1.085-2.227], p=0.016, and PFS, HR 1.564 [95%CI: 1.15-2.129], p=0.004. DTI of ≤7 days was significantly associated with several established markers of poor prognosis in DLBCL, including elevated lactate dehydrogenase (p<0.001), and advanced Ann Arbor stage (III or IV) p=0.034. Other poor prognostic markers such as the revised international prognostic (RIPI) score, cell of origin, Eastern Cooperative Group (ECOG) score ≥2, age >60 years and presence of 'B' symptoms did not show significant associations with a DTI ≤7 days. In comparing the non-trial and trial groups, no statistically significant difference between the aforementioned characteristics was present.

**Conclusion:** These findings confirm that patients requiring emergent treatment for DLBCL experience inferior OS and PFS and are more likely to have elevated LDH and advanced stage disease. The significantly higher median DTI in clinical trial participants suggests these patients are not representative of the general DLBCL cohort. Our findings raise further concerns for significant selection bias against poor risk patients treated on upfront clinical trials in DLBCL. Further work is needed to evaluate the extent of this bias and strategies to ensure patients requiring emergent treatment are included in future clinical trials is essential

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

**Disclosures:** Gilbertson, M: Honoraria: Roche.

## 373
# A RETROSPECTIVE ANALYSIS OF REAL-WORLD OUTCOMES OF CHINESE ELDER PATIENTS WITH DIFFUSE LARGE B CELL LYMPHOMA (DLBCL)

P. Liu | Y. Han | S. Jiang | X. He | Y. Qin | L. Gui | S. Zhou | L. Zhou | J. Yang | S. Yang | T. Wen | Y. Shi

Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

**Background:** Elderly patients with diffuse large B-cell lymphoma (DLBCL) have a worse prognosis compared to the younger population, however, this group is often precluded from clinical trials and population-based studies, optimal treatment strategy for the old patients with DLBCL remains controversial. Here, we describe a Chinese real-world experience of management of elderly DLBCL patients.

**Methods:** Consecutive DLBCL patients aged ≥ 60 were included in this single-center, retrospective analysis. The standard regimens included 3-4 cycles (early stage disease) or 6 cycles (advanced) of R-CHOP like regimens (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) followed by two rituximab doses in fit patients; R-miniCHOP for unfit and R-CE(etoposide)OP for frail elder patients. The primary endpoint was progression-free survival (PFS).

<table><caption>**TABLE 1** Baseline characteristics for 349 patients with diffuse large B-cell lymphoma (DLBCL) aged <70 years and ≥70 years</caption><thead><tr><th></th><th>60-69<br>years</th><th>≥70 years</th><th>All</th><th>p-value</th></tr></thead><tbody><tr><td>Number</td><td>204 (58.5)</td><td>145 (41.5)</td><td>349</td><td></td></tr><tr><td>Male (%)</td><td>108 (53)</td><td>78 (54)</td><td>186 (53)</td><td>0.875</td></tr><tr><td>Extranodal sites</td><td></td><td></td><td></td><td>0.799</td></tr><tr><td>0/1</td><td>153 (75)</td><td>107 (74)</td><td>260 (74)</td><td></td></tr><tr><td>>1</td><td>51 (25)</td><td>38 (26)</td><td>89 (26)</td><td></td></tr><tr><td>Ann Arbor<br>Stage</td><td></td><td></td><td></td><td>0.380</td></tr><tr><td>I-II</td><td>125 (61)</td><td>88 (61)</td><td>213 (61)</td><td></td></tr><tr><td>III-IV</td><td>79 (39)</td><td>57 (39)</td><td>136 (39)</td><td></td></tr><tr><td>B-symptoms</td><td></td><td></td><td></td><td>0.961</td></tr><tr><td>Yes</td><td>37 (18)</td><td>26 (18)</td><td>63 (18)</td><td></td></tr><tr><td>No</td><td>167 (82)</td><td>119 (82)</td><td>286 (82)</td><td></td></tr><tr><td>ECOG<br>performance<br>status</td><td></td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>0-1</td><td>158 (77)</td><td>87 (60)</td><td>245 (70)</td><td></td></tr><tr><td>2-4</td><td>46 (23)</td><td>58 (40)</td><td>104 (30)</td><td></td></tr><tr><td>LDH</td><td></td><td></td><td></td><td>0.878</td></tr><tr><td>Normal</td><td>101 (50)</td><td>73 (50)</td><td>174 (50)</td><td></td></tr><tr><td>Elevated</td><td>103 (50)</td><td>72 (50)</td><td>175 (50)</td><td></td></tr><tr><td>IPI</td><td></td><td></td><td></td><td>0.065</td></tr><tr><td>0-1</td><td>72 (35)</td><td>37 (25)</td><td>109 (31)</td><td></td></tr><tr><td>2-3</td><td>98 (48)</td><td>72 (50)</td><td>170 (49)</td><td></td></tr><tr><td>4-5</td><td>34 (17)</td><td>36 (25)</td><td>70 (20)</td><td></td></tr><tr><td>Treatment</td><td></td><td></td><td></td><td>0.112</td></tr><tr><td>Chemo only</td><td>79 (38.7)</td><td>59 (40.7)</td><td>138</td><td></td></tr><tr><td>Chemo<br>+Rituximab</td><td>113 (55.4)</td><td>75 (51.7)</td><td>188</td><td></td></tr><tr><td>Others</td><td>12 (5.9)</td><td>11 (7.6)</td><td>23</td><td></td></tr></tbody></table>

Abbreviations: LDH, lactate dehydrogenase; ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index.

**Results:** From June 2006 to December 2012, 349 eligible patients were included, in which 204 patients were aged <70 years. 326 patients received chemotherapy or chemo-immunotherapy with rituximab. With a median follow up of 82 months, the 5-year PFS and OS were 45.8% and 51.9%, respectively. Significant difference was seen between patients < 70 years and those ≥70 years in terms of PFS (51.0% vs 38.6%, p=0.030) and OS (58.3% vs 42.8%, p=0.007). Patients with early-stage disease (Ann Arbor Stage I/II) had better 5-year PFS (60.1% vs 23.5%, p<0.001) and OS (65.3% vs 30.9%, p<0.001) than patients with advanced disease stage (Ann Arbor Stage III/IV). In addition, regimen including rituximab significantly improved the survival than chemotherapy alone (5-year PFS: 37.3% vs 64.0%, p<0.001; 5-year OS: 44.5% vs 69.3%, p<0.001), especially in patients ≥70 years, which almost doubled 5-year PFS and OS (5-year PFS:
<figure><img src="image_224.png" /><figcaption>Figure 2 Overall survival (A) and Progression-free survival (B) for elderly patients with DLBCL according to age group</figcaption></figure>

<figure><img src="image_225.png" /><figcaption>Figure 3 Overall survival (A) and Progression-free survival (B) for elderly patients according to Ann Arbor Stage.</figcaption></figure>

<figure><img src="image_226.png" /><figcaption>Figure 4 Overall survival (A) and Progression-free survival (B) for 134 elderly patients ≥70y according to therapy.</figcaption></figure>

<figure><img src="image_227.png" /><figcaption>Figure 5 Overall survival (A) and Progression-free survival (B) for elderly patients with N-DLBCL and EX-DLBCL</figcaption></figure>

<figure><img src="image_228.png" /></figure>

25.4% vs 50.7%, p<0.001; 5-year OS: 28.8% vs 56.0%, p<0.001)
(Figure 3).

**Conclusions:** Older age (≥70 years) and advanced disease stage (Ann Arbor Stage III/IV) are associated with poor PFS and OS in Chinese elder DLBCL patients. The addition of rituximab significantly improves the survival, especially in patients aged ≥70 years. These findings underscore the importance of personalized evaluation and treatment in elder patients with DLBCL.

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

**Disclosures:** LIU, P: Research Funding: CAMS Innovation Fund for Medical Sciences(CIFMS)] (Grant no. 2016-12M-1-001), National Key Technology Support Program (2014BAI09B12 lymphoma).

374
HYPOGAMMAGLOBULINEMIA AND
HYPOCOMPLEMENTEMIA AS STRONG
PROGNOSTIC FACTORS IN NEWLY
DIAGNOSED DIFFUSE LARGE B CELL
LYMPHOMA
<figure><img src="image_229.png" /><figcaption>**Figure 1.** Progression-free survival according to hypogammaglobulinemia (A) and hypocomplementemia (B); overall survival according to hypogammaglobulinemia (C) and hypocomplementemia (D)</figcaption></figure>

W. Xu | B. Pan | H. Zhu | L. Wang | 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

**Introduction:** Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) in all over the world, occupied almost 31% in all NHL. In our study, we analyzed the serum immunoglobulin and complement levels of newly diagnosed DLBCL patients in our hospital in order to evaluate their prognostic value and want to build a new prognostic model.

**Methods:** Five hundred and fifty-three newly diagnosed DLBCL patients between May 2009 and May 2018 were included in the

study. The relationship between hypogammaglobulinemia, hypocomplementemia at diagnosis and progression-free survival (PFS), overall survival (OS) were performed by univariate and multivariate regression analyses.

**Results:** In our study, 105 of 534 (19.7%) DLBCL patients had hypogammaglobulinemia, and 39 of 509 (7.7%) patients had hypocomplementemia. The patients with hypogammaglobulinemia displayed unfavorable PFS (P=0.001) and OS (P=0.002) and hypocomplementemia had the same inferior PFS (P=0.007) and OS (P=0.003) than patients in normal complement level (Figure 1). In addition, we defined a new prognostic system called immunization cumulative prognostic score (ICPS), based on the hazard ratio (HR) of hypogammaglobulinemia (2.048; 95% CI: 1.341-3.126) and hypocomplementemia (2.356; 95% CI 1.339-4.147) for OS. Multivariate
Cox regression analysis revealed that ICPS was independent risk factor for both PFS (HR 1.493; 95% CI: 1.052-2.120; P=0.025) and OS (HR 1.688; 95% CI: 1.101-2.589; P=0.016). And the ICPS + IPI may have a superior predictive effect on prognosis in newly diagnosed DLBCL patients (P =0.037 for OS, P =0.016 for PFS).

**Conclusions:** Both hypogammaglobulinemia and hypocomplementemia at diagnosis had poor prognosis to PFS and OS. New prognostic system ICPS+IPI could be more sensitive to predict survival in newly diagnosed DLBCL patients.

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

## 375
AGE IS NOT IMPORTANT IN FIT ELDERLY PATIENTS WITH AGGRESSIVE LYMPHOMA

O. Ilhan | A. Uslu | G. Cengiz Seval | E. Tap |

U. Basarir | S. Civriz Bozdag | S. Toprak |

M. Kurt Yuksel | P. Topcuoglu | O. Arslan |

M. Ozcan | T. Demirer | H. Akan | G. Gurman

Hematology, Ankara University School of Medicine, Ankara, Turkey

**Introduction:** High-dose chemotherapy followed by autologous hematopoietic cell transplantation (auto HSCT) is an effective salvage therapy for patients with relapsed chemosensitive non-Hodgkin's lymphoma (NHL). Retrospective analyses suggest that the benefit of HDT extends to elderly patients with NHL, which is an important finding considering that the median age at diagnosis is 67 years (range: 65-74) for NHL in United States, using 2010-2014 US SEER data. We aimed to define the efficacy and toxicity of auto HSCT in patients >60 years with NHL.

**Methods:** From January 2005 through January 2019, data from 29 patients (M/F: 21/8; median age: 63 years) with aggressive NHL above 60 years of age who were eligible for auto HSCT according to geriatric assessment (GA) were evaluated. All these data were obtained from the Ankara University Faculty of Medicine, Department of Hematology and Bone Marrow Transplant Unit. Their diagnosis were as following; 17 diffuse large B cell lymphoma (primary refractory or relapsed disease), 8 mantle cell lymphoma (first complete remission), 2 follicular lymphoma, 1 anaplastic large cell lymphoma and 1 peripheral t cell lymphoma. We compared the toxicity profile and outcome between the research group: patient aged 60 years and above and the control group: patient <60 years.

**Results:** All of the patients were stage III or IV at diagnosis; 13 out of 29 elderly patients had active disease at the time of auto HSCT. The median follow-up was 14.1 months (range, 1-60 mos). Prior to transplantation majority (79.3 %) of the elderly patients received BEAM protocol as conditioning treatment. Bone marrow stem cell was used in only 1 patient None of the patient had mobilization failure, the median peripheral CD34 level was 4.75 x10⁶/kg. Twenty-one percent of the patients experienced ≥ grade 2 mucositis and 76 % of the patients had microbiology-documented infection. Fifty-four percent of the patients had diarrhea with median duration of 8 days (range, 5-20 days). Renal toxicity was occurred in 7 (27%) patients while

hepatic toxicity in 3 (12.5 %) patients. Median time to neutrophil recovery was 10 days (range, 8-18 days) and platelet recovery 11 days (range, 10-32 days). Overall response was obtained from all patients (23% CR). At the time of data collection, 4 patients (15%) of patients' ≥ 60 years have deceased. Relapse (n=3) was the main course of death. The probability of 4-year progression free survival (PFS) and estimated overall survival (OS) in elderly patients were 37.5 % and 78.1 %, respectively.

**Conclusions:** Based on this single center study, auto-HSCT is safe and efficacious in the treatment of elderly lymphoma patients. We emphasize the need for further research in order to determine the risk-benefit threshold for HSCT based on age coupled with comorbidity and fragility.

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

## 376
PRE-TREATMENT HEMOGLOBIN AND OUTCOME IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH ANTHRACYCLINE CONTAINING CHEMOTHERAPY

M.R. Clausen<fnref n="1" /> | M. Maurer² | S.P. Ulrichsen³ |

T.S. Larsen⁴ | B. Himmelstrup⁵ | D. Ronnov-Jessen⁶ |

B. Link⁷ | A. Feldman⁸ | S. Slager² |

G. Nowakowski² | C. Thompson² | P.T. Pedersen⁹ |

J. Madsen¹⁰ | R.S. Pedersen¹¹ | J.S. Gørløv¹² |

J.R. Cerhan² | F. d'Amore<fnref n="1" />

Hemoglobin (Hgb) concentration at diagnosis is associated with outcome in cancer. We estimated the prognostic impact of pretreatment Hgb in a nationwide cohort of DLBCL and validated our findings in an independent cohort from the US. We included patients from the Danish Lymphoma Registry (LYFO; N = 3,499) and from the Molecular Epidemiology Resource (MER; N = 1,225), Mayo Clinic and University of Iowa. Four sex-specific Hgb groups were defined: below transfusion threshold, from transfusion threshold to below

<footnote n="1">¹Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; ²Department of Health Sciences Research, Mayo Clinic, Rochester, United States; ³Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; ⁴Department of Hematology, Odense University Hospital, Odense, Denmark; ⁵Department of Hematology, Zealand University Hospital, Roskilde, Denmark; ⁶Department of Hematology, Sygehus Lillebaelt, Vejle, Denmark; ⁷Department of Medicine, University of Iowa, Iowa City, United States; ⁸Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States; ⁹Department of Hematology, Sydvestjysk Sygehus, Esbjerg, Denmark; ¹⁰Department of Hematology, Aalborg University Hospital, Aalborg, Denmark; ¹¹Department of Hematology, Hospitalsenheden Vest, Holstebro, Denmark; ¹²Department of Hematology, Rigshospitalet, Copenhagen, Copenhagen, Denmark</footnote>
<table><caption>**Table 2.** Crude and adjusted HRs for OS according to Hgb for both LYFO and MER</caption><thead><tr><th rowspan="2">Hgb (LYFO)</th><th colspan="3">OS 5-year</th><th colspan="2">OS Unadjusted</th><th colspan="3">OS Multivariable</th><th colspan="2">EFS 5-year</th><th colspan="2">EFS Multivariable</th></tr><tr><th>N</th><th>%</th><th>95% CI</th><th>HR</th><th>95% CI</th><th>N</th><th>HR</th><th>95% CI</th><th>%</th><th>95% CI</th><th>HR</th><th>95% CI</th></tr></thead><tbody><tr><td>&gt;149/&gt;134‡</td><td>755</td><td>79</td><td>71 - 82</td><td>1.00</td><td>Ref.</td><td>739</td><td>1.00</td><td>Ref.</td><td>73</td><td>70 - 76</td><td>1.00</td><td>Ref.</td></tr><tr><td>134-149/118-134†</td><td>1,132</td><td>71</td><td>68 - 73</td><td>1.52</td><td>1.26 - 1.85</td><td>1,103</td><td>1.23</td><td>1.01 - 1.49</td><td>64</td><td>61 - 67</td><td>1.19</td><td>1.01 - 1.42</td></tr><tr><td>98-133/98-117†</td><td>1,246</td><td>54</td><td>51 - 57</td><td>2.74</td><td>2.29 - 3.27</td><td>1,211</td><td>1.51</td><td>1.25 - 1.83</td><td>49</td><td>46 - 52</td><td>1.46</td><td>1.23 - 1.73</td></tr><tr><td>&lt;98</td><td>366</td><td>37</td><td>32 - 42</td><td>4.51</td><td>3.67 - 5.55</td><td>355</td><td>2.05</td><td>1.65 - 2.56</td><td>33</td><td>28 - 37</td><td>1.96</td><td>1.60 - 2.41</td></tr><tr><td>Hgb (MER)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;145/&gt;135‡</td><td>322</td><td>84</td><td>80 - 88</td><td>1.00</td><td>Ref.</td><td>322</td><td>1.00</td><td>Ref.</td><td>73</td><td>68 - 78</td><td>1.00</td><td>Ref.</td></tr><tr><td>135-144/120-134†</td><td>285</td><td>75</td><td>70 - 80</td><td>1.54</td><td>1.12 - 2.12</td><td>285</td><td>1.43</td><td>1.03 - 1.97</td><td>64</td><td>59 - 70</td><td>1.30</td><td>0.99 - 1.70</td></tr><tr><td>99-134/99-119†</td><td>482</td><td>65</td><td>60 - 69</td><td>2.31</td><td>1.75 - 3.06</td><td>482</td><td>1.53</td><td>1.14 - 2.05</td><td>51</td><td>47 - 56</td><td>1.32</td><td>1.03 - 1.68</td></tr><tr><td>&lt;99</td><td>136</td><td>63</td><td>55 - 73</td><td>2.48</td><td>1.72 - 3.57</td><td>136</td><td>1.27</td><td>0.86 - 1.86</td><td>45</td><td>37 - 56</td><td>1.33</td><td>0.97 - 1.83</td></tr></tbody></table>

§ Adjusted for NCCN-IPI, sex, comorbidity, and rituximab treatment, ‡ Hgb cut off value for men/Hgb cut off value for women, † Hgb range for men/Hgb range for women

Hgb; pre-treatment hemoglobin. OS; overall survival. ref; reference. HRs; hazard rate ratios

<figure><img src="image_230.png" /></figure>

lower limit of normal, from lower limit of normal to the population mean, and above the mean. We used multivariable Cox regression to estimate hazard ratios (HR) and 95% confidence intervals for overall (OS) and event-free survival (EFS), adjusting for sex, NCCN-IPI, comorbidity, and rituximab treatment. Approximately half of the patients had Hgb levels below the lower limit of normal. Compared

to patients with Hgb levels above the mean, an inferior OS was observed for patients (LYFO) with Hgb levels in the normal range but below the mean (HR=1.23), below lower limit of normal (HR=1.49), and below transfusion limit (HR=2.03). These findings were replicated in the MER. Based on multivariable analysis, lower pre-treatment Hgb, even within the normal range but below the mean, added
prognostic information to established risk factors such as comorbidity and NCCN-IPI.

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

377
REAL LIFE DATA ABOUT
CHARACTERISTICS, STANDARD
TREATMENT AND OUTCOMES IN
BRAZILIAN ELDERLY PATIENTS WITH
DIFFUSE LARGE B-CELL LYMPHOMA – A
SINGLE CENTER ANALYSIS

**M. Bellesso** | **R. Santucci** | **R. Centrone** | **D. Dias** |
**A. Alves**

Hematology, Instituto Hemomed, Sao Paulo, Brazil

**Introduction:** Diffuse large B-cell lymphoma (DLBCL) is common lymphoma in elderly patients. Unfortunately, it is not possible to prescribe standard classic regimen RCHOP for all. Although, attenuated regimen is suggested for patients older than 80 years old, sometimes is necessary to reduce dose in patients between 60-80 years old due to fragility and other comorbidities. In addition, we do not have data from real life practice in elderly Brazilian patients with DLCBL. We aimed to investigate patients aged over 60 years old with DLBCL treated in a single Brazilian private health service about use of full dose RCHOP and outcomes.

**Methods:** A retrospective observational single center study was conducted to investigate clinical characteristics, frequency of standard RCHOP and outcomes in patients with DLCBL older than 60 years old treated in our institution between January 2007 to July 2017. Data were collected by eletronic medical records. It was excluded patient with AIDS related lymphoma.

**Results:** Fifty-eight patients were analyzed. Median age was 74.2 (range 60.4-88.2) years. Female gender represented 41(70.7%). Twenty-three (57.5%) of forty patients that were possible to evaluated had an International prognostic index score 2-3. Full dose RCHOP was prescribed in 28 (48.2%) cases and 5 (8.6%) did not receive any treatment. Patients older than 80 years old represented

15 (25.9%) and this subgroup was not treated with full dose RCHOP. Patients younger than 65 years old and patients aged between 65 and 80 years old received standard RCHOP 13 (100%) and 15/30(50%), respectively. Complete response (CR) of 53 treated patients was obtained in 37 (69.8%). CR in patients younger than 65, 65-80, and older than 80 years old were: 9(69.2%), 21(70%) and 7(46.6%), p > 0.05. Overall survival (OS) and Progression free survival (PFS) in 2 years was 81.8% and 65.3%, respectively. OS in 2 years in patients older than 80 years and patients aged between 60 and 80 years old were: 64.3% x 87.6%, p=0.018 and PFS in 2 years 64.3% x 66.5%, p > 0.05, respectively.

**Conclusion:** Therefore, it was evidenced patients aged between 65 and 80 years old were considered frail to receive standard full dose RCHOP and patients older than 80 years old presented poor outcomes.

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

378
PREVALENCE AND CLINICAL
SIGNIFICANCE OF HYPERCALCEMIA AT
DIAGNOSIS IN DIFFUSE LARGE B CELL
LYMPHOMA

U. Abadi<fnref n="1" /> | L. Peled² | P. Rotman-Pikielny<fnref n="3" /> |

P. Raanani⁴ | M.H. Ellis<fnref n="1" /> | U. Rozovski⁴ | R. Gurion⁴

**Introduction:** The reported prevalence of hypercalcemia in non-Hodgkin's lymphoma is 1.3% to 7.4%, while the prevalence of hypercalcemia in diffuse large B cell lymphoma (DLBCL) at diagnosis is unknown. Hypercalcemia in patients with cancer has been associated with a poor prognosis. However, it is unknown whether hypercalcemia perse contributes to the poor outcome or whether hypercalcemia is a biomarker for an underlying aggressive biological feature. The

<figure><img src="image_231.png" /></figure>

<footnote n="1">¹Hematology, Meir Medical Center, Kfar Saba, Israel; ²Department of
Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;</footnote>

<footnote n="3">³Endocrinology, Meir Medical Center, Kfar Saba, Israel; ⁴Hematology,
Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel</footnote>
outcome of DLBCL patients with primary hyperparathyroidism (PHPT)-related hypercalcemia compared to lymphoma related hypercalcemia may help clarify this question.

In this study we determine the prevalence of hypercalcemia among newly diagnosed patients with DLBCL and compare the clinical features and outcomes of patients with and without hypercalcemia. We also evaluate the effect of hypercalcemia etiology on outcome.

**Patients and methods:** We performed a retrospective case-control study of patients at two academic medical centers with newly-diagnosed DLBCL, between 2010 & 2016. Patients with a corrected calcium levels above 10.5mg/dl [{4-albumin(g/dl)} x 0.8+calcium (mg/dl)] at diagnosis comprised the study cohort. Age and sex-matched DLBCL patients with normal calcium levels at diagnosis served as controls.

**Results:** Among 250 newly diagnosed patients with DLBCL 46 (18%) had hypercalcemia at the time of diagnosis. Median age was 72 years (31-89), and 60% were males.

Patients with hypercalcemia presented with more advanced stage disease (85% vs 65%), and had higher levels of LDH (median 736 vs 669u/l) compared to patients with normal calcium levels.

The overall response rate (ORR) and complete remission (CR) were similar among hypercalcemic and normocalcemic patients (ORR: 74% vs 83%, P = 0.312, CR: 72% vs 72%). These comparable response rates translated into similar rates of PFS and OS.

