (3018 visits prior to R-SC adoption and 3726 after) for 1503 pts receiving R. Pts receiving R-IV combination therapy had a mean chair time of 203 minutes (min); overall, R-SC injection reduced chair time by a mean of 92 min (p<0.001 vs R-IV). Monotherapy, regardless of route, reduced chair time by a mean of 30 min (p<0.001) compared with combination therapy, and mean chair time was further reduced by 39 min (p<0.001) for R-SC pts receiving monotherapy. Reductions in chair time increased over time following initial adoption of R-SC (p=0.042), and were greater at the lymphoma-specific site than multispecialty oncology infusion centres (p<0.001).

**Conclusions:** Adoption of R-SC results in substantial time savings for both the pt and health system as measured by reduced chair time and improved pt throughput. Given increasing constraints on infusion chair space, increased utilisation of R-SC may improve practice efficiency and pt access to care.

**Acknowledgment:** Third-party editorial assistance, under the direction of Annie Qiu and Sheila Shapouri, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

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

**Keywords:** chronic lymphocytic leukemia (CLL); non-Hodgkin lymphoma (NHL); rituximab.

**Disclosures:** Matasar, M: Consultant Advisory Role: Genentech, Bayer, Merck, Juno Therapeutics, Roche, Teva, Rocket Medical, Seattle Genetics; Stock Ownership: Merck; Honoraria: Genentech, Roche, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Seattle Genetics; Research Funding: Genentech, Roche, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Rocket Medical, Seattle Genetics; Other Remuneration: Genentech, Roche, Seattle Genetics, Bayer. Shapouri, S: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. Ravelo, A: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc. To, T: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc. Dawson, K: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche/Genentech, Inc.

## 517
GRANISETRON TRANSDERMAL DELIVERY SYSTEM USE IN LYMPHOPROLIFERATIVE DISEASE: A SINGLE CENTER EXPERIENCE

P. Minga | C. Muzi | V. Zilioli | E. Meli |

C. Rusconi | M. Deodato | R. Cairoli

Division of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy

**Background:** Chemotherapy induced nausea and vomiting (CINV) represents a major impairment of quality of life in patients who undergo to a single-day and multi-day chemotherapy leading to a lower
adherence to further chemotherapies. The prevention of acute (0-24 h) and delayed (25-120 h) CINV associated with moderately emetogenic chemotherapy (MEC-AC based) and highly emetogenic chemotherapy (HEC) recommended by international guidelines (MASCC, NCCN, ASCO) consists in a combination of corticosteroids (i.e. dexametasone), type 3 serotonin receptor antagonist (5HT3Ra) and neurokinin-1 receptor antagonist (NK1Ra). Granisetron Transdermal Delivery System (GTDS) was developed as 5HT3Ra for CINV prophylaxis over 7 days.

**Methods:** In this retrospective non comparative single center experience a total 19 outpatients were observed from Nov 2016 to March 2019: 13 pts were female and 6 were male, median age of pts in treatment was 52 yrs (range: 26-69). 5 Pts with cHodgkin Lymphoma, 2 pts Marginal Zone Lymphoma, 3 Mantle Cell Lymphoma, 2 Primary Mediastinal Large Cell Lymphoma, 2 pts Follicolar Lymphoma, 4 pts with Diffuse Large B Cell Lymphoma. GTDS was used as second line therapy after Ondansetron iv in MEC (Bendamustine, CHOP) and in HEC (Cisplatin-based CHT) instead was used as third line after palonosetron i.v. and Netupitant-Palonosetron p.o. in Dacarbazine based CHT. A multi-day CHT (range: 2-4 days) was administered in 6/19 pts. A single dose patch granisetron was administered a day before CHT for 7 days continuously. The complete remission consists in complete control (CC) of acute and delayed CINV (no vomiting/retching, no nausea, no other rescue medication). The tolerability was evaluated true reported adverse events and laboratory data as AST, ALT, creatinine and potassium.

**Results:** GTDS was safe and no dizziness, headache or severe constipation were observed. CC was observed in 83% (5/6) of symptomatic pts during acute CINV and 81% (13/16) of pts with delayed CINV. DTDS failed in 19% (3/16) of pts with delayed CINV and other medications such as metoclopramide, promazine and aprepitant were administered. A good control of delayed CINV was evidenced in multi-day CHT's pts. No significant increase of AST and ALT were observed and mild hyperkaliemia was reported only 2/19 pts.

**Conclusion:** The GTDS provides effective, well tolerated control of CINV associated with MEC or HEC in one or multi day chemotherapy.

**Keywords:** ABVD; classical Hodgkin lymphoma (cHL); diffuse large B-cell lymphoma (DLBCL).

518
FUNCTIONAL PREDICTORS OF CHEMOTHERAPY TOXICITY IN ELDERLY LYMPHOMA PATIENTS – A PROSPECTIVE PILOT STUDY

A. Prica¹ | V. Dhir¹ | M. Maganti² | V. Kukreti¹ |

J. Kuruvilla¹ | M. Crump¹

¹Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada; ²Biostatistics, Princess Margaret Cancer Centre, Toronto, Canada

**Introduction:** Treatment of lymphoma often includes curative intent chemotherapy. In older patients, oncologists often rely on their clinical impression and the patient's age to make treatment decisions. More objective measures may be more accurate and reproducible in predicting chemotherapy eligibility and toxicity.

**Methods:** This is a single centre pilot feasibility study in patients ≥70 yrs with lymphoma, planned for systemic chemotherapy. Patients completed geriatric tools (eg. Hurria and CRASH questionnaires, gait speed test and grip strength, CSHA Frailty Scale) and physical tests were repeated with each cycle. Sarcopenia at the L3 level was measured on baseline and follow-up CT scans. Primary outcomes were feasibility, with correlation between chemotherapy toxicity and geriatric tools, as the main 2ry outcomes.

**Results:** 30 patients were enrolled, with a median age of 77 yrs (range 69-90) and 59% being male. The treating diagnosis was DLBCL in most (59%). Chemotherapy treatments most commonly included RCHOP (59%). The chemotherapy was dose reduced from the start in 8 patients (28%), and in 3 pts during tx (10%). Using the Hurria score, 18 pts (60%) were intermediate and 5 (17%) high risk for chemotherapy toxicity. Similarly, CRASH identified 11 (38%) as medium-low, 15 (50%) as medium-high and 2 (7%) as high risk. The Hurria tool on median took 2 min (1-5 min) vs. 20 min (5-30min) for the CRASH score. Sixteen pts (53%) experienced CTCAE grade 3-5 toxicity. The most common gr ≥3 AE was febrile neutropenia (4 pts). Dose delays occurred in 9 pts (31%) and 5 pts (17%) required hospitalization. 2-yr OS was 73%. The CSHA frailty score, grip strength and sarcopenia worsened throughout treatment and had not recovered by the 1 mo visit post-treatment (Figure 1). On univariate analysis, only the CSHA frailty score and Hurria risk score were associated with Grade 3 or higher events (Tables 1). On

<table><caption>TABLE 1 Probability of ≥gr3 AEs</caption><thead><tr><th>UV</th><th>OR(95%CI)</th><th>p-value</th></tr></thead><tbody><tr><td><strong>Hurria</strong></td><td></td><td></td></tr><tr><td>Low (0-5)</td><td>Ref</td><td></td></tr><tr><td>High (10-19)</td><td>7.77 (1.01,59.8)</td><td>0.048</td></tr><tr><td>Int (6-9)</td><td>5.58 (0.835,37.3)</td><td>0.07</td></tr><tr><td>CSHA frailty</td><td>2.53 (1.60,3.99)</td><td>&lt;0.001</td></tr><tr><td>Grip Strength (lbs)</td><td>0.98 (0.95,1.03)</td><td>0.607</td></tr><tr><td>Sarcopenia</td><td>0.69 (0.06,6.94)</td><td>0.75</td></tr><tr><td><strong>MV</strong></td><td><strong>OR(95%CI)</strong></td><td><strong>p-value</strong></td></tr><tr><td><strong>Hurria</strong></td><td></td><td></td></tr><tr><td>Low (0-5)</td><td>Ref</td><td></td></tr><tr><td>High (10-19)</td><td>0.898 (0.076,10.5)</td><td>0.932</td></tr><tr><td>Int (6-9)</td><td>5.20 (0.759,35.6)</td><td>0.093</td></tr><tr><td>CSHA</td><td>2.81 (1.76,4.37)</td><td>&lt;0.001</td></tr></tbody></table>
<figure><img src="image_300.png" /><figcaption>Figure 1</figcaption></figure>

multivariate analysis, the CSHA Frailty score and Hurria risk score retained significance for any AE, but only CSHA frailty for gr. 3 or higher events.

**Conclusions:** Older patients can be treated with full-dose systemic chemotherapy, but the rate of toxicity is high. The Hurria tool, which is much shorter to administer and seems to predict toxicity. The CSHA

Frailty is the most robust predictor of chemotherapy toxicity, and is a very simple measure to administer. We plan routine measurement of these simple tools in all lymphoma patients at our centre.

**Keywords:** elderly; non-Hodgkin lymphoma (NHL).
519

IS THERE A ROLE OF RESPIRATORY TRAINING IN THE SUPPORTIVE CARE OF LYMPHOMA PATIENTS? - SINGLE CENTRE PROSPECTIVE TRIAL

M. Hadrabova¹ | A. Janikova¹ | I. Hrcirikova² |

K. Kapounkova² | J. Simkova¹ | Z. Svobodova² | A. Mala²

¹Dpt. of Internal Medicine, Haematology and Oncology, University Hospital Brno, Brno, Czech Republic; ²Dpt. of Health Promotion, Masaryk University Brno/Faculty of Sports, Brno, Czech Republic

**Introduction:** Better outcome of lymphoma patients calls for improvement in the field of supportive care for the survivors who often struggle with long time side effects of intensive treatment. Fatigue and physical activity intolerance interfering with daily activities remain the most common issue. Physical training improves physical fitness, not only by increasing muscle mass and cardiovascular capacity but - more importantly it restores sympathovagal (SV) balance.

However, not all patients can participate in training. Based on data of disabled cardiological and neurological patients benefits of respiratory training using a pressure threshold device to increase inspiratory and expiratory muscle strength are known. Improvement of respiratory parameters decreases the number of infections and improve quality of life. Moreover, breathing is closely related to SV system. In our pilot project, we analysed feasibility and potential impact of respiratory training on lymphoma survivors.

**Methods:** 11 patients were enrolled (9 Hodgkin lymphoma, 2 Non-Hodgkin), 1 to 3 months after the end of intensive systemic chemotherapy (eBEACOPP or R-CHOP), all in complete remission. We measured the breathing muscle strength using Micro RPM device. The set of additional tests contained: BMI, body composition (the body composition (InBody 203©), aerobic capacity (cycle spiro-ergometry, Lode excalibur©), sympathovagal balance (DiANS PF 8©), and muscle strength (hand grip and leg flexor and extensor test). The respiratory training was performed with Threshold IMT/PEP device. The resistance level was individually set by a physiotherapist based on the patients' initial parameters. Patients were provided by a training lesson and video instruction course with recommended exercises and breathing techniques and subsequently were checked regularly online and every month in person. The resistance was gradually increased up to 30% if tolerated. All above mentioned functional tests were repeated after 8 weeks of training.

**Results:** We observed statistically significant improvement only MIP (maximum inspiratory pressure; p.0153), other parameters - MEP (maximum expiratory pressure; p.28), and FVC (forced vital capacity; p.15) were also improved, though not significantly. The training was

well tolerated, no infections occurred. On the other hand, the respiratory training did not affect BMI, body composition, muscle strength, and cardiovascular fitness or SV balance.

**Conclusion:** Respiratory training led to respiratory parameters improvement of lymphoma survivors, we also proved its feasibility and safety in our patients. Nevertheless, there was no impact on SV balance or physical fitness. We can conclude, that respiratory training cannot replace the physical exercise in lymphoma patients in remission. On the other hand, improvement of respiratory function can be more beneficial for inpatients, especially embedded to avoid respiratory complications.

**Keywords:** immune system; performance status.

520

A CROSS-SECTIONAL STUDY EXAMINING HOW KNOWLEDGE OF LYMPHOMA SUBTYPE AFFECTS THE PATIENT EXPERIENCE

L.E. Warwick¹ | N.M. Dren² | O.A. Bamigbola²

¹Chief Executive Officer, Lymphoma Coalition, Mississauga, Canada;

²Research, Lymphoma Coalition, Mississauga, Canada

**Introduction:** When first diagnosed, many lymphoma patients are told they have non-Hodgkin Lymphoma (NHL). NHL is not a disease, it is a series of 80+ subtypes, each requiring different diagnostic evaluation and treatment approaches. Over one-third of patients are not told their subtype. It is critical that patients be informed on their subtype so they can better understand their diagnosis and treatment options, and more effectively source relevant, case-appropriate information. To examine how knowledge of subtype affects the patient experience, the Lymphoma Coalition (LC) used the 2018 Global Patient Survey (GPS) on Lymphomas and CLL.

**Methods:** The 2018 LC GPS was available in 19 languages and was hosted on a third-party portal from January-March 2018. Globally, 6631 participants took part (70+ countries). Raw data was entered, merged, and cleaned in IBM SPSS v21. For this analysis, two subpopulations were defined and compared. Patients who were informed of their subtype at diagnosis (n=4215) were compared against those who were not/not sure (n=2361) using cross-tabulations and chi-square tests (p=0.05).

**Results:** Subtype knowledge was correlated with how informed patients felt: 41% of patients who were informed of their subtype reported having an adequate level of information overall, compared to only 22% of patients who were not informed/not sure. Additionally, 28% of patients who were informed of their subtype reported receiving enough information at their diagnosis meeting, compared to only 16% of patients who were not informed/not sure.

Importantly, the impact of knowledge of subtype was reflected in
<figure><img src="image_301.png" /><figcaption>Figure 1. Patient's understanding after diagnosis meeting based on knowledge of subtype</figcaption></figure>

© 2018 Lymphoma Coalition GPS on Lymphomas & CLL

patient's understanding of the medical aspects of their lymphoma. Patients who were informed of their subtype reported a greater understanding of all topics surrounding diagnosis and care following their diagnosis meeting (figure 1).

Additionally, patients informed of their subtype reported improved communication with the doctor across key categories. Compared to those who were not informed/not sure, patients who were informed of their subtype felt more confident voicing their concerns to the doctor (59% vs 47%, respectively), sought clarification on things they did not understand more frequently (80% vs 70%), and brought forward questions about side effects more frequently (82% vs 74%).

**Conclusions:** Being informed of subtype at diagnosis was correlated with more self-reported positive healthcare experiences; those informed reported bettered management of their healthcare through

improved understanding and communication. Informing patients of their subtype is the best way to ensure they understand their diagnosis and care and are sourcing the right information, which can translate positively across their experience.

**Keywords:** B-cell lymphoma; non-Hodgkin lymphoma (NHL); T-cell lymphoma (TCL).

521
REDUCED SEXUAL FUNCTION IN LONG-
TERM MALE LYMPHOMA SURVIVORS
AFTER HIGH DOSE THERAPY WITH
AUTOLOGOUS STEM CELL
TRANSPLANTATION

H.S. Bersvendsen<fnref n="1" /> | H.S. Haugnes<fnref n="1" /> | U. Fagerli<fnref n="2" /> |

Ø. Fluge³ | H. Holte⁴ | K.B. Smeland⁵ | C.E. Kiserud⁵

**Introduction:** Autologous stem cell transplantation (ASCT) is associated with long-term effects. However, less is known about sexual health. Our primary aim was to explore sexual health among male long-term lymphoma survivors after ASCT and compare the results to normative controls. Our secondary aim was to investigate the

<figure><img src="image_302.png" /><figcaption>Figure: Odds Ratio and 95% Confidence Interval for sexual problems among ASCT lymphoma survivors compared with controls</figcaption></figure>

<footnote n="1">¹Oncology, Universityhospital of North Norway, Tromsø, Norway;</footnote>

<footnote n="2">²Oncology, St. Olav's Hospital, Trondheim, Norway; ³Oncology, Haukeland Universityhospital, Bergen, Norway; ⁴Oncology, Oslo Universityhospital Radiumhospitalet, Oslo, Norway; ⁵National Advisory Unit for Late Effects After Cancer, Oslo Universityhospital Radiumhospitalet, Oslo, Norway</footnote>
<table><caption>**TABLE 1** Associations between sexual outcomes and population characteristics</caption><thead><tr><th></th><th>Total BSFI unstandardized coefficient β [95% Confidence Intervals]</th><th>Overall satisfaction unstandardized coefficient β [95% Confidence Intervals]</th></tr></thead><tbody><tr><td>Age at survey, in 10 years</td><td>-4.16 [-5.45, -2.87]</td><td>-0.27 [-0.43, -0.11]</td></tr><tr><td>Chronic fatigue</td><td></td><td>-0.46 [-0.87, -0.05]</td></tr><tr><td>Anxiety caseness</td><td>-5.11 [-9.33, -0.90]</td><td>-0.67 [-1.21, -0.14]</td></tr><tr><td>Cardiovascular risk or disease</td><td></td><td></td></tr><tr><td>None</td><td>0 Ref.</td><td></td></tr><tr><td>Risk (body mass index &gt;30, smoking, hypertension, or hypercholesterolemia)</td><td>0.58 [-2.80, 3.95]</td><td></td></tr><tr><td>Diabetes type 1 or 2</td><td>-3.14 [-8.87, 2.60]</td><td></td></tr><tr><td>Cardiovascular disease (transitory ischemic attack, stroke, angina pectoris or myocardial infarction)</td><td>-5.68 [-10.6, -0.75]</td><td></td></tr><tr><td>Sedentary</td><td>-4.19 [-7.09, -1.28]</td><td></td></tr></tbody></table>

associations between sexual health and study group characteristics, somatic and psychological comorbidity.

**Methods:** A national cross-sectional study was conducted from 2012 to 2014 among ASCT lymphoma survivors treated during 1987-2008. In the present study, 67% of eligible men (n=161) with valid questionnaire data were included in analyses. Age-matched controls (1:3) were drawn from a Norwegian normative sample. Brief Sexual Function Inventory (BSFI) was used to assess sexual function domains (drive, erection, ejaculation, problem) and overall sexual satisfaction. Based on the functional items a sum score, total BSFI score, was calculated. Sexual problem caseness was defined based on predetermined cut-off values for BSFI domain scores. Age-adjusted and multivariable linear and logistic regression analyses were used to investigate the associations between survivors' characteristics and BSFI outcomes.

**Results:** Survivors had significantly lower scores on all BSFI domains, compared with controls (all p-values <0.001). Greatest clinical relevance was found regarding erectile and ejaculatory function were the effect sizes were -0.61 and -0.75, respectively. The most prevalent sexual problems among survivors were lack of drive (44%), and erectile dysfunction (53%). Survivors had increased risk for all problems compared with controls (Figure). Among the survivors, we found significant associations between total BSFI score and increasing age, anxiety, cardiovascular disease and physical inactivity in multivariable models. In addition, a lower sexual satisfaction was related to increasing age, chronic fatigue and anxiety (Table).

**Conclusions:** Sexual functions were reduced and sexual problems more frequent among survivors compared with controls. The associations with age, anxiety, cardiovascular disease and physical inactivity illustrate the multifaceted interactions on sexual health. In order to acknowledge the importance of sexual health in life beyond cancer, and to initiate treatment it is pertinent that doctors assess patients sexual health pre- and during treatment and at follow-ups.

**Keywords:** autologous stem cell transplantation (ASCT).

522
QUALITY OF LIFE AND CAREGIVER BURDEN IN MULTIPLE MYELOMA AND LYMPHOMA PATIENTS UNDERGOING OUTPATIENT AUTOLOGOUS STEM CELL TRANSPLANTATION VERSUS INPATIENT TRANSPLANTATION

A. Prica¹ | V. Dhir¹ | L. Zibdawi¹ | O. Espin-Garcia²

¹Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada; ²Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Canada

**Introduction:** The outpatient setting has now become a standard alternative to the traditional inpatient approach for autologous stem cell transplantation (ASCT) for multiple myeloma and lymphoma. Outpatient ASCT involves family/friends assuming round-the-clock caregiving responsibilities, and though it is perceived as potentially providing superior patient quality of life (QOL), supporting evidence is limited. Furthermore, little is known about caregiver QOL and lost opportunity costs for caregivers (i.e., wages/travel time). Our objectives were to compare QOL of patients, and their caregivers, in the inpatient versus outpatient settings, and to delineate costs associated with caregiving.

**Methods:** Patients completed 4 questionnaires (FACT-BMT, FACT-Fatigue, EQ5D, and distress impact thermometer) at 5 timepoints during their ASCT: D0 (baseline), D+7, D+14, D+28, and D+100. Caregivers completed 3 questionnaires (C-QOLC, distress impact, and financial impact), as well as a caregiver financial burden questionnaire (C-SAFE), at the same timepoints.

**Results:** In total, 52 patients and 51 caregivers were enrolled (21 inpatients/31 outpatients). Patients' median age was 57 (range: 18-70), and 67% were male. Majority of caregivers were spouses (73%). In the overall patient population, FACT-BMT scores significantly declined at D+7, then increased to above-baseline by D+100, which is indicative of greater QOL. FACT-Fatigue worsened significantly at D+7, then improved to lower than baseline at D+100. Additionally, EQ5D scores (imaginable health status) significantly declined at D+7 and D+14, then increased to above baseline at D+100 (albeit p>0.05). QOL scores were not significantly different when comparing inpatients vs. outpatients, though general trends existed for less deterioration in QOL in inpatients. Caregiver QOL scores were consistently higher for
<table><caption>**TABLE 1** Changes in QOL scores from baseline (D0) in the overall patient population</caption><thead><tr><th></th><th>FACTBMT</th><th>FACTF</th><th>EQ5D</th><th>CQOLC</th><th>Global p value</th></tr></thead><tbody><tr><td>D+7</td><td>-13.21 (5.59)<br/>p=0.014</td><td>-9.46 (2.66)<br/>p=0.00053</td><td>-21.99 (5.53)<br/>p=0.00012</td><td>11.17 (6.02)<br/>p=0.067</td><td>0.00</td></tr><tr><td>D+14</td><td>-7.76 (6.09)<br/>p=0.20</td><td>-5.98 (93.07)<br/>p=0.053</td><td>-13.84 (6.23)<br/>p=0.028</td><td>12.09 (8.68)<br/>p=0.17</td><td>0.00</td></tr><tr><td>D+28</td><td>3.16 (5.77)<br/>p=0.58</td><td>-5.43 (2.91)<br/>p=0.064</td><td>-5.2 (5.91)<br/>p=0.38</td><td>12.44 (6.3)<br/>p=0.051</td><td>0.00</td></tr><tr><td>D+100</td><td>16.36 (5.92)<br/>p=0.0065</td><td>6.75 (2.98)<br/>p=0.025</td><td>1.56 (6.05)<br/>p=0.08</td><td>21.26 (6.64)<br/>p=0.0019</td><td>0.00</td></tr></tbody></table>

<figure><img src="image_303.png" /><figcaption>**Figure 1.** Serial trends in QOL scores, comparing inpatients (red) versus outpatient (blue)</figcaption></figure>

inpatients, though not statistically significant. Average lost opportunity costs for caregivers was $4195 CAD per caregiver.

**Conclusions:** There was significant deterioration of various aspects of QOL in the overall population. Inpatient caregivers report better QOL than outpatients, though sample size limits further analyses.

**Keywords:** autologous stem cell transplantation (ASCT).
# BY PHYSICAL TRAINING - SINGLE CENTRE PROSPECTIVE TRIAL

M. Hadrabova¹ | A. Janikova¹ | I. Hrncirikova² | Z. Svobodová² | A. Mala² | K. Kapounkova² | J. Mayer¹

¹Dpt. of Hematology, Oncology and Internal Medicine, University Hospital Brno, Brno, Czech Republic; ²Dpt. of Health Promotion, Masaryk University Brno/Faculty of Sports, Brno, Czech Republic

**Introduction:** Despite significantly improved survival of lymphoma patients in the last decades, many remain physically unfit years after their successful treatment. Major complaints include dyspnoe, fatigue and physical activity intolerance which are in concordance with impaired sympathovagal (SV) balance. The predominance of sympathicus is a sign of autonomic nervous system neuropathy caused by the lymphoma itself, as well as combined cytotoxic therapy. SV imbalance is an independent negative prognostic factor for morbidity and mortality, especially due to cardiovascular diseases and metabolic syndrome. Data from cardiological and neurological trials prove the aerobic physical activity as a strong tool to reset the SV balance. The primary aim of this prospective project was to analyze the impact of systemic treatment on parameters of fitness, and to evaluate the efficacy of the supervised training on the lymphoma population comparing to matched controls.

**Methods:** Between 2012 and 2016, 101 patients with Hodgkin (n=23) and Non-hodgkin lymphomas (n=78) were enrolled in the project. After systemic therapy (RCHOP or BEACOPP), the patients who achieved remission, were geographically randomized into training (n=40) or observation group (n=61). The 3-month supervised training program consisted of combined aerobic and anaerobic training (60mins, 3 times/ week). The following parameters were measured in all patients: body mass index (BMI), the body composition (InBody 203©), aerobic capacity (cycle ergometry, Lode excalibur©), sympathovagal balance (DiANS PF 8©), and muscle strength (hand grip tests and leg flexor and extensor test). The evaluation was performed at 3 time points: 1) before start of the therapy (n=19), 2) after the treatment (in remission) (n=65), 3) and after either training or observation 3-6 months since last therapy (n=45).

**Results:** During the treatment, a significant deterioration of SV balance was observed (total score= TS: -1,08 ± 1,86 vs. -1,96 ± 1,57, p= 0.04), whereas other parameters (aerobic capacity p=0.18 and muscle strength p=0.84, body composition p=0.58) changed insignificantly. In the training group, a significant improvement of aerobic capacity (98,33 ± 16,7 vs. 112,2± 17,4, p 0.001) as well as SV balance (TS - 2,27 ± 1,70 vs. -2,27 ± 1,70, p 0.02) was observed. In the control group, no improvement in fitness parameters was observed; the only difference was BMI increase (p 0.01) but without improvement of muscle mass. The adherence to the training program was 80%, no adverse events were reported.

