**Results:** Since 2013, CeVi has collected a total of 1616 samples (6658 vials) from 1297 patients, and more than 1573 samples (>6200 vials) are available. All classic and rarer lymphoma subtypes have been collected in routine practice (Table1).

Cession of CeVi samples is open for both academic researchers and private partnerships (request: partnering@calym.org). CeVi contributed to CALYM research programs and led to 4 publications in rank A journals. Two major industrial partnerships, currently under CDA, will be disclosed in 2019.

**Conclusions:** The generation of a comprehensive collection of lymphoma viable cells is feasible and valuable.

CeVi is a unique human lymphoma viable cell collection from LN, BM and PBMC, clinically and biologically annotated. The collection comprises a critical number of samples with a steady in/out flow, allowing academic and industrial partnerships. CeVi is connected to LYSA/LYSARC databases, including REALYSA real life study, and others projects such as the Lymphoma Data Hub linked to Artificial Intelligence & machine learning.

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

**Disclosures:** NADEL, B: Honoraria: Amgen, Celgene, Gilead, Sanofi; Research Funding: MedImmune, Roche. BASEGGIO, L: Consultant Advisory Role: TAKEDA; Research Funding: TAKEDA. CARTRON, G: Consultant Advisory Role: Roche, Celgene; Honoraria: Sanofi, Gilead, Jansen, Roche. FEST, T: Research Funding: Roche.

325

EPIDEMIOLOGY REVIEW OF LYMPHOMA
IN A SINGLE INSTITUTION IN MALAYSIA

N. Adila

K.W. Tey

P.C. Bee

G.G. Gan

Hematology, University Malaya Medical Centre, Kuala Lumpur, Malaysia

**Introduction:** The subtype distribution of lymphoma reveals diverse geographic and ethnic variations. There is limited information available in regards to the epidemiologic distribution and survival outcome of lymphoma in the South East Asia regions. In this study, we report a single institutional data of patients with lymphoma in Malaysia.

**Methods:** We obtained data of patients diagnosed with lymphoma treated by the adult haematology unit between 1996 and 2018 from the hospital's electronic medical record. The diagnosis were retrieved from the pathology report and then grouped into non Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Demographic data of age, gender, ethnicity and histopathology (HP) pattern were collected. Only patients who had a minimum of 5 years follow up were analysed for survival outcome.

**Results:** A total of 708 cased were identified. The median age of the patients was 55.5 years (range, 14-89 years). The male-to-female ratio was 1.1:1. Majority were of Chinese ethnic origin (52.5%) followed by Malay (34.9%) and Indian (10.6%). 84.7% were diagnosed with NHL and 15.3% were HL. Among the NHL diagnosis, 72.5% were B cell in

origin of which the two leading HP subtypes were diffuse large B-cell lymphoma (DLBCL) (71.7%) and follicular lymphoma (FL) (7.8%). T cell lymphoma constitutes 6.1% of NHL. With a median follow-up duration of 80.75 months, the overall survival (OS) of HL was significantly better than that of patients with NHL (88.4% vs 70.2%, P =0.001). Patient age below 60 years had better OS than older age group (79.7% vs 63.3%, P=0.000). The main cause of death from the available retrieved record were lymphoma related (42.7%).

**Conclusions:** The HP subtypes of lymphoma in Malaysia are similar to what was reported in the Asia regions where HL remains relatively uncommon when compared to the western population. The frequency of FL is uncommon and T cell lymphoma is comparable to what was also reported in other western countries. Compared to other Asian countries, it appeared that the prevalence of DLBCL and HL in Malaysia is higher. The overall survival rates are comparable to other countries. The major cause of death remained as disease related.

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

326

HISTOPATHOLOGICAL AND
IMMUNOHISTOCHEMICAL STUDY OF
MALIGNANT LYMPHOMAS

J.J. Jiménez Galainena¹

J. Lamadrid García¹

Z. Gutiérrez Aleaga¹

M. Amigó de Quesada¹

M. Nazario Dolz¹

E. Gámez Pérez¹

L. Heredia Manzano¹

W. Marcial Martínez¹

A. Columbié Molina¹

R. Guarnaluce Brooks¹

Y. Morales Rizo¹

E. Wilson Batista¹

E. Gracia Medina²

T. González Madruga²

J. Peraza Bordao³

A. Chong López⁴

¹Anatomic Pathology Department, National Oncology Institute, Havana City, Cuba; ²Clinical Oncology, National Oncology Institute, Havana City, Cuba; ³Anatomic Pathology, Instituto de Medicina Tropical Pedro Kouri IPK, Havana City, Cuba; ⁴Anatomic Pathology, Hospital Clínico Quirúrgico Hermanos Ameijeiras, Havana City, Cuba

**Introduction:** The morphologic classification of lymphomas in the field of hematopathology includes different techniques such as immunohistochemistry and genotypic studies in order to appropriately classify and subclassify these entities according to the WHO Classification; so, the patients can receive the best treatment.

**Objective:** The study with immunohistochemical technique was to classify the different anatomopathological entities of these neoplastic lymphoid processes.

**Material and Methods:** We studied 1813 biopsies of different sites diagnosed such as malignant lymphomas at the Pathology Department of the National Oncology Institute, Havana City, Cuba, from the period of 2007 to 2018 with a panel of different antibodies for
hematolymphoid processes employing the technique of immunohistochemistry in paraffin blocks. The manual and automated immunohistochemical staining were used. The visualization systems included the Polymer Detection System and the ultraview Universal DAB Detection Kit.

**Results:** The Non-Hodgkin's B Cell Lymphomas were the most frequent immunophenotypic type (1303 cases)(71,86%). The B Cell Lymphomas CD20 positive were 1184 cases (65,03%). The most frequent histopathological type was the Diffuse Large B Cell Lymphomas (649 cases)(35,79%). The Peripheral T Cell Lymphomas (76 cases) and Anaplastic Large Cell Lymphomas (61 cases) were the most principal types diagnosed in the group of Non-Hodgkin's T Cell Lymphomas (137 cases in total)(7,55%). The extranodal location were 868 cases (47,87%) and the Head and Neck location was the most common site diagnosed in this group (180 cases) (20,73%).

**Conclusion:** The study demonstrated the different histologic types, location and frequencies of the lymphomas in our daily work of a period of time of 12 years in the Immunohistochemistry Laboratory at the Pathology Department.

**Keywords:** anaplastic large cell lymphoma (ALCL); diffuse large B-cell lymphoma (DLBCL); peripheral T-cell lymphomas (PTCL).

## CLL

### 327
PTBP1 REGULATES ALTERNATIVE SPLICING OF APOPTOTIC PROTEIN: IMPLICATIONS IN CLL AND IBRUTINIB RESISTANCE

H. Zhu¹ | X. Li¹ | X. Zheng¹ | J. Wang² |

H. Tang¹ | L. Wang¹ | Y. Xia¹ | J. Liang¹ |

W. Xu¹ | J. Li¹

¹Hematology, Jiangsu Province Hospital, Nanjing, China; ²Physiology, Nanjing Medical University, Nanjing, China

**Introduction:** Ibrutinib, an oral, selective inhibitor of Bruton's tyrosine kinase (BTK), dramatically improved Progression-free survival (PFS) and Overall survival (OS) compared with immunochemotherapy in CLL both in first line and relapsed/refractory patients. However, some patients did progress on ibrutinib with dismal outcome. The underlying mechanism remains to be investigated beyond evolving of BTK and/or PLCg2 mutation, the dysfunction of apoptotic protein and mitochondrial apoptotic dependencies may be involved in ibrutinib resistance. PTBP1 (Polypyrimidine tract binding protein 1), a splicing factor, was found to be necessary for B cell selection in germinal centers. Knocking out PTBP1 in B cell resulted in impaired BCR-mediated B-cell activation and antibody production. Here, we investigate the regulation of PTBP1 on alternative splicing of apoptotic protein and its implications in CLL and ibrutinib resistance.

**Methods:** Eighty-one CLL patients and 5 healthy controls were enrolled in this study from January 2010 to May 2018. The PTBP1 mRNA expression was measured by real-time polymerase chain reaction (RT-PCR) and Western-blot. We analyzed the PTBP1 expression with established CLL prognostic factors such as p53 and IGHV mutation status, and treatment to first treatment (TTFT). Resistant MEC-1 cell line was established by intermittently incubating with ibrutinib at a low concentration for short intervals and then gradually increased to 2-fold of IC50 value. Cells were allowed to recover every time after washing off the drug. RT-PCR was performed for both long and short

<figure><img src="image_196.png" /></figure>
isoform of MCL-1 by using specific primer in both parent and resistant cell lines and paired ibrutinib resistant patients primary cells. Resistant MEC-1 cell line was cultured in RPMI 1640 without ibrutinib for 48hrs before transfection, siRNA targeting with PTBP1 mRNA and non-targeting siRNA were transfected into cells by using lipofectamine 3000. The transfection efficiency was verified by Western blot after 24 h and ibrutinib was added into resistant cell line. Apoptosis was then analyzed using flow cytometry (FCM) after 24 hrs. Receiver operating characteristic curve (ROC) and area under the ROC curve (AUC) were established to verify the best cut-off value in differentiating the high or low expression of PTBP1 mRNA. Time-to-first-treatment (TTFT) interval was defined as interval from diagnosis to first treatment. All statistical analyses were performed using the SPSS software program.

**Results:** The expression of PTBP1 in CLL primary patients was significantly increased than 5 healthy donors (p < 0.01)(A). Patients with IGHV-mutated had higher level of PTBP1 as compared with patients with IGHV-unmutated (p < 0.05). Furthermore, Higher level of PTBP1 was associated with shorter TTFT in whole cohort, also in IGHV-mutated and unmutated subgroup (p < 0.05)(B). We further demonstrated that PTBP1 was aberrant expressed in ibrutinib resistant MEC-1 cell line or ibrutinib resistant primary patients' samples, as compared with parent cell line or patients' baseline samples. We also

found the dysregulation of alternative splicing of MCL-1 in ibrutinib resistant models, presented with increased anti-apoptotic MCL-1<sub>L</sub> and decreased pro-apoptotic MCL-1<sub>S</sub>(C). Moreover, knocking down of PTBP1 sensitized CLL to ibrutinib via switching alternative splicing of MCL-1 to its pro-apoptotic isform MCL-1<sub>S</sub>(D).

**Conclusions:** The splicing factor PTBP1 is involved in the pathogenesis of CLL. Its aberrant expression may lead to the dysregulation of alternative splicing of MCL-1, resulted in increased MCL-1<sub>L/S</sub> ratio. PTBP1 can be as a promising target for the treatment of CLL patients progressed on ibrutinib.

**Keywords:** chronic lymphocytic leukemia (CLL); ibrutinib.

328
EBV-MIR-BHRF1-1 TARGETS P53 GENE:
POTENTIAL ROLE IN EPSTEIN-BARR VIRUS
ASSOCIATED CHRONIC LYMPHOCYTIC
LEUKEMIA

W. Xu | D. Xu | L. Wang | H. Zhu | J. Li |
J. Liang

Hematology, the First Affiliated Hospital of Nanjing Medical University,
Jiangsu Province Hospital, Nanjing, China; Key Laboratory of Hematology

<figure><img src="image_197.png" /><figcaption>**Figure 1.** Time to treatment (TTT) and overall survival (OS) curve of 97 patients with CLL based on EBV-mir-BHRF1-1 by Kaplan-Meier estimation. Low group value is below the cut-off value (0.0012), and high group above the cut-off value.</figcaption></figure>
of Nanjing Medical University, Nanjing, China; Collaborative Innovation
Center for Cancer Personalized Medicine, Nanjing, China

**Introduction:** Epstein-Barr virus (EBV) was the first virus shown to encode viral microRNAs (miRNAs). To date, 44 mature miRNAs of EBV were classified into two clusters (BHRF1 cluster and BART cluster). Our previous study showed that nearly 10.0% of newly-diagnosed chronic lymphocytic leukemia (CLL) patients had high level of EBV-DNA viral load in whole blood. Furthermore, a positive blood EBV-DNA test at diagnosis was significantly associated with inferior time-to-treatment (TTT) and overall survival (OS) in CLL patients. p53 gene has a vital role in the disease-progress, clone evolution and drug-resistance for CLL patients. Until now, no therapies can fully overcome the inferior prognosis caused by p53 aberration even in the era of the emerging of so many molecular targeted drugs such as BTK inhibitor and Bcl-2 inhibitors. One of the members of the BHRF1 miRNAs, EBV-miR-BHRF1-1, was found to bind to the 3'UTR of p53, suggesting that p53 may be a target of EBV-miR-BHRF1-1. These findings provide one of the potential mechanisms by which EBV can promote CLL development through its miRNA functions.

**Methods:** Quantitative reverse transcription-PCR (qRT-PCR) and western blotting were used to quantify EBV-miR-BHRF1-1 and p53 expression in cultured CLL and to validate the role of EBV-miR-BHRF1-1 targeting p53.

**Results:** p53 aberration was associated with higher expression level of EBV-miR-BHRF1-1 (P<0.001) which was also an independent prognostic marker for overall survival (OS) (P=0.028; HR 5.335 [1.193, 23.846]) in 97 newly-diagnosed CLL patients after adjusted with CLL-international prognostic index (CLL-IPI) (Figure 1). In this study, we identified EBV-miR-BHRF1-1 as a viral miRNA regulator of p53. EBV-miR-BHRF1-1 repressed luciferase reporter activity by specific interaction with the seed region within the p53 3' untranslated region. Discordance of p53 messenger RNA and protein expression was associated with high EBV-miR-BHRF1-1 levels in CLL patients and cell lines. EBV-miR-BHRF1-1 inhibition upregulated p53 protein expression, induced cell cycle arrest and apoptosis and decreased cell proliferation in cell lines. EBV-miR-BHRF1-1 mimics downregulated p53 protein expression, decreased cell cycle arrest and apoptosis, and induced cell proliferation in cell lines.

**Conclusions:** The interaction between EBV-miR-BHRF1-1 and p53 may be one of the mechanisms by which EBV-miR-BHRF1-1 promotes EBV-positive CLL. Our results support the potential of EBV-miR-BHRF1-1 as a therapeutic target in EBV-associated CLL with p53 gene aberration.

**Keywords:** chronic lymphocytic leukemia (CLL); Epstein-Barr virus (EBV); P53.

UNFAVORABLE PROGNOSIS IN CHRONIC LYMPHOCYTIC LEUKEMIA

S.G. Papageorgiou¹ | K. Katsaraki² | P. Karousi² |

P. Tsiakanikas² | A. Scorilas² | V. Pappa¹ | C.K. Kontos²

¹Second Department of Internal Medicine and Research Unit, University General Hospital "Attikon", Haidari, Greece; ²Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece

**Introduction:** This original research study evaluated, for the first time, the prognostic potential of internal tRNA-derived RNA fragments (tRFs) bearing the Glycine anticodons GCC (i-tRF-GlyGCC) and CCC (i-tRF-GlyCCC) as novel molecular biomarkers in chronic lymphocytic leukemia (CLL).

**Methods:** Peripheral blood mononuclear cells (PBMCs) from 91 CLL patients and 43 non-leukemic blood donors were evaluated. Cell immunophenotyping showed that most PBMCs isolated from patients' blood samples were leukemic B cells. The mutational status of the immunoglobulin heavy chain variable (IGHV) region was specified using Sanger sequencing. Total RNA was extracted from PBMCs and in vitro polyadenylated using *Escherichia coli* poly(A) polymerase, prior to first-strand cDNA synthesis with an oligo-dT-adaptor primer, using MMLV transcriptase. This reaction was optimized, so as to exclude reverse transcription of complete tRNA molecules. Subsequently, a real-time quantitative polymerase chain reaction (qPCR) method was developed for the quantification of particular tRNA fragments and applied in all samples. The small nucleolar RNAs RNU43 and RNU48 were used as reference genes, to normalize tRF expression.

**Results:** The results show that i-tRF-GlyCCC was downregulated in PBMCs (mostly leukemic B cells) of CLL patients, compared to PBMCs of non-leukemic controls. On the other hand, no significant differences in i-tRF-GlyGCC levels were observed. An optimal cutoff value for each tRF was first defined by statistical analysis. The expression status of each tRF was then compared with other established prognostic factors, in terms of overall survival (OS). In Kaplan-Meier OS analysis of the entire cohort of patients, positive i-tRF-GlyGCC and/or i-tRF-GlyCCC expression proved to be a significant predictor of reduced OS (P≤0.001). Univariate Cox regression analysis for OS revealed a statistically significant hazard ratio (HR) of 3.40 for i-tRF-GlyGCC-positive CLL patients (HR=3.40, 95% CI=1.61-7.18 P=0.001). Bootstrapping Cox in regression analysis enhanced these results. (P<0.001). Moreover, i-tRF-GlyCCC-positive expression was associated with inferior OS of CLL patients (HR=3.95, 95% CI=1.60-9.74, P=0.003, Bootstrap P<0.001). Multivariate Cox regression analysis revealed that the prognostic value of i-tRF-GlyGCC and i-tRF-GlyCCC is independent of other prognostic factors in CLL, including Binet and/or Rai stage, CD38 expression, and IGHVmutational status.

**Conclusions:** To the best of our knowledge, this study shows, for the first time, that internal tRFs bearing the Glycine anticodons GCC and
CCC (namely: i-tRF-GlyGCC and i-tRF-GlyCCC) could be considered
as emerging, molecular prognostic biomarkers in CLL.

**Keywords:** chronic lymphocytic leukemia (CLL).

330
RESULTS OF MUTATIONAL STATUS OF
IMMUNOGLOBULIN HEAVY-CHAIN
VARIABLE GENES ANALYSIS IN A COHORT
OF PATIENTS WITH B-CLL. A SINGLE
CENTRE EXPERIENCE

C. Mardaraz<fnref n="1" /> | F. Sackmann<fnref n="1" /> | C. Pavlovsky<fnref n="1" /> |
M. Pavlovsky<fnref n="1" /> | M. Zerga² | M. Mela Osorio³ |
E. Bullorsky<fnref n="4" /> | A. Pavlovsky<fnref n="1" />

**Background:** The mutational status of the variable region of the Immunoglobulin heavy-chain (IGHV) gene is one of the most robust prognostic markers in Chronic Lymphocytic Leukemia (CLL), allowing the identification of 2 groups with different clinical behavior. Those with no or few somatic mutations (unmutated CLL, UM-CLL) with a more aggressive course of their disease, and those with a heavier load of mutations (mutated, M-CLL), with a more indolent disease. European Research Initiative on CLL (ERIC) has defined clear guidelines for Immunoglobulin gene sequence analysis.

**Materials and Methods:** Patients with CLL in our institution were studied for productive IGHV rearrangements and its mutational status. There were no exclusion criteria for the analysis of this prognostic marker. IGHV-D-J gene rearrangements and mutational status were analyzed between 6/2016 and 2/2019. Nucleic acid used was genomic DNA (gDNA) and ERIC guidelines were followed. High molecular weight DNA was isolated from all patients and amplified using forward Leader primers combined with JH reverse consensus primer. In those cases, in which leader primers were unsuccessful at providing a product that could be sequenced, VH FR1 primers were used. Direct bidirectional sequencing was performed and Stereotype B cell receptors were analyzed.

**Results:** From 150 samples received and analyzed, 138 productive IGHV-IGHD-IGHJ rearrangements were identified, 12 patients had insufficient leukemic cells for the analysis. Of 138 patients 54 (39%) were UM-CLL and 84 (61%) were M-CLL. Within this last group, 12 were considered "borderline" M-CLL. The most frequent IGHV family in this series was IGHV3, followed by IGHV4 and IGHV1. Double rearrangements were detected in 16 of the cases. Stereotype B cell receptors were found in 16 patients.

**Conclusion:** These results show a slightly higher incidence on M-CLL than the published data. We believe this is due to a high proportion of asymptomatic patients with no need of treatment, in this cohort. The most frequent used IGHV family was IGHV-3 while IGHV4 and

IGHV1 were in second and third place, respectively. The frequency of
Stereotyped BCRs was lower from those observed in western coun-
tries cohorts. These results support previous published experience in
other Latin American countries. Longer follow up will be necessary to
determine the impact of this molecular factor in the clinical behavior
of this group of patients.

**Keywords:** gene rearrangement; immunoglobulins (Ig).

331
CHANGES IN CONCENTRATION OF SERUM
FREE LIGHT CHAINS OF
IMMUNOGLOBULINS IN PATIENTS WITH
CHRONIC LYMPHOCYTIC LEUKEMIA AS A
FACTOR FOR EVALUATING
CHEMOTHERAPY EFFECTIVENESS

I. Kogarko<fnref n="1" /> | A. Golenkov² | E. Kataeva² |
T. Mitina² | Y. Chuksina² | B. Kogarko<fnref n="1" /> | I. Ganeev<fnref n="1" />

¹Chembio Processes, Institute of Chemical Physics, Russian Academy of Sciences, Moscow, Russian Federation; ²Hematology Oncology, Moscow Regional Clinical Research and Clinical Institute, Moscow, Russian Federation

**Goals:** To evaluate effectiveness of chemotherapy in patients with chronic lymphocytic leukemia (CLL) by measuring changes in concentrations of serum free light chains of immunoglobulins (sFLC) and light chain (LC) expression on circulating B-lymphocytes of peripheral blood (PB).

**Material and methods:** 10 patients with newly diagnosed CLL were recruited for this study. Concentrations of sFLC were measured by Freelite™ method (The Binding Site, UK). Immunophenotyping of PB lymphocytes was performed by 4 color flow cytofluorometry (BD FACSCalibur, USA). All patients received FCR-therapy (Rituximab 375 mg/m2, i.v.; Fludarabine 25 mg/m2, i.v.; Cyclophosphamide 250 mg/m2, i.v.). The cycle was repeated every 4 weeks. Disease stage and chemotherapy effectiveness were evaluated by IWCLL 2008 criteria. 5 patients had stage II, 5-stage IV Rai. Standard clinical tests, measurements of sFLC concentrations and LC expression on PB B-lymphocytes were performed at the time of diagnosis, before and after chemotherapy cycle. Patients received 6 FCR cycles.

**Results and Discussion:** At presentation 6 of 10 patients had monoclonal increase of sFLC, whereas 4 patients did not demonstrate monoclonal changes in sFLC concentrations. Changes in sFLC concentrations, κ/λ-ratio of LC expression on PB circulating B-lymphocytes, absolute blood lymphocytosis and a clinical response to therapy were analysed. A decrease in serum concentrations of tumor sFLC was achieved on average up to 63,1% (35,0% -83,3%). It correlated with normalization of sFLC κ/λ ratio (normal range 0,4-0,69). Complete remission (CR)-2 patients; partial remission (PR)-2 patients. In those 4 cases, κ/λ ratio of LC on membrane of PB lymphocytes was normalized, and absolute lymphocytosis was approaching the normal range. In the remaining 2 of 6 patients, no decrease in tumor sFLC

<footnote n="1">¹Clinical research, Centro de Hematología Pavlovsky, Buenos Aires,
Argentina; ²Hematology Department, Hospital Alemán, Buenos Aires,
Argentina; ³Clinical research, FUNDALEU, Buenos Aires, Argentina;</footnote>

<footnote n="4">⁴Hematology Department, Hospital Britanico, Buenos Aires, Argentina</footnote>
concentration was observed, whereas κ/λ ratio of LC on PB B-cell lymphocyte was normalized, no absolute lymphocytosis was present, and a clinical improvement was noted. Therefore, sFLC has higher sensitivity in determining residual disease compared with standard treatment evaluation criteria. sFLC κ/λ ratio normalization can serve as an additional criterion for antitumor therapy effectiveness due to visualization of minimal residual disease in CLL patients. In 4 of 10 patients with no initial sFLC clonal changes 1 patient had CR, and 3-PR. In above 4 patients increases in sFLC secretion were polyclonal and reflected the state of normal antibody-producing cells. 1 patient had concentrations of both κ and λ sFLC on the low range, which indicated a humoral deficit.

**Conclusion:** Changes in sFLC concentrations and their κ/λ ratio can serve as a high-sensitivity criterion for evaluating chemotherapy effectiveness in patients with CLL.

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

## 332
### FOXP1, PD-1 AND PD-L1 ARE SIGNIFICANTLY UPREGULATED IN LYMPHOCYTES FROM CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS COMPARED TO AGE-MATCHED HEALTHY DONORS

P. De Silva<fnref n="1" /> | B. Stamatopoulos<fnref n="1" /> | V. Dang Chi<fnref n="1" /> |

S. Garaud² | R. Francois³ | V. Thibaud<fnref n="1" /> |

C. Solinas² | A. Boisson² | H. Duvillier⁴ |

R. Rouas<fnref n="1" /> | P. Lewalle<fnref n="1" /> | K. Willard-Gallo² | D. Bron<fnref n="1" />

**Background:** Age-associated immunodeficiencies increase the probability of developing malignant hemopathies including chronic lymphocytic leukemia (CLL). One reason could be due to the accumulation of genetic/epigenetic changes leading to deregulation of transcriptional programs in lymphocytes. The transcription factor FOXP1 is a key regulator of B cell development and abnormally expressed in B cell malignancies. We investigated the significance of FOXP1 and inhibitory immune checkpoint (PD-1, PD-L1 and TIM-3) expression in the major lymphocyte subsets from CLL patients (pts) to investigate their contribution to a malignant/exhaustion phenotype.