We then stratified patients with hypercalcemia and available PTH levels (27/46) into two groups: those with PHPT-related hypercalcemia (PTH>= 20pg/ml, 44%, n=12/27) and those with lymphoma-related hypercalcemia (PTH< 20pg/ml, 56% 15/27). Patients with lymphoma related hypercalcemia were older, had more advanced stage, higher IPI, higher levels of LDH compared to PHPT-related hypercalcemia. These adverse features were translated to shorter PFS (median 13 months vs 86 months, p=0.016) and OS (median 14 months vs not reached, p=0.016) in patients with lymphoma related hypercalcemia. Patients with lymphoma related hypercalcemia also had shorter PFS (median 13 vs 42 months, p=0.027) and OS (median 14 months vs not reached, p=0.011) compared to patients with normal calcium levels.

**Conclusion:** The findings suggest that in newly diagnosed patients with DLBCL, hypercalcemia is frequent and that lymphoma-related but not PHPT-related hypercalcemia is associated with adverse prognostic factors and adverse clinical outcomes in DLBCL.

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

<figure><img src="image_232.png" /><figcaption>**Figure 1.** Time-dependent ROC curve analysis for three iΔSPD cut-off values.</figcaption></figure>

**Introduction:** Interim response assessment is performed to identify patients whose disease has not responded to or has progressed on induction therapy. The Lugano Response Criteria has been widely used for response assessment for DLBCL. Patients with interim reduction percentage of the sum of the products of the greatest perpendicular diameters for multiple lesions (iΔSPD) between baseline and interim contrast-enhanced computed tomographic (CECT) less than 50% are regarded as non-sensitive to induction therapy and may benefit from a therapy change. However, there is no consensus on the criteria for early therapy change during interim response assessment yet. Here we compared the prognostic value of three iΔSPD cut-off values: 50%, 80% and 100%.

**Methods:** Two hundred and sixty-five newly-diagnosed DLBCL patients with baseline and interim CECT available were enrolled in the retrospective study.

**Results:** The optimal cut-off value of iΔSPD calculated by X-tile was 80%, which yielded the highest difference in OS. The iΔSPD=100% group had significantly superior PFS than 80%≤iΔSPD<100% group (P=0.009), while OS only showed a trend of statistical significance (P=0.07) (Figure 1). A trend for statistical significance (P=0.089) for OS was observed in 50%≤iΔSPD<80% group compared with iΔSPD<50%

<footnote n="1">¹Hematology, 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;</footnote>

<footnote n="2">²Nuclear Medicine, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China, Nanjing, China</footnote>
group while no statistical significance (P=0.247) for PFS were observed between them. The 50%≤iΔSPD<80% group had significantly inferior PFS and OS than 80%≤iΔSPD<100% group (both P<0.001). Compared with 50% and 100%, 80% had the intermediate sensitivity and specificity (57.75% and 86.69% for OS, 48.98% and 92.22% for PFS, respectively), but the maximal Youden Index (0.4744 for OS, 0.4120 for PFS, respectively) (Table) and the maximal areas under the curve (0.737 [0.680, 0.789] for OS). PPV and NPV of 80% cut-off value were 78.69% and 75.49% for PFS, respectively, while 67.21% and 85.29% for OS, respectively. If the status of PFS and OS were considered as "gold standard", 80% was the only cut-off value consistent with PFS (kappa=0.447) and OS (kappa=0.497) status. Cox regression analysis also revealed that iΔSPD<80% could independently predict an inferior OS and PFS (both P<0.001) while neither iΔSPD<50% nor iΔSPD=100% could.

**Conclusions:** iΔSPD with cut-off value 80% is an independent predictor of PFS and OS for patients with DLBCL. During interim response assessment, patients with iΔSPD<80% should change to a more efficient therapy.

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

## 380
TREATMENT PATHWAYS OF DIFFUSE LARGE B-CELL LYMPHOMA IN GERMAN CLAIMS DATA

N. Kurukulasuriya<fnref n="1" />

J. Menzler<fnref n="2" />

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

A.S. Neubauer<fnref n="2" />

A.C. Boehnke⁴

**Introduction:** Routine sick fund claims data provide a meaningful and reliable base for the in- and outpatient treatment landscape. Real world data (RWD) from Germany was used to describe treatment patterns for Diffuse Large B-cell Lymphoma (DLBCL), the most frequent non-Hodgkin lymphoma type in adults.

**Methods:** Claims data from several sick funds of 4.8 million insured were analyzed. Diagnosis of non-follicular Lymphoma (ICD-10 C83) was confirmed in 2,178 patients, DLBCL (ICD-10 C83.3) in 819 patients. The analysis was age- and gender-adjusted, observational period was 2014 and 2015. Treatments were analyzed for hospitalization and medication based on ATC code, Pharma Central Number and coded diagnoses (per ICD). In a second claims cohort analysis from different sick funds, treatment patterns and pathways for 189 DLBCL patients identified 2013-2016, were investigated over time course.

**Results:** In the first [second] claims cohort, mean age of DLBCL patients was 60.3 [66.5] years, with two peaks at 50-54 and 70-74

years. Total yearly costs for patients with DLBCL averaged 25,048 [63,771] EUR versus 1,259 EUR in healthy insured. Per year, mean 3.2 [3.5] hospitalizations with an average of 31.5 [34.5] hospital days were observed. During the observation period less than half of the patients received an oncological treatment, which is supported by published cure rates after first line treatment of approx. 60%, but also includes a share of patients not receiving further treatment anymore. Only few patients received a therapy modality by stem cell transplantation or radiation. Most frequent pharmacological first line treatments were Rituximab (RTX) + CHOP (57%, respectively 56%) in both claims analyses and RTX in combination with Bendamustine (8%, respectively 7%), which is in accordance with German medical guidelines. The second claims cohort confirmed most results -except significantly higher costs. In both analyses consistently 84% of patients did not receive further therapies after a first line DLBCL treatment during the limited observation period.

**Conclusions:** Despite limitations in sick fund claims analyses, these provide a reasonable database for rare diseases. Results from two different sources were well in agreement. They allow standard treatment pathway and longitudinal analyses. However, some relapses may not be identified in the limited observation period of two [maximum four] years. All DLBCL patients frequently required hospitalization and generated significant costs. A high unmet medical need exists for treatments other than palliative care, especially for a tolerable and effective outpatient therapy in elderly relapsed / refractory DLBCL.

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

**Disclosures:** Kurukulasuriya, N: Employment Leadership Position: MorphoSys US Inc. Menzler, J: Research Funding: Morphosys AG. Neubauer, A: Research Funding: Morphosys AG. Boehnke, A: Employment Leadership Position: MorphoSys AG.

## 381
TREATMENT OUTCOMES OF INVOLVED-FIELD RADIOTHERAPY IN ELDERLY PATIENTS WITH HIGH-GRADE OR RECURRENT NON-HODGKIN LYMPHOMA

D. Lee<fnref n="1" /> | Y. Ko<fnref n="2" /> | H. Won<fnref n="2" /> | D. Sun<fnref n="2" />

**Purpose:** This study was designed to evaluate the usefulness and efficacy of involved-field radiotherapy (IFRT) in elderly patients with high grade or recurrent non-hodgkin lymphoma (NHL).

**Materials:** We analyzed the treatment outcomes of 14 patients who had received IFRT between January 2014 and August 2018. IFRT was defined as the involved-site radiotherapy with/without adjacent nodal-station irradiation (ANI) to high risk areas. The median age of study population was 75 (range, 65-83) years and 7 (50%) patients were male.

<footnote n="1">¹Global Medical Affairs, MorphoSys US Inc., Princeton, NJ, United States;</footnote>

<footnote n="2">²Institute for Health- and Pharmaeconomics (IfGPh), München, Germany;</footnote>

<footnote n="3">³Statistics, SCO: SSiS, Berlin, Germany; ⁴Market Access, MorphoSys AG, Planegg, Germany</footnote>

<footnote n="1">¹Radiation Oncology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Gyeonggi-do, Republic of Korea;</footnote>

<footnote n="2">²Medical Oncology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Gyeonggi-do, Republic of Korea</footnote>
Tumor histology was diffuse large B-cell lymphoma in 10 (71.4%), NK/T-cell lymphoma, nasal type in 2 (14.3%), high-grade follicular lymphoma in 1 (7.1%) and recurrent nodal marginal zone lymphoma in 1 (7.1%) patient, respectively. The treatment sites were neck/nasal cavity in 9 (64.3%), neck/abdomen in 1 (7.1%), chest in 1 (7.1%), axilla in 1 (7.1%), neck/chest in 1 (7.1%) and abdomen/pelvis in 1 (7.1%), respectively. ANI was selectively accomplished in 7 patients with neck and axilla origins. The ECOG performance status was 0 in 1 (7.1%), 1 in 10 (71.4%) and 2 in 3 (21.4%) patients, respectively. The majority of the patients (n=10, 71.4%) had aging-related multiple comorbidities.

**Results:** The median follow-up duration was 11 (range, 2.2-56.2) months and 4 (28.6%) patients were dead at the time of this analysis. A total of 10 (71.4%) patients had received upfront chemotherapy before IFRT. Among 8 patients who had received IFRT as a consolidation treatment after chemotherapy, 7 (87.5%) patients maintained major responses during follow-up. One patient experienced both infield and outfield disease progression after initial partial response following IFRT. Among the remaining 6 patients who had received IFRT as a curative or salvage aim, 5 (83.3%) patients achieved major infield responses. One and 2 patients experienced infield and outfield progression, respectively. Major causes of death and worsening of general condition were pulmonary infection and aging-related illness. In 4 dead patients, the median survival duration after IFRT was 3.2 (range, 2.2-12.3) months. There was 6 (42.9%) long-term (≥ 1 year) survivors after IFRT and their median survival duration was 31.2 (range, 14.4-56.2) months.

**Conclusions:** IFRT was efficacious and well tolerated in elderly high grade or recurrent NHL patients. Although durable response and long-term survival was achieved in medically healthy population, watchful management is necessary to avoid deaths from cancer-unrelated causes.

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

382
# OUTCOME AFTER SALVAGE RADIOTHERAPY TO FDG-PET/CT AVID DISEASE POST CHEMOTHERAPY IN ADVANCED STAGE DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

S.A. Gupta<fnref n="1" /> | R. Prasad<fnref n="2" /> | S. Yuen<fnref n="2" /> | K. Lynnhtun³ |
N. Rutherford⁴ | S. Dickson<fnref n="1" />

**Introduction:** Most patients with Diffuse Large B-Cell Lymphoma (DLBCL) present with advanced stage disease and are treated with multi-agent chemotherapy. Despite this some patients will not be in

<table><caption>TABLE 1</caption><thead><tr><th>Patient characteristics</th><th>N (22)</th><th>%</th></tr></thead><tbody><tr><td>Deauville score 1-3 pre radiotherapy</td><td>10</td><td>45</td></tr><tr><td>Deauville score 4-5 pre radiotherapy</td><td>12</td><td>55</td></tr><tr><td>Primary DLBCL</td><td>19</td><td>86</td></tr><tr><td>Relapsed DLBCL</td><td>3</td><td>14</td></tr><tr><td>MYC,BCL2,BCL6 status</td><td></td><td></td></tr><tr><td>Double hit</td><td>1</td><td>5</td></tr><tr><td>Negative</td><td>13</td><td>59</td></tr><tr><td>Unknown</td><td>8</td><td>36</td></tr></tbody></table>

For the entire group local control at 2 years was 81 % (DS 1-3 90% Vs. DS 4-5 75%). Cancer specific survival at 2 years was 64 % (DS 1-3 80% Vs. DS 4-5 50%). Overall survival at 2 years was 59 % (DS 1-3 80% Vs. DS 4-5 41% P value 0.044) (Fig 1)

remission at the end of chemotherapy. Some patients can be salvaged with high dose chemotherapy, but many are not medically fit for treatment escalation or, despite treatment escalation will remain with residual disease. For these patients salvage radiotherapy alone may be offered.

**Method:** We carried out a single centre retrospective review of patients with advanced stage DLBCL treated with salvage radiotherapy alone for PET avid disease after undergoing curative intent chemotherapy. Patients underwent curative intent consolidative radiotherapy to all sites of FDG PET/CT avid disease. Further testing for a double or triple hit was attempted using Fluorescent In Situ Hybridisation testing (FISH)

**Results:** Twenty two patients were treated between 2010 and 2016. The median age was 71 (range 35-81). All patients received at least 30 Gy in 15 fractions with a median dose of 36 Gy in 18 fractions (range 30 Gy-40 Gy)

Of the 13 patients with a FISH confirmed non double/triple hit DLBCL the two year local control, cancer specific survival and overall survival respectively were 92 %, 75% and 69 %. Seven from this group

<figure><img src="image_233.png" /><figcaption>Fig 1. Overall survival</figcaption></figure>

<footnote n="1">¹Radiation Oncology, Calvary Mater Hospital, Waratah, Australia;</footnote>

<footnote n="2">²Haematology, Calvary Mater Hospital, Waratah, Australia; ³Pathology, John Hunter Hospital, New Lambton Heights, Australia; ⁴Nuclear Medicine, Calvary Mater Hospital, Waratah, Australia</footnote>
were treated for residual DS 4-5 disease. The two year local control, cancer specific survival and overall survival respectively were 86%, 71% and 57%.

**Conclusion:** A trend for an improvement in all outcomes was found for patients treated with a DS of 1-3, compared to a DS of 4-5. Given the excellent outcomes in the DS 1-3 patients avoidance of radiotherapy may be appropriate. Some patients with a post-chemotherapy DS of 4-5 can be successfully salvaged with radiotherapy alone. This appeared to especially be the case for non double/triple hit DLBCL.

**Keywords:** "double-hit" lymphomas; Deauville's criteria; diffuse large B-cell lymphoma (DLBCL).

## 383
# R-CHOP VS. R-CHOP+X FOR NEWLY DIAGNOSED DIFFUSE LARGE B-CELL LYMPHOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS

O. Pasvolsky | A. Rozental | P. Raanani |

A. Gafter-Gvili | R. Gurion

Institute of Hematology, Beilinson Hospital, Petah Tikva, Israel

**Introduction:** Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Despite advances in the understanding of the pathophysiology and molecular biology of DLBCL, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has remained standard of care for first-line treatment for almost two decades. However, treatment outcomes are still suboptimal, and approximately 40% of patients have refractory disease or relapse. Recent prospective studies have examined the addition of various drugs to R-CHOP (termed R-CHOP+ X) to improve outcomes.

Our aim was to compare the efficacy and safety of R-CHOP vs. R-CHOP +X for first line treatment for DLBCL.

**Methods:** Systematic review and meta-analysis of randomized controlled trials including patients with DLBCL, comparing first line treatment with R-CHOP to R-CHOP+X (i.e. R-CHOP with the addition of another single drug). The Cochrane Library, MEDLINE, conference proceedings and references were searched until January 2019. Two reviewers appraised the quality of trials and extracted data. Primary outcome was overall survival (OS). Secondary outcomes included overall response rate (ORR), complete response (CR) rate, disease control and safety.

**Results:** Our search yielded five trials conducted between the years 2010 and 2018, including 2020 patients (one abstract, and four published in peer review journals). Median age of patients ranged between 50 to 65 years. The added drug was bortezomib in two trials; gemcitabine, bevacizumab and ibrutinib - each drug in one trial. Three trials included only patients with non-GCB DLBCL while two trials did not have this restriction.

There was no difference in OS between the R-CHOP+X and R-CHOP arms, HR 0.96, [95% confidence interval (CI) 0.74-1.25, I²=0, 1134 patients, 3 trials].

ORR was higher in the R-CHOP arm vs. RCHOP+X, RR 0.93 [95% CI 0.9-0.97, I²=33%, 1974 patients, 5 trials]. There was no significant difference in CR rates between the two groups, RR 0.95 [95% CI 0.88-1.02, I²=34%, 1976 patients, 5 trials]. Disease control did not differ between the two arms, HR 0.99 [95% CI 0.84-1.16, I²=0].

Regarding safety, three trials (N=1200) reported serious adverse events. These adverse events were significantly more common in the R-CHOP+X group, RR 1.42 [95% CI 1.24-1.64. I²=55%]. In addition, grade III/IV thrombocytopenia was significantly higher in the R-CHOP +X arm, RR=6.66 [95% CI 1.59-27.84, I²=70%]. There was no difference in grade III/IV anemia and neutropenia between the arms.

**Conclusions:** The addition of an extra drug to the conventional first line R-CHOP regimen in patients with DLBCL did not improve response rates, disease control or OS. Moreover, R-CHOP+X was associated with an increased risk for serious and grade III/IV adverse events. R-CHOP still remains the "gold standard" of treatment for DLBCL.

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

## 384
# A SYSTEMATIC REVIEW OF THE CLINICAL EFFICACY OF TREATMENTS IN RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (R/R DLBCL)

N. Vander Velde¹ | P. Thuresson² | R. Harvey³* |

P. Gupta⁴ | N. Qayum⁵**

¹Hematology and Medical Oncology, Tulane University School of Medicine, New Orleans, LA, United States; ²Global Access - Center of Excellence, F. Hoffmann-La Roche Ltd, Basel, Switzerland; ³DRG Abacus, Decision Resources Group, Manchester, United Kingdom; ⁴DRG Abacus,

<figure><img src="image_234.png" /></figure>
Decision Resources Group, Bicester, United Kingdom; ⁵Haematology, F. Hoffmann-La Roche Ltd, Basel, Switzerland

*Was employed by DRG Abacus at the time of analysis

**Was employed by F. Hoffmann-La Roche Ltd at the time of the analysis

**Background:** Despite improvements in DLBCL treatment, outcomes for patients with R/R DLBCL remain poor. This systematic literature review (SLR) aimed to summarise current clinical evidence for treatment of patients with stem-cell transplant (SCT) ineligible R/R DLBCL. A secondary objective was to assess the possibility of completing an indirect treatment comparison (ITC) or network meta-analysis (NMA).

**Methods:** Databases were searched in September 2018 (Embase®, MEDLINE®, The Cochrane Library) and November 2018 (ASH 2018 abstracts). Only studies of patients with SCT-ineligible R/R DLBCL were included, per pre-defined eligibility criteria. Identified studies were evaluated in a network-building exercise to identify whether a connected network of evidence could be constructed. To explore a broader evidence base, evidence not meeting the study criteria was evaluated in a *post-hoc* network-building exercise.

**Results:** The SLR identified 36 studies of patients with R/R DLBCL (90 publications); of these, 19 studies (53 publications) met the eligibility criteria. Six of the 19 studies were randomised controlled trials (RCTs [Figure]), and 13 were prospective, observational or single-arm trials. A further three RCTs not meeting the eligibility criteria were identified (Figure). Thirteen included studies had a sample size <60. Across studies, baseline median patient ages ranged from 54-74 years; the proportion of patients with Ann-Arbor stage III-IV disease ranged from 48%-90%; three studies had >65% male patients. All studies reported objective and complete response rates; additional endpoints included median progression-free survival (PFS; 11 studies, range 2.6-17.1 months), overall survival (OS; 11 studies, range 5-22.2 months), safety, and discontinuation. The IWG 1999-NHL guidelines were used by 10/19 studies. As response criteria and PFS definitions varied between studies, cross-study comparisons were limited. Construction of a connected network of evidence was not possible using data from RCTs or the broader post-hoc analysis (Figure). Thus, conducting an NMA was deemed unfeasible.

**Conclusions:** This SLR provides a summary of currently published evidence on treatments for patients with R/R DLBCL. Only nine of 36 identified studies were RCTs, preventing completion of an ITC or NMA. This SLR highlights the paucity of published RCTs to establish the comparative efficacy of R/R DLBCL treatments, and demonstrates a lack of standard of care in this setting.

**Figure:** Network-building analysis of evidence in 9 RCTs

**Treatments:** BR=bendamustine, rituximab; DHAP=dexamethasone, cytarabine, cisplatin; ESHAP=etoposide, methylprednisolone, cytarabine, cisplatin; GDP=cisplatin, dexamethasone, gemcitabine; ICE=ifosfamide, carboplatin, etoposide; R=rituximab. Single-arm studies not shown.

**Blue lines:** RCTs meeting the SLR criteria (SCT ineligible)

**Red lines:** RCTs not meeting the SLR criteria

This abstract was previously submitted to EHA 2019.

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

**Disclosures:** Vander Velde, N: Employment Leadership Position: Tulane University & Southeast Louisiana Veterans Affairs Health Care System; Other Remuneration: Co-author (unpaid) on abstracts in lymphoma and urothelial CA: studies funded by Roche. Thuresson, P: Employment Leadership Position: Roche. Harvey*, R: Employment Leadership Position: Was an employee at DRG Abacus during the time the work was undertaken. Gupta, P: Employment Leadership Position: Decision Resources Group. Qayum**, N: Employment Leadership Position: Roche.

385

EXCELLENT OUTCOMES USING
RITUXIMAB, GEMCITABINE,
CYCLOPHOSPHAMIDE, VINCRISTINE,
PREDNISOLONE (R-GCVP) IN PATIENTS
WITH DLBCL AND CARDIAC
COMORBIDITIES

V. Michalarea¹ | R. Low² | A.A. Kirkwood³ |

P. Harrington⁴ | S. Yadollahi⁵ | F. Djebbari⁶ |

M. Gleeson⁴ | K. Cwynarski² | J. Lambert² |

I. Chau¹ | D. Wrench⁴ | T.A. Eyre⁷ | A. Davies⁸ |

K.M. Ardeshna² | D. Cunningham¹ | P. Fields⁴

¹Department of Medicine, GI and Lymphoma Oncology Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom; ²Department of Haematology, University College Hospitals NHS Foundation Trust, London, United Kingdom; ³Cancer Research UK & UCL Cancer Trials Centre, University College Hospitals NHS Foundation Trust, London, United Kingdom; ⁴Department of Haematology, Guys and St.Thomas' NHS Foundation Trust, London, United Kingdom; ⁵Department of Haematology, University Hospitals Southampton NHS Foundation Trust, Southampton, United Kingdom; ⁶Department of Cancer Pharmacy, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; ⁷Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; ⁸Cancer Sciences Division, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom

**Introduction:** Diffuse large B cell lymphoma (DLBCL) is the most common type of Non-Hodgkin lymphoma with a median age of presentation > 65 years. The gold standard induction regimen is anthracycline based. However, there are patients (pts) who cannot tolerate anthracyclines due to cardiac comorbidities. A unique phase II trial (Fields et al, JCO 2014) investigated the substitution of anthracycline with Gemcitabine (Gem), administered on D1 and D8 (Gem dose750 mg/m2 in Cycle (C)1, escalating to 875mg/m2 in C2 and 1000mg/m2 in C3) in a 3 weekly R-GCVP regimen with encouraging results; overall
<table><caption>**TABLE 1** Patient characteristics</caption><thead><tr><th>Variable</th><th>Characteristic</th><th>N (%)</th></tr></thead><tbody><tr><td>Sex</td><td>Male</td><td>57 (70%)</td></tr><tr><td rowspan="3">Ann Arbor stage</td><td>I-II</td><td>25 (30%)</td></tr><tr><td>III-IV</td><td>56 (69%)</td></tr><tr><td>Unknown</td><td>1 (1%)</td></tr><tr><td rowspan="4">IPI</td><td>0-1</td><td>11 (14%)</td></tr><tr><td>2</td><td>19 (23%)</td></tr><tr><td>3</td><td>23 (28%)</td></tr><tr><td>4 - 5</td><td>29 (35%)</td></tr><tr><td rowspan="3">ECOG PS</td><td>0-1</td><td>55 (67%)</td></tr><tr><td>2</td><td>17 (21%)</td></tr><tr><td>3-4</td><td>10 (12%)</td></tr><tr><td>B symptoms</td><td>Present</td><td>32 (39%)</td></tr><tr><td rowspan="3">Age</td><td>&lt; 60</td><td>8 (10%)</td></tr><tr><td>61-79</td><td>54 (66%)</td></tr><tr><td>&gt;80</td><td>20 (24%)</td></tr><tr><td rowspan="2">Comorbidities</td><td></td><td></td></tr><tr><td>LVEF&lt;50 (n=28)</td><td>LVEF≥50 (n=44)</td></tr><tr><td>IHD + 2 cardiac risk factors</td><td>15</td><td>14</td></tr><tr><td>Cardiac risk factors +1</td><td>6</td><td>8</td></tr><tr><td>Single Cardiac risk factor</td><td>2</td><td>12</td></tr><tr><td>Other</td><td>3</td><td>5</td></tr><tr><td>Nil</td><td>2</td><td>2</td></tr></tbody></table>

response rate (ORR) 61.3%, 2 year Progression Free Survival (PFS) 49.8% and overall survival (OS) 55.8%.

**Methods:** We retrospectively analysed outcomes for 82 pts with de novo DLBCL deemed unsuitable for anthracycline regimens from 5 large UK academic centres. Data were collected via pt records on age, sex, histology, stage, international prognostic index (IPI) score, performance status, ORR, cardiac risk factor comorbidities, left

ventricular ejection fraction (LVEF) and detailed analysis of the Gem dosage schedule. OS was calculated from diagnosis to the death, PFS from diagnosis until first progression or death. Both were censored at the last day of follow up for pts without events. Statistical analysis was performed using STATA v15.1.