**Conclusion:** Our trial proved that physical training in lymphoma survivors is safe, feasible and effective. It significantly improves

cardiovascular fitness and leads to SV balance restoration which might play a major role in life quality, relapse/non-relapse morbidity and mortality.

**Keywords:** BEACOPP; performance status; R-CHOP.

## 524
LYMPHOMA TREATMENT REGIMES AND THEIR IMPACT ON BEHAVIOUR AND COGNITION IN AN ANIMAL MODEL

K. Vales¹ | M. Skurlova¹ | K. Holubova¹ | L. Kleteckova¹ | A. Mikulecka² | T. Kozak³ | H. Kubova² | J. Horacek¹

¹Center for Transfer Technologies and Applied Research, National Institute of Mental Health, Klecany, Czech Republic; ²Developmental Epileptology, Institute of Physiology CAS, Prague, Czech Republic; ³Department of Internal Medicine - Haematology, 3rd Faculty of Medicine, Charles University in Prague, University Hospital Kralovske Vinohrady, Prague, Czech Republic

**Introduction:** Chemotherapy-induced cognitive impairment is defined as clinically and statistically important decrease of cognitive functions often related to chemotherapy. The study focused on neurobiological substrate of chemobrain adapted to an animal model.

**Methods:** Chemotherapeutics have been used according human lymphoma therapies in all phases comprising combinations of drugs: adriamycin, bleomycin, cyclophosphamide, dacarbazine, etoposide, vincristine and prednisone. Weight loss up to 4% was a limiting factor of drug dose used in Wistar rats. Rats were subjected to behavioral testing prior, immediately after, and in 3 months delay to administration of the chemotherapy. At these intervals, blood, and nerve tissue were collected and then immune-histological and neuro-chemical analysis was performed. The battery of behavioral tests comprised of: open field, elevated plus maze, social behavior test, and cognitive tests of the Y-maze.

**Results:** Our behavioral outcomes indicated for a combination of motivation deficit and cognitive impairment after chemotherapy. It should not be neglected that rats generally have lower locomotor activity after post-treatment. This finding could also suggest a "sickness behavior" effect which is less pronounced with much time span after treatment. Lack of habituation indicates for learning and memory problems. We have also measured transient changes in blood cells counts, namely white blood cells (WBC), after ABVD, CHOP chemotherapy. Similarly in both regimes, drugs administration dropped number of WBC up to 30%, which did not fully return to the number before treatment. BEACOPP therapies decreased counts of lymphocytes, which have returned to beginning levels after delay. Immunohistological analysis pointed at a clear decrease in the number of newly emerging neurons in the dentate gyrus. In addition to changes in the number of neurons, there were also differences in morphology of neurons. Following chemotherapy a relatively high percentage of
cells exhibited abnormal orientation and poor or totally absent
arborization.

**Conclusions:** Overall, we have introduced the novel animal model of neurobiological substrate of chemobrain induced by the application of selected chemotherapeutic regimens. This model can be useful to study neuroprotective and precognitive drugs.

**Acknowledgements:** The work was supported from projects number ERDF PharmaBrain CZ.02.1.01/0.0/0.0/16_025/0007444, AZV 16-29857A and NPUI LO1611.

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

524 bis
PROSPECTIVE STUDY OF 3T WHOLE BODY
DIFFUSION WEIGHTED MAGNETIC
RESONANCE (WB DWI MRI) COMPARED
TO PET IN STAGING AND ASSESSMENT OF
TREATMENT RESPONSE IN FDG AVID
LYMPHOMAS

A. Greco<fnref n="1" /> | M. Tridici² | A. Notaristefano<fnref n="3" /> |

A. Mele<fnref n="1" /> | C. De Risi<fnref n="1" /> | R. De Francesco<fnref n="1" /> |

G. Greco<fnref n="1" /> | S. Sibilla<fnref n="1" /> | L. Tonialini<fnref n="1" /> | S. Citiso<fnref n="1" /> |

E. Prete<fnref n="1" /> | E. La Rosa<fnref n="1" /> | M. Morciano<fnref n="1" /> |

R. De Blasi² | V. Pavone<fnref n="1" />

**Introduction:** PET is considered the gold standard for staging and evaluation of treatment response in FDG avid Lymphoma. 3T WB-DWI-MRI may represent an option for detection and better characterisation of tumoral lesions without use of FDG or iodated/paramagnetic contrast medium. We compared 3T WB-DWI-MRI with PET in the evaluation of Hodgkin lymphoma (HL) and Diffuse large cell lymphoma patients (DLBCL).

**Methods:** From may 2016, 25 patients (14 cases of HL and 11 cases of DLBCL) were diagnosed at our institution. PET and 3T WB-DWI-MRI was perfomed at diagnosis and post treatment for a total of 118 nodal sites and 21 extranodal valued sites. DWI imaging was obtained with multi shot sequences (thickness 4 mm) multi-b (b-value: 0, 150, 1000) and ADC cut off value 1.2 for functional evaluation. Morphological images were obtained by using sequences fast spin-echo short time inversion recovery (STIR with thickness 4mm) and Turbo spin-echo (T2-TSE with thickness 4mm) and sequnces T1-FAST-Field-echo (T1-FFE) in and out - phase (thickness 4mm). MRI were compared with PET imaging performed at the same time and assessed blind by radiologist and *Nuclear Medicine* physician.

**Results:** The 3T WB-DWI-MRI and PET results were concordant at the diagnosis after evaluation of 118 nodal site and 21 extra nodal site with Cohen's Kappa coefficient showed agreement to be excellent

(K = 0.82 and 0.84 respectively). When performed after treatment the two methods were not concordant due to the greater sensitivity and specificity of the RMI (high positive and negative predictive value. In 5/25 cases of nodal site and in 2/16 cases of extra nodal site after chemotherapy MRI and PET results were discordant and PET failed complete remission finding (doubts residues after therapy not confirmed at subsequent follow-up).

**Conclusions:** These data suggest that 3T WB-DWI-MRI can be considered a sensitive and specific method for assessing treatment response in Lymphoma without the use of ionising radiation or administration of F-18 Flurodeoxyglucose.

In this population, MRI appears to obtain a better definition of the response after chemotherapy especially in mediastinal, hepatic, waldeyer ring and bone sites.

Further studies are needed to evaluate the optimum ADC values in assessing treatment response in a more large number of patients.

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

525
ABSCOPAL REGRESSION OF LYMPHOMA
AT DISTANT SITES AFTER LOCAL
RADIOTHERAPY, DETECTED BY POSITRON
EMISSION TOMOGRAPHY IN SIX CASES

M.P. MacManus<fnref n="1" /> | B. Campbell<fnref n="1" /> | A. Wirth<fnref n="1" /> |

M. Hofman² | R. Hicks² | J. Seymour<fnref n="3" /> | K. Burbury<fnref n="3" />

¹Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; ²Molecular Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia; ³Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia

**Introduction:** "Abscopal" regression of untreated lymphoma outside radiotherapy (RT) treatment volumes, in the absence of any other therapeutic intervention, is rarely reported. An immune mechanism is likely and results of clinical trials combining RT and immunotherapy are awaited.

**Methods:** We investigated PET-detected abscopal regressions of lymphoma at a comprehensive cancer center.

**Results:** Eight cases were identified and 6 were well-documented on FDG-PET imaging as follows:

1. Male age 54, follicular lymphoma (FL), relapsed after immunochemotherapy, demonstrated abscopal regression of mediastinal disease, following further RT (30 Gy in 15 fractions) to a neck mass (persistent after very low dose RT to 4 Gy in 2 fractions).

2. Male age 38 with multiply relapsed advanced FL had a complete metabolic response (CMR) of all local and systemic disease, after 4 Gy in 2 fractions to large skin lesion. He relapsed after allogeneic stem cell transplantation but with an ongoing CMR to donor lymphocyte infusion and RT.

<footnote n="1">¹Unit of Hematology, Hospital "Pia Fondazione Card. G. Panico", Tricase, Italy; ²Unit of Radiology, Hospital "Pia Fondazione Panico", Tricase, Italy;</footnote>

<footnote n="3">³Unit of Nuclear Medicine, Hospital "Moscati", Statte, (TA), Italy</footnote>
**3:** Female age 67 with untreated advanced FL and severe comorbidities demonstrated both local CMR to 4 Gy in 2 fractions to a 10cm abdominal mass and ongoing complete abscopal regression of mediastinal lymphoma.

**4:** Female age 67 with severe comorbidities, untreated CLL and biopsy proven Richter's transformation to DLBCL in the right breast and painful iliac node. With no systemic therapy, 30 Gy in 10 fractions to pelvis achieved CMR in both pelvis and untreated breast. Circulating lymphocytes reduced from 40 x10⁹/L to 3.4. She later developed progressive disease and died with DLBCL.

**5:** Female age 58, after decades of multiply-relapsed Hodgkin lymphoma received a re-irradiation to 30 Gy in 15 fractions to bone lesion with complete symptomatic response and abscopal CMR in other distant bone lesions. After subsequent relapse she attained ongoing CMR lasting >3 years on nivolumab.

**6:** Female age 75 with multiply relapsed advanced mantle cell lymphoma had 2 Gy x 2 to lower limb disease with complete local CMR and abscopal regression of all measurable systemic disease. She remained free of symptomatic progression for 2 years.

**Conclusions:** Abscopal regression of lymphoma was detected by FDG-PET scanning in 6 cases. It was associated with subsequent durable responses to immunotherapy in 2 cases, it followed a second course of radiotherapy to persistent lesions in 2 and it required only 4 Gy in 2 cases. A better understanding of the biology and frequency of this phenomenon may be of considerable value, both because of its intrinsic therapeutic impact and potential synergy with immunotherapy.

**Keywords:** follicular lymphoma (FL); Hodgkin lymphoma (HL); immune system.

## 526
ABERRANT HYPEREDITING OF MYELOMA TRANSCRIPTOME BY ADAR1 CONFERS ONCOGENICITY AND IS A MARKER OF POOR PROGNOSIS

P. Teoh<fnref n="1" /> | O. An<fnref n="1" /> | T. Chung<fnref n="1" /> | J. Chooi<fnref n="1" /> |

S. Toh<fnref n="1" /> | S. Fan² | W. Wang³ | B. Koh³ |

M. Fullwood<fnref n="1" /> | M. Ooi⁴ | S. de Mel⁴ | C. Soekojo⁴ |

P. Chen<fnref n="1" /> | S. Ng² | H. Yang<fnref n="1" /> | W. Chng⁴

**Background:** While alterations at the DNA level have been extensively studied in multiple myeloma (MM), the genomic changes including mutations, indels and translocations cannot yet fully explain all the biological and molecular abnormalities in MM. Recent years have shown that abnormalities at the RNA levels harbour biological

importance in cancers. Our recent work published in Blood indicated that the aberrancy of the landscape in MM transcriptome has a role in disease pathogenesis. We reported that ADAR1-mediated-RNA-editing is of biological and clinical relevance in MM.

**Methods:** We analysed several publicly available MM datasets, including CoMMpass RNA-seq dataset from the MMRF. We also performed a systematic high throughput RNA-sequencing on normal plasma cells and some primary patient samples (n=17) to identify the ADAR1 expression trend. For the elucidation of ADAR1 protein expression, immunofluorescence was conducted on patient's tissue microarray (n=200). The functional importance of ADAR1 and NEIL1 editing was determined with cell viability, cell cycle and colony formation assays.

**Results:** Our analyses on gene expression microarray datasets, RNA-seq datasets and TMA revealed that ADAR1 was overexpressed in MM; its expression gradually increased along the disease progression route (Normal to MGUS to SMM to MM to Relapsed) and was higher in the high-risk disease subtypes, namely the 4p16 and MAF-translocation groups, signifying the role of ADAR1 in disease progression and in conferring disease aggressiveness. Critically, relative to the normal CD138+ cells, MM transcriptome was found to be aberrantly hyperedited and the global editing events was closely correlated with ADAR1 expression. Manipulation of ADAR1 expression conferred differential level of A-to-G editing, indicating that ADAR1 is a critical player of editing in MM. Notably, multivariate analysis revealed that ADAR1 was a prognostic factor independent of 1q21 amplification. ADAR1 level could also influence patients' responsiveness to different treatment regimes. Physiologically, our functional assays established ADAR1 as oncogenic, acting in an editing-dependent manner. In addition, we identified NEIL1 (base-excision repair gene) as an essential and a ubiquitously edited ADAR1 target in MM. The recoded NEIL1 protein showed defective oxidative damage repair capacity and gain-of-function properties.

**Conclusion:** These data unravelled novel insights into MM molecular pathogenesis at the RNA level.

**Keywords:** bortezomib; epigenetics; multiple myeloma (MM).

## 527
AUTOLOGOUS STEM CELL TRANSPLANT WITH HIGH DOSE MELPHALAN PREPARATIVE REGIMEN IS SAFE AND EFFECTIVE FOR ELDERLY MULTIPLE MYELOMA PATIENTS IN THE ERA OF TRIPLE INDUCTION THERAPY

A. Czyz<fnref n="1" /> | J. Romejko-Jarosinska² | A. Szeremet<fnref n="1" /> |

A. Bogucka-Fedorczuk<fnref n="1" /> | M. Majcherek<fnref n="1" /> |

M. Szymanski² | J. Walewski² | T. Wrobel²

<footnote n="1">¹Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; ²Pathology, National University of Singapore, Singapore, Singapore; ³Orthopaedic, National University Hospital, Singapore, Singapore; ⁴National University Cancer Institute, National University Hospital, Singapore, Singapore</footnote>

<footnote n="1">¹Department of Hematology and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland; ²Department of Lymphoid Malignancies, Maria Sklodowska-Curie Institute-Oncology Center, Warszawa, Poland</footnote>
<figure><img src="image_304.png" /></figure>

**Introduction:** Autologous stem cell transplantation (ASCT) is commonly used in treatment of patients over 65 years of age with multiple myeloma (MM), however the safety and efficacy of this procedure in the era of new agents is controversial.

**Methods:** We conducted a retrospective review of newly diagnosed MM patients treated with triple induction therapy who underwent first ASCT between 2012 and 2018 to evaluate the outcomes across different age groups. The purpose of this retrospective study was to compare the 100-day non-relapse mortality, progression-free survival (PFS) and overall survival (OS) in elderly MM patients (≥ 65 years) with younger patients in the era of triple induction therapy.

**Results:** A total of 162 patients were analysed and categorized by age into group A (28 to 55 y; n=46), B (56 to 64 y; n= 87) and C (65 to 71 y; n=29). The patients received triple combination therapy based on bortezomib (45%) or a combination of cyclophosphamide, thalidomide and dexamethasone (55%) as first line treatment prior to ASCT. The compared groups did not differ significantly in terms of gender, ECOG performance status, HCT-specific comorbidity index (HCT-CI), and disease status at ASCT. Melphalan (MEL) at a dose of 200 mg/m² was used as preparative regimen in 83% of younger patients in group A, 79% of patients in group B, and 59% of the elderly in group C. The dose of 140 mg/m² was used in 13%, 15% and 30% of patients in group A, B and C, respectively. The remaining patients received 100 mg/m² of MEL (4%, 5% and 11%). The dose of MEL was reduced due to HCT-CI >2 or age, at the physician's discretion. In the whole study group there were no transplant related deaths within the first 100 days of ASCT. After the median follow-up of 24 months (range, 3-84 months) for survivors, the estimated OS at 36 months was 79%, 83% and 83% for patients in group A, B and C, respectively (p=0.96). The respective 3-year PFS was 53%, 45% and 58% (p= 0.51). In univariate and multivariate analysis the adverse factors associated with shorter PFS were response to first line treatment worse than very good partial remission (HR 2.09, 95%CI 1.15-3.90; p=0.015) and the dose of MEL lower than 140 mg/m² (HR 5.99, 95%CI 2.32-16.70, p=0.0002)

**Conclusions:** Our data shows that in the era of triple induction therapy ASCT with high dose MEL conditioning is safe in transplant eligible MM patients ≥ 65 years of age and provides similar outcomes as seen in younger patients. The response to first line treatment significantly influences PFS after ASCT with satisfactory outcomes for patients with CR and VGPR. However, the reduction of the dose of melphalan in conditioning to 100 mg/m² is associated with shorter PFS.

**Keywords:** autologous stem cell transplantation (ASCT); elderly; multiple myeloma (MM).

## 528
THE USE MODIFIED RISK STRATIFICATION mSMART 3.0 IN REAL CLINIC PRACTICE IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA

A. Garifullin¹ | S. Voloshin¹ | S. Voloshin² | S. Voloshin³ | I. Martynkevich¹ | M. Bakai¹ | E. Kleina¹

¹Hematology Clinic, Russian Research Institute of Hematology and Transfusiology, Saint-Petersburg, Russian Federation; ²Clinic, Military Medical Academy named after S.M. Kirov, Saint-Petersburg, Russian Federation; ³Clinic, North-Western State Medical University named after I.I. Mechnikov, Saint-Petersburg, Russian Federation

**Background:** Studies over the past decade, have greatly improved our understanding of the molecular basis of multiple myeloma and mechanisms of disease progression. Metaphase cytogenetics and fluorescence in situ hybridization (FISH) help us to identify the most frequent genetic abnormalities. The division of patients into various risk groups based on the chromosomal markers is being utilized by many centers for select and optimize of therapeutic strategy. However, such molecular risk-stratification systems are repeatedly updated in accordance with the emergence of new information about the prognostic impact of anomalies. The role of complex karyotype and combination of genetic abnormalities remains unclear. Aims: to estimate the incidence of genetic abnormalities and their impact on overall and progression-free survival in patients with newly diagnosed multiple myeloma (NDMM).

**Methods:** The study included 159 patients (median age 63 years, range 28 - 83; male: female ratio – 1:1.37) with NDMM. Metaphase cytogenetics on bone marrow samples was done by standard GTG-method. FISH analyses were performed according to the manufacturer's protocol for detection primary IgH translocations, 13q (13q14/13q34) deletion, 1p32/1q21 amplification/deletion, P53/cen 17 deletion (MetaSystems DNA probes). We additional searched the t (4;14), t(6;14), t(11;14), t(14;16) and t(14;20) in patients with IgH translocation. All patient was treated by bortezomib-based programs (VD, CVD, VMP, PAD).

**Results:** The frequency of genetic abnormalities in NDMM patients was 49% (78/159). IgH translocation was detected in 26.4% (42/159)
patients: t(11;14) – 16.3% (26/159), t(4;14) – 5.0% (8/159); TP53/del17p – 5.6% (9/159); 1p32/1q21 amp/del – 12% (19/159); hypodiploidy – 3.1% (5/159); hyperdiploidy – 1.25% (2/159); del5q – 0,6% (1/159); other – not found. Combination two aberrations was discovered in 11.9% (19/159) patients, complex abnormalities (≥3 aberrations) – in 4.4% (7/159) patients.

The median OS in “two aberration” and “complex abnormalities” groups were lower than in standard-risk mSMART 3.0 (normal, t(11;14), hypodiploidy, hyperdiploidy and other): 49 months, 37 months and not reached, respectively (p=.02). The median PFS for these groups was 12 months, 11 months and 30 months, respectively (p=0.004). We modified high-risk mSMART 3.0 by adding “two aberration” and “complex abnormalities” groups on the basis of the OS and PFS results.

The median OS in standard-risk mSMART 3.0 was not reached, in high-risk mSMART 3.0mod – 50 months; 5-years OS was 65% and 38%, respectively (p=0.01). The median PFS was 58 and 29 months, respectively (p=.02).

**Conclusion:** Combination two aberrations and complex abnormalities are unfavorable prognostic markers. The median OS and PFS was higher in standard-risk than high-risk patients mSMART 3.0mod. It can be useful for update risk stratification in future.

**Keywords:** chromosomal translocations; fluorescence in situ hybridization (FISH); multiple myeloma (MM).

MYELOMA; EXPERIENCE FROM A SINGLE CENTER IN SAUDI ARABIA

G.M. Gmati¹ | M. Damlaj¹ | M. Alzahrani¹ |

S. Tamimi¹ | F. Khalid¹ | N. Alherz¹ |

K. Abuelgasim¹ | H. Almuhayani¹ | B. Alahmari¹ |

H. Salama¹ | S. Ghazi¹ | O. Ali¹ | A. Alhejazi¹ |

A. Alaskar²

¹Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia; ²Executive Director, King Abdulla International Medical Research Center, Riyadh, Saudi Arabia

**Introduction:** Autologous stem cell transplantation (ASCT) prolongs progression free survival (PFS) in newly diagnosed multiple myeloma (MM) patients in the era of novel therapy. However, the outcome of MM patients from the Middle East and North Africa (MENA) is much less known due to the paucity of SCT centers.

**Methods:** This is a retrospective analysis of all MM patients that underwent ASCT at our center. All data were retrieved from electronic medical records. Baseline patient characteristics, disease and treatment related variables were reported using descriptive statistics (frequency, median and percentage). Estimates of overall survival (OS) and PFS were computed using Kaplan-Meier method. The treatment protocol includes induction phase with bortezomib based triplet regimen such as VCD or VRD followed by stem cell mobilization. This was followed by melphalan conditioning 200 or 140 mg / m².

**Results:**

<figure><img src="image_305.png" /></figure>
<figure><img src="image_306.png" /></figure>

**A:** Baseline Characteristics. A total of 60 patients were identified and males represented 65% of the cohort. The median age was 53 years (31-70). ISS stage I, II and III were 25, 27 and 45% respectively. Disease subtype was IgG kappa or lambda in 45%, light chain kappa or lambda in 28%, IgA kappa or lambda in 18% and others in 9%. Normal cytogenetic was seen in 57% while the remaining comprised of hyperdiploidy in 22%, complex cytogenetic in 12%, t (11:14) in 6% and 1.5% with trisomy 3 and no cytogenetic result available in the remaining 1.5%. Disease status pre-HCT was stringent complete response (sCR) in 21/60 (35%) patients, complete response (CR) in 17/60 (28%) patient, very good partial response (VGPR) in 10/60 (17%) patient, partial response (PR) in 11/60 (18%) patient and in 1/60 (2%) patient no documentation was available.

**B:** Post ASCT Outcome. The median duration for absolute neutrophil count (ANC) and platelet engraftment was 13 and 14 days respectively. Primary graft failure was observed in one patient (1.7%) leading to transplant related mortality. Evaluable response by day 100 was available in 55 patients and were; sCR 26/55 (47%) patient, CR 17/55 (31%) patient, VGPR 11/55 patient (20%) and disease progression (DP) in 1/55 (2%) patient. Median follow up was 828 days (18-2790). Estimates of PFS at 100 days, 1 year and 5 years were 98.3%, 84.5% and 43.1% respectively while corresponding OS was 98.3%, 94.3% and 70.5% respectively (Fig 1A/B). PFS and OS for combined high risk and non-high risk MM patients at 3 years from CIBMTR were 43% and 78.5% respectively.

**Conclusion:** We observed comparable post ASCT outcome in our emerging transplant center compared with well-established centers worldwide. Given that AHCT remains underutilized in the MENA region, reporting of such data highlights that increased access to such therapy will be of great value to the region.

**Keywords:** IMiDs; peripheral blood stem cell (PBSC).

## 530
THE ROLE OF AUTOLOGOUS STEM CELL TRANSPLANTATION AND TUMOR LOAD IN MULTIPLE MYELOMA

**A. Garifullin¹** | **S. Voloshin¹** | **S. Voloshin²** |

**S. Voloshin³** | **A. Kuzyaeva¹** | **A. Schmidt¹**

¹Hematology Clinic, Russian Research Institute of Hematology and Transfusiology, Saint-Petersburg, Russian Federation; ²Clinic, Military Medical Academy named after S.M. Kirov, Saint-Petersburg, Russian Federation; ³Clinic, North- Western State Medical University named after I.I. Mechnikov, Saint-Petersburg, Russian Federation

**Background:** Multiple myeloma remains an incurable disease despite the emergence of new drugs. The search of optimal therapeutic strategy to increase life expectancy and remission in patients with this disease is continuous. This is facilitated to the achievement of the maximum possible response and eradication of residual tumor load. Existing recommendations for the treatment of multiple myeloma approve the use of autologous stem cell transplantation (autoSCT) to improve disease control.

**Aims:** To determine the impact of autologous stem cell transplantation on efficiency of treatment and tumor load in patients with multiple myeloma.

**Methods.** The study included 89 patients with MM (median age 58 years, male/female – 1.12:1). The induction therapy with Bortezomib-based regimens (VD, CVD, VMP, PAD) was used in 62/89 (69.6%) patients, Immunomodulator-based regimens (Thal+D, RD, VRD, PomD) – in 22/89 (24.8%), chemotherapy – in 4/89 (5.6%). High dose therapy (Mel200) and autoSCT is carried out in 64/89 (71.9%)

**S. Voloshin³** | **A. Kuzyaeva¹** | **A. Schmidt¹**
patients. The efficiency of therapy was evaluated according to IMWG criteria. Tumor load was determined by multicolor flow cytometry (5-colors): 79 patients – after 4-6 courses of induction therapy, 39 patients – after autoSCT; 29 patients – tumor load was performed in dynamics (before and after autoSCT).

**Results.** The sex, age, the variant induction antimyeloma therapy did not affect on response rate and tumor load. CR was achieved in 28/89 (31.4%) before AutoSCT and 50/89 (56.2%) after AutoSCT (p>.05). However, high dose therapy (Mel200) and AutoSCT has increased the possibility of achieving complete response in dynamics: before AutoSCT in 5/29 (17.2%), after AutoSCT – in 13/29 (44.8%) (p<.05).

Tumor load after 4-6 courses of induction therapy (n=79) was 0.28 ±0.34 for CR+sCR, 1.65±2.66 for VGPR, 2.10±2.53 for PR. Tumor load after HDT (Mel200) and AutoSCT (n=39) was 0.06±0.07 for CR+sCR, 0.15±0.46 for VGPR, 0.17±0.22 for PR.

The effect of autoSCT on PFS in 39 patients. The median PFS was 97 months in the group "tumor load after autoSCT <0.01%", 70 months – in the group "tumor load without autoSCT <0.01%", 50 months – in the group "tumor load after autoSCT >0.01%" and 25 months – in the group "tumor load without autoSCT >0.01%"(p=.006).