**Population and methods:** Peripheral blood mononuclear cells were isolated from 101 individuals [40 untreated CLL; 60 healthy donors (HD)]. T and B cells were purified by magnetic bead isolation or FACS sorting. FOXP1, PD-1, PD-L1 and TIM3 transcripts were quantified using RT-qPCR. Nuclear labeling of FOXP1 followed the labelling of membrane markers and data was acquired by flow cytometry. The

prognostic value of FOXP1 expression in purified CD19⁺ leukemic B cells was analyzed retrospectively in a cohort of 184 CLL pts and correlated with clinical parameters.

**Results:** FOXP1 gene/protein expression in CD4⁺, CD8⁺ T cells and leukemic B cells was significantly higher in untreated CLL pts compared to age-matched HDs. Analysis of FOXP1 gene expression in our retrospective CLL cohort confirmed increased expression in the leukemic-B cells. Higher FOXP1 expression was correlated with worse overall survival of CLL patients in this cohort (p=0.0165). There was no correlation between FOXP1 and Binet stages or IGHV mutation status. PD-1 and TIM-3 expression on T cells and PD-L1 expression on B cells was analyzed to determine whether an exhausted phenotype was associated with CLL and aging. These data reveal that PD-1 (transcripts/protein) is significantly upregulated on CD4⁺/CD8⁺ T cells in the older vs younger HD groups and further increased on T cells from CLL pts in comparison with age-matched HD. High PD-L1 expression (transcripts) was significantly correlated with increased age in HD B cells, and again further increased in the leukemic-B cells. A trend toward an inverse correlation between FOXP1 and PD-1 was observed in CD4⁺/CD8⁺ T cells. TIM-3 expression (transcripts/protein) in T cells was very low in our CLL cohort.

**Conclusions:** We show that FOXP1 is significantly upregulated on T and B cells from CLL patients with its higher expression associated with worse overall survival. Higher PD-1 and PD-L1 expression on T and B cells from older HD, which is even more pronounced on CLL patients, suggests that impaired immune functions may in part be due to the inhibitory immune checkpoint expression. Current investigations are examining the role of FOXP1 in T and B cell functionality and immune checkpoint molecule expression with age.

**Keywords:** chronic lymphocytic leukemia (CLL); PD-1; PD-L1.

## 333
### THE IMPACTS OF ZANUBRUTINIB ON IMMUNE CELLS IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA

Y. Zou | H. Zhu | X. Li | Y. Xia | K. Miao |

S. Zhao | Y. Wu | L. Wang | W. Xu | J. Li

*Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China*

**Introduction:** Ibrutinib, a first-generation Bruton tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second-generation BTK inhibitor, has similar effects as ibrutinib remains to be determined.

**Methods:** Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests.

<footnote n="1">¹Hematology, Institut Jules Bordet, ULB, Brussels, Belgium; ²Molecular Immunology Unit, Institut Jules Bordet, ULB, Brussels, Belgium; ³Breast Cancer Translational Research Laboratory, Institut Jules Bordet, ULB, Brussels, Belgium; ⁴Flow Cytometry Core Facility, Institut Jules Bordet, ULB, Brussels, Belgium</footnote>
**Results:** The expression intensity of programmed cell death protein 1 (PD-1) on total CD4⁺, total CD8⁺ and T helper cells, and cytotoxic T lymphocyte-associated antigen-4 on total CD4⁺ (P=0.010) and regulatory T cells (P<0.05) reduced after treatment (P<0.05). There were significant differences in expression intensity of CD19 (P<0.01), C-X-C chemokine receptor type 5 (CXCR5) (P<0.01) and CD49d (P<0.05) on B cells before and after treatment. Down-regulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. The number of B cells and programmed death-ligand 1 expression down-regulated, especially in the young, CLL, normal spleen, normal β2-macroglobulin (β2-MG), abnormal lactate dehydrogenase (LDH) and normal *tumor protein 53* subgroups, while CD49d expression tended to decrease in the male, old, CLL, splenomegaly, abnormal β2-MG and abnormal LDH subgroups after zanubrutinib treatment.

**Conclusions:** These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through down-regulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors.

**Keywords:** BTK inhibitors; chronic lymphocytic leukemia (CLL); immunophenotype.

334

REAL WORLD OUTCOMES OF
OBINUTUZUMAB MONOTHERAPY IN
PATIENTS WITH CHRONIC LYMPHOCYTIC
LEUKEMIA

M.E. Hughes

C. Suen

E. Namoglu

S.J. Schuster

J. Svoboda

D.J. Landsburg

J. Rhodes

A. Loren

E. Stadtmauer

S.D. Nasta

Lymphoma Department, University of Pennsylvania, Philadelphia, United States

**Introduction:** Obinutuzumab (OBI) is approved for use in combination with chlorambucil for patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in both frontline and relapsed/refractory (r/r) settings. OBI has been successfully evaluated as a single agent without significant loss of efficacy (Gay ND, Leuk. Lymphoma 2018). We performed an analysis of all CLL/SLL pts treated with OBI monotherapy at our institution to assess efficacy and safety in any line of therapy.

**Methods:** We conducted a retrospective cohort study of all adult pts who received OBI monotherapy for CLL at the University of Pennsylvania between 2/2013 and 2/2019. Demographics, duration of therapy, reason for discontinuation, overall response, survival, and toxicities were examined. The primary endpoints were progression-free survival (PFS; defined as time from OBI start to disease progression or regimen change, death due to CLL or last-follow-up in remission), and overall survival using the Kaplan-Meier method.

**Results:** We identified 40 pts with CLL/SLL for this analysis. Median age of start was 70 years, Rai stage 2 (35% ≥3), and ECOG performance status 1. Most pts were rituximab naïve (58%) and 20% were rituximab refractory. Frontline use was seen in 53% of pts received OBI frontline and 47% were treated for r/r disease. 9 pts were documented with progression and 4 patients met indication for subsequent therapy. At this time, 7 pts are receiving active OBI treatment. 55% of pts followed the package insert recommended schedule of OBI administration. Overall response rate was 90% (10% CR). The median PFS and OS for the entire cohort was 11.5 and 16.5 months respectively.

At least 1 adverse events (AEs) occurred in 90% of pts. AEs included infusion related reactions (63%), thrombocytopenia (43%), infection (23%), neutropenia (15%), diarrhea (10%), neutropenic fever (8%). All pts with infusion reactions experienced symptoms on the first dose (92% grade 2; 8% grade 3), with 6 pts experiencing more than one infusion reaction in the first cycle. One patient stopped therapy after experiencing a severe grade 3 infusion reaction. One patient had an opportunistic infection (Rhizopus sp.).

**Conclusions:** We describe our experience using OBI as monotherapy. AEs, while expected and manageable, were observed frequently in our

<figure><img src="image_198.png" /></figure>
cohort, suggesting potential overlap with immunodeficiency seen with CLL/SLL pts. Most surprisingly is the high rate of infusion related reactions; however, these were mainly confined to grade 2 reactions and grade 3 reactions were much lower than in the CLL11 trial (Goede V, NEJM 2014). While PFS is shorter compared to CLL11, this reflects both pts not completing therapy, as well as including pts in the r/r setting. Regardless, OBI remains an effective and well tolerated agent in both frontline and r/r pts with CLL/SLL who may not be eligible for other therapies.

**Keywords:** chronic lymphocytic leukemia (CLL); ibutinuzumab.

**Disclosures:** Hughes, M: Consultant Advisory Role: AstraZeneca; Research Funding: Acerta Pharma. Schuster, S: Consultant Advisory Role: Novartis, Nordic Nanovector, Celgene, Merck, Gilead, Pfizer; JS: BMS, Seattle Genetics, KITE, Kyowa, Pharmacyclics; Honoraria: SJS: Genentech, Novartis, Nordic Nanovector, Celgene, Merck, OncLive, Dava Oncology, Physician's Education Source, LLC; Research Funding: SJS: Genentech, Novartis, Nordic Nanovector, Celgene, Merck, OncLive, Dava Oncology, Physician's Education Source, LLC. Svoboda, J: Consultant Advisory Role: BMS, Seattle Genetics, KITE, Kyowa, Pharmacyclics; Research Funding: BMS, Regeneron, Merck, Seattle Genetics, TG Therapeutics, Pharmacyclics. Landsburg, D: Consultant Advisory Role: Celgene, Curis; Research Funding: Triphase, Takeda, Curis. Stadtmauer, E: Consultant Advisory Role: Celgene, Janssen; Research Funding: Abbvie. Nasta, S: Consultant Advisory Role: Celgene; Research Funding: Pharmacyclics, Incyte, Roche, Aileron, Rafael/WF, Debiopharm, Takeda/Millenium; Other Remuneration: Merck: DSMC.

## 335
### ROLE OF CHLORAMBUCIL IN COMBINATION OR NOT WITH ANTI-CD20 AS FRONTLINE THERAPY IN CHRONIC LYMPHOCYTIC LEUKEMIA IN "REAL LIFE"

A. Santamaria Lopez

E. Perez Persona

L. Cuevas Palomares

I. Oiartzabal Ormategui

A. Unamunzaga Cilaurren

I. Parra Salinas

D. Robles de Castro

C. De Miguel Sánchez

M. Gabilondo Jalón

C. Pisón Herrero

G. Mendez Navarro

A. Vega Gonzalez de Viñaspe

J. Guinea de Castro

Hematology, Hospital Universitario de Alava, Vitoria Gasteiz, Spain

**Introduction:** Recently, different studies have shown superiority of ibrutinib in progression-free survival (PFS) over chlorambucil or chlorambucil in combination anti-CD20 in the treatment of chronic lymphocytic leukemia (CLL) in first line. Some guidelines consider that the role of chlorambucil is obsolete. However, despite superiority in PFS, no benefit in overall survival (OS) has been observed. Moreover, anti-CD20 chlorambucil combination has been used in population with comorbidities in which life expectancy, either by age or comorbidities, is short. Therefore, the benefit of ibrutinib in this

<table><caption>TABLE 1 General characteristics of the patients</caption><tbody><tr><td>TOTAL PATIENTS</td><td>n=20</td></tr><tr><td>Sex (M/F)</td><td>80/20</td></tr><tr><td>CIRS ≥6</td><td>15 (75%)</td></tr><tr><td>Binet C</td><td>7 (35%)</td></tr><tr><td>FISH:</td><td></td></tr><tr><td>13q-</td><td>8 (40%)</td></tr><tr><td>+12</td><td>4 (20%)</td></tr><tr><td>11q-</td><td>1 (in combination with 13q-)</td></tr><tr><td>17p-</td><td>0</td></tr><tr><td>No aberrations</td><td>1 (5%)</td></tr><tr><td>Not done</td><td>7 (35%)</td></tr><tr><td>First line therapy:</td><td></td></tr><tr><td>- Clorambucil (Cl)</td><td>2 (10%)</td></tr><tr><td>- Rituximab + Cl</td><td>11 (55%)</td></tr><tr><td>- Obinotuzumab + Cl</td><td>7 (35%)</td></tr><tr><td>DEAD PATIENTS</td><td>n=10</td></tr><tr><td>Desease statys at time of dead:</td><td></td></tr><tr><td>- Active</td><td>5 (50%)</td></tr><tr><td>- In progression</td><td>2 (20%)</td></tr><tr><td>- Complete remission</td><td>3 (30%)</td></tr></tbody></table>

population is controversial, in addition to an exponential increase in drug cost.

**Aims:** Analyze characteristics and the evolution of patients diagnosed of CLL treated with chlorambucil in monotherapy or in combination with antiCD20 in first line, in real life.

**Methods:** A retrospective study of patients with CLL in University Hospital of Alava, between January 2012-2019, whose frontline therapy is chlorambucil in monotherapy or in combination with antiCD20. Comorbidities were assessed using the CIRS scale (Cumulative Illness Rating Scale for Geriatrics), and time to next treatment (TTNT), OS and disease status at the time of death were also recorded.

**Results:** 16 men and 4 women were included, with a median age of 81 years (75-86) and a median CIRS score of 7 (2-15), additional characteristics are shown in table 1. With a median follow-up of 35 months, the PFS was 30 months, while the median TTNT was 40 months and OS was 59 months (figure 1). It should be noted that 7 of the 10 patients died without receiving a second line therapy, although 70% of them had active disease at the time of death. The cause of death were: infections (3), pulmonary thromboembolism (1), sudden death (1), progression to acute leukemia (1) and uncontrolled primary immune thrombocytopenia and hemolityc anemia.

**Conclusions:** In our setting, CLL patients requiring treatment with Chlorambucil +/- antiCD20 are older and have more comorbidities than patients reported in the published clinical trials. 70% of patients died without requiring a second line therapy. Therefore, in terms of therapeutic efficiency and also regarding pharmaco-economy, chlorambucil-antiCD20 continues to be a valid alternative in unfit patients.
<figure><img src="image_199.png" /><figcaption>**Figure 1.**</figcaption></figure>

Keywords: chlorambucil; chronic lymphocytic leukemia (CLL).

336

A PHASE II TRIAL TO EVALUATE THE
EFFICACY AND SAFETY OF THE
COMBINATION OF OBINUTUZUMAB
BENDAMUSTINE TREATMENT IN
PATIENTS WITH RELAPSED /REFRACTORY
CHRONIC LYMPHOCYTIC LEUKEMIA

J. García-Marco<fnref n="1" /> | P. Baltasar Tello² |

E. Gonzalez Garcia³ | E. Ríos Herranz⁴ |

Á. Ramírez Payer⁵ | M. Terol Castera⁶ | D. Champ⁷ |

Á. Medina Pérez⁸ | M. Gironella Mesa⁹ |

A. Rodríguez Fernández¹⁰ | A. Muntañola Prat¹¹ |

A. Suárez Cabrera¹² | J. Puerta Puerta¹³ |

M. Fernández Zarzoso¹⁴ | M. Rodríguez Calvillo¹⁵ |

J. Clavel Piá¹⁶ | V. Dourdil Sahun¹⁷ | C. Ferrá Coll¹⁸ |

E. Pérez Persona¹⁹ | C. Marrero Santos²⁰ |

R. Forés Cachón²¹ | J. Delgado González²²

<footnote n="1">¹Molecular Cytogenetic Unit, Hospital Universitario Puerta de Hierro de Majadahonda, Madrid, Spain; ²Haematological Service, Hospital Universitario la Paz, Madrid, Spain; ³Haematological Service, Hospital</footnote>
<figure><img src="image_200.png" /><figcaption>**Figure 1.** Progression free survival (A), overall survival (B), response duration (C) and time to re-treatment (D).</figcaption></figure>

Universitario de Cabueñes, Gijón, Asturias, Spain; ⁴Haematological Service, Hospital Universitario Nuestra Señora de Valme, Sevilla, Spain;

⁵Haematological Service, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain; ⁶Hematology and Medical Oncology

Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; ⁷Hematology and Skin Disease Area, Roche Farma S.A., Madrid, Spain;

⁸Haematological Service, Hospital Costa del Sol, Marbella, Málaga, Spain;

⁹Haematological Service, Hospital Universitario Vall d'Hebron, Barcelona, Spain; ¹⁰Haematology Unit, Hospital Universitario Virgen Macarena, Sevilla, Spain; ¹¹Clinical Haematology, Hospital Universitari Mútua

Terrassa, Terrassa, Barcelona, Spain; ¹²Haematology, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain; ¹³Haematology, Hospital Universitario Virgen de las Nieves,

Granada, Spain; ¹⁴Haematology-Haemotherapy, Hospital Universitario Dr. Peset, Valencia, Spain; ¹⁵Haematological Service, Hospital de

Navarra, Pamplona, Navarra, Spain; ¹⁶Haematological Service, Hospital General de Castellón, Castelló, Castelló de la Plana, Spain;

¹⁷Haematological Service, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain; ¹⁸Clinical Hematology, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain; ¹⁹Haematological Service, Hospital de

Txagorritxu, Vitoria-Gasteiz, Álava, Spain; ²⁰Haematological Service, Complejo Hospitalario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain; ²¹Haematological Service, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain; ²²Haematological Service, Hospital Clínic de Barcelona, Barcelona, Spain

**Introduction and objective:** The use of combined rituximab(R)-bendamustine(B) has shown to be effective in terms of overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) in pts with relapsed/refractory (R/R) CLL. Based on the enhanced in vitro and in vivo anti-CLL activity of obinutuzumab (Obi) compared to R, we designed this study to evaluate the efficacy of Obi with B in patients (pts) with R/R CLL.

**Methods:** Between April 2014 and April 2017, 72 adult pts with R/R CD20+ CLL and active disease were included in this prospective, multicenter, non-comparative, phase II study. Pts received up to six-28-day cycles of treatment: intravenous (IV) infusion of Obi (1000 mg) on Days 1, 8, and 15 of Cycle 1 and on Day 1 of subsequent cycles, and B (70 mg/m²) by IV infusion on days 2 and 3 of Cycle 1 and on
Days 1 and 2 of subsequent cycles. The primary endpoint was ORR; secondary endpoints: best response rate, OS and PFS, response duration (RD) and minimal residual disease (MRD) rate (flow cytometry; sensitivity: 1 CLL cell in $10^{-4}$ leucocytes). We present the results of an interim analysis at 17 months of last Obi-B cycle with the data cut-off date of 22nd March 2018.

**Results:** Pts were mostly male (66.7%), with a median age of 67.9 years and ECOG 0 in 62.5% of them. RAI clinical stage was 0-II in 52.7% pts and III-IV in 47.3% pts. Expression of CD38 (>30%), CD49D (>20%), ZAP-70 (>20%) was seen in 15.3%, 55.6%, and 39.4% of pts respectively, and IGHV unmutated in 75.0% of pts. Genetic abnormalities detected were: del13q(43.1%), trisomy 12(19.4%), del11q/ATMmutation(43.1%), del17p/p53mutation (26.4%), mutations of BIRC3(2.8%), SF3B1(8.3%) and NOTCH1 (20.8%). Out of 72 enrolled pts, 80.6% and 79.2% completed 6 cycles of treatment with Obi and B respectively. Median treatment duration was 4.9 months and discontinuation rates due to adverse events were 16.7% (Obi) and 18.1% (B). Obi and B doses were modified in 75% and 54.2% of pts, respectively. ORR was 76.4% (CR 27.8%, CRi 8.3% and PR 40.3%), PD (4.2%) and SD (8.3%). After a median follow-up of 23.6 months, median RD and PFS (Fig 1.) were 8.1 and 24.1 months, respectively and median OS was not reached. PFS and OS (Fig. 1) were significantly higher (p<0.001) in pts with negative MRD, mutated IGHV and no p53 aberrations in peripheral blood. Median time to re-treatment was 33.9 months. 64 pts (88.9%) presented at least 1 toxicity, being the most common grade 3/4 neutropenia (52.8%) and thrombocytopenia (20.9%). Two deaths occurred due to toxicities (acute myeloid leukemia and septic shock).

**Conclusions:** This preliminary analysis anticipates that the combination of obinutuzumab with bendamustine is feasible, effective and well-tolerated in relapsed/refractory CLL. Achievement of MRD negativity in peripheral blood correlates with a longer PFS and OS regardless of clinical response and cytogenetic abnormalities.

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

**Disclosures:** García-Marco, J: Consultant Advisory Role: Mundipharma, Glaxo, AbbVie, Roche, Gilead and Janssen and research support from Hoffman-La Roche and Janssen. Baltasar Tello, P: Consultant Advisory Role: AbbVie, Roche, Gilead and Janssen. Ríos Herranz, E: Consultant Advisory Role: Janssen; Honoraria: Roche, Janssen y Abbvie. Terol Castera, M: Consultant Advisory Role: AbbVie; Honoraria: Takeda, AbbVie, Roche and Janssen; Research Funding: Roche and Janssen. Champ, D: Employment Leadership Position: Roche Farma S.A. Puerta Puerta, J: Consultant Advisory Role: Roche, AbbVie and Janssen.

D.A. Bond¹ | Y. Huang¹ | J. Fisher² | A. Ruppert¹ |

D. Owen³ | E. Bertino³ | K. Rogers¹ | S. Bhat¹ |

S. Jaglowski¹ | M. Grever¹ | J. Byrd¹ |

K. Maddocks¹ | J. Woyach¹

¹Division of Hematology, Ohio State University Comprehensive Cancer Center, Columbus, United States; ²Division of Epidemiology, The Ohio State University, Columbus, United States; ³Division of Oncology, Ohio State Comprehensive Cancer Center, Columbus, United States

**Background:** Patients (pts) with chronic lymphocytic leukemia (CLL) suffer morbidity and mortality from CLL and increased risk for second primary neoplasia (SPN). BTK inhibitors (BTKi) are highly effective for the treatment of CLL and are associated with partial restoration of immune function with ongoing treatment. The impact of BTKi on the risk for and patterns of SPN is yet to be characterized.

**Methods:** CLL pts treated with ibrutinib or acalabrutinib at our center were identified retrospectively. Baseline and outcome data were collected including incidence of Richter's transformation (RT), non-melanoma skin cancer (NMSC), and SPN.

Standard incidence ratio (SIR) with 95% confidence intervals (CI) were calculated using expected incidence rates from the Surveillance, Epidemiology, and End Results Program (SEER), assuming a Poisson distribution for the observed incidence. Cumulative incidence rate (CIR) of SPN (excluding RT and NMSC) was calculated from BTKi start date to the diagnosis of SPN; death was a competing risk and pts without event were censored at last follow-up. SPN was correlated with baseline data using the Fine-Gray model.

**Results:** 691 pts were included; the median age was 64 years, median prior lines of treatment was 2 (20% treatment-naïve, 66% with prior chemo-immunotherapy), and 56% were never smokers. At a median follow-up of 44 months, 68 pts (10%) were diagnosed with SPN (SIR 2.4, CI 1.9-3.0) including 13 lung (SIR 3.2, CI 1.7-5.5), 9 melanoma (SIR 6.9, CI 3.1-13), 9 prostate (SIR 1.4, CI 0.6-2.6), 7 bladder (SIR 5.2, CI 2.1-10.6), 4 breast (SIR 1.7, CI 0.5-4.5), and 3 kidney cancers (SIR 2.9, CI 0.6-8.5). CIR of SPN at 3 year was 7.6% (Table). Smoking (hazard ratio (HR) 2.9, CI 1.7-5.0, p<.01) and low baseline CD8 count (HR 0.9 for 2-fold increase, CI 0.8-0.9, p<.01) were associated with higher incidence of SPN. RT was diagnosed in 58 pts (8%) and NMSC in 138 pts (20%). 179 pts had died with 3 year overall survival of 79% (CI 76-82); the most common causes of death were CLL/RT (57%) and SPN (13%).

**Conclusions:** The incidence of SPN in pts treated with BTKi for CLL is increased relative to the general population. With a 5 year CIR of NMSC and SPN of 23% and 12% respectively, these data support consideration of intensive cancer screening for CLL pts receiving BTKi.

**Keywords:** BTK inhibitors; chronic lymphocytic leukemia (CLL).

**Disclosures:** Owen, D: Consultant Advisory Role: Astra Zeneca, L&M Policy Research; Research Funding: Bristol-Myers Squibb, Merck Sharp & Dohme, Genentech/Roche, Palobiofarma. Bertino, E: Consultant Advisory Role: Boehringer Ingelheim. Rogers, K: Consultant
<table><caption>TABLE 1 CIR of Second Cancers</caption><thead><tr><th></th><th>NMSC % (95% CI)</th><th>Other SPN (95% CI)</th></tr></thead><tbody><tr><td>1 year</td><td>7.5 (5.8-9.7)</td><td>2.1 (1.2-3.4)</td></tr><tr><td>3 year</td><td>15.6 (12.8-18.5)</td><td>7.6 (5.7-9.9)</td></tr><tr><td>5 year</td><td>23.0 (19.2-27.1)</td><td>11.5 (8.7-14.8)</td></tr></tbody></table>

Advisory Role: Acerta Pharma; Research Funding: Genentech, Abbvie. Bhat, S: Other Remuneration: Speakers Bureau: Janssen, Pharmacyclics. Jaglowski, S: Consultant Advisory Role: Kite Pharma, Juno Therapeutics, Novartis; Other Remuneration: Patents, Royalties, Other Intellectual Property: Pharmacyclics; Speakers Bureau: E-squared Communication. Grever, M: Consultant Advisory Role: Pharmacyclics; Research Funding: Astra Zeneca. Byrd, J: Consultant Advisory Role: Pharmacyclics, Acerta Pharma, Genentech, Jazz Pharmaceuticals; Research Funding: Janssen, Pharmacyclics, Genentech, Acerta Pharma.

Figure: Cumulative Incidence of Second Cancer

<figure><img src="image_201.png" /></figure>

**Maddocks, K:** Honoraria: Pharmacyclics, Bayer, Novartis, Teva; Research Funding: Pharmacyclics, Britsol-Myers Squibb, Merck. **Woyach, J:** Consultant Advisory Role: Pharmacyclics, Janssen China R&D; Research Funding: Pharmacyclics, Janssen China R&D, Loxo, Abbvie, MorphoSys, Karyopharm Therapeutics.

