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This retrospective study evaluated 66 patients diagnosed with relapsed and/or refractory mantle cell lymphoma (R/R MCL) treated with ibrutinib in Spain in routine clinical practice. At diagnosis, patients had a median age of 64.5 years, 63.6% presented with intermediate/high sMIPI (simplified prognostic index for advanced-stage mantle cell lymphoma), 24.5% had the blastoid variant, and 55.6% had a Ki67 > 30%. Patients had received a median of 2 prior lines of therapy (range 1-2; min-max 1-7). Overall response rate was 63.5%, with 38.1% of patients achieving complete response (CR). With a median duration of ibrutinib exposure of 10.7 months (range 5.2-19.6; min-max 0.3-36), the median progression-free survival (PFS) and overall survival (OS) were 20 months [95% confidence interval (CI) 8.8-31.1] and 32 months (95% CI 22.6-41.3), respectively, and were not reached in patients achieving CR. No grade >= 3 cardiovascular toxicity or bleeding was reported. This study supports that treatment with ibrutinib leads to high response rates and favorable survival outcomes in patients with R/R MCL.

RESUMEN La participación del aparato genitourinario en el contexto de la enfermedad hematológica maligna es bien conocida. No obstante, la afectación ovárica por linfomas es inusual, ya sea de novo o como manifestación tardía de linfoma diseminado. El objetivo de esta comunicación es exponer la aportación diagnóstica de la ecografía tridimensional (3D) en la detección de metástasis ováricas, cuando todavía algunas de las pruebas de imagen estándar como la tomografía computarizada (TAC) son normales. En este caso presentamos una paciente con linfoma B difuso de células grandes mediastínico de crecimiento rápido y diseminación precoz a aparato gastrointestinal y genitourinario.

Context: Ibrutinib is a first-in-class oral inhibitor of Bruton's tyrosine kinase, has been established as a standard-of-care (SOC) treatment for R/R MCL. The clinical benefits with ibrutinib has been demonstrated in multiple trials and real-world studies.1-3 Objective: To describe ibrutinib outcomes in real-world patients in Spain. Design: IBRORS is a retrospective multicentre observational study of patients with confirmed diagnosis of R/R MCL who were treated with ibrutinib from January 2016 to March 2019 (6 months prior to the start of the study). The primary end point was PFS. Disease characteristics, previous therapies used, response rates, and survival outcomes with ibrutinib were also evaluated. Patients or other participants: The analysis included 66 evaluable patients from 24 centres in Spain. Median age at diagnosis was 64.5 years (range 57-72), and 78.8% were male. Baseline comorbidities of interest include: hypertension (47%), dyslipidemia (36.4%), and cardiovascular disorders (21.2%). Interventions: Patients had a median of 2 prior lines of therapy (range 1-8). Among the pre-ibrutinib treatments used, the most common treatment was bendamustine plus rituximab in 20.7% of cases, followed by R-CHOP-like combinations in 19.3% and Hyper-CVAD in 16.4%. Results: With a median follow-up of 14.2 months after Ibrutinib initiation, Ibrutinib treatment led to an ORR of 67.8% with a complete response in 24 patients (36.4%) and partial response in 16 patients (24.2%). Median PFS was 20.0 months (95% CI, 8.8-31.1) and median OS was 32 months (95% CI, 22.6-41.3). Adverse events were reported in 43 patients (65.1%). Atrial fibrillation or associated cardiovascular diseases were reported in 2 patients and no major hemorrhages were reported. Conclusions: IBRORS provides information on the first real-world study of ibrutinib use in clinical practice in Spain. The results suggest that ibrutinib is mostly being used in first and second relapses. The data evaluated confirms the favorable adverse event profile and manageability of ibrutinib in real-world clinical practice. References: [1] Wang et al. Blood. 2015; 126:739-745. [2] Wang et al. NEJM. 2013; 369:507-16. [3] Le Gouill et al. EHA 2019, PS1264.

