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PURPOSE Romidepsin, a histone deacetylase inhibitor, has demonstrated activity in relapsed or refractory peripheral T-cell lymphoma (PTCL) as a single agent. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used as first-line treatment of PTCL; however, it has limited efficacy. Results from a phase Ib and II study showed the feasibility of combining romidepsin with CHOP (Ro-CHOP). METHODS This study is a randomized phase III study of Ro-CHOP versus CHOP in adult patients with previously untreated PTCL. All patients received CHOP in 3-week cycles for six cycles. Romidepsin, 12 mg/m2, was administered intravenously over a 4-hour period on days 1 and 8 of each 3-week cycle for six cycles. The primary end point was progression-free survival (PFS) according to International Working Group 1999 criteria. RESULTS Between January 2013 and December 2017, 421 patients were enrolled (Ro-CHOP, n = 211; CHOP, n = 210). The median PFS for Ro-CHOP versus CHOP was 12.0 months (95% CI, 9.0 to 25.8) versus 10.2 months (95% CI, 7.4 to 13.2) with a hazard ratio of 0.81 ( P = .096). In the Ro-CHOP versus CHOP arms, the median overall survival was 51.8 versus 42.9 months and the objective response rate was 63% versus 60% with complete response plus unconfirmed complete response rates of 41% versus 37% ( P > .1 in all comparisons), respectively. Grade 3 or 4 treatment-emergent adverse events occurring in ≥ 30% of patients in the Ro-CHOP arm included thrombocytopenia (50% v 10% in the Ro-CHOP v CHOP arms, respectively), neutropenia (49% v 33%), anemia (47% v 17%), and leukopenia (32% v 20%). CONCLUSION The addition of romidepsin to CHOP did not improve PFS, response rates, nor overall survival and increased the frequency for grade ≥ 3 treatment-emergent adverse events. Ro-CHOP does not represent a significant advance in the standard of care for patients with previously untreated PTCL.

Producción Científica, Pneumonia is the main cause of hospital admission in COVID-19 patients. We aimed to perform an extensive characterization of clinical, laboratory, and cytokine profiles in order to identify poor outcomes in COVID-19 patients. Methods: A prospective and consecutive study involving 108 COVID-19 patients was conducted between March and April 2020 at Hospital Clínico Universitario de Valladolid (Spain). Plasma samples from each patient were collected after emergency room admission. Forty-five serum cytokines were measured in duplicate, and clinical data were analyzed using SPPS version 25.0. Results: A multivariate predictive model showed high hepatocyte growth factor (HGF) plasma levels as the only cytokine related to intubation or death risk at hospital admission (OR = 7.38, 95%CI—(1.28–42.4), p = 0.025). There were no comorbidities included in the model except for the ABO blood group, in which the O blood group was associated with a 14-fold lower risk of a poor outcome. Other clinical variables were also included in the predictive model. The predictive model was internally validated by the receiver operating characteristic (ROC) curve with an area under the curve (AUC) of 0.94, a sensitivity of 91.7% and a specificity of 95%. The use of a bootstrapping method confirmed these results. Conclusions: A simple, robust, and quick predictive model, based on the ABO blood group, four common laboratory values, and one specific cytokine (HGF), could be used in order to predict poor outcomes in COVID-19 patients., Instituto de Salud Carlos III - ( Proyecto COV20/00491), Consejeria de Educación de Castilla y León - (Proyecto VA256P20), Junta de Castilla y León y Fondo Europeo de Desarrollo Regional (FEDER) - (Proyecto EDU/1100/2017)

Antigen tests or polymerase chain reaction (PCR) amplification are currently COVID-19 diagnostic tools. However, developing complementary diagnosis tools is mandatory. Thus, we performed a plasma cytokine array in COVID-19 patients to identify novel diagnostic biomarkers. A discovery–validation study in two independent prospective cohorts was performed. The discovery cohort included 136 COVID-19 and non-COVID-19 patients recruited consecutively from 24 March to 11 April 2020. Forty-five cytokines’ quantification by the MAGPIX system (Luminex Corp., Austin, TX, USA) was performed in plasma samples. The validation cohort included 117 patients recruited consecutively from 15 to 25 April 2020 for validating results by ELISA. COVID-19 patients showed different levels of multiple cytokines compared to non-COVID-19 patients. A single chemokine, IP-10, accurately identified COVID-19 patients who required hospital admission (AUC: 0.962, 95%CI (0.933–0.992), p &lt, 0.001)). The results were validated in an independent cohort by multivariable analysis (OR: 25.573, 95%CI (8.127–80.469), 0.001) and AUROC (AUC: 0.900, 95%CI (0.846–0.954), 0.001). Moreover, showing IP-10 plasma levels over 173.35 pg/mL identified COVID-19 with higher sensitivity (86.20%) than the first SARS-CoV-2 PCR. Our discover–validation study identified IP-10 as a robust biomarker in clinical practice for COVID-19 diagnosis at hospital. Therefore, IP-10 could be used as a complementary tool in clinical practice, especially in emergency departments.

Pneumonia is the leading cause of hospital admission and mortality in coronavirus disease 2019 (COVID-19). We aimed to identify the cytokines responsible for lung damage and mortality. We prospectively recruited 108 COVID-19 patients between March and April 2020 and divided them into four groups according to the severity of respiratory symptoms. Twenty-eight healthy volunteers were used for normalization of the results. Multiple cytokines showed statistically significant differences between mild and critical patients. High HGF levels were associated with the critical group (OR = 3.51, p &lt, 0.001, 95%CI = 1.95–6.33). Moreover, high IL-1α (OR = 1.36, p = 0.01, 95%CI = 1.07–1.73) and low IL-27 (OR = 0.58, 0.005, 95%CI = 0.39–0.85) greatly increased the risk of ending up in the severe group. This model was especially sensitive in order to predict critical status (AUC = 0.794, specificity = 69.74%, sensitivity = 81.25%). Furthermore, high levels of HGF and IL-1α showed significant results in the survival analysis (p = 0.033 and p = 0.011, respectively). HGF, IL-1α, and IL 27 at hospital admission were strongly associated with severe/critical COVID-19 patients and therefore are excellent predictors of bad prognosis. HGF and IL-1α were also mortality biomarkers.

Producción Científica, Severe status of coronavirus disease 2019 (COVID-19) is extremely associated to cytokine release. Moreover, it has been suggested that blood group is also associated with the prevalence and severity of this disease. However, the relationship between the cytokine profile and blood group remains unclear in COVID-19 patients. In this sense, we prospectively recruited 108 COVID-19 patients between March and April 2020 and divided according to ABO blood group. For the analysis of 45 cytokines, plasma samples were collected in the time of admission to hospital ward or intensive care unit and at the sixth day after hospital admission. The results show that there was a risk of more than two times lower of mechanical ventilation or death in patients with blood group O (log rank: p = 0.042). At first time, all statistically significant cytokine levels, except from hepatocyte growth factor, were higher in O blood group patients meanwhile the second time showed a significant drop, between 20% and 40%. In contrast, A/B/AB group presented a maintenance of cytokine levels during time. Hepatocyte growth factor showed a significant association with intubation or mortality risk in non-O blood group patients (OR: 4.229, 95% CI (2.064–8.665), p < 0.001) and also was the only one bad prognosis biomarker in O blood group patients (OR: 8.852, 95% CI (1.540–50.878), p = 0.015). Therefore, higher cytokine levels in O blood group are associated with a better outcome than A/B/AB group in COVID-19 patients., Instituto de Salud Carlos III (grant COV20/00491), Junta de Castilla y León (grant 18IGOF)

The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph− adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry)

The use of non‐pegylated liposomal doxorubicin (Myocet®) in diffuse large B‐cell lymphoma (DLBCL) has been investigated in retrospective and single‐arm prospective studies. This was a prospective phase 2 trial of DLBCL patients ≥60 years old with left ventricular ejection fraction (LVEF) ≥55% randomized to standard R‐CHOP or investigational R‐COMP (with Myocet® instead of conventional doxorubicin). The primary end point was to evaluate the differences in subclinical cardiotoxicity, defined as decrease in LVEF to, The use of non‐pegylated liposomal doxorubicin (Myocet®) in diffuse large B‐cell lymphoma (DLBCL) has been investigated in retrospective and single‐arm prospective studies. This prospective randomized phase 2 trial of RCOMP versus RCHOP in DLBCL patients ≥60 years and normal cardiac function demonstrated that R‐COMP is a feasible immunochemotherapy schedule for DLBCL patients ≥60 years, with similar efficacy to R‐CHOP. However, the use of non‐pegylated doxorubicin instead of conventional doxorubicin was not associated with less early cardiotoxicity, although some reduced cardiac safety signals were observed.

[Introduction]: Prognosis of Coronavirus disease 2019 (Covid-19) patients with vascular risk factors, and certain comorbidities is worse. The impact of chronic neurological disorders (CND) on prognosis is unclear. We evaluated if the presence of CND in Covid-19 patients is a predictor of a higher in-hospital mortality. As secondary endpoints, we analyzed the association between CND, Covid-19 severity, and laboratory abnormalities during admission., [Methods]: Retrospective cohort study that included all the consecutive hospitalized patients with confirmed Covid-19 disease from March 8th to April 11th, 2020. The study setting was Hospital Clínico, tertiary academic hospital from Valladolid. CND was defined as those neurological conditions causing permanent disability. We assessed demography, clinical variables, Covid-19 severity, laboratory parameters and outcome. The primary endpoint was in-hospital all-cause mortality, evaluated by multivariate cox-regression log rank test. We analyzed the association between CND, covid-19 severity and laboratory abnormalities., [Results]: We included 576 patients, 43.3% female, aged 67.2 years in mean. CND were present in 105 (18.3%) patients. Patients with CND were older, more disabled, had more vascular risk factors and comorbidities and fewer clinical symptoms of Covid-19. They presented 1.43 days earlier to the emergency department. Need of ventilation support was similar. Presence of CND was an independent predictor of death (HR 2.129, 95% CI: 1.382–3.280) but not a severer Covid-19 disease (OR: 1.75, 95% CI: 0.970–3.158). Frequency of laboratory abnormalities was similar, except for procalcitonin and INR., [Conclusions]: The presence of CND is an independent predictor of mortality in hospitalized Covid-19 patients. That was not explained neither by a worse immune response to Covid-19 nor by differences in the level of care received by patients with CND.