338
ANTICOAGULANT THERAPY IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA RECEIVING IBRUTINIB

G.E. Gendlin

E.I. Emelina

I.G. Nikitin

Hospital Therapy N°2, Pirogov Russian National Research Medical University, Moscow, Russian Federation

**Introduction:** The use of new oral anticoagulants (NOAC) in patients with chronic lymphocytic leukemia (CLL) is a difficult task due to the high risk of hemorrhagic complications in these patients associated with the course of CLL. The use of highly effective targeted therapy with ibrutinib (Ib), which affects platelet function, creates an additional risk of bleeding. It is important to assess the use of NOAC in CLL patients receiving Ib, taking into account the frequency and severity of hemorrhagic manifestations, the need to cancel, reduce the dose and replace with another NOAC.

**Methods:** We have examined and observed in the dynamics of 197 patients with CLL who received Ib from 5 to 56 months at a dose of 420 mg per day as 1, 2, 3, and 4 lines of CLL therapy. We included patients with CLL aged 32 to 91 years (66.0 (59.0-72.0) years), of which 70 women aged 39 to 83 years (64.0 (54.0-71.0) years) and 127 men aged from 32 to 91 years (66.0 (60.0-72.0) years). All occurring hemorrhagic manifestations were evaluated in patients receiving Ib and NOAC, taking into account the glomerular filtration rate (GFR) and the level of platelets.

**Results:** The need for NOAC occurred in patients with CLL and atrial fibrillation (AF) (n = 34). Rivaroxaban (n = 16), dabigatran (n = 6), apixaban (n = 12) were prescribed. Hemorrhagic manifestations were observed in 53.6% of patients receiving NOAC and Ib. They were hematomas (n = 12), petechiae (n = 3), nasal (n = 4) and gingival (n = 2) bleedings, hemorrhage into the anterior chamber of the eye (n = 1), gross hematuria (n = 3). A combination of several hemorrhagic manifestations was observed in 40% of CLL patients receiving NOAC. In 4 patients who received rivaroxaban in a dose of 20 mg it was changed to the minimum effective dose of apixaban 2, 5 mg twice a day, due to the development of recurrent nasal bleeding, gross hematuria, large recurrent hematomas. NOAC (rivaroxaban 20 mg per day) was canceled in 6 patients due to the development of thrombocytopenia (less than 100 * 10⁹ / l). In 1 patient, the cancellation of NOAC was due to recurrent gross hematuria, developed on rivaroxaban 20 mg and 15 mg per day and apixaban 2, 5 mg twice a day. We did not reveal significant differences in platelet count indices in groups of patients with and without hemorrhages. In
12 patients receiving rivaroxaban 20 mg once a day (n = 6), dabigatran 150 mg twice a day (n = 2), apixaban 5 mg twice a day (n = 4) for periods ranging from 9 to 25 months with Ib therapy no hemorrhagic manifestations have been observed.

**Conclusions:** Hemorrhagic manifestations occurring in CLL patients receiving NOAC and Ib treatment were not life-threatening, in most cases did not require the abolition of NOAC and a dose reduction of Ib. The development of thrombocytopenia was the main reason for the abolition of NOAC in patients with CLL.

**Keywords:** chronic lymphocytic leukemia (CLL); ibrutinib.

339
# IBRUTINIB ABOVE 79 YEARS OLD FOR CHRONIC LYMPHOCYTIC LEUKEMIA: IMPORTANT TOXICITIES

A. Calleja<fnref n="1" /> | B. Branco² | A. Teste³ | F. Bijou⁴ |

A. Clavert⁵ | A. Brion⁶ | K. Laribi⁷ | L. Oberic² |

R. Guieze³ | A. Michallet⁸ | L. Ysebaert²

**Introduction:** Ibrutinib, covalent inhibitor of bruton tyrosine kinase, is approved for the treatment of 1L and R/R Chronic Lymphocytic Leukemia (CLL). Older patients are more likely to suffer from comorbidities putatively compromising both tolerance and outcomes, but were mostly not represented in pivotal registration trials.

**Methods:** We sought to determine efficacy and tolerance of ibrutinib in a series of 350 cases, including 92 patients over 79y with 1L or R/R CLL, with at least one year of clinical follow-up, in eight French Centers. We studied overall survival (OS), rate of patients on-therapy at 1 year, and causes of death/drug withdrawal. We next compared these result to patients receiving ibrutinib for a Waldenstrom macroglobulinemia (WM) or mantle cell lymphoma (MCL) aged 79+ years.

**Results:** 92 patients with CLL were included, with a FU of 12-50 months, median age was 81 y, 68% were males, median number of previous lines was 2, and 55% presented del17p/mutated TP53 status. At the last FU, 53% of patients had stopped ibrutinib (vs 38% in the <79y population), including 60% during the first year. We noticed that 50% of patients needed a dose reduction to manage toxicities. Reasons for permanent drug discontinuations were: toxicities (66%), disease progression (28%), and secondary cancer (6%). Out of 35 deaths, main causes were toxicities (58%, including infection (18 patients) and cardiovascular events (2 patients)), followed by disease progression (34%) and secondary cancer (5%).

These toxicity/OS outcomes are similar to a series of patients with similar age receiving ibrutinib for other lymphoma entities. 37 patients with lymphoma (6 WM, 31 MCL) were included, median age was 83y. As is CLL we observed ibrutinib discontinuation in 67% of patient (half during the first year). Out of 24 deaths, main causes were also toxicities (13 patients) and disease progression (11 patients).

KM curves showed that patients >82y had a statistically inferior median OS of 18 months, and that median OS of <79y versus 79-82y were comparable.

**Conclusions:** In very elderly patients (> 79y) from our retrospective cohort, tolerance profile of ibrutinib precluded long term exposure. Only 50% of patients are treated more than one year, and therefore this drug did not meaningfully impact OS above 82y. Comprehensive geriatric assessment should be performed to evaluate life expectancy before initiating ibrutinib.

**Keywords:** chronic lymphocytic leukemia (CLL); elderly; ibrutinib.

340
# USING BTK INHIBITORS FOR CHRONIC LYMPHOCYTIC LEUKEMIA: ONLINE EDUCATION SIGNIFICANTLY IMPROVED THE KNOWLEDGE AND COMPETENCE OF HEMATOLOGISTS/ONCOLOGISTS

L. Willis | M. Tanzola

Medscape, LLC, Oncology, New York, United States

**Introduction:** Chronic lymphocytic leukemia (CLL), a type of non-Hodgkin lymphoma, is the most common type of leukemia in adults and can be indolent or aggressive in nature. Hematologists/oncologists (hem/oncs) need to be competent treating this disease in order to optimize patient outcomes. The goal of this initiative was to determine if online education could improve hem/onc knowledge and competence using BTK inhibitors (BTKi) to treat CLL.

**Methods:** The format was an online continuing medical education (CME)-certified activity consisting of a 30-minute video in which 2 expert faculty discussed use of BTKi in CLL. Evidence-based educational feedback was provided following each response. Three multiple-choice competence questions and 1 self-efficacy question were selected from the set of intra-activity questions to be repeated immediately after activity participation. Questions assessed the impact of the education with a repeated pairs pre-assessment/post-assessment study design where each participant served as his/her own control. A chi-square test was used to identify differences between pre- and post-assessment responses. P values were calculated; those < 0.05 were considered statistically significant. The activity launched online Sept 24, 2018 and data were collected through Mar 15, 2019.

**Results:** Results are for those who have completed the pre- and post-assessment questions during the study period (n = 109 hem/oncs).

<footnote n="1">¹Hematology Department, CHU Nice, Nice, France; ²Hematology Department, Institut Universitaire Cancérologie Toulouse-Oncopole, Toulouse, France; ³Hematology Department, CHU Estaing, Clermont-Ferrand, France; ⁴Hematology Department, Institut Bergonie, Bordeaux, France; ⁵Hematology Department, CHU Angers, Angers Cedex 9, France; ⁶Hematology Department, Chru Jean Minjoz, Besançon, France; ⁷Hematology Laboratory, CH Le Mans, Le Mans Cedex 9, France; ⁸Hematology Department, Centre Léon Berrard, Lyon, France</footnote>
Upon completion of the activity, an improvement from pre- to post-assessment was observed in the hem/oncs ability to:

* Determine which patients with relapsed/refractory (R/R) CLL would candidates for acalabrutinib (45% vs 73%, P < .001)

* Recognize the typical presentation of treatment-related adverse effects (TRAEs) with ibrutinib (41% vs 63%, P < 0.001)

* Identify the timeframe that BTK and PCLG2 mutations can become detectable before onset of clinical relapse in patients with CLL receiving ibrutinib (55% vs 77%, P < 0.001)

* Report greater confidence incorporating BTKi in the treatment of patients with B-cell malignancies (total average confidence shift: increase of 15.7%)

**Conclusions:** This online, interactive, CME-certified educational activity led to statistically significant improvements in the knowledge of hem/oncs about TRAEs of BTKi and the relationship of mutations that can precede clinical relapse. Additionally, a statistically significant gain in competence was seen with hem/oncs ability to select patients with R/R CLL who would be candidates for acalabrutinib. The education also increased hem/onc confidence incorporating BTKi into the treatment of patients with B-cell malignancies. The results indicate that unique educational methodologies and platforms, which are available on-demand, can be effective tools for advancing clinical decision making. Additional studies are needed to assess whether improved attitude translates to improved performance during clinical practice.

**Keywords:** acalabrutinib; chronic lymphocytic leukemia (CLL); ibrutinib.

## 341
# IDELALISIB PLUS ANTI-CD20 USED SECOND LINE SHOWS IMPROVED PFS AND COMPARABLE SAFETY COMPARED TO LATER LINE THERAPY OF RELAPSED CLL

J.R. Brown<fnref n="1" /> | R.J. Chan² | G. Xing³ | P. Bhargava² |

B. Ruzicka² | S.M. O'Brien⁴

**Introduction:** Idelalisib (IDELA) is a first-in-class PI3Kδ inhibitor approved for use in combination with rituximab or ofatumumab for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL). Increased incidence of serious adverse events (AEs) observed in the treatment naïve setting has produced a prevailing view that early line use of IDELA may also lead to inferior clinical

outcomes. To address this question, we evaluated the clinical benefit: risk balance for IDELA in early vs. later lines of use in the relapsed setting.

**Methods:** Using clinical outcomes data collected in Gilead-sponsored trials of patients with R/R CLL treated with IDELA + α-CD20 (N=110, Furman et al., N. Engl. J. Med. 2014 and N=173, Jones et al., Lancet Haematol. 2017), we retrospectively compared the overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and AE profile for patients previously treated with 1 prior regimen (IDELA given in the second line setting, 2L), 2 prior regimens (3L), or ≥3 prior regimens (≥4L). PFS and OS were estimated using the Kaplan-Meier method and groups were compared using a log-rank test. The incidence of AEs was compared using the Kruskal Wallis test.

**Results:** Among 283 patients treated with IDELA + α-CD20, 49 (17.3%) received IDELA 2L, 69 (24.4%) received it 3L, and 165 (58.3%) received it ≥4L. Patient characteristics were similar except that patients in the ≥4L group presented with Rai stage III/IV disease more frequently compared to the 2L and 3L groups (70.3% vs. 61.3% and 57.9%, respectively). ORR was similar irrespective of the number of prior regimens (85.7% for the 2L group, 73.9% for the 3L group, and 80% for the ≥4L group, p=0.2866); however, PFS and OS were longer in the 2L group compared to the 3L and ≥4L groups (median PFS= 31.5 months, 16.6 months, and 17.3 months, respectively, [Figure 1] and median OS=47.4 months, not reached (NR), and 34.6 months, respectively). No statistically significant difference was observed across treatment setting groups in the incidence of key treatment-emergent AEs, including cough, diarrhea, infection, transaminitis, and colitis.

**Conclusion:** These analyses indicate that patients with R/R CLL experience comparable or improved efficacy and have a similar safety profile when IDELA + α-CD20 regimens are used 2^nd^ line compared to later lines, after chemo-immunotherapeutic regimens. Longer PFS and OS for patients treated with IDELA in the 2L may reflect shorter time since diagnosis, lower stage disease, or less disease resistance, but also suggest that the efficacy benefit is greater and may better offset potential toxicity in this patient sub-group. These findings support the use of IDELA + α-CD20 in the 2L+ setting for patients with R/R CLL following chemo-immunotherapy.

**Keywords:** chronic lymphocytic leukemia (CLL); idelalisib; PI3K/AKT/mTOR.

**Disclosures:** Brown, J: Consultant Advisory Role: Abbvie, Acerta, Beigene, Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, Novartis, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, Verastem; Honoraria: Janssen and Teva; Research Funding: Gilead, Loxo, Sun and Verastem; Other Remuneration: Morphosys and Invectys. Chan, R: Employment Leadership Position: Gilead; Stock Ownership: Gilead. Xing, G: Employment Leadership Position: Gilead; Stock Ownership: Gilead. Bhargava, P: Employment Leadership Position: Gilead; Stock Ownership: Gilead. Ruzicka, B: Employment Leadership Position: Gilead; Stock Ownership: Gilead. O'Brien, S: Consultant Advisory Role: Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Gilead, Pharmacyclics, TG

<footnote n="1">¹Department of Medical Oncology, Dana-Farber Cancer Institute, Newton, United States; ²Medical Affairs, Gilead Sciences, Inc., Foster City, United States; ³Biostatistics, Gilead Sciences, Inc., Seattle, United States; ⁴Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, United States</footnote>
<figure><img src="image_202.png" /></figure>

Therapeutics, Pfizer, Sunesis; Research Funding: Kite, Regeneron, Acerta, Gilead, Pharmaceutics, TG Therapeutics, Pfizer, Sunesis.

## INDOLENT LYMPHOMA

### 342
CLINICAL OUTCOMES OF PATIENTS WITH INTERMEDIATE-TO-HIGH-RISK FOLLICULAR LYMPHOMA (FL) IN THE GALLIUM PHASE III STUDY

A. Launonen¹ | C. Casulo² | C. Pott³ | C. Rusconi⁴ | J. Hernandez⁵ | A.J. Davies⁶

¹Global Access - Center of Excellence, F. Hoffman La-Roche Ltd, Basel, Switzerland; ²Department of Medicine, Hematology/Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United States; ³Haematology, University Hospital Schleswig-Holstein, Kiel, Germany; ⁴Haematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; ⁵Global Product Development/Medical Affairs, F. Hoffman La-Roche Ltd, Basel, Switzerland; ⁶Cancer Sciences Unit, Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom

**Introduction:** Patients (pts) with a Follicular Lymphoma International Prognostic Index (FLIPI) score of ≥2 represent a subgroup of intermediate-to-high-risk pts in need of better treatment options. We conducted a retrospective analysis to evaluate the clinical outcomes of these pts from the Phase III GALLIUM study (NCT01332968).

**Methods:** Pts (age ≥18 years; advanced disease [stage III/IV or stage II with tumour diameter ≥7cm], ECOG performance status 0-2) with previously untreated FL were randomised to receive either rituximab (R; 375 mg/m² on Day [D] 1 of each cycle) or obinutuzumab (G; 1,000 mg on D1, D8, and D15 of Cycle 1 and D1 of subsequent cycles) in combination with chemotherapy (CHOP, CVP, or bendamustine at the discretion of the investigator site), followed by maintenance with the same antibody for a maximum of 2 years (or until progression of disease [PD]) in pts who achieved at least a partial response at the end of induction therapy. The endpoints of interest for this ad-hoc analysis in the intermediate-to-high-risk FLIPI ≥2 subgroup were investigator-assessed progression-free survival (PFS), overall survival (OS), proportion of patients free of new anti-lymphoma treatment at 4 years, and PD within 24 months (POD24).

**Results:** As of April 2018 (median follow-up of 4.75 years), in the ITT population (n=1202), the estimated PFS hazard ratio (HR) stratified by FLIPI and chemotherapy backbone was 0.73 (95% CI: 0.59-0.90). The treatment effect on PFS appeared to be different between pts with FLIPI <2 and FLIPI ≥2 (interaction test: p=0.02). PFS markedly improved in the FLIPI ≥2 pts (n=952) treated with G-chemo vs R-chemo (HR=0.65 [95% CI: 0.52-0.82]) (Figure). The 4-year OS rate was 91.8% with G-chemo vs 88.7% with R-chemo (HR=0.78 [95% CI: 0.53-1.16]). The proportion of FLIPI ≥2 pts who were free of new anti-lymphoma treatment at 4 years was 81.8% with G-chemo vs 71.2% with R-chemo (HR=0.62 [95% CI: 0.47-0.81]). Fewer POD24 events occurred in FLIPI ≥2 pts treated with G-chemo (43/474; cumulative incidence rate [CIR]: 9.6%)) vs pts treated with R-chemo (85/476; CIR: 18.7%) with a 1-HR based risk reduction of 52.9% (95% CI: 31.9-67.4). The risk of mortality (number of deaths/100 patient-years) following a POD24 event was similar in both arms (17.7 [95%
<figure><img src="image_203.png" /><figcaption>Figure. PFS (investigator assessed) in
FLIPI ≥2 intermediate-to-high-risk pts</figcaption></figure>

CI, confidence interval; FLIPI, Follicular Lymphoma International Prognostic Index; G-chemo, obinutuzumab plus chemotherapy; HR, hazard ratio; PFS, progression-free survival; pts, patients; R-chemo, rituximab plus chemotherapy

CI: 11.5-27.4] vs 17.7 [95% CI: 12.8-24.3], respectively). More FLIPI ≥2 pts experienced Grade ≥3 adverse events [AEs] with G-chemo (79.9%) vs R-chemo (73.1%); the most common was Grade ≥3 infec- tion, which occurred in 20.8% vs 18.9% of pts, respectively. The num- ber of Grade 5 AEs were similar between the G-chemo arm (19 [4.1%]) vs R-chemo (22 [4.6%]).

**Conclusion:** These data suggest that pts with FLIPI ≥2 have a better risk-benefit profile with G-chemo vs R-chemo, than those with FLIPI <2.

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

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

**Disclosures:** Launonen, A: Employment Leadership Position: F. Hoffman La-Roche Ltd; Stock Ownership: Novartis; Other Remuneration: Partner works as a manager at Novartis. Casulo, C: Honoraria: Gilead; Research Funding: Celgene; Other Remuneration: Expenses: Roche, Gilead. Pott, C: Consultant Advisory Role: Roche, Genetech; Honoraria: Roche, Genetech; Research Funding: Roche, Genetech; Other Remuneration: Speakers' Bureau: Roche; Expenses: Roche. Rus-coni, C: Consultant Advisory Role: Takeda, Roche, Celgene, Jannsen; Research Funding: Celgene; Other Remuneration: Expenses: Takeda, Roche. Hernandez, J: Employment Leadership Position: F. Hoffman La-Roche Ltd. Davies, A: Consultant Advisory Role: Roche, Kite, Celgene, Acerta Pharma, MorphoSys, Biolnvent; Honoraria: Roche, Celgene, Kite,

Janssen; Research Funding: Roche, Acerta Pharma, Celgene, Gilead, Karyopharma, GSK; Other Remuneration: Sponsorship to attend confer- ences: Roche, Celgene; Expert Testimony: Roche.

343
EFFICACY AND SAFETY IN HIGH-RISK
RELAPSED OR REFRACTORY INDOLENT
FOLLICULAR LYMPHOMA PATIENTS
TREATED WITH COPANLISIB

M. Dreyling<fnref n="1" /> | A. Santoro² | S. Leppä³ |

J. Demeter⁴ | G.A. Follows⁵ | G. Lenz⁶ |

W.S. Kim⁷ | L. Mollica⁸ | A. Nagler⁹ |

C. Phipps Diong¹⁰ | M. Provencio¹¹ | M. Magagnoli² |

J. Munoz¹² | F. Hiemeyer¹³ | L. Liu¹⁴ |

A. Miriyala¹⁴ | L. Rodrigues¹⁵ | J. Garcia-Vargas¹⁴ |

B.H. Childs¹⁴ | P.L. Zinzani¹⁶

<footnote n="1">¹Department of Medicine III, University Hospital (LMU), Munich, Germany; ²Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy; ³Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; ⁴First Department of Internal Medicine, Semmelweis University, Budapest, Hungary; ⁵Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; ⁶Translational Oncology, University Hospital Münster, Münster, Germany; ⁷Hematology and Oncology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea; ⁸Clinical</footnote>
Research in Hematology and Clinical Oncology, Maisonneuve-Rosemont Hospital Research Centre, Montréal, Quebec, Canada; ⁹Chaim Sheba Medical Center, Tel Aviv University, Tel HaShomer, Israel; ¹⁰Department of Haematology, Singapore General Hospital, Bukit Merah, Singapore; ¹¹Medical Oncology, Health Research Institute, Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, Madrid, Spain; ¹²Hematology and Oncology, Banner MD Anderson Cancer Center Clinic, Gilbert, United States; ¹³Pharmaceutical Division, Bayer AG, Berlin, Germany; ¹⁴Oncology, Bayer HealthCare Pharmaceuticals, Inc., Whippany, United States; ¹⁵Oncology, Bayer SA, São Paulo, Brazil; ¹⁶Institute of Hematology “Seràgnoli”, University of Bologna, Bologna, Italy

**Introduction:** Patients (pts) with follicular lymphoma (FL) who have progression of disease within 24 months of first-line immunochemotherapy (POD24) have worse overall survival (OS). The Phase II CHRONOS-1 study in pts with relapsed or refractory indolent B-cell lymphoma showed durable responses with the intravenous pan-class I phosphatidylinositol 3-kinase inhibitor copanlisib. We explore the outcomes with copanlisib in pts with POD24 in the subset of pts with FL.

**Methods:** Pts with histologically confirmed FL relapsed after or refractory to ≥2 prior lines of treatment, including rituximab and an alkylating agent or regimen (eg R-CHOP), were eligible for the subset analysis. Copanlisib 60 mg was given as a 1-hour infusion on days 1, 8 and 15 of a 28-day cycle. The primary efficacy endpoint was objective response rate per independent assessment after ≥4 cycles. Secondary endpoints included progression-free survival (PFS) and OS. Adverse events (AEs) were reported using MedDRA (v.20.1).

**Results:** 104 pts with FL were treated, with 102 evaluable for POD24: 66.7% with POD <24 months [POD<24] and 33.3% with POD ≥24 months [POD≥24]. R-CHOP was the most common first-line treatment and accounted for 39.7% of pts with POD<24 and 38.2% of pts with POD≥24. The median time from first-line treatment to first POD was 12.0 months in pts with POD<24 and 34.1 months in pts with POD≥24. The median number of lines of prior therapy for both groups was 3.

Responses were similar in both groups (Table), with complete responses exceeding 20% in the POD<24 groups. Median PFS was 11.3 months (range 0-44.2) in pts with POD<24 and 10.8 months (0-35.8) in pts with POD≥24; median OS was 38.3 and 31.0 months, respectively. Results were similar in the FL pts previously treated with R-CHOP (Table).

The median duration of safety follow-up was 7.0 months in pts with POD<24 and 4.7 months in pts with POD≥24. Overall, grade (G) 3 treatment-related AEs were reported in 48.1% of pts, and G4 in 26.0%. Treatment-related serious AEs occurred in 29.8% of pts (15.4% G3; 7.7% G4). There were 3 treatment-related G5 events.

**Conclusions:** This exploratory analysis from the CHRONOS-1 study in relapsed or refractory indolent FL pts having received 2 or more prior lines of therapy demonstrated robust responses in pts with high-risk disease as evidenced by POD24 status on first-line treatment. These

<table><caption>**TABLE 1** Response evaluation in FL patients by independent assessment</caption><thead><tr><th rowspan="3">n (%)</th><th colspan="4">FL patients</th></tr><tr><th colspan="2">Overall (N=102)</th><th colspan="2">R-CHOP subgroup (N=40)</th></tr><tr><th>POD&lt;24 (n=68)</th><th>POD≥24 (n=34)</th><th>POD&lt;24 (n=27)</th><th>POD≥24 (n=13)</th></tr></thead><tbody><tr><td>Complete response</td><td>15 (22.1)</td><td>6 (17.7)</td><td>8 (29.6)</td><td>1 (7.7)</td></tr><tr><td>Partial response</td><td>26 (38.2)</td><td>14 (41.2)</td><td>8 (29.6)</td><td>6 (46.2)</td></tr><tr><td>Stable disease (SD)</td><td>21 (30.9)</td><td>11 (32.4)</td><td>10 (37.0)</td><td>6 (46.2)</td></tr><tr><td>Unconfirmed early SD</td><td>1 (1.5)</td><td>0</td><td>NA</td><td>NA</td></tr><tr><td>Progressive disease</td><td>0</td><td>2 (5.9)</td><td>0</td><td>0</td></tr><tr><td>NA/NE</td><td>5 (7.4)</td><td>1 (2.9)</td><td>1 (3.7)</td><td>0</td></tr><tr><td>Objective response rate</td><td>41 (60.3)</td><td>20 (58.8)</td><td>16 (59.3)</td><td>7 (53.9)</td></tr></tbody></table>

Abbreviations: NA, not available; NE, not evaluable.

results support exploration of copanlisib in combination with chemo-immunotherapy in earlier lines of treatment (NCT02367040; NCT02626455).