Examination of tumor load in the dynamics in 29 patients showed that autoSCT reduces the level of tumor load (before autoSCT = 2.27 ±0.20, after autoSCT – 0.14±0.01). Tumor load <0.01% after autoSCT was detected more often than before autoSCT (14/29 and 5/29 patients, respectively) (p<.05).

**Conclusions.** AutoSCT increase the efficiency of therapy, reduce tumor load and increase the duration of progression free survival in patients with multiple myeloma.

**Keywords:** autologous stem cell transplantation (ASCT); minimal residual disease (MRD); multiple myeloma (MM).
ONGOING TRIALS

OT07
A PHASE 3 STUDY OF ACALABRUTINIB
PLUS BENDAMUSTINE AND RITUXIMAB IN
ELDERLY (AGED ≥65 Years) TREATMENT-
NAIVE PATIENTS WITH MANTLE CELL
LYMPHOMA

M. Wang¹ | D. Belada² | C. Cheah³ | M.P. Chu⁴ |
M. Dreyling⁵ | I. Flinn⁶ | L. Fogliatto⁷ | A. Goy⁸ |
D. Inwards⁹ | W. Jurczak¹⁰ | J. Mayer¹¹ | F. Re¹² |
T. Robak¹³ | S. Spurgeon¹⁴ | S.S. Yoon¹⁵ |
P.L. Zinzani¹⁶ | M. Yin¹⁷ | T. Chen¹⁸ | B. Kahl | on
behalf of the ACE-LY-308 Group¹⁹

¹Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States; ²Charles University Hospital and Faculty of Medicine, Fourth Department of Internal Medicine-Hematology, Hradec Králové, Czech Republic;

³Comprehensive Cancer Centre, Sir Charles Gairdner Hospital, Nedlands, WA, Australia; ⁴Clinician Scientist, Cross Cancer Institute, Edmonton, Canada; ⁵Medizinische Klinik und Poliklinik III, Klinikum der Universität München, LMU München, München, Germany; ⁶Lymphoma Research, Sarah Cannon, Nashville, United States; ⁷Hematology, Irmandade da Santa Case de Misericórdia, Porto Alegre, Brazil; ⁸Lymphoma Division, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, United States; ⁹Hematology, Mayo Clinic, Rochester, United States; ¹⁰Department of Hematology, Jagiellonian University, Krakow, Poland; ¹¹Hematology, Fakultní nemocnice Brno, Brno, Czech Republic; ¹²Hematology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; ¹³Hematology, Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland; ¹⁴Hematology and Medical Oncology, OHSU Knight Cancer Institute, Portland, United States; ¹⁵Hematology, Seoul National University Hospital, Seoul, Republic of Korea; ¹⁶Hematology, Institute of Hematology Serägnoli, University of Bologna, Bologna, Italy; ¹⁷Bio statistics, Acerta Pharma, South San Francisco, United States; ¹⁸Clinical Development, Acerta Pharma, South San Francisco, United States; ¹⁹Department of Medicine, Oncology Division, Washington University School of Medicine, St. Louis, United States

**Background:** Mantle cell lymphoma is an aggressive B-cell non-Hodgkin lymphoma that remains incurable with current therapies, including standard first-line bendamustine and rituximab. There is a medical need for novel strategies to improve disease control in

elderly patients with mantle cell lymphoma. Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor with minimal off-target activities. For patients with relapsed/refractory mantle cell lymphoma, acalabrutinib demonstrated an overall response rate of 81%, with 40% of patients achieving a complete response (Lancet.2018;391:659). Taken together, combining acalabrutinib with bendamustine and rituximab in treatment-naive patients with mantle cell lymphomamay improve disease control and is being explored in an ongoing, global, phase 3 study ACE-LY-308 (NCT02972840).

**Methods:** ACE-LY-308 is a phase 3, randomized, double-blind study with approximately 250 sites. Patients must be aged ≥65 years, have treatment-naive mantle cell lymphoma, and not be intended for stem cell transplant. Patients are excluded for history of central nervous system lymphoma or significant cardiovascular disease (asymptomatic or controlled atrial fibrillation allowed) or if they require treatment with proton-pump inhibitors, warfarin or equivalent vitamin K antagonists, or strong CYP3A inhibitors/inducers. Approximately 546 patients will be randomized 1:1 to receive oral acalabrutinib 100 mg twice daily or placebo twice daily plus 6 cycles of bendamustine (90 mg/m² on days 1 and 2) and rituximab (375 mg/m² on day 1 of each 28-day cycle). Patients achieving partial or complete responses will receive maintenance rituximab every 2 cycles for up to 12 additional doses plus acalabrutinib or placebo. Patients will be treated until progressive disease or unacceptable toxicity. Patients assigned to placebo who have progressive disease on-study can crossover to receive acalabrutinib until second disease progression. The primary endpoint is independent review committee-assessed progression-free survival per the Lugano Classification. Secondary endpoints include overall response rate (≥partial response), duration of response, time to response, overall survival, and safety. Exploratory endpoints include pharmacokinetic and pharmacodynamic assessments, minimal residual disease, patient-reported outcomes, and medical resource utilization. The study opened for enrollment in February 2017. Accrual is ongoing.

**Keywords:** acalabrutinib; mantle cell lymphoma (MCL); rituximab.

**Disclosures:** Wang, M: Consultant Advisory Role: AstraZeneca, Janssen, and MoreHealth; Board of Directors or advisory committees for Celgene and Janssen; Honoraria: Acerta Pharma, Celgene, Dava Oncology, Janssen, and Pharmacyclics; Research Funding: Acerta Pharma, AstraZeneca, Celgene, Janssen, Kite Pharma, Juno, Novartis, and Pharmacyclics. Belada, D: Consultant Advisory Role: Gilead Sciences, Roche, Takeda; Research Funding: Takeda; Other Remuneration: Gilead Sciences, Roche. Cheah, C: Consultant Advisory Role: Roche, Janssen,
Takeda, MSD, Gilead, Bristol Myers Squibb, AstraZeneca; Honoraria: Roche, Janssen, Takeda, MSD, Gilead, Bristol Myers Squibb, AstraZeneca; Research Funding: Celgene, Roche, Abbvie; Other Remuneration: Roche, Amgen. Chu, M: Honoraria: AstraZeneca, Gilead, Celgene. Dreyling, M: Honoraria: Bayer, Celgene, Gilead, Janssen, Roche, Acerta, Bayer, Celgene, Gilead, Janssen, Novartis, Roche, Sandoz; Research Funding: Celgene, Janssen, Mundipharma, Roche; Other Remuneration: Celgene, Janssen, Roche, Takeda. Goy, A: Consultant Advisory Role: Acerta Pharma, Celgene, Kite/Gilead, Pharmacyclics/J&J, and Takeda; Honoraria: Celgene, Pharmacyclics/J&J, and Takeda; Research Funding: Acerta Pharma, Celgene, Genentech, Kite/Gilead, Pharmacyclics/J&J, and Seattle Genetics; Other Remuneration: Acerta Pharma, Celgene, Pharmacyclics/J&J, and Takeda. Inwards, D: Research Funding: Acerta (site PI for current ACE-LY308 study). Jurczak, W: Consultant Advisory Role: Astra Zeneca, Gilead, Sandoz Novartis, Roche, Morphosys; Research Funding: Morphosys, Roche, Sandoz-Novarttis, Celtrione, Celgene, Janssen, Astra Zencea, Gilead, TG Therapeutics, Incyte, Bayer. Mayer, J: Research Funding: Acerta Pharma. Robak, T: Research Funding: Acerta Pharma, AstraZeneca. Yoon, S: Consultant Advisory Role: Amgen, Celgene, AbbVie, Astellas, Janssen, Pfizer, MSD; Research Funding: Genentech. Zinzani, P: Consultant Advisory Role: MSD, BMS, Servier, Janssen, Gilead; Honoraria: MSD, BMS, Servier, Janssen, Gilead. Yin, M: Employment Leadership Position: Acerta Pharma; Stock Ownership: Acerta Pharma. Chen, T: Employment Leadership Position: Acerta Pharma; Stock Ownership: Acerta Pharma.

OT08
ARGO: A RANDOMISED PHASE II STUDY OF ATEZOLIZUMAB WITH RITUXIMAB, GEMCITABINE AND OXALIPLATIN IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA WHO ARE NOT CANDIDATES FOR HIGH-DOSE THERAPY

A.J. Davies<fnref n="1" /> | O. Tansley Hancock<fnref n="1" /> | T. Cummin<fnref n="1" /> |
J. Caddy<fnref n="1" /> | L. Stanton<fnref n="1" /> | C. Burton<fnref n="2" /> | S. Barrans<fnref n="2" /> |
A. Coleman<fnref n="1" /> | W. Osborne³ | P. McKay⁴ |
G. Griffiths<fnref n="1" /> | P. Johnson<fnref n="1" />

**Introduction:** Relapsed and refractory (R/R) diffuse large B-cell lymphoma (DLBCL) patients (pts.) have poor outcomes with only 20-30% alive at 3 years. A large proportion of pts. are not fit enough for high-dose therapy (HDT) and autologous stem cell transplantation (SCT)

following salvage immunochemotherapy. Whilst a significant number progress prior to reaching SCT. This is an area of unmet need in older pts. who may not tolerate HDT followed by SCT. Novel approaches are urgently needed, specifically requiring incorporation of promising agents to improve existing regimens for populations that are not candidates for HDT plus SCT.

Checkpoint inhibitors have revolutionised treatment for several solid tumours and induce frequent responses in Hodgkin lymphoma. Single agent anti-PD-1 monoclonal antibodies (mAbs) have produced responses in DLBCL. Atezolizumab (Atezo) is a mAb that enhances T-cell directed cytotoxicity by targeting PD-L1 in the tumour microenvironment and on malignant cells. Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated efficacy with acceptable toxicity in R/R DLBCL.

**Method:** ARGO is an open-label randomised phase II trial with 3:1 randomisation, stratified by relapsed and refractory patients. Patients in the experimental arm receive 1 cycle of R-GemOx (given every 14 days) followed by 5 cycles of this regimen plus 840mg atezo IV, followed by 8 21-day cycles of 840mg single agent atezo as maintenance. This will be compared with a control arm treated with R-GemOx for 6 cycles. Rituximab is delivered subcutaneously from cycle 2. The study utilises a Case and Morgan 2-stage phase II design (p0=25%, p1=40%, a= 10%, b=90%) requiring 112 participants.

The primary objective is to document durable anti-tumour activity of R-GemOx-Atezo, assessed by progression free survival at 1 year. Secondary objectives are to determine safety, response rate and overall survival rates. Comprehensive translational components are supported by the Bloodwise funded Precision Medicine for Aggressive Lymphoma consortium and include characterising: PD-1, PD-L1 and PD-L2 expression in the tumour (using FISH, immunohistochemistry, and gene expression) and on peripheral blood T-lymphocytes, gene expression signatures (including cell of origin), mutation profile by NGS, T-cell repertoire and dynamic changes in circulating tumour DNA.

The trial opened recruitment in May 2018 and is scheduled to complete recruitment in March 2020. To date 24 pts. have been randomised. It is an investigator initiated study co-ordinated by the Cancer Research UK (CRUK) Southampton Clinical Trials unit and sponsored by University Hospitals Southampton NHS Foundation Trust. It is funded by a grant from F. Hoffman-La Roche (M030090) and endorsed by CRUK, Clinical Research Committee (CRUKE/16/028).

Trial registration ISRCTN11965217

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

**Disclosures:** Davies, A: Consultant Advisory Role: Roche, Kite, Celgene, Acerta Pharma, MorphoSys, BioInvent; Honoraria: Roche, Celgene, Kite, Janssen; Research Funding: Roche, Acerta Pharma, Celgene, Gilead, Karyopharma, GSK; Other Remuneration: Roche, Celgene. Burton, C: Consultant Advisory Role: Roche, Takeda, BMS, Celgene; Honoraria: Roche, Takeda, BMS; Other Remuneration: Roche, Takeda. Barrans, S: Other Remuneration: HTG molecular. Osborne, W: Consultant Advisory Role: Roche, Takeda, Servier, MSD, Gilead; Honoraria: Roche,

<footnote n="1">¹Southampton Cancer Research UK (CRUK) Centre/CRUK Southampton Clinical Trials Unit/CRUK Experimental Cancer Medicines Centre UK, University of Southampton, Southampton, United Kingdom;</footnote>

<footnote n="2">²Haematological Malignancies Diagnostic Service, St James's University Hospital, Leeds, United Kingdom; ³Freeman Hospital, Newcastle, United Kingdom; ⁴Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom</footnote>
Takeda, Pfizer; Other Remuneration: Roche, Takeda, Pfizer. McKay, P: Consultant Advisory Role: Takeda, Celgene, MSD, BMS, Roche; Honoraria: Takeda, Janssen, Gilead, Celgene, MSD, BMS, Roche; Other Remuneration: TAKEDA, Janssen, Gilead, Roche, Royalties from book on Flow Cytometry. Griffiths, G: Research Funding: Hold educational trial grants from numerous companies including Roche. Johnson, P: Consultant Advisory Role: Janssen; Honoraria: Bristol-Myers Squibb, Takeda, Novartis, Celgene, Janssen, Epizyme, Boeringher Ingelheim, Kite, Genmab, Incyte; Research Funding: Janssen, Epizyme.

OT09
A PIVOTAL, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED, TWO-
ARM, PHASE 2 STUDY OF ME-401
INVESTIGATING TWO DOSING
SCHEDULES IN PATIENTS WITH
FOLLICULAR LYMPHOMA (FL) AFTER
FAILURE OF TWO OR MORE PRIOR
SYSTEMIC THERAPIES

A. Zelenetz¹ | P. Zinzani² | C. Buske³ | V. Ribrag⁴ |
D. Cunningham⁵ | W. Jurczak⁶ | P. Abrisqueta⁷ |
R. Agajanian⁸ | A. Chaudhry⁹ | T. Kayyal¹⁰ |
J. Wood¹¹ | J. Llorin-Sangalang¹² | J. Brown¹³

¹Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, United States; ²Institute of Hematology, University of Bologna, Bologna, Italy; ³Life Science Gebaeude, Universitatklinikum Ulm, Ulm, Germany; ⁴Gustave Roussy Cancer Center, Institut Gustave Roussy, Villejuif, France; ⁵Lymphoma Unit, Royal Marsden Hospital NHS, Sutton, United Kingdom; ⁶Department of Hematology, Jagiellonian University, Kraków, Poland; ⁷Department of Hematology, Hospital Vall Hebron, Barcelona, Spain; ⁸Department of Hematology, The Oncology Institute of Hope and Innovation, Cerritos, United States; ⁹Medical Oncology/Hematology, Medical Oncology Associates PS, Spokane, United States; ¹⁰Department of Oncology/Hematology, Renovatio Clinical, The Woodlands, United States; ¹¹Medical Affairs, MEI Pharma, Inc., San Diego, United States; ¹²Clinical Development, MEI Pharma, Inc., San Diego, United States; ¹³Division of Hematologic Malignancies, Dana Farber Cancer Institute, Boston, United States

**Background:** ME-401, a potent and selective oral PI3kδ inhibitor, has demonstrated very high and durable objective response rates (ORR) in both FL and CLL/SL; 76% in 38 patients with relapsed/refractory (R/R) FL and 100% in 12 patients with CLL/SLL (Soumerai 2018, Zelenetz 2018). A continuous dosing schedule resulted in delayed (>cycle 2) grade 3 adverse events of diarrhea and skin rash in ~1/3 of patients, likely related to on-target effects on T-regs resulting in immune-mediated toxicity. Based on the half-life of ME-401 (~26 hours) and the reported kinetics of T-reg regeneration (~10 days) we developed a rational 'intermittent'

dosing schedule of 7 daily doses/28-day cycle after 2 cycles of con-
tinuous daily dosing. We hypothesized that such a schedule would
provide 10-12 days of effective PI3kδ inhibition followed by wash-
out and sufficient time for T-reg recovery. Preliminary evaluation of
this novel schedule resulted in a decrease in delayed Grade
3 immune-related adverse events (irAE's) from 34% to 11%. To
define the optimal balance of safety and efficacy of ME-401 in
refractory R/R FL, we designed this phase 2 study evaluating 2 dos-
ing schedules.

**Methods:** This is a study of ME-401 in patients with FL after failure of ≥2 prior systemic therapies and will enroll 150 patients. Group A will receive 60mg QD on a continuous schedule until disease progression (PD) or toxicity. Group B will receive 60mg QD on a continuous schedule for 2 cycles then QD for the first 7 days of each subsequent cycle. In this group PD will trigger dose modification to the continuous schedule. Subjects who develop grade ≥2 irAE in A or B will trigger dose modification to open label intermittent schedule. The primary objectives are ORR using Lugano Response Criteria, as determined by an Independent Response Review Committee, and tolerability defined as the rate of AE's requiring dose modification or study drug discontinuation. A correlative study will evaluate the effects of ME-401 on T-cell subsets, cytokines and chemokines. The study opened to enrollment in December 2018 with approximately 80 global sites planned. (NCT03768505)

**Keywords:** follicular lymphoma (FL); PI3K/AKT/mTOR.

**Disclosures:** Zelenetz, A: Consultant Advisory Role: MEI, Amgen, Astra Zeneca, Bayer, BeiGene, Celgene, DAVA oncology, Roche/Genentech, Janssen, Gilead, Karyopharm, Morphosys, Novartis, Pharmacyclics/ Abbvie, Pfizer, Verastem. Zinzani, P: Consultant Advisory Role: MSD, Eusopharma, Verastem, Sanofi (both), ad board only - Celltrion, Janssen-Cilag, Gilead, BMS, Sandos, Servier, Immune design, Celgene, Portolo, Roche, KYOWA KIRIN; Other Remuneration: Speaker: MSD, Eusopharma, Verastem, Celltrion, Janssen-Cilag, Gilead, BMS, Servier, Immune Design, Celgene, Portolo, Roche, KYOWA KIRIN. Buske, C: Honoraria: Roche, Janssen, Pfizer, Celltrion, Hexal; Research Funding: Roche, Janssen, Bayer. Ribrag, V: Consultant Advisory Role: Epizyme, Servier, Nanostring, Gilead, Pharmamar, BMS, MSD, Incyte, Roche, Infinity; Research Funding: Epizyme, ArgenX. Cunningham, D: Research Funding: AstraZeneca, Celgene, MedImmune, Bayer, 4SC, Clovis, Eli Lilly, Janssen, Merck. Jurczak, W: Consultant Advisory Role: Astra Zeneca, Gilead, Sandoz, Novartis, Roche, Morphosys; Research Funding: Morphosys, Roche, Sandoz-Novartttis, Celtrione, Celgene, Janssen, Astra Zeneca, Gilead, TG Therapeutics, Incyte, Bayer. Abrisqueta, P: Consultant Advisory Role: Janssen, Abbvie, Roche; Honoraria: Janssen, Abbvie, Roche; Other Remuneration: Speaker: Janssen, Abbvie, Roche. Wood, J: Employment Leadership Position: MEI Pharma, Inc. Llorin-Sangalang, J: Employment Leadership Position: MEI Pharma, Inc. Brown, J: Consultant Advisory Role: Abbvie, Acerta, Astra Zeneca, BeiGene, Gilead, Invectys, June/Celgene, Kite, Loxo, Pfizer, Morphosys, Novartis, Pharmacyclics, Roche/Genentech, Sunesis, TG Therapeutics, Verastem; Honoraria: Janssen, Teva; Research Funding: Gilead, Loxo, Sun, Verastem.
# OT10
## PHASE II FIL-PTCL13 STUDY OF ROMIDEPSIN-CHOEP FOLLOWED BY HIGH-DOSE CHEMOTHERAPY AND TRANSPLANTATION IN UNTREATED PERIPHERAL T-CELL LYMPHOMAS

A. Chiappella¹ | C. Carniti² | A. Evangelista³ |

A. Re⁴ | M.G. Cabras⁵ | V. Stefoni⁶ | C. Castellino⁷ |

A.G. Congiu⁸ | A. Pinto⁹ | M. Zanni¹⁰ |

C. Rusconi¹¹ | A.L. Molinari¹² | R. Ciancia¹³ |

L. Baldini¹⁴ | L. Nassi¹⁵ | F. Re¹⁶ | M. Tani¹⁷ |

F. Ilariucci¹⁸ | F. Cavallo¹⁹ | A. Santoro²⁰ |

S. Volpetti²¹ | A. Dodero²² | S.A. Pileri²³ |

G. Ciccone³ | P. Corradini²⁴

¹Ematologia, AOU Città della Salute e della Scienza di Torino, Torino, Italy;

²Ematologia, Università degli Studi di Milano, Milano, Italy; ³SSD Epidemiologia Clinica e Valutativa, Clinical Trial Center, AOU Città della Salute e della Scienza di Torino e CPO Piemonte, Torino, Italy; ⁴Ematologia, ASTT Spedali Civili di Brescia, Brescia, Italy; ⁵Ematologia, Ospedale Oncologico Armando Businco, Cagliari, Italy; ⁶Ematologia, Policlinico S. Orsola-Malpighi, Istituto di Ematologia "Seragnoli", Bologna, Italy;

⁷Ematologia e Trapianto di Midollo Osseo, AO Santa Croce e Carle, Cuneo, Italy; ⁸Ematologia, Ospedale Policlinico San Martino S.S.R.L. - IRCCS per l'Oncologia, Genova, Italy; ⁹Ematologia Oncologica, Istituto Nazionale Tumori - IRCCS Fondazione G. Pascale, Napoli, Italy; ¹⁰Ematologia, AO SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy; ¹¹Ematologia, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy; ¹²Ematologia, Ospedale degli Infermi, Rimini, Italy; ¹³Oncoematologia, trapianti emopoietici e terapie cellulari, Centro di Riferimento Oncologico CRO, IRCCS, Aviano, Italy; ¹⁴Ematologia, Ospedale Maggiore Policlinico - Fondazione IRCCS Ca' Granda, Milano, Italy; ¹⁵Ematologia, AOU Maggiore della Carità di Novara, Novara, Italy; ¹⁶Ematologia e CTMO, AOU Ospedale Maggiore di Parma, Parma, Italy; ¹⁷Ematologia, Ospedale Santa Maria delle Croci, Ravenna, Italy; ¹⁸Ematologia, Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Italy; ¹⁹Ematologia, Università degli Studi - AOU Città della Salute e della Scienza di Torino, Torino, Italy; ²⁰Ematologia, Istituto Clinico Humanitas, Rozzano, Italy; ²¹Ematologia, ASUI Santa Maria della Misericordia, Udine, Italy; ²²Ematologia, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; ²³Emopatologia, Istituto Europeo Oncologico IRCCS, Milano, Italy; ²⁴Ematologia, Fondazione IRCCS Istituto Nazionale dei Tumori - Università degli Studi di Milano, Milano, Italy

**Introduction:** Peripheral T-cell lymphomas (PTCL), with the exception of anaplastic ALK-positive subtype, have a poor prognosis, when treated with standard CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). The introduction of etoposide (CHOEP) and the consolidation in responsive patients with autologous stem cell transplantation (autoSCT), represents the most common therapeutic option, in patients younger than 65 years. However, 25-30% of patients do not reach the transplant because of primary refractory or

early progressive disease. To increase the response rate pre-autoSCT, we designed the phase I-II FIL-PTCL13 study (NCT02223208), aimed to define the maximum tolerated dose of romidepsin, a histone-deacetylase non-cross resistant agent, in combination with CHOEP (Ro-CHOEP) followed by high-dose chemotherapy and autoSCT. The phase I part of the study was conducted, according to continual reassessment method, from September 2014 to July 2017, and 21 patients were enrolled. Eight dose limiting toxicities were reported; the observed toxicity was 26.1% (95% Credibility Interval: 10.1%-46.3%) and prompted to define 14 mg/ms the recommended dose of romidepsin in addition to CHOEP. On September 2017, the phase II part of the trial was opened.

**Methods:** Inclusion criteria are: stage II-IV patients aged 18-65, with newly diagnosis of PTCL including PTCL-NOS, angioimmunoblastic, ALK negative anaplastic lymphoma; no central nervous system disease; normal organ function; no active infections. Treatment scheme includes an induction phase with 6 courses of Ro-CHOEP every 21 days (romidepsin at the dose of 14 mg/ms on day 1 and 8 of each cycle). Patients in complete (CR) or partial (PR) response after induction, will continue with one cycle of DHAP (cisplatin, citarabine, desamethasone) followed by stem cell harvest. Patients in CR after the 6 Ro-CHOEP will proceed to autoSCT; patients in PR with an available HLA-matched donor, will undergo alloSCT upfront. The primary end-point of the phase II part of the study is progression free survival at 18 months (18m-PFS). Secondary endpoints are: overall response rate and CR (defined according to the Lugano Classification 2014 response criteria), after 6 Ro-CHOEP and after SCT; event free survival, overall survival, any grade III or higher toxicities, treatment-related mortality defined as any death that was not attributable to the lymphoma, and incidence of acute or chronic graft versus host disease in allografted patients. Exploratory endpoint is the evaluation of response biomarkers (GATA3, TBX21, CDKN2A, PTEN). According to the Case and Morgan 2-stage design, to demonstrate an absolute improvement from 55% to 70% of the 18m-PFS, (alpha, 1-tail=0.05; beta=0.10), the target accrual is 110 patients, with the interim analysis planned when the first 75 patients have been enrolled. At now, 60 patients have been enrolled, 57 of which treated at the maximum tolerated dose of romidepsin.

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

**Disclosures:** Chiappella, A: Consultant Advisory Role: advisory board: Celgene, Janssen; Honoraria: lecture fee: Amgen, Celgene, Janssen, Nanostring, Roche, Servier, Teva; Research Funding: Romidepsin was provided free by Celgene in PTCL13 study.

