**Z. Miltényi** | **E. Punk** | **L. Pinczés** | **Á. Illés**

Division of Hematology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary

**Background and aim:** Autologous stem cell transplant (ASCT) is the standard of treatment in patients with refractory/relapsed Hodgkin lymphoma (HL). Several adverse prognostic factors at relapse are known (stage, anaemia, B signs, Karnofsky score, early relapse etc.) to predict the outcome after ASCT. We analyzed the prognostic value of pre-transplant PET/CT retrospectively.

**Methods:** Between January 1, 2007 and December 31, 2018 pre-transplantation ¹⁸FDG-PET/CT scans of Hodgkin-lymphoma patients were performed. Deauville criteria were used for evaluation of PET/CT scans. Positive PET scans were defined, if Deauville score was 4 or 5. We analyzed the effect of PET/CT results for survival (overall-, relapse- and event free), and investigated differences between PET positive and PET negative groups. Statistical analysis was performed using IBM SPSS 25 programme.

**Results:** Sixty-two Hodgkin-lymphoma patients (33 men and 29 women) had PET/CT scan before AHSCT. Median age at the time of AHSCT was 35 (19-65) years. Median follow up time was 55.4 (0-175) months. There were 49 (79%) PET negative and 13 (21%) PET positive patients. Five-year overall survival rate was 80% in PET-group, and 46.2 % in PET+ group (p<0.042). Five-year relapse-free and event-free survival rate for negative and positive groups were 85.5% and 43.5% (p<0.012), and 70.3% and 30.8% (p<0.006). There were 6 relapse and 9 deaths (3 due to HL) in PET- group, and 5 relapse and 6 deaths (due to HL) in PET+ group. Twenty-five of 49 patients in the PET- group got only one type of salvage treatment (DHAP) before AHSCT, against 2 of 13 patients in PET+ group (p=0.046). Patients who acquired PET negative status after DHAP therapy only, had no relapse. Patients who were treated with 2 or more lines of salvage therapy and acquired PET negative status after these treatments, has no significantly better relapse-free survival, than patients who remained PET positive.

**Conclusion:** Clinical routine use of PET/CT before AHSCT is highly suggested based on our investigation. PET- patients have significantly better OS, PFS and EFS. PET negative status attends better prognosis, if it is reached with first salvage treatment.

**Keywords:** autologous stem cell transplantation (ASCT); Hodgkin lymphoma (HL); positron emission tomography (PET).

## 468
MORBIDITY AND MORTALITY IN LONG-TERM SURVIVORS OF HODGKIN LYMPHOMA: A SINGLE CENTER EXPERIENCE

F. Gaudio¹ | T. Perrone¹ | A. Giordano¹ | P. Curci¹ |

F. Laddaga¹ | C. Nardelli² | P. Masciandaro² |

P. Colonna³ | E. Cicinelli² | G. Specchia¹

¹Department of Emergency and Transplantation, Hematology Section, University of Bari Medical School, Bari, Italy; ²Department of Biomedical Science and Human Oncology, Obstetrics and Gynecology Unit, University of Bari Medical School, Bari, Italy; ³Department of Cardiology, University of Bari Medical School, Bari, Italy

Since the introduction of modern radiotherapy and combination chemotherapy, Hodgkin lymphoma (HL) has become a highly curable malignancy with 5-year survival rates of more than 80%. However, the life expectancy and quality of life of HL survivors are reduced by the occurrence of late adverse treatment effects.

This retrospective study was focused on 96 patients with newly diagnosed HL treated at the University Hospital of Bari (Italy) between 2005 and 2008.

Median age at diagnosis was 35 years (range 15-83), 33 pts (34%) presented advanced stage (III-IV), 43 (45%) bulky disease, 45 (47%) presented B symptoms, 26 (27%) extranodal disease.

First line chemotherapy was ABVD in all the patients. The median number of chemotherapy lines was 1 (1-5), 49 patients (51%) had undergone radiotherapy

At the end of treatment, 75 patients (78%) were in CR, and 24 patients (25%) in PR; 18 patients (24%) relapsed after a median follow-up of 54 months (range: 12 - 62 months); 20 (21%) underwent autologous hematopoietic stem cells transplantation, 3 (3%) allogeneic stem cell transplantation.

After a median follow-up of 12 years, 83 patients (86%) remain alive and 13 (14%) have died (4 of A second neoplasia, 1 of infection, 8 of the disease). The 10-year Kaplan-Meier survival estimates were 84%. Three women were pregnant and 3 healthy children were born. The most prevalent chronic conditions At last follow-up were: overweight/obesity (65%), elevated fasting glucose (38%), high total cholesterol (34%), and hypertension (25%).

Results of this study offer indications about how long after the initial treatment the excess deaths from causes other than Hodgkin's disease begin to occur. However, challenges remain in establishing the optimal time to begin screening for potential late complications and in developing better surveillance guidelines. Further work is also needed to identify risk factors that may predict specific late effects.

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

## 469
COGNITIVE IMPAIRMENT AFTER 6 AND 12 MONTHS OF HODGKIN LYMPHOMA TREATMENT

H. Mocikova¹ | L. Gaherova¹ | D. Fayette² |

V. Jurickova² | J. Horacek² | T. Kozak¹

¹Internal Hematology Clinic, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; ²National Institute of Mental Health, Klecany, and Third
faculty of Medicine, National Institute of Mental Health, Klecany, and
Third faculty of Medicine, Klecany, Czech Republic

**Introduction:** Chemotherapy-related cognitive impairment (CRCI) occurs after chemotherapy and other cancer treatments in 17-75% of patients in all age groups and with various malignancies and significantly worsens their quality of life. Certain drugs, such as bleomycin, penetrating the blood-brain barrier may have direct toxic effects on the brain and its functions. The aim of the study is to elucidate the influence of Hodgkin lymphoma and its treatment on neurocognitive performance (sustained attention, short-term, long-term memory and working memory, verbal and cognitive fluency).

**Methods:** Overall 28 pts (46% female) were tested: mean age of 36,5 years and mean years of education of 14,1. Pts received 2 cycles of ABVD + 20GyISRT (initial stages), 2 cycles of BEACOPP escalated combined with 2 cycles of ABVD +30Gy ISRT (intermediate stages) and 6 cycles of BEACOPP escalated ± 30GyRT (advanced stages). Cognitive functions were evaluated by neurocognitive testing battery covering all domains of the International Cognition and Cancer Task Force (ICCTF; Wefel et al., 2011) recommendations for cancer patients: the Hopkins verbal learning test revised, the trail making test A-B, Stroop test, Controlled oral word association, Verbal fluency task, Rey-Osterrieth complex figure, and WAIS-III (Digit span, Comprehension, Picture arrangement, Digit symbol - coding, Logical memory, Letter-number sequencing test) and Continuous Performance Test (CPT). The data were collected before treatment, 6 and 12 months after the initiation of the first-line treatment.

**Results:** Statistical analyses looked at the cognitive performance measured with neurocognitive testing battery covering all domains of the International Cognition and Cancer Task Force (ICCTF; Wefel et al., 2011) recommendations for cancer patients. The results show that in the majority of the test methods, the performance of the repeated measurements was improved in patients with Hodgkin lymphoma. These findings could be interpreted as a practice effect. However, the prolongation of reaction time in CPT after 6 months of treatment did not improve during 6 months period after chemotherapy (1 year after diagnosis). [HJ1]

**Conclusion:** Our data indicate that a) the reaction time could represent the most sensitive domain within chemotherapy-related cognitive impairment, and b) this parameter does not normalize during 6 month post-chemotherapy period.

This work was supported by grant AZV 16-29857A Ministry of Health of the Czech Republic and Research projects Q28 Progres and Q40/08 Progres awarded by Charles University in Prague, Third Faculty of Medicine, Prague, Czech Republic

**Keywords:** bleomycin; chemotherapy; classical Hodgkin lymphoma (cHL).

470
IMPACT OF AUTOIMMUNE CYTOPENIAS ON THE CLINICAL COURSE AND SURVIVAL OF HODGKIN LYMPHOMA

L.I. Pinczés

R. Szabó

Z. Miltényi

Á. Illés

Division of Hematology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary

**Background:** Autoimmune cytopenias (AICP), namely autoimmune hemolytic anemia (AIHA) and autoimmune thrombocytopenia (AITP) often complicate the course of malignant lymphomas. The incidence and clinical significance of AICPs associated with Hodgkin lymphoma (HL) have not been thoroughly defined. Our aim was to retrospectively assess the incidence, clinical features and response to treatment of HL-associated autoimmune phenomena.

**Methods:** Five hundred and sixty-five HL patients were diagnosed and treated at the University of Debrecen between 1990 and 2017. We compared the clinicopathological characteristics of HL patients developing AICPs with those who had no clinical evidence of autoimmune events. We considered an AICP to be a disease-defining event if it led to diagnosis or revealed disease progression, relapse or secondary malignancy. Statistical analysis was performed using Fisher's exact test.

**Results:** We identified 8 cases of AIHA and 8 cases of AITP among 14 patients altogether, one of them presented with Evans syndrome. Two AICPs preceded the diagnosis of HL, 2 of them developed simultaneously with the disease and 11 AICPs occurred during follow-up after first line therapy. During more than 5000 person-years of follow-up, the incidence of AICPs in HL patients was 2,8%. Eighty-one percent of AICPs required treatment, 77% of these patients responded well to intravenous steroid. Treatment of the underlying lymphoma with ABVD combination chemotherapy resulted in the effective control of both the underlying disease and the immune condition, in most cases, where AICPs were identified at the presentation of HL. Almost half of the AICPs (46%) were disease-defining events: 5 cases led to the diagnosis of HL or indicated relapse and 2 events revealed secondary malignancies. AICPs were more frequently observed in patients with advanced stage disease at initial diagnosis (p<0.004). The association of HL and AICPs had no effect on long-term overall- (OS) and progression-free survival, however, short-term (1 year) mortality of HL patients experiencing AICPs was significantly elevated (p<0.022) compared to the majority of patients, who did not have AICPs. Also, the OS rate of HL patients with AICPs at initial diagnosis was significantly lower (p=0.033) compared to patients developing AICPs during follow-up.

**Conclusions:** While AICPs are rare complications of HL, these events can imply clinical significance. Those HL patients who experienced AICPs had a particular disease-related profile. These cytopenias show a good response to steroid treatment. This large series of consecutive, unselected patients demonstrate that the association of HL and AICPs may increase short-term mortality. Our results emphasize the importance of taking into consideration the possibility of an underlying hematological malignancy in newly diagnosed AIHA/AITP cases.

**Keywords:** ABVD; Hodgkin lymphoma (HL); methylprednisolone.
# 471 RELAPSED AND REFRACTORY NODULAR LYMPHOCYTE-PREDOMINANT HODGKIN LYMPHOMA (NLPHL): A US ANALYSIS FROM MD ANDERSON CANCER CENTER

P. Strati¹ | P. Alcedo Andreade¹ | D. Sano¹ |
V. Rao¹ | P. Singh¹ | R. Miranda² | J. Gunther³ |
C. Pinnix³ | B. Dabaja³ | H.J. Lee¹ | R. Steiner¹

¹Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, United States; ²Hematopathology, MD Anderson Cancer Center, Houston, United States; ³Radiation Oncology, MD Anderson Cancer Center, Houston, United States

**Introduction:** The clinical course and optimal treatment of patients with relapsed or refractory NLPHL is not clearly defined.

**Methods:** We retrospectively analyzed the characteristics and outcomes of patients with relapsed or refractory NLPHL, without histological evidence of transformation at time of first relapse, followed at MDACC between 12/1972 and 12/2018.

**Results:** Forty patients were included in the analysis. At time of initial diagnosis, median age was 34 (range, 15-85), 27 (67%) were male, and 20 (50%) had advanced stage. Frontline regimen consisted of chemotherapy ( variably combined with rituximab and/or radiotherapy [XRT]) in 24 (60%) patients (ABVD in 16 patients, CHOP in 6 patients, and NOVP in 2 patients), rituximab (with or without XRT) in 4 (10%) and XRT in 12 (30%). Two (5%) patients were primary refractory, 9 (23%) relapsed within 1 year, and median PFS after frontline treatment (PFS-1) was 45 months (95% CI, 5-85 months).

Thirty-nine patients received 2^nd^ line therapy (and 1 was observed): chemotherapy in 16 (40%) patients (including ABVD in 4, CHOP in 8, and ICE in 4, variably combined with rituximab), biological therapy in 14 (35%)(including rituximab in 11, brentuximab vedotin in 2 and lenalidomide in 1), XRT in 6 (15%), and high-dose chemotherapy followed by autologous stem cell transplant (ASCT) in 3 (8%). The median PFS after 2^nd^ line therapy (PFS-2) was 85 months (95% CI, 1-218 months) with 15 (38%) patients relapsing or progressing. No difference in PFS-2 was observed based on treatment type (p=0.49) (Figure), but a trend for longer PFS-2 was observed for those receiving biological therapy (p=0.13).

Subsequent relapse/progression was observed in 10/15 (67%) patients receiving 3^rd^ line therapy, 2/10 (20%) patients receiving 4^th^ line therapy, both patients receiving 5^th^ line therapy, and 1/2 patients receiving 6^th^ line therapy. Median number of relapses/progressions was 1 (range, 1-5): 1 in 24 patients, 2 in 6 patients, and >3 in 10 patients.

Four (10%) patients transformed (after a median of 69 months) and 6 (15%) received ASCT. A significantly higher transformation rate was observed among patients treated with 2^nd^ line chemotherapy (21% vs 0, p=0.02) and those receiving ASCT (50% vs 3%, p=0.008).

<figure><img src="image_282.png" /></figure>

After a median follow up from time of first relapse/progression of 44 months (95% CI, 22-67 months), 5 (13%) patients died (3 of disease progression, 1 of ASCT-related infection), median OS-2 was not reached, and 5-year OS-2 was 88%. On univariate analysis, the only factor associated with longer OS-2 was absence of transformation (not reached vs 90 months, p=0.002); a trend for longer OS-2 was observed for patients relapsing beyond 1 year of frontline therapy (p=0.18) and patients not receiving ASCT (p=0.11).

**Conclusions:** Patients with relapsed or refractory NLPHL have overall a good prognosis and may not need aggressive treatment.

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

## IMMUNOTHERAPY

# 472 CASE SERIES OF NIVOLUMAB TREATMENT IN PATIENTS WITH RELAPSED/REFRACTORY HIV-RELATED LYMPHOMAS

Y. Rogacheva | M. Popova | A. Nekrasova |

I. Tsygankov | K. Lepik | L. Stelmah | I. Moiseev |

S. Bondarenko | V. Baykov | N. Mikhaylova |

B. Afanasyev

Oncology, Raisa Gorbacheva Memorial Research Institute of Children
Oncology, Hematology and Transplantation, First Pavlov State Medical
University of St. Petersburg, Ministry of Health of Russia, Saint
Petersburg, Russian Federation
<table><caption>Table 1.</caption><thead><tr><th>Pts</th><th>Ds</th><th>Age</th><th>HIV load</th><th>CD4+ cells/mcl</th><th>cART</th><th>Nivo</th><th>N of nivo</th><th>Response</th><th>Followed therapy</th><th>Outcome</th><th>Follow up</th></tr></thead><tbody><tr><td>1</td><td>HL</td><td>33</td><td>&lt;40</td><td>140</td><td>+</td><td>mono 40 [1]</td><td>10</td><td>CR</td><td>Auto-HSCT</td><td>Remission;</td><td>Alive;<br>499 days</td></tr><tr><td>2</td><td>HL</td><td>41</td><td>&lt;40</td><td>45</td><td>+</td><td>BeGe</td><td>12</td><td>PR</td><td>Continued</td><td>Relapse;<br>485 days</td><td>Alive;<br>506 days</td></tr><tr><td>3</td><td>HL</td><td>36</td><td>&lt;40</td><td>362</td><td>+</td><td>mono 40 [1]</td><td>10</td><td>PR</td><td>Continued</td><td>Remission;</td><td>Alive;<br>528 days</td></tr><tr><td>4</td><td>HL</td><td>40</td><td>&lt;40</td><td>490</td><td>+</td><td>BeGe</td><td>7</td><td>CR</td><td>Auto-HSCT</td><td>Remission;</td><td>Alive;<br>427 days</td></tr><tr><td>5</td><td>DLBCL</td><td>33</td><td>3381</td><td>410</td><td>-</td><td>BeGeR [2]</td><td>2</td><td>PD</td><td>-</td><td>Progression;</td><td>Died;<br>45 days</td></tr><tr><td>6</td><td>DLBCL</td><td>38</td><td>&lt;40</td><td>473</td><td>+</td><td>BeGeR [2]</td><td>7</td><td>CR</td><td>Auto-HSCT</td><td>Relapse;<br>266 days</td><td>Alive;<br>397 days</td></tr><tr><td>7</td><td>PBL</td><td>37</td><td>&lt;40</td><td>340</td><td>+</td><td>IGB</td><td>2</td><td>PR</td><td>Continued</td><td>Remission<br>(clinical)</td><td>Alive,<br>27 days</td></tr></tbody></table>

Pts - patients, Ds - diagnose, HL - Hodgkin lymphoma, DLBCL - diffuse large B-cell lymphoma, PBL - plasmablastic lymphoma, BeGeR - bendamustine, gemcitabine, rituximab, IGB - ifosfamide, gemcitabine, bortezomib; Nivo - nivolumab, CR - complete remission, PR - partial remission, PD - progression disease, auto-HSCT - autologous hematopoietic stem cell transplantation

**Introduction:** Nivolumab (nivo) is a salvage option in relapsed/refractory (r/r) HL and NHL. Patients with HIV-related lymphoma may benefit not only anticancer activity of nivo, but also from its potential anti-HIV effect [1]. Just a few cases of HIV-related lymphoma treated with nivo were reported [2,3]. We describe a case series of r/r HIV-related lymphoma receiving nivo in Raisa Gorbacheva Institute of Children Oncology, Hematology and Transplantation (CIC 725).

**Materials and methods:** Seven male patients with r/r HIV-related lymphoma were treated with nivo in 2017-2019. The primary end point was response to therapy. Secondary end points were toxicity, relapse incidence and overall survival (OS) at 12 months after first nivo infusion. CTCAE v4.03 for the toxicity analyse and immune-related adverse effects have been used. LYRIC criteria for assessing FDG-PET/CT were applied.

**Results:** The underlying diseases of observed patients were: HL n=4 (57%), diffuse large B-cell lymphoma (DLBCL) n=2 (28,6%) and one with plasmablastic lymphoma (PBL). Median number of prior lines of therapy

was 2 (range, 2-3). Relapse after ASCT was treated in one patient. Four patients received nivo as a bridge to ASCT; two patients didn't proceed to ASCT. Two patients received nivo as monotherapy, 4 patients in combination with bendamustine and gemcitabine, one in combination with ifosfamide, gemcitabine and bortezomib. The median dose of nivo was 1 mg/kg (range, 0,5-1,5 mg/kg), number of nivo doses - 7 (range, 2-12). The median number of CD4+ was 382 c/mcl (range, 45-490); 86% patients were on cART. Only 5 patients were available for estimating response, one - died before PET/CT was performed from the progression of the diseases, one just has started therapy (clinical response). Overall response rate was 83,3%. Two - partial remission by PET/CT, three (60%) patients had complete metabolic responses. Severe toxicity according to CTCAE of nivo and an immune-related adverse effect was not registered. Relapse of the underlying disease was diagnosed in 2 patients, time to progression were 485 and 266 days. OS at 12 months for the patients with HIV from the time of using nivo was 85,7%. Patient who didn't receive cART died from undetermined cause. Summary of patients are presented on table 1.
**Conclusions:** Overall response rate to nivolumab in patients with HIV-related lymphomas was 83,3% and 60% of them had complete metabolic remission. One-year overall survival was 85,7%. Severe ttoxicity and immune-related adverse effects were not registered. Our preliminary data provide that nivolumab is safety treatment option for HIV-infected patients with relapsed/refractory lymphomas. Further research is needed to clarify the efficacy of nivolumab as for HIV as lymphomas in this cohort of patients.

**Keywords:** human immunodeficiency virus (HIV); immunochemotherapy; non-Hodgkin lymphoma (NHL).

## 473
# INFECTIOUS COMPLICATIONS OF NIVOLUMAB THERAPY IN RELAPSED/REFRACTORY HODGKIN'S LYMPHOMA

Y. Rogacheva¹

M. Popova¹

K. Lepik¹

E. Kondakova¹

Y. Zalyalov¹

L. Stelmah¹

A. Volkova¹

I. Nikolaev¹

O. Goloshchapov¹

I. Barhatov¹

S. Bondarenko¹

I. Moiseev¹

V. Baykov¹

N. Mikhailova¹

N. Klimko²

B. Afanasyev¹

¹Oncology, Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg, Ministry of Health of Russia, Saint Petersburg, Russian Federation; ²Mycology, I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia, Saint Petersburg, Russian Federation

**Introduction:** The clinical development of checkpoint inhibitor-based immunotherapy has ushered in an exciting era of anticancer therapy. Despite of many reports on anti PD-1 antibody therapy for the treatment of Hodgkin's lymphoma (HL), risk of infection among patients receiving nivolumab is still unknown. We are the first to present the real-life data on infection complications in large cohort of r/r HL after nivolumab (nivo) therapy.

**Methods:** Between 2016 and 2018 years 112 patients with r/r HL were observed and treated with nivo (3 mg/kg) in CIC 725. The median age was 31 y.o. (13 -62 years). The median number of nivo courses received was 20 (range, 1-30). 18 patients underwent allo-HSCT after therapy of nivo. The median follow-up period was 1,4 years (1 month-2,6 year). Outcome analysis considered events at one year after first nivo administration and were censored at the date of allo-HSCT or auto-HSCT. Infections were identified by reviewing patient clinical, laboratory data and imaging studies. All patients had a standard anti-infective prophylaxis and treatment according to the international guidelines.

**Results:** During salvage treatment with nivo of r/r HL in 11 (10%) patients were documented infection episodes (n=16): bacterial infections – 37,5% (n=6), invasive fungal diseases (IFD) – 25% (n=4) and

viruses – 37,5% (n=6). The median time to infection episodes was 98 days (12-365) after first nivo administration. Incidence of bacterial infections in study cohort was 5,3% (n=6). Two patients developed pneumonia, others met in one: sinusitis, meningitis cause by Listeria meningitis, colitis and gonitis. Incidence of viral infections was 5,3% (n=6): pneumonia associated with HHP-6 and CMV in 50% and generalized infections in 50% caused by HSV-1,2 and HHV-6. Invasive fungal diseases were diagnosed in 3,6% patients (n=4). The main etiology agent was Aspergillus spp. in 50%. Primary chemoresistant disease before nivo therapy was the only risk factor of infection complications during treatment of r/r HL (p=0,029). Overall survival (OS) at 1 year after first nivo administration in study cohort was 96,5%. The only one death was attributed to infection, patient died due to sepsis unknown etiology.

**Conclusion:** Incidence of infectious complications in r/r HL treated with nivolumab was 10% with the median time of onset – 98 days. Etiology of infectious complications presented by bacterial infections –37,5%, invasive fungal diseases – 25% and viruses – 37,5%. Primary chemoresistance was a risk factor for infection complications. Wherewith infections could be managed successfully and carry favorable prognosis.

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

## 474
# TREATMENT OF RELAPSED/REFRACTORY AGGRESSIVE NON-HODGKIN LYMPHOMA (NHL) WITH LISOCABTAGENE MARALEUCEL IN THE OUTPATIENT SETTING: RESULTS FROM TWO PHASE 2 TRIALS

A. Sehgal¹

J.E. Godwin²

M.B. Maris³

G.C. Hildebrandt⁴

N.S. Trede⁵

A. Kostic⁵

L. Wang⁶

J. Lymp⁷

C.R. Bachier⁸

¹Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, United States; ²Earle A Chiles Research Institute, Providence Cancer Institute, Portland, United States; ³Hematology/Oncology, Colorado Blood Cancer Institute, Denver, United States; ⁴Division of Hematology, University of Kentucky Markey Cancer Center, Lexington, United States; ⁵Clinical Development, Juno Therapeutics, a Celgene Company, Seattle, United States; ⁶Biometrics, Juno Therapeutics, a Celgene Company, Seattle, United States; ⁷Biostatistics, Juno Therapeutics, a Celgene Company, Seattle, United States; ⁸Hematology/Oncology, Sarah Cannon Center for Blood Cancer, Knoxville, United States

**Introduction:** Chimeric antigen receptor (CAR) T cell therapy has generally been limited to inpatient administration at university medical centers. Among US patients (pts) treated for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), about 80% receive
treatment at nonuniversity medical centers where outpatient therapy is often at a distinct site from hospitalization for adverse event management. In the ongoing TRANSCEND NHL 001 study in R/R DLBCL, lisocabtagene maraleucel (liso-cel, JCAR017), an investigational, anti-CD19 CAR T cell product administered at a precise dose of CD4 +/CD8+ CAR T cells, showed high overall response rates with a favorable safety profile (Abramson et al, ASCO 2018). Late onset and low rates of all grade and severe cytokine release syndrome (CRS) and neurological events (NE) support outpatient treatment with hospital admission at the first sign of fever. We report on 2 newly initiated open-label, phase 2 trials that allow outpatient treatment, assessing the safety and efficacy of liso-cel either as third-line therapy (OUTREACH; NCT03744676) or in second-line, transplant noneligible pts (PILOT; NCT03483103).