[Background]: Eltrombopag is useful for immune thrombocytopenia (ITP). However, results of clinical trials may not accurately mirror clinical practice reality. Here we evaluated eltrombopag for primary and secondary ITP in our ≥65‐year‐old population., [Methods]: A total of 106 primary ITP patients (16 with newly diagnosed ITP, 16 with persistent ITP, and 74 with chronic ITP) and 39 secondary ITP patients (20 with ITP secondary to immune disorders, 7 with ITP secondary to infectious diseases, and 12 with ITP secondary to lymphoproliferative disorders [LPD]) were retrospectively evaluated., [Results]: Median age of our cohort was 76 (interquartile range, IQR, 70‐81) years. 75.9% of patients yielded a platelet response including 66.2% complete responders. Median time to platelet response was 14 (IQR, 8‐21) days. Median time on response was 320 (IQR, 147‐526) days. Sixty‐three adverse events (AEs), mainly grade 1‐2, occurred. The most common were hepatobiliary laboratory abnormalities (HBLAs) and headaches. One transient ischemic attack in a newly diagnosed ITP and two self‐limited pulmonary embolisms in secondary ITP were the only thrombotic events observed., [Conclusion]: Eltrombopag showed efficacy and safety in ITP patients aged ≥65 years with primary and secondary ITP. However, efficacy results in LPD‐ITP were poor. A relatively high number of deaths were observed.

BACKGROUND Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), non-candidates for autologous stem-cell transplantation (ASCT), have few treatment options. Ibrutinib is an oral Bruton's tyrosine kinase inhibitor that has shown increased antitumor activity in patients with DLBCL of different subtype from germinal center B-cell like (non-GCB). In the present phase II clinical trial (NCT02692248), we investigated the efficacy and toxicity of the combination of Ibrutinib with the R-GEMOX-D regimen (rituximab, gemcitabine, oxaliplatin and dexamethasone), in patients with non- GCB DLBCL. METHODS We included patients with histological diagnosis of non-GCB DLBCL (according to Hans algorithm), with relapsed or refractory disease after at least 1 line of immunochemotherapy and non-candidates for ASCT. Patients received an induction treatment consisting of 6 (in case of complete remission [CR] after cycle 4) or 8 (in case of partial response [PR] or stable disease after cycle 4) cycles of R-GEMOX-D at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. The primary objective was to evaluate the overall response rate (ORR) after 4 cycles, and the secondary objectives were: CR rate, progression-free survival (PFS), overall survival (OS) and toxicity. Analyses were performed in the intention to treat population (data cut-off 10th April 2020). RESULTS Sixty-four patients (59.4% male) were included between March 2016 and November 2018. Median age was 67 (25-84) years. Patients had received a median of 2 previous lines of treatment; 56.3% were refractory ( Of the 64 patients who started study treatment, 44 and 35 patients, respectively, were evaluated for response after 4th cycle and at the end of induction. Twenty-four (37%) patients started maintenance with ibrutinib, 7 of whom continue or have completed it. Causes of withdrawal from the trial (n=57) were progression (n=40), adverse event (n=6), transplantation (n=5), withdrawal of consent (n=3) and other causes (n=3). ORR and CR rate after 4th cycle were 53.2% and 35.9%, respectively. Patients with relapsed disease had significantly higher ORR (67.9% vs 41.7%, p=0.037) and CR rate (57.1% vs 19.4%, p=0.002) than patients with refractory disease. At the end of induction, ORR and CR rate were 35.9% and 29.7%, respectively. After a median follow-up of 22 months (range: 1 to 39 months), the estimated 2-year PFS and OS were 21% and 25%, respectively (Figure 1A and 1B), being significantly better in patients with relapsed disease (Figure 1C and 1D). In the multivariate analysis, status of lymphoma at study entry significantly influenced PFS (HR 0.45; 95% CI 0.25-0.82; p=0.009) and OS (HR 0.51; 95% CI 0.27-0.94; p=0.0031) independently from the IPI and the number of previous treatment lines. The most frequent adverse events (AE) (present in at least 20% of patients) were thrombocytopenia (67.2%), diarrhea (51.6%), neutropenia (46.9%), anemia (37.5%), fatigue (34.4%), nausea (29.7%) and paresthesia (20.3%). The most frequent grade 3-5 AE (present in at least 10% of patients) were thrombocytopenia (46.9%), neutropenia (35.9%), diarrhea (15.6%) and anemia (14.1%). Three patients presented a grade 5 AE, two of them related (aspergillosis and pneumonia, respectively) and one unrelated (heart failure). CONCLUSIONS The combination of ibrutinib with R-GEMOX-D as salvage therapy for patients with non-GCB DLBCL is associated with high response rates, especially in relapsed patients. The vast majority of refractory patients progress very early, so this regimen could be considered as a bridge to other consolidation therapies. Biological studies analyzing cell of origin by gene expression profiling, minimal residual disease and mutational spectrum are in progress. Disclosures Abrisqueta: Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Giné:Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding. Grande:Janssen: Research Funding. Caballero:Roche: Other: travel; Gilead: Other: travel; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel; BMS: Other: travel; Takeda: Other: travel; Kite: Membership on an entity's Board of Directors or advisory committees. Martin Garcia-Sancho:Roche, Celgene, Janssen, Servier, Gilead: Honoraria; Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy. OffLabel Disclosure: Off-label use of a new combination in the context of a clinical trial. New combination (Ibrutinib + R-GEMOX)

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16 mg/kg) was administered to 73 patients who had >= 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03-13.17) months, with a median number of 12 (range: 1-25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatmentemergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma., This study was funded by Janssen Research & Development, LLC. Editorial and medical writing support were provided by J. Matthew Kuczmarski, PhD, of MedErgy, and were funded by Janssen Global Services, LLC. The data sharing policy of Janssen Pharmaceutical Companies of Johnson& Johnson is available at https://www.janssen.com/clinical-trials/transparency.As noted on this site, requests for access to the study data can be submitted through the Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.

Chronic myeloid leukemia patients display heterogeneous responses to imatinib. Survival depends on baseline clinical characteristics (including prognostic scoring systems) and on early response (such as >10% BCR-ABL/ABL ratio at 3 months of therapy). The results of switching to second-generation tyrosine kinase inhibitors (2GTKIs) may contain a bias since, in the majority of these studies, patients who switch treatment due to intolerance or failure are censored or excluded. We analyzed the Spanish Registry data on switching in an intention-to-treat analysis of patients in standard clinical practice. Switching to 2GTKIs improves responses from 45% to 75% of complete cytogenetic response (CCyR) and from 15% to 45% of major molecular response (MMR) in the group without molecular response 1 (MR1) at 3 months and from 70% to 87% in CCyR and from 52% to 87% in MMR in the group with MR1. The final response rate is poorer in the group with no MR1 at 3 months. Nevertheless, the differences in the rates of response were not translated into differences in major events (transformations or deaths), and the final progression-free survival and overall survival were similar.

Eltrombopag is effective and safe in immune thrombocytopenia (ITP). Some patients may sustain their platelet response when treatment is withdrawn but the frequency of this phenomenon is unknown. We retrospectively evaluated 260 adult primary ITP patients (165 women and 95 men; median age, 62 years) treated with eltrombopag after a median time from diagnosis of 24 months. Among the 201 patients who achieved a complete remission (platelet count >100 × 109/l), eltrombopag was discontinued in 80 patients. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n = 33), platelet count >400 × 109/l (n = 29), patient's request (n = 5), elevated aspartate aminotransferase (n = 3), diarrhea (n = 3), thrombosis (n = 3), and other reasons (n = 4). Of the 49 evaluable patients, 26 patients showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow-up of 9 (range, 6–25) months. These patients were characterized by a median time since ITP diagnosis of 46.5 months, with 4/26 having ITP

Eltrombopag is safe and effective in primary chronic ITP. However, lack of clinical trials avoids a clear demonstration of its utility in newly diagnosed and persistent ITP. Our aim here is to report Spanish results for this type of patients. We retrospectively evaluated 220 adult primary ITP patients. According to standard definition, patients were allocated to newly diagnosed (n = 30), persistent (n = 30), and chronic (n = 160) ITP. Groups were homogenous regarding most relevant parameters. 180 (90%) of 220 patients achieved a platelet response (R) with 167 (75.9%) complete responses (CR) after a 15-month follow-up. No statistical significant differences among groups but a trend towards a greater efficacy in newly diagnosed ITP were observed (93.3% of responses with 86.7% of CR). Efficacy in persistent ITP (83.3% of responses with 80.0% of CR) and chronic ITP (79.4% of responses with 73.1% of CR) was similar. 70 patients (31.8%) experienced adverse events. 15 of them were grade 3–4. Most common adverse effects were headache and hepatobiliary laboratory abnormalities (HBLAs). One persistent ITP had a venous thrombosis and one chronic ITP had grade II myelofibrosis. We consider Eltrombopag use for the early stage ITP as effective and safe as it is in chronic ITP.

In the latest recommendations for the management of chronic-phase chronic myeloid leukemia suboptimal responses have been reclassified as “warning responses.” In contrast to previous recommendations current guidance advises close monitoring without changing therapy. We have identified 198 patients treated with first-line imatinib, with a warning response after 12 months of treatment (patients with a complete cytogenetic response but no major molecular response [MMR]). One hundred and forty-six patients remained on imatinib, while 52 patients changed treatment to a second generation tyrosine kinase inhibitor (2GTKI). Changing therapy did not correlate with an increase in overall survival or progression-free survival. Nevertheless, a significant improvement was observed in the probability of a MMR: 24% vs. 42% by 12 months and 43% vs. 64% by 24 months (P = 0.002); as well as the probability of achieving a deep molecular responses (MR4.5): 1% vs. 17% and 7% vs. 23% by 12 and 24 months, respectively (P =

Prognostic factors in Hodgkin lymphoma (HL) still fail to accurately identify high-risk patients. Tumor microenvironment in HL is a current focus of research for risk definition but few studies have focused on infiltrating lymphocytes. Here, we analyzed the number of tumor infiltrating lymphocytes by flow cytometry in diagnostic biopsies from 96 HL homogeneously treated patients with ABVD with or without radiotherapy. Most lymph node cells were lymphocytes (90 ± 17), with a median T/B/NK distribution of 74%/26%/0.7%, and CD4 T-cell predominance. The amount of CD19 B cells, and NK cells did not show association with disease features. However, high numbers of CD8 and CD4 cells were associated with better and poorer outcomes, respectively. Patients with ≥15% cytotoxic CD8 cells among the total cell population had a longer 10-year freedom from treatment failure (FFTF) (93% vs. 73%, p=.04). In turn, cases with ≥75% of CD4 infiltrating cells showed a significantly decreased FFTF (73% vs. 96%, p=.021). Consequently, CD4/CD8 ratio ≥5 associated with a poorer 10-year FFTF (69.5% vs. 94%, p=.02). This deleterious effect was particularly prominent in advanced disease (n = 58, p=.01). In multivariate analysis, a CD4/CD8 ratio ≥5 was the only independent variable to predict for treatment failure (HR = 4.5, 95% confidence interval, 1.2–16.8). In conclusion, our study shows that high CD4 and low CD8 T-cells infiltrates of tumor specimens associate with poor prognosis in HL patients, and CD4/CD8 ratio might be potentially useful for tailoring therapy.