# OT11
## A MULTICENTER, OPEN LABEL, UNCONTROLLED, PHASE II TRIAL EVALUATING SAFETY AND EFFICACY OF VENETOCLAX, ATEZOLIZUMAB ANDOBINUTUZUMAB IN RICHTER TRANSFORMATION FROM CLL
**M. Montillo**¹ | **D. Rossi**² | **E. Zucca**³ |
**A.M. Frustaci**¹ | **S. Pileri**⁴ | **F. Cavalli**³ | **A. Tedeschi**¹

¹Department of Haematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy; ²Oncology, Università della Svizzera italiana, Institute of Oncology Research; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; ³Oncology, Università della Svizzera italiana, Institute of Oncology Research; Oncology Institute of Southern Switzerland; International Extranodal Lymphoma Study Group, IELSG, Bellinzona, Switzerland; ⁴Haematopathology Division, European Institute of Oncology, Milano, Italy

**Introduction:** Diffuse large B-cell (DLBCL) transformation from chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), Richter Syndrome (RS), has poor prognosis. Venetoclax, Bcl-2 inhibitor, has shown activity either in DLBCL and DLBCL-type RS. Atezolizumab is a humanized immunoglobulin monoclonal antibody (MoAb) targeting PD-L1 on tumor-infiltrating immune cells or tumor cells and prevents interaction with the PD-1 receptor and B7.1. Obinutuzumab, anti CD-20 MoAb compared to rituximab, presents a greater antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis and direct cell death. Preliminary data of atezolizumab alone or in combination with obinutuzumab showed to be safe and promising in heavily pretreated DLBCL. We present a phase II trial evaluating safety and efficacy of venetoclax, atezolizumab, obinutuzumab combination in RS.

**Methods:** Eligible pts are: ≥18 years, ECOG PS ≤2, diagnosis of DLBCL RS from CLL/SLL. Exclusion criteria: pretreated RS, prior therapy with venetoclax or atezolizumab, CNS involvement, history of autoimmune disease. The study consists of 2 phases. In the run-in phase 9 pts will be enrolled in three cohorts of 3 subjects each. If no more than 1 pt in each of the 3 groups experiences during the first 3 cycles: treatment-related death or grade 4 non-infective/non-hematologic adverse event; the expansion phase will follow enrolling up to 31 pts. Treatment consists of 35 cycles with: obinutuzumab (1000 mg C1-8), atezolizumab (1200 mg C1-18), venetoclax (400 mg/d C1-35). Primary endpoint of the study is safety and tolerability for the run-in phase; efficacy (overall response, complete remissions, response duration, progression free and overall survival) for the expansion phase. Safety and efficacy are also secondary endpoints of each phase. Exploratory consists of MRD monitored by flow cytometry and ultra-deep NGS of disease markers; correlation between outcome and disease biomarkers. EUDRACT 2018-005028-40.

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

**Disclosures:** Montillo, M: Consultant Advisory Role: Janssen, Abbvie, Gilead; Honoraria: Verastem, AstraZeneca; Research Funding: Roche. Rossi, D: Consultant Advisory Role: Janssen, Abbvie, Gilead, AstraZeneca, MSD; Honoraria: Janssen, Abbvie, Gilead, Roche, AstraZeneca; Research Funding: Roche, Gilead, Abbvie, Janssen, Cellestia. Zucca, E: Consultant Advisory Role: Celltrion, AstraZeneca,

Roche, Janssen, Celgene; Honoraria: Roche, Gilead, Abbvie. Pileri, S: Consultant Advisory Role: Takeda; Honoraria: Takeda. Tedeschi, A: Consultant Advisory Role: Janssen, Abbvie, Beigene; Honoraria: Sunesis.

# OT12
## BIANCA: A PHASE 2 STUDY OF THE SAFETY AND EFFICACY OF TISAGENLECLEUCEL IN PEDIATRIC PATIENTS WITH RELAPSED/REFRACTORY MATURE B-CELL NON-HODGKIN LYMPHOMA

**V. Minard-Colin**¹ | **B. Burkhardt**² | **S. Maude**³ |
**C. Phillips**⁴ | **C. Diaz de Heredia Rubio**⁵ |
**T.W. Laetsch**⁶ | **K. Curran**⁷ | **S. Newsome**⁸ |
**N. Murray**⁹ | **L. Pacaud**¹⁰ | **J. Buechner**¹¹

¹Child and Adolescent Cancer, Gustave Roussy, Villejuif, France;

²Pediatric Hematology and Oncology, Universitätsklinikum Münster, Münster, Germany;

³Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, United States;

⁴Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States;

⁵Pediatric Oncology and Hematology Service, Hospital Vall D'Hebron, Barcelona, Spain; ⁶Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States; ⁷Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States; ⁸Oncology Biostatistics, Novartis Pharma AG, Basel, Switzerland; ⁹IQVIA, Novartis Pharmaceuticals UK Ltd, Frimley, United Kingdom; ¹⁰Novartis Oncology, Novartis Pharmaceuticals Corporation, East Hanover, United States;

¹¹Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway

**Background:** Pediatric patients with relapsed/refractory mature B-cell non-Hodgkin lymphoma (r/r B-NHL) have very poor prognosis and limited clinical benefit from available salvage therapies. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor-T cell (CAR-T) therapy that was approved for the treatment of pediatric patients with r/r B-cell acute lymphoblastic leukemia in 2017 (Maude et al. NEJM. 2018) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL) in 2018 (Schuster et al. NEJM. 2018) in the United States, and for the treatment of the same patient populations in 2018 in Europe. Very limited experience exists in collecting, producing, and treating pediatric B-NHL patients with CAR-T therapies. Here we introduce BIANCA (NCT03610724), a phase 2 trial investigating the safety and efficacy of tisagenlecleucel in pediatric patients with r/r B-NHL. This will be the first international multicenter trial to assess the feasibility and efficacy of an FDA/EMA-approved CAR-T cell therapy with centralized manufacturing in pediatric r/r NHL.

**Methods:** BIANCA is a phase 2, single-arm, multicenter, open label trial of tisagenlecleucel in pediatric patients with CD19+ r/r B-NHL (including Burkitt lymphoma, DLBCL, primary mediastinal B-cell lymphoma, gray zone lymphoma, and follicular lymphoma). Eligible
patients must be <18 years of age, weight ≥6 kg, and have confirmed B-NHL relapsed or refractory to ≥1 prior lines of therapy. Karnofsky (age ≥16 years) or Lansky (age <16 years) performance status must be ≥60. Patients must not have active central nervous system disease involvement before infusion or prior treatment with any anti-CD19 or gene therapy. Prior therapy can include systemic therapies and allogeneic or autologous hematopoietic stem cell transplant (HSCT) provided it occurred >3 months prior to screening. The primary endpoint of this study is overall response rate by International Pediatric NHL Response Criteria and Lugano 2014 criteria. Secondary outcomes include duration of response, event-free survival, relapse-free survival, progression-free survival, overall survival, pharmacokinetics, immunogenicity, frequency of post-tisagenlecleucel SCT, and biomarkers. Estimated enrollment for this study is 35 patients (at least 26 infused and evaluable).

**Clinical trial information:** NCT03610724.

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

**Disclosures:** Burkhardt, B: Research Funding: Celgene, Roche. Maude, S: Honoraria: Novartis, Kite Pharmaceuticals. Phillips, C: Honoraria: Novartis. Diaz de Heredia Rubio, C: Honoraria: Novartis. Laetsch, T: Consultant Advisory Role: Novartis, Loxo Oncology, Eli Lilly, Bayer; Research Funding: Novartis, Pfizer. Curran, K: Consultant Advisory Role: Novartis, Juno Therapeutics. Newsome, S: Employment Leadership Position: Novartis. Murray, N: Employment Leadership Position: Novartis. Pacaud, L: Employment Leadership Position: Novartis. Buechner, J: Honoraria: Novartis; Research Funding: Novartis.

## OT13
# ELARA: A PHASE 2 TRIAL INVESTIGATING THE EFFICACY AND SAFETY OF TISAGENLECLEUCEL IN ADULT PATIENTS WITH REFRACTORY/RELAPSED FOLLICULAR LYMPHOMA

M. Dickinson<fnref n="1" /> | L. Popplewell² | A. Kolstad³ |

P.J. Ho⁴ | T. Teshima⁵ | M. Dreyling⁶ |

S. Schuster⁷ | C. Thieblemont⁸ | M. Ghosh⁹ |

P. Riedell¹⁰ | N. Yateman¹¹ | K. Lehnhoff¹² |

T. Lawniczek¹³ | L. Pacaud¹⁴ | N. Fowler¹⁵

**Background:** Tisagenlecleucel is an anti-CD19 chimeric antigen receptor-T cell (CAR-T) therapy that was approved in 2017 for the treatment of pediatric and young adult patients up to 25 years of age with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (Maude et al. NEJM. 2018), as well as for the treatment of adult patients with r/r diffuse large B-cell lymphoma in 2018 (Schuster et al. NEJM. 2018). Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the Western hemisphere, with limited treatment options in patients refractory to or relapsing after standard therapies. In a phase 2a study of patients with r/r CD19+ lymphomas, 10 of 14 (71%) patients with r/r FL treated with tisagenlecleucel achieved a durable complete remission at a median follow-up of 28.6 months (Schuster et al. NEJM. 2017). Here we introduce ELARA (NCT03568461), a phase 2 study evaluating the efficacy and safety of tisagenlecleucel in patients with r/r FL.

**Methods:** ELARA is a phase 2, single-arm, multicenter, open label trial. Eligible patients must be ≥18 years of age, have radiographically measurable grade 1, 2, or 3A FL that is refractory to a second or later line of systemic therapy (including an anti-CD20 antibody and an alkylator), or relapsed within 6 months after completion of a second or later line of systemic therapy, or relapsed during anti-CD20 antibody maintenance (following ≥2 lines of therapy as above) or within 6 months after maintenance completion, or relapsed after autologous hematopoietic stem cell transplant (HSCT). Patients with central nervous system involvement, or those who received prior anti-CD19 therapy, gene therapy, adoptive T-cell therapy, or allogeneic HSCT are not eligible. The primary endpoint of this study is complete response rate based on Lugano classification response criteria. Secondary outcomes include overall response rate, duration of response, overall survival, cellular kinetics, immunogenicity, safety, and patient-reported outcomes. Estimated enrollment for this study is 113 patients. The study is currently open to patient enrollment.

**Clinical trial information:** NCT03568461.

**Keywords:** CD19; follicular lymphoma (FL).

**Disclosures:** Dickinson, M: Consultant Advisory Role: Novartis; Honoraria: Novartis. Popplewell, L: Honoraria: Pfizer, Roche, Spectrum. Ho, P: Consultant Advisory Role: Takeda; Other Remuneration: Novartis, Celgene, La Jolla Pharmaceuticals. Teshima, T: Honoraria: Novartis; Research Funding: Novartis. Dreyling, M: Consultant Advisory Role: Acerta, Bayer, Celgene, Gilead, Janssen, Novartis, Roche, Sandoz; Honoraria: Bayer, Celgene, Gilead, Janssen, Mundipharma, Roche; Other Remuneration: Celgene, Janssen, Roche, Takeda. Schuster, S: Honoraria: Celgene, Genentech, Merck, Pharmacyclics, Novartis, Nordic Nanovector, Acerta, Pfizer, Gilead; Research Funding: Celgene,

<footnote n="1">¹Integrated Haematology Service, Peter MacCallum Cancer Centre, Melbourne, Australia; ²Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, United States; ³Department of Oncology, Oslo University Hospital, Oslo, Norway; ⁴Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, Australia; ⁵Department of Hematology, Hokkaido University Hospital, Sapporo, Japan; ⁶Department of Medicine, University Hospital Grosshadern, München, Germany; ⁷Division of Hematology Oncology, University of Pennsylvania, Philadelphia, United States; ⁸Hemato-Oncology Department, Hospital Saint-Louis, Paris, France; ⁹Michigan Medicine Bone Marrow Transplant and Leukemia, University of Michigan, Ann Arbor, United States; ¹⁰Biomedical Sciences, University</footnote>

<footnote>of Chicago, Chicago, United States; ¹¹External, Novartis Pharma AG, Basel, Switzerland; ¹²Global Development Operations, Novartis Pharma AG, Basel, Switzerland; ¹³CAR-T Cell Therapy, Novartis Pharma AG, Basel, Switzerland; ¹⁴Novartis Oncology, Novartis Pharmaceuticals Corporation, East Hanover, United States; ¹⁵Lymphoma and Meyloma, MD Anderson Cancer Center, Houston, United States</footnote>
Genentech, Merck, *Pharmacyclics*, Novartis, Gilead; Other Remuneration: Novartis. **Thieblemont**, C: Honoraria: Gilead, Roche, *Cellectis*, Celgene; Research Funding: Roche. **Ghosh**, M: Research Funding: Incyte, Novartis. **Riedell**, P: Honoraria: Kite Pharma, Bayer, Novartis, Verastem. **Yateman**, N: Employment Leadership Position: Novartis. **Lehnhoff**, K: Employment Leadership Position: Novartis. **Lawniczek**, T: Employment Leadership Position: Novartis. **Pacaud**, L: Employment Leadership Position: Novartis. **Fowler**, N: Research Funding: Celgene, Janssen, Abbvie; Other Remuneration: Celgene, Roche, Janssen, Abbvie, TG Therapeutics.

# OT14
## PORTIA: A PHASE 1B STUDY EVALUATING SAFETY AND EFFICACY OF TISAGENLECLEUCEL AND PEMBROLIZUMAB IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA

U. Jaeger¹ | J. McGuirk² | N. Worel¹ | P. Riedell³ |

I. Fleury⁴ | P. Borchmann⁵ | A. Forcina⁶ | J. Chu⁷ |

M. Leung⁸ | L. Pacaud⁷ | E. Waller⁹

¹Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; ²Hematologic Malignancies and Cellular Therapeutics, Kansas Hospital and Medical Center, Kansas City, United States; ³Biomedical Sciences, University of Chicago, Chicago, United States; ⁴Hematology, Hospital Maisonneuve-Rosemont, Montreal, Canada; ⁵Hematology/Oncology, University Hospital of Cologne, Cologne, Germany; ⁶Novartis Oncology, Novartis Pharma AG, Basel, Switzerland; ⁷Novartis Oncology, Novartis Pharmaceuticals Corporation, East Hanover, United States; ⁸Oncology Clinical Development, Novartis Pharmaceuticals Corporation, East Hanover, United States; ⁹Stem Cell Transplantation and Immunotherapy, Emory University School of Medicine, Atlanta, United States

**Background:** Tisagenlecleucel is an anti-CD19 chimeric antigen receptor-T cell therapy approved for pediatric patients with r/r B-cell acute lymphoblastic leukemia in 2017 (Maude et al. NEJM. 2018) and adult patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) in 2018 (Schuster et al. NEJM. 2018). The JULIET trial showed efficacy and safety of tisagenlecleucel in r/r DLBCL; subgroup analyses suggested an association between PD-1/PD-L1 interaction and lack of response (Agoulnik et al. EHA. 2018). Pembrolizumab after tisagenlecleucel has shown clinical activity in r/r DLBCL (Chong et al. Blood. 2017). We introduce PORTIA, a trial investigating safety and efficacy of tisagenlecleucel plus pembrolizumab in r/r DLBCL.

**Methods:** PORTIA is a phase 1b, multicenter, open-label, dose-timing and dose-expansion trial. Optimal timing of pembrolizumab administration will be based on the estimation of probability of dose-limiting toxicities (DLTs). A 2-parameter Bayesian Logistic

Regression Method guided by the Escalation with Overdose Control principle will guide dose-timing selection together with review of accumulating safety and cellular kinetic data. Eligible patients must be ≥18 years old and have a confirmed diagnosis of r/r DLBCL with measurable disease and no active central nervous system disease; received ≥2 prior lines of therapy, including anti-CD20 and anthracycline-based chemotherapy, relapsing to or not eligible for autologous stem cell transplant (SCT); ECOG performance status must be 0 or 1. Patients treated with prior allogeneic SCT or anti-CD3, anti-CD19, or checkpoint inhibitor therapy are excluded. Primary endpoints are the proportion of patients receiving pembrolizumab per protocol schedule, the incidence of DLTs in the dose-timing selection phase, and overall response rate in the dose-expansion phase. Secondary outcomes include duration of response, progression-free survival, overall survival, safety, cellular kinetics, and immunogenicity. Estimated enrollment is 8-12 patients in the dose-timing and 12-16 patients in the dose-expansion phase. Dose-timing selection is currently ongoing. The first cohort of 4 patients receiving pembrolizumab at day 15 after tisagenlecleucel infusion has been completed.

**Clinical trial information:** NCT03630159.

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

**Disclosures:** Jaeger, U: Honoraria: Novartis, AbbVie, Bioverativ, Celgene, Gilead, Janssen, MSD, Roche, Takeda Millennium, Amgen, AOP Orphan, BMS, Sandoz; Research Funding: Novartis, Bioverativ, Celgene, Gilead, Janssen, Roche; Other Remuneration: Novartis, AbbVie, Celgene, Gilead, Janssen, MSD, Roche, Takeda Millenium, Amgen, APO Orphan, BMS, Sandoz. McGuirk, J: Honoraria: Kite Pharma; Research Funding: Novartis, Kite Pharma, Fresenius Biotech, Astellas Pharma, Bellicum Pharmaceuticals, Gamida Cell, Pluristem Ltd. Worel, N: Honoraria: Novartis.

**Riedell, P:** Honoraria: Kite Pharma, Bayer, Novartis, Verastem. **Fleury, I:** Honoraria: Gilead, Novartis, Roche, Seattle Genetics, Janssen, AbbVie.

**Borchmann, P:** Honoraria: Novartis. **Forcina, A:** Employment Leadership Position: Novartis. **Chu, J:** Employment Leadership Position: Novartis. **Leung, M:** Employment Leadership Position: Novartis.

**Pacaud, L:** Employment Leadership Position: Novartis. **Waller, E:** Stock Ownership: Cambium Medical Technologies, Cambium Oncology, Cerus Corporation, Chimerix; Honoraria: Cambium Medical Technologies, Kalytera, Novartis; Research Funding: Celldex, Novartis, Pharmacycyclics; Other Remuneration: Pharmacycyclics.

# OT15
## MULTI-CENTER PHASE II STUDY OF ORAL AZACITIDINE (CC-486) PLUS CHOP AS INITIAL TREATMENT FOR PERIPHERAL T-CELL LYMPHOMA

J. Ruan¹ | J.P. Leonard¹ | M. Coleman¹ |

S. Rutherford¹ | K. Van Besien¹ | A. Rodriguez¹ |

L. Benderoff¹ | N. Mehta-Shah² | A. Moskowitz³ |

L. Sokol⁴ | L. Cerchietti¹ | G. Inghirami⁵ | P. Martin¹
¹Medicine/Hematology-Oncology, Weill Cornell Medical College, New York, United States; ²Department of Medicine, Washington University in St. Louis, St. Louis, United States; ³Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States; ⁴Department of Medicine, Moffitt Cancer Center, Tampa, United States; ⁵Department of Pathology, Weill Cornell Medical College, New York, United States

**Introduction:** Peripheral T-cell lymphomas (PTCL) are an uncommon and heterogeneous group of non-Hodgkin lymphomas with divergent cells of origin and mechanisms of lymphomagenesis. Cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, the most commonly prescribed initial treatment for systemic PTCL, provides suboptimal complete remission rates and response duration in the majority of non-ALCL patients. Emerging genetic studies have shown recurrent mutations affecting TET2, DNMT3A, IDH2 and RHOA in PTCL subtypes, particularly in nodal peripheral T-cell lymphoma with T-follicular helper phenotype (PTCL-TFH) such as angioimmunoblastic T-cell lymphoma. The association of aberrant DNA methylation with PTCL lymphomagenesis provides rationale for clinical application of hypomethylating agents. Azacitidine is an epigenetic modifier of DNA methylation by inhibition of DNA methyltransferase at low doses. In human PTCL patients, treatment with 5-azacitidine produced sustained responses (ORR 75%, CR/Cru 50%) in R/R AITL in a retrospective cohort study (Lemonnier et al. Blood 2018;132:2305). The feasibility of combining CHOP chemotherapy with azacitidine has been evaluated in 2 phase 1 studies in B-cell lymphoma, one with injectable 5-azaticidine (Clozel et al. Cancer Discov 2013;3:1002), the other with oral azacitidine (CC-486) (Martin et al. Blood 2017;130:192). We initiated a multi-center phase 2 study in 5/2018 to evaluate the efficacy and safety of chemo-sensitization with oral azacitidine (CC-486) in combination with CHOP for initial treatment of PTCL (ClinicalTrials.gov - NCT03542266).

**Methods:** This exploratory phase 2 study prioritizes enrollment of nodal TCL with TFH phenotype (PTCL-TFH). Additional eligible subtypes include PTCL/NOS and ATLL. Subjects receive standard dose CHOP on day 1 of each cycle for a total of 6 cycles. Priming with oral azacitidine (CC-486) at 300 mg daily is administered for 7 days prior to CHOP cycle 1 initiation, and for 14 days (days 8-21) before CHOP cycles 2-6. Supportive care includes mandatory G-CSF and recommended prophylaxis against PCP and VZV. The primary endpoint is CR per 2014 IWG criteria. Secondary endpoints include ORR, safety and survival. The study has a sample size of 20, and follows two-stage minimax design for primary efficacy analysis. Correlative biomarker studies are prospectively planned to assess changes in genome-wide methylation, gene expression and immune profile in response to DNMT inhibitor. The study is actively enrolling patients at Weill Cornell Medicine, with additional 3 US sites due to open in the 2nd quarter of 2019.

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

**Disclosures:** Ruan, J: Consultant Advisory Role: Celgene, Seattle Genetics, AstraZeneca; Research Funding: Celgene, Pharmaceutics, Seattle Genetics, Janssen. Leonard, J: Consultant Advisory Role: Gilead, AstraZeneca, Novartis, Celgene; Research Funding: Celgene. Van Besien, K: Research Funding: Celgene. Mehta-Shah, N: Consultant Advisory Role: Kyowa Hakka Kirin; Research Funding: Verastem, Celgene, AstraZeneca, Roche/Genentech, Bristol Myers Squibb. Sokol, L: Consultant Advisory Role: Celgene, Seattle Genetics and Spectrum Pharmaceuticals. Martin, P: Consultant Advisory Role: Celgene, Janssen, AstraZeneca, Gilead; Research Funding: Celgene.

# OT16 DOSE FINDING STUDY TO ASSESS SAFETY, PK AND EFFICACY OF FIMEPINOSTAT (CUDC-907) WITH VENETOCLAX OR RITUXIMAB PLUS BENDAMUSTINE IN PATIENTS WITH RELAPSED/REFRACTORY LYMPHOMA

A. Younes¹ | C.L. Batlevi¹ | J.B. Cohen² | K. Kelly³ | D.J. Landsburg⁴ | K. Patel⁵ | T. Phillips⁶ | S. Smith⁷ | J. Westin⁸ | A.W. Ma⁹ | D. Grayson⁹ | S. Barta⁴

¹Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States; ²Hematology & Medical Oncology, Emory University Winship Cancer Institute, Atlanta, United States; ³Department of Medicine, University of Southern California, Norris Cancer Center Hospital, Los Angeles, United States; ⁴Department of Medicine, University of Pennsylvania, Perelman Center, Philadelphia, United States; ⁵Oncology, Swedish Cancer Institute, Seattle, United States; ⁶Rogel Cancer Center, University of Michigan, Ann Arbor, United States; ⁷Hematology/Oncology, University of Chicago, Chicago, United States; ⁸Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States; ⁹Research & Development, Curis, Inc., Lexington, United States

**Background:** The 2016 WHO reclassification of lymphoid tumors distinguishes double-hit (DHL) and triple-hit (THL) lymphomas as clinically important subtypes, now classified as high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements. Double-expressor lymphoma with MYC and BCL2 protein overexpression without rearrangement (included within DLBCL-NOS) also has prognostic importance. This reclassification highlights the dismal outcomes for patients with tumors harboring MYC and/or BCL2 alterations. Currently, there are no approved therapies that target MYC. Fimepinostat (F) is an investigational small-molecule dual inhibitor of PI3Ks and HDACs. F inhibited both PI3K and HDAC in non-clinical studies and substantially reduced MYC protein levels. PI3K and HDAC were also inhibited by F in patients. F demonstrated synergistic antitumor effects with venetoclax (V) in DHL and DEL models in vitro and
<table><caption>TABLE</caption><thead><tr><th>Arm</th><th>Cohort: Dose/Schedule</th></tr></thead><tbody><tr><td>F + V</td><td>1: F 30 mg daily, 5/2 + V 400 mg QD<br>2: F 60 mg daily, 5/2 + V 400 mg QD<br>3: F 60 mg daily, 5/2 + V 800 mg QD</td></tr><tr><td>F + B + R</td><td>1: F 30 mg daily, 5/2 + B 90 mg/m<fnref n="2" /> Day 1,2 + R 375 mg/m<fnref n="2" /> Day 1<br>2: F 60 mg daily, 5/2 + B 90 mg/m<fnref n="2" /> Day 1,2 + R 375 mg/m<fnref n="2" /> Day 1<br>3: F 60 mg daily, 5/2 + B 120 mg/m<fnref n="2" /> Day 1,2 + R 375 mg/m<fnref n="2" /> Day 1</td></tr></tbody></table>

in vivo. In clinical studies, F as monotherapy or in combination with rituximab (R) was well tolerated with a favorable safety profile in patients with R/R lymphoma, and resulted in robust and durable objective response rates (ORR) in patients with R/R MYC-altered DLBCL.

**Methods:** CUDC-907-101 is a Phase 1/2, multi-center, dose-finding study that was recently amended to study F in combination with V, or F with R plus bendamustine (B) in pts with R/R lymphoma, including DLBCL or HGBL with MYC and BCL2 alterations. The primary objectives are to determine the MTD, safety and tolerability of each combination, and to assess preliminary efficacy, as measured by ORR and DOR. Pts must be R/R to ≥1 prior regimen, have measurable disease (Lugano criteria), and have archived or fresh tumor tissue. Approximately 12 pts (dose escalation; 3+3 design) and 30 pts (dose expansion) will be enrolled into each combination arm. Clinical trial: NCT01742988.

**Keywords:** "double-hit" lymphomas; high-grade B-cell lymphoma with or without rearrangement of MYC and BCL2 and/or BCL6; MYC.