**Methods:** In both trials, eligible pts had R/R aggressive B-cell NHL, adequate organ function, and prior systemic chemoimmunotherapy (OUTREACH: ≥2 prior lines of therapy and ECOG PS ≤1; PILOT: 1 prior line of therapy and deemed ineligible for autologous hematopoietic stem cell transplantation based on ECOG PS, organ function, and/or age). Liso-cel was administered at $100 \times 10^6$ total CAR+ T cells after lymphodepletion (LD) with fludarabine/cyclophosphamide. Both trials allowed outpatient treatment at nonuniversity (OUTREACH) or at both university and nonuniversity medical centers (PILOT). Outpatient treatment required pts to have a caregiver, safety monitoring education, and to stay close to the site of care. All sites were required to have a multidisciplinary CAR T cell team identified and standard operating procedures for outpatient administration and monitoring in place.

**Results:** At data cutoff, 15 pts were leukapheresed (OUTREACH n=7; PILOT n=8). Age ranged from 60-79 years; 11 pts were female. 13 pts had DLBCL NOS, 2 had DLBCL transformed from indolent lymphoma. 7 pts had LD followed by liso-cel infusion, including 3 outpatients. The remaining 8 pts are awaiting liso-cel treatment. Among the 4 pts with 30 days of follow-up, no CRS, NE, or febrile neutropenia were reported. There were no grade ≥3 nonhematologic treatment-emergent adverse events (TEAEs), grade 5 TEAEs, or ICU admissions. Objective responses were observed in 4/4 pts (1 complete remission; 3 partial remissions). Updated enrollment, incidence of toxicity, intervention for CRS/NE and hospitalizations with longer follow-up data will be presented.

**Conclusions:** In these ongoing phase 2 studies in R/R NHL, pts were successfully treated with liso-cel in the outpatient setting.

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

**Disclosures:** Sehgal, A: Research Funding: Juno/Celgene, Kite/Gilead, Merck. Hildebrandt, G: Consultant Advisory Role: Pfizer, Kite Pharma, Incyte, JAZZ Pharmaceuticals; Stock Ownership: Sangamo Bioscience, Juno Therapeutics, Kite Pharma, Novartis, Insys Therapeutics, Abbvie, GW Pharmaceuticals, Cardinal Health, Immunomedics, Endocyte, Clovis Oncology, Cellectis, Aetna, CVS Health, Celgene, Bluebird Bio, Bristol-Myers Squibb / Medarex, crispr therapeutics, IDEXX laboratories, Johnson & Johnson, Pfizer, Procter & Gamble, Vertex, JAZZ Pharmaceuticals; Research Funding: Takeda, JAZZ Pharmaceuticals, Pharmacyclics; Other Remuneration: Travel, expenses, accommodation: Kite Pharma, Incyte,

Pfizer, Falk Foundation, JAZZ Pharmaceuticals, Astellas Pharma. Trede, N: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Kostic, A: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Wang, L: Employment Leadership Position: Celgene Corporation; Stock Ownership: Celgene Corporation. Lymp, J: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Bachier, C: Honoraria: Sanofi.

## 475
# CORRELATION OF CIRCULATING EPSTEIN-BARR VIRUS-TARGETED CYTOTOXIC T LYMPHOCYTE PRECURSORS (EBV-CTLp) AND CLINICAL RESPONSE FOLLOWING TABELECLEUCEL (TAB-CEL) INFUSION IN PATIENTS WITH EBV-DRIVEN DISEASE

B. Aftab<fnref n="1" /> | D. Munson<fnref n="1" /> | K. Rasor<fnref n="1" /> | P. Foubert<fnref n="1" /> |

D. Tsai² | W. Kai Weng<fnref n="3" /> | A. Ghobadi⁴ |

K. van Besien<fnref n="5" /> | Y. Sun⁶ | M. Hiremath<fnref n="7" /> |

W. Navarrow<fnref n="7" /> | S. Prockop⁸

**Background:** EBV is implicated in a variety of diseases. Tab-cel is an investigational off-the-shelf, allogeneic T-cell immunotherapy utilizing endogenous T cell receptors targeting EBV antigens. We hypothesized the clinical activity of tab-cel is mediated by expansion and persistence of EBV-specific T cells. Therefore, we quantified circulating EBV-CTLp after tab-cel administration and examined the correlation between expansion and clinical response.

**Methods:** Samples from 10 patients with EBV+ post-transplant lymphoproliferative disease (PTLD) and other EBV-associated diseases enrolled in a multicenter expanded access protocol (EAP) study (NCT02822495) were analyzed. To evaluate CTLp frequencies, limited dilution analysis was performed on samples taken at baseline and day 34 post 1st tab-cel dose (end cycle 1). The day 34 persistence of circulating EBV-CTLp from best overall response to initial tab-cel product was tested using the two-tailed Mann-Whitney test. Changes in inflammatory cytokines were also measured.

**Results:** Responders represented in this sampling (n=6; 2 PR and 4 CR) showed a median 5.8-fold increase in circulating CTLp between baseline and day 34 (range: 0.8 to 133-fold). Five of 6 responders showed an increase in EBV-CTLp at day 34 of > 3.8-fold while 1 pt showed no change in CTLp (0.8-fold change). In contrast, the 4 non-responders (3 SD; 1 PD) showed a median 0.3-fold decrease in EBV-

<footnote n="1">¹Preclinical and Translational Science, Atara Biotherapeutics, Thousand Oaks, United States; ²Clinical, Loxo Oncology, Stamford, United States;</footnote>

<footnote n="3">³Internal Medicine, Stanford, Palo Alto, United States; ⁴Internal Medicine, Saint Louis Children's Hospital, Saint Louis, United States;</footnote>

<footnote n="5">⁵Internal Medicine, Cornell, New York, United States; ⁶Biostatistics, Atara Biotherapeutics, Thousand Oaks, United States;</footnote>

<footnote n="7">⁷Clinical Development, Atara Biotherapeutics, San Francisco, United States; ⁸Pediatric Hematology-Oncology, MSK, New York, United States</footnote>
CTLp from baseline (range: 1.2 to 0.02-fold; ns). Cumulative analyses
revealed a statistically significant correlation between the fold-change
of circulating CTLp at day 34 and clinical response (p=0.038) which
did not appear to correlate with the type of the EBV-associated dis-
ease. Inflammatory cytokines showed no meaningful change from
baseline. The safety profile remains consistent with previously
reported data.

**Conclusions:** These data support the correlation of clinical activity of tab-cel with the expansion and persistence of EBV-specific T-cells at day 34 post-treatment, as well as the use of circulating CTLp as a bio- marker for response in clinical studies.

**Keywords:** Epstein-Barr virus (EBV); PTLD; T-cells.

**Disclosures:** Aftab, B: Employment Leadership Position: *Atara Biotherapeutics*; Consultant Advisory Role: none; Stock Ownership: *Atara Biotherapeutics*; Honoraria: none; Research Funding: none; Other Remuneration: none. Munson, D: Employment Leadership Position: *Atara Biotherapeutics*; Stock Ownership: *Atara Biotherapeutics*. Rasor, K: Employment Leadership Position: *Atara Biotherapeutics*; Stock Ownership: *Atara Biotherapeutics*. Foubert, P: Employment Leadership Position: *Atara Biotherapeutics*; Stock Ownership: *Atara Biotherapeutics*. Tsai, D: Employment Leadership Position: *Loxo Oncology*; Consultant Advisory Role: *Bristol Myers, Novartis*; Stock Ownership: *Loxo Oncology*; Honoraria: *Atara Biotherapeutics*. van Besien, K: Stock Ownership: *Hemogenyx*. Sun, Y: Employment Leadership Position: *Atara Biotherapeutics*; Stock Ownership: *Atara Biotherapeutics*. Hiremath, M: Employment Leadership Position: *Atara Biotherapeutics*; Stock Ownership: *Atara Biotherapeutics*. Navarrow, W: Employment Leadership Position: *Atara Biotherapeutics*; Stock Ownership: *Atara Biotherapeutics*, *Bluebird*, *GE*, *Pfizer*.

476
THE ROLES OF PET/CT IN PREDICTING
THE PROGNOSIS OF CHIMERIC ANTIGEN
RECEPTOR T CELL THERAPY TREATED
PATIENTS WITH DIFFUSE LARGE B CELL
LYMPHOMA

Y. Zou¹ | C. Ding² | H. Zhu¹ | L. Wang¹ | 
Y. Xia¹ | J. Liang¹ | L. Fan¹ | W. Xu¹ | J. Li¹

¹Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China; ²Department of Nuclear Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

**Introduction:** Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for relapsed or refractory (r/r) diffuse large B cell lymphoma (DLBCL) patients. Positron emission tomography/computed tomography (PET-CT) played an important role in DLBCL in the era of chemoimmunotherapy, while its value in CAR-T therapy remained undetermined.

**Methods:** In this study, we retrospectively explored the role of PET-CT in 13 r/r DLBCL patients who were receiving CAR-T therapy.

Parameters reflecting tumor metabolic burden, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), were measured before and after CAR-T treatment. These trials were registered at www.clinicaltrials.gov as #NCT02976857 and #NCT03598179.

**Results:** Patients with larger baseline MTV or longer sum of longest diameters had shorter overall survival (OS) than those with low tumor burden. Patients who achieved complete response (CR), partial response (PR) and minor response determined by response evaluation criteria in lymphoma (RECIL) at 12 weeks had superior progression-free survival and OS than those with no response. In addition, we found that 2 patients with residual masses classified as PR by contrast-enhanced CT had complete metabolic response by PET-CT imaging. In general, in r/r DLBCL patients, PET-CT at baseline and at 12 weeks after CAR-T therapy could predict the prognosis, while early PET-CT at 4 weeks failed to predict long-term outcomes. CR rate was higher when detected by PET-CT than contrast-enhanced CT.

**Conclusions:** Therefore, PET-CT showed great value in prognosis assessment and response evaluation in CAR-T-treated r/r DLBCL patients.

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

477
BASELINE CLINICAL AND PET-CT TUMOR
BURDEN PARAMETERS DO NOT PREDICT
OUTCOME OF RELAPSE/REFRACTORY
AGGRESSIVE B CELL LYMPHOMA
PATIENTS TREATED WITH ANTI-CD19 CAR
T-CELLS

A. Avigdor¹ | T. Davidson² | A. Shimoni¹ |
R. Yerushalmi¹ | N. Shem-Tov¹ | I. Danylesko¹ |
O. Itzhaki³ | A. Toren⁴ | E. Jacoby⁴ | M. Besser⁵ |
A. Nagler¹

¹Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Hashomer, Israel; ²Department of Nuclear Medicine, Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Hashomer, Israel; ³Ella Lemelbaum Institute for Immuno-Oncology, Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Hashomer, Israel; ⁴Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Hashomer, Israel; ⁵Ella Lemelbaum Institute for Immuno-Oncology, Chaim Sheba Medical Center and Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Hashomer, Israel

**Background:** Phase II trials have suggested that anti-CD19 CAR T-cell therapy can induce durable responses in around 40% of patients (pts) with relapse/refractory (R/R) aggressive B cell lymphomas (aBCL). We
initiated a single center program in which pts with R/R aBCL were treated with locally produced anti-CD19 CAR T-cells. Eligibility of the pts enrolled reflected a real world setting.

**Aim:** To evaluate the safety, efficacy, and clinical/PET-CT imaging parameters associated with survival outcomes.

**Methods:** Pts with R/R aBCL and adequate organ function were eligible. The approach used autologous T-cells expressing anti-CD19 CAR construct with CD28 co-stimulatory domain. Treatment included lymphodepletion with fludarabine and cyclophosphamide followed by infusion of fresh 1 X 10⁶ CAR T-cells after 9-10 days of culture. Baseline PET-CT scans, which were done within maximum 2 weeks before CAR T-cell treatment, were analyzed for total lesion glycolysis (TLG) and total metabolic tumor volume, using a segmentation algorithm of 41%SUVmax (TMTV41%).

**Results:** Between November 2016 and January 2019, 30 pts with R/R aBCL were included: 25 with diffuse large B cell lymphoma (6 of them were transformed), 3 with primary mediastinal lymphoma and 2 with Burkitt lymphoma. 23 pts were male. Median age was 45 (range 19-66). Median number of prior therapies was 3 (range 2-6). 27 pts (90%) were refractory to their last therapy. 13 (43%) had a prior stem cell transplantation (SCT) (11 - auto, 1 - allo, 1 - auto and allo). The overall response rate was 57% (27% CR). With a median follow-up of 5.1 month (1.2-26.5) median overall and progression free survival (PFS) were 20.7 and 3.7 months, respectively. The estimated PFS at 18 months for the entire cohort was 25%, and 44% among the 17 pts who had an objective response. 11 patients deceased, 9 of them due to disease progression and 2 from transplant related toxicity. No deaths were attributed to CAR T-cell therapy. Cytokine release syndrome occurred in 22 pts (73%), but was severe in only one. 11 pts (37%) experienced neurotoxicity, in 6 (20%) it was grade 3 or 4. Toxicities related to CAR T-cell therapy did not predict survival outcomes. Median baseline TMTV and TLG were 76 (7-1357) and 717 (19-8460), respectively. None of these PET-CT measurements and other baseline patient and disease characteristics, including CRP and stage, predicted OS or PFS. AlloSCT was performed after CAR T-cell therapy in 13/30 patients (43%). Severe acute GVHD and sinusoidal obstruction syndrome were identified in 2/13 patients (15%), each.

**Conclusion:** This prospective analysis of a single center cohort of mostly refractory aBCL pts treated with in-house produced anti-CD19 CAR T-cell therapy suggests that long-term responses may be achieved, particularly in pts who had an objective response. None of the clinical and PET-CT parameters that indicate tumor burden predicted long term survival.

**Keywords:** non-Hodgkin lymphoma (NHL); positron emission tomography (PET); T-cells.

B-CELL LYMPHOMA TREATED WITH
TISAGENLECLEUCEL IN THE JULIET TRIAL

U. Jaeger¹ | C. Tam² | P. Borchmann³ |
J. McGuirk⁴ | H. Holte⁵ | E. Waller⁶ |
S. Jaglowski⁷ | C. Andreadis⁸ | S.R. Foley⁹ |
I. Fleury¹⁰ | J. Westin¹¹ | T. Teshima¹² |
S. Mielke¹³ | G. Salles¹⁴ | P.J. Ho¹⁵ | K. Izutsu¹⁶ |
S. Schuster¹⁷ | V. Bachanova¹⁸ | R. Maziarz¹⁹ |
K. Van Besien²⁰ | M.J. Kersten²¹ |
N. Wagner-Johnston²² | K. Kato²³ | P. Corradini²⁴ |
R. Tiwari²⁵ | A. Forcina²⁶ | L. Pacaud²⁷ | M. Bishop²⁸

¹Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; ²Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, Australia; ³Department of Hematology/Oncology, University Hospital of Cologne, Cologne, Germany; ⁴Division of Hematologic Malignancies and Cellular Therapeutics, Kansas Hospital and Medical Center, Kansas City, United States; ⁵Lymphoma Section, University of Oslo, Oslo; ⁶Hematology and Medical Oncology, Medicine and Pathology, Emory University School of Medicine, Atlanta, United States; ⁷Department of Hematology, Ohio State University, Columbus; ⁸Department of Hematology and Blood and Marrow Transplant, University of California San Francisco, San Francisco, United States; ⁹Division of Clinical Pathology, McMaster University, Hamilton, Canada; ¹⁰Department of Hematology, Hôpital Maisonneuve-Rosemont, Montreal, Canada; ¹¹Department of Lymphoma & Meyloma, MD Anderson Cancer Center, Houston, United States; ¹²Department of Hematology, Hokkaido University Hospital, Sapporo, Japan; ¹³Department of Internal Medicine, University Hospital Wuerzburg, Wuerzburg, Germany; ¹⁴Department of Hematology/Oncology, Hospital Center Lyon-Sud, Pierre-Benite, France; ¹⁵Department of Haematology, Royal Prince Alfred Hospital, Camperdown, Australia; ¹⁶Department of Hematology, National Cancer Center Hospital, Tokyo, Japan; ¹⁷Division of Hematology Oncology, University of Pennsylvania, Philadelphia, United States; ¹⁸Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, United States; ¹⁹Department of Hematology, Oregon Health and Science University, Portland, United States; ²⁰Department of Medical Oncology, Weill Cornell Medicine, New York, United States; ²¹Department of Hematology, Academic Medical Center, Amsterdam, Netherlands; ²²Department of Hematology/Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, United States; ²³Department of Haematology, Kyushu University Hospital, Fukuoka Prefecture, Japan; ²⁴Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy; ²⁵Global Medical Affaris, Novartis Pharmaceuticals Corporation, Hyderabad, India; ²⁶Novartis Oncology, Novartis Pharma AG, Basel, Switzerland; ²⁷Novartis Oncology, Novartis Pharmaceuticals Corporation, East Hanover, United States; ²⁸Section of Hematology/Oncology, University of Chicago, Chicago, United States

**Background:** Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR)-T cell therapy that has demonstrated durable responses and
Box plot of immunoglobulin levels over time by IVIG use (yes vs no)

<figure><img src="image_283.png" /></figure>

a manageable safety profile in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Intra-venous immunoglobulin (IVIG) is commonly used to manage hyp-ogammaglobulinemia following stem cell transplant; hypogammaglobulinemia can also be a consequence of CD19+ B-cell depletion by anti-CD19 CAR-T cell therapy. We report use of IVIG and clinical outcomes for JULIET study pts.

**Methods:** JULIET is a single-arm, pivotal, phase 2 trial of tisagenlecleucel in adult pts with r/r DLBCL. IgG, IgM, and IgA at baseline; d 14, 28; mo 3, 6, 9, 12; and end of follow-up, together with IVIG use and clinical outcomes, were evaluated. Hyp-ogammaglobulinemia was defined as IgG <4 g/L.

**Results:** At data cutoff (21 May 2018; median follow-up: 19 mo), hyp-ogammaglobulinemia was observed in 68 of 115 pts (59%) following

tisagenlecleucel infusion. Among 75 pts with IgG ≥4 g/L prior to tisagenlecleucel, 37 (49%) subsequently developed hyp-ogammaglobulinemia, with a median duration of 70 d (range: 0-726) and median onset of 14 d (range: 14-376). CAR-T transgene levels (copies/µg DNA) were comparable between pts with or without hyp-ogammaglobulinemia at all timepoints after infusion. Immunoglobulin recovery in the overall population according to IVIG use is summa-rized in the **Figure**. Thirty-eight of 115 pts (33%) received IVIG follow-ing tisagenlecleucel infusion; 25 of 38 pts received IVIG in the presence of hypogammaglobulinemia, while 13 received IVIG with levels of IgG ≥4 g/L. Nine of 115 pts (7.8%) received IVIG before infu-sion. Median start of IVIG was 55 d after tisagenlecleucel infusion (range: 5-555). IVIG use in responders vs nonresponders to tisagenlecleucel was 38.3% vs 27.3%, respectively. Within 8 weeks of
tisagenlecleucel infusion, the frequency of grade 3-4 infections was similar between pts who received IVIG (n=8/38, 21%) and those who did not (n=14/77, 18%); however, at later timepoints (>8 wk to ≤1 yr and >1yr), the frequency of grade 3-4 infections was higher in pts receiving IVIG (n=11/35 [31%] and n=3/20 [15%], respectively) vs those who did not (n=7/65 [11%] and n=0/21 [0%], respectively). IgG levels in pts receiving and not receiving IVIG supplementation were comparable over time.

**Conclusions:** Approximately one third of pts received IVIG following tisagenlecleucel infusion; use of IVIG was driven by local institutional practice, with heterogeneity in terms of indication, frequency, and duration of treatment. Although our study was not powered to address this question, no clear pattern associating IVIG use with patient characteristics and conditions was observed. Further research is needed to develop guidance for IVIG use following CAR-T infusion in pts with r/r DLBCL.

**Clinical trial information:** NCT02445248.

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

**Disclosures:** Jaeger, U: Honoraria: AbbVie, Bioverativ, Celgene, Gilead, Janssen, MSD, Novartis, Roche, Takeda Millenium, Amgen, AOP Orphan, BMS, Sandoz; Research Funding: Bioverativ, Celgene, Gilead, Janssen, MSD, Novartis, Roche; Other Remuneration: AbbVie, Celgene, Gilead, Janssen, MSD, Novartis, Roche, Takeda Millenium, Amgen, AOP Orphan, BMS, Sandoz. Tam, C: Honoraria: Novartis. McGuirk, J: Honoraria: Kite Pharma; Research Funding: Novartis, Kite Pharma, Fresenius Biotech, Astellas Pharma, Bellicum Pharmaceuticals, Gamida Cell, Pluristem Ltd. Holte, H: Consultant Advisory Role: Novartis; Honoraria: Novartis. Walter, E: Employment Leadership Position: Cambium Medical Technologies; Consultant Advisory Role: Kalyera, Novartis; Stock Ownership: Cerus Corporation, Chimerix; Honoraria: Cambium Medical Technologies, Kalytera, Novartis; Research Funding: Celldex, Novartis, Pharmacyclics; Other Remuneration: Pharmacyclics. Jaglowski, S: Consultant Advisory Role: Kite Pharma, Juno; Research Funding: Novartis. Andreadis, C: Honoraria: Novartis, Genentech, Seattle Genetics, Gilead, Astellas; Research Funding: Novartis, Cellerant Therapeutics, Incyte, Pharmacyclics, Amgen, Genentech. Fleury, I: Honoraria: Gilead, Novartis, Roche, Seattle Genetics, Janssen, AbbVie. Teshima, T: Honoraria: Novartis; Research Funding: Novartis. Mielke, S: Consultant Advisory Role: Celgene, KIADIS Pharma, Miltenyi Biotec, DGHO, EHA. Salles, G: Consultant Advisory Role: Novartis; Honoraria: Novartis. Ho, P: Other Remuneration: Novartis, Celgene, La Jolla Pharmaceuticals. Izutsu, K: Honoraria: Novartis, Eisal, Kyowa Hakko Kirin, MSD, Takeda, Janssen, Bristol Myers Squib, Dainihon Sumitomo, Mundipharma, Nihon Mediphysics, Chugai, AstraZeneca, AbbVie, Bayer, Ono, Celgene; Research Funding: Novartis, Elsa, MSD, Takeda, Janssen, Mundipharma, Chugai, AbbVie, Bayer, Ono, Gilead, Zenyaku, Celgene, Solasia, Symbio, Astellas, Amgen, Diichi Sankyo. Schuster, S: Honoraria: Celgene, Genentech, Merck, Pharmacyclics, Novartis, Nordic Nanovector, Acerta, Pfizer, Gilead; Research Funding: Celgene, Genentech, Merck, Pharmacyclics, Novartis, Gilead. Bachanova, V: Research Funding: GAMIDA Cell, UNUM, Novartis, GT Biopharm. Maziarz, R: Consultant Advisory Role: Novartis,

Incyte, Juno Therapeutics; Honoraria: Novartis, Incyte, Juno Therapeutics, Kite Therapeutics; Other Remuneration: Athersys, Inc. Van Besien, K: Research Funding: Novartis. Kersten, M: Consultant Advisory Role: Roche, Celgene, Takeda, Novartis, Kite, BMS; Honoraria: Roche, Celgene, Takeda, Novartis, Kite; Research Funding: Roche, Celgene, Takeda. Wagner-Johnston, N: Honoraria: JUNO, ADC Therapeutics, Janssen; Research Funding: Merck, Novartis, Celgene, Astex. Corradini, P: Consultant Advisory Role: Celgene, AbbVie, Amgen, Daiichi Sankyo, Gilead, Janssen, KiowaKirin, Novartis, Roche, Sanofi, Servier, Takeda. Tiwari, R: Employment Leadership Position: Novartis. Forcina, A: Employment Leadership Position: Novartis. Pacaud, L: Employment Leadership Position: Novartis. Bishop, M: Employment Leadership Position: United Healthcare; Consultant Advisory Role: Celgene, Juneau Therapeutics, Novartis; Honoraria: Celgene, Juneau Therapeutics, Novartis.

479

MDS AS A CAUSE FOR PROLONGED HEMATOLOGIC TOXICITY AFTER TREATMENT WITH CD19 TARGETED CAR-T CELL THERAPY IN PATIENTS WITH RELAPSED REFRACTORY LYMPHOMA

G.P. Shouse | T. Xue | A. Herrera | T. Siddiqi |

J. Zain | L. Popplewell | S. Forman | E. Budde

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, United States

**Introduction:** The advent of adoptive cellular therapy utilizing autologous T cells expressing chimeric antigen receptors (CAR-T) against CD19 has revolutionized relapsed and refractory B cell lymphoma treatment. CAR-T cell therapy, however, is not without toxicity. Other than cytokine release syndrome and neurotoxicity, hematologic toxicity occurs commonly as well. Grade 3 and above prolonged neutropenia and thrombocytopenia (longer than 4 weeks since T cell infusion) was seen in 15 to 40% and 18 to 40% of patients treated with CD19 CAR T cells in clinical trials respectively. The exact mechanism underlying the pathogenesis of prolonged hematologic toxicity in CAR-T cell therapy is not well understood. Interestingly, we identified four cases of prolonged cytopenias after CAR-T cell therapy due to the presence of myelodysplastic syndrome in patients receiving this treatment for relapsed refractory B cell lymphoma.