**Results:** The median age was 72y (range 41-92);pt characteristics are shown in Table 1. 28/72 (39%) pts recorded an LVEF >50%, and 44/72 (61%) pts LVEF ≤ 50%. Cardiac risk factors that were present included: ischaemic heart disease (n= 30), hypertension (n=29) and conduction disorders (n=25). The median number of cycles administered was 5 (range 1-6): 33 (40%) pts received 6 cycles, 10 (12%) pts 5 cycles, 11(13%) pts 4 cycles, 9 (12%) pts 3 cycles, 6 (7%) pts 2 cycles, and 6 (7%) pts 1 cycle. Twenty pts escalated to a Gem dose of 1000mg/m2 on C3D1, 10/20 pts maintained the 1000mg/m2 dose in C4D1, 3/20 in C5D1 and 3/20 in C6D1. 23 (27%) pts received involved field radiotherapy. 71 (84%) pts had end of treatment imaging. ORR was 74% (58.5% CR + 15.8% PR) for the whole cohort of 82 pts. The median follow up was 34m (5.2 - 88.4). The median PFS was 48m with 3 year PFS: 64.2% (52.1 - 74.0). The median OS was 54m with 3 year OS: 66.4% (54.3 - 76.0). 3-year PFS for ≥80 year group: 47.1% (21.3 - 69.4) and 3-year OS: 46.8% (21.0 - 69.1) (Figure 1).

**Conclusions:** The R-GCVP regimen achieved responses and survival rates comparable to those in the UK multicentre phase 2 study, confirming efficacy in pts with DLBCL and multiple cardiac comorbidities in a real world clinical setting.

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

386

FIRST-LINE THERAPY OF ELDERLY PATIENTS WITH DLBCL-A COMPARISON OF STUDY PATIENTS TREATED WITH R-CHOP ON THE RICOVER-60 TRIAL AND PATIENTS TREATED WITH R-CYCLOPHOSPHAMIDE, EPIRUBICIN, VINDESINE, PREDNISONE (R-EpiVDSP) AT PEKING UNIVERSITY

S. Yang<fnref n="1" /> | M. Ziepert² | B. Altmann² | V. Pöschel³ | G. Held³ | J. Lu<fnref n="1" /> | N. Schmitz⁴ | X. Huang<fnref n="1" />

**Introduction:** R-CHOP is the standard first-line therapy for patients with diffuse large B-cell lymphoma (DLBCL). Alternative chemotherapy regimens have been proposed to increase efficacy (e.g. R-ACVBP) or decrease toxicity e.g. R-CE(Etoposide)OP, with conflicting results.

<figure><img src="image_235.png" /><figcaption>Figure 1: Overall Survival for patients ≥80 vs patients < 80</figcaption></figure>

<footnote n="1">¹Peking University Institute of Hematology, Peking University People's Hospital, Beijing, China; ²University of Leipzig, Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig, Germany; ³Saarland Medical School, Dep. Internal Medicine 1, Homburg, Germany; ⁴University Hospital, Dep. Internal Medicine A, Muenster, Germany</footnote>
We analyzed how the R-CEpiVDSP regimen frequently used in China performs in comparison to R-CHOP.

**Methods:** We analyzed the outcome of consecutive DLBCL patients (pts) aged 61-80 years treated between May 2009 and April 2018 at People's hospital, a tertiary referral center in Beijing, China. These pts received first-line therapy with rituximab (375 mg/ m2), cyclophosphamide (750 mg/m2), epirubicin (60 mg/ m2) instead of doxorubicin, vindesine (2 mg/m2) instead of vincristine, and prednisone (100mg, days 1-5). Pts diagnosed in early stages I-II received six, pts in advanced stages III-IV received 8 courses of such therapy. In order to compare outcomes progression-free survival (PFS) and overall survival (OS) curves were generated and compared to those DLBCL patients treated with 6 (stages I-II) or 8 (stages III-IV) courses of R-CHOP within the RICOVER-60 trial (Pfreundschuh et al. Lancet Oncology 2008; 9: 105-16)) of the German High-grade Lymphoma Study Group (DSHNHL) using the log-rank test; multivariate Cox models adjusting for IPI factors were calculated.

**Results:** 58 pts (59% male, median age 70 years) from People's Hospital, Peking University, and 243 pts (54% male, median age 69 years) were included in this analysis. Major clinical characteristics including distribution of IPI score (IPI>2 was detected in 41% of RICOVER-60 pts and 48% of Chinese pts) did not significantly differ between both cohorts (p=0.308) except for ECOG >1 pts who were seen more frequently in the RICOVER-60 trial. Three-year-PFS was 66% (95%CI 54-79%) for pts treated with R-CEpiVDSP and 73% (95%CI 67-78%) for pts treated with R-CHOP-14 (p=0.659). OS also did not significantly differ (79% vs. 77%) (p=0.764). No significant differences were seen for pts with low or higher IPI score or any other IPI subgroup. PFS and OS (R-CEpiVDSP vs. R-CHOP) adjusted for IPI factors showed no significant differences, with HR=1.1 for PFS and 0.9 for OS.

**Discussion:** No significant differences in PFS or OS were found between pts treated with 6 (8) x R-CEpiVDSP in China or 6 (8) x R-CHOP-14 administered to elderly pts within the RICOVER-60 trial. Both regimens gave favorable results given the age and frequency of patients with IPI >2. In elderly pts with preexisting cardiac disease or neuropathy the R-CEpiVDSP regimen represents a valuable alternative to R-CHOP with comparable efficacy and potentially less cardiac and neurological toxicity.

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

387
LENALIDOMIDE AND RITUXIMAB (ReRi) AS FRONT LINE THERAPY OF ELDERLY FRAIL PATIENTS WITH DIFFUSE LARGE B-CELLS LYMPHOMA. FIRST PLANNED INTERIM ANALYSIS OF A PHASE II STUDY OF THE FONDAZIONE ITALIANA LINFOMI (FIL)

G. Gini¹ | M. Tani² | R. Bassan³ | A. Tucci⁴ |

F. Ballerini⁵ | M. Sampaolo¹ | F. Merli⁶ | F. Re⁷ |

O. Annibali⁸ | A. Liberati⁹ | C. Visco¹⁰ |

A. Arcari¹¹ | S. Storti¹² | A. Fabbri¹³ |

G. Musuraca¹⁴ | V. Zilioli¹⁵ | M. Cox¹⁶ | S. Luminari⁶

¹Clinica di Ematologia, AOU Ospedali Riuniti Ancona, Ancona, Italy; ²U. O.C. Ematologia, Ospedale Santa Maria delle Croci, Ravenna, Italy; ³U.O. C. Ematologia, Ospedale dell'Angelo, Mestre, Italy; ⁴Ematologia, ASST-Spedali Civili, Brescia, Italy; ⁵Clinica di Ematologia, IRCCS Ospedale Policlinico San Martino Università di Genova, Genova, Italy; ⁶Hematology, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; ⁷Hematology Clinic, AOU di Parma, Parma, Italy; ⁸Unità complessa di Ematologia trapianto di cellule Staminali, Università Campus Bio Medico, Roma, Italy; ⁹SC di Oncoematologia, AO Santa Maria di Terni, Terni, Italy; ¹⁰Department of Hematology and Cell Therapy, Ospedale San Bartolo, Vicenza, Italy; ¹¹Hematology Unit, Ospedale Guglielmo da Saliceto, Piacenza, Italy; ¹²Oncoematologia, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, Italy; ¹³U.O.C. Ematologia, A.O.U. Senese, Siena, Italy; ¹⁴IRST, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; ¹⁵Divisione di Ematologia, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy; ¹⁶Haematology Unit, AOU Sant'Andrea, Roma, Italy

**Introduction:** Treatment of Diffuse Large B cell lymphoma (DLBCL) in the elderly population is challenging as many patients (pts) are not eligible to receive standard curative therapy, due to comorbid conditions and to a higher susceptibility to the side effects of standard anthra-cycline containing regimens.

Among currently available active drugs, Lenalidomide has been used in the setting of relapsed/refractory DLBCL both as monotherapy and in combination with rituximab, showing a good activity and an acceptable safety profile.

We started a prospective, multicenter, single arm, phase II trial to demonstrate activity and safety of lenalidomide + rituximab combination in elderly (≥ 70 years) untreated pts with DLBCL who were prospectively defined as frail according to a simplified comprehensive geriatric assessment (CGA).

**Patients and methods:** Pts were eligible if they were previously untreated DLBCL patients, older than 69 years and defined as frail according to CGA.

The treatment consisted of a 28-day cycle (R2) combining oral Lenalidomide (20 mg/m2/d on days 1 to 21) and i.v. Rituximab (375 mg/m2 on day 1); a maximum number of 6 cycles was planned; response assessment was performed after cycles 4 and 6. At the end of the 6th cycle, patients with partial or complete response continued treatment with Lenalidomide 10mg/d on days 1 to 21 every 28 days, until cycle 12 or unacceptable toxicity. Final response was evaluated within 28 days after the last study drug administration. Primary study endpoint was Overall Response Rate (ORR) after 6 R2 cycles, defined according to Lugano 2014 criteria; co-primary endpoint was the rate of extra-hematological toxicity with CTCAE grade >2 and of death for any cause during the treatment.

The study was planned according to a two stage Simon design. A total of 68 pts had to be enrolled to complete the study: 23 pts were
required in the first stage. Second stage could be activated with at least 12 patients showing a Partial or Complete Response (PR/CR) in stage I. According to the Ray and Rai method less than 15/23 adverse events were also required for the safety coprimary endpoint.

**Results:** From January 2017 to December 2017, 24 newly diagnosed frail DLBCL were enrolled in 8 Italian centers. Median age was 83 years (range 76-89) and 79% had stage III/IV; 42% of pts were male, and 44%, had elevated LDH. All pts were confirmed eligible and started R2 treatment. The planned 6 courses of R2 were completed in 13 pts (54%). The median number of R2 cycles was 4.6. Treatment was discontinued in 11 pts for the following reasons: lymphoma progression in 4 cases, malignancy in 2, extra-hematological toxicities in 2 cases, consent withdrawal and investigator choice after 4 cycles in CR in 1 case each. Response assessment after 6 R2 cycles showed 12 pts in CR, that was higher than the inferior limit of 11 required by the Simon optimal design.

Regarding safety coprprimary endpoint 13 events were reported including 9 extra-hematological toxicities > grade 2 CTCAE (3 cardiovascular and 6 respiratory events, all resolved) and 4 deaths (2 patients due visceral arterial ischemia and 2 due infectious disease). The rate of adverse events was lower than the superior limit of 15 allowed the first stage of the study, according to Ray and Rai method.

**Conclusions:** The results of the planned interim analysis of our study confirmed the initial efficacy and safety hypotheses of R2 combination in untreated elderly pts with DLBCL. Since August 2018 the enrollment in the stage II of the trial has been resumed and it is currently ongoing. Treatment of elderly frail DLBCL pts with R2 holds promise in terms of both ORR and safety.

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

A.F. Herrera<fnref n="1" /> | U. Ogbu² | G. Ku³ | C.Y. Chuo⁴

**Introduction:** Bendamustine is approved for the treatment of indolent lymphomas. However, bendamustine has been studied and used off-label in DLBCL, where it has been shown to have anti-tumour activity and is well tolerated relative to combination chemotherapy. This study describes real-world usage patterns of bendamustine in combination with rituximab (R-Benda) for the management of R/R DLBCL.

<table><caption>TABLE 1 R-Benda utilisation in R/R DLBCL</caption><thead><tr><th rowspan="2">Treatment received</th><th colspan="4">Line of therapy</th></tr><tr><th>2L (N=993)</th><th>3L (N=386)</th><th>4L (N=166)</th><th>5L (N=70)</th></tr></thead><tbody><tr><td>R-Benda, n (%)</td><td>77 (7.8)</td><td>14 (3.6)</td><td>5 (3.0)</td><td>1 (1.4)</td></tr><tr><td>Other (most common) regimens, n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>CODOX-M</td><td>22 (2.2)</td><td>3 (0.8)</td><td>1 (0.6)</td><td>-</td></tr><tr><td>DA-EPOCH</td><td>21 (2.1)</td><td>6 (1.6)</td><td>-</td><td>2 (2.9)</td></tr><tr><td>GemOx</td><td>62 (6.2)</td><td>56 (14.5)</td><td>19 (11.4)</td><td>3 (4.3)</td></tr><tr><td>R monotherapy</td><td>17 (1.7)</td><td>11 (2.8)</td><td>2 (1.2)</td><td>2 (2.9)</td></tr><tr><td>R-CHOP</td><td>68 (6.8)</td><td>9 (2.3)</td><td>2 (1.2)</td><td>-</td></tr><tr><td>R-ICE</td><td>227 (22.9)</td><td>29 (7.5)</td><td>4 (2.4)</td><td>3 (4.3)</td></tr></tbody></table>

Abbreviations: CODOX-M, cyclophosphamide, cytarabine, vincristine, doxorubicin, methotrexate; DA-EPOCH, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; GemOx, gemcitabine, oxaliplatin; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-ICE, rituximab, ifosfamide, carboplatin, etoposide.

**Methods:** This is a retrospective cohort study using Flatiron Health's data on patients with DLBCL diagnosed from 2011 through 2018 at any of 265 cancer clinics in the United States. We included patients with at least one prior line of therapy who initiated treatment within 90 days of their diagnosis.

**Results:** We identified 993 patients receiving second-line (2L) treatment or beyond who were treated between 2011 and 2018 for R/R DLBCL. R-Benda was received by 97 (9.8%) patients in the overall cohort. The proportion of patients receiving R-Benda ranged from 7.8% in 2L to 1.4% in 5L (Table).

The median age of patients receiving R-Benda was 75 years (interquartile range 68-79); 90% of patients were 60 years or older. R-Benda was the second-most common regimen in 2L and the third-most common in 3L. The most common regimen in 2L (and second-most common in 3L) was R-ICE (typically given to prepare patients for transplant). Patients refractory to their last prior line of therapy accounted for 40% of the R-Benda-treated population. For patients who received R-Benda, the median duration of follow up was 7.3 months and the median time to next treatment was 6 months. A dose of 90mg/m² bendamustine in combination with R was prescribed to 70/97 (72%) patients.

**Conclusion:** Treatment patterns in patients with R/R DLBCL vary widely with few regimens accounting for more than a small proportion of treated patients. R-Benda was among the more commonly used regimens in a cohort of unselected patients. Most patients who received R-Benda were older, which suggests the regimen may be favoured in the elderly, transplant-ineligible population. The majority of patients received 90mg/m² of bendamustine.

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

**Disclosures:** Herrera, A: Consultant Advisory Role: Bristol-Myers Squibb, Genentech, Inc., Merck, Adaptive Biotechnologies, Kite; Research

<footnote n="1">¹Hematology Dept, City of Hope Medical Center, Duarte, CA, United States; ²RWD Oncology, PHC Data Science, Genentech, Inc., South San Francisco, CA, United States; ³Product Development - Oncology, Genentech, Inc., South San Francisco, CA, United States; ⁴Product Development Personalized Healthcare, Genentech, Inc., South San Francisco, CA, United States</footnote>
Funding: Bristol-Myers Squibb, Genentech, Inc., Immune Design, AstraZeneca, Merck, Seattle Genetics, Kite Pharma, Gilead Sciences.
Ogbu, U: Employment Leadership Position: Genentech, Inc./Roche; Stock Ownership: Genentech, Inc./Roche. Ku, G: Employment Leadership Position: Genentech, Inc./Roche; Stock Ownership: Genentech, Inc./Roche. Chuo, C: Employment Leadership Position: Roche/Genentech, Inc.; Stock Ownership: Roche; Research Funding: Roche/Genentech, Inc.

389
RITUXIMAB PLUS GEMCITABINE AND
OXALIPLATIN (R-GemOx) IN
REFRACTORY/RELAPSED (R/R) DLBCL. A
REAL LIFE STUDY IN PATIENTS INELIGIBLE
FOR AUTOLOGOUS TRANSPLANTATION

C. Cazelles¹ | K. Belhadj² | H. Vellemans³ |

V. Camus³ | C. Copi-Bergman⁴ | L. Veresezan⁵ |

E. Itti⁶ | S. Becker⁷ | M. Carvalho⁸ | J. Dupuis² |

L. Fabien² | F. Lemonnier² | L. Roulin² |

T. El Gnaoui² | F. Jardin³ | N. Mounier⁹ | H. Tilly³ |

C. Haioun²

¹Hematologie, Necker Hospital, Paris, France; ²Lymphoid Hemopathy, Henri Mondor, Créteil, France; ³Department of Haematology, Universite de Rouen, Centre de Lutte anti Cancer H. Becquerel, Rouen, France; ⁴Pathology, Henri Mondor, Créteil, France; ⁵Pathology, Centre de Lutte anti Cancer H. Becquerel, Rouen, France; ⁶Radiology, Henri Mondor, Créteil, France; ⁷Radiology, Centre de Lutte anti Cancer H. Becquerel, Rouen, France; ⁸Pharmacy, Henri Mondor, Créteil, France; ⁹Hematology, L'Archet 2 Hospital, Nice, France

**Introduction:** There is no standard treatment of refractory or relapsed (R/R) patients (pts) with DLBCL ineligible for stem cell autologous transplantation (ASCT). However, R-GemOx is widely used in these circumstances. We here report the results of a retrospective analysis of a cohort of patient treated in two academic centers in France. The main objectives were to evaluate the activity and safety profile of this regimen in a large series of R/R DLBCL pts in a real life setting.

**Methods:** Patients selected had to have de novo or transformed DLBCL, R/R after at least one line of treatment containing doxorubicin and rituximab, to be ineligible for ASCT and to have received at least one cycle of R-GEMOX. Rituximab 375 mg/m2 was administered on D1, gemcitabine 1000 mg/m2 on D2 and oxaliplatin 100 mg/m2 on D2 as previously described (Mounier N. et al. Haematologica. 2013;98:1726-31.). Cycles were given every 2 weeks and 8 cycles were planned if at least a partial response (PR) was obtained after 4 cycles.

**Results:** Between May 2002 and May 2017, 196 pts were treated. Baseline characteristics were: median age: 72 y (range, 24-89), international prognostic index (IPI) 3-5: 63%, refractory state to last treatment (tx): 42%, history of indolent lymphoma: 45%, prior ASCT: 16%.

The median number of previous line was 1 (range 1-7) with 112 pts having received R-GemOx in second line. One hundred and thirty-six pts received at least 4 cycles, and 61 completed 8 cycles. After 4 cycles, the overall response rate (ORR) according to IWC (Cheson 1999 or 2007) was 54 % and the complete response (CR) rate was 23 %. At the end of treatment, the ORR and CR rates were 38 % and 33 %, respectively. With a median follow-up of 22 months, median (m) progression-free survival (PFS) and overall survival (OS) were 5 and 10 months (mo), respectively. mOS was significantly longer in case of prior history of indolent lymphoma (21 vs 8 mo, p < 0.001), age<75y (16 v 7mo, p < 0.001), IPI <3 (p < 0.001), non-refractory status to last treatment (18 v 7mo, p < 0.001). The mOS of patients who attained a CR was 40 mo. Among pts who were treated with R-GemOx in second line, the CR rate was similar (32%), the same factors influenced the OS and duration of a first remission longer than 12 months was a favorable factor (p=0.006). The most common toxicities during treatment were hematological and manageable. Grade 3-4 toxicities occurred in 23% of pts. Grade 1-2 peripheral neuropathy related to oxaliplatin was observed in 26%.

**Conclusion:** This real life study of R/R DLBCL, confirms the activity and a safety of R-GemOx. This combination represents a possible platform to be combined with targeted therapies as it is currently proposed with nivolumab in the NIVEAU trial (NCT03366272). However, facing this very high unmet medical need, development of new approaches including CAR T-cells should also be considered in this patient population.

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

390
DURABILITY OF COMPLETE RESPONSE
AFTER BLINATUMOMAB THERAPY FOR
REFRACTORY/RELAPSED AGGRESSIVE B-
CELL NON-HODGKIN LYMPHOMA

A. Viardot¹ | G. Hess² | R. Bargou³ |

N.J. Morley⁴ |

G. Gritti⁵ | K. Iskander⁶ | D. Cohan⁶ |

A. Zhang⁶ |

J. Franklin⁶ | L. Coyle⁷

¹Department of Internal Medicine, University Hospital of Ulm, Ulm, Germany; ²Department of Hematology, Oncology and Pneumology, Johannes Gutenberg-University, Mainz, Germany; ³Comprehensive Cancer Center Mainfranken, Würzburg University Medical Center, Würzburg, Germany; ⁴Haematology, Royal Hallamshire Hospital, Sheffield, United Kingdom; ⁵UOC Ematologia, Ospedale Papa Giovanni XXIII, Bergamo, Italy; ⁶Global Medical Organization, Amgen Inc., Thousand Oaks, United States; ⁷Haematology, Royal Northshore Hospital, St Leonards, Australia

**Introduction:** Achieving durable response in patients with relapsed/refractory (R/R) aggressive B-cell lymphoma (B-NHL) is challenging. Blinatumomab, a bispecific T-cell engager (BiTE®) immunotherapy targeting CD19-expressing cancer cells, has shown promising
<table><caption>Table. Results</caption><thead><tr><th>Complete Responders (CR)</th><th>NCT01741792<br>(n = 4)</th><th>NCT02910063<br>(n = 9)</th><th>Pooled<br>(n = 13)</th></tr></thead><tbody><tr><td>KM time to event, mo</td><td></td><td></td><td></td></tr><tr><td>Median (95% CI)</td><td>NE (5.9, NE)</td><td>NE (2.5, NE)</td><td>NE (5.9, NE)</td></tr><tr><td>Range</td><td>5.9, 24.0</td><td>0.3, 10.5</td><td>0.3, 24.0</td></tr><tr><td>Events, n (%)</td><td>2 (50.0)</td><td>1 (11.1)</td><td>3 (23.1)</td></tr><tr><td>Relapse</td><td>2 (50.0)</td><td>1 (11.1)</td><td>3 (23.1)</td></tr><tr><td>Death from any cause</td><td>0 (0.0)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Censored, n (%)</td><td>2 (50.0)</td><td>8 (88.9)</td><td>10 (76.9)</td></tr><tr><td>Alive without relapse</td><td>2 (50.0)</td><td>8 (88.9)</td><td>10 (76.9)</td></tr><tr><td>Median follow up, mo</td><td>23.7</td><td>8.8</td><td>9.1</td></tr></tbody></table>

NE, not estimable.

efficacy in patients with R/R aggressive B-NHL. We report the durability of complete response (DOCR) in patients treated with blinatumomab.

**Methods:** The DOCR in patients with R/R aggressive B-NHL responding to blinatumomab was assessed using data from two phase 2 studies (study 1 [N=25], NCT01741792; study 2 [N=41], NCT02910063) in patients with R/R aggressive B-NHL. Complete response (CR) was assessed using Cheson (study 1) and Lugano (study 2) criteria. Time-to-event variables were analyzed using the Kaplan-Meier (KM) method.

**Results:** Baseline patient characteristics in the pooled analysis were: median age 59 years (range, 41-77); 54% men; 54% treatment refractory; median 2 lines of prior therapy (range, 1-7); and 15% with prior autologous hematopoietic stem cell transplant. Of 25 patients treated with blinatumomab in study 1, 4 (16%) evaluable patients achieved CR. Of 41 patients treated with blinatumomab in study 2, 9 (22%) achieved CR. Median DOCR was not reached (Table). At a median follow-up of 9.1 months in the pooled analysis, 3 patients (23%) had relapsed (study 1, n=2 [50%]; study 2, n=1 [11%]). At 12 and 18 months, the KM probability of maintaining CR in the pooled analysis was 53.0% (95% confidence interval [CI], 8.5, 85.0).

**Conclusions:** For patients with R/R aggressive B-NHL who received blinatumomab, a durable response is possible. Longer-term follow up is needed to fully characterize the durability of complete response to blinatumomab.

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

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

**Disclosures:** Viardot, A: Consultant Advisory Role: Roche, BMS, Amgen, Kite/Gilead, Pfizer; Honoraria: Roche, BMS, Amgen, Kite/Gilead, Pfizer; Other Remuneration: travel fees received from Roche, Celgene, BMS, Abbvie, Kite/Gilead. Hess, G: Consultant Advisory Role: Roche, Janssen, Celgene, Gilead, Servier, Abbvie; Research Funding: Roche, Servier, Celgene; Other Remuneration: Speakers' bureau: Janssen. Bar-gou, R: Honoraria: Amgen, Cellex, GEMOAB, Molecular Partners, Novartis; Other Remuneration: Patent/royalties: Amgen. Morley, N: Consultant Advisory Role: Amgen, Roche; Honoraria: Amgen, Janssen; Other Remuneration: Speakers' bureau: Amgen. Gritti, G: Consultant Advisory Role: Autolus; Other Remuneration: Travel fees received from

Roche, Takeda, and Gilead. Iskander, K: Employment Leadership Position: Amgen; Stock Ownership: Amgen. Cohan, D: Employment Leadership Position: Amgen; Stock Ownership: Amgen. Zhang, A: Employment Leadership Position: Amgen; Stock Ownership: Amgen. Franklin, J: Employment Leadership Position: Amgen; Stock Ownership: Amgen. Coyle, L: Consultant Advisory Role: Amgen.