**Disclosures:** Younes, A: Consultant Advisory Role: BMS, Incyte, Janssen, Genentech and Merck; Honoraria: Genentech, Merck, Takeda, Incyte, BMS, AbbVie; Research Funding: Novartis, Johnson & Johnson, Curis, Roche, BMS.

## OT17

### SOLAR: A PHASE 2, GLOBAL, RANDOMIZED, ACTIVE COMPARATOR STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF COBOMARSEN IN SUBJECTS WITH MYCOSIS FUNGOIDES (MF)

A.M. James<fnref n="1" /> | J. Ruckman<fnref n="1" /> | L.A. Pestano<fnref n="2" /> |

R.D. Hopkins<fnref n="1" /> | R.C. Rodgers<fnref n="1" /> | W.S. Marshall<fnref n="3" /> |

P. Rubin<fnref n="3" /> | D. Escolar<fnref n="1" />

**Introduction:** Mycosis fungoides (MF, the most prevalent subtype of peripheral T-cell lymphomas, is characterized by proliferation of

atypical T lymphocytes in the skin, forming patches, plaques, or nodular tumors. The goal of treatment is to minimize morbidity and limit disease progression; however, most therapies have significant side effects which limit their chronic use.

Cobomarsen is an inhibitor of microRNA-155, which is elevated and plays an important role in the proliferation and survival of malignant cancer cells in MF. In vitro, cobomarsen reduces proliferation and increases apoptosis in lymphoma cells. A Phase I clinical trial of cobomarsen in MF showed improvement in skin disease in 92% of subjects, with a durable response lasting at least 4 months in 77% of those achieving a PR (ORR4 based on mSWAT). The mean duration of response was 276 days and no significant side effects were attributed to cobomarsen.

**Methods:** MRG106-11-201 or SOLAR is a randomized, controlled, open-label study to assess the efficacy and safety of cobomarsen in patients with MF. The active comparator is vorinostat, an HDAC inhibitor approved in the US for the treatment of MF. The trial is currently recruiting subjects with a target of 126 subjects (63 per arm). Eligible subjects must have MF Stage IB-IIIB with a minimum mSWAT score of 10, B0-1, N0-1, no visceral involvement, and no large cell transformation. Prior treatment with an HDAC inhibitor is prohibited. Stratification will be performed based on age and LDH level at diagnosis. The primary endpoint is the proportion of subjects achieving ORR4 using composite global response criteria; secondary endpoints include progression free survival, patient reported outcomes, time to progression, time to next treatment, and overall survival. Subjects will receive weekly cobomarsen 282 mg IV infusions or daily 400 mg oral vorinostat. Assessments include changes in skin lesion severity, disease-associated symptoms and quality of life, as well as the length of time that the subject's disease remains stable or improved. Safety and tolerability will include assessment of the frequency and severity of side effects, as well as laboratory and ECG changes. Treatment will continue until the subject becomes intolerant, develops clinically significant side effects, progresses, or the trial is terminated.

Subjects assigned to receive vorinostat who experience confirmed disease progression during their participation in this study may have the option to enroll in a single arm study of cobomarsen (MRG106-11-203 or PRISM), if they meet the entry criteria for that study.

ClinicalTrials.gov Identifier: NCT03713320

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

**Disclosures:** James, A: Employment Leadership Position: Director, Clinical Operations, miRagen Therapeutics; Stock Ownership: miRagen Therapeutics, Array Biopharma; Ruckman, J: Employment Leadership Position: Director, Regulatory Affairs, miRagen Therapeutics; Stock Ownership: miRagen Therapeutics; Pestano, L: Employment Leadership Position: Senior Director, Translational Science, miRagen Therapeutics; Immediate Family Member - Biodesix; Stock Ownership: miRagen, Sanofi Pasteur, Cascadian Therapeutics, Biodesix; Research Funding: miRagen, Servier; Hopkins, R: Employment Leadership Position: miRagen Therapeutics; Stock Ownership: miRagen Therapeutics; Rodgers, R: Employment Leadership Position: miRagen Therapeutics; Stock Ownership: miRagen

<footnote n="1">¹Clinical & Regulatory, miRagen Therapeutics, Boulder, United States;</footnote>

<footnote n="2">²Translational Science, miRagen Therapeutics, Boulder, United States;</footnote>

<footnote n="3">³Management, miRagen Therapeutics, Boulder, United States</footnote>
**SOLAR:** A Phase 2, Global, Randomized, Active Comparator Study to Investigate the Efficacy and Safety of cobomarsen in Subjects with Mycosis Fungoides

<figure><img src="image_307.png" /></figure>

Therapeutics; Marshall, W: Employment Leadership Position: miRagen Therapeutics; Stock Ownership: miRagen Therapeutics; Research Funding: miRagen Therapeutics, Servier; Rubin, P: Employment Leadership Position: miRagen Therapeutics; Consultant Advisory Role: miRagen Therapeutics; Stock Ownership: miRagen Therapeutics; Research Funding: miRagen, Servier; Escolar, D: Employment Leadership Position: miRagen Therapeutics; Stock Ownership: miRagen Therapeutics.

## OT18
A PHASE 1/1B DOSE-ESCALATION TRIAL EVALUATING CPI-818, AN ORAL INTERLEUKIN-2-INDUCIBLE T-CELL KINASE INHIBITOR, IN PATIENTS WITH RELAPSED/REFRACTORY T-CELL LYMPHOMA

M. Mobasher¹ | R. Miller² | J. Janc³ | L. Kwei⁴ |

C. Barker⁵ | A. Mohammady⁵ | G. Luciano⁵ |

D. Radeski⁶ | Y. Kim⁷ | M. Khodadoust⁷ | S. Horwitz⁸

¹CMO, Corvus Pharmaceuticals, Burlingame, United States; ²CEO, Corvus Pharmaceuticals, Burlingame, United States; ³Pharmacology, Corvus Pharmaceuticals, Burlingame, United States; ⁴Biometrics, Corvus Pharmaceuticals, Burlingame, United States; ⁵Clinical Development, Corvus Pharmaceuticals, Burlingame, United States; ⁶Haematology Department, Linear Clinical Research, Nedlands, Australia; ⁷Department of Medicine, Stanford Cancer Institute, Stanford, United States; ⁸Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States

**Background:** Interleukin-2-Inducible T-Cell Kinase (ITK) is a Tec-family, non-receptor tyrosine kinase expressed in T cells that plays a key role in T-cell receptor (TCR) signaling, which is required for

development of T-cells. In T-cell lymphoproliferative disorders, expression of the TCR and its downstream signaling components are maintained, which suggests that malignant cells may exploit this growth and survival pathway to their advantage. Professional anti-gen-presenting cells abundant in the lymphoma microenvironment may provide antigen to drive TCR signaling through ITK, which is expressed in a variety of T-cell lymphomas including PTCL, CTCL, ALCL, and in a subgroup of T-lymphoblastic leukemia/lymphoma. CPI-818 is a first-in-class, irreversible, covalent-binding ITK inhibitor with a high degree of selectivity for ITK. By inhibiting ITK, CPI-818 blocks signaling pathways that are essential to inflammatory responses and has shown to inhibit tumor growth in animal models. To test this clinically, a phase 1/1b dose-escalation trial of CPI-818 is initiated in subjects with relapsed/refractory T-cell lymphoma.

**Methods:** The trial will include patients with various types of T-cell lymphoma (PTCL and CTCL) who have progressed on, refractory to, relapsed, or intolerant to at least 2 standard therapies; age ≥18 yo; have ECOG status 0-1; adequate organ function; and without any other condition that would contraindicate the use of the investigational product. Dose Escalation with 3 + 3 (+ optional 3) design will consist of up to 6 ascending dose levels (100,200, 400, 600, 900, and 1200 mg BID) of CPI-818. In the Dose Expansion phase, there will be 4 disease-specific expansion cohorts (AITL, PTCL-NOS, CTCL and other T-cell lymphoma), and each cohort may enroll up to a maximum of 28 subjects/cohort based on a 2-stage expansion design- Figure. The objectives of the study are to evaluate the safety and tolerability of CPI-818; establish the maximum tolerated dose or the maximum administered dose of CPI-818; evaluate pharmacokinetics and pharmacodynamics of CPI-818 in humans; assess the anti-tumor activity of CPI-818 and identify potential biomarker signals. Study schema in the figure.

Approximately 151 subjects will be enrolled at approximately 35 sites in the US, South Korea, and Australia.
<figure><img src="image_308.png" /><figcaption>Figure: Study Schema</figcaption></figure>

Others: Other types of T-cell lymphoma (NK/T-cell lymphoma, enteropathy associated T-cell lymphoma, hepatosplenic T-cell lymphoma, anaplastic large cell lymphoma, ATL)

**Keywords:** cutaneous T-cell lymphoma (CTCL); peripheral T-cell lymphomas (PTCL); T-cell lymphoma (TCL).

**Disclosures:** Mobasher, M: Employment Leadership Position: Chief Medical Officer.

## OT19
### ONGOING PHASE 1B/2 TRIALS OF MOSUNETUZUMAB INVESTIGATING NOVEL TREATMENT REGIMENS FOR PATIENTS WITH B-CELL NON-HODGKIN LYMPHOMA (NHL)

L.E. Budde<fnref n="1" /> | A. Vallurupalli<fnref n="2" /> | S. Babu<fnref n="3" /> |
I.S. Lossos⁴ | J.P. Alderuccio⁴ | J.C. Chavez⁵ |
H. Eradat⁶ | H. Holmes⁷ | M. Hamadani⁸ |
V.G. Karur⁹ | A.J. Olszewski¹⁰ | E. Seymour¹¹ |
B. Althaus¹² | B.M. Medeiros¹² | C.C. Li¹³ |
A. Kwan¹⁴ | M.C. Wei¹² | S. Yin¹² | C. O'Hear¹² |
J. Munoz¹⁵

Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; ⁷Division of Medical Oncology - Hematology, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, United States; ⁸Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, United States; ⁹Hematology and Oncology, Bayer Scott & White Clinic, Temple, TX, United States; ¹⁰Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI, United States; ¹¹Department of Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI, United States; ¹²Product Development Oncology, Genentech, Inc., South San Francisco, CA, United States; ¹³Clinical Pharmacology, gRED, Genentech, Inc., South San Francisco, CA, United States; ¹⁴Safety Science Oncology, Genentech, Inc., South San Francisco, CA, United States; ¹⁵Department of Hematology-Oncology, Banner MD Anderson Cancer Center, Gilbert, AZ, United States

**Background:** There is an unmet need for more effective and less toxic treatments for patients (pts) with B-cell NHL. Mosunetuzumab is a CD20/CD3 bispecific antibody that directs T-cells to engage and eliminate CD20+ B-cells. Interim results from a phase 1/1b study show that mosunetuzumab-monotherapy (M) is clinically active with a manageable safety profile in pts with relapsed/refractory (R/R) NHL (Budde et al. ASH 2018). Here we present 3 ongoing phase 1b/2 studies in NHL with mosunetuzumab (Table), 2 in novel combinations, and 1 as monotherapy consolidation after first-line (1L) immunochemotherapy or initial 1L therapy in elderly/unfit pts.

**Methods:** Two randomised, open-label, multicentre combination studies are being conducted to compare the following regimens across B-cell

<footnote n="1">¹Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA, United States;</footnote>

<footnote n="2">²Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States;</footnote>

<footnote n="3">³Fort Wayne Medical Oncology and Hematology, Fort Wayne, IN, United States; ⁴Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, United States; ⁵Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, United States; ⁶Division of</footnote>
<table><caption>**TABLE** Study details</caption><thead><tr><th>Phase 1b/2 study</th><th>Key inclusion criteria</th><th>Regimen(s)</th><th>Target number of pts</th></tr></thead><tbody><tr><td>NCT03677141<br>GO40515</td><td>Phase 1b: R/R B-cell NHL<br>Phase 2: 1L DLBCL<br>ECOG PS ≤2<br>Age ≥18 years</td><td>M + CHOP<br>M + CHP-pola<br>R + CHP-pola</td><td>110-160</td></tr><tr><td>NCT03671018<br>GO40516</td><td>R/R B-cell NHL<br>ECOG PS ≤2<br>Age ≥18 years</td><td>M + pola<br>M-monotherapy<br>R + bendamustine-pola [DLBCL/transformed follicular lymphoma]<br>or obinutuzumab + bendamustine followed by obinutuzumab maintenance or R-CHOP/CVP [follicular lymphoma]</td><td>249-282</td></tr><tr><td>NCT03677154<br>GO40554</td><td>DLBCL<br>ECOG PS ≤2<br>Group A: age ≥18 years; best response of PR to 1L immunochemotherapy<br>Group B: age ≥80 or 60-79 years + unfit for full-dose chemotherapy</td><td>M-monotherapy</td><td>40-60</td></tr></tbody></table>

NHL: mosunetuzumab + cyclophosphamide, doxorubicin, vincristine and prednisone (M-CHOP); mosunetuzumab + cyclophosphamide, doxorubicin, and prednisone (M-CHP) + polatuzumab vedotin (M-CHP-pola); or rituximab-CHP-pola in 1L diffuse large B-cell lymphoma (DLBCL); M-pola compared with M-monotherapy, or immunochemotherapy in R/R NHL. A third study is evaluating M-monotherapy in DLBCL pts, either as consolidation after partial response (PR) to 1L immunochemotherapy or as 1L therapy in pts unfit for full-dose chemotherapy. Safety and efficacy data from these studies will further define the role of mosunetuzumab in the treatment of B-cell NHL.

**Acknowledgement:** These studies are funded by F. Hoffmann-La Roche. Third-party medical writing assistance, under the direction of Lihua Budde, was provided by Louise Profit and Russell Craddock of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

This abstract was previously submitted to ASCO 2019.

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

**Disclosures:** Budde, L: Consultant Advisory Role: Gilead, Genentech, AstraZeneca; Research Funding: Mustang Therapeutics, Merck & Co, Amgen; Other Remuneration: Gilead, AstraZeneca (speakers' bureau). Babu, S: Employment Leadership Position: Fort Wayne Medical Oncology & Hematology; Consultant Advisory Role: Bristol-Myers Squibb, Alexion Pharmaceuticals; Stock Ownership: Fort Wayne Medical Oncology & Hematology, Lutheran Hospital; Honoraria: Bristol-Myers Squibb, Alexion Pharmaceuticals, Lilly, Bayer, AstraZeneca; Research Funding: Bristol-Myers Squibb, Novartis, Genentech, Inc./Roche, AstraZeneca/ MedImmune, HERON, Janssen Oncology, Amgen, Incyte, TG Therapeutics, Seattle Genetics, AbbVie, Lilly, Alexion Pharmaceuticals, Merck, Novartis; Other Remuneration: Alexion Pharmaceuticals (speakers' bureau); Bristol-Myers Squibb, Alexion Pharmaceuticals, Lilly (travel, accommodation and expenses). Lossos, I: Consultant Advisory Role: Seattle Genetics, Janssen Scientific. Alderuccio, J: Consultant Advisory

Role: Agios, Inovio Pharmaceuticals, Puma Biotechnology, Foundation Medicine; Honoraria: Targeted Oncology. Chavez, J: Consultant Advisory Role: Genentech, Inc., Novartis, Kite, Bayer, Karyopharm; Other Remuneration: Genentech, Inc., Kite, AstraZeneca (speakers' bureau). Eradat, H: Consultant Advisory Role: Genentech, Inc., Roche, AbbVie; Honoraria: Genentech, Inc., AbbVie, Pharmacyclics, Takeda; Research Funding: Genentech, Inc., AbbVie, Pharmacyclics, Beigene, Kite, Gilead, Juno, ATARA, Miragen, Verastem; Other Remuneration: Genentech, Inc., AbbVie, Pharmacyclics, Takeda (speakers' bureau). Holmes, H: Consultant Advisory Role: Bayer, Celgene, Gilead, Rigel, Janssen, AstraZeneca; Honoraria: Janssen; Research Funding: Kite, Unum, Celgene, Novartis, Genentech, Inc., Seattle Genetics; Other Remuneration: Kite, Seattle Genetics, Rigel (speakers' bureau). Hamadani, M: Consultant Advisory Role: MedImmune, Cellerant Therapeutics, Janssen Research & Development, Incyte Coporation, Pharmacyclics, ADC Therapeutics, Puma Biotechnology; Honoraria: Celgene; Research Funding: Takeda, Spectrum Pharmaceuticals, Otsuka US, Astellas Pharma, Genzyme; Other Remuneration: Genzyme, Celgene (speakers' bureau). Karur, V: Employment Leadership Position: Baylor Scott and White Hospital. Olszewski, A: Employment Leadership Position: Rhode Island Hospital; Research Funding: Roche/Genentech, Inc., TG Therapeutics, Spectrum Pharmaceuticals. Seymour, E: Honoraria: Karyopharm; Research Funding: Karyopharm, Incyte; Other Remuneration: Karyopharm (travel, accommodation and expenses). Althaus, B: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. Medeiros, B: Employment Leadership Position: Roche/Genentech, Inc.; Stock Ownership: Roche/Genentech, Inc. Li, C: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. Kwan, A: Employment Leadership Position: Genentech, Inc./Roche; Stock Ownership: Genentech, Inc./Roche. Wei, M: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. Yin, S: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc.; Other Remuneration: Genentech, Inc. (travel, accommodation and expenses). O'Hear, C:
Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. Munoz, J: Consultant Advisory Role: Pharmacyclics LLC, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, Bristol-Myers Squibb; Other Remuneration: Kite Pharma, Gilead, Bayer, Pharma-cyclics/Janssen, AstraZeneca (speakers' bureau).

# OT20
## A PHASE 1/2 STUDY OF MT-3724 TO EVALUATE SAFETY, PHARMACODYNAMICS AND EFFICACY OF MT-3724 FOR THE TREATMENT OF PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA

C.A. Burnett¹ | P. Hamlin² | K. Dabovic¹ |

J. Higgins³ | D.O. Persky⁴

¹Clinical Development, Molecular Templates, Inc., Jersey City, NJ, United States; ²Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, United States; ³Manufacturing, Molecular Templates, Inc., Austin, TX, United States; ⁴Division of Hematology and Oncology, University of Arizona Cancer Center, Tucson, AZ, United States

**Introduction:** Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin's Lymphoma accounting for approximately 30-40 percent of NHL cases. Approximately 40% of all newly diagnosed DLBCL subjects develop either refractory or relapsed DLBCL and represent a population with unmet need for new therapeutic strategies to achieve or regain disease remission.

Because of the ubiquity and persistence of CD20 expression in B-cell malignancies, there is strong rationale to develop novel mechanisms of action (MOA) targeting CD20. However, CD20's non-internalizing nature has impeded the development of novel MOAs against this target.

MT-3724 is an engineered toxin body (ETB) comprised of a single chain variable fragment (scFv) genetically fused to Shiga-like toxin A subunit (SLTA). MT-3724 binds CD20 and induces its own internalization; once internalized, MT-3724 is cytotoxic through the novel mechanism of ribosomal inactivation. MT-3724 has been shown to specifically bind and kill CD20+ malignant human B-cells in vitro and in vivo animal models.

As a direct-kill immunotoxin directed against CD20, MT-3724 has achieved malignant cell lysis in patients with refractory or relapsed NHL regardless of the biologic variations of malignant B-cells or the patient's immune status. Thus, MT-3724 could avoid, mitigate or delay the emergence of resistance to anti-CD20 MAb therapy.

**Methods:** MT 3724 is being evaluated as both monotherapy (NCT02361346) and in combination with either a chemotherapy combination (gemcitabine/oxaliplatin) or an immunomodulatory agent (lenalidomide). Adult patients with histologically confirmed,

relapsed or refractory DLBCL who have received prior therapy are eligible.

Patients must have serum rituximab levels <500 ng/mL before the start of treatment to allow adequate binding of MT-3724 and have at least one tumor lesion at screening that is measurable according to the revised Lugano criteria [Cheson 2014, 2016]. Patients receive MT-3724 IV infusions over 1 hour on Days 1, 3, 5, 8, 10 and 12 of a 21-day treatment cycle for the first two cycles and then weekly. Combination therapy will be administered per a usual schedule.

The primary endpoint is objective response rate (ORR) by the revised Lugano Classification for Lymphoma adjusted according to LYRIC assessed by independent, blinded central review. Secondary endpoints include safety, progression-free survival, investigator-assessed ORR and DOR, and overall survival as well as PK, PD, ADA and QOL. Accrual is ongoing.

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

**Disclosures:** Burnett, C: Employment Leadership Position: employee of the trial sponsor. Dabovic, K: Employment Leadership Position: employee of the trial sponsor. Higgins, J: Employment Leadership Position: employee of the trial sponsor; Stock Ownership: ownership of Molecular Templates, Inc. stock.

# OT21
## A FIRST-IN-HUMAN STUDY OF A HALF-LIFE EXTENDED CD19-TARGETING BiTE IN RELAPSED/REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA, MANTLE CELL LYMPHOMA OR FOLLICULAR LYMPHOMA

L. Popplewell¹ | G. Verhoef² | J. Kuruvilla³ |

C. Tuglus⁴ | R. Kischel⁵ | J. Stieglmaier⁶ | A. Ghobadi⁷

¹Toni Stephenson Lymphoma Center, City of Hope, Duarte, United States; ²Department of Oncology, UZ Leuven, Leuven, Belgium; ³Princess Margaret Cancer Centre, Cancer Clinical Research Unit, Toronto, Canada; ⁴Global Biostatistical Sciences, Amgen Inc., Thousand Oaks, United States; ⁵BiTE Technology, Amgen Research (Munich) GmbH, Munich, Germany; ⁶Translational Medicine, Amgen Research (Munich) GmbH, Munich, Germany; ⁷Center for Gene and Cellular Immunotherapy, Washington University School of Medicine, St. Louis, United States

**Introduction:** AMG 562 is a half-life extended (HLE) CD19-targeting BiTE® antibody construct being developed to treat patients with diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL). BiTE® immunotherapy engages the patients' own T cells to potentially eliminate detectable cancer. Adults with relapsed/refractory (R/R) DLBCL treated with blinatumomab, a canonical BiTE® immunotherapy also targeting CD19, have shown durable complete responses. Compared with canonical BiTE® immunotherapy like blinatumomab, the HLE BiTE® construct has an added single-
chain fragment crystallizable (scFc) fragment to prolong its half-life. Preclinical models have demonstrated pharmacodynamic activity by demonstrating hallmarks of BiTE® activity and robust B-cell depletion.

**Methods:** This first-in-human, multicenter, nonrandomized, open-label, phase 1 study with sequential dose exploration will evaluate the safety and tolerability of AMG 562 in adults with R/R DLBCL, MCL, or FL. Target enrollment is 85 subjects. At 18 sites in the US, Canada, Belgium, Germany, South Korea, and Japan, approximately 30 subjects will be enrolled in the dose escalation cohorts (DECs) and up to 55 additional subjects will be enrolled in the dose expansion cohort. Dose escalation is guided by a two-parameter Bayesian logistic regression model. Clinical activity of AMG 562 in the expansion cohort will be examined in R/R DLBCL using a Bayesian predictive probability design.

Patients with ECOG status ≤2 will be eligible with disease refractory to first or later treatment or in 3rd or greater relapse. Adults with DLBCL with transformed disease are eligible and prior autologous transplantation is allowed. Patients with prior CD19-targeted treatment or current central nervous system involvement are excluded. The DECs will estimate the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of AMG 562. At completion of the DECs, additional subjects will be enrolled in a dose expansion cohort. A final estimate of the MTD and recommended phase 2 dose will be evaluated and confirmed utilizing all subjects evaluable for dose-limiting toxicity.

**Results:** As of March 1, 2019, 1 subject is enrolled and has completed 1 cycle of AMG 562 at the lowest investigational dose level.

**Conclusion:** This study will identify initial safety, PK, and efficacy profile of the HLE BiTE® AMG 562 in adults with R/R DLBCL, MCL, and FL.

This is an Amgen-sponsored study.

**Keywords:** CD19; diffuse large B-cell lymphoma (DLBCL); non-Hodgkin lymphoma (NHL).

**Disclosures:** Poplewell, L: Consultant Advisory Role: Spectrum Pharmaceuticals, Hoffman LaRoche, Pfizer. Kuruvilla, J: Consultant Advisory Role: Amgen, BMS, Celgene, Gilead, Janssen, Karyopharm, Lundbeck, Merck, Novartis, Roche, Seattle Genetics; Research Funding: Roche, Janssen. Tuglus, C: Employment Leadership Position: Amgen Inc; Stock Ownership: Amgen Inc. Kischel, R: Employment Leadership Position: Amgen Research (Munich) GmbH; Stock Ownership: Amgen Inc. Stieglmaier, J: Employment Leadership Position: Amgen Research (Munich) GmbH; Stock Ownership: Amgen Inc. Ghobadi, A: Consultant Advisory Role: Amgen advisory board; Research Funding: Amgen.