**Methods:** We performed a retrospective review of four patients with relapsed refractory aggressive B cell lymphoma treated at our institution with CD19 directed autologous CAR-T cells.

**Results:** Median age was 74 (range: 57-76). Two patients had GCB type, 2 had non-GCB type DLBCL. The median number of lines of therapy prior to CAR-T cell therapy was 5. All four patients had prior autologous stem cell transplantation. Median time to MDS diagnosis from CAR T infusion was 3 months (range: 2 to 3). One patient developed MDS after additional chemotherapy was given for relapsed disease. One patient had evidence of a dysplastic clone prior to CAR-T
cell therapy. The remaining two patients did not have evidence of MDS until immediately after CAR-T cell therapy. Two patients developed severe CRS requiring tocilizumab and corticosteroids. One patient showed partial response to CAR-T cell therapy, while three others achieved CR, two of which have since relapsed.

**Discussion:** We identified four patients with prolonged hematologic toxicity after CAR-T cell therapy due to MDS. These patients have multiple risk factors for the development of MDS including advanced age, and heavy pretreatment. In fact, one patient had evidence of MDS prior to CAR-T cell therapy, underscoring the potential benefit of providing CAR-T cell therapy earlier in the course of treatment. In addition, our findings suggest that a bone marrow study should be performed in patients with prolonged cytopenias post CAR T cell therapy. It is not clear if there is any direct contribution of CAR T cells and the resulting immune system disturbance to the development of MDS. Long term follow up of all patients receiving CAR T cell therapy is therefore crucial to assessment true incidence of MDS and establish association.

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

**Disclosures:** Herrera, A: Consultant Advisory Role: Gilead. Siddiqi, T: Consultant Advisory Role: Juno Therapeutics. Budde, E: Consultant Advisory Role: Gilead.

480 WITHDRAWN

481
CAR T-CELLS ARE ARRIVING. IS ALLOGENEIC TRANSPLANT AN OBSOLETE APPROACH FOR DE NOVO/TRANSFORMED DLBCL IN THE CAR

T-CELLS ERA? LONG-TERM FOLLOW-UP
OF A SINGLE CENTRE UNIT

L. Prieto-García<fnref n="1" /> | M. Alcoceba<fnref n="1" /> | E. Pérez-López<fnref n="1" /> |

L. López-Corral<fnref n="1" /> | M. Delgado<fnref n="1" /> | F. Sánchez-Guijo<fnref n="1" /> |

A. Martín<fnref n="1" /> | A. Navarro-Bailón<fnref n="1" /> | M. Baile<fnref n="1" /> |

M. López-Parra<fnref n="1" /> | P. Tamayo² | N.C. Gutiérrez<fnref n="1" /> |

L. Vázquez<fnref n="1" /> | M. Cabrero<fnref n="1" /> | A. Martín<fnref n="1" /> | D. Caballero<fnref n="1" />

**Background:** Allogeneic stem-cell transplant (allo-SCT) has been a curative option in patients younger than 65-70 years with diffuse large B-cell lymphoma (DLBCL) - de novo or transformed from previous indolent B-cell lymphoma - relapsing or non-candidates to standard salvage therapy including autologous stem-cell transplant (auto-SCT). Due to complications, this approach is offered to only a few patients according to registry data. Moreover, many patients did not reach the transplant due to refractory disease. On August 2018, two chimeric antigen receptor (CAR) T-cells anti-CD19 (Yescarta® and Kymriah®) were approved by the European regulatory agency in de novo and transformed DLBCL patients refractory to at least two chemotherapy lines, based on the results of two Phase II trials reporting a best response of 58% and 40% at 12 months (Chow et al., Blood 2018). Unfortunately, CAR T-cells are not yet a realistic option for patients in centres in Spain. Whether allo-SCT should still be offered to these patients is an opening question.

**Methods:** From 130 patients with non-Hodgkin lymphoma out of 1000 patients transplanted in our Unit between 1995 and 2018,

<figure><img src="image_284.png" /><figcaption>**Figure 1.** Duration of response in R/R-DLBCL by best response, A) allo-SCT Salamanca B) CAR T-cells (ZUMA-1).</figcaption></figure>

<footnote n="1">¹Department of Hematology, University Hospital of Salamanca, Salamanca, Spain; ²Department of Nuclear Medicine, University Hospital of Salamanca, Salamanca, Spain</footnote>
40 have been included in this analysis; of them, 23 had a de novo DLBCL and 17 a transformed lymphoma.

**Results:** Median age was 53 (20-66), 85% have received more than three lines of chemotherapy including auto-SCT (70%); 47% were refractory to first-line, and in 64% duration of response after auto-SCT were lower than 12 months. After transplant, complete response (CR) at 100 days was 67.5%, and 82% of the patients remain in CR at 12 months. With a median follow-up of 46 months, 5-year progression-free survival (PFS) and overall survival (OS) were 54% and 48% respectively (Figure 1A). In our series, refractoriness at the time of the transplant was associated with a poorer prognosis, with only two out of nine refractory patients being long term survivors. Although similar results were reported in the ZUMA-1 trial with the best response of 55% CR retained in 79% of them at 12 months, we have to point it out that follow up is much shorter, 15.4 months (Figure 1B).

**Conclusions:** Although very few patients with de novo or transformed DLBCL are offering an allo-SCT (4% of all allo-SCT in our Unit), this is a curative option in chemosensitive patients, and with more mature data and longer follow-up than with CAR T-cell therapy; for these reasons and due to the difficulties still remaining of offering CAR T-cells to these patients, allo-SCT should still be offered to them. Moreover, almost all patients have now available donor, better graft-versus-host disease prophylaxis will decrease TRM and morbidity, and new therapies will make more patients in sensitive disease before allo-SCT. Therefore, allo-SCT and CAR T-cells are strategies to be discussed in every young patient with available donor.

**Keywords:** allogeneic stem cell transplant (alloSCT); diffuse large B-cell lymphoma (DLBCL).

## 482
RESULTS OF PHASE II STUDY OF COMBINED IMMUNOTHERAPY WITH RITUXIMAB PLUS LYMPHOKINE-ACTIVATED KILLER CELLS AS MAINTENANCE IN FOLLICULAR LYMPHOMA PATIENTS

N. Martinez Calle<fnref n="1" /> | A. Diaz De Cerio² | E. Pena² |

R. Garcia Muñoz³ | A. Panizo⁴ | J. Feliu³ |

P. Giraldo⁵ | M. Rodriguez⁶ | C. Grande⁷ |

T. Olave⁸ | M. Andrade-Campos<fnref n="9" /> | E. Bandres⁶ |

J. Nuñez¹⁰ | S. Inoges² | C. Panizo²

<table><caption>**TABLE 1** Adverse events and serious events in the maintenance and follow-up phases</caption><thead><tr><th>Event</th><th>N(%)</th><th></th></tr></thead><tbody><tr><td>Any grade</td><td>219 (100)</td><td></td></tr><tr><td>Grade 0</td><td>141 (64.4)</td><td></td></tr><tr><td>Grade 1</td><td>46 (21.0)</td><td></td></tr><tr><td>Grade 2</td><td>25 (11.4)</td><td></td></tr><tr><td>Grade ≥3</td><td>5 (2.3)</td><td></td></tr><tr><td>UK</td><td>2 (0.9)</td><td></td></tr><tr><td>TRM-related AE,n(%)</td><td>Any grade</td><td>Grade≥3</td></tr><tr><td>All</td><td>29 (100)</td><td>3 (100)</td></tr><tr><td>Diarrhea</td><td>4 (13.8)</td><td>0 (0)</td></tr><tr><td>Neutropenia</td><td>3 (10.3)</td><td>3 (100)</td></tr><tr><td>Infection</td><td>6 (20.6)</td><td>0 (0)</td></tr><tr><td>Arthralgia</td><td>7 (24.1)</td><td>0 (0)</td></tr><tr><td>Asthenia</td><td>4 (13.8)</td><td>0 (0)</td></tr><tr><td>Erytema</td><td>1 (3.4)</td><td>0 (0)</td></tr><tr><td>Anxiety/depression</td><td>1 (3.4)</td><td>0 (0)</td></tr><tr><td>Pyrexia</td><td>1 (3.4)</td><td>0 (0)</td></tr><tr><td>Paresthesia</td><td>1 (3.4)</td><td>0 (0)</td></tr><tr><td>Anorexia</td><td>1 (3.4)</td><td>0 (0)</td></tr><tr><td>SAE,n(%)</td><td>8 (3.7)</td><td></td></tr><tr><td>TRM-relationship, n(%)</td><td>Yes</td><td>No</td></tr><tr><td>All</td><td>0 (0)</td><td>8 (100)</td></tr><tr><td>Urosepsis</td><td>0 (0)</td><td>2 (25.0)</td></tr><tr><td>Prostatitis</td><td>0 (0)</td><td>3 (37.5)</td></tr><tr><td>Female sterilization</td><td>0 (0)</td><td>1 (12.5)</td></tr><tr><td>AMI</td><td>0 (0)</td><td>1 (12.5)</td></tr><tr><td>Prostatectomy</td><td>0 (0)</td><td>1 (12.5)</td></tr></tbody></table>

**Introduction:** Anti-CD20 monoclonal antibodies (mAbs) have shown promise infollicular lymphoma (FL) as post-induction therapy by enhancing antibody-dependent cellular cytotoxicity (ADCC). However, cytotoxic effector cells are reduced in FL patients receiving this treatment. We hypothesized that administration of ex vivoexpanded lymphokine-activated killer (LAK) cells to FL remission patients is safe and improves the efficacy of concomitantly administered anti-CD20 mAbs.

**Methods:** This is a multicenter open, prospective, phase II, single-arm study to assess safety and efficacy of ex vivoexpanded LAK cells in 20 FL remission patients following 24-months bimonthly rituximab maintenance therapy. Peripheral blood cells (PBC) were withdrawn in odd rituximab cycles to isolate mononuclear cells and stimulate them with interleukin-2 for 8 weeks, after which > 5 x 10⁸LAK cells were injected. Cell phenotypes were determined by flow cytometry, and cytotoxic activities of LAK cells were tested against appropriate targets. Patients were followed up for the subsequent 5 years.

<footnote n="1">¹Hematology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; ²Hematology, University Clinic Of Navarre, Pamplona, Spain; ³Hematology, Hospital San Pedro, Logroño, Spain; ⁴Pathology, Hospital Complex of Navarre, Limphoproliferative Group, Health Research Institute Navarre (IDISNA), Pamplona, Spain; ⁵Hematology, Instituto Aragonés de Ciencias de la Salud CIBERER, Zaragoza, Spain; ⁶Hematology, Hospital Complex of Navarre, Pamplona, Spain; ⁷Hematology, Hospital 12 De Octubre, Madrid, Spain; ⁸Hematology, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain;</footnote>

<footnote n="9">⁹Hematology, Hospital Miguel Servet, Zaragoza, Spain; ¹⁰Research support service, University Clinic of Navarre, Pamplona, Spain</footnote>
**FIGURE. Progression free survival.** The Kaplan-Meier estimation of progression free survival of patients during the period comprising 24-months maintenance with rituximab/LAK cells and a subsequent 59.4 (43.8-70.9)-months [median (IQR)] follow-up phase is shown.

<figure><img src="image_285.png" /></figure>

**Results:** At the end of maintenance, PBC phenotype had not changed markedly. *In vitro* NK, LAK and ADCC activities of isolated mononuclear cells increased significantly after rhIL-2 stimulation in all cycles, and ADCC activity was always significantly enhanced in the presence of rituximab. No patients discontinued treatment. There were no treatment-related serious adverse events (table). 3 patients had progressed by the end of follow up. After a median follow-up of 59.4 (interquartile range, 43.8 to 70.9) months, 85% of patients remained free of progression (figure). No deaths occurred. Quality-of-life seems to improve throughout the study.

**Conclusion:** Post-induction concomitant LAK cells and rituximab seem safe at long term. The observed efficacy warrants larger studies to confirm their usefulness in delaying FL disease progression.

**Keywords:** fine-needle aspirate (FNA); follicular lymphoma (FL).

NOVEL TREATMENTS

483
UMBRALISIB AND CARFILZOMIB
POTENTLY INHIBIT CAP DEPENDENT
TRANSLATION IN LYMPHOMA

I. Pal<fnref n="1" /> | A.G. Sardinha<fnref n="1" /> | L. Scotto<fnref n="1" /> | P.S. Mundi² |

O.A. O'Connor<fnref n="1" /> | C. Deng<fnref n="1" />

Medical Oncology, Columbia University Irving Medical Center, New York,
United States

**Introduction:** Umbralisib (TGR-1202) is an investigational drug developed to target the delta isoform of phosphoinositide 3-kinase (PI3Kδ), and is recently found by our group to inhibit casein kinase 1 epsilon (CK1ε)<fnref n="1" />. In the clinic, umbralisib demonstrates a clinical activity in indolent lymphoma that is comparable to idelalisib, the first-in-class PI3Kδ inhibitor; importantly, umbralisib appears to lack the frequent and troubling autoimmune toxicities associated with idelalisib, according to our recent publication². While combining idelalisib and lenalidomide has resulted in mortality, umbralisib and lenalidomide is reported to be well tolerated. These results suggest that umbralisib may be uniquely qualified as a safe partner for combination with various drugs to improve the outcome of DLBCL. Carfilzomib is a proteasome inhibitor approved for multiple myeloma. Interestingly, our previous results demonstrate that umbralisib and carfilzomib synergistically induce apoptosis in DLBCL cells, which is correlated with potent inhibition of phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), and downregulation of c-Myc dependent genes. The objective of this study is to further decipher the mechanism underlying the synergy of umbralisib and carfilzomib.

**Methods:** (1) Cell lines included those of DLBCL and mantle cell lymphoma (MCL). (2) Cell signaling in translational regulation. Western blot was performed to study the following signaling regulators of translation: 4E-BP1, p70S6K, RPS6, eIF4E, and eIF4B. (3) Assembly of eIF4F was studied using the 7-methyl GTP pulldown assay. (4) Polysome profiling. Mono- and poly-risobomes were isolated by ultracentrifugation of cell

<footnote n="1">¹Medicine / Center for Lymphoid Malignancies, Columbia University
Irving Medical Center, New York, United States; ²Medicine / Division of</footnote>
lysates a sucrose gradient, and detected by measuring OD260nm. (5) RNA-seq. The abundance of gene transcripts was determined by RNA sequencing, using the Illumina HiSeq 2500 platform. (6) Proteomic studies were performed using data independent analysis (DIA) Liquid chromatography-mass spectrometry (LC/MS). (7) Data analysis. Omics data were analyzed by gene set enrichment analysis (GSEA) and Virtual Inference of Protein-activity by Enriched Regulon (VIPER) analysis.

**Results:** Umbralisib and carfilzomib in combination, but not the single agents, inhibited phosphorylation of 4E-BP1 in DLBCL and MCL cells. The combination potently inhibited assembly of eIF4F, inhibited polysomes, and selectively downregulated target genes in the following signatures: c-Myc, E2F, G2M checkpoint, and DNA repair. More than 5,000 proteins were detected by LC/MS, and about 400 proteins were significantly decreased. The proteins downregulated were enriched with transcription factors and proteins involved in chromosome/DNA modification. These results suggest that umbralisib and carfilzomib synergistically inhibit cap dependent translation of tumor promoting genes, and represent a promising treatment for lymphoma.

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

**Disclosures:** Pal, I: Research Funding: *Research funding from TG Therapeutics and Amgen.*

484

POTENTIAL THERAPEUTIC ADVANTAGE
FOR DUVELISIB IN MANTLE CELL
LYMPHOMA: PI3Kδ AND OVEREXPRESSED
PI3Kγ IN LYMPHOMA CELLS HAVE
SPECIALIZED FUNCTIONAL ROLES

K.J. Till¹ | J. Gallardo Zapata¹ | T. Marks¹ |

D.T. Weaver² | J.A. Pachter² | M. Abdullah¹ |

N. Kalakonda¹ | A.R. Pettitt¹ | J.R. Slupsky¹

¹Molecular and Clinical Cancer Medicine, University of Liverpool,
Liverpool, United Kingdom; ²Medical Affairs, Verastem Oncology,
Needham, MA, United States

**Introduction:** Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma (NHL) that is aggressive and incurable with existing therapies, presenting a significant unmet clinical need. New treatment strategies that are based upon functional understanding of distinctive features associated with the malignant cells of this disease are required.

**Methods:** Tissue microarrays from B-cell NHLs were analysed by immunohistochemistry and RNAScope for the expression of PI3Kγ. The function of PI3Kγ in MCL was examined using MAVER-1 and JEKO-1 cells and in malignant lymphocytes from patients with MCL. We examined the effects of specific inhibitors of PI3Kα (A66), PI3Kγ (CZC24832), and PI3Kδ (idelalisib) and a dual PI3Kδ/γ inhibitor (duvelisib) on the migration and proliferation of MCL cells.

**Results:** We found that a distinctive feature of primary MCL cells is the elevated expression of PI3Kγ relative to that in other B-cell malignancies (Figure below). Our preliminary data provide compelling hints that high levels of PI3Kγ in MCL cells resident in tissues correlate with poor disease outcome. The functional role of PI3Kγ in MCL cells was differentiated from that of PI3Kδ: CZC24832 and duvelisib inhibited CCL21-induced migration of PI3Kγ-positive MAVER-1 and primary MCL cells but had no effect on PI3Kγ-negative JEKO-1 cells. Interestingly, duvelisib was more effective than CZC24832 in these assays, particularly with respect to migration of primary MCL cells. In contrast, specific inhibition of PI3Kδ with idelalisib did not affect CCL21-induced migration of the MCL cells used in this study, but did block BCR-induced signalling and its effects. These data suggest that when PI3Kγ is aberrantly expressed by MCL cells, these cells become reliant on this PI3K isoform for chemokine-induced migration and tissue residency. Thus, duvelisib may have a therapeutic advantage in

<figure><img src="image_286.png" /><figcaption>**Figure.** Comparison of PI3Kγ immunohistochemical staining scores (= staining intensity x proportion of positive cells) in SLL/CLL (n = 13), DLBCL (n = 15), FL (n = 10), MCL (n = 17), and MZL (n = 7).</figcaption></figure>
MCL by restricting entry and retention of malignant cells within the mantle zone. Further functional analysis showed that inhibition of PI3Kγ with duvelisib and CZC24836 inhibited proliferation of MAVER-1 but not JEKO-1 cells, whereas specific inhibition of PI3Kδ had no effect on cell division in either cell type.

**Conclusions:** These results suggest a functional role of PI3Kγ in MCL cells such that aberrant expression of PI3Kγ by the malignant cells of MCL rewires these cells to promote migration and proliferation. Considering the importance of chemokine- and BCR-induced signals in MCL pathobiology, duvelisib, as a dual inhibitor of PI3Kδ and PI3Kγ, may be particularly effective in the treatment of this disease. These data support clinical trials of duvelisib in patients with MCL.

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

**Disclosures:** Till, K: Research Funding: Verastem Inc. Weaver, D: Employment Leadership Position: Verastem Oncology; Consultant Advisory Role: FemtoDx, Nanogen Therapeutics; Stock Ownership: Verastem Oncology, FemtoDx, Nanogen Therapeutics. Pachter, J: Employment Leadership Position: Verastem Oncology; Stock Ownership: Verastem Oncology. Pettitt, A: Research Funding: Verastem Oncology, Celgene, Chugai, Gilead, GSK/Novartis, Roche; Other Remuneration: Celgene, Gilead. Slupsky, J: Research Funding: Verastem Oncology.

## 485
COMBINATION OF IRAK4 (CA-4948) AND BTK (VECABRUTINIB) INHIBITORS SHOW SUPERIOR EFFICACY IN PRECLINICAL MODELS OF ABC DLBCL TUMORS CONTAINING MYD88-L265P MUTATIONS

R.N. Booher<fnref n="1" /> | M. Borek<fnref n="1" /> | S. DellaRocca<fnref n="1" /> |

M.S. Samson<fnref n="1" /> | J.A. Fox<fnref n="2" /> | P. Taverna<fnref n="2" />

**Introduction:** NF-κB signaling is required for proliferation and survival of activated B cell-like diffuse large B cell lymphoma cells (ABC DLBCL). Alterations in the upstream toll-like receptor (TLR) and B-cell receptor (BCR) signaling pathways contribute to constitutive NF-κB activity. In particular, activating mutations in MYD88 in the TLR pathway and CD79A/B, TNFAIP3 and CARD11 in the BCR pathways are prevalent, and alterations in both TLR and BCR pathways co-occur frequently in ABC DLBCL tumors (Ngo et al 2011, Schmitz et al 2018, Chapuy et al 2018). Thus, a combination strategy whereby inhibiting key enzymes in both pathways may be required for effective drug treatment. Potential targets include the MYD88 proximal IRAK4 kinase in the TLR pathway and the well validated BTK kinase in the BCR pathway. We are developing an IRAK4 kinase inhibitor, CA-4948, as a therapeutic agent for cancers with dysregulated MYD88/ IRAK4 signaling. We previously demonstrated that CA-4948 exhibits

PD and antitumor activity in *in vitro* and *in vivo* models with MYD88 alterations. Vecabrutinib is a selective, reversible, noncovalent BTK inhibitor that has shown potent activity in vitro against both wild type and C481S-mutated BTK, the most common mutation associated with resistance to ibrutinib. In the present study, the efficacy of CA-4948 in combination with vecabrutinib was studied in *in vivo* preclinical ABC DLBCL tumor models.

**Methods:** Two human ABC DLBCL subcutaneous tumor xenograft models in immunodeficient mice were evaluated. OCI-Ly10 (ap-1) is an ABC DLBCL, MYD88-L265P, CD79A mutant cell line. LY0257 is an ABC DLBCL, MYD88-L265P, BCL6 translocation patient-derived xenograft (PDX) tumor (CrownBio). CA-4948 was dosed orally at 75 mg/kg BID and vecabrutinib was dosed orally at 50 mg/kg BID, either as single agent or in combination. The control group was dosed BID with the two respective drug vehicles. Efficacy was determined by measurement of tumor volumes and calculated as percent tumor growth inhibition (%TGI) relative to the vehicle control group.

**Results:** In both tumor models, significant superior efficacy was observed with CA-4948 plus vecabrutinib combination treatment compared to single agent alone treatment (p≤0.001). In the OCI-Ly10 (ap-1) model, CA-4948, vecabrutinib, and combination treatments showed 28%, 42%, and 97% TGI, respectively, after 21 days of treatment. The combination group had a 2% mean body weight loss. In the LY0275 model, CA-4948, vecabrutinib, and combination treatments showed 25%, 56%, and 85% TGI, respectively, with no body weight loss, after 19 days of treatment.

**Conclusion:** These results demonstrate that targeting both TLR/MYD88 and BCR signaling pathways may be an effective therapeutic strategy in ABC DLBCL. The combination of the IRAK4 inhibitor CA-4948 and vecabrutinib, a noncovalent BTK inhibitor, merits further investigation clinically in R/R NHL subtypes.

**Keywords:** BTK inhibitors; diffuse large B-cell lymphoma (DLBCL); MYD88.

**Disclosures:** Booher, R: Employment Leadership Position: Curis, Inc.; Stock Ownership: Curis, Inc. Borek, M: Employment Leadership Position: Curis, Inc.; Stock Ownership: Curis, Inc. DellaRocca, S: Employment Leadership Position: Curis, Inc.; Stock Ownership: Curis, Inc. Samson, M: Employment Leadership Position: Curis, Inc.; Stock Ownership: Curis, Inc. Fox, J: Employment Leadership Position: Sunesis Pharmaceuticals; Stock Ownership: Sunesis Pharmaceuticals. Taverna, P: Employment Leadership Position: Sunesis Pharmaceuticals; Stock Ownership: Sunesis Pharmaceuticals.

## 486
SIMULTANEOUS BET/CREBBP/EP300 TARGETING APPROACH COMPARED TO SINGLE BET OR CREBBP/EP300 INHIBITION IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

<footnote n="1">¹Translational Sciences, Curis, Inc., Lexington, MA, United States;</footnote>

<footnote n="2">²Translational Medicine, Sunesis Pharmaceuticals, South San Francisco, CA, United States</footnote>
F. Spriano¹ | E. Gaudio¹ | C. Tarantelli¹ |

G. Golino¹ | L. Cascione¹ | E. Zucca² | A. Stathis² |

F. Giles³ | F. Bertoni¹

¹Institute of Oncology Research, Università della Svizzera Italiana, Bellinzona, Switzerland; ²Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; ³Developmental Therapeutics Consortium, Chicago, United States

**Background:** Lymphoma cells have frequent deregulation of their epigenome. The Bromodomain (BRD) and Extra-Terminal domain (BET) proteins are key regulators of the transcription process. The acetyltransferases cyclic AMP response element binding protein (CREB)-binding protein (CBP) and the E1A interacting protein of 300 kDa (EP300) are highly homologous BRD-containing transcriptional co-activators and are often mutated in diffuse large B cell lymphoma (DLBCL). Targeting the individual classes of proteins is a new therapeutic approach, as shown especially by BET inhibitors with both preclinical and early clinical anti-lymphoma activity. NEO2734 and NEO1132 are novel oral dual inhibitors of BET and CREBBP/EP300 proteins. Here, we present data exploring their anti-tumor activity in DLBCL models.