391

THE RITUXIMAB MAINTENANCE THERAPY IMPROVES PROGNOSIS OF TRANSFORMED DIFFUSE LARGE B CELL LYMPHOMA

H. Uryu¹ | Y. Mishima¹ | Y. Shirouchi¹ |

T. Fukuta¹ | A. Nishihara¹ | N. Inoue¹ |

Y. Kusano¹ | N. Nishimura¹ | M. Yokoyama¹ |

N. Tsuyama² | K. Takeuchi³ | Y. Terui¹

¹Hematology and Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; ²Division of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; ³Pathology Project for Molecular Targets, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

**Introduction:** Diffuse large B-cell lymphoma (DLBCL) with follicular lymphoma (FL) component at diagnosis has been considered as one of transformed DLBCLs. The prognosis of transformed DLBCL has improved by use of rituximab-contained therapy as same as de-novo DLBCL. However, it is still unclear whether transformed DLBCL can obtain identical outcomes compared to de-novo DLBCL. Furthermore, there are few reports about the effects of rituximab maintenance therapy for transformed DLBCL. We retrospectively analyzed the difference of clinical features and outcomes between transformed DLBCL and de-novo DLBCL and the efficacy of rituximab maintenance therapy for transformed DLBCL.

**Methods:** We studied patients with newly diagnosed as transformed DLBCL or de-novo DLBCL from March 2005 to October 2017 in our institution. The pathological diagnosis was performed based on morphological and immunohistochemical analyses. Transformed DLBCL
was defined in our study as a coexistence with components of FL and DLBCL in the same biopsied tissue at diagnosis. PET-CT scan was used to evaluate the stage at the diagnosis and the response after therapy. The statistical analysis of characteristics of patients were performed by Fisher's exact test. The survivals were calculated by the Kaplan Meier method, and statistical analysis were performed by log rank test. The various factors affecting OS and PFS were evaluated using Cox proportional hazard model.

**Results:** We analyzed patients with 51 transformed DLBCL and 532 de-novo DLBCL. Almost all patients were treated with R-CHOP chemotherapy in both groups. Among transformed DLBCL patients, 19 patients received rituximab maintenance therapy for two years after achieving good PR or more by induction therapy. In the comparison of patients' characteristics, the rate of advanced stage (58.8% vs 33.8%, P=0.001), bone marrow invasion (13.7% vs 5.3%, P=0.025), and GCB subtype (80.0% vs 55.0%, P=0.001) were significantly higher in transformed DLBCL compared to de-novo DLBCL. The median follow-up time was 71 months (range 3-160 months). 5-year PFS was significantly lower in transformed DLBCL than de-novo DLBCL (67.3% and 78.2%, respectively, P=0.0155), however there was no significant difference in 5-year OS (93.5% and 84.9%, respectively, P=0.31). With regard to patients with transformed DLBCL, there was significant difference between the group with rituximab maintenance therapy and the group without maintenance in 5-year OS (100% and 89.7%, respectively, P=0.0306) and 5-year PFS (94.7% and 51.4%, respectively, P=0.0046).

**Discussion and Conclusion:** Our data showed that transformed DLBCL had similar OS compared with de-novo DLBCL under R-CHOP therapy. Shorter PFS in patients without rituximab maintenance might be affected by the indolent component in transformed DLBCL. Our data suggested that rituximab maintenance therapy can control those components and improve outcomes of transformed DLBCL.

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

**Disclosures:** Mishima, Y: Consultant Advisory Role: Chugai-Roche Pharmaceuticals Co LTD. Nishimura, N: Consultant Advisory Role: Chugai-Roche Pharmaceuticals Co LTD. Yokoyama, M: Consultant Advisory Role: Chugai-Roche Pharmaceuticals Co LTD. Terui, Y: Honorary: Bristol-Myers Squibb, Celgene, Janssen, Novartis Pharma and Takeda Pharmaceutical Co LTD.

392
INTENSIVE IMMUNOCHEMOTHERAPY (R-CHOEP) VS HIGH-DOSE IMMUNOCHEMOTHERAPY (R-MegaCHOEP) IN YOUNG PATIENTS WITH AGGRESSIVE B-CELL LYMPHOMA: A 10-YEAR LONG-TERM FOLLOW-UP

F. Frontzek¹ | M. Ziepert² | M. Nickelsen³ |

B. Altmann² | B. Glaß⁴ | M. Hänel⁵ | L. Trümper⁶ |

G. Held⁷ | M. Bentz⁸ | P. Borchmann⁹ |

M. Dreyling¹⁰ | A. Viardot¹¹ | B. Metzner¹² |

F. Kroschinsky¹³ | A.M. Staiger¹⁴ | G. Ott¹⁴ |

A. Rosenwald¹⁵ | M. Löffler² | G. Lenz¹ | N. Schmitz¹

¹Department of Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany; ²Institute for Informatics, Statistics and Epidemiology, University Leipzig, Leipzig, Germany; ³Oncology, Oncology Lerchenfeld, Hamburg, Germany; ⁴Hematology and Stem Cell Transplantation, Helios-Klinikum Berlin-Buch, Berlin, Germany;

⁵Department of Internal Medicine III, Municipal Hospital Chemnitz, Chemnitz, Germany; ⁶Hematology and Oncology, University Göttingen, Göttingen, Germany; ⁷Departement of Internal Medicine I, Westpfalz-Klinikum GmbH, Kaiserlautern, Germany; ⁸Department of Internal Medicine III, Municipal Hospital Karlsruhe, Karlsruhe, Germany;

⁹Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany; ¹⁰Department of Internal Medicine III, Ludwig-Maximilians University of München, München, Germany; ¹¹Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany; ¹²Oncology and Hematology, Hospital Oldenburg, Oldenburg, Germany; ¹³Department Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany; ¹⁴Department of Clinical Pathology, Robert-Bosch Hospital, Stuttgart, Germany; ¹⁵Institute of Pathology, University Würzburg, Würzburg, Germany

**Introduction:** In 2012, we were first to report the results of a randomized trial comparing high-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) to aggressive conventional chemotherapy (R-CHOEP-14) as first-line therapy in young high-risk patients (pts) with aggressive B-cell lymphoma (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). We and others demonstrated that HDT/ASCT does not confer a survival advantage in the rituximab era. Here, we present the 10-year follow-up of the R-MegaCHOEP trial including data on secondary neoplasms and molecular profiles.

**Methods:** In the randomized, prospective phase III R-MegaCHOEP trial younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were included. 130 pts received 8 cycles of CHOEP-14 plus Rituximab; 132 pts were treated with 4 cycles of high-dose therapy necessitating repetitive ASCT (MegaCHOEP-21) with Rituximab. Primary endpoint was event free survival (EFS). This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive, FISH: 14/103 positive), BCL2 (IHC: 65/89 positive, FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive, FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88).

**Results:** After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP14- vs. 51% in the R-MegaCHOEP-arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), OS after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). In total, 12% of pts died due to lymphoma (30 pts), 9% therapy-related (23 pts), 3% of secondary neoplasia
(8 pts) and 2% due to concomitant disease (5 pts). The frequency of secondary malignancies was comparable in both arms (9% vs. 8%) and despite extremely high doses of etoposide (total dose 4g/m² in R-MegaCHOEP) we observed 2 cases of AML and 1 case of MDS per arm only. With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT when taking into account COO or expression- and translocation-status of MYC, BCL2, and BCL6 although the number of double-/triple-hit (n=14) and double-expressor (n=22) lymphomas was limited.

**Conclusions:** This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the encouraging outcome of young high-risk pts following aggressive conventional chemotherapy with 8 x R-CHOEP14. HDT/ASCT still does not confer any survival benefit including pts with poor-risk molecular characteristics. Solid tumors occurred at comparable frequencies in both treatment arms while the addition of etoposide to CHOP, even at very high doses, does not seem to increase the incidence of secondary AML/MDS.

Supported by Deutsche Krebshilfe.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); high-dose therapy (HDT).

**Disclosures:** Nickelsen, M: Consultant Advisory Role: Roche Pharma AG. Held, G: Consultant Advisory Role: BMS, Roche, MSD; Research Funding: Roche, BMS, Spectrum. Dreyling, M: Consultant Advisory Role: Acerta, Bayer, Celgene, Gilead, Janssen, Mundipharma, Roche, Sandoz; Honoraria: Bayer, Celgene, Gilead, Janssen, Roche; Research Funding: Celgene, Janssen, Mundipharma, Roche. Lenz, G: Consultant Advisory Role: Roche, Janssen, Celgene, BMS, Bayer, Novartis, NanoString, AstraZeneca, Morphosys, Amgen, Hexal; Honoraria: Gilead, Roche, Janssen, Celgene, BMS, Bayer, Novartis, NanoString, AstraZeneca, Morphosys, Amgen, Hexal, Sirtex; Research Funding: Roche, Janssen, Celgene, Bayer, AstraZeneca, Novartis, Gilead, AGIOS, Morphosys, AQUINOX, Verastem. Schmitz, N: Consultant Advisory Role: RIEMSER; Stock Ownership: Celgene; Honoraria: Takeda, Gilead Sciences, RiEMSER, Janssen china R&D.

393
TREATMENT OF HIGH RISK AGGRESSIVE B
CELL LYMPHOMAS WITH DA EPOCH R-
THE AUSTRIAN EXPERIENCE

M. Panny<fnref n="1" /> | K. Prochazka² | P. Neumeister² |

T. Nösslinger<fnref n="1" /> | V. Rathkolb<fnref n="1" /> | K. Holzer<fnref n="1" /> |

H. Greinix² | A. Böhm<fnref n="1" /> | F. Keil<fnref n="1" />

**Introduction:** Promising results in patients suffering from Burkitt's lymphoma (BL) and primary mediastinal B cell lymphoma (PMBCL) treated with DA EPOCH R have been reported. Additionally DA EPOCH R seems to be an option in first line treatment in high risk aggressive B cell lymphoma (HR BCL) in phase II trials.

<figure><img src="image_236.png" /></figure>

In our centres HR BCL - defined as DLBCL NOS with double protein expression (DEL) and/or high/ high-intermediate risk NCCN IPI, high grade B cell lymphoma with myc and bcl 2and/or bcl 6 rearrangements and high grade B cell lymphoma NOS - BL and PMBCL are treated with DA EPOCH R.

**Methods:** we performed a retrospective analysis of toxicity and efficacy in DA EPOCH R treated patients.

**Results:** So far 71 previously untreated patients with a median age of 52 years (range 18 – 89) have been treated with a total of 375 cycles of DA EPOCH R: 41 HR BCL, 18 PMBCL, and12 BL.

Dose escalation according to hematological toxicity was possible in 53 (77%) patients – but only in 7 (33%) of 21 patients ≥ 65 years. 29 (62%) of 48 patients aged <below 65 years received at least dose level 3 (144% dose intensity). Due to peripheral sensory neuropathy, vincristine had to be dose reduced in 37% of all cycles. Other CTCAE grade III/IV non-hematological toxicities were infrequent and manageable.

After a median follow up of 21,5 months overall survival (OS) rate is 80% and PFS 60% for all 71 patients. OS and PFS rates are 90% and 92% in BL, 92% and 93% in PMBCL, respectively.

In 41 HR BCL patients OS is 73% and PFS is 44% after a median follow up of 22 month, 2 years PFS is 58%. 2 years PFS for 22 patients in the subgroup of DEL is 51% (figure below), 2 years PFS in 10 patients with high risk NCCN IPI is 50%.

**Conclusion:** Despite limited data, DA EPOCH R is a feasible treatment with acceptable toxicity and a promising response rate. Dose escalation is age dependent. Excellent response rates to DA EPOCH R in BL and PMBCL are confirmed. As presented by Bartlett et al at ASH 2016 DA EPOCH R can not be recommended for standard risk DLBCL, but might be an valuable option for high risk aggressive BCL and can challenge more toxic regimens like R ACVBP or R Hyper CVAD.

<footnote n="1">¹Department of Hematology and Oncology, Hanusch Hospital, Vienna, Austria; ²Hematology, Medical University Graz, Graz, Austria</footnote>
**Keywords:** B-cell lymphoma; DA-R-EPOCH.

394
A PHASE II STUDY OF LENALIDOMIDE AND RITUXIMAB (R<fnref n="2" />) COMBINATION IN PATIENTS WITH HIGH-RISK REFRACTORY/RELAPSED DIFFUSE LARGE B-CELL LYMPHOMA

R. Bouabdallah<fnref n="1" /> | C. Zemmour<fnref n="1" /> |

J. Schiano de Collela<fnref n="1" /> | B. Slama<fnref n="2" /> | J. Bladé<fnref n="3" /> |

N. Belmecheri<fnref n="1" /> | D. Coso<fnref n="1" /> | C. Montes de Oca<fnref n="1" /> |

A. Stoppa<fnref n="1" /> | T. Aurran-Schleinitz<fnref n="1" /> | S. Cournier<fnref n="1" /> |

V. Ivanov<fnref n="4" /> | L. Mescam<fnref n="1" /> | D. Blaise<fnref n="1" />

**Introduction:** Patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis after traditional chemotherapy salvage regimens. Refractory patients and early relapses (<12 months) are particularly refractory to chemotherapy. Lenalidomide (L) is an immunomodulatory drug with pleiotropic anti-neoplastic effects. There are numerous studies of L and Rituximab (R) combination (R<fnref n="2" />) in patients with R/R DLBCL, resulting in a 28% to 41% objective response rate, depending on the status of disease. Herein, we report mature data for safety and efficacy of R<fnref n="2" /> in high-risk R/R DLBCL.

**Methods:** Eligible patient's age ³¹8 years had CD20+ B-cell R/R DLBCL. Cell of origin (COO) was assessed at time of entry in the study. High-risk patients were defined as refractory or relapsing within 12 months, <fnref n="3" /> 3 prior therapy lines, high international prognostic index (IPI) at relapse, histological transformation (HT), and non-germinal center (non-GC) COO signature. L was given orally at 25 mg/day (d) from d1 to d21, for a 28-d cycles, and R at 375 mg/m2 at d8. Treatment was planned for 12 cycles, and was interrupted in case of progression or unacceptable toxicity. Primary objective was response rate. Secondary objectives were progression-free survival (PFS) and overall survival (OS).

**Results:** From 10/2013 to 10/2017, 34 patients were included in the study of whom 32 were evaluable for both toxicity and efficacy. Median age was 69 years (range 40-86), with 22/32 (69%) of patients > 60 years, 21/32 (66%) were male, and 22/32 (69%) had stage III/IV disease. Twenty-six of 32 patients (81%) were considered as high-risk R/R DLBCL: refractory 4, <fnref n="3" /> 3 prior therapy lines 12, High IPI 24, HT 15, non-GC 10. The median number of prior anticancer therapies was 2 (1-4), and 30/32 (94%) received <fnref n="3" /> 2 lines. The median number of L cycles was 2 (1-12) and 8/32 (25%) received less than 2 cycles. Median total dose of L was 1050 mg (300-6200). Toxicity was mainly haematological and the

most common (³10% of patients) grade 3-4 treatment-emergent adverse events consisted in neutropenia and thrombocytopenia. Treatment was interrupted in 27/32 (84%) patients due to progression of disease. Only 4 patients experienced an objective response (12.5%) with 2 complete responses (6%). With a median follow-up of 22.6 months ([9.6-54.8], 95% confidence interval), 1-year PFS and OS were 8% [2%-21%] and 44% [25%-61%] respectively. At the last follow-up, 18/32 (56%) patients were dead all from lymphoma.

**Conclusions:** Our data of the R<fnref n="2" /> regimen in R/R DLBCL were comparable in terms of tolerance to those reported in the literature. However, response and survival rates were very low when compared to previous reports of the combination. This could be due to our population features as the majority of patients in this series could be classified as high-risk R/R. Alternative options should be offered in these situations.

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

395
DA-EPOCH-R VERSUS R-CHOP IN HIGH RISK DLBCL PATIENTS: ANALYSIS OF THE CZECH LYMPHOMA STUDY GROUP (CLSG)

M. Šimkovič<fnref n="1" /> | H. Móciková<fnref n="2" /> | J. Ďuraš<fnref n="3" /> |

K. Kamarádová<fnref n="4" /> | P. Štěpánková<fnref n="1" /> | A. Janíková⁵ |

J. Michalka⁵ | P. Žák<fnref n="1" /> | D. Belada<fnref n="1" /> | M. Trněný⁶

**Introduction:** The prognosis of younger (≤ 70 years) patients (pts) with diffuse large B-cell lymphoma (DLBCL) at high risk (aa-IPI score 2-3) after R-CHOP chemotherapy is suboptimal. Intensification with dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) plus rituximab (DA-EPOCH-R) in unselected patients with DLBCL has not resulted in increased efficacy according to CALGB/Alliance 50303 trial (Wilson et al., ASH 2016). However, the role of DA-EPOCH-R as a regimen for untreated younger patients with high risk DLBCL excluding those with primary mediastinal large B-cell lymphoma (PMBL) remains controversial.

**Methods:** Between 10/2013 and 12/2017, a total of 37 pts with newly diagnosed high risk DLBCL (excluding PMBL) pts treated with

<footnote n="1">¹Hematology, Cancer Center Institut Paoli-Calmettes, Marseille, France;</footnote>

<footnote n="2">²Hematology, Centre Hospitalier Henri Duffaut, Avignon, France;</footnote>

<footnote n="3">³Hematology, Hôpital d'Instruction des Armées, Toulon, France;</footnote>

<footnote n="4">⁴Hematology, Hopital La Conception, Marseille, France</footnote>

<footnote n="1">¹Department of Internal Medicine - Haematology, University Hospital and Medical School Hradec Kralove, Hradec Králové, Czech Republic;</footnote>

<footnote n="2">²Dept. of Internal Medicine and Haematology, Faculty Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic; ³Department of Clinical Hematology, Teaching Hospital Ostrava, Ostrava, Czech Republic; ⁴The Fingerland Department of Pathology, University Hospital and Medical School Hradec Kralove, Hradec Kralove, Czech Republic; ⁵Department of Internal Medicine - Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic; ⁶1st Department of Medicine, First Medical Faculty, Charles University and General University Hospital, Prague, Czech Republic</footnote>
<table><caption>**TABLE 1** Baseline characteristics of patients treated with DA-EPOCH-R (n=37)</caption><thead><tr><th></th><th>N</th><th>%</th></tr></thead><tbody><tr><td>Age, years (median, range)</td><td>56 (20-70)</td><td></td></tr><tr><td>≥60 years</td><td>12</td><td>32</td></tr><tr><td>Females</td><td>12</td><td>32</td></tr><tr><td>Age-adjusted IPI score</td><td></td><td></td></tr><tr><td>High-intermediate/High</td><td>25/12</td><td>68/32</td></tr><tr><td>Ann Arbor stage</td><td></td><td></td></tr><tr><td>II/III/IV</td><td>2/5/30</td><td>5/14/81</td></tr><tr><td>Presence of B symptoms</td><td>18</td><td>47</td></tr><tr><td>Performance status (ECOG)</td><td></td><td></td></tr><tr><td>0-1/2/3-4</td><td>19/13/5</td><td>51/35/14</td></tr><tr><td>Extranodal involvement</td><td>36</td><td>97</td></tr><tr><td>Bulky disease >5.0 cm</td><td>20</td><td>54</td></tr><tr><td>LDH level>ULN</td><td>35</td><td>95</td></tr><tr><td>B2M >ULN</td><td>20</td><td>61</td></tr><tr><td>Bone marrow (involved)</td><td>13</td><td>35</td></tr><tr><td>DEL</td><td>7</td><td>26</td></tr><tr><td>DHL/THL</td><td>3</td><td>12</td></tr><tr><td>Cell of origin (Hans)</td><td></td><td></td></tr><tr><td>GC/Non-GC/Not evaluable</td><td>19/10/8</td><td>51/27/22</td></tr><tr><td>CD5 positivity</td><td>1</td><td>3</td></tr></tbody></table>

B2M beta-2-microglobulin, DHL double hit lymphoma; THL triple hit lymphoma, DEL double expressor lymphoma, GCB germinal center B-cell lymphomas, ULN upper limit of normal, LDH lactate dehydrogenase

DA-EPOCH-R were registered in the Observational Epidemiological and Clinical Study registry NIHIL (govTrial no: NCT03199066). Basic characteristics are summarized in Table 1. The clinical outcomes of DA-EPOCH-R cohort were compared to 117 pts treated with R-CHOP regimen from 2 centres where intensification approach is not introduced. We performed 1:1 matched-pair analysis including these criteria: aalPI, age and performance status.

**Results:** Median age was 56 years (range: 20-70). Median number of administered DA-EPOCH-R cycles was 6 (range, 1-6). Dose escalation to 3rd dose level or above was feasible in 68% pts. The overall response/complete remissions were achieved in 92%/78% pts. At a median follow up of 2.3 years, the median overall survival (OS) and progression-free survival (PFS) had not been reached; estimated 3-year PFS and OS were 70% and 85%, respectively. Predictors of short PFS in univariate analysis were the presence of B symptoms (p=0.006) and increased beta-2-microglobulin level (p=0.034). Serious (CTCAE grade III/IV) infections occurred in 21.6% of pts. 11% pts developed other serious non-hematologic toxicity. No significant differences in PFS and OS were observed between DA-EPOCH-R vs. R-CHOP in the matched-pair analysis (Fig. 1). Estimated 3-year PFS and OS of pts treated with R-CHOP were 66% and 70%, respectively.

(A)

<figure><img src="image_237.png" /></figure>

(B)

<figure><img src="image_238.png" /><figcaption>Fig 1. Kaplan-Meier plot for: (A) PFS for DA-EPOCH-R vs. R-CHOP; and (B) OS for DA-EPOCH-R vs. R-CHOP</figcaption></figure>

**Conclusion:** The DA-EPOCH-R is an active and feasible treatment for high risk DLBCL pts. According to our data, DA-EPOCH-R did not improve PFS or OS compared to standard R-CHOP treatment.

**Financial Support:** This work was supported by the research project PROGRES Q40/08 and by a grant AZV 16-31092A from the Internal Grant Agency of the Czech Ministry of Health.

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

396

UPFRONT AHSCT IN NON HODGKIN LYMPHOMA-BETTER OUTCOME?

N. Adila¹ | K. Tey¹ | A. Teh² |

M.F. Abdul Rahman² | S. Ng² | P. Bee¹ | G. Gan¹

¹Hematology, University Malaya Medical Centre, Kuala Lumpur, Malaysia; ²Hematology, Ramsay Sime Darby Medical Centre, Subang Jaya, Malaysia

**Background:** High dose therapy (HDT) followed by autologous hematopoietic stem cell transplantation (AHSCT) is recognized as a standard of care for relapsed/refractory Non-Hodgkin Lymphoma (NHL). There are many studies which have demonstrated improved disease free survival(DFS) and overall survival(OS) with AHSCT in these patients. There have been also several studies which reported better outcome in patients with high risk NHL who had upfront AHSCT.
**Aims:** This study aims to determine if upfront AHSCT do improve patients' clinical outcome.

**Methods:** This is a retrospective study where patients who had undergone AHSCT from October 1997 to September 2017 in 2 hospitals in Malaysia were included. Patients' demographic data and clinical information were collected. The risk groups were categorized into 2 groups via the International Prognostic Index (IPI); whereby IPI score of 0-2 were defined as low risk and IPI score of 3-5 were considered as high risk.

**Results:** A total of 148 patients (male: female 92:56) were included. Majority of patients had B cell lymphoma (85.1%). The median age at diagnosis was 46 (ranges from 15 – 69) years. The median period of diagnosis to AHSCT was 9.5 (range 2-112) months. Majority of patients (88.5%) were transplanted in complete remission (CR) and the remaining (11.5%) in partial remission (PR). 68% of patients were categorized as low risk and 32% patients were categorized as high risk. The transplant related mortality (TRM) was 3.4%. The overall survival (OS) and event free survival (EFS) at 3 years were 70.1% and 62.6% respectively. Patients who were transplanted in first CR had significantly better OS and EFS, p value of <0.0001. The TRM of 3.4% is similar to what was reported in other centres internationally.

**Summary/Conclusion:** The significantly better clinical outcome of patients transplanted in first CR may suggest that upfront AHSCT is feasible and may improve outcomes. However, further studies would be required to confirm this finding.