BackgroundEltrombopag is effective and safe in chronic immune thrombocytopenia (ITP). However, clinical trials may not accurately reflect what happens in clinical practice. We evaluated the efficacy and safety of eltrombopag in primary chronic ITP in a real-world setting. MethodsA total of 164 primary patients with chronic ITP from 40 Spanish centers, who had been treated with eltrombopag, were retrospectively evaluated. ResultsThe median age of our cohort (72% women) was 63 yr (interquartile range, IQR, 45-75 yr). The median time with ITP diagnosis was 81 months (IQR, 30-192 months). The median number of therapies prior to eltrombopag was 3 (IQR, 2-4). At the time of eltrombopag start, 45 patients (30%) were receiving concomitant treatment for ITP. Forty-six patients (30%) had bleeding signs/symptoms the month before the treatment started. The median platelet count at eltrombopag initiation was 22 x 10(9)/L (IQR, 8-39 x 10(9)/L). A total of 135 patients (88.8%) achieved a platelet response. The median time to platelet response was 12 d (95% CI, 9-13 d). Maintained platelet response rate during the 15-month period under examination was 75.2%. Twenty-eight patients (18.4%) experienced adverse events, mainly grades 1-2. ConclusionEltrombopag is highly effective and well tolerated in unselected patients with primary chronic ITP.

Purpose We analyzed the incidence, risk factors, and outcome of therapy-related myeloid neoplasms (t-MNs) in patients with acute promyelocytic leukemia (APL) in first complete remission (CR). Patients and Methods From 1996 to 2008, 1,025 patients with APL were enrolled onto three sequential trials (LPA96, LPA99, and LPA2005) of the Programa Español para el Tratamiento de Enfermedades Hematológicas and received induction and consolidation therapy with all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy. Results Seventeen of 918 patients who achieved CR developed t-MN (10 with < 20% and seven with ≥ 20% of bone marrow blasts) after a median of 43 months from CR. Partial and complete deletions of chromosomes 5 and 7 (nine patients) and 11q23 rearrangements (three patients) were the most common cytogenetic abnormalities. Overall, the 6-year cumulative incidence of t-MN was 2.2%, whereas in low-, intermediate-, and high-risk patients, the 6-year incidence was 5.2%, 2.1%, and 0%, respectively. Multivariate analysis identified age more than 35 years and lower relapse risk score as independent prognostic factors for t-MN. The median overall survival time after t-MN was 10 months. Conclusion t-MN is a relatively infrequent, long-term, and severe complication after first-line treatment for APL with ATRA and anthracycline-based regimens. Therapeutic strategies to reduce the incidence of t-MN are warranted.

Background: Eltrombopag is effective and safe for treating chronic immune thrombocytopenia (ITP) patients who have not responded to previous therapy. Interestingly, some patients in whom hemostatic platelet counts are achieved with eltrombopag may sustain the platelet response when eltrombopag ceases to be administered. However, the frequency of sustained responses after discontinuing eltrombopag without additional therapy for ITP is largely unknown. Methods: A total of 260 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry were retrospectively evaluated. The study was performed in accordance with the standards of the Helsinki declaration and approved by the Hospital Universitario de Burgos Ethics Committee. Results: The median age was 62 [range, 18–93] years. There were 165 women and 95 men. According to the standard definition, patients were allocated to newly diagnosed (n=29), persistent (n=36) and chronic (n=195) ITP groups. The median time from diagnosis to eltrombopag initiation was 24 [range, 1–480] months. The median number of previous therapies was 3 [range, 0–10], including splenectomy (22%), rituximab (23%) and romiplostim (19%). The initial response rate to eltrombopag was 231/260 (89%), including 77% (n=201) cases of complete remission (platelet count ≥100 x 109/L). The median duration of eltrombopag treatment was 6 [range, 1–54] months. Eltrombopag was discontinued in 80 out of 201 (39.8%) patients who achieved CR. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=33), platelet count >400x109/L (n=29), patient’s request (n=5), aspartate aminotransferase elevation (n=3), diarrhea (n=3), thrombosis (n=3) and other reasons (n=4). For analysis of discontinuation, patients with follow-up < 6 months (n=15), newly diagnosed ITP (n=11) or patients who received concomitant or previous (6 months before) treatments at the start of eltrombopag use (n=5) were excluded. Of the 49 evaluable patients, 22 (45%) had an immediate relapse after stopping eltrombopag. One patient with sustained response after stopping treatment relapsed at 10 months. A total of 26 patients (53%) showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow-up of 9 [range, 6–25] months. These patients were characterized by a median time since ITP diagnosis of 46.5±114.1 months, with 4/26 having ITP The main characteristics (age, gender, duration of ITP, prior anti-ITP lines, prior splenectomy, prior rituximab, prior romiplostim, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 26 patients with sustained response after stopping eltrombopag were compared with those of the 23 patients relapsing after eltrombopag withdrawal. No predictive factors of sustained response after eltrombopag withdrawal could be identified. Conclusion: Platelet response following eltrombopag cessation may be sustained in nearly half of adult patients with primary ITP after CR with eltrombopag. However, reliable markers for predicting which patients will have this response are lacking. Disclosures No relevant conflicts of interest to declare.

Introduccion y objetivos Trabajos experimentales y clinicos sugieren que el tejido necrotico tiene la capacidad de regenerarse. Nuestro grupo ha comenzado un estudio clinico para demostrar que la implantacion intracoronaria de celulas madre es un procedimiento factible y seguro. Presentamos los resultados de nuestros primeros 5 pacientes. Pacientes y metodo Se ha incluido a pacientes con un infarto agudo de miocardio anterior y una lesion unica en la descendente anterior reparada mediante angioplastia primaria o facilitada. A los 10-15 dias del infarto, se procedio a la extraccion de medula osea. El implante celular se hizo por via intracoronaria. El protocolo de seguimiento incluye ecocardiografia con dobutamina, resonancia magnetica y Holter de ECG basal y a los 6 meses. Resultados Ningun paciente ha tenido un evento cardiaco tras 6 meses de seguimiento. En un paciente se observo un accidente isquemico transitorio sin secuelas. No se han demostrado arritmias en ninguno de los pacientes. El volumen telediastolico no vario a los 6 meses (159 ± 25 y 157 ± 16 ml), el volumen telesistolico disminuyo (77 ± 22 y 65 ± 16 ml) y la fraccion de eyeccion aumento (53 ± 7 y 58 ± 8%), aunque no hubo diferencias significativas. En los 3 pacientes en los que la ecocardiografia con dobutamina descarto viabilidad, si hubo una disminucion significativa de los volumenes. Conclusiones El implante intracoronario de celulas madre en pacientes que han tenido un infarto agudo de miocardio parece un metodo seguro y factible, y podria dar lugar a un remodelado favorable.

[Introduction]: Molecular alterations leading progression of asymptomatic CLL-like high-count monoclonal B lymphocytosis (hiMBL) to chronic lymphocytic leukemia (CLL) remain poorly understood. Recently, genome-wide association studies have found 6p21.3, where the human leukocyte antigen (HLA) system is coded, to be a susceptibility risk region for CLL. Previous studies have produced discrepant results regarding the association between HLA and CLL development and outcome, but no studies have been performed on hiMBL. [Aims]: We evaluated the role of HLA class I (-A, -B and -C) and class II (-DRB1 and -DQB1) in hiMBL/CLL susceptibility, hiMBL progression to CLL, and treatment requirement in a large series of 263 patients diagnosed in our center with hiMBL (n = 156) or Binet A CLL (n = 107). [Results]: No consistent association between HLA specificities and hiMBL or CLL susceptibility was found. With a median follow-up of 7.7 years, 48/156 hiMBLs (33%) evolved to asymptomatic CLLs, while 16 hiMBLs (10%) and 44 CLLs (41%) required treatment. No HLA specificities were found to be significantly associated with hiMBL progression or treatment in the whole cohort. However, within antigen-experienced immunoglobulin heavy-chain (IGHV)-mutated hiMBLs, which represents the highest proportion of hiMBL cases (81%), the presence of HLA-DQB1∗03 showed a trend to a higher risk of progression to CLL (60% vs. 26%, P = 0.062). Moreover, HLA-DQB1∗02 specificity was associated with a lesser requirement for 15-year treatment (10% vs. 36%, P = 0.012). [Conclusion]: In conclusion, our results suggest a role for HLA in IGHV-mutated hiMBL prognosis, and are consistent with the growing evidence of the influence of 6p21 on predisposition to CLL. Larger non-biased series are required to enable definitive conclusions to be drawn., This work was supported in part by Grants from the Hematology and Hemotherapy Society of Castilla-León (#1 FUCALHH-2010), and the Instituto de Salud Carlos III (ISCIII), award numbers (#2) RTICC-RD12/0036/0069, (#3) CIBERONC CB16/12/00233, and (#4) Innocampus; CEI-2010-1-0010. All ISCIII funding was co- sponsored by the European Union FEDER program.

To assess the presence of genetic imbalances in patients with myeloproliferative neoplasms (MPNs), 38 patients with chronic eosinophilia were studied by array comparative genomic hybridization (aCGH): seven had chronic myelogenous leukaemia (CML), BCR-ABL1 positive, nine patients had myeloproliferative neoplasia Ph- (MPN-Ph-), three had a myeloid neoplasm associated with a PDGFRA rearrangement, and the remaining two cases were Lymphoproliferative T neoplasms associated with eosinophilia. In addition, 17 patients had a secondary eosinophilia and were used as controls. Eosinophilic enrichment was carried out in all cases. Genomic imbalances were found in 76% of all MPN patients. Losses on 20q were the most frequent genetic abnormality in MPNs (32%), affected the three types of MPN studied. This study also found losses at 11q13.3 in 26% of patients with MPN-Ph- and in 19p13.11 in two of the three patients with an MPN associated with a PDGFRA rearrangement. In addition, 29% of patients with CML had losses on 8q24. In summary, aCGH revealed clonality in eosinophils in most MPNs, suggesting that it could be a useful technique for defining clonality in these diseases. The presence of genetic losses in new regions could provide new insights into the knowledge of these MPN associated with eosinophilia., The study was partially supported by grants from the Spanish Fondo de Investigaciones Sanitarias, FIS 09/01543 and PI12/00281; RD12/0036/0069 from Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF) ‘Una manera de hacer Europa’, ‘Consejería Educación, Junta Castilla y León, Spain’ (HUS272U13), Proyectos de Biomedicina del SACYL (BIO/SA47/13 and BIO/SA31/13).