**Methods:** Lymphoma cell lines were exposed to increasing doses of compounds for 72h. Cell proliferation was measured with the MTT assay.

**Results:** Twenty-seven DLBCL cell lines were exposed to NEO2734 and NEO1132. NEO2734 showed anti-tumor activity with a median IC50 of 157 nM (95% C.I., 135-214), while NEO1132 showed a lower activity compared, with a median IC50 of 400nM (95% C.I., 316-622). For both compounds, cell lines derived from activated B-cell-like (ABC) DLBCL (n.=8) were more sensitive than the ones derived from germinal center B-cell (GCB) DLBCL (n.=19) (P < 0.05). All the cell lines were also exposed to a BET inhibitor (birabresib, OTX015) and to a CREBBP/EP300 inhibitor (CBP30). The median IC50 values of the 2 molecules were 237 nM (95% C.I., 171-344) and 5.5 µM (95% C.I., 4.2-8.3 µM) respectively. The 4 compounds presented a similar pattern of anti-proliferative activity across all the cell lines (p < 0.001) (NEO2734 vs NEO1132, r = 0.99; NEO2734 vs birabresib: r = 0.97; NEO2734 vs CBP30, r = 0.87; birabresib vs CBP30, r = 0.85) but with different degrees of IC50. NEO2734 was more potent (P < 0.05) than birabresib, CBP30 and NEO1132. The higher activity of NEO2734 compared to NEO1132 could be explained by its superior potency in binding CREBBP and EP300. Cell cycle demonstrates that NEO2734 has a cytotoxic activity in 4 out of 5 cell lines tested (3 ABC and 2 GCB-DLBCL) and a slightly higher activity than birabresib in 2 cell lines. Transcriptome profiling on 2 GCB- and 2 ABC-DLBCLs treated for 6h with NEO2734 or birabresib highlighted a very similar effect of the two compounds (r= 0.90, P < 0.001), but also highlighted changes specifically induced by the dual inhibitor.

**Conclusions:** The novel dual BET and CREBBP/EP300 inhibitors NEO2734 and NEO1132 showed robust *in vitro* anti-tumor activity in DLBCL cell lines. Transcriptome changes and antiproliferative activity

demonstrated both some overlap between NEO2734 and birabresib but also distinct features of the dual inhibition approach.

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

**Disclosures:** Giles, F: Consultant Advisory Role: Neomed Therapeutics 1, Epigene Therapeutics Inc. Bertoni, F: Research Funding: Neomed Therapeutics.

## 487

# EG-011 IS A NOVEL SMALL MOLECULE WITH IN VITRO AND IN VIVO ANTI-TUMOR ACTIVITY AGAINST LYMPHOMA

E. Gaudio¹ | F. Spriano¹ | C. Tarantelli¹ |

M. Guala² | E. Riveiro³ | G. Golino⁴ | A. Lupia⁴ |

G. Costa⁴ | R. Rocca⁴ | L. Cascione¹ | S. Jenni⁵ |

Y. Tsai⁵ | B. Bornhauser⁵ | S. Alcaro⁴ |

F. Paduano⁴ | F. Trapasso⁴ | E. Zucca⁶ |

A. Stathis⁶ | N. Pazzi² | F. Cavalli⁶ | F. Bertoni¹

¹Università della Svizzera Italiana, Institute of Oncology Research, Bellinzona, Switzerland; ²Chimete, Tortona, Italy; ³Early Drug Development Group, ris, France; ⁴University "Magna Græcia" of Catanzaro, Catanzaro, Italy; ⁵Children's Hospital Zurich, Zurich, Switzerland; ⁶Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

**Introduction:** Despite the improvements, still too many patients die for their lymphomas and novel compounds are needed. We present a new small molecule, EG-011 (PCT/EP2018/057678), with *in vitro* and *in vivo* anti-cancer activity in lymphoma models.

**Methods:** Lymphoma and solid tumor cell lines were exposed to a large range of concentrations of EG-011 as single agent for 72h, followed by MTT proliferation assay and IC50 calculation. Cell viability of twelve acute lymphoblastic leukemia (ALL) primary patient cells from different high-risk subgroups (VNN2+, E2A-HLF, refractory T and IKZF plus) co-culture with marrow-derived MSCs were assayed after 72h of incubation with EG-011 and controls. Apoptosis assay was measured with annexin V by FACS. Xenografts were established s.c. into the left flanks of female NOD-SCID mice; treatment (200 mg/kg, i.p. 5 days per week) started with already established tumors. Combinations were evaluated with Chou-Talalay combination index (CI): synergism (<0.9), additive (0.9-1.1), antagonism/no benefit (> 1.1) after 72 hr treatments.

**Results:** EG-011 presented a median IC50 of 2.25 mM in 62 lymphoma cell lines (95% C.I. 1-5µM). A higher activity was observed in a group of 21 cell lines that had a median IC50 of 250 nM (95% C.I. 40-600 nM). Among these there were 11 germinal center B cell (GCB) diffuse large B cell lymphomas (DLBCL) (sensitive n=11/21, resistant n=9/41, P < 0.05), 4 mantle cell lymphoma (MCL) (sensitive n=4/21, resistant n=6/41, P n.s.), 3 marginal zone lymphoma (sensitive n=3/21, resistant n=2/41, P n.s.). EG-011 did not show any anti-
proliferative activity in a panel of 25 solid tumor cell lines (IC50s > 10 µM). Among 12 primary ALL samples, 7 were sensitive to EG-011 with IC50 values between 0.3-4.6 µM after 72h, 5 displayed IC50 higher than 20 µM. A dose-dependent increase in cell death (20-55%) was observed in lymphoma cell lines (OCI-LY-19 and REC1) (500 nM and 2 µM; 72h). No cytotoxicity was seen in PBMCs from two healthy donors after treatment at 1 and 10 mM for 24h and 48h. In an in vivo xenograft experiment with the MCL REC-1 cell line, EG-011 delayed tumor growth (Day 6, Day 7, Day 9, P < 0.05) and tumor weight. EG-011-treated tumors were 2.2-fold smaller than controls (P < 0.001). Combinations were tested in DLBCL (OCI-LY-1, OCI-LY-8, TMD8) and MCL (REC1, MINO). EG-011 was synergistic with rituximab, bendamustine, venetoclax, ibrutinib and lenalidomide in all tested cell lines.

**Conclusion:** The selective anti-lymphoma activity, in both *in vitro* and *in vivo* models, and the observed *in vitro* synergisms with FDA approved targeted agents make EG-011 a novel intriguing new drug candidate deserving further preclinical studies.

**Keywords:** B-cell lymphoma.

**Disclosures:** Gaudio, E: Research Funding: from the Foundation IOR for the development of EG-011 (PCT/EP2018/057678). Bertoni, F: Research Funding: from the Foundation IOR for the development of EG-011 (PCT/EP2018/057678).

## 488
THE PHOTOSENSITIZER VERTEPORFIN EXERTED ANTI-TUMOR EFFECT IN DIFFUSE LARGE B-CELL LYMPHOMA VIA DISRUPTING YAP-TEAD COMPLEX

X. Zhou | X. Fang | N. Chen | K. Lu | X. Lv |

X. Wang

Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China

**Introduction:** Hippo-YAP signaling, an evolutionarily conserved growth control pathway, has emerged as a crucial player in the development of human malignancies. However, the function of Hippo-YAP signaling in diffuse large B-cell lymphoma (DLBCL) is still unclear. The aim of this study is to characterize the biological function of Hippo-YAP signaling and the therapeutic value of Verteporfin (VP, one of porphyrin family members) is in DLBCL.

**Methods:** Expression levels of YAP in DLBCL were determined in public database and clinical specimens. The biological function and related mechanisms of Hippo-YAP signaling cascade were evaluated by RNAi-mediated knockdown, CRISPR/Cas9 genomic deletion, and small molecular inhibitor Verteporfin both in vitro and in vivo.

**Results:** We first examined the expression of YAP in ONCOMINE database and discovered the upregulation of YAP mRNA in lymphoma. We further validated the elevated protein expression level of YAP in a cohort of newly diagnosed DLBCL patients (n=60). Survival

analysis revealed that higher expression of YAP associated with more aggressive disease process (p=0.014). Functional enrichment analyses of YAP in DLBCL microarray profiles revealed that YAP was enriched in cellular process, biological regulation and pathways in cancer. Knockdown of YAP (shYAP) significantly suppressed cell proliferation and promoted cell cycle arrest in G0/G1 phase. To further validate the involvement of YAP in DLBCL pathogenesis, we deleted YAP expression by CRISPR/Cas9 genomic-editing system. DLBCL cells with stable YAP knockout (sgYAP) revealed significantly reduction in cell proliferative ability. Moreover, YAP deletion resulted in cell cycle arrest in G0/G1 phase.

The function and mechanism of VP in DLBCL were investigated. Incubation of VP decreased proliferation of DLBCL cells in a dose- and time-dependent manner. Treatment of VP significantly promoted cell apoptosis and cell cycle arrest in DLBCL cells compared to the untreated cells. We next validated the involved mechanism of the anti-tumor effect of VP in DLBCL cells. Protein expression levels of YAP and TEAD were significantly inhibited by VP in dose-dependent manner. In addition, we discovered that treatment of VP strongly restrained the mRNA expression of YAP targeted genes, including CTGF, CYR61 and NF2. To explore the biological function of YAP inhibition in vivo, mouse xenograft lymphoma model was established by LY1 cells with YAP-deletion. Compared to the control group, tumors with YAP-deletion displayed reduced growth and Ki-67 staining.

**Conclusions:** These findings highlight the critical role of YAP in the pathogenesis of DLBCL and suggest that targeting YAP may of therapeutic value. The clinical used photosensitizer Verteporfin exerted anti-tumor effect via disrupting YAP-TEAD complex, which may serve as a potential treatment option for novel therapeutic interventions in DLBCL.

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

## 489
STEM CELLS IN ACUTE LYMPHOBLASTIC LEUKEMIA AND IN-VITRO ASSESSMENT OF THE EFFECT OF PARTHENOLIDE

H. Alsulami

Clinical Lab., AGU, Manamah, Bahrain

**Introduction:** Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, representing around one-third of all childhood malignancies. In Saudi Arabia ALL accounts for around 35% of all childhood cancers. Despite a high cure rate, some cases relapse. Current drug efficacy studies focus on reducing leukemia cell burden. However, if drugs have limited effects on LSCs, these cells may expand and eventually cause relapse. The experimental anti-leukemic drug parthenolide (PTL) acts by inhibiting transcription factor nuclear kappa B (NFκB), activating p53 and increasing reactive oxygen species (ROS) in leukemic cells. In the present study we assessed the in vitro
effect of PTL on immuno-phenotypically defined leukemic stem cells (LSCs) and normal hematopoietic stem cells (HSCs). Because NFκB is constitutively active in LSC, and PTL is a potent inhibitor for it, we also investigated the expression of activated NFκB (NFκBp65) in selected samples.

**Method:** Forty ALL samples and 24 normal bone marrow and cord blood samples were included in this study after obtaining informed consent. The mononuclear cells from ALL and normal samples were isolated using density gradient separation. ALL samples were sorted into 4 LSC populations (CD34+CD38-CD19+, CD34+CD38+CD19+, CD34+CD38-CD19-, and CD34-CD38-CD19-). Unsorted and sorted cells were cultured with different PTL concentrations for 24, 48 and 72 hours. Post-culture cell viability was assessed using 7ADD in a flow cytometry-based test. Normal unsorted marrow and cord blood samples were tested under similar conditions. In addition, colony forming unit assay (CFU) was carried out with normal samples to assess the effect of PTL on HSCs. In selected ALL and normal samples the expression of NFκB was assessed using PE labeled anti-NFκB p65 antibody.

**Results:** In ALL, LSCs form heterogeneous compartments with different percentages of the four LSC populations. This heterogeneity extended across and within cytogenetically classified groups of cases. There was no significant effect of PTL on the viability of normal cells at concentrations of ≤ 50µM; but at 25 µM and 10 µM after 24 and 72 hours respectively it affected the ability of HSCs to form colonies. For ALL-LSCs PTL was significantly toxic at 10 µM and most cases, with the exception of those with +3 karyotype abnormality and CD34-CD38- CD19- LSCs with t(9;22), showed >50% cell-death at 25µM PTL concentration. The CD34+, CD38+, CD19+ LSCs showed significantly higher sensitivity compared to other sub-populations. ALL cases with limited response to PTL expressed significantly higher levels of pNFκB p65 as compared to PTL-sensitive cases.

**Conclusion:** The study concluded that LSCs are heterogeneous within and between cytogenetically classified groups of ALL. Overall, CD34+ CD38- CD19+ and CD34+ CD38- CD19 cells are the predominant LSC populations in B-ALL. PTL has a differential effect on normal HSCs versus ALL cells at lower concentrations in vitro; cord blood HSCs are more resistant than marrow cells. PTL also has a differential effect on LSC subpopulations. PTL sensitivity/resistance in ALL is related to the level of activated NFκB expression in these cells.

**Keywords:** apoptosis; NF-kB.

490

IH2 INHIBITION ENHANCES PROTEASOME INHIBITOR RESPONSIVENESS IN HEMATOLOGICAL MALIGNANCIES

R. Piva¹ | E. Bergaggio¹ | C. Riganti² | N. Vitale¹ |

G. Garaffo¹ | E. Mereu¹ | C. Bandini³ |

E. Pellegrino¹ | V. Pullano¹ | M. Labrador¹ |

F. Bertoni⁴ | S. Deaglio⁵ | A. Neri⁶ | A. Palumbo¹

¹Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; ²Department of Oncology, University of Torino, Torino, Italy; ³Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; ⁴Institute of Oncology Research, Università della Svizzera Italiana, Bellinzona, Switzerland; ⁵Department of Medical Sciences, University of Torino, Torino, Italy; ⁶Hematology Unit, Fondazione Cà Granda IRCCS, Ospedale Maggiore Policlinico di Milano, Milano, Italy

The ubiquitin-proteasome pathway plays a crucial role in protein processing and degradation, and it regulates critical cellular functions. Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma (MM) and mantle-cell lymphoma (MCL). However, patients continuously relapse or are intrinsically resistant to this class of drugs. We have previously identified isocitrate dehydrogenase 2 (IDH2) as a synthetic lethal target that synergizes with the PI carfilzomib (CFZ). Here, we demonstrate that combinations of FDA approved PIs with a pharmacological IDH2 inhibitor (AGI-6780) trigger synergistic cytotoxicity in MM, MCL, Burkitt's lymphoma, and diffuse large B-cell lymphoma cell lines. CFZ/AGI-6780 treatment increases death of primary CD138+ cells from MM patients and exhibits a favorable cytotoxicity profile towards peripheral blood mononuclear cells and bone marrow-derived stromal cells. Mechanistically, CFZ/AGI-6780 combination significantly decreases tricarboxylic acid (TCA) cycle activity and ATP levels, as a consequence of enhanced IDH2 enzymatic inhibition. Specifically, CFZ treatment reduces the expression of nicotinamide phosphoribosyltransferase (NAMPT), thus limiting IDH2 activation through the NAD+-dependent deacetylase SIRT3. Consistently, combinations of CFZ with either NAMPT or SIRT3 inhibitors impair IDH2 activity and increase MM cell death. Finally, we demonstrate that inducible IDH2 knockdown enhances the therapeutic efficacy of CFZ in subcutaneous and systemic xenograft models of MM, resulting in inhibition of tumor progression, bone marrow disease, and extended survival. Taken together, these findings indicate that NAMPT/SIRT3/IDH2 pathway inhibition enhances the therapeutic efficacy of PIs, thus providing compelling evidence for treatments with lower and less toxic doses and broadening the application of PIs to other malignancies. Our preclinical studies, therefore, provide the rationale for the development of novel IDH2 inhibitors directed against wild-type IDH2.

**Keywords:** B-cell lymphoma; multiple myeloma (MM); proteasome.

491

PRE-CLINICAL ANTI-TUMOR ACTIVITY OF A RAPIDLY-SYNTHESIZED MONOCLONAL ANTIBODY TARGETING B-CELL RECEPTOR POSITIVE LYMPHOMA

C.F. Santos | I. Chen | D.J. States | I. Darwech |

A. McCord

Research and Development, Affigen, LLC, Austin, United States
<figure><img src="image_287.png" /></figure>

**Background:** The B-cell receptor (BCR) idiotype represents an attractive immunotherapy target for many non-Hodgkin B cell lymphomas (NHL). The BCR expressed on cancerous cells is unique and clonal, and drives tumor proliferation and survival via its downstream signaling pathways. Here, we report the rapid discovery and characterization of an anti-idiotype (anti-id) monoclonal antibody that demonstrates *in vitro* cell killing and tumor growth inhibition in a xenograft model of NHL.

**Methods:** We sequenced the BCRs from the human B cell malignancy-derived cell lines SUPB8, Raji, Ramos, Mec1, DOHH2 and NALM6, and expressed their respective idiotype for screening using a high-diversity phage display library containing stability- and manufacturability-optimized collection of human donor-derived scFvs. scFv candidates with high binding affinity and predicted manufacturability were reformatted into human IgG1s and characterized for binding affinity, target selectivity, *in vitro* tumor killing, and *in vivo* tumor growth inhibition.

**Results:** For each of the cell lines, 4 rounds of panning against recombinant BCR idiotype baits consistently yielded hundreds of scFv binders with low nM to low µM binding affinity in under a week. We further characterized 298 high-affinity anti-SUPB8 scFv clones. By flow cytometry, 63 unique scFv clones achieved specific to non-specific labeling ratio (SUBB8:PBMC lymphocyte/monocyte) of >10-fold (expected ratio = 1), with 3 clones achieving selectivity ratio of >40-fold. Reformatted improved affinity and avidity and directly produced IgG1 candidates with single-digit nanomolar binding affinity. We observed diminished viability in cultured SUPB8 cells co-incubated with anti-SUPB8 IgG1 clone R7C5 (affinity = 19nM; selectivity ratio = 87.2) as early as 24 hours after antibody addition. In CB17-scid mice inoculated with 2e6 SUPB8 GFP+/Luc+ cells (i.v.) on day 0, treatment with R7C5 (50µg/mouse/day i.p. from day 6 to 13; n=8/treatment) achieved tumor burden reduction on par or superior in effectiveness to treatment with anti-IgM antibody or rituximab by day 36 (Figure). Finally, R7C5 showed no appreciable off-target
binding activity when tested against all 5,300 proteins in the human surfaceome.

**Conclusion:** Our proof-of-concept study demonstrates that, using a pre-optimized high-diversity library, anti-id antibodies highly selective for malignant B cells can be obtained in weeks, thus making feasible a truly personalized antibody therapeutic that can be manufactured on demand and delivered in approximately 60 days, with substantial acceleration possible. By sparing healthy B cells from undesired pharmacological effect, anti-id therapy may offer meaningful safety and efficacy improvements over existing treatment options.

**Keywords:** B-cell lymphoma; B-cell receptor (BCR); monoclonal antibodies (MoAb).

**Disclosures:** Santos, C: Employment Leadership Position: Yes; Stock Ownership: Yes.

then expanded ex vivo to produce WZTL-002, third-generation anti-CD19 CAR T-cells incorporating CD28 and TLR2 co-stimulatory domains.

**Results:** Cytotoxicity of WZTL-002 was assessed *in vitro*. WZTL-002 generated from healthy donors demonstrated potent cytotoxicity against CD19⁺, but not against CD19⁻, K562 target cells. Both an inhibitor of TLR2 dimerisation, ortho-vanillin, and a peptide inhibitor of MYD88 dimerisation, but not their respective control compounds, led to reduced activity of WZTL-002 in the presence of CD19⁺ target cells, consistent with co-stimulatory activity of the TLR2 domain.

**Conclusion:** Our findings support the utility of the TLR2 TIR co-stimulatory domain within WZTL-002, a new third generation CAR. A phase I Trial of WZTL-002 for the treatment of r/r B-NHL is planned.

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

## 492
### THIRD GENERATION CAR T-CELL THERAPY UTILISING TOLL LIKE RECEPTOR 2 CO-STIMULATION

P. George<fnref n="1" /> | B. Mester<fnref n="1" /> | N. Dasyam<fnref n="1" /> | G. Giunti<fnref n="1" /> | Q. Le² | I. Hermans<fnref n="1" /> | P. Li² | R. Weinkove<fnref n="1" />

**Introduction:** Licensed second-generation Chimeric Antigen Receptor (CAR) T-cells directed against CD19 have produced excellent response rates in relapsed or refractory (r/r) B-cell non-Hodgkin Lymphomas (B-NHL), but fewer than 50% of patients remain progression free of disease 12 months after therapy, presenting a need for CAR T-cell therapies exhibiting improved long-term responses.

Human T-cells expressing a third-generation anti-CD19 CAR incorporating a Toll Like Receptor 2 (TLR2) Toll/interleukin-1 receptor (TIR) co-stimulatory domain alongside CD28 exhibit improved cytotoxicity against CD19⁺ target cells both *in vitro* and in xenograft models *in vivo*, compared to second-generation CAR T-cells using the CD28 co-stimulatory domain alone in work carried out in Guangzhou, China. Furthermore, activity against solid CD19⁺ B-cell tumours in xenograft models and efficacy observed in patients with extramedullary B-cell Acute Lymphoblastic Leukaemia (B-ALL) in preliminary results from a Phase 1 Clinical Trial, provides rationale to assess the role of this co-stimulatory domain in B-NHL.

**Methods:** A self-inactivating, third generation lentiviral (LV) vector encoding a third-generation CAR incorporating the TLR2 TIR alongside CD28 and CD3ζ was manufactured in GMP laboratories at the Malaghan Institute of Medical Research under license from Wellington Zhaotai Therapies Ltd (WZTL). Peripheral blood leukocytes were obtained by leukapheresis, and T-cells immunomagnetically enriched and stimulated. Purified T-cells were transduced using the LV vector,

## 493
### SAFETY AND CLINICAL ACTIVITY OF ATEZOLIZUMAB IN COMBINATION WITH TAZEMETOSTAT IN RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA: PRIMARY ANALYSIS OF A PHASE 1B STUDY

M.L. Palomba<fnref n="1" /> | G. Cartron² | L. Popplewell³ | V. Ribrag⁴ | J. Westin⁵ | S. Chitra⁶ | L. Huw⁷ | K. Newberry⁸ | A. Raval⁷ | J. Xu⁶ | F. Morschhauser⁹

**Introduction:** Despite recent treatment advances, patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Here we present the primary analysis of GO29383 (NCT02220842), a phase 1b study evaluating atezolizumab (atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, plus tazemetostat, an EZH2 inhibitor, in pts with R/R DLBCL.

**Methods:** Eligible pts had CD20+ R/R DLBCL, with ≥2 measurable nodal lesions >1.5 cm and ≥2 prior lines of therapy. Primary endpoints were safety and tolerability. Pts received tazemetostat (800 mg bid) on days (D) 1-21 and atezo (1200 mg IV) on D1 of each 21-day cycle until unacceptable toxicity or disease progression (PD) occurred. Tumour response was assessed by PET-CT or CT (Lugano 2014

<footnote n="1">¹Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand; ²Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Guangzhou, China</footnote>

<footnote n="1">¹Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States; ²Department of Clinical Hematology, CHU Montpellier, Montpellier, France; ³Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA, United States; ⁴DITEP, Gustave Roussy Cancer Campus, Villejuif, France; ⁵Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX, United States; ⁶Product Development Oncology, Genentech, Inc., South San Francisco, CA, United States; ⁷Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, United States; ⁸Clinical Development, Epizyme, Cambridge, MA, United States; ⁹Institute of Hematology - Transfusion, Centre Hospitalier Régional Universitaire de Lille, Lille, France</footnote>
<figure><img src="image_288.png" /><figcaption>Figure 1. Tumour burden over time (days) by change in SPD from baseline (%)</figcaption></figure>

criteria). PD-L1 (SP263), FOXP3 and CD8+ expression were studied by immunohistochemistry; EZH2 gene mutation was analysed using the FoundationOne Heme platform. T-effector signature was studied using RNAseq.

**Results:** At the data cut-off (28 Aug 2018), 43 pts had enrolled. Median age was 62 years (range 26–86), 32 (74%) pts were male and 40 (93%) had an ECOG status of 0–1. The majority (81%) were refractory to their last treatment (refractory to anti-CD20 therapy, 44%). All enrolled pts received ≥1 dose of study drug; at the data cut-off, 19 (44%) had discontinued study treatment (death, n=17; withdrawal by subject, n=2). Median duration of treatment was 1.4 months (atezo) and 2.1 months (tazemetostat). Forty-one (95%) pts experienced ≥1 adverse event (AE); the most common treatment-emergent AEs were anaemia (26%) and fatigue (23%). Grade ≥3 AEs were experienced by 20 (47%) pts and 15 (35%) had a serious AE (most common: anaemia [12%], neutropenia [9%], thrombocytopenia [9%]). AEs leading to discontinuation of either study drug occurred in 6 (14%) pts (atezo, n=3; tazemetostat, n=3). Two grade 5 AEs occurred: sepsis, deemed unrelated to treatment; and hyponatraemia, related to both study treatments. Tumour burden is described in **Figure 1**. Median progression-free survival was 1.9 months (95% CI 1.8, 2.8). Best

overall response rate was 16% (complete response [CR], n=2 [5%]; partial response [PR], n=5 [12%]). Eight (19%) pts had stable disease; 19 (44%) had PD. EZH2 mutation was identified in 5/29 (17%) pts (3 pts with a Y646N or Y680L mutation achieved a response [CR, n=1; PR, n=2]; in the remaining 2 pts [Y646N and Y646C mutation], PD occurred before clinical assessment). Correlation between response or tumour shrinkage and T-effector signature as well as baseline PD-L1, FOXP3 and CD8+ expression will be presented.