**Keywords:** autologous stem cell transplantation (ASCT); high-dose therapy (HDT); non-Hodgkin lymphoma (NHL).

397

OUTCOME OF PATIENTS WITH
AGGRESSIVE B-CELL LYMPHOMA WHO
FAILED TO PROCEED TO OR RELAPSED
AFTER HIGH DOSE CHEMOTHERAPY AND
AUTOLOGOUS HEMATOPOIETIC CELL
TRANSPLANTATION

J. Romejko-Jarosinska

E. Paszkiewicz-Kozik

L. Popławska

L. Targonski

M. Szymanski

J. Walewski

Department of Lymphoproliferative Diseases, Maria Sklodowska- Curie
Cancer Center and Institute of Oncology, Warsaw, Poland

**Background:** Patients with high-risk or relapsed aggressive lymphoma are usually treated with high dose chemotherapy (HDT) and autologous hematopoietic cell transplantation (auto-HCT).

**Aim:** We evaluated patients who were referred to auto-HCT and who failed to proceed to or relapsed after auto-HCT.

**Methods:** We evaluated data from 101 consecutive patients with aggressive B-cell lymphoma: DLBCL (n= 86) and PMBL (n=15), who were planned for HDT and auto-HCT at our institution between 2012

and 2017 including 45 female and 56 male, median age (range) of 49 (20-69), clinical stage III/IV in 85 (85%) pts.

**Results:** After first-line treatment, CR and PR was achieved in 51 (50%) and 43 (43%), respectively. Twenty three patients (23%) were not eligible for transplant: 7 pts failed stem cell mobilization, and 16 patients progressed before transplantation. 78 pts underwent HDT and auto-HCT: 21 pts in the first remission, and 57 pts after a median of 2 (2-4) lines of treatment. At transplant, 46 (60%) and 31 (40%) patients were in CR, and PR, respectively. Relapse after transplant occurred in 30 (38%) patients including 6 pts in first remission and 24 pts in subsequent remission (p=0.24), and 12 (26%) pts in CR and 18 (58%) in PR (56%) (p=0.003). The HR for progression in pts with response less than CR was 2.89 (95%CI: 1.51, 6.66) compared to pts with CR at transplant. With a median (range) PFS of 20 months (0-79), 1-year PFS was 66% (95%CI: 56%, 76%). Median (range) PFS for patients who relapsed post-transplant was 3 (0-40) months. With a median (range) follow up of 21 (0-79) months, 1-year OS for all transplanted patients was 69% (95%CI: 59%, 79%). Median (range) OS for pts who relapsed after auto-HCT was 6 (0-40) months. Conclusion: Around 20% of patients with high-risk or relapsed aggressive B-cell lymphoma were not able to proceed to HDT/auto-HCT, and around 40% of those who did, progressed after transplantation. Non-CR at transplant increased the risk of progression after transplantation. Taken together, 60% of patients with aggressive B-cell lymphoma referred to HDT/auto-HCT at our institution might be candidates for novel therapies.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); high-dose therapy (HDT).

**Disclosures:** Romejko-Jarosinska, J: Honoraria: Roche, Takeda; Other Remuneration: Travel grant- Takeda, Servier. Paszkiewicz-Kozik, E: Honoraria: Roche, Takeda; Other Remuneration: Travel grant- Roche.

Popławska, L: Other Remuneration: Travel grant- Roche. Targonski, L: Other Remuneration: Travel grant- Roche, Celgena. Szymanski, M: Other Remuneration: Travel grant- Roche. Walewski, J: Consultant Advisory Role: Roche, Celgene, Takeda, Janssen-Cilag, Servier, Amgen, Incyte Abbvie; Honoraria: Roche, Takeda, Celgene Janssen Cilag, Servier; Research Funding: Roche, GSK/Novartis, Takeda Janssen Cilag; Other Remuneration: Travel grant- Roche.

398

R-IVAC SALVAGE THERAPY IN RELAPSED
AND REFRACTORY DLBCL

J. Casan<fnref n="1" /> | G. Wolyncewicz² | W. Alam<fnref n="1" /> |

S. Opat³ | G. Gregory³ | J. Shortt³ | S. Patil² |

M. Gilbertson<fnref n="1" />

<footnote n="1">¹Haematology, Monash Health, Clayton, Australia; ²Haematology, The Alfred Hospital, Melbourne, Australia; ³School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia</footnote>
<table><caption>TABLE 1</caption><thead><tr><th>Characteristic</th><th>N = 27</th></tr></thead><tbody><tr><td>Age (median, range)</td><td>51.8 (30.4-65.8)</td></tr><tr><td>Male gender</td><td>73%</td></tr><tr><td>ECOG</td><td></td></tr><tr><td>0-1</td><td>21</td></tr><tr><td>≥2</td><td>6</td></tr><tr><td>Ann Arbor Stage median</td><td>2.5</td></tr><tr><td>I-II</td><td>12 (44%)</td></tr><tr><td>III-IV</td><td>15 (56%)</td></tr><tr><td>>1 Extranodal sites</td><td>8 (30%)</td></tr><tr><td>Bulky disease</td><td>11 (41%)</td></tr><tr><td>R-IPI</td><td></td></tr><tr><td>0</td><td>6</td></tr><tr><td>1-2</td><td>11</td></tr><tr><td>≥3</td><td>10</td></tr><tr><td>Prior lines of therapy (median, range)</td><td>1 (1-2)</td></tr><tr><td>Time to relapse:</td><td></td></tr><tr><td><12 months or refractory disease</td><td>22 (82%)</td></tr><tr><td>>12 months</td><td>5 (18%)</td></tr></tbody></table>

**Introduction:** Despite advances in novel therapy for diffuse large B-cell lymphoma (DLBCL), salvage chemotherapy prior to autologous stem cell transplant (HSCT) remains the standard approach at relapse. However, there is no consensus salvage regimen and practice varies considerably. Refractory DLBCL or short remission duration cases have particularly poor outcomes (Gisselbrecht, 2010). R-IVAC is an infusional protocol incorporating etoposide (60mg/m² Day 1-5), ifosfamide (1.5g/m² Day 1-5), cytarabine (2g/m² BD Day 1-2) in addition to Rituximab (375mg/m²).

**Methods:** We retrospectively analysed 27 patients treated at two teaching hospitals to determine the safety and efficacy of R-IVAC for relapsed DLBCL. Disease response was assessed by PET (Lugano 2014 criteria).

**Results:** Patient characteristics are summarised in Table 1. 13 patients (48%) were refractory to their previous therapy and 9 patients (33%) had relapsed in <12 months. 70% of patients received 2 cycles of treatment (range 1-3) and 92.5% received rituximab with IVAC.

In 26 evaluable patients, the overall response rate (ORR) was 54% (42% complete response, 12% partial response). In patients with disease relapsing after ≥12 months, the ORR was 100%, versus 43% in relapses <12 months or refractory disease. 21 patients were referred for HSCT, and 10 (37%) patients proceeded (9 autograft, 1 allograft). Stem cell mobilisation succeeded in 90% of patients. 2 patients declined HSCT, 8 did not proceed due to inadequate disease control. With a median duration of follow-up in surviving patients of 30 months, 2-year progression-free survival (PFS) of the whole cohort

was 25% and 2-year overall survival (OS) was 32%. Patients who responded achieved 2-year PFS of 53% and OS of 62%. In HSCT recipients, 2-year PFS and OS were 44% and 66%.

Hematologic toxicity was considerable with grade 3/4 neutropenia and thrombocytopenia in 92.5% and 100% patients respectively. 25 patients experienced febrile neutropenia, but only 1 patient died of treatment-related toxicity. The mean hospital length of stay per cycle was 15.6 days. 18 patients required an unplanned admission.

**Conclusion:** R-IVAC demonstrated significant therapeutic efficacy and manageable toxicity in a cohort overwhelmingly composed of refractory or early relapse DLBCL, perhaps suggesting therapy intensification to be effective in refractory disease. Judicious patient selection is required given the rate of toxicity.

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

**Disclosures:** Opat, S: Consultant Advisory Role: Roche, Janssen, Celgene, Takeda, Novartis, Abbvie, Gilead, Bristol-Myers Squibb, Merck, Sanofi, Mundipharma; Honoraria: Roche, Janssen, Celgene, Takeda, Novartis, Abbvie, Gilead, Mundipharma; Research Funding: Roche, Janssen, Celgene, Takeda, Novartis, Abbvie, Gilead, Beigene, Merck; Other Remuneration: Roche, Bristol-Myers Squibb. Gregory, G: Consultant Advisory Role: Roche; Honoraria: Roche; Other Remuneration: Roche. Gilbertson, M: Honoraria: Roche.

E. Paszkiewicz-Kozik<fnref n="1" /> | W. Michalski² | M. Taszner³ |

W. Knopinska-Posłuszny⁴ | M. Mordak-Domagała⁵ |

J. Najda⁶ | A. Borawska<fnref n="1" /> | J. Romejko-Jarosińska<fnref n="1" /> |

M. Chełstowska⁷ | M. Świerkowska<fnref n="1" /> |

A. Dąbrowska-Iwanicka<fnref n="1" /> | A. Malenda⁷ |

A. Druzd-Sitek<fnref n="1" /> | R. Konecki<fnref n="1" /> | B. Kuniega⁸ |

M. Osowiecki<fnref n="1" /> | B. Ostrowska<fnref n="1" /> | T. Szpila⁷ |

K. Domańska-Czyż<fnref n="1" /> | M. Szymański<fnref n="1" /> | Ł. Targoński<fnref n="1" /> |

L. Poplawska<fnref n="1" /> | M. Kotarska<fnref n="1" /> | S. Giebel⁶ |

A. Lange⁵ | A. Pluta⁸ | K. Warzocha⁷ | J. Zaucha⁹ |

G. Rymkiewicz¹⁰ | J. Walewski<fnref n="1" />

<footnote n="1">¹Department of Lymphoid Malignancies, Maria Sklodowska-Curie Institute - Oncology Center, Warszawa, Poland; ²Biostatistics Unit, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland;
³Hematology Department, Medical University, Gdansk, Poland;
⁴Hematology Department, Independent Public Health Care of the Ministry of the Internal Affairs with the Oncology Centre, Olsztyn, Poland; ⁵Hematology Department, Lower Silesia Cell Transplantation Center, Wrocław, Poland; ⁶Hematology Department, Maria Sklodowska-</footnote>
Curie Institute - Oncology Center, Gliwice, Poland; ⁷Lymphoma Department, Institute of Hematology and Transfusiology, Warszawa, Poland; ⁸Hematology Department, Oncology Centre of the Podkarpackie Province, Brzozów, Poland; ⁹Oncology Department, Maritime Hospital, Gdynia, Poland; ¹⁰Pathology Department, Maria Sklodowska-Curie Institute - Oncology Center, Warszawa, Poland

**Introduction:** Second or subsequent line chemotherapy for DLBCL patients who relapse or progress after R-CHOP induction treatment involve different cytotoxic agents but there is no alternative to anti-CD20 antibody rituximab available. In addition, rituximab is not reimbursed for recurrent DLBCL in Poland. We hypothesized that a combination of ofatumumab - type II anti-CD20 antibody with different mechanism of action than rituximab, with dose-intensive chemotherapy IVAC (ifosfamide, etoposide, and cytarabine) will be active in relapsed/refractory DLBCL patients who are not candidates for high-dose chemotherapy and autologous hematopoietic cell transplantation (ASCT).

**Methods:** Patients with DLBCL not suitable for ASCT who progressed on or relapsed after R-CHOP treatment were eligible. Patients received O-IVAC regimen (ofatumumab + IVAC) that was dose-modified for age ≥ 60. Primary endpoint was objective response rate (ORR = CR + PR, CR complete remission, PR partial remission). Secondary endpoints were: progression-free survival (PFS), event-free survival (EFS), overall survival (OS), safety and tolerability. The minimum patient follow-up was 1 year after treatment completion. The baseline ECOG performance status, age, systemic (B) symptoms, Ann Arbor stage, number of prior salvage therapies and time since last therapy (TSLT) were analyzed as potential prognostic factors. The PLRG-8 study is registered with ClinicalTrials.gov at NCT01481272. The study was supported by the research grant from GSK/Novartis (OMB114361).

**Results:** Between November 2011 and May 2016, 77 eligible patients were enrolled in the study, received at least one cycle of O-IVAC and were included in the final analysis. The average age was 56,8 (+/-13,6) yrs, ≥60 yrs- 50,6%, male - 57,1%, ECOG 1-2 - 61%, ≥3 - 39%, systemic symptoms - 48,1%, Ann Arbor stage 1-2/3-4 - 22,1%/77,9%, number of prior salvage therapies ≥1 - 58,5%. The ORR was 51.9% (95% CI: 40.7%, 63.1%) with 10% CR (n=8). The presence of systemic symptoms was the only statistically significant (p=0.031) factor for ORR with the odds ratio of 2.77 (95% CI: 1.10, 6.98). Treatment related mortality was 15.5%. 1-year PFS, and EFS were 61% (95% CI: 49.8%, 72.2%) each, and 1-year OS was 84.4% (95% CI: 76.1%, 92.5%). Estimated 5-year OS was 30.6% (95% CI: 20%; 41.2%). ECOG score and TSLT were statistically significant factors for survival endpoints. Age was significant for OS, and the number of therapy lines - for PFS and EFS. The most frequent adverse events were hematological.

**Conclusions:** O-IVAC regimen was an active salvage regimen for DLBCL patients who failed R-CHOP induction treatment with ORR rate of 51% and estimated 5-year OS of 30%. This outcome compares favorably to the outcome reported in Scholar-1 study (Blood 2017;

130: 1800) with ORR of 26%, and 2-year OS of 20%. Further clinical evaluation of the O-IVAC regimen is justified.

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

**Disclosures:** Paszkiewicz-Kozik, E: Honoraria: lecture honoraria: Roche, Takeda; Other Remuneration: Roche travel support. Taszner, M: Research Funding: Roche, Takeda travel grant. Knopińska-Posłuszny, W: Research Funding: Roche travel grant. Borawska, A: Other Remuneration: Roche travel support. Romejko-Jarosińska, J: Honoraria: lecture honoraria: Servier, Novartis; Other Remuneration: Takeda travel support. Świerkowska, M: Other Remuneration: Roche travel support. Dąbrowska-Iwanicka, A: Honoraria: lecture honoraria: Amgen; Other Remuneration: Roche travel support. Osowiecki, M: Other Remuneration: Roche travel support. Szymański, M: Other Remuneration: Roche travel support. Giebel, S: Employment Leadership Position: Polish Lymphoma Research Group President; Consultant Advisory Role: Novartis; Honoraria: Novartis. Zaucha, J: Employment Leadership Position: Polish Lymphoma Research Group Vice President; Consultant Advisory Role: Roche; Honoraria: Roche; Other Remuneration: Roche travel support. Rymkiewicz, G: Other Remuneration: Roche travel support. Walewski, J: Employment Leadership Position: Maria Sklodowska-Curie Institute-Oncology Centre, Polish Lymphoma Research Group Vice President; Consultant Advisory Role: Roche, Celgene, Takeda, Janssen-Cilag, Servier, Amgen, BMS, Incyte, Abbvie; Honoraria: Roche, Celgene, Takeda, Janssen-Cilag, Servier; Research Funding: Roche, GSK/Novartis, Takeda, Janssen-Cilag; Other Remuneration: Roche travel support.

## 400 EFFICIENCY AND SAFETY OF STEM CELL MOBILIZATION FOLLOWING GDP SALVAGE IN PATIENTS WITH RELAPSED OR REFRACTORY LYMPHOMA

C. Tang¹ | O. Espin-Garcia² | A. Prica¹ |
V. Kukreti¹ | R. Kridel¹ | A. Keating¹ | J. Kuruvilla¹ |
M. Crump¹

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

**Background:** High-dose chemotherapy and autologous stem cell transplant (ASCT) remains a key treatment strategy in patients (pts) with relapsed/refractory (R/R) aggressive lymphoma. After CCTG study LY.12 (Crump, et al, JCO 2014) established gemcitabine, dexamethasone and cisplatin (GDP) as standard salvage chemotherapy regimen at our centre, we replaced our previous mobilization strategy using cyclophosphamide + etoposide (CE) with PBSC collection using GDP. The aim of this study was to compare the efficiency, resource use and ASCT outcomes of PBSC mobilisation with GDP to CE.
**Methods:** All pts undergoing PBSC mobilization following salvage GDP for R/R lymphoma from 1/2012 to 8/2018 were included in this analysis. CE comprised C 2 g/m² d1, E 200mg/m² d 1-3 + GCSF 10µg/kg d4-12, with apheresis planned d13. For collection following GDP, GCSF was added 10µg/kg d9-14, apheresis starting d15. Leukapheresis started when the blood CD34 count was >10 cells/µl (target ≥5 x 10⁶ CD34 cells/kg). From May 2014 plerixafor 24 µg/kg was added to GCSF for slow or inadequate mobilization. Primary outcomes were PB CD34 count on planned day of apheresis and total CD34 cell yield. Secondary outcomes included number of apheresis days, febrile neutropenia after mobilisation, engraftment, hospital stay, transfusions, PFS and OS.

**Results:** A total of 339 pts underwent PBSC mobilisation, 210 following GDP and 129 after CE. Pts in GDP group had more delays from planned to actual day of collection (mean 0.7 vs 0.4 days, p=0.006) and required more days of apheresis (mean, 1.7 vs 1.5 days, p = 0.001). The percentage of GDP pts collected on planned day of harvest and who required only one day of apheresis were 71% and 50%, versus 84% and 69% respectively after CE. In multi-variable analysis, CE led to both higher PB CD34 count on planned day of harvest and higher total CD34 yield (both p<0.001), despite a higher rate of plerixafor use in the GDP group (36/210 vs y/129). When considering a target CD34 yield ≥5x10⁶/kg there was no difference between mobilization regimens (p=0.66). Similarly, on multivariable analysis, febrile neutropenia during mobilization, days to engraftment, ASCT admission duration and platelet transfusions did not differ between the two strategies; pts mobilized with CE required more RBC transfusion during ASCT (p=0.04). Prior BM involvement and plerixafor use were independent predictors for longer engraftment (p=0.013 and p=0.007 respectively), irrespective of regimen and CD34 yield. In multi-variable Cox analyses, disease status at time of ASCT was the main predictor of PFS and OS.

**Conclusions:** CE+GCSF appears to be a more efficient mobilization method than GDP+GCSF with regard to number and timing of leukapheresis in pts undergoing GDP salvage for R/R lymphoma; however this did not translate to significant differences in engraftment or length of hospital admission.

**Keywords:** autologous stem cell transplantation (ASCT); gemcitabine; salvage treatment.

401
ALLOGENEIC HEMATOPOIETIC CELL
TRANSPLANTATION IMPACTS ON
IMMUNE EVASIVE MECHANISMS IN
RELAPSED/REFRACTORY DIFFUSE LARGE
B-CELL LYMPHOMA – A SINGLE CENTER
EXPERIENCE

**C.S. Sauter** | **R.J. Lin** | **C. Ho** | **S.M. Devlin** |
**M.A. Maloy** | **M. Perales** | **P.B. Dahi** | **H. Schoder** |

A.A. Jakubowski | J.N. Barker | E.B. Papadopoulos |
S.A. Giralt

Medicine, Adult BMT Service, Memorial Sloan Kettering Cancer Center,
New York, United States

**Introduction:** Allogeneic hematopoietic cell transplantation (allo-HCT) produces durable remission in a subset of relapse/refractory (r/r) DLBCL. Chemoresistance, remission status, age, comorbidities, and performance status are known predictors of outcomes from previous single center and registry studies. However, it remains unclear whether the graft-versus-lymphoma effect through allo-HCT could overcome established immune evasive mechanisms deployed by r/r DLBCL including MHC downregulation, TP53 overexpression, or c-myc overexpression.

**Methods:** We retrospectively reviewed 114 patients who had undergone first allo-HCT for r/r DLBCL at our institution from 2000 to 2018. We examined the association of clinical, disease, and transplant characteristics with outcomes post-allo-HCT. We explored pathological correlations between MHC downregulation and TP53 or c-myc overexpression using immunohistochemistry and transplant outcomes. Standard COX proportional hazard model statistical analysis was performed.

**Results:** One hundred fourteen patients were included in the analysis and their baseline characteristics were summarized in Table 1. With median follow-up of 4.1 years (range 0.8-17.5) for survivors, the 4-year overall survival (OS) and progression-free survival (PFS) is 53% (95% CI 43-63) and 43% (95% CI 34-52), respectively (Figure 1). The 2-year cumulative incidence of relapse and non-relapse mortality is 24% (95% CI 16-32) and 28% (95% CI 20-37), respectively (Figure 2). In multivariate analysis, only transformed disease was borderline significantly associated with improved OS (HR 0.58, 95% CI 0.32-1.06, p=0.077); while Deauville score 4-5 (HR 1.71, 95% CI 0.95-3.07, p=0.072) and prior ASCT (HR 1.76, 95% CI 0.94-3.28, p=0.077) were borderline significantly associated with inferior PFS. Thirty-eight patients had available tumor specimens prior to allo-HCT, and 16 of them had MHC downregulation (either class I or II), 11 of them had TP53 overexpression (≥30%), and 8 of them had c-myc overexpression (>40%). There was no difference in either OS or PFS among patients with or without these immune evasive mechanisms.

**Conclusions:** We demonstrate here that allo-HCT for r/r DLBCL could achieve favorable long-term survival in nearly half of heavily pretreated patients. Allo-HCT might overcome several established lymphoma immune evasive mechanisms in the subset of patients with available pathologic samples, although our dataset is limited in statistical power toward this analysis. While requiring confirmation from a larger study, our data supports expanded consideration of allo-HCT for r/r DLBCL.

**Keywords:** allogeneic stem cell transplant (alloSCT); diffuse large B-cell lymphoma (DLBCL); immune system.
<table><caption>Table 1. Baseline Characteristics</caption><thead><tr><th></th><th>N (%)</th></tr></thead><tbody><tr><td><strong>Number of patients</strong></td><td><strong>114</strong></td></tr><tr><td>Patient age, years (median, range)</td><td>53.9 (18.8-78.7)</td></tr><tr><td>Female Gender</td><td>33 (29)</td></tr><tr><td>Disease status by PET-CT (Deauville score)</td><td></td></tr><tr><td>1-3</td><td>55 (56)</td></tr><tr><td>4-5</td><td>44 (44)</td></tr><tr><td>Missing information</td><td>15</td></tr><tr><td>Pre-transplant ISRT</td><td></td></tr><tr><td>No</td><td>97 (85)</td></tr><tr><td>Yes</td><td>17 (15)</td></tr><tr><td>Previous Lines of Therapy</td><td></td></tr><tr><td>1-2</td><td>35 (31)</td></tr><tr><td>3 or more</td><td>79 (69)</td></tr><tr><td>Chemosensitivity</td><td></td></tr><tr><td>No</td><td>27 (24)</td></tr><tr><td>Yes</td><td>87 (76)</td></tr><tr><td>ATG/Campath</td><td></td></tr><tr><td>No</td><td>81 (71)</td></tr><tr><td>Yes</td><td>33 (29)</td></tr><tr><td>Prior ASCT</td><td></td></tr><tr><td>No</td><td>83 (73)</td></tr><tr><td>Yes</td><td>31 (27)</td></tr><tr><td>Transformed from Indolent Lymphoma</td><td></td></tr><tr><td>No</td><td>60 (53)</td></tr><tr><td>Yes</td><td>54 (47)</td></tr><tr><td>Karnofsky Performance Score (KPS)</td><td></td></tr><tr><td>≥90</td><td>60 (55)</td></tr><tr><td>&lt;90</td><td>50 (45)</td></tr><tr><td>Missing information</td><td>4</td></tr><tr><td>HCT-Ci</td><td></td></tr><tr><td>0-2</td><td>61 (54)</td></tr><tr><td>≥3</td><td>52 (46)</td></tr><tr><td>Missing information</td><td>1</td></tr><tr><td>Donor HLA-match</td><td></td></tr><tr><td>Matched</td><td>78 (68)</td></tr><tr><td>Mismatched</td><td>36 (32)</td></tr><tr><td>Conditioning Intensity</td><td></td></tr><tr><td>Myeloablative</td><td>23 (20)</td></tr><tr><td>NMA/RIC</td><td>91 (80)</td></tr><tr><td>GVHD Prophylaxis</td><td></td></tr><tr><td>Conventional</td><td>91 (80)</td></tr><tr><td>CD34+ selected</td><td>13 (11)</td></tr><tr><td>PT-Cy</td><td>10 (9)</td></tr></tbody></table>

<figure><img src="image_239.png" /><figcaption>Figure 2. Cumulative Incidence</figcaption></figure>

<figure><img src="image_240.png" /></figure>

Currently the association between hepatitis C virus and DLBCL widely accepted. The result of evidence from epidemiological and clinical studies carried out in the last decades. The majority of studies are

## 402 ANTIVIRAL THERAPY AND IMMUNOCHEMOTHERAPY IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) WITH HEPATITIS C (HCV)

S. Lepkov<fnref n="1" /> | I. Subortceva² | G. Tumian³ |

O. Kolomiytcev³ | Y. Ribykhina³ | N. Kokosadze³ |

N. Kuprishina³ | R. Ivashenko⁵ | S. Borisovskay⁴ |

K. Savkina⁵ | E. Sholokhova⁵ | P. Zeynalova³ |

O. Ettinger<fnref n="1" /> | I. Nikitin<fnref n="1" />

<footnote n="1">¹Therapy, Russian National Research Medical University named by N.I. Pirogov, Moscow, Russian Federation; ²Hematology, National Medical Research Center for Hematology, Moscow, Russian Federation; ³Oncology, National Medical Research Center of Oncology. N. N. Blokhina, Moscow, Russian Federation; ⁴Therapy, Clinical Hospital by V.M. Buyanova, Moscow, Russian Federation; ⁵Radiology, Clinical Hospital by V.M. Buyanova, Moscow, Russian Federation</footnote>
related to antiviral therapy (AT) consisting of interferon (IFN) and ribavirin (RBV). New antiviral regimes without interferon allowed to obtain a high percentage of cure of patients from viral infection. There were limited data about efficacy of the new direct-acting antiviral agents (DAAs) in the treatment of patients DLBCL+HCV.

