Abstract: Bone marrow infiltration (BMI), categorized as an extra‐nodal site, affects stage and is associated with poor prognosis in newly diagnosed lymphoma patients. We have evaluated the accuracy of PET/CT and bone marrow biopsy (BMB) to assess BMI in 372 lymphoma patients [140 Hodgkin Lymphoma (HL) and 232 High Grade B‐cell non‐Hodgkin Lymphoma (HG B‐NHL), among them 155 Diffuse Large B‐Cell Lymphoma (DLCL)]. For HL cases, and taking into account PET/CT, sensitivity, negative predictive value (NPV) and accuracy were 96.7, 99.3, and 99.3% while those of BMB were 32.3, 83.8, and 85%, respectively. For HG B‐NHL and considering PET/CT, sensitivity, NPV, and accuracy were 52.7, 81.7, and 84.1%, while those of BMB were 77.6, 90.2, and 90.7%, respectively. In the HG B‐NHL group, 25 patients would have been under‐staged without BMB. These results lead us to recommend PET/CT and the avoidance of BMB to assess BMI in HL. In the case of HG B‐NHL, bone marrow status should be assessed firstly by means of PET/CT; only in either focal or diffuse PET/CT with low borderline SUV max values or in negative cases, should BMB be carried out afterwards. In the HG B‐NHL setting and at the present moment, both techniques are complementary. Am. J. Hematol. 90:686–690, 2015. © 2015 Wiley Periodicals, Inc.

Abstract: Background: The intake of anthracyclines in blast cells could be affected by several transporters, including influx transporters (SLC22A16 and SLCO1B1) and efflux pumps of ABC family. Previous studies suggested that single nucleotide polymorphisms (SNPs) of genes coding for anthracyclines transporters may influence their effectiveness or toxicity, although their impact in acute myeloid leukemia (AML) induction therapy remains undetermined Methods: SNPs of anthracycline transporter genes (ABCB1: rs1128503, rs1045642, rs2032582 and haplotype; ABCC1: rs4148350; ABCC2: rs8187710; ABCG2: rs2231142, rs2231137; SLCO1B1: rs4149056; SLC22A16: rs12210538, rs714368) were evaluated in 225 adult patients at initial diagnosis from AML using a Sequenom (iPLEX) mass spectrometry-based multiplex genotyping assay (Sequenom, San Diego, CA). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA-LMA 99, 2007 and 2010 trials). Efficacy of first induction cycle was evaluated comparing complete remission (CR) vs. partial remission or resistance. Patients dying during induction were considered as no evaluable for efficacy. Based on WHO grading scale, toxicities were grouped as binary variables (grade 0-1 vs. grade 2-4). The grade of toxicity assigned to an organ group was the maximum grade of all the specific toxicities within that group. Renal and hepatic toxicities were also evaluated with analytic markers (renal function with urea and creatinine; hepatic function with bilirubin, AST, ALT, FA and GGT). Hematologic toxicity was measured with the time to neutropenia and thrombocytopenia recovery since first day of chemotherapy. Genotypes were studied with co-dominant model. Association between variables was assessed using linear and logistic regression adjusting for age, gender, ECOG, leukocyte and platelet count at diagnosis (R® version 3.1.2). Results: The median age of patients was 51.1 years (16-78 years). There were no statistically significant differences in CR or hematologic toxicities. Nevertheless, several associations were obtained between transporter genes polymorphisms and toxicities (significant toxicities were summarized in table 1 and 2). Variant allele of ABCB1 SNPs was previously related with lower activity of ABCB1 pump in kidney cells and lower anthracycline clearance. Accordingly, we obtained nephrotoxicity associated with these SNPs. Association between cardiac toxicity and ABCG2 polymorphisms was found in agreement with previously published works. The ocular toxicity associated with SLCO1B1 was also correlated with low platelet count at diagnosis in multivariable analysis. Table 1. Significant association between SNPs in gene transporters and different toxicities Toxicity Gene/SNP Genotypes Grade 0-1 