Introduction: TKIs introduction in the treatment of chronic myeloid leukemia (CML) has offered an outstanding improvement in prognosis, especially in survival. Data about TKIs were obtained from clinical trials but little is known about their translation to real life. In addition, clinical trials are mainly based on efficacy analysis to just one line of therapy, rather than treatment sequences (due to failure or intolerance). Objectives: To analyze the long-term survival of patients outside clinical trials in response to TKI treatment, describing the pattern of sequential treatments the patients actually received. Patients and methods: CML patients in first chronic phase, treated with TKIs (imatinib, nilotinib, dasatinib) either as monotherapy or in sequence, outside clinical trials. The setting was a multicentric, hospital-based registry. Survival and their potentially associated variables were studied. Results: Demographics, risk and treatment distribution: 696 patients (423 men, 273 women) with a median age at diagnosis of 41y (14-94y) were included with a follow up of 85±7 months (m) from diagnosis, 78±6.6 m from first treatment, and 69±6 m from first TKIs; 106 patients (15%) were over 70y. The risk distributions were as follows: Sokal: low (L) 48%, intermediate (I) 38% and high (H) 13%; Euro score: L 51%, I 45% and H 4%; EUTOS L: 91% and H 9%; EUTOS LT: L 68%, I 25% and H 7%. Treatment groups were the following: Group 1: IFN alpha and then imatinib or 2¼ GTKIs (176 patients); Group 2: imatinib only (340 patients); Group 3: imatinib and then nilotinib, dasatinib or both due to failure or intolerance (131 patients) and Group 4: 2¼GTKIs in first line (49 patients). Survival: Estimated survival by 10 years was 80%. Ninety-one patients have died (27 due to unknown reasons, 33 due to progression or BMT, 7 due to second neoplasias and 21 due to cardiac or neurological disease). Variables associated with survival: In the univariate survival analyses (log rank test) either from diagnosis, first therapy or first TKIs, the Sokal, Eutos, Euro and EUTOS LT scores as well as age over 70y were the only statistically significant variables associated with survival.(figure 1). In the multivariate analysis (Cox model), only Sokal and Eutos LT scores, and age over 70y were independent variables. Patients older than 70 years at diagnosis had a 50% probability of survival by 8 years. It is worth mentioning that, although the probability of overall survival from diagnosis was higher in the group receiving imatinib after IFN alpha, this difference was not seen when measuring the probability of survival after the first treatment o first TKI. This is probably explained by the higher proportion of low-risk score in patients having had previous IFN. Whereas the cause of death was progression in half of the patients aged equal or less than 70 years, in patients older than 70 years, two third of the deaths were not related to progression of CML. Conclusions: 1.These results show that the probability of survival by 10 years is roughly 80%, and extend the findings of our previous work showing that this probability is not different across different sequential treatments (imatinib before IFN, alone or switched to 2»GTKis due to intolerance o failure)(1). This fact emphasizes the rescue potential of available TKI therapies. 2. We have validated for the first time the Eutos LT score in real life population. 3. Patients over 70 years have shorter survival due to reasons different than progression, opening an interesting field of research, and a non-negligible room of improvement. Figure 1 (1)Casado LF, et al Cancer Med. 2015 Mar 10. Figure 1. (1)Casado LF, et al Cancer Med. 2015 Mar 10. Disclosures Casado Montero: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Steegmann:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

Background: Eltrombopag is an oral thrombopoietin receptor agonist (TPO-RA) drug approved in primary chronic ITP. Lack of clinical trials in secondary ITP avoids a clear demonstration of its potential in terms of safety and efficacy on secondary ITP. Aims: To evaluate the efficacy and safety of eltrombopag in secondary ITP patients in daily clinical practice in Spain. Methods: Ninety-eight secondary ITP patients (aged 18 years or more) from 30 Spanish centers, treated with eltrombopag and included in the Spanish Eltrombopag Registry were retrospectively evaluated. Our study was performed in accordance with the standards of the Helsinki declaration and approved by the Hospital Universitario de Burgos Ethics Committee. Results: Our case series included 98 patients we allocated to four categories: immune disorders (n=47), infections (n=23), lymphoproliferative disorders (n=20), and neoplasms (n=8). The median age of the cohort was 62 (IQR, 40-71) years with 38 men and 60 women. At diagnosis, 34 patients had a Charlson Comorbidity Index score of 2 or more. Median time from ITP diagnosis to eltrombopag initiation was 13 (IQR, 2-66) months. Median number of therapies against thrombocytopenia before eltrombopag was 2 (IQR, 1-3), including rituximab (24), splenectomy (18) and romiplostim (13). Median platelet count when treatment started was 15 x 109/L (IQR, 5-43 x 109/L). Meanwhile, 44 patients had bleeding symptoms. Concomitant therapy was administered to 55 ITP (corticoids in 33) (Table I). Whole cohort eltrombopag response rate was 59% of responses (R; platelet count ≥30 x109/L and at least 2-fold increase the baseline count and absence of bleeding) with 52% of complete responses (CR; platelet count >100 x 109/L). Regarding the disease associated to ITP we observed high response rates in immune disorders and infection groups (67% of R, 76 % of R, respectively). Nevertheless, in lymphoproliferative disorders and neoplastic groups efficacy rates were much lower (36 % of R, 37 % of R respectively). The proportion of patients achieving platelet response was quite similar regardless the other studied parameters: age, sex, concomitant treatment, bleeding and platelet count at start of eltrombopag treatment. 30 adverse events were reported with eltrombopag, being 18 of them grade 3-4. 14 deaths were observed but only two were caused by bleeding. The remaining causes of death were: 4 because of bacterial sepsis and another 4 due to progression of basal disease. 2 secondary neoplasms, 1 aspergillosis and one death due to a non-treated severe anemia were also reported (Table II). Conclusion: The use of eltrombopag for treating secondary ITP is effective and safe. To point out, its efficacy in lymphoproliferative disorders and in neoplasm-associated ITP is lower than in benign diseases. Certainly, more studies are needed to confirm usefulness of TPO-RAs in secondary ITP cases. Table 1. Patient characteristics Variable Total(n = 98) Type of disease, n Immune disorders SLE 13 Evans Syndrome 8 Antiphospholipid Syndrome 6 Sjögren Syndrome 5 Rheumatoid Arthritis 3 Immunodeficiencies 3 Autoimmune Hepatitis 2 Primary Biliary Cirrhosis 2 Psoriatic arthritis 1 Evans Syndrome-Immunodeficiencies 1 Evans Syndrome-HCV 1 Graves-Basedow disease 1 Inflammatory Bowel disease 1 Lymphoproliferative disorders Lymphoproliferative diseases 16 HCV-Lymphoma 3 HIV-Lymphoma 1 Infections Hepatitis C Virus 16 HIV 5 HCV-HIV 2 Neoplasms Myeloid Neoplasms 8 Age, years, median [Q1;Q3] 62[40;71] Men/Women n 38/60 Bleeding at start of eltrombopag treatment, n 44 Concomitant treatment, n 55 Corticoids 33 Immunoglobulins 6 Corticoids and Immunoglobulins 7 Table 2. Adverse events with Eltrombopag Variable n Total, n 30 Serious Adverse Events (Grade 3-4), n 18 Progression of basal disease 4 Severe Bacterial Infections 3 Deep venous thrombosis 3 Stroke 2 Medullary fibrosis 2 Severe Bleeding 1 Aspergillosis 1 Pulmonary Embolism 1 Secondary neoplasms 1 Acute Pancreatitis 1 Acute Myocardial Infarction 1 Deaths, n 14 Bacterial Infections 4 Progression of basal disease 4 Secondary neoplasms 2 Severe Bleeding 2 Aspergillosis 1 Severe Anemia due to negative of patient to transfusion 1 Disclosures Off Label Use: We describe the possibility of using eltrombopag, an oral thrombopoietin receptor analog, for secondary ITP patients..

Background: Eltrombopag is a thrombopoietin receptor agonist approved for primary chronic ITP patients. Due to the non-existence of clinical trials using eltrombopag in persistent and newly diagnosed ITP, there are no clear data about its usefulness in this setting. Aims: To evaluate efficacy and safety of eltrombopag in persistent, newly diagnosed and chronic ITP in routine clinical practice in Spain. Methods: Two hundred and twenty adult ITP patients from thirty Spanish centers who had been treated with eltrombopag and included in the Spanish Eltrombopag Registry were retrospectively evaluated. This study was performed in accordance with the standards of the Helsinki declaration and approved by the Hospital Universitario de Burgos Ethics Committee. Results: Here we report efficacy and safety results of primary ITP Spanish Eltrombopag Registry cohort. According to the standard definition, patients were allocated to newly diagnosed (n=30), persistent (n=30) and chronic (n=160) ITP groups. Each group is described separately in Table I. There are no statistical significant differences regarding response and duration of response among ITP groups. There is a trend towards a greater efficacy in newly diagnosed ITP with 93.3% of responses (platelet count ≥30 x109/L and at least two-fold increase the baseline count and absence of bleeding) and 86.7% of complete responses (CR; platelet count >100 x 109/L). Persistent ITP achieved 83.3% of responses and 80.0% of CR. Similarly 79.4% of responses with 73.1 of CR were observed in chronic ITP. Response rates were similar in all groups regardless all other studied parameters. Another trend towards a longer response duration in persistent ITP was found, with a median of 424 (IQR, 288-664) days. Response durations were similar in chronic ITP (median, 370 days; IQR, 174-624) and in newly diagnosed ITP (median, 378 days; IQR, 154-485). In newly diagnosed ITP, eight adverse events (AEs) with only three grade 3-4 AEs were observed. We reported three deaths; Two of them were due to upper respiratory tract infections in previously diagnosed pulmonary patients. A cerebral hemorrhage was the only death directly related to thrombocytopenia. In persistent ITP, four grade 1-2 AEs and two grade 3-4 AEs (one stroke, one cerebral bleeding) were reported. The only observed death was secondary to the mentioned cerebral hemorrhage. Twenty-one grade 1-2 AEs, ten grade 3-4 AEs and eight deaths (only two caused by bleeding) occurred in chronic ITP. Conclusion: Use of eltrombopag for treating persistent and newly diagnosed ITP is effective and safe. However, more studies are needed to confirm usefulness of TPO-RAs in this setting. | Variable | Newly-Diagnosed ITP (n = 30) | Persistent ITP (n=30) | Chronic ITP (n=160) | | | ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | -------------------------------------------------------------------------------- | --------------------------------------------------------------------------------- | ------------------------------------------------------------------------------------------------ | | | Age, years, median [Q1;Q3] | 66[46;79] | 66[47;76] | 61[47;75] | | | Men/Women n | 12/18 | 15/15 | 47/113 | | | Charlson comorbidity Index > 1, n (%) | 7(25.9) | 5(17.2) | 25(16.7) | | | Months with ITP, median [Q1;Q3] | 1[1;2] | 6[4;10] | 79[30;193] | | | Past ITP treatments, median [Q1;Q3] Rituximab, n (%) Splenectomy, n (%) Romiplostim, n (%) | 2[1;3] 3(10.7) 2(7.1) 3(10.7) | 2[1;3] 5(17.2) 4(13.8) 4(13.8) | 3[2;4] 43(28.3) 47(30.7) 37(24.3) | | | Platelet count at start of eltrombopag treatment, (x109/L), median [Q1;Q3] Bleeding at start of eltrombopag treatment , n (%) Concomitant treatment, n (%) Corticoids Immunoglobulins Corticoids and Immunoglobulins | 15[7;29] 13(43.3) 10(33.3) 6(60) 0 2(20) | 14[6;26] 10(33.3) 9(30) 7(77.8) 0 2(22.2) | 22 [9;38] 50 (31.3) 46 (28.8) 27 (57.4) 10 (21.3) 8 (17) | | Table 1. Patient characteristics Disclosures Off Label Use: We describe the possibility of using eltrombopag, an oral thrombopoietin receptor analog, for persistent and newly diagnosed ITP patients..