**Conclusions:** The safety profile of atezo in combination with tazemetostat was tolerable and no new safety signals were identified. Three pts with EZH2 mutation showed response; however, the combination did not demonstrate promising efficacy in pts with R/R DLBCL and no further studies with this combination are planned.

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

**Keywords:** diffuse large B-cell lymphoma (DLBCL); EZH2; tazemetostat.

**Disclosures:** Palomba, M: Consultant Advisory Role: Merck, Pharmacyclics; Stock Ownership: Seres; Honoraria: Flagship Ventures,
Novartis, Evelo, Seres, Jazz Pharmaceuticals, Therakos, Amgen, Merck; Other Remuneration: Seres, Juno. Cartron, G: Consultant Advisory Role: Celgene, Roche; Honoraria: Roche, Jansen, Gilead, Sanofi. Popplewell, L: Consultant Advisory Role: Roche; Honoraria: Pfizer, Spectrum. Ribrag, V: Employment Leadership Position: Abbvie, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Eli Lilly, Exelixis, Forma, Gamamabs, Genentech, Inc., Glaxosmithkline, H3 Biomedicine, Inc, Hoffmann La Roche Ag, Innate Pharma, Iris Servier, Janssen Cilag, Kyowa Kirin Pharm. Dev., Inc., Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Milennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre, Roche, Sanofi Aventis, Taiho Pharma, Tesaro, Inc, Xencor; Consultant Advisory Role: Epizyme, Servier, Nanostring, Gilead, Pharmamar, BMS, MSD, Incyte, Roche, Infinity; Research Funding: Epizyme, ArgenX, Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Other Remuneration: Non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. Westin, J: Consultant Advisory Role: Kite, Novartis, Juno, Celgene Genentech, Jansson; Research Funding: Kite, Novartis, Juno, Celgeve, Genentech, Janssen. Chitra, S: Employment Leadership Position: Genentech, Inc. Huw, L: Employment Leadership Position: Roche. Newberry, K: Employment Leadership Position: Roche; Stock Ownership: Roche. Xu, J: Employment Leadership Position: Genentech, Inc., Roche; Stock Ownership: Roche. Morschhauser, F: Consultant Advisory Role: Gilead; Honoraria: Celgene, Roche, Janssen, Bristol-Myers Squibb, Servier and Epizyme.

## 494
A PHASE IIA STUDY EVALUATING THE SAFETY AND TOLERABILITY OF UMBRALISIB AND IBRUTINIB IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA

M. Lunning | P. Bierman | R. Bociek | J. Armitage |

P. Heires | S. Blumel | M. Hohenstein | L. Lyden |

J. Vose

Hematology/Oncology, University of Nebraska Medical Center, Omaha, United States

**Introduction:** Relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) remains an unmet medical need. Umbralisib (UMB) a dual PI3K delta/CK-1ε inhibitor and Ibrutinib (IBR) a Bruton's Tyrosine kinase (BTK) inhibitor have activity in DLBCL. Pre-clinical data

demonstrated synergistic activity of UMB-IBR against DLBCL cell lines. We report the complete results of a phase IIa study.

**Methods:** Eligible patients (pts) had rel/ref DLBCL with adequate hematologic and organ function. UMB was dosed at 800 mg daily in AM and IBR 560 mg daily in PM. Treatment stratification was performed on a 1:1:1 design to Cohort A (UMB), B (IBR), or C (UMB +IBR). In cohorts A/B the combination was initiated at day 8. A cycle was 28 days. The primary endpoint was monitoring for cumulative toxicity events (CTEs) occurring during cycles 1-4. Stopping rules for CTEs and efficacy were employed. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, progression-free survival (PFS), time to response (TTR), and duration of response (DOR).

**Results:** 13 pts with rel/ref DLBCL were enrolled. Median age was 71 years (range 27-81) and 9 were male. Median number of prior therapies was 2 [range 1-7]. 62% were refractory to last therapy. DLBCL subtypes were GCB in 7 and non-GCB in 6 pts. Cohorts A (n=1) and B (n=1) included pts that consented to optional biopsies. Cohort C (n=11) included the first 3 pts enrolled into the study and those thereafter that did not consent to optional biopsies. Two CTEs were seen: G3 rash and G3 C. diff diarrhea. No CTEs occurred during cycle 1. Notable serious or recurrent adverse events (SAEs or AEs) of interest occurring across all cycles regardless of attribution included elevated AST/ALT 0% G 3-4 (all G 31%), nausea 15% G 3-4 (all G 54%), and diarrhea 15% G 3-4 (all G 31%). One patient in CR was taken off study in recurrent C. diff infection despite dose reductions. The ORR of the UBR-IBR regimen was 31% with 3 PRs and 1 CR. The median PFS was 3 months [95 % CI 0.85, 3.4].

**Conclusion:** UMB-IBR was well tolerated with only 2 CTEs and limited AEs. The evaluation of CTEs was limited by the PD in many pts seen prior to 4 cycles of therapy. The ORR of the UMB-IBR was 31% surpassing the pre-planned efficacy stopping rule. However given the limited durability in responding patients and difficulty in obtaining biopsies for planned correlative analyses, this study was closed.

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

**Disclosures:** Lunning, M: Consultant Advisory Role: AbbVie, Bayer, Celgene, DAVA, Gilead Sciences, Inc Janssen, Juno Therapeutics, Kite, Novartis, OncLive, Portola, Seattle Genetics, Spectrum, TG Therapeutics, VANIUM, Verastem; Research Funding: Celgene, Curis, Janssen Scientific Affairs, LLC Juno Therapeutics, MiRagen, TG Therapeutics. Vose, J: Honoraria: Epizyme; Roche; Novartis; Legend; Abbvie; Research Funding: Novartis; Celgene; Incyte; Bristol Myers Squibb; Seattle Genetics; Acerta Pharma; Kite Pharma; Merck.

## 495
PHASE 1/2 TRIAL OF ANTI-PD-LIGAND 1 (DURVALUMAB) +/- LENALIDOMIDE IN PATIENTS WITH CUTANEOUS T CELL LYMPHOMA: PRELIMINARY RESULTS OF PHASE 1 AND CORRELATIVE STUDIES
C. Querfeld<fnref n="1" /> | J. Zain² | T. Jovanovic-Talisman<fnref n="3" /> |

D.L. Wakefield<fnref n="3" /> | S. Kil⁴ | R. Estephan⁴ |

P. Young⁴ | J. Sanchez⁴ | X. Martinez⁵ | T. Stiller⁶ |

J. Palmer⁶ | S.T. Rosen²

**Background:** T cells in CTCL are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, targeting exhausted T cells and distinct cells within their environment. Lenalidomide, an oral IMiD and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses.

**Methods:** A Phase 1 portion is ongoing to evaluate the safety and tolerability of the durvalumab and lenalidomide combination. Pts are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (cohort 1 = 10 mg; cohort 2 = 15 mg; cohort 3 = 20 mg) to characterize safety, efficacy and antitumor activity. Serial skin and blood samples were collected to assess the impact on the tumor microenvironment using single molecule super-resolution microscopy and multiplex imaging.

**Results:** Nine pts (7 males/2 females, age 29-59 y) with refractory/advanced CTCL, clinical stages IB (1), IIA (3), IIB (3), IIIA (1), and aggressive epidermotropic CD8+ CTCL (1) have been enrolled. Duration time on treatment was 3 to 18+ months. Seven pts showed improvement of skin disease, with 2 pts achieving PR plus >90% improvement of skin disease by mSWAT. Three pts developed PD. No DLTs or serious AEs were observed. The most frequently reported AEs were fatigue (n=6), skin pain (n=4), chills (n=4), anemia (n=3), and leukopenia (3). All treatment-related AEs were Grade 1/ 2 in severity. One grade 3 rash occurred in one patient. Using multispectral microscopy, we analyzed expression panels of several checkpoints (PD1, PD-L1 & ICOS) on baseline skin bx. Detectable levels of PD-L1 but low levels of ICOS are observed in responding pts vs. high PD-L1 and ICOS levels in non-responders. Quantitative super-resolution microscopy detected nanoscale clusters of PD1 in T cells from responders vs. no clustering in non-responders.

**Conclusions:** Durvalumab/lenalidomide has significant clinical activity in refractory/advanced CTCL, which will be formally evaluated in the

Phase 2 portion. Responses were durable and ongoing, and treatment was well tolerated. Dose escalation is up to lenalidomide 20 mg daily. Our preliminary results from pts on trial demonstrated that immune signatures on skin biopsies at baseline may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance.

**Keywords:** cutaneous T-cell lymphoma (CTCL); immunomodulators (IMIDs); PD-1L.

**Disclosures:** Querfeld, C: Consultant Advisory Role: MiRagen, Medivir, Bioniz, Actelion, Kyowa Kirin; Research Funding: Celgene. Rosen, S: Consultant Advisory Role: Novartis Pharmaceuticals Corp; Pepromene Bio, Inc; Exicure; Apobiologix/Apotex Inc, Seattle Genetics; NeoGenomics; Aileron Therapeutics, Inc; Honoraria: Celgene; Global Education Group and Paradigm.

496

PHASE 1/2A CLINICAL TRIALS OF BI-1206, A MONOCLONAL ANTIBODY TO FCγRIIB, ADMINISTERED AS A SINGLE AGENT OR IN COMBINATION WITH RITUXIMAB IN SUBJECTS WITH B-CELL MALIGNANCIES

I. Karlsson<fnref n="1" /> | S. Traub² | K. Järäs<fnref n="3" /> | D. Edwards² |

E. Gramming<fnref n="3" /> | M. Lindell Andersson<fnref n="3" /> | Y. To² |

L. Mårtensson<fnref n="1" /> | I. Teige<fnref n="1" /> | G. Acton² | M.J. Dyer⁴ |

J. Radford⁵ | G.P. Collins⁶ | M. Jerkeman<fnref n="7" /> |

B. Frendéus<fnref n="1" /> | A. McAllister<fnref n="3" /> | A. Davies<fnref n="8" />

**Introduction:** BI-1206 is a fully-human anti-FcγRIIB antagonistic antibody that is thought to work by enhancing the activity and overcoming resistance to anti-CD20 antibody treatments (Roghanian et al., 2015).

**Methods:** BI-1206 is currently being tested in two parallel Phase 1/2a clinical trials CRUKD/16/001 and 17-BI-1206-02, in the UK and the US/EU respectively.

CRUKD/16/001 includes patients with FcγRIIB-positive B cell malignancy. The phase 1 comprises a dose escalation to determine the maximum tolerated dose or maximum administered dose, and recommended phase 2 dose (RP2D) of BI-1206, in two parallel arms: 1) BI-1206 administered as a single agent. 2) BI-1206 administered in combination with rituximab (not open to recruitment yet). The phase 2a is an expansion phase using the RP2D from each arm.

<footnote n="1">¹Div. of Dermatology and Beckman Research Institute, City of Hope, Duarte, United States; ²Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, United States; ³Molecular Medicine, City of Hope, Duarte, United States; ⁴Beckman Research Institute, City of Hope, Duarte, United States; ⁵Div. of Dermatology, City of Hope, Duarte, United States; ⁶Biostatistics, City of Hope, Duarte, United States</footnote>

<footnote n="1">¹Preclinical Research, BioInvent International AB, Lund, Sweden; ²Centre for Drug Development, Cancer Research UK, London, United Kingdom;</footnote>

<footnote n="3">³Clinical Development, BioInvent International AB, Lund, Sweden; ⁴Ernest and Helen Scott Haematological Research Institute, University of</footnote>

<footnote>Leicester, Leicester, United Kingdom; ⁵Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom; ⁶Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford, United Kingdom;</footnote>

<footnote n="7">⁷Department of Oncology, Skane University Hospital, Lund, Sweden;</footnote>

<footnote n="8">⁸University of Southampton, Cancer Research UK Centre, Southampton, United Kingdom</footnote>
17-BI-1206-02 includes the indolent B-cell non-Hodgkin lymphoma (NHL) forms of follicular lymphoma, marginal zone lymphoma, and mantle cell lymphoma (MCL) and evaluates the safety and tolerability of BI-1206 in combination with rituximab. Phase 1 is a dose escalation for selection of the RP2D. Phase 2a is an expansion cohort at the RP2D.

In both trials, subjects in each phase receive one cycle of induction therapy. BI-1206 and rituximab (375 mg/m²) are administered as intravenous infusions once weekly for a period of 4 weeks.

Subjects who show clinical benefit are eligible to continue onto maintenance therapy (Q8W).

The pharmacokinetic (PK) is assessed by measuring the blood serum concentrations of BI-1206 and rituximab. Pharmacodynamic analysis (PD) includes B cell depletion, FcγRIIB expression and BI-1206 receptor occupancy (RO).

**Results:** In CRUKD/16/001 twelve patients have received BI-1206 single agent therapy with up to 4 weekly doses of 100 mg. In 17-BI-1206-02, five patients have received up to 4 weekly doses of 100 mg BI-1206 in combination with rituximab.

PK/PD analysis is available for patients administered with BI-1206 in the dose range 0.4-100 mg. The PK parameters were calculated by non-compartmental analysis. The Cmax and exposure increased with the dose. A one-compartment elimination profile of BI-1206 could be observed. RO is dose proportionate and anticipated to yield high levels of receptor blockade at clinically relevant doses of BI-1206. Decrease in clearance and supra-proportional increase in exposure indicates that target-mediated drug disposition did not seem to be overcome yet. Interestingly, PD analysis showed a loss of peripheral B cells, including circulating MCL cells during the initial week of induction therapy of BI-1206 in combination with rituximab.

**Conclusions:** BI-1206 is a first-in-class therapeutic approach that utilizes a unique mechanism of action, circumventing anti-CD20 mAb internalization by FcγRIIB and thereby it may enhance the therapeutic activity. We report on the first data from our ongoing phase 1/2a clinical trials where BI-1206 is given as single agent and/or in combination with rituximab.

**Keywords:** B-cell lymphoma; mantle cell lymphoma (MCL); rituximab.
**Disclosures:** Karlsson, I: Employment Leadership Position: *Biolnvent International AB. Järås*, K: Employment Leadership Position: *Biolnvent International AB*; Stock Ownership: *Biolnvent International AB. Gramming, E: Stock Ownership: *Biolnvent International AB. Lindell Andersson, M: Employment Leadership Position: *Biolnvent International AB. Mårtensson, L: Employment Leadership Position: *Biolnvent International AB*; Stock Ownership: *Biolnvent International AB. Teige, I: Employment Leadership Position: *Biolnvent International AB*; Stock Ownership: *Biolnvent International AB. Dyer, M: Research Funding: *Biolnvent International AB. Jerkeman, M: Research Funding: Celgene, Janssen, Abbvie and Gilead. Frendéus, B: Employment Leadership Position: *Biolnvent International AB*; Stock Ownership: *Biolnvent International AB. McAllister, A: Employment Leadership Position: *Biolnvent International AB*; Stock Ownership: *Biolnvent International AB. Davies, A: Consultant Advisory Role: Roche, Kite, Celgene, Acerta Pharma, MorphoSys, Biolnvent*; Honoraria: Roche, Celgene, Kite, Janssen;

Research Funding: Roche, Acerta Pharma, Celgene, Gilead, Karyopharma, GSK; Other Remuneration: sponsorship to attend conferences: Roche, Celgene; Expert Testimony: Roche.

## 497
# A PHASE 2 CLINICAL TRIAL OF RITUXIMAB AND β-GLUCAN PGG IN RELAPSED/REFRACTORY INDOLENT B-CELL NON-HODGKIN LYMPHOMA

C.A. Jacobson¹ | R. Redd² | C. Reynolds¹ |

M. Fields¹ | P. Armand¹ | D.C. Fisher¹ |

E.D. Jacobsen¹ | A.S. LaCasce¹ | N. Bose³ |

N. Ottoson³ | A. Freedman¹

¹Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; ²Biostatistics, Dana-Farber Cancer Institute, Boston, MA, United States; ³Translational Immunology, Biothera Pharmaceuticals, Eagan, MN, United States

**Introduction:** Rituximab (R) as a single agent is effective in indolent B-NHL (iB-NHL), but response rates and durability fall in relapsed/refractory (r/r) disease. Resistance is in part due to variable complement activation. Imprime PGG (IPGG) is a yeast-derived β-glucan that, when complexed with anti-β-glucan antibodies (ABA) and opsonized by iC3b, activates innate immune cells through CR3. Combining IPGG with R, then, may improve responses in r/r iB-NHL through complement-dependent cytotoxicity (CDC).

**Methods:** Twenty-five patients with iB-NHL were enrolled on this study from Dec 2014-July 2018. IPGG (4mg/kg) and R (375mg/m²) were given IV qwk x4. CT scans were done at 10wks and at 6 and 12m. No maintenance was given. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and duration of response (DOR). Assuming an ORR of 30% for R alone (GAUSS study), an ORR of 44% (11/25) was considered promising. Immunopharmacodynamic (IPD) analyses, such as cytokine and ABA levels, and assessment of IPGG binding to, and the immunophenotype of, innate immune cells, was done pre- and post-therapy.

**Results:** Patient characteristics will be presented. The majority had follicular lymphoma (64%). Over 1/3 had R-refractory disease. Median number of prior therapies was 2 (range 1-5). The ORR was 46% (11/24), with one CR. Median DOR was 12m and mPFS was 14m (Fig1 A,B). There was no association between response and histology, FLIPI, number of prior therapies, time from last therapy, or prior response to R. Prior response to R did not predict for DOR or PFS; patients treated in ≥4th line had an inferior PFS (7m vs NR, p=0.028). Treatment was well tolerated, with only 1 grade 3 toxicity (neutropenia); all others were grade 1/2 with infusion reactions, fatigue, and arthalgias most common. Increased levels of MCP-1, MIP-1b, MIP-1a, IP-10, and IL1-RA were seen after therapy, and IPGG binding to neutrophils and monocytes was detected, as was an increase in CD16+
<figure><img src="image_289.png" /><figcaption>Figure 1. Duration of response (A) and progression-free survival curves (B). Examples of post-treatment cytokine changes (C), IPGG binding to myeloid cells (D), and increasing CD16 expression in monocytes (E) following treatment in representative individual patients.</figcaption></figure>

monocytes, which are known for enhanced cytotoxicity as well as M1-polarizing functions (Fig1C-E). The relationship between ABA status and response is being investigated.

**Conclusions:** R-IPGG is well tolerated with a promising ORR of 46% in a r/r population. Importantly, treatment with R-IPGG resulted in a cytokine profile that is associated with M1-macrophage polarization and enhanced antigen presentation, and resultant expansion and

activation of tumor infiltrating T cells. These IPD responses are not only important for the immune effector mechanisms required for combination with antitumor antibodies, like R, but also for the activity of immune checkpoint inhibitors. IPGG has been combined with pembrolizumab in solid tumors (NCT02981303), and pre- and on-treatment biopsies demonstrate increased M1-macrophage and activated T-cell tumor infiltration. These data support a trial exploring the
triplet combination of R-IPGG with checkpoint inhibition in r/r indolent B-NHL.

**Keywords:** B-cell lymphoma; complement-dependent cytotoxicity (CDC); immunoconjugates.

**Disclosures:** Jacobson, C: Consultant Advisory Role: Kite Pharma, Novartis, Pfizer, Bayer, Celgene, Precision Biosciences, Humanigen; Research Funding: Kite Pharma, Pfizer. Jacobsen, E: Consultant Advisory Role: Bayer. LaCasce, A: Consultant Advisory Role: Humanigen, Bristol-Meyers Squibb. Bose, N: Employment Leadership Position: Biothera Pharmaceuticals; Stock Ownership: Biothera Pharmaceuticals. Ottoson, N: Employment Leadership Position: Biothera Pharmaceuticals; Stock Ownership: Biothera Pharmaceuticals. Freedman, A: Consultant Advisory Role: Bayer.

## 498
# TREATMENT EMERGENT ADVERSE EVENTS VARY WITH DIFFERENT PI3K INHIBITORS

F.T. Awan¹ | R.J. Chan² | L. Gu³ | G. Xing³ |

P. Bhargava² | B. Ruzicka² | M. Dreyling⁴ |

P. Zinzani⁵ | A.K. Gopal⁶

¹Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States; ²Medical Affairs, Gilead Sciences, Inc., Foster City, United States; ³Biostatistics, Gilead Sciences, Inc., Seattle, United States; ⁴Department of Medicine III, University Hospital of the Ludwig Maximilians University Munich, München, Germany; ⁵Institute of Hematology "L. e A. Serågnoli", University of Bologna, Bologna, Italy; ⁶Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, University of Washington, Seattle, United States

**Introduction:** Idelalisib (IDELA) and duvelisib (DUVA), both oral agents, and copanlisib (COPA), an IV agent, are PI3K inhibitors approved as monotherapy for relapsed / refractory (R/R) follicular lymphoma (FL). IDELA and DUVA are also listed in the National Comprehensive Cancer Network (NCCN) guidelines as monotherapy for R/R CLL. We compared safety profiles for IDELA vs. COPA and IDELA vs. DUVA and evaluated the effect of preexisting conditions on IDELA-induced TEAEs.

**Methods:** Using the Safety Analysis Set (SAS) for IDELA-treated patients (pts) with R/R iNHL (median duration of treatment [mDoT] 27 weeks [wks]) and TEAEs reported for COPA-treated pts with FL and other hematologic malignancies (Aliqopa® USPI, mDoT 22 wks, Dreyling et al., J. Clin. Oncol. 2017 mDoT 22 wks, Dreyling et al., Blood. 2017 mDoT 26 wks) or the SAS for IDELA-treated pts with R/R iNHL or CLL (mDOT 28.1 wks) and TEAEs reported for DUVA-treated pts with hematologic malignancies (Copiktra™ USPI, mDOT 39.1 wks), we compared all grade (aGr), grade 3/4 (Gr3/4, for IDELA vs. COPA) or grade ≥3 (Gr≥3, for IDELA vs. DUVA) TEAEs and the effect of preexisting comorbidities on selected IDELA-mediated AEs.

Comparisons are reported as estimate difference in proportions with p-values based on Fisher's exact test.

**Results:** IDELA-treated pts demonstrated significantly increased aGr and Gr3/4 AST and ALT elevation and diarrhea compared to COPA-treated pts. In contrast, COPA-treated pts showed significantly increased aGr and Gr3/4 hyperglycemia and hypertension relative to IDELA (Table 1A). IDELA-treated pts experienced significantly more Gr≥3, but not aGr, AST and ALT elevation than DUVA-treated pts. DUVA-treated pts experienced significantly higher aGr and Gr≥3 diarrhea + colitis, lower respiratory tract infection, anemia, and neutropenia; aGr mucositis, musculoskeletal pain, and thrombocytopenia; and Gr≥3 rash and fatigue than IDELA-treated pts (Table 1B).

We evaluated the effect of co-morbidities in IDELA-treated patients on emergence of Gr3/4 or Gr≥3 TEAEs observed more commonly in COPA- or DUVA-treated pts, respectively. IDELA-treated pts with pre-existing diabetes mellitus experienced more Gr3/4 hyperglycemia; however, pre-existing hypertension had no impact on aGr or Gr3/4 hypertension seen with IDELA. Concomitant systemic steroids also did not increase hyperglycemia or hypertension in IDELA-treated pts. A predisposition to diarrhea did not increase the incidence of diarrhea + colitis and a history of rash did not increase rash in IDELA-treated pts.

**Conclusion:** Although the approved PI3Kδ inhibitors may be perceived to be associated with synonymous AE profiles, this intra-class comparison highlights specific AE risks associated with each compound. Drug exposure differences and major limitations of cross-trial comparisons should be noted.