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

**Disclosures:** Dreyling, M: Consultant Advisory Role: Acerta, Bayer, Celgene, Gilead, Janssen, Mundipharma, Roche, and Sandoz; Research Funding: Celgene, Janssen, Mundipharma, Roche; Other Remuneration: Bayer, Celgene, Gilead, Janssen, and Roche. Santoro, A: Consultant Advisory Role: BMS, Servier, Gilead, Pfizer, Eisai, Bayer, MSDI, and Arqule; Other Remuneration: Takeda, BMS, Roche, Abb-Vie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer, and MSD. Leppä, S: Consultant Advisory Role: Celgene, Janssen-Cilag, Merck, Novartis, Roche, Takeda; Honoraria: Merck, Roche, Takeda; Research Funding: Bayer, Celgene, Janssen-Cilag, Roche, Takeda. Lenz, G: Consultant Advisory Role: Bayer, Bristol-Myers Squibb, Celgene, Hexal, Johnson & Johnson, Novartis, Roche; Research Funding: AstraZeneca, Bayer, Celgene, Gilead, Johnson & Johnson, Novartis. Kim, W: Consultant Advisory Role: Celltrion; Honoraria: Celltrion; Research Funding: Dong-A, Johnson & Johnson, Kyowa Kirin, Mundipharma, Novartis, Roche, Takeda. Provencio, M: Consultant Advisory Role: BMS, AstraZeneca, MSD, Novartis, Pierre Fabre, Takeda, Roche, Boehringer Ingelheim; Research Funding: Roche, Boehringer Ingelheim; Other Remuneration: BMS, Novartis, Takeda, MSD, BMS, AstraZeneca, MSD, Novartis, Pierre Fabre, Takeda, Roche, Boehringer Ingelheim. Munoz, J: Consultant Advisory Role: Alexion, Bayer, Bristol-Myers Squibb, Genetech, Gilead/Kite Pharma, Juno/Celgene, Kyowa, Pfizer, Pharmacyclics/Janssen; Other Remuneration: AstraZeneca, Bayer, Gilead/Kite Pharma, Pharmacyclics/Janssen. Hiemeyer, F: Employment Leadership Position: Bayer AG. Liu, L: Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. Miriyala, A: Employment
Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. Rodrigues, L: Employment Leadership Position: Bayer SA. Garcia-Vargas, J: Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. Childs, B: Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. Zinzani, P: Consultant Advisory Role: Eusapharma, MSD, Sanofi, BMS, Celgene, Celltrion, Eusapharma, Gilead, Immune Design, Janssen-Cilag, Kyowa Kirin, Portola, Roche, Sandoz, Servier, Verastem; Other Remuneration: BMS, Celgene, Celltrion, Eusapharma, Gilead, Immune Design, Janssen-Cilag, Kyowa Kirin, MSD, Portola, Roche, Servier, Verastem.

344
# SAFETY ANALYSIS OF PATIENTS WITH A MEDICAL HISTORY OF RESPIRATORY DISORDERS TREATED WITH COPANLISIB FROM THE CHRONOS-1 STUDY IN RELAPSED OR REFRACTORY INDOLENT B-CELL LYMPHOMA

P.L. Zinzani¹ | A. Santoro² | S. Leppä³ |

J. Demeter⁴ | G.A. Follows⁵ | G. Lenz⁶ |

W.S. Kim⁷ | L. Mollica⁸ | A. Nagler⁹ |

C. Phipps Diong¹⁰ | M. Provencio¹¹ | M. Magagnoli² |

J. Munoz¹² | A. Miriyala¹³ | L. Liu¹³ | M. Zhang¹³ |

J. Garcia-Vargas¹³ | B.H. Childs¹³ | M. Dreyling¹⁴

¹Institute of Hematology "Serågnoli", University of Bologna, Bologna, Italy; ²Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy; ³Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; ⁴First Department of Internal Medicine, Semmelweis University, Budapest, Hungary; ⁵Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom;

⁶Translational Oncology, University Hospital Münster, Münster, Germany;

⁷Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; ⁸Clinical Research in Hematology and Clinical Oncology, Maisonneuve-Rosemont Hospital Research Centre, Montréal, Quebec, Canada; ⁹Chaim Sheba Medical Center, Tel Aviv University, Tel HaShomer, Israel; ¹⁰Department of Haematology, Singapore General Hospital, Bukit Merah, Singapore; ¹¹Health Research Institute, Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, Madrid, Spain; ¹²Hematology and Oncology, Banner MD Anderson Cancer Center Clinic, Gilbert, United States; ¹³Oncology, Bayer HealthCare Pharmaceuticals, Inc., Whippany, United States;

¹⁴Department of Medicine III, University Hospital (LMU), Munich, Germany

**Introduction:** ESMO guidelines for patients with relapsed follicular lymphoma (FL) state that treatment of patients in the relapsed setting with the phosphatidylinositol 3-kinase (PI3K) inhibitor idelalisib may have increased mortality risk due to pulmonary morbidity, including atypical pneumonias and pneumonitis, such that prophylaxis is strongly recommended (Dreyling et al. Ann Oncol 2016). The

intravenous intermittently administered pan-class I PI3K inhibitor copanlisib was approved by the FDA in 2017 for treatment of relapsed FL with no black box warnings or recommendation for prophylaxis for opportunistic infections. We sought to examine whether patients with a medical history of respiratory disorders from the CHRONOS-1 trial in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL) treated with copanlisib had higher rates of respiratory-related adverse events (AEs).

**Methods:** Patients with histologically confirmed iNHL who relapsed after or were refractory to ≥2 prior lines of treatment, including rituximab and an alkylating agent or regimen (eg R-CHOP), were eligible for this subset analysis. Copanlisib 60 mg was given as a 1-hour infusion on an intermittent schedule (days 1, 8 and 15 of a 28-day cycle). Prophylaxis for opportunistic infections was not required. AEs were reported using MedDRA (v.20.1).

**Results:** 142 patients with iNHL were treated, of whom 39 had medical histories of respiratory disorders and 103 did not; 46% and 56%, respectively, were non-smokers. The median duration of treatment was 4.8 months (range 0.5-32.7) and 6.2 months (range 0.2-44.2), respectively. The objective tumour responses per independent assessments were similar: 59.0% and 61.2%, respectively. The incidence of respiratory-related AEs was similar across the two groups (Table). There were 3 grade 5 AEs attributed to the study drug, including 1 lung infection in a patient with a history of bronchiectasis and 1 respiratory failure in a patient with multifactorial etiology, including pre-existing chronic obstructive pulmonary disease.

**Conclusions:** This exploratory analysis in patients with relapsed or refractory iNHL treated with copanlisib demonstrated a low overall incidence and no difference in incidence or severity of respiratory-related AEs in patients based on medical histories of respiratory disorders. These results are further evidence of the favourable safety profile of copanlisib and support the use of intermittent intravenous dosing in this setting.

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

**Disclosures:** Zinzani, P: Consultant Advisory Role: Eusapharma, MSD, Sanofi, BMS, Celgene, Celltrion, Eusapharma, Gilead, Immune Design, Janssen-Cilag, Kyowa Kirin, Portola, Roche, Sandoz, Servier, Verastem; Other Remuneration: BMS, Celgene, Celltrion, Eusapharma, Gilead, Immune Design, Janssen-Cilag, Kyowa Kirin, MSD, Portola, Roche, Servier, Verastem. Santoro, A: Consultant Advisory Role: BMS, Servier, Gilead, Pfizer, Eisai, Bayer, Arqule, and MSD; Other Remuneration: Takeda, BMS, Roche, Abb-Vie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer, and MSD. Leppä, S: Consultant Advisory Role: Celgene, Janssen-Cilag, Merck, Novartis, Roche, Takeda; Honoraria: Merck, Roche, Takeda; Research Funding: Bayer, Celgene, Janssen-Cilag, Roche, Takeda. Lenz, G: Consultant Advisory Role: Bayer, Bristol-Myers Squibb, Celgene, Hexal, Johnson & Johnson, Novartis, Roche; Research Funding: AstraZeneca, Bayer, Celgene, Gilead, Johnson & Johnson, Novartis. Kim, W: Consultant Advisory Role: Celltrion; Honoraria: Celltrion; Research Funding: Dong-A, Johnson & Johnson, Kyowa Kirin, Mundipharma, Novartis, Roche, Takeda.

**Provencio, M:** Consultant Advisory Role: BMS, AstraZeneca, MSD, Novartis, Pierre Fabre, Takeda, Roche, Boehringer Ingelheim; Research
<table><caption>**TABLE 1** Respiratory-related treatment-emergent AEs (TEAEs)</caption><thead><tr><th>TEAEs (all grade/G3/G4)</th><th>History of respiratory disorders (n=39)</th><th>No history of respiratory disorders (n=103)</th></tr></thead><tbody><tr><td>Pneumonia</td><td>10.3%/5.1%/0%</td><td>15.5%/10.7%/1.9%</td></tr><tr><td>Upper respiratory tract infection</td><td>12.8%/0%/0%</td><td>15.5%/1.9%/0%</td></tr><tr><td>Lung infection</td><td>7.7%/2.6%/0%</td><td>2.9%/0%/0%</td></tr><tr><td>Pneumocystis jiroveci pneumonia</td><td>2.6%/2.6%/0%</td><td>1.0%/0%/1.0%</td></tr><tr><td>Dyspnoea</td><td>7.7%/2.6%/0%</td><td>8.7%/2.9%/0%</td></tr><tr><td>Pneumonitis</td><td>7.7%/0%/0%</td><td>5.8%/1.9%/0%</td></tr><tr><td>AE grouping - lower respiratory tract infection</td><td>30.8%/7.7%/0%</td><td>27.2%/11.7%/1.9%</td></tr><tr><td>AE grouping - non-infectious pneumonitis</td><td>7.7%/0%/0%</td><td>8.7%/3.9%/0%</td></tr><tr><td>AE grouping - respiratory tract infections</td><td>53.8%/10.3%/0%</td><td>41.7%/12.6%/1.9%</td></tr></tbody></table>

Funding: Roche, Boehringer Ingelheim; Other Remuneration: BMS, Novartis, Takeda, MSD; travel support: BMS, AstraZeneca, MSD, Novartis, Pierre Fabre, Takeda, Roche, Boehringer Ingelheim. Munoz, J: Consultant Advisory Role: Alexion, Bayer, Bristol-Myers Squibb, Genetech, Gilead/Kite Pharma, Juno/Celgene, Kyowa, Pfizer, Pharmac cyclics/Janssen; Other Remuneration: AstraZeneca, Bayer, Gilead/Kite Pharma, Pharmac cyclics/Janssen. Miriyala, A: Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. Liu, L: Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. Zhang, M: Employment Leadership Position: Bayer HealthCare Pharmaceuticals,

Inc. Garcia-Vargas, J: Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. Childs, B: Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. Dreyling, M: Consultant Advisory Role: Bayer, Celgene, Gilead, Janssen, Novartis, Sandoz, and Roche; Research Funding: Celgene, Janssen, Mundipharma, Roche; Other Remuneration: Bayer, Celgene, Gilead, Janssen, and Roche.

345
A PHASE II TRIAL OF
RITUXIMAB/LENALIDOMIDE FOLLOWED
BY LENALIDOMIDE MAINTENANCE IN
UNTREATED AND RELAPSED INDOLENT
LYMPHOMA: LONG TERM FOLLOW UP
AND CORRELATIVE ANALYSIS

C. Poh

A. Brunson

J. Tuscano

Hematology/Oncology, University of California, Davis, Sacramento,
United States

**Introduction:** Lenalidomide is a potent immunomodulator that has demonstrated activity in a broad spectrum of lymphoma subtypes. The combination of lenalidomide and rituximab has been shown to be effective in patients with previously untreated and relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (NHL). Here, we report long term follow up of a phase II trial assessing efficacy and correlative analysis for lenalidomide plus rituximab followed by indefinite lenalidomide maintenance in patients with advanced stage untreated and R/R indolent NHL.

**Methods:** We conducted a phase II, open-label trial involving patients with advanced stage previously untreated and R/R indolent NHL.

Overall Survival and Time to Progression for Patients with Indolent Lymphoma

A. Survival among Untreated Indolent Lymphoma Patients

<figure><img src="image_204.png" /></figure>

B. Survival among Relapsed/Refractory Indolent Lymphoma Patients

<figure><img src="image_205.png" /></figure>
Patients received oral lenalidomide 20 mg daily on days 1-21 of a 28-day cycle and intravenous rituximab 375 mg/m2 weekly for 4 or 8 doses starting day 15 of cycle 1 followed by lenalidomide maintenance until progression or toxicity. The primary endpoint was best overall response rate (ORR). Secondary endpoints included progression free survival (PFS), time to next therapy (TTNT), overall survival (OS) and safety.

Correlative analysis included serum cytokine levels (IFN-γ, GM-CSF, CXCL-10, IL-2, TNF-α, IL-6, IL-10, IL-1, IL-8 and IL-12) and immune cellular subset analysis (B cell, cytotoxic T cell, T cell) at baseline, days 15, 30, 60, 120 of treatment and at treatment discontinuation. Unpaired student's t test was used to assess correlation with response.

**Results:** A total of 60 patients were enrolled (30 untreated and 30 R/R). Median follow-up was 52 months (range 9.2 to 97 months) for the previously untreated group and 113 months (range 4.3 to 129 months) for the R/R group. The ORR was 89% and 75%, respectively. Median progression-free survival was 64.6 months (95% CI, 20.4 to 94) and 12 months (95% CI, 6.8 to 17), respectively. The 9 R/R patients who achieved complete remission remained in continuous remission on lenalidomide maintenance for 16 to 126 months. In patients with disease progression, median time to next therapy was not reached in the untreated group and 15.6 months (95% CI, 7.6 to 40.2) in the R/R group. Median overall survival was not reached in both groups. Most common grade 3/4 adverse events were neutropenia (55%), lymphopenia (45%), fatigue (23%) and hyponatremia (9%). Increased cytokine, INF-γ, IL-2, CXCL-10 and GM-CSF levels on day 15 correlated with response. Increased T cell, cytotoxic T cell and decreased B cell levels on day 30 also correlated with response.

**Conclusions:** Rituximab plus lenalidomide followed by lenalidomide maintenance is effective and associated with acceptable toxicity in patients with both previously untreated and R/R advanced stage indolent NHL. This regimen produces durable remissions, even in previously treated patients, with some lasting greater than 10 years. Increased INF-γ, IL-2, CXCL-10, GM-CSF, T cells and decreased B cell levels correlated with response.

**Keywords:** indolent lymphoma; lenalidomide.

**Disclosures:** Tuscano, J: Honoraria: Celgene; Research Funding: Celgene.

346 - WITHDRAWN

347 - WITHDRAWN

348
GRADE 3A FOLLICULAR LYMPHOMA CAN BE EFFECTIVELY CONTROLLED WITH VERY LOW DOSE RADIATION THERAPY

**B.S. Imber**¹ | **K. Chau**¹ | **E. Goldberg**² | **E. Joffe**³ |
**J. Yahalom**¹

¹Radiation Oncology, Memorial Sloan Kettering Cancer Center,
New York, United States; ²School of Medicine, Mount Sinai, New York,
United States; ³Lymphoma Service, Memorial Sloan Kettering Cancer
Center, New York, United States

**Introduction:** Very low dose radiotherapy (4Gy; VLDRT) has been demonstrated as an effective treatment for low-grade (1-2) follicular lymphoma (FL) and offers the advantage of a shorter course and better side effect profile compared to full dose RT regimens (24 Gy). Whether this treatment can be applied to higher grade (3A) FL remains an open question and is generally not recommended. We reviewed outcomes of a pilot cohort of patients with grade 3A FL treated with VLDRT.

**Methods:** We analyzed 9 consecutive patients (78% female) with median age of 70 years (range 52-92) who received 2 Gy x 2 fractions for grade 3A FL between 2010-2018. Post treatment response at the first follow-up after VLDRT (median 1.9 months) was analyzed by CT and PET if available using the Lugano criteria. Freedom from local failure (FFLF) was analyzed per treated field and defined as time from VLDRT to LF. For FFLF, patients were censored at the start of a subsequent line of therapy if the VLDRT-treated site had not yet progressed. Freedom from distant failure (DF) was analyzed per patient. FFLF and FFDF were analyzed using Kaplan-Meier.

**Results:** The cohort was heterogeneous and reflective of the diverse utility of RT for treating indolent lymphomas. Two (22%) received VLDRT palliatively for newly diagnosed disease, 3 (33%) were treated for progressive disease after initial observation (range 19-87 months) and the remaining 4 (44%) had relapsed/refractory disease and all received 3 prior lines of therapy. All were PET staged before VLDRT with roughly equal distribution of early stage (n=5, 56%) and advanced stage (n=4, 44%). Four (44%) received VLDRT to exclusively nodal sites, 3 (33%) to exclusively extranodal sites and 2 (22%) to mixed nodal/extranodal. The median maximum diameter of a treated lesion was 3.1 cm (range 1.9-5.0) and median maximum pre-treatment SUV on PET was 8.0 (range 5.6-15.6). Despite heterogeneity, overall response rate at the first post-treatment visit was 100% (complete response, CR: 6, partial response, PR: 3). With median follow-up of 27 months post VLDRT, there was only 1 in-field LF at 6.3 months which corresponds to a 1-year FFLF of 86%. Overall, there were 3 DF, corresponding to a 1-year FFDF of 74%. Two of these patients received additional RT and systemic therapy whereas the third was observed. Only one patient had transformation to diffuse large B cell lymphoma (DLBCL). There was 1 non-disease related death in a patient alive with FL.

**Conclusions:** This is, to our knowledge, the first reported series of patients with high grade FL treated with VLDRT. Our data suggests that grade 3A FL behaves similarly to low grade disease, demonstrating outstanding radiographic responses and local control to only 4 Gy.
These findings support an expanded evaluation of VLDRT in patients with higher-grade FL.

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

349
CONSOLIDATION THERAPY USING ⁹⁰Y-IBRITUMOMAB TIUXETAN AFTER BENDAMUSTINE AND RITUXIMAB FOR RELAPSED FOLLICULAR LYMPHOMA; A MULTICENTER, PHASE II STUDY (BRiZ2012)

M. Kanno<fnref n="1" /> | K. Miura<fnref n="2" /> | Y. Masaki³ |
H. Tsujimura⁴ | M. Iino⁵ | J. Takizawa<fnref n="6" /> |
Y. Maeda⁷ | K. Yamamoto<fnref n="8" /> | S. Tamura<fnref n="9" /> |
A. Yoshida<fnref n="10" /> | H. Yagi¹¹ | I. Yoshida<fnref n="12" /> |
K. Kitazume¹³ | T. Masunari¹⁴ | I. Choi<fnref n="15" /> |
Y. Kakinoki¹⁶ | R. Suzuki¹⁷ | T. Yoshino¹⁸ |
S. Nakamura¹⁹ | T. Yoshida<fnref n="20" />

**Introduction:** The role of consolidation therapy with ⁹⁰Y-ibritumomab tiuxetan (⁹⁰YIT) for patients with relapsed follicular lymphoma (FL) who receive re-induction immunochemotherapy has not been established. Therefore, we conducted a multicenter prospective phase

II trial evaluating the efficacy and toxicities of bendamustine and rituximab (BR) followed by ⁹⁰YIT for patients with relapsed FL.

**Methods:** This study included patients who had biopsy-proven, relapsed FL (Grade 1/2 or 3a); one or two prior therapies; age of 20-74 years; ECOG performance status of 0-2; measurable lesion(s); no severe organ dysfunction; 3 months or longer life expectancy; and written informed consent. BR consisted of rituximab (375 mg/m<fnref n="2" />, day 1) and bendamustine (90 mg/m<fnref n="2" />, day 2 and 3), and repeated every 4 weeks up to 4-6 cycles. As the consolidation therapy, 14.8 MBq/kg of ⁹⁰YIT was administered to patients who achieved complete response (CR) or partial response after BR therapy. The primary endpoint was 2-year progression-free survival (PFS) after the consolidation with ⁹⁰YIT. The secondary endpoints were response rates after BR therapy, response rates after consolidation with ⁹⁰YIT, 2-year overall survival (OS) rate after the consolidation with ⁹⁰YIT, and toxicities.

**Results:** A total of 30 patients were registered between 2013 and 2015. Of these patients, 6 were excluded from the study because of pathological diagnoses other than FL in the central review (n = 3), unmet criteria (n = 2), and the other advanced cancer found (n = 1), respectively. Thus, 24 patients with a median 60 years of age (range 47-74 years) and a median of 6.7 years (range 1.6-14.8 years) of duration from the initial diagnosis were evaluated. Among them, R-CHOP based chemotherapy was the most common initial treatment (92%). The FLIPI2 score at the time of registration was high in 3, intermediate in 7, and low in 14 patients, respectively. After re-induction treatment with BR, 22 patients (92%) ultimately received consolidation with ⁹⁰YIT, resulting in an overall response rate of 95% and a CR rate of 91%, respectively. Within the 2-year observation period, 10 patients relapsed and 3 of them had a histological transformation to diffuse large B-cell lymphoma. Severe non-hematological toxicities were rare and no treatment-related mortality was observed. Within the observation period, one patient died of disease progression. Second primary malignancies were not observed. Consequently, the 2-year PFS and OS rates after the consolidation were 58%, and 94%, respectively.

<figure><img src="image_206.png" /></figure>

<footnote n="1">¹Oncology Center, Nara Medical University Hospital, Kashihara, Japan;</footnote>

<footnote n="2">²Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan; ³Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa, Japan; ⁴Division of Medical Oncology, Chiba Cancer Center, Chiba, Japan; ⁵Department of Medical Oncology, Yamanashi Prefectural Central Hospital, Kofu, Japan;</footnote>

<footnote n="6">⁶Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Japan; ⁷Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan;</footnote>

<footnote n="8">⁸Department of Hematology, Okayama City Hospital, Okayama, Japan;</footnote>

<footnote n="9">⁹Department of Hematology/Oncology, Kinan Hospital, Tanabe, Japan;</footnote>

<footnote n="10">¹⁰Department of Hematology, Toyama Prefectural Central Hospital, Toyama, Japan; ¹¹Department of Hematology and Oncology, Nara Prefecture General Medical Center, Nara, Japan; ¹²Department of Hematologic Oncology, National Hospital Organization, Shikoku Cancer Center, Matsuyama, Japan; ¹³Department of Hematology, Showa General Hospital, Kodaira, Japan; ¹⁴Department of Infectious Diseases, Chugoku Central Hospital, Fukuyama, Japan; ¹⁵Department of Hematology, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan; ¹⁶Department of Hematology, Asahikawa City Hospital, Ashikawa, Japan; ¹⁷Department of Oncology/Hematology, Innovative Cancer Center, Shimane University Hospital, Izumo, Japan; ¹⁸Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; ¹⁹Department of Pathology and Biological Response, Nagoya University Graduate School of Medicine, Nagoya, Japan; ²⁰Member, Society of Lymphoma Treatment in Japan (SoLT-J), Kanazawa, Japan</footnote>

<footnote n="12">¹²Department of Hematologic Oncology, National Hospital Organization, Shikoku Cancer Center, Matsuyama, Japan; ¹³Department of Hematology, Showa General Hospital, Kodaira, Japan; ¹⁴Department of Infectious Diseases, Chugoku Central Hospital, Fukuyama, Japan; ¹⁵Department of Hematology, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan; ¹⁶Department of Hematology, Asahikawa City Hospital, Ashikawa, Japan; ¹⁷Department of Oncology/Hematology, Innovative Cancer Center, Shimane University Hospital, Izumo, Japan; ¹⁸Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; ¹⁹Department of Pathology and Biological Response, Nagoya University Graduate School of Medicine, Nagoya, Japan; ²⁰Member, Society of Lymphoma Treatment in Japan (SoLT-J), Kanazawa, Japan</footnote>

<footnote n="15">¹⁵Department of Hematology, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan; ¹⁶Department of Hematology, Asahikawa City Hospital, Ashikawa, Japan; ¹⁷Department of Oncology/Hematology, Innovative Cancer Center, Shimane University Hospital, Izumo, Japan; ¹⁸Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; ¹⁹Department of Pathology and Biological Response, Nagoya University Graduate School of Medicine, Nagoya, Japan; ²⁰Member, Society of Lymphoma Treatment in Japan (SoLT-J), Kanazawa, Japan</footnote>

<footnote n="15">¹⁵Department of Hematology, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan; ¹⁶Department of Hematology, Asahikawa City Hospital, Ashikawa, Japan; ¹⁷Department of Oncology/Hematology, Innovative Cancer Center, Shimane University Hospital, Izumo, Japan; ¹⁸Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; ¹⁹Department of Pathology and Biological Response, Nagoya University Graduate School of Medicine, Nagoya, Japan; ²⁰Member, Society of Lymphoma Treatment in Japan (SoLT-J), Kanazawa, Japan</footnote>

<footnote n="20">²⁰Member, Society of Lymphoma Treatment in Japan (SoLT-J), Kanazawa, Japan</footnote>
**Conclusions:** Consolidation therapy with ⁹⁰YIT after BR re-induction therapy was feasible in patients with relapsed FL. Clinical efficacy was comparable, but the long-term effect should be further investigated.