Introduction: Diffuse large B-cell lymphoma (DLBCL) is one of the most common malignant neoplasms in elderly patients, potentially curable when optimum treatment is administered. The combination of rituximab with CHOP chemotherapy (R-CHOP) is considered standard for these patients, but randomized studies published to date are limited to the range of age from 60 to 80 years, so that in patients over this age treatment election is not so clear, usually opting for palliative treatment or a "full" treatment at a reduced dose. This retrospective study is primarily aimed to analyze the influence of the type of treatment and comorbidity scales in overall survival (OS) of a large series of patients >80 years with aggressive B-cell lymphoma. Methods: Eligible patients were aged ≥ 80 years, diagnosed of DLBCL, follicular lymphoma grade 3B or transformed lymphoma. The main patient characteristics were obtained retrospectively from the medical records, including a complete geriatric assessment (CGA, "comprehensive geriatric assessment") and the Charlson comorbidity index. The Ethics Committee of the University Hospital of Salamanca approved the study. Results: 288 patients from 19 GELTAMO hospitals were registered in the study, of which 234 (60% women) were evaluable and have been included in this preliminary analysis. The median age was 84 years (80-94) and the vast majority (94%) were DLBCL. According to the Charlson index, 65% of patients were low-intermediate risk, and according to CGA, 63% of patients were considered "fit". A higher proportion (60% v 44%, p = 0.03) of patients with low or intermediate comorbidity index were treated with a curative intent (CHOP +/- rituximab), as compared with patients with high or very high index. With a median follow up of 41 (range 9-142) months, the median OS was 11.5 months (33% estimated at 3 years). The median OS for patients treated with R-CHOP-like (N=96) was 35.3 months, significantly better (p Conclusions: In patients over 80 years with DLBCL, treatment with R-CHOP-like was associated with the best results in terms of OS. Therefore, its administration must be considered whenever possible. Disclosures Sancho: CELLTRION, Inc.: Research Funding.

7 páginas, 2 figuras, 2 tablas.-- This is an open-access paper.-- et al., [Background]: Internal tandem duplications of the FLT3 gene (FLT3-ITDs) are frequent in patients with acute promyelocytic leukemia (APL), however its clinical impact remains controversial. [Design and Methods]: We analyzed the prognostic significance of FLT3-ITD mutant level and size, as well as FLT3-D835 point mutations, PML-RARα expression and other predictive factors in 129 APL patients at diagnosis enrolled on the Spanish LPA96 (n=43) or LPA99 (n=86) PETHEMA trials. [Results]: FLT3-ITDs and D835 mutations were detected in 21% and 9% of patients, respectively. Patients with increased ITD mutant/wild-type ratio or longer ITD size displayed shorter 5-year relapse-free survival (RFS) (P=0.048 and P10×109/L) (P=0.018) were independent predictors for shorter RFS. We identified a subgroup of patients with high WBC, long FLT3-ITD and low NCN of transcripts that showed an extremely bad prognosis (5-year RFS 23.4%, P, This work was supported by Grants 89/A/06 from the Spanish “Gerencia Territorial de Salud (SACYL)” and FIS/PI061351 from the Spanish “Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS)”. MCC and MES were supported by contracts FIS CA/07/00077 and FIS CA/08/00202, respectively.

We have evaluated 9 new molecular markers (ERG, EVI1, MLL-PTD, MN1, PRAME, RHAMM, and WT1 gene-expression levels plus FLT3 and NPM1 mutations) in 121 de novo cytogenetically normal acute myeloblastic leukemias. In the multivariate analysis, high ERG or EVI1 and low PRAME expressions were associated with a shorter relapse-free survival (RFS) and overall survival (OS). A 0 to 3 score was given by assigning a value of 0 to favorable parameters (low ERG, low EVI1, and high PRAME) and 1 to adverse parameters. This model distinguished 4 subsets of patients with different OS (2-year OS of 79%, 65%, 46%, and 27%; P = .001) and RFS (2-year RFS of 92%, 65%, 49%, and 43%; P = .005). Furthermore, this score identified patients with different OS (P = .001) and RFS (P = .013), even within the FLT3/NPM1 intermediate-risk/high-risk subgroups. Here we propose a new molecular score for cytogenetically normal acute myeloblastic leukemias, which could improve patient risk-stratification.

[Background]: The gene for preferentially expressed antigen of melanoma (PRAME) has been shown to be over-expressed in acute promyelocytic leukemia, but its actual incidence and clinical impact are still unknown. [Design and Methods]: We studied PRAME expression at diagnosis using real-time quantitative polymerase chain reaction in 125 patients with acute promyelocytic leukemia enrolled in the Spanish PETHEMA-96 (n=45) and PETHEMA-99 (n=80) clinical trials. In addition, PRAME expression was evaluated as a marker of disease activity in 225 follow-up samples from 67 patients with acute promyelocytic leukemia. [Results]: At diagnosis, PRAME expression in patients with acute promyelocytic leukemia was significantly higher (p100-fold PRAME expression (86% vs. 74%; p=0.03), and this cut-off established two sub-groups with different relapse-free survival rates among patients with a white cell count 109/L, although differences were not statistically significant. In multivariate analysis, white cell count >109/L (p90% (p=0.001), and PRAME expression 10-fold increase in PRAME expression levels. [Conclusions]: Low PRAME expression defines a subgroup of patients with acute promyelocytic leukemia with a short relapse-free survival. This marker could be useful as a secondary marker for monitoring patients with acute promyelocytic leukemia. ©2008 Ferrata Storti Foundation., This work was partially supported by grants PI061351 from the Spanish “Fondo de Investigaciones Sanitarias de la Seguridad Social”, and 89/A/06 from the “Gerencia Regional de Salud, Junta Castilla y León”, CIC, IBMCC (USAL-CSIC), Spain and by funding from the CR-USA Foundation-Spanish National Research Council (CSIC) Cooperative Agreement.

Background: Progressive transformation of germinal centers (PTGC) is a disease of mostly young adults that generally presents as asymptomatic, localized or generalized lymphadenopathy. Although PTGC usually seen as nodal disease, it can occur at extranodal sites. In the differential diagnosis of chronic lymphadenopathies, infection, lymphoproliferative disorders and progressive transformation of germinal centers should be considered. The most significant entities in the differential diagnosis with PTGC are nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and lymphocyte rich classical Hodgkin lymphoma. PTGC may precede, follow, or be concurrent with lymphomas. Objectives: To review the clinical and pathological features of PTGC, and PTGC’s relationship with lymphoid neoplasia in adult population. Material and Methods: The data of 33 patients who was diagnosed with PTCG at Hospital of Ege University School of Medicine, Pathology Department, between January 2000 and December 2014 were analyzed retrospectively. Clinical and Pathological Features: The median age of the patients was 43.8 years (26-66 years), and of 16 (48.5%) males and 17 (51.5%) females. Biopsy regions were; cervical lymph nodes (LN) 9 (27.3%), axillary LN 9 (27.3%), inguinal LN 6 (18.2%), submandibular LN 3 (9.1%), submental LN 2 (6.1%), parapancreatic LN 1 (3.0%), intraparotid LN 1 (3.0%), supraclavicular LN 1 (3.0%) and intramammarian LN 1 (3.0%). Recurrent PTGC was detected in only one (3.0%) patient. Diffuse large B cell lymphoma (DLBCL) and nodular lymphocyte predominant hodgkin lymphoma (NLPHL) was detected concurrent with PTGC in two cases. Also PTGC was detected 3 years after the diagnosis of DLBCL, NLPHL and T cell rich B cell lymphoma in 3 cases. There was no relapse in these 3 cases and no progression to lymphoma during follow-up of other patients. Conclusion: PTGC is not considered a premalignant condition but development of lymphoma have been reported rarely. If PTGC occurs in the follow of lymphoma cases, follow-ups may be intensified. NLPHL is the most important entity in differantial diagnosis of PTGC and patients should be carefully examined in terms of NLPHL.

We here describe a primary large B cell non-Hodgkin lymphoma of the right testicle in a 73-year-old male diagnosed with echography and magnetic resonance imaging. Treatment was based upon orchiectomy and chemotherapy, without any recurrence 2 years later. Ultrasonography and magnetic resonance findings with normal serum tumoural markers (AFP and B-HCG) can differentiate these tumors from germinal testicular tumors.