OT22
AN ONGOING PHASE 1/1B TRIAL
INVESTIGATING NOVEL TREATMENT
REGIMENS WITH MOSUNETUZUMAB IN
RELAPSED/REFRACTORY B-CELL NON-
HODGKIN LYMPHOMA

W.S. Kim¹ | S. Assouline² | N.L. Bartlett³ |
F. Bosch⁴ | L.E. Budde⁵ | C. Cheah⁶ |
G.P. Gregory⁷ | J. Hong⁸ | M. Ku⁹ | P. Marlton¹⁰ |
M. Matasar¹¹ | L. Nastoupil¹² | C. Panizo¹³ |
L.H. Sehn¹⁴ | D. Tzachanis¹⁵ | W. Chu¹⁶ |
M.G. Hernandez¹⁶ | A. Kwan¹⁶ | C.C. Li¹⁶ |
I. Sison¹⁶ | M.C. Wei¹⁶ | S. Yin¹⁶ | K. Yousefi¹⁷ |
S. Yoon¹⁸

¹Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; ²Division of Hematology, Jewish General Hospital, Montréal, QC, Canada; ³Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, United States; ⁴Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain; ⁵Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, United States; ⁶Linear Clinical Research and School of Medicine, University of Western Australia, WA, Australia; ⁷School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia; ⁸Department of Oncology, ASAN Medical Center, Seoul, Republic of Korea; ⁹Department of Haematology, St Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia; ¹⁰Department of Medicine, University of Queensland School of Medicine and Princess Alexandra Hospital, Brisbane, QLD, Australia; ¹¹Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States; ¹²Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; ¹³Haematology and Haemotherapy Department, Clinica Universidad de Navarra, Pamplona, Spain; ¹⁴Medical Oncology, BC Cancer Centre for Lymphoid Cancer and University of British Columbia, Vancouver, BC, Canada; ¹⁵Department of Medicine, University of California San Diego, La Jolla, CA, United States; ¹⁶Product Development Oncology, Genentech, Inc., South San Francisco, CA, United States; ¹⁷Product Development, Biometrics, Biostatistics, Genentech, Inc., South San Francisco, CA, United States; ¹⁸Division of Hematology/Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea

<table><caption>TABLE Patient enrolment</caption><thead><tr><th rowspan="2">Group</th><th colspan="2">No. of patients (enrolled as of January 25, 2019)</th></tr><tr><th>Dose-escalation</th><th>Dose-expansion*</th></tr></thead><tbody><tr><td>D: mosunetuzumab (SC)</td><td>10 enrolled</td><td>R/R DLBCL/tFL;<br>FL; MCL<br>Target = 60</td></tr><tr><td>E: mosunetuzumab (IV) +<br>atezolizumab</td><td>17 enrolled</td><td>R/R DLBCL/tFL;<br>FL; MCL<br>Target = 180</td></tr></tbody></table>

<footnote>*Dose-expansion is also ongoing for Group B</footnote>
**Background:** Mosunetuzumab is a novel CD20/CD3 bispecific anti-body that directs T-cells to engage and eliminate malignant B-cells. Interim results from an ongoing, open-label, multicentre, phase 1/1b study (NCT02500407; GO29781) indicate that mosunetuzumab mon-otherapy administered intravenously (IV) induces durable complete responses with favourable safety in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) (Budde et al. ASH 2018). We report details of 2 other ongoing dose-escalation groups from this study: Group D assesses mosunetuzumab administered subcutane-ously (SC) as an approach intended to minimize cytokine-driven toxic-ities; Group E combines mosunetuzumab and atezolizumab for potentially enhanced clinical efficacy with the addition of immune checkpoint blockade. Dose-expansion cohorts in patients with R/R diffuse large B-cell lymphoma (DLBCL)/transformed follicular lym-phoma (tFL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) are ongoing.

**Methods:** Patients with R/R NHL (age ≥18 years; ECOG performance status of 0 or 1) in Group D receive a fixed dose of mosunetuzumab SC on Day 1 of each 21-day cycle, up to a maximum of 17 cycles; patients in Group E receive ascending doses of mosunetuzumab IV on Day 1, Day 8 and Day 15 of Cycle 1 (step-up dosing), then from Cycle 2 onwards, a fixed dose on Day 1 of every 21-day cycle with concurrent administration of atezolizumab (1200 mg IV), up to a maximum of 17 cycles. Primary outcome measures are maximum tolerated dose (MTD) based on dose-limiting toxicities, tolerability, pharmacokinetics and best objective response. Dose-expansion cohorts are enrolling patients with R/R DLBCL/tFL, FL, or MCL and patients will receive doses of mosunetuzumab up to the MTD. Details of patient enrol-ment for the dose-escalation and dose-expansion cohorts are pro-vided (Table).

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

This abstract was previously submitted to ASCO 2019.

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

**Disclosures:** Kim, W: Research Funding: Roche, Takeda, Eisai, Mundipharma, Pfizer, Celtrion, Kyowa-Kirin, J&J. Assouline, S: Consul-tant Advisory Role: Pfizer, Roche; Other Remuneration: Pfizer, Janssen (speakers' bureau); Roche (travel, accommodation and expenses). Bart-lett, N: Consultant Advisory Role: Pfizer, Seattle Genetics, ADC Thera-пеutics; Research Funding: Seattle Genetics, Genentech, Inc., Kite Pharma, Merck, Bristol-Myers Squibb, Celgene, Immune Design, Forty Seven, Affirmed Therapeutics, Janssen, Pharmacyclics, Millennium, Gilead Sciences. Bosch, F: Consultant Advisory Role: Roche, Janssen, Celgene, AbbVie, Novartis, Gilead; Honoraria: Roche, Janssen, Celgene, AbbVie, Novartis, Gilead; Research Funding: Roche, Janssen, Celgene, AbbVie, Novartis, Gilead, Sobi, Bayer; Other Remuneration: Roche, Janssen, Celgene, AbbVie, Novartis, Gilead (speakers' bureau). Budde, L: Consul-tant Advisory Role: Gilead, Genentech, AstraZeneca; Research Funding:

Mustang Therapeutics, Merck & Co, Amgen; Other Remuneration: Gil-ead, AstraZeneca (speakers' bureau). Cheah, C: Consultant Advisory Role: Roche, Janssen, Takeda, MSD, Gilead, Bristol Myers Squibb, AstraZeneca; Honoraria: Roche, Janssen, Takeda, MSD, Gilead, Bristol Myers Squibb, AstraZeneca; Research Funding: Celgene, Roche, AbbVie; Other Remuneration: Roche, Amgen (travel, accommodation and expenses). Gregory, G: Consultant Advisory Role: Gilead; Honoraria: Roche; Research Funding: BeiGene, AbbVie, Janssen, Merck; Other Remuneration: Roche (speakers' bureau and, travel, accommodation and expenses). Hong, J: Consultant Advisory Role: Takeda, Roche; Hono-raria: Takeda, Roche, Janssen, Celgene, Mundipharma, Celtrion, Eisai; Research Funding: Janssen, Boryung Pharmaceutical. Marlton, P: Con-sultant Advisory Role: Roche, Janssen-Cilag, Novartis, Amgen, Pfizer, Takeda, AbbVie; Honoraria: Roche, Janssen-Cilag, AbbVie, Novartis, Pfizer, Amgen, Takeda; Other Remuneration: Janssen-Cilag (speakers' bureau); Roche, Takeda (travel, accommodation and expenses). Matasar, M: Consultant Advisory Role: Genentech, Bayer, Merck, Juno Therapeu-tics, Roche, Teva, Rocket Medical, Seattle Genetics; Stock Ownership: Merck; Honoraria: Genentech, Roche, Bayer, Pharmacyclics, Janssen, Seattle Genetics; Research Funding: Genentech, Roche, Bayer, Pharmacyclics, Janssen, Seattle Genetics; Other Remuneration: Gen-entech, Roche, Seattle Genetics, Bayer (travel, accommodation and expenses). Nastoupil, L: Honoraria: Celgene, Genentech, Inc., Gilead, Janssen, Novartis, Spectrum, TG Therapeutics; Research Funding: Celgene, Genentech, Inc., Janssen, Merck, TG Therapeutics. Panizo, C: Consultant Advisory Role: Bristol-Myers Squibb, Kyowa Kirin; Other Remuneration: Roche Pharma (speakers' bureau, and travel, accommo-dation and expenses), Janssen (speakers' bureau). Sehn, L: Consultant Advisory Role: AbbVie, Amgen, Roche/Genentech, Apobiologix, AstraZeneca, Acerta, Celgene, Gilead, Janssen, Kite, Karyopharm, Lundbeck, Merck, MorphoSys, Seattle Genetics, Teva, Takeda, TG Thera-пеutics; Honoraria: AbbVie, Amgen, Roche/Genentech, Apobiologix, AstraZeneca, Acerta, Celgene, Gilead, Janssen, Kite, Karyopharm, Lundbeck, Merck, MorphoSys, Seattle Genetics, Teva, Takeda, TG Thera-пеutics; Research Funding: Roche/Genentech, Inc. Tzachanis, D: Con-sultant Advisory Role: Jazz; Other Remuneration: Takeda (speakers' bureau). Chu, W: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. Hernandez, M: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc. Kwan, A: Employment Leadership Position: Genentech, Inc./Roche; Stock Own-ership: Genentech, Inc./Roche. Li, C: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. Sison, I: Employment Lead-ership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc. Wei, M: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. Yin, S: Employment Leadership Position: Gen-entech, Inc.; Stock Ownership: Genentech, Inc.; Other Remuneration: Genentech, Inc. (travel, accommodation and expenses). Yousefi, K: Employment Leadership Position: Roche; Other Remuneration: Roche (travel, accommodation and expenses). Yoon, S: Consultant Advisory Role: Novartis, AbbVie, Amgen, Celgene, Roche; Research Funding: Roche.
# OT23
## SPIReL: PHASE 2 STUDY DPX-SURVIVAC WITH INTERMITTENT LOW DOSE CYCLOPHOSPHAMIDE AND PEMBROLIZUMAB IN PATIENTS WITH RECURRENT/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA

N.L. Berinstein¹ | I.A. Bence-Buckler² | P. Laneuville³ |

D. Stewart⁴ | L. Smyth¹ | C. Kerr⁵ | G. Klein⁵ |

N. Pennell⁶ | K. Roos-Assar⁵

¹Medical Oncology/Hematology, Sunnybrook Health Sciences Centre, Toronto, Canada; ²Hematology, The Ottawa Hospital Research Institute, Ottawa, Canada; ³Experimental Medicine, McGill University Health Centre, Montreal, Canada; ⁴Oncology, Tom Baker Cancer Centre, Calgary, Canada; ⁵Centre for Clinical Trial Support, Sunnybrook Research Institute, Toronto, Canada; ⁶Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada

**Introduction:** Patients with relapsed diffuse large B cell lymphoma (DLBCL) who have failed autologous stem cell transplant (ASCT), or are ASCT ineligible, have few effective options and a poor prognosis. Chimeric antigen receptor (CAR) T cell is a new treatment option; however, its use is limited due to significant toxicities and financial cost.

Survivin, an inhibitor of apoptosis, is overexpressed in up to 60% of relapsed refractory DLBCL. DPX-Survivac, a novel T cell activating therapy, elicits a cytotoxic T cell response to tumor cells expressing survivin. Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Low dose intermittent cyclophosphamide is used for its immunomodulator effect. Pre-clinical studies have demonstrated synergistic activity with this drug combination in control of tumor growth with resultant improved survival (Weir,GM et al., J Immunother Cancer. 2016 Oct 18;4:68).

**Methods:** This is a Phase 2 non-randomized, open label, efficacy and safety study. Study participants will receive two initial doses of 0.5 mL of DPX-Survivac 21 days apart and up to six 0.1 mL subsequent

doses every two months. Intermittent low dose cyclophosphamide will be taken (50mg BID oral) for a rotating schedule of 7 days on followed by 7 days off. Pembrolizumab 200 mg will be administered every 3 weeks. Study participants continue active therapy for up to one year or until disease progression, whichever occurs first. Patients are eligible if they have DLBCL, including double hit lymphoma, with confirmed survivin expression. They must have recurrent disease post ASCT or are ineligible for ASCT.

The primary endpoint is to document the objective response rate to this treatment combination, using the modified Cheson criteria, in patients with recurrent, survivin-expressing DLBCL. Secondary endpoints include duration of response, immune-related response, and safety. Exploratory endpoints include; T cell response by antigen-specific ELISpot assay, tumour immune cell infiltration by multiplex immunohistochemistry and gene expression assay using the nCounter ®PanCancer Immune Profiling panel (Nanostring Technologies).

Up to 25 patients will be enrolled in this national, multi-centre study, over 36 months. Preliminary data will be available on enrolled participants. Trial design is shown below.

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

**Disclosures:** Berinstein, N: Honoraria: received honoraria from Merck for ad hoc ad boards. Stewart, D: Honoraria: received honoraria from Merck for ad hoc ad boards.

# OT24
## PHASE IB/II STUDY OF IBRUTINIB AND VENETOCLAX IN RELAPSED AND REFRACTORY FOLLICULAR LYMPHOMA

C. Ujjani¹ | H. Wang² | L. Leslie³ | M. Johnson² |

B.D. Cheson²

¹Medical Oncology, Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center, Seattle, United States; ²Georgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC, United States; ³Hackensack University Medical Center, John Theurer Cancer Center, Hackensack, United States

**Background:** Despite high response rates to front-line chemoimmunotherapy, patients with follicular lymphoma (FL) inevitably

<figure><img src="image_309.png" /></figure>
relapse and further treatment options are necessary. The BTK inhibitor, ibrutinib, has demonstrated an overall response rate (ORR) of 21% and median duration of response of 19 months in relapsed/refractory disease (Gopal A, et al. JCO 2018). Venetoclax, a selective inhibitor of the pro-survival BCL-2 protein, has demonstrated an ORR of 38% and median PFS of 11 months in previously treated FL (David M, et al. JCO 2017). Preclinical data have shown synergy with these agents in B-cell non-Hodgkin lymphoma cell lines (Kuo H, et al. Mol Cancer Ther. 2017) Based on these observations, we proposed the first clinical trial to evaluate the combination of a BTK inhibitor and a BCL-2 inhibitor in FL. Correlative studies include next-generation sequencing, assessment of BCL-2 family member proteins, and tissue co-culture models to assess mechanisms of resistance.

**Methods:** This phase Ib/II study in relapsed/refractory FL is being conducted at Lombardi Comprehensive Cancer Center, John Theurer Cancer Center, and Seattle Cancer Care Alliance. Eligibility criteria include WHO grade 1-3a FL, at least 1 prior systemic therapy, measurable disease warranting therapy by standard criteria, ECOG performance status <2, and adequate marrow, hepatic, and renal function. All FLIPI risk groups are eligible. The primary and secondary objectives in the phase I portion are to determine the recommended phase II doses and pharmacokinetics of ibrutinib and venetoclax when administered together in FL. The primary and secondary objectives in the phase II portion are efficacy and safety, respectively. Patients will be enrolled in a standard phase I 3+3 design at a starting dose level (DL) of ibrutinib 420 mg daily and venetoclax 400 mg daily (DLO). The highest dose level is DL3: ibrutinib 560 mg daily and venetoclax 800 mg daily. Patients will receive the combination until progression or unacceptable toxicity. Once the maximum tolerated dose is determined, there will be a 17-patient phase II study for a maximum of 41 patients. To date, 8 patients have been enrolled. Clinical trial information: NCT02956382.

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

**Disclosures:** Ujjani, C: Honoraria: *Pharmacyclics*, Abbvie; Research Funding: *Pharmacyclics*, Abbvie. Cheson, B: Consultant Advisory Role: Abbvie, AstraZeneca, *Pharmacyclics*, Gllead, Bayer, TG Therapeutics; Research Funding: Abbvie, AstraZeneca, *Pharmacyclics*, Gllead, TG Therapeutics.

## OT25
A WINDOW STUDY OF IXAZOMIB IN UNTREATED B-NHL

S.A. Graf<fnref n="1" /> | R.C. Lynch<fnref n="1" /> | C. Ujjani<fnref n="1" /> | D.G. Coffey<fnref n="1" /> |

S.D. Smith<fnref n="1" /> | M. Shadman<fnref n="1" /> | E.H. Warren<fnref n="1" /> |

E.N. Libby III<fnref n="1" /> | C. Godwin<fnref n="1" /> | R.D. Cassaday<fnref n="2" /> |

T. Gooley³ | J.R. Fromm⁴ | A.K. Gopal<fnref n="1" />

United States; ⁴Laboratory Medicine, University of Washington, Seattle, United States

**Background:** Standard initial treatment of indolent B-cell non-Hodgkin lymphoma (iB-NHL) includes intravenous or subcutaneous treatment requiring regular infusion center appointments. These can be burdensome, especially for patients living remotely from a cancer care facility. Furthermore, most patients with iB-NHL will have survival comparable to age matched controls. Thus, therapies that are sufficiently effective and minimally toxic while being maximally convenient are sought. Ixazomib, an orally bioavailable proteasome inhibitor, showed promising activity in a single study that included a small number of patients with relapsed/refractory iB-NHL (Assouline et al., 2014). As the maximum activity of a therapy is typically in the treatment-naïve setting, we designed a frontline "window" study to assess the potential ceiling of activity of ixazomib monotherapy in iB-NHL.

**Methods:** This single-arm, open-label investigator-initiated phase II trial (NCT 02339922) is being conducted at the University of Washington / Fred Hutch Cancer Research Center. Patients must have a diagnosis of one of the following iB-NHL: follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, or Waldenstrom's macroglobulinemia / lymphoplasmacytic lymphoma. Additional eligibility criteria include a clinical indication for treatment, an Eastern Cooperative Oncology Group performance status of ≤2, and having received no prior standard systemic anti-neoplastic treatment except in cases of mucosa-associated marginal zone lymphoma relapsed after or refractory to antibiotics.

Ixazomib is administered at 4 mg orally once a week on consecutive 28-day cycles until disease progression or unacceptable toxicity. The window period closes after 6 cycles, with four doses of weekly rituximab added during the 7th cycle. Ixazomib continues concurrently with rituximab and thereafter. Addition of rituximab is included to assure that all patients receive a standard therapy as part of their initial treatment.

The primary endpoint is investigator-assessed response rate performed every 2 cycles. The null hypothesis that the true response rate is ≤40% will be tested against the alternative hypothesis that the true response rate is ≥60% with a type I error rate of 8% and a power of 85%, requiring an overall response rate of ≥19 of 36 to conclude promising efficacy. Secondary endpoints include duration of response, progression free survival, time to next treatment, and safety / tolerability. Tumor tissue is being collected for gene expression profiling using the NanoString platform and immunohistochemical evaluation of molecular pathways associated with proteasome inhibition. The study is supported by Takeda Oncology.

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

**Disclosures:** Graf, S: Research Funding: TG Therapeutics, Acerta Pharma, BeiGene. Lynch, R: Research Funding: TG Therapeutics, Rhizen Pharmaceuticals, Incyte, Takeda, Juno Therapeutics. Smith, S: Consultant Advisory Role: AstraZeneca, Merck Sharp and Dohme Corp.;

<footnote n="1">¹Medical Oncology, University of Washington, Seattle, United States;</footnote>

<footnote n="2">²Hematology, University of Washington, Seattle, United States; ³Clinical Research Division, Fred Hutch Cancer Research Center, Seattle, United States;</footnote>
Research Funding: Acerta Pharma BV, Astrazeneca, Ayala (spouse), Bristol Myers Squibb (spouse), De Novo Biopharma, Genentech, Ignyta (spouse), Incyte Corporation, Merck Sharp and Dohme Corp., Pharmacyclics, Portola Pharmaceuticals, Seattle Genetics. 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 (spouse); Consultant Advisory Role: Amgen, Pfizer; Stock Ownership: Seattle Genetics (spouse); Research Funding: Amgen, Incyte, Kite/Gilead, Merck, Pfizer. Gopal, A: Consultant Advisory Role: Seattle Genetics, Pfizer, Janssen, Gilead, Spectrum, Amgen, Incyte; Honoraria: Aptevo, BRIM Bio, Seattle Genetics, Sanofi; Research Funding: Teva, Bristol-Myers Squibb, Merck, Takeda, TG Therapeutics, Effector.

## OT26
### ONGOING STUDY OF OBINUTUZUMAB SHORT DURATION INFUSION IN PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED FOLLICULAR LYMPHOMA

M. Canales<fnref n="1" /> | J. Mason<fnref n="2" /> | J. Hernandez³ |

M. Tomiczek³ | K. Hübel⁴

La Jolla, California, United States; ³Global Product Development/Medical Affairs, F. Hoffman La-Roche Ltd, Basel, Switzerland; ⁴Department of Internal Medicine 1, Uniklinik Köln, Cologne, Germany

**Introduction:** In the Phase III GALLIUM study, obinutuzumab (G) in combination with chemotherapy (G-chemo) demonstrated improved progression-free survival (PFS) and a similar tolerability profile compared with rituximab (R)-chemo, the current standard of care for first-line treatment of follicular lymphoma (FL). Administration of G can take about 4 hours using an infusion-related reaction (IRR) risk-reduction strategy. Shorter infusion times would improve convenience by yielding substantial time savings for patients (pts) and benefiting outpatient infusion facilities. Previous studies with R have led to the development of a 90-minute short duration infusion (SDi), which is now widely used if the first dose of R is well tolerated. Results of the Phase II GATHER study, in pts with previously untreated advanced diffuse large B-cell lymphoma (DLBCL) (Sharman et al. Leuk Lymphoma 2018) and the Phase II GATS study in Japanese pts with previously untreated non-Hodgkin Lymphoma (NHL) (Ohmachi et al. Jpn J Clin Oncol 2018) indicated that G can be safely administered as a 90-minute SDi, after the initial cycle. Here we report GAZELLE (NCT03817853; MO40597), an ongoing Phase IV study investigating the safety of G administered as a 90-minute SDi in pts with previously untreated advanced FL, who have received G-chemo at the standard infusion rate without experiencing a Grade (Gr) 3 or 4 IRR.

**Methods:** Pts with CD20-positive, previously untreated stage III or IV FL, or stage II bulky disease (GELF criteria for initiating

<figure><img src="image_310.png" /><figcaption>Figure. GAZELLE study design</figcaption></figure>

<footnote n="1">¹Haematology Department, Hospital Universitario la Paz, Madrid, Spain;</footnote>

<footnote n="2">²Division of Hematology and Oncology, Scripps Clinic Torrey Pines,</footnote>
treatment, ECOG PS 0-2, life expectancy ≥12 months) will receive G (1000 mg) intravenously on Day (D) 1, D8, and D15 of cycle (C) 1, and on D1 of subsequent cycles (Figure). The standard infusion rate will be administered in C1, starting on D1 at 50 mg/hour, then increase by 50 mg/hour every 30 minutes to a maximum of 400 mg/hour. If no IRR or a Gr 1 IRR occurs, C1D8 (and subsequently C1D15) will start at 100 mg/hour, then increase by 100 mg/hour every 30 minutes to a maximum of 400 mg/hour. If a Gr 2-3 IRR occurs during C1D1 or C1D8, the next infusion (C1D8 or C1D15, respectively) will be administered at the same rate as C1D1. If no Gr ≥3 IRR occurs in C1, all subsequent infusions will be administered via a faster 90-minute SDi; 100 mg/hour for 30 minutes, then 900 mg/hour for 60 minutes. If a Gr 3 IRR occurs during any SDi administration, the next dose of G will be administered at the standard infusion rate. The investigator will decide if the pt can restart with the SDi. The primary endpoint is incidence of Gr ≥3 IRRs during C2 in pts who had previously received G at the standard infusion rate during C1 without experiencing a Gr ≥3 IRR. Secondary safety endpoints include adverse events, time to IRRs, type and duration of Gr ≥3 IRRs and duration of G administration by cycle. Secondary efficacy endpoints include overall response rate, PFS, overall survival and complete response at 30 months. It is estimated that 112 pts will be enrolled.

**Acknowledgment:** Third-party medical writing assistance, under the direction of Miguel Canales, was provided by Russell Craddock and Louise Profit of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

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

**Disclosures:** Canales, M: Consultant Advisory Role: Amgen, Celgene, Gilead, Janssen, Novartis, Roche, Sandoz, Servier; Other Remuneration: Speakers' Bureau: Amgen, Janssen, Roche, Servier, Takeda; Expenses: Gilead, Janssen, Novartis, Roche, Sanofi. Mason, J: Employment Leadership Position: Scripps Clinic Medical Group. Hernandez, J: Employment Leadership Position: F. Hoffmann-La Roche Ltd. Tomiczek, M: Employment Leadership Position: F. Hoffmann-La Roche Ltd. Hübel, K: Consultant Advisory Role: Roche, Sanofi, Servier, Celgene, Hexal; Research Funding: Roche, Janssen, Servier; Other Remuneration: Speakers' Bureau: Roche, Sanofi, Servier, Celgene; Expenses: Roche, Celgene.

## OT27
# THE CANNABINOID STUDY - 01: INVESTIGATING THE EFFECTS OF CANNABINOIDS IN INDOLENT LEUKEMIC B-CELL LYMPHOMA

C.M. Melén<fnref n="1" /> | M. Merrien² | A.M. Wasik² |

K. Sonnevi<fnref n="1" /> | H. Junlén<fnref n="1" /> | B. Christensson² |

B. Sander² | B.E. Wahlin<fnref n="1" />

**Introduction:** The endocannabinoid system has been suggested as a possible target for cancer treatment. Case-reports have suggested that cannabinoids could have an effect on certain difficult to treat patients with acute lymphoblastic leukemia (Sing, Y and Bali, C. *Case Rep Oncol* 2013). Agonists to the cannabinoid receptor-1 and cannabinoid receptor-2 (CB1; CB2) have been showed to induce cell-death of overexpressing lymphoid cell lines (Gustafsson, K. et al. *Int J Cancer* 2008). CB1 is most commonly found in the central nervous system where as CB2 is found in the peripheral nervous system and in lymphocytes and myeloid cells (Bouaboula, M. et al. *Eur J Biochem* 1993). In this study we aim to investigate how a controlled amount of cannabinoids affects malign and benign white blood cells (WBCs) in vivo by administering an oral mucosal spray containing both the CB1/CB2-agonist tetrahydrocannabinol (THC) and the partial CB1-antagonist cannabidiol (CBD).

**Methods:** We are including patients into an open-label, non-randomized clinical study (EudraCT 2014-005553-39) which have been approved by the regional ethics board and the Swedish Medical Products Agency. The patients included have indolent, non-symptomatic leukemic B-cell lymphoma, (mostly chronic lymphocytic leukemia). The first part of the study has identified a maximum tolerated dose with respect to side effects. Further inclusion of patients is now ongoing.

Patients are given a single dose of the oral spray mix of THC and CBD at 9 in the morning and sampled at 0, 1, 2, 4, 6, 24, and 168 hours. We investigate if THC and cannabidiol might affect white blood cell subsets, particularly if this single dose might reduce leukemic cell numbers, and, if so, by what mechanism. By also sampling the patients on a separate day (prior to the cannabinoid exposure) at the same hours, we control for any confounding natural circadian variations in blood leukocyte subset levels. Further analyses include standard clinical chemistry measurements, THC- and CBD-concentrations in plasma/urine/saliva/exhaled air, flow cytometry of lymphocyte subsets, analysis of cannabinoid receptors mRNA expression by quantitative polymerase chain reaction (qPCR), in vitro assays of the effect of cannabinoids on ex vivo isolated lymphoma cells (cell death, cell proliferation, cell migration) as well as cytokine analyses.