*Trial protocol number: UMIN000008793, release date: 03. September 2012*

**Keywords:** 90-yttrium; follicular lymphoma (FL); radioimmunotherapy (RIT).

**Disclosures:** Kanno, M: Research Funding: NPO-ACRO (Advanced Clinical Research Organization).

## 350
INTERIM ANALYSIS OF CENTRAL REVIEW
OF END-OF-THERAPY PET IN FOLL12
TRIAL FOR FOLLICULAR LYMPHOMA

L. *Guerra*¹ | F. *Bergesio*² | A. *Versari*³ |
A. *Franceschetto*⁴ | S. *Peano*⁵ | F. *Fallanca*⁶ |
G. *Storto*⁷ | S. *Luminari*⁸ | L. *Rigacci*⁹ |
A. *Gallamini*¹⁰ | M. *Federico*¹¹ | S. *Chauvie*²

¹Nuclear Medicine, San Gerardo Hospital - ASST Monza, Monza, Italy;

²Medical Physics, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy;

³Nuclear Medicine, AUSL-IRCCS of Reggio Emilia, Reggio Emilia, Italy;

⁴Nuclear Medicine, University of Modena and Reggio Emilia, Modena, Italy; ⁵Nuclear Medicine, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy; ⁶Nuclear Medicine, San Raffaele Scientific Institute, Milano, Italy;

⁷Nuclear Medicine, IRCCS-CROB Referral Cancer Center of Basilicata, Rionero in Vulture, Italy; ⁸Department of Diagnostic Medicine, Clinical and Public Health, University of Modena and Reggio Emilia, Modena, Italy; ⁹Haematology and Stem Cells Transplantation Unit, San Camillo Forlanini Hospital, Roma, Italy; ¹⁰Research and Clinical Innovation,

Antoine Lacassagne Cancer Center, Nice, France;

¹¹CHIMOMO, University of Modena and Reggio Emilia, Modena, Italy

**Introduction:** WIDEN® platform, is a tool that allows the management of medical images through the internet network in multicenter trials. WIDEN® platform is currently used in FOLL12 trial for ¹⁸F-FDG PET/CT (PET) images exchange and reviewing. The aim of the current study is: to assess (1) the feasibility and effectiveness of WIDEN® platform in PET image management and (2) the agreement among the PET reviewers.

**Methods:** FOLL12 trial (EUDRACT NUMBER 2012-003170-60) is an ongoing multicenter, phase III, randomized study to evaluate the efficacy of a response-adapted strategy to define the role of maintenance treatment after standard chemoimmunotherapy in patients with advanced-stage Follicular Lymphoma. PET scans are performed at staging and after induction therapy (EoT-PET). In the experimental arm EoT-PET and minimal residual disease (MRD) persistence are key points for selecting patients for maintenance therapy vs observation. Upon EoT-PET upload on WIDEN® by the local site, the image quality is checked automatically for required standard fitting and an email

alert is sent to reviewers (LG, AV, AF, SP, FF, GS) to urge the PET revision. The reviewer has 120 hours (5 days) to review EoT-PET from receipt of email alert and to upload the review form on WIDEN®. EoT-PET scans were compared to baseline PET scan and reviewed according to a Blinded Independent Central Review (BICR) modality using the Deauville Score. The first three concordant revisions in terms of negativity (Score 1-3) or positivity (Score 4-5) adjudicate the final result to the EoT-PET.

**Results:** At the time of writing, 762 baseline and 733 EoT anonymized PET have been uploaded on WIDEN® by the local sites. The median time for PET uploading was 1.3 minutes. Reviewers downloaded 733 pairs of baseline and EoT-PET; the median time for the download was 1.5 minutes. Currently, 733 EoT PET have been reviewed by Nuclear Medicine Reviewers according to BICR. The median time duration of review, calculated as the number of hours elapsed from the alert to the review submission, was 76h. The percentage of reviews done by the single reviewer that concurred to the final results (the first three concordant) were 89%, 68%, 71%, 81%, 78% and 37% for reviewer 1,2,3,4,5 and 6 respectively. The concordance between pairs of reviewers with respect to binary reporting (positive vs. negative) measured using the Krippendorf alpha-coefficient was 0.62.

**Conclusions:** WIDEN® platform is an efficient tool for image exchange in multicentre trials allowing fast downloading and uploading PET scans by common HTTPS internet based protocol. The concordance among the reviewers in term of positivity/negativity was good confirming the reliability of the BICR for PET studies in multicenter clinical trials.

**Keywords:** follicular lymphoma (FL); positron emission tomography (PET).

**Disclosures:** Luminari, S: Consultant Advisory Role: Roche, Celgene, Gilead, Sandoz. Gallamini, A: Consultant Advisory Role: Takeda, Roche; Honoraria: Takeda, Roche. Federico, M: Honoraria: Jannsen, Gilead, Astra Zenca, Takeda, Roche, Sandoz. Chauvie, S: Employment Leadership Position: Co-Founder of Dixit srl, spin-off of University of Torino and INFN; Honoraria: IAEA, CONSIP and Sirtex; Research Funding: Grants from La Roche, Takeda, Fondazione Cassa di Risparmio di Cuneo and AIRC; Other Remuneration: travel/accommodation from GE Healthcare, Philips Medical System, Sirtex, BTG, Terumo.

## 351
CLINICAL SIGNIFICANCE OF UPTAKE
VALUE ON F18-FDG PET/CT AND
HISTOLOGICAL GRADE IN 164 PATIENTS
WITH FOLLICULAR LYMPHOMA
INCLUDING TRANSFORMATION - A
SINGLE CENTER RETROSPECTIVE STUDY
M. Yuasa¹ | M. Shiiba² | D. Kaji¹ | K. Kageyama¹ |

A. Nishida¹ | S. Takagi¹ | H. Yamamoto¹ |

Y. Asano-Mori¹ | N. Uchida¹ | M. Ishihara² |

K. Izutsu³ | S. Taniguchi¹ | G. Yamamoto¹

¹Hematology, Toramono Hospital, Tokyo, Japan; ²Diagnostic Imaging Center, Toramono Hospital, Tokyo, Japan; ³Hematology, National Cancer Center Hospital, Tokyo, Japan

**Introduction:** Follicular lymphoma is the most common indolent non-Hodgkin lymphoma, but has heterogeneous clinical behavior. PET-CT scan has the central role of determining of clinical staging and its five-point Deauville scale to grade response has been widely accepted in the management of follicular lymphoma. PET-CT scan also plays a significant role of predicting transformation of follicular lymphoma by considering high uptake of standardized uptake value (SUV). However, the SUV cut-off values distinguishing transformation are not determined and are different in each study, and clinical significance of SUV value on FDG PET/CT is not considered in detail yet.

**Methods:** We retrospectively analyzed 275 patients who were diagnosed as follicular lymphoma including transformed form in our hospital between January 2008 and November 2018. One patient had also been diagnosed as rectal cancer as well as follicular lymphoma, as we excluded this patient from our study.

**Results:** We first investigated the relationship between histological grade and SUV value on FDG PET/CT. One hundred and ninety-eight biopsies were conducted at the same time of PET-CT. The median SUVmax value was 6.6 (range, 0-34.1) in FL grade 1 patients (n=89), 7.4 (0-23.9) in FL grade 2 patients (n=59), 12.1 (4.6-26.5) in FL grade 3a patients (n=33), and 14.8 (6.5-34.4) in FL grade 3b (n=17) (p<0.01).

We then analyzed clinical impact of SUVmax value on follicular lymphoma grade 1-3a. Patients with follicular lymphoma grade 3b, or lack of information were excluded, so we finally analyzed 164 patients. Median follow-up of survivors was 47.5 (0.4-10989) months. The median age at diagnosis was 62 (31-90) years. Ninety patients were male. Thirty-two patients were diagnosed as duodenum follicular lymphoma. Ninety-four patients were advanced clinical stage (III/IV). Using FLIPI2 score, 32 patients (20%) were in the low risk group, 105 (64%) in the intermediate group, and 27 (16%) in the high risk group. Thirty-six patients had high tumor burdens defined by GELF criteria. The median SUVmax value was 7.5 (range, 0-34.1). As first line treatment strategy, 83 patients (51%) received watch and wait strategy, 38 (23%) received R-CHOP, 3 patients (2%) received R-CVP, 14 (9%) received R-Benda, 20 (12%) received RIT, and 6 (4%) received others. High uptake value (SUV max ≥ 10 vs. SUV max < 10) correlated with high tumor burden (p<0.01), but did not affect OS and time to next treatment (97.3% vs. 98.9% in 5-year OS (p=0.79), 54.6% vs. 72.3% in time to next treatment (p=0.07)).

**Conclusion:** Uptake value of SUVmax correlated with histological grade of follicular lymphoma and high tumor burden, but did not affect OS and TTT after first line treatment therapy.

**Keywords:** F-18-fluorodeoxyglucose (FDG); follicular lymphoma (FL); positron emission tomography (PET).

## 352
FOLLICULAR LYMPHOMA: PRE-TREATMENT TEP/CT SCAN TEXTURE PARAMETERS AS PREDICTIVE BIOMARKERS OF PROGRESSION FREE SURVIVAL AND TIME TO NEXT TREATMENT

E. Durot¹ | S. Mulé² | D. Morland³ | D. Jolly⁴ |

A. Delmer¹ | C. Hoeffel⁵ | C. Durot⁵

¹Department of Hematology, University Hospital of Reims, Reims, France;

²Radiology, Henri Mondor University Hospital, Créteil, France; ³Nuclear Medicine, Jean Godinot Institute, Reims, France; ⁴Department of Research and Innovation, Reims University Hospital, Reims, France;

⁵Radiology, University Hospital of Reims, Reims, France

**Purpose:** To determine whether texture analysis features on pretreatment non-enhanced computed tomography (CT) images derived from FDG-TEP-CT scan can predict progression free survival (PFS), time to next treatment (TTNT) and overall survival (OS) in patients with follicular lymphoma treated with immuno-chemotherapy and maintenance.

**Materials and Methods:** This institutional-approved retrospective study included 72 patients with follicular lymphoma. Texture analysis of 360 lesions was performed on CT scanners obtained within one month before treatment. Mean grey-level, entropy, kurtosis, skewness, and standard deviation values were derived from the pixel distribution histogram before and after spatial filtration at different anatomic scales (SSF), ranging from fine to coarse. Lasso penalized Cox regression analyses were performed to identify independent predictors of PFS, TTNT and OS. FLIPI score and T-MTV were tested as well.

**Results:** Median PFS, TTNT and OS were 1304 days (range 63-3294), 1392 days (range 63-3294) and 1572 days (range 111-3528) respectively.

Kurtosis at zero texture scale (SSF=0; HR (CI 95%) = 1.25 (1.05, 1.48), p=0.012), skewness at fine texture scale (SSF=2; HR (CI 95%) = 3.43 (1.03, 11.48), p=0.045), sexe (HR (CI 95%) = 4.996 (1.77, 14.13), p=0.002) and performans status (HR (CI 95%) = 6.86 (1.83, 25.65), p=0.004) were independent predictors of PFS. Kurtosis at zero texture scale (SSF=0; HR (CI 95%) = 1.28 (1.05, 1.54), p=0.012), skewness at fine texture scale (SSF=2; HR (CI 95%) = 4.94 (1.03, 17.81), p=0.045), sexe (HR (CI 95%) = 4.59 (1.66, 12.70), p=0.003) and performans status (HR (CI 95%) = 6.05 (1.48,
24.75), p=0.012) were independent predictors of TTNT. Sexe (HR (CI 95%) = 19.00 (1.66, 217.82), p=0.018) and FLIPI score (HR (CI 95%) = 6.43 (1.35, 30.66), p=0.019) were independent predictors of OS.

**Conclusion:** Pretreatment TEP scan texture analysis-derived tumour kurtosis and skewness may act as predictive biomarkers of PFS and TTNT in patients with follicular lymphoma treated with immuno-chemotherapy and maintenance.

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

353

THE ROLE OF SURVEILLANCE COMPUTED TOMOGRAPHY IN PATIENTS WITH FOLLICULAR LYMPHOMA

S. Hatta<fnref n="1" /> | S. Fukuhara<fnref n="1" /> | T. Fujino<fnref n="1" /> | Y. Saito<fnref n="1" /> |

Y. Ito<fnref n="1" /> | S. Makita<fnref n="1" /> | W. Munakata<fnref n="1" /> |

D. Maruyama<fnref n="1" /> | M. Kusumono<fnref n="2" /> | K. Izutsu<fnref n="1" />

**Introduction:** Surveillance computed tomography (sCT) has been performed in patients with lymphoma as a follow-up procedure after initial therapy. Several studies have demonstrated the lack of benefit of routine sCT in patients with curable subtypes such as diffuse large B-cell lymphoma and Hodgkin lymphoma. However, few studies have evaluated the clinical benefit of sCT in patients with incurable subtypes such as follicular lymphoma (FL).

**Methods:** We retrospectively reviewed the medical records of patients with FL grade 1-3a who achieved complete response (CR) or CR unconfirmed (CR/CRu) with first-line treatment between 2000 and 2016 at our institution. In accordance with the practice policy at our institution, patients had generally undergone sCT at 6-month intervals for the first 5 years, then at least annually before relapse. In patients who experienced first relapse, we examined the clinical characteristics at relapse and the prognosis after relapse according to the method of relapse detection.

**Results:** Of the 248 patients with FL who achieved first CR/CRu following initial therapy, 109 experienced relapse of FL with a median follow-up of 11 years, and 100 were evaluated in this study (Fig. 1). Among 100 patients, 61 relapses were detected by sCT (sCT group) and 39 were detected by clinical signs, including patient-reported symptoms, physical findings, and blood abnormalities (clinical signs group). There were no significant differences in patient characteristics at relapse between the two groups, except for a higher incidence of extranodal involvement in the clinical signs group. Histological transformation (HT) at relapse was confirmed in 8.2% of the sCT group and 7.7% of the clinical signs group by rebiopsy, with no significant difference. The proportion

<figure><img src="image_207.png" /><figcaption>Fig1. Flow diagram of patients in this study</figcaption></figure>

of patients who had received cytotoxic treatments after relapse was 50.8% in the sCT group and 64.1% in the clinical signs group, with no significant difference. The two groups also showed no significant difference in the time from relapse to the next cytotoxic treatment. Moreover, there was no significant difference between the two groups in overall survival from relapse.

sCT is thought to facilitate early detection of relapse only in cases of deep lesions such as mesenteric or retroperitoneal lymph nodes that would not be identified without imaging modalities. In this study, 54.1% of patients in the sCT group and 15.4% of those in the clinical signs group had only deep lesions at relapse.

**Conclusion:** Our results showed that the sCT and clinical signs group exhibited no significant differences in patient characteristics at relapse, incidence of HT, proportion of patients receiving next cytotoxic treatment, time to next cytotoxic treatment, and survival from relapse. In addition, the percentage of patients in the sCT group who had only deep lesions at relapse was higher than that in the clinical signs group.

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

354

PATTERNS OF CHANGE IN TREATMENT, SURVIVAL, HISTOLOGICAL TRANSFORMATION, AND SECONDARY MALIGNANCIES OF FOLLICULAR LYMPHOMA OVER THE LAST 4 DECADES: A SINGLE CENTER EXPERIENCE

P. Mozas<fnref n="1" /> | L. Magnano<fnref n="2" /> | A. Rivas-Delgado<fnref n="1" /> |

A. Rivero<fnref n="1" /> | F. Nadeu³ | L. Veloza⁴ |

B. González-Farré⁴ | T. Baumann<fnref n="1" /> | O. Balagué⁴ |

<footnote n="1">¹Hematology, National Cancer Center Hospital, Tokyo, Japan;</footnote>

<footnote n="2">²Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan</footnote>
<table><caption>TABLE 1</caption><thead><tr><th>Characteristic</th><th>Entire cohort (N=727)</th><th>Decade 1 (1980-1989) (N=79)</th><th>Decade 2 (1990-1999) (N=163)</th><th>Decade 3 (2000-2009) (N=254)</th><th>Decade 4 (2010-2017) (N=231)</th><th>P value</th></tr></thead><tbody><tr><td>Age (median)</td><td>57</td><td>54</td><td>54</td><td>57</td><td>61</td><td>&lt;0.001</td></tr><tr><td>Male sex (%)</td><td>47</td><td>58</td><td>44</td><td>46</td><td>46</td><td>NS</td></tr><tr><td>Histologic grade 1 or 2 (%)</td><td>84</td><td>NA</td><td>89</td><td>83</td><td>83</td><td>NS</td></tr><tr><td>Performance status, ECOG ≥2 (%)</td><td>9</td><td>21</td><td>11</td><td>6</td><td>7</td><td>&lt;0.001</td></tr><tr><td>Ann Arbor stage IV (%)</td><td>60</td><td>57</td><td>62</td><td>59</td><td>62</td><td>NS</td></tr><tr><td>Elevated LDH (%)</td><td>19</td><td>25</td><td>22</td><td>19</td><td>17</td><td>NS</td></tr><tr><td>High-risk FLIPI (%)</td><td>25</td><td>30</td><td>27</td><td>17</td><td>29</td><td>0.009</td></tr><tr><td>Initial watch &amp; wait strategy (%)</td><td>15</td><td>3</td><td>3</td><td>13</td><td>30</td><td>&lt;0.001</td></tr><tr><td>Rituximab-containing frontline regimen (%)</td><td>54</td><td>0</td><td>0</td><td>69</td><td>99</td><td>&lt;0.001</td></tr><tr><td>CR/Cru rate (%)</td><td>65</td><td>45</td><td>53</td><td>74</td><td>70</td><td>&lt;0.001</td></tr><tr><td>5-year PFS (%)</td><td>48</td><td>40</td><td>27</td><td>57</td><td>61</td><td>&lt;0.001</td></tr><tr><td>5-year OS (%)</td><td>81</td><td>77</td><td>74</td><td>83</td><td>86</td><td>&lt;0.001</td></tr><tr><td>5-yearrisk of HT (%)</td><td>8</td><td>8</td><td>10</td><td>5</td><td>8</td><td>NS</td></tr><tr><td>5-yearrisk of SM (%)</td><td>6</td><td>2</td><td>6</td><td>7</td><td>5</td><td>NS</td></tr><tr><td>Death due to progression (%)</td><td>54</td><td>61</td><td>66</td><td>42</td><td>45</td><td>0.023</td></tr></tbody></table>

E. Giné<fnref n="1" /> | J. Delgado<fnref n="1" /> | N. Villamor<fnref n="2" /> | E. Campo⁴ | A. López-Guillermo<fnref n="1" />

**Introduction:** Follicular lymphoma (FL), the most frequent type of indolent non-Hodgkin lymphoma, exhibits a long survival but a pattern of continuous relapses. With the advent of immunotherapy, both progression-free (PFS) and overall survival (OS) have improved significantly, but early progression and histologic transformation (HT) still confer a much poorer prognosis. However, few single-center series have been published describing the changes in outcomes of FL patients over the last decades.

**Methods:** 727 patients (338 M / 389 F; median age: 57 years) diagnosed with grade 1-3a FL at Hospital Clínic of Barcelona between 1980 and 2017 were categorized into 4 groups according to the decade (D) of diagnosis: D1, 1980-1989; D2, 1990-1999; D3, 2000-2009; and D4, 2010-2017. Baseline and follow-up characteristics were assessed retrospectively and compared among decades.

**Results:** Baseline characteristics, treatment modalities, response, survival, rate of HT and secondary malignancies (SM), and causes

of death are detailed in the Table and plotted in the Figure. Median follow-up for the entire series was 7.6 years. Initial features were not significantly different across decades, except for the more advanced age at diagnosis in D4 and worse performance status in D1. An initial watch & wait strategy was adopted more frequently in D3 and D4. Rituximab was not part of the frontline regimen in D1 and D2, while it became an essential part of treatment in D3 and D4. A steady increase in the rate of complete responses was seen over the decades. The median PFS for treated patients was 4.6 years, and 10-year PFS was 35%, with a significant increase over time. Eighty-one patients experienced HT, and no significant differences were found in the risk of HT over the decades. Hematological malignancies were the most frequent type of secondary neoplasm (20%), and the risk of SM remained stable over time. Median OS for the entire cohort was 17.6 years, and the 10-year OS rate was 65%, with a significant increase in OS over the decades. When analyzing the causes of death over the decades, we saw a reduction in the percentage of patients dying due to FL progression.

**Conclusions:** Over the past 4 decades, presumably due to advances in therapy and supportive care, significant improvements have been seen in the response rate, PFS, OS, and the proportion of patients dying due to FL. The risk of HT and SM have essentially remained unchanged.

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

<footnote n="1">¹Hematology, Hospital Clínic de Barcelona, Barcelona, Spain;</footnote>

<footnote n="2">²Hematopathology Unit, Pathology Department, Hospital Clínic de Barcelona, Barcelona, Spain; ³Lymphoid Malignancies, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; ⁴Pathology, Hospital Clínic de Barcelona, Barcelona, Spain</footnote>
<figure><img src="image_208.png" /><figcaption>Figure. (A) PFS. (B) OS. (C) Risk of HT. (D) Risk of SM. All curves are plotted according to the decade of diagnosis.</figcaption></figure>

355

CHARACTERISTICS AND OUTCOMES OF
PATIENTS WITH RELAPSED FOLLICULAR
LYMPHOMA FOLLOWING RETREATMENT
WITH SECOND-LINE RITUXIMAB-
CONTAINING CHEMOTHERAPY

J. Liu<fnref n="1" /> | J.L. Biccler² | D. Stewart³ | A. Fontaine⁴ |

A. Peters⁴ | I. Fleury⁵ | L. Mollica⁵ | A. Prica⁶ |

R. Buckstein⁷ | J. Kuruvilla⁶ | D. Villa⁸

Margaret Cancer Centre, Toronto, ON, Canada; ⁷University of Toronto,
Odette Cancer Centre - Sunnybrook Health Sciences Centre, Toronto,
ON, Canada; ⁸University of British Columbia, BC Cancer Centre for
Lymphoid Cancer, Vancouver, BC, Canada

**Background:** The prognosis of follicular lymphoma (FL) is considered favorable with rituximab-containing first-line chemotherapy (R-CHEMO1). However, many patients will eventually require second line therapy, for which there is no current standard. Generally, patients receive a second course of rituximab-containing chemotherapy (R-CHEMO2) even though there are no prospective trials backing this approach.

**Methods:** We did a retrospective study of consecutive patients from 6 Canadian centres treated with R-CHEMO2 for relapsed biopsy-proven grade 1-3A FL initially treated with R-CHEMO1 ± maintenance rituximab (MR), and excluded transformed FL and second line radiotherapy or chemotherapy alone.

<footnote n="1">¹Division of Adult and Pediatric Hematology, University of Toronto,
Toronto, Canada; ²Department of Clinical Medicine, Aarlborg University,
Aarlborg, Denmark; ³Tom Baker Cancer Centre, University of Calgary,
Calgary, Canada; ⁴Cross Cancer Institute, University of Alberta,
Edmonton, AB, Canada; ⁵Universite de Montreal, Hôpital Maisonneuve-
Rosemont, Montreal, QC, Canada; ⁶University of Toronto, Princess</footnote>
**Results:** 129 patients with FL, 48% female, were included. R-CHEMO1 was R-CVP in 95 (74%), R-CHOP in 29 (23%), BR in 4 (3%), and FR in one patient. 73 (57%) received MR1. 49 (38%) patients progressed within 24 months of R-CHEMO1 (POD24), with a median time from start of R-CHEMO1 to start of R-CHEMO2 of 36 months (range 2-145). At start of R-CHEMO2, the median year was 2011 (range 2004-2017), the median age was 60 (range 22-82). 80% had stage III/IV, 44% high-risk FLIPI, 39% high LDH. R-CHEMO2 included 40 (31%) BR, 19 (15%) R-CHOP, 19 (15%) R-CVP, 17 (13%) FR, 17 (13%) platinum-containing, and 17 (13%) other regimens. Overall response rate was 80%, complete response 37%. 40 (31%) patients received autologous stem cell transplantation (ASCT), 34 (26%) received MR2, and 5 received radiotherapy.

With a median follow-up of 5.2 years (range 1.1-13.3) after R-CHEMO2, 56 (43%) patients progressed (PROG2). 20 were biopsied (7 DLBCL, 13 FL) and 36 were not (34 had indolent behavior). Median PFS2 was 6.4 years (95% CI 3.0-9.9) and 5-year PFS2 was 54% (95% CI 53-55). 31 (24%) patients progressed within 6 months of R-CHEMO2 or MR2. Age >60 (HR 1.75, 95% CI 1.04-2.95, p=0.036), ASCT (HR 0.26, 95% CI 0.13-0.53, p<0.001), and CR to R-CHEMO2 (HR 0.22, 95% CI 0.11-0.44, p<0.001) were associated with PFS2. Median OS2 was not reached and 5-year OS2 was 81% (95% CI 80-82). 27 patients died at the time of last follow up including 20 from lymphoma. Elevated LDH (HR 3.22, 95% CI 1.42-7.28, p=0.005), high FLIPI (HR 5.13, 95% CI 2.04-12.86, p<0.001), ASCT (HR 0.19, 95% CI 0.06-0.64, p=0.007) and CR to R-CHEMO2 (HR 0.31, 95% CI 0.11-0.89, p=0.029) were associated with OS2.

Third line therapy was given to 53/56 patients with PROG2: 35 received R-CHEMO3, 3 ASCT, 9 allogeneic SCT, and many received novel/experimental agents. The median time to third line therapy was 1.5 years (range 0.13-8.1). 5-year OS3 of 57% (95% CI 55-59) did not differ according to indolent vs. aggressive behavior (p=0.306).

**Conclusions:** Relapsed FL after R-CHEMO1 can be successfully treated with R-CHEMO2 and lead to prolonged PFS2 and freedom from third-line treatment. Age <60, ASCT, and achieving CR are associated with improved PFS2. Outcomes at progression after R-CHEMO2 are less favorable, highlighting the need for other therapies in these patients.