Introduction The inherited platelet disorders (IPD) are a heterogeneous group of rare diseases including quantitative and/or qualitative platelet defects. Classically, patients with IPD are first functionally tested to know the possible defect before sequencing a single or a few genes. Phenotipyc diagnostic of IPD often requires light transmission aggregometry, quantitative analysis of receptors by flow cytometry and fluorescence and electron microscopy. This diagnostic strategy is complex, poorly standardised and time consuming. In addition, the phenotype can seldom guide the singles candidates genes for conventional Sanger squencing. Therefore, many patients remain without a accurate diagnosis of their IPD. Next generation sequencing (NGS) enables the simultaneous analysis of large groups of candidate genes in IPD and may be useful for rapid genetic diagnosis. The aim of this study was to design and validate a NGS panel for IPD. Patients & Methods We describe a strategy for rapid genetic diagnosis of IPD with Illumina sequencing of 60 candidates genes previously associated with IPD (table1). The baits were designed to tile 400 kb of gDNA sequence corresponding to the exons and splice sites in all known transcripts of the candidate genes identified. The bait library was tested by enriching the candidate IPD genes from 50 ng DNA obtained and sequencing by Nextera Rapid Custom Enrichment system. Results were analysed by Variant Studio system and Sequencing Analysis Viewer. A total of 21 patients were studied. For the validation process, DNA samples of 9 unrelated patients with IPD and their mutation known were used: two patients with Glanzmann Thrombasthenia (ITGA2B, p.Ala989Thr, p.Val982Met and p.Glu538Stop; ITGB3, p.Leu222Pro and p.Tyr216Cys), one Hermansky-Pudlak Sd. (HPS1, p.Glu204 Stop), another with Bernard-Soulier Sd. (GPIX, p.Phe71Stop), a case of Congenital Amegakaryocytic Thrombocytopenia (MPL, p.Arg102Cys), and 2 patients with Chediak Higashi Sd. (LYST, p.Gly3725Arg and p.Cys258Arg). Once validated, the NGS panel was used for genetic diagnostic of 8 patients with suspected IPD. Results Eleven mutations, previously identified in another center by conventional sequencing, were detected by our panel NGS (100% success in the validation process). We then tested this strategy for patients with suspected of IPD without diagnosis: I. a 13 years old girl with agenesis of the corpus callosum, facial dysmorphia, renal agenesis and thrombocytopenia was diagnosed of Thrombocytopenia FLNA-related and Periventricular Nodular Heterotopia (PNHV)[mutation in the FLNA was detected (p.Thr1232Ile)]. II. A two years old patient with severe thrombocytopenia and recurrent infections was diagnosed of Wiskott-Aldrich Sd (WAS, p.Arg268Gly fs Stop40). III. A patient with deafness, macrothrombocytopenia, and Döhle bodies was diagnosed by MYH9 deletion (MYH9; p.Asp1925Thr fs Stop23). IV. Six members of a family (2 of them with symptoms of mucocutaneous bleeding, and macrothrombocytopenia), in which an insertion in NBAL2 (p.Gly1142Arg fs Stop49) gene was found. Therefore, Gray Platelet Sd was diagnosed. Moreover, one patient with “aspirin-like syndrome” showed a P2RY12 mutation (p.Val279Met). Finally, mother and son with mild Hemophilia A (F8; p.Gln2208Arg) were detected. Conclusions This NGS panel enables a rapid genetic diagnostic of IPD. The use of NGS-based strategy is a feasible tool for the diagnosis of IPD that could be added to the screening of these disorders. Five mutations have not previously been described in the literature. Table 1: Sixty candidates' genes previously associated with IPD: Inherited Platelet Disorders Genes = 60 Cytoskeletal Assembly and Structural Proteins GP1BA, GP1BB, GP5, A2M, GP9, VWF, ITGA2, ITGA2B, ITGB3, ABCA1, ANO6,FERMT3, ACTN1, MASTL Disorders of agonist platelet receptors P2RX1, P2RY1, P2RY12, TBXA2R, TBXAS1, ADRA2A, GP6, CD36 o GP4, DTNBP1 Disorders signal transduction GNAI3, GNAQ, GNAS, PLA2G7, PLCB2PTS, GGCX, DPAGT1, DHCR24 Disorders of platelet granules NBEAL2, GFI1B, PLAU, HPS1, HPS3, HPS4, HPS5, HPS6, LYST, MLPH, BLOC1S3, BLOC1S6, AP3B1, VIPAS39, VPS33B, RAB27A, MYO5A, USF1 Thrombocytopenias and syndromes WAS, MYH9, FLNA, FLI1, STIM1, HOXA11, ANKRD26, MPL, RBM8A RUNX1, GATA1 Disclosures No relevant conflicts of interest to declare.

Background: The trombopoietin receptor agonists (TRAs) romiplostim and eltrombopag are effective and safe in the treatment of chronic immune thrombocytopenia (ITP). However, when no response is achieved or when adverse events occur with one TRA the value of the sequential use of romiplostim and eltrombopag has not been clearly established. Here we have evaluated the efficacy and tolerance of using eltrombopag after romiplostim in ITP. Methods: Fifty-one primary ITP patients (aged 18 years or more) who had been sequentially treated first with romiplostim and then with eltrombopag in the Spanish Eltrombopag Registry were retrospectively evaluated. In accordance with the usual standards, complete response was defined as a platelet count of 100x109/L and a response as a platelet count of 30x109/L or a count of at least twice the initial (pre-treatment) value. This study was performed in accordance with the standards of the Helsinki declaration and approved by the Hospital Universitario de Burgos Ethics Committee. Results: The median age of our cohort was 49 [range, 18–83] years. There were 32 women and 19 men. According to the standard definition, patients were allocated to newly diagnosed (n=2), persistent (n=5) and chronic (n=44) ITP groups. The median number of therapies prior to administration of eltrombopag was 4 [range, 2–9], including splenectomy (39%), rituximab (33%) and romiplostim (100%). The median duration of romiplostim use before switching to eltrombopag was 12 (IQR 5–21) months. The reasons for switching from the romiplostim to eltrombopag were: lack of efficacy of romiplostim (n=25), patient's preference (n=16), platelet-count fluctuation (n=6), and side-effects (n=4). The initial response rate to eltrombopag was 41/51 (80.5%), including 67% (n=34) of cases with complete remission. After a median follow-up of 13 months with eltrombopag, 39 patients maintained their response. When eltrombopag was used for patients who were refractory to the maximum romiplostim dose the initial response rate of eltrombopag was 25%. However, 83% of patients who relapsed after their initial response to romiplostim responded to eltrombopag. Sixteen romiplostim responders requested their physicians to switch them to eltrombopag because they preferred an oral drug. The efficacy was maintained after switching in all 16 patients. In the platelet-count fluctuation group, the initial response rate was also 100%. All 4 patients who were switched to eltrombopag because they experienced side-effects of romiplostim achieved complete remission with eltrombopag and their adverse events were resolved. 16 / 51 (33%) patients experienced one or more adverse event during treatment with eltrombopag. The frequency of grade 3–4 adverse events during treatment with eltrombopag was 9.8%. Conclusion: The use of eltrombopag after romiplostim for treating ITP is effective and safe. The reason for discontinuing romiplostim was associated with the response to eltrombopag. Disclosures No relevant conflicts of interest to declare.

Background and Objectives: B-cell chronic lymphoid leukemia (CLL) is a lymphoproliferative disorder where specific microenvironment between B-cells and nurse-like Cells (NLC) seem to be involved in disease progression providing cell survival, proliferation and drug resistance. Consequently, functional screening platforms that can assess drug candidates within this microenvironment are needed. Our aim is to show the ability of the Exvitech® automated flow cytometry platform to screen agents that interfere with the microenvironmentxs protective scenario such as ibrutinib or idelalisib or standard CLL drugs such as fludarabine or prednisolone. This approach will allow us to select candidates in an in vitro assay and could personalize the treatment according the response to the drugs. Patients and methods: We have adapted Jan Burger's published assay1. Peripheral blood mononuclear cells (PBMCs) from not previously treated CLL patients were isolated by density gradient centrifugation over Ficoll-Pacque and were used fresh (N=14) or cryopreserved (N=6). B-cells were assessed to be >90% viable by flow cytometry. NLC co-cultures were stablished by suspending PBMCs from CLL patients in complete RPMI medium with 10% FBS to a concentration of 2x107/ml. Cells were incubated for 14 days in 96-well plates and presence of NLC was confirmed by microscopy. After that, viability was investigated in B-cells treated with 8 concentrations of ibrutinib, idelalisib, fludarabine and prednisolone after 72h of incubation with annexin-V and the appropriate CLL flow cytometry markers. Drug response was evaluated as a depletion survival index of the B-cell population relative to the average of the control wells with NLC but without drug. Results: As expected, depletion of B-cells cultured without NLCs were significant greater than with NLC after the 72h incubation supporting the assay where NLCs protect B-CLL cells from in vitro spontaneous apoptosis. In a similar way, viability of fresh samples with NLC was higher than the corresponding frozen samples (84% vs 25%), though both could be used. Our results show a lower pharmacological median potency, measured as a higher EC50, when we work with NLC versus without NLC for ibrutinib (10µM vs 4µM), idelalisib (17µM vs 0.4µM) and prednisolone (3.5µM vs 1.5µM). However, the effect of fludarabine seems to be independent of the presence of the NLC in the cell culture (7µM vs 6µM). This is consistent with the protective role of microenvironment; more pronounced for ibrutinib and idelalisib. Interestingly with NLC, for each drug there is a significant interpatient variability (Figure 1); each line correspond to a different patient, reflecting the possibility that patients might be more sensitive or resistant to a certain drug in this particular scenario. There is a higher degree of patient sample stratification for idelalisib, fludarabine or prednisolone, where there are still an important % of B-cells alive for some patients after drug exposure at high concentration, supporting the notion of drug resistance. Synergism between some of these drugs was evaluated in 3 samples, with some samples being more synergistic than other, requiring a larger number of samples. Conclusions: Cellular and molecular interactions between B-cells and the microenvironment represented here with the NLC, have become an attractive target for CLL therapy. Because novel drugs such as ibrutinib or idelalisib are transforming CLL therapy targeting the microenvironment, novel technologies that could predict its effect are necessary. Here we have adapted a Nurse-Like Cell assay mimicking the microenvironment published by Burger1 to our ExviTech platform. The automated platform enables scaling of the data points acquired with this assay supporting characterization of drug activity by pharmacological dose response curves, as well as exploring synergistic interactions. As showed in the results and illustrated in Figure 1, there is a interpatient variability of the pharmacological profile for the studied drugs, if clinically validated, could help guiding a personalized treatment selection; measuring the drug activity inside this particular microenvironment responsible of drug resistance. 1.- Burger JA et al. Blood. 2000 Oct 15;96(8):2655-63. Figure 1: Figure 1:. Disclosures Primo: Vivia Biotech: Employment. Martinez:Vivia Biotech: Membership on an entity's Board of Directors or advisory committees. Gorrochategui:Vivia Biotech: Employment. Espinosa:Vivia Biotech: Employment. Arroyo:Vivia Biotech: Employment. Ballesteros:Vivia Biotech: Employment. Hernandez:Vivia Biotech: Employment.

Bone marrow mononuclear cells (BMCs) from 20 patients with extensive reperfused myocardial infarction (MI) were used to assess their myocardial regenerative capability “in vitro” and their effect on postinfarction left ventricular (LV) remodeling. Human BMCs were labeled, seeded on top of cryoinjured mice heart slices, and cultured. BMCs showed tropism for and ability to graft into the damaged mouse cardiac tissue and, after 1 week, acquired a cardiomyocyte phenotype and expressed cardiac proteins, including connexin43. In the clinical trial, autologous BMCs (78±41×10 6 per patient) were intracoronarily transplanted 13.5±5.5 days after MI. There were no adverse effects on microvascular function or myocardial injury. No major cardiac events occurred up to 11±5 months. At 6 months, magnetic resonance showed a decrease in the end-systolic volume, improvement of regional and global LV function, and increased thickness of the infarcted wall, whereas coronary restenosis was only 15%. No changes were found in a nonrandomized contemporary control group. Thus, BMCs are capable of nesting into the damaged myocardium and acquire a cardiac cell phenotype in vitro as well as safely benefiting ventricular remodeling in vivo. Large-scale randomized trials are needed now to assess the clinical efficacy of this treatment.