**Keywords:** chronic lymphocytic leukemia (CLL); follicular lymphoma (FL); PI3K/AKT/mTOR.

**Disclosures:** Awan, F: Consultant Advisory Role: AbbVie, Gilead, Pharmacyclics, Janssen, Sunesis, AstraZeneca, Dava Oncology; Honoraria: Abbvie, AstraZeneca; Research Funding: Pharmacyclics. Chan, R: Employment Leadership Position: Gilead Sciences, Inc.; Stock Ownership: Gilead Sciences, Inc. Gu, L: Employment Leadership Position: Gilead Sciences, Inc.; Stock Ownership: Gilead Sciences, Inc. Xing, G: Employment Leadership Position: Gilead Sciences, Inc.; Stock Ownership: Gilead Sciences, Inc. Ruzicka, B: Employment Leadership Position: Gilead Sciences, Inc.; Stock Ownership: Gilead Sciences, Inc. Dreyling, M: Consultant Advisory Role: Acerta, Bayer, Celgene, Gilead, Janssen, Mundipharma, Roche, Sandoz; Honoraria: Bayer, Celgene, Gilead, Janssen, Roche; Research Funding: Celegene, Janssen, Mundipharma, Roche. Zinzani, P: Consultant Advisory Role: Verastem, MSD, Eusapharma, Sanofi, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, Immune Design, Celgene, Portola, Roche, Kyowa Kirin; Honoraria: Verastem, MSD, Eusapharma, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Immune Design, Celgene, Portola, Roche, Kyowa Kirin. Gopal, A: Consultant Advisory Role: Gilead; Honoraria: Aptevo, BRIM Bio, Seattle Genetics and Sanofi; Research Funding: Teva, Bristol-Myers Squibb, Merck, Takeda, TG Therapeutics, and Effector; Other Remuneration: Seattle Genetics, Pfizer, Janssen, Gilead, Spectrum, Amgen and Incyte.
<table><caption>Table 1A. Treatment Emergent AEs or Lab Abnormalities in IDELA- vs. COPA-Treated Patients.</caption><thead><tr><th colspan="2">IDELA mDOT = 27 wks</th><th colspan="3">All Grade (aGr)</th><th colspan="3">Grade 3/4 (Gr3/4)</th></tr><tr><th colspan="2">COPA mDOT = 22 - 26 wks</th><th colspan="3">COPA</th><th colspan="3">COPA</th></tr><tr><th>TEAE or<br>Lab Abnormality</th><th>IDELA<br>N=163<br>n (%)</th><th>IDELA<br>N=142 or 168<br>n (%)</th><th>P-Value</th><th>IDELA<br>N=163<br>n (%)</th><th>IDELA<br>N=142 or 168<br>n (%)</th><th>P-Value</th></tr></thead><tbody><tr><td>Colitis</td><td>7 (4.3)</td><td>1 (0.7)</td><td>0.0719</td><td>4 (2.5)</td><td>1 (0.7)</td><td>0.3769</td></tr><tr><td>Diarrhea</td><td>77 (47.2)</td><td>60 (35.7)</td><td>0.0347</td><td>22 (13.5)</td><td>8 (4.8)</td><td>0.0068</td></tr><tr><td>Fatigue</td><td>51 (31.3)</td><td>37 (26.1)</td><td>0.3753</td><td>2 (1.2)</td><td>3 (2.1)</td><td>0.6667</td></tr><tr><td>Hyperglycemia</td><td>11 (6.7)</td><td>90 (53.6)</td><td>&lt;.0001</td><td>2 (1.2)</td><td>66 (39.3)</td><td>&lt;.0001</td></tr><tr><td>Hypertension</td><td>9 (5.5)</td><td>59 (35.1)</td><td>&lt;.0001</td><td>2 (1.2)</td><td>46 (27.4)</td><td>&lt;.0001</td></tr><tr><td>Infection (multiple preferred terms)</td><td>24 (14.7)</td><td>35 (20.8)</td><td>0.1539</td><td>17 (10.4)</td><td>23 (13.7)</td><td>0.4018</td></tr><tr><td>Nausea</td><td>51 (31.3)</td><td>43 (25.6)</td><td>0.2737</td><td>3 (1.8)</td><td>1 (0.6)</td><td>0.3653</td></tr><tr><td>Neutropenia (including febrile neutropenia)</td><td>44 (27)</td><td>53 (31.5)</td><td>0.3987</td><td>35 (21.5)</td><td>42 (25)</td><td>0.5156</td></tr><tr><td>Pneumonitis</td><td>7 (4.3)</td><td>11 (7.7)</td><td>0.2297</td><td>4 (2.5)</td><td>2 (1.4)</td><td>0.6889</td></tr><tr><td>Pyrexia</td><td>54 (33.1)</td><td>38 (26.8)</td><td>0.2608</td><td>4 (2.5)</td><td>6 (4.2)</td><td>0.5228</td></tr><tr><td>Rash (including exfoliative skin reactions)</td><td>35 (21.5)</td><td>26 (15.5)</td><td>0.2017</td><td>4 (2.5)</td><td>3 (1.8)</td><td>0.7200</td></tr><tr><td>Thrombocytopenia</td><td>28 (17.2)</td><td>20 (14.1)</td><td>0.5293</td><td>8 (4.9)</td><td>7 (4.9)</td><td>1.0000</td></tr><tr><td>Increased ALT (lab parameter)</td><td>85 (52.1)</td><td>32 (22.7)</td><td>&lt;.0001</td><td>29 (17.8)</td><td>2 (1.4)</td><td>&lt;.0001</td></tr><tr><td>Increased AST (lab parameter)</td><td>71 (43.6)</td><td>39 (27.7)</td><td>0.0042</td><td>21 (12.9)</td><td>2 (1.4)</td><td>0.0001</td></tr></tbody></table>

<table><caption>Table 1B. Treatment Emergent AEs or Lab Abnormalities in IDELA- vs. DUVA-Treated Patients.</caption><thead><tr><th colspan="2">IDELA mDOT = 28.1 wks</th><th colspan="3">All Grade (aGr)</th><th colspan="3">Grade ≥3 (Gr≥3)</th></tr><tr><th colspan="2">DUVA mDOT = 39.1 wks</th><th colspan="3">DUVA</th><th colspan="3">DUVA</th></tr><tr><th>TEAE or<br>Lab Abnormality</th><th>IDELA<br>N=261<br>n (%)</th><th>IDELA<br>N=442<br>n (%)</th><th>P-Value</th><th>IDELA<br>N=261<br>n (%)</th><th>IDELA<br>N=442<br>n (%)</th><th>P-Value</th></tr></thead><tbody><tr><td>Anemia (lab parameter)</td><td>84 (32.2)</td><td>198 (44.8)</td><td>0.0011</td><td>13 (5.0)</td><td>66 (14.9)</td><td>&lt;.0001</td></tr><tr><td>Arthralgia</td><td>17 (6.5)</td><td>46 (10.4)</td><td>0.1004</td><td>0</td><td>1 (0.2)</td><td>1.0000</td></tr><tr><td>Constipation</td><td>27 (10.3)</td><td>57 (12.9)</td><td>0.3377</td><td>0</td><td>1 (0.2)</td><td>1.0000</td></tr><tr><td>Cough</td><td>80 (30.7)</td><td>111 (25.1)</td><td>0.1115</td><td>4 (1.5)</td><td>2 (0.5)</td><td>0.2019</td></tr><tr><td>Diarrhea or colitis</td><td>109 (41.8)</td><td>222 (50.2)</td><td>0.0347</td><td>30 (11.5)</td><td>101 (22.9)</td><td>0.0002</td></tr><tr><td>Dyspnea</td><td>36 (13.8)</td><td>52 (11.8)</td><td>0.4793</td><td>7 (2.7)</td><td>8 (1.8)</td><td>0.4325</td></tr><tr><td>Fatigue</td><td>88 (33.7)</td><td>126 (28.5)</td><td>0.1503</td><td>5 (1.9)</td><td>22 (5.0)</td><td>0.0433</td></tr><tr><td>Lower respiratory tract infection</td><td>4 (1.5)</td><td>46 (10.4)</td><td>&lt;.0001</td><td>1 (0.4)</td><td>11 (2.5)</td><td>0.0381</td></tr><tr><td>Mucositis</td><td>0</td><td>61 (13.8)</td><td>&lt;.0001</td><td>0</td><td>6 (1.4)</td><td>0.0897</td></tr><tr><td>Musculoskeletal pain</td><td>10 (3.8)</td><td>90 (20.4)</td><td>&lt;.0001</td><td>1 (0.4)</td><td>6 (1.4)</td><td>0.2681</td></tr><tr><td>Nausea</td><td>68 (26.1)</td><td>104 (23.5)</td><td>0.4683</td><td>3 (1.1)</td><td>4 (0.9)</td><td>0.7146</td></tr><tr><td>Neutropenia (lab parameter)</td><td>138 (52.9)</td><td>276 (62.4)</td><td>0.0140</td><td>74 (28.4)</td><td>184 (41.6)</td><td>0.0005</td></tr><tr><td>Pneumonia (multiple preferred terms)</td><td>47 (18.0)</td><td>91 (20.6)</td><td>0.4328</td><td>41 (15.7)</td><td>67 (15.2)</td><td>0.9138</td></tr><tr><td>Pneumonitis</td><td>10 (3.8)</td><td>22 (5.0)</td><td>0.5761</td><td>6 (2.3)</td><td>NA*</td><td>N/A**</td></tr><tr><td>Rash (multiple preferred terms)</td><td>70 (26.8)</td><td>136 (30.8)</td><td>0.3035</td><td>8 (3.1)</td><td>41 (9.3)</td><td>0.0019</td></tr><tr><td>Thrombocytopenia (lab parameter)</td><td>75 (28.7)</td><td>170 (38.5)</td><td>0.0089</td><td>27 (10.3)</td><td>65 (14.7)</td><td>0.1059</td></tr><tr><td>Increased ALT (lab parameter)</td><td>114 (43.7)</td><td>177 (40)</td><td>0.3834</td><td>41 (15.7)</td><td>34 (7.7)</td><td>0.0014</td></tr><tr><td>Increased AST (lab parameter)</td><td>108 (41.4)</td><td>163 (36.9)</td><td>0.2616</td><td>32 (12.3)</td><td>24 (5.4)</td><td>0.0022</td></tr></tbody></table>

BRENTUXIMAB VEDOTIN POPULATION PHARMACOKINETIC (POPPK) MODELLING IN ADULT AND PAEDIATRIC PATIENTS (PTS) WITH RELAPSED/REFRACTORY (R/R) HEMATOLOGIC MALIGNANCIES

A. Suri<fnref n="1" /> | D.R. Mould² | G. Song³ | J. Kinley⁴ | K. Venkatakrishnan<fnref n="1" />

Inc., Cambridge, United States; ²Projections Research, Inc., Phoenixville, United States; ³Oncology Statistics, Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Inc., Cambridge, United States; ⁴Oncology Clinical Research, Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Inc., Cambridge, United States

**Introduction:** Prior PK analyses of brentuximab vedotin PK in paediatric pts with R/R hematologic malignancies found a trend for decreased area under the curve (AUC) for antibody-drug conjugate (ADC) in low body-weight pts receiving the adult brentuximab vedotin dose (1.8 mg/kg Q3W). POPPK analyses utilizing data from paediatric

<footnote>*NA = not available; **N/A = not applicable.</footnote>

<footnote n="1">¹Quantitative Clinical Pharmacology, Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited</footnote>
<figure><img src="image_290.png" /></figure>

<figure><img src="image_291.png" /></figure>

(NCT01492088) and adult studies (NCT00412282) were performed to quantify sources of variability, including body size effects, on ADC and monomethyl auristatin E (MMAE) PK in paediatric pts with classical Hodgkin lymphoma (cHL).

**Methods:** POPPK base-models were based on previously reported models. A full model was developed including all statistically-relevant prespecified covariate effects; a final model was chosen by retaining only the significant covariate effects (p<0.001). Model parameters were estimated using NONMEM (v7.3). The final model was used to simulate mg/kg or body surface area (BSA)-based dosing scenarios in paediatric pts to inform selection of posology that provides exposures matching those achieved in adults with weight-based (mg/kg) dosing.

**Results:** Data were collected from 84 pts with a median age of 25.7 years (range 7–87, 34 of whom [40.5%] were aged <18 years), median weight of 67 kg (range 21–154), and median BSA of 1.8 m² (range 0.86–2.8). ADC PK was described by a linear 3-compartment model with zero-order input and first-order elimination. In covariate analyses, BSA was the best predictor of body size effects on ADC PK, and was a strong predictor of clearance (CL), V₁, and V₃; anti-drug antibodies were predictors of ADC CL.

POPPK simulations of 1.8 mg/kg Q3W dosing found lower AUC values in small/moderate body weight paediatric pts (<28 kg/ 28–49 kg) compared with larger paediatric/adult pts (50–100 kg). Dosing at 71.5 mg/m² had comparable AUC values across all body weight ranges and a similar AUC to the reference scenario of 1.8 mg/kg dosing in the 50–100 kg group.

Simulations of low dose Q2W BV dosing (1.2 mg/kg and 47.7 mg/m²), found similar results to the adult Q3W 1.8 mg/kg regimen. These results provide a hypothesis to further evaluate the relative performance of BSA-based vs weight-based dosing as an approach to minimize inter-patient variability in pediatric PK. AUC distributions with BSA-based dosing at 47.7 mg/m² across the weight ranges (including the <28 kg group) were similar to those achieved in the adult weight range (50–100 kg) with body weight-based dosing at 1.2 mg/kg (Figure). POPPK results for MMAE will be presented.

**Conclusions:** ADC POPPK results support the evaluation of a BSA-based dosing regimen (48 mg/m² Q2W) as an alternative dosing option in a phase 1/2 study to evaluate frontline A+AVD efficacy and safety in paediatric cHL pts (NCT02979522). Model-informed

approaches to pediatric oncology drug development enable dose selection aimed at minimizing inter-pt variability during clinical evaluation of safety and efficacy.

**Keywords:** anaplastic large cell lymphoma (ALCL); brentuximab vedotin; classical Hodgkin lymphoma (cHL).

**Disclosures:** **Suri, A:** Employment Leadership Position: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. **Mould, D:** Consultant Advisory Role: Diane R Mould was a paid consultant. **Song, G:** Employment Leadership Position: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. **Kinley, J:** Employment Leadership Position: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. **Venkatakrishnan, K:** Employment Leadership Position: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

## 500 EXCEPTIONAL RESPONSE OF REFRACTORY ATLL WITH MDM4 AMPLIFICATION TO NOVEL STAPLED PEPTIDE DUAL MDM4/2 INHIBITOR

M. Janakiram¹ | H.B. Ye² | L. Carjaval³ |

A. Villaorduna² | K. Ramesh² | U. Shah⁴ |

N. Kornblum² | K. Fehn² | I. Braunschweig² |

K. Ueda² | V. Thiruthuvanathan² | B. Will² |

D. Pinchasik³ | M. Aivado³ | S. Goel² | U. Steidl² |

A.K. Verma²

¹HOT, University of Minnesota, Minneapolis, United States; ²Oncology, Albert Einstein College of Medicine, Bronx, United States; ³ALRN Therapeutics, MA, United States; ⁴Oncology, Memorial Sloan Kettering Cancer Center, New York, United States

Adult T cell leukemia lymphoma is an aggressive T cell leukemia caused by HTLV-1, which is resistant to most conventional chemotherapies during relapse. Herein we report the successful treatment of a chemo-refractory ATLL patient with a novel stapled peptide, ALRN-
<figure><img src="image_292.png" /><figcaption>Fig 1a & 1b- Response to chemotherapy and ALRN-6924</figcaption></figure>

<caption>Fig 1c - Increased expression of p53 and p21, is seen on malignant leukemic cells as early as 4 hours after infusion of ALRN-6924</caption>

6924 that inhibits MDM4 and MDM2 and restores the function of p53 on a Phase 1 clinical trial [NCT02264613]. The stapled peptide is a small molecule comprised of the α-helical portion of p53 stabilized by a hydrocarbon cross-linker retaining the molecular target specificity of the underlying peptide with minimal off target effects.

A 52 yr old female presenting with tiredness, weight loss, hypercalcemia (17.5 mg/dl), high LDH (411 u/l) and lymphocytosis (14.8 k/ul) was diagnosed with acute ATLL based on a lymph node biopsy and peripheral blood flow cytometry. She was initially diagnosed with T cell lymphoma in 1995 (further details unknown) and underwent 5 cycles of CHOP. She received a cadaveric renal transplant for IgA nephropathy in 2016 and her immunosuppression was promptly decreased upon diagnosis. She was treated with polychemotherapy-ICE on 8/8/18, EPOCH on 8/31/18 with only a transient clinical response, and the disease progressed within 15 days (Fig 1a, 1b).

Targeted NGS showed wild type P53 and FISH showed MDM4 amplifications.

She was enrolled in the NCT02264613 clinical trial and started on ALRN 6924 on 9/19/18 and within 2 cycles, her hypercalcemia and lymphocytosis resolved. Response assessment after 4 cycles found her in a PR by revised ATLL criteria and IWG criteria.

Pharmacodynamic studies performed during drug treatment showed significant upregulation of p53 one day after ALRN-6924 infusion in this patient's leukemia cells (Fig. 1c). We also observed activation of the p53 target gene p21 in the patient's leukemia cells post infusion, demonstrating functional activation of p53 in vivo.

Several aspects are unique to this case. We found MDM4 amplifications (copy number=3) by FISH in this case, accounting for functional inactivation of the p53 gene, thus providing a possible explanation for the chemo-refractory nature of this patient's leukemia. The
remarkable response to single-agent therapy with ALRN-6924, a sta-
pled dual MDM4/MDM2-inhibiting peptide, suggests particularly
impressive efficacy of this novel targeted therapy for
MDM4-amplified cases, and implies clinically detectable cytogenetic
MDM4 amplifications as a possible biomarker to guide future use and
patient selection.

**Keywords:** human T-lymphotropic virus (HTLV); P53; T-cell lymphoma (TCL).

Disclosures: JANAKIRAM, M: Honoraria: miRagen, Seattle Genetics; Ye, H: Honoraria: miRagen, Seattle Genetics.

501
PRELIMINARY RESULTS OF ASTX660, A NOVEL NON-PEPTIDOMIMETIC cIAP1/2 AND XIAP ANTAGONIST, IN RELAPSED/REFRACTORY PERIPHERAL T-CELL LYMPHOMA AND CUTANEOUS T CELL LYMPHOMA

F. Samaniego¹ | A. Hollebecque² | F. Foss³ |

J. Lister⁴ | M. Mita⁵ | N. Wagner-Johnston⁶ |

M. Dyer⁷ | B. You⁸ | A. Prica⁹ |

F. Hernandez-Llizaliturri¹⁰ | R. Ferraldeschi¹¹ |

D. Chan¹¹ | J. Zhang¹¹ | A. Mehta¹²

¹Lymphoma & Myeloma, UT MD Anderson Cancer Center, Houston, United States; ²Early Drug Development (DITEP) Gastro-Intestinal Oncology, Institute Gustave Roussy, Villejuif, France; ³Internal Medicine, Hematology, Yale Cancer Center, New Haven, United States; ⁴Division of Hematology and Cellular Therapy, Allegheny Health Network Cancer Institute, Pittsburgh, United States; ⁵Experimental Therapeutics, Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center, Los Angeles, United States; ⁶Oncology, Johns Hopkins University, Baltimore, United States; ⁷Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom; ⁸Medical Oncology, Centre Hospitalier Lyon Sud, Pierre Benite, France; ⁹Hematology, Princess Margaret Cancer Centre Mount Sinai Hospital, Toronto, Ontario, Canada; ¹⁰Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, United States; ¹¹Clinical Development, Astex Pharmaceuticals, Inc., Pleasanton, United States; ¹²Hematology and Oncology, University of Alabama at Birmingham, Birmingham, United States

**Background:** ASTX660 is an oral, novel nonpeptidomimetic, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). ASTX660 is currently being evaluated in a first-in-human phase 1-2 study in patients (pts) with advanced solid tumors and lymphoma (ClinicalTrials.gov NCT02503423). In the phase 1 part of the study, the recommended phase 2 dose (RP2D) was identified with a favorable safety profile and initial evidence of clinical activity in a pt with mycoses fungoides (Mita et al, presented at the

AACR-NCI-EORTC Conference 2017, abs #A091). Herein we report
preliminary efficacy and safety data from the relapsed/refractory (r/r)
peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma
(CTCL) Phase 2 cohorts.

**Methods:** Pts receive treatment with ASXT660 at the RP2D 180mg/day on Days 1 to 7, and 15 to 22 in a 28-day cycle. The primary endpoint is response rate as assessed by the investigator according to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Adverse events (AEs) are assessed per CTCAE V4.03.

**Results:** As of 15 January 2019, 16 PTCL pts and 13 CTCL pts have received ASTX660. Pt characteristics: median (range) age: PTCL: 59 (39-81) years and CTCL: 57 (23-75) years; median prior therapies: PTCL: 3 (1-7) and CTCL: 3 (1-9). In the PTCL cohort the ORR is 28% (4/14); 2 pts have yet to reach their first assessment. Three responding pts remain on study drug for 7-10 months. Responses have been observed in pts with AITL and PTCL-NOS. In the CTCL cohort the global response is 25% (3/12); 1 pt has yet to reach their first assessment. Two responding pts remain on study drug for 4-6 months. Responses have been seen in pts with large cell transformation, sezary syndrome and visceral metastases. Among all pts, the most common related AEs of any grade (≥ 15%) were lipase elevation (38%), amylase elevation (34%), ALT elevation (28%), elevation (24%) and rash (24%). Related AEs ≥ Grade 3 occurring in ≥3 pts were rash (n=5) and lipase elevation (n=4). Accrual continues; updated efficacy and safety data will be presented at the meeting.

**Conclusion:** In ongoing Phase 2 cohorts ASTX660 has shown activity against PTCL and CTCL with manageable safety profile. These early data support continued development of ASXT660 for the treatment of r/r PTCL and CTCL. Correlative studies are aimed at identifying predictors of response.

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

**Disclosures:** Hollebecque, A: Consultant Advisory Role: Amgen, Spectrum Pharmaceuticals, Lilly; Research Funding: Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi. Foss, F: Consultant Advisory Role: Celgene, Seattle Genetics, Spectrum Pharmaceuticals, Eisai, Verastem, miRagen, Mallinckrodt; Research Funding: Miragen, Kura, Astex, Kyowa Hakko Kirin, Sankyo, Eisai; Other Remuneration: Speakers Bureau: Seattle Genetics. Wagner-Johnston, N: Consultant Advisory Role: Gilead, Bayer, Juno, ADC Therapeutics, Janssen. Dyer, M: Research Funding: Astex Pharmaceuticals, Inc. Hernandez-Llizaliturri, F: Consultant Advisory Role: Celgene, Amgen, Seattle Genetics, Karyopharm, Kite. Ferraldeschi, R: Employment Leadership Position: Astex Pharmaceuticals, Inc. Chan, D: Employment Leadership Position: Astex Pharmaceuticals, Inc. Zhang, J: Employment Leadership Position: Astex Pharmaceuticals, Inc. Mehta, A: Consultant Advisory Role: I-MAB, BMS, Seattle Genetics, Kyowa Kirin, Celgene; Honoraria: Gilead, Seattle Genetics, Kyowa Kirin, Spectrum, Kite Pharmaceuticals, Pharmacyclics; Research Funding: Roche, Rhizen, Incyte, Seattle Genetics, Forty seven Inc, BMS, Merck, Takeda, Juno.
## 502
DECITABINE PLUS R-CHOP IN PATIENTS WITH NEWLY DIAGNOSED DIFFUSE LARGE B-CELL LYMPHOMA: INTERIM RESULTS OF A PHASE I/II STUDY

M. Zhang¹ | P. Xu¹ | S. Cheng¹ | L. Wang² | W. Zhao²

¹Hematology, State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine, Shanghai, China; ²Hematology; Laboratory of Molecular Pathology, State Key Laboratory of Medical Genomics; Shanghai Institute of Hematology; Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine; Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Shanghai, China

**Background:** Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma and is heterogeneous in clinical, immunophenotypic and genetic features. Approximately 30-40% of the patients eventually experience disease progression or relapse upon R-CHOP treatment, particularly in the intermediate and high risk group. The benefit of high-dose chemotherapy combined with autologous stem cell transplantation as first-line consolidation therapy remains controversial. Novel agents in combination with R-CHOP need to be investigated to improve clinical outcome in this subset of DLBCL patients.

Abnormal DNA methylation can be observed in DLBCL patients. Aberrant DNA hypermethylation of tumor suppressor genes can result in transcriptional silencing and thus contributing to resistance to chemotherapy. Low doses of DNA methyltransferase inhibitor (DNMTI) can induce DNA demethylation and cell death with minimal DNA damage in susceptible DLBCL cells, and restore responsiveness to doxorubicin in chemotherapy-resistant DLBCL cells. Therefore, we conducted a phase I/II study to evaluate safety, tolerability and efficacy of decitabine in combination with R-CHOP in patients with newly diagnosed DLBCL (NCT02951728).

**Methods:** Patients with newly diagnosed DLBCL, aged 15-75 years, Eastern Cooperative Oncology Group (ECOG) score of 0-2, and International prognostic index (IPI) ≥ 2 were included. The primary objective of phase I study was to determine the maximum tolerated dose (MTD) of decitabine with a standard R-CHOP regimen. Patients received decitabine 10 mg/m², 15 mg/m² or 20 mg/m² on days 1-5, followed by standard dose of R-CHOP on days 6-11, every 28 days for a total of 6 cycles. Safety of the recommended phase II dose was then assessed in a dose-expansion population.

**Results:** From December 2016 to November 2018, a total of 58 patients were enrolled (phase I: 8, phase II: 50). Median age was 55.5 years (range, 25-74) and 79% of patients had IPI ≥ 3. The MTD of decitabine was 10 mg/m². The most common grade ≥ 3 toxicities were hematological adverse events (AEs), including neutropenia (grade 3: 46%, grade 4: 74%), thrombocytopenia (grade 3: 24%, grade

4: 17%), anemia (grade 3: 33%). Grade ≥ 3 neutropenia most frequently occurred during the first cycle with a short duration, median 4 days (range, 3-6). Granulocyte-colony stimulating factor prophylaxis was given from the second cycle. Grade 3 infection and dosage modification occurred predominantly in elderly patients. No major non-hematological AEs were observed. There was no death related with AEs. To date, 35 patients have completed treatment and were valuable for response evaluation. Thirty patients (86%) received a response, of which 26 received complete response and 4 received partial response. After a median follow-up of 12 months (range, 6-27), 25 patients were still in remission.