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

356
PREDICTIVE VALUE OF PRIMA-
PROGNOSTIC INDEX (PRIMA-PI) IN FIRST
RELAPSE OF FOLLICULAR LYMPHOMA

J. Šuraš<fnref n="1" /> | V. Procházka<fnref n="2" /> | D. Belada³ |

A. Janíková⁴ | H. Móciková⁵ | K. Kopečková⁶ |

R. Hájek<fnref n="1" /> | M. Trněný⁷

**Introduction:** The FLIPI (Follicular Lymphoma International Prognostic Index) is most commonly used prognostic index in follicular lymphoma (FL). Recently a new simple prognostic score (PRIMA-PI), based on bone marrow involvement and serum beta2 microglobulin was proposed for patients (pts) treated with immunochemotherapy (Bachy E. et al, Blood 2018). Predictive value of this score in setting of relapsed disease hasn't been tested.

**Aim:** To evaluate PRIMA-PI in prediction of secondary overall survival (sOS) and progression free survival (sPFS) and to compare this index with FLIPI in first relapse of FL.

**Methods:** This retrospective analysis is a part of an observational clinical study NiHiL (GovTrial No NCT03199066). 436 pts in first relapse of FL grade 1-3a after first line treatment including rituximab (R) or obinutuzumab (G) were identified. Of these, 199 pts with full data set required for PRIMA-PI available were included into the analysis. sPFS and sOS were calculated from the time of first relapse.

Median age at the time of relapse was 61 years (range 30-86), 58% were females, 63% had clinical stage III-IV, 46% had elevated LDH, 12% had performance status ECOG ≥2, median time from initial diagnosis to first relapse was 32.2 months (range 3.7-148.1), 38% has progressed within 24 months of first line treatment. First line treatment was mainly R-CHOP/G-CHOP/R-CHOP-like regimen (78%) or R-CVP (12%). In relapse R, G or ofatumumab were used in 84% of pts, 31% were treated with platinum based regimen, high dose chemotherapy with autologous stem cell transplant was performed in 20% of pts. Local radiotherapy was used in 5% and watch and wait strategy in 11% of pts. Median follow up from date of relapse was 5.5 years.

**Results:** Secondary PRIMA-PI at the time of first relapse was low in 133/199 (66.8%), intermediate in 27/199 (13.6%) and high in 39/199 (19.6%) pts. Secondary FLIPI score was low in 58/199 (29.1%), intermediate in 53/199 (26.6%), high in 59/199 (29.6%) and unknown in 29/199 (14.6%) pts. 5-year-sPFS and sOS in PRIMA-PI low/intermediate/high group (Fig 1a) was 42.2% vs. 39.8% vs. 23.1% (p=0.0067) and 74.8% vs. 81.0% vs. 49.1% respectively (p=0.0023). 5-year-sPFS and sOS in FLIPI low/intermediate/high group (Fig 1b) was 50.4% vs. 32.5% vs. 32.2% (p=0.0136) and 83.8% vs. 66.1% vs. 62.4% respectively (p=0.0274).

**Conclusions:** PRIMA-PI maintains its prognostic value for predicting both sPFS and sOS in first relapse of FL. Particularly high risk PRIMA-PI is associated with significantly worse prognosis. However, at least

<footnote n="1">¹Department of Haematooncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic;</footnote>

<footnote n="2">²Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic; ³Department of Internal Medicine - Hematology, University Hospital Hradec Kralove and Charles University in Prague, Hradec Kralove, Czech Republic; ⁴Department of Hematology and Oncology, University Hospital Brno, Brno, Czech Republic; ⁵Department of Internal Medicine and Haematology, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; ⁶Department on Oncology, University Hospital Motol, Prague, Czech Republic; ⁷First Dept. of Medicine - Hematology, Charles University General Hospital and First Faculty of Medicine, Prague, Czech Republic</footnote>
<figure><img src="image_209.png" /><figcaption>Fig. 1b</figcaption></figure>

<figure><img src="image_210.png" /></figure>

<figure><img src="image_211.png" /></figure>

<figure><img src="image_212.png" /></figure>

in our cohort, the index hasn't divided pts proportionally (67% of pts with low risk), furthermore, survival curves of low and intermediate risk groups seem to overlap. FLIPI was also predictive for both sPFS and sOS, especially low risk FLIPI was associated with long sOS. This work was supported by Czech Ministry of Health AZV 16-31092A and PROGRES Q28/LF1 grants.

**Keywords:** follicular lymphoma (FL); prognostic indices.

357
COPANLISIB TREATMENT OF PATIENTS
WITH RELAPSED OR REFRACTORY
MARGINAL ZONE LYMPHOMA

P. Panayiotidis<fnref n="1" /> | A. Kellner² | G.A. Follows³ |
L. Mollica⁴ | A. Nagler⁵ | M. Özcan⁶ | A. Santoro⁷ |
F. Hiemeyer⁸ | L. Liu⁹ | J. Garcia-Vargas⁹ |
B.H. Childs⁹ | P.L. Zinzani¹⁰ | M. Dreyling¹¹

**Introduction:** Marginal zone lymphoma (MZL) is an indolent B-cell malignancy, comprising >10% of non-Hodgkin lymphomas. In 2017, the FDA approved the BTK inhibitor ibrutinib for treatment of patients with relapsed/refractory MZL based on outcomes from a study of 60 patients, wherein an objective response rate (ORR) of 48% (3% complete responses [CR]) and a median progression-free survival (PFS) of 14.2 months were reported (Noy et al. Blood 2017). We report here on the results from 23 heavily pretreated patients with relapsed or refractory MZL from the Phase II CHRONOS-1 study (NCT01660451; Part B) with the pan-class I phosphatidylinositol 3-kinase inhibitor copanlisib.

<footnote n="1">¹School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; ²Hematology, Kaposi Mór Teaching Hospital, Kaposvár, Hungary; ³Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; ⁴Clinical Research in Hematology and Clinical Oncology, Maisonneuve-Rosemont Hospital Research Centre, Montréal, Quebec, Canada; ⁵Chaim Sheba Medical Center, Tel Aviv University, Tel HaShomer, Israel; ⁶Hematology, Ankara University, Ankara, Turkey; ⁷Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy; ⁸Pharmaceutical Division, Bayer AG, Berlin, Germany; ⁹Oncology, Bayer HealthCare Pharmaceuticals, Inc., Whippany, United States; ¹⁰Institute of Hematology "Seràgnoli", University of Bologna, Bologna, Italy; ¹¹Department of Medicine III, University Hospital (LMU), Munich, Germany</footnote>
**Methods:** Patients enrolled in the CHRONOS-1 trial with histologically confirmed MZL relapsed after or refractory to ≥2 prior lines of treatment, including rituximab and an alkylating agent, were included in the subset analysis. Copanlisib 60 mg was administered via a 1-hour infusion on days 1, 8 and 15 of a 28-day cycle. Treatment continued until progression or unacceptable toxicity. The primary efficacy endpoint was ORR after ≥4 cycles, per independent assessment (Cheson et al. J Clin Oncol 2007). Secondary efficacy endpoints included duration of response (DoR), PFS and overall survival (OS). AEs were reported using MedDRA (v.19.1). The last patient was enrolled in February 2016. The initial data cut-off was June 2016; the long-term follow-up is based on a data cut-off of February 2018.

**Results:** The 23 MZL patients enrolled included 15 (65%) nodal MZL and 4 each (17%) with mucosa-associated lymphoid tissue (MALT) lymphoma and splenic MZL. Median age was 69 years (range 39-81). Patients had a median of 3 (range 2-9) prior lines of therapy; 48% were refractory to the last regimen and 44% were refractory to the last rituximab regimen.

As of February 2018, patients received a median of 5.8 cycles of treatment, with a median treatment duration of 23 weeks (range 1-191). Objective responses by independent assessment were observed in 18 patients (ORR 78%) and CRs in 3 patients (13%); ORRs were 50% (2/4 patients) in MALT MZL, 87% (13/15 patients) in nodal MZL and 75% (3/4 patients) in splenic MZL. Overall median DoR was 17.4 months (range 0-37.6). Median PFS was 24.2 months (range 0-41.1) and median OS was not reached, with an estimated 83% alive at 2 years. The most common treatment-emergent AEs (TEAEs; all grade/grade 3+) for the total MZL population were fatigue (52.2%/13.0%), hyperglycaemia (52.2%/43.5%) and diarrhoea (47.8%/13.0% grade 3). Laboratory toxicities of interest were principally grade 1, including increased AST (31.8% all grade/22.7% grade 1) and increased ALT (27.3%/13.6%). No grade 5 TEAEs were reported.

**Conclusions:** MZL patients with 2 or more lines of prior therapy treated with copanlisib had durable responses and PFS exceeding previous benchmarks.

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

**Disclosures:** **Panayiotidis, P:** Research Funding: Bayer. **Santoro, A:** Consultant Advisory Role: BMS, Servier, Gilead, Pfizer, Eisai, Bayer, MSD, Arqule; Other Remuneration: Takeda, BMS, Roche, Abb-Vie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer, and MSD. **Hiemeyer, F:** Employment Leadership Position: Bayer AG. **Liu, L:** Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. **Garcia-Vargas, J:** Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. **Childs, B:** Employment Leadership Position: Bayer HealthCare Pharmaceuticals, Inc. **Zinzani, P:** Consultant Advisory Role: Eusapharma, MSD, Sanofi, BMS, Celgene, Celltrion, Eusapharma, Gilead, Immune Design, Janssen-Cilag, Kyowa Kirin, Portola, Roche, Sandoz, Servier, Verastem; Other Remuneration: BMS, Celgene, Celtrion, Eusapharma, Gilead, Immune Design, Janssen-Cilag, Kyowa Kirin, MSD, Portola, Roche, Servier, Verastem. **Dreyling, M:** Consultant Advisory Role: Bayer, Celgene, Gilead, Janssen, Novartis, Sandoz and Roche; Research Funding: Celgene, Janssen, Mundipharma, Roche; Other Remuneration: Bayer, Celgene, Gilead, Janssen and Roche.

358
CHARACTERIZATION OF DUVELISIB IN
PATIENTS WITH REFRACTORY MARGINAL
ZONE LYMPHOMA: DATA FROM THE
PHASE 2 DYNAMO TRIAL

E. Jacobsen¹ | J. Ďuraš² | K. Ardeshna³ |

M. Cherry⁴ | F. Offner⁵ | J. Mayer⁶ | F. Bijou⁷ |

M. Tani⁸ | G. Musuraca⁹ | M. Merli¹⁰ |

R. Marasca¹¹ | D.T. Weaver¹² | S. Lustgarten¹² |

H. Youssoufian¹² | P. Zinzani¹³

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; ²University Hospital Ostrava and Faculty of Medicine, University Hospital Ostrava, Ostrava, Czech Republic; ³Department of Oncology, University College London Hospitals National Health Service Foundation Trust, London, United Kingdom; ⁴Department of Medical Oncology, Atlantic Health Systems, Morristown, NJ, United States;

⁵Department of Hematology, University Hospital Ghent, Gent, Belgium;

⁶Department of Internal Medicine, Fakultní Nemocnice Brno, Brno, Czech Republic; ⁷Department of Medical Oncology, Institut Bergonie, Boredeaux, France; ⁸Hematology Unit, Santa Maria delle Croci Hospital, Ravenna, Italy; ⁹Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; ¹⁰Department of Hematology, Ospedale di Circolo e Fondazione Macchi, Varese, Italy; ¹¹Department of Medical Sciences, Section of Hematology, Università di Modena e Reggio Emilia, Modena, Italy; ¹²Medical Affairs, Verastem Oncology, Needham, MA, United States; ¹³Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy

**Introduction:** Duvelisib (DUV), a first-in-class oral phospoinositide 3-kinase-δ,γ inhibitor, was approved by the US FDA for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after ≥ 2 prior therapies and for follicular lymphoma (FL) after ≥ 2 prior systemic therapies. DYNAMO is a phase 2 trial that evaluated the safety and efficacy of DUV monotherapy in a double-refractory iNHL population (NCT01882803; Flinn J Clin Oncol 2019), which included patients (pts) with marginal zone lymphoma (MZL). Here, we characterize the efficacy and safety of DUV for patients with MZL from the DYNAMO trial.

**Methods:** DYNAMO was an open-label, single-arm trial in pts with FL, CLL/SLL, or MZL whose disease was double refractory to rituximab (monotherapy or as part of a combination regimen) and to chemotherapy or radioimmunotherapy. Pts received DUV 25 mg BID in 28-day treatment cycles until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) as assessed by an independent review committee (IRC) per revised International Working Group (IWG) criteria. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, time to response, adverse events (AEs), and other safety parameters. Pneumocystis jiroveci prophylaxis was mandated for all pts.
**Results:** Of the 129 pts in the DYNAMO study, 18 (14%) were pts with MZL histology, of which 50% were of extranodal subtype, 22.2% nodal subtype, and 27.8% splenic subtype. Median age was 67 years (range, 61-77 years), and 72% (n = 13) were male. Median number of prior regimens was 2 (range, 1-8 prior), and 67% (n = 12) were refractory to ≥ 2 regimens. Median exposure to DUV was 8.35 months (range, 0.9-31.3 months).

The ORR per IRC was 39% (7 pts; 95% CI, 17.3%-64.3%), including 1 CR (ORR by subtype: 0% extranodal, 75% nodal, 80% splenic). Median time to response was 3.7 months. As of the data cutoff (18May2018) the median duration of response had not been reached. With a median follow-up of 31.2 months, the median PFS by IRC was 15.5 months (95% CI, 3.6-27.8 months).

AEs were mostly gr 1/2. Most common gr ≥ 3 AEs (> 15%) were neutropenia (28%) and diarrhea (17%). 33% of pts discontinued DUV due to an AE, including 3 who were in PR at the time of discontinuation. Follow-up imaging is not available for 1 pt, but the other 2 had sustained responses of > 1 year as of most recent imaging after treatment discontinuation. There was 1 gr 5 non-PD related AE of pan-colitis (classified as potentially related to DUV).

**Conclusions:** DUV monotherapy demonstrated clinically meaningful antitumor activity in pts with MZL. DUV had a manageable safety profile, consistent with previous reports. These preliminary findings suggest that DUV represents a promising treatment option that warrants further investigation in pts with double-refractory MZL for whom limited treatment options exist.

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

**Disclosures:** Jacobsen, E: Consultant Advisory Role: AstraZeneca, Merck, Seattle Genetics; Research Funding: Celgene, Pharmacyclics.

**Ardeshna, K:** Consultant Advisory Role: Gilead, Celgene, Roche, Takeda, ADCT Therapeutics; Honoraria: Gilead, Celgene, Roche, Takeda, ADCT Therapeutics. **Cherry, M:** Employment Leadership Position: Director, Hematology - Atlantic Health System - Morristown, NJ; Consultant Advisory Role: Abbvie, Celgene. **Mayer, J:** Research Funding: Infinity Pharmaceuticals, Inc. Weaver, D: Employment Leadership Position: Verastem Oncology; Consultant Advisory Role: FemtoDx, Nanogen Therapeutics; Stock Ownership: Verastem, FemtoDx, Nanogen Therapeutics. **Lustgarten, S:** Employment Leadership Position: Verastem Oncology; Stock Ownership: Verastem Oncology. **Youssoufian, H:** Employment Leadership Position: Verastem Oncology; Stock Ownership: Verastem Oncology. **Zinzani, P:** Consultant Advisory Role: Verastem Oncology, Celltrion, Gilead, Janssen-Cilag, Bristol-Myers Squibb, Servier, Sandoz, MSD, Immune Design, Celgene, Portola, Roche, Eusapharma, Kyowa Kirin; Other Remuneration: Verastem Oncology, Celltrion, Gilead, Janssen-Cilag, Bristol-Myers Squibb, Servier, MSD, Immune Design, Celgene, Portola, Roche, Eusapharma, Kyowa Kirin.

359
A PROGNOSTIC SCORE FOR
TRANSFORMED WALDENSTRÖM
MACROGLOBULINEMIA

<table><caption>TABLE 1</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td><strong>Entire cohort (n = 133)</strong></td><td></td></tr><tr><td>Median age (years)</td><td>64 (range, 32-86)</td></tr><tr><td>Sex male/female (ratio)</td><td>75/58 (1.3/1)</td></tr><tr><td>Prior MGUS history</td><td>20 (15%)</td></tr><tr><td><strong>WM characteristics (concurrent WM and HT excluded) (n = 116)</strong></td><td></td></tr><tr><td>Serum IgM level (g/L)</td><td>17.7 (range, 1.4-66.7)</td></tr><tr><td>IPSS score (n = 76)</td><td></td></tr><tr><td>0-1</td><td>31 (41%)</td></tr><tr><td>2</td><td>30 (39%)</td></tr><tr><td>≥ 3</td><td>15 (20%)</td></tr><tr><td>Median number of regimens</td><td>1 (range, 0-9)</td></tr><tr><td>Therapies (n = 98)</td><td></td></tr><tr><td>Chlorambucil</td><td>43 (44%)</td></tr><tr><td>Fludarabine-based regimens</td><td>41 (42%)</td></tr><tr><td>Bendamustine +/- rituximab</td><td>19 (19%)</td></tr><tr><td>CHOP +/- rituximab</td><td>17 (17%)</td></tr><tr><td>Bortezomib-based regimens</td><td>15 (15%)</td></tr><tr><td>RCD</td><td>14 (14%)</td></tr><tr><td>Ibrutinib</td><td>5 (5%)</td></tr><tr><td>Autologous stem-cell transplantation</td><td>4 (3%)</td></tr><tr><td>Rituximab (alone or in combination)</td><td>67 (50%)</td></tr><tr><td><strong>HT characteristics (n = 133)</strong></td><td></td></tr><tr><td>Median age (years)</td><td>68 (range, 33-89)</td></tr><tr><td>PS (0-1/≥ 2)</td><td>59/48 (55%/45%)</td></tr><tr><td>B symptoms</td><td>56 (47%)</td></tr><tr><td>Extranodal involvement</td><td>111 (86%)</td></tr><tr><td>Serum IgM level (g/L)</td><td>6.9 (range, 0-66.6)</td></tr><tr><td>Absolute neutrophils (x 10<sup>9</sup>/L)</td><td>4.1 (range, 0.2-20.2)</td></tr><tr><td>Absolute lymphocytes (x 10<sup>9</sup>/L)</td><td>0.9 (range, 0.1-56)</td></tr><tr><td>Hemoglobin (g/L)</td><td>104 (range, 46-155)</td></tr><tr><td>Platelets (x 10<sup>9</sup>/L)</td><td>172 (range, 9-610)</td></tr><tr><td>Elevated LDH</td><td>85 (72%)</td></tr><tr><td>Albumin level < 3.5 g/dL</td><td>62 (56%)</td></tr><tr><td>Stage III or IV</td><td>96 (86%)</td></tr><tr><td>IPI score (n = 99)</td><td></td></tr><tr><td>Low risk (0-1)</td><td>8 (8%)</td></tr><tr><td>Low-intermediate risk (2)</td><td>17 (17%)</td></tr><tr><td>High-intermediate risk (3)</td><td>33 (33%)</td></tr><tr><td>High risk (4-5)</td><td>41 (41%)</td></tr><tr><td>Median number of lines</td><td>1 (range, 0-5)</td></tr><tr><td>Therapies (n = 127)</td><td></td></tr><tr><td>CHOP-like regimen +/- rituximab</td><td>102 (80%)</td></tr><tr><td>DHAP +/- rituximab</td><td>10 (8%)</td></tr><tr><td>GEMOX +/- rituximab</td><td>3 (4%)</td></tr><tr><td>Rituximab-containing regimen</td><td>110 (87%)</td></tr><tr><td>Autologous stem-cell transplantation</td><td>20 (16%)</td></tr><tr><td>Allogeneic stem-cell transplantation</td><td>6 (5%)</td></tr></tbody></table>
E. Durot¹ | L. Kanagaratnam² | S. D'sa³ |
C. Tomowiak⁴ | B. Hivert⁵ | E. Toussaint⁶ |
T. Guerrero-Garcia⁷ | G. Itchaki⁷ | J. Vos⁸ |
A. Michallet⁹ | S. Godet¹ | J. Bomsztyk³ |
P. Morel¹⁰ | V. Leblond¹¹ | S.P. Treon⁷ |
A. Delmer¹ | J.J. Castillo⁷

¹Department of Hematology, University Hospital of Reims, Reims, France;

²Department of Research and Innovation, University Hospital of Reims,
Reims, France; ³Department of Hematology, University College London
Hospitals (UCLH) NHS Foundation Trust, London, United Kingdom;

⁴Department of Hematology, University Hospital of Poitiers, Poitiers,
France; ⁵Department of Hematology, Hospital of Lens, Lens, France;

⁶Department of Hematology, University Hospital of Strasbourg,
Strasbourg, France; ⁷Department of Hematology, Dana-Farber Cancer
Institute, Harvard Medical School, Boston, United States; ⁸Department of
Hematology, Academical Medical Center, Amsterdam, Netherlands;

⁹Department of Hematology, Centre Léon Bérard, Lyon, France;

¹⁰Department of Hematology, University Hospital of Amiens, Amiens,
France; ¹¹Department of Hematology, Pitié-Salpêtrière Hospital, Paris,
France

**Introduction:** Transformation of Waldenström macroglobulinemia (WM) into diffuse large B-cell lymphoma is a rare complication usually associated with a poor but heterogeneous prognosis. Factors predicting survival in this setting are unknown. The objective of this study was to develop a prognostic index for overall survival in transformed WM patients.

**Methods:** We developed the scoring system from a cohort of 133 patients with transformed WM treated between 1995 and 2017 in French centers (n = 80), Dana-Farber Cancer Institute (Boston, n = 36), UCLH (London, n = 13) and Nieuwegein (Netherlands, n = 4). Clinical and biological characteristics were retrospectively collected. Multivariate analyses using cox proportional hazard model were performed to investigate the factors independently associated with 2-year overall survival and a risk score was created. Internal validation was performed.

**Results:** At the time of transformation, the median age was 68 years (range, 33-89) and the median time from WM diagnosis to histological transformation (HT) was 4.3 years [95% confidence interval (CI), 1.1-8.7]. The median number of therapies received for WM was 1 (0-9), including half of the patients receiving rituximab. At HT, patients presented with high-risk features. Extranodal involvement was found in 86% of patients and elevated LDH in 72%. First-line treatment for transformation consisted of R-CHOP-like regimen in 80% of patients. The median OS was 19 months (95% CI, 12-31) for the entire cohort. In univariate analysis, variables that predicted shorter 2-year OS were ≥ 1 previous treatment for WM (p = 0.02), prior rituximab exposure (p = 0.01), time to transformation ≥ 5 years (p = 0.006), elevated LDH (p = 0.003), B symptoms (p = 0.02) and platelet count < 100 x 10⁹/l (p = 0.007). By multivariate analysis, three independent prognostic factors were identified: elevated LDH (p = 0.003; HR 3.6, 95% CI, 1.53-8.5), platelet count < 100 x 10⁹/l (p = 0.03; HR 1.8, 95% CI, 1.04-3.19) and ≥ 1 previous treatment for WM (p = 0.04; HR 2, 95% CI, 1.04-3.94). Three risk groups were defined: low risk (0-1 point, 24% of patients), intermediate risk (2-3 points,

<figure><img src="image_213.png" /></figure>
59% of patients) and poor risk (4 points, 17% of patients). Two-year OS rates were 81%, 47%, and 21%, respectively (p < 0.0001) (figure).

**Conclusion:** This easy-to-compute scoring index may allow the identification of groups of transformed WM patients with different outcomes and could be used for improving treatment choices.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); prognostic indices; Waldenström's macroglobulinemia (WM).

## MANTLE CELL

### 360
SERUM BIOMARKERS ARE ASSOCIATED WITH TREATMENT RESPONSE IN RELAPSED MANTLE CELL LYMPHOMA

L. Lokhande<fnref n="1" /> | V.K. Emruli<fnref n="1" /> | A. Kolstad<fnref n="2" /> |

M. Hutchings<fnref n="3" /> | R. Räty⁴ | J.D. Rodrigues<fnref n="1" /> |

M. Jerkeman⁵ | S. Ek<fnref n="1" />

**Introduction:** Recent advances in therapeutic strategies have provided novel treatment regimens for MCL, that until recently, was associated with dismal prognosis of 3-5 yrs median overall survival. However, strategies to guide patient stratification are still lacking in both diagnostic and relapsed setting. Non-invasive methods based on liquid biopsies would facilitate the continuous sampling of patients over time and identification of companion diagnostic biomarkers is warranted. For this purpose, we have used an antibody-based platform to identify serum proteins in relapsed patients that are homogeneously treated as per the Nordic MCL6 clinical trial (Philemon). We hypothesize that, the platform can identify if the immune status at treatment start can influence the response to combinatorial immune-directed therapies. We also intend to study how treatment can influence the immune status across time.