The research objective is to analyze clinical, laboratory, morphological parameters and treatment results in patients with DLBCL+HCV who received DAA together with chemotherapy.

Our study included 16 patients with DLBCL+HCV, who received DAA and immunohypotherapy (R-CHOP) from 2016 to 2019 at National Medical Research Center of Oncology named after N. N. Blokhin and Russian National Research Medical University named after N.I. Pirogov. The median age of patients was 48 years (32-75). Man/woman ratio of was 10/6. All 16 patients had III-IV stages. B-symptoms were present in 50% (8) of patients. Bulk disease occurred in 62%(10) of patients. Histological variants: 3 patients had GCB type DLCBCL, 13 patients - non-GCB type DLBCL. Spleen lesion was present in 37%(6) patients, bone marrow - in 31% (5) of patients, liver lesion - in 37%(6) of patients. Hb≤14,0g/dl were found in 37%(6) and platelets ≤100x10⁹/l in 25%(4) of patients. Before the treatment: increase level of LDH ≥450 IU/l was in 81%(13) of patients, ALT ≥40 IU/l - in 100%(16) of patients, AST ≥40 IU/l - in 85%(14) of patients, GGTP ≥ 35IU/l in 44%(7) of patients, and albumin ≤35g/l in 37%(6) of patients. HCV RNA were detect in blood of all patients. In all patients the viral RNA was more then 1.6x10⁶ IU/l. The 1st genotype of the virus was found in 63%(10) of patients.

Before immunochemotherapy all patients received DAA therapy, according on the virus genotype. After 30 days of DAA therapy virology remission obtained in 94%(15) of patients. The level of ALT≤40 IU/l decreased at 81%(13) patients, AST ≤40 IU/l-62%(10) patients. DAA conducted during 4-6 months together with immunochemotherapy.

The total response (ORR) of R-CHOP+DAA therapy was 50%. The 2-year survival without progression of the disease (PFS) was 25%. Median follow-up was 24 months. 56% of patients had a relapse of lymphoma. Median of OS was 20 months. Median DFS was 11 months.

**Conclusion:** DAAs therapy makes it possible to complete the therapy program without complications for all patients with DLBCL + HCV. Safety, rapidity and efficacy of DAA in obtaining a virological response, as well as a good profile of tolerance DAA therapy can be used in combination with chemotherapy.

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

403
HAPLOIDENTICAL HEMATOPOIETIC STEM
CELL TRANSPLANTATION COMPARED
WITH HLA-MATCHED STEM CELL
TRANSPLANTATION FOR REFRACTORY OR
RELAPSED AGGRESSIVE NON-HODGKIN
LYMPHOMA

H. Huang | Q. Zhu | L. Zhang | S. Liu | D. Wu

Department of Hematology, The First Affiliated Hospital of Soochow
University, Suzhou, China

**Objective:** To examine the efficacy of haploidentical stem-cell transplantation (haplo-SCT) for patients with refractory relapsed(R/R) aggressive non-Hodgkin lymphoma (NHL) by comparing with those who contemporaneously receiving HLA-matched SCT in myeloablative conditioning settings.

**Methods:** One hundred and fifty-one patients who had undergone haplo-SCT (n=81) or HLA-matched SCT (n=70, sibling or unrelated) in our center between January 2006 and December2018 were enrolled. A median age at alloSCT was 30(5-59) years old. All patients received a myeloablative conditioning (MAC) consisting of total body irradiation (12 Gy) combined cyclophosphamide or busulphan plus cyclophosphamide, and followed by infusion of granulocyte-colony stimulating factor-primed bone marrow (G-BM) and/or peripheral blood stem cells without in vitro T cell depletion. In the case of haplo-SCT and HLA-matched unrelated donor for SCT, the GVHD prophylaxis consisted of antithymocyte globulin, cyclosporine A, mycophenolate mofetil and a short course of methotrexate. The clinical effect, hematopoietic reconstitution, and transplant-related complications were retrospective analyzed.

**Results:** One hundred and forty-five (96%) patients engrafted with a median time to neutrophil and platelet recovery of 12 and 15 days, respectively. At a median follow-up of 20 months, 72 of 151 patients were alive (48%) and 57 (38%) were dead (34 disease recurrence, 23 transplantation-related mortality (TRM)). Between the haplo-SCT and HLA-matched SCT group, the corresponding progress free survival (PFS) rate was 60.5% and 54.3% (P = .938), respectively; and

<figure><img src="image_241.png" /><figcaption>Image:</figcaption></figure>
overall survival (OS) rate were 67.9% and 55.7% (P = .460), respectively. The cumulative incidences of relapse (RI) were 23.5% and 21.5% (P = .482), and those of NRM were 20.0% and 28.2% (P = .44), respectively. And cumulative incidences of chronic GVHD were 42.3% and 39.6%(P=0.46), respectively. These data showed no difference in every major HSCT endpoint between two groups. Multivariate analysis suggested that occurrence of grade III-IV aGVHD had a significant worse outcome, primary chemorefractory was the strongest factors for relapse.

**Conclusion:** Our results indicate that the outcomes of haplo-SCT are equivalent to HLA-matched SCT, and that MAC followed by haplo-SCT can be an acceptable and feasible alternative for patients with R/R NHL who having no access to a HLA-matched donor.

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

## 404
A NATIONAL RETROSPECTIVE ANALYSIS OF CLINICAL OUTCOMES FOLLOWING ALLOGENEIC TRANSPLANTATION FOR HIGH GRADE B-CELL LYMPHOMA (HGBL)

R. Brodie<fnref n="1" /> | G. Lee<fnref n="1" /> | V. Broderick<fnref n="1" /> | E. Higgins<fnref n="1" /> |

R. Flavin² | N. Gardiner³ | P. Browne<fnref n="1" /> |

P. Hayden<fnref n="1" /> | E. Conneally<fnref n="1" /> | E. Tuohy<fnref n="1" /> | C. Flynn<fnref n="1" /> |

C.L. Bacon<fnref n="1" /> | E. Vandenberghe<fnref n="1" />

**Introduction:** Patients with either primary refractory or relapsed/refractory High Grade B-Cell Lymphoma have a poor outcome with convention therapy as illustrated by the Scholar 1 Study (Crump et al.). High-Grade B-Cell Lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements, often referred to as Double Hit Lymphoma (DHL) also have a poor outcome with a published overall survival (OS) of 23.3% to 58% (Niitsu et al, Johnson et al). More recently novel therapies such as CAR-T therapy have shown the potential to improve outcomes in these patients (Schuster et al). These patients were considered for allogeneic transplantation from 2007 to 2017 and we performed a retrospective analysis of the outcomes, prior to the introduction of a CAR-T program.

**Methods:** Consecutive patients transplanted for HGBL between 2007-2017 in the EBMT database were included. Data collected included age, sex, pathology subtype (HGBL (including subtypes), Transformed follicular lymphoma (tFL), DHL), disease status at SCT, conditioning (myeloablative vs reduced intensity), engraftment, day 100 outcome, development of graft versus host disease

(GvHD), Non-relapse mortality (NRM), OS and eligibility for CAR-T therapy.

**Results:** Fifty patients (29M, 21F) with a median age 47 at diagnosis and 50 at SCT were included. The subtypes included were HGBL (n=29), tFL (n=11) and DHL (n=10). Indications for SCT were: primary refractory (n=17), relapse <12 months after primary treatment (n=12), previous Autologous-SCT (n=10) and DHL (n=11). The median lines of therapy was 4 (range 1 to 6). Conditioning used was myeloablative (n= 23) or reduced intensity (n= 27 ). The day 100 mortality was 8% (progressive disease 4%, NRM 4%) with an OS of 56% and mortality due to progressive disease 22% and NRM 16%. 23 patients were eligible for a licensed CAR-T product. Disease subtype influenced outcome with an OS for primary refractory HGBL, relapsed HGBL, tFL and DHL respectively of 53%, 58%, 57% and 89%. Disease status at time of SCT significantly influenced outcome with an OS of 74% for patients in PET negative remission at time of SCT vs 36% for patients with PET positive disease.

**Conclusion:** In this retrospective analysis patients with high risk HGBL had an overall survival of 56%. The most common cause of mortality was relapsed disease. Patients with PET negative remission at time of transplant have a good outcome with an OS of 74%. In our cohort patients with DHL have a particularly good outcome; it is likely some of these patients with a non-immunoglobulin gene associated MYC translocation could be managed more conservatively based on recent evidence (ASH Sehn). This analysis will provide a baseline outcome in the national transplant centre in a challenging disease cohort prior to the introduction of a CAR-T program.

**Keywords:** allogeneic stem cell transplant (alloSCT); diffuse large B-cell lymphoma (DLBCL); high-grade B-cell lymphoma with or without rearrangement of MYC and BCL2 and/or BCL6.

## 405
THE ADDITION AT DAY 9 OF HD-MTX TO THE (DA)-EPOCH SCHEME WITH OR WITHOUT RITUXIMAB IS AN EFFECTIVE REGIMEN IN UNTREATED ADVANCED STAGE HIGH RISK LYMPHOMA: A FEASIBILITY STUDY

G. Farina | S. Iaccarino | M. Troiano | M. Iovine |

M. Vigliotti | E. Attingenti | A. Camera | F. Frigeri

Hematology-Oncology Unit, AORN "Sant'Anna e San Sebastiano", Caserta, Italy

DA-EPOCH is an infusional regimen designed to improve the response rate in highly proliferative tumors by prolonging cell exposure to low concentrations of chemotherapeutic agents. It was demonstrated as effective regimen in both T and B cell high grade lymphomas with an elevated proliferative index. Moreover, the

<footnote n="1">¹Haematology Department, St. James Hospital, Dublin, Republic of Ireland; ²Histopathology Department, St. James Hospital, Dublin, Republic of Ireland; ³Stem Cell Laboratory, St. James Hospital, Dublin, Republic of Ireland</footnote>
addition of Rituximab is currently the standard of care in any B cell
lymphoma treatment strategy. Previous studies have shown that high
dose methotrexate (HD-MTX) therapy is better than intrathecal MTX
administration to prevent CNS relapse, but so far few data are avail-
able that explore the feasibility of combination therapy including HD-
MTX and DA-EPOCH with or without Rituximab. Our pilot study
reported the result of the above combination therapy in a series of
high risk advanced stage lymphoma patients (pts).

Five patients were enrolled in this feasibility study: 3 pts were affected by Diffuse Large B Cell Lymphoma (DLBCL) no GC type, 1 pt had a diagnosis of Primary Mediastinal Diffuse Large B Cell Lymphoma (PMDLBCL) and 1 pt had an ALK+ Anaplastic Large Cell Lymphoma (ALCL). All pts showed a stage IV disease with ³ 2 extranodal sites, high LDH level, a very high proliferation index evaluated by Ki67 (median 90%, range 60-100%) and intermediate/high IPI score (3). High risk of CNS relapse was present in all pts because of type of extranodal sites (gut, bone, liver, heart, mediastinum, pancreas) and for high proliferation rate. The combination therapy included classical DA-EPOCH-R scheme with exception of Rituximab in ALCL with the addition of high dose (3.5 g/m²) Methotrexate at day 9 after urine alkalinization and hydration. All patients were scheduled to receive a total of 6 courses of therapy including 4 courses of the classic DA-EPOCH scheme and 2 combined therapy cycles. G-CSF prophylaxis was administered to all patients starting on day +9 and day +12 in the case of DA-EPOCH or combination therapy, respectively. The aim of the study was to evaluate the impact of adding HD-MTX to DA-EPOCH on the time between DA-EPOCH- (R) cycles. Secondary endpoints were response rate, PFS, toxicity, and CNS relapse rate.

After a total of 9 courses administered of combination therapy, no delay in DA-EPOCH-(R) schedule of 21 days was observed. All patients showed a very favorable toxicity profile with only G3 neutropenia without infectious complications and G2 hepatotoxicity with elevations in transaminases. Three out of 5 pts completed the treatment strategy obtaining a CR and are now in follow-up, while the others are still on treatment. No CNS relapse were observed.

Our preliminary results showed the feasibility of the combination
therapy DA-EPOCH-R/HD-MTX with satisfactory results on control-
ling very aggressive disease. However, only prospective trials can
define the optimum scheduling of this regimen and the possibility to
use as standard therapy in very aggressive lymphomas with high risk
of CNS relapse.

**Keywords:** DA-R-EPOCH; high-dose methotrexate; non-Hodgkin lymphoma (NHL).

406

DIFFUSE LARGE B CELL LYMPHOMA WITH
SECONDARY CENTRAL NERVOUS SYSTEM
INVOLVEMENT: CAN MRI PATTERN HELP
PREDICTING OUTCOME?

B. Dabaja¹ | M. Gule-Monroe² | J.R. Gunther¹ |

S. Milgrom¹ | T. Sheu¹ | R. Nair³ | S. Ahmed³ |

R. Steiner³ | P. Strati³ | L. Nastoupil³ |

S. Neelapu³ | C. Pinnix¹ | N. Fowler³

¹Radiation Oncology, University of Texas MD Anderson, Houston, United States; ²Neuro-Radiology, The University of Texas MD Anderson, Houston, United States; ³Medical Oncology-Lymphoma Myeloma, The University of Texas MD Anderson, Houston, United States

**Purpose:** To assess the prognostic significance of baseline neuroimaging for patients with secondary central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL).

**Methods:** After obtaining institutional review board approval, we reviewed 44 patients between 2006-2016. Patient's clinical and treatment-related factors were examined. An experienced neuro-radiologist and radiation oncologist reviewed baseline imaging studies and grouped them into three cohorts: leptomeningeal disease (LMD), corpus callosum/basal ganglia (CCBG), or intraparenchymal disease (IPD).

**Results:** Median age was 55 years (range 23-83); 68% were male (n=30). Germinal center histology in 12 of 44 patients. Of the 44 patients, 3 had CNS involvement at presentation and 41 had CNS disease at relapse. Majority (75%) received R-CHOP (rituximab, cyclophosphamide, Adriamycin, vincristine, and prednisone) as front-line chemotherapy, 21 presented with LMD, 13 with IPD, and 10 with CCBG. Cerebrospinal fluid (CSF) evaluation was performed in 42 patients with cytopathologic evidence of CSF involvement in 20 patients (12/21 LMD (2 unknown), 2/13 with IPD, and 6/10 CCGB). Extra-nodal disease systemic disease at presentation was seen in 14/21 with LMD, 0/13 of IPD, 3/10 CCGB. Prior to administering RT, 30 patients (68%) were given CNS-directed chemotherapy. Whole brain RT (WB) in 42 patients with a median dose of 30 Gy (range 19-30); 13 received boost to the gross disease, median of 9 Gy (range 5-20). At a median follow up of 31 months from RT (range 1-120), 35 patients died. The cause of death was secondary to CNS DBLCL in 14, disease progression outside of the CNS in 16 and unknown in 6. Median survival for the entire cohort was 7 months. Median survival for LMD patients was 9 months with 4/21 patients alive at 20, 33, 87, and 120 months; most patients died from progression of distant disease (11/21). Median survival for IPD patients was 10 months with 5/10 patients alive at 99, 95, 48, 31 and 25 months, and, interestingly, as opposed to those with LMD (9/21 distant disease), all 5 patients died secondary to CNS disease. On the other hand, the median survival for patients with CCGB was only 5 months with only 1/10 surviving to 72 months. All nine patients died secondary to progression of disease both distant and in CNS in less than 8 months.

**Conclusions:**

1-The best survival was observed in patients with IPD, who seemed to derive the greatest benefit from radiation, in stark contrast to those with disease in the perivascular/corpus callosum area who all died except one.
Corpus callosum/basal ganglia

<figure><img src="image_242.png" /></figure>

Intraparenchymal disease

<figure><img src="image_243.png" /></figure>

Leptomeningeal disease

<figure><img src="image_244.png" /></figure>

2-It also appears that local control, perhaps with radiation, is of prime importance for patients with IPD as all causes of death were secondary to disease in the brain.

3-Patients with LMD can enjoy long term survival if distant disease in under control thus comprehensive radiation might be worth attempting in selected cases.

**Keywords:** germinal center (GC); non-Hodgkin lymphoma (NHL); whole brain radiotherapy (WBRT).

407

TOLERABILITY OF HIGH DOSE INTRAVENOUS METHOTREXATE FOR CNS PROPHYLAXIS INTERCALATED WITH R-CHOP – A SINGLE CENTRE RETROSPECTIVE ANALYSIS

<footnote>M.R. Wilson¹</footnote>

<footnote>C. Feather²</footnote>

<footnote>M. Leach¹</footnote>

<footnote>P. McKay¹</footnote>
¹Haematology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; ²School of Medicine, University of New South Wales, Sydney, Australia

**Introduction:** Central nervous system (CNS) relapse in diffuse large B cell lymphoma (DLBCL) is rare but is associated with poor outcomes. The majority of CNS relapses in DLBCL occur in the brain parenchyma and are therefore unlikely to be prevented by intrathecal prophylaxis. There is increasing evidence to support use of high dose intravenous methotrexate (HDMTX) as a prophylactic regimen in selected high-risk patients. As most CNS relapses occur early in the disease course, ideally prophylaxis should be delivered as early as possible. There remains concern that HD MTX carries a risk of toxicity, especially renal, which could result in delays to systemic chemotherapy if delivered in an intercalated fashion. We performed a single centre, retrospective analysis of 45 patients who received HDMTX intercalated with R-CHOP chemotherapy with a focus on toxicity rates and subsequent delays in systemic therapy.

**Methods:** 45 consecutive patients receiving HDMTX as CNS prophylaxis alongside R-CHOP chemotherapy for HIV negative DLBCL between 2012-2018 were identified and medical records analysed for toxicity rates, timing of chemotherapy cycles and evidence of CNS relapse. 60% were male (n=27) and median age was 60 years (range 37y-80y). The majority (78%) had stage IV disease and the median CNS IPI was 3, with 31% (n=14) falling in the high risk (4-6) CNS IPI group. Patients with known CNS disease at presentation were excluded. Local guidelines stipulated that 2 cycles of HDMTX at 3g/m2 should be delivered at day 14 following the R-CHOP courses 2 and 3.

**Results:** 73% (n=33) received at least 2 cycles of MTX. Reasons for only delivering 1 cycle of MTX in 12 patients were patient fitness/frailty (n=7), renal toxicity (n=2) and mucositis (n=3). 5 (11%) patients experienced renal toxicity according to CTCAE definitions (3 = grade 2, 2 = grade 3). All patients had recovery of renal function without the need for invasive intervention. Mucositis occurred in 13 (29%) patients (grading not recorded). Hepatotoxicity was seen in 2/45 (4%) patients. 80 cycles of HD MTX were delivered in total. Neutrophil count on the scheduled day of subsequent R-CHOP chemotherapy was >1.0 in 73/80 (91%) cycles. 5/45 (11%) patients experienced a delay of subsequent R-CHOP chemotherapy (7 or more days) directly attributable to methotrexate. 3/45 (7%) of patients suffered CNS relapse with median follow up of 32 months – all relapses were parenchymal and 2/3 had only received 1 cycle HDMTX.

**Discussion:** This retrospective analysis demonstrates that HDMTX can be delivered intercalated with R-CHOP chemotherapy with acceptable rates of toxicity and few delays in systemic chemotherapy. The rate of renal toxicity was low and was reversible in all patients. Although the numbers are small, the rate of CNS relapse (7%) was low in this selected, high-risk group. Careful assessment of patient fitness is required prior to consideration of HDMTX, but the median age of 60 years in our study suggests that age alone should not be a barrier to delivering this treatment.

**Keywords:** CNS prophylaxis; diffuse large B-cell lymphoma (DLBCL); methotrexate (MTX).

408
# SANDOZ RITUXIMAB FOR TREATMENT OF DIFFUSE LARGE B-CELL LYMPHOMA: INTERIM SAFETY RESULTS OF THE NON-INTERVENTIONAL, OBSERVATIONAL, MULTICENTER, OPEN-LABEL REFLECT STUDY

M. Welslau<fnref n="1" /> | N. Marschner² | T. Wolff³ |

B. Otremba<fnref n="4" /> | J. Topaly<fnref n="5" /> | L. Bittencourt da Silva⁶

**Introduction:** Sandoz rituximab (SDZ-RTX) is approved in Europe for all indications of reference rituximab. Approval was based on the totality of evidence for biosimilarity, including: extensive physicochemical and structural data; preclinical and clinical pharmacokinetic, pharmacodynamic, and immunogenicity data; and also clinical trials, including a Phase III confirmatory study in patients (pts) with follicular lymphoma. REFLECT, a real-world study of SDZ-RTX as curative therapy for treatment-naïve CD20⁺ diffuse large B-cell lymphoma (DLBCL), is the first biosimilar rituximab post-approval study in DLBCL.

**Methods:** The study includes pts aged ≥18 years with CD20⁺ DLBCL, eligible for rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP). Exclusion criteria include any prior DLBCL treatment or contraindication to rituximab. R-CHOP is administered according to product label. The primary endpoint is complete response rate at the end of treatment. Secondary endpoints include: overall response rate; 12-month progression-free survival; quality of life; and adverse events (AEs). Data are collected at baseline and every study visit for 12 months (efficacy) and ≥30 days after last SDZ-RTX dose (safety). No imputation for missing data is planned; endpoints are summarized descriptively.

**Results:** In an interim analysis (cut off: Sep 6, 2018; recruitment approx. 50% complete), the full analysis set comprised 80 pts: 38 males (47.5%) and 42 females (52.5%), with median age of 68.5 years; 70% of pts were aged ≥60 years. In total, 6 pts have discontinued. Most pts had little or no restriction in daily activities; >80% had an ECOG score of 0 (34%) or 1 (50%). Baseline disease characteristics are reported in the Table. Most pts had early stage (I-IIIB: 64%), low to intermediate risk disease (IPI score 0-2: 61%). B-symptoms were reported in 15 pts (19%).

A summary of safety is reported in the Table. AEs were reported in 53 pts (66%), serious AEs were reported in 19 pts (24%), and

<footnote n="1">¹Onkologie Aschaffenburg, Aschaffenburg, Germany; ²Onkologische Praxis, Freiburg, Germany; ³Onkologie Lerchenfeld, Hamburg, Germany;</footnote>

<footnote n="4">⁴Onkologische Praxis Oldenburg/Delmenhorst, Oldenburg, Germany;</footnote>

<footnote n="5">⁵MVZ Klinikum Osnabrück GmbH, Osnabrück, Germany; ⁶Medical Affairs, Sandoz Group, a Novartis division, Holzkirchen, Germany</footnote>
<table><caption>**TABLE 1** Summary of baseline disease characteristics and safety</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td>n (%)</td><td>All patients N=80</td></tr><tr><td>Disease stage</td><td></td></tr><tr><td>I</td><td>26 (32.5)</td></tr><tr><td>IIA</td><td>17 (21.3)</td></tr><tr><td>IIB</td><td>8 (10.0)</td></tr><tr><td>III</td><td>17 (21.3)</td></tr><tr><td>IV</td><td>10 (12.5)</td></tr><tr><td>Not available</td><td>1 (1.3)</td></tr><tr><td>Missing</td><td>1 (1.3)</td></tr><tr><td>International Prognostic Index (IPI) score</td><td></td></tr><tr><td>0</td><td>7 (8.8)</td></tr><tr><td>1</td><td>22 (27.5)</td></tr><tr><td>2</td><td>20 (25.0)</td></tr><tr><td>3</td><td>14 (17.5)</td></tr><tr><td>4</td><td>4 (5.0)</td></tr><tr><td>Missing</td><td>13 (16.3)</td></tr><tr><td>Extranodal infiltration</td><td></td></tr><tr><td>Extranodal infiltration</td><td>40 (50.0)</td></tr><tr><td>Bulky disease</td><td>9 (11.3)</td></tr><tr><td>Spleen involvement</td><td>2 (2.5)</td></tr><tr><td>Unknown</td><td>8 (10.0)</td></tr><tr><td>Not available</td><td>20 (25.0)</td></tr><tr><td>Missing</td><td>1 (1.3)</td></tr><tr><td>Safety</td><td>All Treatment-related</td></tr><tr><td>AE</td><td>53 (66.3)</td><td>13 (16.3)</td></tr><tr><td>Serious AE</td><td>19 (23.8)</td><td>2 (2.5)</td></tr><tr><td>AE leading to discontinuation</td><td>6 (7.5)</td><td>1 (1.3)</td></tr><tr><td>AE leading to dose interruption</td><td>6 (7.5)</td><td>2 (2.5)</td></tr><tr><td>Death</td><td>0</td><td>-</td></tr></tbody></table>

treatment-related AEs were reported in 13 pts (16%). The most frequent AEs were polyneuropathy (n=10, 13%), anemia (n=8, 10%), and fatigue (n=8, 10%).