Several studies have reported uneven results when evaluating the prognostic value of bone marrow biopsy (BMB) and PET/CT as part of the staging of diffuse large B‐cell lymphoma (DLBCL). The heterogeneity of the inclusion criteria and not taking into account selection and collinearity biases in the analysis models might explain part of these discrepancies. To address this issue we have carried a retrospective multicenter study including 268 DLBCL patients with a BMB and a PET/CT available at diagnosis where we estimated both the prognosis impact and the diagnostic accuracy of each technique. Only patients treated with R‐CHOP/21 as first line (n = 203) were included in the survival analysis. With a median follow‐up of 25 months the estimated 3‐year progression‐free survival (PFS) and overall survival (OS) were 76.3% and 82.7% respectively. In a multivariate analysis designed to avoid a collinearity bias with IPI categories, BMB‐BMI [bone marrow involvement](+) (HR: 3.6) and ECOG PS > 1 (HR: 2.9) were independently associated with a shorter PFS and three factors, age >60 years old (HR: 2.4), ECOG PS >1 (HR: 2.4), and abnormally elevated B2‐microglobulin levels (HR: 2.2) were independently associated with a shorter OS. In our DLBCL cohort, treated with a uniform first‐line chemotherapy regimen, BMI by BMB complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort BMI by PET/CT could not independently predict a shorter PFS and/or OS.

Criteria of response and definition of resistance and intolerance to hydroxyurea (HU) in polycythemia vera (PV) were proposed by the European LeukemiaNet (ELN). Such criteria were evaluated in 261 PV patients (median follow-up, 7.2 years) treated with HU for a median of 4.4 years. Complete response, partial response, and no response were observed in 24%, 66%, and 10% of patients, respectively. Achieving ELN response (complete or partial) or hematocrit response did not result in better survival or less thrombosis and bleeding. On the contrary, having no response in leukocyte count was associated with higher risk of death (HR, 2.7; 95% confidence interval [CI], 1.3%-5.4%; P = .007), whereas lack of response in platelet count involved a higher risk of thrombosis and bleeding. Resistance and intolerance to HU was registered in 11% and 13% of patients, respectively. Resistance to HU was associated with higher risk of death (HR, 5.6; 95% CI, 2.7%-11.9%; P < .001) and transformation (HR, 6.8; 95% CI, 3.0%-15.4%; P < .001). In summary, fulfilling the ELN definition for response to HU was not associated with a benefit in the clinical outcome in PV, whereas response in platelet and white blood cell counts were predictive of less thrombohemorrhagic complications and better prognosis, respectively. Resistance to HU was an adverse prognostic factor.

Standardized criteria of response to treatment and a unified definition of resistance/intolerance to hydroxycarbamide (HC) in essential thrombocythaemia (ET) have been proposed by the European LeukaemiaNet (ELN). We have retrospectively evaluated such criteria in 166 ET patients treated with HC for a median of 4·5 years. Overall, 134 patients achieved a complete clinicohaematological response (CR) and 25 a partial response. Thirty-three patients met at least one of the ELN criteria defining resistance (n = 15) or intolerance (n = 21) to HC. Fifteen cases developed anaemia with thrombocytosis, which was associated with a high incidence of myelofibrosis and death from any cause. Other definitions of resistance were less useful. Factors determining the thrombotic risk were a history of prior thrombosis and a baseline leucocyte count >10 × 10⁹/ l. Of note, patients achieving a CR, even if sustained during the entire follow-up, did not benefit from a lower incidence of thrombosis or an improved survival. In conclusion, most ET patients respond to HC, but the achievement of response, as defined by the ELN, does not correlate with the patients' outcome. The best discriminating ELN criterion of resistance to HC was the detection of anaemia, which also identified a subgroup of patients with poor prognosis.