**Methods:** Sequential serum samples from 44 patients treated with Lenalidomide, Ibrutinib and Rituximab (Philemon trial) were processed on the IMMRay™ platform (Immunovia). We processed serum samples from 4 time-points; at baseline and 12, 24 and 36 weeks of treatment which corresponds to cycle 4, 7 and 10, of the trial. The platform, allows the analysis of 380 different epitopes among approximately 150 unique proteins. It focuses on soluble immune-related proteins such as cytokines, chemokines and complement factors, as well as, several cancer-related markers. In brief, antibody fragments are produced and printed on a solid support. Samples are biotinylated and detected using a fluorescent marker

after hybridization to the array. Spot recognition and raw data processing was performed using standard operating procedure according to the IMMRay guidelines (Immunovia). Normalization and further bioinformatic and biostatistical analysis were performed using standard tools which includes R, Qlucore and SIMCA; and several other in-house built softwares developed in conjunction to the experimental platform.

**Results:** Preliminary results using COX regression analysis shows that, at baseline, a signature of approximately 6-8 relevant proteins are associated with PFS. Further investigations are needed to validate this in an independent cohort of patients. Current investigations aim to identify if additional prognostic and biological information related to the treatment can be derived by comparing samples at baseline, cycle 4 and beyond.

**Conclusion:** We have showed that prognostic information can be derived from serum samples collected from relapsed MCL patients. To our knowledge, this is the first time that an antibody-based array is used as a tool to assess the possibility of developing serum-based signatures useful for treatment selection in relapsed MCL patients.

**Keywords:** B-cell lymphoma; immune system; mantle cell lymphoma (MCL).

### 361
HIGH VIRAL LOADS OF CIRCULATING EPSTEIN-BARR VIRUS DNA COPY NUMBER IN PERIPHERAL BLOOD IS ASSOCIATED WITH INFERIOR PROGNOSIS IN PATIENTS WITH MANTLE CELL LYMPHOMA

W. Xu | X. Zhou | J. Liang | L. Wang | H. Zhu |

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:** Mantle cell lymphoma (MCL) is a distinct subtype of B cell non-Hodgkin lymphoma. No research has yet documented to investigate the prognostic implications of Epstein-Barr virus (EBV) infection in MCL. The objective of this study was to examine whether EBV DNA load may influence the heterogeneity in the course of the disease in MCL patients.

**Methods:** Eighty-eight MCL patients were retrospectively enrolled in the study. EBV DNA load was detected by real-time quantitative PCR for quantification. The univariate and multivariate Cox proportional hazards models were established for the estimation of prognostic factors.

**Results:** Twenty-seven patients were detected positive for EBV DNA ad the median virus titer was 1.72×10⁴ copies/mL (range, 8.20×10² to 4.14×10⁵ copies/mL). With a median follow-up of 39 months (range, 9 to 120 months), patients in EBV DNA-positive group

<footnote n="1">¹Department of Immunotechnology, Lund University, Lund, Sweden;</footnote>

<footnote n="2">²Department of Oncology, Oslo University Hospital, Oslo, Norway;</footnote>

<footnote n="3">³Department of Haematology, Rigshospitalet, Copenhagen, Copenhagen, Denmark; ⁴Department of Hematology, Helsinki University Central Hospital, Helsinki, Finland; ⁵Department of Oncology, Skane University Hospital, Lund, Sweden</footnote>
<figure><img src="image_214.png" /><figcaption>**Figure 1.** Progressive-free survival (PFS) and overall survival (OS) for 88 patients with the analysis of pretreatment Epstein-Barr virus (EBV) DNA status.</figcaption></figure>

displayed unfavorable progression-free survival (PFS) (P=0.012) and overall survival (OS) (P=0.004) than patients in EBV DNA-negative group (Figure 1). Multivariate Cox regression analysis revealed that EBV DNA-positivity was independent risk factor for both PFS (HR, 2.04; 95% CI, 1.07 to 3.92; P=0.031) and OS (HR, 2.68; 95% CI, 1.20 to 6.00; P=0.016). Reduction in EBV copies was significantly associated with therapy-response.

**Conclusion:** Circulating EBV DNA load in whole blood proved to be a significant predictor of prognosis in patients with MCL, which needs further validation in large-scale clinical studies.

**Keywords:** Epstein-Barr virus (EBV); mantle cell lymphoma (MCL); prognostic indices.

362
# OBINUTUZUMAB THERAPY IN PATIENTS WITH MARGINAL ZONE AND MANTLE CELL LYMPHOMA

M.E. Hughes | C. Suen | E. Namoglu | S.J. Schuster | J. Svoboda | A. Loren | S.D. Nasta

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

**Introduction:** Obinutuzumab (OBI) is FDA approved in chronic lymphocytic leukemia and follicular lymphoma, with favorable efficacy profiles noted in both settings. While there was a small subpopulation of marginal zone lymphoma (MZL) and mantle cell lymphoma patients (pts) in the GAUSS trial and GADOLIN/GAUGUIN trials respectively, there is little clinical experience in using OBI in these patient populations outside the context of a clinical trial. We describe a real world experience of OBI use in MZL and MCL pts off clinical trial.

**Methods:** We conducted a retrospective cohort study of all adult pts who received OBI for MZL and MCL at the University of Pennsylvania

between 2/2013 and 2/2019. Demographics, duration of therapy, reason for discontinuation, overall response, survival, and toxicities were examined. The primary endpoints were progression-free survival (PFS; defined as time from OBI start to disease progression or regimen change, death due to MZL/MCL or last-follow-up in remission), and overall survival using the Kaplan-Meier method. All other analyses were descriptive.

**Results:** We identified a total of 10 pts for the entire cohort, 6 with MZL and 4 with MCL. The median age at start of OBI was 64 years (Range 50-92). 80% of pts were stage 4, had a median of 2 prior therapies (1 MZL patient treated frontline), median ECOG status 0, and one MZL patient had an MYD88 mutation. One patient was rituximab naïve, but 70% were rituximab refractory. The median number of cycles administered of OBI was 7 (Range 1-31) respectively. 50% of pts received OBI in combination, 3 pts with bendamustine, 1 with chlorambucil, and 1 with ibrutinib. Overall response rate was 90% (10% CR). Median PFS and OS were 11.5 and 13.5 months respectively. Two pts progressed following OBI therapy; one patient with MZL who subsequently was treated with ibrutinib and one with MCL subsequently treated with venetoclax.

50% of pts experienced at least one Adverse event(AE). AEs included: Infusion related reactions (40%), thrombocytopenia (40%), diarrhea (30%), neutropenia (20%), infection (10%). Three pts were on growth factor during OBI administration. One patient discontinued therapy secondarily to an infusion related reaction.

**Conclusions:** OBI therapy was well tolerated in our cohort of MZL and MCL pts. We observed a high ORR and durable PFS and OS opportunity. Only two pts experienced progression following OBI therapy, both of whom are currently controlled with novel oral agents. The AE profile of OBI was well tolerated, with toxicities consistent with current package labeling. Additional clinical trials and/or pooled data from retrospective observational studies will help confirm OBI therapy's durable efficacy benefit for pts with MZL and low-risk MCL.

**Keywords:** mantle cell lymphoma (MCL); marginal zone lymphoma (MZL); obinutuzumab.
<figure><img src="image_215.png" /></figure>

<figure><img src="image_216.png" /></figure>

**Disclosures:** Hughes, M: Consultant Advisory Role: AstraZeneca; Research Funding: Acerta Pharma. Schuster, S: Consultant Advisory Role: Novartis, Nordic Nanovector, Celgene, Merck, Gilead, Pfizer; Honorary: Genentech, Novartis, Nordic Nanovector, Celgene, Merck, OncLive, Dava Oncology, Physician's Education Source, LLC; Research Funding: Genentech, Novartis, Nordic Nanovector, Celgene, Merck, OncLive, Dava Oncology, Physician's Education Source, LLC. Svoboda, J: Consultant Advisory Role: BMS, Seattle Genetics, KITE, Kyowa, Pharmacyclics; Research Funding: BMS, Regeneron, Merck, Seattle Genetics, TG Therapeuitics, Pharmacyclics. Nasta, S: Consultant Advisory Role: Celgene; Research Funding: Pharmacyclics, Incyte, Roche, Aileron, Rafael/WF, Debiopharm, Takeda/Millenium; Other Remuneration: Merck: DSMC.

⁵Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, United States; ⁶Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, United States; ⁷Knight Cancer Institute, Oregon Health and Sciences University, Portland, United States; ⁸Lineberger Cancer Institute, University of North Carolina, Chapel Hill, United States; ⁹Hematology, Northwestern University, Chicago, United States; ¹⁰Hematology and Medical Oncology, Levine Cancer Institute, Charlotte, United States; ¹¹Hematology, The Ohio State University James Cancer Center, Columbus, United States; ¹²Hematology and Oncology, Medical College of Wisconsin, Milwaukee, United States; ¹³Siteman Cancer Center, Washington University, St Louis, United States

363

MAINTENANCE RITUXIMAB IS
ASSOCIATED WITH IMPROVED OVERALL
SURVIVAL IN MANTLE CELL LYMPHOMA
PATIENTS RESPONDING TO INDUCTION
THERAPY WITH BENDAMUSTINE +
RITUXIMAB (BR)

B.T. Hill<fnref n="1" /> | J.M. Switchenko² | P. Martin³ |
M.C. Churnetski⁴ | Y. Sawalha<fnref n="1" /> | S. Goyal² |
K. Shanmugasundaram⁴ | O. Calzada⁴ | B. Kolla⁵ |
V. Bachanova⁵ | J.N. Gerson⁶ | S.K. Barta⁶ |
E. Maldonado⁷ | M. Gordon⁷ | A. Danilov⁷ |
N.S. Grover⁸ | S. Mathews⁸ | M. Burkart⁹ |
R. Karmali⁹ | N. Ghosh¹⁰ | S.I. Park¹⁰ |
N. Epperla¹¹ | D.A. Bond¹¹ | T. Badar¹² |
K.A. Blum⁴ | J. Guo³ | M. Hamadani¹² |
T.S. Fenske¹² | M. Malecek¹³ | K. Maddocks¹¹ |
C.R. Flowers⁴ | B.S. Kahl¹³ | J.B. Cohen⁴

**Introduction:** Bendamustine + rituximab (BR) is frequently utilized as initial treatment for patients (pts) with mantle cell lymphoma (MCL). Following induction BR, the role of maintenance rituximab (MR) is controversial and practice patterns vary. MR improves overall survival (OS) in younger pts following autologous stem cell transplantation (ASCT) and in older pts following R-CHOP. However, a preliminary analysis of the randomized phase 3 MAINTAIN study revealed neither a progression-free survival (PFS) nor OS benefit for MR versus observation for MCL pts (Rummel, ASCO 2016). We evaluated the impact of MR following BR in a non-trial population.

**Methods:** We reviewed outcomes for MCL pts treated with frontline BR at 12 U.S. medical centers from 2011 - 2017. After BR, pts were treated with or without MR based on individual physician/patient preferences. We compared baseline pt characteristics using chi-squared test, Fisher's exact tests, or ANOVA. Descriptive statistics, comparisons, and OS using the Kaplan-Meier method were first stratified by response status as determined by the treating site (complete response (CR) only, partial response (PR) only, and CR/PR), and were then evaluated for pts who did not receive ASCT in first remission.

**Results:** 206 pts were treated with frontline BR. 73% achieved CR 73%, 16%, PR, 2% stable disease 9% and progressive disease. Among these who did not undergo consolidation ASCT, 114 pts achieved a CR (n=91) or PR (n=23) to BR and had available data regarding MR. The median age was 70 (range 50 – 89) years and 65% were male. 68 pts (60%) received MR and 46 (40%) received no maintenance. Baseline MIPI score was low (11%), intermediate (39%), or high

<footnote n="1">¹Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, United States; ²Biostatistics, Emory University, Atlanta, United States; ³Hematology/Oncology, Weill Cornell Medical College, New York, United States; ⁴Hematology and Medical Oncology, Emory University - Winship Cancer Institute, Atlanta, United States;</footnote>
<figure><img src="image_217.png" /></figure>

<figure><img src="image_218.png" /></figure>

<figure><img src="image_219.png" /></figure>

**Figure: Outcomes of pts treated with BR without consolidation ASCT, followed by MR vs. no maintenance.** Panel A: OS for pts in CR or PR; Panel B, OS for patients in CR; Panel C, OS for patients in PR.

(50%) among 88 patients with available data and did not differ between treatment cohorts. With a median follow up of 2.9 years, median OS was not reached for pts who received MR vs. 6.1 years for those who received no maintenance (Figure Panel A, P = 0.008). Use of MR vs. no maintenance was associated with a significant improvement in OS for pts in PR at the end of induction therapy (Figure Panel B, median not reached vs. 2.4 years, P = 0.0226), but there was no statistically significant OS difference for pts in CR (Figure Panel C, median not reached vs. 11.5 years, P = 0.387).

**Conclusions:** Contrary to the prospective MAINTAIN randomized study, in this multi-center retrospective analysis, MR was associated with an improvement in OS in pts receiving frontline BR without consolidative ASCT, with benefit primarily for pts in PR after induction therapy. Because patient selection may have influenced outcomes,

additional prospective data are needed to clarify the possibility of an OS benefit to RM after BR and to further delineate the possibility of differential benefit of RM based on depth of response to frontline BR.

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

**Disclosures:** Hill, B: Consultant Advisory Role: *Pharmacyclics, Abbvie, Seattle Genetics, Novartis, Genentech, Gilead, Seattle Genetics, Novartis*; Research Funding: *Genentech, Amgen. Calzada, O*: Research Funding: *Seattle Genetics. Bachanova, V*: Consultant Advisory Role: *Kite Pharma*; Research Funding: *GT Biopharma, Gamida Cell. Barta, S*: Consultant Advisory Role: *Janssen*; Research Funding: *Merck, Takeda, Celgene, Seattle Genetics, Bayer*; Other Remuneration: *Curis. Danilov, A*: Consultant Advisory Role: *Gilead, Genentech, Verastem, Bayer, Astra Zeneca, TG Therapeutics*; Research Funding: *Takeda, Aptose Biosciences. Grover, N*: Consultant Advisory Role: *Seattle Genetics. Karmali,*
**R:** Other Remuneration: *Astra Zeneca*, *Gilead. Park*, **S:** Consultant Advisory Role: BMS, Rafael Pharma, G1 Therapuetics, Teva; Research Funding: Takeda, Teva, Seattle Genetics, BMS; Other Remuneration: Gilead, Seattle Genetics. *Blum*, **K:** Research Funding: Morphosys, Seattle Genetics, Celgene, Novartis. *Hamadani*, **M:** Consultant Advisory Role: Janssen, Celgene, Cellerant, MedImmune; Research Funding: Merck, MedImmune, Takeda, Otsuka, ADC Therapeutics, SAnofi; Other Remuneration: Sanofi. *Flowers*, **C:** Consultant Advisory Role: Abbvie, Bayer, Denovo Biopharma, Genentech, Gilead, Karyopharm, Spectrum, Janssen, Pharmacyclics, OptumRx; Research Funding: Abbvie, Genentech, Gilead, Acerta, BeiGene, Celgene, Janssen, Pharmacyclics, TG Therapeutics, Burroughs Wellcome Fund, ECOG, NCI, V Foundation. *Kahl*, **B:** Consultant Advisory Role: Seattle Genetics, Genentech; Research Funding: ADC Therapeutics. *Cohen*, **J:** Consultant Advisory Role: Celgene, Seattle Genetics, Genentech, Janssen, PHarmacyclics; Research Funding: BMS, Takeda, Novartis, BioInvent, Genentech.

364

MANTLE CELL LYMPHOMA: TWO
REFERENCE CENTER'S RESULTS

**H. Goker**¹ | **M. Okay**¹ | **O. Meletli**² | **E. Kelkitli**² |
--- | --- | --- | ---
**F. Tekin**¹ | **M. Turgut**² | **H. Demiroglu**¹ | **Y. Buyukasik**¹

¹Hematology, Hacettepe University, Ankara, Turkey; ²Hematology, Ondokuz Mayıs University, Samsun, Turkey

**Introduction:** Mantle cell lymphoma (MCL) is a B-cell neoplasm with CCND1[t(11;14)(q13;q32), cyclin D1] translocation (1). In the guidelines recommend various treatment recommendation based on the age, performance status (fitness status), comorbidities (2). In this retrospective study, we have sought out to analyze the clinical characteristic features and evaluate prognostic factors on the survival of 78 MCL patients.

**Methods:** This is a retrospective study. We analyzed patients' information who applied two reference center Hacettepe University and Ondokuz Mayıs University, Hematology Department between January 2001 and September 2018. Categorical and continuous data were expressed as ratio (%) and median (range) and they were compared by Chi-square and Mann Whitney U tests, respectively. The primary endpoint of study was overall survival and disease free survival. Parameters related to survival were investigated by cox regression univariate and multivariate analyses.

**Results:** The median age of patients was 62 years (34-86 years). 78.2% of patients were male. For initial therapy, only one patient had no chemotherapy because of age and poor general status. The other treatment choices were 42.3% RCHOP, 26.9% R-Bendamustin, 9% HyperCVAD, 7.7% RCHOP/RDHAP alternating. Only 13 patients

<figure><img src="image_220.png" /><figcaption>Figure 1. Overall Survival According to Neutrophil Count Groups.</figcaption></figure>
underwent ASCT. Median overall survival (OS) duration was 77.8 months (53.8-101.8). Median disease-free survival (DFS) duration was 20.6 months (14.2-26.9), for the whole MCL group. The univariate analysis showed that MIPI and neutrophil count was effecting the OS (p=0.047 and p=0.001). The multi-variate analyses showed that the neutrophil count at diagnosis was independent prognostic risk factor (p=0.005) for OS. The univariate and multi-variate analysis showed that age <65 effect was prominent DFS(p=0.074).

**Conclusions:** Mantle cell lymphoma (MCL) one of Non-Hodgkin's lymphomas has a poor prognosis (3). The median OS duration is somewhat prolonged in the last years with new treatment approaches but MCL is still an incurable disease. Herein, we have reported two referral centers of MCL results. Similarly in the literature, the neutrophil count was independent prognostic risk factor for OS.

## References

1. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90.

2. Dreyling M, Campo E, Hermine O, Jerkeman M, Le Gouill S, Rule S, et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2017;28(suppl_4):iv62-iv71.

3. Hoster E, Rosenwald A, Berger F, Bernd H-W, Hartmann S, Loddenkemper C, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: results from randomized trials of the European mantle cell lymphoma network. Journal of Clinical Oncology. 2016;34(12):1386-94.

**Keywords:** mantle cell lymphoma (MCL); non-Hodgkin lymphoma (NHL); prognostic indices.

## 365

### OUTCOMES FOR PATIENTS WITH MANTLE CELL LYMPHOMA EXPERIENCING FRONTLINE TREATMENT FAILURE: A MULTICENTER RETROSPECTIVE STUDY

D.A. Bond<fnref n="1" /> | J. Switchenko² | K. Maddocks<fnref n="1" /> |
M. Churnetski³ | S. Goyal² | K. Shanmugasundaram⁴ |
O. Calzada³ | B. Kolla⁵ | V. Bachanova⁵ |
J. Gerson⁶ | S. Barta⁶ | B. Hill⁷ | Y. Salwaha⁷ |
P. Martin⁸ | E. Maldonado⁹ | M. Gordon⁹ |
A. Danilov⁹ | N. Grover¹⁰ | S. Mathews¹⁰ |
M. Burkart¹¹ | R. Karmali¹¹ | N. Ghosh¹² |
S. Park¹² | N. Epperla<fnref n="1" /> | T. Badar¹³ | J. Guo⁸ |
M. Hamadani¹³ | T. Fenske¹³ | M. Malecek¹⁴ |
B. Kahl¹⁴ | C. Flowers³ | K. Blum³ | J. Cohen³

Medicine, Emory University School of Medicine, Atlanta, United States;
⁵Department of Hematology, University of Minnesota, Minneapolis, United States; ⁶Hematology, Abramson Cancer Center, University of Pennsylvania, Pennsylvania, United States; ⁷Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, United States;
⁸Department of Medicine, Weil Cornell Medicine, New York, United States; ⁹Hematology and Oncology, Oregon Health and Science University, Knight Cancer Institute, Portland, United States;
¹⁰Hematology and Oncology, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, United States; ¹¹Hematology and Oncology, Northwestern University, Feinberg School of Medicine, Chicago, United States; ¹²Hematology and Oncology, Atrium Health, Charlotte, United States; ¹³Hematology and Oncology, Medical College of Wisconsin, Milwaukee, United States; ¹⁴Hematology and Oncology, Siteman Cancer Center, Washington University, St. Louis, United States

**Background:** Early progression (EP) after intensive initial treatment (tx) for mantle cell lymphoma (MCL) is associated with inferior overall survival (OS; Dietrich Ann Oncol 2014), but its impact after less intensive tx and the appropriate management of patients with EP is not understood. We examined outcomes for MCL pts with EP stratified by tx intensity and described the impact of 2nd line tx selection on progression free survival (PFS) after EP.

**Methods:** We reviewed clinical data and examined outcomes for MCL pts treated between 2000 and 2017 at 12 centers with EP defined by progression of disease within 1 year (y) of tx initiation. OS was defined as time from 1st progression to death or last follow-up for pts with EP. Post-EP PFS was defined from 1st progression to either 2nd progression or death or last follow-up. OS and PFS were estimated using the Kaplan-Meier method and compared using log rank test. Intensive tx was defined as receipt of high dose cytarabine and/or autologous transplant in 1st remission. Patient characteristics were compared across intensive and less intensive tx using ANOVA.

**Results:** Of 1119 pts treated at the centers, 473 experienced progression and 153 had EP. Median follow-up after initial progression was 1.3 y for patients with EP. Baseline characteristics for pts with EP included median age 65 y, 72% male, Ki67 > 30% in 62% (52/83 with available data), complex karyotype in 27% (12/44 with available data), MIPI risk score high in 49% and intermediate in 26%. Frontline tx was intensive in 33%. Pts receiving intensive frontline tx were younger; median age 59 vs 67 y (p<0.001). Second line salvage tx was known for 111 pts with EP; salvage tx included BTK inhibitor (BTKi; single agent 19% and in combination 9%), bendamustine (benda) based chemoimmunotherapy (CIT) in 13%, other salvage CIT in 33%, lenalidomide and/or bortezomib (len/bortez) in 16%, and other tx (6%), with 3% of pts receiving no salvage tx. Twenty-four pts underwent allogeneic transplant at any time after progression. Median PFS was 1.4 y (95% confidence interval (CI) 0.8-2.4). No salvage tx was associated with superior PFS (p=0.38); median PFS for single agent BTKi was 1.2 y (CI 0.5-2.9), for benda was 0.7 y (CI. 0.3-1.7), for len/bortez was 0.4 y (CI 0.3-3.3), and for other CIT was 2.3 y (CI 0.5-not reached). PFS after EP did not differ between intensive

<footnote n="1">¹Division of Hematology, Ohio State University Comprehensive Cancer Center, Columbus, United States; ²Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, United States; ³Department of Hematology and Medical Oncology, Winship Cancer Institute, Atlanta, United States; ⁴Department of Internal</footnote>
Figure:

Overall Survival All Patients with Early Progression

<figure><img src="image_221.png" /></figure>

Overall Survival: Early Progression Intensive vs Less Intensive Therapy

<figure><img src="image_222.png" /></figure>

and less intensive frontline tx; median PFS 0.8 vs 1.2 y (p=0.056). The
median OS for pts with EP was 2.0 y (CI 1.1-2.6), with no difference
between intensive vs less intensive frontline tx (2.3 vs 2.0 y, p=0.39).

**Conclusions:** Relapse of MCL within one y of frontline tx is associated with very poor outcomes for all pts regardless frontline tx and post-EP PFS was poor for all current 2nd txs. MCL pts experiencing EP represent an unmet medical need and a target population for novel approaches.

**Keywords:** mantle cell lymphoma (MCL); salvage treatment.

**Disclosures:** Maddocks, K: Honoraria: Teva, Bayer, Novartis, Pharmacyclics; Research Funding: Pharmacyclics, Merck, Bristol-Myers Squibb. Calzada, O: Research Funding: Seattle Genetics. Barta, S: Consultant Advisory Role: Janssen; Research Funding: Merck, Takeda, Celgene, Seattle Genetics, Bayer. Hill, B: Consultant Advisory Role: Pfizer, Pharmacyclics, Abbvie, Genentech, Novartis, Seattle Genetics; Honoraria: Pfizer, Pharmacyclics, Novartis, Abbvie, Seattle Genetics, Genentech; Research Funding: Amgen. Martin, P: Consultant Advisory

Role: Janssen, Gilead, Astra Zeneca/ Acerta, Karyopharm, Sandoz.
**Danilov, A:** Consultant Advisory Role: Astra Zeneca, TG Pharmaceuti-cals, Bayer, Verastem, Genentech, Gilead; Research Funding: Verastem, Genentech, Aptose Biosciences, Bayer, Takeda, Gilead. **Grover, N:** Con-sultant Advisory Role: Seattle Genetics. **Karmali, R:** Other Remunera-tion: Gilead- Speakers Bureau, Astra Zeneca- Speakers Bureau. **Park, S:** Consultant Advisory Role: Rafael Pharma, BMS, G1 Therapeutics, Teva; Research Funding: BMS, Seattle Genetics, Teva, Takeda; Other Remu-neration: Gilead- Speakers Bureau, Seattle Genetics- Speakers Bureau.
**Hamadani, M:** Consultant Advisory Role: Cellerant, Celgene, MedImmune, Janssen; Research Funding: MedImmune, Sanofi Genzyme, Ostuka, Takeda, ADC Therapeutics, Merck; Other Remuneration: Sanofi Genzyme: Speaker's Bureau. **Kahl, B:** Consultant Advisory Role: Gen-entech, Seattle Genetics; Research Funding: ADC Therapeutics. **Flowers, C:** Consultant Advisory Role: Denovo Biopharma, Spectrum, Pharmacyclics, Bayer, Gilead, OptumRx, Genentech/Roche, Abbvie, Karyopharm; Research Funding: Celgene, ECOG, Gilead, BeiGene,
Pharmacyclics, TG Therapeutics, Burroughs Welcome Fund, V Founda-
tion, Abbvie, Janssen, Takeda, Abbvie, Genentech/ Roche, Acerta. Blum,
K: Research Funding: Seattle Genetics, Novartis, Celgene, Morphosys.
Cohen, J: Consultant Advisory Role: Celgene, Infinity Pharmaceuticals,
Abbvie, Millenium, Novartis, Pharmacyclics, Biolnvent, Seattle Genetics;
Research Funding: BMS, Janssen, Novartis, Takeda, Seattle Genetics.