**Conclusion:** Decitabine is well tolerated when added to R-CHOP, and could improve responses in patients with DLBCL.

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

## 503
PHASE I DOSE-ESCALATION STUDY OF VENETOCLAX PLUS BEAM FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANT (ASCT) FOR CHEMORESISTANT, RELAPSED/REFRACTORY, OR HIGH-RISK NON-HODGKIN'S LYMPHOMA (NHL); PRELIMINARY RESULTS

J. Maakaron | Q. Zhao | M. Puto | R. Von Derau |

J. Robinson | J. Brammer | S. Penza | R. Baiocchi |

B. Christian | K. Maddocks | A. Saad | S. Wall |

D. Benson | Y. Efebera | A. Rosko | S. Ayyappan |

N. Grieselhuber | S. Vasu | K. Larkin | N. Epperla |

S. Devarakonda | H. Choe | M. Chaudhry |

B. Blaser | J. Blachly | B. Bhatnagar | L. Alinari |

A. Mims | S. Jaglowski | B.M. William

Hematology, The Ohio State University, Columbus, United States

Autologous stem cell transplant (ASCT) using carmustine, etoposide, cytarabine, and melphalan (BEAM) is standard treatment for patients with chemosensitive, relapsed, non-Hodgkin's lymphoma (NHL). Rational approaches to patients who relapse post-ASCT remains an unmet need. Venetoclax is an oral BCL-2 inhibitor that has significant single-agent and combination activity in r/r NHL. In this trial, we aim to test the safety of the combination of venetoclax plus BEAM followed by ASCT. We hypothesize that venetoclax will help overcome the chemoresistance of these tumors and decrease post-ASCT relapse.

We designed an open-label, single-center, phase I trial (NCT03583424) of venetoclax in combination with BEAM and ASCT for patients with r/r or high-risk NHL. Venetoclax is administered for 10 days at three dose levels (400, 800, 1200 mg) using a brief ramp-up schedule (Table 1). Accrual is planned in a standard 3+3 fashion to establish the maximum tolerated dose (MTD) of venetoclax with a
<table><caption>TABLE 1</caption><thead><tr><th></th><th>D-17</th><th>D-16</th><th>D-15</th><th>D-14</th><th>D-13</th><th>D-12</th><th>D-11</th></tr></thead><tbody><tr><td></td><td>Allopurinol</td><td colspan="5">Mobilization and collection</td><td></td></tr><tr><td></td><td>D-10</td><td>D-9</td><td>D-8</td><td>D-7</td><td>D-6</td><td>D-5</td><td>D-4</td></tr><tr><td></td><td>Venetoclax* 100 mg PO</td><td>Venetoclax 200 mg PO</td><td>Venetoclax 400 mg PO</td><td>Venetoclax* per dosing cohort Coh 1 = 400 Coh 2 = 800 Coh 3 = 1200</td><td>Venetoclax per dosing cohort BCNU 300 mg/m2</td><td>Venetoclax Etoposide 100 mg/m2 IV bid Cytarabine 100 mg/m2 IV bid</td><td>Venetoclax Etoposide 100 mg/m2 IV bid Cytarabine 100 mg/m2 IV bid</td></tr><tr><td></td><td>D-3</td><td>D-2</td><td>D-1</td><td>D-0</td><td colspan="3"></td></tr><tr><td></td><td>Venetoclax Etoposide 100 mg/m2 IV bid Cytarabine 100 mg/m2 IV bid</td><td>Venetoclax Etoposide 100 mg/m2 IV bid Cytarabine 100 mg/m2 IV bid</td><td>Venetoclax Melphalan 140 mg/m2</td><td colspan="3"></td></tr></tbody></table>

planned 10 patient expansion at the MTD. Inclusion criteria consists of adult, fit patients with B and T-cell NHL refractory after upfront induction therapy, in partial remission after induction therapy, with progression after salvage requiring ≥ 3 lines of therapy, or relapsed within 1 year of induction. Patients with chronic lymphocytic leukemia and central nervous system involvement by lymphoma are excluded. Toxicities were graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03 until BEAM regimen starts and then using the Bearman scale (for regimen-related toxicity) after.

Cohort 1 has fully accrued with 3 patients with r/r diffuse large B-cell lymphoma. All are males with median age of 64 (55-69) years. All 3 patients fully engrafted and were discharged home; with median time to neutrophil and platelet engraftment of 10 (11-13) and 12 (10-14) days respectively. Safety data for cohort 1 is presented in Table 2. After starting BEAM, only one patient experience grade 1 stomatitis, diarrhea and liver toxicity by the Bearman scale. We have not observed any tumor lysis syndrome. One patient developed pneumonia and respiratory failure (G3) after engraftment and hospital

discharge but he had an underlying obstructive airway disease and he fully recovered. We are currently enrolling patients on cohort 2.

**Keywords:** autologous stem cell transplantation (ASCT); non-Hodgkin lymphoma (NHL); venetoclax.

MISCELLANEA

504

EBV LEAVES ITS MARK: NEW EVIDENCE OF <<HIT AND RUN>> HYPOTHESIS IN B-CELL LYMPHOMAS FROM NON-CONVENTIONAL METHODS

L. Mundo¹ | M.R. Ambrosio¹ | L. Del Porro¹ |

M. Granai¹ | V. Mancini¹ | G. Schiavoni² |

I. Anagnostopoulos³ | B. Falini² | S. Lazzi¹ |

E. Tiacci² | L. Leoncini¹

¹Section of Pathology, Department of Medical Biotechnology, University of Siena, Siena, Italy; ²Section of Hematology and Clinical Immunology, Department of Medicine, University and Hospital of Perugia, Perugia, Italy; ³Section of Pathology, University of Florence, Florence, Italy

<table><caption>TABLE 2 Demographics and safety data for cohort 1 (D-17 to D-6)</caption><thead><tr><th>Adverse Event CTCAE</th><th>Grade 1-2</th></tr></thead><tbody><tr><td>Anemia</td><td>3</td></tr><tr><td>Platelet count decreased</td><td>3</td></tr><tr><td>Hyperglycemia</td><td>3</td></tr><tr><td>Alkaline phosphatase increased</td><td>2</td></tr><tr><td>Lymphocyte count decreased</td><td>1</td></tr><tr><td>Back pain</td><td>1</td></tr><tr><td>Cough</td><td>1</td></tr><tr><td>Fatigue</td><td>1</td></tr><tr><td>Hypercalcemia</td><td>1</td></tr><tr><td>Abdominal pain</td><td>1</td></tr><tr><td>Alanine aminotransferase increased</td><td>1</td></tr><tr><td>Nausea</td><td>1</td></tr><tr><td>Peripheral sensory neuropathy</td><td>1</td></tr></tbody></table>

**Introduction:** Epstein-Barr virus (EBV) infection is a common feature of B cell lymphoproliferative disorders, including Burkitt lymphoma (BL) and diffuse large B cell lymphoma (DLBCL), with a frequency ranging from 10% to 100% in endemic BL cases. The role of EBV to B-cell lymphomas pathogenesis is largely unknown. EBV might be associated with all BL cases, including those diagnosed as EBV negative by routine methods [immunohistochemistry – IHC and EBV-encoded RNAs (EBER) in situ hybridization – ISH] thanks to a mechanism of hit-and-run. To escape the immune system, the viral genome is progressively lost from the host human cell.

**Aim:** The aim of this study was to identify the presence of EBV in a series of “EBV negative” B-cell lymphomas by applying conventional
(IHC and EBER-ISH) and non-conventional methods (EBV viral load measurement; EBV-encoded miRNAs detection, RNAscope assay).

**Material and methods:** We investigated a total of 179 cases: 16 BL, 34 DLBCL, 50 FL, 44 cHL, 10 T-LL, 20 HCL, 5 MCL. We performed EBER-ISH in all samples and then we screened by RT-qPCR targeting regions of EBV genome: BamH1 W and EBNA-1.

**Results:** We diagnosed 10 EBER-positive and 6 EBER-negative BL, 4 EBER-positive and 30 EBER-negative DLBCL, 47 EBER-negative FL and 3 EBER-positive, 12 EBER-positive and 32 EBER-negative HL. By qPCR, all cases reported a significant presence of the virus in 6/6 of BL, 11/30 DLBCL, 3/47 FL and 16/32 of HL cases, demonstrating EBV infection also in those samples diagnosed as "EBV negative". An higher viral loads in BL-EBER negative compared with the DLBCL, FL, HL EBER-negative cases was detected. The presence of the virus was also assessed and confirmed by the expression of EBV-encoded miRNAs (BART9-5p, BART10-3p, BART19-3p). In addition, we performed the RNAscope assay for targeting EBNA1 mRNA molecule and identify which cells were EBV positive. The positive staining was observed in few tumour cells of all lymphomas found to be EBV-positive by qPCR. Finally, considering the ability of EBV to manipulate the cellular epigenome that result in stable and heritable alterations, we studied the methylation status of *MGMT*, *E-cadherine* known to be significant hypermethylated by the virus. The level of methylation in EBER-negative samples but qPCR positive was higher in respect to EBER-negative cases where both genes were hypomethylated.

**Conclusions:** Though our findings do not represent a definitive proof of EBV presence inside the neoplastic cells, they highlight for the first time the possibility that EBV might contribute to the development of more cancers than simply those remaining viral genome-positive. Whether confirmed on a larger cohort of cases and different tumor types, the current study may support the rationale for strengthening the effort toward EBV vaccines that could potentially prevent the development of EBV-associated neoplasms independently of the presence or absence of viral genomes in the neoplastic cells, thus affecting the worldwide epidemiology of lymphomas.

**Keywords:** B-cell lymphoma; Epstein-Barr virus (EBV).

## 505

### SINGLE-CENTER ANALYSIS OF POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD) OUTCOMES WITH EPSTEIN BARR VIRUS (EBV) ASSESSMENTS

M.O. Kamal | J. Moyers | L. Liu | M. Kim |

H. Mo | R. Villacana | C. Chen | H.L. Cao

Dept of Hematology Oncology, Loma Linda University, Loma Linda, United States

**Background:** EBV is associated with the majority of cases of PTLD, a serious complication after solid organ and hematopoietic stem cell transplantation. EBV serum viral loads have been used to identify

<table><caption>TABLE 1</caption><thead><tr><th></th><th></th><th>All</th><th>Pediatrics</th><th>Adults</th></tr></thead><tbody><tr><td rowspan="4">Histology</td><td>Polymorphic</td><td>15</td><td>13</td><td>2</td></tr><tr><td>M-DLBCL</td><td>33</td><td>15</td><td>18</td></tr><tr><td>HL</td><td>7</td><td>4</td><td>3</td></tr><tr><td>M-Burkitt's</td><td>4</td><td>4</td><td>0</td></tr><tr><td rowspan="2">Antiviral Used</td><td>Yes</td><td>57</td><td>38</td><td>19</td></tr><tr><td>No</td><td>9</td><td>3</td><td>6</td></tr><tr><td rowspan="2">M-DLBCL Treatment</td><td>Rituximab</td><td>16</td><td>12</td><td>4</td></tr><tr><td>Rituximab + Chemotherapy</td><td>15</td><td>4</td><td>11</td></tr></tbody></table>

those at risk of this disease in EBV-positive cases. We aimed to characterize the clinical presentation, pathologic diagnosis and prognostic implications of EBV viral load and its response to treatment.

**Methods:** This is a retrospective observational study approved by IRB including all organ transplant patients with histologic diagnosis of PTLD between 2000 and 2018 at Loma Linda University Medical Center. Data wascollected by chart review. Kaplan-Meier survival estimates were used to determine primary outcomes of overall survival and progression-free survival.

**Results:** 68 patients (41 male, 27 female) were identified who developed PTLD following solid organ transplantation (22 kidney, 37 heart, 6 liver, 3 multi-organ). Median time from transplant to PTLD diagnosis was longest among neonatal transplants 12.0 years versus 3.76 in pediatric and 6.43 in adult transplantations. EBER positive histology was observed in 93% (39/42) of pediatric population versus 52% (12/23) of the adult population. During treatment 16 (23%) experienced acute rejection with 5 (7%) graft losses. The largest subset, monomorphic diffuse large B-cell lymphoma (n = 34), had a median overall survival of 15.1 years. M-DLBCL with high levels of EBV copy load > 10,000 IU/mL had a trend toward worse overall survival of 9.0 versus 15.1 years in < 10,000 IU/mL (HR 2.74, p = 0.14). Treatment resulted in complete serologic EBV copy load response in 15/19 and a trend toward improved overall survival with a median OS not yet reached versus 13.7 years in incomplete responders (HR 0.76, p = 0.76).

**Conclusions:** Our study introduces the hypothesis that initial EBV viral loads and treatment response may have prognostic importance. The characteristics, pathologic diagnosis, and treatment response for this cohort of patients will be presented.

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

## 506

### A RETRO-PROSPECTIVE STUDY IN HIV+ PATIENTS AFFECTED BY LYMPHOMA: THE MUSTHAL MULTICENTER EXPERIENCE IN NORTHERN ITALY
<figure><img src="image_293.png" /><figcaption>Figure 1</figcaption></figure>

Follow-up (months)

<figure><img src="image_294.png" /></figure>

24-months OS of different DLBCL subtypes according to cytogenetic and immunohistochemical features

G. Rindone<fnref n="1" />

A. Bandera²

F.A. Brioschi<fnref n="1" />

D. Dalu<fnref n="3" />

F. Pagni⁴

P. Vitiello<fnref n="5" />

M. Mena⁶

C. Fasola<fnref n="3" />

M. Rossi<fnref n="5" />

F. Crippa⁷

E. Suardi⁷

R. Epifani⁸

C. Zeroli⁹

G. Serio¹⁰

F. Cocito<fnref n="1" />

E. Doni<fnref n="1" />

O. Giglio¹¹

R.S. Rossi¹²

A. Gori²

C. Gambacorti Passerini<fnref n="1" />

L. Verga<fnref n="1" />

Oncology Unit, Sant'Anna Hospital, Como, Italy; ⁹Department of Internal Medicine, Infectiuos Disease Unit, ASST Valle Olona, Busto Arsizio Hospital, Busto Arsizio, Italy; ¹⁰Pathology Department, Pathology Unit, ASST Valle Olona, Busto Arsizio Hospital, Busto Arsizio, Italy;

¹¹Department of Internal Medicine, Infectious Disease Unit, Sant'Anna Hospital, Como, Italy; ¹²Pathology Department, Pathology Unit, « L. Sacco» Hospital, University of Milan, Milan, Italy

**Introduction:** HIV+ people carry a higher risk of developing lymphomas. Combined antiretroviral therapy (cART) improves survival, but HIV+ patients (pts) with lymphoma are still considered poorly treatable. Our aim was to describe biopathological features of a cohort of HIV+ pts affected by lymphoma and their clinical implications.

**Methods:** we conducted a retrospective and prospective multicentre study collecting clinical and immunovirological data in HIV+ pts affected by non-Hodgkin lymphoma (NHL) from 2003 and 2017 in six centres in Northern Italy, to evaluate overall (OS) and progression-free survivals (PFS). We collected biopathological data in 50 NHLs to better define the differences in term of outcome among diffuse large B-cell lymphomas (DLBCL) not otherwise specified (NOS), DLBCL

<footnote n="1">¹Clinic of Hematology, ASST Monza « San Gerardo » Hospital, University of Milano-Bicocca, Monza, Italy; ²Departement of Internal Medicine, Department of Pathophysiology and Transplantation, School of Medicine and Surgery, University of Milan, Milan, Italy, Infectious Diseases Unit Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy;</footnote>

<footnote n="3">³Department of Oncology, Oncology Unit, « L. Sacco » Hospital, University of Milan, Milan, Italy; ⁴Surgical Department, Pathology Unit, ASST Monza « San Gerardo » Hospital, University of Milano-Bicocca, Monza, Italy;</footnote>

<footnote n="5">⁵Clinic of Infectious Disease, ASST Monza, «San Gerardo Hospital», University of Milano-Bicocca, Monza, Italy; ⁶Medical Area Department, Infectious Disease Unit, Legnano Hospital, Legnano, Italy; ⁷Department of Health Sciences, Infectious and Tropical Disease Unit, San Paolo Hospital, University of Milano, Milan, Italy; ⁸Department of Oncology,</footnote>
double/triple expressors (DE/TE) and high grade B-cell lymphomas (HGBL). Differences in survival were tested with $\chi^2$ or Mann-Whitney tests. OS was estimated by Kaplan Meyer. Hazard ratios (HR) for mortality for each biopathological subtype were corrected for IPI score and T CD4+ lymphocyte count (CD4+) at diagnosis.

**Results:** 127 pts were enrolled: 86 DLBCL, 18 Burkitt lymphomas (BL), 6 primary central nervous system lymphomas (PCNSL), 11 plasmablastic lymphomas (PBL), 3 primary effusive lymphomas (PEL) and 3 anaplastic large T-cell lymphoma (ALCL). Median age was 48.9 years. 30% of the pts were on cART at NHL diagnosis. The burden of disease was usually high at diagnosis. 80/127 pts received R-CHOP and 40/127 pts R-DA-EPOCH or more intensive regimens. Median follow up is 28 months. 2-years OS and PFS were 69.3% and 61.3%, respectively. No differences in OS among different lymphoma subtypes were noted. We observed 33 progressions and 3 relapses after 1° line treatment (36/127, 28.3%). Factors significantly associated with a worse survival in multivariate analysis were Age, high IPI score and CD4+ < 200/µl at diagnosis. Pts with CD4+ < 200 cells/µl at diagnosis had a significantly higher HR for lymphoma-related deaths, especially those with a low disease burden (HR 4,136 if IPI ≤ 3). The use of cART at diagnosis had no impact on OS. The 50 pts screened for biopathological features resulted in 36 DLBCL NOS, 8 DLBCL DE/TE and 6 HGBL. HGBL showed a particularly high risk of poor response and early mortality as 6/6 pts died within 13 months, despite aggressive treatment schedules (Figure 1).

**Conclusions:** Usual lymphoma prognostic scores were found to be reliable in our cohort of HIV+ pts; an independent effect of CD4+ at diagnosis on NHL survival was noted. Biopathological analyses should be standardised to find rapidly HGBL-affected pts also in HIV+ population, as the response to chemotherapy seems to be poor. The majority of pts who progressed after first line of therapy died without receiving autologous bone marrow transplant. We advocate the possibility to create new studies and treatment protocols in these pts.

**Keywords:** high-grade B-cell lymphoma with or without rearrangement of MYC and BCL2 and/or BCL6; human immunodeficiency virus (HIV).

## 507
CHEMOTHERAPY IN HIV-POSITIVE PATIENTS WITH NON-HODGKIN LYMPHOMA: A SINGLE INSTITUTION RETROSPECTIVE STUDY

D. Dalu<fnref n="1" /> | C. Fasola<fnref n="1" /> | G. Bombonati<fnref n="1" /> |

D. De Francesco²

**Background:** HIV-positive (HIV+) patients (pts) have a 25-fold higher risk of developing non-Hodgkin's lymphomas (NHL). Two independent

prognostic factors influence the incidence and prognosis of HIV+ pts: highly active antiretroviral therapy (HAART) and the CD4+ lymphocyte (CD4+) count.

The diagnosis of NHL can occur simultaneously with the diagnosis of HIV infection (naïve patients) or after the diagnosis of HIV infection and during HAART (experience-patients).

Our aim is to compare the characteristics, the response to treatment and the survival of the NHL treated with first line chemotherapy, between naïve patients and experience-patients.

**Methods:** This is a single institution retrospective cohort study conducted in Ospedale Luigi Sacco Milan, Italy. We selected pts aged >18 years with diagnosis of HIV infection and NHL from January 2007 to January 2017. We included HIV+ on HAART treated with first line R-CHOP-like chemotherapy regimens.

Differences between naïve and experience-pts were assessed using Chi-square, Fisher's exact or Wilcoxon Rank-sum test. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were compared across groups using the log-rank test or Cox regression model.

**Results:** We enrolled 46 HIV+ pts: 11 naïve-pts and 35 experience-pts (exp-pts). No difference was observed in median age at diagnosis (49 vs 48 ys p=0.40), sex (male 72.7% vs 85.7 p=0.37), characteristic histological types PEL, PSNCL, BL, PBL (p=0.13).

Naïve-pts had higher stage at diagnosis (stage IV 90.9% vs 41.2% p=0.05). No difference was observed in frequency of B symptoms (40% vs 41% p=0.99), bulky masses (18.2% vs 20.6% p=0.99), ≥ 2 extranodal sites (45.5% vs 40% p=0.61), CNS involvement (44.4% vs 38.2% p=0.99), AIDS-defing diseases (44.4% vs 28.6% p=0.43) HCV/HBV infection (p=0.08/0.99). Naïve-pts were more likely to be in advanced aaIPI (intermediate-high risk: 90.0% vs 58.1% p = 0.11). As expected at NHL diagnosis naïve-pts had lower median CD4 + count (102 vs 222/mcl p=0.05).

During R-CHOP-like chemotherapy naïve-pts developed more frequently infectious toxicity (50% vs 10.7% p=0.02).

During a median (IQR 2-44) follow-up of 12 months no difference was observed in RR (CR 60% vs 62.5% p=0.85), median OS (67 mts vs 69.4 mts p=0.3) and PFS (p=0.8).

**Conclusions:** CD4+ count is the independent prognostic factor with the greatest influence on OS [exp vs naïve-pts: OS HR 0.83 (95% CI); OS/CD4+ HR 1.80 (95% CI)]. Our study supports the role of immediate start of HAART in combination with chemotherapy in naïve patients. A compromised immune status in HIV+ pts does not require modification of chemotherapy schedule; therefore naïve-pts should be treated with standard chemotherapy regimens.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); human immunodeficiency virus (HIV).

## 508
DOSE-ADJUSTED EPOCH FOR LYMPHOMA-ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: A STONE TWO BIRDS

<footnote n="1">¹Oncology Unit, Ospedale L. Sacco-Polo Universitario ASST FBF-Sacco, Milan, Italy; ²Department of Infection and Population Health, UCL, London, United Kingdom</footnote>
<figure><img src="image_295.png" /><figcaption>**Figure 1.** Trial profile (abbreviations: HLH=hemophagocytic lymphohistiocytosis; NHL=non-Hodgkin's lymphoma; NK=natural killer; PD=progressive disease)</figcaption></figure>

W. Xu | J. Liang | L. Wang | H. Zhu | Y. Xia |

W. Wu | L. Fan | J. Li

Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China; Key Laboratory of Hematology of Nanjing Medical University, Nanjing, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, China, Nanjing, China

**Purpose:** Lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH) has a high fatality rate and the worst outcome. The major cause of LA-HLH is aggressive non-Hodgkin's lymphoma (NHL), especially T/NKT cell lymphomas. Until now, there is no recommended therapeutic schedule for this fatal disease. Dose-adjusted (DA) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) shows effective activity in patients with aggressive NHL, which also contains the critical drugs for HLH of HLH-94/04. The investigators therefore developed DA-EPOCH regimen to treat non-Hodgkin's lymphoma with hemophagocytic lymphohistiocytosis and assess its clinical outcome including safety and efficacy.

**Methods:** We did a single-arm, open-label, phase 2 clinical trial in previously untreated patients diagnosed as NHL with HLH (NCT01818908). We planned for B-NHL patients with HLH to receive six cycles of the DA-EPOCH-R regimen while for T/NK-NHL patients with HLH to receive six cycles of the DA-EPOCH regimen. Also, after achieving more than partial response (PR) after six cycles of DA-EPOCH±R regimen, autologous stem cell transplantation (ASCT) for

B-NHL or allogeneic stem cell transplantation (allo-SCT) for T/NK-NHL was followed as consolidation therapies. The DA-EPOCH±R regimen included etoposide (50 mg/m²), vincristine (0.4 mg/m²), and doxorubicin (10 mg/m²) at daily doses by continuous intravenous infusion over 96 hours (days 1–4); cyclophosphamide (750 mg/m², intravenous bolus, day 5), prednisone (60 mg/m² bid, days 1–5) with or without rituximab (375 mg/m², day 0). The cycle was repeated every 3 weeks. The primary endpoint was the overall response rate (ORR).

**Results:** We enrolled 26 B-NHL and 29 T/NK-NHL patients between March, 2013 and Dec, 2015 (Figure 1). The median cycle was six (range 1-6) for all B-NHL patients and three (range 1-6) for T/NK-NHL patients. The overall response rate was 80.7% for B-NHL while only 13.8% for T/NK-NHL. With a median follow-up of 52 months (35-75 months) for B-NHL with HLH, 5-year progression-free survival (PFS) and overall survival (OS) was 56.7 ± 9.9% and 73.1 ± 8.7%. B-NHL patients who received ASCT (12 patients) have significantly superior PFS (P<0.001) and OS (P=0.033) than patients not (9 patients). For the T/NK-NHL with HLH, 6-month PFS and OS rate was 10.3 ± 5.7% and 24.1 ± 7.9%. Grade 3/4 neutropenia toxicities occurred on 43.9% of all cycles.

**Conclusions:** DA-EPOCH-R regimen as front-line treatment followed by ASCT as consolidation treatment demonstrates a highly effective and safe strategy for B-NHL patients with HLH while DA-EPOCH cannot improve outcomes for T/NK-NHL patients with HLH.