Background: High serum levels of soluble intercellular adhesion molecule-1(s-ICAM-1/s-CD54) have been associated with adverse clinical features and poor outcome in chronic lymphocytic leukemia, Hodgkin’s disease and non-Hodgkin’s lymphoma, but their value in the different subtypes of non-Hodgkin’s lymphoma has not been well addressed. Patients and methods: Our aim was to study the serum levels of s-ICAM-1 in diffuse large B-cell lymphoma (DLBCL) and to correlate them with clinical characteristics and outcome. We analyzed the serum levels of s-ICAM-1 in a series of 55 patients with DLBCL diagnosed in a single institution. s-ICAM-1 levels were quantified by an immunoenzymatic assay. Median age was 62 years (range 22–96); 29 (53%) were male. Twenty-eight (51%) presented with advanced clinical stage (III/IV), 32 (58%) had extranodal involvement, 28 (51%) had high serum lactate dehydrogenase (LDH) and 23 (43%) had high β2 -microglobulin levels. All patients received anthracycline-containing regimens. Correlation between clinical variables and s-ICAM-1 levels were tested with the Mann–Whitney U-test and survival was plotted by the Kaplan–Meier method, and curves compared with the log-rank test. Results: Serum levels of s-ICAM-1 were significantly increased in patients with DLBCL compared with normal controls (589 ± 487 versus 279 ± 65 ng/ml, respectively; P

The hallmark for Chroniclymphocytic leukemia (CLL) is a highly variable clinical course. An international prognostic index (CLL-IPI) is a promising tool to improve the precision of prognostic counseling and to identify patients who deserve closed monitoring. The CLL-IPI is a risk-weighted model comprising the risk factors age, stage, del(17p)/TP53 mutation, IGHV mutation status, and β2-microglobulin (β2-M)(LancetOncol 2016). The aims of the study were 1) to determine the IGHV status as well as the IGHV repertoire 2) to assess/validate the applicability of the CLL-IPI in general practice. We included all patients diagnosed of CLL according to the National Cancer Institute Working Group guidelines in our institution between 1986 and 2014 who had at least a 24 months follow-up. Amplification and sequence analysis of IGH rearrangements were performed on either DNA or cDNAusing the BIOMED-2 protocol. Sequence data were analyzed using the IMGT database and tools. Clinical and biological data were extracted from medical records and included age, stage, CD38 and ZAP-70 expression, serum LDH, β2-M, cytogenetics and lines of treatment. Overall survival (OS) was calculated from diagnosis to last follow-up or death, time to first treatment (TFT) from diagnosis to first treatment administration or last follow-up. 209 CLL patients were originally included but complete data to calculate the CLL-IPI was only available in 176 pts. Median age of the series was 65 years (range, 33 to 92), and a slight male predominance 102 (58.5%). The main clinical characteristics are detailed in Table 1. Median follow-up of patients was 71.5 months (range, 24-315). We identified 105/209 patients (50%) with unmutated IGHV. Somatic mutations among IGHV gene subgroups display a hierarchy of mutations (IGHV3>IGHV1>IGHV4). Among the functional IGHV genes, the most frequently encountered were IGHV1-69 (31; 14.6%). It was the most recurrently used in the unmutated group. The most represented IGHV gene within the mutated subset was IGHV4-34, which was used in 15 cases (7.1%). We have observed 39 IGHV genes. The most frequents are showed in Figure1. As previously described, patients with unmutated status showed a higher expression of CD38 and ZAP-70, unfavorable cytogenetics and a higher proportion of treated patients. The CLL-IPI index identified four groups of patients: low risk (0-1 points) n=74 (42%), intermediate (2-3) 67 (38.1%), high (H) (4-6) 29 (16.5%) and very high (VH) 6 (3.4 %). The 5-year OS and 5-year TFT of the CLL-IPI risk groups differed significantly (p< 0.0001, log-rank test) between the low (OS 92.2%, TFT 74.1%), intermediate (OS 83.2%, TFT 34.6%) and high-very high groups (OS 61.5%, TFT 22.8%). We only identified 6 patients (3.4%) with a VH, with no difference in terms of OS and TFT between the VH and high (H) risk groups, probably due to the small number of patients. When we considered the H and VH altogether, the CLL-IPI identified three groups with significantly different TFT and OS (Figure 2) In summary, in our cohort the frequencies of the IGHV genes used in BCR rearrangements were similar to those described in the Mediterranean area and confirm a geographical-dependent leukaemic repertoire. We confirm that the CLL-IPI is a useful tool for real-life practice as it identifies three risk groups with significantly different time to first treatment and overall survival curves. In our experience, the CLL-IPI applied to the whole CLL population at diagnosis discriminates a smaller proportion of patients in the high (16.4%) and very high groups (3.4 %) compared to the original training cohort based on treated patients included in clinical trials. Our results are closely similar to the MAYO cohort that included patients consecutively diagnosed and observed. Table 1 Patient characteristics at diagnosis included in CLL-IPI analysis (n=176) Table 1. Patient characteristics at diagnosis included in CLL-IPI analysis (n=176) Figure 1 Distribution of rearrangements of the 12 most frequent IGHV genes according to mutational status. Figure 1. Distribution of rearrangements of the 12 most frequent IGHV genes according to mutational status. Figure 2 a) Overall survival b) Time to first chronic lymphocytic leukaemia treatment according to the CLL-IPI risk groups Figure 2. a) Overall survival b) Time to first chronic lymphocytic leukaemia treatment according to the CLL-IPI risk groups Disclosures No relevant conflicts of interest to declare.