**Conclusions:** Interim baseline data are as expected for treatment-naïve pts with CD20⁺ DLBCL; safety results are as expected for rituximab-based treatment. The study is ongoing. Biosimilar rituximab has the potential to provide savings for healthcare systems, broaden pt access to rituximab-based chemotherapy, and support the sustainability of cancer care.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); monoclonal antibodies (MoAb); rituximab.

**Disclosures:** Welslau, M: Consultant Advisory Role: Sandoz. Mar-schner, N: Consultant Advisory Role: Sandoz; Stock Ownership: iOMEDICO (contract research organization that runs the REFLECT study).

**Otremba, B:** Consultant Advisory Role: Sandoz. Topaly, J: Consultant Advisory Role: AbbVie, BMS, Hexal, Janssen, MSD, and Roche; Other Remuneration: Travel Grants: AbbVie, BMS, Hexal/Sandoz, Gilead, Ipsen, Janssen and Sanofi. Bittencourt da Silva, L: Employment Leadership Position: Sandoz Group, a Novartis Division.

409
REAL WORLD EFFECTIVENESS AND
SAFETY OF CT-P10 IN DIFFUSE LARGE B-
CELL LYMPHOMA: INTERIM RESULTS
FROM A EUROPEAN NON-
INTERVENTIONAL POST-AUTHORISATION
SAFETY STUDY

P. Zinzani¹ | D.L. Turner² | S.R. Marshall³ |
V. Conteh⁴ | H. Kang⁵ | S. Kim⁵ | Y. Lee⁵ |
M.J. Bishton⁶

¹Institute of Hematology "Seràgnoli", University of Bologna, Bologna, Italy; ²Department of Haematology, Torbay and South Devon NHS Foundation Trust, Torquay, United Kingdom; ³Department of Haematology, Sunderland Royal Hospital, City Hospitals Sunderland NHS Trust, Sunderland, United Kingdom; ⁴Cancer Services, Royal Free London NHS Foundation Trust, Barnet Hospital, Barnet, United Kingdom; ⁵Medical Affairs, Celltrion Healthcare, Incheon, Republic of Korea; ⁶Department of Haematology, Nottingham City Hospital, Nottingham, United Kingdom

**Introduction:** In February 2017, CT-P10 became the first biosimilar of rituximab to be approved in Europe for treatment of rheumatic diseases and specific blood cancers including non-Hodgkin's lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) is the commonest type of NHL, representing an estimated 40-58% of cases (Sant et al, 2010). The aim of the current study was to evaluate the real world clinical effectiveness and safety of CT-P10 in patients with DLBCL in Europe.

**Methods:** This non-interventional post-authorisation safety study is in progress in five European countries (France, Germany, Italy, Spain and the United Kingdom [UK]), and involves collection of data from the medical records of consenting adult patients with DLBCL who were treated with CT-P10 as part of their routine clinical care. Effectiveness and safety data are being collected for an observation

<figure><img src="image_245.png" /><figcaption>Figure 1: Best responses to CT-P10 during the observation period</figcaption></figure>
period of 30 months after the index date (date of CT-P10 initiation) or until death, if sooner. The primary objective is to describe the effectiveness of CT-P10 (overall survival, progression free survival, CT-P10 responses), with secondary objectives to describe the safety profile and CT-P10 treatment pathways. Response to CT-P10 is as documented by the local investigator. Here we report interim results (patients' baseline characteristics and preliminary response/safety data), based on a data cut on 18 January 2019. Where n is less than the total number of patients, data were missing.

**Results:** The interim analysis includes 151 patients enrolled from sites in the UK and Spain, with a median 8.9 months (interquartile range [IQR] 6.1-12.6) post-index observation at the cut-off. Patients are receiving CT-P10 as a first-line (n=138, 91%), second-line (n=9, 6%) or third-line (n=4, 3%) DLBCL treatment. Ninety-five (63%) patients are male. Other patient characteristics at index: median age 70.9 years (IQR 61.5-76.0) (n=149); median disease duration 20 days (IQR 10.5-41.0) (n=147); Eastern Cooperative Oncology Group performance status (n=98): 0 (n=45, 46%), 1 (n=36, 37%), 2 (n=11, 11%), 3 (n=4, 4%) or 4 (n=2, 2%); Ann Arbor stage (n=77): I (n=8, 10%), II (n=9, 11%), III (n=18, 21%), IV (n=40, 48%) or other (n=2, 2%; recorded as 'at least stage II'). Best responses to CT-P10 (evaluable in n=128) are shown in Fig. 1. Safety of CT-P10 was evaluable in 128 patients, of whom 118 (92%) experienced adverse events (AEs) during the observation period (732 AEs recorded in total, including infusion-related reactions), 77 (60%) had AEs of grade 3 and above and 11 (9%) discontinued CT-P10 due to AEs.

**Conclusions:** Early results from this ongoing study suggest that a high proportion of patients with DLBCL treated with CT-P10 in the real world achieve complete or partial responses, similar to the response rates reported previously for reference rituximab (Horvat et al, 2017). Continued recruitment and extended follow-up will enable more comprehensive analyses of CT-P10 effectiveness and safety.

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

**Disclosures:** Zinzani, P: Consultant Advisory Role: Verastem, MSD, Eusapharma and Sanofi; Honoraria: Verastem, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, MSD, Immune Design, Celgene, Portola, Roche, Eusapharma and Kyowa Kirin. Kang, H: Employment Leadership Position: Celltrion Healthcare. Kim, S: Employment Leadership Position: Celltrion Healthcare. Lee, Y: Employment Leadership Position: Celltrion Healthcare.

410
A PROSPECTIVE REGISTRY STUDY OF PEG-G-CSF PROPHYLAXIS FOR PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA (CISL 1403)

S. Jeong¹ | S. Kim² | J. Hong³ | Y. Park⁴ |

H. Kang⁵ | Y. Koh⁶ | G. Lee⁷ | W. Lee⁸ |

D. Yang⁹ | Y. Do¹⁰ | M. Kim¹¹ | K. Yoo¹² |

W. Yun¹³ | J. Yi¹⁴ | J. Jo¹⁵ | H. Eom¹⁶ |

J. Kwak¹⁷ | H. Shin¹⁸ | B. Park¹⁹ | J. Lee²⁰ |

S. Yi²¹ | J. Kwon²² | S. Oh²³ | H. Kim²⁴ |

B. Sohn²⁵ | J. Won²⁶ | D. Hong²⁷ | H. Lee²⁸ |

C. Suh³ | W. Kim²

¹Department of Hematology-Oncology, Ajou University Hospital, Suwon, Republic of Korea; ²Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea; ³Department of Oncology, Asan Medical Center, Seoul, Republic of Korea; ⁴Department of Internal Medicine, Korea University Anam Hospital, Seoul, Republic of Korea; ⁵Department of Internal Medicine, Korea Cancer Center Hospital Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea; ⁶Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; ⁷Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea; ⁸Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Republic of Korea; ⁹Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea; ¹⁰Department of Medicine, Dongsan Medical Center, Daegu, Republic of Korea; ¹¹Department of Medicine, Yeungnam University College of Medicine, Gaegu, Republic of Korea; ¹²Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea; ¹³Department of Internal Medicine, Chongnam National University Hospital, Daejeon, Republic of Korea; ¹⁴Department of Interanl Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea; ¹⁵Department of Hematology-Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea; ¹⁶Hematology-oncology clinic, National Cancer Center, Goyang, Republic of Korea; ¹⁷Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea; ¹⁸Department of Internal Medicine, Pusan National University Hospital, Busan, Republic of Korea; ¹⁹Department of Interanl Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea; ²⁰Department of Hematology-oncology, Wonju Severance Christian Hospital, Wonju, Republic of Korea; ²¹Department of Internal Medicine, Inje University Ilsan Hospital, Goyang, Republic of Korea; ²²Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea; ²³Department of Internal Medicine, Dong-A University Medical Center, Busan, Republic of Korea; ²⁴Department of Interanl Medicine, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea; ²⁵Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, Republic of Korea; ²⁶Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Republic of Korea; ²⁷Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea; ²⁸Department of Internal Medicine, Kosin University Gospel Hospital, Busan, Republic of Korea

**Background:** Febrile neutropenia (FN) is the most important side effect of chemotherapy in diffuse large B cell lymphoma (DLBCL) causing not only treatment-related morbidity but also suboptimal chemotherapy delivery. Prophylactic use of granulocyte colony
<table><caption>**TABLE 1** Patients characteristics</caption><thead><tr><th>Characteristics</th><th>This cohort (N=992)</th><th>PROCESS cohort (N=487)</th><th>P value</th></tr></thead><tbody><tr><td>Age-years</td><td></td><td></td><td>0.019</td></tr><tr><td>median</td><td>62</td><td>59</td><td></td></tr><tr><td>range</td><td>19-86</td><td>20-89</td><td></td></tr><tr><td>Gender</td><td></td><td></td><td>0.855</td></tr><tr><td>M</td><td>56.5%</td><td>56.7%</td><td></td></tr><tr><td>F</td><td>43.5%</td><td>43.3%</td><td></td></tr><tr><td>ECOG</td><td></td><td></td><td>0.734</td></tr><tr><td>0,1</td><td>91.3%</td><td>88.6%</td><td></td></tr><tr><td>≥2</td><td>8.7%</td><td>11.4%</td><td></td></tr><tr><td>Stage</td><td></td><td></td><td></td></tr><tr><td>1,2</td><td>48.7%</td><td>48.9%</td><td></td></tr><tr><td>3,4</td><td>51.3%</td><td>51.1%</td><td>0.494</td></tr><tr><td>Extranodal involvement</td><td></td><td></td><td>0.358</td></tr><tr><td>0 or 1</td><td>62.8%</td><td>65.3%</td><td></td></tr><tr><td>≥2</td><td>37.2%</td><td>34.7%</td><td></td></tr><tr><td>LDH elevation</td><td></td><td></td><td>0.229</td></tr><tr><td>Yes</td><td>52.6%</td><td>48%</td><td></td></tr><tr><td>no</td><td>47.4%</td><td>52%</td><td></td></tr><tr><td>IPI</td><td></td><td></td><td>0.091</td></tr><tr><td>0 or 1</td><td>36.6%</td><td>44.1%</td><td></td></tr><tr><td>2</td><td>25.9%</td><td>20.5%</td><td></td></tr><tr><td>3</td><td>20.7%</td><td>19.5%</td><td></td></tr><tr><td>4 or 5</td><td>16.8%</td><td>15.9%</td><td></td></tr><tr><td>Albumin</td><td></td><td></td><td>0.521</td></tr><tr><td>≥3.5mg/dl</td><td>74.8%</td><td>76.1%</td><td></td></tr><tr><td>&lt;3.5mg/dl</td><td>25.2%</td><td>23.9%</td><td></td></tr></tbody></table>

stimulating factor (G-CSF) or pegylated G-CSF (Peg-G-CSF) is known to reduce the incidence of both neutropenia and FN. We conducted a prospective registry study to evaluate prophylactic effect of Peg-G-CSF in DLBCL patients treated with R-CHOP regimen (ClinicalTrials.gov Identifier: NCT02474550).

**Patients and Method:** Since January 1st 2015, after written informed consent, patients receiving R-CHOP therapy with curative intent were registered and prospectively monitored. All patients were pathologically confirmed with DLBCL according to World Health Organization Classification 2008. Prophylactic Peg-G-CSF (pegfilgrastim 6mg) was administered 24 hours after R-CHOP chemotherapy subcutaneously. The incidence of neutropenia and neutropenic fever were studied. Febrile neutropenia (FN) is defined as an oral temperature >38.5°C or two consecutive readings of >38.0°C for 2h and an absolute neutrophil count <0.5 × 10⁹/l, or expected to fall below 0.5 × 10⁹/l. We compared the outcomes of the cohort with those of the PROCESS cohort*. This analysis was performed as of December 11st 2018.

**Results:** A total of 5357 cycles in 992 patients of this cohort and 2581 cycles in 487 patients from the PROCESS cohort were included

<table><caption>**TABLE 2** Febrile neutropenia with Peg-G-CSF prophylaxis</caption><thead><tr><th>Characteristics</th><th>Giraffe B</th><th>Process</th><th>P value</th></tr></thead><tbody><tr><td>Neutropenia (grade4)</td><td></td><td></td><td></td></tr><tr><td>patients</td><td>28.8%</td><td>69.1%</td><td>&lt;0.001</td></tr><tr><td>cycles</td><td>11.7%</td><td>44.4%</td><td>&lt;0.001</td></tr><tr><td>FN</td><td></td><td></td><td></td></tr><tr><td>patients</td><td>13.4%</td><td>23.7%</td><td>&lt;0.001</td></tr><tr><td>cycles</td><td>4.2%</td><td>16.2%</td><td>&lt;0.001</td></tr><tr><td>TRM</td><td>3.1%</td><td>5.5%</td><td>0.032</td></tr><tr><td>infection-related</td><td>1.6%</td><td>4.5%</td><td>0.001</td></tr></tbody></table>

FN: febrile neutropenia

TRM: treatment-related mortality within 6months

in the analysis. Base-line characteristics were summarized in Table 1. Median age at diagnosis was 62 (19-86) with a predominance of males (56.5%). Most patients had extranodal involvement (90.2%) and 369 patients (37.2%) had two or more extra-nodal involvements. The most common extranodal involvement sites were stomach (15.6%), bone (12.3%), intestine (9.7%) and lung (7.6%). All clinical characteristics were well-matched between the two cohorts other than age at diagnosis. Grade 4 neutropenia was developed in 286 patients (28.8%) with an overall incidence of 11.7% in the cycles and FN developed in 133 (13.4%) patients with an overall incidence of 4.2%, which were significantly lower in this cohort (Neutropenia 11.7% vs. 38.1% p=0.000; FN 13.4% vs 23.7% p=0.000) (Table 2.). Forty-seven patients (35.9%) had multiple episodes of FN. Most patients (80.4%) experienced the first episode of FN within three cycles. Treatment-related mortality (TRM) was significantly lower in this cohort (3.1% vs. 5.5%, p=0.032), mainly due to the low incidence of early infection-related death (1.6% vs. 4.5%, p=0.0001) (Table 2). In this cohort, 765 (77.1%) patients completed 6 cycles of R-CHOP therapy. Dose delays more than 3days and 5days were less common (18.1% vs. 23.7%, p=0.000; 12.0% vs 18.3% p=0.000) with Peg-G-CSF prophylaxis compared to the PROCESS cohort (Table 3). Dose reductions more than 20% in delivery of cyclophosphamide and doxorubicin happened in 13.3%

<table><caption>**TABLE 3** Delivery of R-CHOP with prophylactic Peg-G-CSF</caption><thead><tr><th>Chemotherapy</th><th>This cohort (n=992)</th><th>Process cohort (n=487)</th><th>P value</th></tr></thead><tbody><tr><td>Completion of 6 cycles</td><td></td><td></td><td></td></tr><tr><td>Dose delay</td><td>77.1%</td><td>75.1%</td><td>0.401</td></tr><tr><td>&gt;3 days</td><td>18.1%</td><td>23.7%</td><td>&lt;0.001</td></tr><tr><td>&gt;5 days</td><td>12.0%</td><td>16.5%</td><td>&lt;0.001</td></tr><tr><td>Dose reduction &gt;20%</td><td>13.3%</td><td>15.0%</td><td>0.046</td></tr><tr><td>cyclophosphamide</td><td>19.5%</td><td>15.5%</td><td>&lt;0.000</td></tr><tr><td>doxorubicin</td><td>73.2%</td><td>70.9%</td><td>0.039</td></tr><tr><td>*ARDI ≥80%</td><td></td><td></td><td></td></tr></tbody></table>

*ARDI: average relative dose intensity - ARDI was calculated by averaging the delivered RDIs of cyclophosphamide and doxorubicin
<table><caption>**TABLE 4** Incidence of febrile neutropenia according to clinical characteristics</caption><thead><tr><th>Characteristics</th><th>N (%)</th><th>P value</th></tr></thead><tbody><tr><td>Age</td><td></td><td>&lt;0.001</td></tr><tr><td>≤65</td><td>45/566 (8.0)</td><td></td></tr><tr><td>&gt;65</td><td>88/426 (20.7)</td><td></td></tr><tr><td>Gender</td><td></td><td>0.037</td></tr><tr><td>male</td><td>64/560 (11.4)</td><td></td></tr><tr><td>female</td><td>69/432 (16.0)</td><td></td></tr><tr><td>BM involvement</td><td></td><td>0.415</td></tr><tr><td>no</td><td>121/882 (13.7)</td><td></td></tr><tr><td>yes</td><td>12/110 (10.9)</td><td></td></tr><tr><td>Ann arbor Stage</td><td></td><td>0.011</td></tr><tr><td>I to III</td><td>75/656 (11.4)</td><td></td></tr><tr><td>IV</td><td>58/336 (17.3)</td><td></td></tr><tr><td>LDH</td><td></td><td>0.668</td></tr><tr><td>normal</td><td>63/451 (14.0)</td><td></td></tr><tr><td>elevated</td><td>68/541 (12.6)</td><td></td></tr><tr><td>ECOG Performance</td><td></td><td>&lt;0.001</td></tr><tr><td>0 or 1</td><td>105/906 (11.6)</td><td></td></tr><tr><td>≥2</td><td>28/86 (32.6)</td><td></td></tr><tr><td>Extranodal involvement</td><td></td><td>0.497</td></tr><tr><td>0 or 1</td><td>80/623 (12.8)</td><td></td></tr><tr><td>≥2</td><td>53/369 (14.4)</td><td></td></tr><tr><td>Albumin</td><td></td><td>&lt;0.001</td></tr><tr><td>&lt;3.5mg/dl</td><td>57/249 (22.8)</td><td></td></tr><tr><td>≥3.5mg/dl</td><td>80/740 (10.8)</td><td></td></tr><tr><td>ANC at diagnosis</td><td></td><td>0.224</td></tr><tr><td>&lt;1500</td><td>2/19 (10.5)</td><td></td></tr><tr><td>≥1500</td><td>132/973 (13.6)</td><td></td></tr></tbody></table>

and 19.5% of the cycles, respectively. Overall, more patients received ≥80% ARDI (average relative dose intensity, cyclophosphamide and doxorubicin) with a prophylactic use of Peg-G-CSF (73.2% vs. 70.9%, *p*=0.039). Among pretreatment clinical characteristics analyzed, age over 65, female gender, ECOG performance status 2 or higher, stage IV, and albumin level less than 3.5mg/dl were related with the development of FN (Table 4.). Multivariate analysis showed that age, gender, ECOG PS and albumin level were significantly related to FN (Table 5).

**Conclusion:** Prophylactic use of Peg-G-CSF reduced the incidence of neutropenia and FN significantly in patients with DLBCL receiving R-CHOP therapy when compared to the control cohort, which resulted in the reduction of early infection-related deaths. In addition, Peg-GCSF support significantly improved dose-delay and ARDI. However, the patients who were elderly, female gender, with poor performance status and low albumin level still had high incidence of FN.

1. Kim SJ, Hong JS, Chang MH, Kim JA, Kwak JY, Kim JS, Yoon DH, Lee WS, Do YR, Kang HJ, Eom HS, Park Y, Won JH, et al. Highly elevated serum lactate dehydrogenase is associated with central nervous system

<table><caption>**TABLE 5** Multivariate analysis of risk factors for febrile neutropenia</caption><thead><tr><th>Characteristics</th><th>Odds ratio</th><th>95% CI</th><th>P value</th></tr></thead><tbody><tr><td>Age &gt;65</td><td>2.618</td><td>1.757-3.903</td><td>&lt;0.001</td></tr><tr><td>Female Gender</td><td>1.573</td><td>1.068-2.316</td><td>0.022</td></tr><tr><td>ECOG PS ≥2</td><td>3.447</td><td>2.025-5.857</td><td>&lt;0.001</td></tr><tr><td>Stage IV</td><td>1.126</td><td>0.744-1.702</td><td>0.575</td></tr><tr><td>Albumin &lt;3.5mg/dl</td><td>3.021</td><td>1.992-4.584</td><td>&lt;0.001</td></tr></tbody></table>

*The PROCESS Cohort

relapse in patients with diffuse large B-cell lymphoma: results of a multicenter prospective cohort study. Oncotarget. 2016;7:72033-43.

2. Hong JS, Kim SJ, Chang MH, Kim JA, Kwak JY, Kim JS, Yoon DH, Lee WS, Do YR, Kang HJ, Eom HS, Park Y, Won JH, Mun YC, Kim HJ, Kwon JH, Kong JH, Oh SY, Lee S, Bae SH, Yang DH, Jun HJ, Lee HS, Yun HJ, Lee SI, Kim MK, Yi JH, Lee JH, Kim WS, Suh C. Improved prognostic stratification using NCCN- and GEMTAMO- international prognostic index in patients with diffuse large B-cell lymphoma. Oncotarget. 2017;8:92171-82.

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

## 411
CLINICAL OBSERVATION OF METRONOMIC CHEMOTHERAPY COMBINED WITH CLEARING HEAT AND DETOXICATING TRADITIONAL CHINESE MEDICINE IN THE TREATMENT OF REFRACTORY AND RELAPSED ELDERLY LYMPHOMA

X. Sun | X. Dai | J. Pang | Y. Zhao | T. Ou |

B. Ma

Hematology Dept, Jiangsu Province Hospital of TCM, Nanjing, China

**Objective:** The elderly patients with malignant lymphoma had poor response to standard chemotherapy, high relapse rate after remission, short survival time and poor quality of life. Guidelines recommended salvage therapy for patients with relapsed and refractory lymphomas, while the elderly cannot tolerate high-dose chemotherapy and hematopoietic stem cell transplantation, a new protocol suitable for this population has been under discussion. Studies have shown that low-dose metronomic chemotherapy has a unique therapeutic effect in the treatment of mouse malignant tumors. Our previous clinical observations have shown that it can induce remission, improve the quality of life and prolong survival in some patients. Traditional Chinese Medicine believes that the elderly patients with lymphoma often have congenital deficiency of kidney essence, resulting in deficiency of vital qi, viscera, meridians, yin and yang, qi and blood disorder. To recover the feelings of six sexual feelings or warm heat evil, so that the evil influence into the viscera and bone marrow, resulting in the stagnation of
Qi and blood stasis, phlegm and blood stasis are intertwined. According to the theory of "Wei Qi Ying Xue" from the "Fu Qi Qi Ying Xue" to treat and detoxify.

Metronomic chemotherapy has good tolerance and prolongation of survival in the treatment of malignant tumor. Modern pharmacological studies have found that many Chinese herbs for clearing away heat and detoxification could inhibit the proliferation of lymphoma cells, inhibit angiogenesis and regulate immune function. Fully accord with the concept of metronomic chemotherapy, the combination of Qingrejiedu decoction and oral chemotherapy is a new combination of metronomic chemotherapy. In order to verify the efficacy of low-dose continuous oral chemotherapy combined with Qingrejiedu decoction, we made a preliminary attempt for the treatment of elderly lymphoma with refractory or recurrence.

**Methods:** Sixty-three cases of refractory or relapsed non-Hodgkin's lymphoma were treated with metronomic chemotherapy combined with Qingrejiedu decoction and Qingrejiedu decoction, and were treated with Qingrejiedu decoction and metronomic chemotherapy. Aged 66 to 93 years, median age 74 years, male 37 cases, female 26 cases. According to the Chinese medicine diagnosis, 3 cases of deficiency of qi and blood were classified according to syndrome differentiation, There were 37 cases of deficiency of liver and kidney yin and 23 cases of deficiency of spleen and kidney. They were treated with traditional Chinese medicine based on dialectical treatment. Patients were treated with selective low-dose dexamethasone, thalidomide, Lenalidomide, methotrexate or etoposide according to their condition and economic condition. The median follow-up was 15 months and 46 patients survived with a total survival rate of 73%. Seventeen patients died, of which 15 were disease progression; One patient died of lung infection. Another died of sudden cardiac death. Metronomic chemotherapy combined with heat-clearing and detoxifying Chinese herbs showed mild side effects, such as mild leukopenia, mild asthenia, mild diarrhea or constipation, which were the main side effects of grade I. The quality of life has improved markedly.