So far 23 patients have been included. Adverse events have been manageable (no grade 3-4 events) and all patients have been able to return home in the afternoon. We plan to end inclusion of patients in the summer of 2019.

**Keywords:** B-cell lymphoma; chronic lymphocytic leukemia (CLL); indolent lymphoma.

## OT28
# A PILOT TRIAL OF ADRIAMYCIN, PEMBROLIZUMAB, VINBLASTINE AND DACARBAZINE (APVD) FOR PATIENTS WITH UNTREATED CLASSICAL HODGKIN LYMPHOMA

<footnote n="1">¹Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden; ²Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden</footnote>
R.C. Lynch¹ | S.D. Smith¹ | M. Shadman² |
C.S. Ujjani¹ | D.M. Kurtz³ | H. Coye⁴ | B.G. Till² |
E.H. Warren² | A.R. Shustov⁵ | D.G. Maloney² |
Y.D. Tseng⁶ | A.K. Gopal¹

¹Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, United States; ²Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States; ³Divisions of Hematology and Oncology, Stanford University Medical Center, Stanford, United States; ⁴Hematologic Malignancies, Seattle Cancer Care Alliance, Seattle, United States; ⁵Department of Medicine, Division of Hematology, University of Washington, Seattle, United States; ⁶Department of Radiation Oncology, University of Washington, Seattle, United States

**Background:** ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) forms the backbone of frontline management of classical Hodgkin lymphoma (CHL) in North America regardless of stage. Expected cure rates with upfront therapy approach 75% in advanced stage, and 85-90% in early stage. A novel regimen incorporating brentuximab vedotin sought to improve upon ABVD in untreated advanced stage CHL patients. While it demonstrated a modest modified PFS benefit, it was associated with notable toxicities including higher rates of neuropathy and infection. PD1 inhibition is highly effective in relapsed/refractory CHL, leading to the FDA approval of nivolumab and pembrolizumab in this setting. The first-line setting may represent the ideal time for a PD1 inhibitor, with relatively intact host immunity and coexistence of malignant cells and T cells in the microenvironment. Using a proven chemotherapy backbone, we designed a trial adding pembrolizumab to AVD chemotherapy for untreated CHL (NCT03331341).

**Methods:** We designed a non-randomized, single arm pilot study combining pembrolizumab with AVD in untreated CHL of any stage. Eligibility requires ECOG 0-1, adequate organ function, and measurable disease. The trial intends to enroll 30 patients. AVD is given at standard doses on days 1 and 15 of a 28 day cycle. Pembrolizumab (200 mg IV) is given starting cycle 1 day 1 and every 21 days thereafter (cycle 1 day 22, cycle 2 day 15 etc.). The primary objective is to estimate the safety of delivering 2 cycles of APVD. The study will be determined a success if >85% of subjects are able to complete 2 cycles of therapy without a dose delay >3 weeks. Operationally, the stopping rule will be activated if the lower limit of the 95% confidence interval of toxicity crosses 15%. Thus, the trial would stop if 4/10, 7/20, 8/25, or 9/30 had a dose delay of >3 weeks due to toxicity. The secondary objective is to estimate the FDG-PET2 negative (Deauville score 1-3) after 2 cycles of APVD. Exploratory objectives include overall and progression free survival, predictive capacity of PET2 after APVD, and analysis of ctDNA. After PET2 response assessment, subjects may continue APVD for up to 6 total cycles, or pursue treatment deemed appropriate for their stage/risk factors (including alternate systemic therapy or radiotherapy) at investigator discretion.

**Keywords:** chemotherapy; Hodgkin lymphoma (HL); Pembrolizumab.

**Disclosures:** Lynch, R: Research Funding: Rhizen Pharmaceuticals, TG Therapeutics, Incyte Corporation, Takeda, Juno Therapeutics. Smith, S: Consultant Advisory Role: Merck Sharp and Dohme Corp, Astrazeneca;

**Research Funding:** Acerta Pharma BV, Astrazeneca, Ayala (spouse), Bristol Myers Squibb (spouse), De Novo Biopharma, Genentech, Ignyta (spouse), Incyte Corporation, Merck Sharp and Dohme Corp. (Self, spouse), Pharmacyclics, Portola Pharmaceuticals, Seattle Genetics. **Shadman, M:** Consultant Advisory Role: Abbvie, Genentech, Sound Biologics; Verastem, ADC therapeutics and Atara Biotherapeutics; Research Funding: Mustang Biopharma, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Acerta Pharma, Merck. **Kurtz, D:** Consultant Advisory Role: Roche Molecular Diagnostics. **Till, B:** Research Funding: Mustang Biopharma; Other Remuneration: Patient/royalties: Mustang Biopharma. **Shustov, A:** Research Funding: Seattle Genetics. **Maloney, D:** Honoraria: Roche/Genentech, Janssen Scientific Affairs, Seattle Genetics; Research Funding: GlaxoSmithKline, Juno Therapeutics. **Gopal, A:** Consultant Advisory Role: Seattle Genetics, Pfizer, Janssen, Gilead, Spectrum, Amgen, Incyte, Aptevo, BRIM Bio, Sanofi; Research Funding: Teva, Bristol-Myers Squibb, Merck, Takeda, TG Therapeutics, Effector, Seattle Genetics, Pfizer, Janssen, Gilead, Spectrum, Amgen, Incyte.

## OT29
### EVITA: PHASE I/II STUDY OF EVEROLIMUS PLUS ITACITINIB IN RELAPSED/REFRACTORY CLASSICAL HODGKIN LYMPHOMA

J. Svoboda | S. Barta | S. Nasta | D. Landsburg |

J. Gerson | M. Ruella | T. Waite | C. King |

S.A. Emanuel | H. Ballard | S. Schuster

*Lymphoma Program, University of Pennsylvania, Philadelphia, United States*

**Introduction:** There is an unmet need for patients (pts) with relapsed/refractory classical Hodgkin lymphoma (cHL) who failed or cannot tolerate immune check point inhibitors and brentuximab vedotin (BV). Biology of cHL is characterized by scant Hodgkin Reed Sternberg cells (HRS) within a pro-inflammatory tumor microenvironment (TME). Both HRS and TME are rich with therapeutic targets. One of those is Akt which is constitutively activated in cHL-derived cell lines and its downstream effectors include mTOR substrates. Other promising targets in cHL are components of JAK/STAT pathway as genetic alterations in multiple genes (including STAT3, STAT5B, JAK1, JAK2, PTPN1) have been demonstrated in cHL. In pre-clinical studies, co-treatment of mTOR and JAK inhibitors resulted in synergistic activity against the proliferation of JAK mutated cell lines. Everolimus (oral inhibitor of mTOR) is clinically active in cHL with overall response rate (ORR) 40%, but low complete response rate (CR) of 5%. Ruxolitinib (oral JAK1/2 inhibitor) monotherapy produced only modest responses in cHL. Itacitinib adipate is another oral JAK inhibitor with potent selectivity for JAK1, but limited data in cHL. Itacitinib also inhibits STAT protein phosphorylation and pro-inflammatory cytokines including IL-6 which is expressed on HRS/TME and its expression has been associated with B symptoms. To our knowledge, no clinical studies
have been done with concurrent mTOR/JAK inhibition in cHL. We hypothesize that targeting multiple pathways in HRS/TME using combination of everolimus and itacitinib will result in deeper disease control compared to everolimus monotherapy.

**Methods:** An open-label, single-group study of everolimus in combination with itacitinib is currently opened at the University of Pennsylvania. Eligible pts must have relapsed/refractory cHL after at least 2 prior systemic therapies and must have relapsed after or be ineligible for autologous stem cell transplant. They also must have progressed after treatment with, be intolerant to, or are not a candidate for BV and pembrolizumab/nivolumab. Phase I will evaluate the safety and tolerability of the combination using a standard 3 + 3 design with dose-escalation or de-escalation. The starting dose of everolimus is 5 mg daily and of itacitinib is 300 mg daily with treatment planned for 2 years or until progression/intolerance. Phase II will evaluate the efficacy of the combination in cHL as demonstrated by CR (the null hypothesis is set at CR rate of 5%). Secondary objectives include progression free/overall survival, ORR, duration of response. Exploratory analyses include impact on quality of life/B symptoms. Ancillary studies exploring tumor biology/biomarkers are planned. Since opening in January 2019, 2 pts have been enrolled. The goal is to enroll 23 pts over a period of 3 years.

**Keywords:** Hodgkin lymphoma (HL); JAK/STAT; mTor inhibitors.

**Disclosures:** Nasta, S: Research Funding: Incyte.

# OT30
## UK: NATIONAL COHORT STUDY
### INVESTIGATING MAJOR LATE EFFECTS OF HODGKIN LYMPHOMA TREATMENTS ON BEHALF OF THE ENGLAND & WALES HODGKIN LYMPHOMA FOLLOW-UP GROUP

A. Macklin-Doherty

Genetics & Epidemiology, The Institute of Cancer Research, London,
United Kingdom

**Background:** Dramatic improvement in Hodgkin Lymphoma (HL) survival rates over recent decades is one of the greatest success stories in modern Oncology. However it has come at a significant cost: treatment-related toxicity. These issues are epitomised in female HL patients treated at young ages, who have many decades to accumulate late effect burden, and are additionally susceptible to sex-specific outcomes such as breast cancer and premature menopause. In 2003, a national cohort comprising all young women (under <36 years) treated for HL with radiotherapy above the diaphragm in England and Wales since 1960 was established (5,000 women). This quantified the significantly raised risks of breast cancer, particularly those treated with high dose radiotherapy to the breast around menarche. Increased risk of other second malignancies and mortality are also known to be serious consequences of HL treatments. It is hoped de-intensification of treatments will attenuate risk of these long-term effects but this has not yet been definitively demonstrated. These outcomes have been studied in relation to treatment largely in those treated in childhood or in smaller populations than our UK cohort. We have expanded this cohort to include women treated more recently, until 2010, and to encompass all treatment types, to investigate risk factors for the most severe long term effects of HL treatments, and whether risks have diminished over time.

**Methods:** 10,000 women diagnosed with HL under 36 years have been identified from English and Welsh Cancer Registries from the 1960-2010 with >99% complete follow up for mortality until 2018 and are in the process of linking to causes of death. We are currently obtaining treatment and second cancer information for each patient from NHS hospital records across the country. We have achieved this for 7,000 patients so far. We have also obtained linked second cancers from national cancer registrations. Once complete, this will be the much the largest cohort of its kind worldwide, to enable high power analyses of risk factors for a range of serious late effects in Hodgkin Lymphoma.

**Keywords:** Hodgkin lymphoma (HL).
AUTHOR INDEX (By Abstract No.)

Abadi, U., 378

Abbasi, A., 439

Abdul Rahman, M.F., 396

Abdul-Hay, M., 259

Abdullah, M., 484

Aboukameel, A., 266

Abouzaid, S., 181

Abraham, J., 019

Abraham, Y., 082

Abramson, J.S., 122, 247

Abreu, A., 091

Abrisqueta, P., 126, 139, 267, OT09

Abuelgasim, K., 460, 529

Acton, G., 496

Adib, D., 105

Adila, N., 325, 396

Adjei, A., OT04

Adkins, S., 256

Adélaïde, J., 152

Adriaens, L., 052

Advani, R., 032, 051, 052, 077, 125, 227, 228, 438

Advani, R.H., 097

Aeppli, S., 234

Afanasyev, B., 261, 441, 463, 465, 472, 473

Afanasyev, B.V., 462

Aftab, B., 475

Agajanian, R., OT09

Agarwal, S., 142

Agoram, B., 051

Agostinelli, C., 092

Agoulnik, S., 254

Ahmed, M., 022

Ahmed, S., 042, 185, 256, 367, 406

Ai, W., 283

Aivado, M., 500

Aizpuria, F., 370

Akan, H., 375

Akhtar, S., 097

Akilov, O., 232

Aksu, S., 317

Aladag, E., 317

Alahmari, B., 460, 529

Alam, W., 398

Alaskar, A., 460, 529

Alcaide, M., 004, 036, 037

Alcantara, M., 014

Alcaro, S., 487

Alcedo Andreade, P., 471

Alcoceba, M., 312, 481

Alderuccio, J.P., OT19

Aldoss, I., 117

Aldouri, M., 168

Aldridge, F., 297

Aleman, B.M., 455

Alexis, M., 219

Alfonso Estevez, D., 432

Alfonso, G., 370

Alhejazi, A., 460, 529

Alherz, N., 529

Ali, O., 529

Alinari, L., 439, 503

Alizadeh, H., 142

Allan, J., 052

Allan, J.N., 029

Alland, L., 128

Allison, J.P., 260

Almuhayani, H., 529

Alonso, R., 158, 301

Alpdogan, O., 284

Alperovich, A., 103

Al-Sawaf, O., 007, 046, 047, 062

Alsulami, H., 489

Althaus, B., OT19

Altmann, B., 058, 386, 392

Altmeyer, S., 145

Alvarez, I., 175

Alves, A., 377

Alzahrani, M., 460, 529

Amaki, J., 222

Amara, N., 091, 152

Ambarkhane, S., 124

Ambati, S.R., 052

Ambinder, R., 077

Ambrosetti, A., 066

Ambrosio, M.R., 504

Amengual, J., 006, 079

Amengual, J.E., 129, 259

Amigó de Quesada, M., 326

Amigo Fernandez, I., 322

Amssoms, K., 082

An, O., 526

Anagnostopoulos, I., 504

Anand, K., 257

Ananthakrishnan, R., 122

Anargyrou, K., 212

Anders, S., 039

Andersen, P.L., 141

Anderson, M.A., 064

Ando, K., 436

Ando, T., 222

Andorsky, D., 070, 187

André, M., 152

Andrade-Campos, M., 482

Andre, M., 124, 240

Andre, M.P., 455

Andreadis, B., 283

Andreadis, C., 247, 254, 478

Andreadis, C.B., 271

Angelillo, P., 201

Angelopoulou, M.K., 174, 212

Angrilli, F., 194

Annibali, O., 387

Anquetin, M., 324

Ansell, E., 372

Ansell, S., 052, 077, 098, 134, 227

Ansell, S.M., 018, OT04, 128, 180, 235

Antic, D., 510

Antolino, A., 066

Antonio De Souza, C., 229

Anz, B., 133, 163

Anzalone, N., 109

Araf, S., 094

Arafat, S., 256

Arancio, O., 079

Arasaretnam, A., 297

Arat, M., 244

Arboe, B., 141

Arcaini, L., 016, 104, 132

Arcari, A., 190, 194, 198, 201, 387

Ardeshna, K., OT01, OT05, 358

Ardeshna, K.M., 054, 385, 457
Arenas, F., 102
Aresu, L., 010
Arfi-Rouche, J., 278
Argnani, L., 208, 241
Arico', E., 262
Ariza Heredia, E., 256
Armand, P., 098, 128, 242, 454, 464, 497
Armitage, J., 494
Arnason, J., 052
Arranz, R., 057
Arribas, A., 038, 263, 264
Arslan, O., 375
Arthur, S., 004
Arthur, S.E., 037
Asano, N., 222, 288
Asano-Mori, Y., 351
Asch, A., 051
Asch, A.S., 127
Ashton-Key, M., 094
Asnafi, V., 157, 218
Assaf, C., 453
Assouline, S., 004, 255, OT22
Atsuta, Y., 206, 211, 436, 447
Attar, R., 082
Attingenti, E., 405
Atwal, S., 191
Audas, T., 037
Aurer, I., 240
Aurran-Schleinitz, T., 394
Autio, M., 150
Au-Yeung, R., 155
Avenoso, D., 423
Avery, E.J., 048
Avettand-Fenoel, V., 218
Avigdor, A., 099, 477
Awan, F.T., 498
Ayyappan, S., 439, 503
Azim Jr, H.A., OT06
Azmi, A.S., 266
Babenko, E., 465
Babu, S., OT19
Bacac, M., 053
Bacalari, E., 301
Baccini, V., 451
Bachanova, V., 254, 363, 365, 478
Bachier, C.R., 474
Bachy, E., 136, 219, 225, 246
Bacon, C.L., 404
Badar, T., 363, 365
Badillo, M., 011, 012
Badoux, X., 075
Bagir, E.K., 287
Baglio, M., 033

Bagot, M., 034, OT06, 231, 453
Bahleda, R., 278
Bahlo, J., 007, 045, 046, 047, 062
Bai, B., 113
Baile, M., 312, 481
Baiocchi, R., 284, 439, 444, 449, 503
Bairey, O., 061, 200
Bajaj, M., 454
Bakai, M., 528
Bakshi, S., 031
Balagué, O., 137, 295, 354
Balasubramanian, S., 093
Baldacini, M., 184
Baldini, C., 278
Baldini, L., OT10
Ballard, H., OT29
Ballerini, F., 387
Balser, C., 007
Baltasar Tello, P., 336
Balzarotti, M., 016, 190, 194, 198, 236
Bamigbola, O.A., 520
Bandera, A., 506
Bandini, C., 490
Bandres, E., 482
Banerjee, L., 126
Bannerji, R., 052
Banos, A., 303
Baptista, M.J., 132
Barau, C., 324
Barcena, C., 301
Bargay Lleonart, J., 189
Bargetzi, M., 234
Bargou, R., 272, 390
Barhatov, I., 473
Barilà, G., 233
Barker, C., OT18
Barker, J.N., 401
Baron, M., 215
Barot, S., 110
Barr, P.M., 050, 061, 108
Barrans, S., OT05, 078, 094, 095, 146, 239, OT08
Barrena, S., 312
Barreto, W.G., 179
Barrett, M.T., 148
Barrientos, J., 050, 167
Barrington, S., OT01
Barta, S., 077, 284, 365, OT16, OT29
Barta, S.K., 363
Bartelt, J., 025
Bartlett, N., 228
Bartlett, N.L., OT04, 051, 128, 248, 255, 438, OT22

Basarir, U., 375
Baseggio, L., 136, 159, 175, 324
Bassan, R., 387
Basso, M., 419
Bastos, M., 057
Bastos-Oreiro, M., 509
Batlevi, C., 142, 196, 204, 279
Batlevi, C.L., 103, 118, 210, OT16
Battle, A., 312
Battiato, K., 164
Battistini, R., 099
Baumann, T., 137, 295, 354
Bavishi, K., 511
Bayer, G., 209
Baykov, V., 441, 463, 465, 472, 473
Baykov, V.V., 462
Bazarbachi, A., 244
Bazemore, J., 088
Bazeos, A., 089, 300
Bæch, J., 141
Bödör, C., 142
Bea, S., 132
Bechter, O., 232
Becker, P.S., 073
Becker, S., 138, 389
Bedi, C., 416
Bee, P., 396
Bee, P.C., 325
Beelen, D., 261
Befani, M., 174
Behan, S., 457
Bei, J., 155
Beijert, M., 455
Beishuizen, A., 026, 027
Beishuzen, A., 024
Beiske, K., 150
Bekkers, M., 082
Belada, D., 005, 213, 228, 274, 356, 371, 395, 433, 446, OT07
Belardelli, F., 262
Beldi-Ferchiou, A., 014
Beldjord, K., 175
Belhadj, K., 299, 389
Beligoy, L., 370
Bellanger, C., 323
Bellei, M., 057, 229
Bellesso, M., 377
Belmecheri, N., 394
Beltrán, B., 430
Ben Amor, I., 412
Ben Neriah, S., 106
Benbrahim, O., 459
Bence-Buckler, I.A., OT23
Bender, B., 255
Benderoff, L., OT15
Bene, M., 147, 184, 323
Benesova, K., 371, 433, 446
Benitez Caballero, B., 432
Bennani, H., 159
Bennani, N.N., 249
Ben-Neriah, S., 036
Benson, D., 503
Bent-Ennakhil, N., 453
Bentley, M., 094
Bentz, M., 392
Bentzen, H., 188
Berchialla, P., 021
Berdini, C., 262
Berdou, M., 451
Berg, S., 110
Bergaggio, E., 490
Bergesio, F., 350
Bergua, J.M., 005
Berinstein, N.L., OT23
Bernal, Y., 118
Bernard, S., 175, 190, 246
Berry, D.A., 195
Bersvendsen, H.S., 521
Berthold, M., 263
Berti, V., 017
Bertino, E., 337
Bertoldero, G., 201
Bertolotti, L., 099
Bertoni, F., 038, 040, 072, 084, 263, 264, 268, 270, 486, 487, 490
Besser, M., 477
Bessi, L., 138
Besson, C., 314
Bewarder, M., 145
Bewicke-Copley, F., 094
Beylot-Barry, M., 034
Bhagat, G., 085, 129, 132
Bhargava, P., 341, 498
Bhat, S., 162, 337
Bhatnagar, B., 503
Böhm, A., 393
Böhmer, L., 043
Bhojwani, D., 027
Bhutani, D., 266
Bianco, R., 512
Bicciato, S., 040
Biccler, J.L., 355
Bierman, P., 494
Biggar, E., 279
Bijou, F., 237, 303, 339, 358
Bilgi, M., 119

Bilgin, Y., 043
Billett, A., 025
Bilmon, I., 511
Binkley, M.S., 097
Binte Mohd Kahliab, K., 154
Biondo, J.M., 300
Birnbaum, D., 152
Birrell, M.R., 030
Bishop, M., 254, 478
Bishton, M., 282, 514
Bishton, M.J., 409
Bittencourt da Silva, L., 408
Björkholm, M., 086
Blachly, J., 162, 503
Blachnio, K., 140
Bladé, J., 394
Blahovcova, P., 213, 446
Blaise, D., 243, 245, 394
Blamek, S., 414
Blaser, B., 503
Bloehdorn, J., 047, 311
Blommestein, H., 197
Blum, K., 365
Blum, K.A., 363
Blumel, S., 494
Blyth, E., 085
Béné, M., 290
Bobillo, S., 057, 139, 196, 267, 298
Bobillo, S.V., 210
Bocchia, M., 309
Bocomini, C., 103, 104
Bociek, R., 494
Bock, T., 145
Bodaghi, B., 215
Boddu, P., 185
Bodet-Milin, C., 014
Boehnke, A.C., 380
Boettcher, S., 046
Bogucka-Fedorczuk, A., 527
Bohers, E., 138
Bohle, R., 145
Boidol, B., 450
Boisson, A., 332
Boix, J., 267
Bolen, C., 063
Bolen, C.R., 143
Bolis, S., 099, 104
Bolognese, J., 032
Bombonati, G., 507
Bommier, C., 136
Bomsztyk, J., 182, 359
Bomsztyk, J.A., 425, 426
Bond, D.A., 337, 363, 365

Bondarenko, S., 472, 473
Bonell, O., 430
Bonfichi, M., 236
Boni, J., 055
Boninsegna, E., 419
Bonnacorso, S., 370
Bonnafous, C., 157, 218
Bonnet, A., 147
Bonzheim, I., 096
Booher, R.N., 485
Booth, S., 457
Borawska, A., 399
Borchmann, P., 254, 392, 478, OT14
Bordas, M., 039
Bordignon, C., 109
Borek, M., 485
Borel, C., 459
Borges, N., 466
Borgioni, S., 262
Borin, A., 419
Borisovskay, S., 402
Borisovskaya, S., 418
Bornhauser, B., 487
Bornhäuser, B., 081
Boros, A., 455
Borysiuk, A., 140
Borzenkova, E., 441, 463, 465
Borzenkova, E.S., 462
Bosch, F., 081, 139, 166, 255, 267, 269, OT22
Bose, N., 497
Bosq, J., 278
Bossard, C., 147, 290, 323
Botella-Garcia, C., 303
Bottelli, C., 194
Botto, B., 241
Bouabdallah, K., 014, 058, 175, 303
Bouabdallah, R., 019, 031, 225, 243, 245, 394, 459
Bouard, L., 323
Boudawara, T., 412
Boughan, K., 277
Boughan, K.M., 251
Boulland, M.L., 071
Boumendil, A., 189, 244, 261
Bourbon, E., 136
Bournazou, E., 125
Bourquin, J., 081
Boutsikas, G., 174
Boutsis, D., 212
Bouyer, S., 159
Bower, M., 297
Boyer, M., 063
Boyle, M., 036
Boz, A., 287
Bozzoli, V., 016
Brady, J.L., 097
Bramanti, S., 243, 245
Brammer, C., 170
Brammer, J., 033, 283, 284, 439, 503
Brammer, J.E., 444, 449
Branco, B., 339
Brander, D.M., 050, 073
Braunschweig, I., 248, 448, 500
Braunstein, Z., 449
Bárcena, C., 158
Brück, O., 150
Brem, E., 284
Brennan, B., 125
Brenner, M.K., 119
Brentjens, R., 118
Bressel, M., 172
Bret, C., 324
Breuleux, M., 300
Brice, P., 108, 459
Briere, J., 019
Brion, A., 339
Briones, J., 126, 179
Briones Mejjide, J., 125
Brioschi, F.A., 506
Brière, J., 147
Brisou, G., 324
Brülisauer, D., 234
Broccoli, A., 208, 241
Broderick, V., 404
Brodie, R., 404
Broeske, A., 053
Broglio, K.R., 195
Bron, D., 261, 332
Brors, B., 039
Brousset, P., 091, 152, 324
Brouwer-Visser, J., 125
Brouzes, C., 218
Brown, C., 199
Brown, H., 020
Brown, J., 167, OT09
Brown, J.R., 052, 088, 341
Brown, L., 232
Brown, P., 086
Brown, P.D., 141, 180
Browne, P., 404
Bruch, P., 039
Brugiatelli, M., 104
Brugières, L., 026
Bruneau, J., 157, 218, 219
Bruno, A., 041, 512