**Keywords:** DA-R-EPOCH; histiocytes; non-Hodgkin lymphoma (NHL).
509

A VALIDATION, WITH NEW CLINICAL
APPLICABILITY, OF A CLINICAL-GENETIC
RISK MODEL THAT PREDICTS
THROMBOSIS WITH HIGH SENSITIVITY IN
PATIENTS WITH LYMPHOMA

M. Bastos-Oreiro<fnref n="1" /> | J. Ortiz<fnref n="1" /> | V. Pradillo<fnref n="1" /> |

C. Martinez-Laperche<fnref n="1" /> | E. Salas² | I. Buño Borde<fnref n="1" /> |

J. Díez-Martín<fnref n="1" /> | J. Soria² | C. Pascual<fnref n="1" />

The incidence of venous thromboembolic events (VTE) in patients with lymphoma is estimated around 10%, increasing the morbidity and mortality for this group of patients. Khorana scale has been developed to assess VTE risk in cancer patient but it is not useful for lymphoma patients. Recently, a new risk score has been developed to predict VTE in this specific population (Throly). Likewise, the incorporation of genetic variables into a VTE risk model improved VTE risk assessment in solid tumors (TiC-ONCO). In this context, the aim of our study was to evaluate if the same approach of TiC-ONCO is applicable to patients with lymphoma.

Between 2014 and 2018, 254 lymphomas were diagnosed in our center, 33 of them presented VTE. The F5 rs6025, F5 rs4524, F13 rs5985, SERPINA10 rs2232698, in addition to clinical variables (immobilization, tumor type, Ann Arbor score, mediastinum extension, and personal thrombotic history) were significant associated to VTE

risk and used to build the TiC-ONCO-associated Lymphoma score (TiC-Lympho). The Khorana, ThroLy and TiC-Lympho scores were compared through predictive value and area under the curve (AUC). We observed a cumulative incidence of VTE of 9% (Fig.1). The results of sensitivity, specificity, predictive value and AUC of the Khorana, Throly, and TiC-Lympho are shown in Table 1 and Table 2.

Our results demonstrated that the incorporation of genetic-clinical data to assess VTE risk it is not only valid to solid tumors, but it is also relevant in lymphoma. In fact, it is the first time that this approach has been applied to haematological patients. It is noteworthy that the predictive capacity for VTE in lymphoma patients of our score far exceeds that obtained by the Khorana and Throly scores. Therefore, TiC-Lympho will allow us to categorize lymphoma patients adequately at diagnosis and offering an individualized thromboprofilaxis.

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

510

NEUTROPHIL TO LYMPHOCYTE RATIO,
PLATELET TO LYMPHOCYTE RATIO, AND
RISK OF THROMBOEMBOLISM IN
PATIENTS WITH LYMPHOMA RECEIVING
CHEMOTHERAPY

D. Antic<fnref n="1" /> | V. Otasevic<fnref n="1" /> | N. Milic² |

T. Virijevic-Salak³ | V. Vukovic<fnref n="1" /> | V. Djurasinovic<fnref n="1" /> |

K. Tomic<fnref n="1" /> | B. Mihaljevic<fnref n="1" />

<table><caption>Table 1</caption><thead><tr><th>Score</th><th>Sensitivity</th><th>Specificity</th><th>PPV</th><th>NPV</th></tr></thead><tbody><tr><td>Tic-Lympho</td><td>93,55</td><td>54,49</td><td>23,36</td><td>97,98</td></tr><tr><td>Khorana</td><td>35,48</td><td>71,79</td><td>16,60</td><td>84,41</td></tr><tr><td>Throly</td><td>45,16</td><td>64,74</td><td>50</td><td>86,63</td></tr></tbody></table>

<table><caption>Table 2</caption><thead><tr><th>Score</th><th>AUC</th><th>(95% CI)</th><th>p</th></tr></thead><tbody><tr><td>Tic-Lympho</td><td>0,783</td><td>(0,721-0,837)</td><td>&lt;0,0001</td></tr><tr><td>Khorana</td><td>0,503</td><td>(0,431-0,574)</td><td>0,902</td></tr><tr><td>Throly</td><td>0,579</td><td>(0,50-0,648)</td><td>0,0319</td></tr></tbody></table>

<figure><img src="image_296.png" /><figcaption>Figure 1. Cumulate incidence of Thrombosis</figcaption></figure>

<footnote n="1">¹Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; ²Hematology, Hospital Universitario de la Santa Creu i Sant Pau, Barcelona, Spain</footnote>

<footnote n="1">¹Lymphoma Centre, Clinic for Hematology, Clinical Centre of Serbia, Belgrade, Serbia; ²Institute for Statistics, Faculty of Medicine, University</footnote>
of Statistics, Belgrade, Serbia; ³Hematology, University Clinic of Republic of Srpska, Banja Luka, Bosnia and Herzegovina

**Introduction:** Thromboembolism (TE) is common and one of major causes of morbidity and mortality in patients with malignancy. The neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) are biomarkers for systemic inflammation. Principal advantage of NLR and PLR is their modest computability from complete blood count (CBC). Several publications showed predictive strength of high NRL for development of venous thromboembolism (VTE) in cancer patients receiving chemotherapy. However, the prognostic values of the NLR and PLR in patients with lymphoma have not been elucidated. We aimed to investigate the association between NLR, PLR and future risk of TE, in a prospective cohort of lymphoma patients receiving chemotherapy.

**Methods:** A total of 484 patients who were diagnosed with lymphoma (including non-Hodgkin and Hodgkin lymphoma; excluding chronic lymphocytic leukemia/small lymphocytic lymphoma) at the Clinic for Hematology, Clinical Centre of Serbia, were prospectively included in the study. Data for newly diagnosed and relapsed patients who had completed a minimum of one chemotherapy cycle were collected for all venous and arterial TE events from time of diagnosis to 3 months after the last cycle of therapy. NLR and PLR were calculated according to the CBC. TE was diagnosed objectively based on radiographic studies, clinical examination, and laboratory evaluation. Logistic regression analysis and ROC curve were performed to assess the association of NLR and PLR with TE.

**Results:** The mean patients' age was 53 years (range, 18-89 years); 52.3% were males. Most patients were newly diagnosed and had advanced stage disease: Ann Arbor stage III 21.1% and stage IV, 42.5%. A total of 242 patients (50.0%) had high-grade NHL; 137 (28.3%) had low-grade NHL; 84 (17.4%) had HL; 21 (4.3%) had other forms. 35 (7.2%) patients developed thromboembolic events. There were 30 patients with venous TE (6.2%), and 6 with arterial TE (1.2%), while one patient had both. NLR and PLR were significantly higher in TE patients compared to patients without TE (p=0.001 and p=0.002, respectively). The NLR was positively associated with PLR (p<0.001). A positive NLR was considered 3.1 or higher, while a positive PLR was a ratio of 10 or more. The ROC curve analysis demonstrated acceptable specificity and sensitivity of NLR and PLR in predicting TE. NLR and PLR were found to be prognostic factors for the TE in lymphoma patients (relative risk [RR] = 4.1, 95% confidence interval [CI] = 1.9-8.7, p<0.001 and RR=2.9, 95% CI =1.3-6.3, p=0.008, respectively). In multivariate model NLR was found to be independent prognostic factors for the TE (RR=4.5, 95% CI=2.1-9.9, p<0.001).

**Conclusion:** The NLR and PLR demonstrated significant powerfulness in prediction of future risk of TE in lymphoma patients. Simplicity, effectiveness, modesty and practicability qualify these new tools for routine TE prognostic assessment.

**Keywords:** chemotherapy; immunochemotherapy; prognostic indices.

## 511
CLINICAL OUTCOMES FROM VENETOCLAX BASED THERAPY IN PATIENTS WITH RELAPSED/REFRACTORY B-CELL LYMPHOMAS

K.L. Lewis¹ | M. Dowling² | K. Bavishi³ |
A.K. Øvlisen⁴ | N. Hamad⁵ | P. Choi⁶ | A. Grigg⁷ |
S. P'Ng⁸ | R. Filshie⁹ | D.S. Ritchie¹⁰ | I. Bilmon¹¹ |
H.M. Prince² | M. Wolf² | M. Hertzberg¹² |
H. Chuah¹³ | T.C. El-Galaly⁴ | C.S. Tam¹⁴ |
J.F. Seymour¹⁰ | C.Y. Cheah¹

¹Department of Haematology, Sir Charles Gairdner Hospital, Perth, Australia; ²Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia; ³Department of Haematology, Cairns Hospital, Cairns, Australia; ⁴Department of Haematology, Aalborg University Hospital, Aalborg, Denmark; ⁵Department of Haematology, St Vincent's Health Australia, Sydney, Australia; ⁶Department of Haematology, The Canberra Hospital, Canberra, Australia; ⁷Department of Haematology, Austin Hospital, Melbourne, Australia; ⁸Department of Haematology, Fiona Stanley Hospital, Perth, Australia; ⁹Department of Haematology, St Vincent's Hospital, Melbourne, Australia; ¹⁰Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia; ¹¹Department of Haematology, Westmead Hospital, Sydney, Australia; ¹²Department of Haematology, Prince of Wales Hospital and UNSW, Randwick, Australia; ¹³Department of Haematology, Rockingham General Hospital, Perth, Australia; ¹⁴Department of Haematology, Peter MacCallum Cancer Centre, St Vincent's Hospital and University of Melbourne, Melbourne, Australia

**Background:** B-cell non-Hodgkin lymphomas (B-NHL) are frequently characterised by deregulation of the B-cell leukaemia/lymphoma-2 (BCL2) family of anti-apoptotic proteins. Venetoclax is a BCL2-specific inhibitor approved for chronic lymphocytic leukemia (CLL), with activity in other B-cell malignancies in small cohorts. Venetoclax has been available for patients (pts) with relapsed/refractory B-NHL via the Abbvie compassionate access scheme or as off label treatment, however data regarding effectiveness in this setting are scarce.

**Methods:** We performed a multicentre, international, retrospective study of the clinical outcomes and safety of pts with B-NHL (excluding CLL) who received venetoclax either as monotherapy or as combination treatment in Australia or Denmark between 7/2016 and 12/2018.

**Results:** The baseline characteristics of the 24 eligible pts are summarised in the table (Figure 1a). Target daily dose varied from 400-1200mg and was reached in 77%. Among all pts, the objective response rate (ORR) was 35%, clinical benefit rate (SD/PR/CR) 65% and CR rate 8%; one patient each with MCL and transformed follicular lymphoma. The Waldenstrom macroglobulinaemia patient
a

<table><thead><tr><th colspan="2">Patient characteristics, n=24</th></tr><tr><th>Characteristic</th><th>Study patient cohort, n (%)</th></tr></thead><tbody><tr><td>Sex</td><td></td></tr><tr><td>Male</td><td>14 (58%)</td></tr><tr><td>Female</td><td>10 (42%)</td></tr><tr><td>Median age (years) at starting Venetoclax (range)</td><td>64 (46-78)</td></tr><tr><td>Diagnosis</td><td></td></tr><tr><td>Mantle cell lymphoma</td><td>12 (50%)</td></tr><tr><td>Diffuse large B cell lymphoma</td><td>5 (22%)</td></tr><tr><td>Transformed follicular lymphoma</td><td>2 (8%)</td></tr><tr><td>Richter's transformation of CLL</td><td>2 (8%)</td></tr><tr><td>Follicular lymphoma</td><td>1 (4%)</td></tr><tr><td>Waldenstrom macroglobulinaemia</td><td>1 (4%)</td></tr><tr><td>Unspecified</td><td>1 (4%)</td></tr><tr><td>TP53 mutated or 17p deleted</td><td>5/9 (56%)</td></tr><tr><td>MCL</td><td>3/5</td></tr><tr><td>Richter's transformation of CLL</td><td>2/5</td></tr><tr><td>ECOG performance status</td><td></td></tr><tr><td>0-1</td><td>14/19 (74%)</td></tr><tr><td>2-4</td><td>5/19 (26%)</td></tr><tr><td>Unknown</td><td>5/19 (26%)</td></tr><tr><td>B symptoms</td><td>11/22 (50%)</td></tr><tr><td>Ann Arbor Stage</td><td></td></tr><tr><td>I-II</td><td>1/21 (5%)</td></tr><tr><td>III-IV</td><td>20/21 (95%)</td></tr><tr><td>Median no. of prior therapies (range)</td><td>4 (1-7)</td></tr><tr><td>Prior Autologous stem cell transplant</td><td>7/24 (29%)</td></tr><tr><td>Prior BTK inhibitor therapy</td><td>14/24 (58%)</td></tr><tr><td>Best response to most recent prior therapy</td><td></td></tr><tr><td>PD</td><td>11 (46%)</td></tr><tr><td>SD</td><td>4 (17%)</td></tr><tr><td>PR/VGPR/CR</td><td>9 (37%)</td></tr><tr><td>Concurrent systemic therapy</td><td>8 (33%)</td></tr><tr><td>Ibrutinib</td><td>4</td></tr><tr><td>Rituximab</td><td>1</td></tr><tr><td>Steroids/other</td><td>3</td></tr><tr><td>Concurrent radiotherapy</td><td>6 (25%)</td></tr></tbody></table>

<figure><img src="image_297.png" /></figure>

<figure><img src="image_298.png" /><figcaption>Figure 1.</figcaption></figure>

a) Patient baseline and treatment characteristics

b) Progression free survival (all patients)

c) Overall survival (all patients)

achieved a MR with monotherapy, improving to a PR when cyclophosphamide and dexamethasone were subsequently added. The ORR was 50% and 27% for pts treated with venetoclax combined with additional systemic therapy and monotherapy respectively. The ORR was 42% in MCL (ORR 66%, n=2 in those receiving combination treatment, and ORR 33%, n=3 in BTK inhibitor refractory pts) and 0% in DLBCL. 1/5 patients bearing TP53 aberrations (n=5 [MCL n=3, Richter's n=2]) had a response (PR). Median time on venetoclax, PFS and OS for all pts were 2.7, 2.4 and 3.1 months respectively (Figure 1b,c). 5 pts had a PFS >6 months (maximum 20.4 months), and 6 pts (25%) were alive at last follow-up, with 4 (17%) remaining on venetoclax. 75% (n=3) of these received concurrent therapy (ibrutinib n=2) and 25% (n=1) received monotherapy. Causes of death included progressive lymphoma (78%,

n=14) and infection (11%, n=2). 10 (50%) discontinued therapy due to PD and 4 (20%) due to adverse events. The most frequent grade 3/4 adverse events were neutropenia (35%, n=6), febrile neutropenia (18%, n=3), tumour lysis syndrome (laboratory 33%, n=8 [MCL n=6, DLBCL n=1, Richter's n=1], clinical 8%, n=2 [MCL n=2]), thrombocytopenia (17%, n=4) infection (12%, n=3) and anaemia (8%, n=2), and diarrhoea (4%, n=1)

**Conclusions:** In a heavily pre-treated population of pts with various B-NHL, venetoclax resulted in modest activity and an adverse event profile similar to published trials. Response rates were numerically higher in patients receiving concurrent systemic therapy, suggesting potential synergy, especially with ibrutinib. Venetoclax had limited activity in the low numbers of pts with MCL refractory to BTK inhibitors, and minimal activity in DLBCL and pts with TP53 aberrations.
**Keywords:** B-cell lymphoma; venetoclax.

**Disclosures:** El-Galaly, T: Employment Leadership Position: Roche.

**Tam, C:** Honoraria: Abbvie; Research Funding: Abbvie. Seymour, J: Consultant Advisory Role: Abbvie, Roche 7, Janssen; Honoraria: Abbvie, Roche 7, Janssen; Research Funding: Abbvie, Roche 7, Janssen; Other Remuneration: Abbvie, Roche 7, Janssen, (speaker). 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 expenses).

## 512
INCREASED CYTOMEGALOVIRUS (CMV) REACTIVATION IN PATIENTS TREATED WITH BENDAMUSTINE BASED REGIMEN IS CORRELATE WITH DRAMATICAL REDUCTION OF CD4+ T LYMPHOCITES

L. Pezzullo | A. Bruno | G. Cassiodoro | R. Bianco |

G. Villani | E. Vaccaro | R. Rosamilio |

M. Martorelli | R. Fontana | R. Guariglia | B. Serio |

C. Selleri

Hematology, Salerno Medicine University, Salerno, Italy

Bendamustine (BENDA) alone or in combination with other drugs is being increasingly used in the treatment of chronic lymphocytic leukaemia (CLL), non-Hodgkin lymphomas (NHL), and multiple myeloma (MM) due to its safety and efficacy. Variable infection rates both in BENDA monotherapy and in BENDA-containing regimens have been documented, while it is reported that CD4+ lymphocytes are severely reduced during BENDA therapy, that their recovery is impaired and that CD4+ lymphopenia persists for a long time after the end of BENDA administrations.

Since January 2017 we started monitoring levels of CD4+ lymphocytes of patients undergoing to a treatment with schedules BENDA based. At today 51 consecutive patients, 15 female and 36 male with median age of 70 old years (range 40-88 years), had at least one CD4+ lymphocytes detection. All the patients had a B-NHL diagnosis. 34 patients were treated with BENDA plus Rituximab (R-BENDA), while 17 with BENDA plus Rituximab plus Dexamethasone (RD-BENDA).

In 41 new patients, our measurements started before the beginning of BENDA courses, with a median of basal CD4+ lymphocytes of 617 cells/mm3 (range 154-1278 cells/mm3). After 2/3 BENDA courses, it dropped to 42 cells/mm3 (range 0-118 cells/mm3). (P value <0.004) 30 patients are evaluable on their last planned BENDA course (4 to 6 courses). Their median of CD4+ lymphocytes was 53 cells/mm3 (range 15-160 cells/mm3).

25 patients are evaluable after 3 months from the end of the therapy. Their median of CD4+ lymphocytes was 94 cells/mm3 (range 41-288 cells/mm3).

After 6 months, CD4+ lymphopenia is still present in 15 evaluable patients. Their median of CD4+ lymphocytes was 186 cells/mm3

(range 114-399 cells/mm3). In 15 (30%) patients we have documented the reactivation of CMV virus; 7 in the group RD-Benda and 8 in the group R-Benda (41% and 23% of treated patients).

This single-center study provides further evidence that BENDA regimens for lymphoproliferative diseases are associated with a deep reduction of CD4+ lymphocytes which persists even after 6 months off-therapy and requires an adequate monitoring and prophylaxis to avoid infections.

**Keywords:** Bendamustine; CD4.

## 513
OFF-LABEL USE IN LYMPHOMA PATIENTS IN SWITZERLAND

A.K. Herbrand¹ | A.M. Schmitt¹ | M. Joerger² |

L.G. Hemkens³ | B. Kasenda⁴

¹Department of Medical Oncology, University Hospital Basel, Basel, Switzerland; ²Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland; ³Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland; ⁴Department of Hematology/Oncology and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany

**Background:** Off-label use (OLU) of drugs in haematology/oncology is increasing, however, little is known on the frequency of OLU in lymphoma therapy and whether it is more common than for solid tumors. It is also unclear how often requested OLU is actually reimbursed by health insurers.

**Methods:** We conducted a cross-sectional study using information from routinely collected health data. We included all patients treated for a malignant disease between January 2015 and July 2018 in the Department of Medical Oncology of the University Hospital Basel and manually screened their electronic patient records. For all patients, for which at least one request for OLU reimbursement was issued, we extracted information on patient demographics, disease characteristics, treatment history and correspondence with the health insurer. We defined OLU as intentional drug use outside of the Swissmedic label. Main outcomes were the drug type and approval/rejection of an OLU request. We used descriptive statistics to investigate the prevalence of OLU for lymphoma therapy compared to solid tumors and to determine whether health insurers more often reimburse intended OLU for lymphoma compared to solid tumors.

**Results:** We screened health care records of 1865 patients. 159 (8.5%) had a lymphoma and 1706 (91.5%) a solid tumor. Among lymphoma patients, OLU requests are more prevalent than among patients with a solid tumor (30 of 159 requests [18.9%] versus 214 of 1706 requests [12.5%]). Preliminary results show that top three lymphomas with OLU requests were follicular lymphoma (N=7), diffuse large B-cell lymphoma (DLBCL, N=7) and primary central nervous system lymphoma (PCNSL, N=4). Most frequently requested drugs were rituximab (N=18), obinutuzumab (N=4) and thiotepa (N=4). There was more intended
OLU in first line treatment of lymphoma than for solid tumors (23 of 30 [76.7%] versus 125 of 214 [58.4%]). Requests for OLU for lymphoma patients were less frequently rejected by health insurers (3 of 30 [10.0%] versus 64 of 214 [29.9%]). In two cases, OLU of the same drug and the same lymphoma therapy indication was approved by one health insurer for reimbursement but rejected by another.

**Conclusion:** In Switzerland, off-label use seems to be more frequent in lymphoma patients than in patients with solid tumors. Their chances for reimbursement of OLU also seem to be higher. However, reimbursement decisions seem to be inconsistent, which reflects intransparency of the current decision making process on OLU reimbursement requests by health insurers. Reasons for these differences remain to be elucidated and further data will be presented at the meeting.

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

514
# CT-P10 RAPID INFUSION IN PATIENTS WITH NON-HODGKIN'S LYMPHOMA OR CHRONIC LYMPHOCYTIC LEUKAEMIA: INTERIM RESULTS FROM A NON-INTERVENTIONAL POST-AUTHORISATION SAFETY STUDY

M. Bishton¹ | S.R. Marshall² | V. Conteh³ |

A. Rodríguez Fernández⁴ | H. Kang⁵ | S. Kim⁵ |

Y. Lee⁵ | P. Zinzani⁶

¹Department of Haematology, City Hospital Nottingham, Nottingham, United Kingdom; ²Department of Haematology, Sunderland Royal Hospital, City Hospitals Sunderland NHS Trust, Sunderland, United Kingdom; ³Cancer Services, Royal Free London NHS Foundation Trust, Barnet Hospital, Barnet, United Kingdom; ⁴Department of Haematology, Hospital Universitario Virgen Macarena, Sevilla, Spain; ⁵Medical Affairs, Celltrion Healthcare, Incheon, Republic of Korea; ⁶Institute of Hematology "Serågnoli", University of Bologna, Bologna, Italy

**Introduction:** CT-P10 is the first rituximab biosimilar approved in Europe for treatment of rheumatic diseases and specific blood cancers including non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). To minimise the risk of infusion-related reactions (IRRs), the recommended rituximab administration protocol is a slow initial infusion rate with gradual up-titration; however, rapid infusion protocols are now used widely for second and subsequent infusions in patients with no serious complications from their first infusion. A recent meta analysis (Polwart, 2017) reported an IRR rate of 8.8% for rapidly infused rituximab; there are limited data for CT-P10. This study aimed to evaluate the safety and effectiveness of rapidly infused CT-P10 in patients with NHL or CLL in a real world setting.

**Methods:** This non-interventional post-authorisation safety study is ongoing in 4 European countries (United Kingdom [UK], Spain, France, Italy) and involves collection of data from the medical records of

consenting adult patients with NHL or CLL who received rapidly infused CT-P10 (i.e. total infusion time ≤90 minutes) during routine care. Index date (day 1): date of first rapid CT-P10 infusion, given in the second or a subsequent cycle. Safety and effectiveness data are collected for 6 months post-index (or to death, if sooner). Primary outcome: incidence of IRRs on day 1 or 2 post-index. Response to CT-P10 is as documented by the local investigator. Interim results are based on a data cut on 18 Jan 2019. Where n is less than the total number of patients, data were missing.

**Results:** The interim analysis includes 110 patients enrolled from the UK and Spain. 98 patients (90%) have NHL (68 [62%] diffuse large B-cell lymphoma, 30 [28%] follicular lymphoma) and 11 (10%) have CLL (n=1 diagnosis missing). Other patient characteristics at index: 66 (60%) male; median age 68 years (interquartile range [IQR] 59-74) (n=109); median disease duration 0.2 years (IQR 0.1-0.3) (n=109); 22 (20%) patients with prior NHL/CLL treatment (n=109); Eastern Cooperative Oncology Group performance status (n=71): 0 (n=34, 48%), 1 (n=27, 38%), 2 (n=3, 8%), 3 (n=6, 8%) or 4 (n=1, 1%); Ann Arbor stage for NHL (n=52): I (n=4, 8%), II (n=5, 10%), III (n=7, 13%) or IV (n=36, 69%); Binet stage for CLL (n=7): A (n=4, 57%), B (n=1, 14%) or C (n=2, 29%). 8/106 patients with data available (8%) had IRRs recorded on day 1 or 2 post-index. Ten IRRs were reported (fatigue [n=3], oropharyngeal pain, vomiting, nausea, rash, headache, generalized oedema, peripheral oedema [all n=1]), of which 8 were grade 1 (mild), 1 was grade 2 (moderate) and 1 was grade 3 (severe [oropharyngeal pain during cycle 2, unlikely to be related to CT-P10 according to local investigator opinion]). Best responses to CT-P10 during the observation period are shown in Fig. 1.

**Conclusions:** This is the first multi-country study to investigate the safety and effectiveness of rapidly infused CT-P10 in a real world setting. Early results suggest that the IRR rate for rapidly infused CT-P10 is similar to rates previously reported for reference rituximab.

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

**Disclosures:** kang, H: Employment Leadership Position: Celltrion Healthcare. Kim, S: Employment Leadership Position: Celltrion

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