Introduction and objectives. Experimental and clinical studies suggest that necrotic myocardium may have the capacity to regenerate. We have started a clinical study to demonstrate that the intracoronary implantation of stem cells is feasible and safe. The results in our first 5 patients are presented here. Patients and method. We included patients with anterior acute myocardial infarction and isolated stenosis of the left anterior descending artery that was successfully repaired by primary or facilitated angioplasty. Patients received an intracoronary infusion of bone marrow-derived cells 10-15 days after the infarction. The follow-up protocol included low-dose dobutamine echocardiography, magnetic resonance studies and ECG Holter monitoring. Results. The procedure was carried out with no complications. No patient had a cardiac event during the first 6 months. One patient had a transient ischemic attack without sequelae. No arrhythmias were found. Left ventricular end-diastolic volume remained the same at 6 months (159 [25] ml, 157 [16] ml), left ventricular end-systolic volume decreased (77 [22] ml, 65 [16] ml), and the ejection fraction increased (53 [7]%, 58 [8]%) although no statistically significant differences were found. In the 3 patients in whom dobutamine echocardiography ruled out viability, we found a significant reduction in both volumes. Conclusions. Intracoronary bone marrow-derived cell transplantation after an acute myocardial infarction seems to be safe and feasible, and might lead to favorable remodeling.

Emphysematous gastritis is a life-threatening disease. It is characterized by the presence of gas within the wall of the stomach. The etiology includes firstly infections with gas-forming organisms; other predisposing causes are the ingestion of corrosive substances and alcohol abuse. Diagnosis is based on radiological techniques, mainly computed tomographic scan (CT). The election treatment is antibiotics and surgery. The evolution is generally fatal. We present the first known case reported, which is associated with aplastic anemia with immunosuppressive therapy, its evolution with medical treatment and a literature review.

Interferon-alpha (IFN-alpha) is a therapy of unquestionable efficacy in chronic myeloid leukemia (CML) patients. The best dose of IFN-alpha in the treatment of CML still remains controversial. Our primary objective was to compare cytogenetic responses in patients treated with intermediate versus high doses of IFN-alpha. A multicenter randomized controlled trial was conducted involving 109 patients with untreated CML in chronic phase from 26 Spanish hospitals. Patients were assigned to receive either an intermediate (2.5 MU/m(2) per day) or high (5 MU/m(2) per day) target dose of IFN-alpha. Hydroxyurea was allowed in both groups. In total, 108 patients were analyzed, 53 in the intermediate- and 55 in the high-dose group. Median follow-up was 47.5 months. The dose of IFN-alpha actually given was lower in the intermediate-dose group (3.83 MU/day) than in the high-dose group (6.6 MU/day) ( p0.001). The rate of complete cytogenetic response was 24.5% in the intermediate- and 12.7% in the high-dose group (NS). A partial cytogenetic response was obtained in 7.5% and 10.9%, respectively. Cox analysis did not reveal any influence of the randomization arm on cytogenetic response rate. Ten patients in each group discontinued IFN-alpha because of toxicity. Albeit not our primary objective, no differences were found in terms of survival or transformation rate between both groups. Median survival was 73 months; 64% of patients remained free of transformation at 5 years. In terms of cytogenetic response, intermediate doses of IFN-alpha are as effective as high doses in the treatment of CML.

We analyzed serum triglyceride (TG) levels in 22 chronic myeloid leukemia (CML) patients treated with interferon-α (IFN-α). Hypertriglyceridemia was present in one-half of patients at diagnosis, and IFN-α treatment was associated with a further increase in 90% of the total group of patients. This increase was maximal during the first months of therapy. Four patients (18%) reached levels higher than 1,000 mg/dl. This is the first report describing this secondary effect in CML patients treated with IFN-α. © 1995 Wiley-Liss, Inc.

Abstract 3764 Introduction: In CML-CP patients showing resistance or intolerance to imatinib, rescue therapy with second generation 2GTKIs produced nearly 50% of complete cytogenetic responses (CCyR). However, in the long term, a high percentage (roughly 70%) of patients abandoned the targeted treatment. The information about the outcome of patients treated in third line with TKI's is scarce, and come mostly form clinical trials. In these experiences CCyR were obtained in approximately 20%, and the duration of MCyR was around 18 months. Aims: To describe the evolution of patients who interrupted 2GTKI, given as 2nd line treatment, outside clinical trials. Patients and methods: In our registry, we have identified 105 patients treated with second generation TKI in second line out of 487 patients treated with imatinib as first TKI. Reasons for treatment change were failure in 53%, intolerant in 33% and suboptimal in 14%. Sokal risk indexes were 40%, 47% and 13% for low, intermediate and high risk, respectively. 33% of patients had received interferon prior to imatinib. Cummulative incidence of CCyR and major molecular responses (MMR) with a median follow up of 85.59 (8.93–130) months, were 65% and 49%. Fifty two (49%) withdrew treatment because of failure (22%), intolerance (18%), suboptimal response (7%) and exitus (8%). Results: A total of 31 patients started third-line therapy with a third TKI, representing 29% of patients who started second-line treatment and 78% of patients who discontinued the treatment. The reasons for starting the 3rd line treatment was failure in 55% and intolerance, in 44%. With a median follow up of 9 months, probabilities of achievement a complete hematological response (CHR) and CCR was 93% and 30%. These responses were influenced depending on the indication of treatment, with cummulative indidence of CCyR of 18% and 50% for resistant and intolerant patients, respectively (p = 0.031). The corresponding figures for transformation-free survival and overall survival were 61% vs 76, and 72% vs 88% for failure and intolerance settings, respectively. Conclusions: In this registry-based experience, outside clinical trials, 2GTKI have offered a substantial benefit to patients resistant or intolerant to Imatinib. However, the experience in 3rd line in patients resistant to 2GTKI in 2nd line, has been dismal, with less than 20% of CCyR. In this particular subgroup, BMT must be considered, and new experimental therapeutic schemes are necessary for those patients who are not suitable candidates for BMT. Disclosures: Casado: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Steegmann:Pfizer: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

Abstract 3768 Introduction: Tyrosine kinase inhibitors (TKIs) have dramatically changed chronic myeloid leukemia prognostic. The European Leukemia Net guidelines are widely used for patients treated with TKIs. While strategies for patients with optimal response and failure after imatinib are clear, there are doubts about the best treatment option for patients with suboptimal response (SubR), specially for late SubR (patients with complete cytogenetic response (CCyR) but not mayor molecular response (MMR) after 18 months of treatment). Patients with MMR seem to have better outcomes than patients with CCyR but not MMR, but at this time, there are few data showing the benefits of treatment change in this group of patients. Aims: To identify the benefits of treatment change in patients with late SubR, outside clinical trials, in the setting of a multicenter hospital-based registry. Patients and methods: We have studied retrospectively a group of 488 CML chronic phase patients treated with imatinib as first TKI, identifying 96 patients (19%) with SubR criteria (following the ELN recommendations) after 18 months of treatment. These patients have been classified according to the strategy followed by their physician after SubR identification. Group 1 includes 65 patients (67%) continuing with imatinib (either initial dose or higher dose) and group 2 includes 31patients (33%) that were changed to second generation TKI (2GTKI: dasatinib or nilotinib). Sokal risk index was high in 17% and 9%; intermediate 44 % and 41%; and low in 39% and 50 % for group 1 and 2, respectively. 31% and 30% of patients had received interferon prior to imatinib. Molecular response was analyzed after 12 months of identifying late SubR (for group 1) or after switching to 2GTKI, for group 2. Results: The use of 2G TKIs resulted in significant benefit to patients in terms of improving molecular responses. Complete molecular responses (CMR) and MMR rates were 3.8% vs 27% and 41.5% vs 69% for group 1 and 2 respectively (p=0.006). Time for the achievements the best molecular responses was significantly lower for patients receiving second generation TKI (4.1 vs 20.2 months, p=0.004). Probabilities of treatment failure, defined as loss of CCR, were also higher in patients remaining with imatinib (15.4% vs 5.7% (p=0.12). Progression free survival was 93.8% vs 97.2% (p=0.18) for group 1 and 2 respectively. Changing treatment for late SubR patients was also safe, and only 17% of patients needed to switch to another TKI due to intolerance. Conclusions: In CML patients treated with Imatinib with late SubR, and outside clinical trials, switching to second generation TKI increased probabilities of achievement a deeper molecular response, with a good safety profile. Disclosures: Casado: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Steegmann:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau.

Abstract 3762 Introduction: In late 2009 it was published the second version of the international recommendations for CML monitoring and treatment with Imatinib and other tyrosine kinase inhibitors(TKI) (Bacarrani M et al JCO 2009). Although widely distributed and discussed, there has not been any report describing the adherence of hematologists to those guidelines, or analyzing the differential outcomes in the setting outside clinical trials. Objectives: To study the association between the compliance to ELN 09 recommendations in every timepoint, and the response to TKI treatment. Methods and patients: CML patients in first chronic phase, treated upfront with imatinib, outside clinical trials. The adherence to ELN 09 in the given timepoint was classified, as orthodox if, monitoring and treatment were done accordingly, and heterodox, if monitoring or treatment were done disaccordingly. Study variables: Best complete cytogenetic response (CCyR) and major molecular response (MMR) with Imatinib and second line TKI, and progression rates. Besides, we analyzed the association between response grades considering the value obtained in the precedent timepoint. Results: 374 patients (229 men, 145 women) were included. The Sokal risk distribution was: low (L): 138(39%), intermediate (I): 172 (48%), and high (H): 44(12%). Correspondent values for Euro score were 170(48%), 165(47%) y 19(5%). EUTOS score: L: 294(91%), H: 30(9%). Median age: 52 years (15–88). Median follow-up 59.3 months (0,6–131,9). A summary of the results is shown in Table 1. Most of the patients were evaluated on time (73–90%), and 2/3 of the patients were monitored and managed in an orthodox way in the specific timepoints. The rate of CCyR and MMR were significantly higher in patients managed in an orthodox way. In contrast, progression rates were significantly higher only in those patients whose management was heterodox at 3 months. Besides, a better response at any given timepoint was associated with better ulterior responses. Conclusions: Our results reinforce the use of ELN 09 recommendations, showing that those patients whose monitoring and treatment is done according to these recommendations have a higher probability of response. An orthodox management in the first trimester of treatment is specially important, because it is associated with a lower progression rate. Disclosures: Casado: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Martínez-López:Celgene: Honoraria. Steegmann:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau.