**Conclusion:** Heat-clearing and detoxifying Chinese herbs combined with metronomic chemotherapy is a simple and effective method for treatment, It is a well-tolerated and effective method to improve the quality of life, which is suitable for outpatient treatment and follow-up. It is helpful to improve the prognosis, improve the quality of life, prolong the survival and lighten the economic burden of the patients by treating the patients with refractory lymphoma in the elderly.

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

## 412
OUTCOME OF CHILDREN AND ADOLESCENTS WITH LYMPHOBLASTIC LYMPHOMA TREATED WITH THE EORTC 58951 PROTOCOL

I. Frikha¹ | M. Medhaffer¹ | Y. Fakhfakh¹ |

S. Hdijji¹ | H. Mnif² | W. Feki³ | I. Ben Amor¹ |

O. Kassar¹ | M. Charfi¹ | F. Kallel¹ | M. Ghorbel¹ |

T. Boudawara² | Z. Mnif³ | M. Elloumi¹

¹Hematology, Hedi Chaker Hospital, Sfax, Tunisia; ²Anatomopathology laboratory, Habib Bourguiba Hospital, Sfax, Tunisia; ³Radiology Department, Hedi Chaker Hospital, Sfax, Tunisia

**Introduction:** Lymphoblastic lymphoma (LBL) are the second most common subtype of non-hodgkin lymphoma (NHL) in children and adolescents. The aim of this study was to characterize the clinical course of children and adolescents with LBL treated in our department.

**Patients and Methods:** This is a retrospective study concerning patients aged 25 years or younger with LBL admitted between January 2009 and August 2018 in the hematology department of Hedi Chaker Hospital of Sfax, Tunisia. Patients were treated according to the EORTC protocol used for pediatric acute lymphoblastic leucemia. Diagnosis was based on biopsy of tumor for all patients. We analyzed in our study complete remission, relapse, death and the event free survival (EFS: using Kaplan-Meier method).

**Results:** We collected 12 children and adolescents with LBL. The median age at diagnosis was 8 years (range, 2-23 years). There was a predominance of males. LBL had T-cell type in 10 patients (83%). The most common primary manifestation in T-cell LBL was mediastinal involvement, in 9 patients (90%). Testicular involvement was the manifestation in 2 patients with precursor B-LBL. A cutaneous tumor was the initial manifestation in one patient with B-LBL. Seven patients (58%) had advanced disease (Stage III or IV) at diagnosis. Eleven patients (92%) achieved complete clinical remission and one patient was not evaluable (died at day 14 of induction course). After a median follow-up of 69 months, 8 patients (67%) were alive in first complete remission. Four children (33%) died, one of them soon after admission and three after relapsing. At 5 years of follow up, EFS was 72%.

**Conclusion:** LBL comprise approximately 30% of the NHL that occur in children and young adults. In the literature, the most frequent phenotype was T (85 - 90%) similar to in our study. During the last decades, several systematic clinical trials contributed to the controlled optimization of treatment. Using acute lymphoblastic leukemia type treatment regimen to treat children with LBL was an important development in the treatment with EFS can be achieved 75-90%. Our findings confirm the favorable prognosis of children with LBL with an intensive chemotherapy regimen derived from ALL therapy.

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

## EXTRANODAL LYMPHOMA

## 413
FIRST LINE SYSTEMIC TREATMENT IN MUCOSA-ASSOCIATED LYMPHOID TISSUE
<figure><img src="image_246.png" /></figure>

(MALT) LYMPHOMA NOT ELIGIBLE FOR
H. PYLORI ERADICATION – DO WE NEED
CHEMOTHERAPY?

B. Kiesewetter<fnref n="1" /> | W. Lamm<fnref n="1" /> | M.E. Mayerhoefer² |

W. Dolak³ | J. Lukas⁴ | I. Simonitsch-Klupp<fnref n="5" /> |

M. Raderer<fnref n="1" />

**Background:** There is still no clear therapeutic algorithm for MALT lymphoma patients beyond H. pylori eradication and while recent data on chemotherapy based regimens +/- rituximab (R) have potentially set new standards for patients in need of systemic treatment, it appears of interest to investigate also chemotherapy-free strategies.

**Methods:** We have retrospectively assessed all patients with histologically verified MALT lymphoma treated at the Medical University Vienna 1999-2019, and identified patients receiving first line systemic treatment defined as either chemotherapy (=classical cytostatic agents +/- R) or immunotherapy (=immunomodulatory agents or anti-CD20 antibodies). Primary endpoint was comparison of progression-free survival (PFS) following chemo- and immunotherapy.

**Results:** A total of 159 patients received upfront systemic treatment (median age 65 years, female-male ratio 1.3) with the median follow-up being 66 months (IQR 33-101). Naturally, the majority of patients had extragastric disease (80%) but we identified also 32 patients (20%) with H. pylori negative gastric lymphoma treated with systemic therapy. At initial diagnosis, 64% had stage I/IIE and 36%

disseminated disease (IIIE/IV) and MALT-IPI predicted low risk in 39%, intermediate risk in 46% and high risk in 15% of cases. Looking at the type of first line systemic treatment and outcome, 46% (74/159) received chemotherapy-based regimens and 54% (85/159) immunotherapy including IMiDs lenalidomide/ thalidomide (36%), anti-CD20 monotherapy rituximab/ ofatumumab (27%), macrolides clarithromycin/ azithromycin (27%) and proteasome inhibitor bortezomib (9%). Median estimated PFS after first line treatment for the entire collective was 76 months (95% CI 50-102) and while the overall response rate (90% vs 68%, p<0.01) and the complete remission rate (75% vs 43%, p<0.01) was significantly higher in the chemotherapy group, there was no difference in PFS between the chemotherapy (median 81 months, 95% CI 47-115) and the immunotherapy cohort (median 76 months, 95% CI 50-103) (p=0.57), suggesting comparable efficacy in terms of long-term outcome. Interestingly, there was a non-significant trend towards a decrease in relapse rates for immunotherapy, consequently resulting in a tentatively lower number of patients in need of second line treatment (39% vs 50%, p=0.15).

**Conclusion:** Our data show higher response rates with chemotherapy compared to immunotherapy, but this did not translate into a superior PFS. Thus, given the biological background of MALT lymphoma being a disease highly dependent on the microenvironment and in view of the favorable toxicity profile particularly of novel immunotherapeutic approaches such as IMiDs and macrolides, we suggest that chemo-free systemic treatment is active and should be further investigated in clinical trials.

**Keywords:** extranodal marginal zone lymphoma of MALT type; immunochemotherapy; indolent lymphoma.

<footnote n="1">¹Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria; ²Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; ³Department of Medicine III, Clinical Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; ⁴Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria;</footnote>

<footnote n="5">⁵Department of Pathology, Medical University of Vienna, Vienna, Austria</footnote>
## OUTCOME IN 55 PATIENTS. POLISH LYMPHOMA RESEARCH GROUP STUDY

J. Romejko-Jarosinska¹ | E. Paszkiewicz-Kozik¹ |

J. Sokołowska-Drozd² | A. Waszczuk-Gajda² |

M. Kotarska¹ | S. Blamek³ | M. Kulma-Kreft⁴ |

P. Kurczab⁵ | B. Kumiega⁶ | W. Sawczuk⁷ |

J. Zaucha⁴ | J. Walewski¹

¹Department of Lymphoproliferative Diseases, Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland; ²Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland; ³Department of Radiotherapy, Maria Sklodowska-Curie Cancer Center and Institute, Gliwice, Poland;

⁴Hematology Department, Maritime Hospital, Gdynia, Poland; ⁵Oncology Department, MRUKMED, Rzeszów, Poland; ⁶Hematology Department, Specialistic Hospital Nowy Sącz, Nowy Sącz, Poland; ⁷Oncology Department, Maria Sklodowska-Curie Bialystok Cancer Oncology Center, Bialystok, Poland

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of aggressive large B cell lymphoma (DLBCL). Here we describe pathological and clinical feature, adverse factors of outcome in PB-DLBCL patients (pts) treated over fifteen-year period. Methods: We retrospectively collected data on PB-DLBCL patients diagnosed between 2002-2017 at seven oncology centers from the Polish Lymphoma Research Group. Results: Fifty-five female with a diagnosis of PB-DLBCL were identified. Median age (range) was 62 (17-90), 13 pts (24%) were 75 or older. On review of orginal biopsy material we found 2 cases of high grade B lymphoma, one case of Burkitt lymphoma, two cases anaplastic large cell lymphoma, and 50 cases DLBCL including 4 cases of CD5+ DLBCL. Bulky disease was present in 28 pts (50%), 44 pts (80%) had low/low-intermediate IPI score. Rituximab and CHOP was given to 46 patients (80%) and the rest of patients received CHOP alone, 11 pts (20%) received intrathecal CNS prophylaxis. Adjuvant radiotherapy was applied in 13 (25%) patients. In 52 pts evaluable for response post first-line therapy the overall response rate was 88% and complete remission rate was 73%. After a median (range) follow up of 30 (1-186) months, median progression free survival (PFS) and overall survival (OS) for entire group were 25 and 30 months, respectively. 2-year PFS and 2-year OS were 62% (95%C.I. 48%, 76%), and 75% (95%C.I. 64%, 86%). In patients who received rituximab, 2 year PFS was 75% (95%C.I. 61%, 89%) (p=NS) and 2 year OS was 84% (95%C.I. 73%, 95%) (p=0.09). High-intermediate/high IPI score increased the risk of death with the HR of 3.35 [95%C.I (1.34-8.14), p<0.01] and the risk of progression with HR of 3.57 [95%C.I (1.52-8.22), p<0.01] compared to low/low-intermediate IPI. No other adverse factors for OS or PFS were found. After initial treatment, 18 (32%) patients subsequently progressed or relapsed: 8 pts (14%) in the ipsilateral breast, 8 pts (14%) in CNS, and 4 pts had disseminated disease. Median time to relapse was 9 months with range 1-186 months, the 5-year cumulative risk of CNS relapse was 12,7% with median time to CNS relapse 7 months. Primary breast

diffuse large B cell lymphoma is a rare disease with a substantial risk of secondary CNS involvement and progression to ipsilateral breast and other extranodal sites. High-intermediate/high IPI score was the only adverse factor which increased the risk of death and the risk of progression.

**Keywords:** B-cell lymphoma; extranodal lymphomas.

**Disclosures:** Romejko-Jarosinska, J: Honoraria: Servier, Novartis; Other Remuneration: Travel grant- Takeda, Servier. Paszkiewicz-Kozik, E: Honoraria: Roche, Takeda; Other Remuneration: Travel grant Roche.

Zaucha, J: Other Remuneration: Travel grant- Roche. Walewski, J: Consultant Advisory Role: Roche, Celgene, Takeda, Janssen-Cilag, Servier, Amgen, Incyte Abbvie; Honoraria: Janssen, Roche Takeda, Servier Celgene; Research Funding: Roche, GSK/Novartis, Takeda Janssen Cilag; Other Remuneration: Travel grant- Roche.

## 415 IMMUNOCHEMORADIOTHERAPY OR IMMUNOCHEMOTHERAPY ONLY IN PATIENTS WITH EXTRANONAL DIFFUSE LARGE B-CELL LYMPHOMA OF STOMACH

J. Vinogradova | A. Chumachenko | V. Ryabchikova |

K. Kaplanov | N. Ilyin

Radiation and Combination Treatments, Russian Scientific Center for
Radiology and Surgical Technologies named after Academician
A.M. Granov, St-Petersburg, Russian Federation

**Introduction:** Radiation therapy (RT) is an effective method for treating indolent lymphomas of the stomach (Yahalom, 2006), but the results proving its role in patients with extranodal diffuse large B-cell lymphoma with predominant lesions of the stomach during chemoradiation treatment are few and conflictive (Metijharissi et al., 2017, Mehmood, 2017).

**The purpose of the study:** is to evaluate the effectiveness of immunochemoradiotherapy (ICT + RT) compared with only ICT in patients with extranodal diffuse large B-cell lymphoma of the stomach.

**Methods:** The study included 66 primary patients aged 25-90 years (mean age - 59 years), who received and completed in the period 2006-2017. ICT + RT (26 patients) or ICT only (40 patients). Of these, men - 32; women - 34; Stage I - 6, II - 30; III - 3; IV - 27. The average observation period of the group - 45 months. 63 patients received 4-8 cycles of ICT R-CHOP-21, 3 patients - DA-EPOCH-R. RT was performed after ICT at doses of 30-40 Gy for the entire volume of the stomach and in perigastric lymph nodes. In 10 patients before treatment, 3 weeks after ICT (20 patients) and 4 weeks after RT (15 patients), a full body PET scan with 18F-FDG was performed. The groups were comparable in terms of the main prognostic factors for the IPI criteria. Patients, who received surgical treatment were not included into the study. Five patients from the ICT group with a lack
of efficacy of R-CHOP-21 were treated with 2 therapy lines, 1 - the third line of therapy.

**Results:** A complete response after R-CHOP-21 was established in 48 of 66 (73%) patients. After subsequent RT in all 26 patients of the group of ICT + RT, complete remission was achieved in terms from 7 to 93 months. (average - 50 months.). In the group of ICT only, 5 patients died (4 of them in stage IV), including 4 from the underlying disease advance, 1 - from relapse in the central nervous system. The average follow-up period for this group was 42 months, the deceased patients - 10 months. The overall 5-year survival rate of the combined treatment group is 100%, ICT is 72%. In patients with PET positive results after PCT after irradiation, the metabolic activity of the tumour was not detected.

**Conclusion:** ICT+RT is the optimal method of treating patients with extranodal aggressive lymphoma with gastric lesions.

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

## 416
### INCIDENTAL RADIATION TO THE SPLEEN AFTER TREATING GASTRIC LYMPHOMA WITH RADICAL RADIOTHERAPY - SHOULD WE RECOMMEND PROPHYLACTIC IMMUNISATION AND AN OAR DOSE CONSTRAINT?

F. Yuille | M.J. Kyle | C. Bedi | W. Urquhart

Clinical Oncology, Edinburgh Cancer Centre, Edinburgh, United Kingdom

**Introduction:** Radiotherapy (RT) is an effective treatment for gastric lymphoma, the majority of which is low grade Mucosal-Associated Lymphoid Tumour (MALT) subtype. In view of its close proximity to the stomach, the spleen receives a significant dose of radiation which can affect its subsequent function. This leads to the potential for increased risk of infection, which could be life-threatening. We therefore reviewed doses to the spleen, and aim to calculate a RT dose constraint for the spleen as an organ at risk (OAR).

**Methods:** A retrospective analysis was performed of 15 patients (pts) with gastric MALT and 1 with DLBCL who received radical RT from 2012 to 2018 at our centre. Doses to the spleen were analysed to evaluate the effect of radiation dose in relation to lymphocyte count and infection rates.

Splenic Dose Volume Histogram (DVH) parameters were reported as mean splenic dose (MSD), maximum splenic dose (MxSD) and V5, V20 and V30 for the spleen.

Lymphopenia was defined as absolute lymphocyte count (ALC) <1.5 and infection was defined as any infection noted within hospital records.

**Results:** 14 pts received 30Gy in 20 fractions and 2 pts received 24Gy in 12 fractions. Median MSD 19Gy (range 14-27) and Median MxSD

32Gy (26-34). Median V5 91.5% (63.6-100), Median V20 52.3% (30.6-94) and Median V30 23.6% (6.1-59.2).

All pts regardless of lymphocyte count before RT were found to be lymphopenic in the first 2 years (yrs) following treatment. Beyond 2 yrs, return to normal lymphocyte count was variable. However, between yrs 2 and 4 post RT, 50% had lymphopenia, then from yr 5 onwards all lymphocyte counts were normal.

**Conclusion:** There appears to be no direct correlation between MSD, MxSD, V5, V20, V30 and rates of lymphopenia but all patients became lymphopenic for the first 2 years following RT. Therefore, minimising dose to the spleen should be achievable to limit long term reduced function of this important organ, and prophylactic immunisations should be considered to protect these pts against potentially life-threatening infections.

**Discussion:** RT can reduce the function of the spleen after gastric irradiation for lymphoma (and for solid tumours). Routinely, the spleen has not been considered an important OAR. However, our data shows that lymphopenia occurs in all patients for the first 2 yrs following RT, and can continue for several more yrs, leaving pts at risk of infection. To prevent infection, in the UK, we would recommend immunisation for at least 2 yrs after receiving RT with the following vaccines: seasonal Influenza, Pneumococcal, Haemophilus influenza type B, Meningococcal C, Meningococcal ACWY conjugate and Meningococcal B.

Introducing a formal OAR dose constraint would be useful for clinicians treating upper abdominal organs with RT. As we were able to achieve a MSD of 14Gy, we would suggest 15Gy as a starting point. This could then be used to gather further data and relate to levels of lymphopenia and infection with a prospective audit.

**Keywords:** extranodal marginal zone lymphoma of MALT type.

## 417
### PROGNOSTIC IMPACT OF PD-L1 EXPRESSION, DOUBLE EXPRESSOR LYMPHOMA, AND PROGRESSION OF DISEASE WITHIN 24 MONTHS IN PRIMARY GASTROINTESTINAL DIFFUSE LARGE B-CELL LYMPHOMA

E. Ishikawa<fnref n="1" /> | K. Kohno² | K. Shimada<fnref n="3" /> |

T. Yamamura⁴ | M. Nakamura<fnref n="1" /> | M. Fujishiro<fnref n="1" /> |

S. Nakamura²

**Introduction:** Diffuse large B-cell lymphoma (DLBCL) is heterogeneous and the most common gastrointestinal lymphoma, accounting

<footnote n="1">¹Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan; ²Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan;</footnote>

<footnote n="3">³Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan; ⁴Endoscopy, Nagoya University Hospital, Nagoya, Japan</footnote>
<figure><img src="image_247.png" /></figure>

<figure><img src="image_248.png" /></figure>

for 39%-58%. The prognostic/predictive indicators and treatment strategies among patients with gastric and intestinal DLBCL (giDLBCL) still remain controversial beyond their anatomical sites. We investigated the clinical utility of newly emerging prognostic/predictive indicators in patients with giDLBCL with an emphasis on PD-L1 immunostain of neoplastic and non-neoplastic immune cells, double expressor lymphoma (DEL) with co-expression of MYC and BCL2, and progression of disease within 24 months (POD24) after diagnosis.

**Methods:** This retrospective study included 302 patients with primary gastric (n=243) and intestinal DLBCL (n=59) between 1995 and 2018. Survival analyses were performed among patients treated with rituximab-containing chemotherapy.

**Results:** Compared to gastric DLBCL, intestinal DLBCL had a significantly higher rate of perforation (11% vs. 0.4%, P<0.001) and advanced Lugano stage (71% vs. 46%, P=0.001). Neoplastic PD-L1 expression on tumor cells (≥5%) was detected in only three of 183 cases with early relapse and/or aggressive clinical course. PD-L1 expression on microenvironment immune cells (≥20%, miPD-L1) was observed in 35 (64%) and 61 (48%) gastric and intestinal cases examined, respectively, with a statistically marginal difference (P=0.054). A total of 205 (69%) patients received rituximab-containing chemotherapy, most frequently R-CHOP. The intestinal group had significantly worse overall survival (OS) compared to the gastric group (P=0.0369). Notably, the curves delineated by localized or advanced Lugano stage
almost overlapped beyond their anatomical sites. The miPD-L1-positive cases showed significantly better OS compared to the negative cases in both gastric and intestinal DLBCL (P=0.0430 and P=0.0115). DEL was found in 11 gastric (9%) and 6 intestinal cases (12%), with significantly worse OS than the others in each anatomical group (P=0.0012 and P=0.0008, respectively). Among patients with complete remission, 21 (16%) of 134 gastric and 6 (17%) of 36 intestinal DLBCL patients had recurrence. Differences in survival, calculated from recurrence, were significant between gastric DLBCL patients with and without POD24 (P=0.0427), but did not work in prognostic delineation of intestinal cases (P=0.563). Multivariate analysis revealed that advanced Lugano stage (P<0.001), DEL (P<0.001), and miPD-L1 negativity (<20%, P=0.027), but not intestinal site (P=0.171), were significant prognostic factors for OS of giDLBCL.

**Conclusion:** The anatomical site of disease did not influence outcome in giDLBCL in the rituximab era. Lugano stage, PD-L1 expression on microenvironment immune cells, and MYC/BCL2 co-expression provide therapeutic guidance for patients with giDLBCL.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); PD-1L; rituximab.

418

IMPACT OF DIFFERENT TYPES OF ANTIVIRAL THERAPY ON PROGNOSIS OF HEPATITIS C VIRUS POSITIVE MARGINAL ZONE LYMPHOMAS

S. Lepkov<fnref n="1" /> | G. Tumyan² | O. Kolomiytcev² |
J. Ribykhina² | P. Zeynalova² | N. Kokosadze² |
J. Kluchagina³ | N. Kuprishina² | V. Ivanova⁴ |
I. Lazarev⁴ | O. Zacharov⁴ | S. Borisovskaya⁵ |
R. Ivashenco⁵ | I. Suborteva⁶ | O. Ettinger<fnref n="1" /> | I. Nikitin<fnref n="1" />

**Background:** The association between hepatitis C virus (HCV) and marginal-zone lymphomas (MZL) is now widely accepted, as a result of evidence from epidemiological and therapeutic studies carried out in the last decades. The large number of studies demonstrated that antiviral therapy (AT) is an active therapeutic option in the patients with HCV-positive MZL. The use of AT, consisted of interferon (IFN) and ribavirin (RBV), at any time during the life of these patients (pts) is able to induce high anti-tumor response rate and associated with improved

outcome. There were limited data about efficacy of the new direct-acting antiviral agents (DAAs) in the treatment of pts HCV+ MZL.

**Aims:** The purpose of our study is evaluated clinical feature and outcomes of HCV+ MZL patients depending on the availability and type of antiviral treatment.

**Methods:** We retrospectively selected 64 pts affected by MZL and infected by HCV, defined as HCV-RNA positivity, and who were treated since 2005-2018 in N.N. Blokhin National Cancer Research Center. The median age was 50 years (31-75), 59% were male, 55 pts (86%) had advanced stages, B-symptoms were revealed in 14 pts (22%). The distribution of MZL subtypes were as follows: nodal 13 (20%), extranodal MALT 11 (17%), splenic 21 (33%), disseminated MZL 19 (30%) pts. Depending on the treatment, the patients were stratified into three groups (G): 26 (41%) pts did not receive any kinds of antiviral therapy (G1), 27 (42%) pts were treated with IFN-based antiviral regimen (G2), the 11 (17%) pts (G3) receive direct antiviral agents (sofosbuvir-based regimen). The most common anti-tumor treatment regimen in the G1 was the R-CHOP\R-CVP (21 out of 26 pts).

**Results:** The overall response rate (ORR) were comparable in all three groups (87% vs 82% vs 73% respectively, p=ns). In contrast, the duration of response was significantly higher in the groups of pts receiving antiviral therapy, estimated 3-year progression-free survival (PFS) were 38% (G1) vs 67% (G2) vs 58% (G3) respectively (p=0, 03). In median follow-up was 36 months, 24 (38%) pts had relapse. Most relapses developed in pts (63%) receiving systemic antitumor therapy without any kind of antiviral therapy.

**Conclusion:** Antiviral therapy is a preferential first-line option in patients with HCV-associated MZL. Because of DAAs' safety, rapidity, and efficacy in obtaining a virologic response, as well as good tolerance profile, DAA therapy should be preferred to IFN-based antiviral treatment. Our preliminary data suggest a similar activity of IFN-based and INF-free regimen in HCV+ MZL, but limited number of pts and length of follow-up provide a strong rational background for a larger prospective series to determine precisely the impact of AT in HCV-infected patients with MZL.

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

<figure><img src="image_249.png" /></figure>

<footnote n="1">¹Hospital Therapy, N.I. Pirogov Russian National Research Medical University, Moscow, Russian Federation; ²Hematology and Bone Marrow Transplantation, N. N. Blokhin National Medical Research Centre of oncology, Moscow, Russian Federation; ³Oncology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation; ⁴Hematology, Moscow City Hematological Center by S.P. Botkin, Moscow, Russian Federation; ⁵Hospital Therapy, Moscow Clinical City Hospital by V.M. Buyanov, Moscow, Russian Federation; ⁶Hematology, National Medical Research Center for Hematology, Moscow, Russian Federation</footnote>