Brunson, A., 345
Brunson, A.M., 044
Brunt, M., 170
Bruscaggin, A., 132
Bryan, L.J., 284
Büttner, R., 035
Buckstein, R., 355
Budde, E., 479
Budde, L.E., 255, OT19, OT22
Buechner, J., OT12
Buffardi, S., 026
Buggy, J.J., 265
Bullorsky, E., 330
Bunn, V., 232
Bunworasate, U., 224
Buño Borde, I., 509
Burbury, K., 525
Burel, L., 138
Burger, J., 061
Burkart, M., 363, 365
Burke, A., 027
Burke, J.M., 133, 271, 454
Burkhardt, B., 027, OT12
Burner, D., 284
Burnett, C.A., OT20
Burney, C., 261
Burney, C.N., 189
Burroni, B., 184
Burrows, F., 032
Burton, C., OT05, 078, 094, 095, 146, 239, OT08
Bushell, K., 004
Bushell, K.R., 037
Buske, C., 072, 134, 183, OT09
Buslei, R., 145
Bussolari, J., 082
Butcher, B.E., 199
Buyukasik, Y., 317, 364
Byrd, J., 337, 449
Byrd, J.C., 162
Bystydzienski, Z., 140
Caballero, D., 032, 057, 158, 261, 481
Cabras, M., 175, 198
Cabras, M.G., 194, OT10
Cabrera, M., 229, 430
Cabrero, M., 481
Caccione, R., 370
Cacheux, V., 014, 225
Caddy, J., OT05, OT08
Çağlayan, Ç., 192
Cai, Q., 155, 221
Caimi, P., 054, 055
Caimi, P.F., 251, 277

Cairo, M., 027
Cairoli, R., 517
Cake, S., 199
Calabretto, G., 233
Calaminici, M., 094
Calcagno, E., 079
Califano, C., 236
Calimeri, T., 109, 131, 201
Calleja, A., 339
Calmels, B., 243, 245
Calzada, O., 363, 365
Camacho, F., 301
Camara-Clayette, V., 278, 324
Camarillo, J.M., 079
Cambron-Mellott, M., 456
Came, N., 064
Camera, A., 405
Campbell, B., 525
Campbell, P., 048, 105
Campbell, V., 083
Campo, E., 096, 102, 137, 295, 354
Campr, V., 213, 371, 433
Camus, V., 138, 389
Canales, M., 031, OT26
Canales Ruiz, I., 020
Cangemi, M., 262
Canioni, D., 014, 147, 184
Cantonetti, M., 099
Cao, H.L., 505
Cao, J., 059
Cao, L., 443
Capone, I., 262
Capote, J., 301
Capp, A., 172
Capponi, M., 066
Carabia, J., 139, 267
Carella, A., 461
Carella, A.M., 179
Carella, M., 208, 236
Carey, J., 093
Carjava!, L., 500
Carlei, D., 262
Carlo-Stella, C., 053, 054, 236, 243, 245
Carlson, J., 199
Carlsson, A., 292
Carney, D., 064
Carnicero González, F., 203
Carniti, C., OT10
Caron, P., 279
Carr, R., 023
Carras, S., 157
Carreras, J., 102
Carrillo Cruz, E., 057
Carroll, A.S., 425, 426
Carruthers, S., OT01
Carter, J., 127
Carter, M., 078
Cartron, G., 058, 071, 225, 246, 280, 324, 493
Carvalho, M., 389
Carver, J., 164
Casadebaig, M., 087
Casadei, B., 208
Casali, C., 370
Casali, M., 017
Casan, J., 372, 398
Casasnovas, O., 019, 031, 068, 071, 147, 179, 225, 459
Casasnovas, R., 274
Cascavilla, N., 461
Cascione, L., 038, 040, 084, 130, 263, 264, 268, 270, 486, 487
Casey, J., 085
Cashen, A., 167, 249
Caspar, C., 234
Casper, C., 284
Cassaday, R.D., 074, 258, OT25
Cassiodoro, G., 512
Cassoux, N., 215
Castagna, L., 189, 243, 245
Castagnari, B., 175
Castaldo, P., 262
Castellino, C., 109, OT10
Castellví, J., 267
Castellví, J., 139
Castiello, L., 262
Castillo, J., 134
Castillo, J.J., 359, 430
Castrejón de Anta, N., 137, 295
Castro Uriol, D.A., 430
Castro, Y., 301
Casulo, C., 006, 097, 342
Cattaneo, D., 109
Cavalli, A., 268
Cavalli, F., 045, 130, 132, 487, OT11
Cavallo, F., 005, 031, 104, 194, 198, OT10
Cazelles, C., 389
Cecchetti, C., 109, 131, 201
Cen, X., 226
Cencini, E., 194, 309
Cengiz Seval, G., 375
Centrone, R., 377
Cerchietti, L., OT15
Cereceda, L., 158, 301
Cerhan, J.R., 180, 376
Ceriani, L., 041, 072

Cervera, P., 306
Cervi, P., 168
Cesaretti, M., 175
Cespedes, D.H., 267
Chabannon, C., 243, 245
Chahine, C., 278
Chaidos, A., 105
Chalabi, T., 451
Chalandon, Y., 244, 261
Chamorey, E., 237
Chamoun, K., 251
Champ, D., 336
Champlin, R., 185
Chamuleau, M., 197
Chamuleau, M.E., 161
Chan, D., 501
Chan, E., 149, 275, 304
Chan, K., 100
Chan, R.J., 341, 498
Chan, T., 155
Chancharunee, S., 224
Chang, J., 276
Chang, N., 126
Chansung, K., 224
Chao, M.P., 051
Chao, T., 302
Chapuis, N., 159
Charalambos, A., 249
Charfi, M., 412
Charnas, R., 052
Chartier, L., 240
Chassagne-Clément, C., 152
Chau, I., 297, 385
Chau, K., 348
Chau, K.W., 173, 205
Chaubard, S., 219
Chaudhary, N., 300
Chaudhry, A., OT09
Chaudhry, M., 503
Chauvie, S., 021, 099, 104, 198, 236, 350
Chavez, E.A., 106
Chavez, J., 052, 134
Chavez, J.C., 133, OT19
Cheah, C., 022, OT07, OT22
Cheah, C.Y., 133, 199, 511
Cheah, D., 154, 155
Chechlinska, M., 140
Chee, Y.L., 149, 304
Chelius, M.R., 173
Cheminant, M., 157, 218
Chen, B., 321
Chen, C., 302, 505
Chen, I., 466, 491

Chen, J., 083, 155, 321
Chen, N., 488
Chen, P., 259, 526
Chen, R., 238, 282
Chen, R.W., 128
Chen, S., 167
Chen, T., 048, OT07
Chen, W., 011, 012, 185
Chen, X., 148, 274, 431
Chen, Z., 221, 318
Chenard, M., 152
Cheng, B., 440
Cheng, C., 155
Cheng, S., 502
Cheng, W.A., 117
Cheong, J., 235
Cherry, M., 358
Chesne, E., 125
Cheson, B., 275
Cheson, B.D., 029, 050, 164, OT24
Chełstowska, M., 399
Cheung, B., 297
Cheung, L.W., 163
Cheung, M., 004, 100
Chhabra, S., 271
Chia, B., 155
Chiappella, A., 005, 016, 040, 092, 190, 194, 229, OT10
Chiattone, C., 229, 430
Chihara, D., 211, 447
Childs, B.H., 343, 344, 357
Chiodin, G., 045
Chiorazzi, N., 167
Chiron, D., 290, 323
Chisesi, T., 430
Chiti, A., 198
Chitra, S., 068, 493
Chloupkova, R., 371, 433
Chng, W., 155, 526
Chng, W.J., 149, 304
Choe, H., 503
Choe-Juliak, C., 128
Choi, H.W., 149
Choi, I., 222, 349
Choi, J.K., 025
Choi, P., 511
Choi, Y., 435
Chong, E.A., 090
Chong, E.R., 090
Chong, G., 282
Chong, L.C., 106
Chong López, A., 326
Choo, S.N., 149
Chooi, J., 526
Choquet, S., 031, 215, 314
Chott, A., 096
Chou, L.L., 281
Choufi, B., 019
Chow, E., 154
Christensson, B., OT27
Christian, B., 439, 503
Christiansen, I., 141
Christie, D., 171
Chu, J., 254, OT14
Chu, M.P., OT07
Chu, W., 255, OT22
Chu, X., 113
Chuah, H., 511
Chuang, C., 291
Chuang, H., 042, 367
Chuksina, Y., 331
Chumachenko, A., 415
Chun, J., 286
Chung, C., 439
Chung, E., 268, 448
Chung, H., 286
Chung, K., 054
Chung, T., 526
Chuo, C.Y., 388
Church, A., 425, 426
Churnetski, M., 365
Churnetski, M.C., 363
Chyla, B., 063
Ciancia, R., OT10
Ciarrocchi, A., 017
Ciavarella, S., 092
Ciccone, G., 198, OT10
Cicconi, S., 168
Ciceri, F., 109, 201
Cicinelli, E., 468
Cid, M., 102
Ciftciler, R., 317
Cimminiello, M., 099
Citiso, S., 524 bis
Civallero, M., 116, 229
Civriz Bozdag, S., 375
Clancy, L., 085
Clasen-Linde, E., 141
Clausen, M.R., 376
Clavel Piá, J., 336
Clavert, A., 219, 339
Clavier, D., 451
Clear, A., 094
Clementel, E., 455
Clifton-Hadley, L., 170, 239
Climent, F., 158, 301

Cochrane, T., 199
Cocito, F., 506
Coffey, D.G., OT25
Coffey, G.P., 030
Cogliatti, S., 132
Cohan, D., 390
Cohen, J., 077, 098, 365
Cohen, J.B., 006, 271, 363, OT16
Cojocaru, R., 037
Cole, P.D., 026
Coleman, A., OT08
Coleman, M., 029, 070, 187, 274, OT15
Collins, G., OT05, 051, 055, 282, 457
Collins, G.P., 496
Colomer, D., 102
Colonna, P., 468
Columbié Molina, A., 326
Comenencia-Ortíz, E., 515
Conconi, A., 130
Condoluci, A., 045
Congiu, A.G., OT10
Conley, P.B., 030
Conneally, E., 404
Connolly, P., 082
Connors, J.M., 037, 106, 107, 235
Consoli, U., 236, 423
Constine, L.S., 097
Conte, G., 109
Conteh, V., 409, 514
Contentin, N., 138
Cook, L., 297
Cooper, B., 277
Cooper, B.W., 251
Cooper, S., 026
Copi-Bergman, C., 389
Copie Bergman, C., 147
Copie-Bergman, C., 019, 096, 299
Coppo, P., 306
Corbera, M., 102
Cordeiro, P.G., 056
Cordoba, R., 125, 126, 158, 301
Cornic, M., 138
Corning, C., 455
Corona, K., 031
Corradini, P., 057, 104, 132, 241, 254, 261, 478, OT10
Corrado, C., 274
Corrales Otero, D., 432
Corront, B., 019
Corti, A., 109
Corti, M.E., 131
Coso, D., 394
Costa, G., 487

Cottereaup, A., 019, 225
Cotteret, S., 278
Coulibaly, C., 459
Coupland, S.E., 168
Cournier, S., 394
Couronné, L., 219
Courtre, S., 061
Cowan, A.J., 074
Cox, C., 262
Cox, K., 078
Cox, M., 190, 387
Cox, M.C., 016, 194
Coye, H., OT28
Coyle, L., 390
Cragg, M., 078
Cramer, P., 007
Creasey, T., 457
Crespo, M., 139, 267
Crespo Maull, M., 081
Crippa, F., 506
Cristaldo, N., 430
Croix, M., 152
Crosbie, N., 094
Cross, M., 297
Cruciani, G., 264
Crucitti, L., 190
Crump, M., 004, 053, 400, 518
Cruz Camejo, Y., 432
Cruz, H., 055
Cucco, F., 095
Cuevas Palomares, L., 335
Cugliari, S., 370
Cull, E.H., 454
Cull, G., 191
Cummin, T., 094, OT08
Cummin, T.E., OT05, 078
Cummings, M., 082
Cunningham, D., 087, 108, 192, 193, 297, 385, OT09
Curci, P., 468
Curnow, J., 199
Curnutte, J.T., 030
Curran, K., OT12
Curry, R., 032
Cutrona, G., 045
Cwynarski, K., 297, 385, 457
Cymbalista, F., 165, 166
Czerwinski, D., 076
Czuczman, M., 005, 069, 177, 178
Czyz, A., 527
Czyz-Domanska, K., 140
Da Cunha, K., 324
Dabaja, B., 406, 471
Dabovic, K., OT20
Dabrowska, M., 140
Dagada, C., 303
D'agostino, G., 262
Dahi, P., 445
Dahi, P.B., 204, 401
Dahiya, S., 249
Dai, S., 061
Dai, X., 411
Dai, Y., 313
Daigle, S., 004
Dakhova, O., 119
Dalal, M., 453
Dalal, M.R., 456
Dalmasso, F., 021
Dalu, D., 506, 507
Damaj, G., 240
Damaj, G.L., 058
Damlaj, M., 460, 529
d'Amore, F., 043, 376
Dang Chi, V., 332
Daniels, P., 284
Danilov, A., 363, 365
Danu, A., 278
Danylesko, I., 477
Dartigues, P., 278, 324
Darwech, I., 491
Das, M., 315
Dasyam, N., 492
Davagnanam, I., 425, 426
David, K., 077, 110
Davids, M.S., 088, 165, 166, 167, 450
Davidson, J., 004, 037
Davidson, T., 477
Davies, A., 055, 078, 094, 095, 372, 385, 496
Davies, A.J., OT05, 342, OT08
Davis, R., 042
Davis, R.E., 022, 367
Davis, S., 171
Daw, S., 026
Dawson, K., 515
Dawson, K.L., 516
Dąbrowska-Iwanicka, A., 399
De Blasi, R., 524 bis
de Boer, J., 153
de Boer, M., 153
De Carolis, L., 066
De Celis, I.A., 016
De Croon, F., 161
De Filippi, R., 273
De Francesco, D., 507
De Francesco, R., 524 bis

De Guibert, S., 459
de Jong, D., 043, 153, 294
de Jong, J., 027
de Jongh, E., 043
de Keizer, B., 043
De la Cruz, F., 031
de la Cruz Vicente, F., 203
de la Cruz Vincente, F., 032
de la Cruz-Merino, L., 203
De La Serna, J., 048
de las Heras, N., 057
De Leval, L., 058, 114, 132, 225
de Lima, M., 251, 277
De Lord, C., 297
De Lorenzo, D., 201
De Mario, M., 125
De Mel, S., 149, 304, 526
De Miguel Sánchez, C., 335
de Nully Brown, P., 043, 087, 101
de Ona Navarrete, R., 032
De Paoli, L., 045
de Philippis, C., 243, 245
De Risi, C., 524 bis
De Silva, P., 332
De stefano, G., 370
De Summa, S., 092
de Vos, S., 030, 089, 275
Deaglio, S., 490
Deambrogi, C., 045
Dean, J.P., 061
Dean, R., 277
Deau-Fisher, B., 303
Debaigt, C., 237
Debliquis, A., 159
Decroos, A., 157
Dehner, C., 247
Deidda, M., 198
Del Giudice, I., 104
Del Porro, L., 504
Delecluse, S., 085
Delfau-Larrue, M., 225
Delfau-Larue, M., 014, 299
Delfau-Larue, M.H., 071
Delgado González, J., 336
Delgado, J., 045, 137, 165, 166, 295, 354
Delgado, M., 481
Dell Aringa, J., 122
Della Seta, R., 066
DellaRocca, S., 485
Delmer, A., 058, 225, 352, 359
Deloumeaux, J., 451
Delwail, V., 014
DeMarini, D., 274

Demeter, J., 343, 344
Demina, E., 458
Demirer, T., 375
Demirkan, F., 163
Demiroglu, H., 317, 364
DeNardis, P., 182
Deng, C., 129, 259, 483
Deng, S., 079
Deodato, M., 517
Deol, A., 248, 249
Deonarine, I., 164
Derenzini, E., 092, 133, 423
Desai, K., 464
DeSelm, C., 204
Dessi, D., 194
Dessi, D., 198
Detolle, A., 278
Devarakonda, S., 503
Devata, S., 128
Devereux, S., 061
Devillier, R., 243, 245
Devlin, S.M., 401
Dewan, A., 315
Díez-Martín, J., 509
Dharnidharka, V., 110
Dhir, V., 518, 522
Döhner, H., 047
Dhouly, I., 057
Di Blasi, R., 246
Di Landro, F., 262
Di Napoli, A., 262
Di Rocco, A., 016, 201
Di Simone, C., 275
Di Veroli, A., 264
Diamonte, C., 118
Dias, D., 377
Diaz De Cerio, A., 482
Diaz de Heredia Rubio, C., OT12
Diaz Velez, N., 370
Dickinson, M., 125, OT13
Dickinson, M.J., 053
Dickson, S., 382
Dieckmann, K., 024
Diefenbach, C., 126
Diefenbach, C.M., 255
Diefenbach, C.S., 077
Dietrich, S., 039, 081, 132
Diez-Martin, J., 244
DiLea, C., 271
Dimier, N.J., 053
Dimitrakopoulou, A., 174
Dimopoulos, M., 212
Dimopoulos, M.A., 183
Ding, C., 379, 476
Dinmohamed, A., 197
Dinmohamed, A.G., 160
Dirnberger-Hertweck, M., 124
Dirnhofer, S., 041, 072
Dixon, J.G., 192, 193
Dixon, M., 046
Djebbari, F., 385
Djurasinovic, V., 510
Do, Y., 410, 435
Dobber, J.A., 161
Dokowska, E., 282
Dodero, A., OT10
Dogan, A., 056, 196, 210, 279, 298, 445
Dojcinov, S., 096
Dolak, W., 207, 209, 413
Dolan, S., 048
Dolcetti, R., 262
Domańska-Czyż, K., 399
Domingo-Domenech, E., 032, 128
Domingo-Domènech, E., 098
Dominietto, A., 244
Domper Rubio, N., 087
Donati, B., 017
Donati, S., 262
Dondi, A., 104
Dong, Z., 117
Doni, E., 506
Doorduijn, J.K., 160
Dorritie, K.A., 065
Dorsey, C., 050, 073, 164
Dotti, G., 119
Doubek, M., 045
Dourdil Sahun, V., 336
Dowling, M., 511
Downer, M.K., 300
Doyle, C.J., 173
Drachtman, R., 024
Drachtman, R.A., 026
Dragosky, M., 370
Drandi, D., 175
Dreger, P., 058, 244, 261
Dren, N.M., 520
Drenou, B., 159
Dreyling, M., 013, 124, 179, 343, 344, 357, 392, 498, OT07, OT13
Driessen, C., 273
Dürig, J., 169
Drill, E., 210
Drill, E.N., 516
Dropulic, B., 251
Dörr, J.R., 144
Druzd-Sitek, A., 399

D'Sa, S., 182, 359, 425, 426
Du, J., 028
Du, M., 095
Duan, C., 454
Dubovsky, J.A., 065
Duell, J., 052, 124
Dufner, V., 272
Duggal, R., 315
Duh, M., 464
Dulery, R., 243, 459
Duléry, R., 219
Dummer, R., 231, 232
Duncombe, A.S., 168
Dupeux, M., 306
Dupuis, J., 299, 324, 389
Duras, J., 213, 371, 433
Durot, C., 352
Durot, E., 352, 359, 459
Dussiot, M., 218
Duvic, M., 034, 232, 438
Duvillier, H., 332
Dyer, M., 501
Dyer, M.J., 496
Ebbesen, L.H., 141
Ebnöther, M., 234
Eckart, M., 007
Eckhardt, K., 072
Edenfield, W., 275
Edwards, D., 496
Edwards, J.P., 082
Eek, R., 075
Efebera, Y., 503
Egan, C., 096
Egle, A., 169
Egyed, M., 031
Ehrhardt, M., 025
Eich, H., 097
Eichhorst, B., 007, 046, 047, 062, 063
Eisenmann, J.C., 071
Ek, S., 292, 360
Ekwattanakit, S., 224
El Alami Thomas, W., 147
el Cheikh, J., 244
El Gnaoui, T., 299, 389
Eldering, E., 063
Eldjerou, L., 254
Elemento, O., 040
El-Galaly, T.C., 141, 180, 511
Elgedawe, H., 259
Eliadis, P., 282
Ellis, M.H., 378
Elloumi, M., 412
Elmets, C., 034

Elsayed, Y., 082
El-Sharkawi, D., 297
Elshiekh, M., 094
Elstrom, R., 015, 191
Elwell, J., 073
Emanuel, S.A., OT29
Emelina, E.I., 338
Emruli, V.K., 360
Enjeti, A.K., 199
Enjuanes, A., 137, 295
Ennishi, D., 037
Ensor, J., 257
Eom, H., 410
Epifani, R., 506
Epperla, N., 363, 365, 439, 503
Eradat, H., 232, OT19
Ergin, M., 287
Ericson, S.G., 253
Escobar, C., 276
Escoda, L., 267
Escolar, D., OT17
Escudero, L., 139
Escudié, F., 152
Eskelund, C.W., 186, 188, 292
Espin-Garcia, O., 400, 522
Estefania, G., 057
Estephan, R., 495
Etancelin, P., 138
Etienne, G., 166
Ettinger, O., 402, 418
Evangelista, A., 016, OT10
Evens, A.M., 110
Everaus, H., 087
Eyre, T., OT01, 134
Eyre, T.A., 385
Fabbri, A., 016, 194, 201, 236, 309, 387
Fabbri, M., 092
Fabiani, B., 306
Fabien, L., 389
Facchetti, F., 132
Facchinelli, D., 419
Facco, M., 233
Fadle, N., 145
Fagerli, U., 086, 188, 521
Fakhfakh, Y., 412
Falchi, L., 129
Falcucci, P., 066
Falini, B., 066, 504
Fallanca, F., 109, 350
Faller, D., 284
Fama, A., 017
Fan, L., 060, 361, 369, 374, 379, 443, 476, 508
Fan, S., 149, 304, 526
Fan, W., 221
Fanale, M., 438
Fang, C., 302
Fang, X., 221, 427, 488
Fanning, S., 070, 187
Fanti, S., 241
Farah, R.J., 281
Farazi, T., 247
Farina, G., 405
Farooqui, M., 242, 276
Fasola, C., 506, 507
Fataccioli, V., 152, 219
Favero, F., 141, 186
Favre, S., 303
Fay, K., 274
Fayad, L., 011, 012, 022, 042, 185, 256, 367
Fayette, D., 469
Feather, C., 407
Federico, M., 057, 103, 104, 116, 229, 240, 350, 455
Fedorov, V., 282
Fedorova, L., 465
Fegueux, N., 246
Fehn, K., 500
Fehr, M., 234
Feingold, J., 054, 055
Feki, W., 412
Feldman, A., 376
Feldman, A.L., 180
Feldman, T., 098, 228, 284
Feldman, T.A., 030
Feliu, J., 482
Felizzi, F., 202
Fend, F., 096
Feng, L., 022, 155, 249
Feng, R., 015, 049
Feng, S., 049
Fenske, T., 077, 110, 365
Fenske, T.S., 363
Ferchiou, A., 225
Ferlini, C., 053
Fernandez, D., 370
Fernandez Garcia, S., 322
Fernandez-Miranda, I., 158, 301
Fernández, R., 312
Fernández Zarzoso, M., 336
Ferrá Coll, C., 336
Ferra, C., 244
Ferraldeschi, R., 501
Ferrari, S., 041, 066
Ferrarini, M., 045
Ferreri, A., 229

Ferreri, A. J., 109
Ferreri, A.J., 131, 201
Ferrero, S., 016, 104, 175, 194
Fest, T., 071, 324
Feugier, P., 019, 071, 089, 175, 280
Fiad, L., 430
Fiaschi, N., 052
Fidalgo, J., 023
Fields, M., 497
Fields, P., 055, 385
Fierro, M., 231
Fijnheer, R., 043
Filshie, R., 199, 511
Finel, H., 189, 244, 261
Fink, A., 046, 047, 062
Fink, A.M., 007
Fink, L., 085
Finke, J., 217, 261
Fiorito, J., 079
Fischer, K., 007, 046, 047, 062
Fischer, N., 234
Fischer-Nielsen, A., 141
Fischman, L., 370
Fisher, D.C., 034, 088, 497
Fisher, J., 337
Fisher, R., 171
Fiskvik, I., 368
Fitoussi, O., 019, 303
Fitzgibbon, J., 094, 142
Fix, P., 200
Flament, J., 192, 193
Flavin, R., 404
Flavio, C., 109
Flenghi, L., 194
Flerlage, J., 024, 025
Fleury, I., 254, 355, 478, OT14
Flinn, I., 051, 069, 167, 177, 178, 235, 255, OT07
Flinn, I.W., 050, 075, 089, 163, 165, 166, 181
Flümann, R., 035
Florence Nguyen-Khac, F., 081
Flores, G., 370
Flowers, C., OT02, 192, 193, 202, 365
Flowers, C.R., 363
Fluge, Ø., 086, 521
Flynn, C., 404
Foà, R., 045, 066
Foa, R., 189
Fogarty, P., 184
Fogliatto, L., 069, 177, 178, OT07
Fogliatto, L.M., 046, 181
Folber, F., 422

Foley, S.R., 254, 478
Follows, G., 031, 457
Follows, G.A., 343, 344, 357
Fonseca, G., 050
Fontaine, A., 355
Fontaine, J., 136
Fontana, R., 512
Foon, K., 070, 187
Foppoli, M., 109
Forcade, E., 244
Forcato, M., 040
Forcina, A., 478, OT14
Forconi, F., 045
Forero-Torres, A., 128
Forman, S., 238, 479
Forman, S.J., 117
Fornecker, L., 184
Forés Cachón, R., 336
Forslund, A., 454
Fortpied, C., 240, 455
Foss, F., 032, 501
Foss, F.M., 033
Foster, M., 195
Foubert, P., 475
Fowler, N., 011, 012, 022, 069, 177, 185, 256, 406, OT13
Fowler, N.H., 133, 178, 181
Fox, C., 168
Fox, C.P., OT01
Fox, J.A., 485
Fraga, M., 301
Franceschetto, A., 350
Francescone, M.F., 129
Franchi-Rezgui, P., 459
Francis, S., 026, 108
Francoeur, K., 088
Francois, R., 332
Frank, M.J., 076
Franklin, J., 390
Frattarelli, N., 066
Frauhammer, F., 039
Frederiksen, H., 180
Freedman, A., 497
Freeman, C.L., 107
Freiburghaus, C., 292
Freier, W., 007
Freise, K., 282
Frendéus, B., 496
Freud, A., 444, 449
Frezzato, M., 201
Fröhling, S., 039
Fricker, H., 217
Friedberg, J.W., 006, OT02