n (%) Grade 2-4 n (%) OR (95%IC) P Cardiotoxicity ABCG2 rs2231142 CC CA 171 (83.0) 9 (47.4) 35 (17.0) 10 (52.6) 5.64 (1.86-17.80) 0.002 Lung toxicity ABCG2 rs2231142 CC CA 174 (84.5) 12 (63.2) 32 (15.5) 7 (36.8) 3.37 (1.09-10.40) 0.031 Skin toxicity SLCO1B1 rs4149056 TT TC 112 (71.8) 21 (48.8) 44 (28.2) 22 (51.2) 2.43 (1.17-5.06) 0.015 Nephrotoxicity ABCB1 haplotype Other genotypes TT/TT/TT 175 (89.3) 21 (72.4) 21 (10.7) 8 (27.6) 3.74 (1.24-10.85) 0.002 Ocular toxicity ABCC1 rs4148350 GG GT/TT 205 (99.0) 16 (88.9) 2 (1.0) 2 (11.1) 13.7 (2.08-90.47) 〈 0.001 Ocular toxicity SLCO1B1 rs4149056 TT CC 155 (99.4) 23 (92.0) 1 (0.6) 2 (8.0) 9.97 (1.39-71.39) 0.019 Table 2. Significant association between SNPs in gene transporters and analytic markers of renal and hepatic function Hematologic toxicity Gene/SNP Genotypes Mean values (mg or U/dL) Logarithm of the difference (95%IC) P Urea ABCB1 rs1045642 CC TT 57.98 70.89 0.20 (0.01 to 0.40) 0.044 Urea ABCB1 rs2032582 GG TT 56.34 72.07 0.23 (0.03 to 0.42) 0.021 Urea ABCB1 haplotype Other genotypes TT/TT/TT 59.29 78.14 0.24 (0.04 to 0.43) 0.019 Bilirubin ABCB1 rs1045642 CC CT TT 1.77 2.59 2.91 0.021 (0.01 to 0.40) 0.39 (0.12 to 0.65) 0.036 0.004 ALT SLCO1B1 rs4149056 TT TC 90.92 161.02 0.30 (0.01 to 0.60) 0.049 Conclusions: This study shows a prognostic impact of transporter genes polymorphisms in adult AML patients regarding induction chemotherapy efficacy and toxicity. Further studies with larger population are needed to validate these associations, which could be useful biomarkers in clinical practice. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction. Ibrutinib is a first-in-class, oral, once-a-day Bruton's tyrosine kinase inhibitor that achieves high overall response rates and durable remissions in patients with chronic lymphocytic leukemia (CLL) including those with high-risk features (unmutated IGHV, TP53 abnormalities, 11q deletion). Survival with continuous single-agent ibrutinib in previously-untreated CLL patients is comparable to an age-matched general population (Figure 1). IBRORS is an observational, retrospective, multicentre study to describe the characteristics and clinical outcomes of patients with CLL treated with single-agent ibrutinib in routine clinical practice in Spain. This present analysis reviews the subset of patients in IBRORS who received ibrutinib as the first-line of treatment. This series includes a significant number of patients with high risk cytogenetic/molecular alterations (del17p/TP53 M), which corresponds with the approved indication for first-line CLL patients in Spain at the time. Methods. Adult patients diagnosed with CLL treated with single-agent ibrutinib in first-line, or at first or second relapse since its commercialization in Spain (between January 2016 to January 2019) were included in the IBRORS study. Clinical characteristics of patients, efficacy and tolerability of ibrutinib as first-line treatment were analyzed here. A Kaplan-Meier analysis was performed for overall survival (OS) and progression-free survival (PFS). Results. 84 patients, from a total of 269 included in IBRORS, received single-agent ibrutinib as first-line treatment. The median age was 71.3 years (range 63-77) at the time of ibrutinib initiation. 56.3% of patients presented with an intermediate/high-risk Rai-Binet stage, and the majority of patients (98.6%) had an ECOG PS of 0-1. 91.7% of patients had at least 1 high risk molecular cytogenetic factor (unmutated IGHV, TP53 abnormalities, 11q deletion or complex karyotype) described in table 1. Baseline comorbidities of patients are described in table 2. Concomitant medication included anticoagulants (9.5% patients; vitamin K antagonist [n=4], Apixaban [n=1] and LMWH [n=3] patients), antiplatelet agents (11.9% patients), and antihypertensives (50% patients). The overall response rate (ORR) was 79.5%; 14/84 (16.6%) achieved a complete response (CR), 14/84 (16.6%) achieved CR unconfirmed, 27/84 (32.14%) achieved a partial response (PR) and 12/84 (14.2%) a PR + lymphocytosis. The median PFS and OS were not reached, and the estimated PFS at 24 months was 84.5% (73.4-95.6%). OS and PFS curves are represented in figure 2. The PFS of each patient subgroup with high-risk cytogenetic characteristics was similar to that of all patients in the first-line cohort: del17p/TP53 mutation (HR = 0.963 [95% CI 0.188-4.928]; p = 0.964), del11q (HR = 0.042 [95% CI 0.000-682.736] ; p=0.521), unmutated IGHV (HR = 0.391 [95% CI 0.110-1.394]; p = 0.148). The median duration of exposure to ibrutinib was 17.3 (11.9-25.6) months. Dose reduction of ibrutinib occurred in 17/84 (20.2%) patients, 8/84 (9.52%) due to toxicity (4 hematologic toxicity and 4 non-hematologic toxicity). 27/84 (32.1%) patients had temporary interruption of treatment. 15/84 (17.8%) patients permanently discontinued ibrutinib including 6 (7.14%) patients due to progression, 4 (4.76%) due to toxicity and 5 for other reasons. Safety: 49/84 (58.3%) patients developed at least one adverse event (AE), while 12/84 (14.2%) patients developed at least one serious adverse event (SAE). Twelve (14.3%) patients reported at least one haematological toxicity while 53 patients (63.1%) recorded at least one non-haematological toxicity. Only 1 patient experienced grade 3 atrial fibrillation, which did not lead to discontinuation. The most common AEs are described in table 3. Conclusion. This population of previously-untreated CLL patients, enriched for high-risk genomic features, reflects the initial approval of ibrutinib for the treatment of first-line patients with del17p in Spain. Single-agent Ibrutinib as the first-line treatment in this real world population was effective regardless of risk factors and well tolerated, with a low rate of discontinuation due to toxicity. Findings are consistent with those reported in clinical trials. Disclosures Loscertales: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Arguiñano:AbbVie: Honoraria; Janssen: Honoraria; BMS-Celgene: Honoraria; Novartis: Honoraria. Hernandez-Rivas:Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees. Pérez Persona:Amgen: Consultancy; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Jannsen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy. Loriente:Janssen Cilag: Current Employment. Villanueva:Janssen Cilag: Current Employment.

Abstract: Background: Single nucleotide polymorphisms (SNPs) within the genes involving drug detoxification enzymes of anthracyclines could lead to interindividual differences in treatment outcome. Several studies suggested, in different kinds of cancer, that SNPs of genes coding anthracyclines metabolism may influence their effectiveness or toxicity, being well-known their association with cardiotoxicity. The impact of these polymorphisms in adult acute myeloid leukemia (AML) patients treated with the combination of cytarabine and anthracyclines for induction remains undetermined. Methods: SNPs of anthracycline metabolism genes previously associated with clinical significance in other malignances (CBR3:rs1056892, rs8133052, NQO1 rs1800566, NQO2 rs1143684, NOS3:rs1799983, rs2070744, MnSOD rs4880) were evaluated in 225 adult patients at initial diagnosis from AML using a Sequenom (iPLEX) mass spectrometry-based multiplex genotyping assay (Sequenom, San Diego, CA). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA-LMA 99, 2007 and 2010 trials). Efficacy of first induction cycle was evaluated comparing complete remission (CR) vs. partial remission or resistance. Patients dying during induction were considered as no evaluable for efficacy. Based on WHO grading scale, toxicities were grouped as binary variables (grade 0-1 vs. grade 2-4). The grade of toxicity assigned to an organ group was the maximum grade of all the specific toxicities within that group. Hematologic toxicity was measured with the time to neutropenia and thrombocytopenia recovery since first day of chemotherapy. Genotypes were studied with co-dominant model. Association between variables was assessed using linear and logistic regression adjusting for age, gender, ECOG, leukocyte and platelet count at diagnosis (R® version 3.1.2). Results: The median age of patients was 51.1 years (16-78 years). There were no statistically significant differences in CR. Nevertheless, several associations were obtained between NQO1, NQO2, NOS3 and MnSOD polymorphisms and toxicities (significant toxicities were summarized in table 1 and 2). Table 1. Significant association between SNPs in gene metabolizers and different toxicities Toxicity Gene/SNP Genotypes Grade 0-1 n (%) Grade 2-4 n (%) OR (95%IC) P Cardiotoxicity NQO2 rs1143684 TT TC 119 (86.2) 74 (94.9) 19 (13.8) 4 (5.1) 0.26 (0.07-0.77) 0.025 Neurotoxicity NOS3 rs1799983 GG GT 71 (84.5) 101 (94.4) 13 (15.5) 6 (5.6) 0.28 (0.09-0.80) 0.022 Skin toxicity NOS3 rs1799983 GG GT TT 45 (53.6) 78 (72.9) 26 (76.5) 39 (46.4) 29 (27.1) 8 (23.5) 0.44 (0.24-0.82) 0.36 (0.14-0.88) 0.010 0.030 Skin toxicity NQO1 rs1800566 CC CT 78 (60.9) 64 (74.4) 50 (39.1) 29 (25.6) 0.53 (0.28-0.97) 0.042 Skin toxicity NQO2 rs1143684 TT CC 5.49 (1.19-38.9) 0.044 Gastrointestinal toxicity NQO2 rs1143684 TT CC 91 (65.9) 2 (25.0) 47 (34.1) 6 (75.0) 5.5 (1.19-38.99) 0.043 Mucositis NQO1 rs1800566 CC TT 119 (93.0) 8 (72.7) 9 (7.0) 3 (27.3) 6.1 (1.03-33.1) 0.035 Mucositis NQO2 rs1143684 TT CC 128 (92.8) 5 (62.5) 10 (7.2) 3 (37.5) 8.8 (1.53-45.60) 0.010 Nephrotoxicity MnSOD rs4880 TT CC 47 (81.0) 55 (94.8) 11 (19.0) 3 (5.2) 0.23 (0.05-0.86) 0.042 Nephrotoxicity NQO1 rs1800566 CC TT 114 (89.1) 8 (72.7) 14 (10.9) 3 (27.3) 6.66 (1.07-38.35) 0.033 Hepatotoxicity grades 3-4 NOS3 rs2070744 CC CT 19 (24.8) 100 (67.1) 20 (51.3) 49 (32.9) 0.44 (0.20-0.94) 0.035 Table 2. Significant association between SNPs in gene metabolizers and hematologic toxicities Hematologic toxicity Gene/SNP Genotypes Mean days Logarithm of the difference (95%IC) P Time to neutropenia recovery NOS3 rs2070744 CC TT 32.7 26.7 -0.17 (-0.35 to -0.01) 0.048 Time to thrombocytopenia recovery NOS3 rs1799983 GG GT TT 35.6 28.8 30.3 -0.17 (-0.17 to -0.06) -0.15 (-0.28 to -0.01) 0.002 0.034 Conclusions: This study reveals that, as in other cancers, there is a prognostic impact of anthracycline metabolism gene polymorphisms in adult AML patients. Further studies with larger population are needed to validate these associations, which could be useful biomarkers in clinical practice. Disclosures No relevant conflicts of interest to declare.

Abstract: 〈 b 〉 〈 i 〉 Objective: 〈 /i 〉 〈 /b 〉 Liver transplantation (LT) has traditionally been associated with major blood loss and consequently high blood transfusion requirements. Our objective was to analyze transfusion management and incidence of immunohematologic complications in patients undergoing LT at our institution. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 A retrospective analysis of immunohematologic events and transfusion outcomes was carried out at La Fe University Hospital in Valencia. Data from 654 patients were reviewed: 654 underwent only one LT while 36 underwent second LT. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Patients received a median of 3 red blood cell (RBC) concentrates, 2 platelets concentrates (PCs) and 2 fresh frozen plasma units (FFPs). Variables significantly influencing RBC transfusions were: the MELD score, hemoglobin levels, and the platelet counts before LT. 27 patients (4.1%) had a positive antibody screening before transplant. Immunohematologic events occurred in 8% of the patients, mostly in the first month after LT, and involved hemolysis in 13 cases. Mortality was significantly higher in patients developing immunohematologic disorders (42.8 vs. 18.3%; p 〈 0.001). In the multivariable analysis, only ABO minor incompatibility between donor and recipient significantly increased the appearance of immunohematologic incidences (OR 4.92, 95% CI 2.31-10.50; p 〈 0.001). 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 Transfusion management of patients that underwent LT can be complicated by immunohematologic problems. Blood banks should implement the DAT test in each transfusion to detect them.