Abstract 1237 Background: The RELMC is a multicentric, 17-hospitals-based cancer registry whose aim is to describe the treatments received by patients with CML, their outcomes, and the variables that influence treatment choices. Aim: To study the response and survival outcomes, in newly diagnosed CML patients treated with Imatinib (Im) as first line treatment. Patients and methods: 249 newly diagnosed CML patients have been included. They are distributed in the following subgroups according to treatments received Im400. 166 patients received only Im400. Result: A summary of response and outcome is included in Table 1. Complete cytogenetic response with regards to the best response, the CCyR rate was lower in patients with Im400-HDIm-2GTKI (60%) and Im400-2GTKI (62%). The rates were 84% in Im400, 83% in Im400-HDIm and 85% in HDIm; P Chi2 8,381(a) p=0,079. The CCyR cumulative incidence was also lower in patients with Im400-HDIm-2GTKI and Im400-2GTKI in comparison to the other groups, although second line response was faster in patients who changed to 2GTKI after Im400. The frequency of CCyR as best response in the Hasford high risk patients was low in all groups (66%,50%,50%,50&55%). Major molecular response MMR as best response was lower in patients with Im400-HDIm-2GTKI (50%) and Im400-2GTKI (47%). The rates were 83%, 81% and 77% in the Im400, Im400-HDIm and HDIm groups respectively; P Chi2 19,4(a)p=0,001. The MMR cumulative incidence was higher in the HDIm group, lower in those treated with Im400-HDIm-2GTKI, and intermediate and similar in the other three groups. MMR as best response in the Hasford high risk patients was also low in all groups (60%, 75%, 50%, 50% & 33%). Complete molecular response regarding best response, the CMR rate was lower in patients with Im400-HDIm-2GTKI (37,5%), Im400-2GTKI (31,6%) and Im400-HDIm (34%). In the other groups, the rate was 48% (Im400), and 72% (HDIm); P Chi2 17,4(a) p=0,002. The CMR cumulative incidence was higher in the HDIm group, and nil in those treated with Im400-HDIm-2GTKI. Salvage therapy after suboptimal response (SR) or Failure (F). Two-thirds of patients with SR or F were able to obtain an optimal response and avoid transformation with a timely therapy change. All but one of the options (Im400-HDIm-2GTKI group) were similarly effective. Survival: 6 patients progressed (2,4%) (4 AP, 2 BC), and died; 6 patients changed to allo BMT and were censored; 6 patients died of non-CML related causes. Conclusion: Disclosures: Palomera: Janssen Cilag: Honoraria. Steegmann:Bristol-Myers Squibb: Honoraria, Participated in advisory boards, Research Funding; Novartis: Participated in advisory boards, Research Funding.

Abstract 931 Purpose: Multicentre phase II study in newly diagnosed Mantle cell lymphoma patients to determine the feasibility, overall response (OR) and failure free survival (FFS) of intensive chemotherapy type Hyper-CVAD followed by in vivo purging with Rituximab previous peripheral stem-cell transplantation. Treatment scheme consisted in four cycles of Hyper-CVAD chemotherapy as is described by Romaguera et al. After chemotherapy four weekly Rituximab courses (375mg/m2) were administrated previously to peripheral stem-cell collection. Rituximab was not added at the same time as chemotherapy cycles; its role consisted in working as a purging agent previous stem-cell mobilization. After Rituximab administration peripheral blood progenitors were collected. Mobilization was performed using Cyclophosphamide plus G-CSF at dose of 10 μg/Kg/day. If the first mobilization was unsuccessful, a second scheme was used, using Ifosfamide (10 g/m2 in 72 hours infusion on day 1), Mesna (10 g/m2 days 1 and 2), VP16 (150 mg/m2 days 1 to 3) plus G-CSF at dose of 5 μg/Kg each 12 hours. The aim was obtain 2×106 CD34 cells/Kg. After mobilization peripheral autologous stem-cell transplantation (PASCT) was performed using BEAM (BCNU, Ethoposide, Ara-C and Melphalan) as conditioning regimen. .A week after platelet recovery (>50×109/L) another four weekly Rituximab courses (375mg/m2) were added. Patients were followed after treatment in each centre. Forty-four patients diagnosed of mantle cell lymphoma and previously not treated were enrrolled from fifteen Spanish Institutions from 2000 to 2006. The median age of the patients were 55.77 year old. Male/female rate was 3:1. Forty patients had an Ann-Arbor stage IV, and gastrointestinal involvement was present in twenty-nine. Marrow was infiltrated in 83.3% of the cases. Age IPI adjusted were ≥2 in 45% of the cases respectively (table 2). Blastic mantle cell lymphoma was diagnosed in 5 patients (11.9%). The median follow-up of the patients was 75,07 months. In the intention to treat, of the forty-four patients only 26 patients receive all the treatment (59%). Autologous peripheral stem-cell transplantation was not performed in 16 patients. The causes of not complete the treatment schedule was: three patients refuse to be transplanted; mobilization failure in four; death before ABMT in four patients and progression of the lymphoma during HyperCVAD treatment in five patients (table 2). Two patients have a compatible sibling and an allogenic bone marrow was performed; these patients are not included in the series, as protocol violation. Results: Median overall survival (OS) was 77.37 months. The OS of the patients who performed all the planned treatment was 73.6% and 61.96% at three and five years. At the end of the study 21 of the patients were alive. Univariate analysis showed that prolonged overall-free survival was associated to initial ECOG, response achieve (CR or uCR vs PR, non Remission or progression), non-blastic morphology, bone marrow infiltration and performing ASCT. The median FFS was 52.53 months. A plateau was observed in the FFS plot at 72 months. FFS was of 63% at three years of surveillance and 32% at six years for all the patients. For the patients who complete autologous stem-cell transplantation FFS at three and five years were 75.91% and 42.70%. The latest relapse occurred at 73 months after treatment. Nowadays four patients are in remission more than 82 months after diagnosis. Univariate analysis showed that factors that influence were: blastic subtype of MCL, achievements of CR or uCR., and if the patient complete ASCT. Recently two groups have published his results conducting protocols similar with our scheme of protocol. Disappointingly, our results contrast with the rather more optimistic of the Nordic Lymphoma Group with a shorter median follow up (median 3.9 years, 46,8 months) and with the recent up-date of the M.D. Anderson (Blood 2009). In both phase II essays, the 4 year FFS was of 63% and the 6 year PFS of 46% respectably. We noted that even though this prolonged relapse free survival we have relapses up to 6 years of surveillance. Differences with Nordic Lymphoma Group might be caused by not using Rituximab concomitantly with Hyper-CVAD regiment and perhaps increased toxicity of Hyper-CVAD regimen. Disclosures: Palomera: Janssen-Cilag: Honoraria; Celgene: Honoraria.

Background and objective Fludarabine in combination with cyclophosphamide (FC) plus rituximab (R) is an effective treatment for newly diagnosed as well as relapsed follicular lymphoma (Tam 2004; Keating 2005; Sacchi 2007). Maintenance treatment with R, after different induction treatments, improves overall and progression-free survival (Forstpointner 2006; van Oers 2006). Therefore, we aimed to evaluate the efficacy and safety of the FC-R regime followed by maintenance doses of R. Patients and Methods We present an intermediate report of the one-arm study in which 75 previously untreated patients with a diagnosis of follicular non-Hodgkin’s lymphoma in Ann Arbor stage II–IV were included between October 2004–2006. Seventy four were assessed for safety after receiving at least one FC-R dose (F: 3x25 mg/m2 and C: 1 g/m2; R: 375mg/m2), and 72 for response to treatment. Patients aged 53.4 years in average, one in five showed bulky disease and 72.2% Ann Arbor IV staging. FLIPI index determined 23.9% patients with low (0–1) score, 38% with intermediate (2) and 38% with poor score (3). A total of 47 patients presented some molecular alteration in PB or BM. Results Induction therapy was delivered throughout 4–6 courses, resulting in 91% complete responses (CR) and 9% partial responses (PR) (Table 1). From the patients who presented monoclonal population at diagnosis, 40 were evaluated for molecular response after induction and only 1 remained MDR positive for bcl2/IgH. Overall survival (OS) at 24 months was 87.5%, and two patients presented progressive disease within this period. The median OS has not been reached at this evaluation. To the date, 262 adverse effects grade 3–4 (32.6%) have been documented (80.9% neutropenias) and 80 infectious complications were recorded (23.8% grade 3–4). Three patients died from respiratory diseases, two from acute leukemia, and six from other causes. Table 1 EVOLUTION OF RESPONSE Evaluated Response at End of Induction Therapy Evaluated Response Post-Course 3 Assesable End Ind. (n=67) Missing End Ind. (n=5) CR: complete response; uCR: unconfirmed CR; PR: partial response; NE: not evaluated; WD: withdrawn; EX: exitus. Assesable PC3 (n=70) CRITERIA CR PR NE WD EX 14 CR 12 - 1 1 - 32 uCR 31 - 1 - - 24 PR 16 6 - - 2 2 Missing PC3 (NE) 2 - - - - 72 Total 61 6 2 1 2 Conclusions The FC-R has proven a potent antitumoral activity in untreated follicular lymphoma patients, rendering very high clinical and molecular responses. However, as reported in similar studies (Hochster 2007 ASCO), the high incidence of prolonged neutropenias and lymphopenias developed as consequence of the chemotherapy regime, questions the safety of the induction treatment.

One randomized trial showed that tandem transplant resulted in a significantly longer EFS and OS in patients failing to achieve CR or near-CR with a single transplant. However, other studies failed to show benefit from a second transplant. The aim of our study was to investigate the efficacy in terms of response improvement and survival from a second transplant intensification in patients with chemosensitive disease who failed to achieve CR or near-CR with a first high-dose procedure. Patients diagnosed with MM from Oct 1999 to Dec 2004 younger than 70 years received 6 courses of VBMCP/VBAD and responding patients were intensified with busulphan/melphalan or MEL-200 followed by stem cell support. Patients not achieving CR or near-CR were planned to undergo a second transplant (second auto with CVB - cyclophosphamide, etoposide and BCNU - or MEL-200 intensification or an allo-RIC with Fludarabine/MEL-140 conditioning, if sibling donor available). Eighty-eight patients received a second autologous transplant while 26 underwent an allo-RIC. Thirty-seven percent of the patients given a second autologous transplant improved their response status (CR 11%, near-CR: 6%, PR: 9% and MR 11%) while 63% showed “no change”, progressive disease or early death. A response was observed in 45% of patients undergoing the allo-RIC (CR: 33%, PR: 4%, MR: 8%). The CR rate was significantly higher with allo-RIC (33% vs. 11%, p= 0.02). There was a trend towards a higher TRM with the allo-RIC (5% vs. 16%, p=0.09). Although the median EFS (26 vs 19 m) and OS (57 m vs not reached in allo-RIC) from the second high-dose procedure were not significantly different, there is a plateau in the “allo-RIC” group beyond 3 years of the second procedure not observed in the autologous arm. Conclusions: an allo-RIC transplant after an autologous procedure results in a significantly higher CR rate than a second autologous transplant, and despite the lack of significant differences in survival between the two transplant modalities, there is a plateau in the allogeneic group not observed in the autologous arm.