Standardized criteria of response to treatment and a unified definition of resistance/intolerance to hydroxycarbamide (HC) in essential thrombocythaemia (ET) have been proposed by the European LeukaemiaNet (ELN). We have retrospectively evaluated such criteria in 166 ET patients treated with HC for a median of 4·5 years. Overall, 134 patients achieved a complete clinicohaematological response (CR) and 25 a partial response. Thirty-three patients met at least one of the ELN criteria defining resistance (n = 15) or intolerance (n = 21) to HC. Fifteen cases developed anaemia with thrombocytosis, which was associated with a high incidence of myelofibrosis and death from any cause. Other definitions of resistance were less useful. Factors determining the thrombotic risk were a history of prior thrombosis and a baseline leucocyte count10 × 10⁹/ l. Of note, patients achieving a CR, even if sustained during the entire follow-up, did not benefit from a lower incidence of thrombosis or an improved survival. In conclusion, most ET patients respond to HC, but the achievement of response, as defined by the ELN, does not correlate with the patients' outcome. The best discriminating ELN criterion of resistance to HC was the detection of anaemia, which also identified a subgroup of patients with poor prognosis.

The optimal approach to obtain an adequate graft for transplantation in patients with poor peripheral blood stem cell (PBSC) mobilization remains unclear. We retrospectively assessed the impact of different strategies of second-line stem cell harvest on the transplantation outcome of patients who failed PBSC mobilization in our institution. Such patients were distributed into three groups: those who proceeded to steady-state bone marrow (BM) collection (group A, n = 34); those who underwent second PBSC mobilization (group B, n = 41); those in whom no further harvesting was carried out (group C, n = 30). PBSC harvest yielded significantly more CD34+ cells than BM collection. Autologous transplantation was performed in 30, 23 and 11 patients from groups A, B and C, respectively. Engraftment data and transplantation outcome did not differ significantly between groups A and C. By contrast, group B patients had a faster neutrophil recovery, required less platelet transfusions and experienced less transplant-related morbidity, as reflected by lower antibiotics needs and shorter hospital stays. In conclusion, remobilization of PBSC constitutes an effective approach to ensure a rapid hematopoietic engraftment and a safe transplantation procedure for poor mobilizers, whereas unprimed BM harvest does not provide any clinical benefit in this setting.