366
ONLINE EDUCATION SIGNIFICANTLY
IMPROVED THE COMPETENCE OF
HEMATOLOGISTS/ONCOLOGISTS AND
NURSES REGARDING THE USE OF BTK
INHIBITORS FOR MANTLE CELL
LYMPHOMA

L. Willis | M. Tanzola

Medscape, LLC, Oncology, New York, United States

**Introduction:** Mantle cell lymphoma (MCL) is an aggressive, rare, form of non-Hodgkin lymphoma. Due to the rarity of MCL, it is important that hematologists/oncologists (hem/oncs) and nurses are competent utilizing treatments in order to optimize patient outcomes. The goal of this initiative was to determine if online education could improve hem/onc and nurse clinical knowledge and competence using BTK inhibitors (BTKi) to treat MCL.

**Methods:** The format was an online continuing medical education (CME)-certified text-based activity composed of 2 patient cases with interactive questions. Evidence-based educational feedback was provided following each response. Three multiple-choice competence questions and 1 self-efficacy question were selected from the set of intra-activity questions to be repeated immediately after activity participation. Questions assessed the impact of the education with a repeated pairs pre-assessment/post-assessment study design where each participant served as his/her own control. A chi-square test was used to identify differences between pre- and post-assessment responses. P values were calculated; those < 0.05 were considered statistically significant. The activity launched online September 20, 2018 and data were collected through March 15, 2019.

**Results:** Results are for those who have completed the pre- and post-assessment questions during the study period (n = 166 hem/onc; n = 363 nurses). Upon completion of the activity, an improvement from pre-to post-assessment was observed in the hem/oncs and nurse's ability to:

* Determine when a BTK inhibitor would be appropriate for a patient with relapsed MCL (hem/oncs: 84% vs 93%, P < .05; nurses: 58% vs 72%, P < .001)

* Differentiate between first and second generation BTKi (hem/oncs: 48% vs 93%, P < 0.001; nurses: 28% vs 53%, P < .001)

* Manage treatment-related adverse events (TRAEs) for patients receiving BTKi (hem/oncs: 59% vs 95%, P < 0.001; nurses: 31% vs 78%, P < .001)

* Report greater confidence incorporating BTKi in the treatment of patients with B-cell malignancies (total average confidence shift; hem/oncs: increase of 17.3%; nurses: increase 18.3%)

**Conclusions:** This online, interactive, case-based CME-certified educational activity led to statistically significant improvements in the knowledge and clinical competence of hem/oncs and nurses regarding selection of patients with MCL to receive BTKi, the differences between first and second generation BTKi, and management of TRAEs for patients receiving BTKi. The results indicate that unique educational methodologies and platforms, which are available on-demand, can be effective tools for advancing clinical decision making. Additional studies are needed to assess whether improved aptitude translates to improved performance during clinical practice.

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

AGGRESSIVE LYMPHOMA

367
VERY EARLY FDG PET/CT SCAN MAY
PREDICT OUTCOMES IN RELAPSED OR
REFRACTORY DLBCL PATIENTS TREATED
WITH SALVAGE THERAPY

J.R. Westin | L. Nastoupil | L. Fayad |

F. Hagemeister | K. Young | T. McDonnell |

S. Neelapu | R.E. Davis | M. Green | S. Ahmed |

R. Nair | R. Steiner | H. Lee | M. Rodriguez |

S. Parmar | H. Chuang

Lymphoma & Myeloma, MD Anderson Cancer Center, Houston, United States

**Background:** Standard therapy for first relapsed Diffuse Large B-cell Lymphoma (DLBCL) is platinum-based chemotherapy (PBC) and autologous stem cell transplant (AutoSCT), however only half of patients respond. To date, there are no patient or tumor factors that are predictive for response. Early identification of lack of response could allow for alternative therapy selection, avoidance of toxic and futile therapy, and potentially impact clinical outcomes. Positron emission tomography-computed tomography (PET-CT) is commonly utilized to assess response after two cycles of PBC, but the utility at earlier time points remains unknown. We conducted an investigator initiated pilot study (NCT02405078) of PET-CT on day 4 and day 21 of therapy for patients with relapsed DLBCL in comparison with standard time points, along with paired collection of blood for circulating tumor (ct) DNA analysis.

**Methods:** Adult patients with relapsed DLBCL who were eligible for PBC and AutoSCT were eligible. Therapy was selected by the treating physician and not restricted per protocol. The primary objectives were
to evaluate the ability of early PET-CT to predict response to standard immunochemotherapy, in comparison with PET-CT at standard time points and with blood based detection of a ctDNA. Patients underwent standard ¹⁸F-fluorodeoxyglucose (FDG) PET-CT during screening and at the conclusion of 2 cycles of PBC per standard clinical practice, and research FDG PET-CT on day 4 and day 21 of cycle 1 of PBC. Treating physicians were not blinded to the research PET-CT results, but were encouraged to manage the patients per standard practice.

**Results:** The protocol has accrued 28 patients from February 2016 to March 2019. The median age was 62 years (range: 25-82), and 36% were female. 61% had poor risk IPI, 71% had advanced stage. 24 patients had a PET-CT on day 4 (4 missing due to patient status factors and logistical issues). The response rates on day 4 were: complete response 21% (CR, n=5), partial response 33% (PR, n=8), stable disease 37.5% (SD, n=9), and progressive disease 8% (n=2). Among the 5 patients with CR on day 4, all had CR at the end of therapy and have not relapsed. Among the 8 patients with PR on day 4, 2 achieved a CR at the end of therapy and 6 had progressive disease. Among the 11 patients with SD or PD on day 4, 2 patients achieved a PR but both had eventual relapse and all others had PD at end of therapy. Additional data from day 21 PET-CT and ctDNA testing may be presented at the meeting.

**Conclusions:** Our pilot study suggests that very early FDG PET-CT may be able to predict for end of therapy response in patients with relapsed DLBCL. Patients who achieve less than a complete response on day 4 of salvage chemotherapy have a high probability of therapeutic failure and could be considered for alternative therapeutic options. The limitations of our study include small patient numbers, heterogeneity of therapy, and availability of PET-CT at very early time points off study.

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

368

PROGNOSTIC VALUE OF BASELINE FDG PET PARAMETERS IN HIGH RISK DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS

I. Fiskvik<fnref n="1" /> | C. Stokke<fnref n="2" /> | L.G. Mikalsen<fnref n="2" /> |
A. Loimaala³ | J. Schildt³ | S. Leppa⁴ | H. Holte⁵

**Introduction:** In treatment of diffuse large cell lymphoma (DLBCL) PET/CT is currently used as interim risk stratification and response evaluation. Here, a high risk cohort of patients included

in a Nordic multi-centre study was analysed to evaluate possible associations between baseline FDG-PET parameters and patient outcome.

**Methods:** Patients with available baseline PET/CT were included for study. Patients were treated with dose-dense chemo-immunotherapy, and data on overall survival (OS) and progression-free survival (PFS) were available for all patients. The following PET parameters were derived for each lesion: Standardized uptake value (SUV) max, metabolic tumour volume (MTV) and total lesion glycolysis (TLG). Total MTV and TLG values (tMTV and tTLG) were evaluated as possible predictors of outcome. Each variable was divided at the median and high vs. low values were entered into Cox regression. Analyses were adjusted for age and international prognostic index (IPI) score.

**Results:** Fifty-one patients were included for study. Median age was 52 years and 29 % were female. Median follow-up time was 42 months (5-66). During follow-up, nine patients died, and ten patients relapsed. Median baseline values (range) for tMTV, SUVmax and tTLG were 567.0 (3.1 – 13505.9), 20.5 (5.1-79.0) and 4615.3 (15.3– 46393.3), respectively.

In adjusted analyses, tMTVwas significantly associated with both increased mortality (HR 5.2, 1.1-11.3-, p=0.037) and relapse or death (HR 4.7, 1.0-10.4, p=0.046). No significant associations were seen for SUVmax or tTLG.

**Conclusion:** Baseline tMTV could be a promising marker for risk stratification at baseline. However, this is a small study sample of high risk DLBCL patients, and results must be interpreted with caution. A larger study of baseline parameters and outcome seems warranted.

**Keywords:** B-cell lymphoma; positron emission tomography (PET); prognostic indices.

369

C-REACTIVE PROTEIN-TO-ALBUMIN RATIO IS AN INDEPENDENT POOR PROGNOSIS AND IMPROVING NCCN-IPI SCORE IN NEWLY DIAGNOSED DIFFUSE LARGE B-CELL LYMPHOMA: A CLINICAL ANALYSIS OF 414 CASES

W. Wei Xu | B. Pan | L. Wang | H. Zhu |
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:** In recent years, increasing evidences have validated that cancer-associated systemic inflammation and malnutrition had exact prognostic impact on the majority of patients with malignancies. Numerous circulating inflammatory and nutritive indicators have been proposed as prognostic indicators for malignant tumors including

<footnote n="1">¹Department of radiology, Diakonhjemmet hospital, Oslo, Norway;</footnote>

<footnote n="2">²Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway; ³Dept of Nuclear Medicine, Helsinki University Hospital, Helsinki, Finland; ⁴Dept of Oncology, Helsinki University Hospital, Helsinki, Finland; ⁵Dept of Oncology, Radiumhospitalet, Oslo, Norway</footnote>
<figure><img src="image_223.png" /><figcaption>**Figure 1.** Time to treatment (TTT) and overall survival (OS) curve of 97 patients with CLL based on EBV-mir-BHRF1-1 by Kaplan-Meier estimation. Low group value is below the cut-off value (0.0012), and high group above the cut-off value.</figcaption></figure>

DLBCL. Among them, the Glasgow Prognostic Score (GPS), the modified Glasgow Prognostic Score (mGPS) are novel inflammatory indicators which consist of C-reactive protein (CRP) and albumin (ALB) and reflect both the systematic inflammatory response and nutritional status. Recently, the ratio of CRP-to-ALB (CAR) has been identified as another serum-based inflammatory indicator and several studies have reported that the CAR is significantly related to prognosis in various types of cancers.

**Methods:** Four hundred and fourteen newly-diagnosed DLBCL patients were enrolled in the retrospective study. The univariate and multivariate Cox proportional hazards models were established for the estimation of prognostic factors. Receiver-operator characteristic (ROC) curves and the corresponding areas under the curve (AUC) were calculated to predict probability of variables.

**Results:** With a median follow-up of 40 months (range, 0 to 105 months), patients with higher CAR displayed unfavorable progression-free survival (PFS) (P<0.001) and overall survival (OS) (P<0.001) (Figure 1). Multivariate Cox regression analysis validated that CAR was independent risk factor for both PFS (HR, 1.548; 95% CI, 1.224 to 1.958; P<0.001) and OS (HR, 1.763; 95% CI, 1.291 to 2.335; P<0.001). It was demonstrated that CAR + NCCN-IPI had a superior prognostic significance than NCCN-IPI alone (P=0.0028 for PFS, P=0.0011 for OS).

**Conclusions:** The pre-existing high CRP-to-ALB ratio was an independent prognostic factor for PFS and OS. Synchronously, adding the criterion of high CAR evidently improved the prognostic capacity of the National Comprehensive Cancer Network -International Prognostic Index (NCCN-IPI) for predicting PFS and OS in DLBCL.

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

370
RELATIONSHIP BETWEEN
SOCIOECONOMIC FACTORS AND DELAY
IN DIAGNOSIS AND INITIAL TREATMENT
IN PATIENTS WITH DIFUSSE LARGE B CELL
LYMPHOMA (DLBCL). DO THESE FACTORS
IMPACT ON THE RESPONSE RATE?
RESULTS OF A MULTICENTRIC
ARGENTINIAN STUDY

M.E. Zerga<fnref n="1" /> | M. Dragosky² | S. Isnardi³ |
G. Stemmelin⁴ | S. Yantorno³ | R. Caccione⁵ |
V. Otero⁶ | M. Marquez⁷ | D. Gotta⁸ | A. Suero⁹ |
G. Alfonso¹⁰ | L. Beligoy¹¹ | G. Flores¹² |
L. Fischman¹² | M. Martinez¹³ | A. Rodriguez¹⁴ |
N. Diaz Velez⁷ | P. Luchetta¹⁵ | V. Welsh¹⁶ |
N. Tartas¹⁷ | N. Schutz⁶ | L. Zoppegno³ |
S. Bonnacorso¹³ | M. Pujol¹⁸ | G. Garate¹⁹ |
C. Mahuad¹⁹ | A. Vicente¹⁹ | G. De stefano<fnref n="1" /> |
S. Cugliari<fnref n="1" /> | M. Miodosky<fnref n="1" /> | L. Melillo<fnref n="1" /> |
D. Fernandez<fnref n="1" /> | L. Kornbliytt¹³ | C. Casali¹⁹ |
F. Aizpuria¹⁹

<footnote n="1">¹Hematology, Instituto Roffo, Buenos Aires, Argentina; ²Hematology, Instituto Henry Moore, Buenos Aires, Argentina; ³Hematology, Hospital San Martin De La Plata, La Plata, Argentina; ⁴Hematology, Hospital Britanico, Buenos Aires, Argentina; ⁵Hematology, Cemic, Buenos Aires;</footnote>
⁶Hematology, Hospital Italiano, Buenos Aires, Argentina; ⁷Hematology, Hospital Marie Curie, Buenos Aires, Argentina; ⁸Hematology, Cemic, Buenos Aires, Argentina; ⁹Hematology, Unidad Asistencial Dr Cesar Milstein, Buenos Aires, Argentina; ¹⁰Hematology, Hospital Posadas, El Palomar, Argentina; ¹¹Hematology, Hospital Perrando, Resistencia, Argentina; ¹²Hematology, Hospital Durand, Buenos Aires, Argentina; ¹³Hematology, Hospital De Clinicas, Buenos Aires, Argentina;

¹⁴Hematology, Academia Nacional De Medicina, Buenos Aires, Argentina;

¹⁵Hematology, Hospital Naval, Buenos Aires, Argentina; ¹⁶hematology, Instituto Oncohematologico Formosa, Formosa, Argentina;

¹⁷Hematology, Instituto Alexander Fleming, Buenos Aires, Argentina;

¹⁸Hematology, Hospital Angela Llano, Corrientes, Argentina;

¹⁹Hematology, Hospital Aleman, Buenos Aires, Argentina

**Introduction:** Immunochemotherapy (ICT) with R-CHOP (or R-CHOP-like) is the standard of care for patients (pts) diagnosed with DLBCL. Due to the aggressiveness of these lymphomas and their potential curability treated with the standard of care, treatment should be initiated without delay.

**Objectives:** To define the impact generated by the delay in the different diagnostic-therapeutic stages, from the onset of symptoms to the administration of ICT, on therapeutic response rates in a series of pts diagnosed with DLBCL from various institutions from Argentina (public and private). We focused our analysis on the reasons of delay and their relationship with socioeconomic factors.

**Patients and methods:** We designed a multicentric, descriptive, retrospective study in which patients diagnosed with DLBCL between 2/2004 and 4/2015 in the participating institutions were registered. Variables of interest were: date of beginning of the symptoms, 1st consultation, date of anatomopathological diagnosis, beginning and end of treatment. All causes of identified delay on the process of diagnosis and treatment were recorded. The place of residence, educational level, health care coverage, availability of rituximab (R) in 1st cycle and response rate, completed the studied variables.

**Results:** 278 pts were recorded (Male/female ratio: 1.007/1). Median age was 54 years old (19-88 years). The interval between symptoms onset and 1st consultation was variable (258 pts): <3 months: 65.11%; 3-6 months: 24.03%; 6-12 months: 7.36%, and more 1 year: 3.48%. The delay was not related to social coverage or educational level, but related to psychological factors: reluctance to consultation in the majority of pts (probably negation).

**Clinical presentation:** ECOG PS: 75% of pts had scores 0-1, only 3% had ECOG:4. 49% of pts had advanced disease (Ann-Arbor III-IV); 18.54% were stage I. Bulky disease was present in 21.08%, and 46% of pts had B symptoms. Extranodal (EN) compromise was present in 55.3% (141/255pts: EN 1: 87.23%; EN 2: 11.34%; EN 3: 1.41%). LDH was increased in the half of pts. Distribution by IPI score was: low: (0-1): 49.09%, Int/low (2): 25.45%, Int/high (3): 16.72% and High (4-5): 8.72%. 55.09 % of pts had social security, 21.50% private medicine and 23.39% had public health system assistance. 12.33% of pts came from rural areas and 11.03% were

foreigners (neighbor countries). The 26.25% had university education, 36.25% completed high-school, 36.87% primary and 0.62% were illiterate.

The interval between diagnosis and onset of ICT (data from 252 pts) was 1 month in 37.3%; 1-3 months: 21.82% and, ≥ 4 months: 5.55% of pts (delay was due to staging process and variable access to ICT). There were no delays in the availability of chemotherapy drugs, but the 27.34% (73/267) did not receive R in 1st cycle due to lack of access. 10.11% received R for advancement from the institution. Only in 62% of pts (167/267) R was available from the 1st cycle by the health coverage.

The response rate among the 250 pts treated and evaluable was: 75.60% CR, 12.40% PR, 1.60% SD and 10.40% PD. Surprisingly there was no correlation between CR rate and delay to the 1st consultation (p=0.31), as well as CR rate and the interval between diagnosis and time to ICT onset (probably due to the low number of cases). Not receiving R from the 1st cycle of ICT was inversely correlated to CR rate (p=0.0063), although these patients completed all doses of rituximab.

**Discussion:** Argentina has a very heterogeneous health system (public, social security and prepaid medicine). The availability of chemotherapeutic drugs is guaranteed by law, but there are differences and delays in the access to high-cost drugs, depending on the payers. Our patients population receive attention in public and private hospitals with different funding sources and access to high cost medication, such as monoclonal antibodies. To emphasize this aspect, our results show that the only variable with impact in the response rate was the fact of not receiving R from the 1st treatment cycle.

**Conclusion:** A prompt beginning of ICT is essential to obtain CR in pts diagnosed with DLBCL. An unacceptable proportion of our DLBCL pts (30%) receive the ICT with some degree of delay, which decreases their chances of achieving CR.

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

## 371
PROGNOSTIC VALUE OF THE INTERVAL BETWEEN RELAPSE AND THERAPY INITIATION IN DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS. ANALYSIS FROM THE CZECH LYMPHOMA STUDY GROUP DATABASE

A. Janikova<fnref n="1" /> | R. Chloupkova² | V. Campr³ |

N. Kopalova<fnref n="1" /> | P. Klener⁴ | K. Benesova⁴ |

J. Hamouzova⁴ | D. Belada⁵ | A. Sykorova⁵ |

V. Prochazka⁶ | J. Pirnos⁷ | J. Duras⁸ |

H. Mocikova⁹ | J. Michalka<fnref n="1" /> | M. Trneny⁴

<footnote n="1">¹Department of Internal Medicine - Hematology nad Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic; ²Institute of Biostatistics and Analyses, Faculty of Medicine Masaryk University</footnote>
Brno, Brno, Czech Republic; ³Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University Prague and Motol University Hospital, Prague, Czech Republic; ⁴First Internal Clinic - Clinic of Hematology, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic; ⁵The 4th Department of Internal Medicine - Hematology, University Hospital and Faculty of Medicine in Hradec Králové Charles University, Hradec Kralove, Czech Republic; ⁶Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Olomouc, Czech Republic; ⁷Department of Oncology, Hospital Ceske Budejovice, Ceske Budejovice, Czech Republic; ⁸Department of Haematooncology, University Hospital Ostrava and Medical Faculty of the Ostrava University, Ostrava, Czech Republic; ⁹Internal Clinic of Haematology, University Hospital Kralovske Vinohrady Prague and Third Faculty of Medicine, Charles University Prague, Prague, Czech Republic

**Introduction:** Patients with relapsed/progressed diffuse large B-cell lymphoma (rDLBCL) survive globally with median 12 months since relapse and majority of deaths is attributed to lymphoma. There is urgent need of efficient therapy for rDLBCL, but clinical trials cannot find efficient therapy up to now. Regardless the selection bias of inclusion/exclusion criteria in clinical trials, time to therapy initiation seems to be a critical point for the trial enrollment.

**Methods:** As a data source for this retrospective analysis, the CLSG (Czech Lymphoma Study Group; Govtrial NT 03199066) database was used. Patients with the first relapse/progression of DLBCL (initial diagnosis 2000-2017) and without CNS involvement were included. The date of relapse was defined as the first documented manifestation (clinical symptoms, radiological finding or the date of biopsy confirming DLBCL). According to time between diagnosis of relapse and start of therapy, patients were divided into three subgroups: 1) <7 days, 2) 7-21 days, and 3) ≥21 days, and the comparison of overall survival (OS) was carried out.

**Results:** Totally, 587 patients with DLBCL relapsed with median 12.8 months (range; 1.6 to 152.3) since diagnosis, 304/587 (51.8%) were males, median age was 67 yrs (range 22-95) at the relapse, 351/587 (49.9%) patients had stage III/ IV, bone infiltration was found in 51/587 (8.7%) cases. B-symptoms appeared in 140/587 (23.9%) cases, ECOG>2 showed 61/587 (10.4%) and bulky disease (≥7.5cm) 129/587 (22%) patients. LDH>norm was present in 387/587 (65.9%) cases. First line systemic therapy was administered in 98% patients, the most frequent chemotherapy backbone was CHOP (70%), anti-CD20 was given to 84% patients (including 99% of rituximab). The therapy of rDLBCL was based on systemic immuno/chemotherapy in 81.9% of patients (40% platinum-based regimen).

Median time between diagnosis of rDLBCL and therapy start was 20 days (1-851 days), 136 pts (23.2%) initiated therapy in <7 days, 166 (28.2%) pts between 7-21days, and 285 (48.6%) ≥21 days. Shorter interval between relapse and treatment was associated with shorter 5-year OS (17.4% vs. 20.5% vs. 42.2%; p<0.001). Subgroups with time to therapy intervals <7 days vs. ≥ 21 days

showed significant differences in clinical and laboratory parameters: B-symptoms (32.8% vs. 18.6%; p.015), limited stage I/ II (31.1% vs. 44.6%; p.031), ECOG ≥3 (19.7% vs. 5%; p.001), bulky disease ≥ 7.5cm (40.2% vs. 19.6%; p.001), elevated LDH (80.8% vs. 58.9%; p.002).

**Conclusions:** The short time between relapse/progression and therapy initiation in rDLBCL is associated with significantly shorter OS and mirrors real clinical behavior of DLBCL represented by worse clinical and laboratory parameters. Unfortunately, this high-risk proportion of patients requiring urgent therapy (< 7 days; 23%) usually fails to enter into majority of clinical trials.

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

## 372
SHORT DIAGNOSIS-TO-TREATMENT INTERVAL IS ASSOCIATED WITH HIGH RISK AND POOR OUTCOMES IN DIFFUSE LARGE B-CELL LYMPHOMA

J. Casan¹ | E. Ansell¹ | A. Davies¹ | M. Gilbertson¹ | S. Opat²

¹Haematology, Monash Health, Clayton, Australia; ²School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia

**Introduction:** Recent evidence has demonstrated associations between adverse risk characteristics and survival outcomes in diffuse large B-cell lymphoma (DLBCL) patients with a shorter diagnosis-to-treatment interval (DTI) (Maurer et al, 2018). The imperative for exigent therapy in aggressive DLBCL presentations may select against the recruitment of such patients to clinical trials and introduce significant bias. We sought to confirm the relationship between DTI and risk status and to compare cohorts of patients receiving standard therapy versus a clinical trial as initial treatment.

**Methods:** Treatment and outcome data were collected for patients with newly diagnosed DLBCL (as per WHO criteria) treated at our institution either with standard therapy or an upfront clinical trial. Associations between DTI and clinical characteristics and outcomes were investigated. Overall survival (OS) and progression free survival (PFS) were modelled using Cox regression. Differences in patient and disease characteristics were analysed with the Mann-Whitney U test or Chi-square test.

**Results:** 455 patients receiving non-trial therapy with reliably determined DTI were identified. An additional 21 patients received upfront treatment on a clinical trial. The median DTI of the non-trial treatment group was 14 days, compared to 20 days for the clinical trial group (p=0.031). 1 patient was treated on a clinical trial within 7 days of diagnosis (5%) vs 122 (26.8%) patients receiving non-trial treatment. Patients with a DTI of >7 days demonstrated superior OS, HR 1.555 [95%CI: