ALBERT

Description: Background: Nivolumab, an immune checkpoint inhibitor, has been tested in patients with classical Hodgkin lymphoma (cHL) who failed standard treatment options and has demonstrated remarkable activity with acceptable safety profile in clinical trials. After the impressive results of nivolumab phase I study, a significant number of patients were granted early access to nivolumab through a Name Patient Program (NPP) or compassionate use in Spain. Demonstrating that results of nivolumab use in real-life are similar to those in clinical trials is of major clinical relevance. Objective: The aim of this retrospective study was to analyze the efficacy and safety profile of nivolumab for the treatment of relapsed/refractory (RR) cHL in a real-life context. Methods: We retrospectively collected data from 34 GELTAMO centers. Eligible patients included RR cHL patients treated with at least one cycle of nivolumab. The primary end-point was to describe the overall response rate (ORR). Secondary objectives were to assess the complete response rate (CR), safety of nivolumab, and clinical outcomes (overall survival [OS], and progression free survival [PFS]). Results: Between September 2015 and May 2018, 74 patients with RR cHL received nivolumab monotherapy dosed at 3mg/kg once every 2 weeks (97%). The median age was 38 years (range 17-78). Patients have received a median of 4 (1-15) prior therapy lines; all but 2 were previously treated with brentuximab vedotin (97%), and 38 (51%) of them underwent a hematopoietic stem cell transplantation (HSCT) (n=33 autologous, autoHSCT, and n=5 allogeneic, alloHCST). Median number of nivolumab cycles was 8 (1-65). Ten (14%) patients are still on treatment. Reasons for nivolumab discontinuation were disease progression in 23/64 (36%), referral to HSCT in 27/64 (42%), adverse events (AE) in 8/64 (13%), patient or physician's decision in 5/64 (8%), and unknown in 1/64 (1%). Treatment related AE were reported in 42/69 (61%). Half of them (21, 30%) were probably immune related AE: grade 1-2, 67% (cutaneous n=5, hepatitis n=3, hypothyroidism n=3, gastrointestinal n=3, suprarenal insufficiency n=1); grade 3-4, 24% (pneumonitis n=2, hepatitis n=1, encephalitis n=1, hypothyroidism n=1); grade 5, 3% (pneumonitis n=1, Stevens-Johnson syndrome + hepatitis + nephritis n=1). ORR was 58% (CR 21/72 patients, partial response [PR] 21/72). Stable disease (SD) was achieved in 9 patients (13%). After an initial response (4 PR and 3 SD), 7 patients developed lymphoma progression. A total of 40 (54%) patients finally underwent HSCT, 4 autoHSCT and 36 alloHCST. AlloHSCT was performed after a median of 63 days (41-115) and 8 patients received prior salvage therapy. Complications after alloHSCT consisted of non-infectious fever requiring steroid treatment in 13 (36%), acute graft-versus-host disease in 19 (53%) (2 of them grade 3-4, 1 death), hepatic venocclusive disease in 2 (6%, 1 death), and non-infectious pulmonary complications in 2 (6%). Five (14%) patients died due to transplant complications. At the last follow-up, all autoHSCT patients and 23/36 alloHSCT were in CR. The 2-year OS for the whole series (n=74) was 54% (median not reached). After a median follow-up of survivors patients of 12.5 months (1-31), 29 (39%) were alive in CR. Conclusions: Our real-life experience confirms the efficacy of nivolumab in very heavily pretreated cHL patients with an ORR of 58%. The safety profile of our cohort is comparable with that previously reported in clinical trials with manageable side effects and low treatment related mortality. In our study the percentage of patients who bridged to transplantation was significantly higher to that previously reported indicating this preference for Spanish physicians. AlloHSCT post-nivolumab showed encouraging results and toxicity seemed comparable to that previously described with other treatment regimens. Authors thank Bristol Myers Squibb for its support in this study. Disclosures Martinez: BMS: Research Funding; Takeda: Consultancy. García-Sanz:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Hospira: Research Funding; Pharmacyclics: Research Funding; Spanish Government: Research Funding; Gilead: Research Funding; Amgen Inc.: Research Funding; Incyte: Consultancy.

Description: Intro Allogeneic-HCT is recommended for AML patients (pts) in CR2, in CR1 with poor-risk cytogenetics, and should be considered for those in CR1 with intermediate-risk. Non-relapse mortality (NRM) and GVHD remain major causes of treatment failure. Ex vivo TCD can prevent GvHD but large case series have not been published. Methods A retrospective chart review was conducted to evaluate 178 pts with AML in CR1 and CR2 undergoing TCD-HCT between 2001 and 2011. All pts received myeloablative-conditioning. The majority received ATG for graft rejection prophylaxis. Acute (A) and chronic(c) GVHD were assessed by standard criteria. No GVHD prophylaxis was administered post-transplant. Soybean agglutination+sheepRBC rosetting (sRBCR) was used for BM TCD. CD34+ selection +/- sRBCR was used for PBSC TCD. Pt characteristics were compared using Pearson's chi-squared and Fisher's exact tests. Prognostic factors relating to overall survival (OS) and DFS, including age, gender, leukemia etiology, cytogenetic-risk group, donor-type, TCD-method, conditioning-regimen, HLA match grade, HCT-specific comorbidity index and immune reconstitution were evaluated using log-rank test statistics. Differences in cumulative incidence (CI) rates were evaluated using Gray's test. Cox proportional-hazards regression was used to further adjust for pt risk factors for OS and DFS. Results Pt characteristics and outcomes are summarized in Tables 1 and 2. Median follow-up of survivors is 52 mo (12-134). 177 pts engrafted. One died pre-engraftment, 7 developed late graft-failure (GF), and 3 are alive after a 2nd HCT. One yr incidence of aGVHD was low (grade 2-4 13%, 3-4 3%). Only 1 pt developed cGVHD by NIH consensus criteria. Univariate association between CR status (1 vs 2), OS and DFS was not statistically significant (p=0.17 and 0.16, respectively). After adjusting for HLA status, age, sex, cytogenetic risk, and regimen, CR2 pts had an increased risk of death (HR: 1.90 (1.14-3.16), p= 0.014). In CR1 pts, cytogenetics was associated with relapse incidence (p=0.003) and was highest in patients with adverse cytogenetics (31%, 95%CI 16-48) and

Description: Introduction Ex vivo TCD Allogeneic-HCT results in long-term relapse-free (RFS) and overall survival (OS) in patients with AML in CR or MDS, with a low incidence of acute and chronic graft-versus-host disease (GVHD). The HCT-CI predicts non-relapse mortality (NRM) and 1-year survival in recipients of conventional grafts. We investigated whether HCT-CI also predicted outcomes in ex vivo TCD-HCT in order to improve patient selection. Methods A retrospective chart review was conducted to evaluate 218 pts (median age 50.4) with AML in CR (n=155) or MDS (n=63) undergoing TCD-HCT between 1997-2008. All pts received myeloablative conditioning. The majority received ATG for graft rejection prophylaxis. No GVHD prophylaxis was administered post-transplant. TCD of BM utilized soybean agglutination+sheepRBC rosetting (sRBCR). CD34+ selection +/- sRBCR was used for PBSC TCD. HCT-CI was determined according to Sorror et al. (Blood 2005). Prognostic factors relating to OS and RFS, including age, conditioning-regimen (TBI vs. chemo), HLA match (identical vs. other), and HCT-CI were evaluated using log-rank test statistics. Univariate and multivariate Cox proportional-hazards regression were performed for OS & RFS. Results The median HCT-CI score was 2 (range 0-9). HCT-CI score was 0 (low) in 25% patients, 1-2 (intermediate) in 36% and ≥3 (high) in 39%. Median follow-up of survivors is 70 months (range 6.1-182.6). Outcomes of the univariate and multivariate analysis are summarized in Table 1. Age and HCT-CI score were significantly associated with OS and RFS by univariate and multivariate analysis. In addition, in the multivariate analysis, HLA-match was associated with OS and RFS, while regimen was only associated with RFS. Patients with a high HCT-CI had significantly lower OS and RFS than those with a low or intermediate HCT-CI (Figure 1). Furthermore, while the cumulative incidence of relapse did not differ based on HCT-CI, patients with a high HCT-CI had a significantly higher incidence of NRM compared to patients with low or intermediate HCT-CI (not shown). Conclusions These results support the use of the HCT-CI to stratify patients with AML and MDS who are eligible for myeloablative TCD-HCT and identify patients who are candidates for other approaches. Interestingly, unlike conventional grafts, we do not see worse outcomes (OS/RFS/NRM) in patients with intermediate vs. low HCT-CI, suggesting that patients with intermediate HCT-CI may better tolerate a TCD-HCT than a conventional HCT. A planned prospective three arm randomized Phase III, comparing two calcineurin inhibitor-free strategies for GVHD prophylaxis (CD34-selection and post-HCT Cy) to standard tacrolimus and methotrexate (BMT-CTN 1301) will further address these questions. Disclosures: No relevant conflicts of interest to declare.

Description: Follicular lymphoma (FL) is a common indolent B-cell lymphoma that can transform into the more aggressive transformed FL (tFL). However, the molecular process driving this transformation is uncertain. In this work, we aimed to identify microRNA (miRNA)-binding sites recurrently mutated in follicular lymphoma patients, as well as in transformed FL patients. Using whole-genome sequencing data from FL tumors, we discovered 544 mutations located in bioinformatically predicted microRNA-binding sites. We then studied these specific regions using targeted sequencing in a cohort of 55 FL patients, found 16 recurrent mutations, and identified a further 69 variants. After filtering for QC, we identified 21 genes with mutated miRNA-binding sites that were also enriched for B-cell-associated genes by Gene Ontology. Over 40% of mutations identified in these genes were present exclusively in tFL patients. We validated the predicted miRNA-binding sites of five of the genes by luciferase assay and demonstrated that the identified mutations in BCL2 and EZH2 genes impaired the binding efficiency of miR-5008 and miR-144 and regulated the endogenous levels of messenger RNA (mRNA).

Description: INTRODUCTION: The use of Peripherally Inserted Central Catheters (PICCs) has increased significantly in the last years due to their advantages compared to the other types of central catheters: easier and protocolized insertion by specialized nurse-led teams; cost-effectiveness; ease of management, ... However, an increase in the incidence of Catheter Related Thrombosis (CRT) has been observed with this type of device, especially in cancer patients and in the critical care setting. The main objective of this study is to determine the incidence of PICC related deep venous thrombosis in oncologic and onco-hematologic patients at the Donostia University Hospital, in Spain. The secondary outcome is the identification of possible risk factors associated with this event. METHODS: Using the database created and handled by the nurse-led Intravenous Therapy Team (ITT) in our center, in which all inserted PICCs are prospectively and consecutively included since 2011, a retrospective analysis was conducted on oncology and hemato-oncology-derived adult patients (over 18 years old) with a PICC inserted between May 15th 2018 and December 15th 2019. In the total population, several characteristics of the patient, of the PICC and of the thrombotic event were descriptively analyzed, and a bivariant analysis of four potential risk factors was carried out using Pearson's Chi-squared test. Patient and CRT treatment-associated risk factors were more exhaustively analyzed in the subgroup of patients with CRT. The missing data were obtained from the electronic clinical history records. RESULTS: The final study sample consisted of 1024 PICCs (n=1024), 19,10% (n=313) derived from the Hematology department and 43,62% (n=715) from the Oncology department (tables 1 and 2). The global incidence of CRT was 4,9% (n=50): 5.8% in hematologic patients and 4.5% in patients derived from Oncology. In the bivariant analysis no significant association was found between the selected potential risk factors (department of origin, PICC lumen number, PICC material and the catheter-to-vessel ratio) and CRT (table 3). In terms of the treatment administered to patients presenting CRT, in 80% of the cases (n=40) a Low Molecular Weight Heparin (LMWH) at therapeutic dose was initiated; in 10% (n=5) LMWH at a lower dose, and in 2 patients treatment could not be initiated because of thrombopenia. Finally, the PICC was withdrawn in only 8 patients after the diagnosis of the thrombotic event. CONCLUSIONS: The majority of the studies on PICC associated venous thrombosis in cancer patients are small, observational, retrospective, and without comparison groups. Here we present a work with an important sample size, a homogeneous population and with a prospective data collection. The CRT incidence has been similar to that described in the literature and significant association has not been found between the included potential risk factors and CRT. In conclusion, this study reflects the need of more trials on this subject, in particular to identify CRT risk factors in order to design effective prevention strategies. Disclosures No relevant conflicts of interest to declare.