Background B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease with a highly variable clinical outcome. Recent studies have identified a number of different molecular prognostic markers (including mutational status of the IgVH gene, ZAP70 and CD38 expression) that allow to discriminate patients in prognostic subgroups. However, different expression patterns of angiogenic factors as VEGF, VEGFR1 and bFGF have been related with B-CLL susceptibility and treatment requirements. We have analyzed the polymorphisms: -710 C/T in VEGFR1, rs1109324, rs1547651, rs3025039 (936C/T) and rs833052 in VEGF and rs1449683 (223 C/T) in bFGF in order to determine the possible association with susceptibility in B-CLL. Methods Peripheral blood samples from 230 B-CLL patients and 476 healthy controls were genotyped using probes TaqMan SNP Genotyping Assays. Samples were providing from the Hospital Clinic of Valencia. Four SNPs in the VEGF gene, one SNP in the bFGF gene and one SNP in the VEGFR1 gene were evaluated. Statistical analysis was performed using SNPStats program (Catalan Institute of Oncology) and Fisher's exact test was applied to evaluate the significance. Results We have observed an increased frequency of the T allele in the rs1449683 SNP [OR 1.62 (95% CI: 0.98-2.66) p-value =0.063] and in the rs1547651 SNP [OR 0.72 (95% CI: 0.51-1.03), p-value=0.072] in our B-LLC patients when compared to control subjects. Moreover we observed that T allele carriers of rs3025039 (VEGF) have a significant protective effect concerning this disease [OR 0.59 (95% CI: 0.39-0.89) p-value=0.009]. Conclusion Our data indicate an increased frequency of the T allele in polymorphisms rs1449683 (bFGF) and rs1547651 (VEGF) in the group of patients, which possibly account for the individual susceptibility to develop B-CLL. On the other hand the data provided suggest that the T allele of VEGF rs3025039 is likely important genetic marker of susceptibility to B-CLL. Further studies regarding the role of pro-angiogenic markers in B-CLL would be beneficial to help elucidate pathogenic pathways in this disease. Disclosures: No relevant conflicts of interest to declare.

Abstract 3917 INTRODUCTION VEGF is an important pro-angiogenic factor involved in survival and dissemination of chronic lymphocytic leukemia cells. At high concentrations such as those present in bone marrow niches, VEGF reduces MMP9 production and favours bone marrow retention. But on the other hand, it is well known that autologous VEGF and CD49d are required for B-CLL cell migration. In other cancer cell lines, this effect seems to be mediated by CXCR4/SDF-1 axis. In this work we studied the role of exogenous VEGF on B-CLL migration as well its relationship with the G-coupled proteins CXCR4, CXCR7 and CD49d. MATERIALS AND METHODS We obtained peripheral blood mononuclear cells from 33 patients diagnosed of CLL according to established clinical and laboratory protocols at our institution after informed consent. We also used the CLL cell line Mec-1. B-lymphocytes were purified by Ficoll-Hypaque density gradient centrifugation anti-CD19 conjugated Dynabeads and stored in liquid nitrogen. Then we analysed by flow cytometry the expression of several chemokines and adhesion molecules, CXCR4, CXCR7 and CD49d before and after exogenous VEGF exposure (50 ng/mL), VEGF-R2 inhibitor (70 nM) or both. In order to evaluate the role of VEGF in the motility of these cells, we performed an in vitro 24-hours transmigration assay towards a media containing (or not) SDF-1. B-CLL (5 × 105 cells) cells were incubated on the upper chamber of transwell filters coated with human umbilical vein endothelial cells in the presence or absence (control) of vascular endothelial growth factor (VEGF) ([50 ng/ml], 24 hours), VEGFR2/KDR inhibitor [70nM] or both simultaneously. We quantified the migration ratio between those stimulated with VEGF compared with non-stimulated controls, inhibitor-treated cells versus control and both (R2-inh plus VEGF) versus inhibitor-treated cells. Migration ratio was given as mean ± SD. Statistical analysis was performed by non-parametric Wilcoxon test using SPSS statistical software (version 19.0). RESULTS Basal CXCR4, CXCR7 and CD49d expression levels of B-CLL cells were highly variable among the 33 patients analyzed. Mean fluorescent intensity (MFI) of CXCR4 expression was significantly higher on cells treated with VEGF versus untreated cells (average increase, 9.64 ± 95, p=0.028). However, we did not detect a significant difference in the percentage of cells expressing this receptor. On the other hand, VEGF treatment did not influence either the mean fluorescent intensity or the number of CXCR7 and CD49d expressing cells. Exposure to a VEGFR2 inhibitor reduced the percentage of cells expressing CXCR4 and CXCR7, suggesting a potential regulatory role of this receptor in the expression of these chemokines. Concerning B-CLL migration, we observed a significant increase in cell migration of cells treated with exogenous VEGF versus the control ones in both the Mec-1 cell line and the primary cells (27.66 ± 69.97 p= 0.03). Furthermore, the treatment with VEGFR2 inhibitor reduced significantly the migration index (−23.18 ± 33.5, p= 0.001) and the motility was restored by the addition of VEGF to the R2-inhibitor treated cells (36.04 ± 39.33, p=0.001). DISCUSSION This preliminary data suggest that VEGF seems to be involved in B-CLL migration through the regulation of CXCR4 expression levels. Detailed molecular mechanisms implicated in this process should be further studied. New therapeutic strategies focussed in blocking both the SDF1-CXCR4 axis and/or VEGF pathway could have a potential therapeutic implication by decreasing B-CLL cell migration into lymph nodes and bone marrow microenvironment. Disclosures: No relevant conflicts of interest to declare.

Abstract 4035 Introduction: Bendamustine is a dual alkylating agent with demonstrated efficacy in de novo multiple myeloma (MM) and in relapsed/refractory (R/R MM). We present the preliminary results from the experience of Spanish compassionate use registry of this agent in different treatment schedules of R/R MM, promoted by the GEM/PETHEMA Group (Benda-MMRR-11). This study has been approved by local ethical committee, CEIC, HUP, Madrid, Spain. Patients and Methods: 72 patients, 42 males and 30 females, with advanced R/R MM after several lines of previous treatment received a schedule containing Bendamustine (Levact®, Mundipharma, UK). Median age was 66 (35–86), with a median of 4 previous salvage lines (1–11). Bendamustine dose used ranged between 60 and 120 mg/m2 iv on days 1 and 2 for each 28 days cycle. The median of cycles was 2 (1–9). The combinations used were: Bendamustine + Prednisone in 27 patients, Bendamustine + Thalidomide + Prednisone in 11 cases, Bendamustine + Dexamethasone in 14 patients, Bendamustine + Bortezomib + Dexamethasone in 7 patients, Bendamustine + Bortezomib + Prednisone in 3 patients, Bendamustine + Thalidomide + Dexamethasone in 2 cases, Bendamustine monotherapy in 5 patients, Bendamustine + Thalidomide in 1 case, Bendamustine with Caelyx in 1 case and Bendamustine with Rituximab in 1 case. Results: In the 69 evaluable patients, the response was: overall response rate (ORR) 30.24%%, with complete response (CR) 11.5%, partial response (PR) 13.04%. Minimal response (MR) was 5.7%, and stable disease (SD) was 17.39%. Progression was documented in 52.1% of patients. In general, treatment was well tolerated; the most common adverse effect was hematological toxicity with grade 3–4 neutropenia in 31.8%, grade 3–4 thrombocytopenia in 30.4% and grade 3–4 anemia in 17.3%. Other toxicities included grade 3–4 infections in 27% of patients and grade 3–4 asthenia in 11.5%. Clinical results will be updated with more details regarding TTP, OS and efficacy and toxicity with each schedule. Comments: Bendamustine is an effective salvage therapy in patients with advanced R/R MM. Our results are consistent with previous published data in larger series of patients. More experience is needed with this agent to define the best combination and to assess its grade of efficacy that will be probably superior in earlier stages of myeloma evolution. Disclosures: Off Label Use: compassionate use.